Abstracts of the 2nd International Meeting on Antimicrobial Chemotherapy

in Clinical Practice, Portofino, Italy, October 21–24, 2001

Guest Editors: D. Bassetti, M.D., M. Bassetti, M.D., G. Tillotson, M.Sc., S. Watson, Ph.D.

(Pharmacotherapy 2001;21(11 Pt 3):331S–392S)

Prions: health scare and biological challenge

1. The immunobiology of prion diseasesAdriano AguzziInstitute of Neuropathologie, University Hospital Zurich,CH-8091 Zurich, SwitzerlandMice deficient in the normal prion protein are resistant toexposure to prion infectivity, and expression of the normalprion protein by neurons is necessary for the developmentof histological damage. But how do prions reach the brainafter entering the body from peripheral sites? Neuroinvasion,i.e., the process by which prions march through the body ofthe host towards the brain, is dependent upon expression ofthe normal prion protein in a non-hematopoieticextracerebral site. We therefore developed the hypothesisthat neuroinvasion takes place in two distinct steps: first thelymphoreticular system is diffusely colonized by the agent,while at a later time infectivity progresses fromlymphoreticular organs to the central nervous system,probably via sympathetic nerves. There is an absoluterequirement for B-lymphocytes in peripheral prionpathogenesis. Surprisingly, the presence of the normal prionprotein is not necessary on B-lymphocytes to enable them tosupport this process. The mechanism of action of Blymphocytes may consist of presentation of lymphotoxin-bto follicular dendritic cells. This paves the way to post-exposure prophylaxis strategies that exploit the anti-prioneffect of soluble lymphotoxin-b receptors.Why do follicular dendritic cells accumulate prions? Wetested the hypothesis that prion uptake may be complement-mediated. Indeed, certain components of the complementsystem (C1q, CR1/2) proved to play an important role inpathogenesis.Progress in the understanding of pathogenesis andelucidation of possible therapeutic and prophylacticapproaches must go hand-in-hand with diagnosticprocedures. With this in mind, we initiated a screen forplasma proteins that bind specifically disease-associatedprion protein. Plasminogen was identified as such a protein.This fact may be exploitable as the basis of a sensitivediagnostic assay for BSE and for human prion diseases.

Injectable cephalosporins in the management ofimmunocompromised patients

2. Nosocomial pneumonia and the relationships between blactam pharmacokinetics, pharmacodynamics, andantibiotic efficacy and bacterial resistanceJerome J. Schentag, Pharm.D.

Professor of Pharmacy and Pharmaceutics, State Universityof New York at Buffalo, School of Pharmacy; Buffalo, NewyorkPatients with serious infections like nosocomial pneumoniarequire bactericidal antimicrobial activity. Studies in ourlaboratory demonstrate that the minimum effectiveantimicrobial action is an area under the inhibitory titer(AUIC) of 125, where AUIC is calculated as the 24-hourserum AUC divided by the MIC of the pathogen. This targetAUIC may be achieved with either a single antibiotic or itcan be the sum of AUIC values of two or more antibiotics.There is considerable variability in the actual AUIC value forpatients when antibiotics are given in their usuallyrecommended dosages. Examples of this variance will beprovided using aminoglycosides, and b-lactams. Theachievement of minimally effective antibiotic action,consisting of an AUIC of at least 125, is associated withbacterial eradication in about 7 days for b lactams, becausethey exhibit time dependent bacterial killing, and an AUICof 125 is the result of 80–100% time above MIC. WhenAUIC is increased to 250, the b lactams do not eliminatebacteria more rapidly than at AUIC of 125. Protein bindingfor some organisms may justify the calculation of free AUIC,and these situations will be considered for highly proteinbound cephalosporins like ceftriaxone.Adding an aminoglycoside to b-lactams may produce aslight increase in their rate of bacterial killing in vivo, butbecause of their narrow therapeutic window and theassociated low doses in relation to MIC, there are situationswhere the aminoglycosides may be unable to add sufficientadditional AUIC. Antibiotic activity indices allowclinicians to evaluate individualized patient regimens.Furthermore, antibiotic activity is a predictable clinicalendpoint with predictable clinical outcome. This value isalso highly predictive of the development of bacterialresistance. Antimicrobial regimens that do not achieve anAUIC of at least 125 cannot prevent the selective pressurethat leads to overgrowth of resistant bacterial sub-populations.These indices can assist with patient management strategiesin a prospective manner, and allow comparison of outcomeswith different treatment regimens and dosing strategies.Our studies demonstrate that calculations of AUIC can beused to prospectively target regimens to improve thechances of cure with nosocomial pneumonia and otherserious infections. A clinical intervention team has beenorganized to optimize antimicrobial regimens as early intherapy as possible, so as to lower the high cost events likefailure and acquired bacterial resistance.

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3. The therapeutic management of neutropenic cancerpatientsClaudio ViscoliUniversity of Genova and National Institute for CancerResearch, Genova, ItalyAmong about 800 documented bacteraemias observed in the8 therapeutic trials (I, II, III, IV, V, VII, IX and XI) performedby the International Antimicrobial Therapy Co-operativeGroup (IATCG) of the European Organization for Researchand Treatment of Cancer (EORTC) from 1978 to 1994, theoverall mortality rate decreased from 21% to 7%. This islikely due to the strategy of the rapid institution ofempirical, broad-spectrum antibacterial therapy with veryactive antimicrobial compounds at the development of feverduring neutropenia. However, the specific composition ofthe empirical regimen remains controversial and subject tochange, due to the changing pattern of pathogens, the rapiddevelopment of bacterial resistance, the emergence of newclinical entities, and the availability of new effective drugs.The classic b-lactam-aminoglycoside combination has longbeen considered the best therapeutic approach, because ofits wide spectrum of action, its potential synergistic activityagainst Gram-negative rods and its potential ability toreduce the emergence of resistant strains, both in the singlepatient, during treatment and in the environment over time.Pitfalls include poor activity against staphylococci andstreptococci, possible development of resistance in Gram-negative rods, aminoglycoside-related toxicity, and the needto administer multiple daily doses of both antibiotics. Apivotal development in this area has been the demonstrationthat single daily dosing (with ceftriaxone and amikacin) is afeasible, effective and safe practice. Single-agent therapybecame feasible and safe when broad-spectrum antibiotics,such as 3rd and 4th generation cephalosporins with anti-Pseudomonas activity (ceftazidime and cefepime) andcarbapenems became available. At this time, availableevidence suggests that at the end of the neutropenic periodthere should be little difference (if any) in terms of survival,between febrile and neutropenic patients who started withmonotherapy and those who received combinations. Severaltrials, including a recent one from the IATG-EORTC showedthat the empirical use of glycopeptide antibiotics is notindicated. In recent years, several reports have underlinedthe increasing role of fungal infections as a cause ofmorbidity and mortality in compromised patients, includingthose with cancer.

4. Role of clinical experience for selecting optimal therapyof febrile neutropeniaJ. KlasterskyProfessor and Chief of Medicine, Institut Jules Bordet,BrusselsEmpirical treatment, i.e., broad spectrum antimicrobialtherapy without waiting for microbiological and/or clinicaldocumentation of an infection, is justified in patients withfever and neutropenia (FN), by the high frequency of severeinfection that is associated with a low granulocyte count.Moreover, signs and symptoms of infections are ofteninconspicuous in patients with FN in whom sepsis may havea fulminant course, possibly killing the patient beforesignificant microbiological information is available.Various pronostic factors for patients with FN have beenidentified in recent years ; the choice of empirical therapy ofFN should be adapted accordingly, as the population ofpatients with FN is obviously heterogeneous.A substantial proportion of patients at low risk of

complications during FN can be safely identified on thebasis of the initial presentation, using predictive rules suchas the MASCC score (J Clin Oncol. 2000 Aug;18:3038–51).In these patients at low risk of complications, variousantimicrobial regimens have been tested ; among them oralamoxicillin/clavulanate plus ciprofloxacin was found aseffective as intravenous ceftriaxone plus amikacin (oncedaily) or standard ceftazidime. Other regimens, likely to beeffective, should be further evaluated in prospective studies.All other patients with FN should be hospitalised forempirical therapy adapted to their clinical andhaematological presentation. In patients whose neutropeniais moderate, and especially if it is expected to be short-lived,single agent IV therapy covering most gram-positive andgram-negative pathogens is appropriate. Agents such ascefepime, ceftazidime, imipenem, meropenem andpiperacillin/tazobactam are probably adequate. It should bestressed that none of these antibiotics covers methicillin-resistant coagulase-negative staphylococci; these are verycommon as a cause of FN but have a low pathogenicity,allowing to delay specific therapy with glycopeptides untilthe microbiological diagnosis is made.Although, monotherapy for empirical treatment of FN hasbecome widely accepted, however, in patients presentingclinical signs predictive of gram-negative sepsis, namelyhigh fever and hypotension, combination therapy with anaminoglycoside should remain the rule. When serious gram-positive infection is strongly suspected, as in unstablepatients with a infected IV line or extensive mucositis of theoral cavity and/or digestive tract, addition of a glycopeptideis warranted.Thus clearly there are clinical clues, at the onset of anepisode of febrile neutropenia, that can be used to select themost appropriate therapy in a given patient. Adaptingtherapy to the clinical needs may result in improved efficacy,quality of life and cost-effectiveness.Score Derived from the Logistic Equation of the MASCCPredictive Model (1386 patients with febrile neutropenia)

Characteristics PointsBurden of illness

No or mild symptoms 5Moderate symptoms 3

No hypotension 5No chronic obstructivepulmonary disease 4

Solid tumor or no previousfungal infection inhaematological tumor 4

Outpatient status 3No dehydration 3Age < 60 years 2

The purpose of the scoring (maximum score: 26) is to selectlow-risk patients having a high probability of favourableoutcome: score ≥ 21 predicting less than 5 % of severecomplications.

5. OPAT in immunocompromised patientsGary MilkovichFounding Director of RJM, Northern Virginia, USALife-threatening infection is a significant complication inpatients undergoing intensive myelosuppressive therapy fortreatment of malignancy. As more aggressive chemotherapeuticregimens are used, the degree of immunosuppressionbecomes more pronounced and periods of resultantneutropenia become more prolonged. The undesired effectsthat chemotherapeutic agents have on the gastrointestinal

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mucosa put the patient at high risk for invasive infectionfrom both endogenous and hospital-acquired bacteria.For the past three decades, empiric antibiotic therapy hasbeen widely accepted in the initial management of febrileneutropenic patients with early signs of possible infection(e.g., unexplained fever). Early antimicrobial therapy, whichis associated with a decrease in patient morbidity andmortality, has become the recommended practice, instead ofwithholding therapy until positive cultures aredemonstrated or focal findings appear.In the past, when infection is microbiologically documented,gram-negative aerobic bacilli, particularly Escherichia coli,Klebsiella pneumoniae, and Pseudomonas aeruginosa, were thepathogens most frequently isolated. However today, withincreased usage of vascular access lines, gram-positiveorganisms are increasing in this patient population as asource of infection.Since the 1970s, the most frequently used empiricantibacterial therapy has consisted of two or three-drugregimens. usually combining a cephalosporin, anti-pseudomonal penicillin, or both, with an aminoglycoside.The rationale for this approach is based on (A) the widerange of potential gram-positive and gram-negativeorganisms necessitating coverage and (B) evidence that com-bination therapy result in additive or synergistic bactericidalactivity.The availability of new broader spectrum cephalosporins,carbapenems, monobactams and quinolones has led toconsiderable controversy regarding the use of these agents asmonotherapy for empiric antibacterial treatment of thefebrile compromised host. Most clinicians continue to favorthe use of a regimen combining a b-lactam with anaminoglycoside particularly in patients with persistent neu-tropeniaThe strategy of OPAT has facilitated the early discharge ofthese patients to settings that afford the patient a high levelof care at a cost that is substantial less than an inpatient stay.

6. The present and the future of antifungal agents: old andnew classesBen E. De Pauw, M.D., Ph.D.University Medical Center St Radboud Nijmegen, TheNetherlands.So far 3 classes of compounds with recognized systemicactivity are available for clinical usage: amphotericin B, 5-flucytosine, and the azoles.Amphotericin B has been the drug of choice for all invasivefungal infections in severely ill patients for more than 30years. This broad-spectrum polyene acts by increasing thepermeability of the fungal cell membrane by bindingergosterol components. The drug has a very narrowtherapeutic index. Its administration is accompanied by anumber of unpleasant effects. The most serious toxic effectof amphotericin is nephrotoxicity as manifested by renal lossof potassium, resulting in clinically relevant hypokalemiaand less impairment of renal function. The dose-dependenttoxicity of amphotericin B was the major rationale forbinding amphotericin B to other lipid carriers, aiming at asignificant reduction of toxicity and, by consequence, anincreased therapeutic index. Formal randomizedcomparisons with standard amphotericin B deoxycholate inlarge clinical trials have never been made. Encouragingclinical data regarding the use of lipid formulations ofamphotericin B are emerging. One study, a randomizedmulticenter trial has reported superior efficacy and safety of5 mg/kg/day liposomal amphotericin B when compared with

1 mg/kg/day amphotericin B deoxycholate in the treatmentof neutropenic patients with either a documented invasivemycosis or a suspected invasive pulmonary aspergillosis.Azoles have shown a better tolerability and certainlyconstitute an acceptable alternative to intravenousamphotericin B for many indications. However, whilst incomparison to amphotericin B they possess a different, moremanageable spectrum of toxicity, they share each other’starget for activity, i.e., the fungal cell membrane.Fluconazole and itraconazole are both better tolerated thanketoconazole and have, therefore, become populartherapeutic alternatives to amphotericin B for many seriousfungal infections. The limitation of this group of antifungalcompounds is their propensity to interact withcoadministered drugs. Increasing resistance of fungalorganisms to fluconazole, especially the Candida species isbecoming troublesome for the safest of all antifungal drugs.In patients with chronic aspergillosis as well as in those whohave been treated during acute phase with intravenousamphotericin B, itraconazole has become a frequentlyfavoured alternative. There are theoretical concerns about apossible antagonism between azoles and polyenes, butsequential use of the agents did not bear out this concern.5-Fluorocytosine is a pyrimidine analog, interfering withboth protein and DNA synthesis. A major limitation is thedevelopment of drug resistance. The drug has side effects,including hepatotoxicity and bone-marrow suppression.An totally new class of antifungal agents, candins act byinterference with the synthesis of chitin, an important cell-wall component, and results in lysis of the fungal cell. Thesedrugs have fungicidal activity against Candida species,including fluconazole-resistant species. Promising activityagainst Aspergillus species in conjunction with a notable lackof activity against Cryptococcus neoformans and Zygomycetes.The different mechanism of action offers the potential of acombination of candins with other antifungal compounds.

New therapeutic approaches for Gram-positiveinfections

Global antibiotic resistance trends and impacts: old andemerging problemsGC Schito (Italy)No abstract available

Using pharmacokinetics/pharmacodynamics as predictorsof antimicrobial successW Craig (USA)No abstract available

6a. Novel therapies for Gram-positive infectionsE Rubinstein (Israel)Gram positive infections, particularly those resistant tovancomycin, are reported from all corners of the world.Thus, for example, glycopeptide resistant and intermediateStaphylococcus aureus (GISA) and vancomycin resistantenterococci (VRE) have become frequent isolates inhospitals and penicillin resistant pneumococci have becomethe rule, rather than the exception, in the community.Among newer agents that are active against resistant grampositive pathogens, several deserve mentioning. Linezolid,the first oxazolidinone has a bacteriostatic action that isdependent on its C-5-acyl-amino-methyl group and the SJ-configuration-5. Newer oxazolidinones are now underdevelopment by more than one company and in the future,we probably will witness more than one compound from

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this family. Quinupristin/dalopristin is a mixture of twomolecules with extended activity against vancomycinresistant and susceptible gram positive pathogens. Thecompound is bactericidal and has acted well in patientsfailing or intolerant to vancomycin, with clinical andmicrobiological results in the range of 70%. Daptomycin is acyclic lipopeptide which has a rapid cidal activity againstgram positive cocci. Its initial clinical data are encouragingand have revealed far lesser toxicity in recent studies than ininitial studies that used higher and more frequentadministrations. Among patients in Phase II trials, theclinical success was 92% and microbiological success 100 %.Glycyclines are a new modification of the tetracycline familywith extended activity of resistant gram positive pathogens,including chlamydia. They have acceptable pharmacokineticsin animals and static activity against resistant gram positivepathogens, animal experiments provide the base for clinicaltrials. Oritavancin, a semisynthetic glycopeptide is a newmember of the glycopeptide family, with extended activityagainst gram positive pathogens. It inhabits the peptoglycanbiosynthesis at the site as in vancomycin, while it alsoinitiates with cell membrane and acts as an inhibitor of transglycosylating enzyme. The MIC90 are similar to those ofvancomycin and teicoplanin against vancomycin susceptiblestaphylococci and enterococci but is highly active againstvancomycin resistant gram positive cocci with rapid onset ofcidal effect, favourable pharmacokinetics, The drug is underintense clinical evaluation at the present time. The recentchallenge of resistant gram positive infections has been metby the development of antibiotics with activity against thesepathogens, most of the agents have reached pre-clinical orclinical trials with results that are successful. It seemstherefore that the threat of those infections will soon be met.

Role of new agents in the ambulatory setting: clinicalevidenceD Nathwani (UK)No abstract available

Biological warfare—what to do about it?E. Rubinstein (Israel)

Update on quinolones

Overview on quinolone resistanceJ Acar (France)No abstract available

6b. GatifloxacinH. Lode, BerlinCommunity-acquired pneumonia (CAP) remains a commonand serious illness, inspite of the availability of potent newantimicrobials and effective vaccines. In Europe about 3–4Mill. cases of CAP occur annually and this disease is thefifth leading cause of death. CAP is increasingly recognizedamong older patients and those with co-morbidity. Leadingpathogens in the etiology of CAP are S. pneumonia, H.influenzae, Mycoplasma, Chlamydia pneumonia, Legionellaspecies, respiratory viruses and in the elderly patientpopulation also enteric Gram-negative bacteria. No singlediagnostic test is presently available which can identify allpotential pathogens, and each diagnostic test haslimitations. Resistance by a variety of mechanisms hasbecome an increasing problem among several etiologicbacteria. Especially penicillin and macrolide resistantpneumococci have become a major concern worldwide.Guidelines in the last three years are dividing CAP patients

into three groups on the basis of place of therapy, thepresence of coexisting cardiopulmonary disease, and thepresence of modifying factors, which include the presence ofrisk factors for drug resistant pneumococci, the presence ofrisk factors for Gram-negative infection, and the presence ofrisk factors for P. aeruginosa. Based on these factors fourpatient groups could be defined; risk factors should be alsoused to make an appropriate decision for hospitalization ofpatients. All patients should have a chest x-ray, blood count,blood chemistry, blood gas analysis, at least two bloodcultures and if possible sputum Gram-stain and culture orbronchoscopically collected samples. At least in the hospitalcurrently introduced measurements of urinary antigens fordiagnosis of pneumococcal and legionella infections are veryhelpful. On the basis of the well defined four differentpatient groups a rational empiric antibiotic treatment ispossible. However, antibiotic treatment should be focusedafter having received a precise microbiological information.Empirical antibiotic treatment has also to consider the localresistance pattern, costs and the optimal application forms.

MoxifloxacinJA Garcia Rodriguez (Spain)No abstract available

7. Next generation quinolonesGS TillotsonPHRI, NYC, and Fusion MD, CT, USAThe pharmacore of the quinolone family was developed byLescher and colleagues in the early 1960’s. Modification ofthis core at the 8 position and addition of a fluorine at theC6 site yielded the 6-fluoroquinolone group. To date therehave been >10,000 congeners of this group most notablyciprofloxacin, levofloxacin, norfloxacin and most recentlygatifloxacin and moxifloxacin. At least 4 group membershave been approved for clinical use but have been eitherwithdrawn or severely limited in use for a variety of safetyreasons. The continued expansion of this group, in theforms of clinafloxacin and sitafloxacin have been checkeredmainly for safety issues. Thus we seem to have hit athreshold in terms of a potency and safety balance; hencenovel modifications are now being explored. These include:2,4 difluoro-5-aminophenyl derivatives (WQ 3330 & WQ2942), a series of 6- des-6 fluoroquinolones from BMS andProcter and Gamble ( BMS 284756, PGE 926 2932,PGE 4175997, PGE 9509924) and a collection of benzene-sulfonylamido-piperazinyl quinolones.The 6-des-6 fluoroquinolones are being primarily developedfor community respiratory infections e.g. MIC 90’s for S.pneumoniae being; PGE 926 2932 0.016,PGE 95099240.06,PGE 4175997 0.03, BMS 284756 0.06mg/l). Therelative activities and initial safety/preclinical toxicologydata for these agents will be compared. Most data exists forBMS 284756, which at this stage appears to be a safe andpotent addition to the quinolone group.

8. Safety of quinolonesPeter Ball, FRCP, Ed.University of St Andrews, Fife, ScotlandAfter 20 years of second/third generation fluoroquinolones,class adverse drug reactions (ADRs), structure-relatedproblems and idiosyncratic effects are well recognised,quantified and, at least in part, avoidable by appropriatemolecular design. Established agents, e.g. ciprofloxacin,levofloxacin and the methoxy-quinolones (moxifloxacin andgatifloxacin) have excellent Phase III/IV safety profiles andlarge denominators (10–300 M treatments) for post

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marketing surveillance (PMS), thus allowing comparison ofrare events. For example, QTc class effects of variable(usually minor) degree result in cardiac arrhythmias in lessthan 1 per million exposures, usually with multiplepredisposing factors. Immunological and associated organtoxicity, possibly explained by 1-difluoro-phenylsubstitution (trovafloxacin and temafloxacin), are not seenwith other quinolones. New des-fluoroquinolones havelower potential for joint and other toxicity which, untilrecently, precluded routine paediatric use. Extendedpaediatric use will undoubtedly follow and trials areproceeding with several agents.PMS studies confirm these safety profiles, ADR incidencesbeing 10% of clinical trials. Incidences vary betweencountries, often methodological, and notably in Japan,where lower dosage (and other factors) results in very lowclass ADR frequencies. In comparison with longerestablished antibiotic classes, quinolone have emerged asamongst the safest and best tolerated.

Pediatric infections

9. New antibiotics for the pediatricians —problems andhopesUrs B. Schaad, M.D.University Children’s Hospital, Basel, SwitzerlandGeneral ReflectionsMany new antimicrobials have, or are about to become,clinically available for use in pediatrics. This reflects thedrug development program we have witnessed during thelast decades: research was able to keep up the conspicuouscycle leading from introduction of a new antibiotic, toemergence of resistance, to replacement by a new antibioticwith improved activity for the resistant isolates. The zenithhowever in “easy” development of new antimicrobials hasbeen reached some years ago, and introduction of newagents has slowed dramatically. The principal reasons arethat most of the easy antimicrobial targets have beendiscovered and extensively modified, and that expenses andrisks (e.g., unpredictable toxicity in clinical use) ofdeveloping new antimicrobials have come to oftenunacceptable extents.As we enter the new millennium, our position for treatinginfectious diseases is precarious, to say the least. Theemergence of pathogens with resistance to availableantibiotics is an increasing threat worldwide. The answer isno longer waiting for new drugs - but decreasing emergenceof resistance. Bacterial resistance is usually selected byoveruse or inappropriate use of antibiotics. Overuse (e.g.,for viral infection, as prophylaxis, many veterinarianindications) usually reflects inadequate knowledge andunavailable diagnostic methods. Appropriate use includesnot only classical selection of an optimum antibiotic, butalso individual optimization of both dosage and duration oftherapy.

The MacrolidesThe spectrum of activity of the recently available macrolidesencompasses not only many common gram-positive andgram-negative bacterial pathogens, but also includes atypicalpathogens (e.g., Mycoplasma, Chlamydia and Ureaplasma),Mycobacteria sp, spirochaetes, and selective protozoa. Thesenew drugs have improved gastrointestinal tolerance, longerserum half-lives and greater tissue concentrations. For thediscussion of potential new indications, one has, in additionto these drug characteristics, to take into consideration the

growing global problem of antimicrobial resistance.Besides the traditional and well established use of themacrolides in respiratory tract and skin and soft tissueinfections, there is increasing and promising data on theirusefulness in diseases caused by atypical mycobacteria,Helicobacter pylori (e.g., peptic ulcer disease) and Bartonellahenselae (e.g., cat scratch disease). Also neonatal infectionscaused by either Chlamydia or Ureaplasma, and pertussisduring infancy, favourably respond to the new macrolides.Their potential for protozoal infections (e.g., toxoplasma,giardia) or causative therapy of arthritis (e.g., reactiveforms), asthma (e.g., related to Mycoplasma pneumoniae) oratherosclerosis (e.g., related to Chlamydia pneumoniae)remains investigational for the time being. Various in-vitroand in-vivo experimental studies suggest hypothetical non-antibiotic uses of the marcrolide compounds, includingstimulation of gastrointestinal motility and modulation ofimmunologic, inflammatory or even neoplastic processes.

The QuinolonesThe use of quinolones in children has been limited becauseof their potential to induce arthropathy in juvenile animals.This extraordinary form of age-related drug toxicity hasbeen demonstrated with all quinolones tested thus far andhas led to important restrictions; their use has beenconsidered to be contraindicated in children, in growingadolescents and during pregnancy and lactation. However,since the mid-1980s, many children have received treatmentwith fluoroquinolones, mainly ciprofloxacin, because theyare the only oral antimicrobials with potential activityagainst such multiply resistant and difficult-to-treatinfections as Pseudomonas aeruginosa infections in childrenwith cystic fibrosis, complicated urinary tract infections, andenteric infections in developing countries. Manyinvestigators have reported their experience in the use ofciprofloxacin and other fluoroquinolones on “compassionate-use”-based protocols. Results indicate that prolongedtherapy with the fluoroquinolones is effective and well-tolerated in pediatric patients with no significant evidence ofarthropathy, bone abnormalities or other serious adverseevents.To date, potential pediatric indications for the availablefluoroquinolones (especially ciprofloxacin; for someindications, also ofloxacin and norfloxacin) includebronchopulmonary exacerbation in cystic fibrosis,complicated urinary tract infection, and invasivegastrointestinal infection. Based on preliminary experiencewith some of the newest quinolones (e.g., gatifloxacin,gemifloxacin, des-F(6)-quinolone) further potentialpediatric indications that clearly require additionalcontrolled studies are chronic suppurative otitis media,neutropenia in cancer patients, eradication ofnasopharyngeal carriage, and CNS infections.Based on the remaining potential toxicity problems and theincreasing multi-drug resistance among human pathogens(e.g., Streptococcus pneumoniae) it is concluded that thequinolone antibiotics should never be used in pediatrics forroutine treatment when alternative safe and effectiveantimicrobials are known.

10. Must we wait for clinical failure to react to bacterialresistance?Pierre DellamonicaNice, FranceIncreasing use of antibiotics has led to the selection ofresistant mutants. To result in clinical failure, bacteria mustreach MIC/MBCs well above the antibiotic concentrations

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within the infected site. Concurrent mechanisms also favoursurvival of bacteria in situ, such as immune defects, mainlyconcerning granulocytes and immunoglobulin subclasses, orspecific local bacterial growth conditions. This is the case inparticular for infected foreign material, where bacteria are inslow-growing phase and often protected by slime, so that theusual parameters of the MIC/MBC and concentrationcorrelation are no longer valid. Cultured bacteria undergoexponential growth and appear deceptively susceptible. Theproblem must therefore be considered from two angles, onefor acute infections due to resistant bacteria in which theclassical parameters MIC/MCB and concentrations havegood predictive values, and the other for infections due tobacteria that are susceptible in vitro but resistant in vivo.For instance in meningitis, proof of the relationship betweenincrease of MIC/MBC and failure has been establishedseveral years ago and it is becoming so for pneumonia.Infection is due to resistant rhinopharyngeal carriagebacteria selected through inappropriate antibiotic use insimple infections: colds, rhinosinusitis, otitis. In acutepneumococcal pneumonia, this correlation is beingmonitored and it is becoming positive. Steps are being takenin certain countries to improve the quality of prescriptionand compliance with antibiotic treatments in order to avoidselection of resistant mutants which might lead to invasiveinfections. Prevention of their transmission is also a problemwhich appears to be related to the density of the targetpopulation.The other situation is that in which the methods formeasuring bacterial susceptibility are not predictive, as isthe case for infections on foreign material. In such cases, theuse of predictive bacteriological techniques must beadvocated to limit failure as in these infections selection forresistance takes place similarly.To sum up, in the two most common situations, a majoreffort must be made on one hand to limit selection anddispersal of resistant bacteria. On the other hand in certainparticular situations the availability of predictive techniquesallowing improved assessment of bacterial susceptibilitywould improve the quality of prescriptions and avoid theincidence of failure.With regard to present practice, which leads to increasedresistance resulting in failure, it is urgent to improvespecialisation in antibiotic therapy.

11. Conjugate vaccines: potential impact on antibiotic use?D. AdamChildren’s Hospital University of Munich, Munich, GermanyConjugate vaccines against bacterial infections for exampleH. influenzae invasive infections (e.g., meningitis,epiglottitis) or pneumoccal infections (e.g., meningitis,pneumonia) are highly effective and have reduced thesediseases in a remarkable manner. This also might have animpact on antibiotic use and development of resistance.So for example more than 90% of resistant strains of S.pneumoniae belong to vaccine serotypes. Recently publishedand as yet unpublished data allow a reasonable estimate ofthe annual burden of pneumococcal disease. Pneumococcaldiseases are clearly a frequent course of morbidity andmortality. Children and the elderly are the most vulnerablegroups, mainly as a result of invasive disease andpneumonia. The efficacy of pneumococcal conjugate vaccinefor example can elicit serotype-specific antibodies andprotect against both invasive disease as well as acute otitismedia caused by vaccine serotypes of S. pneumoniae.Immunisation can also place selective pressure on

nasopharyngial flora creating the possibility that newpathogens will emerge as important courses of acute otitismedia as well as lead to a decrease of macrolide andpenicillin resistant pneumococci usually responsible foracute infections in pediatrics and the elderly. On the otherhand perhaps new pathogens will emerge as importantcauses of AOM for example. An increase in carriage of nonvaccine’s serotypes with low resistant rates was observedafter pneumococcal conjugate vaccine immunisation. Thepotential for non-vaccine-serotypes to produce acute otitismedia has already been shown in several studies of AOMfrom children in the U.S., Israel and Eastern Europe, inwhich 35 different serotypes of S. pneumoniae wereidentified from middle ear fluid. A high proportion of theisolates were non-vaccine-serotypes. Also it appears thatnon-vaccines-serotypes compete less effectively for coloni-sation of the nasopharynx and invasion of the middle ear.In the presence of vaccine-serotypes, it is likely that theywill become more frequent in children immunised withpneumococcal conjugate vaccine.A similar situation can be expected with conjugate vaccinesfor Moraxella catarrhalis as well as for H. influenzae.It can be assumed that if pneumococci are used as anexample 80% of the penicillin resistant and 90% of theerythromycin resistant strains can be reduced with a 7-valente pneumococcal vaccine. Nevertheless this assumptiondepends on the frequency of vaccination of a population,but might have an impact on antibiotic use. Antibiotic usealways also correlates with the situation of resistance in aspecial place.

The role of quinolones in the GI pediatric infectionsE Gotuzzo (Peru)No abstract available

Advantages of combination therapy in thetreatment of infectious diseases

12. Correlation between phenotypic/genotypic resistanceand therapeutic strategies in HIVProf. N. ClumeckHead of Division of Infectious Diseases C.H.U. Saint-Pierre,Brussels, BelgiumIn the last decade, a significant decrease in morbidity andmortality has been observed in HIV-1 infected patientsreceiving antiretroviral therapy. Despite the potentantiretroviral activity of various combination regimens,treatment failure is often observed. Adverse effects, pooradherence, drug-drug interactions, pharmacologic factors orviral resistance emergence are important reasons forvirological failure. HIV-1 resistance to antiretroviralinhibitors can be determined at the genotypic level by thedetection of mutations that are known to confer phenotypicresistance. Alternatively, it can be determined at thephenotypic level by measuring the ability of an HIV-1 isolateto grow in the presence of an inhibitor.Viral resistance testing can be a helpful tool in the clinicalmanagement of HIV-1 infected patients. Variousretrospective and prospective studies have alreadydemonstrated a strong correlation between genotypic orphenotypic resistance and short-term virologic outcome inpatients.Important issues that remain include: the furtheroptimisation and evaluation of resistance assays, not only onsubtype B but also on non-B subtypes; the determination ofthe mutations among minor variants that are predictors for

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drug failure; the determination on the optimal point in HIV-1 plasma viral load at which the therapy should be changedin order to minimize the accumulation of points mutationsin HIV-1 genome and to improve long-term clinicaloutcome. Research in clinical setting should also beperformed to clarify the phenotypical threshold at which aspecific inhibitor becomes ineffective in vivo.

13. Power and tolerability of HAART: what balanceStefano Vella, M.D.Istituto Superiore di Sanità, Rome, ItalyDespite the impressive progress to date, with the dramaticimpact on the natural history of HIV, and the unprecedentedchanges in disease progression and mortality, much workremains to be done with antiretroviral therapy of HIVinfection. Even with the most potent regimens available,there exists a significant proportion of patients who fail tohave a complete response after their first line treatment.This population is at high risk of experiencing a virologicrebound, and of being be less responsive to subsequentantiretroviral regimens, also due to the limited number oftherapeutic options currently available. Incompleteresponse rate and limited durability of the response are notthe only shortcomings of the current regimens, otherproblems including: complexity of the regimens, short andlong-term toxicity, cross resistance among drugs of the sameclass, unfavorable pharmacokinetics. These problems areparticularly evident in patients with high plasma HIV-1 RNAlevels, extensive prior treatment, and advanced disease.While the general principle of maximally suppressing viralreplication is likely to be remain firm in the next revisionsof current therapeutic guidelines, the situation has quitechanged with respect to “when to start” issue.The goal of therapy is to maintain the patient in a healthystate, and to avoid opportunistic complications. Because ofthe long-term adverse effects of therapy are sufficientlyserious, it is now considered not appropriate to initiatetherapy, in the asymptomatic individual, at a time when theCD4 count indicates the patient is at no appreciable risk forserious opportunistic infections (i.e., when CD4+lymphocytes are above 350 cells/mm3). Initiating therapy atthis point will prevent most serious opportunistic infections,and appears to be the most reasonable approach at present.Indeed, an earlier initiation of treatment may expose thepatients to unnecessary medication-related risks, whichrange from adherence problems and impact on quality oflife, to the potential for early development of resistance toantiretroviral agents, and the possibility of serous metaboliccomplications.To achieve the goal of a complete suppression of HIV inplasma, at least in subjects at their first antiretroviraltreatment, several strategies are now available. These includeprotease inhibitor (PI)-containing and PI-sparing regimens.PI-containing regimens have several advantages, whichinclude potency, extensive experience, evidence for long-term (> 3 years) durability, potentially exploitable drug-druginteractions, widely known toxicity profile, evidence ofeffectiveness in patients at all levels of plasma HIV-1 RNA.Due to these characteristics, for long time PI-containingregimens have been the first choice for patients initiatingtheir antiretroviral treatment. Nevertheless, somedisadvantages may limit their acceptability. These include: a)complexity of the regimens, which creates a challenge toadherence; b) cross-resistance between different PIs, whichmay limit the utility of the future PI regimens should initialtherapy fail and c) the growing concern over long-term

toxicities, particularly the metabolic abnormalities andlypodistrophy. For these reasons, and with the availability ofnew potent inhibitors of reverse transcriptase, PI-sparingregimens have been introduced into clinical researchinitially, and clinical practice thereafter. In this context, non-nucleoside reverse transcriptase inhibitors (NNRTI) havegained in popularity for their potential role in PI-sparingregimens. A durable suppression of plasma HIV-1 RNA hasbeen demonstrated for regimens including both efavirenzand nevirapine. These results have provided convincingevidence that NNRTI regimens offer a suitable alternative toPI-containing combinations for initial antiretroviral therapyin treatment-naive patients. NNRTI-containing regimens,besides the potential advantage of deferring the introductionof PIs, in some instances allow for a lower pill burden thanPI-containing regimens. On the other hand, they are notwithout potential disadvantages. Among these, the low“genetic barrier” of these drugs and the rapidity with whichresistance develops if regimens are not completelysuppressive represent the main cause of concern. Onaddition, cross-reactivity exists among drugs of this sameclass.Recently the use of triple NRTI therapy as a PI-and NNRTI-sparing regimen has been proposed. Most data refer tocombinations which include. This combination appears tohave equivalent activity to a “standard” PI containingregimens and the main attraction of an all-NRTI regimen isdeferral of the use of PIs, while sparing the NNRTI andplacing only a single class of agents “at risk” fordevelopment of resistance. However, also in this case thelong-term efficacy and toxicities of multinucleosideregimens are unknown. In addition there is concern over thepossible selection of multinucleoside-resistant variantscarrying either the Q151M or T69SSS mutation complexes.With short-term clinical trials indicating comparablepotency and efficacy of PI-, NNRTI- and all NRTI-containingregimens, the attention should be rather focussed on theirdifferences with regard to long-term outcome, toxicity,constraints on future regimens, and the effect on viralreservoirs in non-lymphoid compartments. The answers tothese questions and the advantages/disadvantages ratio ofthese different treatment strategies will only come from theresults of well-controlled strategic clinical trialsPharmacokinetic/pharmacodynamic properties ofantimicrobial combinations for Gram-negative bacteriaW Craig (USA)No abstract available

13a. Combination therapy for serious infectionsL Mandell (Canada)The use of combination therapy of serious infections is animportant and often controversial topic. For the purposes ofthis discussion I will limit myself to antibacterial agents andwill not include the use of combinations of ntibacterials andantifungals or antivirals or more than one antifungal/antiviraldrug. The in vitro effects of more than one antibacterial maybe either additive, synergistic or antagonistic. This will varydepending upon the nature of the micro-organism and theantibiotics used. Clinically however, combinations ofantibiotics have been used for a number of reasons andinclude the following general indications: to broadenantibacterial coverage; to provide synergistic coverageagainst a particular pathogen; and to minimize theemergence of resistance.

Broaden Antibacterial CoverageA number of infections such as peritonitis and diabetic foot

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infections to name a few are typically polymicrobial innature. Combinations of antibiotics were employed tobroaden the spectrum of pathogens which the therapeuticagents could cover. With the development of broadspectrum drugs such as the carbapenems and certain b-lactam b-lactamase inhibitors however, the use ofcombination therapy for some of these indications has fallenby the wayside.There are still situations however in which the suspectedpathogens may require the use of more than one antibiotic.A typical example would be patients in an ICU setting inwhom methicillin resistant staphylococcus aureus (MRSA) aswell as aerobic gram negative rods and possibly anaerobesmay play a role. In such situations there is no single drugwhich is able to provide sufficiently broad coverage.SynergySpecific situations in which combinations of antibiotics withdocumented in vitro-synergistic activity have resulted inimproved outcomes include: enterococcal endocarditis andbacteremia caused by methicillin-sensitive S. aureus. Inthese two situations a b-lactam such as ampicillin orpenicillin plus gentamicin or a penicillinase resistant semi-synthetic penicillin plus gentamicin respectively can beused. The use of combination therapy against Pseudomonasaeruginosa in the setting of bacteremia has also been shownto have a beneficial effect.Minimize emergence of resistanceThis has clearly been documented to be important in thetreatment of tuberculosis and there are some data supportingthe use of rifampin and anti staphylococcal agents yet thereis very little if any evidence to suggest that the use of morethan one anti bacterial drug agent results in the suppressionof resistance to one or both of the drugs.The use of combination therapy has been used in immunocompromised hosts particularly the febrile neutropenicpatient in the hope that such regimens would providebroader coverage as well as synergistic activity against theetiological agents. The use of combination therapy in suchsituations as well as selected other clinical situations will bediscussed.

Contemporary management issues in bacterialmeningitis

14. Community acquired bacterial meningitis: principlesand practice in 2001Vincent QuagliarelloYale University School of Medicine, New Haven,Connecticut, USAThis lecture will summarize the state of the art formanagement of bacterial meningitis in adults in 2001.Specific issues discussed will begin with epidemiologictrends of therapeutic importance including the impact ofHaemophilus influenzae type b vaccination, and evolvingtrends in b lactam resistance for Streptococcus pneumoniae.New information about clinical and laboratory diagnosticswill be discussed as well as a brief review of pathogenesisand pathophysiology. The largest part of the discussion willfocus upon new information about practical bedsidemanagement (including the role of CT scanning beforelumbar puncture), as well as the principles and practice ofantimicrobial therapy (including data describing the impactof antibiotic timing on clinical outcome). Specificrecommendations for antibiotic selection based on CSFGram’s stain and culture will be outlined for the current eraof antimicrobial resistance.

Therapeutic options in an era of evolvinghospital bacterial resistance: maximizing power,minimizing risk

15. Hospital bacterial resistance: a global battleJD WilliamsLondon, UKAntibiotic resistance is a problem for everyone who usesantibiotics—hospital doctors, doctors in the communitytreating ambulant patients and for veterinarians.Although only 10% of weight of all antibiotics are used inhospital (and the remainder in the community or on thefarm), the worst problems are experienced in hospitals withmulti-resistant Staphylococcus aureus, vancomycin-resistantenterococci, resistant Gram-negative organisms and Candida.The prevention of acquisition and spread of such organismsis a global problem and all persons working in these threemain areas of use are well aware of the problems. Somequestions related to the control of antibiotic resistance willbe addressed.Will alteration of usage in one area, e.g., on the farm, affectresistance in other areas of use? The evidence suggests thathospitals are little affected by use of antibiotics in thecommunity and on the farm. The solutions to the hospitalproblems must be sought inside the hospital rather thanoutside.Will strict policies on hospital use of antibiotics influencethe evolution and spread of antibiotic resistance in hospital?It is fair to say that most attempts to prevent resistance bycurbing prescribing have failed. Optimal use of antibioticsrequires more than simple rules related more to cost-containment than improvement of health-care.What is more important—prevention of acquisition ofresistance or prevention of resistant clones? Theepidemiology of MRSA, resistant enterobacteria andpseudomonads suggests the latter.Why is resistance such a problem in the hospital? Onefactor is the openness of immunologically weakenedpatients to infection by organisms of low pathogenicity. Thehospitals are full of such patients and methods of preventingpatients from being colonised by such strains in hospital aredifficult to implement

Clinical relevance of antibiotic resistanceJ Garau (Barcelona, Spain)No abstract available

Antibiotic treatment decisions: an overview of the arsenalR. Moellering (Boston, USA)No abstract available

Treatment of prosthetic infections: revisiting the optionsF. Waldvogel (Geneva, Switzerland)No abstract available

16. Appropriate use of antibiotics: improving the oddswith concordant therapy when an antibiotic is needed.Helen Giamarellou, M.D., Ph.D.4th Department of Internal Medicine, Athens UniversitySchool of Medicine, Sismanoglio General Hospital, Athens,Greece.Tertiary hospitals and ICUs are epicenters of antibioticresistance and the principal sources of endemic multi-resistant bacteria. The most important risk factors areantibiotic overuse and misuse that exert selective pressureon normal floras, suboptimal application of hygienicpractices, overcrowding, the frequent use of invasive devices

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and the increase of the immunocompromised patients.Infections due to antibiotic-resistant bacteria have a majorimpact on morbidity while mortality is higher in countrieswith high rates of nosocomial infection and even higher inthose with high rates of resistant microorganisms. MRSA,VRE and multiresistant gram-negatives (P. aeruginosa, A.baumannii, E. cloacae, and K. pneumoniae) are thepredominant multiresistant pathogens. Very often antibioticprescribing, given the severity of underlying infections, isempiric. Appropriate antibiotic utilization is crucial not onlyin ensuring an optimal outcome, but in curtailing theemergence of resistance and containing costs.The choice ofempiric antibiotic therapy requires: (I) reliable andcontinuous information on predominant organisms andtheir resistance patters in each hospital ; (II) identificationof prevalent bacteria in outbreaks after applying modernmolecular techniques. In several recent ICU studies it wasproven that either cycling of antibiotics and/or rationalrestriction of the appropriate antimicrobials can result insignificant decrease of resistant rates. On the other handbasic infection control procedures such as hand-washingmust be implemented, whereas the organization of the so-called “Antibiotic Team” (composed by an InfectiousDiseases Physician, a Clinical Microbiologist and a hospitalPharmacist) who will monitor antibiotic rational use isindispensable. Approaching the “End of Antibiotics”research in our hospital settings aiming to curtail or revertresistance is vitally important in guiding antibioticprescription practices.

