CLINICAL MICROBIOLOGY REVIEWS,0893-8512/97/$04.0010

July 1997, p. 477–504 Vol. 10, No. 3

Copyright © 1997, American Society for Microbiology

Antifungal Prophylaxis during Neutropenia and ImmunodeficiencyOLIVIER LORTHOLARY1,2 AND BERTRAND DUPONT2*

Service de Medecine Interne, Centre de Recherches en Pathologie Infectieuse et Tropicale, Hopital Avicenne,Universite Paris-Nord, 93009 Bobigny Cedex,1 and Unite de Mycologie and Centre National de Reference

des Mycoses et des Antifongiques, Institut Pasteur, 75724 Paris Cedex 15,2 France

INTRODUCTION .......................................................................................................................................................478General Comments .................................................................................................................................................478Who Is Susceptible to Fungal Infections?...........................................................................................................479

Neutropenic patients ..........................................................................................................................................479Bone marrow transplant recipients..................................................................................................................479Solid-organ transplant recipients.....................................................................................................................479

(i) Generalities ................................................................................................................................................479(ii) Kidney........................................................................................................................................................480(iii) Liver..........................................................................................................................................................480(iv) Pancreas....................................................................................................................................................480(v) Heart, lung, and heart-lung ....................................................................................................................480

HIV-infected individuals ....................................................................................................................................480Other high-risk groups ......................................................................................................................................481

(i) Qualitative defects of neutrophils...........................................................................................................481(ii) Connective tissue diseases ......................................................................................................................481(iii) Other immune deficits............................................................................................................................481

Which Pathogens To Consider?............................................................................................................................481Candida spp.

(i) Mucosal infection ......................................................................................................................................481(ii) Systemic infection ....................................................................................................................................481

Aspergillus spp. ....................................................................................................................................................482Cryptococcus neoformans .....................................................................................................................................482Endemic mycoses ................................................................................................................................................482Emerging fungal pathogens...............................................................................................................................482

When To Administer Drugs?.................................................................................................................................483COMMON PROPHYLACTIC MEASURES FOR ALL IMMUNOCOMPROMISED INDIVIDUALS ..........483

Candida spp. ............................................................................................................................................................483Aspergillus spp. ........................................................................................................................................................483Zygomycosis (Mucormycosis)................................................................................................................................483Cryptococcus neoformans .........................................................................................................................................483Endemic Mycoses....................................................................................................................................................483Other Fungal Pathogens ........................................................................................................................................484

NEUTROPENIC PATIENTS OTHER THAN TRANSPLANT RECIPIENTS ...................................................484Nonabsorbed Oral Therapy...................................................................................................................................484

Topical azoles ......................................................................................................................................................484(i) Clotrimazole ...............................................................................................................................................484(ii) Oral miconazole .......................................................................................................................................484

Oral polyenes.......................................................................................................................................................484(i) Oral amphotericin B versus placebo or no treatment .........................................................................484(ii) Nystatin suspension versus no treatment.............................................................................................484(iii) Nystatin suspension versus topical clotrimazole................................................................................484

Systemic Therapy ....................................................................................................................................................485Intravenous amphotericin B..............................................................................................................................485Systemic azoles versus placebo or no treatment ............................................................................................485

(i) Intravenous miconazole............................................................................................................................485(ii) Ketoconazole .............................................................................................................................................485(iii) Fluconazole ..............................................................................................................................................485(iv) Itraconazole ..............................................................................................................................................486

Systemic azoles versus oral polyenes ...............................................................................................................486(i) Azoles versus nystatin...............................................................................................................................486

* Corresponding author. Mailing address: Service des Maladies In-fectieuses et Tropicales, Hopital de l’Institut Pasteur, 209-211, rue deVaugirard, 75724 Paris Cedex 15, France. Phone: (33 1) 45 68 81 96.Fax: (33 1) 45 68 82 18. E-mail: bdupont@pasteur.fr.

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(ii) Azoles versus oral amphotericin B ........................................................................................................486(iii) Azoles versus intravenous amphotericin B .........................................................................................487

Azoles in association with oral or intravenous amphotericin B ..................................................................487Comparison of oral azoles .................................................................................................................................487

Specific Prevention of Invasive Aspergillosis......................................................................................................487Hematopoietic Growth Factors and Other Cytokines .......................................................................................488Prophylaxis against Relapse..................................................................................................................................488

AUTOLOGOUS OR ALLOGENEIC BONE MARROW RECIPIENTS .............................................................489Low-Dose Intravenous Amphotericin B...............................................................................................................489

Amphotericin B deoxycholate............................................................................................................................489Lipid formulations of amphotericin B.............................................................................................................489

Azoles........................................................................................................................................................................489Ketoconazole........................................................................................................................................................489Fluconazole ..........................................................................................................................................................489Itraconazole .........................................................................................................................................................490

SOLID-ORGAN TRANSPLANT RECIPIENTS .....................................................................................................490Kidney.......................................................................................................................................................................490Liver..........................................................................................................................................................................490Pancreas and Kidney-Pancreas ............................................................................................................................491Heart, Lung, and Heart-Lung ...............................................................................................................................491

HIV-INFECTED INDIVIDUALS ..............................................................................................................................491Mucosal Candidiasis ..............................................................................................................................................491

Primary prophylaxis ...........................................................................................................................................491Suppressive therapy............................................................................................................................................491

Cryptococcosis .........................................................................................................................................................492Primary prophylaxis ...........................................................................................................................................492Suppressive therapy............................................................................................................................................492

Histoplasmosis Due to Histoplasma capsulatum ..................................................................................................492Primary prophylaxis ...........................................................................................................................................492Suppressive therapy............................................................................................................................................492

(i) Amphotericin B..........................................................................................................................................492(ii) Itraconazole...............................................................................................................................................493(iii) Fluconazole ..............................................................................................................................................493

Coccidioidomycosis .................................................................................................................................................493Primary prophylaxis ...........................................................................................................................................493Suppressive therapy............................................................................................................................................493

Aspergillosis.............................................................................................................................................................493Primary prophylaxis ...........................................................................................................................................493Suppressive therapy............................................................................................................................................493

Infection Due to Penicillium marneffei ..................................................................................................................493Other Mycoses.........................................................................................................................................................493

QUALITATIVE DEFECTS OF NEUTROPHILS...................................................................................................493CONCLUSION............................................................................................................................................................493ACKNOWLEDGMENTS ...........................................................................................................................................495REFERENCES ............................................................................................................................................................496

INTRODUCTION

General Comments

Systemic mycoses are defined as infections that invade be-yond the superficial surfaces into tissues that are normallysterile. During the past three decades, dramatic alterationshave occurred in our clinical environment (use of broad-spec-trum antibacterial agents and vascular access devices) and pa-tient immune defenses (resulting from chemotherapy andradiation, neutropenia, and lymphopenia of human immuno-deficiency virus [HIV] infection). These changes have providedopportunities for fungal pathogens to assume major roles ininfectious diseases. Such pathogens in immunocompromisedhosts may be separated into those that are community acquired(endemic mycoses and Cryptococcus neoformans infection) andthose that are nosocomially acquired (Candida and Aspergillusspp.). The rate of candidal bloodstream infection has increasedby as much as 487% throughout the 1980s (258). Other fungi

are also being observed more frequently (1) and pose majorchallenges owing to the lack of effective therapies (357).

The incidence of invasive fungal infections is determined by theinteraction between epidemiological factors and the degree ofimmunosuppression. The advent of AIDS has dramatically in-creased the problems of mucosal candidiasis, cryptococcosis, his-toplasmosis, and coccidioidomycosis, as well as, more recently,penicilliosis in southeast Asia and particularly Northern Thailand.

To prevent antifungal colonization and mainly to counterthe rise of severe systemic mycoses, for which the response tocurative treatments remains suboptimal, antifungal prophy-laxis has been expanded. However, it has also been responsiblefor rising costs and the emergence of (naturally or not) resis-tant fungal strains. Simultaneously, indirect ways to preventinvasive fungal infections in immunocompromised hosts havebeen developed to better control the immune deficiency itself,for example the use of hematopoietic growth factors in neu-tropenic patients, the effective prevention of graft versus hostdisease (GVHD) in allogeneic bone marrow transplant (BMT)

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patients (139, 146, 288), and the use of more efficient antiret-roviral agents in double or triple combination, including pro-tease inhibitors, during AIDS.

When prescribing an antifungal agent for prophylaxis, phy-sicians should be aware of which immunosuppressed patientsto treat; which types of pathogens they want to cover in thetherapeutic spectrum; the best time for the introduction ofantifungal prophylaxis; the potential for emergence of resistantstrains; concomitant organ dysfunctions; the potential for druginteractions, especially in transplant recipients treated withcyclosporine or tacrolimus; the effects on survival and qualityof life; and the total cost of the treatment.

This paper presents a general review based on articles andrecent abstracts published from January 1976 to January 1997.It reports our current knowledge of antifungal prophylaxis inneutropenic and other immunocompromised patients with anemphasis on clinical trials that have demonstrated the efficacyand safety of such treatments. Although anecdotal reportshave documented the efficacy of topical chlorhexidine (96),this, like prophylaxis against Pneumocystis carinii, which hasrecently been reclassified by taxonomists as a fungus, will notbe further detailed here.

Who Is Susceptible to Fungal Infections?

Neutropenic patients. Neutropenic patients are at high riskfor developing deep mycoses. Autopsy data show that 5% ofpatients with solid tumors, 12% of patients with lymphoma,and up to 25% of patients with leukemia have histologicalevidence of invasive fungal infections (27). One-third to one-half of the patients who die during prolonged episodes ofneutropenia have deep mycoses at autopsy (158, 212). Dissem-inated candidiasis is associated with a 30 to 40% mortality ratein patients with solid tumors (378). Neutropenic patients rep-resent the most appropriate group in which to study antifungalprophylaxis. Indeed, many of the data available on this topichave been obtained in this population.

However, all neutropenic patients with solid or hematolog-ical malignancies do not have the same risk for developing afungal infection, which depends on the magnitude and theduration of the neutropenic phase (28, 124, 375). Indeed, be-cause of the short duration of neutropenia (up to 7 days), noantifungal prophylaxis should be given during cycles of adju-vant chemotherapy (78). Patients with acute myeloblastic leu-kemia or severe myelodysplasia who require intensive chemo-therapeutic regimens need particularly close surveillance forinvasive fungal infections. Other patients who should be con-sidered for prophylaxis are those in whom a prolonged courseof neutropenia may occur (339). This is the population that wehave targeted for our discussion of antifungal prophylaxis. Be-cause of the high incidence of invasive fungal infections incancer patients, difficulties in obtaining an early diagnosis (be-cause of difficulties in isolating fungi in cultures and interpret-ing the results and because of an inability to perform invasiveprocedures in patients with coagulation disorders), and theiradverse effect on patient outcome, the need for antifungalprophylaxis is strong. The data obtained from these numerousstudies are often difficult to interpret and there is still nodefinitive consensus on preventive modalities in these patients.The type of underlying disease and thus the type of antineo-plastic chemotherapy, mucosal damage, and duration of neu-tropenia have to be clearly defined before the efficacy of anykind of antifungal prophylactic strategy can be evaluated.

Bone marrow transplant recipients. During clinical trials,BMT recipients should be separated from patients with othercauses of neutropenia. The most important factor predisposing

BMT recipients to fungal infections is the duration of neutro-penia. The incidence of fungal infections has been estimated tobe 21% in BMT recipients whose neutropenia lasted less than3 weeks compared with 57% in those whose neutropenia per-sisted for 6 weeks or more (215). Of 60 deaths in BMT patientswith systemic candidiasis, fungal infection was directly respon-sible for 19 (32%) (344). Among 85 autopsies of BMT recip-ients (216), Milliken and Powles determined that 26% of thepatients had fungal infections. Aspergillosis remains a partic-ularly difficult problem in allogeneic BMT recipients; over 90%of infected patients die (11, 124).

Marrow allograft recipients run the highest risk of invasivefungal infections, not only during the neutropenic phase butalso during the months following transplantation, especiallywhen GVHD occurs (118, 124, 223). Autologous BMT recip-ients who undergo total-body irradiation in association withchemotherapy appear to have a duration of neutropenia sim-ilar to that observed in intensively treated patients with acutemyeloblastic leukemia. For patients who receive intensive che-motherapy followed by stem cell transfusion and treatmentwith cellular growth factors, the overall risk of infections andthat of invasive mycoses is dramatically reduced (243), as thesepatients have a median duration of neutropenia of 12 days(224). In that study, 2.3% of 219 patients developed invasivefungal infections. It is therefore important to separate thesetwo subpopulations of patients undergoing autografts whenselecting candidates for antifungal prophylaxis (357).

