Correspondence and Reprint requests : Prof. Sunit Singhi,Head, Pediatric Emergency and Intensive Care Units, AdvancedPediatrics Centre, PGIMER, Chandigarh 160 012, India

[Received September 20, 2007; Accepted August 27, 2008]

Special Article

Invasive Candidiasis in Pediatric Intensive Care Units

Sunit Singhi and Akash Deep

Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research,Chandigarh, India

ABSTRACT

Candidemia and disseminated candidiasis are major causes of morbidity and mortality in hospitalized patients especially inthe intensive care units (ICU). The incidence of invasive candidasis is on a steady rise because of increasing use of multipleantibiotics and invasive procedures carried out in the ICUs. Worldwide there is a shifting trend from C. albicans towards nonalbicans species, with an associated increase in mortality and antifungal resistance. In the ICU a predisposed host in one whois on broad spectrum antibiotics, parenteral nutrition, and central venous catheters. There are no pathognomonic signs orsymptoms. The clinical clues are: unexplained fever or signs of severe sepsis or septic shock while on antibiotics, multiple,non-tender, nodular erythematous cutaneous lesions. The spectrum of infection with candida species range from superficialcandidiasis of the skin and mucosa to more serious life threatening infections. Treatment of candidiasis involves removalof the most likely source of infection and drug therapy to speed up the clearance of infection. Amphotericin B remains theinitial drug of first choice in hemodynamically unstable critically ill children in the wake of increasing resistance to azoles.Evaluation of newer antifungal agents and precise role of prophylactic therapy in ICU patients is needed. [Indian J Pediatr2009; 76 (10) : 1033-1044] E-mail: sunit.singhi@gmail.com, dr_singhi@yahoo.com

Key words : Candidemia; Invasive candidiasis; Nosocomial infections; Non-albicans candida

Candida species particularly C. albicans is a normalcommensal of humans and may be found in therespiratory, gastrointestinal, genitourinary tracts, skin andmucous membranes.1 In hospitalized and immune-suppressed hosts it may turn into pathogen causingopportunistic local and systemic infection.2 We decided toreview this important topic because invasive candidiasis(candidemia and disseminated candidiasis) prolongshospital stay, increases treatment costs and is associatedwith high crude and attributable mortality. We havediscussed the epidemiology, clinical features , diagnosticmodalities available and the various pharmacological andnon-pharmacological methods available to treatdisseminated candidiasis. Publications in the scientificliterature were retrieved using a computerised MEDLINE/PUBMED search from 1995 -2007 using the termscandidemia, invasive candidiasis; nosocomial infectionsor non-albicans candida. Based on review of titles andabstracts relevant articles were retrieved

Candidemia and disseminated candidiasis are majorcauses of morbidity and mortality in hospitalizedpatients especially in the intensive care units (ICU). ICUs

contribute 29-45% of all Candida species blood streaminfections (BSI).3 It has been estimated that approximately10 – 20% of all nosocomial blood stream infections inICUs are due to Candida species.4 Candida species are thethird most common pathogens as cause of nosocomialblood stream infections in premature infants5 and fourthcommonest cause of blood stream infections in pediatricICU patients.6 In the recent years, the incidence ofnosocomial candidiasis has increased throughout theworld, starting in tertiary care centers and spreading tocommunity hospitals.7 In our hospital there is a vastvariation in Candida BSI rates between different ICUs. Thedifference may reflect the different patient characteristicsin each ICU, different levels of medical interventions andthe prophylactic use of fluconazole.

Incidence and Trends in the Disease Burden

In the 1960s and 1970s, Candida albicans accounted formost of the cases of nosocomial candidemia but in recentyears the proportion of cases due to species other thanCandida albicans has increased markedly.7-9 These speciesinclude C. tropicalis, C. glabrata, C. parapsilosis, C. krusei, C.guilliermondii and newer species such as C. lipolytica, C.kefyi and C. pelliculosa. McDonald et al10 reported thatfrom 1988 to 1992, 58% of candidemia cases in childrenwere caused by non-albicans Candida species. C.parapsilosis has emerged as the predominant non-albicans Candida species causing candidemia in

Indian Journal of Pediatrics, Volume 76—October, 2009 1033

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1034 Indian Journal of Pediatrics, Volume 76—October, 2009

children.11 In our PICU, 70% of all candida isolates fromblood were non-albicans candida spp., C. tropicalis beingthe commonest (48.4%).12 The neonatal unit of ourhospital had a similar predominance of C. tropicalis(41%) over C. albicans (27%) between 1990 and 1996.13

The increased incidence of non-albicans candida bloodstream infections among ICU patients may be animportant consideration for the intensivists becausesome of the species especially C. glabrata are resistant toazole therapy, thus making species identificationcrucial.14 It is not enough for the microbiology laboratoryto give the results as “Candida species” or “Candida non-albicans” because species differ in their susceptibility toantifungal agents. The frequency of species of yeastcausing candidemia vary widely amongst differentinstitutions and may be influenced by multiple factorsincluding geographical factors, antimicrobial andantifungal use, cytotoxic chemotherapy and underlyingdisease. This may also be due to intrinsic differencesbetween different populations sampled. For instance,malnutrition may favor the presence of yeast speciesother than C. albicans. Neutropenic children colonizedwith C. tropicalis are at higher risk for disseminationcompared to those colonized with C. albicans.