Strategies for the management of infection insurgery

17. IntroductionFausto de LallaDepartment of Infectious Diseases, San Bortolo Hospital,Vicenza, ItalyAntibacterial prophylaxis of post-operative infections isfirmly established within clean-contaminated procedures.For clean procedures, prophylaxis has traditionally beenreserved for operations involving foreign-body implantation.However, evidence that post-operative infections from non-prosthetic clean procedures are highly under-reportedsuggests that prophylaxis could also be advisable at least forsome non-prosthetic procedures, such as breast surgery andherniorrhaphy. Although cefazolin is recommended bycurrent guidelines, cefuroxime and cefamandole have abroader antimicrobial spectrum and should be preferred inclean prosthetic surgery prophylaxis. In this type of surgeryglycopeptides are not recommended for routine use but mayhave a role for major prosthetic implantation in units with ahigh incidence of methicillin-resistant Staphylococcus aureus.In the case of clean-contaminated procedures, cefazolin isrecommended for routine use, although colorectalprocedures require an agent with improved anti-anaerobicactivity. In addition, experience has shown thatobstetric/gynecologic, gastro-duodenal and biliary tractsurgery and appendectomy all require broad-spectrumantibacterial prophylaxis. Suitable agents include cefoxitin,cefotetan, ureidopenicillins and b-lactam/b-lactamaseinhibitor combinations. The traditional surgicalclassification scheme needs to be replaced with aclassification that additionally accounts for patient-specificrisk factors. The limitations of the current scheme maypartly explain why current guidelines are so seldomfollowed in clinical practice.

Role of infection in surgery and transplantationG Basadonna (USA)No abstract available

Antibiotic therapy and prophylaxis in surgeryG Sganga (Italy)No abstract available

18. Early presumptive antimycotic therapy andprophylaxis in surgeryJacques Bille, M.D.Head, Clinical Microbiology Laboratory, University Hospital,Lausanne, Switzerland.Invasive fungal infections (and particularly invasivecandidiasis [IC]) are mostly seen in oncohematologic,transplant, and surgical ICU patients. The diagnosis of IC isdifficult and the related mortality very high, thusprophylaxis or presumptive administration of safe antifungaldrugs (azoles in particular) is very appealing. Antifungalprophylaxis has been shown to be beneficial in BMT andsolid organ transplant patients (liver, pancreas, lung). Incritically ill surgical patients, the few studies published sofar have shown conflicting results, either due to insufficientnumber of patients enrolled or too broad entry criteria.When restricted to highly selected surgical patients,fluconazole prophylaxis has significantly reduced thedevelopment of Candida colonization (Garbino 1997),Candida peritonitis (Eggimann 1999), proven invasivecandidiasis (Pelz 1999), or candidemia (Garbino 1997).Current recommendations however lack of consensus at thepresent time. Recent prospective studies have betterquantified the general risk (about 1%) and defined riskfactors for Candida bloodstream infections in surgical ICUpatients, putting at highest risk patient with abdominalsurgery.Another parameter important for the choice of presumptiveantifungal treatment is the local epidemiology of fungal (andparticularly Candida) pathogens. With the increasingnumber of antifungal agents available, selection of the mostappropriate drugs will be based on efficacy, antifungalsusceptibility trends, and safety profile.Today, antimycotic prophylaxis should be strictly targeted tohighly selected situations and surgical patients are noexception.

Serious Gram-positive infections in immuno-compromised host

Epidemiology of MR Gram positive pathogens in hospitalsetting: the new threatGC SchitoNo abstract available

19. Traditional and new therapeutic approaches of gram-positive infections in transplanted patients.Paolo GrossiClinica Malattie Infettive e Tropicali Università degli Studidell’Insubria – Ospedale di Circolo e Fondazione Macchi,21100 Varese, ItalyInfections remain the most common life-threateningcomplication following solid organ transplantation. Gram-positive bacteria are the most frequently reported agents. Ofgreat concern is the increasing incidence of seriousnosocomial infections caused by Gram positive-bacteriawith acquired multidrug resistance. The emergence ofenterococci with resistance to vancomycin (VRE), seenpredominantly in the species E. faecium, has been followed

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by an increase in the frequency with which this species isrecovered. Worldwide methicillin-resistant staphylococci,both MRSA and coagulase-negative strains, are numericallythe greatest problem. For more than 30 years, vancomycinhas been a reliable treatment for gram-positive bacterialinfections. Since 1996 VISA strains (vancomycin MIC =8–16 µg/ml) have been identified in Europe, Asia andUnited States. To date, no resistant S. aureus isolate(vancomycin MIC ≥ 32 µg/ml) has been reported, howeverit seems likely that vancomycin-resistant S. aureus (VRSA)will emerge as a nosocomial pathogen. New antibioticsactive against multidrug-resistant Gram-positive cocci willbe shortly on the market and their use has already beenshown to be followed by a high success rate. Quinupristin/dalfopristin is a semi-synthetic injectable streptogramincomposed of two synergistic components that has excellentactivity in vitro against a range of Gram-positive organisms,including methicillin-resistant staphylococci, penicillin-resistant pneumococci, and vancomycin-resistantEnterococcus faecium (but not Enterococcus faecalis).Quinupristin/dalfopristin is given at the dosage of 7.5 mg/kgq 8 hours as an i.v. solution in 250 ml of D5W. Becauseinfusion through a peripheral vein has been associated withskin irritation at the infusion site, the infusion through acentral line is recommended. The drug is currently licensedin the United States and in Europe, including Italy. A newclass of antibiotics, the oxazolidinones, will soon be addedto the physician’s armamentarium. Linezolid the first in thisnew class of antibiotics has a unique mechanism of actionthat disrupts the initiation of bacterial protein synthesis atan earlier stage of the cycle than other antibiotics. The drugis currently licensed in the United States and in phase IIIclinical trials in Europe. Clinical studies have shown thatlinezolid is effective against medically significant Grampositive cocci, including MRSA, penicillin-resistantpneumococci and VRE. Linezolid is given at the dosage of600 mg b.i.d. as i.v. or oral formulation that are both 100%bioavailable. At this dosage blood levels of the drug exceedthe concentration required to inhibit bacterial growth in thetest tube.

Traditional and new therapeutic approaches of Grampositive infections in neutropenic patientsP Martino (Italy)No abstract available

Enterococcal infections in immunocompromised host: howto treat an untreatable pathogenR Moellering (USA)No abstract available

New frontiers in the management of chronichepatitis C: therapeutic innovation and clinicalbenefits

Kinetic of HCV infection under antiviral treatmentJM Pawlotsky (France)No abstract available

19a. Improved outcome with pegylated interferons inchronic hepatitic C patientA Craxi (Italy)Treatment of chronic hepatitis C (CHC) with pegylatedinterferons monotherapy has resulted in sustained virologicresponse (SVR) rates of 25% to 39%. Recent evidenceindicates that combining pegylated interferons with ribavirinfurther improves SVR rates. In one pilot study of mostly

(80%) genotype 1 patients treated with the branched-chainpeginterferon alfa-2a (40KD) [PEGASYS®] plus ribavirin,overall SVR was 50% while SVR was 100% in those patientswho had genotype non-1 virus. In an international,multicenter, Phase III study, a SVR of 57% was reported withpeginterferon alfa-2a (40KD) plus ribavirin; SVR was 46% inpatients infected with HCV genotype 1. The tolerability ofthe peginterferon alfa-2a (40KD) / ribavirin combinationwas comparable to that of peginterferon alfa-2a (40KD)alone. However, the peginterferon alfa-2a (40KD) / ribavirincombination offered the added advantage of a lowerincidence of flu-like symptoms (pyrexia, myalgia, rigors)and neuropsychiatric adverse effects (depression) thaninterferon alfa plus ribavirin.In a multinational Phase III study using peginterferon alfa-2b (12KD) [PEG-Intron®] in combination with ribavirin,54% of all patients and 42% of genotype 1 patients receivingpeginterferon alfa-2a 1.5 µg/kg plus ribavirin achieved anSVR. In this study, the tolerability and safety ofpeginterferon alfa-2a plus ribavirin was reported ascomparable to those for standard interferon alfa-2a plusribavirin.More recently, researchers have begun evaluating the efficacyand safety of peginterferon alfa-2a (40KD) in combinationwith other antiviral and immunomodulatory agents such asamantadine and mycophenolate mofetil, in addition toribavirin. After 24 weeks of combination treatment withpeginterferon alfa-2a (40KD), undetectable HCV RNA levelswere achieved in 53% of the mycophenolate combinationgroup, 67% of the amantadine combination group, and 58%of the amantadine plus ribavirin combination group,compared with 58% of the group treated with standard IFNa-2b plus ribavirin. HCV RNA levels were reduced by morethan 2 logs from baseline in 66% to 81% of the patients onthe new combinations, compared with 62% of those on IFNa-2b plus ribavirin. The efficacy of these new combinationsare at least equivalent to, or greater than, that of standardcombination therapy with ribavirin. Additional studies areassessing the efficacy of these new combinations in patientswho have not responded or who have relapsed on IFN a-2bplus ribavirin therapy. After 24 weeks of treatment withthese peginterferon alfa-2a (40KD) combination regimens,virologic response rates varied from 32% to 58% innonresponders and 65% to 88% in relapsers to IFN a-2bplus ribavirin.Confirmation of these encouraging results of combinationregimens of peginterferon alfa-2a (40KD) will offer patientsan increasing range of therapeutic options and increasingoptimism for achieving SVR even in the most difficult-to-treat patients.

20. Which therapy for patients with HCV infection andCirrhosis?K. Rajender Reddy M.D.University of Miami School of Medicine, Miami, FloridaU.S.AHepatitis C infection is common around the world with anestimated 170 million people infected with this virus. Thisis approximately 3% of the world population. The infectionhas a great propensity to progress on to chronic states. Therisk of cirrhosis is approximately 20% within 20 years and30% within 30 years. There is a well appreciated mortalityrelated to cirrhosis which is approximately 2% to 5% a yearand, currently, the leading predisposing cause for primaryliver cancer is hepatitis C related cirrhosis and it isapproximately 3–10% per year.

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Combination therapy with interferon and ribavirin haseclipsed interferon monotherapy as the standard of care forchronic hepatitis C. Two large multi-center multinationaltrials have observed sustained virologic response (SVR) ratesbetween 38 and 43%. Interferon monotherapy alone hasachieved a sustained virologic response rate of 13 to 19%after 48 weeks of therapy. Genotype 1 patients did betterafter 48 weeks of therapy compared to 24 weeks of therapy,whereas genotype 2 and 3 patients did equally well witheither 24 or 48 weeks of therapy. Further, low viral load (≤2 million copies/ml).age less than 40 years,and femalegender were associated with better response rates. Non-genotype 1 patients have been observed to have a responserate of 65% after either 24 weeks or 48 weeks of therapy.Previously, patients with even compensated cirrhosis weregenerally considered to be difficult to treat.In these trialsthat included a small small number of patients withadvanced fibrosis and even cirrhosis, response rates in suchpatients were similar to those who did not have advancedfibrosis.A pivotal study by Heathcote et al involving a uniquepopulation of advanced fibrotics/cirrhotics treated withPegasys (pegylated Interferon alfa-2a) monotherapy at adose of 180 µg given once a week for 48 weeks, reported asustained virologic response rate of 30 % which iscomparable to an approximately 35–39% response rates innon-cirrhotics. There are no unique tolerability issues andadverse events related to these patients with advanceddisease. Recently, data from a multinational, multicentertrial of Pegasys plus ribavirin was presented The three armsof the study were Pegasys 180 µg weekly plus placebo,Rebetron (interferon alfa-2b plus ribavirin), and Pegasys 180µg weekly for 48 weeks plus ribavirin, 1,000–1,200 mg aday. There were 1,l49 patients from 81 sites in 18 countriesthat participated in the trial. Twelve to fifteen percent ofpatients had cirrhosis. The overall sustained virologicresponse with Pegasys plus ribavirin was 56% compared to30% in the Pegasys plus placebo group and 45% in theRebetron group. Patients with HCV genotype 1 had a 46%SVR with Pegasys plus ribavirin and genotypes 2 and 3 hada 76% SVR with that treatment. More importantly,theresponse in patients with cirrhosis was similar to patientswithout cirrhosis. Similarly encouraging response rates havebeen described from PEG-Intron and ribavirin treatmenttrials.The disease burden from HCV is likely to rise exponentiallyover the next 10–20 years. The increase in the condition ofcirrhosis over the next 8 to 10 years could be in the order of500% with increasing demands placed on livertransplantation. Thus, given the magnitude of the problemwith HCV even in the virologic non-responder patients theremight be a role for therapy to improve liver histology, slowdisease progression and reduce the risk of hepatocellularcarcinoma. Interferon is known to have an anti-inflammatory and anti-fibrotic effect and thus can providehistologic benefit although it is most impressive in virologicresponders and less so in bio-chemical responders. Severalstudies evaluated histologic response, as defined by animprovement of at least 2 points in the overall histologicactivity index (HAI), following Pegasys (peginterferon alfa-2a).A histologic response was found in 57 % of treatedpatients and this was most evident in those patients withSVR, in whom 83% responded. However, it is important tonote that even the non-responders derived histologicbenefit, with 47% having a histologic response. Thesehistologic response rates are not unique to Pegasys. Similar

histologic response rates have been observed in studiesinvolving PEG-Intron, with the histologic response beinghighest in the patients who achieved SVR as compared tothe relapsers and non responders. Thus overall there isreason to be optimistic in treating patients with advancedfibrosis/cirrhosis and not necessarily view it as an ominousdisease.

21. HCV and hepatocellular carcinoma: does treatmentprevent cancer?Antonino PicciottoDepartment of Internal Medicine, University of Genoa, ItalyChronic infection with hepatitis C virus (HCV) is asignificant risk factor for developing hepatocellularcarcinoma (HCC). The risk is directly related to the liver cellproliferative activity and to the liver disease severity.Moreover advanced age, male sex and history of alcoholabuse are important predictors of HCC.The real efficacy of a prevention of HCC by antiviral therapyis still an open issue. Most data concerning the effect ofinterferon (IFN) in reducing the incidence of HCC derivefrom retrospective studies and therefore selection bias couldlimit the reliability of the results.Antiviral treatment of chronic hepatitis C decreases thenumber of patients potentially developing cirrhosis.1

Consequently the long-term incidence of HCC should bereduced. However, until now there is no definitive evidencethat IFN therapy in patients with established cirrhosis mayprevent HCC development. The only two availableprospective randomised controlled trials (RCTs) reportopposite results.2, 3 A recent prospective non-randomisedcontrolled trial shows that IFN treatment prevent or delaythe HCC development.4 The results of retrospective trialssuggest a lower incidence of HCC in treated patients.5

Large prospective RCTs in patients with cirrhosis are neededto define the role of IFN or other agents for HCCprevention.61. EASL consensus statement. J Hepatol 31 (suppl 1), 3–8, 19992. Nishiguchi S et al. Lancet 357, 1051–1055, 19953. Valla DC et al. Hepatology 29, 1870–1875, 19994. Gramenzi et al. Gut, 48, 843–848, 20015. Baffis V et al. Ann Intern Med 131, 696–701, 19996. EASL panel of experts on HCC. J Hepatol 35, 421–430, 2001

The management of HCV/HIV coinfected patientT Santantonio (Italy)No abstract available

The world of respiratory tract infections

Respiratory tract pathogens: overview on resistanceG. Cornaglia (Italy)No abstract available

Sinusitis and AECBS. Esposito (Italy)No abstract available

22. Community-acquired pneumonia (CAP)L Mandell (Canada)Community acquired pneumonia (CAP) is a serious diseasewith considerable morbidity and mortality associated withit. It is the 6th leading cause of death overall in NorthAmerica and the number one cause of death from infection.Its impact on health care and health care economics isconsiderable as it is estimated that there are 3–4 millioncases per year resulting in over 600,000 admissions tohospital, 64million days of restricted activity and 45,000

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deaths annually in the United States.The most important etiological agents are S. Pneumoniae andthe atypical pathogens (Mycoplasma pneumoniae, chlamydiapneumoniae, and Legionella pneumophila). In selected cases,aerobic gram negative rods may be important as wellincluding pseudomonas aeruginosa. One of the majorconcerns over the past few years has been the increase inresistance among various pathogens particularly S.pneumoniae. Penicillin, macrolide and more recentlyquinolone resistance have all become important issueshowever, it is not always clear that in vitro susceptibilitycorrelates with clinical results. Data from over 200 centresin the U.S. suggest that of pneumococcal isolates from bloodthat are penicillin sensitive, only 4% are resistant tomacrolides. However, of those isolates that are penicillinresistant, 59% are also macrolide resistant. Thecorresponding figures for respiratory isolates are 5.9% and75.4% respectively.One of the most important decisions other than initialtreatment is the site of care decision. This has a significantimpact not only on the cost of treatment but on the type oftreatment and the number and types of diagnostic testswhich will be preformed. A recent paper by Fine in the NewEngland Journal of Medicine established a two stepprediction rule for mortality associated with CAP. While itwas not initially intended as a triage rule, it has assumedthis role for the present at least. The rule assigns points topatients based on age, underlying disease and abnormalphysical and laboratory findings and relegates them to oneof five classes. Those in class 1and 2 can be treated as out-patients while those in class 4 and 5 should be admitted tohospital. Ideally those in class 3 should be admitted for aday or two for observation.There are essentially two treatment alternatives whendealing with CAP. These are “directed” or “empiric” therapy.The former involves the use of relatively narrow spectrumdrugs aimed at specific pathogens whereas the latteressentially involves an educated guess and the use ofbroader spectrum agents. There is no question that directedtherapy is the more desirable option since it limitspolypharmacy, reduces costs and adverse drug reactions,minimizes antibiotic selection pressure and is less likely toresult in the emergence of resistance pathogens.Unfortunately however, until our diagnostic methodsimprove we will have to rely upon an empiric approach forinitial therapy of most patients with CAP.Guidelines have recently been published by the CanadianInfectious Disease Society (CIDS), the Infectious DiseasesSociety of America (IDSA), the Centres for Disease Control(CDC), and the American Thoracic Society (ATS). Thesewill be presented and reviewed.

23. Nosocomial pneumonia: “the Tarragona strategy”J.RelloHospital Universitari Joan XXIII, Tarragona, Spain.We implemented an antibiotic management program basedon evidences focusing four objectives: broad-spectrumcoverage followed by de-escalation, high and individualizeddoses based on location and pharmacodynamicconsiderations, immediate iniation of antibiotic treatmentand choice of antimicrobial based on lung penetration.This approach to nosocomial pneumonia has been called“the Tarragona strategy.”Key Points are:

Antibiotic therapy should be started without delay.Choice of antibiotic should be based on the regimen that

each patients has received previously.Antibiotic choice can be targeted based on direct stains.The antibiotic regimen should be modified based on

microbiological findings.Patients with COPD or one week of ventilation should

receive combination therapy.Methicillin-susceptible Staphylococcus aureus should be

dtrongly suspected if Glasgow Coma Score < 8.Methicillin-resistant (MRSA) is not expected inabsence of prior antibiotic administration.

Vancomycin administration for VAP is associated withvery poor outcome.

Antifungal therapy is not required for VAP even inpresence of Candida sp. colonization.

Prolonging antibiotic treatment does not preventrecurrences.

Guidelines should be regularly updated and customizedto local patterns.

Role of atypical pathogens in CAPF Blasi (Italy)No abstract available

23a. Patients’ attitudes to antibioticsJC Pechere (Switzerland)In an attempt to better evaluate the patients’ contribution inantibiotic use, 5379 subjects from nine countries (UK,France, Belgium, Spain, Italy, Turkey, Thailand, Morocco,Columbia) who had received a course of antibiotics, or hadgiven one to their child for a respiratory tract infection inthe last 12 months, were questioned through a standardisedtelephone interview. The respiratory infection was felt aspotentially severe by a majority of interviewees, especiallythe mothers. Antibiotics are perceived as strong, efficientdrugs, but they were said to undermine immunity.Interviewees believe that most respiratory infections, exceptcommon cold, would require antibiotic therapy, and 11% ofthem had to exaggerate their symptoms for getting antibioticprescription from their physician. About one patient out offour saved part of the antibiotic course for further use. Sixtynine percent of the patients claimed to have taken thecourse until the end (United Kingdom: 90% ; Thailand:53%), essentially because they felt better, and 75% claimedthat they actually took all the daily doses. In all countries, ithas been possible to get antibiotics from the pharmacistwithout medical prescription. This study shows that patientsexert pressure to their doctor for getting antibiotics andshould allow to design precise educational action toward thepublic for a better control of antibiotic use in the community.

Ketolides: an innovative solution to an evolvingworld of respiratory pathogens

Microbiological profile of telithromycin, the first ketolideantimicrobialS. Stefani (Italy)No abstract available

24. Pharmacodynamic and pharmacokinetic considerationsin antimicrobial selection: focus on telithromycinF. ScaglioneDep. of Pharmacology. University of MilanPharmacokinetic analyses provide information onbioavailabilty, distribution and disposition within the humanbody—on the delivery of the drug to the site of infectionand its persistence there—as well as the potential of druginteraction and adverse effects. However, neither

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microbiological activity nor pharmacokinetic data alone canadequately describe the complex interaction betweenpathogen, host and antimicrobial during the disease process.A relatively new discipline, pharmacodynamics, seeks tointegrate both microbiological and pharmacokinetic data inorder to describe the relationship between in vivo drugconcentrations and antimicrobial activity. Telithromycin is anew semi-synthetic drug belonging to a new chemicalfamily, the ketolides. The antimicrobial spectrum oftelithromycin covers: gram-positive cocci, gram-negativecocci, some gram-negative bacilli such as H. influenzae, M.catarrhalis, intracellular pathogens (Chlamydia pneumoniae,Legionella pneumophila), and Mycoplasma pneumonia. As aketolide, telithromycin is active against gram-positive cocciresistant to erythromycin A by an efflux mechanism (e.g.,S. pyogenies, S. pneumoniae) or by an inducible MLSB

mechanism (gram-positive cocci). Furthermore,telithromycin is unable to induce resistance to macrolides.From a pharmacokinetic point of view, after a single oraladministration of 800 mg in young adult subjects, plasmaconcentrations of telithromycin peaked within 1 to 3 hoursand mean maximum plasma concentration (Cmax) was onaverage 2.0 mg/L. The plasma elimination of telithromycinover time displayed a biphasic profile. The mean half-life ofthe first elimination phase is around 2 hours and that of theterminal phase is about 10 hours. Twenty-four hours afteradministration, concentration of telithromycin in plasmawas 0.02 mg/L. Food does not modify the bioavailability oftelithromycin administered as tablet. The oral absolutebioavailability of telithromycin administered as tablet isaround 60%. After repeated once daily administration of 800mg, steady state is reached by the second day of treatment.At steady state, the mean Cmax was about 2.0 mg/L and meantrough concentrations (Cmin) were 0.035 to 0.05 mg/L.Thein vitro plasma protein binding of telithromycin isapproximately constant at 60% to 70% over theconcentration range tested (up to 11.7 mg/L) and obtainedin clinical studies. The principal component of binding isthe albumin, with some involvement of a1-acid glycoproteinand lipoproteins. The volume of distribution (Vss) is around150 L. Telithromycin exhibited a good penetration inrespiratory tissues with maximal concentrations of 5.4 mg/Lin epithelial lining fluid, of 2.2 mg/kg in bronchial tissue, of3.9 mg/kg in tonsil tissue. It exhibited also a goodpenetration in blister fluid (a model for extracellular fluid)with an extracellular fluid/plasma ratio of 1.4.Telithromycinis eliminated mainly by metabolism by CYP3A4, while renalexcretion represents a less important route of elimination.From a pharmacodynamic point of view telithromycinexhibited a concentration dependent activity and thepeak/MIC ratio (or AUC/MIC ratio) is the parameter relatedto the activity. Preclinical and clinical studies suggested thatinfections caused by pathogens with telithromycin MICs upto 2–4 mg/L could be successfully treated with an 800 mgonce-daily dose of this agent.

Infectious disease management in the newmillennium: practical issues

25. Antibiotic resistance in your neighborhood and aroundthe worldR. Gómez-Lus, G. Garcia, J. Castillo, C. Seral, A. Clavel,M.C. RubioDepartment of Microbiology, University Hospital, Zaragoza,SpainBacterial resistance to antibiotics in gram-negative bacilli is

commonly mediated by R plasmids and by genes carried bytransposons (Tn) and integrons (In). In gram positive-coccithe conjugative chromosomal transposons are fundamentalfor antibiotic resistance. They are characterized by theirrelated features to R plasmids, bacteriophages and the classictransposons such as TN5 and TN10. At the UniversityHospital Lozano Blesa (UHLZ) and other hospital centers inZaragoza, research has been carried out regarding theevolution and spread of antibiotic resistance over the last 30years. In 1974 we characterized the plasmid pUZ1 from astrain of P. aeruginosa coming from the Center ofTraumatology, near the UHLZ. The 68 kb plasmid belongsto P incompatibility group, and it was transferable to E. coliJ62 by conjugation. The donor as well as the recipientstrain coded resistance to Ap, Tc, Gm, Km, Sm, Spc, Cm, Suand Cl2Hg. Plasmid pUZ1 contained two transposons, theTn3, which carries the blaTEM-1 gene and a new transposon,Tn1696, which bears the genes aacC1, cmIA, aadA1, sul1and mer. Four years later, we isolated different strains ofenterobacteria and P. aeruginosa which contained also 68 kbIncP plasmids, with identical restriction patterns as pUZ1.In 1976 we detected a 73 kb IncM plasmid, and thustransferable only to enterobacteria. The plasmid conferredresistance to Ap, Tc, Gm and Tm. Following this, numerousenterobacterial strains were isolated which also carriedplasmids from the IncM group, with identical genotypic andphenotypic properties. One of this plasmid (pUZ3644)bears a 27kb fragment (Tn2922), carrying the blaTEM-1 andthe accC5 genes, flanked by two copies of an IS140.Extended spectrum b-lactamases (ESBLs) were firstidentified in the early 1980s. Since this time, ESBLs havebeen identified worldwide and have been found in K.pneumoniae, E. coli, P. mirabilis and Salmonella species.ESBLs are typically encoded on 80- to 300-kb plasmids thatcan be exchanged between bacterial species. K. pneumoniaeisolates with ESBL phenotype is more prevalent in LatinAmerica (45.4%), followed by Western Pacific region(24.6%), Europe (22.6%), the United States (7.6%), andCanada (4.9%). Very recently, in Europe these enzymeswere found in 23% of klebsiellae isolated in 35 ICU’s. Thehighest figures come from Portugal (49%) and Turkey(59%). In our region, K. pneumoniae, and E. coli expressingan ESBL phenotype ranged from 6.4 to 2.7%. Isolation of S.pneumoniae resistant to macrolides, penicillin and otherantibiotics has been noted in our region with increasingfrequency during the last decade. The constitutive MLSB

mechanism was the most common (85%), with 15% of Mphenotype due to efflux mechanism. Using PGR, we haveconfirmed that all examined with the cMLSB (91.7%), and M(8.7%) resistance patterns contain erm (B) and mef (A)genes, respectively. The most prevalent patterns associatedwith resistance to Em (erm (B)) were resistance to Tc [tet(M)] and Cm (cat pC194) (48.2%) or resistance to Tc alone(42.2%). In our isolates of S. pneumoniae there was a strongassociation of the erm (B) and tet (M) genes with Tn1545-related elements. In addition, S. pyogenes resistance to Embegan to emerge as a serious problem worldwide in the early1990’s. In Spain, EmR has increased from 3% in 1991–1992to 27% in 1996–1997. We have found that M phenotype isthe most prevalent in S. pyogenes (86%), with a 14% ofcMLSB, corresponding to the expression of mef (A), and erm(B) genes, respectively.

Examining the contributions of oral cephalosporins in thetreatment of bacterial infections in children and adultsJA Garcia Rodriguez (Spain)

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Drug, dose, duration—the 3D effectA Novelli (Italy)No abstract available

26. Treatment of febrile neutropenia: revisiting the optionsLowell S. Young, M.D. (USA)Three decades of clinical trials provide the clinical basis forempiric initial therapy of febrile neutropenia. Riskassessment is a critical initial step as treatment must betailored to the clinical circumstances and the underlyinghost status. For patients whose circulating neutrophilcounts are likely to decline below 500/mm3 and remainthere for a week or more, initial antibiotic treatment optionsinclude: (a) single broad-spectrum b-lactam agent such ascefepime or imipenem; (b) the addition of a glycopeptide tothe initial broad-spectrum b-lactam regimen; (c)combination therapy with a broad-spectrum b-lactam andan aminoglycoside. The likelihood of a catheter-associatedinfection and/or recovery of the white count in the setting ofa non-hematologic disorder will effect the choice of therapyand whether it can be accomplished at a hospital or homesetting. After 4–7 days of persistent fever, consensus favorsadding amphotericin B but whether an azole may suffice isconjectural.Clinical approaches are now influenced by guidelines, suchas those issued by Infectious Disease Society of America.Optimal therapy for specific clinical situations may notnecessarily be the same as appear in such guidelines. Inview of mounting costs of complex medical therapies furtheremphasis should be placed on rapid diagnostic proceduresthat increase the accuracy of treatment and cost-effectiveness of each specific intervention. The role offluoroquinolones for prophylaxis and treatment of febrileneutropenia and the indications for colony-stimulatingfactors in reversing the underlying neutropenia remaincontroversial. Risk assessment models make it more feasibleto treat some patients on an outpatient basis, but factorssuch as rapid access to hospitalized care will influence thedecision making model as well. In viewing theaccomplishments of the last quarter century, there iscertainly need for improved therapies against gram-positivepathogens such as coagulase-negative staphylococci and themore increasingly antibiotic resistant gram-positivepathogens like Enterococcus. Some centers have seen aresurgence in problematic gram-negative bacillary infectionsand in the area of anti-fungal treatment a broadenedtherapeutic armamentarian is now available.

27. The role of penicillin in the next centuryAntonio BoccazziPediatric Department,University of MilanThe spectrum of penicillin activity in the last 40 years hasbeen progressively limited by the wideworld expression ofb-lactamases as acted by the most important bacterialspecies responsible for human diseases or, more recently, bythe modification of the target PBP. This phenomenon hasgreatly reduced the range of infections where penicillinadministration is still effective as initial therapy. Amongrespiratory pathogens, Haemophilus influenzae and Moraxellacatarrhalis are completely insensitive, while S. pneumoniaeshows variable indexes of resistance among differentcontinents and nations, but also within the same nationalborders, making it necessary, at least in severe clinicalconditions i.e., sepsis and meningitis, to investigate itssensitivity profile. Only group A streptococci remainexquisitely sensitive to penicillin and no signs of resistancehave been documented so far leaving penicillin as the drug

of choice in infections both local and invasive due to thispathogen.Many alternatives to penicillin are available, but penicllinstill allows a narrow therapeutical spectrum coupled with avery low cost, still making it an attractive and effectiveantibiotic both for low income nations and for regionswhere antibiotic pressure has not yet induced the emergenceof resistances which might require the implementation ofmore active compounds.

28. Regaining control—the need for new antibacterials?Pramod M. ShahJ. W. Goethe University, D-60590 Frankfurt/Main, GermanySeveral aspects could make treatment of infectious diseasesand/or complications arising from infectious diseasesdifficult. Resistance of pathogen to available drugs is one ofthe most obvious aspects and attention generally focuses onthis area. Worrying is increasing resistance reported inpathogens frequently associated with morbidity andmortality, such as Streptococcus pneumoniae to penicillin andmacrolide, Streptococcus pyogenes against macrolide orStaphylococcus aureus against oxacillin and glycopeptide andmultiple resistance in nosocomial pathogens. Resistance isnot the only factor responsible for outcome. In septicaemicinfections caused penicillin sensitive pneumococci mortalityremains high, even when correct antibiotic treatment isinitiated early in disease. Host associated factors, whichcould not be influenced, are mainly responsible foroutcome. Another examples of high mortality rates areseptic shock and infections in neutropaenic patients. Effortsto modulate pathophysiology of infectious diseases orimmune response, such as use of monoclonal antibodies toneutralise endotoxins or to bind cytokine receptor sites havefailed. Clinical observation has shown that at the presenttime the most important factor for outcome of an infectiousdisease is correct antimicrobial treatment from the start.Most patients related factors, such as age and co-morbiditycan not be influenced, thus attention should be focused onmost likely pathogen involved and its resistance to availableantimicrobials. Due to increasing resistance in commonpathogens new agents are urgently needed. Among newagents which will be available soon are linezolid (for multi-resistant staphylococci or enterococci), quinolones andketolides (with activity against multi-resistant pneumococci).

Oral communications and poster presentations

AIDS

29. HIV-related neoplasms of the head and neckR. Bottin MD*, A.M. Cattelan MDo, L. Boccuto MD**Department of Otolaryngology, oDepartment of InfectiousDiseases, University/General Hospital of Padua (Italy)Clinical manifestations in acquired immunodeficiencysyndrome (AIDS) are generally opportunistic infections andin some cases malignant neoplasms. Some tumours arediagnostic of AIDS, such as Kaposi’s sarcoma and non-Hodgkin’s lymphomas (NHL), while others are less commonbut are reported to be on the increase, such as Hodgkin’sdisease (HD), squamous cell carcinoma (SC) and other solidand haematologic tumours.Between 1984 and 1997, HIV-infected patients treated at theDepartment of Infectious Diseases of the General Hospital ofPadua who presented signs of head-neck pathologies, wereadmitted to ENT assessment. This led to identification of 38patients with malignant tumours of the head and neck.Thirty-one were followed up, while 7 were untraceable and

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thus omitted from the study.The patients (23 males and 8 females) were aged between 28and 58 years, with a mean age of 39.2 years.In 20 cases, the tumour was lymphonodal (18 NHL and 2HD), while in 11 cases it was extranodal (7 NHL and 4 SC).The extranodal neoplasms were oral in 4, endocranial in 4and rhinopharyngeal in 3 cases.The four cases of SC were only diagnosed on autopsy.The mean time elapsing between identification of HIV-infection and tumour diagnosis was 65.5 months. If one caseof liD is excluded, where the tumour and HIV infection werediagnosed simultaneously, thereby preceding seroconversionby approximately 24 months, the neoplasm was identified inall other cases (97%) after seroconversion. Moreover, in allthe latter patients, the CD4+ marker blood count at the timeof diagnosis of HIV infection was lower than 200 cell/µL,while in the only case of liD it was 380 cell/µL.The authors discuss the clinical course of patients with HIV-related tumours in the head and neck in relation to CD4+count at the time of diagnosis of HIV infection.

30. Sensitivity of HIV-1 to antiretroviral agents—an IndianexperiencePai Chitra*, Panchal Kumkum, Hira Subhash KDept of Infectious Diseases and Dept of Microbiology,M.G.M Medical College, Navi Mumbai, India and TheUniversity of Texas-Houston, USA.INTRODUCTION: The treatment of HIV infection is one ofthe most rapidly evolving fields in medicine. Highly activeantiretroviral therapy (HAART) is increasingly being used inIndia due to reduced cost of drugs. Utilization of HAART islikely to increase over the next few years.OBJECTIVE: To determine the pattern of antiretroviral(ARV) drug sensitivity among patients with HIV-1 disease inMumbai, India.PATIENTS AND METHODS: Starting May 1999, 47 patientswith HIV-1 associated illnesses were staged according toCDC classification and prescribed HAART. The ARVsensitivity tests were conducted using tissue culture baseddilution technique; the tests being repeated twice in 11patients and thrice in 2 patients. Briefly, 10 ml of bloodsample was taken in EDTA and lymphocytes separated usingFicoll Hypaque. Lymphocytes were activated with PHA afterwhich ARV drugs were added in concentrations of 10mg/ml.Following an incubation of 72 hours, a small volume of thesupernatant was collected and P-24 antigen ELISAestimation was done. The remaining culture was continuedfor further 72 hours after addition of IL-2. The supernatantwas collected for P-24 antigen ELISA estimation. Ascompared with controls, a >30% reduction in the pcg levelsin the P-24 ELISA was considered as sensitive while21%–30% reduction was considered as partly sensitive and <20% reduction was taken as resistant (McGill University,Canada protocol).RESULTS:

AZT d4T 3TC Ddi ddI

n 32 22 38 16 10S (%) 14(43.7) 12(54.5) 16(42) 7(43.7) 5(50)PS (%) 11(34.4) 3(13.6) 7(18.4) 3(18.7) 3(30)R (%) 7(21.9) 7(31.8) 15(39.4) 6(37.5) 2(20)

Aba Nevi Saq Rito Indi

n 4 19 32 21 12S (%) 3(75) 11(57.9) 19(59.4) 18(85.7) 9(75)PS (%) 1(25) 3(15.8) 6(18.7) 1(4.8) 2(16.6)R (%) — 5(26.3) 7(21.9) 2(9.5) 1(8.3)

Nelf

n 6S (%) 5(83.3)PS (%) —R (%) 1(16.6)

S - sensitive; PS - partly sensitive; R - resistant.Aba - Abacavir; Nevi - Nevirapine; Saq - Saquinavir; Rito -Ritonavir; Indi - Indinavir; Nelf - Nelfinavir

CONCLUSION: Nucleoside reverse transcriptase inhibitors,which were introduced earlier in India, seem to havedeveloped fairly high levels of antiretoviral drug resistance.Adequate monitoring of HAART using drug sensitivity willhelp control the emergence of resistant strains.

31. Onset of lipoma during therapy with proteaseinhibitor: case reportA. Collidà*1, A. Beltrame1, G. Mazzarello1, M. Feasi1, M.Marturano1, L. Papa1, P. Pedemonte1, G. Flocchini§, T. Testa§,G. Spinelli2, D. Bassetti1

∞Department of Infectious Diseases, University of Genoa,Italy2Center of Surgery Pathology 1, University of Genoa, ItalyINTRODUCTION: Treatment with protease inhibitors isassociated with a syndrome of lipodystrophy manifesting asa peripheral lipoatrophy, relative central adiposity, increaseof breast dimension, insulin resistance, serum lipidabnormalities. Onset of benign tumors of adipose tissueduring this therapy is not frequent. We observed a case oflipoma in a patient on treatment with saquinavir inassociation with stavudine and lamivudine.PATIENT: A male, 24 years old, hemophiliac with HIVinfection from 1985, on therapy with saquinavir inassociation with 3TC and d4T from October 1996 reportedat November 2000 onset of abdomen new-formation, soft,painful; no other clinical symptom is present. He didn’treport similar manifestation and hadn’t important sideeffects in the past.Before this therapy he was on treatment with only AZT fromFebruary 1989 to September 1994; AZT in association withddI from September to October 1994 (stopped for abdomenpain and diarrhoea); AZT with ddC from October 1994 toOctober 1996.Last cell CD4+ count and viral load determination beforecomparison of lipoma were: 454 CD4+ (14%) and 10,800copies/ml. He hadn’t manifestation of lipodystrophy and lastserum lipid were: tryglycerides 64 mg/dl and cholesterol 126mg/dl. He was operated at 15/2/2001 and new formationwas removed; histologic analysis determined lipoma withpolymorphous aspect.CONCLUSION: Therapy with protease inhibitor seems tocause benign tumor of adipose tissue in some patients, butwe don’t know pathogenesis of these events: probably, theyare a late effect of HAART wuch as lipodistrophy but alipoma can develop without other manifestations. It isimportant to study these clinical events and side effects ingeneral to avoid cessation of therapy and eventuallymalignant neo-formation.32. Cardiac involvement of AIDS patients: Experience of14 years observation, before and after HAART adoptionLuisa Generro, Luisa Sarasso, Gian Carlo Orofino* andAgostino PuglieseSection of Clinical Microbiology, Un. Of Turin and *DivisionA of Infectious Diseases-Amedeo di Savoia Hospital, Turin, ItalyAccording to different case reports described in medical

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literature, before a regular HAART adoption, cardiacalterations in HIV-infected patients regarded a percentage ofsubjects varying between 10 to 42% of cases. More frequentmanifestations were: dilated cardiomyopathy, ventriculardysfunction, arrhythmias, pulmonary hypertension withright heart involvement, endocarditis, myocarditis andpericarditis. The frequency of these manifestations washighly reduced with the improving of antiretroviral therapyby combined treatments. In our previous study we reportedthe incidence of cardiac implication of over 1000 HIV-1positive patients admitted to the Amedeo di Savoia Hospitalof Turin from 1989 to 1998 (XII ANLAIDS Congress,Genova, November, 22–25 1998). In this study was relevantthe high percentage of arrhythmias, hischaemias, dilatedcardiomyopathy (total or partial) and pericarditis orendocarditis. In particular, until 1998 the mean incidence ofcardiac involvement in HIV-positive patients was on averageone third, with a range of 18% during 1992 and 49% during1990. 1/5 of cases corresponded to more severemanifestations which included: endocarditis (7.9% ofcardiac manifestations), myocarditis (2.1%), pericarditis(19.6%), ischaemic manifestations (15.3%), dilatedcardiomyopathy (10%; 6.7% in the complete form),pulmonary hypertension (2.7%). Besides, rhythm andconduction alterations were more common manifestationsregarding about 40% of patients with cardiac involvement.Now, we report some data regarding the period 1999–2001(July) in which most of the patients were treated withHAART and we compare the previous with more recent data.Among 500 patients examined in the last 3 years, only onecase of endocarditis (Staphyloccus aureus), 2 or pericarditis(one of mycobacterial etiology and other or reactive origin),7 cases of myocardiac ischaemic manifestations (amongthem 2 cases of hearth infarct) were found. Moreover, onecase of hypokinetic cardiomyopathy with severe arrhttmiasand one case of arterious hypertension with left ventricularipertrophy were signaled. In particular, these patientspresented the following laboratory values: CD4 + Tcells =424 ± 194/mm3; ratio (CD4/CD8 T cells) = 0.43 ± 0.17; Hb =13.5 ± 1.6 g/dL; HIV RNA loads = 22590 ± 20160 copies/mL.In the 1997–98 period, mean of HIV RNA loads were248975 ± 110865.The difference between the mean values of the patients withcardiac involvement of the period of 1997–98 and of the lastthree years was significant for p < 0.001. Moreover, CD4+ Tcells mean concentration was 91 ± 40 in the case of cardiacinvolvements of HIV-positive patients during the period of1994–98, and 180 ± 99 cells/mm3 in not involved patients(means difference significant for p < 0.001); the meansdifference between the values of patients with cardiacinvolvement during the last three years and the previousperiod was significant for p < 0.001. Besides, the ratio wasrespectively: 0.11 ± 0.04 in the patients with cardiacinvolvement during the period of 1994–98 and 0.26=/- 0.14in those without cardiac involvement (significant differenceof the means for p < 0.001). Hence, comparing the values ofthe patients, with cardiac involvenent, evaluated during theperiod of 1999–2001 and those studied in the previousperiod, the difference of means was also significant for p <0.001. At last we report that CPK and LDH mean valueswere respectively: CPK =131.5 ± 147 in the period1994–1998 and 164 ± 131 in the period of 1999–2001 (notsignificant difference), LDH = 715 ± 118 and 381 ± 70 (p <0.001). Our data demonstrate a suprising reduction ofcardiac involvement in HIV-positive patients treated withmore recent therapeutic schedule, together with a marked

improvement of immuno-hematologic state. However, moreeasy manifestations could also escape because the HAARTpatients feel good conditions.

33. HIV disease among immigrants in Italy: demographic,epidemiological and clinical featuresRoberto Manfredi, Leonardo Calza, Francesco ChiodoDepartment of Clinical and Experimental Medicine,Division of Infectious Diseases, University of Bologna, S.Orsola Hospital, Bologna, ItalyA 1:4 case-control cross-sectional study was performed tocompare the features of HIV disease in 45 patients comingfrom outside the European Union and followed for at least12 months, with those of 180 European Union nationalsrandomly selected among a cohort of 972 European Unionpatients, and matched according to age, gender and follow-up period. The 45 extra-European Union subjectsrepresented 4.4% of our whole patient cohort, were femalesin 46.7% of cases, and had a median age of 33 years.Heterosexual exposure was the most common risk factor(75.5%), followed by vertical HIV infection (11.1%), whilei.v. drug addiction and homosexual transmission werecomparably rare. Only 28.9% out of 45 patients were awareof HIV infection before (7 cases) or after (6 patients) theirimmigration in our country. On the other hand, no case ofHIV-2 infection or co-infection was demonstrated in theentire cohort. The majority of our patients (64.4%) camefrom Central Africa (24 cases) or Northern Africa (5subjects), followed by Eastern Europe (20%), Latin America(8.9%), and Asia (6.7%). Compared with European Unionpatients, those coming from abroad had a predominantheterosexual and perinatal HIV transmission (p<.001), and ashorter mean duration of known seropositivity (12.3±3.1versus 22.6±9.1 months; p<.001). Although clinical andimmunologic features of HIV disease were similar (asexpressed by 6 versus 28 cases of AIDS, and negligibledifferences in the last mean CD4+ lymphocyte count), extra-European Union patients had a higher mean viremia at thelast control (4.0±0.6 versus 3.2±0.5 Log10 HIV-RNAcopies/mL: p<.001), and a viral load <50 copies/mL wasreached in 23 patients compared with 127 controls (p<.02).These features were probably due to the shorter mean timeon anti-HIV therapy of extra-European Union patients, andtheir mean shorter follow-up time (p<.001). No significantdifference was detected as to resort to highly activeantiretroviral therapy (HAART) and related compliancelevels (>90% and >85% in both patient groups, respectively),as well as to selected drug regimens, while extra-EuropeanUnion patients had a lower rate of therapy changes due totoxicity or poor tolerability (p<.008). The diagnosis of HIVdisease is an emerging clinical feature among immigrants inItaly: 4.4% of patients presently followed at our tertiary carecentre come from extra-European Union countries, showinga greater prevalence of the female gender, and heterosexualand perinatal transmission. Although a similar clinical andlaboratory course of HIV disease is expected, this patientpopulation deserve an individualized approach, taking intoaccount of the different psychological, sociological, andcultural impact of HIV disease among immigrants.