In the allograft recipients, one study identified age, acuteGVHD, and donor mismatch as risk factors for invasive can-didal infection (118). Another study (344) demonstrated thatneutropenia was an independent factor associated with theoccurrence of systemic candidal infections, as well as increas-ing age, detection of one or more positive surveillance culturesfor Candida spp., and total-body irradiation. Positive cytomeg-alovirus (CMV) serologic test results and age of 18 years orolder were significant risk factors for non-Candida fungal in-fections in allogeneic BMT recipients (223). Pretransplant con-ditioning regimens and T-cell depletion are also recognizedrisk factors, as are underlying disease, remission status, muco-sal damage, and GVHD prophylaxis (244, 359).

Rossetti et al. recently analyzed fungal liver infection aftermarrow transplantation and found the following predictive fac-tors: any deep fungal infection after transplantation; coloniza-tion or superficial infection with fungi after transplantation;severe liver dysfunction caused by venoocclusive disease of theliver; and/or GVHD (285). Interestingly, in that paper, imagingstudies performed during the last 15 days of life had a sensi-tivity of only 18% for detecting fungal liver lesions. Other riskfactors are the same as those described in nongrafted neutro-penic patients.

Sable and Donowitz separated several periods of risk forinfections during BMT (293). During the pretransplantationperiod, the risk of fungal infection is low. The engraftmentperiod, from days 0 to 30, is associated with an increased riskof invasive fungal infections. During the postengraftment pe-riod, from days 30 to 100, any mold infection may occur, buthepatosplenic candidiasis may also occur. During the late post-transplantation period (day 100 or later), systemic fungal in-fections are unusual and oropharyngeal candidiasis is the mostfrequent fungal infection (293).

Solid-organ transplant recipients. (i) Generalities. The suc-cess rate of solid-organ transplantation has greatly improved asa result of advances in surgical techniques, immunosuppressivetherapy, and medical management. However, infections andallograft rejection remain major causes of morbidity and mor-tality during solid-organ transplantation. Occasionally, the

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transplanted organ itself is the source of transmission of infec-tion (138). Fungal infections are reported in all types of solid-organ transplantation and are associated with high mortality(27 to 77%) (250), with Aspergillus infections being responsiblefor the highest death rate. The incidence of fungal infections insolid-organ transplant recipients varies according to the immu-nosuppressive treatment, transplanted organ, and transplanta-tion team: it is lowest in renal transplant recipients and highestin liver and pancreas transplantees, in whom underlying dis-ease and complicated abdominal surgery play important roles(138). This incidence has been estimated to be 2 to 14% ofkidney, 18 to 38% of pancreas or pancreas-kidney, 2 to 42% ofliver, 0 to 32% of heart, and 15 to 35% of lung/heart-lungtransplantations (126, 250, 251, 253, 351).

Immunosuppressive therapy and the use of corticosteroids,particularly when administered as an intravenous bolus for thetreatment of acute rejection, are important predisposing fac-tors (88, 127), in association with the type of underlying diseaseand other factors during the posttransplantation period, in-cluding the presence of immunomodulating viral infections,such as Epstein-Barr virus, CMV, and HIV (126). There is stilla debate concerning the increased incidence of fungal infec-tions in lung transplant recipients receiving tacrolimus (250).

(ii) Kidney. There is a significant relationship between thetotal dose of steroids given to renal transplant recipients andthe subsequent development of invasive aspergillosis (125). Inthis population, some precise risk factors for fungal infectionshave been identified: diabetes, cadaveric allograft, increasedcorticosteroid use (to prevent or control rejection), retrans-plantation, and recent CMV infection (126). Recipients ofkidney transplants are at high risk for the development ofcandiduria, including asymptomatic colonization of the blad-der, and renal parenchymal diseases may shorten graft survival.In a recent series of 50 transplant recipients (197), 228 epi-sodes of infection were documented (4.5 per patient), 11% ofwhich were fungal; 47% of these episodes occurred within thefirst 2 months after transplantation. Candida spp. were the onlyetiological agents isolated. In that prospective study, pyelone-phritis due to Candida spp. was the only infection associatedwith a high risk of allograft loss.

(iii) Liver. Liver transplant recipients are at high risk fordeveloping invasive fungal infections (51), especially when or-thotopic liver transplantation is performed. The reasons arethe longer duration of the procedure, the frequency of coloni-zation with Candida spp. (166), and surgical complicationssuch as bile duct obstruction and vascular anastomotic prob-lems, which are more common than in other transplant oper-ations (359). In one study, the median posttransplantation timeto the first episode of fungal infection has been reported to be60 days (251). The incidence of invasive fungal infections wasreported to be as high as 42% (352). Infections of the abdom-inal cavity are frequently observed, but urinary tract and chestinfections also occur (351), with Candida spp. being responsi-ble for 87% of all deep mycoses (62, 127).

The risk factors for systemic fungal infections were retro-spectively analyzed in 186 orthotopic liver transplant proce-dures performed in 152 patients (37). The total incidence ofinvasive fungal infections was 16.5% (25 of 152). The incidenceof disseminated candidiasis, aspergillosis, and combined can-didiasis plus aspergillosis was 6.5, 7.2, and 2.6%, respectively.The mortality rate associated with invasive fungal infectionswas 80%. Of 10 patients with disseminated candidiasis, 4 sur-vived; of 11 patients with invasive aspergillosis, only 1 survived.Acute renal failure requiring hemofiltration and the amount offresh plasma transfused because of poor initial function of theliver allograft were independent significant risk factors for in-

vasive fungal infections. Requirement for intensive care, me-chanical ventilation before transplantation, operative time,type of anastomosis, and operative transfusion requirementswere also defined as risk factors for fungal infections in livertransplant recipients (51, 251, 352, 384). Enhanced immuno-suppression with steroids, OKT3 monoclonal antibody treat-ment of rejection, and prior CMV infection may facilitate thedevelopment of invasive fungal infections. In a multivariateanalysis of factors associated with invasive lung aspergillosisafter liver transplantation (167), high creatinine levels at thetime of Aspergillus isolation and use of OKT3 monoclonalantibody were significant risk factors. In that study, respiratorysecretions and wound drainage positive for Aspergillus organ-isms were associated with invasive disease.

(iv) Pancreas. In pancreas transplant recipients, the mostcommon sites of fungal infections are surgical wounds and theurinary tract. Infectious complications following pancreatictransplantation were recently analyzed in 34 consecutive recip-ients. In 27 recipients who developed severe infectious epi-sodes, 26% of the infections were caused by fungi (87% byCandida spp.) (192). In a recent retrospective study, intra-abdominal fungal infections occurred after pancreatic trans-plantation in 41 (9.2%) of 445 patients (20). In that study, therate of infections was higher for enteric-drained (21%) thanfor bladder-drained (10%) transplants, for organs donated byliving relatives (16%) than for those from cadavers (9%), andfor pancreas-after-kidney (12%) and simultaneous pancreas-kidney (11%) than for pancreas-only (5%) recipients. The rateof fungal infections was 6% in patients receiving prophylaxis(fluconazole, 400 mg/day for 7 days) compared with 10% inthose without prophylaxis. It should be noted that the 1-yeargraft survival rate was significantly decreased for recipientswith infection.

(v) Heart, lung, and heart-lung. Fungal infections frequentlyoccur during the first month posttransplantation. Most fungalinfections in these patients are caused by Candida and Aspergil-lus spp. (155). Some risk factors are more specifically associ-ated with the surgical procedures used in heart or lung trans-plantees: colonization of the donor trachea by Candida spp. isa notable risk factor for pneumonia, anastomotic dehiscence,and mediastinitis in the recipient (69, 84).

In a series of 100 consecutive heart transplant recipients,Waser et al. (360) reported only one lethal case of Candidasepsis (originating from a peritoneal dialysis catheter) and onelethal case of invasive aspergillosis occurring 27 months post-operatively.

Kramer et al. (162) published a retrospective analysis of 200episodes of serious infections in 73 heart-lung recipients. Four-teen percent were fungal, with Aspergillus spp. (14 episodes)and C. albicans (12 episodes) being the most common patho-gens. C. albicans infected mainly the upper tracheobronchialtree and was the second most common pathogen in patientswith obliterative bronchiolitis. Aspergillus spp. tended to dis-seminate and were responsible for the death of three patients.However, in these recipients, it is sometimes difficult to distin-guish between Aspergillus infection and colonization (162).Preoperative colonization with Aspergillus spp. in patients withcystic fibrosis, intercurrent infection with CMV, neutropenia,and steroid therapy has been reported to increase the inci-dence of the disease (155).

HIV-infected individuals. Opportunistic fungal infectionsare common in patients with HIV infection and representmajor causes of morbidity (10, 373). Their incidence increaseswith the progression of the HIV infection and reduction of theCD4 lymphocyte counts. Specific risk factors for each oppor-tunistic fungus are detailed below. Decisions to administer

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primary prophylaxis must consider the prevalence and severityof these infections, the efficacy and safety of antifungal treat-ment, the risk of emergence of resistant fungal species, thequality of life and the survival time in control groups of pa-tients without prophylaxis, and the cost of antifungal treat-ment. Indeed, it was estimated in 1994 that antifungal prophy-laxis for 100,000 AIDS patients in the United States would costover half a billion dollars yearly (368). The impact on overallsurvival is minimal, since the incidence of systemic fungal in-fections is low.

Other high-risk groups. (i) Qualitative defects of neutro-phils. Chronic granulomatous disease is a hereditary abnor-mality of phagocytic cells and causes microbicidal defects dueto a lack of production of reactive oxygen species necessary formicrobicidal activity. Aspergillus and Candida spp. were iso-lated in 20.4% of a large series of 245 patients and werefrequently responsible for infection (60). In a French series, 14of 37 affected children who presented with invasive aspergillo-sis were characterized by a paucity of symptoms (225). Myelo-peroxidase deficiency, a hereditary defect of the lysosomalenzyme myeloperoxidase, may also favor Candida infections(294).

(ii) Connective tissue diseases. Despite the intensive immu-nosuppressive regimens administered and the use of prolongedsteroid therapy during systemic inflammatory diseases, patientswith connective tissue diseases are not specifically prone todeveloping deep fungal infections. Invasive fungal infections inthese populations have been reported in the literature but notto a degree that requires general recommendations for theirprophylaxis (183). However, monitoring for fungal coloniza-tion to ensure rapid diagnosis of such infections should beperformed in patients with prolonged neutropenia or profoundCD4 lymphocyte depletion, in particularly patients with We-gener’s granulomatosis or systemic lupus erythematosus (183).

(iii) Other immune deficits. Other defects can be classifiedas chronic quantitative neutrophil deficiencies, in which sys-temic candidiasis and invasive aspergillosis are most common,or as cellular immune deficits, such as idiopathic low-CD4syndrome, in which Cryptococcus neoformans, candidal muco-sal infection, and dimorphic fungal infections are more likelyto develop. Infants with severe combined immunodeficiencymay also develop fungal infections, particularly candidiasis(320, 361). Thus, these patients should be managed with anti-fungal prophylaxis according to the nature of their immuno-deficiency, which indicates the probable type of fungal infec-tions to prevent.

No specific study has addressed the use of antifungal pro-phylaxis in these last two populations. Thus, they will not befurther discussed here.

Which Pathogens To Consider?

Aspergillus and Candida spp. are the most common fungalpathogens isolated from neutropenic patients and represent90% of all fungal infections (343). They are thus the mostcommon fungal targets of prophylaxis in all types of immuno-deficiencies.

Candida spp. (i) Mucosal infection. In neutropenic patients,predisposition to mucosal Candida infections is facilitated byantineoplastic chemotherapeutic regimens and radiation,which cause mucosal ulcerations. The use of broad-spectrumantibiotics with anaerobic activity (295) or glycopeptides (280)also promotes the growth of Candida spp. Thus, trials of pro-phylaxis against Candida spp. should include groups of patientswith similar exposure to antibiotics (386). Mucosal infectionsare also more common in patients with T-cell deficiencies, like

those observed during lymphomas. Interestingly, recovery ofCandida spp. from the mouths of neutropenic patients is pre-dictive of the subsequent occurrence of oropharyngeal candi-diasis (389).