Risk Factors and Pathogenesis

Invasive candidiasis is essentially an opportunisticinfection resulting from depleted immune response in acritically ill patient and invasive procedures. The portalsof entry usually are lesions of the gastrointestinal tract,oral mucosa or skin puncture sites, and organisms aredisseminated by the hematogenous route to the tissues ofone or more organs.

Three components interact in the pathogenesis ofinvasive candidiasis:

1. Increase in fungal colonization is the most importantpostulate in the pathogenesis of invasive candidiasis.Candida species are known to adhere to epithelial layers,endothelial cells, blood clots, plastic and acrylicproducing a number of adhesive molecules that enhancestheir ability to persist, invade and disseminate.

2. Breakdown of normal mucosal, epithelial or skinbarrier due to a number of invasive procedures, both fordiagnostic and therapeutic purposes.

3. Loss of immune mechanisms responsible forprevention of dissemination of candidiasis in deep tissuesand organs.

A number of risk factors for invasive candidiasis ininfants and children have been confirmed in variousstudies, these are shown in table 1.15-21 Some of the wellrecognized risk factors include presence of central venouscatheters, other invasive interventions and severity ofprimary illness (high PRISM Score). In developingcountries like India the situation is compounded by the

presence of severe malnutrition which is responsible forconsiderable immunosuppression. Prolonged ICU stayhas been recognized to increase the likelihood of fungalinfection.22 Zaoutis et al identified persistently positiveblood cultures for Candida with a central venous catheterin place (odds ratio, 3.0;95% CI,1.2,7.8;p=0.02) andimmunosuppression as the independent risk factors fordisseminated candidiasis in children.23 Central venouslines act as a nidus for Candida species to adhere to forma biofilm which is relatively resistant to attack byantifungal agents.24,25 Broad spectrum antibioticssuppress gastrointestinal bacterial flora which permitsunopposed Candida proliferation resulting inovergrowth.26 This overgrowth may be associated withtissue invasion and eventual dissemination.27,28 TPNcauses glutamine mediated mucosal atrophy,immunological depression and supports fungal growth.These risk factors are situational and host specific.Several of these risk factors are likely to be presentsimultaneously in individual patients, e.g., it is notpossible to manage patients on total parenteral nutritionwithout indwelling central venous catheter. Specific riskfactors associated with non-albicans candida BSIinclude use of azoles (e.g., fluconazole) renal failure,colonization at 2 sites28 and gastrointestinal injury.29

Outcome

Invasive candida infections are associated with highmortality though it is somewhat lower in children ascompared to adults. In a Canadian study, the overallmortality rate in adults was 46% and in children 27%.30 Inanother series among pediatric patients with candidemia,19% died.31 Delayed diagnosis because of lack ofpathognomonic symptoms and absence of a reliablerapid diagnostic test contributes to the high mortality.

TABLE 1. Risk Factors for Invasive Candidiasis (15 - 21)

Immunosuppression

• Malnutrition• Treatment with steroids• T-cell immunodeficiency• Prematurity

Treatment in ICU with invasive procedures

• Central venous lines• PD catheters• Endotracheal intubation and mechanical ventilation• Urinary catheter• Renal failure and hemodialysis

Enhanced colonization of muco-cutaneous surfaces

• Treatment with broad spectrum antibiotics• Use of H2 receptor antagonist like ranitidine

Miscellaneous

• Recent surgery• Total parenteral nutrition especially intravenous lipids• Mesenteric ischaemia/ Gastrointestinal pathology• Previous fungal colonisation

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Indian Journal of Pediatrics, Volume 76—October, 2009 1035

The question which is often raised is whether themorbidity and mortality in patients with invasivecandidiasis is directly attributable to candidemia orshould it be attributed to the critical nature of theunderlying disease. Wey et al found excess mortalityattributable to candidemia apart from the underlyingdisease was 38%.32 These patients spent 30 extra days inthe hospital than did the controls. Armenian et alidentified that patients with fungemia in pediatric ICUsdied more frequently because of blood stream relatedinfections.33 A systematic review of matched cohort andcase-control studies also confirms considerable mortalityassociated with candidemia that is attributable to infectionitself.34 An analysis of Kid’s Inpatient Database 2000 fromUSA, revealed that in pediatric patients, candidemia wasassociated with 10% increase in mortality and a meanincrease in hospital stay by 21 days.35 Virulence of non-albicans candida species is believed to be far greater thanC. albicans. In the study from our centre; one of thevariables significantly associated with mortality wasisolation of non-albicans species especially C. tropicalis(12). Costa et al observed an overall mortality rate of 41%from candidemia and 71% for patients with C. tropicalisinfection.36 Viudes et al found neutropenia, corticosteroidtherapy, lack of antifungal treatment and failure to replacethe central venous catheters as the risk factors for death inpatients with candidemia.37 In a population basedsurveillance conducted by the Barcelona CandidemiaProject Study Group the risk of early death with Candidabloodstream infections was independently associatedwith hematological malignancy whereas treatment withantifungal agents and removal of central venous catheterswere protective.38

