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Antifungal Prophylaxis in Hematopoietic Stem Cell Transplant Recipients

Antifungal Prophylaxis in Hematopoietic Stem Cell Transplant Recipients

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 in
hematopoetic stem cell transplant (HSCT) recipients are candidiasis and
aspergillosis. Infections caused by Candida species fall into the distinct
syndromes of acute bloodstream infection and chronic infection, or hepatosplenic
candidiasis. In both cases, Candida species are primarily acquired from the
gastrointestinal tract. Candida parapsilosis is the exception to this rule, as
this organism is acquired via the intravenous (IV) catheter route, possibly in
association with infected infusates.[1] Aspergillosis is exogenously acquired,
via aerosolization. Current debate has focused on the hospital and environmental
sources of exposure, as Aspergillus species have been recovered from both air
and water supplies.

Risk factors for candidiasis and aspergillosis are summarized in Figure
1
.
The highest risk for candidiasis is during the neutropenic period, especially in
patients who are colonized with the organism during conditioning-related
mucositis. The period of greatest risk is followed by an extended period of risk
for both candidemia and chronic candidiasis, particularly in association with
graft-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 has
demonstrated an incidence spike in the summer months.[2] However, several
centers have documented that the greatest risk period now occurs late after
transplantation in allograft recipients, in the setting of acute and chronic
graft-vs-host disease. This late risk, particularly when it occurs more than 100
days after transplantation, might constitute the most difficult period to
address in terms of disease prevention; generally, this has not been accounted
for in prophylaxis trials.

Therapy: Optimal and Available

What is optimal antifungal therapy in HSCT patients? For prophylaxis, the
characteristics of optimal therapy would include the ability to administer drug
for a long duration (especially in allograft recipients), with low toxicities,
low cost, ease of delivery, predictable drug interactions, and both anti-Candida
and antimold activity. Since we currently lack sensitive and specific diagnostic
techniques, optimal empiric therapy should have broad activity against suspected
agents. However, increased toxicity and greater cost may be acceptable if such
broad activity can be achieved. For treatment of documented infection, the
primary requirement is adequate efficacy.

Currently Available Agents

Currently available antifungal agents consist of conventional IV and lipid
formulations of amphotericin B, 5-flurocytosine (5-FC [Ancobon]), and the azole
drugs, including the imidazoles (clotrimazole [Lotrimin, Mycelex], ketoconazole
[Nizoral], and miconazole) and triazoles (fluconazole [Diflucan] and
itraconazole [Sporanox]).

Investigational agents include a liposomal formulation of nystatin among the
polyenes; the new mold-active azoles voriconazole, posaconazole, and
ravuconazole; and a number of echinocandins.

Amphotericin B

Drawbacks associated with amphotericin B treatment include infusion-related
and renal toxicities.[3] In addition, there have been reports of resistance
among several Aspergillus species, C krusei and C glabrata, and other non-Aspergillus
molds.[4] Also, this agent is systemically available only via the IV route, and
the lipid formulations are expensive.

The results of several studies agree that the lipid formulations AmBisome and
Abelcet cause fewer infusion-related toxicities and nephrotoxicities compared to
conventional amphotericin B.[5] Recent debate has focused on whether the
decreased toxicities warrant use of expensive products as first-line therapy in
either the empiric or therapeutic settings and which product is better.

Fluconazole

Among the azole agents, fluconazole is easy to administer (oral and IV forms)
and has low toxicity rates and predictable drug interactions. However, it is
active only against C albicans. It is currently indicated for use in mucosal
candidiasis, prophylaxis, hepatosplenic candidiasis, and candidemia. It is
important to note that effectiveness in candidemia has not been demonstrated in
randomized trials in compromised hosts, and results of retrospective studies
remain controversial.[4]

Itraconazole

Itraconazole is now available in an IV formulation and an oral solution form
with improved bioavailability, and it is active against both Candida species and
molds. Although this drug has been used widely in Europe, it has not been well
studied in the HSCT population. Results of several ongoing studies are favorable
with regard to absorption, although more information regarding drug interactions
is needed. It is currently indicated for maintenance therapy in aspergillosis,
but randomized trial data are lacking in the settings of candidemia/candidiasis
and antifungal prophylaxis.

Investigational Agents

Among the investigational agents, voriconazole has been developed in both
oral and IV forms and has in vitro activity against molds comparable to that of
amphotericin B. Notably, this agent has increased activity against Zygomycetes.

Posaconazole has been developed in an oral form, and may exhibit increased
activity against Fusarium species.

Ravuconazole has been developed in oral form and exhibits an extended
half-life; it may be associated with less potential for cytochrome P450 system
interactions than other azoles. Studies evaluating safety and efficacy of these
compounds are underway.

Current Status of Preventive Treatment

Efforts at preventing disease in HSCT recipients have yielded demonstrable
benefits in improving patient outcomes. The ability of prophylaxis or preemptive
treatment to reduce morbidity and mortality has perhaps best been documented in
the case of cytomegalovirus disease, but use of antifungal prophylaxis also
appears 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, debate
continues regarding optimal dose and duration of drug administration, and no
antimold prophylactic treatment has as yet been demonstrated to be effective.
Further, although it has been demonstrated that empiric treatment of febrile
neutropenia is an important component of prevention, it is also clear that fever
is not a sensitive indicator of fungal infection. Better diagnostic methods are
needed to improve prevention efforts.

