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Italian Guidelines for Diagnosis, Prevention, and Treatment of InvasiveFungal Infections in Solid Organ Transplant Recipients

P.A. Grossi, D. Dalla Gasperina, F. Barchiesi, G. Biancofiore, G. Carafiello, A. De Gasperi, G. Sganga,F. Menichetti, M.T. Montagna, F. Pea, M. Venditti, P. Viale, C. Viscoli, and A. Nanni Costa

ABSTRACT

Use of various induction regimens, of novel immunosuppressive agents, and of newer prophylacticstrategies continues to change the pattern of infections among solid organ transplant (SOT)recipients. Although invasive fungal infections (IFIs) occur at a lower incidence than bacterial andviral infections in this population, they remain a major cause of morbidity and mortality worldwide.In March 2008, a panel of Italian experts on fungal infections and organ transplantation convenedin Castel Gandolfo (Rome) to develop consensus guidelines for the diagnosis, prevention, andtreatment of IFIs among SOT recipients. We discussed the definitions, microbiological andradiological diagnoses, prophylaxis, empirical treatment, and therapy of established disease.Throughout the consensus document, recommendations as clinical guidelines were rated accordingto the standard scoring system of the Infectious Diseases Society of America and the United Stated

Public Health Service.

From the Department of Clinical Medicine (P.A.G., D.D.G.),Section of Infectious Diseases, University of Insubria, Varese;National Centre for Transplantation (P.A.G., A.N.C.), Rome;Department of Biomedical Science (F.B.), Clinic of InfectiousDiseases, University Politecnicadelle Marche, Ancona; Anesthe-sia and Intensive Care Unit SSN (G.B.), Azienda Ospedaliera-Universitaria Pisana, Pisa; Department of Radiology (G.C.), Uni-versity of Insubria, Varese; Anesthesia and Intensive Care Unit(A.D.G.), Transplantation Department, Ospedale Niguarda CaGranda, Milan; Division of General Surgery and Organ Trans-plantation (G.S.), Policlinico “A Gemelli,” Department of Surgery,Catholic University, Rome; Infectious Diseases Unit (F.M.),Azienda Ospedaliera-Universitaria Pisana, Pisa; Department ofBiomedical Science and Human Oncology (M.T.M.), Universityof Bari; Department of Experimental and Clinical Pathology andMedicine (F.P.), Medical School, Institute of Clinical Pharmacol-ogy and Toxicology, University of Udine; Department InfectiousDiseases (M.V.), Policlinico Umberto I Hospital, University “LaSapienza,” Rome; Clinic of Infectious Diseases (P.V.), Depart-ment of Internal Medicine, Geriatrics and Nephrologic Diseases,University of Bologna; and Infectious Diseases Department(C.V.), University of Genoa, Genoa, Italy.

Address reprint requests to Prof. Paolo Antonio Grossi, Pro-fessor of Infectious Diseases, Department of Clinical Medicine,Section of Infectious Diseases, University of Insubria, Ospedaledi Circolo e Fondazione Macchi, Viale Borri, 57, 21100 Varese,

USE of induction regimens, of novel immunosuppressiveagents, and of newer prophylactic strategies continues

to change the pattern of infections among solid organtransplant (SOT) recipients.1,2 Despite showing lower inci-dence than bacterial and viral infections, invasive fungalinfections (IFIs) remain a major cause of morbidity andmortality in this population worldwide.3 Fungal infectionsamong the various types of solid organ transplantation showdifferent incidences, underlying pathogenic mechanisms,and modes of clinical presentation. Two genera, Aspergillusand Candida, are responsible for the vast majority of fungalinfections in SOT recipients. They account for more than80% of IFIs, which typically occur within the first monthafter transplantation.1,2 Recent epidemiological studies

ave suggested the emergence of resistant strains of Can-ida as well as mycelial fungi other than Aspergillus toroduce infections in these patients.4,5 Guidelines for therevention and treatment have been published by themerican Society of Transplantation (AST) and more

ecently by the Infectious Diseases Society of AmericaIDSA).6–11 However, the management of fungal infectionsaries widely among transplantation centers. Large multi-enter randomized controlled trials have not yet beenerformed to evaluate risk factors, diagnoses, prophylaxis,nd treatment strategies for fungal infections among SOTecipients. Consequently, there is no uniform consensus

egarding these facets. Clinical practice has evolved mainly Italy. E-mail: paolo.grossi@uninsubria.it

© 2011 by Elsevier Inc. All rights reserved. 0041-1345/–see front matter360 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2011.06.020

Transplantation Proceedings, 43, 2463–2471 (2011) 2463

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2464 GROSSI, DALLA GASPERINA, BARCHIESI ET AL

from case series, anecdotal experiences, and single-centertrials.

In March 2008, a panel of Italian experts on fungalinfections and organ transplantation was convened in Cas-tel Gandolfo, Rome, Italy, to develop consensus guidelinesfor the diagnosis, prevention, and treatment of IFIs in SOTrecipients. The topics included definitions, microbiologicaland radiological diagnoses, prophylaxis, empirical treat-ment, as well as therapy of established disease. Throughoutthis document, recommendations were rated according tothe standard scoring system of the IDSA and United StatedPublic Health Service (Table 1).

DEFINITIONS

In 2002, a consensus group of the European Organizationfor Research and Treatment of Cancer/Invasive FungalInfections Cooperative Group (EORTC) and the NationalInstitute of Allergy and Infectious Diseases Mycoses StudyGroup (MSG) published definitions for IFIs in clinical andepidemiological research. The original definitions wererestricted to patients with cancer and to recipients ofhematopoietic stem cell transplantations. However, IFIs areknown to affect other populations. For this and otherreasons, the 2008 revised definitions have been extended toother patient groups including SOT recipients.12 The defi-nitions assign 3 levels of probability for the diagnosis of IFI:“proven,” “probable,” and “possible.” They may be appliedto SOT recipients with the aim of harmonizing clinical andepidemiological research. SOT recipients display some pe-culiar factors.