CLINICAL FEATURES

The spectrum of infection with candida species rangefrom superficial candidiasis of the skin and mucosa tomore serious life threatening infections, variouslydescribed as deep, deep seated, deeply invasive, systemic,invasive, disseminated and hematogenouslydisseminated.39 Hematogenously spread candidiasis candisseminate to virtually any organ.40 Disseminatedcandidiasis is defined as systemic candidiasis due toCandida species with deep organ involvement. This isfrequently associated with multiple deep organ infectionsor may involve single organ infection. The history of apatient with presumptive disseminated candidiasisreveals a fever unresponsive to broad-spectrumantimicrobials and negative results from blood culture.Physical examination reveals fever (may be the onlysymptom) with an unknown source and sepsis and septicshock. Frequent sites of infection in patients withdisseminated candidiasis include lungs, kidneys, liver,spleen, and brain. The clinical manifestations depend onthe sites involved and the extent of involvement (Table 2).In infants and children the clinical manifestation may benonspecific, similar to those of sepsis caused by other

organisms.12

Oral candidiasis can be an early sign of illness ordisease progression in HIV/ AIDS. The sites commonlyinvolved are buccal mucosa, dorsum and lateral surfacesof tongue. There may be submucosal edema and bleedingwhile plaques are removed. Presence of ocular lesions ofendophthalmitis and maculopapular rash in a setting ofimmunocompromised state suggest a possibility ofcandida sepsis. The skin lesions consist of generalizedrashes or discrete, firm, erythematous papules measuring0.5 to 1 cm in diameter.

Esophageal candidiasis is one of the important clinicalmanifestations of candida infection in immunocom-promised host. Patients may have concurrentoropharyngeal candidiasis, odynophagia, retrosternalpain, fever, nausea, vomiting, drooling, dehydration,hoarseness and upper gastrointestinal bleeding.

Candida respiratory infection and Pneumonia

Candida species are frequent asymptomatic colonizers ofthe upper respiratory tract, especially in hospitalizedpatients. Candida respiratory infection may involveairways from pharynx and epiglottis to bronchi. Childmay have hoarseness of voice, low grade fever, tachypneaor non-specific findings on physical examination.

Candida pneumonia may appear in 2 forms:(a) Primary candida pneumonia: Aspiration of candida

laden oropharyngeal material leads to infectionlimited to the lungs.41 Candida albicans is the mostcommon cause; C. tropicalis and C. parapsilosis are the

TABLE 2. Spectrum of Invasive Candida Infection

Blood stream infectionCandida pneumonia

PrimarySecondary

Gastrointestinal

PeritonitisSepsis syndrome resembling Necrotizing enterocolotis

Ophthalmological

Endophthalmitis ( most common)UveitisHypopyonLens abscess

Central nervous system

MeningitisVentriculitisCerebritisAbscess

Renal systemUrinary tract infectionNon-oliguric renal failureFungal balls in renal pelvisRenal micro-abscesses, papillary necrosisHypertension

Bone and joint invovement

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1036 Indian Journal of Pediatrics, Volume 76—October, 2009

common non albicans species implicated.(b) Secondary candida pneumonia: Hematogenously

disseminated candidiasis produces pulmonary lesionsalong with the involvement of multiple other organs.It can cause multiple small abscesses throughout thelungs, which manifests as perivascular pulmonaryinfiltrates on chest X-ray. These may progress orcoalasce into large abscess and empyema.

Pulmonary candidiasis has no characteristicfeatures and cannot be differentiated from most othercauses of pneumonia. Common symptoms are fever,tachypnea, and dyspnea and chest pain. SecondaryCandida pneumonia presents as a part of the complex ofsymptoms related to the concomitant episodes ofinvasive candidiasis. It can present with increasingoxygen and ventilatory requirements, or as a non-resolving pneumonia.42 Majority of them are severally ill,with multiple organ failure and some degree of alteredmental status.

Gastrointestinal Manifestations

Gastrointestinal candidiasis may occur in children withimmune deficiency disorders, cancer and after surgery. Itmay involve the stomach, intestine, or hepatobiliarysystem.

Candida peritonitis occurs in ICU patients who haveundergone peritoneal dialysis or abdominal surgerywith gut wall perforation. Clinical manifestations arenon-specific and include: abdominal distension, fever,vomiting and abdominal pain. Sometimes, the infectionis fulminant and can present as sepsis syndrome.Spontaneous intestinal perforation along withnecrotizing enterocolitis is recognized manifestation ofsystemic candidiasis.43 Isolation of Candida by directexamination of peritoneal fluid is an independent riskfactor for a poor outcome.44 Studies suggest that prompt,effective and adequate use of antifungal prophylaxis inhigh-risk surgical patients may prevent intra-abdominalcandidiasis and peritonitis.45

Urinary Candidiasis

Urinary candidiasis is one of the most confusing formsof candidiasis. The line between colonization and realinfection is often blurred. On one hand isolation ofcandida in urine is believed to represent colonization orcontamination and at the other candiduria may be aharbinger of candidemia or significant invasive renalcandidiasis.46 It may serve as a source of candidemiaduring invasive urologic procedures. In the critically sickchildren in PICU candiduria was an important predictorof candidemia.46 C. albicans was isolated in half of thecases of urinary candidiasis followed by C. glabrata in15% and more than one species in 10% cases.47 Renalinvolvement in children with candidemia is relativelycommon and includes: renal micro-abscesses, papillarynecrosis, calyceal distortion, obstruction due to fungal

ball or perinephric abscesses.

Central Nervous System (CNS)

Meningitis is the most common form of CNS candidiasisbut other forms have been reported (Table 2). Themanifestations include feed intolerance, bradycardiaand thermal instability. In newborns, abnormal increasein head circumference, new onset seizures, focalneurological signs or abnormal finding on cranialultrasound should be viewed with great suspicion inthose having blood steam infection.48 Some neonateswith CNS involvement may be apparently normal; hencea lumbar puncture for fungal staining and cultureshould be obtained in all neonates with candidemia orsevere invasive candidiasis at other sites.

