Dr. Thomas Walsh from the National Cancer Institute gave a keynote address entitled
“Preventative Aspects of Antifungal Therapy—Making Sense of
Presumptive vs Preemptive vs Prophylactic vs Maintenance Strategies.” He
stressed that clinical interventions physicians use to manage patients at risk
of developing invasive fungal infections (IFI) have a solid foundation in
pre-clinical science. This gives clinicians confidence when they intervene with
particular treatment strategies. Subsequent clinical investigations have made
it possible to identify patients at high risk for developing IFI so that
physicians can administer antifungal therapy earlier. Dr. Walsh identified a
number of patient groups likely to benefit from early treatment: cancer and BMT
patients, HIV/AIDS, SOT, ICU and surgical patients, along with low-birth-weight
infants, individuals with inherited immunodeficiencies, and even patients with
metabolic disorders such as diabetes. He chose to focus his presentation on
cancer and BMT patients and outlined 3 strategies that are currently being used
to reduce the incidence of IFIs during neutropenia in these patient
populations. These strategies—prophylaxis, empirical therapy, and
preemptive therapy—have been shown to improve outcomes in both pre-clinical
and clinical studies.
Prophylactic therapy : The initiation of antifungal therapy at or near the time of the
beginning of antineoplastic therapy, or prior to the stem cell transplantation
preparative regimen.
Empirical therapy : A risk-based intervention for patients with persistent fever and
neutropenia despite broad-spectrum antibiotics.
Preemptive therapy : Similar to empirical therapy;
a risk-based intervention for patients with persistent fever and neutropenia
despite broad-spectrum antibiotics, with additional evidence of the presence of
a fungal infection.
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Dr. Walsh defined prophylaxis as the initiation of antifungal therapy at or near the time
of beginning anti-neoplastic therapy or prior to the stem cell transplantation
preparative regimen. Prophylactic treatment may be continued beyond the period
of neutropenia and through the high-risk period of post-engraftment. To
illustrate the importance of pre-clinical science as a foundation for
prophylactic strategies, Dr. Walsh reviewed several studies of disseminated
candidiasis in animals. For example, the efficacy of fluconazole in the
prevention of invasive candidiasis in high-risk neutropenic patients was
predicted in animal models. In vitro experiments with the echinocandins have
shown that they are active against both
Candida albicans and non-
albicans species, including
Aspergillus species. These results have
guided the clinical trial development of this new class of drugs, such as the
randomized, multicenter trial (MSG-46) of micafungin versus fluconazole in the
treatment of IFI in BMT patients. Dr. Walsh summarized the results of this
trial by saying, “We found the activity [of micafungin] was similar to
fluconazole in prevention of invasive candidiasis. We also found that there was
a trend towards a greater reduction of invasive aspergillosis; it was not
statistically significant, but the trend was nonetheless there.” There
was also a significant reduction in the use of empirical antifungal therapy.
Empirical therapy was defined by Dr. Walsh as a risk-based intervention for patients with
persistent fever and neutropenia despite broad-spectrum antibiotics, typically
patients with acute leukemia, or those receiving intensive myeloablative
therapy or an aggressive autologous transplant. Empirical therapy has two
goals: early treatment of occult IFI, and the prevention of subsequent
breakthrough fungal infections in high-risk patients. Randomized studies
conducted in the 1980s demonstrated that amphotericin B reduced the incidence
of breakthrough fungal infections in neutropenic patients with continued fever
treated with antibiotic therapy, and provided the necessary evidence to make
empirical therapy the standard of care in these patients.
Reporting on the recently published voriconazole vs liposomal amphotericin B trial,
1
Dr. Walsh emphasized once again that the clinical development of voriconazole
was based on a strong foundation in pre-clinical science. For example, the
activity of voriconazole against various fungal pathogens was consistent with
pre-clinical data in this trial; voriconazole showed activity against
Aspergillus and
Candida, but not against the Zygomycetes.
Preemptive therapy was defined as a form of empirical therapy with additional evidence of
the presence of a fungal infection such as a positive surveillance culture, a
sinusoid calcification, a pulmonary infiltrate, or a positive galactomannan
antigen.
Dr. Walsh concluded by stating that, in the future, the introduction of the
second-generation triazoles and the echinocandins into clinical trials will
challenge the current strategies for preventing IFI in high-risk patients. He
hopes that rigorous clinical trials will be conducted to test the hypotheses
that are being generated in pre-clinical studies.
References:
1. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with
liposomal amphotericin B for empirical antifungal therapy in patients with
neutropenia and persistent fever. N Engl J Med 2002;346(4):225–34
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