Working Party Report Chemoprophylaxis for candidosis and ... · disseminated candidosis caused by C. krusei increases in incidence substantially with fluconazole use. One reports

Journal of Antimicrobial Chemotherapy (1993) 32, 5-21

Working Party Report

Chemoprophylaxis for candidosis and aspergillosis in neutropenia andtransplantation: a review and recommendations

Working Party of the British Society for Antimicrobial Chemotherapy

Introduction

Antifungal drugs are used in immunosuppressed patients in several ways other than forthe treatment of denned episodes of fungal infection. Chemoprophylaxis may beinitiated as soon as a risk factor, such as profound neutropenia, becomes evident—primary chemoprophylaxis; antifungal drugs may be continued (possibly in areduced dosage or with an alternative drug) after an episode of proven mycosis hasbeen treated—suppressive therapy of relapse or reinfection. Also antifungal drugs maybe started some time after the risk period begins, often when fever occurs andparticularly after it has failed to respond to antibiotics, and sometimes withoutsubsequent definitive proof of fungal infection—delayed antifungal use. The results ofstudies of all these various approaches are relevant to the consideration of drug choicein antifungal prophylaxis against invasive aspergillosis or candidosis in the prolongedimmunosuppression associated with HIV infection, transplantation or neutropenia.This article confines its attention to non-AIDS related immunosuppression, and toaspergillosis and candidosis although infections with other fungi are increasinglydescribed in the immunosuppressed. Almost all the studies have been carried out inpatients with haemic malignancy and the dearth of studies in solid organ transplan-tation is striking. Nevertheless, we consider that recommendations for solid-organtransplant recipients are important and have included some recommendations untilsubstantive studies are reported.

Risk factors

Invasive candidosis and aspergillosis may occur in the patient whose immune system isnot grossly compromised. For example, disseminated infections and fungaemia withCandida parapsilosis and Candida albicans are well described in infection related tointravascular cannulae and prosthetic replacement surgery in non-neutropenic patients.

Correspondence to: Dr R. E. Warren, Clinical Microbiology and Public Health Laboratory, RoyalShrewsbury Hospital, Mytton Oak Road, Shrewsbury SY3 8XQ, UK.Members of the working group; Prof. J. Cohen (Chairman), Royal Postgraduate Medical School, London;Dr D W. Denning, University of Manchester, Monsall Hospital, Manchester; Prof. R. J. Hay, UnitedMedical and Dental Schools of Guy's and St Thomas's Hospitals, London; Prof. D. W. R. Mackenzie,Central Public Health Laboratory, London, Dr A. G. Prentice, Derriford Hospital, Plymouth; Dr T. R. F.Rogers, Charing Cross and Westminster Medical School, London; Prof. D. C. E. Speller, University ofBristol, Bristol; and Dr R. E. Warren (Rapporteur), Royal Shrewsbury Hospital, Shrewsbury, UK.

50305-7453/93/070005+17 $08.00/0 © 1993 The British Society for Antimicrobial Chemotherapy

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6 Working Party of the BSAC

However, invasive candidosis and invasive aspergillosis are much more common inpatients with compromised immune systems.

Risk factors for all invasive fungal infection include in leukaemia and lymphoma thenature of the primary malignant disease and its associated chemotherapy. Duration ofneutropenia, particularly after first fever is an important determining factor (Wiley etal., 1990). In invasive aspergillosis, the major risk factors are occupation of rooms notsupplied with HEPA-filtered air (Sherertze/ al., 1987), and building work in the vicinity(Weber et al., 1990). Historical controls are therefore inadequate for studies ofantifungal chemoprophylaxis for invasive aspergillosis since exposure may vary withchanges in these important environmental factors. Additional less important factorsinclude graft-versus-host disease and graft rejection requiring treatment, and perhapsthe total dosage of steroids prescribed.

Candidosis arises usually from an endogenous source. Colonization of the mouth orgut with Candida tropicalis in neutropenic patients has been associated with a very highincidence of disseminated candidosis (Sandford et al., 1980; Wingard et al., 1980;Pfaller et al., 1987) but there is no information on this after solid organ transplantation.The presence of C. albicans in surveillance cultures in neutropenic patients is said notto be predictive of invasive candidosis, reflecting the low incidence of disseminatedcandidosis in those colonized (Wingard et al., 1980; Fainstein et al., 1981 A; Kostiala etal., 1982; Pfaller et al., 1987). Nevertheless, recovery of Candida from the mouthcertainly predicts the subsequent development of oropharyngeal candidosis (Yeo et al.,1985; Bodey, Samonis & Rolston, 1990). In patients receiving placebo in comparativestudies, 30-50% of those with positive cultures for Candida at the onset of the trial, butno features of clinical candidosis, developed clinically overt mucosal candidosis (Yeo etal., 1985; Bodey et al., 1990; Samonis et al., 1990). In some short-term studiesdisseminated candidosis was confined to those from whom earlier cultures frommucosal sites were positive (Buchanan et al., 1985). Opinions differ as to whether thepresence of the organisms in more than one non-contiguous surveillance site increasesthe predictive value for disseminated candidosis (Sandford et al., 1980; Martino et al.,1989a,b). Absence of C. albicans in surveillance site cultures has a high predictive valuefor the absence of disseminated candidosis in patients with lymphoma, leukaemia, ormarrow transplantation (Sandford et al., 1980; Pfaller et al., 1987).