Ocular Candidiasis

It is one of the most dreaded complications ofdisseminated candidiasis because it may lead topermanent blindness.49 Endophthalmitis is the mostcommon manifestation of eye involvement incandidemia. A recent study found ocular Candidachorioretinitis in 26% of the 31 patients with invasivecandidiasis.50 The reported incidence in neonates is 6%.51

The lesions appear as multiple yellow white elevatedspots in the posterior fundus mainly around the macula.With adequate therapy the long term visual prognosis isgood except in cases of extensive macular involvement.Other ocular manifestations include uveitis, fungalhypopyon and lens abscess. It is now mandatory to get acomplete ophthalmological examination in all cases ofinvasive candidiasis.52

When to Suspect Invasive Candidiasis

In the ICU a predisposed host in one who is on broadspectrum antibiotics, parenteral nutrition, and centralvenous catheters. The clinical clues are: unexplainedfever or signs of severe sepsis or septic shock onantibiotics, multiple, non-tender, nodular erythematouscutaneous lesions.

Monitoring for colonization may help in predictingsubsequent infection with identical strains in critically illchildren being treated in PICU. In a prospectiveobservational study of patients on broad spectrumantibiotics for more than 5 days, we found colonizationby Candida species in 69% patients by end of 2 weeks’stay in PICU; independent predictors of candidemia inthese patients were colonization and PRISM score. In arecent effort to create a rule that identifies subjects at highrisk for invasive candidiasis in the intensive care setting,Ostrosky-Zeichner et al found that any systemic antibiotic(days 1-3) or presence of a central venous catheter (days1-3) and at least two of the following- total parenteralnutrition (days 1-3), any dialysis (days 1-3), any majorsurgery, pancreatitis, any use of steroids, orimmunosuppressive agents could capture 34% of the

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Indian Journal of Pediatrics, Volume 76—October, 2009 1037

patients in the unit with relative risk 4.36, sensitivity0.34, specificity 0.90, positive predictive value 0.01, andnegative predictive value 0.97. They concluded that thisrule may identify patients at high risk of invasivecandidiasis.53 Monitoring for colonization may,therefore, offer opportunity for interventions such asprophylactic topical or systemic antifungal therapy toprevent candidemia and reduce the cost of ICU care.

DIAGNOSIS

The early diagnosis of invasive candidiasis is achallenge both for the intensivists and themicrobiologists. There are no pathognomonic signs orsymptoms. Endoscopy is useful for diagnosis ofesophageal candidiasis. Tissue samples can be stainedand cultured, and the addition of potassium hydroxideto specimens may help to identify yeast andpseudohyphae. For retinal candidal infections,ophthalmologic examination identifies characteristicsfindings. Candidal infections in solid organs may be seenon CT or ultrasound studies, but characteristics findingstypically occur late in the course of the disease. Fourultrasound patterns of hepatosplenic candidiasis have beendescribed.54 The first pattern, described as having a “wheel-within-a-wheel” appearance, consists of a centralhypoechoic area of necrosis containing fungi andsurrounded by an echogenic zone of inflammatory cells. Ahypoechoic rim is noted at the periphery. The secondpattern is `bull’s-eye’ configuration consisting of a centralechogenic nidus surrounded by a hypoechoic rim. Ingeneral, this second pattern occurs in patients with activefungal infection and a relatively normal white blood cellcount. The third pattern consists of a uniformly hypoechoicnodule and is the most common pattern; however, it is theleast specific appearance of candidiasis and may simulatemetastatic disease or lymphoma. The fourth pattern consistsof echogenic foci with variable degrees of posterior acousticshadowing. This pattern occurs in later stages of infectionand generally indicates early resolution.54 In contrast-enhanced CT, fungal microabscesses usually appear asmultiple round, discrete areas of low attenuation, generallyranging from 2 to 20 mm.

The approach to the laboratory diagnosis of candidalinfections is similar to that for bacterial infections and thevarious diagnostic modalities are summed up in table 3.

Microscopy: Wet films and gram stained smears fromlesions or exudates show budding gram positive cells. Ascandida can be seen on normal skin or mucousmembrane, it is significant only if it is present inabundance. Microscopic examination of calcoflor stainedbuffy coat smear (obtained by centrifugation of blood inmicro-hematocrit tubes) can be used for rapid diagnosisof fungal invasion in blood.55

Culture: Culturing Candida species from a normallysterile body site other than urine is usually diagnostic of

the disease. Culturing them from sites as sputum,broncho-alveolar lavage, abdominal drains, epithelial ormucocutaneous sources can cause confusion.56

Blood culture: The ability to detect Candida species inblood cultures is the most substantial advance inconventional technique. Cultures can be obtainedreadily on Sabourard’s agar. The sensitivity of bloodculture for diagnosis of invasive candidiasis with oneorgan system affected is 30%, with 2-3 organ involvementsensitivity is 60% and with 4 or more organs involved thesensitivity reaches 80%.57 To improve the sensitivity,which is around 50%, various methods have been triedincluding BACTEC system and lysis centrifugation. Toavoid validity of the specimen being affected, the culturesshould be sent as soon as possible. Rapid differentiationof C. albicans from non-albicans species by germ tube testcan be done directly from BactAlert blood culturebottles.58