Mucosal candidiasis contributes markedly to the morbidityof HIV-infected patients in both developed and developingnations, as it is the most common fungal infection in thispopulation (373). The increasing resistance of C. albicans,which occurs in 7 to 15% (89, 234) (but up to 41% in a recentreport [195]) of HIV-infected patients undergoing long-termfluconazole therapy to control mucosal candidiasis, has be-come a major problem (16, 47, 99, 260, 278, 290, 298, 299). Inthis population, fluconazole MICs correlated with the clinicaloutcome (105, 278). In three recent studies, prior use of azoletherapy was identified as a risk factor associated with the emer-gence of resistant candidiasis (194, 195, 337). The recent ex-tension of Candida resistance to other antifungal drugs is wor-risome (159, 174). Chronic administration of low doses offluconazole may also facilitate the emergence of C. glabrataand C. krusei, but the precise impact of azoles on these speciesremains controversial (259). These species have been isolatedfrom the oral cavity of AIDS patients (55, 75, 290), but theirpathogenicity in HIV-infected individuals remains to be eluci-dated. Indeed, in a recent study, none of 10 patients fromwhom only non-albicans species of Candida were isolated hadactive thrush (195). For patients harboring resistant or less-susceptible strains of C. albicans, C. krusei, and C. glabrata,strict hygienic procedures must be used to avoid transmissionwithin the hospital (347). Such transmission has also beenclearly documented between sexual partners and may explainthe discovery of azole-resistant Candida spp. isolated frompreviously untreated patients (85).

(ii) Systemic infection. Systemic infections are of both en-dogenous (61) and exogenous (259) origins. The insertion ofcentral venous catheters predisposes neutropenic patients tofungemia, especially those receiving parenteral nutrition (100).Hematogenous candidiasis also follows colonization of themouth or gastrointestinal tract (42, 72, 297), as reported forpatients hospitalized in surgical intensive care units (263). Col-onization of multiple noncontiguous sites in contrast to colo-nization of a single site, is highly predictive of invasive candi-diasis in neutropenic patients (198). Because the duration ofprophylactic treatment is short, the appearance of fluconazole-resistant C. albicans is less likely to be problematic for patientswith cancer (379). Whether these patients need more protec-tion when they are housed next to HIV units requires furtherinvestigation. The major problem in this neutropenic popula-tion is the emergence of fluconazole-resistant C. krusei (204,208, 256, 380) and C. glabrata (92, 236, 381). C. parapsilosis(187, 362) may also emerge as a significant pathogen, particu-larly in patients receiving parenteral nutrition.

Systemic candidal infections have been reported in 11.4 to12.5% of BMT recipients (118, 344) within a median time of 15days after transplantation (118). In one study, the incidence ofcandidal infections was similar in allogeneic and autologousmarrow recipients (344). The mortality is 39% for candidemiaalone and 90% when tissues are involved with or withoutfungemia (118). Candida infection of multiple organs was di-agnosed postmortem in 26 of 132 patients (344). In BMTpatients, C. albicans remains by far the most frequent pathogenresponsible for fungal infections (313), but C. tropicalis hasemerged as another frequent pathogen (359). In liver trans-plant recipients, more than 85% of invasive fungal infectionsare candidal (138) and occur early after transplantation (62).The incidence of candidal infection in pancreas transplant re-cipients approaches 100% (137).

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The occurrence of candidemia in HIV-infected children(356) and adults (173) cannot be ignored, especially in AIDSpatients with central venous catheters for prolonged periods(115). Fungemia due to fluconazole-resistant albicans and non-albicans Candida species are now being reported in this pop-ulation (168, 173, 336).

Aspergillus spp. Aspergillus fumigatus and A. flavus are themost common pathogenic species, but other species are alsoresponsible for human infections. Aspergillus spp. are observedmainly in patients with prolonged neutropenia, those withqualitative disturbances of their neutrophil function, or thosereceiving steroids (100). Invasive aspergillosis has recentlybeen described in patients with lymphoid hematological ma-lignancies who are receiving purine analogs (56). The risk wascalculated by Gerson et al., who estimated it to be from 1% perday after the first 3 weeks of neutropenia to 4.5% per day after5 weeks (104). The risk of developing invasive aspergillosis isalso dependent on the environment; therefore, historical con-trols cannot be used for studies on Aspergillus chemoprophy-laxis (386).

Invasive aspergillosis was most often reported in patientswith acute leukemia or in allogeneic BMT recipients, espe-cially those with GVHD (205); it is a leading cause of death inthe latter group (79). The incidence of invasive aspergillosismay be as high as 25% in some allogeneic BMT populations(287). More recent data were summarized by Denning (77)and showed that the incidence varied between 3.8 and 8.7% inallogeneic BMT recipients and between 0.6 and 4.5% in au-tologous BMT recipients. Aspergillus spp. were the most prev-alent fungi responsible for brain abscesses following marrowtransplantation in one recent report (128).

The incidence of invasive aspergillosis among renal trans-plant recipients was estimated to be around 3% in the early1980s (125, 363); it was 5.5% and 14 to 19% in liver and hearttransplant recipients, respectively (77, 155). A recent studyreported an incidence of 16.5% in orthotopic liver transplantrecipients (145), and the eyes were the second most commonsite of infection. The outcome of infection in the solid-organtransplant recipient population depends on the extent of thefungal disease (79, 359).

In HIV-infected patients, aspergillosis is becoming moreprevalent as a consequence of longer survival and complica-tions of other therapies (160, 188). A higher risk for invasiveaspergillosis is observed when patients have a CD41 cell countbelow 50/mm3 and when they have recently taken corticoste-roids or recently been neutropenic. However, the last twofactors are not always present, and aspergillosis may also com-plicate preexisting lung damage (188).

Cryptococcus neoformans. Cryptococcosis is observed mainlyin patients with impaired T-lymphocyte–monocyte/macro-phage interactions, such as HIV-infected individuals (58),those with Hodgkin’s disease, and those receiving high-dosecorticosteroids. C. neoformans infection rarely occurs duringthe first 4 to 6 months after organ transplantation (138). Arecent paper reported 10 cryptococcal infections occurring af-ter liver transplantation within a median of 3.5 months aftertransplantation (148). In that study, the incidence of crypto-coccal infection was 0.25%. In France, 14% of cryptococcaldiseases occur in non-HIV-infected immunodeficient individ-uals (86).

In most areas of the world, this fungal infection occurs in 5to 10% of HIV-infected patients (86, 262), but in Africa itaffects up to 30% (217), and it may become an even largerproblem in Thailand (147). By contrast, recent results of amultistate population-based surveillance showed a decrease inthe incidence of cryptococcal infection in North America

(129). The risk of cryptococcosis among HIV-infected individ-uals is highest at CD41 lymphocyte counts below 100/mm3.

Endemic mycoses. Endemic systemic mycoses are geograph-ically restricted and include histoplasmosis, blastomycosis,paracoccidioidomycosis, coccidioidomycosis, and penicilliosis.However, the transformation of endemic mycoses into oppor-tunistic diseases is now being noted. In immunocompromisedpatients, they may be observed as primary infections, reinfec-tion, or reactivation which may occur much later, sometimesseveral years after the person has left the area of endemicinfection (138). Such mycoses are particularly problematic inpatients with AIDS because of their high incidence in areas ofendemic infection and their major comorbidity.

Histoplasmosis due to the H. capsulatum has been reportedin 2 to 5% of patients with AIDS in areas of endemic infectionin the United States and up to 25% in selected cities (367). Ina recent survey in France, we found 56 AIDS patients whodeveloped the disease sometimes up to 21 years after they hadleft the area of endemic infection (182). Most cases have beenobserved during the last 5 years, which should serve as an alertto physicians. By contrast, Histoplasma duboisii histoplasmosisis rare in the immunocompromised host. Indeed, in a recentnational survey in France involving 25 patients, we found thisorganism in only 2 HIV-infected individuals (90).

During the early 1990s, the incidence of Coccidioides immitisinfection increased dramatically (161). Disseminated coccid-ioidomycosis has been reported in 602 AIDS patients in theUnited States (151).

Penicilliosis is increasing sharply in Thailand (325), SouthChina (76), and Hong Kong (57) and has become the thirdmost common infection associated with AIDS after extrapul-monary tuberculosis and cryptococcal meningitis in NorthernThailand (325). Paracoccidioidomycosis is still rare in this pop-ulation, with 27 cases reported in the literature (111), as isblastomycosis (249). Antifungal prophylaxis might have thegreatest impact on HIV-infected patients with less than 100CD41 T cells living in areas where these pathogens are hyper-endemic.

In transplant recipients, histoplasmosis is the most frequentendemic fungal infection, causing primarily disseminated butalso chronic forms of disease (138). Coccidioidomycosis hasbeen reported mostly in renal, heart, and heart-lung transplantrecipients (138, 162), but blastomycosis is rarely reported(307).

Emerging fungal pathogens. The members of the Mucoralesare ubiquitous molds that cause invasive fungal infections inneutropenic patients whether or not the patients have under-gone BMT (100). The most frequent organisms responsible forzygomycosis are Rhizopus arrhizus, Absidia corymbifera, andRhizomucor pusillus (359). Zygomycoses also arise in pro-foundly immunocompromised HIV-infected individuals (341).They may also be observed in transplant recipients treated withsteroids (250), usually several months after transplantation.However, a case occurring 5 days after heart transplantationhas also been reported (227).

Several other species are becoming increasingly recognizedas the source of deep fungal infections in cancer patients (13,254); they include Fusarium spp. (102, 207), Trichosporon asa-hii (beigelii), Blastoschizomyces capitatus (254, 358), and Sce-dosporium spp. (11). Disseminated fusariosis frequently man-ifests itself as cutaneous lesions, and the fungus has frequentlybeen isolated from blood cultures (207). Potentially severeinfections caused by Acremonium spp., Malassezia furfur, anddematiaceous fungi have also been reported (254). They areoften resistant to one or several antifungal agents (357), andeffective antifungal prophylaxis remains to be found. Interest-

482 LORTHOLARY AND DUPONT CLIN. MICROBIOL. REV.

ingly, twelve different unusual fungal pathogens were isolatedfrom cancer patients at M. D. Anderson Hospital between1974 and 1986 (13).

In HIV-infected patients, invasive fungal infections due tounusual pathogens have also been found (65, 185).

When To Administer Drugs?

When antifungal prophylaxis is used in neutropenic patients,it should be started at the time chemotherapy is initiated so asto be active when the neutrophil count drops. Once the neu-trophil count recovers, the prophylaxis should be discontinued(339).

In BMT recipients, prophylaxis must be continued, regard-less of the neutrophil count, because of the risk of systemicfungal infections should the patient develop GVHD. Particularattention must be paid to patients who need high-dose steroidsto counter transplant rejection and those with active CMVinfection. Although no optimal duration of antifungal prophy-laxis has been defined for this population, a recent recommen-dation proposed a duration of 3 months posttransplantation(386).

For solid-organ transplant recipients, this question remainsunanswered, but antifungal prophylaxis might be indicated forat least the first month posttransplantation.

In HIV-infected patients, the risk of systemic fungal infec-tions dramatically increases below a level of 100 CD41 lym-phocytes/mm3. Thus, studies on primary prophylaxis shouldtarget these patients. Lifelong suppressive therapy should begiven to patients who previously experienced a systemic fungalinfection.

COMMON PROPHYLACTIC MEASURES FOR ALLIMMUNOCOMPROMISED INDIVIDUALS

Careful barrier nursing is essential for all immunosup-pressed patients (269). In addition, specific measures are takenfor certain fungal agents.

Candida spp.

The most important prophylaxis against candidiasis is tominimize the factors predisposing to Candida infections. Indi-vidual major risk factors for systemic candidiasis in the immu-nocompromised host were defined in at least four case-controlstudies (40, 156, 280, 365). Risk factors for candidemia mainlyinclude the use of invasive procedures, neutropenia, and ad-ministration of at least two broad-spectrum antibiotics (364).Several clusters or outbreaks of candidiasis have been reported(100, 259, 283). Therefore, it is absolutely essential that phy-sicians, nurses, and people visiting the patients be made awareof the potential transmission of Candida species by their hands(323) and be taught strict hygienic (handwashing) practices.These steps will permit prophylactic drugs to play their role.

Aspergillus spp.

Aspergillus spp. are ubiquitous in nature. The incidence ofinvasive aspergillosis is increased during hospital renovationand/or construction and when air filtration is inadequate (100,286, 359). However, a recent study failed to demonstrate anytemporal association between periods of high Aspergillus sporecounts and cases of aspergillosis (116).

Exposure to plants is strongly contraindicated (78), as isconsumption of raw vegetables and pepper (70), and food mustbe properly cooked. Regular cleaning and maintenance of adust-free environment, especially wall surfaces, are important.

Modern equipment such as high-efficiency particulate air fil-ters, laminar air flow, positive room air pressure to the corri-dor, well-sealed rooms, and high rates of room air changes canreduce the incidence of aspergillosis (100, 279, 310, 363), butthese precautions are not available everywhere.