34. HIV-infected patients still on dual nucleoside analoguetreatment in the year 2001: how we have to manage them?Roberto Manfredi, Leonardo Calza, Francesco ChiodoDepartment of Clinical and Experimental Medicine,Division of Infectious Diseases, University of Bologna, S.Orsola Hospital, Bologna, ItalySince the introduction of highly active antiretroviral therapy

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(HAART), no apparent place is expected to remain forisolated dual nucleoside analogue therapy, so that limitedand not updated figures are available about these regimensin the HAART era. In order to assess the frequency,background, role, and long-term outcome of antiretroviraltherapy including two nucleoside analogue only, a cross-sectional study was performed in 1017 HIV-infected subjecsfollowed at our tertiary care outpatient centre at June 2001.Actually, an appreciable proportion (182 out of 903: 20.2%)of patients receiving antiretrovirals for 12 months or morestill takes dual nucleoside analogues, with lamivudine-stavudine as the leading combination (49.5%), followed byzidovudine-lamivudine, didanosine-stavudine, zidovudine-didanosine, and zidovudine-zalcitabine. The large majorityof these patients (77.5%) began their treatment withnucleoside analogue monotherapy (61 cases), or dualtherapy (80 patients), while the other 41 subjectsexperienced a previous HAART, but declined a thirdcompound (other than dual nucleoside analogues) aftersuffering from clinical or laboratory toxicity. When startingthe current dual nucleoside analogue therapy, the meanviremia was 3.7±0.9 Log10 HIV-RNA copies/mL, and theCD4+ lymphocyte count was 359.2±102.7 cells/µL. After afollow-up of at least 24 months (range 24–58 months),72.5% of patients had a stable disease course, characterizedby a viral load below 5000 copies/mL and absence of a >1.0Log10 rise of plasma viral load anytime during treatment(persistently undetectable viremia was shown in 55.5% ofpatients), a maintained immunologic competence (asexpressed by a stable CD4+ cell count), and absence ofdisease progression (i.e. absence of novel or relapsing HIV-associated diseases), regardless of the selected nucleosideanalogue combination, prior antiretroviral therapy, andbaseline laboratory outline. The remaining 50 patients hadat least one episode of viremia above 5000 copies/mL and abroad genotypic mutation profile involving mostly viralcodons 184, 215 and 41, but they noteworthy refused theadministration of a triple-drug HAART based on eitherprotease inhibitors or non-nucleoside reverse transcriptaseinhibitors. An immunological deterioration (as expressed bya drop of CD4+ lymphocyte count exceeding 150 cells/µL or20% versus baseline), occurred in 34 patients only (18.7%),all but one experiencing a virologic rebound above 5000copies/mL. In conclusion, although 62.6% of patients stillreceiving dual nucleoside analogue therapy in our serieswere not antiretroviral-naïve, a better outcome was seencompared with prior reports describing naïve subjectsfollowed for a shorter time, probably due to the lower meanbaseline viremia of our patients (below 104 copies/mL).Controlled studies could notably contribute to establishwhether the shift to HAART may add significantly to HIV-infected patients at low risk of disease progression while ondual nucleoside analogues, and/or isolated dual nucleosideanalogue administration may maintain indications in theHAART era.

35. Increase of haemoglobin values and HAART in HIVinfected patientsM. Marturano*1, M. Feasi1, L. Papa1, A. Collidà1, P.Pedemonte1, E. Rossi2, G. Mazzarello1, D. Bassetti1

1Dept. of Infectious Diseases, University of Genoa, SanMartino Hospital, Genoa2Dept. of Hematology, San Martino Hospital, Genoa, ItalyBACKGROUND: Hematological abnormalities are verycommon in patients with HIV infection; in patients treatedwith HAART, we observed an increase of haemoglobin

values that in some cases could be considered abnormal.This study has the purpose to describe the effects of HAARTon this hematological parameter.PATIENTS AND METHODS: 134 HIV infected patients,coming to our Department, have been retrospectivelystudied. We considered sex, risk factors for HIV infection,number of smoked cigarettes and treatment with zidovudinein HAART. We reported values of haemoglobin at the firstvisit in our ambulatory, before starting HAART and thehighest value of haemoglobin reached during therapy.Assuming HIV infection as a chronic disease, we consideredas abnormal values Hb>15 g/dl for men and Hb>14 g/dl forwomen: we divided the patients into two groups accordingto this abnormal increase.RESULTS: We observed an increase of Hb in 43 (32%)patients. In this group 35 were males and 8 females; the riskfactor in 28 (65%) patients was drug addiction, in 7 (16%)was homosexuality, in the other 7 was heterosexualtransmission and in one case (3%) the patient washaemophylic; 23 (53%) patients smoked less that 30cigarettes, 12 (27%) smoked more than 30 cigarettes, while8 (20%) were non-smokers; 18 (42%) patients were intreatment with zidovudine. The mean of haemoglobinvalues at first visit was 14.3 g/dl (median 14.2, range11.1–17.3), before starting HAART it was 11.9g/dl (median11.9, range7.2–16.7) and during therapy Hb reached themean value of 16.3 (median 16.5, range 14.3–18.7). In theother group 58 (63%) patients were males and 33 (37%)were females. The risk factor was in 44 (49%) drugaddiction, in 33 (36%) heterosexual transmission, in 12(13%) homosexuality and in 2 cases (2%) the patients werehaemophylics; 64 (70%) patients smoked less than 30cigarettes, 6 (7%) more than 30 cigarettes and 21 (23%)were non-smokers. Zidovudine was in HAART therapy in 43(47%) patients. In this group the mean value ofhaemoglobin at first visit was 13.4 g/dl (median 13.1, range9.4–16.8), before starting HAART it was 12.8 g/dl (median13.4, range 8.5–18.4) and during therapy it reached themean value of 13.2 g/dl (median 12.6, range 10.2–15)CONCLUSIONS: During HAART an increase in HB valueshas been observed: this demonstrates that therapy reduceschronic anemia, related to HIV infection. In 68% of cases,the patients showed an increase of Hb comparable withstarting values, while in the other 32% we observed anabnormal increase. The two groups of patients had notdifferent characteristics in risk factors, number of cigarettessmoked and in treatment with AZT. We draw that probablythere is an effect of HAART on increase of Hb, but we needto study the iatrogenic mechanisms, evaluating differencesin haematologic parameters.36. Intestinal parasites in AIDS Mexican childrenJarillo D., Muñoz R., Cárdenas C., Ramírez ML., OrtegaM.,Alpuche-Aranda C., Santos JI.,Pavía-Ruz N*Depto. de Medicina Experimental, UNAM/Hosp. General deMéxico. Mexico, D.F.BACKGROUND: Common complications in personsinfected with AIDS are chronic diarrhea and wastingsyndrome. In many cases, diarrhea can be attributed toinfections with one o more “common” or opportunisticenteric pathogen. We present the frequency of intestinalparasite in Mexican children with AIDS.METHODS: In a prospective study we collected stoolsamples from 3 groups: A) AIDS children (n=43), B) healthychildren in contact with AIDS patients (n= 35), C) healthychildren without contact with AIDS patients (n=92). Weanalyzed three fresh stool samples for parasite identification:

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saline wet mount, concentration methods, trichrome bluestain (TS) modified, kinyoun-modified stain, indirectimmunofluorescence assay anti-Encephalitozoon sp Mab 3B6(IFA).RESULTS: In-group A we had 24 children (55.8%) withchronic diarrhea and 17 (70%) of them were Microsporidiapositive by IFA, four children had chronic diarrhea andCryptosporidium, one child with Giardia lamblia, most of thepatients had moderate to severe immunosupresion. In groupB we had 14 children positive for Microsporidia by IFA, onlytwo patients had chronic diarrhea and one of them withCryptosporidium; two children with Ascaris lumbricoides andone child with Giardia lamblia and another with Trichuristrichiura In group C we had 22 patients positive forMicrosporidia by IFA; four children with Giardia lamblia andtwo children with Ascaris lumbricoides.CONCLUSIONS: In our study population the frequency ofmicrosporidia is higher than others reports regarding adultAIDS population. The Cryptosporidium frequency was 11.1%similar to others publications. We observed relative lowerfrequency of “common” intestinal parasites in AIDSchildren.

37. Cervico-Vaginal dysplasia HPV-induced in HIV-1+women: a Turin case reportLucia Andronico, Gloria Gallo*, Luisa Gennero, ValerioVidotto & Agostino PuglieseSection of Clinical Microbiology, Un. of Turin and * FAROFoundation of Turin, ItalyCervico-vaginal dysplasias (CVD) or invasive carcinoma(IC) HPV-induced are pathologies that can complicate HIV-infection. In particular, IC represents a clinical manifestationcharacterizing AIDS condition. We studied 31 HIV-1-positive women (CD4+T cells/mm3 = 137 ± 42; mean age =37 ± 8.4, range: 31–62 years) admitted to the Amedeo diSavoia Hospital of Turin, for clinical manifestations of HIV-1infection, 28 HIV-1 positive women unaffected by CVD ofdifferent severity and 20 healthy women. All the groups hada similar mean age. The data of some immuno-hematologicmean values of the three groups are reported in thefollowing table.

CD4+ HbSubjects (Cells/mm3) Ratio (g/dL)

HIV+/CVD+ 137 ± 42 0.2 ± 0.05 10.4 ± 1.6(31 cases)(a)HIV+/CVD-(28 cases)(b) 278 ± 197 0.46 ± 0.22 10.9 ± 2.2Controls (c)(20 Women) 922 ± 184 1.6 ± 0.36 14.9 ± 0.7 Significancelevels aÆb=p<0.001 aÆb=p<0.001 aÆb=NS

(Student’s aÆc=p<0.001 aÆc=p<0.001 aÆc=p<0.001t est) bÆc=p<0.001 bÆc=p<0.001 bÆc=p<0.001

HIV-RNAloads

Subjects (Copies/mL)

HIV+/CVD+ 254950 ± 208132(31 cases)(a)HIV+/CVD-(28 cases)(b) 206000 ± 319000Controls (c)(20 Women)Significancelevels NS(Student’s t est)

Moreover, comparing Hb mean values of CIN1 patients(12.5 ± 0.99 g/dL; 15 women) and CIN2 patients (11.4 ±1.0; 5 women) we detected a significant difference for p =

0.046 and for p<0.001 considering CIN3 and IC patients(CIN3 = 9.5 ± 0.8; 5 women - IC = 8.4 ± 1.2; 5 women). Anegative linear correlation was found between Hb meanvalues and the evolution of dysplastic/anaplastic disease (r =0.83; p<0.001). In the case of CD4+ T cells mean values andof ratio values (CD4+/CD8+ T cells) a negative correlationwas also found with the same dysplastic evolution(respectively: r = 0.79; p = 0.002 and r = 0.60; p = 0.038). Inparticular, CD4+T cells mean values were: 207 ± 98/mm3 inthe case of CIN1 patients; 133 ± 67 in that of CIN2 (p = NS,evaluating the significance of difference of mean values);109 ± 12 in that of CIN3 (p = 0.041) and 100 ± 75 in that ofIC affected women (p = 0.039). Besides, mean ratio valueswere 0.26 ± 013 in CIN1 patients; 0.23 ± 0.13 in thoseCIN2; 0.19 ± 0.06 in those CIN3 and 0.11 ± 0.06 in thoseaffected by IC (significant difference with CIN1 only in thecase of IC value: p<0.001). At last, we underline that asignificant difference in mean values between CIN1 andCIN2 groups was found only in the case of Hbconcentration (p = 0.046) and also between CIN2 and CIN3(p = 0.01). Moreover, significant differences were detected inthe cases of CD4+ T cells concentration (p = 0.041), Hb (p <0.001) and HIV.RNA loads (p < 0.001) between CIN1 andCIN3; besides, between CIN 3 and IC, only in the case ofHIV-RNA loads ( p = 0.007). In particular, in the last casethe mean values of RNA viral copies were 65250 ±30995/mL in CIN1 patients; 56400 ± 34660 in CIN2 ones(not significant difference); 339150 ± 112400 in CIN3(significant difference with CIN1 for p < 0.001) and 559000± 310000 in IC patients (p < 0.001). Besides, we underlinethat HAART patients have not found evolution of dysplasticdiseases, after one year of treatment.

38. Compassionate use of lopinavir-ritonavir in pre-treatedchildren: preliminary dataR. Rosso*, S. Vasile, C. Iozzi, B. Ciravegna, S. Ratto, A.DiBiagio and D. BassettiDepartment of Infectious Diseases, G. Gaslini Institute,University of Genoa, GenoaOBJECTIVE: To evaluate clinical efficacy, immunologicaland virological response and tolerability of lopinavir-ritonavir (L-R) in pre-treated children during 6 monthsfollow-up (Dec. 2000–June 2001).METHODS: We considered 6 perinatally HIV-infectedchildren (3 male and 3 female), followed at our Department,receiving L-R capsules. One 4-year-old child received L-Roral solution (with 2 NRTI), but stopped it after just 15 daysfor poor palatability. Mean age was 13.8 years (r=11-15).CDC stage was: C3 (3), B3 (1) and A2 (2). All children havealready been treated with at least 1 PI (1 pt 3PI, 4 pts 2PI, 1pt 1PI). Mean age of start of the first PI was 9.8 years. 4children took L-R in combination with 2 NRTI, 1 child with3 NRTI and 1 with 1 NRTI+1 NNRTI. 4 patients were underPCP prophylaxis. We evaluated the trend of CD4+ T-cellabsolute count, %CD4, viral load and adverse events.RESULTS: Mean baseline CD4+ T-cell was 212/mmc (r =40–525/mmc), CD4 % 17.1 (r=4.2%–41.9%); in 3 childrenviral load was >100000 copies/ml Amplicor (r =12000–790000).After 2 months of therapy, mean CD4+ T-cell was 342/mmc(r=70–1045/mmc) and % CD4 was 19.1 (r=8.1%–41.4%).After 4 months, mean CD4+ T-cell count was 285/mmc; in 4children viral load was <500 copies/ml (in 2 viral load wasundetectable) and only in one case we didn’t observevirological response. Furthermore, we stopped PCPprophylaxis in 3 patients. 5 children with significative

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response to therapy showed a positive improvement in bodyweight and stature. We observed in 4 caseshypertriglyceridemia (in 1 case of severe degree according tothe ALECS (European group for the study of lipodistrophyand metabolic disorders during antiretroviral therapy)classification); in 3 cases hypercolesterolemia (2 of milddegree and 1 of moderate) and 1 case of moderatehypertransaminasemia after 4 months; furthermore 2patients revealed a fat redistribution. Finally, herpes zosteroccurred in 2 children.CONCLUSIONS: These preliminary results suggest thattreatment with L-R is an effective choice in multi-treatedchildren; it has a remarkable impact on immunological andvirological improvement. L-R revealed a good tolerability.Further follow-up is mandatory in HIV infected childrenreceiving it.39. Hyperlipidemia and lipodystrophy in HIV-infectedchildren treated with HAARTL. Papa, N. Bobbio, R. Rosso*, A. Beltrame, P. Fiore1 and D.BassettiDepartment of Infectious Diseases, G. Gaslini Institute,University of Genoa, Italy1Service of Dietetics, G. Gaslini Institute, Genoa, ItalyOBJECTIVE: Protease inhibitors (PI) cause in adult patientsa syndrome of lipodystrophy manifesting as peripherallipoatrophy, relative central adiposity, increase of breastdimension, insulin resistance, serum lipid abnormalities. Wewanted to evaluate if these adverse events are also inchildren HIV + (pts) on treatment with PI, particularlyserum lipid abnormalities.PATIENTS AND METHOD: We observed 34 pts (19 malesand 15 females), all perinatally HIV infected, on therapywith PI in the period between July 1997 and May 2001.Median age was 99 months (range 3–163 months). Weprospectively measured blood levels of triglycerides (TG)and cholesterol (CH) (normal values: 30–154 mg/dl and96–200 mg/dl) at baseline and every 2–4 months duringtreatment. We considered following grades of toxicity: grade1: TG 277–338 mg/dl (≥3 years) or 220–268 mg/dl (<3years), CH 360–440 mg/dl; grade 2: TG 254–862 mg/dl or281–683 mg/dl, CH 460–1120 mg/dl; grade 3: 878–1540mg/dl or 695–1200 mg/dl, CH 1140–2000 mg/dl.RESULTS: We evaluated 57 treatments in 34 pts. There wasno one increase of CH during the treatment, while we sawsome cases of hypertrygliceridemia. 27 pts were on therapywith nelfinavir (NFV): 4 of these had grade 1 increase ofTG, two grade 2 and one toxicity of grade 1 followed atoxicity of grade 2. 12 pts were on therapy with ritonavir(RTV): we observed two cases of hypertrygliceridemia grade1, one case of grade 2, two cases with grade 1 and then 2,and one case of grade 4. One of six pts on treatment withlopinavir/ritonavir (LPV/r) had grade 3 toxicity (this childhad the same side effect with RTV and NFV). 5 pts were ontherapy with indinavir (IDV): two children had grade 2toxicity; no one of 2 pts on treatments with saquinavir(SQV) had adverse event. Three pts took RTV + SQV and weobserved one patient (pt) with a grade 2 and then 4 and onept with grade 2 toxicity. One (pt) was in treatment withRTV+amprenavir (APV) and she had important increase ofTG (grade 3).CONCLUSIONS: Overall 13 children (38.2%) had anincrease of TG: four took only with RTV, four only NFV, onetook NFV then RTV+SQV and RTV+APV, one took RTV thenNFV then LPV/r; one took IDV, then NFV; one took IDV andRTV, one NFV then RTV+SQV. Hypertriglyceridemia seemsthe most frequent abnormality of plasma lipid levels, while

hypercholesterolomia was always below grade 1 of toxicity;no one had glucose metabolism alterations. Changes in bodyfat distribution have been observed in 4 pts: 1 pt had acushingoid appearance with dorsocervical fat accumulation(“buffalo hump”) (BH), 1 pt had only BH, 1 pt breastenlargement and 1 pt facial thinning with peripherallipoatrophy. All 13 children received a hypolipidemic dietassociated to a suggested physical exercise, 7 no respondersreceived alpha omega three acid or bezafibrate. Thesetreatments seem to be associated with a favourabletolerability, but further studies are necessary.

40. Simultaneous A an E hypervitaminosis in an HIV-infected child: case reportR. Rosso*, P. Fiore1, N. Marchese†, B. Ciravegna, G. Gatti, D.BassettiDepartment of Infectious Diseases, G. Gaslini Institute,University of Genoa, 1Service of Dietetics,G. Gaslini Institute, Chemistry Laboratory, G. GasliniInstitute.INTRODUCTION: No reports have appeared in literature todate of hypervitaminosis in HIV-infected child. This reportdescribes the nutritional status (NS) changes occurring inan 8-year-old little girl with vertical acquired HIV infectionreceiving HAART, and its side effects on lipid metabolism.METHODS: She presents with an 8 year history of severespastic “paraparesys” due to encephalopathy HIV-related.Two years ago, for a global impairment of NS due tocomplete refusal of food intake, even in the absence oforganic lesions of mouth and esophagus, percutaneousendoscopic gastrostomy (PEG) was performed in order toadminister a physiological and adequate nutritional intake.At the last clinical examination, she appeared in a goodgeneral state of health and NS with only a significativeheight stunting. [Height-for Age <5th percentile NCHS (-2.2sds); Weight-for-Age 39th percentile; Weight-for-Height>95th percentile], with a good adherence to her HAART(Amprenavir (APV) syrup 240 mg BID + Ritonavir syrup 80mg BID + Abacavir (ABC) syrup 187 mg BID + Nevirapina(NVP) syrup 160 mg BID, started in August 2000). Her CD4cell count was 1275 cells/mm3 and her serum viral load was43300 copies/mL. Besides she presented very high retinol(VA) 7,23 µmol/L (r: 0.266–3.63 µmol/L), a-tocopherol(VE) 178,8 µmol/L (r: 5.41–34.34 µmol/L), triglyceridemia(TG) 1232 mg/dL (r: 30–154 mg/dl) and cholesterolemia(CH) 214 mg/dL r: 96–200 mg/dl). No clinical signs ofchronic hypervitaminosis A and E with also possiblenegative influences on coagulation function were observed.RESULTS: On the basis either her virological failure,hyperlididemia, and hypervitaminosis, we planned tochange her HAART. Serum viral load was 46200 mg/dL andCD4 cell count was1238/mmc; the patient had always toxicserum levels of VA (6.52 µmol/L) and VE (157.9 µmol/L),and high levels of serum TG (742 mg/dL) and serum CH(211 mg/dL). She started a new HAART with ABC 180 mgBID + Stavudine 20 mg BID + NVP 160 mg BID +Didanosine 100 mg BID (all syrup formulations). After 10days we observed an improvement of lipid profile withserum TG concentration of 419 mg/dL and normalcholesterol value. Vitamins A and E were in normal range(VA: 3.3 µmol/L; VE: 27.9 µmol/L).CONCLUSION: We observed an important and significativemodification on lipide metabolism and serum level ofvitamins only switching from protease inhibitors (IP)- basedantiretroviral therapy to IP sparing-ARV. We know thatformulation of APV contains 46 IU of VE/ml of oral solution

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and an increased concentration of VLDL and LDLlipoproteins can contribute to the VE values. But if APV-switch could be able to explain the decreasing level of VE, itdoesn’t help us to explain the decreasing level of VA,because in general children infected with HIV have normalor decreased VA serum levels compared to normal childrenand no antiretroviral drug contains VA. So one couldspeculate that IP have an effect on VA metabolism and ashyperlipidemia is common among HIV-infected individualsreceiving IP, perhaps hypervitaminosis, with its side effectsrelated, could be common too. The impact on VA, VE andlipid profile and metabolism of ART merits further studies.Our findings suggest that a careful monitoring of liposolubilA and E vitamins plasma concentration is mandatory inHIV-infected children receiving HAART.

41. Tuberculosis in HIV positive and negative patients:three-year surveyR. Rosso*, C. Iozzi, C. Montaldo, A. Di Biagio, A. Beltrame,G. Cenderello, M. Bassetti, and D. BassettiDepartment of Infectious Diseases, S. Martino Hospital,University of Genoa, Genoa, ItalyOBJECTIVE: Tuberculosis (TBC) is a very importantproblem of public heart care in the world. We evaluate itsincidence in HIV + (pts+) and HIV – patients (pts-)hospitalized from January 1999 to June 2001 in ourDepartment (Dpt).METHODS: We retrospectively reviewed the clinical chart ofall pts+ and pts- who were admitted with a suspected orproved diagnosis of TBC in out Dpt.RESULTS: There were 14 pts+ (13 male and 1 female) and17 pts- (8 male and 9 female) treated for TBC. About pts+,the median CD4+ cell count was 252/mmc (r=30–686), theviral load was >10000 in 9 pts+ (3 had >100000), in therange 100–1000 in 4 pts+, only 1 had an undetectable value.CDC classification before diagnosis of TBC was: 2 C3, 2 C1,1 B3, 3 B2, for 6 pts TBC was the first manifestation of HIV.About pts- the mean age was 54.8 years (r=17–87). 7 pts+and 10 pts- had pulmonary infection, 6 and 7 respectivelyextrapulmonary, while only 1 pts+ had sepsis. 6 pts+ and 6pts- were PPD+, 3 and 4 respectively PPD-, while 5 and 7 ptshaven’t done it. Mycobacterium was isolated from clinicalspecimen in 20 pts (8 pts+ and 12 pts-) and 6 strains in 6different pts (1 pts+ and 5 pts-) showed resistance torifampin (3) or etambutolo (1) or piraldine (2). No one ptshave done TBC prophylaxis. All pts received isoniazid (dueto adverse events, 2 pts- interrupted and changed it) incombination with two or three standard agents (rifampin 8pts+ and 14 pts-, etambutolo 13 pts+ and 16 pts+,streptomycin 3 pts+ and 2 pts-, piraldina 12 pts+ and 13 pts-, ciprofloxacin 3 pts+ and 5 pts-, rifabutin 1 pts+, 1 pts-piridossina).CONCLUSIONS: Our experience shows that in the pts+,TBC continues to be one of the most frequent AIDS definingevents after HAART, but this infection is an importantclinical event also in pts-. The problem of resistance to oneor more drugs, marker of poorer prognosis, is present inevery kind of patient and suggest to perform alwayssusceptibility test in clinical practice.

42. Free HIV-AIDS treatment and clinical trials sponsorshipAhmed Shafik, Department of Surgery and Research, CairoUniversity, Faculty of Medicine, Cairo, Egypt.MM-1 is a safe, natural and cost-effective, alternativetreatment for persons with HIV/AIDS, which has beenused successfully Internationally on more than 10,000persons with HIV/AIDS, in all phases of clinical trials in

Kinshasa, Zaire (DRC-Africa) from 1987—1993. Theproposed new sponsored MM-1 clinical trials will assistthose persons with HIV/AIDS to obtain the MM-1 HIV/AIDStreatment FREE of CHARGE, IF they qualify for the ClinicalTrials Study. In addition, we hope to be able to finally get theFDA approval for MM-1, as well as get the long overdue(since 1989) USA Patent for MM-1. Although clinical trialswith MM-1 have already been successfully completed onpersons with HIV/AIDS between 1987 and 1993 inKinshasa, Zaire (DRC, Africa), we are still interested inhaving new and more diversified clinical trials done withMM-1, and also in combination with other treatments aswell. Our goal is to prove that MM-1 is indeed a safe, naturaland cost-effective alternative treatment for persons withHIV/AIDS, which has been used successfully internationallyon more than 10,000 patients since 1987 with no toxic sideeffects. We are trying to get HIV groups, agencies &organizations, NGOs, CVOs, medical institutions, universityresearch centers, pharmaceutical companies, privatebusinesses, corporations, government agencies &organizations, individuals and communities aware, informedand interested in MM-1 HIV AIDS treatment, so that theycan consider its use, and help to sponsor and finance thenew proposed MM-1 Clinical Trials Project. We hope thatthis information will prove to be useful and informative tothose individuals with HIV/AIDS, and to thoseorganizations, institutions, agencies and corporations doingresearch on HIV/AIDS, or working with, sponsoring, orassisting those Persons with HIV/AIDS. MM-1 is anantiviral and immunopotentiating drug, which containsactive ingredients of amino-acids, peptones and enzymes.MM-1 has a very low toxicity and wide safety margin. It hasa stimulating effect on the immune system, both humoraland cellular, producing a significant increase in the totallymphocyte count as well as the B and T lymphocytes. MM-1 stimulates the hemopoietic and lymphatic systems of thebody, causing an increase in hemoglobin, total leukocyticcount, neutrophils and lymphocytes, as well as albumin andglobulin. The safety studies done on laboratory animalsrevealed that prolonged administration of MM-1 in differentdoses up to 9-fold the therapeutic dose did not reveal anytoxic effects.MM-1 has an inhibitory effect on the replicationof many viruses. It appears that MM-1 penetrates anddestroys the virus cover, thus preventing its adsorption tocell membrane. Animal studies demonstrated that MM-1 hasno acute, subchronic or chronic toxic effects at doses morethan 100 times the maximum human dose. The studiesshowed also that the drug has no teratogenic mutagenic orcarcinogenic effect. Clinical trials 1987–1993 MM-1 clinicaltrials results showed that there were clinical andimmunological improvement, and the drug was welltolerated, with no adverse effects. In some patients therewere minor side effects of: fever, chills, soreness at theinjection site and occasional pruritus and sterile abscess atthe injection site. The patients showed no side effects orsigns of renal, hepatic or cardiac dysfunction that could beattributed to the MM-1 compound. MM-1 is a safe, natural& cost-effective antiretroviral treatment which stimulatesthe hemopoetic and lymphatic systems of the body causingan increase in hemoglobin, total leukocytic count,neutrophils and lymphocyte, albumin and globulin. MM-1is a one-time treatment of 20 (5cc IM injections each) givenover a period of 65 days (usually with a two week restperiod in between). The patient then gets booster dosesevery year, after the initial booster series is given (dependingon the clinical & immunological evaluation and results). It

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appears that MM-1 penetrates and destroys the virus cover,thus preventing its adsorption to the cell membrane. MM-1also has an inhibitory effect on the replication of manyviruses. MM-1 has a immunostimulating property, causing asignificant increase in the immunoglobulin serum levels,and cellular immunity. MM-1 restores the underlyingimmunodeficiency in HIV/AIDS patients to within normallevels, opportunistic infections improved during MM-1therapy, with the exception of Kaposi Sarcoma (KS which isnot affected by MM-1). The hemopoietic immuno-modulating effect of MM-1 was studied to explore the effectof MM-1 on animals with Immunosuppression induced bychemotherapeutic agents. The results showed that MM-1could help in the treatment of patients with anergyassociated with malignancy and immunodeficiency disease.MM-1 can also be used in the treatment of the myelo andimmunosuppression status which follows administration ofthe different chemotherapeutic agents in malignancy.Adverse reactions from MM-1: None. Side effects: fever,chills, soreness at injection site, occasional pruritus andsterile abscess at injection site. There were NO signs ofrenal, hepatic, or cardiac dysfunction attributed to MM-1.Compliance of treatment: MM-1 treatment and schedule waswell tolerated as it was done on an out-patient basis withthose patients who did not need hospitalization. Thepatients were all able to stay home with their families andcontinue their (ADL) activities of daily living. They cameregularly to the Clinic site for their MM-1 injection,laboratory work & physical assessment. (counseling isplanned to be offered in any future MM-1 treatment clinics).In conclusion, MM-1 can be used as a very safe, natural,cost-effective and alternative treatment for HIV/AIDS, withno toxic side effects. In addition MM-1 also allows personswith HIV/AIDS to live out their lives in peace, comfort andwith dignity and to continue their activities of daily living(ADL).

Antibiotic therapy in intensive care unit

43. Epidemiologic study of Pseudomonas aeruginosa in theintensive care unit (ICU) and non ICU inpatient area inthe Lavagna HospitalLorusso Carolina, Sampietro Francesca, Polero Laura,Gasparini Laura, Alloisio Sergio*, Boreanaz Teresa*,Bonfiglio Monicaº, Franco Massimoº, Casigliani Rinaldoº,Rebolini Giorgio.U.O. Sert ASL 4 Chiavarese; *Microbiology Unit LavagnaHospital; ºIntensive Care Unit Lavagna HospitalINTRODUCTION: Pseudomonas aeruginosa is a commoncause of nosocomial infection, particularly in intensive careunits (ICUs). The aim of this study is to value theantimicrobial susceptibility of Pseudomonas aeruginosa inclinical isolates of patients of our Hospital. Patients admittedto intensive care units are at a higher risk of acquiringnosocomial infection than patients in other hospital areas.This is the consequence of both a greater severity of illnesswith its implications (manipulation, invasiveness) andcrossed infection from reservoir inside the ICU. The mostfrequent nosocomial infection is invasive ventilation-associated pneumonia (VAP) which leads to an importantincrease in morbidity and mortality.OBJECTIVE: Our object was to evaluate the relationshipbetween antimicrobial use and susceptibility in the intensivecare unit and non ICU inpatient area in the LavagnaHospital. From December 2000 in our Hospital a newintensive care unit is active. 120 patients were recovered in

Intensive Care Unit from December 2000 until May 2001. Itleads to emphasize the importance to a strongepidemiological surveillance and strategies of preventionwith hand washing and universal precaution.RESULTS: We analyzed the rate of antimicrobial resistancepattern in pseudomonas isolates from intensive care unitand other nosocomial inpatient areas.Antimicrobial resistance was as follows:Dept an amc am azm

% % % %ICU 0 49 8 55 9 26 4Non-ICU 17 2 68 8 74 9 41 5

Dept tax cf cip fos

% % % %ICU 48 8 53 9 35 6 14Non-ICU 62 7 79 9 54 6 42

Dept gm imi na fd

% % % %ICU 34 6 21 3 49 8 52 9Non-ICU 45 5 9 75 9 76 9

Dept nor pip tcc tob

% % % %ICU 35 6 12 2 28 5 32 5Non-ICU 46 5 11 1 36 4 34 4

Dept sxt

%ICU 76 5Non-ICU 76 9an=amikacina; amc=amoxicillina clavulanico; azm=aztreonam;tax=cefotaxime; taz=ceftazidime; cf=cefalotina; cip=ciprofloxacina;fos=fosfomicina; gm=gentamicina; imi=imipenem; na=acido nalidixico;fd=nitrofurantoina; nor=norfloxacina; pip=piperacillina; tcc=ticarcillinaclavulanico; tob=tobramicina; sxt=trimetoprim/sulfametossazolo

CONCLUSIONS: Data shows an increase of antimicrobialmultiresistance that makes it a difficult choice for anadequate therapeutic regimen. To avoid the spread ofantimicrobial resistance it is very important to cooperatewith local guidelines of treatment based upon theknowledge of the most frequently isolated bacterial flora andtheir susceptibilities in different clinical settings.

44. The in vitro activity of amikacin and cefuroxime aloneand in combination against extended-spectrum b-lactamase (ESBL)-producing Escherichia coli and KlebsiellapneumoniaeMerlyn C. Cruz, Angeles University Foundation, PhilippinesBernard C. Silvala, Angeles University Foundation,PhilippinesBACKGROUND: Resistance to broad-spectrum b-lactamdrugs among clinical isolates of Escherichia coli andKlebsiella pneumoniae have been noted in the Philippines.Microorganisms identified to produce extended-spectrum b-lactamase (ESBL) enzymes are now beginning to emerge andpose a threat on the field of antibiotic theraphy. As animmediate response, a preliminary experimental study onthe combined effectiveness of amikacin and cefuroximeagainst ESBL-producing Escherichia coli and Klebsiellapneumoniae was conducted.METHOD: Out of 42 clinical isolates of Escherichia coli andKlebsiella pneumoniae suspected for ESBL-production orthose resistant to any one of the 3rd generationcephalosporins, like ceftazidime, cefotaxime or ceftriaxoneor to either aztreonam or cefpodoxime, from patientsadmitted at Angeles University Medical Center withinOctober–March 1999, 11 isolates (4 Escherichia coli and 7Klebsiella pneumoniae) were detected positive for ESBL

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production by double-disk synergy test. The minimuminhibitory concentraion (MIC) of amikacin and cefuroximefor these organisms were determine by agar dilutionmethod. Time-kill synergy test was performed to evaluatethe combined killing activities of amikacin and cefuroximeat three concentrations: one dilution below, above andequivalent to the drugs’ MICs. Viable counts weredetermined at 0,6,12 and 24 hr.RESULT: MIC determination showed that the organismswere susceptible to amikacin at 32–64 ug/mL and tocefuroxime at 32–128 ug/mL. For 73% of the isolates (8/11of isolates tested and concentrations considered), there wasan increase of more than or equal to 2log10 in the rate ofkilling after 24 hours with the combination in comparisonwith more active drug alone, suggesting synergy betweenamikacin and cefuroxime.CONCLUSION: The results suggest that amikacin andcefuroxime have greater bactericidal activity when used incombination than when used alone.

Bacterial meningitis

45. Pre-admission antibiotic treatment of meningococcaldisease Roznovsky L., Struncova V., Kasal E., Dostal V., Plisek S.,Burget I., Chalupa P. Dlouhy P., Svejda J., Kriz1 PDept. of Infectious Diseases, National Inst. of Public Health1,Czech RepublicOBJECTIVES: Early recognition, immediate antibiotictreatment and aggressive treatment of septic shock canreduce mortality of meningococcal disease. Pre-admissionantibiotic treatment is not compulsory in patients withsuspected invasive meningococcal disease in the CzechRepublic.DESIGN: Investigation of pre-admission parenteral and non-parenteral antibiotic treatment was performed in 137patients (62 females, 75 males) with invasive meningococcaldisease, who were treated at 5 university hospitals in theCzech Republic from January, 1996 to June, 2001.Meningococcal meningitis was proved in 27 patients,septicaemia in 41 patients and meningitis/septicaemia in 69patients. Eleven patients died, 8 of them suffered bysepticaemia and 3 of them by meningitis/septicaemia. Thehighest morbidity and mortality were in the age groups 0–4years (52 children, 5 deaths) and 15–19 years (41 patients,5 deaths).The serogroups C and B were absolutely predominant, newemerging clone Neisseria meningitidis C:2a:P1.2,P1.5, ET-15/37 was the most frequent strain.RESULTS: Pre-admission antibiotic treatment was used in100 patients before transfer to special intensive care unit,only 6 of them (6.0%) died. Thirty-seven patients were nottreated before admission to special intensive care unit andalso 5 of them (13,5%) died. Pre-admission treatment wasused in 25 of 41 patients with septicaemia (5 treatedpatients of 8 deaths), in 58 of 69 patients withmeningitis/septicaemia (1 treated patient of 3 deaths) and in17 of 27 patients with meningitis (0 death in this group).The mortality of patients with and without pre-admissionantibiotic treatment were 1.7% and 18.2% formeningitis/septicaemia, 20.0% and 18.8% for septicaemiaand identically 0% for meningitis. Parenteral treatment (especially cefotaxim, ceftriaxon andpenicillin G) was administered in 90 patients, 5 of themreceived peroral and then parenteral antibiotics. Onlyperoral treatment (preferably b-lactam antibiotics) was used

in 10 patients. All 6 patient with pre-admission antibiotictreatment who subsequently died received parenteraltherapy.The parenteral therapy was started in local hospital beforepatients transport to special intensive care unit in universityhospital. General practitioners and physicians of out-patients departments started antibiotic therapy sporadically(in 13 patients) and preferred peroral treatment except onepatient with parenteral treatment.CONCLUSIONS: Approximately three-quarters of patientswith meningococcal disease in the Czech Republic receivedpre-admission antibiotic treatment. The mortality of patientswith pre-admission antibiotic treatment was more thantwice lower then in patients without treatment (6.0% vs.13.5%). The therapy was started usually in local hospitalbefore transfer to university hospital, however antibiotictreatment was initiated rarely by general practitioners.Grant support: Grant Agency Czech Republic N.310/96/K102.

46. Analysis of bacterial isolates from cerebrospinal fluidin a tertiary care hospitalMarta Wroblewska, Agnieszka Tkaczuk, Miroslaw LuczakCentral Clinical Hospital in Warsaw, Poland; Department ofMedical Microbiology, Medical University in Warsaw, PolandAIM OF THE STUDY: Evaluation of bacterial isolatescultured from cerebrospinal fluid (CSF) samples frompatients hospitalised in a tertiary care hospital in Warsaw(1200 beds)in the period 1998–2000.MATERIALS AND METHODS: CSF samples were culturedusing a BacT/Alert computerised system (Organon Teknika)or standard microbiological methods. Isolates wereidentified using API test strips (bioMerieux) or VITEK.Susceptibility testing was done using ATB (bioMerieux) orVITEK tests.RESULTS: In total 524 specimens of CSF were cultured: 351(67,0 %) from surgical wards and 173 (33,0 %) frominternal medicine wards. Most of the specimens were fromneurosurgery (282) and neurology(95)wards. BacT/Alertsystem was used in 347 samples (66,2 %) and conventionalmethods in 177 CSF samples (33,8 %). There were 170culture-positive samples (53,8 %) comprising 180 bacterialstrains. Among them predominated coagulase-negativestaphylococci (CNS)- 71 strains (39,4 %), non-fermentingrods - 52 (28,9 %), Enterococcus spp. - 14 (7,8 %), Gram-negative bacilli of the Enterobacteriaceae family - 13 (7,2 %)and S. aureus - 11 strains (6,1 %). Resistance of CNS strainsto methicillin was 61,1 %. Only 11,4 % of strains of non-fermenting rods was susceptible to ceftriaxone. Ten strainsof Enterococcus spp. were HLAR strains. AmongEnterobacteriaceae isolates dominated K. pneumoniae - all 6strains were ESBL-positive.CONCLUSIONS: 1. Non-fermenting rods and enterococcicomprise a significant percentage of bacterial isolates in CSFof patients hospitalised in the CCH in Warsaw. 2. There is ahigh percentage of bacterial strains resistant to ceftriaxone.3. Automated BacT/Alert system contributes to fasterdetection of bacterial growth in CSF samples.

Bioterrorism

47. A scenario of bioterrorism in the BalkansG. Pappas, N*. Akritidis*Department of Internal Medicine, University Hospital ofIoannina, Greece*Department of Internal Medicine, General Hospital “G.

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Hatzikosta” of Ioannina, GreeceOBJECTIVE: To determine the evolution and the impact of apossible bioterrorism attack in an area of NorthwesternGreeceMETHODS: A purely fictional scenario, based on currentmedical, geographical, historical, and social perspectives.HYPOTHESIS: An attack of an outlaw Albanian organizationin the area of Epirus, in Northwestern Greece, using variousbiological weapons.DISCUSSION: We describe the variable evolution of theepidemic caused by a variety of agents, such as anthrax,smallpox, plague, botulinum toxin, brucella, or chemicalweapons. Depending on the agent, the time between thestart of the attack and the recognition of the attack as such,the means of intervention, the mortality and morbidity rate,and further medical and political implications, vary widely(Sarin anybody?). The most important parameter of thescenario is that, although highly impossible, it would resultin significant morbidity and mortality, due to the, still, lowawareness of bioterrorism as a form of modern weapon.

Clinical significance of antibiotic resistance

48. Managing paediatric malaria in Lagos, Nigeria in theface of increasing drug resistanceThomas, Bolaji N*,1, Fagbenro-Beyioku, Adetayo F2,Isokpehi, Raphael1. Medical Microbiology and Parasitology, University ofLagos, Idiaraba, Lagos, PMB 12003, Nigeria2. Department of Medical Microbiology and Parasitology,University of Lagos, Idiaraba, Lagos, PMB 12003, NigeriaChloroquine has been and still remains the drug of choicefor the treatment of acute malaria. With the mergence andspread of resistance to this drug and other availableantimalarials, managing patients especially childrenpresenting with acute malaria becomes a very seriousproblem. Though varying degrees of resistance has beenreported from different parts of the country, this drugremains quite reliable. This study was designed to examinethe present effectiveness of chloroquine for managingpaediatric malaria infection in Lagos, Nigeria. Four hundredand fifty children (age range 1–60 months) and whopresented to the hospital with clinical symptoms of acutemalaria were selected. However, only 222 with purePlasmodium falciparum infection were recruited into thestudy. They we re all treated with the standard 3-daychloroquine regimen, while resistance was assessed with the“7-day test”. Chloroquine was found to be very sensitive inmanaging the infection [sensitivity was 81.8% (44.6% inmales and 36.5% in females)] with cases of resistanceoccurring in 18.9% (13.5% in males and 5.4% in females).There was gradation in resistance with figures increasing asage increases. Highest prevalence of resistance was seen inthe age group 49–60 months with the lowest in age group1–12 months. Majority of the resistance to chloroquine wasat the R I level (14.8%) while the rest 4.1% of respondentshad R II resistance. Patients with resistance were promptlytreated with pyrimethamine-sulfadoxine and healthrestored. Although no R III resistance was seen, this clearlyshows the increasing prevalence of chloroquine resistanceamong children in Lagos and the imperative for alternativesduring management.

49. Susceptibility of Clinical Isolated Strains ofHelicobacter pylori to Antibiotics in IranKhaki. P., Vandyousefi. J., Eliasi. H., Bidhendi. S.M.