Surveillance cultures of blood and from selected bodysites may help early diagnosis of candida in units withhigh incidence of invasive candidiasis. In our PICU highrisk surveillance blood cultures helped in early diagnosisof half the patients with candidemia; approximately 50%of patients growing candida on surveillance culturesbecame symptomatic within 72 hours of obtainingsample for culture.12 Kicklighter also reports the use of

TABLE 3. Diagnosis of Candida Infection

Direct microscopic examination

Potassium hydroxide (KOH) preparationPAS stainGrocott methanamine silver stainCalcoflor staining of buffy coat smear

Culture of specimens

Blood cultureBroncho-alveolar lavageAbdominal drains/peritoneal fluid

Surveillance culturesHistopathologySerology

Antibody detection test

Agglutination and complement fixation testsFluoroscent antibody testsELISARadioimmunoassay

Antigen detection tests

MannanEnolaseProteinaseGlycoproteinsCytoplasmic antigens

Presumptive diagnosis

Germ tube formation (Reynolds Braude phenomenon)BactiCard Candida test

Murex C.albicans test

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high risk surveillance strategy to diagnose andadminister prophylactic treatment for candida in infantswith birth weight less than 1500 grams.59

Serology: Because of the low sensitivity of blood culture andthe time involved, ancillary methods of diagnosing Candidainfections have been developed. Attention has been given todetect the presence of Candida antigen and antibody in theserum. Tests for direct detection of candida antigen are gainingpopularity (Table 3). Beta D-glucan, a major component offungal cell wall has been used to develop an assay which hasa sensitivity of 85%.60 Elevated D-arabinitol (major metaboliteof Candida species) to L -arabinitol ratio (D/L ratio) has beenshown to have more than 94% sensitivity. Among otherantigens, detection of enolase and cell wall mannan arepromising. The sensitivity and specificity of mannan detectionfor diagnosis of invasive candidiasis by variousimmunoassays range from 31-92% and 68- 100% respectively.Mannan concentration is considered to be an importantindicator of invasive candidiasis with concentration greaterthan 2-3 ng/ml being a presumptive indicator of infection. Insome studies including one at our institution positive mannanantigenemia had a high sensitivity to diagnose systemicinfection due to Candida.61 A Polymerase chain reaction (PCR)technique may be helpful and is being evaluated.62

Antibody detection has the problem of low sensitivity inimmunocompromised patients and inherent difficulty indistinguishing invasion from colonization. Tests measuringantibody to Candida antigens are not currently useful. Up to50% of patients with invasive Candida infections have negativetests. Tests such as radio-immunoassay (RIA) and Enzymelinked Immuno-Assay (EIA) do not distinguish patients withinvasive infection from patients who are merely colonized. Atour institute we use agglutination test to detect the presence ofantibodies to candida antigens. Titers of 1:256 and above aretaken as suggestive of candida infection.

Presumptive Diagnosis of Candida albicans

It can be made within 90 minutes by germ-gube formationwhen incubated in human serum at 370C (Reynolds BraudePhenomenon) Two commercial products, BactiCard Candidatest and Murex C. albicans test, are available for the presumptiveidentification of Candida albicans and may serve as a substitutefor the more intensive germ tube test.

These tests test for enzymes proline aminopeptidase and b-galactosaminidase and are based on the principle that C.albicans produces both these enzymes while other yeastsproduces one or neither of these enzymes. The tests give theresult within 30 seconds. One study found these enzymatictests rapid and accurate alternatives to the conventional germtube test.63

Can Candiduria Predict Invasive Candidiasis?

The results of studies evaluating candiduria as an indicator ofsystemic candidiasis are conflicting. It appears that candiduria

is more likely a predictor of disseminated infection in patientshaving non albicans candidemia. In a study from our unit, ofthe 37 patients in whom non albicans Candida species wasisolated in urine, 22 (59.5%) had candidemia. On the otherhand only 33.3% of patients with C. albicans in urinedeveloped candidemia. In this study the sensitivity andspecificity of candiduria with non-albicans candida species topredict candidemia was 75.9% and 68.1% respectively.47

TREATMENT

Treatment of candidiasis follows two fundamental elements.First is identification and removal of the most likely source offungemia and second is drug therapy to speed up theclearance of infection and to assist the clearance of undetectedfoci of hematogenous spread.64

In the non-neutropenic ICU patient with an intravascularcatheter, catheter is the most likely source and prompt removalof such infected catheter is recommended. Other commonsources are the urinary tract and localized infections;indwelling urinary catheters should be removed andlocal conditions at these sites should be treated. Febrileneutropenic patients are more likely to get candidemiadue to gut translocation.

For long time systemic antifungal therapy waslimited to only one drug- amphotericin B; use of whichwas dominated by fear of toxicity rather thanknowledge of efficacy. Introduction of azoles group ofantifungals and lipid formulations of amphotericin hasrevolutionized the systemic antifungal therapy. Thevarious antifungals currently available for use inchi ldren are shown in table 4.