Fluconazole

Fluconazole has been shown to be effective in preventing candidiasis after
HSCT.[8-9] However, review of major randomized studies indicates that host
characteristics affect outcome in an important manner. In a study by Goodman et
al,[9] placebo was compared with fluconazole (400 mg daily) until engraftment in
a population in which 52% of patients were allograft recipients. Fluconazole was
associated with significant reductions in Candida infections and candidiasis-related
mortality, but no reduction in overall mortality was observed.

In a subsequent single-center study by Slavin et al[10] placebo was compared
with fluconazole (400 mg daily) for 75 days after transplantation in a
population that was at higher risk (88% of patients were allograft recipients).
Administration of study drug was associated with significant reductions in
fungal infections, infection-related mortality, and overall mortality. The
findings of this latter study have engendered debate, since the overall
mortality benefit could not be statistically explained by the decrease in
infection-related mortality. Importantly, this analysis defined fungal
infections as those caused by both Candida and Aspergillus species, the latter
of which fluconazole has no activity against.

We have subsequently performed an analysis of 8-year survival in this patient
population, finding that fluconazole was associated with significant long-term
survival benefit in allograft recipients (17% reduction; P = .0018), and the
benefit is associated with prevention of candidiasis and related mortality.[8]
These findings emphasize both that fluconazole is effective prophylaxis for
candidiasis and that preventive efforts and treatment trials must distinguish
between patient types and types of fungal infection.

Rates and distribution of Candida infections in HSCT patients at Fred
Hutchinson Cancer Research Center (FHCRC) prior to (1980 to 1986) and after
(1994 to 1997) the introduction of fluconazole prophylaxis are shown in Figure
2
.

The use of fluconazole prophylaxis was associated with a decrease in
incidence of candidiasis from > 10% to 4.6% during these periods. As can be
seen, the frequency of C albicans infection has been dramatically reduced,
whereas there has been some emergence of infection due to C glabrata and
C
krusei.
[1] Importantly, the increase in C parapsilosis infection is associated
with an outbreak of infected intravenous infusate during 1994, not with the use
of fluconazole. Concomitant with the dramatic decrease in candidiasis,
aspergillosis has become the predominant infection over the past decade. The
1-year cumulative incidence of disease has steadily increased at FHCRC since
1993, with current rates exceeding 10% in allograft recipients (data not
published).

As noted, the optimal dosage of fluconazole (400 vs 200 mg) necessary for
prophylaxis has not been defined. However, no dose studies are likely to be
performed in this setting, due to the warranted focus on investigation of
treatments to address aspergillosis in HSCT patients. A number of studies of
aspergillosis prophylaxis have been performed; however, these studies have
involved patient populations that have an underlying low incidence of
aspergillosis, weakening statistical analyses with inadequate sample sizes.

Amphotericin B

In a study of twice-daily aerosolized amphotericin B vs a standard
amphotericin B regimen in a patient population including low-risk leukemic
patients,[11] no significant difference in rates of aspergillosis were observed
(4% vs 7%) and rates of amphotericin B toxicity were high.

Itraconazole

In a study of itraconazole vs placebo in 405 neutropenic patients,[12]
itraconazole was associated with a lower rate of candidiasis, but equivalent
rates of aspergillosis. In a study of itraconazole vs fluconazole in 445
neutropenic patients,[13] itraconazole was associated with lower rates of both
candidiasis and aspergillosis. However, the small number of proven aspergillosis
cases in each of these studies impairs our ability to evaluate efficacy of
prevention.

Randomized trials evaluating prophylaxis with both itraconazole and
posaconazole in higher-risk HSCT patients are ongoing. In addition, a study of
the echinocandin FK463 in allogeneic and autologous HSCT patients has been
initiated.

Lipid Amphotericin B

Comparative trials in febrile neutropenia have included a study of liposomal
amphotericin B (AmBisome) vs conventional amphotericin B in 338 patients[14] in
which the liposomal formulation (1 and 3 mg/kg) was associated with a reduced
incidence of nephrotoxicity (10% to 12% vs 24%, respectively). In another
comparison of liposomal with conventional amphotericin B,[5] liposomal
amphotericin B was found to be associated with reduced toxicity and a decrease
in breakthrough infections. However, the observation that most breakthrough
infections were caused by azole-susceptible species (C albicans or C tropicalis)
raises a concern about whether the difference in breakthrough rates is
associated with differences in type and effectiveness of antifungal prophylaxis
between the two arms.

In a study comparing AmBisome at 3 and 5 mg/kg with the amphotericin B lipid
complex Abelcet, AmBisome at 5 mg/kg was associated with decreased rates of
infusion-related toxicity and nephrotoxicity. [15]

Ongoing studies include a comparison of liposomal amphotericin B and
voriconazole and a comparison of liposomal amphotericin B and the echinocandin
caspofungin. Although decreased toxicities associated with the lipid products
have led to increasing use over conventional amphotericin B, it must be realized
that one potential shortcoming of the studies performed to date is that overall
efficacy is difficult to assess with only a short (1 to 2 week) duration of
follow-up.

Fewer randomized trials have been performed to evaluate treatment of
confirmed infection. The results of one study, which evaluated outcome of
suspected and proven infections in patients who were randomized to receive
either liposomal amphotericin B (5 mg/kg) or conventional amphotericin B (1.0
mg/kg/d), suggest that efficacy of treatment might be greater with the
lipid-based product.[16] These studies generally have shown a decrease in
toxicity with liposomal products, but efficacy continues to be debated; it is
important to note that interpretation of efficacy outcomes in these treatment
trials is also made difficult by inclusion of mixed patient populations. One
ongoing trial is comparing conventional amphotericin B and voriconazole in HSCT
patients, and more are needed.

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