Helicobacter pylori is an important etiological agent of activechronic gastritis, peptic ulcers and gastric cancer in humans.This bacterium is sensitive to a wide range of antibiotics invitro.We isolated 100 strains of H. pylori from gastric antralmucosa of patients with upper gastrointestinal complaint.The aim of the study was to compare susceptibility of thedifferent strains of H. pylori to antibiotics including:tetracycline, amoxicillin, erythromycin, chloramphenicol,ampicillin, gentamicin, penicillin, kanamycin, nitrofuration,nalidixic acid, cotrimoxazole, streptomycin and cephalothin.We assayed with disc diffusion (Kirby-Baure) method. Mostof the clinical isolates were sensitive to tetracycline,amoxicillin, erythromycin, chloramphenicol, ampicillin andcephalothin, also were resistant against penicillin, nalidixicacid and cotrimoxazole. 4 of 100 (4%) clinical isolatedstrains against erythromycin and 2 (2%) of them againstamoxicillin were resistant. Also 2 (2%) of them weresensitive to nalidixic acid. The result suggested that there isno difference between clinical isolated strains from Asia andEurope.

50. Ethical issues relating to the use of antimicrobialtherapy in older adultsEsther-Lee Marcus (1), A. Mark Clarfield (1,3) Allon E.Moses (2) 1) Geriatric Division, Sarah Herzog Hospital,Jerusalem, Israel 2)Department of Clinical Microbiology andInfectious Diseases, Hadassah University Medical Center,Jerusalem, Israel 3) Division of Geriatric Medicine, SirMortimer B. Davis-Jewish General Hospital, McGillUniversity, Montreal, CanadaBACKGROUND: In many cases decisions over the use ofantimicrobials involve not only “medical” issues such as thenature and severity of the infectious disease and the resultsof the appropriate cultures but also ethical considerations.Most of the literature regarding ethics of end-of-life care andthe approach to the severely demented refers to resuscitationor use of high technology medicine. The ethical issuesconcerning antibiotic administration are much lessdiscussed.AIMS OF STUDY: We aim to critically review the literaturerelating to the ethics of antibiotic prescribing decisions inolder adults. We shall in particular examine the current useof antibiotics in the frail and terminally-ill elderly and thosestudies exploring the opinions of patients, families andprofessionals regarding such therapy. In addition we raisesome pertinent issues and offer some guidelines for decisionmaking.METHODS: A computer search of the following data-basis:MedLine, BioEthicsLine and AgeLine for the terms “ethics,”“antibiotics” was performed.RESULTS AND DISCUSSION: According to many studies,most patients and their family members wish to receiveantibiotics even when terminally ill or when suffering fromadvanced dementia. Health care professionals are alsofrequently reluctant to deny the use of such medications inthose situations. We suggest that the decisions as towithholding antibiotics should be based upon considerationof the ethical principles of autonomy, beneficence, non-maleficence and justice. A major consideration in decidingwhether to withdraw or withhold antimicrobials is whethersuch care is considered “futile.” “Medical futility” refers toan intervention that is unlikely to produce any significantbenefit for the patient. Public health issues are also a majorconcern. In an era of increased antibiotic resistance, oneethical conflict rests between the individual patient’s right to

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receive the “best” antibiotic and the need to decrease futureresistant pathogens for the common good. The emergence ofantibiotic resistance necessitates administration of expensivesecond the third generation antimicrobial agents. In the caseof terminal illness when the benefit of antibiotics is lesscertain, the balance between the potential advantage to theindividual tilts more towards the interest of collective. Wesuggest that in the relevant clinical situation and wheredanger of rare complications (such as aplastic anemia) isless relevant consideration may be given to the use of“obsolete” antibiotics such as for example chloramphenicol.This particular drug has excellent bioavailability and coversmany gram positive, gram negative bacteria as well asanaerobes. In addition it is a remarkably inexpensive drug.The infectious diseases consultant should involvehim/herself in those ethical deliberations, despite the factthat they have traditionally been considered to be in thedomain of the attending physician only. We feel thatalthough occasionally patients and families and physiciansmay choose to administer antibiotics even in terminally illpatients, logic suggests that the ethical approach toantibiotic administration should be similar to that of otherlife-sustaining treatments such as mechanical ventilation.

51. Clinical significance of multi-drug resistant Pseudomonasaeruginosa bloodstream infectionsE.Tacconelli1, M. Tumbarello1, *R. Citton1, S. Bertagnolio1,A. Cataldo1, K. de Gaetano Donati1, T. Spanu2, R. Cauda1

Dept. of 1Infectious Diseases and 2Microbiology, CatholicUniversity, Rome, ItalyBACKGROUND: Recent surveys have shown the emergenceof imipenem-resistant and ciprofloxacin-resistantPseudomonas aeruginosa bloodstream infections increasingup to 24% and 37%, respectively.OBJECTIVES: We investigated the prevalence and theclinical findings of multidrug-resistant (MDR) P. aeruginosabloodstream infections in a large Italian university hospitalover a 10-year period. We also examined how these antibioticpattern relate to antimicrobial use in the single hospital ward.MATERIAL AND METHODS: All consecutive patients withthe first episode of community or nosocomially acquiredPseudomonas spp. bacteraemia were included in the analysis.The term MDR P. aeruginosa bloodstream infection definedthe presence of resistance to ciprofloxacin, ceftazidime,imipenem, gentamicin and piperacillin. We calculated thedefined daily dose (DDD) for ciprofloxacin, ceftazidime,imipenem, gentamicin and piperacillin in the single wardper year, analyzing the hospital pharmacy data. For eachward, mean rates for the study were calculated by dividingthe total number of DDDs by the total number of patient-days reported over the study period and they were expressedas DDDs per 1,000 patient-days. Two tailed tests ofsignificance at the p < 0.05 level were used for determinestatistical significance.RESULTS: In the study period, among 379,190 hospitalizedpatients, P. aeruginosa was isolated in 358 patients. Theannual incidence of P. aeruginosa bloodstream infection wasstable (0.9 per 1,000 hospital admissions/year). Markedchanges in resistance to ceftazidime (p < 0.01), gentamicin(p = 0.01), imipenem (p = 0.04), ciprofloxacin (p = 0.04),and piperacillin (p = 0.03) were observed over the studyperiod. The prevalence of MDR strain increased from 8% ofthe cases (3/37) in 1993 to 17% (9/54) in 1999 (p = 0.03).Overall, we observed 51 cases of MDR P. aeruginosabloodstream infections (51/358; 14%), being 96%nosocomially acquired. The prevalence of MDR on the total

P. aeruginosa bloodstream infections per ward was thefollowing: medical wards 3% (95% CI = 0.5%–10%); surgicalwards, 8% (95% CI = 3%–15%); hematological ward, 14%(95% CI = 4%–30%); intensive care units, 22% (95% CI =15%–31%); and infectious diseases ward (in HIV-infectedsubjects, only), 40% (95% CI = 26%–54%). The overallmortality rate was 31%. The mean DDDs for the abovementioned antibiotics were higher in ICUs, infectiousdiseases and hematological wards but, we found a significantcorrelation between previous use of antibiotics andpercentage of MDR P. aeruginosa bloodstream infections inICUs and infectious diseases ward, only.CONCLUSIONS: During the past five years there has beenan impressive increase in MDR nosocomial bloodstreaminfection caused by P. aeruginosa. The findings that 14% of P.aeruginosa bloodstream infections were multidrug resistantis worrisome and reflects the worldwide growing problem ofantimicrobial resistance. In particular, the notice ofemerging problem in HIV-infected subjects in addition toindividuals with cystic fibrosis can alert to the need ofcontinued worldwide surveillance on P. aeruginosa inimmunocompromised subjects.

52. Antimicrobial resistance profiles and transferable R-factor in Salmonella abortusovis strains of IranHassan Tadjbakhsh and *Gholamreza NikbakhtResistance to antibiotics and especially multidrug resistanceis a problem that confronts all of us, concerning treatment ofhuman and animals. The increasing resistance of Salmonellaspecies to antimicrobial agents has been noted throught theworld. Particular interest has focused on Salmonella strainsthat are resistant to these drugs and capable of transfer toother strains and pathogens. A distinct strain of Salmonellaenterica serotype Abortusovis, known as host restrictedserovar has been a major cause of abortion in sheep flocks inthe Middle east and some parts of the Europe. We intendedto compare current antibiotic resistance of S. abortusovisisolated from sheep in Iran and study the prone to R-factortransferability. Moreover the determination of antimicrobialresistance patterns has commonly been used to evaluate andtrace epidemic strains. This kind of survey will help us forepidemiological investigations. All together 37 SalmonellaAbortusovis strains, isolated from sheep aborted fetuses werestudied in this experiment. All srains were resistant toampicillin (Am) and amoxicillin (Amx). Except these two,streptomycin was the most common resistance. Resistanceto amicacin (AN) and tetracyclin (Te) was very low (about2%). All strains were susceptible to chloramphenicol (C),nalidixic acid (Na), kanamicin (K) and enrofloxacin (En).The most prominent multiresistance pattern was belongedto Be - Amx (100%) and Am - Amx – S (9%) respictively.Just in one case the profile of am - Amax - SXT - AN – Tewas developed. Among the total isolates, 3 cases (8%) wereable to transfer some part of their resistance factors to E. coliK12. In all three cases only resistance to ampicillin weretransmitted.Generally antibiotic resistance in S. abortusovis is not thathigh and rarely were transmited to other bacteria. Butpresence of resistant to five drug in this serotype is animportant marker for future awkward resistance.

Community-acquired pediatric infections

53. Efficacy of co-trimoxal+ rifampine in treatment ofchildhood brucellosisHassanjani Roushan M.R; Zahedpasha Y

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Department of infectious Diseases, Yahyanejad Hospital,Babol, Iran.OBJECTIVE: Brucellosis is a common infectious disease inIran. Since different therapeutic methods for childhoodbrucellosis are suggested, this study was performed toevaluate the efficacy of co-trimoxasol and rifampine in thetreatment of children with brucellosis.METHODS: This study was conducted on 96 cases ofchildhood brucellosis in Babol during 1997 to 2000.All patients recieved co-trimoxasol+rifampine for six weeksand then followed for 12 months.RESULTS: From a total of 96 cases, 53 (55%)were male and43 (45%) were female. Mean age was 10.3 ± 3.4 years.Themean interval between presentation of disease and the finaldiagnosis was 27 ± 17days. 82 cases completed thetreatment and followed up for 12 months, and 2 cases(2.4%) had relapses.CONCLUSION: Combination thrapy with co-trimoxasoland rifampine for six weeks is a good regimen with a lowrelapse rate,however further controlled trials must confirmthese results.

54. Brain abscess in childhood: our experienceMantero E.*, Majabo M.J.,Ceccarelli R.,Cama A.°,andRavegnani MClinica Malattie Infettive Università di Genova. °DivisioneNeurochirurgia Ist.G.Gaslini, GenovaBrain abscess is an important infection in childhood due topeculiar pediatric predisposing factors as congenitalcyanotic heart disease (CCHD), meningitis, otitis and tointerdisciplinary aspects of the management. For thesereasons we reviewed our experience by a retrospective studyto evaluate etiology, diagnosis, treatment and outcome. Thisstudy include 26 patients with brain abscess (16 males and10 females) hospitalized between January 1978 andDecember 2000. Their ages ranged from 1 month to 16years (average age 5 years and 10 months). The mostimportant predisposing factors were CCHD (7 cases, 27%,average age 6 years) otomastoiditis (27%, 7 cases, averageage 6 years), meningitis (5 cases, 19%, average age 9months), sinusitis and CNS malformations ( 3 cases, 11%,average age 12 and 5 years respectively). Twenty abscesseswere single and 6 multiple. The most common anatomicalsites were: frontal lobe: 6 cases (22 %), temporal lobe: 5cases (18.5 %), parietal lobe and cerebellum: 2 cases (7.5%). The presenting symptoms such as fever (50%), headache(46%), nausea and vomiting (42%) and neurological signs(23%) were important but not always enough for thediagnosis. The imaging techniques (TC and RM), resultedvery important for diagnosis and monitoring of lesions.Weperformed bacterial cultures in 24 patients (92%), and 17(65 %) resulted positive: the prevalent strains isolated wereGram- positive cocci in otogenic abscesses and anaerobicbacteria in patients with CCHD. No bacterial resistance wasfound in most cases; only 2 strains of coagulase negativestaphylococci were oxacillin resistant. In most cases thetherapy included either antibiotic either neurosurgicaltreatment. Third-generation cephalosporin as ceftriaxone,and chloramphenicol (15 cases, 57.7%) were the mostcommon antibiotics used; recently glycopeptides (7 cases,27 %) and rifampin (5 cases 19.2%) were added. Antibiotictherapy was continued for 6.5 weeks on average. Excision ofthe abscess was the most common neurosurgicalmanagement in the first 10 years of the study whilestereotactic aspiration was performed in most cases of thelast 10 years. Two cases (7.7 %) (one patient inoperable due

to a severe CCHD and another patient affected by a smallabscess without neurological signs) received onlyantibiotics. The mortality was 7.7%; the patients who diedhad been hospitalized during the first decade of thestudy.Fourteen patients (53.8%) were cured, 11 (42.3%)showed radiological sequaele, in 7 of these (27%), treated byexcision of the abscess remained low density or ischemicareas and in 4 cases (15.3%) multicavitary hydrocephalus.These latest showed previous intraventricular rupture ofbrain abscess (IVROBA). Nine patients (34.6%) showedclinical sequaele: psycomotor retardation, strabismus,hemiparesis, VI cranial nerve palsy. Four patients (15.3%)with sequaele were treated with brain abscess excision. Westatistically determined the factors influencing outcomeusing parametric and no parametric tests. We sawstatistically significant the younger age (P=0.0043),thatresulted a predisposing factor for multicavitaryhydrocephalus (P=0.00143),the first period of study(P=0.0063), in which the patients were treated by abscessexcision, IVROBA (P=0.001), and multiple abscesses(P=0.001).Our experience suggest some considerations: a)The average age of patients is low and below school period;it is very low in patients with meningitis (< 1 year). b)There is a correlation between the abscess site and thepredisposing factors: multiple abscesses occur in patientswith meningitis or CCHD; frontal lobe abscesses occur inpatients with sinusitis or CCHD; temporal lobe abscessesappear in patients with otomastoiditis or CCHD; parietallobe abscesses in patients with CCHD or with Rendu-Oslerdisease, cerebellar abscesses in patients with otomastoiditisor disembriogenetic cysts. The abscess site is easy supposedin patients with contiguous foci of infection; thus in patientswith hematogenous spread from a distant focus,brainabscess can occur in every part of the brain.c) Imagingtechniques resulted the diagnostic procedure of choice toconfirm the clinical suspicion and to monitor the efficacy ofthe treatment. d) The main factors influencing pooroutcome resulted lower age, multiple abscesses, IVROBAand excision of abscess. e) Our experience suggests theseadvices for treatment: 1) Therapy with antibiotics only isuseful in patients with small brain abscesses and goodneurological conditions and in inoperable patients due to asevere clinical status. This choice needs to be verified by CTor RM monitoring every 15 days. 2) Neurosurgical andantibiotic treatment together is the standard treatment.Stereotactic aspiration, less traumatic and more effective inorder to prevent the IVROBA is now preferred to excisionaccording to our statistical results. 3) The microbiologicalpattern in our experience was similar to this reported inliterature.The bacterial strains were predictables on the basisof the abscess site. The bacterial resistance was rarelyobserved. Considering these data we can suggest thisschedule of rational antibiotic therapy waiting coltural data:- In case of contiguous infectious focus is useful a thirdgeneration cephalosporin (ceftriaxone)in added of aneffective drug on anaerobic bacteria(chloramphenicol ormetronidazole). - In patients with CCHD is useful apenicillin( penicillin G or ampicillin) with chloramphenicolor metronidazole. -In selected cases (surgical infections,penetrating traumas, immunocompromised patients, orunknown predisposing factors, we can start a treatment witha third generation cephalosporin, chloramphenicol ormetronidazole and a glycopeptide. - The therapy shouldcontinue for at least 4–6 weeks, adjusted on the basis ofclinical, microbiological and neuroradiological data.

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55. Streptomycin and isoniazid resistant tuberculosisMelica G., Mantero E., Ferrando S., Moroni C., CiravegnaB., and Bassetti D.Clinica Malattie Infettive Università di GenovaTuberculosis resistance has been an increasing problem sincethe late 1980s, when incident tuberculosis cases began toincrease and reached a peak in 1992. Multidrug resistanttuberculosis (MDR-TB) is defined as resistance to at leastisoniazid and rifampin: actually widespread drug resistanceis considered as result of deficiencies in infection control asreported in several surveys. Until now in our pediatricexperience we never found these strains; however we canreport a case resulting from infection with an organismprimary resistant to streptomycin acquired from her motherand which becameprobably resistant to isoniazid in a secondtime.The patient, a 2-year-old girl, was admitted to ourdepartment with a 9 months history of isoniazid prophylaxisbecause pulmonary TB had been diagnosed and treated toher mother on July 2000. One month before the admissionparents referred an oval, elastic and mobile swelling on herneck right side, in absence of symptoms and physical signsof intrathoracic involvement. The Mantoux skin test waspositive with a 15 mm infiltration; there was nodemonstration of acid fast bacilli in stained smear ofsputum. A first chest and neck soft tissues computedtomography (CT) revealed a “right sovraclavear adenopathywith disomogeneous structure continuing in a mediastinalfocus attached to tracheal right side, being considered asright sided subcarinal lymphadenopathy”. Before treatingthe patient we considered the factors possibly involved intuberculosis resistance: in our case we dealt with theisolation of a strain resistant to streptomycin from mother’scolture (high probability of transmission of an alreadyresistant strain) and the rising of adenopathy after 9 monthsof isoniazid treatment. Excluding Isoniazid andStreptomycin, we decided to treat the patient with rifampin,ethambutol and amikacin given parenterally; pyrazinamideand ethionamide were given orally. After receiving such afive-drugs regimen for two weeks, the right-sidedsovraclavear initial focus enlarged and developed a caseouscentre, as revealed by a second CT. To prevent sloughinginto adjacent trachea and skin fistulization we decided todrain and remove the lesion’s colliquated centre;demonstration of acid fast bacilli and colture were negative,polymerase chain reaction was borderline and pathologicalexamination revealed granulomatous necrotizinglymphadenopathy. At 4 and 6 weeks of parenteral therapy(lacking the child of other sign or symptoms of disease) thefocus enlarged again and draining was performed, withoutCT scanning control; in both cases acid fast bacilli, cultureand PCR were negative; the hystologic aspect was asdescribed before. Two months after the admission weperformed a third CT showing a significant reduction of theextrathoracic sovraclavear adenopathy with slightmodification of the mediastinal involvement. At this time,fundus oculi and audiometric test being normal, wesuspended therapy with amikacin and delivered the girl (11Kg.) with oral therapy: rifampin (200 mg daily po),ethambutol (200 mg daily po), pyrazinamide (250 mg dailypo) and ethionamide (125 mg daily po). As reported in ourexperience, treatment of tuberculosis resistant to any singlefirst line drug is accomplished by using other first lineagents and second line drugs. A good result in term ofdisease management can be achieved, as described. In ourexperience, we can suggest some considerations:

1. clinical outcome can require prolonged time forimprovement; we point out the need for prolongedparenteral chemotherapy,based on clinical,laboratoryand imaging follow–up.

2. standardization of TB antimicrobial prophylaxis, withcareful monitoring of the patient treated avoidingstrategy’s mistakes, is mandatory.

3. conservative therapy without aggressive surgery maybe sufficient in absence of direct tracheobronchialinvolvement or mediastinal shift.

56. Pott’s disease in childhood: case reportC. Moroni*, E. Mantero, B. Ciravegna, G. Melica, D. BassettiClinic of Infectious Diseases, University of Genoa, G.Gaslini Children HospitalOne quarter to one-half of cases of skeletal tuberculosisoccur in the spine, as a result of remote hematogenous foci,contiguos disease, or lymphatic spread from pleural disease.The earliest focus is in the anterior superior or inferior angleof the vertebral body. This usually spreads to theintervertebral disk and adjacent vertebra, producing theclassic roentgenographic picture of anterior wedging of twoinvolved vertebral bodies and destruction of theintervertebral disk. The lower thoracic spine is involvedmost frequently, the lumbar next and the cervical and sacralleast.In the countries where tuberculosis is prevalent, Pott’sdisease usually occurs in older children and young adults. Indeveloped countries tuberculous spondylitis has become adisease of older persons. We report a case of Pott’s diseaseoccurred in a twenty-two-month-old Italian child. G.G.,born February 2, 1998, was admitted to the Clinic ofInfectious Diseases-University of Genoa the January 1, 1999;her anamnestic history revealed good general conditionsuntil the age of eleven months (January 1999), when shewas admitted to the regional hospital because of high fever.She was discharged after a few days with the diagnosis oftonsillitis. In the same period, a diagnosis of pulmonarytuberculosis and pleuritis was made to her uncle. In June ’99the patient began to limp; the symptom disappeared withoutmedical or pharmacological procedures. In October aswelling in the right mamillary area appeared. A CT scanwas performed with the evidence of a structural damage ofthe spongiosa of the last thoracic metamere; the picture wascharacteristic for an abscess. A biopsy was done with thehistological finding of a tubercular infection and anantimicrobial therapy with Rifampin was started. Isoniazidwas added after a short time because she was again lame. InDecember ’99 the child was admitted at the 1st OrthopedicDepartment of G. Gaslini Children Hospital where differentradiological procedures were performed:Magnetic resonance of the lumbar and sacral spine:presence of damage in D XI and D XII with collapse of D XI;the intervertebral space is modified; wide anterior andlateral paraspinal abscess involving D X, D XI, D XII withcentral colliquation; wide destruction of the body of L III.Left knee roentgenography: lysis of the medial part of thefemoral condylus.According to the clinical history and the radiologicalfindings an antitubercolar treatment was started usingrifampin, isoniazid, ethambutol and pyrazinamide orally.After one month the therapy was given intravenously fortwo months because of worsening of the radiological picturewhich demonstrated initial lesions of the intervertebral diskof L III and the body of D IX and D X; furthermore theparaspinal abscess had lengthened to DVIII-DVII. To reduce

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movements the spine was immobilized with a plaster. Afterone month of therapy, streptomycin was added for a totalcourse of 90 days. The femoral localization needed a surgicaltreatment; the histological examination revealed anecrotizing granuloma. After a six-month therapy there wasan improvement of the vertebral lesions and after 16 monthsa complete resolution of the damage in D XII and LIII wasseen. No differences in the leg’s length were seen.The child is still undergoing an antibiotic treatment withisoniazid and rifampin.Conclusions: Our case is occurred in a little child and this isnot so usual in developed countries where the disease isseen in older age. We will underline the delay of thediagnosis and the poor consideration of the epidemiologicaldata concerning the possible familiar source. In this case atubercular prophylaxis should have been done.Medical therapy is successful in most cases; we emphasizethe use of a multiple antibiotic therapy (four or five drugs)given also intravenously for a better penetration in the bonetissue. Streptomycin should be added when caseation ispresent in large amount, for its extracellular activity.Orthopedic surgery is limited only in specific cases:laminectomy should be undertaken if there is ademonstration of anatomic cord compression withneurological signs or of a severe anatomic instability of thespine.

57. Prevention of tuberculosis in children: a collaborativeprotocol at The University of Turin (Italy)Tardivo I. °, Benech P. °, Contino G. °, Bagnasco G.2,Gomirato G.^, Fabris C. ^, Valera M.^, Scolfaro C.^,Gallone A. #, Miniero R. °*° Divisione di Pediatria.Ospedale S. Luigi di Orbassano - Università di Torino; 2

Divisione di Pneumotisiologia. Ospedale S. LuigidiOrbassano; # ASL 5 - Regione Piemonte; ^ Ospedale OIRM-S.Anna -Università di TorinoThe prevalence of tubercolosis (TB) in Italy is relatively low(10/100,000 prs). The identification of “contacts” of patientswith infectious TB is one of the most important preventionmeasures. In fact the risk of TB infection for the contacts isabout 8%. The goal is to prevent further transmission of thedisease during the 2 years following the infection. Childrenand adolescents have a high-risk to be infected and todevelop TB: for the contacts the intradermal injection ofPPD (Mantoux test), the chest x-ray (CXR ) and thechemoprophylaxis with Isoniazid are recommended. TheItalian national guidelines are the following:

• Mantoux (M)+ CXR+ : disease = treatment• M+ CXR- = chemoprophylaxis with isoniazid for 6

months• M- CXR- = chemoprophylaxis with isoniazid for 2

months; then reevaluation of Mantoux. M- = stop; M+CXR- = isoniazid for further 4 months; M+ CXR+ =laboratory assessment and treatment.

From January 1999 to April 2001 we observed 23 children(8 females, 15 males) aged 1 day - 15 years (mean: 5 years, 4months) TB contacts: 14 children were M- CXR- at bothcontrols and they were treated with isoniazid for 2 months;5 children with M+ CXR- at the first visit = isoniazid for 6months; a 14-year-old-boy with M+ CXR- at the secondcontrol = received isoniazid for 6 months; a newborn ofmother with miliary TB before pregnancy treated withpolichemotherapy was negative for congenital TB (M- andBAAR test -) = no therapy and at the moment is in follow-up; ¨ a newborn of mother with diagnosis of TB at deliverytime, had M- and CXR- = chemoprophylaxis with isoniazid

for 2 months; after this period M was negative andchemoprophylaxis was interrupted; a newborn exposed toinfectious pulmonary TB of the mother (with poorcompliance of therapy), with M- and CXR- = isoniazid for 6months (negative to follow-up). No patient had adverseseffects during therapy. Mean follow-up is 6 months; nonehad acquired TB and, at the moment, all patients are well.Conclusions: in our study we observed 26% of contacts tobe infected from Mycobacterium tubercolosis (M+). This rateconfirm that the precocious control of contacts of TB isreally necessary to identify subjects with infection and toprevent further cases of disease.

Epidemiology of bacterial resistance

58. Endemic horizonal spread of ceftazidime resistance bya plasmid among nosocomial Klebsiella pneumoniaeC. Daza(1), R. Morfin(2), D. Alcantar(1), S. Esparza(2), A.Carlo(1), G. Juarez(1), C. Gayosso(1), R. Leaños(2), J.Heredia(2), G. Atilano(2), E. Llanos(2), E. Rodriguez-Noriega(2), JI. Santos(1), C. Alpuche-Aranda(1). (1)MedSchool UNAM, Mexico, DF, (2) Hosp. Civil de Guadalajara,Mexico.A molecular epidemiological study was conducted to definethe frequency and characteristics of Extended Spectrum b-lactamases (ESBL) producing Klebsiella pneumoniae (Kp)causing nosocomial infections (NI) at a tertiary careteaching hospital in Mexico.METHODS: Kp strains isolated from NI in Guadalajara,Jalisco, from Feb1999–Nov 2000 were analyzed.Antimicrobial susceptibility patterns to ceftazidime (CAZ)and cefotaxime (CTX) and some other antibiotics weredetermined by disk diffusion method. E-test and isoelectricpoint (pI) focusing were used to characterize ESBL.Genotyping of the strains was defined by restrictionendonuclease analysis and pulsed field gel electrophoresis.Plasmid profiles were determined and ESBL production bytrans-conjugation was demonstrated. PCR analysis was usedto define TEM or SHV b-lactamases.RESULTS: During the study 67 Kp strains were identified.Two outbreaks occurred at neonatal intensive care units(NICUs) in year 2000: in August at NICU-1 and inSeptember at NICU-2 (UCINEX). 51% of the Kp were frombloodstream infections and NICUs had 80% of isolation. Allthe strains were resistant to ampicillin, 79% to amikacin,75% to CAZ (Kp-CAZr), and 55% to CTX. The Kp-CAZrwere 53 and corresponded to 13 different clones. Thepredominant clones were A, F and Q. Clone F and Q causedthe outbreak at NICU-1 and at UCINEX respectively. 1–5plasmids per clone were present and all of them shared a 53-Kb plasmid capable of transferring the multiresistantphenotype including ESBL production. All the Kp-CAZrclones and transconjugants produced a b-lactamase with pI8.2 alone or combined with others (pI 5.4 or 7.6 but the Cazhidrolysis is mediated by the pI 8.2 b-lactamase that it ispart of SHV family.CONCLUSION: The frequency of CAZr was 75% in the Kpcausing NI in this hospital. A multiresistant phenotype is co-transferred with ESBL production in a 53-Kb plasmid thatcould explain the dissemination among the different clones.In the two outbreaks, clonal dissemination was evident.

59. Patient satisfaction at the 18th month of a two-dayquadruple Helicobacter pylori eradication therapy1)Serpil Aydyn, 2)Tankut Koseoglu, 3)Guler YayliUniversity of S. Demirel, Faculty of Medicine,Department of

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1)Family Medicine, 3) Clinical Micrpbiology and InfectiousDiseases,Isparta, Turkey 2) Ankara Numune Hospital, Clinicof Gastroenterology, Ankara, TurkeyAs Helicobacter pylori infection was defined to be the mostseen in the world, many researches were held to find aneffective therapy regimen. Long-term regimens are giving uptheir situations to the short-term regimens as they causemore side effects and coherent patients can’t be find easily.Our aim was to determine the efficacy of a short-termtherapy regimen and patient satisfaction by holding atelephone survey at the 18th month. The patients withupper gastrointestinal system complaints who had appliedto gastroenterology day clinic in Ankara Numune Hospitalwere chosen for this study. They were evaluated by theirhistorical, physical, laboratory, endoscopic andhistopathological findings. Patients who were foundHelicobacter pylori in their stomach, but no other symptomsor disorders were given a two-day amoxicillin, ornidazoleand tribismuthsubcitrate therapy after a five-daylansoprazole therapy. The valuation was repeated one monthafter the regimen. A telephone survey was held 18 monthsafter this therapy to the patients who were completelyeradicated, and they were asked if they had any complaintduring this 18-month interval. We applied the eradicationtherapy to 36 people. Complete eradication was obtained in31 of them. We couldn’t reach 5 people because of addressand telephone changing.fifteen people had told that theyhadn’t got any drug and 12 people had no complaint duringthis period. Six patients had got H2 receptor blockerirregularly and, 5 patients had our regimen once again bythemselves. They all had told that they had satisfied withour therapy regimen. Our regimen can be considered as aneffective eradication therapy.

60. Bacteraemia in Tripoli Central Hospital: a preliminaryreportBen Darif W., Ghenghesh KS., El-Trouuq SM., Abodia FI.,Barka SF. and Aribi NH.Tripoli Central Hospital and Faculty of Medicine, Al-FatehUniversity, Tripoli-Libya.Bacteraemia is a major cause of morbidity and mortality inthe hospital setting. Data regarding the causative agents ofbacteraemia in Libyan hospitals is rare if not lacking.Included in the present study 95 patients aged 3-80 years(mean=36.1 years), with body temperature of equal to ormore than 38oC, attending the different departments ofTripoli Central Hospital. Clinical history of each patientincluding type of antibiotic given was recorded. Bloodsamples obtained from patients were processed using bloodbottles (Oxoid, UK). Isolated organisms were identifiedusing standard bacteriological procedures. Bacterial agentswere isolated from 17(17.9%) of patients. Of these, 5(29.4%) were Staphylococcus epidermidis, 2(11.8%) S. aureus,3(17.6%) Streptococcus species (1 S. pneumoniae, 1 S.pyogenes, 1 S. faecalis), 3(17.6%) Serratia marcescens, 2(11.8%) other Gram-negative bacilli, and 2 (11.8)Peptostreptococcus anaerobius. Antibiotic susceptibilitytesting of the isolated organisms resulted in most of theisolates being resistant to b-lactams and cephalosporins.Furthermore, more than 95% of the patients were givenantibiotics (mainly b-lactams and 3rd generationcephalosporins) before blood sample collection. Thepreliminary findings of this study showed that the use ofbroad-spectrum antibiotics by medical doctors in thehospital is very common and sometimes is not justified. Thehospital administration was advised to set up an infectious

disease committee to supervise the use of antibiotics in thehospital and educate the medical staff on the propercollection of blood samples that require culturing.

61. Trypanocidal potentials of metronidazole andchloroquine in trypanosoma vivax infectionThomas, Bolaji N, Fagbenro-Beyioku, Adetayo F, Mbah,Jovita ITrypanosomiasis remains a disease of global importance.Present drugs seem incapable of curtailing disease trend,made worse by the adverse effects of these drugs.Eflornithine, proven to be very effective is made useless byits unaffordablity and the fact that it is administered in ahospital setting. Considering unquantifiable risk imposed bythe disease and the absence of a cheap, effective, tolerabledrug, it is imperative that new therapeutic agents arediscovered. This study was designed to evaluate thetrypanocidal potentials of metronidazole and chloroquineboth singly and in combination and with different doseregimens against Trypanosoma vivax infection. Groups ofmice were inoculated intraperitoneally with 1000 parasitesand administered with metronidazole (0.4mg/kb b.w),chloroquine (0.36mg/kg b.w) and a combination of the twodrugs at different hours post infection (24, 48, 72 hours). Aset of mice served as control animals and was not treated.The results shows that both drugs have some level oftrypanocidal activity but metronidazole offer a betterprotection when compared to chloroquine. Moreover,multiple dose regimens of the drugs prolonged the life of theanimals more than a single dose (Mean survival days,MSDme=36.47 days compared to 30.67 and MSDcq=26.66days cp 24.66). Combination of these drugs gave the bestresults with 60% of the mice surviving beyond the 40 dayscut-off date for the experiment. The possible role ofmetronidazole and chloroquine as trypanocidal products hasbeen outlined. However, more studies are required tocritically add ress the ppropriateness or otherwise of thesedrugs as worthy of trypanocidal products.

62. MRSA outside the hospital: a new emergingbattlefrontA. Camporese*, G. Tizianel, P. CappellettiClinical Microbiology and Antibiotic Therapy Unit - ClinicalPathology Department “S.Maria degli Angeli” Hospital – ViaMontereale, 24 - 33170 Pordenone (Italy)Methicillin resistant Staphylococcus aureus (MRSA) is amajor nosocomial pathogen, with hospital-based outbreaksoccurring worldwide. Up to now one of the most seriousaspects as far as treatment of Staphylococcus aureusinfections is concerned is resistance to methicillin, which inclinical terms indicates resistance to all b-lactam antibiotics.Now, from a major problem almost exclusively encounteredin hospitalized patients, MRSA infection has become a causeof urinary tract, skin, soft tissue and even systemicinfections outside the hospital, but the true extent of MRSAin the community is not still really known. Recent reportsindicate that community-acquired MRSA infections areincreasing anyway and may now involve also personswithout risk factors predisposing for acquisition. Thechanging epidemiology of MRSA bears striking similarity tothe emergence of penicillinase-mediated resistance inStaphylococcus aureus decades ago. Even though the originof the emerging MRSA strains is not known, the prevalenceof these strains in the community seems likely to increasesubstantially. Our study was conducted between January1998 and June 2001 to estimate the evolution of MRSA inour community, according to microbiological samples

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collected in that period. The aim of this study was toestimate the incidence of MRSA not in colonized people, butin acute and chronic outpatients with community infections.During the study, a total of 423 Staphylococcus aureus strainswere isolated from outpatients: 93 in 1998, 117 in 1999, 149in 2000 and 64 in the first six months of 2001.All theisolates were obtained from various clinical specimens, aswound and deep tissue exudates (about 40%), urine samples(13%), pus (10%), and others, obtained from outpatientswith acute and chronic infections.Identification of strains was performed with routinetechnique and susceptibility testing was done using KirbyBauer disk diffusion method according to NCCLSrecommendations (Q.C.: ATCC 25923 Staphylococcusaureus).The methicillin resistance rate for Staphylococcus aureusstrains isolated from outpatients was only 9.7% during the1998, but respectively 18.1% in 1999, 20.5% in 2000 and24.8% in the first six months of 2001. On the contrary, themethicillin resistance rate for Staphylococcus aureus strainsisolated from nosocomial patients seems to be stable on asteady-state rate: in fact, that percentage was 29.7% in 1998,34.7% in 1999, 36.1% in 2000 and 36% in the first sixmonths of 2001. Most of Staphylococcus aureus isolated inour region, either MRSA or MSSA (methicillin susceptibleStaphylococcus aureus) demonstrated resistance also to otherantibiotics, like erythromycin (18.3% in 1998, 29.1% in1999, 30.2% in 2000, 33.1% in 2001), ciprofloxacin (12% in1998, 21.4% in 1999, 22.8% in 2000, 21.1% in 2001)gentamycine (18.3% in 1998, 29.1% in 1999, 34.2% in 2000,and 23% in 2001). Our data show that the rate of MRSA inour region increased during the years and that increasingseems to be extended over all to acute and chronicoutpatients with several community infections and cancause persistent, recurrent and drug-resistant infections.The growing incidence of MRSA community infections, theMRSA multidrug resistance, the several reservoirs ofresistant strains and the facility to cause outbreaks willrequires efficacious and rapid infections control measures:there is a lack of data wich should convince doctors thatchanging their prescribing and infection control habits isworthwhile today. Our data suggest, infact, that MRSArepresent today an important emerging communitypathogen, so hospital infection control strategies will haveto be redefined as antibiotics policy and communityapproaches developed to reduce trasmission and preventoutbreaks: previous hospitalizations and cross trasmissionsbetween community and non-hospital care centers seem tobe, as other studies show, the main risk factors for theacquisition of MRSA in our community.

63. The resistance of the Shigella strains to the usualantibiotics in 1977–2000I. Diaconescu, Lucia Godeanu, Constanta Ciobanu,Valentina Ionescu, Magdalena Peter, Vasilica StratulatThe Bacillary Dysentery still remains a problem todeveloping countries. The resistance to antibiotics ispermanently necessary to be known.MATERIAL AND METHODS: We studied the resistance tousual antibiotics (disk diffusion method) of the Shigellastrains which were isolated, in stool cultures, in a hospital ofinfectious disease of Romania in 1977–2000: 93 strains in1977 (Shigella flexneri 92, Shigella sonnei 1), 199 strains in1983 (Shigella flexneri 175, Shigella sonnei 24), 114 strainsin 1989 (Shigella flexneri 91, Shigella sonnei 23), 281 strainsin 1995 (Shigella flexneri 228, Shigella sonnei 53), 81 strains

in 2000 (Shigella flexneri 52, Shigella sonnei 29). OtherShigella strains were very seldom isolated. It was considerateresistant also the strains with intermediate resistance.RESULTS: The weight of Shigella sonnei in Dysenteryetiology increase from 1% in 1977 to 38.8% in 2000. Theresistance to antibiotics of the Shigella flexneri in 2000 was:ampicillin 88.4%; cloramphenicol 63.4%,TMP/SMP 78%,tetracycline 72.5%, colistin 54.9%, ac.nalidixic 23.5%,ciprofloxacin 19.6%. Comparative with 1977 the resistancehas increase significant for all antibiotics withoutnitrofurantoin (38% in 1977 and 19.6% in 2000, p≤0.02).Shigella sonnei has significant smaller resistance comparativewith Shigella flexneri for ampicillin and cloramphenicol in2000 (ampicillin 69%, cloramphenicol 17.2%; p≤0.03 andp≤0.0001). The resistance to antibiotics for Shigella sonneihas significant increase in 1977–2000, withoutnitrofurantoin. From Shigella Flexneri and Sonnei isolated in2000, 8.8% were multiresistent.CONCLUSIONS: The most common etiology of BacillaryDysentery was Shigella flexneri, but Shigella sonnei hadsignificant increase in 1977–2000. The resistance increasedfor all antibiotics (without nitrofurantoin). The leastresistance was for Shigella sonnei comparative with Shigellaflexneri for ampicillin and cloramphenicol. From Shigellaflexneri and sonnei isolated in 2000, 8.8% weremultiresistente.

64. Bacterium RightsK.S. GhengheshDept. of Medical Microbiology, Faculty of Medicne, Tripoli-Libya.In the final years of last century the emergence of new andre-emergence of old pathogens was considered a majorthreat to health of the world community. Furthermore, theproblem was made worst by the emergence of organismsthat are resistant to nearly all known antimicrobialarmaments. Within the medical community, particularlythose who deal with the treatment of infectious diseases,there is a strong belief that in the 21st century we will befaced by certain types of bacteria that can not be treatedwith antibiotics. This view is strongly supported by theemergence of vancomycin-resistant Staphylococcus aureus(VRSA) and Mycobacterium tuberculosis-resistant toantimycobacterial drugs. Among the established reasons forthe emergence of this problem is the misuse of antibiotics inclinical practice and in the community as a whole. Thiscould be simplified in other terms that we are mistreatingbacteria and in turn they are fighting back, which islegitimate, for their survival. These organisms are becomingmore resistant to antibiotics and even more virulent. Thesolutions we have are very few and most of them are verycostly. In the new millenium we need to establish a charterfor bacterium rights in line with human and animal rights.In this charter it should be stated, among other statements,that antibiotics and other antimicrobial agents should onlybe used when they are truly needed (in self defense). Thisrequires the collaborations of every individual in themedical community in establishing a well-written charterwith the hope of implementing it in the future. This mayreduce the need of antimicrobial agents in clinical practicein the 21st century.

65. Antibacterial resistance pattern of Eschericha coli inthe southeast of IranS. Mansouri and S. SharifiDuring 5 months study (1 March –30 July 2000), samples ofEscherichia coli were isolated from patients with urinarys

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tract infecions (311 UTI samples) and the stool culture ofpatients reffered to clinical laboratories regardless of thecausative agent (189 Sc samples). Sensitivity of the isolateswas evaluated against 12 antibacterial agents using standarddisk diffusion method. Comparison of the resistance patternof UTI samples with that of SC samples demostrated thatonly tetracycline resistance was higher in UTI samples(P=0.0079). The antibacterial agents were placed in 6groups based on the statistically significant differenceobserved between the sensitivity of the isolates: group 1:ceftizoxime, ceftriaxone (99.2%–99.4%); group 2:gentamycin, ciprofloxacin, nitrofurantoin (92%–97.8%);group 3: cephazoline, nalidixic acid (84.6%–85.6%); group4: chloramphenicol, cephradine, tetracycline (63.2%–71.65),group 5: trimethoprim -sulfamethoxazol (41.6%) and group6: ampicillin (23.2%). Resistance to 3 or more antibacterialagent (multdrug- resistant) were noticed in 209 (41.8%) ofthe isolates and the predominant phenotype among multi-drug-resistant isolates includes resistance to ampicillin andtrimethoprim-sulfamethoxazole in combination with eithertetracycline, cloramphenicol,cephradine or nalidixic acid.

66. In vitro activity of fosfomycin against gram-negativeurinary pathogens in an era of increasing antibioticresistanceA. Marchese, M. Dolcino, L. Gualco, E.A. Debbia, G.C.Schito, Inst. of Microbiol., Univ. Genoa,BACKGROUND: Escherichia coli and other Enterobacteriaceaehave become less susceptible to agents commonly used forurinary tract infections (UTI) in several geographic areas. Itseems therefore appropriate to reassess the potency of theavailable drugs according to local and present epidemiologicaldata.METHODS: 441 gram-negative strains causinguncomplicated UTI, isolated during September–November2000 at our Institution were studied. Minimal inhibitoryconcentrations (MICs) were determined by the agar-dilutionmethod according to NCCLS 2000 guidelines. Fosfomycinwas compared with amoxicillin/clavulanate, ciprofloxacin,norfloxacin, nitrofurantoin and co-trimoxazole.RESULTS: E. coli accounted for 87.7% of the gram-negativeuropathogens isolated followed by P. mirabilis (5.4%) and K.pneumoniae (3.4%). The remaining species represented lessthan 4 % of the strains recovered. Rates of susceptibilityamong E. coli and other microorganisms are shown in Table:

Antibiotics % of susceptible strains

Microorganism FOS AMC CIP NOR SXT NIT

E. coli (387) 99 89 88 85 76 97P. mirabilis (24) 87.5 100 96 92 67 0K. pneumoniae (15) 53 93 93 93 89 79E. cloacae (5) 60 0 40 40 20 80S. marcescens (4) 0 0 75 75 50 0M. morganii (3) 0 0 100 100 67 0C. freundii (3) 100 33 100 67 67 67

FOS: fosfomycin, AMC: amoxicillin/clavulanate, CIP:ciprofloxacin,NOR:norfloxacin, SXT: co-trimoxazole, NIT: nitrofurantoin, -: not tested

CONCLUSION: Co-trimoxazole was the least active drugand quinolones appear to suffer in our environment aselsewhere from development of resistance. Fosfomycin, thesecond most prescribed drug in Italy after quinolones foruncomplicated urinary tract infections, despite many yearsof use exhibited extremely low incidence of resistance. Manyfactors may have contributed to this situation, includingconsumption of fosfomycin only in the community, limitedexposure time, extremely high urinary concentrations andabsence of cross-resistance with other drugs. In addition,

preliminary evidence indicates that the mechanismconferring fosfomycin resistance may also interfere withimportant physiological properties of uropathogens leadingto decrease or loss of virulence.