Amphotericin B

Amphotericin B ((dose: 0.5-0.7mg/kg/day IV for 6weeks) remains the drug of first choice in a critically ill

TABLE 4. Antifungal Agents Available for Candidiasis

1. Conventional Amphotericin BLipid preparations of Amphotericin B

• Amphotericin B lipid complex (ABLC)• Amphotericin B colloidal dispersion (ABCD)• Liposomal amphotericin B

2. Triazoles

Conventional NewerFluconazole VoriconazoleItraconazole Posaconazole

Ravuconazole3. Echino Candins

CospofunginMicafungin Antidulafungin

child. However, the classic deoxycholate formulation ofamphotericin B has significant dose limitingnephrotoxicity and infusion related toxicity. Lipidformulations of amphotericin-B have been developed

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Indian Journal of Pediatrics, Volume 76—October, 2009 1039

with the hope of reducing toxicity and improvingefficacy. These agents get incorporated into liposomes,are rapidly taken by reticulo-endothelial system (RES)and concentrated mainly in liver, spleen, lymph nodeand very small amount goes to the kidney, thus limitingtheir nephrotoxicity. The pharmacokinetics of lipidformulations of amphotericin B vary substantially fromeach other and also from amphotericin B.

Lipid formulations of amphotericin B appear to be atleast as effective as amphotericin B in patients havingfever and neutropenia. Current information suggests that3-5mg/kg/day of a lipid formulation of amphotericin B isgenerally adequate for invasive candidiasis..65, 66,67 It hasbeen found that patients who receive the liposomal drugshave significantly fewer infusion-related reactions (17% vs44%), chills or rigors (18% vs 54%), nephrotoxicity (19% vs34%). The cost of lipid formulations is several times higherthan the conventional preparation. Table 5 shows theaccepted indications for use of lipid preparations ofamphotericin-B.

Fluconazole

Fluconazole is a fungistatic triazole. It has the

Group found that fluconazole and amphotericin B hadsimilar clinical response rates and survival among non-neutropenic candidemia patients; however, drug relatedadverse events were more frequent with amphotericin B.69

Lately, an increased resistance to fluconazole is beingreported.

Itraconazole

Itraconazole is available for oral/enteral administration.Peak concentration is attained with in 1.5-4 hrs of oraladministration. It is a highly protein bound drug and isextensively metabolized by the liver and excreted intobile and urine as inactive metabolite.70 Metabolism ofitraconazole is not affected by renal dysfunction anddose modification is not indicated under thesecircumstances. In a retrospective study we found thatoral itraconazole may be an effective treatment optionwhere non-albicans candida species predominate.71

These findings were further supported by a smallrandomized study that compared fluconazole withitraconazole in treatment of candidemia in PICU; boththe drugs achieved a cure rate of about 85% and weredevoid of significant side-effects.72

New Triazols

There are three new triazols available for clinical usage:voriconazole, posaconazole and ravuconazole. Theseagents are derivatives of either fluconazole oritraconazole and have good in vitro activity againstCandida species. Voriconazole is a synthetic derivative offluconazole. It is more potent and has a broaderantifungal spectrum than fluconazole: it is active againstC. krusei and C. glabrata. It is available both as intravenousand oral formulation and has good penetration into CNS.Intravenous formulation is contraindicated in patientswith renal insufficiency. A recent study suggestsexistence of cross-resistance to voriconazole among 25%of candida spp that were resistant to fluconazole.73 Acomparison of pharmacological properties between theolder and newer triazols is shown in table 6.

Flucytosine

Flucytosine is available for enteral use only. Flucytosineis used in combination with conventional amphotericinB for CNS fungal infections because of its synergisticaction and increased CNS penetration. Addition offlucytosine is required when there is persistence ofCandida in CSF or CNS tissue despite optimum doses ofamphotericin B.

Echinocandins

Echinocandins are rapidly fungicidal against mostCandida species including azole resistant ones. Theyhave long half life (10-12 hrs) and are therefore givenonce daily. Caspofungin is a member of theechinocandins, which has been approved for use inpediatric population. A study in pediatric patients

TABLE 5. Indications for Use of Lipid Formulations ofAmphotericin-B. These are Approved as 2nd LineTherapy in Following Categories of Patients

1. Intolerant or refractory to therapy with conventionalamphotericin B.

2. Initial renal insufficiency (creatinine clearance < 25ml/min)3. A significant rise in creatinine levels ≥1.5mg/dl in children.4. At high risk of intolerance to amphotericin B e.g.,

concomitent use of another nephrotoxic agents.5. Severe toxicity related to acute administration.

advantage of being water soluble and reliable linearpharmacokinetics independent of the route ofadministration. It is well absorbed following oraladministration and is unaffected by food or gastric pH.Peak plasma concentration occurs one to two hours afteringestion. Most of the given dose of the drug is excretedas unmetabolised drug in the urine necessitating doseadjustments in patients with renal failure. Because of itsmore rapid clearance in children fluconazole should beadministered at 6 mg/kg every 12 hrly. Though half lifein neonates is 55-90 hrs, yet, in disseminated diseaseonce daily dose of 5mg/kg should be used.

Kontoyianns et al conducted a meta analysis of sixrandomized clinical trials conducted in late 90s, tocompare efficacy of fluconazole with amphotericin B inthe treatment of candidemia.68 The analysis concludedthat fluconazole was as efficacious as amphotericin Bbut less toxic in stable patients who were at low risk fordeath; however, it was less effective than amphotericin Bin patients having candidemia caused by non albicansCandida species. The Canadian Candidemia Study

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found it extremely safe drug with good anti-Candidaefficacy.74, 75 A systematic review of randomizedcontrolled trials also evaluated the efficacy ofcaspofungin in the treatment of fungal infections.76

Micafungin and Anidulafungin are two otherechinocandins which have recently become available.Micafungin has excellent in vivo activity againstCandida spp. Success was seen with this drug (1.2 mg/kg) in 83.3% patients with new or refractorycandidemia.77

Practice guidelines for management of disseminatedCandidiasis

Evidence-based guidelines for the treatment ofcandidiasis were published by the Infectious DiseaseSociety of America (IDSA) in 2004.78 According to theguidelines, first-line therapy includes Amphotericin B andfluconazole, which are approved for use in pediatrics.Caspofungin is indicated for first-line treatment in adults.