Lung transplant recipients exhibit unique clinical featuresof aspergillosis,13 namely, colonization and tracheobronchi-tis due to Aspergillus species. The airway colonizationoccurs both pretransplantation and posttransplantation.The true predictive value of Aspergillus airway colonizationfor the development of invasive aspergillosis (IA) is hard todetermine because the data are confounded with the use ofantifungal prophylaxis or pre- emptive treatment. Aspergil-lus tracheobronchitis was the most common presentation ofIA following lung transplantation, namely, 37% of patientsin a literature review.14 Tracheobronchitis is characterizedby involvement of the anastomotic airway site withoutextension to the lung parenchyma. The necrosis, ulceration,and pseudomembrane formation usually occur within thefirst 3 months following transplantation and are diagnosedusing bronchoscopy. A timely initiation of antifungal treat-ment may prevent extension of the process to the lungparenchyma.

Candidemia is the most frequent clinical manifestation ofCandida species infection, regardless of the transplanted or-gan. It typically occurs within 2 months of transplantation,particularly during hospitalization in an intensive care unit(ICU). Candida colonization of ICU patients has been shownin some studies to be an independent risk factor for candi-demia. Although the proof of infection is not disputed, the

definition of probable versus possible infection in non-neutro-

enic critically ill adults, including SOT recipients, is difficult.n this population, we propose this definition of possiblenvasive Candida infection: fever (temperature �38°C) de-pite persistent broad-spectrum antibacterial therapy for �96ours plus Candida colonization for the same Candida speciesrom at least 2 noncontiguous (including nonsterile) sites.

Risk factors show variable contributions to the develop-ent of fungal infections. The evolution varies according to

he pathogen and the transplanted organ. Some risk factorsre observed among all types of organ transplantations,hereas others may be relevant for only a particular type ofllograft. It is important to note that the presence andntensity of certain risk factors may vary throughout theosttransplantation course.

MICROBIOLOGICAL DIAGNOSIS

An early, specific microbiological diagnosis is essential toguide treatment of IFIs and to minimize exposure tononessential antimicrobial agents. Invasive diagnostic pro-cedures are often required for an accurate, timely diagno-sis.2 Currently available laboratory methods to diagnoseIFIs involve traditional (microscopic direct test, culturewith identification genus and species, susceptibility tests),histopathologic, immunologic (�-1-3-D-Glucan, galacto-

annan test, and glucuronoxylomannan), and molecularpolymerase chain reaction [PCR], nucleic acid sequence-ased amplification) approaches. A proven diagnosis ofFIs depends on recovery with microscopic evidence orsolation from cultures of fungal elements from a sterileody site or in diseased tissue (AIII; Table 1). Unfortu-ately, cultures, especially blood cultures, are an insensitiveeans to identify patients with IFIs, ie, candidemia. There-

Table 1. IDSA–US Public Health Service Grading System forRanking Recommendations in Clinical Guidelines

Category, Grade Definition

Strength ofrecommendation

A Good evidence to support arecommendation

B Moderate evidence to support arecommendation

C Poor evidence to support arecommendation

Quality of evidenceI Evidence from �1 properly randomized,

controlled trialII Evidence from �1 well-designed clinical

trial, without randomization; fromcohort or case-controlled analyticalstudies; from multiple time-series, orfrom dramatic results fromuncontrolled experiments

III Evidence from opinions of respectedauthorities, based on clinicalexperience, descriptive studies, or

reports of expert committees

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INVASIVE FUNGAL INFECTIONS 2465

fore, the development of nonculture-based diagnosticmethodology is especially important. The role of immuno-logic tests, such as detection of galactomannan and �-D-lucan in serum, remains somewhat controversial; however,hey have been included as mycological criteria for probableFI in the updated definitions.12 The utility of the galacto-

mannan test for the early diagnosis of IA has been evalu-ated in a limited number of studies in SOT recipients.According to a recent meta-analysis, the assay may showgreater utility among hematopoietic stem cell transplantthan SOT recipients, in whom the test sensitivity andspecificity were 22% and 84%, respectively (BII; Table 1).15

The sensitivity of the galactomannan assay for the diagnosisof IA in SOT recipients may be improved by testingbrochoalveolar lavage (BAL) (BII; Table 1).16–18 The re-cently commercially approved �-D-glucan assay shows asensitivity and specificity of 70% and 87%, respectively,among patients who have proven invasive candidiasis(IC).19–21 At present, this assay is only approved as andjunct to the diagnosis of IC (BII; Table 1).7 Cryptococcalntigen in cerebrospinal fluid (CSF), serum, or BAL is theecommended test for the initial diagnosis of cryptococcosisn SOT (AII; Table 1).22–24 Despite encouraging studies,

molecular methods such as PCR, to detect fungi in clinicalspecimen, have not been included in the definitions, be-cause there is as yet no standard, and because none of thetechniques have been clinically validated. PCR-based mo-lecular diagnostic tests for Aspergillus are not commerciallyvailable; their precise role in the diagnosis and manage-ent of IA in SOT recipients remains to be determined

CII; Table 1).10,25

Identification of fungal isolates at the genus and specieslevel is critically important to select antifungal therapy, andto a lesser extent, to predict outcome (AII; Table 1).Susceptibility testing for all clinically significant Candidaisolates is recommended, but this is not practical for manycenters (AII; Table 1). Generally, antifungal susceptibilitycan be predicted on the basis of the species and the localepidemiology. Antifungal susceptibility testing has beensuggested for clinical situations where azole resistance isstrongly suspected and in cases of treatment failure (CIII;Table 1).7,9

MICROBIOLOGICAL SCREENING OF ORGAN DONORS

Fungal infections have been transmitted via organ andtissue allografts. Pretransplantation screening is designed toprevent serious posttransplantation infections, either byexcluding a donor or by defining the need for specificantimicrobial therapy after grafting.1,26 The first step increening donors to detect unknown infections is a thor-ugh medical history and physical examination (by theurgical team as well) during the procurement process (AII;able 1). The initial evaluation, travel, animal, and envi-

onmental exposure histories may reveal a current or an

ctive infection that should be addressed prior to organ e

rocurement. An accurate medical and social history ismportant; the donor’s recent and remote exposures arerucial to assess eligibility.26 Screening procedures shouldnclude blood, urine, BAL, or tracheal swab cultures as wells a review of recent microbiological data and past infec-ions when possible (AII).