67. Multicenter evaluation of levofloxacin activity onItalian streptococcal isolates with different levels ofsensitivity to macrolides and penicillinA. Mazzariol1, F. Luzzaro2, G. Manno3, R. Rescaldani4, M. P.Ronchetti5, S. Cresti6, D. Savoia7, S. Esposito8, A. Giammanco9,A. Mosca10, E. Muresu11, P. Nicoletti12, R. Fontana1 andG. Cornaglia1

Dipartimento di Patologia, Sezione di Microbiologia,Università degli Studi di Verona1; Servizio di Microbiologia,Ospedale Multizonale, Varese2; Lab. Ricerca e Diagnostica eInfettivologica, Università degli Studi di Genova3; Servizio diMicrobiologia, Ospedale San Gerardo, Monza4; ClinicaMalattie Infettive, Università “La Sapienza”, Roma5; ClinicaMalattie Infettive, Università di Siena6; Dipartimento diScienze Cliniche e Biologiche, Università di Torino7; Istitutodi Malattie Infettive, Seconda Università di Napoli8;Dipartimento di Igiene e Microbiologia, Università degliStudi di Palermo9; Istituto di Microbiologia, Università degliStudi di Bari10; Istituto di Igiene, Università di Sassari11;Laboratorio di Microbiologia e Virologia, AziendaOspedaliera Careggi, Firenze12; Italy.Macrolides can hardly be accepted as first-line therapy forstreptococcal infections occurring in Italy, where resistanceto those compounds is a major cause of concern. Theresistance levels observed among Streptococcus pyogenes inthis country are still among the highest ever measuredworldwide and high rates of pneumococci that are highlyresistant to macrolides have been reported, too. Low levelsof penicillin susceptibility among Italian Streptococcuspneumoniae are also reported at increasingly frequency, thusprompting the need for alternative drugs.We assayed the activities of levofloxacin and of otherreference antibiotics on 192 S. pneumoniae and 268S. pyogenes isolated from 12 different Italian centers ofvarious geographic areas. The genotypes of allerythromycin-resistant strains were investigated by PCR.All streptococcal isolates proved susceptible to levofloxacin,regardless of their sensitivities to penicillin or macrolides.The MIC50 and MIC90 values of levofloxacin forS. pneumoniae were 0.5 µg/ml and 0.75 µg/ml, respectively(range: 0.19–1 µg/ml). The MIC50 and MIC90 values oflevofloxacin for S. pyogenes were 0.38 µg/ml and 0.5 µg/ml,respectively (range: 0.19–1.5 µg/ml). The levels oflevofloxacin activity showed no correlation with thedifferent genotypes of erythromycin resistance.By converse, 32.3% of S. pneumoniae and 21.2% ofS. pyogenes, respectively, proved erythromycin-resistant; allthe erythromycin-resistant strains were also resistant toazithromycin and clarithromycin. 21.8% of all S. pneumoniaeisolates were non-susceptible to penicillin (7.8% resistantand 14% intermediate), and 6.8% of S. pneumoniae provednon-susceptible to both macrolides and penicillin.The evolving patterns of streptococcal susceptibility wouldsuggest an increasing need to consider the newer quinolonesas empirical first-choice agents for lower respiractory tractinfections, in all those instances in which a single agentwould be preferred and quinolones may offer a cleartherapeutic advantage.

68. Evaluation of susceptibility of Staphylococcus aureusisolated from Ahvaz University hospitals environment andstaffs.

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Ali Reza Samarbaf-Zadeh (Ph.D), Mhmood JamshidianDVM, MSc.Staphylococcus aureus is a significant cause of nosocomialinfection particularly in surgery, cancer, nursery andchildren wards. Emergence of resistant S. aureus is frequentduring antibiotic therapy. Since 1970s emergence of resistantS. aureus especially methicillin-resistants (MRSA) have beenreported from many countries. The main sources ofdissemination of this strain, are patients and staffs who carrythis bacterium, and the anterior nares of the carriers, is themain reservoirs of this agent. In this study we havedetermined the carrier state of Ahvaz hospitals andsusceptibility of the isolates have been determined bymodified Kirby-Bauer method against penicillin G,ampicillin, cephalothin, cloxacillin, erythromycin,lincomycin, cefoxitin, and methycillin. Thirty six percent(65%) of hospital personals were carriers of S. aureus, and9% of the specimens collected from hospitals environmentwere positive for the bacterium. Coordination coefficientbetween contamination of hospital environments andcarriers was +0.5, which shows relative coordinationbetween these two variables. Susceptibility of isolated S.aureus to penicillin G, ampicillin, cephalothin, cloxacillin,erythromycin, lincomycin, vancomycin, cefoxitin, andmethycillin were 2%, 2%, 88%, 68%, 81.5%, 75%, 97.5%,88% and 84.5%, respectively.

69. Evaluation of multiresistant bacterial isolates in auniversity hospital—a three-year experienceMarta Wroblewska, Jolanta Rudnicka, Miroslaw LuczakCentral Clinical Hospital in Warsaw, Poland; Department ofMedical Microbiolgy, Medical University of Wasaw, PolandAIM OF THE STUDY: Analysis of frequency ofmultiresistant isolates cutured from clinical specimens in auniversity-affiliated hospital (1200 beds) over a period ofthree years (1998–2000).METHODS: Samples comprised pus, sputum, tracheostomytubes, swabs (of the throat, wounds, ear, nose and eye).Cultured strains were identified using the API (bioMerieux)or VITEK tests. Susceptibility to antimicrobials wasestimated by the disk diffusion method, supplemented withVITEK or E-tests. In addition assays for methicillinresistance of staphylococci, high-level aminoglycosideresistance of enterococci (HLAR)and extended-spectrum b-lactamase (ESBL) production by gram-negative rods weredone.RESULTS: In 1999 for the first time a strain of vancomycin-resistant enterococcus (VRE) was isolated, followed by 3strains in 2000. In the analysed period 1998–2000enterococci (926 strains) highly resistant to gentamicin weredetected in 63.5%, 57.0% and 51.7%, respectively. Among1336 strains of P. aeruginosa resistance to imipenem wasobserved in 16.7%, 21.8% and 33.8%, respectively. Amongstrains of Gram-negative rods ESBL production was mostoften detected in the following species: S. marcescens(54.2%), K. pneumoniae (47.4%), C. freundii (28.0%) and K.oxytoca (23.1%). Methicillin resistance of S. aureus (MRSA)declined from 53.3% of strains in 1998 to 41,8% in 2000,while methicillin-resistant strains of coagulase-negativestaphylococci (MR-CNS)- from 65.3% to 56.5 %, respectively.CONCLUSIONS: 1. In the analysed period VRE for the firsttime emerged in our hospital. 2. Frequency of imipenem-resistant P. aeruginosa strains rises. 3. There was a significantincrease in ESBL-positive strains of S. marcescens and K.pneumoniae. 4. Percentage of MRSA and MR-CNS remainshigh.

Fungal infections

70. Long term survival in rhinocerebral mucormycosisA.Ghoubontini(1),M. Ben Salah(2), M. Ferjaoui(2) T. BenChaabene(1)(1)Department of infectious diseases la Rabta Hospital 1007Jebbari Tunis Tunisia (2)Departement of Oto rhinolaryngology Charles Nicolle Hospital Tunis TunisiaMucormycosis refers to a group rapidly progressive infectioncaused by fungi belonging to the order Mucorales.Rhinocerebral mucormycosis is the most common form anddevelops in individuals with diabetes mellitus. It wasconsidered to be uniformly fatal disease. We reported thecase of 41-year-old man with diadetes mellitus whodeveloped a rhinocerebral mucomycosis and a temporalabscess caused by Rhizopus oryaze. The treatment wasconsisted in a large excision of the infected tissuesassociated with intravenous amphotericin B and control ofthe diabetes mellitus. The patient is followed more than 18months and he is free from relapse. Combination of medicaland surgical treatment, including rapid diagnosis, the adventof systemic antifungal agents, large surgical excision, andcontrol of the underlying disease process, can permit thesuccess of the management in-patients with rhinocerebralmucormycosis.

71. Terbinafine high doses during pregnancy: tolerabilityand safety (case report)GF. Schiraldi*, 1B. Rho, E. DeJuli, 1V. Filippazzi, 1A. Vaghi, S.LoCicero, Pneumology Division, Niguarda Hospital and1Garbagnate Hospital, Milan, Italy.Ten cases of pregnancy, during a terbinafine treatment (250mg/os) with no adverse effects, appear in current literature.A first case is reported of a high dose terbinafineadministration (1 g/day) for the overall course of pregnancy.Case: White woman, 29 years, previous pulmonarytuberculosis, hospitalized with hemophthisis, vomica,pyrexia. Thorax CAT, bronchoscopy, culture tests, and anti-aspergillus precipitins suggest a chronic necrotizingaspergillosis. After failed therapeutic attempts withitraconazole and amphotericin-B, discontinued because oftoxicity and clinical inefficacy, terbinafine is given (1g/day/os). The patient became pregnant during treatment,refuses abortion. Results: Subsidence of clinical and x-raypicture; satisfactorily tolerated treatment, absence of clinicaladverse events or blood chemistry alterations; full-termnatural delivery, newborn with no malformation.Conclusions: the clinical course of this case proposesTerbinafine as a first-choice, safe and effective drug in thetreatment of pulmonary aspergillosis in the course ofpregnancy.

72. Allergic bronchopulmonary aspergillosis (ABPA) as aninfectious disease: treatment with terbinafineGF. Schiraldi, P. Bulgheroni2, S. LoCicero2, E. DeJuli2, G.Ziglio2, P. Capone and L. Casali.Pavia High Pneumology School 2Pneumology Division,Niguarda Hospital, Milan, Italy.We considered and treated ABPA in terms of a diseasecharacterized by a primary infectious causative factor on thebasis of the following considerations: 1) ABPA onset is to beascribed to an initial colonization of the bronchial tree byAspergillus spp (A); a complex immunitary movementoccurs subsequently, producing a complete expression of theinfection 2) the presence of Aspergillus spp in all biologicalmaterials in a frequency rate from 58 to 95 % 3) an additionof steroids to an Aspergillus culture definitely promotes a

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colonies growth 4) Aspergillus spp produces elastase,alkaline protease and various compounds inhibiting theopsonization and the chemotaxis that favor and undue thepermanence and cause injuries to the surrounding tissues 5)ABPA, despite an adequate corticosteroid treatment, evolves,in a quite relevant percentage of cases, to a steroid-dependent chronic asthma, pulmonary fibrosis andrespiratory insufficiency requiring O2 long term therapy.DIAGNOSIS: The diagnosis has been established on thebasis of: presence of asthma, plasma eosinophilia, Aspergillusfumigatus (AF) in the bronchial aspirate or in sputum, Pricktest-IgE Rast and positive anti-aspergillus antibodies,evidence of bronchiectasis ± pulmonary thickenings.CASES: 9 patients (3F, 6M); age range: 28–84 years withdemonstrated ABPA.Treatment: Formoterol spray (36 mcg/day), prednisone (25mg/day/p.os) for 14 days; terbinafine (5–10 mg bid/p.os)respectively for 53-84-122-264-123-180-178-181-335 dayson the basis of the clinical and instrumental pattern ofevaluation.RESULTS: At the end of the treatment and of the subsequentfollow-up period (7-13-18-24-5-24-12-5-10 monthsrespectively), the following evidence was observed:regression of asthma with a PFT normalization; absence ofAF, present at the start in 4/5 patients; a precipins decreasefrom 3-3-3-2-4-3-1-2-2 to 1-2-0-0-1-0-0-0-1 arches; an IgEdecrease from > 100 to levels <0.35 KU/l; cutaneousinfiltrate decrease-Prick-test-from >2 cm to <1 cm;subsidence of pulmonary thickenings.CONCLUSIONS: All these favorable preliminary resultsdefinitely seem to confirm the assumption of a primaryinfectious pathogenesis of ABPA and reconfirm the efficacyof Terbinafine in pulmonary aspergillosis, and also promptus to require our colleagues cooperation for a nextrandomized trial.

73. Susceptibility of viruses, bacteria and fungi to newlysynthetized derivatives of Sesquiterpenes of LactariusoriginKrawczyk E 1; Kobus M 1; Barycki R 2; Daniewski W 2;Przybylski M 1; Luczak M 1

1 Dept. of Medical Microbiology, Medical University ofWarsaw, Poland, 2 Institute of Organic Chemistry, PolishAcademy of Sciences, PolandINTRODUCTION AND OBJECTIVES: In our previouslyconducted experiments we found that within the group ofN-acylphenylisoserinates of Lactarius sesquiterpenoidalcohols a various compounds show different antiviralactivity. To this series series of experiments three the mostactive compounds, which belong to different chemicalgroups, were selected: isolactarorufin 8-[N-benzoyl-(2’R,3’S)-3’-phenylisoserinate], methyl N-benzoyl-phenylisoserinate and isolactarorufin- 8alpha-[(2’R,3’S)-N-acetyl-3’-phenylisoserinate]. The aim of this study was toevaluate their activity (in vitro) against viruses which belongto different taxonomic groups and also against variousbacteria and fungi.MATERIAL AND METHODS: The doses of the compoundswere selected on the basis of results of cytotoxicity tests(made using the MTT assay). In the first part of ourexperiments we tested an antiviral activity of thecompounds. The cell cultures (Vero, RD and LLC-MK2)were infected with various viruses: Vero cell line with HSV-1MC, EMC or VSV viruses; RD cells with Coxsackie B2virus and LLC-MK2 cells with parainfluenza-3 virus. Testedcompounds were added in different concentrations to the

cell cultures after viral infection. The titre of viruses wasexpressed in TCID50/ml at particular stages of theexperiments. In the second part of the experiments wetested an antibacterial and antifungal activity of thecompounds. Bacteria: S. aureus, E. faecium, E. coli, P.mirabilis, B. fragilis and C. albicans fungus were incubated inATB fluid media (bioMerieux) with tested compounds indifferent concentrations. After incubation microorganismswere inoculated on solid media with calibrated loops andthe colonies were quantified.RESULTS: Isolactarorufin 8-[N-benzoyl-(2’R,3’S)-3’-phenylisoserinate], methyl N-benzoylphenylisoserinate andisolactarorufin- 8alpha-[(2’R,3’S)-N-acetyl-3’-phenylisoserinate]significantly inhibited proliferation of the HSV-1MC.Isolactarorufin- 8alpha-[(2’R,3’S)-N-acetyl-3’-phenylisoserinate]also inhibited proliferation of VSV. None of the testedcompounds showed significant activity against EMC,Coxsackie B2 and parainfluenza-3 viruses. Also none of thetested compounds showed antibacterial or antifungalactivity.

74. Susceptibility of Trichosporon fungi isolated fromclinical specimens to antifungal agentsSwoboda Kopeæ E 1,2; Wróblewska M 1,2; Sulik-Tyszka B 2;Krawczyk E 1; Luczak M 1,21 Dept. of Medical Microbiology, Medical University inWarsaw, Poland2 Laboratory of Microbiology, Central Clinical Hospital inWarsaw, PolandAIM OF THE STUDY: Analysis of frequency of isolation ofTrichosporon spp. from different hospital wards in theperiod 1996–2000.MATERIAL AND METHODS: Clinical specimens comprised:urine, sputum, wound swabs, blood, stool, throat swabs, earswabs and drainage catheters.Microbiological assessment and identification of culturedisolates were done according to the standard procedures (bioMerieux, Sanofi Pasteur). Susceptibility of fungi toantifungal compounds was estinated by use of Fungitest(Sanofi Pasteur).RESULTS: In total 4201 fungal isolates have been culturedfor clinical samples, including 4057-Yeast-like fungi. Therewere 34 isolates of Trichosporon spp., which constituted0,8%. Six species of Trichosporon spp. have been obtained,with T. cutaneum being a predominant species. Trichosporonisolates were most often cultured from urine (17), sputum(6),and wounds (4). Analysis of the susceptibility patternsshows sensitivity of 50% of strains to 5FC and ketoconazole,while 70% of strains were susceptible to amphotericin B and60 % to miconazole.CONCLUSIONS:1. Trichosporon spp. are most often cultured from urine.2. A high frequency of resistance of isolated strains toantifungal compounds is observed.

Infection control in hospital

75. A study on the effect of Amygdalus communis onClostridium difficileAtaee RA*,. Behzadian Nejad Q**.* - Department of Microbiology, Faculty of Medicine,Baghyatollah(a.s) University of Medical Sciences, Theran,I.R. of IRAN, ** - Department of Microbiology, Faculty ofMedical Science,Tarbiat Modares University, Theran, I.R. ofIran.It has been known that the etiologic agent of colitis and

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pseudomembranus colitis in man is Clostridium difficile.With respect to traditional use of almond paste in thetreatment of infantile diarrhoea. This study began toinvestigate the aquoeus extract of AmygdalusCommunis(AEAC) on Clostridium difficile in the RabbitLigated ileal Loop. Three group of male new Zealand whiterabbits (1.5–2 Kgr) were used in all studies. each ligatedrabbit small intestinal segment (4–5 cm) were injected whit1 ml mixture of vegetative cells of Clostridium difficile andConcentration of AEAC, 1 ml mixture of pured Toxin A andB and AEAC, and 1 ml suspansion of Bacterium (10000 CPU/ ml) lonely.Results of this study revealed that AEAC at concenterationabove 80 mg/ml completly inhibited the growth ofClostridium difficile. Although, concentration below 80mg/ml of AEAC did not block the bacterial growth, butinhibiting synthesis or excretion of toxin A and B. Injectionthe mixture of AEAC and toxin A and B in to the rabbit ilealloop yielded a positive result with no fluid accumulation atlevel acceptable for a diarrhae status in comparison withpositive control. Although, inoculation of bacterialsuspension plus AEAC in to the ileum of the animal modle,resulted in inhibition of colonization of bacteria, growth andtoxin production but the results varied in accordance withconcentration of bacteria and AEAC. The importance of theresults in relation to the traditional use of almond paste intreatment of accute diarrhoea disease in children, we believethat to prove and expanded of this method, further study isnecessary.

76. Successful isolation of micro-organisms in bloodcultures emanating from the Foggia Hospital from1999–2001A. Carretta, P.E. Conte, A. Mangano, V. Pagano, G.B.Tantimonaco, A. DiTaranto*, R. AntonettiU.O. Infectious Diseases, Microbiological Laboratory*,Azienda Ospedale-Università, Foggia, ItalyINTRODUCTION: Taking cognisance of the localepidemiological situation in the hospital is essential in orderto apply a targeted antibiotic therapy aimed at controllingthe rise resistances. With this in mind, blood culturesbecome a vital diagnostic tool.AIM OF THE STUDY: To evaluate the frequency of theisolation of micro-organisms in the samples taken duringthe period between January 1999 and June 2001 fromFoggia General Hospital.MATERIALS AND METHODS: All samples have beenanalysed using the Bactec system of the Becton-Dickinsonwhich automatically reports any positive results. The bloodculture samples were sown in common soils and the bacteriadeveloped in these fields were identified using traditionallyaccepted methods with or without the UITEK system.RESULTS: In the period of time targeted by this study, 1840blood cultures were taken. All positive cultures obtainedfrom the entire hospital unit were then compared with thoseobtained by the U.O. of Infectious Diseases (Inf. Dis.),namely:

Emocultures

Total Total Positives

Year Total Positive Inf. Dis. Inf. Dis.

1999 473 41 159 192000 900 110 373 362001 467 58 170 16

The isolation percentage of the bacteria was divided asfollows:

Year E. Coli Tot. S. Aureus Tot. S. Pneumoniae

1999 29% Tot. 14% Tot. Dis 9% Tot.36% Inf. Dis. 0% Inf. 21% Inf. Dis

2000 18% Tot. 14% Tot. —16% Inf. Dis 14% Inf. Dis

2001 13% Tot. 12% Tot. —31% Inf. Dis 6% Inf. Dis

Year C. Albicans Brucella

1999 9% Tot. —0% Inf. Dis

2000 4% Tot. 6% Tot. 0 % Inf. Dis 19% Inf. Dis

2001 — 12% Tot. 31% Inf. Dis

CONCLUSIONS: The data suggests an important increase inthe blood cultures taken during the course of the years. Ourstudies also show different isolations prevail in each yearalthough the percentage of positive Gram remains high. Wehave also found that Brucella has appeared in the bloodcultures in the past two years. The monitoring of bloodcultures therefore remains crucial and indispensable in asmuch as it furnishes the medical staff with the appropriatedata on the spreading of micro-organisms in the hospitalenvironment, data necessary in order to apply targetedantibiotic therapy.

77. Antibiotic prophylaxis and cesarean section in anItalian hospitalA. Di Biagio*, M. Nelliº, G.B. Andreoliº, P. Fabbriº, N.Cenderelloº, M.P. Crisalli2, N. Piersantelli2, I. Cagliani#Department of Infectious Disease, University of Genoa,ºHospital Management and 2 Division of Infectious DiseaseGalliera Hospital of Genoa, #Santa Corona Hospital, PietraLigure, ItalyBACKGROUND: Despite advances in the management ofthe obstetric surgery, puerperal fever is an actual anddangerous complication. Prophylactic antibiotics forcesarean section have been shown to reduce the incidence ofmaternal postoperative infectious morbidity. Many differentantibiotic regimens have been reported to be effective. Thisstudy estimates the frequency of postcesarean surgicalwound infections, underlines the most common responsiblemicroorganisms and factors or risk, examines appropriateuse of antibiotics and guidelines in order to controlnosocomial infection.PATIENTS AND METHODS: Data was collected in theDivision of Obstetrics and Gynecology at Galliera Hospital,from 1 July to 30 September 1999. We considered 41patients (pts), 32 pts in emergency and 9 pts planned. Meanage was 32.71 years. 35 pts (90%) received first dose ofantibiotic prophylaxis at the moment of section of umbilicalcord and the second administration after 6 hours.RESULTS: In each time 41 cesarean operation was executed,the most common factors of risk were: exploration duringlabour 6 pts (31%), anemia 4 pts (21%), obesity 4 pts (21%)and others 5 pts (26%).In 35 pts were used amoxicilline-clavulanate (94%) at 2.2 gev, in one case (2.4%) ceftizoxime 1 g ev and in another caseclarithromycin 500 mg p.o. (2.4%). Four patients receivedno antibiotics. 13 pts demonstrated fever (32%), recorded atemperature over 37º, but only 3 pts (7%) developed likelywound infection, all didn’t receive antibiotic prophylaxis.The average stay in hospital was 14.25 days compared to5.49 days in absence of infectious complications (fever andwound infections).CONCLUSIONS: In the Galliera Hospital postcesarean

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surgical infections are uncommon compared to otherexperience (until 80%). This study confirms that antibioticprophylaxis is useful only if molecule, dose, administrationand timing are correct.

78. Risk factors associated with surgical site infection in apediatric hospital in Mexico CityDíaz R RD, Martínez de la Vega M MC, Penagos PM,Miranda NMG, Solórzano SF.OBJECTIVES: To determine the frequency of surgical siteinfection (SSI) at the Pediatric Hospital, National Medicalcenter XXI Century (PH NMC) To determine the risk factorsassociated to SSI at PH NMCMATERIALS AND METHODS: Design: retrospective, case-control study. Subjects who had surgery at PH NMC duringthe year 1999 were included. Patients under 17 years of age,who underwent elective or emergency surgery withoutimplants were followed for 30 days after surgery. Medicalrecords of each subject were reviewed to obtaindemographic and clinical information, as well as theoutcome. Sample size were calculated based on theexpected frequencies of SSI for each risk factor. Statistycalanalysis: Kolmogorov-Smirnov test, mean, interquantileintervals, frequencies, Mann-Whitney U test, Chi Square,Mantel-Haenszel or Fisher’s exact test for comparing groupsas well as for estimating odds ratios and 95% confidenceintervals. In the multivariate logistic regression analysis weidentified factors that were statistically significant at p <0.25 in the bivariate analysis.RESULTS: Five hundred and forty five patients met theinclusion criteria. The study group consisted of 54% (294)male and 46% (251) female. The SSI frequency was 9.7%(54), of them, 62% (33) were superficial incisions, 8% (4)were deep incisions, and 30% (16) were organs and spaces.SSI frequency was 14% in patients less than 30 months oldand SSI frequency was 5.2% in older patients. Risk factorsin the bivariate analysis were: post- surgical stay in hospital(SIH) greater than nine days, general SIH greater than threedays contaminated or dirty injury, ASA IV or V, emergencysurgery, third degree chronic malnutrition, pre-surgical SIHgreater than three days, and presence of post-surgicaldrainage. The only risk factor independently associatedwith SSI was the age less than 30 months old.CONCLUSIONS: Our results are different from other inpediatric population. The most important risk factorassociated to SSI was age less than 30 months. In thisgroup, we did not found relation with surgical procedurelike others, and maybe, the genesis of SSI in this group isrelated with a multiple association of risk factors. We needanother type of investigations to answer this problem.

79. Sensitivity to selected antibiotics of strains ofEnterococcus spp. isolated from blood of patientshospitalized in CCH in Warsaw 1999–2001Luczak M 1,2; Marchel H 2; Tkaczuk A 21 Dept. of Medical Microbiology, Medical University inWarsaw, Poland; 2 Laboratory of Microbiology, CentralClinical Hospital in Warsaw, PolandOBJECTIVES: Comparison of prevalence and sensitivity toselected antibiotics of strains of Enterococcus spp. isolatedfrom blood of the patients hospitalized in various wards ofCCH in Warsaw in 1999, 2000 and the first half-year of2001.METHODS: The material comprised blood cultures tested inthe period: Jan 1, 1999–June 30, 2001. Out of all bloodsamples 95% comprised peripheral blood and 5% - bloodobtained through a catheter. Incubation of blood samples

and detection of microbial growth was done with the use ofa computerized system BacT-Alert (Organon-Teknika). Thecultured bacteria were identified using GPI tests or API 20Strep (bio-Merieux). Sensitivity to selected antibiotics wasdetermined by disk diffusion method according to NCCLSrecommendations or VITEK system (bio-Merieux).Resistance to vancomycin was confirmed by E-tests. Non-repetitive strains were used for the quantitative analysis ofisolates cultured from the blood and their drug susceptibilitypatterns.RESULTS: The most commonly isolated bacteria in theanalysed period were Gram-positive cocci (67%) and strainsof Enterococcus spp. were cultured with a frequency of 8%.Among them 71% were sensitive to ampicillin, 51% showedhigh level resistance to gentamicin and 53% - high levelresistance to streptomycin. In 1999 one strain wascharacterized by an intermediate level resistance tovancomycin. No strains resistant to teicoplanin weredetected. Among the isolates of Enterococcus spp. cultureduntil June 30, 2001 two strains were characterized byresistance to vancomycin and teicoplanin.CONCLUSIONS:1. Sensitivity of Enterococcus spp. strains to vancomycinshould be closely monitored due to possible emergence ofresistant isolates.2. Consistent realization of rational antibiotic policypreventing the selection of strains of Enterococcus spp. isnecessary, as well as isolation of the patients colonized orinfected with such strains.

80. A Microbiological investigation upon the agentsimplicated in septicemia among burn patients in AhwazTalegani Burn Hospital (Iran)M. Amin, M.H. Pipelzadeh, A. Farajzadeh-ShaihkThe most common cause of mortality and morbidity amongin patients in burn units, following skin infection, issepticemia. In this descriptive study, the causativemicroorganisms implicated in septicemia among 308hospitalized patients were investigated over a period of 3years from 1997 to 1999. Following the diagnosis ofsepticemia by the attending physicians, three blood cultures,in TSB, were prepared. 24, 72 h later and weekly for up tothree weeks, sub-culturing in solid BA and EMB wereperformed. Identification of the bacterial species was madeby biochemical and microbiological methods. In addition,for evaluation of sensitivity of the isolated microorganismsto a variety of antibiotics, disk diffusion method was used.The results showed that 104 (33.7%) of blood cultures werepositive for microbial infection. Among these cases, P.aeruginosa 71(68.3%), S. aureus 11 (10.5%), Enterobacterspp 9 (8.6%), E. coli 5 (4.8%), S. epidermidis 3 (2.9%), C.albicans 2 (1.9%), group A b hemolytic Streptococcus 1(0.9%), Proteus spp. 1 (0.9%) and non-hemolyticStreptococcus 1 (0.9%). Antibiogram results showed thehighest rate of resistance was among P. aeruginosa with95.7% to gentamycin, 90.1% to amikacin, and 100% tocephtozoxime, carbenicillin and cephazolin. The rate ofresistance was least against ceprofloxacin (40%). The datafound in this study demonstrate that the rate of infectiondue to P. aeruginosa is higher than other burn centers anddictates more stringent infection control strategies againstthis killer microorganism.

Infection in compromised host81. Acute pancreatitis due to sulfamethoxazole-trimethoprim in an HIV-1 infected patient

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N. Garrido; L. Tavares; E. Monteiro; R. Sérgio; J. Salcher; R.Resina.Acute pancreatitis is a rare complication of HIV infectionand occurs especially in association with some anti-retroviral drugs. We have observed an HIV infected patientwith severe acute pancreatitis caused by sulfamethoxazole-trimethoprim (CTX). A 44-year-old female with sexuallyacquired HIV infection was admitted to the Intensive CareUnit in April 99 with respiratory failure (pA O2 and pACO242 and 26 mmHg respectively), secondary to a bilateralpneumonia. She was febrile (39 ºC), confused, with a nonproductive cough, and a respiratory rate of 38/min. She wasplaced under controlled mechanical ventilation and alsotreated with systemic corticosteroids and CTX since anempirical diagnosis of P. carinii pneumonia was admitted.The laboratory evaluation disclosed an increased LDH (1728IU/L), a positive HIV-1 serology with a CD4-cell count of18/µl and a viral load of >790000 copies/ml. P. carinii wasidentified in secretions obtained by bronchoalveolar lavage.At the 3rd day a routine laboratorial evaluation showed aserum amylase of 1045 IU/L and also an increased urinaryamylase. An abdominal CT-scan was compatible with acuteedematous pancreatitis. CTX was replaced by clindamycinplus primaquine and the laboratory gradually returned toclose to normal values by the 15th day when she wasdischarge from the ICU, asymptomatic. Sulphonamides arerarely related to pancreatic damage. There are a few casesreported of CTX-induced pancreatitis in HIV infectedpatients when CTX is used in induction treatment as well aswhen used as secondary prophylaxis for P. carinii infection.This case emphasizes the importance of pancreatic enzymemonitoring of HIV infected patients particularly when theclinical picture and evaluation of pancreatitis is difficultsuch as is the case of patients under mechanical ventilation.The contributory role of CTX to pancreatic lesion in HIV-infected patients also treated with some RT nucleosideanalogues deserves further studies.

82. Developing of method for immune antibacterial plasmareceiving and experiemental investigation of its efficiencyfor infections in compromised hosts.M.I.Grutman, L.V.Parkhomenko, L.V.Timokhina.Institute of Epidemiology and Infectious Diseases, Kyiv,Ukraine.Treatment of infections especially nosocomial for patientswith compromised immune system presents itself a seriousproblem for medicine. Amount of antibiotic-resistant strainsrises, they include strains carrying plasmids of multipleresistance. Applications of antibiotics even most modernones for patients with immunodeficiency not always allowsto kill bacteria which cause serious infections or purulentcomplications in burns, surgical, oncological andgynecological hospitals. For such patients besidesbactericidal or bacteriostatic action of antibiotics forelimination of infection agents it is necessary alsostimulation of immune system. As a rile agents of seriousinfections carry surface antigens mainly polysaccharidescapsule-like formations. These are K-antigens of Escherichiacoli, K-antigens of spp. Proteus, slime of P. aeruginosa whichdefend bacteria from opsonization and phagocytosis.Practically the most useful method to rise efficiency ofantibioticotherapy for patients with immunodeficiency is totreat them with plasma preparations containing high levelsof antibodies against antigens capsule-like formations, i.e.,provide opsonization and phagocytosis. We elaboratetechnology of receiving of complex antigenic preparations

containing surface antigens of bacteria genera Escherichia,Proteus, Pseudomonas and conducted investigation ofimmune plasma protective action.The plasma was received from rabbits after immunization bycomplex surface antigens preparations in liposomal form. Inexperimental conditions we studied how immune plasmawith high antibody titres against K-antigens E.coli, K-antigens bacteria genera Proteus and slime of P. aeruginosadefends normal animals and animals with compromisedimmune system against infection caused by bacteria of thatgenera. Investigation was conducted using the next method.White mice with 18–20 g mass were infected intra-peritoneal by 18-hours cultures pf E. coli K1, P. mirabilis, P.aeruginosa O2. Three times after 1h, 24h and 48 h they wereinjected by 0.25 ml of corresponding immune plasma.Control group of mice was injected by 0.25 ml of 0.15 M(isotonic) solution of NaCl at the same time. Immuneplasma (1:960) with antibodies against K1 antigens of E. colidefended from death 100% of normal mice under injection 4LD50 of culture E. coli K1. LD50 E. coli K1 for mice thatwere X-rayed 5 days before infecting with doze 250roentgens was 3.4 times lower than for normal mice.Immune plasma against K-antigens of Escherichia defendedfrom death 100% of X-rayed mice under injection of 3 LD50(for X-rayed mice) E. coli K1. Rabbits immune plasma(1:1920) with antibodies against extracellular slime ofPseudomonas defended from death 100% of normal miceunder injection 4 LD50 P. aeruginosa O2. LD50 P. aeruginosafor mice that were X-rayed with doze 250 roentgens 5 daysbefore infecting was 5.2 times lower than for normal mice.Immune plasma against extracellular slime of Pseudomonasdefended from death 100% of X-rayed mice under injectionof 4 LD50 (for X-rayed mice) P. aeruginosa O2. Rabbitsimmune plasma (1:960) with antibodies against K-antigensof Proteus defended from death 100% of normal mice underinjection of 4 LD50 of culture P. mirabilis. LD50 P.mirabilisfor mice that were X-rayed 5 days before infecting with doze250 roentgens was 4.5 times lower than for normal mice.Immune plasma against K-antigens of Proteus defended fromdeath 100% of X-rayed mice under injection of 3 LD50 (forX-rayed mice) P. mirablis. From the results of conductedexperiments it is possible to draw the conclusion thatimmune plasma containing antibodies against K-antigensspp. Proteus, Escherichia coli and extracellular slime of P.aeruginosa in sufficiently high titres can significantlyincrease defense efficiency of immune-compromisedmacroorganism against infections. Besides that weinvestigated 400 donors serums and establishes that 7.2% ofthe serums contained antibodies against K-antigens ofEscherichia coli in titres 1:480 and higher. 6.5% of serumshad antibodies against extracellular slime of P. aeruginosa intitres 1:480 and higher and 2.25% of serums had antibodiesagainst K-antigens of Proteus in titres 1:960 and higher.Presence in donors serums of antibodies in high titresagainst constructed by us complex antigenic polysaccharidepreparations carrying determinants of the whole bacteriagenera allow to select donors blood samples for immuneplasma receiving. These preparations of antibacterial plasmacontain specific antibodies against polysaccharide K-antigens of Escherichia, Proteus, extracellular slime of P.aeruginosa. Results of experimental control allow us tosuppose their high efficiency for serious patients treatment.

83. CMV seropositivity in immunocompetent patients:clinical perspectivesG. Pappas, G. Giannoutsos, A. Kostoula*, N. Akritidis**

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E. Tsianos Department of Medicine,and *Department ofMicrobiology, Medical School, University of Ioannina,Ioannina, Greece. **Internal Medicine Department, GeneralHospital “G. Hatzikosta” of Ioannina, GreeceAIM: To determine the clinical syndromes associated withacute cytomegalovirus (CMV) infection in immuno-competent patients.PATIENTS AND METHODS: 0ne hundred patients thattested positive for IgM antibodies versus CMV, in a period ofnine months. Patients were evaluated for the presence ofunderlying conditions predisposing to immunodeficiency.48 patients were considered immunocompetent, bothinitially, and in repeat evaluation, one year later. In allpatients, the clinical course subsided along with a decreasein serum IgM antibody titre.RESULTS: 27 patients presented with an acute systematicfebrile illness, accompanied by mild hepatitis as determinedby an increase in serum aminotransferases. 17 patientspresented with a clinical syndrome mimicking upperrespiratory system infection (fever, sore throat, and/or mildlymphadenopathy). 2 patients presented with a “chronicfatigue” syndrome accompanied by low fever. 2 patientspresented with a moderate, reversible pancytopenia.CONCLUSIONS: Although the importance of CMVinfection in immunocompromised patients has well beenascertained, the effect of CMV in immunocompetent hostshas drawn little interest. Most cases are benign andtreatment was not deemed necessary in any of our patients.Still, acute CMV infection should always be considered inthe differential diagnosis of certain clinical syndromes.

84. The testing of the employment of immune antibacterialplasma for the treatment of patients with infections causedby bacteria Pseudomonas and Escherichia underimmunodeficiences.V.N.Parkhomenko, I.M.Grutman, A.D.Zamkovoi,L.V.Parkhomenko.Institute of Epidemiology and Infectious Diseases, Kyiv,Ukraine.The main goal of this work was to estimate the efficacy ofantibacterial immune plasma in the treatment of patientsserious infections caused by Pseudomonas and Escherichiabacteria. For this the groups of patients were taken withburns and spread peritonitis, illness, in which infections areone of the leading links of their pathogenesis bring aboutthe clinical appearance end outcome. Bacterial invasion byhospital strains of microorganisms leads to development ofserious infection complications, often conditioning thedeath of patients. It must be taken into account that inconnection with pollution of great region by radioactiveisotopes as result of Chernobyl disaster, the situation withthe treatment of patients suffered by serious infectiousprocesses changed to worse mainly due to suppression ofimmune system in people. High antibiotic resistance ofagents under these infections creates significant difficultiesin choosing of local and general antimicrobial therapymeans. It should be emphasized that at the incoming ofburned patients into the hospital from their wounds it canbe selected predominantly antibiotic sensitive coccalbacteria, whereas after several days of staying in hospital themain species are gram negative bacteria: P. aeruginosa,Escherichia, Proteus. Among the bacteria that cause infectionunder peritonitis, according to different authors, one of theleading roles has Escherichia along with anaerobic bacteriaBacteroides, Clostridium). Lethality under spread peritonitismay achieve more than 40%. Necessity is appeared in the

development of methods for the treatment of patients byapplication of immunobiological preparations that improvethe work of immune mechanisms of patient’s organism. Byour research group was created the method for selecting ofhealth donor blood samples that contain in high titers theantibodies against extracellular slime of P. aeruginosa and K-antigens of Escherichia coli (E. coli). For the studying ofimmune plasma efficacy there were taken two groups ofpatients (12 human in each) with spread burns of 3–4powers, that were complicated by infections caused by P.aeruginosa. These patients are immuno compromised, theyhave decreased chemo taxis and phagocytosis bymacrophages and neutrophills, as well as decreased quantityand suppressed function of T-lymphocytes. Patients ofcontrol group received the common accepted treatment,including antibiotics, sensitivity of P. aeruginosa to whichwas determined by method of serial dilutions in vitro.Patients of test group received the same treatment and,additionally, immune plasma (of the same blood group) thatcontained antibodies against extra cellular slime of P.aeruginosa in titer 1:480 and higher. Plasma was injectedintravenous by drops 250 ml once a day during three days.In control group from 12 patients three died. In test groupfrom 12 patients no one died. Between groups there wasstatistical significant difference with probability 99%. Fortesting of efficacy of immune plasma with antibodies againstK-antigens of E. coli there was taken two groups of patients(17 in each) with spread peritonitis, agent of which was E.coli. Previously in these patients it was established the signsof immunodefficiences. Patients of control group receivedthe common accepted treatment, including detoxicationprocedures, washing of abdominal cavity by solutions ofantiseptic means and complex of antibiotics acting on E.coli.Patients of test group received the same treatment and,additionally, immune plasma (of the same blood group) thatcontained antibodies against K-antigens E. coli in titer 1:480and higher. Plasma was injected intravenous by drops 250ml once a day during three days. In control group from 17patients six died. In test group from 17 patients one died.Between groups there was statistical significant differencewith probability 95%. Thus we can make conclusions: 1)injection of immune plasma containing antibodies againstextra cellular slime of P. aeruginosa to patients with seriousburns, that complicated by infection caused by P. aeruginosa,essentially decrease the lethality in these patients, 2)injection of immune plasma containing antibodies againstK-antigens of E. coli to patients with spread peritonitis, oneof the main agents of which are E. coli, essentially decreaselethality in these patients.

85. Staphylococcus aureus bacteremia in patients withhematological malignancies: retrospective clinical andmicrobiological analysisMario Venditti, Alessandra Micozzi, Fabrizio Taglietti, PaoloCarfagna, Pietro Serra, Pietro MartinoBacteremia due to S. aureus is an emerging problem becauseof the increase in the clinical practice of the use ofintravascular devices. Anyway few data in the InternationalMedical Literature exist about these infections in patients(pts) with hematological malignancies. These pts are at highrisk of bacteremia and S. aureus represents a leadingmicroorganism. To determine morbidity and mortality of S.aureus bacteremia, we retrospectively reviewed clinical dataof 53 S. aureus bacteremia in pts with hematologicalmalignancies from January 1997 to December 1999. Themedian age was 41 years; 38 (72%) pts were male, 30 (79%)

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pts had acute non-lymphoid leukemia, 7 (18%) had acutelymphoid leukemia, 5 (13%) had lymphoma, and 11 (29%)had other hematological malignancies. S. aureus infectionwas nosocomially acquired in 81% of the cases. Most ptswere granulocytopenic (60%), had received cytotoxictherapy (77%) and oral prophylaxis with quinolones (57%),and had a central venous catheter (62%). Most pts receiveda single daily dose regimen with ceftriaxone plus amikacinas empiric therapy with addition of teicoplanin (400 mg ivevery 24h) after blood culture results. Eventually, therapywith in vitro active antibiotics was performed in 48 pts(90%) (ceftriaxone ± amikacin or piperacillin-tazobactam ±amikacin for 13 methicillin-susceptible S. aureus infections;teicoplanin was eventually added in the remaining 38infections): of these, 28 (58%) responded favorably, 7 (15%)relapsed, but were cured after a second course of antibiotictherapy, 5 remained febrile for the underlying disease, and 8(17%) eventually died. Five pts received inappropriatetherapy, and only 1 died. Central venous catheter removalwas required in 6/33 (18%) pts. During follow-up no casesof endocarditis or osteomyelitis have been observed. S.aureus bacteremia in pts with hematological malignanciesmay represent in most instances a low inoculum bacteremiaassociated with poor morbidity and mortality

86. A neglected case of Brucella osteomyelitisGuler Yayli1, Huseyin Yorgancigil2, Orhan Oyar3

S. Demirel University, Faculty of Medicine, Departments of1) Clinical Microbiology and Infectious Diseases, 2)Orthopaedics, 3) Radiology, Isparta, TurkeyA case of osteomyelitis around the knee without anydiagnosis for 20 years is presented here for it is a rarecomplication of brucellosis. A male farmer presented withswelling and limited motion of his right knee, stating thathis initial complaints started 20 years ago and resolved onlywith aspiration of some fluid without any furtherinvestigation or treatment. On laboratory tests, acute phasereactives and blood culture was negative. Brucellaagglutination tests on serum specimens, including Coombstest were also negative. Joint fluid was macroscopicallyturbid and cell count was 3000/mm3 consisted of 80%monocytes and no microorganisms were detected on Gramstained smears. Brucella melitensis was cultured in jointfluid. Plain X-rays and MRI showed lytic lesions in proximaltibia and distal femur adjacent to the knee joint.Scintigraphy revealed inflammatory hyperactivity in relevantsites and a CT guided biopsy was performed.Histopathological and microbiological inspection of biopsyspecimens revealed chronic Brucella infection. The patientreceived medical treatment with doxycyclin 100 mg bid,rifampicin 300 mg bid, ciprofloxacin 500 mg bid for sixmonths, concerning the bone and joint involvement. He wasalso given anti-inflammatory agents together withphysiotherapy. There weren’t any symptoms such as swellingor pain that implicate a recurrence of the infection, throughout the follow-up period. At the last control examination at18 months, there was a complete clinical recovery.Serological and biochemical parameters were normal, as itwas during admission.