Simplification of the procedures used for the care of neu-tropenic patients, including outpatient management, shouldspecifically address the risk of fungal infection. It has beenproposed that all high-risk neutropenic patients should be ex-amined for possible colonization by Aspergillus spp. in the nasalcavity and the upper respiratory tract before high-dose chemo-therapy is given or prior to BMT (364). This practice is notstandard and is costly but may provide data with which toinitiate preemptive therapy. Particularly rigorous precautionsshould be taken when renovation, repair, and/or constructionwork is under way in medical units for care of HIV-infectedindividuals.

Although inhaled spores have been thought to be the majorsource of invasive aspergillosis, reactivation of endogenousAspergillus spp. can also be responsible for the disease (283).Recent studies that investigated the epidemiology of aspergil-losis by molecular techniques provided limited evidence for areadily identifiable environmental source of Aspergillus strainsthat can be shown to be responsible for either sporadic cases oroutbreaks of aspergillosis (106, 189). Ideally, prevention ofinvasive aspergillosis involves action at two different levels:environmental control to avoid acquisition, and chemoprophy-laxis of already colonized patients (283).

Zygomycosis (Mucormycosis)

There is no recognized method to prevent systemic infec-tions with members of the Mucorales. Housing patients withsevere neutropenia in rooms supplied with laminar-flow-puri-fied air has been shown to reduce the risks of aspergillosis andmucormycosis (324). Replacing deferoxamine by hydroxypyr-idinone chelators may be one approach to decreasing the riskof developing mucormycosis in patients requiring such therapy(31). Deferoxamine allows a significant uptake of iron by Rhi-zopus spp. and promotes the in vitro growth of these patho-gens.

Cryptococcus neoformans

The lungs are the major portal of entry of Cryptococcusneoformans through inhalation of yeasts or basidiospores ofthe fungus. The fungus is ubiquitous in the soil; therefore,there is no way to avoid inhalation. Bird (pigeon and canary)droppings are a source of contamination of dust and soil,although there is no proof that droppings are the primaryenvironmental source of cryptococcosis (262). In any case,patients with cellular immunodeficiency, AIDS, or on high-dose corticosteroids should probably avoid close contact withbirds (262). There is no documented interhuman transmissionof cryptococcosis, and no special recommendation can be givenfor hospital practice.

Endemic Mycoses

Educational efforts should be made to better acquaint thepublic with histoplasmosis in areas of endemic infection andthe types of leisure or work activities that can increase the riskof contracting infections. For severely immunocompromisedpatients not living in regions of highly endemic infection, travelin these areas should be discouraged. For European travelers,the French Antilles and French Guiana should be consideredhigh-risk areas. Visiting caves should also be proscribed for

VOL. 10, 1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 483

these patients because of possible contamination by animaldroppings (130). Immunocompromised patients should remainindoors during dust storms in areas where of Coccidiodes im-mitis is endemic (203).

It is important to look for serological evidence of previousexposure to Histoplasma capsulatum or C. immitis when immu-nodeficiency is diagnosed or before transplantation in peoplewho have lived or traveled in areas of endemic infection. Nogeneral recommendation can be made for the prevention ofblastomycosis in immunocompromised individuals, and sero-logical tests to determine possible exposure to Blastomycesdermatitidis are not reliable. Immunocompromised individuals,especially those infected with HIV, should be aware of Peni-cillium marneffei endemicity in Southeast Asia, South China,and Hong Kong. Finally, immunocompromised individualsshould not work in mycology laboratories.

Other Fungal Pathogens

The remaining pathogens may be assigned to two categories:endogenous fungal flora, including yeasts such as Trichosporon,Malassezia, Rhodotorula, and Saccharomyces spp.; and exoge-nous, mainly filamentous fungi, such as Fusarium, Scedospo-rium, Penicillium, Curvularia, Bipolaris, and Alternaria spp.(254). The portal of entry of endogenous fungi is the digestivemucosa or skin; exogenous fungi are generally contracted byinhalation of spores. As a rule, to prevent these yeast infec-tions, the integrity of the skin and mucosal barriers must bepreserved and the use of antibiotics and intravenous lines mustbe limited. For the filamentous fungi, the main prophylacticmeasure is efficient air filtration and laminar air flow.

NEUTROPENIC PATIENTS OTHER THANTRANSPLANT RECIPIENTS

Nonabsorbed Oral Therapy

Nonabsorbed oral treatments have been designed to reducefungal colonization and infection of the digestive tract and arenot used for primary prophylaxis of invasive aspergillosis.

Topical azoles. (i) Clotrimazole. Clotrimazole troches (10mg three times a day [t.i.d.]) were studied versus placebo in 84patients (this study also included 47 patients who had under-gone renal transplantation). Clotrimazole was superior to pla-cebo in preventing oral candidiasis in patients with solid tu-mors but not in those with leukemia; however, both groupswere small (246). A prospective, randomized, double-blindstudy involving the same dosage of clotrimazole versus placeboin patients with acute leukemia showed fewer oral candidalinfections in the clotrimazole group (67). A third study evalu-ated clotrimazole (10 mg t.i.d.) versus no treatment andshowed the superiority of clotrimazole in preventing oral can-

didiasis (1% became infected versus 27% in the untreatedgroup) (389).

These three studies suggest that topical clotrimazole is aneffective alternative for the prevention of oral candidiasis incancer patients, but there are no data to support its use for theprevention of systemic infections (211).

(ii) Oral miconazole. Oral miconazole as capsules or buccalgel is marketed in some countries. As capsules, the drug ispoorly absorbed, and gastrointestinal intolerance and side ef-fects are frequent. Very few data concerning its use in theprophylaxis of fungal diseases are available (38). The buccalgel, a formulation available in France, represents an effectivetopical treatment against oropharyngeal candidiasis in our clin-ical practice; however, no comparative randomized study hasbeen undertaken to assess its use as a prophylactic agent.

Oral polyenes. (i) Oral amphotericin B versus placebo or notreatment. Amphotericin B is inactivated in feces (142), so thathigh doses are necessary to obtain antifungal activity (81). Oneold study demonstrated that oral amphotericin B (200 mg/d)was significantly superior to placebo in preventing dissemi-nated candidiasis (this formulation is not available in theUnited States (95). Amphotericin B (tablets or in suspension)has sometimes been shown to be effective in preventing can-didiasis, but these formulations are poorly tolerated by patients(206), which may greatly affect the outcome. Yamada et al.reported that oral amphotericin B in combination with nor-floxacin was able to lower the rate of fungal infections com-pared with amphotericin B alone (388). Resistant fungalstrains have been found in patients receiving topical polyenes(267). Because of the lack of convincing data showing that oralamphotericin B is effective as antifungal prophylaxis, theWorking Party of the British Society for Antimicrobial Ther-apy did not recommend its use alone (386), as had been pre-viously suggested (73, 314).

(ii) Nystatin suspension versus no treatment. It has beendemonstrated in healthy volunteers that there is no inhibitoryconcentration of nystatin against C. albicans in the feces, de-spite treatment with as much as 12 3 106 U/day (141). In anuncontrolled study, nystatin could not eradicate existing Can-dida colonization or prevent colonization in patients with ini-tially negative cultures (17). The results of studies on nystatinsuspension vs no treatment are summarized in Table 1.

An old study reported that nystatin used in association withantibiotics had a poor efficacy against disseminated candidiasis,which was not attenuated, regardless of the dose (350). Inanother study reported by the same group, filamentous fungiwere acquired significantly more frequently by patients receiv-ing a combination of trimethoprim-sulfamethoxazole plus nys-tatin than those receiving nalidixic acid plus nystatin (349).

(iii) Nystatin suspension versus topical clotrimazole. Clo-trimazole (25 mg t.i.d.) was more effective and better toleratedthan oral nystatin for the prevention of oropharyngeal candi-

TABLE 1. Studies on nystatin prophylaxis versus no treatment in neutropenic patients

Population No. of patients Method Main resultsb Reference

Acute leukemia in children 67 Randomizeda No reduction of FUO; reduction in hospitalization 172Cancer 164 Comparative Reduction of multiple-site colonization; no change

in IFI rate42

Acute leukemia 70 Retrospective No reduction of OPC; no reduction ofdisseminated candidiasis

72

Leukemia in children 94 Historical comparative Reduction of clinical candidiasis 49Acute leukemia 56 Randomized No difference 376

a In association with trimethoprim-sulfamethoxazole.b FUO, fever of unknown origin; IFI, invasive fungal infection; OPC, oropharyngeal candidiasis.

484 LORTHOLARY AND DUPONT CLIN. MICROBIOL. REV.

diasis in 63 patients (54). Patient compliance with nystatintherapy is moderate, as it has an unpleasant taste and digestivedisorders are dose related (339). In addition, oral nystatin hasa poor bioavailability.

Thus, use of nystatin for fungal chemoprophylaxis in neu-tropenic patients has not given consistently favorable resultsand has no effect on the prevention of hematogenously spreadcandidiasis; its role in this indication is minor.

Systemic Therapy

Intravenous amphotericin B. Amphotericin B has been pro-posed as a prophylactic antifungal agent because it has a broadspectrum of antifungal activities, but its potential for immedi-ate toxicity (nausea, fever, and chills) and renal damage, whichis further enhanced in combination with other nephrotoxicdrugs, may limit its use in clinical practice. A recent studydemonstrated that patients without myocardial or renal dys-function receiving hydrocortisone and diphenhydramine cantolerate central line infusions of prophylactic amphotericin Bfor 2 h (237). At present, its parenteral use is not associatedwith the emergence of resistant strains.

Systemic azoles versus placebo or no treatment. Most of theregimens described here were used for anti-Candida prophy-laxis.

(i) Intravenous miconazole. Only one double-blind study hasevaluated intravenous miconazole (5 mg/kg t.i.d.) versus pla-cebo (180 patients were studied): the overall incidence of fun-gal sepsis was significantly lower in the miconazole group, butdeaths resulting from fungal sepsis were not statistically differ-ent between the groups (382). Miconazole was well tolerated inthis study, but severe side effects, mainly nausea and vomiting,pruritus, phlebitis, and cardiac arrhythmias, have been re-ported by others. Wiley et al. (375) demonstrated in a multi-variate analysis that administration of intravenous miconazole(5 mg/kg t.i.d.) to children with acute leukemia, beginning atthe onset of the first fever during neutropenia, was a negativerisk factor for the development of invasive fungal infections.

(ii) Ketoconazole. Ketoconazole was the first systemic imi-dazole investigated for antifungal prophylaxis (39, 94, 209).Ketoconazole (400 mg/day) versus placebo was investigated ina prospective, randomized, double-blind study: no fungal in-fection occurred in the ketoconazole group, but there was nodifference between the groups in terms of the number of fe-

brile days, the number of days during which antibiotics wereadministered, or the need for amphotericin B (132). A pla-cebo-controlled study suggested a reduction in fungal coloni-zation in patients receiving ketoconazole, but no significanteffect on the incidence of documented fungal infections ormortality was found (247). One study of patients with solidtumors reported that 400 mg was more effective than 200mg/day in preventing colonization (306).

Different published trials with ketoconazole demonstratethat it may be useful in preventing oropharyngeal disease andreducing yeast colonization. Ketoconazole has no activityagainst Aspergillus spp. and members of the Mucorales; it mayselect for some resistant fungal strains; its absorption may beimpaired in cases of achlorhydria, whether induced by drugs ornot; it may interact with other drugs such as cyclosporine intransplant recipients (222); and its potential liver toxicity is amatter of concern. Thus, it can no longer be recommended asa first-line prophylactic regimen for patients with neutropenia.

(iii) Fluconazole. Fluconazole is water soluble and has fa-vorable pharmacokinetic properties, including a large volumeof distribution and high-level penetration into most tissues. Ithas a long half-life and few interactions with other drugs dur-ing its absorption phase and metabolism (36, 109). Fluconazolebioavailability is not affected by changes of gastric acidity.Fluconazole is also available in an intravenous form and cantherefore be administered to patients who have difficulty inswallowing. Its safety has been demonstrated.

Fluconazole is effective in the treatment of oropharyngealcandidiasis (109), chronic disseminated candidiasis in leukemicpatients (12, 98, 158), and candidemia (277). A recent papersuggested that it could minimize or prevent acute mucositis inassociation with sucralfate in patients undergoing radiationtherapy above the diaphragm (8). However, the respective roleof each drug remains unknown, and no mycological data werereported in the paper. Walsh et al. demonstrated that flucon-azole was most effective against disseminated candidiasis inpersistently granulocytopenic rabbits when used for preventionor early treatment of infection (354).

Therefore, the availability of fluconazole led to large multi-center protocols to evaluate the drug for prophylaxis in neu-tropenic patients. The main studies of fluconazole versus pla-cebo or no treatment in neutropenic patients are summarizedin Table 2.