Candida overgrowth (or indeed presence and persistence) may be more likely withparticular antibacterial regimens in cancer patients but this has not been systematicallyand prospectively investigated. A retrospective study in acute lymphocytic leukaemiasuggested that administration of vancomycin (route unspecified) in the absence ofantifungal prophylaxis was a major risk factor for disseminated candidosis and wasassociated with increased colony counts of Candida in the gastrointestinal tract (Richetet al., 1991). In another study the addition of oral vancomycin to oral nystatin andgentamicin prophylaxis was also associated with new persistent oral colonization withyeasts (Bender et al., 1979). Oral vancomycin suppresses oral Gram-positive bacteria(Borthen-Svinhufvud, Heimdahl & Nord, 1988) and this may have relevance to thedevelopment of candidosis. Yeast colonization has not been studied prospectively withparenteral vancomycin or related antibiotics, such as teicoplanin.

There is no convincing evidence that increased counts of Candida in the faeces ispredictive for those who will develop candidaemia (Karabinis et al., 1988), despiteexperimental evidence that large inocula of Candida given by mouth are associated withpersorption (translocation) across the gastrointestinal mucosa (Seelig 1966; Krause,

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Antifungal chemoprophylaxis 7

Matheis & Wulf, 1969). Other factors may be important in persorption, as in animalstudies, persorption is reduced if animals are fed by mouth on a single occasion, ratherthan being starved (Inoue et al., 1989).

We consider that, in view of the evidence that previous fungal colonization deter-mines the chances of subsequent invasion and the lack of data on factors controllingthis, trials of prophylaxis against Candida should contain groups of patients with asimilar prevalence of initial Candida colonization and subsequent exposure to anti-bacterial chemotherapy. In the case of invasive aspergillosis, there is some evidence thatepisodes of fungal pneumonia, even if not proven to be caused by aspergillus spp.,predispose to recurrence in subsequent episodes of neutropenia (Robertson & Larson,1988). There is also some retrospective evidence that prior nasal colonization withAspergillus spp. prediposes to fungal pneumonia (Aisner et al., 1979; Martino et al.,1989*). Hence these factors also need to be controlled in the design of any trial.

Not all patient groups have been fully assessed as having a risk of invasive mycosisthat can be prevented by chemoprophylaxis. Primary antifungal chemoprophylaxis hasbeen judged to be beneficial in preventing disseminated candidosis in concurrentplacebo controlled trials in bone-marrow transplant recipients, neutropenic leukaemicpatients (Williams et al., 1977; Hughes et al., 1983; Estey et al., 1984; Buchanan et al.,1985; Hansen et al., 1987; Goodman et al., 1992), patients with solid tumours andlymphoma undergoing remission induction chemotherapy (Yeo et al., 1985), renaltransplant recipients (Owens et al., 1984), patients in surgical intensive care units(Slotman & Burchard, 1987), and pre-term neonates weighing < 1250 g (Sims et al.,1988). Its use in hepatic transplant recipients, including those in acute hepatic failure,and in burn patients (Desai & Herndon, 1988), has only been examined againsthistorical controls, and, in the former, in combination with antibacterial drugs, as partof selective gut decontamination (Wiesner, 1990).

We regard the use of prophylaxis as established only in solid tumour, lymphoma andleukaemia remission induction therapy, and this is largely on the basis of efficacyagainst oral candidosis. Independent confirmation of the efficacy of prophylaxis isrequired for other indications although the high incidence of invasive candidosis insome of these groups, such as liver transplant recipients, is accepted. All studiesinvolving prophylaxis against disseminated mycoses proven by culture or histologyhave been individually small and the assessment of prophylactic efficacy againstculture-proven systemic mycosis is impaired by the likelihood of a statistical Type IIerror. Future studies of chemoprophylaxis should be considered as being intendedeither for oral or for both oral and disseminated mycosis and both study types must beadequately assessed statistically for sample population size.