Miscellaneous

87. Infections in hip prosthetic surgery: micribiologicalsuggest.L.Molfetta, F.Raffelini, A.Salerno**, A.Palermo and F.PipinoOrthopaedic Dept.University of Genoa, Italy, **Microbiologic

Institute, University of Genoa, ItalyThe prosthetic infections are the most dangerouscomplication in the hip prosthetic surgery for the difficultclinical management and for the functional and generalconsequences to the patients. In the period January1994–August 1998, 170 prosthetic hip revisions have beenmade in the Orthopedic Dept. of the University of Genoa,Italy. Every total hip re-implantation has been done in one-stage with the use of antibiotics impregnated bone cement.The diagnostic hypothesis has been formulated on the basisof the clinic, hemato-chemical, scintigraphic signs andconfirmed by the microbiological and histologicalexaminations. The microbiological screening protocol hasconsisted of a previous pre-surgery evaluation and afollowing examination during reimplantation. Thepresurgery phase of the microbiological evaluation consistedof the microscopic view and culture performance of the peri-prosthetic fluids drawn by an arthrocentesis controlled withUS. Standard multiple samples of peri-prosthetic tissue wereobtained infra-surgery. Gram stained and cultured by directand enrichment methods. The isolation of an indistin-guishable microorganism from three or more independentspecimens was considered predictive of infection. Using thisscoring system we diagnosed infection in 7% of prosthesesrevised. Staphylococcus aureus (13.3%) and coagulasenegative staphylococci (80%) are represented the almostwhole of the specimens (in three patients were isolated morethan one pathogens). Staphylococci methicillin resistantwere 54%. The other antibiotic resistance in Staphylococcistrains are the followed: erythromycin and clindamycin in64%, rifampin in 35%, ciprofloxacin in 21%, gentamycinand cotrimoxazole in 7%. Small-colony variants (SCVs) ofthe Staphylococcus aureus has been isolated from one patientwith persistent infection. The emergence of multiresistantmicroorganisms suggests that the surgery infectionsprevention is the most significant device for the economicadvantage in the prosthetic hip surgery.

88. Aspects pleading for relationships between agglutininsand other virulence factors in V. cholerae O1 strainsAnca-Michaela Israil, Mariana Carmen Balotescu,Cantacuzino Institute, Bucharest, RomaniaThe cell-associated MSFH, MRFR and HA/P (detachase,caseinase) haemagglutinins are implicated in the process ofbacteria attachment to enteral cells whereas slime agglutininin adhesion to abiotic surfaces. For this reason agglutininsmay be considered as virulence factors in pathogenic V.cholerae strains, but until now there is no clear evidence inthe literature about the relationship between the presence ofhaemagglutinins and the other virulence factors in V.cholerae strains. In the present work, we have studied 166strains of V. cholerae O1 isolated from clinical cases (161)and environment (5 water sources) during the choleraepidemics of Romania between 1987–1995 in the purpose todetect any putative relationship between the HA patternsand other virulence factors. All strains (previouslycharacterized by serological, biochemical and by phagetyping methods) were simultaneously investigated for theirHA aspects, adhesion ability (by slime test) and the presenceof 9 enzymatic virulence factors using haemolysis by spotmethod, CAMP test and Kanagawa test, esculin hydrolysis,mucinase, amylase, lecithinase, lipase and DNA-seproduction. Out of 166 V. cholerae strains, 157 (95%)exhibited HA activities with chicken erythrocytes, i.e., 135(81%) MSHA, 17 (8%) FSHA, 108 (65%) MSFRHA, but35(21%) strains exhibited also atypical HA with human (O

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group) erythrocyets, these atypical HA aspects beingconcentrated in strains isolated in 1993. Out of 166 V.cholerae strains, 87%, 86%, 85%, 83%, 75% and 60% ofstrains were positive for lipase, amylase, lecithinase, DNA-se, Kanagawa hemolysin and caseinase, respectively.Concerning the other studied enzymes 41%, 12%, 7.8% ofstrains were positive in spot haemolysis, esculin andmucinase respectively; 48% of strains showed adherenceability to abiotic (borosilicate) surfaces evidenced in slimetest, but only 19% of these last strains exhibited a surfacepellicle. Our results demonstrated a high correspondence of62% between MSHA haemagglutinins and caseinase activity,48 % between slime agglutininin and caseinase and 44%between the same MSHA and slime agglutinins. All 5 V.cholerae strains isolated in water sources showed Kanagawaand lecithinase positivity but their adhesion aspects werepoorly represented (only 2 slime, 2 haemagglutinant and 1caseinase activities) demonstrating that in the externalmedium, V. cholerae O1 strains can preserve a high potentialof toxigenicity (Kanagawa toxin), but scant adhesion abilityto abiotic surfaces, this aspect probably explaining the lowerresistance of V. cholerae O1 strains as compared to V. choleraenonO1 strains (unpublished results) in the externalmedium. It is also to be mentioned that out of 166 V.cholerae strains, one strain isolated in a child with acutediarhhoea exihibiting MSHA was negative for all the otherinvestigated virulence factors. Our results showed that in V.cholerae O1 strains, caseinase and mucinase proved to betwo independent activities (only 8.5% correlation)suggesting the presence of two distinct enzymes, our resultsbeing different from the data cited by Finkelstein et al, 1992.Concerning the frequency of different enzymes implicated invirulence of V. cholerae O1 strains, our results, whencompared with other data from the literature (Ingole et al.,1998) proved to be similar for caseinase (69 % vs 60%) andlipase (87% vs 65.38%) but showed great discordanciesespecially for lecithinase (85% vs 0%) and DNA-se (83% vs19.23%).

89. Production, extraction and activity measurement ofClostridium botulinum type A neurotoxin on basis ofquantitative parametersBehzadian Nejad, Q1, Ataee, R A2, Satari, M1., Riazi, GH3

1. Department of Microbiology, Faculty of Medical Science,Tarbiat Modares University, Theran, I.R. of IRAN. 2.Department of Microbiology, Faculty of Medicine,Baghyatollah(a.s) University of Medical Sciences, Theran,I.R. of IRAN. 3. Department of Biochimistry, I B B. Theranuniversity, I.R. of IRAN.The purpose of this study was to quantify the mousebehaviors, caused by botulinum toxin type A. Acidprecipitation of the whole culture was prepared at pH = 3.5by addition of 3M of H2SO4 and then centrifuged at 10,000rpm for 10 min, at 4° C. The pellet washed three times withdistilled water and was homogenized in 100 ml of 0.1 MSodium citrate buffer with pH = 5.5 for one hour at 35° C.The sample was recentrifuged at 10,000 rpm for 20 min toobtain the supernatant which was considered to contain thetoxin. Partial purified toxin was prepared by addition of 70percent saturated ammonium sulphate to the samplesolution. The precipitation was redissolved in 0.1Mphosphate buffer with pH = 6.5 and the solution wasdialysed against the same buffer at 4° C. Proteinconcentration was examined by Bradfored method and thendetermined 1–2 µg/ml. Parallel to concentration, the toxicitytest was performed by intraperitoneal injection of 0.1, 0.2,

0.3 and 0.3 ml of toxin solution. In order to change thequalitative parameters to quatitative onse, movementresponses of animal to different toxin concentration wasgraded from one to five and the results were analysedTherefore, with changing the qualitative parameters toquantitative ones, it could be possible to define thebiological activity of Botulinum toxin type A.

90. Cervical fasciitis: clinical courseRaffaele Bottin MD and Lara Salvadori MDDepartment of Otolaryngology-University of Padua (Italy)Since the advent of antibiotics, bacterial infection of thefascial spaces of the neck has become a relatively infrequentpathology, which often goes unrecognized andunderestimated. Nonetheless, it is still an extremely seriousevent and may lead to death of the patient. This severepathology onsets with an apparently banal inflammationstarting in the neck regions. It is thought to be caused bysynergism between different types of anaerobic (generallybacteroid and fusobacterial) and aerobic bacteria(prevalently group-A b-haemolytic streptococcus,Staphylococcus aureus, Escherichia coli, Proteus vulgaris,Klebsiella, Pseudomonas aeruginosa, Enterococcus, Serratia,Diplococcus pneumoniae). Phlebothrombosis of the adjacentvessels and subsequent necrosis of the surrounding tissues,which are massive in said inflammations, prevent antibioticsfrom reaching these regions in effective quantities.Consequently, the inflammation rapidly spreads through themediastinal and cervical fascial spaces, often prompting theneed for surgical intervention in the infected areas andexcision of necrotic regions.Between January 1998 and August 2000, fifty patients (34males and 16 females) aged between 16 and 79 years (meanage 46 years), affected by infection of the fascial spaces ofthe neck, were assessed and treated at the Department ofOtolaryngology of the University of Padua. Patients withsimple peritonsillar abscess, infectious post-surgicalcomplications, iatrogenic pathology or neoplasia of the headand neck region, were excluded from the study. Thesymptoms for which patients most frequently presented formedical attention were dysphagia (70%) and cervicalgia(68%). The most frequent clinical signs on first observationwere swelling of the neck (82%) and trismus (20%). Onobjective examination, the site of onset of the infectionproved to be dental (44%) and orophayngeal (44%). At thetime of presentation, 24 patients (48%) had hyperpyrexia.The time elapsing between onset of symptoms andpresentation at our Emergency Room was between 1–30days (mean 5.52 days). At the time of hospital admission,home treatment was already being taken, in the form ofantibiotics by 28 (56%), NSAID by 22 (44%) andcorticosteroids by 8 patients (16%). In-patients wereadmitted to imaging therapy (CT, ultrasonography,orthopantomography), enabling the site and extension ofthe inflammation to be more precisely defined. Outcome ofprescribed treatment (antibiotic associated, where necessary,with surgery) was positive, with complete resitutio adintegrum, in 48 patients (96%), but death occurred in 2patients (1 case of massive haemorrhage and 1 case of septicshock). The authors discuss the guidelines for treatment ofthis dangerous pathology.

91. Detection of toxoplasmosis and salmonellosis in meatjuice: experimental and surveillance studiesOsama N. Mohamed, Sonia R. Allam, Safeya M. Ali andLobna A. El-Zawawy.Public health and economic impact of toxoplasmosis and

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salmonellosis in meat is considerable in terms of morbidityand even mortality in humans. Up to date, there is nosuitable method for diagnosis in meat of slaughteredanimals.The present study evaluated the meat juice as a sample fromexperimentally infected mice with Toxoplsama gondii (T.gondii) or Salmonella typhimurium (S. typhimurium) fordetection of anti-Toxoplasma or anti-Salmonella antibodiesby an indirect enzyme linked immunosorbent assay (ELISA)technique.The results of the current study revealed that there were nostastically significant differences when comparing results ofmuscle juice ELISA to those obtained from serum samples ofmice with strong correlation between the two samples. Thisindicated that, meat juice is as efficient as blood in diagnosisof toxoplasmosis and salmonellosis. Moreover, thesuperiority of meat juice lies in its ability for diagnosis whenblood is not obtainable. The use of this sample was appliedin surveillance study which was done on randomly collectedbeef and chicken meat. The antibodies against T. gondii andS. typhimurium were detected in 31%,22% and 14%, 7%respectively. This justifies the importance of meat juice to beused in the future large scale meat screening programs.

92. Experimental ocular toxoplasmosis: clinical,histopathological, immunological and therapeutic studiesNibal A. Hammoda, Sonia R. Allam, Lobna A.El-zawaway,Safyea M. Ali, Ashraf S. Galal

The present study aimed to investigate clinical,histopathological and immunological features of anexperimental model of ocular toxoplasmosis in sensitizedand non sensitized rabbits and to assess the infleunce oftreatment by interleukin 2(IL-2) on ocular lesions.Two groups of rabbits, sensitized (previously infected withcysts of KSU strain of Toxoplasma gondii [T. gondii])and nonsensitized were used to carry out this study. Both groups ofanimals were intraocularly (I.O.) inoculated withtachyzoites of RH strain of T. gondii. IL-2 was systemicallyadministrated and the assessement of its effect on ocularlesions wa evaluated through; clinical, histopathological andimmunological studies.Toxoplasma retinochoroiditis developed in both groups ofrabbits with more pronounced effect in non senstizedanimals. Adminstration of IL-2 improved ocular lesions inboth groups with more evident effect in sensitized rabbits.Immunological findings were consistent with clinical andhistopathological observations.These results indicated that, ocular lesions were manifestedin non sensitized rabbits more than in sensitized ones. IL-2revealed a significant impact on improving the host defenseagainst Toxoplasma infection in eye. Immunotherapy withIL-2 would open the way for a new range of treatmentsbased on immunomodulation.

93. The immunogenicity of M. vaccae used as an adjuvantwith killed L. major to study the shift of Th2 to Th1responses in Leishmania infection.Lavinia Khoushabeh, Pasteur Institute of Iran,Mycobacteriology Dep.In this study we chosed M. vaccae as an adjuant to be usedas a potential candidate vaccine. Leishmaniasis with 1.5–2.0million new cases per year and prevalence of 12 million inthe world is a health problem in 88 countries especially indeveloping ones. Due to the increase of population, increasein the areas under irrigating and many other factors, studiesare needed to develop a suitable vaccine to be used asprotective and preventive against Leishmaniasis.

Mycobacterium vaccae was isolated from Uganda soil(Stanford, 1996). It is a varaibly photochromogenicenvirommental saprophytic and rapidly growingmycobacterium which has never been associated withcertainty with human diseases. Several studies have shownthat using M. vaccae can either shift the Th2 response toTh1 response (Stanford, 1997). In this study we investigatethe effeciency of Mycobacterium vaccae as an adjuvant withKLM (killed L. major) or ALM (autoclaved L. major) indifferent doses for treatment of Leishmaniasis. In recentyears, it has been shown that resistance and susceptibility toL. major correlates with the preferential expansion of Th1and Th2 cells respectively. A Th1-like line, that produced IL-2 and INF-a, was able to protect Balb/c mice againstleishmaniasis. A Th2-like lines that produced IL-4 and IL-5exacerbated disease in these mice. Cell mediated immunity,rather than antibody, is protective and necessary to overcomthe infections with Leishmania parasite.In this work we have chosen two different groups of mice.Balb/c which are sensitive to L. major and C57bl6 which areresistant to L. major. Each groups have received M. vaccae(High dose 10 or Low dose ) or BCG subcutaneously as anadjuvant with ALM or KLM,two boosters after the firstinjection. Post immunization, all three group of mice havebeen challenged with L. major, humoral and cellularimmunity were evaluated befor and after the challenge. Ourmotive in this study is to improve the existing treatment byM. vaccae and compare the result with groups that receivedBCG. The aim is to determine whether it is possible togenerate Th1 responses by M. vaccae or BCG ?Conclusion: There was statistical differences observed onlyin the test group received BCG and M. vaccae in low dosemeasuring the diameter ulcer Induration. The total IgG titrebefor and after challenge has been determined, it has beenshown that in all groups the total IgG titre increased, andthe total IgG in group which received BCG and group whichreceived M. vaccae in low dose is lower than all othergroups.

94. Treatment of lymph node tuberculosisA. Ghoubontini, F. Zouiten, H. BenSaid, B. Kilani, F.Kanoun, H. Tiouiri, T. Ben ChaabeneDepartment of infectious diseases la Rabta Hospital 1007Jebbari Tunis TunisiaWe have studied the management of 61 cases of lymph nodetuberculosis (LNTB)treated between 1990 and 1999.Eighteen patients are co-infected by HIV. Positive histologyor bacteriology in 56 cases (89%) supported the diagnosis.All patients were treated by antituberculous combination,with isoniazid, rifampicin, pyrazinamide and ethambutol orstreptomycin. 39 patients were followed until the end oftheir treatment. The mean duration of treatment was 11months, and more, when the patient have anotherlocalisation of tuberculosis Clinical remission was observedin 59% of patients in the ninth month of the treatment. Fivepatients were died with disseminated tuberculosis, four ofthem were co-infected by HIV Six patients are having aclinical resistance of their disease and they were also treatedby surgery. Definite or suspected drug toxicity was reportedin 17 patients (28%), often with isoniazid (12%) orpyrazinamide (20%). The LNTB can be treated only withantituberculous combination, medical treatment must to bemaintained minimally nine months because the clinicalremission is observed clearly only after the ninth month ofthe treatment. Surgery can be proposed in-patients withpersistent lymph node.

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New and emerging pathogens

95. Diarrhoea in elderly people: aetiology, clinical andepidemiological characteristicsASG Faruque, MA Malek, AI Khan, and S Hoque. ICDDR,B:Centre for Health and Population Research. GPO Box 128,Dhaka 1000, BangladeshDiarrhea in elderly people: aetiology, clinical andepidemiological characteristics.OBJECTIVE: Diarrhea is a leading cause of morbidity amongchildren and young adults. However, little is known aboutdiarrheal morbidity among elderly people. In this study, weexamined the aetiology, clinical and epidemiologicalcharacteristics of a sample of elderly people who reported toa diarrhoeal disease health facility in Bangladesh.DESIGN: A 2% systematic sample of 498,400 patients whocame to the ICDDR, B’s hospital located in Dhaka, thecapital city of Bangladesh during 1996–1999, was studied.SUBJECTS: Patients aged 60 years or more (3%, n=341)were included for analysis.RESULTS: An organism was isolated for 54% of the elderlypatients screened for all pathogens; 21% had a mixedinfection with two or more agents. V. cholerae O1 was themost common enteropathogen (22%), followed by ETEC(12%), EPEC (12%), Shigella (11%), V. cholerae O139 (9%),Campylobacter jejuni (4%), Salmonella (2%), rotavirus (4%),and E. histolytica (2%). Aeromonas was isolated from 16%patients. Fifty-eight percent of the elderly people reportedprior use of medicines, and 76 % had used oral rehydrationtherapy before coming to ICDDR, B health facility.Compared to children of less than 5 years (56%, n=5550),the detection rates of V. choleare O1 (22% vs 14%), V.cholerae O139 (9% vs <1%), Shigella (11% vs 6%),particularly S. flexneri (7% vs 3%), Aeromonas (16% vs 8%),and E. histolytica (2% vs <1%) were significantly higheramong elderly individuals presented with diarrhoea. Theyhad significantly frequent presence of blood in stool (10% vs1%), history of higher (?16 per 24 h) stool frequency (28%vs 13%), severe dehydration (39% vs 6%), shorter duration(0–72 h) of illness before reporting (89% vs 66%),hospitalization in short-stay ward (83% vs 56%), IV fluidtherapy requirement (54% vs 14%), shorter duration (0–23h) of stay (74% vs 60%), referral to other health facility (2%vs <1%), and attendance of female patients (47% vs 39%).In comparison with young adults (15–44 years old, 25%,n=2499), the detection rates of V. cholerae O139 (9% vs 6%),Shigella (11% vs 6%), particularly S. flexneri (7% vs 4%),and Aeromonas (16% vs 11%) were significantly higheramong elderly patients. They had significantly morepresence of blood in stool (10% vs 5%), hospital stay for?24h (26% vs 16%), and referral to other health facility (2%vs <1%). Hot dry summer (May) and fall (October) peaks ofdiarrhea morbidity were observed for elderly individuals.CONCLUSIONS: For elderly people, more directedhealthcare, such as oral rehydration therapy, IV rehydrationtherapy, early referral, vaccines or other preventive measuresmight be more beneficial.

96. Multi-resistant Pseudomonas aeruginosa (MRPA)Fibbia GC, Costa P, Tomasoni D, Miccolis S, Gattuso G,Morandini B, Perboni G, Scalzini A. Divisione di MalattieInfettive – Azienda Ospedaliera C. Poma, Mantova - ItalyWe describe three clinical cases of MRPA infection withisolation of the same strains from urine and sputum in threepatients in our hospital. First case: a 56-year-old woman wasadmitted to the surgical department for an acute pancreatitisand was recovered in intensive care unit for necrotic-

hemorragic complications and multiorgan failure. In surgeryshe underwent laparotomy with insertion of a peritonealdrainage. She became septic and a new surgical procedurewas performed for get out purulent fluid from the peritonealspace. From the drainages, a Pseudomonas aeruginosa wasisolated; it was resistant to b-lactams, carbapenems,aminoglycosides and quinolones. The patient wassuccessfully treated with colistin.. Second case: a 53-year-oldman was admitted in intensive care unit for respiratoryfailure, intubated and mechanically ventilated. After threedays he was transfered to the neurology department, hebecame septic with high fever (41°C) and chills. Multi-resistant Pseudomonas aeruginosa was isolated from urineand the patient was treated with colistin but he died after 5days. Third case: a 48-year-old man affected from severalyears of Alzheimer’s disease and with an urinary indwellingcatheter was admitted for recurrent urinary tract infectionsand sepsis with fever, sweats and chills. A MRPA wasisolated from sputum and urine, in many samples, but notfrom the blood. The patient had been treated in the lastyears with several antibiotics without any result but thefever resolved only with the association of imipenem andamikacin.Conclusions: in these clinical cases the factors related to theinfection with MRPA seem to be the admission in intensivecare unit and the prolonged use of antibiotics. Controversyremains on the best treatment for the MRPA and, even ifthere is a susceptibility for colistin these regimen sometimedoesn’t work, the association of carbapenems andaminoglycosides is still unlikely. The emergency of thesepathogen can be a threath, mainly in ICU, and precautionalmeasures should be taken in the hospital departments whereMRPA is isolated.

97. Proximal tubular dysfunction in the course ofLeptospirosisLiberopoulos E, Alexandridis G, Tsiara S, Tzalas C*,Bairaktari E*, *Pappas G, Elisaf M, Tsianos E.Department of Internal Medicine and *Department ofBiochemistry, School of Medicine, University of Ioannina,GreeceAIM: To describe evidence of a reversible proximaltubulopathy in patients with leptospirosis.CASE REPORTS: The first patient was a 57-year-old manwho presented with acute febrile illness, markedhyperbilirubinemia, acute renal failure and low normalserum potassium levels (K+ 3.55 mmol/L) withinappropriate kaliuresis (fractional excretion [FE] ofpotassium 25%). The second patient was a 39-year-oldwoman who presented with fever and a Fanconi-likesyndrome: serum K+ 3.3 mmol/L, FE K+ 12%, transtubularpotassium gradient (TTKG) 5, serum phosphate 2.1 mg/dl,FE phosphate 24%, serum uric acid 2.4 mg/dl, FE uric acid19.2%. The third patient was a 72-year-old man with fever,marked hyperbilirubinemia (total bilirubin 26 mg/dl),normal renal function and evidence of proximaltubulopathy: serum K+ 3.9 mmol/L, FE K+ 35%, serumphosphate 2 mg/dl, FE phosphate 88%, serum uric acid 1.0mg/dl, FE uric acid 57%. In all cases the increased urineexcretion of a1 and a2 microglobulin was compatible withthe diagnosis of proximal tubulopathy, whereas increasedIgM ELISA antibodies against Leptospira interrogansconfirmed the diagnosis of leptospirosis. Forty to sixty daysafter the initiation of appropriate therapy complete recoveryof proximal tubulopathy was recorded in all patients.CONCLUSION: Dysfunction of proximal tubules is

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common in patients with leptospirosis, whereas obstructivejaundice, when present, can also contribute to the observedFanconi-like syndrome. Leptospirosis should be included inthe differential diagnosis in febrile patients with evidence ofproximal tubulopathy regardless of the presence of jaundiceor acute renal failure

98. Changes in serum lipid lipoproteins and apolipoproteinsin patients with acute infectionLiberopoulos E, *Pappas G, Alexandridis G, Tsiara S,Milionis H, Tzalas C*, Bairaktari E*, Tsianos E, Elisaf M.Department of Internal Medicine and *Department ofBiochemistry, School of Medicine, University of Ioannina,GreeceBACKGROUND: Transitory changes in the serum levels oflipids, and particularly hypocholesterolemia, have beenobserved in the course of acute infections. However, thereare limited data on the effect of acute inflammatory responseon the serum levels of apolipoproteins (Apo) AI, B, E andlipoprotein (a) [Lp(a)].AIM: To examine the incidence of hypocholesterolemia andthe changes of serum lipid parameters during acuteinfection in patients hospitalized in an internal medicineclinic.PATIENTS AND METHODS: Serum lipid parameters weremeasured in 3.000 patients who were admitted to our clinicduring a period of one year. Hypocholesterolemia wasdefined as serum total cholesterol <120 mg/dl.Hypocholesterolemic patients with acute infection werecompared with 116 age and sex matched healthyindividuals. Serum lipid parameters of 20hypocholesterolemic patients with acute infection werefollowed up after their discharge. All values are expressed inmg/dl.RESULTS: Hypocholesterolemia was found in 120 patients(4%). 58 patients (48.3%) had acute infection [45 patients(77.5%) had bacterial infections, 8 patients (13.8%) viralinfections and 5 patients (8.7%) leishmaniasis]. Comparedwith control patients, hypocholesterolemic patients withacute infection had significantly lower levels of totalcholesterol (98 ± 19 vs 204 ± 42, p<0.001), HDL cholesterol(20 ± 8 vs 42 ± 8, p<0.01), LDL cholesterol (59 ± 19 vs 120± 36, p<0.001), ApoAI (64 ± 22 vs 146 ± 24, p<0.01) andApoB (66 ± 20 vs 102 ± 26, p<0.01), whereas serumtriglycerides were unaffected (127 ± 61 vs 120 ± 98).Interestingly, ApoE levels were significantly higher (47 ± 23vs 39 ± 11, p<0.05) and Lp(a) levels were significantly lower[median 3.85 (range 0.8–33.2) vs 7.9 (0.8–56)] comparedwith the control population. During the follow-up the levelsof total cholesterol, HDL cholesterol, LDL cholesterol andApoAI were increased by 48.7% (p<0.001), 45.5% (p<0.05),79.4% (p=0.002) and 88.3% (p<0.001), respectively.Furthermore, ApoE levels were significantly reduced by 36%(p<0.05), while Lp(a) levels were significantly increased(from a median value of 2.5 to a median value of 9.6,p<0.05).CONCLUSION: Infection-induced hypocholesterolemia is afrequent metabolic disorder in hospitalized patients. Ourdata point out that Lp(a) may be a negative acute phasereactant. Furthermore, we show for the first time that serumApoE levels are elevated during the acute inflammatoryresponse.

New antibacterial and antifungal agents99. Evaluation of therapeutic efficacy of Calendulaofficinalis extract in dermatophytose on guinea-pigs

Aghili S.R.*, Asgari- rad H., Shabankhani B.Todays the ointment and oil extract of calendula are used asanti-inflammatory and anti-septic in skin lesions. Theointment (1.5%) and oil extract (1%) were prepared in thelab. For causing exprimental dermatophytose theinoculation of trichophyton mentagrophytes on guinea pigswas done. Then the effect of oil extract and ointment on theillness was studied. The changes of lesion symptoms duringthe treatment and the growth of fungus in culture of skinpieces were analyzed by x2 (chi) test and Fisher exact test.The method was blind case- control. A four-score evaluationcriterion was used (0–3) in order to show the lesion. At theend of the test, the pieces of skin were cultured in Sccmedia. In comparison to control group, in the change oflesion symptoms, the group in which the ointment was usedhad a significant difference after 5 days but the group thatoil extract was used showed the same results after 10 days(p<0.05). After 10 days application, the ointment and oilextract eliminated 73.4% and 53.4% of fungus in skin blockscultured in media. This study shows the positive effect ofcalendula (ointment and oil extract) in the treatment ofdermatophytose caused by trichophyton mentagrophytes onguinea pigs. During 10 days application the ointment had abetter effect.

100. An Evaluation of Fluoroquinolone Expenditures andCiprofloxacin Susceptibility ofP. aeruginosa Among U.S. HospitalsS.M. Bhavnani, W.A. Callen, A. Forrest, K.K. Gilliland, D.A.Collins, J.A. Paladino, and J.J. Schentag.SUNY-Buffalo Clinical Pharmacokinetics Laboratory atMillard Fillmore Hospital, Buffalo, NY.Presented in part at the 39th Interscience Conference onAntimicrobial Agents and Chemotherapy, San Francisco,CA, September 26, 1999. Supported in part by anunrestricted educational grant from Bayer Corporation.BACKGROUND: The impact of fluoroquinolone (FQ)usage, as measured by expenditures, on the susceptibilitypatterns of P. aeruginosa (PA) to CIP was examined in U.S.hospitals participating in the Benchmarking Program from1993–1999.METHODS: Hospitals that provided FQ expenditure dataand inpatient susceptibility patterns of PA to FQs wereincluded in this analysis. Annual FQ expenditures werenormalized by occupied bed (OB), the product of licensedbeds and the average occupancy rate. General linearmodeling (GLM) and repeated-measures mixed effectsmodeling were carried out to determine factors predictive ofPA susceptibility toCIP. Independent variables consideredincluded: annual expenditures/OB for ciprofloxacin (CIP),ofloxacin (OFL), and levofloxacin (LEV), hospital type, OBsize, study year, geographical region, case mix index,average length of hospital stay (LOS), total inpatient days,and scope of antibiotic management activities includingstreamlining and switching from IV to PO.RESULTS: 174 hospitals met the inclusion criteria, eachproviding 1–6 years (median = 3 years) of data for a total of416 hospital-years. The distribution of hospital-years bytype was: 45.9% community teaching, 39.2% communitynon-teaching, 11.3% university and 3.6% government.Median FQ expenditures, which increased gradually from$229.75/OB in 1993 to $399.91/OB in 1998, increased by$219.94/OB (55%) between 1998 and 1999. The proportionof CIP expenditures and LEV expenditures relative to totalFQ expenditures, changed from 76% and 9% in 1998 to 36%and 47% in 1999, respectively. Median PA susceptibilities to

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CIP decreased over the study period from 84% to 71%. PAsusceptibility patterns to other FQ agents were notcommonly reported, and could not be evaluated. By GLM,examining at one variable at a time, increasing expendituresof both OFL expenditures and LEV expenditures weresignificantly associated with decreasing PA susceptibility toCIP, but not with CIP EXP. Increases in CIP, OFL and LEVexpenditures of $100/OB were associated with a -0.23%(p=0.27), -1.44% (p=0.0005), and -1.25% (p=0.00002)decrease in PA susceptibility to CIP, respectively. In the finalmultivariable repeated–measures mixed effects model, thefollowing were associated with decreases in susceptibility:each study year after 1993 (-1.85%, p<0.001), every $100 ofOFL expenditures above $45.39 (-1.20%, p=0.039), andeach day of LOS beyond 5.92 days (-2.17%, p=0.067).CONCLUSION: When the relationship betweenexpenditures for each individual FQ and PA susceptibility toCIP was examined, one drug at a time, increases in bothOFL expenditures and LEV expenditures were significantlyassociated with decreased susceptibility. In themultivariable analyses, study year, OFL expenditures, andLOS were significantly associated with PA susceptibility.LEV expenditures were excluded from the final model due,we believe, to a strong autocorrelation with study year. CIPexpenditures, for which we had the most data and power,showed no association with PA susceptibility changes to CIP.

101. Successful treatment with linezolid of VRE meningitisin a patient with external CSF shuntB. Castiglioni, B. Nocita, M. Langer, P. Marone, L. Minoli, P.Grossi*Clinica di Malattie Infettive IRCCS San Matteo–Univ. degliStudi di Pavia *Dipartimento di Medicina e Sanità Pubblica,Università degli Studi dell’Insubria, Varese, ItalyBACKGROUND: VRE are an increasing cause of severeinfections in the hospital setting in the USA and Europe.Thus far 12 cases of VRE meningitis, occurring primarily inpatients undergoing neurosurgical procedures, have beenreported in the literature. We describe a case of VREmeningitis occurred in a patient with external ventricularshunt (EVS) successfully treated with linezolid (LNZ).CASE REPORT: A 67-years-old female was admitted in ICUbecause of coma due to subarachnoid hemorrage (SAH).Angiography was negative for aneurysms and the patientunderwent EVS placement. Within 24 h the patient arousedwith significant improvement of her neurological status. Thepatient developed a severe bilateral aspiration pneumoniawith high fever. On day 13 after surgery MRSA andAcinetobacter spp were isolated from BAL and blood culturegrew MRSA. She was initially treated with meropenem andamikacin and vancomycin was added on day 14. On day 18post-op, despite discontinuation of the sedation, the patientshowed a decline in the level of consciousness associatedwith meningismus. On the same day the CSF from spinaltap grew VRE without biochemical evidence of meningitis.On day 20 and 21 the CSF were consistent with meningitis(231 cells/mm3 in the CSF obtained from EVS, 620cells/mm3, glucose 31 mg/dl, proteins 159 mg/dl in the CSFobtained from spinal tap); both CSF cultures grew VREwhich was isolated also from the rectal swab collected onday 22. On the same day she was started on LNZ (600 mgb.i.d. i.v.) for 15 days. (Pharmacia & Upjohn PNU-100766;protocol n° 766INF0026-083). On day 25 she was afebrilewith significant neurological improvement, despite thepersistence of meningismus. CSF was normal (1 cell/mm3,glucose 67 mg/dl, proteins 2 mg/dl), but still grew VRE. EVS

was removed and the culture of the tip was negative. CSFobtained on day 31 and on 41 were negative. Patient wastransferred to a subintensive care unit on day 42 withcomplete neurological recovery.CONCLUSIONS: Preliminary PK data indicates that LNZpenetrates into the CSF and its penetration is enhanced inthe presence of inflamed meninges. In the present case theuse of LNZ allowed to achieve clinical and microbiologicalcure of VRE meningitis.

102. Linezolid in the treatment of pneumonia: the resultsfrom the Department of Phthisiopneumonology in Zabrzein the years 1998–2000

Janusz Kaminski, Jerzy Kozielski, Remigiusz KaletaDepartment of Phthisiopneumonology Silesian MedicalUniversity Indirizzo: Zabrze 41-803, Kozio?ka 1, tel/fax: +4832 2745664, e-mail: januszkam@hot.pl PolandLinezolid represents a new group of antibiotics,oxazolidinones. Linezolid is a valuable drug for thetreatment of infections caused by many Gram positivebacteria, including multiresistant species of Streptococcusand Enterococcus. There were 21 patients treated withlinezolid, 7 women and 14 men, age range 18–69 years inthe Department of Phthisiopneumonology in Zabrze in theyears 1998–2000. The indication for linezolidadministration in case of 7 patients was previously untreatedpneumonia with bacteriological or clinical features ofStreptococcus pneumonia infection (Group A). The secondgroup of 14 patient was formed by the patients withpneumonia caused by Gram positive bacteria, confirmedeither by specimen culture or on the ground of clinicalpresentation. These patients were included to linezolid-based regimen of treatment only if they were previouslyunsuccessfully treated, or if there were any counter-indications, e.g., allergy, for the administration of standardpneumonia therapy (Group B). In all the cases when theaetiology of pneumonia was not bacteriologically confirmed,linezolid was administered in combination with aztreonamand/or metronidazole, if it was necessary, on the ground ofclinical presentation. The treatment was administered in7–15 consecutive days, a follow-up visit was performed. 2weeks after the treatment’s termination. The treatment wascompleted by 19 patients, 2 patients died during the study(1 patient form group A, one patient from group B), in thecourse of accompanying disorders, with no relation toadministered treatment. In 5 patients from the group A(71,4%) and 11 patients from the group B (78,6%) acomplete of all the signs and symptoms of pneumonia wasachieved. We didn’t state any side-effects of linezolid–basedtreatment regimens in the analysed groups of patient.Conclusions: 1. Linezolid is an effective and safe antibioticin the treatment of pneumonia, both as a drug of the firstchoice and in the case of the patients with a severepneumonia, in a poor clinical status, also if a previouslyadministered, conventional treatment was not effective. 2. Ina case when no bacteriological confirmation of infection’saetiology is achieved, there is a possibility to administerlinezolid in combination with other chemiotherapeutics inorder to provide a highly effective therapy. Resolution of allthe signs and symptoms of pneumonia was achieved.

103. In vitro evaluation of three synthesized quinolonederivativesS. Mansouri, A. Foromadi, K. Kiani and A. RahmaniThe minimum inhibitory concentration (MIC) of three N-[5-(5-Nitro-2-thienyl)-1,2,3-thiadiazol-2-yl] piperazinyl

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quinolones (compound A,B,and C) were determined againststandard laboratory strains of Staphylococcus aureus,Staphyloccus epidermidis, Bacillus subtilis, Escherichia coli,Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacteraeroginosa, and 20 clinical isolates of S. aureus, usingconventional agar dilution procedure. For comparision ofthe activity ciprofloxacin, enoxacin and norfloxacin wereused as standard antibacterial agents. All the synthesizedderivatives were found to be more active than the standardagents against gram positive bacteria, while their activityagainst gram negative bacteria were much lower than thestandard drugs. Based on the MIC levels compound C wasthe most active agent against S. epidermidis and B. subtilis(MIC=0.0075 µg/ml) and S. aureus (MIC=0.0125 µg/ml).The activity of this compound against clinical isolates of S.aureus was also remarkable and the MIC range was muchlower than the standard antibacterial agents. The highactivity of compound C makes it a good cadidate for furtherstudies.

104. Evalution of the in vitro antibacterial activity of N-piperazinyl quinolon derivatives with 5-nitrofuryl groupM. H. Moshafi, A. Foroumadi, R. AshrafaskariINTRODUCTION: Flouroquinolones are a group ofsynthetic antibacterial agents that exhibite a broadantibacterial spectrum both to Gram-positive and Gram-negative bacteria. In this investigation the in vitroantibacterial activity of N-[5-(5-nitro-2-furyl)-1,3,4-thaidiazol-2-yl] piperazinyl quinolones were determinedagainst Gram positive and Gram negative bacteria usingconventional agar dilution procedure. In this experimentnorfluxacin, ciprofloxacin, and enoxacine were used as arefrence drugs.MATERIALS AND METHODS: The In-vitro antibacterialactivity of the test compounds was investigated incomparison to three standard quinolons against Gram-positive (Staphylocuccus aureus, Bacillus cereus andStaphylocuccus epidermidis) and Gram–negative (Serrathiamarcescens, Klebsilla pneumoniae and Entrobacter aregenes)bacteria using conventional agar dilution procedures. Twofold serial dilutions of the test compounds and referencedrug was prepared in Muller Hinton agar. Petri dishes wereinoculated with (1–5)x105 colony forming units andincubated at 37°C for 18h. The minimum inhibitoryconcentration (MIC) was the lowest concentration of testcompounds that yielded no visible growth on the plate. Thetests were performed in triplicate.RESULTS AND DISCUSSION: The nitrofuryl derivativeswere potent than norfluxacin, ciprofloxacin and enoxacineagainst Gram-positive bacteria but their effect on Gram-negative bacteria were less. The MIC values of testderivatives indicate that these have a potent antibacterialactivity in comparison to refrence drugs against Gram-positive bacteria (MIC = 0.0005–0.002 µg /ml).

105. Antimicrobial and chemical properties of theessential oils from Thymus x-porlock and Salvia officinalis.Iraj Rasooli, Ph.D. (Microbiology)Department of Biology, College of Basic Sciences, ShahedUniversity, Vali Asr - Taleqani Cross, Tehran, I.R.Iran Tel:+98-21-6418580, Fax: +98-21-6418589 e.mail address:irasooli@yahoo.comAn antimicrobial effect of essential oils extracted by steamdistillation from Thymus x-porlock and Salvia officinalis, onE.coli and S. aureus were studied. Disc diffusion method wasused to evaluate the zone of microbial growth inhibition atvarious concentrations of the essential oils. The

antimicrobial effect was also studied against three differentconcentrations of microbial suspension to find out MIC(Minimal Inhibitory Concentration) and MBC (MinimalBactericidal Concentration). Both the oils were bactericidal.Bactericidal concentrations of the oils were determined.They were very effective against E.coli. S.aureus showedslightly more resistance than its Gram negative counterpartto the lethal effects of the oils. Chemical compositions of theessential oils were analyzed by Gas Chromatography andMass Spectrometry (GC and GC/MS). Eight commonchemical compounds at various concentrations in both theoils. Major components of essential oil of Thymus x-porlockwere 1,8-Cineole (54.52%), Sabinene hydrate (5.03%) andthymol (7.89%). Major components of essential oil of Salviaofficinalis were b-pinene (16%), berneol (9.4%), glubulol(9.3%), a-humulene (8.4%), a-thujene (6.4%), a-pinene(5.5%), camphene (5%). Probable contributions of thechemical compositions to the lethal effects of essential oilsagainst microbial genera used are discussed.Key words: Essential oils, Antimicrobial, Thymus x-porlock,Salvia officinalis

106. Synthesis and studies of bacteriostatic activity of 2-aminothiazoleSakalova T.N., Kravchenia N.A.Earlier we have synthesized diamides of dicarboxylic acids,amide components of which are 5-nitrothiazole on the onehand, and urea, biuret, benzolsulphamides, triazol, on theother hand. All the above compounds exhibit bacteriostaticactivity towards certain microorganisms (Khimicheskii iFarmakologicheskii Zhurnal, Vestsi AN Belarusi. – 1993, -No 4, - s.61–63). For further studies of bacteriostatic activityof amides and diamides of dicarboxylic acids, as well as fordetermination of “structure-activity” relationship, we havesynthesized a range of monoamides of 5-nitro- (1a-d) or 5-sulpho-2-aminothiazole (2a-f); that of monoamides of 2-(3a-c) or 4-aminopyridines (4a-b); as well as that of diamides ofdicarboxylic acids, with their amide component being 5-nitro- (5a-f) or sulpho-thyazole-2-yl (6a-c) on the one hand,and 2-or-4-pyridyl on the other hand.

1(a-d) 5-NO2-thiazolyl-2-NH-CO-(CH2)n-COOH(n=3,4,7,8);

2(a-f) 5-SO3H-thiazolyl-2-NH-CO-R (n=C2-7-alcyl);3(a-c) pyridil-2-NH-CO-(CH2)n-COOH (n=3,4,7);4(a-b) pyridil-4-NH-CO-(CH2)n-COOH (n=4,7);5(a-f) 5-NO2-thiazolyl-2-NH-CO-(NH2)n-CO-R

(n=3,4,7, R= pyridyl-2-NH- or pyridyl-4-NH-).);6(a-c) 5-SO3-H-thiazolyl-2-NH-CO-(CH2)n-CO-R

(n=4,7, R= pyridyl-2-NH- or pyridyl-4-NH-).Antimicrobial activity of the synthesized compounds wasstudied in vitro with the use of the method of double seriesdilution in a liquid broth. For this purpose, approximately50 various gram-positive and gram-negativemicroorganisms: Staphylococcus aureus, Bacillus subtilis,Serratia marchescens, Escherichia coli, Proteus morganii,Micrococcus lisodeicticus, Staphylococcus epidermidis, Shigellasonnei and others. These included strains obtained frompatients (E. coli 026, S. aureus 877 st, S. epidermidis 994).Minimum inhibitory concentration was expressed inmkg/ml. Nitazole was used as a comparison substance. Theobtained data demonstrate that diamides of dicarboxylicacids containing a pyridine cycle possess at least the samebacteriostatic activity as nitazole or have a wider activityrange. They inhibit growth of S. aureus in concentration of240 µg/ml, as well as those of S. marchescens inconcentration of 480 µg/ml, P. morganii in concentration of

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62 µg/ml, S. epidermidis in concentration of 250 µg/ml, S.aureus 877 st in concentration of 125 µg/ml, E. coli inconcentration of 125 µg/ml. Compared to Micrococcuslisodeicticus 60 µg/ml and Bacillus subtilis 30 µg/ml,diamides of azelainic acid turned out to be strongerbacteriostatics than nitazole 9103 µg/ml. All mono-(5-nitrothiazole-2-yl) amides of dicarboxylic acids did notexhibit any more antimicrobial activity than nitazole inrelation to all the microorganisms under study with theexception of E. coli K-12 240 µg/ml. Monopyridilamidesproved to be inactive. All similar mono- and diamides of 5-sulpho-2-aminothiazole proved inactive too. Analysis of theobtained results makes it obvious that heterocycles functioninadditively in the studied diamides. The diamides’bacteriostatic effect is due to synergic activity of heterocyclesof thiazole and pyridine. Diacyl radical, too, providesinsignificant effect.

107. Candida inconspicua—a therapeutic problemSwoboda-Kopeæ E 1,2; Bednarska A 2; Krawczyk E 1;Stelmach E 2; Luczak M 1,21 Dept. of Medical Microbiology, Medical University inWarsaw, Poland, 2 Laboratory of Microbiology, CentralClinical Hospital in Warsaw, PolandAIM OF THE STUDY: Estimation of isolation of C.inconspicua from different hospital wards and assessment oftheir susceptibility patterns over a period of 5 years(1996–2000).MATERIAL AND METHODS: Different clinical specimenstested for thr presence of fungi were obtained from patientshospitalized in internal medicine wards, surgical wards,intensive care unit (ICU) and haematological oncologyward.Mycological tests were done according to the standardprocedures (bioMerieux, Sanofi Pasteur). Sensitivity ofisolates to antifungal agents was assayed with Fungitest(Sanofi Pasteur).RESULTS: Strains of C. inconspicua have been isolated fromthe following materials: sputum, tracheostomy tube,peritoneal fluid, stool, urine, drainage catheters, throatswabs and blood. Among 4201 isolated fungi C. inconspicuacomprised 33 strains. The great majority of these isolates(19) originated in the haematological oncology ward. C.inconspicua was most often cultured from tracheostomy tube(1/3 of cases). Susceptibility testing showed sensitivity of thecultivated strains in 75,8% to amphotericin B and 69,7% -ketoconazole. However, sensitivity to 5FC and miconazolewas low (45,5% and 36,4%, respectively).