Fluconazole is presently the most effective agent to prevent

TABLE 2. Studies on fluconazole prophylaxis versus placebo or no treatment in neutropenic patients

Population No. of patients Method Regimena Main resultsa Reference

Solid-organ malignancies 112 Double-blind Flu (50 mg/day) versusplacebo

Less OPC (2 versus 28%); no otherfungal infection in two groups

296

Acute leukemia 257 Double-blind Flu (400 mg/day) versusplacebo

Less fungal colonization (29 versus68%); less superficial fungalinfection (6 versus 15%); nochange of IFI rate, AmB use, ordeaths

383

Acute leukemia and BMT 47 Double-blind Flu (400 mg/day) versusplacebo

Less superficial fungal infection(34 versus 79%); fewer febriledays before AmB use; reductionof AmB use (22 versus 58%)

52

Hematological or solid-organ malignancies

70 Randomized Flu (400 mg/day) versusno treatment

Less IFIb 387

Hematologicalmalignancies

96 Double-blind Flu (400 mg/day) versusplacebo

Delayed AmB use; fewer febriledays; prevention of OPC; noeffects on IFI, outcome, and costs

303

a Flu, fluconazole; OPC, oropharyngeal candidiasis; IFI, invasive fungal infections; AmB use, intravenous amphotericin B given empirically.b Mycological evaluation questionable.

VOL. 10, 1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 485

oropharyngeal candidiasis in neutropenic patients, but severalstudies did not demonstrate a protection against deep mycoses(303, 383). Interpretation of these results, including empiricalamphotericin B use in fluconazole prophylactic studies, is dif-ficult to assess, because no consensus exists between theUnited States and Europe regarding the optimal time of am-photericin B initiation for persistent fever. In the Americanstudy reported by Winston et al. (383), 64% of patients re-ceived empirical amphotericin B (383) compared with 24.2%in the European study by Philpott-Howard et al. (261). Theoptimal daily dose of fluconazole for prophylaxis in neutro-penic patients has not yet been clearly defined; it varies be-tween 50 and 400 mg for adults and between 1 and 4 mg/kg inchildren (48, 175). In the United States, higher doses are usedfor prophylaxis than in Europe, but no cost-effectiveness studyis yet available. There is no conclusive evidence to favor highdoses of fluconazole (400 versus 50 to 100 mg/day). The Work-ing Party recommended a dose of 50 mg/day in 1993 (386). Asrecommended for the HIV-infected population, a careful fol-low-up of the susceptibility of C. albicans strains is required inthis population (379). It has recently been reported that pa-tients with an indwelling central venous catheter and underfluconazole prophylaxis can develop fluconazole-susceptiblecandidemia, thereby suggesting that this regimen fails to pre-vent catheter colonization and subsequent dissemination (107).

Although the activity of fluconazole against C. albicans wasdemonstrated in the reported studies, its use also potentiallyled to the selection of resistant strains, such as C. krusei, re-sponsible for colonization and infection (5, 50, 187, 256, 380),and less susceptible strains, such as C. glabrata (143, 381). Theepidemiology of such non-albicans Candida strains is variable,since some centers using fluconazole have not reported anincrease in the number of such strains (165) and other centershad observed these infections before fluconazole was intro-duced. It is also possible that elimination of other fungal in-fections by prophylactic fluconazole (53, 383) leaves thesefungi as persistent pathogens without necessarily increasingtheir absolute incidence. Finally, intravenous amphotericin Bshould be promptly administered to persistently febrile neu-tropenic patients who are colonized at multiple sites by anyCandida spp., whether or not they had recently received anyantifungal prophylaxis.

(iv) Itraconazole. Itraconazole is highly lipophilic and bindsstrongly to proteins. Its degree of absorption varies as a func-

tion of gastric acidity, which may lead to reduced levels inserum and tissue and, consequently, to therapeutic failures insome cases. Because intestinal absorption can be impaired,itraconazole levels should be measured after 1 week of treat-ment in all patients and regularly thereafter in patients withdysphagia, gastrointestinal damage, or GVHD or those takingantacids, H2-receptor antagonists, or drugs that enhance he-patic drug metabolism (355, 386). It is the only commonlyavailable azole active in vitro against Aspergillus spp., and itsactivity against various forms of aspergillosis has been demon-strated (177).

When itraconazole (200 mg/day) was first compared versusno treatment in a study involving a small number of neutro-penic patients, there was no difference in terms of the totalnumbers of episodes of invasive fungal infections (270). Itra-conazole (100 mg twice a day [b.i.d.]) was also investigated ina noncomparative study: 18% of the subjects developed micro-biologically proven fungal infections, 12.5% of which were fatal(32). In that study, itraconazole was not effective when thelevels in plasma were below 250 ng/ml.

A prospective, randomized, double-blind, placebo-con-trolled study reported a lower incidence of C. albicans infec-tions in patients treated with itraconazole (200 mg b.i.d.) thanin those given a placebo, but the treatment had no significanteffect on the overall incidence of fungal infections, the dura-tion of fever, or the use of intravenous amphotericin B (348).The bioavailability of itraconazole was not monitored in thattrial. Superinfections with C. krusei and C. glabrata have alsobeen reported in patients treated with itraconazole (32).

Systemic azoles versus oral polyenes. (i) Azoles versus nys-tatin. Studies with ketoconazole are described and their find-ings are summarized in Table 3. Table 4 gives the major find-ings from several studies comparing fluconazole with oralpolyenes. For itraconazole, one study demonstrated that theprophylactic use of 400 mg of drug/day in neutropenic patientsreduced the incidence of invasive fungal infections when com-pared with a recent historical control group receiving nystatin(327).

(ii) Azoles versus oral amphotericin B. The results derivedfrom one study of ketoconazole are reported in Table 3. Theresults of the ketoconazole study did not demonstrate sufficientefficacy against mucosal Candida infections and indicated norole for the prevention of deep mycoses. The available data forfluconazole are summarized in Table 4. In most of these stud-

TABLE 3. Studies on ketoconazole prophylaxis versus oral polyenes in neutropenic patients

Population No. ofpatients Method Regimena Main results for azolesa Reference

Hematological or solid-organmalignancies

72 Randomized Keto (400 mg/day)versus Ny 1 AmB

Less OPC and genital candidiasisb 131

Hematological malignancies 36 Randomized Keto (200 mg/day)versus Ny

Less fungal esophagitis andvaginitis; no disseminatedcandidiasis in either group; nobetter prevention against OPC

152

Leukemia 51 Randomized Keto (400 mg/day)versus Ny

No reduction of OPC; nosignificant reduction of IFI(23 versus 33%)

346

Lymphoma 32 Randomized Keto (200 mg/day)versus Ny

Less mucosal fungal infection(8 versus 16%)

338

Acute leukemia 48 Randomized Keto (400 mg/day)versus AmBc

No reduction of fungalcolonization

83

a Keto, ketoconazole; Ny, nystatin; AmB, oral amphotericin B; OPC, oropharyngeal candidiasis; IFI, invasive fungal infections.b Except in allogeneic BMT recipients (due to decreased bioavailability in this population).c Ketoconazole was administered in comparison or in association with oral amphotericin B.

486 LORTHOLARY AND DUPONT CLIN. MICROBIOL. REV.

ies, fluconazole was reported to lower the incidence of coloni-zation and sometimes of mucosal candidiasis but did not re-duce invasive fungal infections and empirical amphotericin Buse. The apparent inefficacy of low doses of fluconazole toprevent systemic yeast infections in neutropenic patients mayreflect the protective effects of polyenes given to the controlgroup. According to Preston and Briceland, for neutropenic,non-BMT recipients, fluconazole at high doses provides noevident improvement over lower doses and is far from beingcost-effective (272). Finally, low-dose fluconazole is appropri-ate in high-risk neutropenic patients colonized at multiple sitesby C. albicans.

(iii) Azoles versus intravenous amphotericin B. Amphoter-icin B administered intravenously three times a week at indi-vidual doses of 0.5 mg/kg was compared with fluconazole (400mg/day) in 90 patients with acute leukemia (30). Efficacyagainst fungal infection was similar in both groups, but therewere more side effects in the amphotericin B-treated groupthan in the fluconazole cohort. Indeed, 58% of patients as-signed to the amphotericin B group successfully completedprophylaxis compared with 80% assigned to receive fluconazole.

Azoles in association with oral or intravenous amphotericinB. At present, no clear recommendation has been formulatedconcerning the combination of azoles and amphotericin B inclinical practice, especially in prophylactic regimens. Oralamphotericin B and systemic azoles need to be specificallystudied in combination in the light of azole selection of resistantC. krusei and C. glabrata strains (386). Caution is advised becauseantagonism between ketoconazole and amphotericin B has beendemonstrated in vitro and in neutropenic mice (302).

Comparison of oral azoles. Table 5 describes the observa-tions made in clinical trials of oral azoles in neutropenic pa-tients. They suggest that itraconazole may lower the invasivefungal infection rate in comparison with ketoconazole.

Specific Prevention of Invasive Aspergillosis

Oral decontamination with polyenes or nonabsorbableazoles or administration of ketoconazole or fluconazole doesnot prevent invasive aspergillosis.

As respiratory colonization is known to precede invasiveaspergillosis (3), inhalant forms of amphotericin B have beendeveloped and were reported to be effective in rat models ofpulmonary aspergillosis (239, 305). In humans, nasal instilla-tion of 10 mg of amphotericin B was first reported by Meunier-Carpentier et al. to control an epidemic of aspergillosis (214).Since then, others have reported results on aerosol adminis-tration with conflicting results in controlled trials (150, 153). Ina placebo-controlled trial, colonization (but not invasive as-pergillosis) was decreased by intranasal amphotericin B spray(66). The efficacy of such prophylactic procedures has not beenclearly proven (19, 25, 26, 63, 122, 136, 228), and the optimaldaily dosage for both efficacy and patient tolerance has notbeen determined. Thus, in the absence of a definitive demon-stration of efficacy in randomized trials, no recommendationcan be advanced for the application of these regimens in neu-tropenic patients. Furthermore, some side effects, such ascough, bad taste, and nausea, were reported and led to termi-nation of aerosol amphotericin B prophylaxis by patients in23% of treatment cycles (19). Asthmatic patients are moreprone to experience a drop in peak pulmonary air flow than areothers (87).

In a murine model of pulmonary aspergillosis, AmBisome, aliposomal formulation of amphotericin B, was more effectivethan conventional amphotericin B when given as a prophylac-tic aerosol (7). This finding should lead to clinical studies ofaerosolized AmBisome.

Oral itraconazole (200 mg/day) combined with intranasalamphotericin B (10 mg/day) was prescribed as prophylaxis for

TABLE 4. Studies on fluconazole prophylaxis versus oral polyenes in neutropenic patients

Population No. ofpatients Method Regimena Main resultsa Reference

Hematological malignancies or BMT 248 Comparative Flu (50 mg/day) versuspolyenes

Less suspected fungal infection(27 versus 45%)

35

Hematological or solid-organmalignancies

536 Randomized Flu (50 mg/day) versuspolyenes

Less OPC (1.6 versus 8.6%); nochange of fungal colonization,IFI, and AmB use

261

Hematological or solid-organmalignancies in children

502 Randomized Flu (3 mg/kg/day)versus polyenes

Reduction of mucosal infection;no reduction of IFI and colo-nization

240

Hematological malignancies 69 Randomized Flu (100 mg/day) versusNy

Reduction of OPC (3 versus16%) and new oropharyngealcolonization; no reduction ofAmB use

340

Hematological malignancies or BMT 89 Randomized Flu (400 mg/day) versusNy 1 aer Mic

Delayed AmB use; no reductionof OPC, IFI, and AmB use

91

Hematological malignancies 51 Randomized Flu (200 mg/day) versusAmB

No reduction of fungal infectionand AmB use

4

Hematological malignancies or BMT 59 Randomized Flu (200 mg/day) versusAmB

No reduction of fungal infectionand AmB use

210

Acute leukemia 50 Randomized Flu (50 mg/day) versusAmB

Less fungal colonization of theoropharynx but not of thelower digestive tract; no re-duction of severe local fungalinfection and IFI

289

Acute leukemia 820 Randomized Flu (150 mg/day) versusAmB

No reduction of OPC, AmBuse, and IFI

206

a Flu, fluconazole; Ny, nystatin; aer Mic, aerosolized miconazole; AmB use, empirical administration of intravenous amphotericin B; OPC, oropharyngeal candidiasis;IFI, invasive fungal infections.

VOL. 10, 1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 487

164 patients with hematological malignancies (328). In thatstudy, which included recent untreated historical controls, theincidence of proven aspergillosis was lower, as was the mor-tality rate. However, more experience is needed before thisdrug combination can be recommended for daily clinical prac-tice because, as reported above for ketoconazole, antagonismbetween itraconazole and amphotericin B has also been noted(301).