Resistant strains and timing of prophylaxis

A potential disadvantage of a chemoprophylactic programme is selection for anti-microbial-resistant species. Ketoconazole may select for Candida (Torulopsis) glabrata(Acuna, Winston, & Young, 1981; De Jongh et al., 1982; Shepp et al., 1985) althoughthis does not always occur (Kauffman et al., 1984). Clotrimazole resistance emerging inthis species on serial in-vitro passage is also well recorded (Plempel et al., 1974).Fluconazole does not eliminate the rarer Candida krusei which usually becomes thepredominant cause of disseminated yeast infection (Brammer 1991; Winston 1991;Goodman et al., 1992). There are no data on the role of C. krusei in local mucosal

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infection. In one prospective study there was no significant increase in colonizationwith C. krusei or C. glabrata in patients receiving fluconazole when compared withthose receiving placebo (Goodman et al., 1992). C. krusei colonization and fungaemiaoccurred before fluconazole was introduced and an association of fungaemia withsevere gastrointestinal cytotoxic damage was suggested (Merz et al., 1986). Some of thepatients had been receiving miconazole. Recent retrospective reports suggest thatdisseminated candidosis caused by C. krusei increases in incidence substantially withfluconazole use. One reports an incidence of 8.3% of patients on fluconazole deve-loping C. krusei sepsis compared with 1.2% in those not receiving the drug. Thiscompares with an incidence of 3% of patients receiving no fluconazole who developedC. albicans fungaemia and 3% C. tropicalis fungaemia and the absence of thesefungaemias in those receiving fluconazole (Wingard et al., 1991). There is, as yet, littleinformation on selection of fluconazole- or itraconazole-resistant strains of C. albicansother than in AIDS patients. There is no evidence that ketoconazole selects for themore pathogenic species, C. tropicalis, but in one trial it was notably ineffective againstfungaemia due to this species (Fainstein et al., 1987). Parenteral polyene antifungalagents apparently do not select for amphotericin B resistance but such resistantinvasive strains do occur in patient populations in which topically applied polyenes areused (Powderly et al., 1988). There is some experimental evidence in vitro and inanimals that the use of clotrimazole, ketoconazole, or miconazole prophylaxis may leadto resistance to amphotericin B in aspergillus (Schaffner & Frick, 1985) and yeasts(Beggs, Sarosi & Steele 1976; Sud & Feingold 1983). Prophylaxis with the newertriazole antifungal drugs, fluconazole and itraconazole, has not been reported to selectfor amphotericin B resistant strains and there is no information on apparent antago-nism in clinical use. Trials to assess whether combinations of oral polyenes withtriazoles or imidazoles would prevent or promote appearance of resistant species orstrains are needed and are particularly important in the light of fluconazole selectionfor C. krusei which remains amphotericin B susceptible (Wingard et al., 1991).Examination of the data from a small study in patients with leukaemia and positiveoral yeast cultures before chemoprophylaxis started suggested that addition of oralamphotericin to ketoconazole reduced the amount of 'yeast overgrowth' but did notaffect the need for empirical parenteral amphotericin B (Donnelly et al., 1984). Werecommend that yeast speciation and susceptibility testing in a reference centre shouldbe undertaken when invasive infections arising from failures of chemoprophylaxis orchemotherapy are assessed.

Studies in experimental animals suggest that chemoprophylaxis for yeasts may fail ifcompleting bacteria have previously been eliminated. We therefore recommend thatantifungal chemoprophylaxis should begin in time to be effective locally beforebacterial elimination takes place. If oral antibacterial decontamination is used inneutropenic patients, we believe that antifungal prophylaxis should always be used andstarted with (or before) antibacterial agents, some 3 to 4 days (or 5-6 days in the case ofitraconazole) before anticipated neutropenia. If oral digestive tract decontamination isnot used but broad-spectrum antibacterial drugs are needed it is not clear whenprophylaxis against Candida should be started. The integration of immediate use ofantifungal drugs with empirical antibacterial chemotherapy has not been comparedwith delayed use of antifungal drugs started after failure of the antibacterial regimen.Immediate use may affect evaluation of the initial empirical antibacterial regimen forfever, however candidosis is common with prolonged use of broad spectrum anti-bacterials. Between courses of cytotoxic drugs in neutropenic patients when neutrophil

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counts recover, antifungal prophylaxis against yeasts is not required and preferablyshould be stopped to reduce the risk of selection of resistance. In allogeneic bonemarrow and solid-organ transplantation, the risk of invasive aspergillosis extendsbeyond the period of neutropenia (if any). In centres where filamentous fungalinfections are common, extended prophylaxis based on whether high steroid doses aregiven, or active graft versus host disease or CMV infection occur is probably required.The optimal duration and precise criteria for prophylaxis are unknown. In the absenceof clear data, we believe that a 3-month period of prophylaxis after grafting isreasonable, although potentiation of cyclosporin nephrotoxicity would also be animportant factor for consideration.