The aim of antifungal therapy in this form ofcandidiasis is to resolve the signs and symptoms ofassociated sepsis, to sterilize the blood stream of anyclinically evident sites of hematogenous disseminationand to treat occult sites of hematogenousdissemination.

If feasible, initial non- medical management shouldinclude removal of all existing central venous catheters,especially in non-neutropenic patient population. Thechoice of drug depends upon both the clinical status ofthe patient as well as on the involved species and itsantifungal susceptibility pattern.

Currently fluconazole is the agent of choice forempirical treatment of disseminated candidiasis inneutropenic hemodynamically stable patients, unlessan azole resistant species is suspected.79 Fluconazoletherapy should also be used in clinically stable patientsin intensive care units (ICUs) where the predominantcandidal pathogen is Candida albicans and for yeastspecimens identified as Candida albicans. ,For otherspecies of Candida, empiric therapy with AmphotericinB should be initiated while awaiting culture results.80

Treatment with amphoterecin B is preferred inpatients who are unstable or neutropenic and infectedwith an unknown species. Neonates with disseminatedcandidiasis are usually treated with amphotericin B.

For C. glabrata majority prefer Amphotericin B (0.7/kg/day) or Fluconazole (12mg/kg/day), for C. krusei –amphotericin B (1mg/kg/day), for C. lusitaniae –fluconazole (6mg/kg/day) (Resistant to Amphotericin

TABLE 6. Pharmacologic Differences Between the Trizoles

Fluconazole Itraconazole Variconazole Posaconazole

Spectrum Narrow, limited mostly Similar Candida coverage Broad spectrum, active Broadest-spectrum triazole,to C. albicans, C. tropicalis, as fluconazole, also covers against Candida, potent activity againstC. parapsilosis and Aspergillus spp Aspergillus, and fusarium Candida and Aspergillus spp.C. glabrata at higher doses. spp.No activity againstAspergillus spp.

Oral absorption Excellent in tablet form Capsule-irregular, stomach Tablet-excellent Oral suspension-improvedpH-dependent, Oral absorption with multiplesolution-improved daily dosing and high-fatabsorption meal

Intravenous Available Available Available PendingFormulationClearance 80% renal Hepatic Hepatic Excreted in faeces (90%)

Serum half-life 24 24-35 6-24 8-24(hrs)Cerebrospinal Excellent Poor Excellent Poor-moderatefluid penetrationAdverse + ++ ++ ++effects-rashAdverse Occasional nausea and Nausea and vomiting, Nausea and vomiting, Nausea and vomiting, fevereffect-other vomiting, increase in diarrhoea with solution increase in hepatic

hepatic transaminases formulation, increase in transaminases,hepatic transaminases, transient visualcongestive heart failure disturbanceswith prolonged oral with intravenoustherapy infusion

Contraindicated No, but dosage adjustment Oral–no Oral – no Oral – nowhen CrCl< required Intravenous– yes Intravenous – Yes30mL/min

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B). In adult patients, Echinocandins or high dosepolyenes are preferred for treatment of infections with C.glabrata or C. krusei.

Treatment of ocular candidiasis

A combination of partial or complete vitrectomy,intraocular amphotericinB and other antifungal drugs isthe usual therapeutic choice for candida species eyeinfections. Fluconazole alone or in combination with otheragents especially amphotericin-B, voriconazole andcaspofungin appear to be quite efficacious.81 Intravitrealinjection of caspofungin and voriconazole was effectiveagainst C.albicans endophthalmitis in the experimentalrabbit models.82 Intracameral amphotericin B was shownto be an effective adjunctive treatment modality of fungalkeratitis unresponsive to conventional anti-fungaltherapy, although cataract may occur.83 In a case seriespublished by Sen P et al intravitreal voriconazole wasefficacious in even amphotericin-B and fluconazoleresistant fungal endophthalmitis.84 The usual duration oftherapy ranges from 2 to 8 weeks.85

Treatment of Candida Peritonitis

Removal of the peritoneal dialysis catheter and systemicantifungal therapy are advised. There is no role forinstillation of amphotericin B in the peritoneum; it mightcause pain and fibrosis.

Urinary Candidiasis

Candiduria should be treated in symptomatic patients,neutropenic patients and LBW infants. It may be the onlymicrobiological evidence of disseminated candidiasis.Fluconazole is a good choice for isolated urinary tractinvolvement as 70% of the drug is excreted unchanged inurine. Lipid formulations of amphotericin B penetraterenal tubules poorly86 and hence should not be used totreat renal fungal involvement. If serum creatinine isincreased, dosing interval of conventional amphotericin Bshould be increased from 24 hours to 48 hours along withaddition of fluconazole. Renal fungal balls may persistdespite sterilization and these should not be used forguiding duration of therapy. Surgical intervention in formof insertion of nephrostomy tubes, direct irrigation withamphotericin B, nephrectomy and removal of fungal ballsis rarely required now a days.

