Efforts at preventing and treating fungal infection in hematopoietic stem cell transplant (HSCT) recipients must take into account the types of infections likely to be encountered during the different risk periods in hosts with different underlying risks. Given the emergence of molds as prevalent pathogens and the long duration of risk in allogeneic HSCT recipients, optimal antifungal prophylaxis would consist of treatment that can be given over a prolonged period and that would provide both anti-Candida and anti-Aspergillus activity. Optimal empiric therapy would consist of a broad-spectrum agent in the absence of more sensitive and specific methods for microbial diagnosis. Fluconazole (Diflucan) is currently the standard prophylactic agent for candidiasis, although mold-active agents and alternative strategies for polyene administration are being investigated. The gold standard for empiric therapy is currently a polyene antifungal, yet an increased appreciation for amphotericin B-resistant yeasts and molds, and less toxic mold-active alternatives, might lead to the use of other compounds in the future. The recent development of multiple alternatives emphasizes our need to establish treatment algorithms that consider both the likely pathogens and potential toxicities. [ONCOLOGY 15(Suppl 9):15-19, 2001]
ABSTRACT: Efforts at preventing and treating fungal infection in hematopoietic stem cell transplant (HSCT) recipients must take into account the types of infections likely to be encountered during the different risk periods in hosts with different underlying risks. Given the emergence of molds as prevalent pathogens and the long duration of risk in allogeneic HSCT recipients, optimal antifungal prophylaxis would consist of treatment that can be given over a prolonged period and that would provide both anti-Candida and anti-Aspergillus activity. Optimal empiric therapy would consist of a broad-spectrum agent in the absence of more sensitive and specific methods for microbial diagnosis. Fluconazole (Diflucan) is currently the standard prophylactic agent for candidiasis, although mold-active agents and alternative strategies for polyene administration are being investigated. The gold standard for empiric therapy is currently a polyene antifungal, yet an increased appreciation for amphotericin B-resistant yeasts and molds, and less toxic mold-active alternatives, might lead to the use of other compounds in the future. The recent development of multiple alternatives emphasizes our need to establish treatment algorithms that consider both the likely pathogens and potential toxicities. [ONCOLOGY 15(Suppl 9):15-19, 2001]
The fungal infections of primary concern inhematopoetic stem cell transplant (HSCT) recipients are candidiasis andaspergillosis. Infections caused by Candida species fall into the distinctsyndromes of acute bloodstream infection and chronic infection, or hepatospleniccandidiasis. In both cases, Candida species are primarily acquired from thegastrointestinal tract. Candida parapsilosis is the exception to this rule, asthis organism is acquired via the intravenous (IV) catheter route, possibly inassociation with infected infusates. Aspergillosis is exogenously acquired,via aerosolization. Current debate has focused on the hospital and environmentalsources of exposure, as Aspergillus species have been recovered from both airand water supplies.
Risk factors for candidiasis and aspergillosis are summarized in Figure1.The highest risk for candidiasis is during the neutropenic period, especially inpatients who are colonized with the organism during conditioning-relatedmucositis. The period of greatest risk is followed by an extended period of riskfor both candidemia and chronic candidiasis, particularly in association withgraft-vs-host disease.
Early risk for aspergillosis is also associated with the neutropenic period;in addition, analysis of cases at the Fred Hutchinson Cancer Research Center hasdemonstrated an incidence spike in the summer months. However, severalcenters have documented that the greatest risk period now occurs late aftertransplantation in allograft recipients, in the setting of acute and chronicgraft-vs-host disease. This late risk, particularly when it occurs more than 100days after transplantation, might constitute the most difficult period toaddress in terms of disease prevention; generally, this has not been accountedfor in prophylaxis trials.