RADIOLOGICAL DIAGNOSIS

The challenge of fungal infections supports a rapid diag-nostic approach. The clinical suspicion for these pathogensshould be investigated by imaging studies, biopsies, andcultures. The radiological procedures may include ultra-sound or computed tomography (CT) scan or magneticresonance imaging (MRI) to highlight suspicious lesions forguided biopsies. The radiological appearance of Aspergillusor other mould infections of the central nervous system(CNS) is variable; it depends upon the patient’s immunestatus. In cases of a clinical suspicion of cranial fungalinfections, the recommended procedures are the CT (IIB;Table 1) and MRI (IIA; Table 1). Several patterns ofcerebral aspergillosis involvement have been reported: in-farction, solid enhancing lesions referred to as aspergillomaor “tumoral form,” abscess-like ring-like enhancing lesions,and edematous or hemorrhagic lesions. MRI is more sen-sitive than CT imaging to detect the number of lesions andthe presence of cryptococcoma.24,27

Chest CT is recommended whenever invasive pulmonaryaspergillosis is suspected because its sensitivity is muchgreater than a chest radiograph (IIA; Table 1).28 Commonradiographic findings include focal areas of consolidation orinfiltration as well as nodular lesions with or withoutcavitation. Pulmonary aspergillosis in SOT recipients lacksa distinguishing radiographic finding, in contrast to bonemarrow transplant patients.3,29 The halo sign, an importantarly radiological finding for the diagnosis of pulmonaryspergillosis in neutropenic and stem cell transplant recip-ents, shows a low sensitivity in SOT recipients; indeed, it isften absent.14 Rhino-sinusitis fungal infections with boneestruction are often dramatically revealed by CT, whereasoft tissue abnormalities are visualized with better sensitiv-ty by MRI (IIA; Table 1). Contrast-enhanced CT or MRIs necessary to investigate the intracranial vessels andnternal carotid artery (IIIA; Table 1).30 Ultrasonography

(IIIB; Table 1), CT, or MRI (IIA; Table 1) may visualizefungal abscesses in the liver, kidney, or spleen. CT is moresensitive than ultrasonography to detect liver micro-abscesses. An arterial multiphasic contrast-enhanced heli-cal CT should be performed in addition to a portal venousphase CT to assess focal liver lesions in immunocompro-mised patients who are suspected of harboring hepato-splenic fungal infections.31 Contrast-enhanced dynamic

RI may be superior to contrast- enhanced CT to detectesions of hepatosplenic candidiasis or other fungal dis-

ase.32,33

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TREATMENT STRATEGIES

Transplant recipients are complex and fragile. Successfultreatment of an established fungal infection requires anearly diagnosis, aggressive debridement when possible, re-duction in immunosuppression, and fungicidal therapy.Amphotericin B (AmB) deoxycholate has been regarded asthe gold standard for therapy, but its administration is oftenassociated with renal toxicity and infusion-related sideeffects. The lipid-associated amphotericin compounds,mainly the liposomal formulation, have the main advantageto decrease nephrotoxicity, but there are no data thatdirectly compare these agents with AmB for their efficacy totreat the transplant population. The azole antifungal agentshave a long-standing role in antifungal therapy. However,their interactions with the cytochrome P450 (CYP) enzymesystem produces 3- to 5-fold increased levels of cyclosporineand tacrolimus in most patients. New antifungal agentscurrently available require evaluation in SOT recipients.34

The possible strategies for IFI management in SOTrecipients are as follows: (1) prophylaxis (universal prophy-laxis or targeted prophylaxis), (2) pre-emptive therapy, (3)empirical therapy, and (4) treatment of an establishedinfection.

PROPHYLAXIS

The use and choice of agents for antifungal prophylaxis forSOT recipients remains controversial. Large randomizedtrials are lacking; single-center experiences have insufficientnumbers of patients. Given these circumstances, the abilityto develop evidence-based recommendations for antifungalprophylaxis in SOT recipients is extremely limited.

Universal Prophylaxis

Universal prophylaxis means the administration of an anti-microbial agent to the entire population to prevent theoccurrence of infection. Currently, there are insufficientdata to recommend universal prophylaxis against IFI inSOT recipients (CIII; Table 1).35,36

Targeted Antifungal Prophylaxis

A more rational approach is targeted antifungal prophy-laxis: the use of an antifungal agent in a subgroup oftransplant recipients with predisposing conditions thatplace them at higher risk of developing IFIs (CIII; Table 1).This strategy may be adapted to specific risk factors,continuing for a variable period depending on the persis-tence of the risk factors. Targeted antifungal prophylaxis inSOT recipients is based on both risk and epidemiologicalfactors because there is no clinically validated indirect testor molecular method to detect fungi in clinical specimens.Identifying patients at the highest risk of infection is crucialfor the development of effective approaches to antifungalprophylaxis. The ideal antifungal agent for prophylaxis mustbe proven to be efficacious, safe to the allograft and other

organs, predictable or with no drug interactions, easy to

dminister, with minimal/manageable side effects, and af-ordable. It is also important to determine whether theatient is at risk for a Candida or mould infection, partic-

ularly due to Aspergillus, because this requires the choice ofan agent with good antimold activity (Table 2).

For SOT recipients at risk of Candida infection, targetedprophylaxis with fluconazole (200–400 mg [3–6 mg/kg]daily) may be recommended; in transplantation centerswith a high incidence of Candida non-albicans infections orfor SOT recipients at risk for Aspergillus or other moldnfections, liposomal AmB (1–2 mg/kg daily) can be used.nhaled AmB or a lipid preparation of AmB has been usedy lung recipients postoperatively.37 The duration of pro-hylaxis is not clearly defined because the studies have noteen designed to examine this issue. As a general rule,rophylaxis should be guided by persistence of risk factorsnd by surveillance fungal cultures.