108. Quinolones in veterinary practiceG. Tillotson1,M. Vaughan,2 Copeland 2

1. Fusion MD, Cheshire, CT, USA2. Bayer Animal Health,Kansas City, KS, USASince the Swann report in 1967 there has been controversysurrounding the use of antimicrobials in animal husbandry,especially for growth promotion. In the last decade therehas been much discussion concerning the use offluoroquinolones (FQ) in food related livestock with specificregard to the potential detrimental impact on human health.In 1995 sarafloxacin was approved followed by enrofloxacinin 1996, for use in very specific infections in poultry.Despite subsequent monitoring programs and improvementsin meat-production processes, the concern over the newfluoroquinolones prompted further investigations asconcerns over campylobacteriosis in humans arose.Data from the National Antimicrobial Resistance MonitoringSurveillance program has shown that FQ resistance in

campylobacter isolated from chickens has remained stablefrom 1998–2000. Also the actual incidence ofcampylobacter cases in humans has decreased. At least twoindependent studies have shown acquisition of FQ resistantcampylobacter to be related to foreign travel, eating inrestaurants, as well as other risk factors. These findings arenot surprising as fluoroquinolones are used sparingly totreat pneumonia in chickens under strict veterinarysupervision. Data presenting susceptibility, incidence,consumption and changes over time will be shown.

109. Anaerobic infections and the role of fluoroquinolonesG.S. Tillotson,1 P.B. Iannini2

1PHRI, NYC and Fusion MD, CT, USA; 2Dept. of Medicine,Danbury Hospital, Danbury, CT, USAObligate anaerobic bacteria are pathogens in a wide range ofinfections, including intra-abdominal, pelvic, vascularinsufficiency ulcers, diabetic fetid foot, aspirationpneumonia, maxillo-facial and in pleuro-pulmonary disease.Frequently these infections are polymicrobic, with bothanaerobes and facultative aerobic species such as Gram-negative bacilli or streptococci. Earlier fluoroquinolones hadpoor in vitro activity against anaerobic species, and agentssuch as ciprofloxacin were not bactericidal under conditionsof reduced oxygen. More recently developed compoundssuch as trovafloxacin, gatifloxacin, and moxifloxacin havesignificantly enhanced activity under anaerobic conditions.Studies in the literature have demonstrated that earlierquinolones, such as levofloxacin selected for resistance totrovafloxacin, suggesting that inappropriate use of lessactive agents may compromise the newer agents. Of thenew class members, moxifloxacin has superior in vitroactivity to that of gatifloxacin: B fragilis MIC90 1 vs 2;Peptostreptococcus spp 1 vs 2–4 respectively. Moxifloxacinhas also been shown to be highly bactericidal asmonotherapy in the rabbit intra-abdominal sepsis model.The improved potency against anaerobes, excellent tissuelevels and efficacy in animal models suggest thatmoxifloxacin may be appropriate as monotherapy in mixedinfections.

110. Safety profiles of new fluoroquinolones: perceptionsversus expectationsG S Tillotson1, S J Watson1, P B Iannini2

1Fusion MD, CT, USA; 2Dept. of Medicine, DanburyHospital, Danbury, CT, USAThe fluoroquinolones have been in clinical practice since1987 with over 450 million patients treated worldwide bythe end of 2000. These agents are generally regarded asbeing safe and well tolerated, however since the withdrawalof temafloxacin due to haemolytic uraemic syndrome(including hypoglycemia) there has been heightenedawareness of occasional idiosyncratic reactions that havebeen reported. As these reactions occur, the regulatorybodies further tighten the process for approval and willalter/update product labeling to include reactions notedsince launch. Of the recent fluoroquinolones approved inthe USA, moxifloxacin and gatifloxacin have beenprescribed to 2 and 3.5 million patients respectively.Examination of the FDA Spontaneous Adverse Events (SAE)Database shows some reactions not noted during Phase IIIstudies, including hypoglycemia: gatifloxacin 12 cases,moxifloxacin 2 incidents; torsade de pointe: gatifloxacin 5;moxifloxacin none in USA (but 3 of 8 million treatedglobally). Of these observations, only the glycemic reactionwas considered worthy of inclusion in new labeling and theexisting similar cardiac labeling for both drugs remained

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unchanged. Further analysis of the FDA SAE Database willbe presented and the data put into perspective relative toother currently available fluoroquinolones.

111. Impact of fluoroquinolone substitution on Pseudomonalsusceptibility rates and antimicrobial use.P.B. Iannini 1, G.S. Tillotson 21-Danbury Hospital, Danbury CT, USA; 2- Fusion MDCheshire CTT, USAThe antimicrobial activity of the fluoroquinolone (FQ) classhas expanded markedly over the last decade. Ciprofloxacinis still the most potent anti-pseudomonal FQ and wasprescribed in our hospital for this period with minimal lossof antibacterial activity. For economic reasons levofloxacinwas added to our hospital formulary in 1999 for thetreatment of CAP and HAP, while intravenous ciprofloxacinwas restricted to cases approved by an infectious diseasespecialist.. Within 12 months the proportion of patientsgiven a FQ who received levofloxacin increased from <2% ofFQ prescriptions in Q4 1999 to >22% in Q2 2000. Howeverthe overall FQ usage did not decrease as anticipated.Concurrently the use of parenteral anti-pseudomonalantimicrobials rose to a peak in Q3 2000 in parallel withincreasing FQ pseudomonal resistance, further adding to thehospital antimicrobial use and costs in the hospital. After Q32000 the use of gentamicin, imipenem, ceftazidime andpiperacillin/tazobactam slowly decreased as quinolonesusceptibilities returned to 77% in Q2001. During theperiod Q1 1998 to Q2 2001, the susceptibility ofPseudomonas aeruginosa to ciprofloxacin decreased by 11%(82%–71%). In the latter part of 2000 levofloxacin wasremoved from the hospital formulary with a subsequent 6%increase in susceptibility to ciprofloxacin occurring over thenext 4 fiscal quarters along with a reduction in the use ofnon-FQ anti-pseudomonal agents. Further analysis of theinfluence of quinolone substitutions and other anti—pseudomonal agents on antimicrobial costs andsusceptibility will be reported. The introduction oflevofloxacin did not achieve the expected cost reductionshospital wide. Levofloxacin appears to have affectedpseudomonal susceptibility to the FQ class with theresultant reduction in ciprofloxacin’s utility.

112. Hematological adverse events (AE) potentiallyassociated with antimicrobialsG.S. Tillotson,1 P.B. Iannini,2 D. Kuter3

1. PHRI, NYC, USA, 2. Danbury Hospital, Danbury, CT,USA, 3. Mass. General Hospital, Boston, MA, USAThe direct and indirect effect of antimicrobials areappreciated by clinicians but poorly understood. The bestknown direct effect is that of chloramphenicol-inducedhemolytic anemia but the range of hematologic effects caninclude thrombocytopenia, leukcopenia and anemia. TheseAE have been reported at varying incidences with severalother classes of antimicrobial agents. The extent, severityand duration of each of these effects are variable, with manyresolving on drug cessation. Recent reports have focused onthe oxazolidinone, linezolid, with transient, mild-moderatethrombocytopenia and anemia occurring at a rate of 1 in750. Analysis of the FDA Spontaneous Adverse EventReport (SAER) database for the 3-year period 1998–2000revealed the following incidences of hematologic effectswith other commonly prescribed antimicrobial agents:Cetfriaxone was associated with the following events indescending frequency thrombocytopenia (7 per millionscrips), decreased hemoglobin and neutropenia each 5 casesper million), leucopenia/leucocytosis (<3.5 per million) and

anemia ( 3 per million). Vancomycin was reported to belinked with neutropenia 4 per million, eosinophilia,leucopenia > 3 per million and anemia 2 per million.Neither piperacillin/tazobactam nor ampicillin/sulbactamwere associated with a significant number of hematolicalreports to the FDA SAER database.

113. A comparison of adverse event profiles of antimicrobialagents used for serious gram-positive infectionsG.S. Tillotson,1 P.B. Iannini2

1. PHRI, NYC, USA, 2. Danbury Hospital, Danbury, CT,USAThe recent increase in multiple antibiotic resistant Gram-positive cocci (GPC) has caused an increase in the usage ofpreviously infrequently used antimicrobial agents and asearch for new agents. These drugs include theglycopeptides, fusidic acid, quinupristin-dalfopristin andmore recently, the oxazolidinone, linezolid. Prior to 1999vancomycin was the only available antimicrobial agent forserious GPC infections (GPCI) so an acceptance of a widerange of adverse events, some serious, was necessary asthere were no true alternatives. Nathwani et al reported a14% premature discontinuation rate with vancomycin.Since 1999 the introduction of quinupristin-dalfopristin andlinezolid has fostered the re-evaluation of the safety profilesof vancomycin and and other drugs used in serious GPCI.The FDA SAER database receives an estimated 5 to 10% ofpossible serious adverse events (SAE), thus the data are anunderestimate of their true incidence.Antimicrobials used for the treatment of serious Gram-Positive infections include vancomycin, ceftriaxone,piperacillin/tazobactam, ampicillin/sulbactam as well as thenewer agents. Vancomycin has been associated in the SAERdatabase with neutropenia, eosinophilia, and anemia, as wellas a low incidence of other abnormal lab. values e.g., raisedbilirubin, hyperglycemia; the CNS effects of vancomycininclude lethargy, headache, and dizziness. Ceftriaxone hasbeen linked with a range of abnormal lab values includingmarkedly altered hepatic markers e.g., ALT, gamma-GT,alkaline phosphatase etc, as well as a range ofhaematological values; thrombocytpoenia, neutropenia andanemia. Some CNS effects were reported with ceftriaxonee.g confusion, lethargy, and agitation seem most common,whereas piperacillin/tazobactam (P/T) has rarely been linkedwith these types of reaction. Indeed the most commonevents observed with P/T include gastro-intestinal reactionssuch as diarrhea & vomiting. Currently the spontaneousreports for quinupristin-dalfopristin and linezolid are fewerin number and quite varied in type, this is probably due totheir recent introduction and extent of use. We await furtherdata and experience with the newer agents, while acknowl-edging the “tolerance” often seen with traditional/olderagents as clinical “experience” grows.

114. Fluoroquinolones and the treatment of acuteexacerbations of chronic bronchitis—focus onmoxifloxacinS J Watson and G S Tillotson,Fusion MD, Cheshire, CT, USAIn recent years, extensive efforts have been made to developnew fluoroquinolones with improved activities againstGram-positive organisms, such as S. pneumoniae. The role ofmoxifloxacin, an 8-methoxyquinolone, for the treatment ofacute bacterial exacerbations of chronic bronchitis (AECB)is reviewed. Moxifloxacin is highly active against H.influenzae, the most common pathogen associated withAECB, and shows excellent activity against the other major

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pathogens, M. catarrhalis, S. pneumoniae, as well as minorpathogens. In comparative trials involving commonly usedtreatment regimens, moxifloxacin (400mg daily for 5d)achieved bacteriologic and/or clinical success rates of 90%or higher. Moreover, in community practice-based studiesdesigned to assess patients sign and symptom resolution,moxifloxacin was reported to provide marked relief and insome studies made patients feel better faster than themacrolide comparators. With its excellent tissuepenetration, re-assuring safety profile and excellentpredictable activity against all common respiratorypathogens, moxifloxacin is an effective, safe, convenientcost-effective, and well-tolerated option in the treatment ofacute exacerbations of chronic bronchitis. The relief ofsymptoms by day 3 or 4 experienced by moxifloxacin-treated patients offers tenable additional advantages formoxifloxacin over current alternative therapies.

115. Comparative in vitro activity of BMS-284756 againstGram positive clinical isolatesM. Bassetti*1, L M. Dembry1,2, P. A. Farrel2, D. A. Callan2 andV. T. Andriole1

1Yale Univ. School of Medicine and 2Yale-New Haven Hosp.,New Haven, CT, USABACKGROUND: BMS-284756 (BMS) is a novel des-fluoro(6) quinolone that has shown excellent potency against awide variety of pathogens. We studied the comparative invitro activity of BMS with gatifloxacin, moxifloxacin,ciprofloxacin, imipenem, amoxicillin/clavulanic acid,tazobactam/piperacillin against 494 clinically isolated Grampositive (GP) organisms.METHODS: E-test methodology was used for allsusceptibility testing.RESULTS: MIC90 (µg/ml) values for BMS, ceftriaxone(CRO), ciprofloxacin (CIP), imipenem (IPM),piperacillin/tazobactam (TZP), amoxicillin/clavulanic acid(AMC), moxifloxacin (MXF) and gatifloxacin (GAT) areshown below:Organisms no strains BMS CIP CRO

S.pneumoniae 65 0.064 3 1S.pyogenes 17 0.125 0.75 0.064S.agalactiae 15 0.125 2 0.064Group G streptococci 10 0.064 1.5 0.032S.viridans 32 0.125 4 1S.aureus MS, Pen S 62 0.047 0.38 4S.aureus MS, Pen R 20 0.047 0.38 4S.aureus MR 75 4 >32 >32S.aureus MR, CIP R 20 4 >32 >32S.epidermidis MS 20 1.5 12 >32S.epidermidis MR 25 4 >32 >32Coag. neg staph. MS 37 0.094 0.38 12Coag. neg. staph.MR 40 3 >32 >32E.faecalis 25 0.38 2 >32E.faecium 25 24 >32 >32

Organisms IPM TZP AMC MXF

S.pneumoniae 0.38 3 1.5 0.25S.pyogenes 0.016 0.094 0.016 0.19S.agalactiae 0.032 0.25 0.047 0.25Group G streptococci 0.016 0.064 0.016 0.19S.viridans 0.25 3 0.75 0.25S.aureus MS, Pen S 0.047 2 1 0.125S.aureus MS, Pen R 0.047 2 1 0.125S.aureus MR >32 >256 32 8S.aureus MR, CIP R >32 >256 32 8S.epidermidis MS 0.25 1.5 3 1S.epidermidis MR >32 64 12 6Coag. neg staph. MS 0.094 2 0.75 0.19Coag. neg. staph.MR >32 128 16 3E.faecalis 2 4 0.75 0.5

E.faecium >32 >256 128 >32

Organisms GAT

S.pneumoniae 0.38S.pyogenes 0.38S.agalactiae 0.5Group G streptococci 0.38S.viridans 0.5S.aureus MS, Pen S 0.125S.aureus MS, Pen R 0.125S.aureus MR 16S.aureus MR, CIP R 16S.epidermidis MS 3S.epidermidis MR 6Coag. neg staph. MS 0.19Coag. neg. staph.MR 4E.faecalis 0.75E.faecium >32MS: methicillin sensitive; MR: methicillin-resistant; CIP R: ciprofloxacinresistant; Pen S: penicillin sensitive; Pen R: penicillin resistant.

CONCLUSIONS: BMS possesses superior activity against GPorganisms when compared to other quinolones and b-lactams making it a promising new quinolone for clinicaluse in treating GP infections, such as community acquiredpneumonia, skin and soft tissue infections, and enterococcalurinary tract infections.

New antiviral agents: HIV, herpes, influenza

116. The effectiveness of specific therapy of herpesvirusencephalitisKazmirchuk Vladimir, Panchenko Ludmila, *)PopovaNatalya, Radchenko Elana, Brusnik Svetlana, TorianikInna Academy of Medical Science, Mechnikoff Institute ofMicrobiology and Immunology, Kharkiv, UkraineOBJECTIVE OF THE STUDY: To determine the terms andindications for specific therapy prescription in CNS affectionprovoked by herpes simplex virus (HSV).METHODS: Clinical assessment of ill children condition:examination, blood, urine and cerebrospinal fluid test,echoencephaloscopy, brain nucleic magnetic resonancetomography, immunofermental HSV infection markersdetection (HSV antigen and anti-HSV Ig M and anti-HSV IgG detection in blood and cerebrospinal fluid). DNA of HSVin blood and cerebrospinal fluid was carried out by PCR.RESULTS: On the basis of clinical and laboratory evidencein 11 from 86 (12.8%) children admitted to hospital inreanimation and in-tensive care department with grave acuteCNS affection, herpesvirus encephalitis was diagnosed. Sideby side with pathogenic therapy, zovirax/virolex in dosage20–30 mg/kg of body mass every 8 hours intravenously wasadministrated to all the patients from the very moment oftheir admission. Such a therapy lasted to 10–12 days. As aresult of conducted treatment 8 from 11 children weredischarged from hospital in satisfactory state, 2 of them,with residuals, such as hemiparesis, mental unsoundness.Unfortunately, one child died because of late hospitalization.Necrotic encephalitis with large areas of brain tissuedestruction was seen in pathologicoanatomic investigation.CONCLUSION: In children with acute herpesvirusencephalitis early intravenous administration (not than 5days later from the beginning of the disease) of antiherpeticpreparations (Zovirax/Virolex) in dosage 20–30 mg/kg of thebody mass is indicated. The effectiveness of this treatmenthas been proved.

117. Complex treatment of children suffering fromCytomegalovirus (CMV) enterocolitis

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Makarenko Vera, Panchenko Ludmila, KazmirchukVladimir, Radchenko Elena, Popova Natalya, Torianik Inna,Brusnik Svetlana, Academy of Medical Science, MechnikoffInstitute of Microbiology and Immunology, Kharkiv, UkraineOBJECTIVE OF THE STUDY: To determine the role of CMVin gastrointestinal tract affection in children and to evaluatetherapeutic effectiveness of recombinant a-2b interferon.METHODS: CMV markers detection in blood of the patientby immunofermental method (anti-CMV Ig M and anti-CMV Ig G), DNA of CMV with the help of DNAhybridization.RESULTS: By means of accurate bacteriological investigationin 35 from 121(28.1 %) children under 3 years of agehospitalized in connection with serious gastrointestinal tractdisorders, pathogens were not detected. On the basis ofpositive results of immunofermental test and DNAhybridization, CMV enterocolitis was diagnosed in them.For treatment of these children side by side with etiotropic(virolex) and pathogenetic preparations recombinant a-2binterferon (IFN) - laferon was applied. The preparation wasadministered in dosage of 30–50 thousands i.u. of the bodymass intramuscularly and by rectum in microenemas 100thousands i.u. daily during 3 to 7 days according to theseriousness of the case. Therapeutic effectiveness of such atreatment was demonstrated by quicker temperaturereaction and intoxication symptoms decrease, by 2 timesshortening of diarrhea duration if compared with thechildren group where complex treatment with IFN therapywasn’t applied.CONCLUSION: The main reasons for IFN administration tochildren under 3 years of age were the following ones:1) physiological immunodeficiency in young children;2) CMV proves to be a weak interferon inductor, whichinfluences the seriousness and duration of infectiousprocess;3) toxicity of preparations generally prescribed for CMVtreatment (foscarnet, gantcyclovir) Recombinant a-2binterferon was well assimilated by children and had no sideeffects.

Pharmacodynamics and pharmacokinetics ofantimicrobial agents

118. A study of nelfinavir pharmacokinetic variability andvirologic response in PI naïve or experienced HIV+childrenG. Gatti*, G. Castelli-Gattinara1, S. Bernardi1, C. De Pascalis,E. Pontali, L. Papa, F. Miletich, M. Bassetti, D. Bassetti,Gaslini Children Hospital, Genoa, and Bambin Gesu’Children Hospital, Rome1, ItalyOBJECTIVES: To study PK/PD characteristics of NFV inpediatric patientsMETHODS: Thirty-five HIV+ children (25 PI naïve and 10PI experienced, all NRTI experienced) treated withnelfinavir (NF) + 2 NRTIs were studied. Demographicparameters were as follows (mean+SD): age: 7.6+2.9 and10.5+3.8 years, weight 21.0+6.9 and 29.3+9.7 kg, baseline%CD4 23.1+11.4 and 14.1+6.4, baseline viral load: 5.1+0.6and 5.1+0.7 log copies/ml, for PI naïve and experiencedchildren, respectively. Twenty children received a meandosage regimen (range) of 47.2 (32.9–62.5) mg/kg BID and15 received 25.8 (17.4–35.7) mg/kg TID, taken with food.Peak and trough plasma concentrations of NFV weredetermined by HPLC (LLQ=0.1 ug/ml) following at least 1month of treatment. The relationship between NFV troughand decrease of viral load at 24 weeks was evaluated for PI

naïve children.RESULTS: NFV trough did not correlate with age, weight, orbaseline %CD4. There was no difference in the mean troughconcentrations for the BID vs. the TID dosage regimen: 2.34(range: not detectable - 6.08) vs. 1.94 (0.13–5.22) ug/ml,respectively. However, there were 8 patients with troughconcentration < 1 ug/ml (wild type IC90, protein bindingcorrected) in the BID regimen and only 2 in the TIDregimen.There was no correlation of dose/kg vs. troughconcentrations, reflecting an extremely high inter-individualpharmacokinetic variability. In PI naïve children there wasno difference in the mean (SD) decrease of viral load at 24weeks of treatment: -2.8 (0.7) vs. –2.1 (1.2) log copies/ml inthe BID and TID groups, respectively.DISCUSSION: In spite of the lower exposure in the BIDregimen the virologic efficacy in PI naïve children did notdiffer from the one observed in the TID regimen, possiblybecause of a higher patient adherence to the BID regimen.The high inter-individual variability of NFV trough suggeststhat TDM may find an application for optimizing NFVdosage regimen in HIV infected children.

119. Pharmacokinetic interaction between indinavir andCHOP (Adriamycin, cyclophosphamide, vincristin).G. Gatti*, C.R. De Pascalis, G. Toffoli1, G. Di Gennaro1, F.Miletich, M. Bassetti, E. Vaccher1, U. Tirelli1, D. Bassetti.Infectious Diseases – DiSEM – University of Genoa, GenoaCentro di Riferimento Oncologico di Aviano (PN)1, ItaliaBACKGROUND: The study had the purpose ofcharacterizing indinavir (IDV) pharmacokinetics in patientswith AIDS undergoing chemotherapy for non-Hodgkinlymphoma HIV-related.METHODS: Nine patients were enrolled at the OncologyCenter of Aviano. They had been on treatment with IDV(800 mg q8h) in combination with two nucleoside reversetranscriptase inhibitors (NRTIs) for at least 3 months Theywere eligible for CHOP chemotherapy (CHOP protocol: fourcycles of chemotherapy alternated by three weeks ofinterval; adriamycin 75 mg/m2, cyclophosphamide 1200mg/m2, vincristin 1.4 mg/m2). Demographic parameterswere: median age (range) 42 (34–59) years, weight 70.1(48–87) kg, gender:8 male. Baseline values of CD4+ cellsand viral load were 280 (72–760) cells/µl and 3.72(1.69–5.08) log copies/ml, respectively. Blood samples forIDV PK were drawn in two occasions for each patients: PIwithout CHOP (controls) before the beginning of the firstcycle of chemotherapy or, at least two weeks after a cycle;PI+ CHOP the same day of CHOP administration. Indinavirplasma concentrations were determined by HPLC at time 0(predose), 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours following amorning dose; the calibration curve ranged between0.025–20 mg/L. The following parameters were comparedbetween study days: AUC, Cmax and Tmax, CO(concentration at time 0) and C8 (concentration at 8 hrfollowing administration) (two tail paired t test).RESULTS: Results were the followings, shown as mean value(SD):

IP without CHOP IP + CHOP p

AUC (mgxh/L) 15.7 (9.7) 21.5 (9.3) 0.03C0 (mg/L) 0.27 (0.26) 0.35 (0.17) NSC8 (mg/L) 0.35 (0.41) 0.15 (0.16) NS

CONCLUSIONS: We observed a statistically significantdifference between the AUC of IDV+CHOP compared to theAUC of IDV without CHOP. The AUC of IDV+CHOP was

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comparable to the AUC reported in literature, while the IDVAUC without CHOP was lower. Based on the results of oursmall study, a modification of IDV dose during the co-administration of CHOP chemotherapy is not required. Theobservation of a lower-than-average AUC of IDV in thispatient population with non-Hodgkin lymphoma (IDVwithout CHOP) needs further verification.

120. Clinical and pharmacokinetic advantages of once-daily dosing of Gentamicin in malnourished childrenA. M. Khan, N. H. Alam, T. Ahmed, A. K. Chowdhury, G. J.FuchsInternational Centre for Diarrhoeal Disease Research,Bangladesh, Dhaka, BangladeshBACKGROUND: Previous clinical studies suggest that oncedaily regimen of gentamicin might be more or equallyeffective and less toxic than the conventional regimen. Toour knowledge, this has not been adequately evaluated inmalnourished children.METHODS: Treatment efficacy, pharmacokinetics andtoxicity of two regimens of gentamicin were evaluated in anopen, randomized clinical trial where 310 moderate toseverely malnourished under five children with diarrhea andpneumonia were studied; 148 received gentamicin 5mg/kg/day once daily (OD) and 162 received the sameamount in 3 divided doses (TD) intramuscularly in additionto ceftriaxone 75 mg/kg/day. Vestibulocochlear function wasevaluated and serum creatinine estimations were doneserially. We also studied pharmacokinetics of gentamicin in59 of OD and 43 of TD group respectively. Results: Baselinecharacteristics were comparable between two groups. Fullrecovery was noted in 64% of OD and 54% of TD(P=0.1)and partial clinical response was identified in 25% ofOD and 27% of TD (P=0.3) group respectively. Responses ofother children were not evaluable. Five patients died in eachgroup. Toxicity was not detected in any patient. Mean±SDof serum gentamicin concentrations in OD were, trough:0.23±0.1, peak at 1h: 11.7 ± 4.1, at 3h: 4.4±1.2, at 5h:2.08±0.9, at 8h: 1.01±0.6, at 23h: 0.24± 0.1; and in TD,trough: 0.45±0.2, peak at 1h: 4.7±1.8 mg/L. Serum peaklevel of gentamicin in OD and trough level in TD weresignificantly higher (P<0.001)compared to correspondingvalues.CONCLUSION: Gentamicin once daily regimen appears tobe safe, equally effective and advantageous compared togentamicin thrice daily regimen in malnourished childrenwith diarrhea and pneumonia.

121. The use of quinolones in Salmonella osteomyelitis: aconvenient treatmentG. Pappas*, N. Akritidis,M. MastoraDepartment of Internal Medicine, General Hospital “G.Hatzikosta” of Ioannina, Greece* Department of Internal Medicine, University Hospital ofIoannina, GreeceTesto: We describe a case of nontyphoidal Salmonellaosteomyelitis of the lumbar spine in a 63-year-old man, andsupport the use of fluoroquinolones as the treatment ofchoice in similar infections. The patient was admitted to theInternal Medicine Department due to spiking feveraccompanied by lumbar pain. Vertebral osteomyelitis wasdiagnosed through Magnetic Resonance Imaging and bonescan, and was attributed to nontyphoidal Salmonella speciesthrough means of blood cultures and serologic tests. Thepatient was successfully treated, initially withchloramphenicole 1g iv qds and later with ciprofloxacin,500 mg bid po for a total period of 80 days. There is no

specific antibiotic of choice in the treatment of Salmonellaosteomyelitis. The use of quinolones has been widelysupported in the current literature. Furthermore, thesuggested duration of treatment in Salmonella osteomyelitisis around 60 days, so the total dose of chloramphenicolmight be high enough to induce aplastic anemia. Finally, theadequate concentration of ciprofloxacin in bone and softtissues after oral dosage has been ascertained. The need forthe patient to complete the treatment, thus minimizing therisk for recurrence, means that a more convenient therapyshould be selected. Ciprofloxacin with its oral dosage twicedaily seems to meet this criterion more sufficiently thanother antibiotics. The proposed antibiotic of choice couldwell be the result of a random therapeutic decision, or itcould be based on subjective criteria. Our proposed choicetreatment is an effective and convenient treatment, whichfacilitates a full antibiotic dosage and, reduces the risk ofrelapse.

122. Evaluation of nitric oxide effect on gentamicinenephrotoxicity by measurement of urinary enzymeactivitiesShams S., Faghihi M., Kadkhodaee M. Ghaznavi R.Faculty of Medicine, Tehran Medical Sciences University,Tehran, IRANThe role of nitric oxide (NO) on renal physiology andphatology is controversial. It has been suggested that NOmay ameliorate renal injury in acute renal failure (ARF). Inthis study, the effects of inhibition or induction of NOsynthase (NOS) on renal toxicity of gentamicine wasinvestigated using measurements of urinary lactatedehydrogenase (LDH) and alkaline phosphatase (ALKP)activities. Kidneys from male albino rats (n=48) wereperfused in situ for 115 min and the urinary samples werecollected at 70, 90, and 110 min of perfusion for 5 min. Sixgroups of rats were studied in which L-Name was used asNOS inhibitor and L-Arginine was used as a precursor ofNO. The groups were as follows:

1) Control with no treatment2) L-Arg (2mM)3) L-Name (0.1mM)4) gentamicine (0.5mg/ml)5) gentamicine +L-Arg6) gentamicine +L-Name

Activities of LDH & ALKP in urine samples were measuredby IFCC methods on Hitachi 704 analyzer. Groups 2,3 and 5didn’t show significant differences in enzyme activitiescompared with control (ALKP 285 vs 280 U/L) and (LDH130 vs 122.5 U/L). In group 4, significant increase inenzyme activities was seen compared with control (ALKP686 vs 280 U/L) and (LDH 280 vs 122.5 U/L) P<0.01.Discussion: Perfusion with L-arginine before gentamicinesignificantly decreased toxicity while perfusion with L-Namebefore gentamicine increased toxicity significantly,compared with gentamicine group (P<0.001). This studysuggests that NO can protect the kidney from gentamicinetoxicity.Key words: Nitric oxide, gentamicine, kidney, ALKP, LDH

Pharmacoeconomic approach to antibiotics andcontrol in hospital use

123. Economic and clinical features of HIV diseaseevolution todayRoberto Manfredi1, Leonardo Calza1, Antonio Gramegna1,Franco Bocci1, Paola Fiacchi2, Daniela Corsini2, Francesco

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Chiodo1

Department of Clinical and Experimental Medicine,Division of Infectious Diseases, University of Bologna1 andDepartment of Pharmacy2, S. Orsola-Malpighi Hospital,Bologna, ItalyIn order to provide an updated balance of the clinical,assistance, and economic evolution of HIV infection andAIDS, the major clinical end-points of HIV diseasemorbidity and mortality were compared with the health careresource use, the progressively increasing employment ofhighly active antiretroviral therapy (HAART) and the use ofother prescription drugs, in an 8-year study involving ourcohort of ~1000 patients followed every year, and includingboth the pre-HAART and the HAART era. Directexpenditures for antiretroviral agents reached even 95.8% ofoverall costs attributable to administered drugs and bloodderivatives of our entire Division in the year 2000 (versus66% registered in 1995; p<.001), while costs related to otherprescription drugs and blood derivatives remainedsubstantially stable through time (Table: costs expressed inITL).Overall pharmaceutical expenditures

Years Antiretrovirals All other drugs

1994 642,800,000 data not available1995 825,000,000 382,274,0001996 1,086,800,000 503,156,0001997 4,650,300,000 294,628,0001998 6,184,100,000 421,755,0001999 10,129,800,000 490,434,0002000 9,557,000,000 259,544,000

Years Blood derivatives Total

1994 data not available —1995 42,730,000 1,250,004,0001996 37,750,000 1,627,706,0001997 127,391,000 5,072,319,0001998 51,534,000 6,657,389,0001999 177,151,000 10,797,385,0002000 159,338,000 9,975,882,000The huge increase of costs related to anti-HIV drugsdescends from a significant rise of patients who underwentassociated antiretroviral therapy through time (from 32.2%in 1994, to over 79% in the year 2000; p<.001), and themean number of administered drugs per single treatedpatient (from one in 1994, to over 3.1 in the year 2000;p<.001). On the other hand, a clear shift towards outpatientassistance of HIV infection was realized during recent years(with only 33.7% of all inpatients suffering from HIV-relateddisorders in 1997, compared with an average rate of 60–70%during previous years). This situation allowed an increasedand greatly varied spectrum of infectious diseaseshospitalized at our inpatient and Day-Hospital units,compared with years preceding HAART introduction(Table). In fact, a reduction

Inpatient admissions

Years HIV-pos. HIV-neg. Total1994 228 147 3751995 318 181 4991996 281 204 4851997 192 377 5691998 198 361 5591999 151 374 5252000 137 237 3742001 (June 30) 78 89 167

Day-Hospital admissions

Years HIV-pos. HIV-neg. Total1994 109 20 1291995 96 19 115

1996 78 8 861997 101 70 1711998 118 135 2531999 76 139 2152000 143 164 3072001 (June 30) 76 99 175

AIDS cases

Years Notified Deceased1994 66 361995 79 411996 56 301997 38 91998 21 71999 15 72000 11 52001 (June 30) 6 2

of HIV-related inpatient admissions occurred immediatelyafter large-scale HAART introduction occurred in 1997(p<.001), while patients admitted to our Day-Hospitalservice for non-HIV-related diseases dramatically raisedduring recent years (+42.8% in 2000, and an estimated+62.8% for the year 2001), with a parallel decrease of HIV-associated admissions (from 83–90% until 1996, to53.4–64.6% from 1998 to 2001 (p<.001). The reduction ofprolonged HIV inpatient admissions and the proportionalincrease of hospitalizations due to other infectious disease,led to a progressive rise of absolute number of admissions(from 406/year in tbe pre-HAART era, to 483/year since1997; p<.0001), and an even more evident increase ofpatients admitted to Day-Hospital unit (from around110/year until 1996, to nearly 297/year in the HAART era(p<.001). In the meantime, a significant drop of both AIDSnotifications and related deaths occurred since 1997(p<.001). Thanks to the significant reduction of inpatientexpenditures, even the very elevated costs of management ofHIV disease based on HAART and periodic virological andimmunological monitoring, are expected to remain justifiedand cost-effective, at least during the next few years. Therelevant modifications occurred in both epidemiology andassistance needs of HIV infection following HAARTintroduction require structural and organizativemodifications, adequate to the different profile of patientshospitalized at Infectious Disease divisions, a revision ofhuman, economic, and technical available resources, and theprovision of novel assistance models for the upcoming years.A long-term pharmacoeconomic balance does not seempossible at this time, due to the continuously “movingtarget” represented by changes occurred in both monitoringand treatment of HIV disease, and its varying natural history.Anyway, obtaining a clinical stabilization of a disease whichwas frequently invalidating or lethal since five year ago,seems to fully justify the use of all available scientific andhealth care supports from a social and ethical point of view(even more than from a strictly pharmacoeconomic one),pending further promising solutions.124. Impact of a glycopeptide restriction policy in a largeItalian hospitalB.Rebesco*, G.Cenderello, C.Ghersi*, M.Bassetti, A.DiBiagio, M.E.Amalfitano* and D.Bassetti.Department of Infectious Diseases University of Genoa,Genoa-Italy*Dept. of Pharmacy, San Martino Hospital Genoa- ItalyBACKGROUND: The use of glycopeptides has beenrecommended by international guidelines (CDC, IDSA,SHHEA) only for culture confirmed infections sustained byGram positive bacteria, as Staphylococcus aureus andEpidermidis meticillin resistant (MRSA and MRSE). In fact,

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the overuse of these molecules has selected Gram positiveresistant strains: Enterococci vancomicin resistant (VRE)and Staphylococcus aureus vancomicin resistant (VISA,VRSA).AIM OF THE STUDY: The aim of this study is to examineand to analyse the way of prescriptions in order to evaluatethe appropiateness and to plan strategies for prescriptioncontrol.MATERIAL AND METHODS: From January 2001 the singlepatient demand has been introduced for glycopeptides, onthis form physician has to sign:

• Gender• Underlying disease• Kind of infection• Previous antimicrobial therapy• Microbiological result• Infectious diseases specialist ‘s opinion• Scheduled therapy(and dosage)

In this work we are analysing the preliminary results aboutone month of survey.RESULTS: During the month of survey 82 treatments havebeen administrated to 77 pts. (43 male and 38 female);1008 gr of vancomycin and 138 gr of teicoplanin wereprescribed. 25% of patients were admitted in oncologydepartments (dpts), 17% in internal medicine dpts, 10 insurgery dpts, and 5% in orthopaedic dpts. 17% of infectionstreated were pneumonia, 14% abdominal, 11% sepsis orfever of unknown origin. Glycopeptides were used inphrophylaxis only in 7% of single patient demand form.In62% of treatment Glycopeptides have been used on thebasis of a confirming culture but only in 5% these antibioticsrepresent the unique therapeutic chance. Comparing thedrugs use in the same period in February 2000, we canobserve a deep reduction of expenditure for these molecules.Reduction is about 33%, and it is more clear in surgerydepartments (41%) than in Internal Medicine (26%); thesedata show how there was an over use of these drugs mainlyrelated to surgery phrophylaxis.CONCLUSIONS: As already claimed by many scientificpapers, glycopetides use is frequently inappropriate. Evenin a big hospital as San Martino Hospital, where activeguidelines in antimicrobial therapy are working and wherean antimicrobial optimisation policy has been applied since1996, we have relieved a misuse or overuse of thesemolecules when other therapeutical options are available.

125. Changing cost of antiretroviral therapy in pediatricsItalian HIV serviceR. Rosso*, A. Di Biagio, T. Emanueliº, A. Beltrame, R. Rossiºand D. BassettiDept. of Infectious Disease, University of Genoa, ºPharmacyService G. Gaslini, Genoa, ItalyBACKGROUND: New therapeutic strategies and newdiagnostic methodologies have improved the quality and thelifetime of HIV-infected patients (pts); however theseadvances have produced a steady increase of the health caresystem. This study analyzes the changing cost of drugtherapies in children with HIV infection (HIV+) between 1January 1995 to 1 January 2001 in the Department ofInfectious Disease at Gaslini Institute.METHODS: For each years we have calculated the numberof pts followed by day hospital structure, mean age, meanbodyweight, the number of pts in antiretroviral therapy, thetype of highly antiretroviral therapies prescribed (HAART),the total monthly cost of the antiretroviral therapy (ART)and IVIG prophylaxis and the mean cost per patient-month

for ART and Ig. We considered HAART only the association≥3 drugs.RESULTS:

1995 1996 1997 1998

Nº pts 32 37 37 47Nº pts in ART 25 32 27 40Mean age (years) 7 7 8 8Body-weight (Kg) 20 22 26 26Total monthly cost ART £ (106) 9.7 11.5 14.0 42.0ART mean cost per patient-month £ (106) 0.4 0.3 0.5 1.0Total monthly cost IVIG £ (106) 10.6 15.6 16.8 17.0IVIG mean cost per patient-month £ (106) 0.5 0.6 0.6 0.6HAART — — 2 15

1999 2000 2001

Nº pts 51 49 48Nº pts in ART 45 45 44Mean age (years) 9 10 10Body-weight (Kg) 28 29 31Total monthly cost ART £ (106) 61.0 72.0 71.0ART mean cost per patient-month £ (106) 1.3 1.6 1.6Total monthly cost IVIG £ (106) 14.6 9.8 6.1IVIG mean cost per patient-month £ (106) 0.7 0.7 0.8HAART 31 34 35

CONCLUSIONS: In the study we report HAART efficacy,proved by increase number of the patients, the mean age andthe increase of body weight; while the use of IVIG isprogressively decreased, because of their low protectiveeffect for serious bacterial infection observed in ourexperience, with a consequently incidence in the global costof the pts. In any case we believe that the considerableexpenditure in antiretroviral drugs are well worthy whencompared to improvement of quality and prolongation oflife.

Progress in hepatitis

126. Hepatitis-B Vaccine and Murine SchistosomiasisOssama N. Mohamed*, Safeya M. Ali, Lobna A. El-Zawawyand Sonia R. AllamMicrobiology Department, High Institute of Public Health*and Parasitology Department, Faculty of Medicine,Alexandria University, Alexandria, Egypt.In tropical countries, the effect of some infection on theimmunological response to vaccination regimens should beconsidered.Schistosomiasis, which is a major health problem in theseareas, results in a suppressed immune response to a varietyof antigens. Conversely, some killed bacteria or viruses havebeen reported to elicit protective effect against schistosomalinfection.The aim of the present study was to investigate the influenceof schistosomal immunosuppression on the antibodyresponse to Hepatitis-B Vaccine (HBV) and to study if thevaccine has any protective effect on experimentalSchistosoma mansoni (S. mansoni) infection.Swiss strain Albino mice vaccinated with HBV were infectedwith S. mansoni cercariae at varying intervals. Results of thepresent study revealed that S. mansoni infection reduced theserum antibody level against HBV. Parasitological and

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histopathological findings showed significant protectionagainst S. mansoni infection. In order to reduce theincidence of virus-B infection especially in schistosomiasisendemic areas, public health officials should evaluate apolicy for regulation of HBV booster vaccination to enhancethe population immunity against hepatitis-B infection.

127. HIV-HCV co-infection: an Italian reportP. Pedemonte*, M. Marturano, M. Feasi, L. Papa, A. Collidà,G. Mazzarello, D. BassettiDepartment of Infectious Diseases- San Martino Hospital-GenoaBACKGROUND: The co-infection by HVC and HIV is quitecommon, because both viruses share the same transmissionroutes; a high prevalence of co-infection was especiallyobserved among injection drug users. A number of studiessuggest that HIV infection worsens HCV diseaseprogression. Several series have observed an increased riskof hepatotoxicity in patients receiving HAART, whichdepends on the specific antiretroviral agent but may be alsothe result of the immune reconstitution in course of therapy.Few data are available about treatment of HCV infection inpatients co-infected by HIV; on the basis of these data, theresponse to treatment doesn’t differ from patients withoutHIV infection, but safety and interaction with other drugs,especially antiretroviral agents, of interferon and ribavirinneed to be explored more.PATIENTS AND METHODS: We evaluated retrospectivelyfor age, sex, risk factors, CD4 cells count, antiretroviraltherapy, HCV and HBV serology, levels of serum alanineaminotransferase (ALT) and aspartate aminotransferase(AST) 400 patients infected with HIV observed in ourDepartment between July 00 and July 01.RESULTS: Among the 400 patients examined, 152 (38%)were female and 248 (62%) male; the main risk factor wasinjection drug use in 236 patients (59%), then sexual risk,in 106 (26.5%) with opposite-sex partner and in 38 (9.5%)with same-sex partners. HCV serology was positive in 250patients (62.5%) and negative in 150 (37.5%). Amonginjection drug users, HCV serology was positive in 95.8%; infact, the main risk factor for HCV positive patients wasinjection drug use (90.4%), while most HCV negativepatients had a sexual risk (89.3%) and 10 patients only(2.5%) were injection drug users. Moreover, there weremore male patients (68%) among HCV positive than HCVnegative (52%). Last ALT and AST levels of patients withHCV infection, were within normal range in 110 subjects(44%), 1 or 2 to time upper limit of normal (ULT) in 82(32.8%) and more than 2 time ULT in 58 (23.2%). At thesame moment, 164 (65.6%) patients were receivingantiretroviral therapy. ALT and AST levels in these subjectswere upper normal range in 102 (62.2%), in 46 (28%) morethan 2 time ULT, while in patients not receiving anyantiretroviral drug (88), AST and ALT levels were over 2time ULT in 12 patients only (13.6%).CONCLUSIONS: In our study, prevalence of HCV-HIV co-infection was particularly high (62.5%). This, probably, is aconsequence of high frequency of injection drug use in theobserved patients. Our data confirm that the main HCVtransmission route is injection drug use, while sexualtransmission is rare, since only 4% of patients with co-infection HIV-HCV had a sexual risk. Male HCV positivewere more numerous because of more frequency of maleamong injection drug users. We considered ALT and ASTlevels as hepatic disease index, since histological evaluationwas available in few patients only. High frequency of AST

and ALT levels ULT in observed patients (56%) suggeststhat HIV co-infection may worsen HCV disease progression.Moreover, higher frequency of ALT and AST levels over 2times ULT in patients who receive antiretroviral therapy,should confirm a rule of HCV infection in hepatotoxicityobserved in course of HAART.