What is optimal antifungal therapy in HSCT patients? For prophylaxis, thecharacteristics of optimal therapy would include the ability to administer drugfor a long duration (especially in allograft recipients), with low toxicities,low cost, ease of delivery, predictable drug interactions, and both anti-Candidaand antimold activity. Since we currently lack sensitive and specific diagnostictechniques, optimal empiric therapy should have broad activity against suspectedagents. However, increased toxicity and greater cost may be acceptable if suchbroad activity can be achieved. For treatment of documented infection, theprimary requirement is adequate efficacy.
Currently Available Agents
Currently available antifungal agents consist of conventional IV and lipidformulations of amphotericin B, 5-flurocytosine (5-FC [Ancobon]), and the azoledrugs, including the imidazoles (clotrimazole [Lotrimin, Mycelex], ketoconazole[Nizoral], and miconazole) and triazoles (fluconazole [Diflucan] anditraconazole [Sporanox]).
Investigational agents include a liposomal formulation of nystatin among thepolyenes; the new mold-active azoles voriconazole, posaconazole, andravuconazole; and a number of echinocandins.
Drawbacks associated with amphotericin B treatment include infusion-relatedand renal toxicities. In addition, there have been reports of resistanceamong several Aspergillus species, C krusei and C glabrata, and other non-Aspergillusmolds. Also, this agent is systemically available only via the IV route, andthe lipid formulations are expensive.
The results of several studies agree that the lipid formulations AmBisome andAbelcet cause fewer infusion-related toxicities and nephrotoxicities compared toconventional amphotericin B. Recent debate has focused on whether thedecreased toxicities warrant use of expensive products as first-line therapy ineither the empiric or therapeutic settings and which product is better.
Among the azole agents, fluconazole is easy to administer (oral and IV forms)and has low toxicity rates and predictable drug interactions. However, it isactive only against C albicans. It is currently indicated for use in mucosalcandidiasis, prophylaxis, hepatosplenic candidiasis, and candidemia. It isimportant to note that effectiveness in candidemia has not been demonstrated inrandomized trials in compromised hosts, and results of retrospective studiesremain controversial.
Itraconazole is now available in an IV formulation and an oral solution formwith improved bioavailability, and it is active against both Candida species andmolds. Although this drug has been used widely in Europe, it has not been wellstudied in the HSCT population. Results of several ongoing studies are favorablewith regard to absorption, although more information regarding drug interactionsis needed. It is currently indicated for maintenance therapy in aspergillosis,but randomized trial data are lacking in the settings of candidemia/candidiasisand antifungal prophylaxis.
Among the investigational agents, voriconazole has been developed in bothoral and IV forms and has in vitro activity against molds comparable to that ofamphotericin B. Notably, this agent has increased activity against Zygomycetes.
Posaconazole has been developed in an oral form, and may exhibit increasedactivity against Fusarium species.
Ravuconazole has been developed in oral form and exhibits an extendedhalf-life; it may be associated with less potential for cytochrome P450 systeminteractions than other azoles. Studies evaluating safety and efficacy of thesecompounds are underway.
Efforts at preventing disease in HSCT recipients have yielded demonstrablebenefits in improving patient outcomes. The ability of prophylaxis or preemptivetreatment to reduce morbidity and mortality has perhaps best been documented inthe case of cytomegalovirus disease, but use of antifungal prophylaxis alsoappears to have improved outcomes over the past decade.[6-8] There is, however,a clear need for improvement in preventive efforts.
Although an effective anti-Candida regimen has been established, debatecontinues regarding optimal dose and duration of drug administration, and noantimold prophylactic treatment has as yet been demonstrated to be effective.Further, although it has been demonstrated that empiric treatment of febrileneutropenia is an important component of prevention, it is also clear that feveris not a sensitive indicator of fungal infection. Better diagnostic methods areneeded to improve prevention efforts.
Fluconazole has been shown to be effective in preventing candidiasis afterHSCT.[8-9] However, review of major randomized studies indicates that hostcharacteristics affect outcome in an important manner. In a study by Goodman etal, placebo was compared with fluconazole (400 mg daily) until engraftment ina population in which 52% of patients were allograft recipients. Fluconazole wasassociated with significant reductions in Candida infections and candidiasis-relatedmortality, but no reduction in overall mortality was observed.