Prophylaxis against candidosis

Antiseptics

Topical chlorhexidine mouth rinse may reduce oropharyngeal candidosis and candi-daemia in bone marrow transplant recipients (Ferretti et al., 1988; Weisdorf et al.,1989) but does not affect the incidence of mucositis or oral ulceration (Ferretti et al.,1988; Raether et al., 1989). Chlorhexidine dental gels have not been adequatelyassessed.

Non-absorbed polyene suspensions and tablets and clotrimazole

Candidaemia may occur from persorption across the gastrointestinal mucosa. Invasionacross the oropharyngeal mucosa and spread from localized infection also occurs andnon-absorbed oral drugs were used initially in prophylaxis against candidaemia. It isthought that antifungal prophylaxis may be more necessary when combined withantibacterial prophylaxis but this has not been examined in controlled studiescomparing polyene antifungal drugs with placebo, although it has for ketoconazole.Topical nystatin suspension was not a very effective prophylactic agent against eitheroropharyngeal candidosis (Bodey & Rosenbaum, 1974) or disseminated candidosis inleukaemic patients (Dekker et al., 1981; DeGregorio, Lee, & Ries 1982; Barrett 1984;Buchanan et al., 1985). Poor efficacy seems to be dose-independent in the case ofdisseminated candidosis, even 26 megaunits/day (Wade et al., 1981) (combined withoral gentamicin) being ineffective in prophylaxis against disseminated candidosis.Nystatin is almost insoluble and amphotericin B is inactivated in faeces so that highoral doses of either are needed to produce detectable antifungal activity in those sites(Hofstra et al., 1979; Hofstra, de Vries-Hospers & van der Waaij 1982; van Saene et al.,1985).

There is little evidence that oral amphotericin B suspension or 10 mg lozenges aresubstantially better as prophylaxis against disseminated candidosis, although thefindings at autopsy in one otherwise unreported and consequently poorly-defined,placebo-controlled study did suggest that the large dose of 200 mg/day, as tablets, waseffective (Ezdinli et al., 1979). Little data are provided in this and other studies oncompliance with alternative regimens and poor compliance is likely to have a majorimpact on outcome. Better efficacy in prophylaxis and treatment of oropharyngealcandidosis may be achieved with sucked pastilles, tablets and troches but comparativeformulation data are scanty (de Vries-Hospers et al., 1982) and the patient with severecytotoxic-induced mucositis may not be able to suck or swallow tablets. The value of

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both nystatin and amphotericin B suspensions and swallowed tablets in prophylaxis is,at best, unimpressive and the Working Party do not recommend their use alone.

Clotrimazole troches (available in the USA) prevented oropharyngeal candidosis inthe short-term in leukaemic patients undergoing remission induction, but were notparticularly effective in eliminating culture-proven Candida colonization present at theoutset (Yeo et al., 1985; Cuttner et al., 1986). A similar observation was made withtopical miconazole (Brincker 1978). Another study reports that the overall impact ofextended use of clotrimazole troches was unimpressive in leukaemic patients (Owens etal., 1984), perhaps because the drug induces enzymes responsible for its own destruc-tion. In patients with solid tumours assessed over short periods, clotrimazole seemedmore effective in preventing symptoms (Yeo et al., 1985). In a dosing study, nystatinpastilles (containing 400,000 units) were more effective at clearance of Candida aftertherapy for Candida stomatitis than clotrimazole troches applied equally frequently, butthe difference was small (Conrad, Lentnek, & Bendush 1988). Polyene and clotrimazoletablets, troches, and pastilles have not been compared with triazole antifungal drugs inprophylactic regimens.

Ketoconazole

Systemically absorbed drugs that maintain adequate serum levels may be more effectivein chemoprophylaxis. Antifungal chemoprophylaxis with ketoconazole has been studiedwith and without concurrent co-trimoxazole. A small, four-armed, double-placebocontrolled, comparative study showed that the use of co-trimoxazole to preventbacterial infection was associated with an increased incidence of invasive fungalinfection but this was prevented by addition of 200 mg ketoconazole once daily to theregimen. Ketoconazole in the absence of co-trimoxazole also prevented major fungalinfection (Estey et al., 1984). Similar studies of prophylaxis should be undertaken usingmore recently introduced antifungal agents given concomitantly with fluoroquinoloneprophylaxis. In a number of small placebo-controlled trials ketoconazole (400 mg/day)prevented oral and usually oesophageal, but not necessarily disseminated, candidosis(Brincker 1983; Donnelly et al., 1984; Hansen et al., 1987). A dosing study suggestedthat 400 mg od ketoconazole was more effective than 200 mg od in preventing colon-ization, but not infection (Scrimgeour & Anderson, 1985). This result does not justifythe use of the higher dose in chemoprophylaxis. Little difference in efficacy was seenwhen ketoconazole (200 mg/day) and oral miconazole (250 mg qds) were compared inneutropenic patients (Meunier-Carpentier, Cruciani & Klastersky, 1983). Ketoconazole(200-mg/day) was no more effective than 0-5 megaunits 6-hourly of nystatin suspensionin preventing oropharyngeal candidosis but did protect better against oesophagitis andvaginitis, as might be expected (Jones et al., 1984).