The prophylactic prescription of itraconazole could be ex-panded if it were adapted to an intravenous formulation in-volving beta-hydroxycyclodextrins. Such an innovation couldfavor itraconazole as prophylaxis against fungal infections inallogeneic BMT recipients for whom amphotericin B is oflimited value for treatment of or even prophylaxis against as-pergillosis (223). The new oral solution formulation of itracon-azole is absorbed much better and can be used in BMT recip-ients (271). A large, double-blind, multicenter study comparingitraconazole solution plus placebo in tablets versus placebo insolution plus oral amphotericin B has now been completed inEurope, but the data are still being analyzed.

Although no definitive data are available suggesting thatitraconazole may be an effective primary prophylaxis againstaspergillosis, the administration of the drug to untransferablepatients managed without laminar-flow air purification (386)should be considered in centers where there is a high incidenceof aspergillosis or where building construction or renovation isin progress or about to be undertaken.

The development of new antifungal agents active againstAspergillus spp. will diminish the possible contribution of aero-solized amphotericin B for the prophylaxis of invasive aspergil-losis. Unfortunately, the studies published to date have in-cluded relatively small numbers of patients and, at present,provide insufficient data for definitive recommendations con-cerning systematic primary prophylaxis (44). Nevertheless,neutropenic patients with any Aspergillus-positive cultureshould probably be given early curative antifungal treatment.

Hematopoietic Growth Factors and Other CytokinesProphylactic granulocyte transfusions are no longer used in

neutropenic patients and give only moderate results. Cyto-kines, by stimulating the natural host defenses, offer new ther-apeutic approaches to fungal infections (29, 135, 231). Their

effects on fungal infections have been widely studied in vitroand in animal models. Whether the stimulation of normalgranulocyte donors with granulocyte colony-stimulating factor(G-CSF) before leukophereses (22) can be used to preventinvasive fungal infections has not been studied. G-CSF (68),macrophage-colony stimulating factor (M-CSF), and granulo-cyte-macrophage colony-stimulating factor (GM-CSF) (178)stimulate the production and/or improve the function of thepolymorphonuclear and mononuclear phagocytic cells. Theycannot prevent neutropenia but can shorten its duration andattenuate the nadir of the neutropenic episode following my-elotoxic chemotherapy. These factors have been shown tolower the number of bacterial infectious episodes, but there isno clear evidence yet of any impact on the incidence of fungalinfections, especially candidiasis or aspergillosis in cancer pa-tients. However, in one recent study, the use of growth factorwas associated with a decrease in the number of fungal infec-tions in autologous BMT recipients (224).

Interleukin-1, interleukin-3, tumor necrosis factor alpha,and gamma interferon have been shown to be effective againstfungal infections in vitro and in animal models. A recent papersuggested a protective role for GM-CSF, G-CSF, or interleu-kin-3 in preventing fungal infections in 145 patients who re-ceived high-dose chemotherapy with or without stem cell trans-plantation (257). Further controlled clinical trials of thesecytokines should be encouraged in humans to assess their pre-ventive effects and also as potential curative therapies (24, 232,233).

Prophylaxis against RelapseThe prevention of relapse is mostly discussed for hosts who

are persistently immunocompromised (by diseases or drugs)and who previously experienced an episode of invasive as-pergillosis. In fact, there is a risk of reactivating a previousfungal infection, primarily aspergillosis (282), during subse-quent chemotherapy of cancer patients.

Secondary prophylaxis against aspergillosis must be system-atically used for patients who will undergo subsequent antican-cer treatments. High doses of amphotericin B have classicallybeen given during all neutropenic episodes (157, 205, 339).Surgical excision of a persistent fungal lesion is advised forpatients who undergo additional cycles of chemotherapy with

TABLE 5. Studies comparing oral azoles in neutropenic patients

Population No. ofpatients Method Regimena Main resultsa Reference

Cancer 88 Randomized Mic (1 g/day) versus Keto(200 mg/day)

No difference in fungalcolonization; withdrawalfor digestive intolerance in7% (Keto) and 15% (Mic)

213

Hematological malignancies andBMT

90 Randomized Flu (200 mg/day) versusClotrim 1 Ny

Less fungal colonization withFlu; less severe fungalinfection with Flu;increased chance ofsurvival with Flu

92

Hematological malignancies 97 Comparative Itra (400 mg/day) versusKeto (400 mg/day)

Fewer deaths due to IFI(particularly aspergillosis)with Itrab

333

Hematological and solid-organmalignancies in children

81 Comparative Itra (50 to 100 mg/day)versus Keto (10 mg/kg)

No difference in colonizationand infection

241

Acute leukemia 82 Historical comparison Itra (200 mg/day) versusKeto (200 mg/day)

Less IFI with Itra 335

a Mic, oral miconazole; Keto, ketoconazole; Flu, fluconazole; Clotrim, clotrimazole; Ny, nystatin; Itra, itraconazole; IFI, invasive fungal infections.b In this study, itraconazole protection against fatal fungal infection was significantly better among patients who were neutropenic for more than 25 days and among

patients with acute lymphoblastic leukemia.

488 LORTHOLARY AND DUPONT CLIN. MICROBIOL. REV.

or without BMT (46, 180, 193, 221, 304). For patients forwhom surgery or prolonged amphotericin B is contraindicated,itraconazole may be used successfully (177), although the num-ber of reported cases is still small (64, 180, 199). Itraconazolelevels in serum should also be monitored in these patients.

AUTOLOGOUS OR ALLOGENEIC BONEMARROW RECIPIENTS

Low-Dose Intravenous Amphotericin B

Amphotericin B deoxycholate. A total of 182 patients under-going autologous BMT received low-dose intravenous ampho-tericin B (0.1 mg/kg/day) or placebo when their leukocytecounts dropped below 1,000/mm3 (255). Oropharyngeal yeastcolonization was lower and survival evaluated 6 weeks post-transplantation was longer in the amphotericin B group than inthe placebo group, but they could not be attributed to theprevention of fungal infections. The need for treatment oforopharyngeal candidiasis and the frequency of isolation offungi from normally sterile sites did not differ between thegroups. In that study, infusion-related adverse events werehigher in the amphotericin B group but the incidence of sys-temic toxicities was similar in both groups.

Low-dose intravenous amphotericin B administered duringthe pretransplantation and peritransplantation periods low-ered the incidence of and the mortality attributable to aspergil-losis in 186 allogeneic BMT patients compared with historicalcontrols (287). Intermittent intravenous amphotericin B com-bined with nasal instillation of amphotericin B also comparedfavorably with historical controls in pediatric BMT recipients(334). Low-dose intravenous amphotericin B continuing for 2to 3 months posttransplantation was reported to decrease theincidence of all fungal infections in allogeneic BMT recipientsfrom 30 to 9% (244). In that study, those who received am-photericin B also had lower cyclosporine levels, which led to anincreased rate of GVHD. Within the first 30 days after trans-plantation, no systemic fungal infection developed in 17 BMTrecipients blindly randomized to receive amphotericin B (0.1mg/kg/day) (281). In the placebo group, 5 (28%) of 18 patientsdeveloped documented systemic fungal infections, but 1 caseof invasive aspergillosis developed in the amphotericinB-treated group after 56 days.

Patients treated prophylactically with low-dose intravenousamphotericin B required fewer days of high-dose amphotericinB and fewer days of antibiotics. Low-dose amphotericin B wasassociated with significantly prolonged survival among the sub-group of allogeneic transplant recipients (281). In one study,prophylactic amphotericin B was prescribed for all patientswith GVHD (205). Low-dose intravenous amphotericin B (0.2mg/kg/day) was also compared to fluconazole (400 mg/day) in190 patients undergoing BMT. There was no significant differ-ence in the incidence of invasive fungal infections among thesepatients (385). The doses used for prophylaxis during theseclinical studies were often too low to eradicate pathogens, suchas Aspergillus spp., for which a minimal dose of 1 mg/kg/day isrequired (43).

The role of low-dose intravenous amphotericin B in primaryprophylaxis remains undetermined, since no study has demon-strated that it was able to lower the subsequent need for higherdoses of the drug to treat fever of unknown origin (343, 377).Its use as a prophylactic agent is also limited by its toxicity inallogeneic BMT recipients, in whom deep mycoses may beobserved during GVHD.

Lipid formulations of amphotericin B. Lipid formulationswere recently reviewed (34, 140) and reported to be valuable

for curative treatment of fungal infections in neutropenic pa-tients (45, 220). Liposomal amphotericin B showed a protec-tive effect against C. albicans infection in neutropenic mice(179). In a study of patients undergoing BMT, Tollemar et al.reported that significantly fewer patients were colonized byfungi in an AmBisome-treated group (1 mg/kg/day) comparedwith placebo (33 and 62%, respectively), but AmBisome af-forded no significant reduction of the incidence of invasivefungal infections (330). However, no definitive conclusion canbe drawn from this paper, because only 76 patients were eval-uated.

To date, the efficacy of AmBisome as a prophylactic agenthas not been sufficiently investigated in humans. The optimaldosage for such an indication remains unknown (perhaps 1mg/kg/day), and these drugs are expensive (322) and are notavailable in all countries.

Azoles

Ketoconazole. Ketoconazole (400 mg/day) was tested versusnystatin in 56 allogeneic BMT recipients (309). Ketoconazolemore effectively lowered the number of positive cultures fromthe mouth, genital tract, and rectum and reduced the incidenceof oral mucositis. Two nystatin-treated patients developed dis-seminated invasive fungal infections. Tolerance to and compli-ance with the drug regimen was better in the ketoconazolegroup. Ominously, however, C. glabrata colonization of therectum and vagina increased in ketoconazole-treated patients(309).

In a randomized, double-blind, placebo-controlled trial, ke-toconazole administration to children with yeast colonizationof the digestive tract led to higher percentages of yeast erad-ication. Children who were not initially colonized had lowerrates of colonization, but there was no difference in terms ofdocumented fungal infection and the percentage of childrenwho required intravenous amphotericin B was similar in thetwo groups (21). Administration of a multiagent regimen con-taining povidone-iodine, nystatin, and ketoconazole to 16 con-secutive pediatric BMT recipients resulted in less oropharyn-geal colonization, and none of the patients developedoropharyngeal candidiasis or invasive fungal infections (23).

Fluconazole. According to the two largest studies shown inTable 6 (117, 313), which were also well designed, fluconazole(400 mg/day) was able to decrease both the number of systemicfungal infections and the overall mortality or death due tofungal infection. However, as mentioned above for neutro-penic non-BMT recipients, the optimal dose of fluconazole forantifungal prophylaxis has not yet been determined. Indeed, atlow doses, it has been reported to significantly lower the inci-dence of fungemia, C. albicans colonization, and the need forempirical amphotericin B in BMT recipients (6), but someauthors have noted colonization and occasional fungemiacaused by C. glabrata when 100 mg/day was used (6, 218). Aretrospective study described the increased frequency of colo-nization and infection by C. krusei and C. glabrata in BMTpatients who were receiving fluconazole prophylaxis (380). Inthe study by Goodman et al., fluconazole prevented infectionswith all strains of Candida except C. krusei (117). These ob-servations could be due to the eradication of the more patho-genic fungal organisms, mainly C. albicans and C. tropicalis,and overgrowth by the other yeasts. Lam and Althaus (171)suggested in their review that C. krusei and C. glabrata gener-ally do not contribute to increased mortality and that mostpatients infected by these organisms recover after prompt ini-tiation of intravenous amphotericin B treatment.

In the studies by Goodman et al. and Slavin et al., the

VOL. 10, 1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 489

incidence of GVHD was higher in the fluconazole-treatedgroup; this can be explained by the longer survival of thesepatients (117, 313). Fluconazole levels in serum following adose of 400 mg/day were comparable in BMT recipients andhealthy volunteers. No increase in cyclosporine toxicity wasrecorded with prolonged administration of fluconazole (400mg/day) (313). Because of greater efficacy and better toler-ance, oral fluconazole should be preferred to topical antifungalagents in this population (274).

Itraconazole. In one small study, itraconazole concentra-tions in the serum of BMT patients appeared to be below theaverage MIC for Aspergillus spp. That result led the authorsnot to recommend itraconazole for the prevention of aspergil-losis in BMT recipients (326). However, it must be kept inmind that the efficacy-MIC relationship remains to be eluci-dated. However, there is still no definitive answer regardingthe effectiveness of itraconazole in this high-risk population.