PRE-EMPTIVE TREATMENT

The low frequency of IFIs in patients undergoing solidorgan transplantation, and the absence of reliable surrogatemarkers for a prompt diagnosis, follow-up, and monitoringof response to therapy are the major limiting factors forpre-emptive treatment in this patient population (CIII;Table 1).

EMPIRICAL TREATMENT

Criteria for starting empirical antifungal therapy in non-neutropenic patients remain poorly defined. Early initiationof antifungal therapy may reduce morbidity, mortality, andlength of stay in the hospital in SOT recipients, but thewidespread use of these agents must be balanced againsttheir toxicities, costs, and emergence of resistance. Empir-ical antifungal therapy should be considered for critically illpatients with risk factors for IFIs and no other known causeof fever. It should be based upon clinical suspicion, sero-logic markers for IFIs, and/or preliminary data from cul-tures obtained from nonsterile sites (BIII).

The possible criteria to begin empirical treatment forsuspected invasive candidiasis in SOT recipients are asfollows: (1) Persistent fever (�38°C) despite broad-spectrum antibacterial therapy for �96 hours. and (2) noother known cause of fever. plus (3) Candida colonizationor the same Candida species from at least 2 noncontiguousincluding nonsterile) sites and/or (4) the presence ofpecific risk factors and/or, (5) clinical-radiological suspi-ion of IC (CIII; Table 1) and/or detection of �-D-glucan inerum.

In SOT recipients admitted to the ICU the “Candidacore” (CS) may be applied to discriminate between Can-ida species colonization and IC, providing the basis toccurately select patients who would benefit from earlyntifungal treatment. CS has recently been developed forhe colonized non-neutropenic critically ill patients; CS �3n selected patients shows them to be at high risk for IC.38,39

The rounded CS for a cutoff value of 3 (sensitivity 61%,

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INVASIVE FUNGAL INFECTIONS 2467

specificity 86%) were as follows: total parenteral nutrition1, plus surgery � 1, plus multifocal Candida colonization �1, plus severe sepsis � 2.38 All variables were coded asabsent � 0 or present � 1.

Empirical antifungal therapy for invasive aspergillosis(IA) or other mold infections is not recommended for SOTrecipients, unless other findings indicate the presence of anIFI (BIII; Table 1). The possible criteria for startingempirical treatment for suspected IA in SOT recipients maybe the following (CIII; Table 1): (1) presence of specific riskfactors: heart, lung, or liver transplantation, renal failureparticularly requiring replacement therapy, and rejection oraugmented immunosuppression, particularly the use of amonoclonal antibody postgrafting or high, prolonged ad-

Table 2. Risk Factors

Spec

Candida

Liver Prolonged or repeat operationRetransplantationCandida colonizationCholedocojejunostomyHigh transfusion requirement

RetransplaRenal failur

therapyPretransplaReoperatioUse of mo

ung Broad spectrum antibiotics andduration of antibiotic use

Central venous cathetersRenal replacement therapy

PretransplaAspergill

Early airwaAnastomotSingle lungCMV infectRejection a

immunosAcquired h

�400 mgeart Broad spectrum antibiotics and

duration of antibiotic useCentral venous cathetersRenal replacement therapy

Isolation oftract cult

ReoperatioCMV infectPosttranspExistence o

programheart tra

ancreas Enteric drainageVascular thrombosisPostperfusion pancreatitis

mall bowel Graft rejection/dysfunctionAnastomotic disruptionAbdominal reoperationMultivisceral transplantation

Abbreviations: CMV, cytomegalovirus; Ig, immunoglobulin.

ministration of corticosteroids; (2) microbiological criteria:

isolation of Asperigillus species upon respiratory tract sur-veillance cultures, positive galactomannan test in serum orBAL, and detection of �-D-glucan in serum; and (3) clinicalcriteria: tracheo-bronchitis, sinusitis, focal neurological def-icit, and pneumonia despite receipt of broad-spectrumantibacterial therapy. General principles for the empiricaltreatment of IFI in SOT recipients remain the same as inother patient populations, based on the recently publishedIDSA guidelines.7,8

For IC, preference should be given to an echinocandin inhemodynamically unstable patients, in patients previouslyexposed to an azole, and in those known to be colonizedwith azole-resistant Candida species (BIII; Table 1). Lipo-somal AmB is an alternative to an echinocandin, but the

Is in SOT Recipients

sk Factors for IFIs in SOT

Aspergillus Other Mold

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ZygomicosisRenal failureRejection and augmented

immunosuppressionCorticosteroid usageExposure to antifungals not active

against zygomycetes (ie,voriconazole)

Poorly controlled diabetes mellitusProlonged neutropeniaIron chelation with deferoxamineFusariosisProlonged neutropeniaImpaired macrophage function

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zole may be considered for noncritically ill SOT recipientswho are known to be colonized with azole-susceptibleCandida species or who have no prior exposure to azoles(BIII).

For empirical therapy in SOT recipients with suspectedIA, use of voriconazole or liposomal AmB may be recom-mended. Liposomal AmB is considered to be a primarytherapy for patients developing therapy-limiting toxicitywith a contraindications to voriconazole, or previouslyexposed to an azole or showing suspected non-Aspergillusmold infection, such as zygomycosis (CIII; Table 1).