Ketoconazole (400 mg/day) when compared with nystatin in patients receivingvancomycin, gentamicin and colistin antibacterial chemoprophylaxis reduced the inci-dence of oral mucositis and the isolation of C. albicans from the mouth, genital tractand rectum but increased significantly isolation of C. glabrata from the rectum and tosome extent from the vagina (Shepp et al., 1985). Compliance was better withketoconazole than nystatin. In patients receiving neomycin, colistin, and co-trimoxa-zole, ketoconazole was compared with a combination of amphotericin B and nystatintablets and nystatin suspension. Although yeasts persisted in the faeces in more patientson polyenes, the incidence of culture-proven invasive mycosis was equally low in bothgroups. Gas liquid chromatographic detection of presumed fungal products in serum is

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of uncertain significance but positive results were rarer in the ketoconazole group. Theclear effect demonstrated was reduction in oropharyngeal candidosis and genitalcandidosis in the ketoconazole treated group in those who were neutropenic and hadnot received an allogenic transplant (Hann et al., 1982). Allogenic marrow transplan-tation was associated with low serum levels of ketoconazole and no better effect thanwas achieved with the oral polyenes (Hann et al., 1982). Ketoconazole is also poorlyabsorbed in those taking antacids and H2 histamine antagonists but there are no datawith cytoprotectives such as sucralfate. Drug absorption has not been assessed inrecipients of bone-marrow autografts or with differing cytotoxic regimens. As well ascausing rare hepatic adverse drug reactions, ketoconazole interacts with mammalianP450 cytochrome oxidase enzymes increasing cyclosporin levels and the incidence ofassociated nephrotoxicity (Morgenstern et al., 1982). We cannot therefore recommendthe use of ketoconazole in allogenic transplantation of any organ and its role inprophylaxis in neutropenic patients must be reconsidered as fluconazole and itracona-zole have now been introduced.

Triazole antifungal drugs

Data from animal experiments suggest that fluconazole is more effective in prophylaxisand early treatment than in therapy of advanced disseminated candidosis (Walsh et al.,\990a,b). In a placebo-controlled study in prophylaxis in cancer patients only 2% ofpatients receiving 50 mg/day fluconazole developed oropharyngeal candidosiscompared with 28% of controls. This difference was largely associated with the manypatients with initially positive cultures for Candida but no evidence of candidosis, whowere cleared of the organisms by fluconazole but not placebo (Bodey et al., 1990;Samonis et al., 1990). This clearance is a significant difference from previous experiencewith ketoconazole and miconazole and might be expected to be associated with delayedrelapse when antifungal drugs are stopped. Delayed relapse has been described inanother study of cancer patients which otherwise demonstrated only equal efficacy ofketoconazole and fluconazole in oropharyngeal candidosis (Meunier, Aoun, & Gerard1990). Most experience in comparing ketoconazole and fluconazole has been gained inpatients with AIDS where ketoconazole absorption is poor and there is some evidencethat suggests that fluconazole is more effective (de Wit et al., 1989). The minimaladequate prophylactic dose of fluconazole, which has a long plasma half-life and maybe suitable for less than daily use, is not established in neutropenic patients. It has alsonot been established whether infrequent dosage is more likely to be associated withcolonization and infection with resistant strains. In one study in non-neutropenicpatients with AIDS weekly prophylaxis with 150 mg fluconazole proved effective (Leenet al., 1990). Comparison with a range of polyene regimens suggested that 50 mg/dayfluconazole was an effective prophylactic regimen for oropharyngeal candidosis(Brammer, 1990). Absorption has been assessed in a limited number of patientsundergoing marrow autografting and is satisfactory, though excretion may be delayedwith resulting reduction in dosage requirements (Milliken et al., 1989). Absorption isnot pH dependent (Thorpe, Baker, Bromet-Petit, 1990) but absorption studies have notbeen reported in allograft recipients. In the presence of dysphagia due to cytotoxicdrugs' suspensions or parenteral prophylaxis may be needed but these have not beenassessed.