SOLID-ORGAN TRANSPLANT RECIPIENTS

Kidney

The risk of aspergillosis is low in the kidney transplant re-cipient population, and probably only patients given bolus cor-ticosteroids for acute rejection would benefit from protectionagainst environmental contamination during high-dose steroidtherapy. Regarding the low incidence of Candida infections inthis population, no recent study on the azole prophylaxis ofsuch infections has yet been undertaken.

Initial studies reported that clotrimazole troches were moreeffective than placebo in a placebo-controlled, double-blindstudy of the prevention of oropharyngeal candidiasis (246).These troches were also compared to nystatin suspension (1.5MU 6 times/day). No patient in either group developed mu-cosal candidiasis, but patient compliance was much higher inthe clotrimazole group (113). A prospective trial of anti-CMVimmune globulin showed a decrease in the number of invasivefungal infections (318).

For the time being, in the light of the low incidence of severeCandida infections in this population and the lack of experi-

mental data, no systematic antifungal prophylaxis can be rec-ommended.

Liver

Given the high incidence of invasive fungal infections in livertransplant recipients, the choice of appropriate agents for pro-phylaxis and therapy becomes particularly relevant. Becausecandidal infections occurred early in the postoperative period,institution of selective digestive decontamination preopera-tively may be of value (250), and liver transplant recipients maybenefit from systemic prophylaxis with fluconazole. However,the risk of infection with species resistant to fluconazole needsto be prospectively evaluated. Selective decontamination withoral polyene plus fluconazole might reduce intestinal coloni-zation, including that due to C. glabrata or C. krusei; such astudy would be worthwhile.

Nystatin suspension may be useful in reducing Candida col-onization (374). One study reported that selective bowel de-contamination with quinolones and nystatin might prevent in-vasive candidal infections (119). Oral clotrimazole and nystatinappeared equally effective for the prevention of mucosal can-didiasis in these transplantees (291).

Others advocate the peritransplantation use of low-dose in-travenous amphotericin B (10 mg/day) (219), oral amphoteri-cin B (6,000 mg/day), or oral or intravenous fluconazole (200mg/day) (345). However, failures of low-dose intravenous am-photericin B (0.5 mg/kg/day) have been reported with the si-multaneous occurrence of aspergillosis and candidemia (312).A randomized, placebo-controlled study demonstrated thatAmBisome (1 mg/kg/day) administered for 5 days starting dur-ing the transplant surgery completely protected the patientsagainst invasive fungal infections during the first month,whereas 16% of the patients in the placebo group developedsuch infections. Furthermore, prophylaxis with AmBisome wasmuch less expensive than treatment of proven deep mycoses inthe placebo group (329). Four recent studies documented theefficacy of fluconazole in this population (Table 7). However,only one was randomized (191).

A prospective trial of anti-CMV immune globulin adminis-

TABLE 6. Studies on fluconazole prophylaxis in BMT recipients

No. ofpatients Methoda Regimena Main resultsa Reference

356 Double-blind Flu (400 mg/day) versusplacebo

Fewer positive surveillance cultures(29.6 versus 67.2%), and superficial(8.4 versus 33.3%) and systemic (2.8versus 15.8%) fungal infections; nochange in overall mortality; noreduction in AmB use

117

300 Double-blind Flu (400 mg/day) versusplacebo

No superficial and fewer systemic (7versus 18%) fungal infections withFlu; increased overall survival; lessfungal colonization (77 versus 86%)and AmB use; no C. albicanscolonization with Flu

313

191 Historical comparison Flu (100 to 200 mg/day)versus no treatment

Less fungemia; reduction ofcolonization due to C. albicans; lessAmB use

6

89 Randomized historical comparisonwith Flu (50 mg/day)

Flu (300 mg/day) versusItra (400 mg/day)

No difference between Flu and Itra 15

113 Open Flu (50 mg/day) 1 oralAmB

Low need for AmB (7%); mortalityrate 5 3.5%

74

59 Randomized Flu (100 mg/day) versusKeto (400 mg/day)

No difference in colonization ormucosal or systemic mycoses

108

a Flu, fluconazole; AmB use, intravenous amphotericin B given empirically.

490 LORTHOLARY AND DUPONT CLIN. MICROBIOL. REV.

tration showed a decrease in the number of cases of invasivefungal infections (317). The exact role of itraconazole in theprevention of fungal infections after liver transplantation re-mains to be evaluated. In addition, the absorption of itracon-azole, which is a lipid-soluble azole, is less predictable in thispopulation because the bile is often drained by a T-tube duringthe first few weeks posttransplantation (71). Therefore, nodefinitive recommendations can be advanced for liver trans-plant recipients at this time (250, 275, 316), but fluconazolemight be given during the first month post transplant.

Pancreas and Kidney-Pancreas

Research of infection in pancreas and kidney-pancreastransplant recipients is greatly lacking. Nonetheless, the gen-eral rule for Aspergillus prophylaxis applies to these patients,who should avoid exposure to contamination by environmentalsources. Because fungal prophylaxis applied universally to allpancreas and kidney-pancreas patients is costly and bears therisk of allowing the emergence of resistant strains, epidemio-logical studies are needed to better identify the patients at riskand the time of high risk after transplantation.

Heart, Lung, and Heart-Lung

In heart, lung, and heart-lung transplant recipients, the pre-vention of fungal infections requires technically impeccablesurgery, precisely managed immunosuppression, and preven-tive antifungal regimens. The use of effective air filtration isreasonable, but no data exist about the potential protectiveefficacy of aerosolized amphotericin B or oral itraconazole.

Lung transplantation for patients suffering from cystic fibro-sis is of particular concern when the patients are colonized byAspergillus spp. prior to transplantation. Success has been re-ported in such a setting in patients treated prophylacticallywith intravenous amphotericin B or oral itraconazole. How-ever, no consensus has been reached on the usefulness and thechoice of antifungal prophylaxis.

Fungal infections in 6 of 26 recipients of left ventricularassist devices have recently been described (112). Three ofthese six patients died, and the other three underwent ortho-topic heart transplantation. The authors demonstrated that thecombination of fluconazole prophylaxis (200 mg/day), dailynystatin, empirical fluconazole treatment for culture-negativesepsis, and daily dressing changes around drivelines success-fully treated the three recipients monitored over the shortterm.

In their analysis of a series of 25 cases of invasive Aspergillusinfection between 1985 and 1991 (6% incidence), Hummel et

al. (144) concluded that repeated microscopic findings of typ-ical septated and dichotomously branched hyphae in bronchialor tracheal secretions are an indication of endobronchial col-onization and are usually associated with invasive aspergillosis.Thus, treatment is indicated to prevent or, more precisely, tocure the early invasion.

Oropharyngeal Candida infections can be avoided by the useof prophylactic medication, either fluconazole or amphotericinB suspension when available (144). Although some authors rec-ommended topical agents such as nystatin (162) and amphoteri-cin B to prevent oral candidiasis, the efficacy of these agentsremains to be evaluated in prospective randomized trials.

Itraconazole was reported to be effective for prophylaxisagainst aspergillosis in lung transplant recipients (229). In thispopulation, monitoring of drug levels in serum is also manda-tory (252). In addition to difficulty in obtaining an early diag-nosis, a major concern is the use of certain antifungal drugsbecause of their toxicity or interaction with immunosuppres-sive drugs, particularly cyclosporine.

HIV-INFECTED INDIVIDUALS

Mucosal Candidiasis

Mucosal candidiasis is the most common opportunistic in-fection in HIV-infected patients, occurring in up to 90% ofthese patients at some time during the course of their disease(276).

Primary prophylaxis. Mucosal candidal lesions are not tar-gets for primary prophylaxis, because they are easily treatedwith topical or oral antifungal agents with no important con-sequences (101) and because the possible risk of selectingresistant strains is high. Primary prophylaxis cannot be pre-scribed in a general manner, although one recent prospectivestudy demonstrated that oral fluconazole (200 mg/day), as op-posed to clotrimazole troches, was associated with fewer epi-sodes of esophageal candidiasis (3 of 217 versus 17 of 211patients) and oropharyngeal candidiasis (5.7 of 100 versus 38.1of 100 patient-years) over a mean follow-up period of 35months (266). Results of a double-blind, randomized study ofweekly (400 mg) versus daily (200 mg) oral fluconazole showedsimilar effectiveness for deep fungal infections in AIDS pa-tients, but a weekly regimen was less effective than a dailyregimen in suppressing thrush (63.7 and 28.4 episodes per 100patient years, respectively) (133).

Suppressive therapy. Relapses are common after a first ep-isode of mucosal candidiasis, and several studies have proventhe efficacy of maintenance treatment with 50 mg (93, 154) to100 mg (321) of oral fluconazole per day or 150 mg of oral

TABLE 7. Studies on fluconazole prophylaxis in liver transplant recipients

No. ofpatients Method Regimena Main resultsa Reference

75 Prospective Flu (200 mg/day) versus oral AmB (6 g/day) Better prevention and clearance ofCandida colonization with Flu; noeffect of Flu on C. glabrata and C.krusei colonization; administrationof Flu more convenient

331

117 Historical comparison With and without Flu (100 mg/day) Reduction of fungal deaths with Flu 16475 Retrospective AmB 1 selective digestive decontamination

1 Flu (200 mg/day)Only 1 case of C. glabrata fungemia 71

143 Prospective randomized Flu (100 mg/day) versus oral Ny Less Candida colonization with Flu;less superficial and invasivecandidiasis with Flu

191

a Flu, fluconazole; AmB, oral amphotericin B; Ny, nystatin.

VOL. 10, 1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 491

fluconazole per week (176). The risk of selecting fluconazole-resistant strains has led other authors to prefer treating eachepisode with topical agents when possible (when there is noassociated esophageal candidiasis). Therefore, systematic life-long suppressive therapy is not recommended. Anecdotally,central venous catheter infection caused by Rhodotorulaminuta was reported in a patient taking suppressive doses offluconazole (110).

For patients experiencing frequent relapses, intermittenttreatment with topical clotrimazole (10 mg 3 5/day) or nystatin(500,000 U 5 times/day) or azoles, such as ketoconazole (200mg/day) or fluconazole (50 to 100 mg/day), can be prescribed.Ketoconazole should be used with caution in this populationbecause of drug absorption problems (170), and fluconazolemay increase rifabutin levels in plasma (332) and thus thepotential toxicity of rifabutin (245). In a recent trial, long-termcontinuous therapy with fluconazole was more effective thanintermittent therapy (134). As recently emphasized, compli-ance with prophylactic regimens must be verified in cases ofclinical failure (103).

Fluconazole is more effective than ketoconazole in the treat-ment of esophageal candidiasis (169) and is also effective assecondary prophylaxis (2), but because fluconazole is moreexpensive, ketoconazole is probably a valid alternative, espe-cially in developing countries. Other antifungal agents underevaluation for the treatment of oropharyngeal candidiasis re-sistant to azoles may also prove effective for long-term sup-pressive therapy (120, 121).

Cryptococcosis

Primary prophylaxis. Several studies have recently ad-dressed primary prophylaxis of cryptococcosis. The AIDS Clin-ical Trial Group demonstrated that fluconazole (200 mg/day)was more effective than clotrimazole troches (10 mg 3 5/day)for the primary prevention of cryptococcal meningitis (0.9 and7.1%, respectively), but there was no influence on survival(266). The benefit obtained with fluconazole was greater inpatients with fewer than 50 CD41 lymphocytes/mm3. The sameresults were also observed in another case-control study, whichfound 0.3% cryptococcemia in 329 patients receiving flucon-azole (100 mg/day) versus 4.7% cryptococcemia in 337 patientswho were untreated for approximately 165 days (238). Anotherstudy comparing 18 patients with cryptococcal meningitis to 72patients without this infection found that fluconazole effec-tively and significantly protected against this infection (273).Finally, a linear tendency in risk reduction as a function ofincreasing dosage (.150 mg/day) was demonstrated in a recentcase-control study in which 34 matched controls took a signif-icantly higher average daily dosage of fluconazole than didHIV-infected patients with cryptococcosis (9). A retrospectivestudy of 1,200 HIV-infected patients with CD41 cell countsbelow 200/mm3 showed a significantly smaller number of pa-tients with cryptococcal infection in a group prophylacticallytreated with low-dose fluconazole than in an untreated controlgroup (196). Postmortem records of 145 HIV-infected patientsshowed that there were 15 cases of disseminated cryptococcalinfection and that 13 of these occurred in patients who did notreceive prophylactic fluconazole (100 mg/week) (235). Re-cently, Singh et al. demonstrated the efficacy of low-dose flu-conazole (200 mg orally three times a week) as primary pro-phylaxis for cryptococcal infection, with only 1 of 218 patientsdeveloping the disease (311). However, it must be noted that18% of their patients developed mucocutaneous and/or esoph-ageal candidiasis.