TREATMENT OF AN ESTABLISHED INFECTION

There are no randomized studies of IFI treatment amongSOT recipients. Thus, therapeutic approaches to thesepatients are generally based on large randomized studies ina heterogeneous group of patients that include organtransplant recipients as a small component. Treatment ofIFI in SOT recipients should be based on the pathogenrecovered as well as on the clinical syndrome and site(s) ofinvolvement. Clinicians should become familiar with strat-egies to optimize efficacy through understanding relevantpharmacokinetic properties of the systemic antifungalagents. Dosing of antifungal agents must be adjusted forrenal and hepatic dysfunctions. Drug interactions of anumber of antifungal agents with immunosuppressantsmust be carefully considered when treating these recipients.The triazole agents are potent inhibitors of CYP34A isoen-zymes with the potential to increase the levels of calcineurininhibitors as well as sirolimus and everolimus.40 Reductionsin calcineurin inhibitor doses may be necessary as guided bypharmacokinetic studies40 (AIII; Table 1). Therapeutic

rug monitoring (TDM) of immunosuppressants is recom-ended for all SOT recipients undergoing treatment with

riazole agents to avoid a toxicity that may be observed atigher concentrations and to reduce the risk of treatmentailure at lower concentrations (AIII). Duration of therapyust be individualized according to the fungal pathogen,

he resolution of the process, and the individual is net statef immunosuppression as guided by clinical, microbiologi-al, or radiological means.

CANDIDA INFECTIONS

Fluconazole (loading dose of 800 mg [12 mg/kg], then 400mg [6 mg/kg] daily) remains the standard therapy for SOTrecipients with candidemia. It is considered to be thefirst-line therapy among patients with mild to moderateillness, who are clinically stable, with no recent azoleexposure and with infection due to an organism that is likelyto be susceptible to fluconazole, eg, C albicans, C parapsi-losis, and C tropicalis (AIII; Table 1). The echinocandinaspofungin (loading dose of 70 mg, then 50 mg daily),icafungin (100 mg daily), and anidulafungin (loading dose

f 200 mg, then 100 mg daily) demonstrate rapid fungicidalctivity against all Candida species, favorable safety profile,

nd few drug-drug interactions.41–43 The echinocandins are

avored as initial therapy for patients with a recent historyf azole exposure, moderately severe to severe illness, aistory of allergy or intolerance to azoles, or a high risk for

nfection due to C krusei or C glabrata7,9 (AIII; Table 1).ollowing a short course of intravenous echinocandin ther-py (3–5 days), fluconazole is a reasonable choice fortep-down therapy, provided that the organism (C albicans,

parapsilosis, and C tropicalis) is predictably susceptible touconazole and that the patient is clinically stable7,9 (AII;able 1). There are reports of decreased susceptibility of Carapsilosis to the echinocandins, but the clinical signifi-ance of this observation is unknown. However, it may berudent to choose an alternative to an echinocandin as therst-line therapy for invasive infections due to this organ-

sm44,45 (BIII; Table 1). The echinocandins are sufficientlysimilar that they are interchangeable. Liposomal AmB (3–5mg/kg daily) is an alternative if there is intolerance to orlimited availability of other antifungal agents or pharmaco-kinetic and pharmacodynamic hazards (AI). LiposomalAmB is not recommended for infections due to C lusitaniae;for this organism, the expert panel favors the use offluconazole or an echinocandin over AmB because of theobservation of in vitro polyene resistance (AIII; Table 1).

For Candida infections with evidence of involvement ofprotected sites, ie, CNS or vitreous body, the choice of anantifungal agent may be guided according to pharmacolog-ical criteria of drug diffusion into the relevant tissue; azoleand liposomal AmB are generally favored (BIII; Table 1).Removal of central venous catheters, when feasible, isstrongly recommended for patients with candidemia. Inaddition, all patients with candidemia should undergo adilated funduscopic examination and repeated blood cul-tures at 48- to 72-hour intervals until they are negative forCandida species. If there are no metastatic complications,the duration of antifungal therapy is 14 days after resolutionof signs and symptoms attributable to the infection andclearance of Candida species from the bloodstream ispparent.

ASPERGILLUS INFECTIONS

Voriconazole (loading dose of 6 mg/kg every 12 hours for 2doses, then 4 mg/kg every 12 hours) is now regarded to bethe drug of choice for primary treatment of IA in all hosts,including SOT recipients, (AI; Table 1), independent of thesite of involvement (AIII; Table 1). Voriconazole is formu-lated as a tablet or as a sulfobutyl-ether cyclodextrinsolution for intravenous (IV) administration. The paren-teral formulation is recommended for seriously ill patients(AIII; Table 1). Because the cyclodextrin molecule isrenally cleared, accumulation of the vehicle may occur inindividuals with renal insufficiency. The consequences ofplasma accumulation of sulfobutyl-ether cyclodextrin areuncertain at this time, but caution is advised when using theIV formulation in patients with renal impairment (CIII).Because of the potential for cyclodextrin accumulation

among patients with significant renal dysfunction, IV vori-

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conazole is not recommended for SOT recipients whosecreatinine clearance level is �50 mL/min46 (AIII; Table 1). Inritically ill patients, we recommend the administration ofrushed voriconazole tablets via a nasogastric tube47 (BIII).DM should be considered for patients receiving voriconazole

target minimum concentration (Cmin) � 1.0–5.5 mg/L),ecause drug toxicity has been observed at higher serumoncentrations and reduced clinical responses have been ob-erved at lower concentrations48 (BIII; Table 1).

AmB is considered to be an alternative primary therapyfor SOT recipients developing toxicity or with contraindi-cations to voriconazole (AI; Table 1). Because the use ofdeoxycholate AmB may result in increased nephrotoxicityin association with calcineurin inhibitors, liposomal AmB(3–5 mg/kg daily) is recommended if a polyene is consid-ered in the SOT recipient (AIII; Table 1). Aspergillusspecies such as A terreus are typically resistant to polyenesbut susceptible to voriconazole. However, only 5%–6% ofIA in SOT recipients are due to A terreus.49 Posaconazoleand echinocandins are rational choices for alternative,salvage therapy for IA (AII; Table 1). Caspofungin hasbeen used successfully as a single agent for salvage therapyin IA as well as in combination with other drugs.50,51 To

ate limited experience exists with the use of posaconazole,icafungin, or anidulafungin for the treatment of IA in

OT recipients.52–54 The role of itraconazole and AmBipid complex is limited to secondary therapeutic optionsAIII).