A higher dose of 400 mg/day fluconazole, combined with a very liberal policy for

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employing empirical intravenous amphotericin B, has been assessed in a large study(Winston, 1991) of prophylaxis in neutropenic patients and shown to be effective inreducing the incidence of disseminated candidosis, oral and faecal colonization andlocal infection with all yeasts except C. krusei. No effect on the incidence of infectionwith filamentous fungi was seen (Winston, 1991). A similar randomized multicentretrial in marrow transplant recipients reported a reduction in systemic fungal infectionfrom 28/177 (158%) receiving placebo to 5/179 (2-8%) receiving 400 mg fluconazole(Goodman et al., 1992), and reduced associated deaths from 10 to 1. Lower doses ofchemoprophylaxis (50 mg/day fluconazole) were assessed in comparison with oralpolyenes against systemic candidosis and candidaemia in 536 patients undergoingremission induction therapy and showed a less convincing reduction because of ahigher incidence of filamentous fungal infection (Brammer, 1991). This study, however,did show complete prevention of infection due to C. albicans and C. glabrata, althoughas in the two previous studies C. krusei infection was seen (Brammer, 1991). Theinactivity of fluconazole against C. krusei is offset by its more reliable action againstC. tropicalis and C. glabrata when compared with ketoconazole. Nevertheless, theincidence of C. krusei colonization may rise to 40% in those taking fluconazole and asubstantial incidence of candidaemia may occur with this previously uncommon species(Persons et al., 1991; Wingard et al., 1991). Fluconazole does induce and inhibitdifferent hepatic drug-metabolizing enzymes (Lavrijsaen et al., 1990) but the rise incyclosporin levels is not consistent nor frequently clinically toxic if constant dosing isused (Kruger et al., 1988; Canafax et al., 1991). The Working Party thereforerecommends a dose of 50 mg/day fluconazole for prophylaxis against yeast infection inneutropenic patients. Combining fluconazole with polyenes might be effective inpreventing overgrowth with C. krusei but this has not yet been investigated and cannotbe confidently recommended.

Reported experience with itraconazole in comparative studies is much smaller(Prentice & Bradford 1989). In a large open study in patients with solid tumours andlymphoma itraconazole 100 mg/day given prophylactically for a mean time of twoyears, oropharyngeal candidosis was reported in 15% of patients (Miihldorfer & Konig1990) It is not clear if this is due to the impact of poor absorption from the formulationof itraconazole used. Fluconazole and itraconazole have not been compared directly.

Delayed antifungal drug usage

An alternative approach to primary oral chemoprophylaxis is use of antifungal drugsas both delayed antifungal prophylaxis and parenteral 'therapy' in febrile episodes,which are not documented as fungal in aetiology. This is widely used but seldomassessed for its prophylactic component. It is usual to withhold antifungal treatmentuntil the patient has failed to respond initially to antibacterial agents and then useamphotericin B (Pizzo et al., 1982). Against historical controls, this empirical anti-fungal drug use appears to reduce the rate of systemic fungal infection detected atautopsy (Zimmerman-Hosli et al., 1989). The distinction between therapy and prophy-laxis can be blurred. Systemic prophylaxis with intravenous miconazole started at theonset of first fever and continued for the duration of neutropenia has been shown toprevent invasive candidosis in adult (Wingard et al., 1987) and paediatric leukaemicpatients (Fainstein, Elting & Bodey 1981a), although the studies are small. Parenteralmiconazole may have adverse effects associated with the vehicle of administration

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(Fainstein, et al., 1981a) and alternative antifungal agents and routes should beassessed. Oral triazole antifungal drugs have not been assessed as additional thera-peutic components of regimens for fever in neutropenia, nor for continuationchemoprophylaxis.

In experimental animals, parenteral liposomal amphotericin B exerts a prophylacticeffect against candidosis in animals which, unlike that of non-liposomalamphotericin B, endured for a 7-day period, an effect not explained by serum levels(Lopez-Berestein et al., 1984). There are no corresponding data on human use.

Prophylaxis for aspergillosis

Amphotericin B

Use of intravenous amphotericin B 30 mg thrice weekly as prophylaxis has been shownnot to prevent aspergillus infection in unselected neutropenic patients (Bodey &Anaissie, 1991) or bone marrow autograft recipients (Warren et al., 1990) and unlessamphotericin B were given in one of its lipid formulations toxicity problems mightpreclude general prophylactic use at a higher dosage. The place of aerosols of topicalagents has also been reconsidered recently in invasive aspergillosis and mucormycosiswhich are usually acquired from the air and had been thought to require systemicallyactive drugs. The use of a thrice-daily topical nasal amphotericin B spray or aerosol asprophylaxis in leukaemic patients was reported as being successful in three studies(Meunier-Carpentier et al., 1984; Conneally et al., 1990; Jeffrey et al., 1991) but failedin another (Jorgensen et al., 1989). Unfortunately all used historical controls andalthough additional data suggested that aspergillus exposure had continued (Jeffrey etal., 1991) only studies with concurrent matched controls, with data on episodes andrecurrences of pneumonia and fever unresponsive of antibiotics, would be clearlyinterpretable. Aerosols of amphotericin B are protective in animal models of invasiveaspergillosis (Schmitt et al., 1988) although there is no work on the optimum particlesizes of the aerosol (which is known to be important in pentamidine prophylaxisagainst Pneumocystis carinii infection. More work in this area with concurrent controlsis a major priority and would be justified in units without HEPA filtration. Although ithas not been subjected to a controlled clinical trial, systemic amphotericin B prophy-laxis started two days before anti-leukaemia therapy seems successful in preventingreactivation in most patients with prior invasive aspergillosis and tomographic evidenceof continuing pulmonary infection (Karp, Burch & Merz, 1988). The Working Partyrecommend this approach in patients with proven invasive aspergillosis or patientswhere a presumptive diagnosis was made and there are residual cavities. Itraconazoleor liposomal amphotericin B should also be assessed formally for this indication.