128. Diagnostic and evolutinoary aspects in HCV-HIVcoinfected childrenF. Toscanini, G. Cenderello, S. Vasile, E. Pontali, R. Rosso,B. Ciravegna, D. BassettiDept. of Infectious Diseases, University of GenoaINTRODUCTION: HIV infection is progressively becominga chronic disease, characterised by longer life-expectanciesand a better quality of life. So, HCV-coinfection could be animportant prognostic factor because of its possiblecomplications. Besides, immune system restoration, inducedby potent antiretroviral therapy, could increase cell-mediateddamage in liver. Literature data concerning these matters arestill unclear and poor, and even less is known in paediatricage.METHODS: We considered the paediatric patients with HIV-HCV coinfection among the 50 HIV-infected childrenfollowed by our Department. For each child we evaluatedage, sex, CDC classification for HIV infection, antiretroviraltherapy, presence of anti-HCV antibodies (Ab), qualitativeand quantitative HCV-RNA determination, genotype, courseof hepatic enzymes, US scan and histological examination ofliver biopsy.RESULTS: Our cohort included 8 children, 5 males and 3females; mean age was about 11.5 years. All their mothershad been i.v. drug-addicts. According to 1994 paediatricCDC classification, children belonged to the followingcategories: 1 A1; 1 A2; 2 A3; 1 B1; 2 B2; 1 C3. They all wereunder antiretroviral combination therapy: 3 with 2-drugregimens, 5 with 3-drug regimens. At the moment of thestudy, all patients presented anti-HCV Ab. Two of them hadpresented persistent hypertransaminasemia longer than oneyear, in absence of anti-HCV Ab; in these cases, diagnosiswas obtained on the basis of HCV-RNA; later, anti-HCV Abappeared. All 8 patients presented HCV-RNA in plasma; itsmedian level at last visit was 9.8 x 105 copies/ml (range 6.9x 102–3 x 106). The 7 available genotypes were: four 3a, two1a, one 2a/2c. Course of hepatic enzymes during the last 12months was: constantly normal in 2 patients, and elevated inthe remaining 4; 1/4 pt. presented AST steadily below 80UI/L, whereas 3/4 showed AST values always higher than 80UI/L.Three out of 5 patients evaluated for autoimmunitypresented auto-Ab: ASMA in 1, c-ANCA in 1, ANA in 1. Sixpatients underwent US abdomen scan; 3 patients presented anormal aspect, 1 showed mild hepatomegaly, another 1revealed hepatosplenomegaly, the last one showedhepatosplenomegaly in association with indirect signs ofportal hypertension and hepatoduodenal linfoadenopathies.We obtained 3 recent liver biopsy specimens: in 1 case onlymild steatosis was present, in the others we found importanthistological abnormalities (fibrosis grade 2 in 1 pt and grade3 in the second one; inflammation grade 2–3 in both ofthem following SCHEUR classification). No extra-hepaticcomplications were present.CONCLUSIONS: In our cohort, HCV disease progression isnot related to the severity of HIV disease, as it has insteadreported in adults. However, the evolution towards cirrhosisis possible, as documented in one of the children. Nocorrelation between HCV-RNA levels, hepatic enzymeslevels and autoimmunity was observed. Identified genotypes

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belonged to the most frequently observed ones in drug-addicts in our region. Moreover, we must remember that it isworth searching HCV-RNA in all HIV+ paediatric patientswith persistent hypertransaminasemia, even withoutdetectable anti-HCV Ab.Our study is not large enough todraw general conclusions, but, in consideration of thepotential hepatoxycity of almost all antiretroviral agents,HCV-HIV coinfected children’s hepatic function should bemore strictly monitored. Finally, consideration must begiven about possible future treatment of these patients,because of drug interactions and possible effects on growth.

Respiratory tract infections

129. Diagnostic and therapeutic approach of bacterialpneumonia (in the absence of sputum culture), based ondiagnostic information of risk factors (sensitivity,specificity, PVP, PVN)E.Anevlavis, Niki Petroglou, S.Anevlavis, * GeorgiaKalpakou, A. Tzavaras, Maria. Papadaki, Spyridoula KitsouKonstantopoulio General Hospital, N. Ionia “Agia Olga”,GreeceOBJECTIVE: Microbiological diagnosis of pneumoniapresents problems, due to the unreliability of the sputumcultures. We propose clinical etiological diagnosis, based onthe presence or absence of risk factors that may help in thechoice of antimicrobial therapy.PATIENTS/METHODS: Prospective study of 320 patients,with pneumonia. Inclusion criteria: pulmonary infiltrate(CXR), fever >38.2 o C (rectum), WBC ≥ 15,000 ( ≥ 75%PMN), ESR>50, productive cough, purulent sputum, clinicalsigns of pulmonary consolidation. Patients were included inthe study if sputum culture yielded the same microorganismas the one observed in the Gram stain examination of thesame sample (e.g., gram positive diplococci and culture:Streptococcus pneumoniae). Acceptable sputum specimen:sum of the points (Table 1) for the epithelial cells and PMNpositive number. In each patient the following risk factors(RF) were recorded: None, COPD, Alcoholic (ALC), age >65, hospital acquired pneumonia (HAP: 72 hours afteradmission). Determination of Sensitivity (SE), Specificity(SP), Predictive Value Positive (PVP) and Negative (PVN).95% CI was calculated. The pneumonia was divided intopneumococcal and non-pneumococcal. PNC: Pneumococcus,ST: Staphylococcus, HIN: Haemophilus influenzae, GNB:Gram negative bacilli.RESULTS/CONCLUSION: 1. RF 2, 3, 4, 5 have a PVP fornon pneumococcal pneumonia above 0.7 and patients withthis combination of factors should not be treated withpenicillin G. 2. Absence of any RF has a PVP forpneumococcal pneumonia above 0,7 (Strept. pneumoniaeincidence of 41%) 3. ROC curves for the different RF will beuseful and have been constructed.

130. The efficacy of moxifloxacin compared to levofloxacinand amoxicillin clavulanate in reducing “practice timeuse” for the treatment of acute bacterial sinusitisG. Corcoran,1 A. Roselli, 2 D. Haverstock,1 C. Pause,1 M.Faruqi,1 and D. Church1

1Bayer Corporation, West Haven, CT; 2Physicians ResearchNetwork, Avon, CTBACKGROUND: Annually, approximately 16% of adults inthe U.S. are diagnosed with acute bacterial sinusitis (ABS).Such infections are not only associated with a reducedquality of life for patients, but also significant direct costs tothe health care system resulting from second prescriptions

for the same indication, laboratory and clinical testing, aswell as surgical intervention.METHODS: In this multicenter, randomized, open labelclinical trial, patients with ABS received treatment for 10days with one of the following: moxifloxacin (MXF) 400 mgPO qD, levofloxacin (LEVO) 500 mg PO qD, or amoxicillinclavulanate (AMOX/CLAV) 875/125 mg PO BID. Theprimary efficacy variable was the effect of therapy on“practice time use,” measured by the rate of secondprescriptions (for sinusitis or treatment of medication sideeffects) during therapy and for the 14-day period after theend of antibiotic therapy. The secondary efficacy parameterevaluated the rate of symptom relief at day 3 of therapy asmeasured by the Sino-Nasal Outcomes Test-16.RESULTS: Within a subset of 746 patients in the intent-to-treat population, rates of “second prescriptions” were 12%(30/247), 14% (35/251) and 18% (44/248) for MXF, LEVOand AMOX/CLAV, respectively. Differences between groupsdid not reach statistical significance. A similar pattern interms of symptomatic relief was observed (n=715), with45% (104/233) of MXF-, 42% (102/242) of LEVO- and 40%(97/240) of AMOX/CLAV-treated patients reportingsymptomatic relief by day 3 of therapy.CONCLUSION: With clinical equivalence usuallyestablished between comparator drugs used in the treatmentof sinusitis, other outcome measures become increasinglyrelevant. While not statistically significant, these resultssuggest that MXF-treated patients not only required fewersecond prescriptions but also reported feeling better fasterthan those treated with LEVO and AMOX/CLAV,respectively. The consistent, favorable patterns exhibited byMXF in this study suggest significant benefits to payors,physicians and patients in terms of cost savings and overallsatisfaction.

131. Community acquired pneumonia (CAP) guidelines:evaluation of antibiotics, outcomes, and cost in a largeteaching hospitalDebra A. Goff, Pharm.D., Sondra J. Sierawski, R.Ph., TheOhio State University Medical Center, Columbus, OH, USAInadequate empiric antibiotic therapy is an independent riskfactor for mortality in-patients with (CAP). The mostappropriate empiric antibiotic choice for CAP will dependupon local antibiotic resistance patterns, patientdemographics, epidemiological data, and cost. Empirictherapy of CAP is directed against Streptococcus pneumoniae,Haemophilus influenzae, and the atypical pathogens such asMycoplasma pneumoniae, Chlamydia pneumoniae, andLegionella pneumophilia. Antibiotic guidelines for treatmentof CAP vary from hospital to hospital. The Ohio StateUniversity Medical Center (OSUMC) is a 700-bed teachinghospital. We developed a practice guideline for CAP thattook into account local resistance patterns, patientdemographics and cost of antibiotic therapy. The OSUMCantibiogram reported 6% penicillin resistant streptococcuspneumoniae (PRSP). Azithromycin + ampicillin/sulbactamwas recommended for empiric coverage unless the patientwas critically ill or had modifying factors such as suspectedPRSP. Levofloxacin was the preferred antibiotic for thecritically ill patient when PRSP was suspected ordocumented. The purpose of this study was to assess theclinical and economic outcome of patients who receivedazithromycin or levofloxacin for CAP, with a secondary goalto determine the appropriateness of the guidelines.METHODS: This was a retrospective analysis of all patientswho received azithromycin or levofloxacin between Sept

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1999–May 2000, for the treatment of CAP. Demographic andepidemiologic data included age, gender, and theenvironment of the patient prior to hospitalization. Theenvironments included home, prison, nursing homes, ortransfers from outlying hospitals. Antibiotic use prior tohospitalization at OSUMC was recorded. Clinical andmicrobiological outcomes were recorded. Clinical successwas defined as resolution or improvement of clinical andlaboratory signs of infection. Microbiologic success wasdefined as eradication by culture or presumed eradicationwith a favorable response. Adverse drug reactions (ADR)and discharge antibiotics were identified. Hospital length ofstay and total cost of care were calculated.RESULTS: A total of 163 hospitalized patients with CAPwere evaluated. Azithromycin was given to 124 patients: 40as monotherapy, 41 in combination with ampicillin/sulbactam, 35 in combination with anti-pseudomonalantibiotics, and 8 in combination with others. Meanage=63.9+17.5, 53% male. Environment prior tohospitalization was 80% from home, 9% transfer from otherhospital, 5% nursing home, and 6% prison. Prior tohospitalization, 26 (21%) patients failed or had intoleranceto oral outpatient antibiotics. Microbiologically evaluablepatients were 4% (5/109) with bacteremia; 2 streptococcuspneumoniae (1 PRSP), 1 a-hemolytic streptococcus, 1enterococcus faecalis, 1 staphylococcus aureus, and 29%(22/77) positive sputum cultures (1 PRSP). Microbiologicsuccess was 98%. Clinical success was 98%. Mortality was1%. ADR’s were diarrhea (1%). Discharge oral antibioticswere azithromycin 23, amoxicillin/clavulanate 41,azithromycin + amoxicillin/clavulanate 24, levofloxacin 5,other 20, none 11. Mean hospital LOS=4.6+3.1 days. Meancost=$4,850+3,540 USD. Levofloxacin was given to 39patients: 23 as monotherapy, 7 in combination withampicillin/sulbactam, 9 in combination with others. Meanage=61+17.9, 67% male. Environment prior to hospitalizationwas 72% from home, 7% transfer from other hospital, 15%nursing home, and 5% prison. Prior tohospitalization, 13 (33%) patients failed or had intoleranceto oral outpatient antibiotics. Microbiologically evaluablepatients were 3% (1/39) with Klebsiella pneumoniaebacteremia, and 58% (14/24) positive sputum cultures(1PRSP). Microbiologic success was 90%. Clinical successwas 85%. Mortality was 8% (3/39). ADRS’s were C. difficlediarrhea (10%). Discharge oral antibiotics were levofloxacin22, azithomycin 5, metronidazole 2, other 4, none 6. Meanhospital LOS=4.7+4.4 days. Mean cost = $5,590+7,444 USD.CONCLUSION: Good clinical outcomes support theOSUMC practice guideline for CAP. The low rate ofdocumented PRSP (<2%) supports the use of azithromycinas the preferred antibiotic unless modifying factors arepresent. Levofloxacin is preferred in critically ill patientswhen PRSP is suspected or documented. The mortality, costof care, and ADR’s were higher in the levofloxacin group.The severity of illness and admission to the intensive careunit may explain the higher mortality and cost. Weidentified several inappropriate orders for dischargeantibiotics, therefore revisions to the guideline will includerecommendations for appropriate discharge antibiotics.

132. An open, controlled, randomised, national studycomparing oral levofloxacin 500 mg OD vs ciprofloxacin750 mg BID for 7 days in the treatment of patients withacute exacerbations of chronic bronchitisC. Grassi * and the Italian Multicenter AECB Study Group* Direttore Scuola di Specializzazione in Malattie

dell’Apparato Respiratorio Università degli Studi di PaviaPatients affected by chronic bronchitis frequently experienceepisodes of acute disease superimposed on the chroniccondition. These acute exacerbations are characterized byfactors such as a worsening cough and respiratory distressand an increase in sputum volume and purulence. The mostcommonly isolated bacteria are H. influenzae, S. pneumoniaeand M. catarrhalis. These episodes, besides influence thepatient quality of life, sensibly worses the prognosis,reducing the respiratory functionality; moreover, manypatients are empirically treated at home, so antibiotictherapy has to be started as soon as possible and the drug ofchoice should be effective against the majority of potentiallyinvolved bacteria. Levofloxacin is a new fluoroquinolonewith a broad antibacterial spectrum, pharmacokineticcharacteristics allowing a once-a-day administration, and agood safety profile. Aim of this study was to compareclinical and bacteriological efficacy and safety oflevofloxacin 500 mg OD and ciprofloxacin 750 mg BID for 7days in adult outpatients affected by acute exacerbation ofchronic bronchitis (AECB) (type I and II of Anthonisen’sclassification). The following results refer to the analysiscarried out on preliminary data (intention-to-treat analysis)obtained in 324 patients, enrolled in 28 Italian Centers. Of324 patients, 162 received levofloxacin and 162ciprofloxacin. In levofloxacin group 117 and 45 patientswere suffering from Anthonisen’s type I and type II AECBrespectively; in ciprofloxacin group AECBs were classified astype I in 124 and II in 38 patients. The infection severitywas mostly mild to moderate in both groups of treatment. Atthe end of therapy, the clinical response was classified as“success” in 95.1% of patients in levofloxacin group, and in93.2% of patients in ciprofloxacin group. At the follow up(7–10 days after the end of therapy), in the patientsclassified as success after treatment, the success has beenconfirmed in 98.1% in levofloxacin group, and in 96.7% inciprofloxacin group; three patients in ciprofloxacin groupand one in levofloxacin group relapsed. The bacteriologicalresponse at the end of therapy was higher than 90% in bothgroups of treatment. Adverse events, of mild to moderateseverity in both groups, occurred in 9.9% of patients in levogroup and 16% in cipro group. In conclusion, the results ofthe present study confirm that levofloxacin administered500 mg once-a-day is an effective and safe therapeuticchoice in the treatment of patients affected by acuteexacerbation of chronic bronchitis, and therefore assure areliable empiric therapy in this pathology.

133. Usefulness of chain ligase reaction assay for thediagnosis of extra-pulmonary tuberculosisM. Pergolini, P. Stati, M. Pacelli, T. Barletta, G. Leone, A.Mammarella, L. CoppotelliDepartment of Medical Therapy University of Rome “LaSapienza”INTRODUCTION: tuberculosis is an infection, often oflifelong duration, caused by two species of mycobacteria:M. tuberculosis and M. bovis. It can result in disease invirtually every organ system in the body, most prominentlythe lungs, but lymphadenitis is the most frequent of extra-pulmonary tuberculosis. In the industrialized world caserates had declined progressively, except during the waryears, from the first half of the nineteenth century. From themid-1980s, however there was a dramatic change: in thedeveloped countries, the rate of decline slowed and hasbegun to climb. In the developing world the number ofcases has begun to rise at an alarming rate in some areas.

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This change seems to be largely attributable to HIVinfection, though migration and social deprivation haveprobably contributed. In our countries tuberculosis ispredominantly a disease of elderly people, recentimmigrants from third world or from countries of near east,members of ethnic minorities, and the immunocompromised.With regard to extra-pulmonary tuberculosis, in 1994 inItaly on more than 5200 cases of total tuberculosis notified,more than 1000 was just of extra-pulmonary tuberculosis.PATIENT AND METHODS: We report the case of a 49-year-old Peruvian woman, with, since two months, a not sad andhard-elastic swelling in right supraclavicular fossa, Here’shistory: tonsillectomy at 30 years of age; typhoid fever andcholecystectomy about 20 years ago; four years agobrucellosis; in last years relapsing pharyngitis. In here’sfamily history: the father, 73 years old, affected bytuberculosis; the mother deceased at 65 years of age owingto uterine neoplasia. At physical examination only thesupraclavicular swelling was evident. The chest ray wasnegative. Tuberculin test was weakly positive. Anultrasonography scan showed three hypo-echogenformations reported to lymph gland. Anti HIV Elisa wasnegative. ESR, blood cells count, protein electrophoresis,blood copper, C-reactive protein, immunologic study, theamount of the protein of the acute phase were normal.Culture of fine needle aspiration of lymphatic node wasnegative and cytology directed toward a phlogistic process.Computed thomography total body showed a bulkyconglobated adenopathic process, partially necrotic, inright supraclavicular space, that compressed and dislocatedthe right internal jugular vein. This process was surgicallyremoved: a cultural examination was negative, butdetection of Mycobacterium tuberculosis in lymph node byligase chain reaction (LCx) was positive. Finally thehistologic examination revealed chronic granulomatous,epithelioid, Langherans giant cells lymphadenitis with largeconfluent areas of caseous necrosis; hystochemical Ziehl-Neelsen stain showed, in the cytoplasm of giant cells, somealcohol-acid resistant bacilli, confirming the results of LCx.A multidrug treatment, based on rifampin 600 mg PO,isoniazid 300 mg PO and ethambutol 800 mg PO (15mg/kg) daily, according to standardized protocol, wasestablished: the follow-up at three and six monthsconfirmed a complete release of the disease.DISCUSSION AND CONCLUSIONS: The use of nucleicacid amplification methods in routine clinical microbiologylaboratories is becoming increasingly widespread. Thesensitivity and specificity, equal respectively to 92.9 and95.8 %, of LCx in detection of suspected tuberculosis iselevated in all specimens and similar to other semiautomateddirect amplification test. Moreover LCx M. tuberculosis Assaywill provide rapid and valuable information for thediagnosis of extrapulmonary tuberculosis. However, itsclinical interest appears to be limited in our population withlow mycobacterial prevalence because of its cost.

134. Empiric therapy of ENT infections: our experiencewith levofloxacinS. Ponzo, M. Castelli (*), R. VitielloENT Department, SS Annunziata Hospital, Savigliano, ItaliaProper empiric treatment of infections is based on clinical,microbiological, epidemiological and pharmacologicalknowledge. Among ENT infections, we present ourexperience on Acute Sinusitis (AS) and Acute Otitis Externa(AOE) of the adult. Empiric therapy of AS and AOE isoften mandatory because of the acute onset and the severity

of symptoms, as well as the possibility of life threateningcomplications, should the treatment be delayed waiting forthe microbiological results.AS are commonly caused by Streptococcus pneumoniae,Haemophilus influenzae, Moraxella catarrhalis, Staphylococcusaureus, Streptococcus pyogenes, and, less commonly, byenteric bacteria; anaerobic bacteria, Pseudomonas aeruginosaand fungi are often found in immunocompromised patientsor in patients with cystic fibrosis.AOE (as skin and skin structure infections) are usually dueto Staphylococcus aureus and epidermidis, Streptococcuspyogenes, Proteus vulgaris, Escherichia coli; Pseudomonasaeruginosa is often found as superinfecting agent and inmalignant otitis externa.Most bacteria tend to develop resistance to the commonlyused antibiotics, and most patients come to our attentionhaving been previously treated with large spectrumantibacterial agents. In particular Haemophilus influenzae,Moraxella catarrhalis, Staphylococcus aureus are often b-lactamase producers. Moreover, more than one third ofstrains of Streptococcus pneumoniae may have an anti-microbial resistance due to mutations in the site for linkingto the b-lactam antibiotic. We therefore prefer an antibioticlike levofloxacin, which has a large spectrum and maintainsa bactericidal activity against these bacteria too, as well aslow side effect rate and good tolerability.96 patients affected by AS and 148 patients affected by AEOwere treated with levofloxacin 500 mg per os, once a day, for10 days: we expose the clinical results, also consideringside-effect profile.

135. Changes in the spectrum of bacterial agents ofcommunity-acquired lower respiratory tract infections inhospitalized patients.Ruggeri Paolo, Giacobbe Giovanni, Crisafulli Ernesto,Girbino GiuseppeDepartment of Pulmonary Diseases, University of Messina, Italy.There is general agreement that gram positive pathogens likeStreptococcus pneumoniae, Haemophilus influenzae andMoraxella catarrhalis represent the prevaling bacterialpathogens of community-acquired lower respiratory tractinfections (CA-LRTIs) while gram negative pathogens isimplicated in hospital acquired lower respiratory tractinfections (HA-LRTIs). However the specific incidence ofbacterial pathogens as causative agents is known to varyeven profoundly depending on geographic location and thesame holds true for the rates of resistance to antimicrobialdrugs. In this study, the authors assessed the incidence,aetiology and antimicrobial susceptibility of bacterial CA-LRTIs. From February 1998 to December 1999 426 patientswith CA-LRTIs, admited to University RespiratoryDepartment of Messina, were enrolled. Sputum andbronchial aspirate adequate for microbiologicalinvestigations were obtained in 30% of patients (n=131).The three more common organisms isolated were unusual(pseudomonas spp, enterobacter spp and serratia spp). Thesusceptibility to common antimicrobial drugs were assessed.The motivations (serious impairment of lung function andseveral comorbidity) of these uncommon results areanalyzed. These epidemiological data might represent aguide for the choice of empiric antimicrobial treatment inCA-LRTIs in hospitalized patients and an important elementof antimicrobial pharmacoeconomic estimation.

136. Thiamphenicol glycinate hydrochloride in thetreatment of acute lower respiratory tract infections due toChlamydia pneumoniae

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T. Todisco, Pulmonary and Critical Care Div., SilvestriniHosp., Perugia, ITBACKGROUND: The aim of this study was to evaluate theefficacy and tolerability of thiamphenicol glycinatehydrochloride (TGH) in the treatment of acute lowerrespiratory infections due to Chlamydia Pneumoniaediagnosed serologically.METHODS: Twenty patients (16 males; 4 females) withradiological evidence of lower respiratory tract infections(18 pneumonia, 1 bronchiolitis, 1 rhinobronchial syndrome)and IgM and/or IgA titers > 1:16 and/or IgG titers > 1:512(by microimmunofluorescence assay specific for C.Pneumoniae) were assigned to 10 days treatment of TGH1500 mg daily administered i.m. in two doses. Clinical andserologic status and safety were assessed at baseline, on-therapy, at end-of-therapy and at follow-up. Safety andtolerability assessments involved recording of adverse eventsand blood/urine testing during treatment.RESULTS: 17 patients (85%) were considered both a clinicaland radiological success (Binomial test: p<0.01). 2 patientswere a clinical and radiological failure and one was a clinicalsuccess only. 12 patients (60%) showed a decrease in IgGvalues. 2 patients had an increase in IgG values (therapeuticfailure). All patients with positive IgA and/or IgM values atbaseline were negative at end of therapy and at follow-up.Blood/urine values presented no clinically significantvariations. 8 patients reported discomfort at the site ofinjection. 5 also reported pain. These adverse events endedonce the treatment was completed.CONCLUSION: These are the first results confirming invivo the recent in vitro evidence (GIMMOC 2000; IV:5–10)that TGH is effective against Chlamydia pneumoniae acutelower respiratory tract infections. However furtherrandomized controlled studies would be useful as Chlamydiapneumoniae infections are a rather frequent event especiallyin patients with chronic respiratory diseases (Eur Respir J1993;6:19–22).

Serious gram-positive infections

137. Successful treatment with linezolid of MRSAendocarditis in a 77-year-old woman. Case reportG. Cenderello, M. Mancini*, V. del Bono, E. Rossi*, A. diBiagio, L. Ottonello*, F. Dallegri*, and D. BassettiDepartment of Infectious Diseases University of Genoa,*Department of Internal Medicine University of GenoaBACKGROUND: Methicillin resistant S. aureus (MRSA)endocarditis represents a serious, potentially life-threateningclinical event, particularly in patients with severe underlyingdiseases. The relevant treatment is based on administrationof glycopeptides and/or other drugs (i.e., rifampin +ciprofloxacin), depending on susceptibility testing.Linezolid (LZD) is a new oxazolinidone compound, withgood in vitro and in vivo activity vs. MRSA. It has beenshown to be effective in MRSA infections treatment inpatients unable to take glycopeptide drugs. Here we report acase of a patient with MRSA endocarditis treated with LZDbecause of a severe allergic reaction to teicoplanin.CASE REPORT: A 77-year-old woman was admitted toInternal Medicine Dept. because of ataxic disorders andintermittent fever. Her recent medical history showed aprogressive impairment of her cognitive functions due toatherosclerotic cerebral vascular disease. At the admissionthe patient was febrile, anemic (Hgb was 9.7 gr/dl), therewas mild neutrophilic leukocytosis (12.900 WBC), both ESRand CRP were strongly elevated (120 and 98, respectively).

Both chest X-rays and transthoracic echocardiography(TTE) were negative as well as several sets of blood andurine cultures. Initially, the patient showed a low-gradeintermittent fever and only symptomatic drugs wereadministered. Eventually, beginning from day 8 both urineand blood cultures yielded a MRSA strain susceptible solelyto glycopeptides and rifampin; further blood cultures,performed in the following days, yielded the same strain. Asecond TTE was performed, which showed vegetations onboth mitralic and aortic valves. Treatment with teicoplanin,600 mg iv ad and rifampin, 600 mg iv bid was started. After28 days of therapy with good clinical and laboratoryresponse, a severe allergic reaction, characterized byerithemathous rash, angioedema and wheezing occurred.Antibiotic therapy was therefore discontinued and after afew days of antihistaminic treatment the allergic symptomssubsided. At antibiotic therapy discontinuation time, thepatient was afebrile, WB cell count was 5,400, Hgb was 10.7gr/dl while both CRP and ESR were still elevated. A thirdTTE did not show any improvement in valve lesions. Afterfive days a new febrile episode occurred, together a rise inESR and CRP values. Blood cultures were still negative. Wedecided therefore to enroll the patient in a multicenter openlabel trial sponsored by P&U in order to complete a 30-daycourse of therapy with LZD. LZD (600 mg bid) was givenintravenously for three days and then orally for 27 days. Thepatient became afebrile starting from the third day oftreatment; TTE performed after 12 days of treatment showedan evident decrease of vegetations size on aortic valve and asharp reduction of inflammatory indexes (CRP 20 mg/dl)has been observed at the 23rd day of treatment. The patientwas in good clinical condition and discharged at the end ofLZD treatment.CONCLUSIONS: This observation suggests that LZD maybe an effective drug, despite its bacteriostatic activity, for thetreatment of severe infections due to MRSA or other Grampositive bacteria, even in peculiar anatomic sites, such ascardiac valves, in which antibiotics could not achievetherapeutic levels.

138. Paravertebral abscesses: our experienceF. Dodi, A. Alessandrini, M. Camera, L. Gaffuri, N. Morandiand G. Pagano.Department of Infectious Diseases-San Martino Hospital,Genoa, ItalyDespite advances in neuroimaging and neurosurgicaltreatment, spinal paravertebral abscesses remain achallenging problem for the physician. Early diagnosis isoften elusive and treatment is delayed. The optimalmanagement of these diseases is not clearly defined andmorbidity and mortality remain high. The epidemiologicalrisk factors are: trauma, irradiation, tattooing, epiduralanalgesia, intravenous drug abuse, prior spinal surgery orneck instrumentation procedures, prior faringeal or frontalsinusitis surgery for abscesses or their spontaneous rupture.Diabetes mellitus, immunodeficiency, tuberculosis,rheumatoid disease, bacterial and fungal osteomyelitis,brucellosis, endocarditis, spondilodiscitis, recurrentpilonidal cyst, hematooncological diseases are predisponentcauses. All tracts of spinal axis are equally involved. Thepredominant aetiologic microorganism is Staphylococcusaureus (67%), sometimes (15%) with methicillin resistance,Streptococcus spp. in 8% and, with a lesser extent, Gramnegative bacteria and fungi. Meningitis due tohaematogenous spread or fistula formation is frequent andpsoas is often involved.

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We describe our last three years experience: 5 males, meanage 51.8 years, 3/5 had diabetes mellitus, 3/5 had lumbararthrosis and lumbar hernia discalis, 1/5 received epiduralanaesthesia for severe sciatalgia, 1/5 had incidental lumbartrauma. All the patients complain of low grade fever, severeand acute lumbar pain irradiated to the legs with laesafunctio and laboratory evidence of acute inflammation. In allcases abdominal TC demonstrated paravertebral lumbarabscesses with involvement of psoas in three. In 3/5 patientspus culture yielded MSSA; in 2/5 S. viridans. In thesepatients S. viridans sustained also purulent meningitis, inone case with liquorrhaea. All patients immediately startedlong term aethiological antibiotic therapy. Two patientsunderwent a surgical procedure, 3/5 (among which thepatients with meningitis) only TC assisted abdominaldrainage. In all cases, we observed a favorable outcome withcomplete recovery.The aim of our observation is to enhance and improve thediagnostic procedures for early detection and treatment ofthis severe disease, with life threatening clinicalcomplications. The modern technologies allow a new, lessinvasive, approach for treatment of paravertabral abscess.

139. Prospective surveillance of methicillin resistancelevels of Staphylococcus aureus in selected high-riskhospital wards*Roberto Manfredi1, Anna Nanetti2, Roberta Valentini2,Leonardo Calza1, Francesco Chiodo1

Department of Clinical and Experimental Medicine,Division of Infectious Diseases1 and Division ofMicrobiology2, University of Bologna, S. Orsola Hospital,Bologna, ItalyMethicillin resistance is an emerging feature of a number ofgram-positive cocci (Staphylococcus aureus, coagulase-negative staphylococci, enterococci, and othermicroorganisms), especially when immunocompromisedpatients and/or nosocomially-acquired infection are ofconcern. In order to assess the frequency and temporal trendof methicillin-resistant S. aureus isolates, and their antibioticsensitivity profile, all bacterial strains isolated frombronchial aspirate, bronchoalveolar lavage, protectedbronchial brushing or blood cultures in six wards at highrisk for nosocomial disease of immunocompromisedpatients, including general, surgical, pediatric andspecialized intensive care units, pneumology and transplantsurgery departments, were evaluated, from 1998 to 2000.Only one isolate was considered when multiple positivecultures were obtained from a single patient within 30 days,apart from microbial strains characterized by a significantlydifferent in vitro antimicrobial susceptibility profile.Antibiotic sensitivity assays were carried out by a brothmicrodilution method, interpreted according to updatedNCCLS recommendations. Of 535 S. aureus strains causingdocumented pneumonia or sepsis, 334 (62.4%) testedmethicillin resistant. No significant difference of methicillinresistance levels was observed throughout the study period(62.5% in 1998, to 60% in 2000), and with regard to thespecimen origin (respiratory secretions versus bloodcultures). Methicillin-resistant strains were more frequentlyisolated from lower airways than from blood (p<.001): 18episodes of sepsis of 25 occurred in intensive care units. Themajority of methicillin-resistant S. aureus strains came fromthe general intensive care unit (42.5%), followed by therespiratory critical care unit (18.2%), the pneumologydepartment (16.5%), the heart surgery intensive caredivision (8.4%), the pediatric/neonatal intensive care unit

(7.5%), and the transplant department (6.9%). Methicillin-resistant pathogens prevailed over sensitive ones in all wardsbut pediatric/neonatal intensive care unit, where a 37.3%resistance rate was found. Methicillin-resistant S. aureusstrains did not prove susceptible to all b-lactam antibiotics,while a variable sensitivity to cotrimoxazole (79.3%),chloramphenicol (76.3%), rifampicin (57.5%), clindamycin(8.1%), and macrolides (3.3%), was demonstrated. Theaminoglycoside resistance rate (mean 56.9%) significantlyincreased over time (p<.001), while a 100% susceptibility toglycopeptides (teicoplanin and vancomycin), wasmaintained. In conclusion, when considering high-riskwards of a large teaching hospital, methicillin-resistant S.aureus isolates largely prevailed over sensitive S. aureusstrains in the three-year study period, exceeding the rate ofprior literature reports, including those focusing on criticalcare units (Barakate MS, J Hosp Infect 2000; 44:19; NicolettiG, Int J Antimicrob Agents 2000; 15:265; Reed RL, Surg ClinNorth Am 2000; 80:895; McGowan JE, Crit Care Med 2001;29 Suppl. 4:N69). Long-term surveillance programs arewarranted to update local methicillin resistance profile of anumber of key pathogenetic gram-positive cocci (inparticular, staphylococci and enterococci), and to select andfocus both chemoprophylaxis and empiric therapy ofimmunocompromised patients at risk for these relevantinfectious complications.

140. Endocarditis due to penicillin-resistant streptococcusmitisMelica G., Moroni C., Ferrando S., Majabo M.J., CiravegnaB., Bassetti D.Clinic of Infectious Diseases University of Genoa, G. GasliniChildren HospitalThe management of patients with bacterial endocarditis dueto streptococci is featured by some remarkable clinicalproblems, where local biology and a sharp decline inpenicillin sensitivity constitute the issues of major concern.In the first case, the concern has related to the difficulty ofattaining appropriate bactericidal concentrations of drugs,particularly in presence of a prosthetic valve (eitherheterologous or homograft). In the second case, over thepast 15 years penicillin resistance has been an increasingproblem not only in the treatment of infections due toStreptococcus pneumoniae but also in those due tostreptococci of the viridans group and S. mitis in particular.We report a case (March–May 2001) of a patient withendocarditis due to Streptococcus mitis with high-levelresistance to penicillin.The patient, a 21-year-old woman, showed an endocarditison a pulmonary valve homograft implanted in 1988; she hada history of congenital pulmonary valve stenosis andinterventricular defect. In January 2001, patient underwenta low risk dental procedure; for prophylaxis againstinfectious endocarditis she received 3 grams of amoxicillinone hour before the dental procedure and 1.5 grams after sixhours. After about one month the patient had fever,increased C-Reactive-Protein and blood sedimentation rate,hypergammaglobulinemia, anaemia and dry coughassociated to temperature peaks. A first trans-thoracicechocardiography revealed a calcification of the homograftand a hyperechogenic image on the valve, although it wasnot confirmed by a further trans-oesophageal echography.From March 21 to March 24, 10 blood cultures were positivefor Streptococcus mitis: the minimal inhibitory concentration(MIC) of penicillin was 4 µg/ml, while it was 24 µg/ml foroxacillin.

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The isolate was susceptible to vancomycin (MIC 0.38µg/mg) and gentamicin (MIC 1.5 µg/ml). The patient wasthen given an association of vancomycin (800 mg everytwelve hours) and gentamicin (60 mg every twelve hours)for two weeks. One week after the therapy had been started,patient reported a posterior pain on her right flank, with anobjective finding of pleural rubbing. Thorax spiral CT-scanning revealed an intraparenchymal thickening inconnection with patient’s posterior costo-diaphragmaticcavity, probably due to an embolus.Given the poor bactericidal activity of patient’s serum(sampling before antibiotic administration 1:2 and afterantibiotic administration 1:4) gentamicin was withdrawnand piperacillin (MIC 2 µg/ml) was associated tovancomycin for another two weeks; then the previousassociation was restored because of an important allergicreaction to piperacillin.In the same period, however, a trans-thoracic echocardio-graphy revealed a size increase of the hyperechogenic imageon the homograft with an evidence of floating. Thus, giventhe worsening of the echographic picture and the negativeresults of blood cultures as from March 24, 6 weeks after thebeginning of the antibiotic therapy the patient underwentreplacement of the pulmonary homograft.The histopathological examination revealed morphologicalfindings possibly related to a previous inflammation; in theGram’s microscopic examination, many positive cocci inchains were identified while the culture showed no bacterialgrowth.The patient continued the therapy with vancomycin (600mg every twelve hours) and gentamicin (30 mg every twelvehours) for another three weeks.She was then discharged in a good haemodynamiccompensation, apyretic and with normal phlogosis indexes.54 days after operation, the patient was found in goodhealth. A cardiological check-up with electrocardiogram andtransthoracic echography revealed a good short-termhaemodynamic result, while differential blood counts,phlogosis index and blood cultures were either normal ornegative.The analysis of our case suggests us to stress some key-points:First microbiology, as the increase in strains of streptococciof the viridans group, including S. mitis, with a high levelresistance exceeding the 20% seems to be a matter ofparticular concern. Should additional endocarditis casesshowing such values be reported, relevant prophylacticstandards shall undergo substantial changes to prevent anylack of prophylactic effect, as experienced in our case.The frequent failure of the sole medical therapy in case ofendocarditis on prosthetic valve highlights the need for aninterdisciplinary approach involving both infectious diseasespecialists and surgeons. In these cases, it is important toevaluate the predictive parameters and optimal times forprostheses surgical replacement. In particular,microbiological sensitivity tests and serum bactericidalpower are capable to show chances and limits of theantibiotic therapy, while echocardiography (trans-oesophageal echocardiography being the safest one) is themost reliable monitoring system as far as morphologicalfindings and therapeutic effect are concerned.In our experience, the decision to replace the pulmonaryhomograft was taken on the basis of a worsenedechocardiography result, concomitant to a poor efficacy ofthe antibiotic therapy. As blood culture results were negativefor so long in the course of the therapy, we could cover the

surgical option with an acceptable risk of infection anddefinitely satisfactory short- and medium-term results.

Urinary tract infections: risk, diagnosis,prevention, and therapy

141. Pediatric urinary tract infections in teaching hospitalsof Tripoli-Libya: antibiotic resistance and treatment.Gebreil TM. and Ghenghesh KS*. Microbiology Laboratory,Tripoli Central Hospital and Dept. of MedicalMicrobiology*, Faculty of Medicine, Al-Fateh University,Tripoli-Libya.During 12 months period of 1998, urine specimens werecollected from 1021 pediatric patients (336 inpatients and685 outpatients) with urinary tract infections (UTIs)attending the Pediatric Departments of the 3 teachinghospitals of Tripoli, Libya. Patients were aged between a fewdays and 15 years. Urine specimens were examined foruropathogens (UPs), within 2 hours from collection, usingstandard bacteriological procedures. Significant bacteruriawas detected in 326 (32%) specimens; 109 (33.5%) frominpatients and 217 (66.5%) from outpatients. Of the 326UPs detected 174 (53.4%) were Escherichia coli, 45 (13.8%)Klebsiella pneumoniae, 19 (5.8%) Acinetobacter species, 17(5.2%) Pseudomonas aeruginosa, 16 (4.9%) Enterobacterspecies, 17 (5.2%) other Gram-negative bacilli, 25 (7.7%)Gram-positive cocci and 4 (1.2%) Candida species. E. coliwas detected significantly more from outpatients than frominpatients (64% vs 32%, P<0.00001). On the other hand K.pneumoniae and Acinetobacter species were foundsignificantly more from inpatients than from outpatients(21% vs 10%, P<0.003) and (12% vs 3%, P<0.0004)respectively. Of the E. coli isolates 74.7% were resistant toampicillin (Amp), 33.9% to amoxicillin-clavulanic acid(Aug), 64.9% to trimethoprim-sulphamethoxazole (TMP-SMZ), 34.5% to cephalexin (Ceph), 13.2% to nalidixic acid(NA), 5.8% to nitrofurantoin (NF), 3.5% to gentamicin(GM) and all were susceptible to ciprofloxacin (Cip). Of K.pneumoniae isolates 10.9 % were resistant to NA and noneto Cip, however, 42–95.4% of them were resistant to otherantibiotics. Acinetobacter species and P. aeruginosa isolatesshowed very high resistant rates that reached to 100% forAmp. Only Acinetobacter species from inpatients showedresistance to Cip (38%). In general isolates from inpatientswere more resistant to antibiotics than isolates fromoutpatients. Beta-lactamase was detected in 62% of E. coli,69% of K. pneumoniae and in 52% of Acinetobacter species. Atotal of 100 General Practitioners (GPs) were asked on howthey manage children with suspected UTIs. Of these, 63%said they prescribe antibiotics blindly and request forinvestigation. Types of antibiotics prescribed by GPs wereAmp (9%), Aug (21%), TMP-SMZ (44%), NF (10%) and NA(11%). Furthermore, only 2% of GPs asked for urine cultureand sensitivity alone, 11% for dipstick and microscopicexamination, while the rest (87%) asked for both. Thefindings of this study shows that UPs in the populationstudied are highly resistant to antibiotic particularly b-lactams and TMP-SMZ and the management of childrenwith UTIs by GPs in Tripoli hospitals is poor.

142. A study of urinary culture and antibiogram in Iranianchildren.Parisa Mokhlesi Khameneh1, MD, Mehdi Mirsaidi2, MD,Hossein Sarmadian2, MD, Anick Bérard3, PhD.1 Welfare Organization, Preventive Medicine Office, Tehran,Iran; 2 Labafi Hospital, Division of Infectious Disease,

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Shahid Beheshti University, Tehran, Iran; 3 Albert EinsteinCollege of Medicine, Department of Epidemiology and ofEmergency Medicine, New York, NY, USA.BACKGROUND: Despite increasing advances in medicine,urinary tract infection (UTI) remains one of the mostprevalent problems in children. Although antibiotics areindicated for the treatment of UTI, they are seldom usedappropriately; incorrect or incomplete antibiotics use haveresulted in high level resistance for the common UTI agentsin the pediatric population.OBJECTIVE: The aim of this study was to determine in vitroantibiotic resistance pattern in children with UTI admittedto Bau-Ali Hospital in Iran. Method: 76 children, 12 yearsold or younger, with suspected UTI were included in thisstudy. The study period was from January to December1999. Clinical assays were used. All subjects were visited bya pediatrician and an infectious disease specialist. Cleancatch midstream urine were sampled and cultured. Bacterialtyping, drug sensitivity testing according to Kirby-Bauer,WHO criteria and NCCLS methods were done for allsubjects’ samples. We excluded the contaminated samplesand only studied samples with ≥ 100,000 cfu/ml.RESULTS: Most subjects were between 7 and 12 years old(45%). Urine cultures were positive for UTI in 67 children(88%); the tip list tested for Ecoli in 78% of the samples,Klebsiella in 9% of samples, and Proteus in 5% of samples.In the antibiogram study, 85% were sensitive and 19%resistant to nalidixic acid; 75% were sensitive and 15%resistant to nitrofurantoin.CONCLUSION: The results show that the most commonagents were E. coli, Klebsiela and Proteus. In vitro studiesdemonstrated that nalidixic acid, nitofurantoin, amikacineand ceftizoxime were the best agents. We recommend urine

culture and antibiogram screening for guidance for UTIantibiotics therapy in children.

143. Asymptomatic bacterermia in school children in adeveloping countryGuler Yayli1, SerpilAydin2, S. Demirel Univercity,Faculty ofMedicine, Department of 1) Clinical Microbiyolgy andInfectious Diseases, 2) Family Medicine,Isparta, TURKEYAIM: Our aim was to determine the rate of asymptomaticbacteriuria of school children in Isparta, Turkey.MATERIALS-METHODS: Urine samples were collected fromschool children of aged 6–14 who had no complaints ofurinary tract infections. Microscopic examinations and twoseparate cultures of clean catch midstream specimens ofurine were performed. All the asymptomatic bacteriuriacases were suggested to have urological and radiologicalexaminations. The urine samples were recollected from theasyptomatic bacteriuric students twelve after the firstevaluation. None was cured. Chi square test was performedfor statistical results.RESULTS: Among the 10289 children, asymptomaticbacterermia was found in only thirty-eight students. Therewas no statisticaly difference among the age groups except6–7 aged, or socioeconomical status but a very significantdifference was seen in girls rather than boys. In 30 of them,the bacteriological agent was Escherchia coli. At the twelvethmonth, in only seven girls asymptomatic bacteriuria wasfound again.CONCLUSION: As urinary tract infection is the mostcommen of bacterial infections in childhood, screeningchildren for asymptomatic bacteriuria is recommended inorder to prevent renal scarring and pyelonephritis. Ourresults tend to be lower than in developed countries.

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