The role of combination antifungal therapy for IA hasot been fully defined. In the absence of a well-controlled,rospective clinical trial, routine administration of combi-ation therapy for primary therapy is not routinely recom-ended (BII; Table 1). However, in the context of salvage

herapy, an additional antifungal agent might be added tourrent therapy, or a combination of antifungal drugs fromifferent classes other than those in the initial regimen maye used (BII; Table 1). Pharmacodynamic considerationsuggest that the combination therapy of echinocandins andriazole or polyene agents may be a rational choice; we doot recommend simultaneous combinations of triazoleslus polyenes or triazoles, polyenes, and echinocandinsBII; Table 1).

The optimal duration of therapy for IA depends on theesponse to therapy, and the patient’s underlying disease(s)r immune status. Treatment is usually continued for ainimum of 6–12 weeks; however, the precise duration of

herapy must be guided by the clinical response rather thany an arbitrary total dose or duration (BIII; Table 1). Aeasonable course continues therapy until all clinical andadiographic abnormalities have resolved, and readily ob-ained cultures do not yield Aspergillus.10 Reversal of im-

munosuppression that includes withdrawal of corticoste-roids or reduction of their dosage is often critical for asuccessful outcome in IA (AIII). For patients who requirelarge doses of immunosuppressive therapies, long-termantifungal therapy is recommended until it is feasible to

reduce exposure to these agents (AIII; Table 1). Following s

discontinuation of therapy, patients should be monitoredfor disease relapse.

Surgical excision or debridement remains an integral partof the management of IA for both diagnostic and therapeu-tic purposes. Specifically, surgery is indicated for persis-tent or life- threatening hemoptysis, for lesions in prox-imity to the great vessels or pericardium, for sino-nasalinfections, for single cavitary lung lesions that progressdespite adequate treatment, as well as for lesions invad-ing the endocardium, pericardium, bones, and subcuta-neous or thoracic tissue8 (BII; Table 1). Surgical resec-ion is also indicated for intracranial abscesses dependingn their location, accessibility, and neurological se-uelae. Pneumonectomy has led to a successful outcome

n a lung transplant recipient with progressive, refractoryngio-invasive aspergillosis whose disease worsened de-pite conventional antifungal therapy.55

NON-ASPERGILLUS MOLD INFECTIONS

Infections caused by non-Aspergillus molds have becomeincreasingly common among SOT recipients in the pastdecade.11,56 The reasons for this trend are not exactly

nown. It may be a consequence of the current antifungalrophylaxis or changes in the type and potency of immu-osuppression. Nonetheless, these changes are worrisomeecause many of these fungi are resistant to conventionalherapy.

Therapy of zygomycosis involves extensive debridementf necrotic tissue, control of predisposing metabolic condi-ions, correction of neutropenia, and cessation or reductionf immunosuppression in conjunction with systemic anti-ungal agents. The antifungal susceptibility profile of zygo-ycetes presents few options. The standard for primary

herapy is liposomal AmB at a starting dose of 5 mg/kgaily, which may be increased if tolerated to 12.5 mg/kgaily. Most data have documented maximum benefit at 7.5g/kg daily when combined with aggressive surgical de-

ridement. Often multiple debridements may be necessaryo assure clean margins11,57 (AII; Table 1). High-dose

liposomal AmB (10–15 mg/kg daily) has been used for CNSor refractory disease, but its efficacy has not been comparedsystematically with the standard dose (5 mg/kg daily) and itis more toxic.58 Posaconazole (200 mg 4 times daily withood) is useful as a step-down therapy following liposomalmB (BII) or as salvage therapy (CIII; Table 1).59,60

Because there are no clinical studies comparing theefficacy of various antifungal agents in fusariosis, therapeu-tic decisions are often guided by outcome data from sub-group analyses of drug comparison studies. Fusarium spe-ies are resistant to echinocandins, whereas they showariable susceptibility to AmB, voriconazole, and posacona-ole.61 However, various species may display different pat-erns of susceptibility. F solani and F verticillioides aresually resistant to azoles, exhibiting higher AmB Minimumnhibitory Concentrations (MICs) than other Fusarium

pecies. By contrast, F oxysporum and F moniliforme may be

vcdTahrcpmbl

2470 GROSSI, DALLA GASPERINA, BARCHIESI ET AL

susceptible to voriconazole and posaconazole.62 The rele-vance of these in vitro data is not clear because there arenot sufficient data documenting a correlation betweenMICs and clinical outcomes. High-dose liposomal AmB(5–15 mg/kg daily) remains the treatment of choice (BIII;Table 1).62 Although there are limited data supportingoriconazole or posaconazole for the initial therapy, vori-onazole (6 mg/kg twice daily on day 1 then 4 mg/kg twiceaily) has been proposed to be an alternative to AmB (BIII;able 1). Both azoles are useful, as are combined polyene-zole regimens for salvage therapy (CIII).63 Treatmentsave included surgical resection of localized skin disease,emoval of infected foreign bodies such as intravascularatheters, and correction of neutropenia. In organ trans-lants with limited foci of fusarial disease, surgical resectionay be sufficient for cure. However, recurrent disease has

een observed despite repeat debridement and prolongediposomal AmB.

ACKNOWLEDGMENTS

Editorial assistance was provided by Luca Giacomelli and SiobhanWard.