Itraconazole

Newer absorbed antifungal agents are now being assessed in prophylaxis of invasiveaspergillosis. Published clinical trials of itraconazole therapy or prophylaxis in theimmunocompromised patient are few. Itraconazole 200 mg bd was compared withketoconazole 200 mg bd as a prophylactic agent in patients with prolonged neutro-penia who had not received bone marrow transplants but had been given antibacterialchemopropylaxis and nursed without HEPA filtration (Tricot et al., 1987). The trialcompared patients given itraconazole with a group of historical controls given ketoco-

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nazole and was acknowledged by the authors to be flawed as there was no formalcontrol for exposure to aspergillus spp. The major finding was reduced mortality frombiopsy and culture proven invasive aspergillosis in the itraconazole group. Amongstpatients neutropenic for > 25 days 57% of those receiving kctoconazole and 9% ofthose receiving itraconazole died of invasive mycoses, predominantly invasive aspergil-losis. This high incidence suggests nosocomial acquisition. Surprisingly there was noreduction in empirical amphotericin B usage. Patients with itraconazole levelsmeasured by HPLC as < 250 ng/mL for > 7 days were more than twice as likely tohave invasive mycoses with itraconazole-susceptible strains. Only one patient withadequate serum concentrations developed invasive aspergillosis compared with five inthe group with inadequate levels, an internal control that suggests that differences inpatient exposure to aspergillus was not the sole, although a possible, reason fordifferences between the two trial periods (Tricot et al., 1987). However, low concentra-tions were reported in 50% of assessed patients. The dose of itraconazole for prophy-laxis requires assessment. Our starting dose is low. Itraconazole absorption from asingle dose was reduced but not to an extent distinguishable from intersubject variationafter H2 receptor antagonists (Stein et al., 1989). More infections due to C. albicansoccurred in the ketoconazole group and more due to C. glabrata in an itraconazolegroup gives 200 mg/day but the numbers of invasive yeast infections were small(Boogaerts et al., 1989).

It will be important to carry out further prospective comparative adequatelycontrolled trials with itraconazole to define more clearly the indications for its use andany potential disadvantages such as invasive yeast infection. An improved formulationwhich overcomes the problems of erratic absorption is needed. Meanwhile we note thatthe current licensed formulation of itraconazole may be of benefit in patients nursedwithout HEPA filters, where there is a proven high incidence of invasive aspergillosis orwhere building works are being undertaken. Itraconazole should also be substituted forother antifungal prophylaxis in such institutions in patients neutropenic for more than20 days. With current formulations, itraconazole levels should be regularly measuredwhenever used. It seems prudent to measure them one week after commencing the drugand thereafter weekly if there is dysphagia, any chance of cytotoxic drug-inducedgastrointestinal damage, evidence of GVHD, or the use of antacids, H2 receptorantagonists, or drugs with capacity to enhance hepatic drug metabolism. If none ofthese predisposing factors is evident and levels are satisfactory then assays can be lessfrequent, perhaps monthly in solid organ allografts. It should be noted that intra-patient variation in levels is substantial (Bradford et al., 1991) and measurements mustbe repeated including during subsequent periods of neutropenia. It is not clear whetheradditional prophylaxis against yeasts is ever required but this seems likely if the drug isnot absorbed. If serum levels of itraconazole are inadequate in patients susceptible toyeast infection, we recommend that fluconazole should be substituted. In such patientswho are additionally susceptible to aspergillosis, the use of nebulized amphotericin B,in addition to fluconazole, should be considered, at least until discharge from hospital.In allograft recipients no longer susceptible to yeast infection but susceptible toaspergillosis nebulized amphotericin B may be used alone if itraconazole levels areinadequate. Itraconazole is said to induce and inhibit hepatic drug-metabolizingenzymes and renal toxicity may occur in allograft recipients receiving cyclosporin(Kramer et al., 1990), although the drug may be particularly valuable in this group ofpatients because of their susceptibility to invasive aspergillosis. Cyclosporin dosageshould be reduced at once if itraconazole is used in therapy and levels of both drugs

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measured. There are no published data on the prophylactic use of itraconazole aftersolid organ transplantation, although this may seem sensible if there is a high risk ofinvasive aspergillosis.