In a subsequent single-center study by Slavin et al placebo was comparedwith fluconazole (400 mg daily) for 75 days after transplantation in apopulation that was at higher risk (88% of patients were allograft recipients).Administration of study drug was associated with significant reductions infungal infections, infection-related mortality, and overall mortality. Thefindings of this latter study have engendered debate, since the overallmortality benefit could not be statistically explained by the decrease ininfection-related mortality. Importantly, this analysis defined fungalinfections as those caused by both Candida and Aspergillus species, the latterof which fluconazole has no activity against.
We have subsequently performed an analysis of 8-year survival in this patientpopulation, finding that fluconazole was associated with significant long-termsurvival benefit in allograft recipients (17% reduction; P = .0018), and thebenefit is associated with prevention of candidiasis and related mortality.These findings emphasize both that fluconazole is effective prophylaxis forcandidiasis and that preventive efforts and treatment trials must distinguishbetween patient types and types of fungal infection.
Rates and distribution of Candida infections in HSCT patients at FredHutchinson Cancer Research Center (FHCRC) prior to (1980 to 1986) and after(1994 to 1997) the introduction of fluconazole prophylaxis are shown in Figure2.
The use of fluconazole prophylaxis was associated with a decrease inincidence of candidiasis from > 10% to 4.6% during these periods. As can beseen, the frequency of C albicans infection has been dramatically reduced,whereas there has been some emergence of infection due to C glabrata and Ckrusei. Importantly, the increase in C parapsilosis infection is associatedwith an outbreak of infected intravenous infusate during 1994, not with the useof fluconazole. Concomitant with the dramatic decrease in candidiasis,aspergillosis has become the predominant infection over the past decade. The1-year cumulative incidence of disease has steadily increased at FHCRC since1993, with current rates exceeding 10% in allograft recipients (data notpublished).
As noted, the optimal dosage of fluconazole (400 vs 200 mg) necessary forprophylaxis has not been defined. However, no dose studies are likely to beperformed in this setting, due to the warranted focus on investigation oftreatments to address aspergillosis in HSCT patients. A number of studies ofaspergillosis prophylaxis have been performed; however, these studies haveinvolved patient populations that have an underlying low incidence ofaspergillosis, weakening statistical analyses with inadequate sample sizes.
In a study of twice-daily aerosolized amphotericin B vs a standardamphotericin B regimen in a patient population including low-risk leukemicpatients, no significant difference in rates of aspergillosis were observed(4% vs 7%) and rates of amphotericin B toxicity were high.
In a study of itraconazole vs placebo in 405 neutropenic patients,itraconazole was associated with a lower rate of candidiasis, but equivalentrates of aspergillosis. In a study of itraconazole vs fluconazole in 445neutropenic patients, itraconazole was associated with lower rates of bothcandidiasis and aspergillosis. However, the small number of proven aspergillosiscases in each of these studies impairs our ability to evaluate efficacy ofprevention.
Randomized trials evaluating prophylaxis with both itraconazole andposaconazole in higher-risk HSCT patients are ongoing. In addition, a study ofthe echinocandin FK463 in allogeneic and autologous HSCT patients has beeninitiated.
Lipid Amphotericin B
Comparative trials in febrile neutropenia have included a study of liposomalamphotericin B (AmBisome) vs conventional amphotericin B in 338 patients inwhich the liposomal formulation (1 and 3 mg/kg) was associated with a reducedincidence of nephrotoxicity (10% to 12% vs 24%, respectively). In anothercomparison of liposomal with conventional amphotericin B, liposomalamphotericin B was found to be associated with reduced toxicity and a decreasein breakthrough infections. However, the observation that most breakthroughinfections were caused by azole-susceptible species (C albicans or C tropicalis)raises a concern about whether the difference in breakthrough rates isassociated with differences in type and effectiveness of antifungal prophylaxisbetween the two arms.