REFERENCES

1. Fishman JA: Infection in solid-organ transplant recipients.N Engl J Med 357:2601, 2007

2. Fishman JA and the ATS Infectious Diseases Community ofPractice: Introduction: infection in solid-organ transplant recipi-ents. Am J Transplant 9:S3, 2009

3. Silveira FP, Husain S: Fungal infections in solid organ trans-plantation. Med Mycol 45:305, 2007

4. Pfaller MA, Pappas PG, Wingard JR: Invasive fungal patho-gens: current epidemiological trends. Clin Infect Dis 43:S3, 2006

5. Pappas PG, Alexander BD, Andes DR, et al: Invasive fungalinfections among organ transplant recipients: results of the Trans-plant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis 50:1101, 2010

6. Fungal infections. Am J Transplant 4:110, 20047. Pappas PG, Kauffman CA, Andes D, et al: Clinical practice

guidelines for the management of candidiasis: 2009 update by theInfectious Diseases Society of America. Clin Infect Dis 48:503,2009

8. Walsh TJ, Anaissie EJ, Denning DW, et al: Treatment ofaspergillosis: clinical practice guidelines of the Infectious DiseasesSociety of America. Clin Infect Dis 46:327, 2008

9. Pappas PG, Silveira FP, and the ATS Infectious DiseasesCommunity of Practice. Candida in solid organ transplant recipi-ents. Am J Transplant 9:S173, 2009

10. Singh N, Husain S, and the ATS Infectious Diseases Com-munity of Practice: Invasive aspergillosis in solid organ transplantrecipients. Am J Transplant 9:S180, 2009

11. Kubak BM, Huprikar SS, and the ATS Infectious DiseasesCommunity of Practice: Emerging & rare fungal infections in solidorgan transplant recipients. Am J Transplant 9:S208, 2009

12. De Pauw B, Walsh TJ, Donnelly JP, et al: Revised defini-tions of invasive fungal disease from the European Organizationfor Research and Treatment of Cancer/Invasive Fungal InfectionsCooperative Group and the National Institute of Allergy andInfectious Diseases Mycoses Study Group (EORTC/MSG) Con-sensus Group. Clin Infect Dis 46:1813, 2008

13. Silveira FP, Husain S: Fungal infections in lung transplant

recipients. Curr Opin Pulm Med 14:211, 2008

14. Singh N, Husain S: Aspergillus infections after lung trans-plantation: clinical differences in type of transplant and implica-tions for management. J Heart Lung Transplant 22:258, 2003

15. Pfeiffer CD, Fine JP, Safdar N: Diagnosis of invasive asper-gillosisusing a galactomannan assay: a meta-analysis. Clin InfectDis 42:1417, 2006

16. Husain S, Paterson DL, Studer SM, et al: Aspergillus galac-tomannan antigen in the bronchoalveolar lavage fluid for thediagnosis of invasive aspergillosis in lung transplant recipients.Transplantation 83:1330, 2007

17. Clancy CJ, Jaber RA, Leather HL, et al: Bronchoalveolarlavage galactomannan in diagnosis of invasive pulmonary aspergil-losis among solid-organ transplant recipients. J Clin Microbiol45:1759, 2007

18. Husain S, Clancy CJ, Nguyen MH, et al: Performancecharacteristics of the platelia Aspergillus enzyme immunoassay fordetection of Aspergillus galactomannan antigen in bronchoalveolarlavage fluid. Clin Vaccine Immunol 15:1760, 2008

19. Ostrosky-Zeichner L, Alexander BD, Kett DH, et al: Mul-ticenter clinical evaluation of the (1– �3) beta-D-glucan assay as anaid to diagnosis of fungal infections in humans. Clin Infect Dis41:654, 2005

20. Persat F, Ranque S, Derouin F, et al: Contribution of the(1–�3)-beta-D-glucan assay for diagnosis of invasive fungal infec-tions. J Clin Microbiol 46:1009, 2008

21. Obayashi T, Negishi K, Svzvki T, et al: Reappraisal of theserum(1–�3)-beta-D-glucan based assay for the diagnosis of inva-sive fungal infections-A study based on autopsy cases from 6 years.Clin Infect Dis 46:1864, 2008

22. Saha DC, Goldman DL, Shao X, et al: Serologic evidencefor reactivation of cryptococcosis in solid-organ transplant recipi-ents. Clin Vaccine Immunol 14:1550, 2007

23. Singh N, Alexander BD, Lortholary O, et al: Pulmonarycryptococcosis in solid organ transplant recipients: clinical rele-vance of serum cryptococcal antigen. Clin Infect Dis 46:e12, 2008

24. Singh N, Forrest G, and the ATS Infectious DiseasesCommunity of Practice: Cryptococcosis in solid organ transplantrecipients. Am J Transplant 9:S192, 2009

25. Espy MJ, Uhl JR, Sloan LM, et al: Real-time PCR in clinicalmicrobiology: applications for routine laboratory testing. ClinMicrobiol Rev 19:165, 2006

26. Grossi P, Fishman JA, and the ATS Infectious DiseasesCommunity of Practice: Donor-derived infections in solid organtransplant recipients. Am J Transplant 9:S19, 2009

27. Saag MS, Graybill RJ, Larsen RA, et al: Practice guidelinesfor the management of cryptococcal disease. Clin Infect Dis 30:710,2000

28. Caillot D, Couaillier JF, Bernard A, et al: Increasing volumeand changing characteristics of invasive pulmonary aspergillosis onsequential thoracic computed tomography scans in patients withneutropenia. J Clin Oncol 19:253, 2001

29. Paterson DL, Singh N: Invasive aspergillosis in transplantrecipients. Medicine (Baltimore) 78:123, 1999

30. Aribandi M, McCoy VA, Bazan C: Imaging features ofinvasive and noninvasive fungal sinusitis: a review. Radiographics27:1283, 2007

31. Metser U, Haider MA, Dill-Macky M, et al: Fungal liverinfection in immunocompromised patients: depiction with multi-phasic contrast-enhanced helical CT. Radiology 235:97, 2005

32. Semelka RC, Shoenut JP, Greenberg HM, et al: Detectionof acute and treated lesions of hepatosplenic candidiasis: compar-ison of dynamic contrast-enhanced CT and MR imaging. MagnReson Imaging 2:341, 1992

33. Semelka RC, Kelekis NL, Sallah S, et al: Hepatosplenicfungal disease: diagnostic accuracy and spectrum of appearanceson MR imaging. AJR Am J Roentgenol 169:1311, 1997