HEPA filtration of air substantially reduces the risk of invasive aspergillosis althoughoccasional cases presumably associated with incubating or recrudescent infection mayoccur. Substantial problems with this condition always call for urgent investigation intopossible sources of nosocomial infection (as outbreaks are now being commonlydescribed), or for improved ventilation systems. Our view is that itraconazole is usuallynot required as prophylaxis whilst neutropenic patients are nursed in HEPA filtered air.The lack of substantial published clinical trials of itraconazole prophylaxis or clearanceof Candida together with the problems with its absorption should limit its use at theoutset of neutropenia, when the extensive data on prevention of yeast infections withfluconazole are considered. Until such data are published for itraconazole, we cannotadvocate its general prophylactic use in neutropenia. Nevertheless, ultimately itracona-zole may prove preferable to fluconazole in prophylaxis, because the latter appears notto have activity against invasive aspergillosis at economic doses and because of the high

Table. Summary of the recommendations of the Working Party of the BSAC onchemoprophylaxis of fungal infections in immuno-compromised patients

1. Prophylaxis in neutropenia

With selective digestive tract decontamination—primary prophylaxisCommence fluconazole"* 50 mg/daily with prophylactic antibacterials four days beforeanticipated neutropenia [ < 10 x 109/L].Stop if patient is given empirical intravenous amphotericin B for duration of infusion.Stop' when neutrophils > 05 x 109/L.

Without selective digestive tract decontaminationCommence fluconazole"* 50 mg/daily with initiation of first course of antibiotics duringneutropenia [ < 10 x 109/L] or if yeasts grown from oral flora earlier.Stop if given empirical intravenous amphotericin B (for duration of infusion).Finish course' when neutrophils > 05 x 109/L.

2. Prophylaxis in allogenic solid organ transplantation

Hepatic transplantation

Consider prophylaxis with fluconazole in first postoperative month unless high institutionalincidence of aspergillosis when consider prophylaxis with itraconazolec.

Other solid organ transplantationGeneral prophylaxis not recommended.

"Ketoconazole 200 mg/day may be substituted for fluconazole in patients who are not receiving antacids,cyclosporin A, or H2 receptor antagonists but may be less effective in prophylaxis of disseminated candidosis.

*Use, or change to, itraconazole 200 mg/day at once if:—(i) neutropenic > 20 days AND

(ii) not in HEPA filtered air AND(Hi) not allogenic transplant.

OR0) not in HEPA filtered air, AND

(ii) building works in close vicinity.

If serum levels are adequate, continue. If levels are inadequate substitute nasal amphotericin B spray andoral fluconazole.

If allogenic transplant AND either GVHD or CMV infection occurs, change to itraconazole 200 mg dailyand, if serum levels are adequate, continue for 3 months. If levels are inadequate substitute nasalamphotericin B spray.

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fatality rate of that disease. Itraconazole has little activity in mucormycosis which canoccasionally be seen in similar airborne outbreaks associated with fatalities.

Conclusion

The Working Party summarizes its views in the Table. It considers the evidencesuggests that absorbed antifungal agents appear more effective than clotrimazole,miconazole, and oral amphotericin B or nystatin in prophylaxis and prevention ofrelapses of oropharyngeal candidosis. It is likely but not proven that this extends todisseminated candidosis and more rigorous clinical trials should be undertaken. Thereappear to be advantages to using fluconazole rather than ketoconazole in allogenictransplant recipients requiring prophylaxis and receiving cyclosporin, or in susceptiblepatients receiving antacids or H2-histamine receptor blockers. Only preliminary datafor itraconazole are available, despite the time that has elapsed since its introduction,so its role is uncertain in prophylaxis of either candidosis or invasive aspergillosis. Thepreliminary evidence of efficacy against Aspergillus spp., suggests that itraconazole maybe useful where effective control of the quality of air supply to a unit caring forsusceptible patients cannot be ensured. More data are required in solid organ trans-plants. For all chemoprophylactic antifungal agents, careful consideration should begiven to the prevalence of invasive mycosis (for which there are inadequate surveillanceand autopsy data in Europe) and the timing of prophylaxis in relation to periods whenthe patient is most susceptible. Prophylactic antifungal regimens can then be restrictedto minimize the selection of resistant fungi.

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(Received 10 March 1992; revised version accepted I February 1993)

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Working Party Report Chemoprophylaxis for candidosis and ... · disseminated candidosis caused by C. krusei increases in incidence substantially with fluconazole use. One reports