It must also be stressed that this strategy is very expensive

and runs the risk of facilitating the emergence of resistantstrains of a variety of fungi; therefore, it cannot be routinelyconsidered in clinical practice.

Suppressive therapy. The rate of relapse after initial treat-ment of cryptococcosis in AIDS patients is 50 to 60% (82, 265).The contribution of secondary prophylaxis was demonstratedin a double-blind study versus placebo that evaluated oralfluconazole (100 to 200 mg/day). The relapse rate was 3% inthe fluconazole group compared with 37% in the placebogroup (33). In addition, fluconazole (200 mg/day) was shown tobe more effective than amphotericin B (1 mg/kg/week) (1.8 and18%, respectively) and generated fewer side effects (268). Thesame dose of fluconazole has also been recently shown to bemore effective than itraconazole (200 mg/day) in preventingrelapses of cryptococcal meningitis: (3.8 and 23.6%, respec-tively) (292). However, the itraconazole dose given was lowerthan that usually prescribed during HIV infection. A retrospec-tive study indicated that the 400-mg/day dose of fluconazolewas probably more effective than the 200-mg/day dose (230).

Taken together, these results demonstrate that fluconazoleis currently the prophylaxis of choice against relapsing crypto-coccosis during the course of HIV infection (262). Amphoter-icin B (50 mg administered intravenously once or twice weekly)and itraconazole ($200 mg/day), should be considered as al-ternatives in cases of intolerance to fluconazole. As reportedfor other fungal diseases during HIV infection, the potentialrisk of acquired resistance should not be forgotten.

Histoplasmosis Due to Histoplasma capsulatum

Primary prophylaxis. The benefit of primary prophylaxisagainst histoplasmosis during the evolution of AIDS has re-cently been demonstrated by a trial of itraconazole versusplacebo (200) conducted in U.S. cities where the incidence ofthis opportunistic infection is high (Indianapolis, Kansas City,Memphis, and Nashville). In a retrospective study, oral flucon-azole (100 mg/day) did not lower the incidence of histoplas-mosis in AIDS patients in Dallas (238). Anecdotally, one pa-tient taking fluconazole (50 mg/day) developed histoplasmosis(308) and another patient on maintenance therapy for crypto-coccosis developed histoplasmosis (264). In a recent evaluationof oral fluconazole (200 mg/day) prophylaxis during HIV in-fection, no protective effect against histoplasmosis was ob-served (266). In France, we have also found that several HIV-infected patients developed histoplasmosis while receiving lowdoses of fluconazole (182). In addition, the potential risk ofselecting Histoplasma strains resistant to azoles must be takeninto account in the context of primary prophylaxis (370). Cost-benefit studies should also be undertaken, particularly for thepossible application of these therapies in regions of endemicinfection in third-world nations.

Suppressive therapy. Relapses without maintenance therapyoccur in 35 to 80% of patients with histoplasmosis (300, 371).Thus, lifelong secondary prophylaxis is indicated.

(i) Amphotericin B. Administration of amphotericin B everyweek or every other week is more effective than administrationof ketoconazole (80 to 97% and 50%, respectively) in prevent-ing relapses, with a median survival time of 13 to 17 months(201, 202, 371). Neither amphotericin B nor ketoconazole isindicated as maintenance therapy in patients with central ner-vous system involvement (14, 366). Bacteremias, catheter in-fections, and thrombophlebitides often arise during secondaryamphotericin B prophylaxis (202). With side-effect and relapserates as high as 20% during amphotericin B prophylaxis, theevaluation of azoles for this indication was not only needed buthighly justified.

492 LORTHOLARY AND DUPONT CLIN. MICROBIOL. REV.

(ii) Itraconazole. Itraconazole (200 mg b.i.d.) was shown tobe well tolerated and highly (95%) effective as maintenancetherapy in 42 patients who had received amphotericin B induc-tion therapy (15 mg/kg [total dose]). The median survival timewas 109 weeks (369). Indeed, itraconazole represents the main-tenance therapy of choice in patients who are able to absorb it(315) and are not taking another medication that could inter-fere with it. Itraconazole has proven effective as maintenancetherapy for especially severe forms of disease, like endocarditis(181) and central nervous system involvement (366).

(iii) Fluconazole. In a retrospective study (242), relapseswere noted in 12% of 76 patients receiving 100 to 400 mg offluconazole per day, after induction therapy with amphotericinB, itraconazole, or fluconazole. The relapse rate was higher inthose receiving 100 mg of fluconazole per day, but these datawere insufficient to establish the optimal dosage of fluconazolefor this indication. Survival was longer in patients who hadreceived 1 g of amphotericin B initially. The survival time wasshorter in patients receiving fluconazole (94 weeks) than thatobserved in the study evaluating the efficacy of itraconazole(369). In another study (372), the relapse rate in patients given400 mg of fluconazole per day was 32% in patients who hadreceived fluconazole as induction therapy. Thus, the majorityof reports indicate that fluconazole ($200 mg/day) is to bereserved for patients who cannot tolerate itraconazole or thosewith drug interaction problems (130).

CoccidioidomycosisPrimary prophylaxis. No study has actually proven the use-

fulness of primary prophylaxis against coccidioidomycosis dur-ing HIV infection. Some patients developed coccidioidomyco-sis while they were receiving ketoconazole for anotherindication (97). Prophylactic administration of fluconazole(200 mg/day) is currently being evaluated in regions of en-demic infection in the United States (367). HIV-infected pa-tients whose coccidioidal serological status is positive are prob-ably good candidates for prophylaxis (203).

Suppressive therapy. Lifelong maintenance therapy is indi-cated for patients with a history of coccidioidomycosis (203).However, treatment modalities have not yet been specified(186). Daily fluconazole (200 to 400 mg/day) or weekly am-photericin B can be prescribed (373). Ketoconazole cannot beused (390), and itraconazole has not been tested for this indi-cation.

AspergillosisPrimary prophylaxis. Primary prophylaxis cannot be given

to all patients with a low level of CD41 lymphocytes because ofthe rarity of the disease. Therapy could be considered forpatients in the late stages of AIDS when they are exposed torenovation and/or construction and possibly for patients with apositive sputum or bronchoalveolar lavage sample without ev-idence of lung invasion.

Suppressive therapy. The idea of secondary prophylaxisagainst invasive aspergillosis during AIDS has not been ad-dressed in light of the poor short-term prognosis of this infec-tion (160, 188). In some cases that are diagnosed early, induc-tion therapy can nevertheless be effective, especially in patientswith aspergillosis affecting the sinuses or tracheobronchial tree(160, 184). After at least 14 days of intravenous amphotericinB, long-term itraconazole (400 mg/day) may be prescribedwhen no concomitant counterindicated medications are beingtaken. A loading dose of itraconazole (600 mg/day) should beadministered for 4 days, and itraconazole levels in serumshould be determined after 7 days of treatment.

Oral itraconazole solution has the best bioavailability andneeds to be tested for prophylaxis in patients at risk.

Infection Due to Penicillium marneffei

The percentage of relapses with P. marneffei is high aftercessation of antifungal therapy (325), indicating the need forsecondary prophylaxis. Itraconazole (200 mg/day) is a validsuppressive therapy. Its use for primary prophylaxis in areas ofhigh endemicity, such as Northern Thailand, is under investi-gation.

Other Mycoses

No clear recommendations can be made for rare systemicmycoses, such as blastomycosis, sporotrichosis, and paracoc-cidioidomycosis, that develop during AIDS (185).

QUALITATIVE DEFECTS OF NEUTROPHILS

Of 30 children with chronic granulomatous disease enrolledin one center from 1985 to 1991 who received itraconazole (5to 10 mg/kg/day), 3 developed pulmonary aspergillosis. This10% rate of aspergillosis in children taking itraconazole waslower than that observed in a historical untreated group(34.4%) (226).

CONCLUSION

Precise guidelines are difficult to draw up from the publishedliterature, because of the lack of international consensus onthe definition of fungal disease and end points for antifungaltreatments. It is obvious that the best drug regimen has yet tobe determined for almost every group of immunocompromisedpatients at risk of fungal infections. In addition, among theparameters to be considered, cost-effectiveness must also beaddressed (353). Without specifying the targets, host, and fun-gal species, optimal antifungal prophylaxis cannot be obtained.It can even have deleterious effects by increasing the risk ofinfections caused by resistant fungi and also by lowering theguard of the clinician, who, confident that the patient is pro-tected against fungal infections, fails to monitor drug levels inserum and potential sites of colonization.

The only real consensus in the prevention of fungal diseasesis that it is mandatory to control exposure to environmentalsources of fungi: hand-washing for Candida spp., using efficientair filtration and limiting construction or renovation work nearhematology units for airborne fungi like Aspergillus spp., avoid-ing soil heavily contaminated with pigeon droppings for C.neoformans and bat guano for H. capsulatum, and remainingindoors during dust storms for C. immitis.

For HIV-infected patients (Fig. 1), results of well-designedprotocols have demonstrated the value of suppressive thera-pies with fluconazole for cryptococcosis or itraconazole forhistoplasmosis. For patients with CD41 cell counts below 100/mm3, primary prophylaxis has recently been demonstrated tobe effective in areas of endemic infection (histoplasmosis) or isunder investigation (penicilliosis, coccidioidomycosis). Forother opportunistic fungal infections, such as mucosal candi-diasis or cryptococcosis, at least in Western countries, system-atic prophylaxis is of little benefit considering its cost, sideeffects, and inability to prolong survival. Increased use of newantiretroviral agents including protease inhibitors should lowerthe incidence of mycoses and contribute to the better controlof patients who previously experienced opportunistic fungalinfections, particularly those harboring resistant strains.

The most hotly debated topics remain aspergillosis and he-

VOL. 10, 1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 493

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494 LORTHOLARY AND DUPONT CLIN. MICROBIOL. REV.

matogenous candidiasis in neutropenic patients, BMT and sol-id-organ transplant recipients and how, when, and how long toprescribe prophylaxis.

In our opinion and from this literature review (Fig. 2), an-ticandidal prophylaxis should be considered in high-risk neu-tropenic patients (i.e., those with prolonged neutropenia) andprescribed only when Candida spp. colonize more than onesite. For C. albicans, fluconazole is the preferred drug, whilefor other Candida spp., their prevalence and frequency of azoleresistance in individual units has to be taken into account. Itshould be noted that prophylactic fluconazole administrationhas resulted in a decrease in deaths attributable to invasiveCandida infections and sometimes overall mortality in malig-nant hematological diseases including BMT. In general, keto-conazole and oral nonabsorbable polyenes have given disap-pointing results in severely neutropenic patients or BMTrecipients, but the latter should now probably be evaluated ona large-scale basis (123), particularly for the prevention ofhematogenous dissemination in patients colonized with non-albicans Candida species.

Systematic primary prophylaxis against aspergillosis remainsinvestigational, but despite the lack of conclusive data, itracon-azole may be considered for patients who cannot be trans-ferred during renovation within the hospital. In the BMT pop-ulation, prophylaxis should probably also be given to cover theGVHD period and might be prolonged in the setting of CMVdisease or steroid therapy. For patients with hematologicalmalignancies receiving extensive chemotherapy, the use of he-

matopoietic growth factors will also probably reduce the risk offungal infections.

In solid-organ transplant recipients, abdominal surgery (liv-er and pancreas transplantations) should probably be associ-ated with fluconazole prescription at least during the firstmonth after grafting. In these patients, colonization of bron-chial secretions with Aspergillus spp. should prompt the admin-istration of antifungal therapy.

For non-HIV immunocompromised patients who contractnoncandidal systemic infections, prophylaxis against relapseshould be given until recovery from the immune deficit.

In the future, vaccines (80, 114, 248) may be added to thearsenal of antifungal prophylactics, particularly against en-demic mycoses and cryptococcal infection, and new antifungalagents under development (18, 120, 121) and cytokines (41, 59,149, 163, 190, 232, 233, 284, 319, 342) should be evaluated asalternatives to existing azoles in immunocompromised pa-tients.

Finally, prevention of fungal infections also includes con-tinuing education of physicians and clinical microbiologists tomake them aware of emerging fungal species and of the factthat any fungus is a potential pathogen in immunocompro-mised hosts.

ACKNOWLEDGMENTS

We especially thank Janet Jacobson for her careful review of themanuscript; Francoise Dromer for her sound advice; Dominique Ber-deu, Laurence Briat, Rafaelle Pineau, and Anne-Marie Stucky for

FIG. 2. Proposed algorithm for the prevention of systemic fungal infections in high-risk neutropenic patients.

VOL. 10, 1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 495

their help in procuring the documents cited here; and Martine Mercierfor secretarial assistance.

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