34. Grossi P: Clinical aspects of invasive candidiasis in solid

organ transplant recipients. Drugs 69:15, 2009

Cins

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INVASIVE FUNGAL INFECTIONS 2471

35. Cruciani M, Mengoli C, Malena M, et al: Antifungal pro-phylaxis in liver transplant patients: a systematic review andmeta-analysis. Liver Transpl 12:850, 2006

36. Playford EG, Webster AC, Sorell TC, et al: Antifungalagents for preventing fungal infections in solid organ transplantrecipients. Cochrane Database Syst Rev 3:CD004291, 2004

37. Palmer SM, Drew RH, Whitehouse JD, et al: Safety ofaerosolized amphotericin B lipid complex in lung transplant recip-ients. Transplantation 72:545, 2001

38. León C, Ruiz-Santana S, Saavedra P, et al on behalf ofEPCAN Study Group: A bedside scoring system (“Candida score”)for early antifungaltreatment in nonneutropenic critically ill pa-tients with Candidacolonization. Crit Care Med 34:730, 2006

39. León C, Ruiz-Santana S, Saavedra P, et al on behalf of theava Study Group: Usefulness of the “Candida score” for discrim-

nating between Candida colonization and invasive candidiasis inon-neutropenic critically ill patients: a prospective multicentertudy. Crit Care Med 37:1624, 2009

40. Saad AH, DePestel DD, Carver PL: Factors influencing theagnitude and clinical significance of drug interactions between

zole antifungals and select immunosuppressants. Pharmacother-py 26:1730, 2006

41. Mora-Duarte J, Betts R, Rotstein C, et al: Comparison ofaspofunginand amphotericin B for invasive candidiasis. N EnglMed 347:2020, 200242. Reboli AC, Rotstein C, Pappas PG, et al: Anidulafungin

ersus fluconazole for invasive candidiasis. N Engl J Med 356:2472,00743. Pappas PG, Rotstein CM, Betts RF, et al: Micafungin versus

aspofungin for treatment of candidemia and other forms ofnvasive candidiasis. Clin Infect Dis 45:883, 2007

44. Walsh TJ: Echinocandins-an advance in the primary treat-ent of invasive candidiasis. N Engl J Med 347:2070, 200245. Weiderhold NP, Lewis RE: The echinocandin antifungals:

n overview of the pharmacology, spectrum, and clinical efficacy.xpert Opin Investig Drugs 12:1313, 200346. von Mach MA, Burhenne J, Weilemann LS: Accumulation

f the solvent vehicle sulphobutylether beta cyclodextrin sodium inritically ill patients treated with intravenous voriconazole underenal replacement therapy. BMC Clin Pharmacol 6:6, 2006

47. Mohammedi I, Piens MA, Padoin C, et al: Plasma levels oforiconazole administered via a nasogastric tube to critically illatients. Eur J ClinMicrobiol Infect Dis 24:358, 200548. Pascual A, Calandra T, Bolay S, et al: Voriconazole thera-

eutic drug monitoring in patients with invasive mycoses improvesfficacy and safety outcomes. Clin Infect Dis 46:201, 2008

49. Singh N, Limaye AP, Forrest G, et al: Combination oforiconazole and caspofungin as primary therapy for invasive

mC

spergillosis in solid organ transplant recipients: a prospective,ulticenter, observational study. Transplantation 81:320, 200650. Carby MR, Hodson ME, Banner NR: Refractory pulmonary

spergillosis treated with caspofungin after heart-lung transplanta-ion. Transpl Int 17:545, 2004

51. Forestier E, Remy V, Lesens O, et al: A case of Aspergillusediastinitis after heart transplantation successfully treated with

iposomal amphotericin B, caspofungin and voriconazole. EurClin Microbiol Infect Dis 24:347, 200552. Walsh TJ, Raad I, Patterson TF, et al: Treatment of invasive

spergillosis with posaconazole in patients who are refractory to orntolerant of conventional therapy: an externally controlled trial.lin Infect Dis 44:2, 200753. Denning DW, Marr KA, Lau WM, et al: Micafungin

FK463), alone or in combination with other systemic antifungalgents, for the treatment of acute invasive aspergillosis. J Infect3:337, 200654. Lodge BA, Ashley ED, Steele MP, et al: Aspergillus fumiga-

us emphysema, arthritis, and calcaneal osteomyelitis in a lungransplant patient successfully treated with posaconazole. J Clin

icrobiol 42:1376, 200455. Sandur S, Gordon SM, Mehta AC, et al: Native lung

neumonectomy for invasive pulmonary aspergillosis followingung transplantation: a case report. J Heart Lung Transplant8:810, 199956. Husain S, Alexander BD, Munoz P, et al: Opportunisticycelial fungal infections in organ transplant recipients: emerging

mportance of non-Aspergillus mycelial fungi. Clin Infect Dis 37:21, 200357. Sun HY, Forrest G, Gupta KL, et al: Rhino-orbital-cerebral

ygomycosis in solid organ transplant recipients. Transplantation0:85, 201058. Chen S-A, Playford EG, Sorrell T: Antifungal therapy in

nvasive fungal infections. Current Opinion Pharmacol 10:1, 201059. Greenberg RN, Mullane K, Van Burik JA, et al: Posacona-

ole as salvage therapy for zygomycosis. Antimicrob Agents Che-other 50:126, 200660. Ibrahim AS, Gebremariam T, Schwartz J, et al: Posacona-

ole mono-or combination therapy for treatment of murine zygo-ycosis. Antimicrob Agents Chemother 53:772, 200961. Alastruey-Izquierdo A, CuencaEestella M, Monzon A, et al:ntifungal susceptibility profile of clinical Fusarium spp. isolates. Jntimicrob Chemother 61:805, 200862. Nucci M, Anaissie E: Fusarium infections in immunocom-

romised patients. Clin Microbiol Rev 30:695, 200763. Perfect JR, Marr KA, Walsh TJ, et al: Voriconazole treat-

ent for less-common, emerging, or refractory fungal infections.lin Infect Dis 36:1122, 2003