Treatment of CNS infection

CNS fungal infections are difficult to treat and may requirecombination of amphotericin B and flucytosine orfluconazole. If one or two agents are unable to ensure cure,lipid formulations of amphotericin B should have apotential role because of better CSF penetration and abilityto be given at higher doses. Among other combinationtherapies adding caspofungin to fluconazole oramphotericin B may be beneficial.87 Any contaminateddevices in CNS e.g., shunts should be removed.

Occasionally even optimum systemic therapy may not beable to establish cure and necessitate intrathecal/intraventricular administration. Therapy should becontinued for two weeks after at least two CSF cultures aresterile as relapses after one sterile culture have beenreported.88

Use of Susceptibility Testing to Guide Therapy

The National committee for clinical laboratory standardshas published guidelines for standardized antifungalsusceptibility testing that have been widely accepted.89 Ifthe implicated Candida species is known, the susceptibilityof the species to the various antifungal agents can bepredicted. Candida albicans is usually sensitive to theavailable antifungal agents i.e., amphotericin-B,fluconazole and itraconazole. However, sporadic azoleresistance is now well described in critically ill patientswith invasive candidasis. C. krusei and C. glabrata are eitherprimarily or secondarily resistant to fluconazole.90 Someare even resistant to amphotericin-B. Therefore,susceptibility of the isolated candida species to theavailable antifungal agents may be extremely important inguiding therapy.

Antifungal resistance and its clinical relevance

One of the causes of treatment failure is resistance to theused antifungal agents. Anti-fungal resistance can beeither clinical or in vitro. In vitro resistance can be eitherprimary or secondary. Clinical failure is due to low levelsof drug in serum or tissues for a variety of host / or drugrelated factors including poor patient compliance. Otherfactors that contribute to antifungal resistance includedrug interactions that decrease the antifungal levels andpatients with significant immunosuppression.

Empiric antifungal therapy

In the absence of reliable rapid diagnosis, it is necessary touse empiric therapy in patients strongly suspected ofhaving candidemia. In such situations a delay in treatmenttill the diagnosis is confirmed is associated with increasedrisk of mortality. In a study from Canada, that included202 children and adults with candidiasis between 1993-1996, the mortality among 47 patients who did not receiveempiric antifungal therapy was 68% as compared 39% inthose who received the therapy.91 In our hospital, thecrude mortality rate in those who were empirically treatedwith antifungal therapy was 19% compared with anoverall mortality of 37.5% among symptomaticcandidemia patients.12

Piarroux et al showed that targeted preemptive strategymay efficiently prevent acquisition of proven candidiasisin critically ill surgical patients.92 However, further studiesare required to assess cost-effectiveness of this strategyand its impact on selection of azole-resistant Candidastrains on a long term basis. In ICU patients, acombination of risk factors such as fever, rising CRP,

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1042 Indian Journal of Pediatrics, Volume 76—October, 2009

multiple antibiotics, central venous catheterization,patients on total parenteral nutrition, candida colonizationwould warrant empiric antifungal therapy. The drug ofchoice for empiric therapy should be both effective and safe:we use fluconazole for stable patients and Amphotericin Bfor unstable patients.

Prevention

There are no specific preventive strategies for Candidaspecies. Infection control measures to reduce nosocomialtransmission like handwashing by healthcare workers,keeping catheter in situ for only as much time as required,must be emphasized. The role of prophylaxis in the non-neutropenic ICU patient is currently the focus of intensivediscussion and research. Researchers have tried to extend theidea that the success of the use of antifungal prophylaxis inpatients with cancer might be extended to patients in theICU without neutropenia. Current data however do notsupport general use of prophylaxis in this setting93 except incertain specific situation like bone marrow transplant andpossibly other neutropenic patients. A recently publishedstudy supports prophylactic use of oral amphotericin B forprevention of candida blood stream infections in ventilatedpatients in PICU.94 However, prophylactic use is not withoutdangers and studies need to address concerns regardingemergence of drug resistance and long term safety of suchpolicy.

CONCLUSION

Invasive candidiasis is recognized as a leading contributor tomortality and morbidity in patients with onco-hematologicalmalignancies, HIV infection, primary immunodeficiencies,prolonged neutropenia, diabetes and critically ill patietnsbeing treated with corticosteroids broad-spectrum antibiotics,intravenous hyperalimentation, and central venous lines.The incidence of invasive candidasis is on a steady risebecause of increasing use of multiple antibiotics and invasiveprocedures carried out in the PICU. Worldwide there is ashifting trend from C. albicans towards non albicans species,with an associated increase in mortality and antifungalresistance. Recovery of Candida species from several bodysites in a critically ill child should raise the possibility ofdisseminated candidasis. Monitoring for colonization ofcandida, may help. There are conflicting reports of the role ofprophylactic antifungal therapy. Surveillance blood culturesin high risk patients and early empiric antifungal therapymay be helpful. Amphotericin –B remains the initial drug offirst choice in hemodynamic unstable critically ill children inthe wake of increasing resistance to azoles. Evaluation ofnewer antifungal agents and precise role of prophylactictherapy in PICU patients is needed.

Contributions: SS Singhi, Conceptualized, did literature search andprepared the final manuscript; Akash, Did literature search andprepared the draft of manuscript.

Conflict of Interest: None

Role of Funding Source: None

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