In a study comparing AmBisome at 3 and 5 mg/kg with the amphotericin B lipidcomplex Abelcet, AmBisome at 5 mg/kg was associated with decreased rates ofinfusion-related toxicity and nephrotoxicity. 
Ongoing studies include a comparison of liposomal amphotericin B andvoriconazole and a comparison of liposomal amphotericin B and the echinocandincaspofungin. Although decreased toxicities associated with the lipid productshave led to increasing use over conventional amphotericin B, it must be realizedthat one potential shortcoming of the studies performed to date is that overallefficacy is difficult to assess with only a short (1 to 2 week) duration offollow-up.
Fewer randomized trials have been performed to evaluate treatment ofconfirmed infection. The results of one study, which evaluated outcome ofsuspected and proven infections in patients who were randomized to receiveeither liposomal amphotericin B (5 mg/kg) or conventional amphotericin B (1.0mg/kg/d), suggest that efficacy of treatment might be greater with thelipid-based product. These studies generally have shown a decrease intoxicity with liposomal products, but efficacy continues to be debated; it isimportant to note that interpretation of efficacy outcomes in these treatmenttrials is also made difficult by inclusion of mixed patient populations. Oneongoing trial is comparing conventional amphotericin B and voriconazole in HSCTpatients, and more are needed.
The current standards for preventive therapy, and issues that remain to beaddressed to identify optimal treatment can be summarized as follows.
For prophylaxis, the current gold standard for Candida infection prophylaxisin HSCT patients is fluconazole administered until engraftment or through graft-vs-hostdisease in allograft recipients, although this treatment provides no activityagainst mold infection. The role of antimold azoles has not yet beenwell-defined; ongoing randomized trials may provide important information inthis regard.
The potential role of echinocandins requires further study. Although thesecompounds most certainly will have a significant role for treatment ofcandidiasis, activity against Aspergillus species needs to be confirmed.
The role of amphotericin B formulations for prevention remains unclear. Thedesign of prevention strategies should consider the fact that the source andtype of stem cell product might be associated with a decreased or increased riskfor either candidiasis or aspergillosis.
With regard to empiric therapy, a primary consideration is activity againstAspergillus, particularly given that prophylaxis may not provide antimoldactivity. The current standard is a polyene; however, it remains unclear whetherlipid formulations pose an advantage in efficacy over standard amphotericin B,and it is debatable whether the nephrotoxicity associated with polyene treatmentshould constitute a reason for using lipid products as first-line therapy.
There is clearly a role for mold-active azoles in this setting, and it ishoped that ongoing studies will better define this role. There may also be arole for echinocandins if sufficient activity against Aspergillus can bedemonstrated.
Finally, another primary issue to be addressed is the development of areliable diagnostic test, or a screening test to guide preemptive therapy. Thegalactomannan enzyme-linked immunosorbent assay and a polymerase chainreaction-based assay might be useful for diagnosis of aspergillosis in thefuture.
Given our lack of sensitive and specific diagnostic methods and highly toxic(or expensive) alternatives, one favorable approach is to tailor bothprophylactic and empiric therapy to the patient. Patients who are at high riskfor aspergillosis (ie, cord blood stem cell recipients) might benefit frominvestigational mold-active regimens for prophylaxis through specific riskperiods.
Development of empiric strategies also should consider the risk forAspergillus species vs Candida species as the primary breakthrough fungalpathogen. Empiric therapy in patients who have a high risk for invasive moldinfections and in patients who have a minimal reserve for associated toxicitieswarrants consideration for first-line therapy with a less toxic, possibly moreeffective lipid amphotericin B formulation.
Success in development of antifungal compounds has enabled us to finally havealternatives for the treatment of fungal infections. Many more studies arenecessary to define how these products should be used.
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