Among the most significant complications a neutropenic patient can experience is an invasive fungal infection. In this issue of Oncology, Drs. Wingard and Leather thoroughly review the epidemiology, clinical presentation, and empiric treatment of these infections, particularly those associated with Candida and Aspergillus. They emphasize the need for better methods of identifying individuals at high-risk for invasive fungal infections because those individuals are more likely to benefit from antifungal prophylaxis or empiric therapy. The goal of such a targeted approach is to limit the amount of antifungal agents given, thereby decreasing the number of adverse effects and diminishing the selection of antifungal-resistant species.
Among the most significant complications a neutropenic patientcan experience is an invasive fungal infection. In this issue of Oncology, Drs.Wingard and Leather thoroughly review the epidemiology, clinical presentation,and empiric treatment of these infections, particularly those associated with Candida and Aspergillus. They emphasize the need for better methods ofidentifying individuals at high-risk for invasive fungal infections becausethose individuals are more likely to benefit from antifungal prophylaxis orempiric therapy. The goal of such a targeted approach is to limit the amount ofantifungal agents given, thereby decreasing the number of adverse effects anddiminishingthe selection of antifungal-resistant species.
Early Diagnosis Imperative
For empiric therapy to be most effective, invasive fungalinfections must be diagnosed early. Unfortunately, only half of patients withdisseminated Candida infections have positive blood cultures. Moreover,surrogate laboratory markers for Candida and Aspergillus are eitherinvestigational or have limited predictive value; newer molecular-basedtechniques may be more applicable.[2,3] Consequently, recognizing the variousrisk factors listed in Table 4 of the Wingard and Leather article is essential.
Beyond those listed, there are several risk factors for invasivefungal infections unique to bone marrow transplant (BMT) recipients. Theseinclude allogeneic transplantation with donor mismatch, grade III and grade IVacute graft-vs-host disease, extensive chronic graft-vs-host disease, a donorseropositive for herpes simplex virus, veno-occlusive disease of the liver,recipient age greater than 40 years, and bacteremia during the aplastic phase ofBMT.[4-8] However, beyond the level and duration of neutropenia, the particularcontribution of any of these factors on the risk of invasive fungal infectionsis unclear.
A study from England recently showed the value of a targetedapproach. They used bronchoalveolar lavage and high-resolution computedtomography scanning of the thorax to establish an early diagnosis of invasivepulmonary aspergillosis in patients with acute leukemia (a group at high-riskfor invasive fungal infections). The overall incidence of proven or probableaspergillosis was 9%. By treating the suspected patients with a liposomalamphotericin B product, they increased the survival of infected patients fromunder 15% to 84%. By combining risk factor assessment with diagnostictechniques in a high-risk population, the investigators were also able todecrease mortality. Nevertheless, this approach may not be as valuable for otherneutropenic populations or for other types of fungal infections. Therein liesthe complexity of empiric antifungal therapy.
While we await advancements in the diagnosis of fungalinfections, there remains a role for antifungal prophylaxis. In the era beforeantifungal prophylaxis was used, 11.4% of BMT recipients developed Candidainfections within 3 months after transplant. Currently, that incidence isless than 4% when antifungal prophylaxis is used.
Furthermore, the University of Washington detected a long-termsurvival advantage in allogeneic BMT recipients who received fluconazole(Diflucan) prophylaxis. Patients who received prophylaxis had an 8-yearsurvival of 45%, whereas those who did not receive prophylaxis had a survival of28%. The authors postulated that this may "be associated with decreased gutgraft-vs-host disease, a persistent protection against disseminated candidalinfections and candidiasis-related death, resulting in an overall survivalbenefit in allogeneic BMT recipients."
Whether this prolonged benefit exists for other groups ofpatients, or even at other centers, remains to be determined. Nevertheless, therole of prophylaxis in allogeneic BMT recipients seems compelling. The onlyother triazole extensively studied for prophylaxis itraconazole (Sporanox).Although effective, it is not well tolerated. In one study, 53% ofparticipants discontinued itraconazole because of gastrointestinal sideeffects. At this point, fluconazole remains the preferred agent forprophylaxis.
Despite the efficacy of such therapy, fluconazole-resistantnon-Calbicans species have been problematic for oncology centers employing triazoleprophylaxis throughout the 1990s. A disturbing increase in infections withfluconazole-resistant C albicans is now at hand.[14,15] Furthermore, neutropenicpatients are faced with a new opportunistic, resistant species, C dubliniensis. Increased gastrointestinal colonization with theseresistant species can occur during triazole prophylaxis.
Another concern is the observation that triazole prophylaxis mayincrease the risk of infection with other fungi, such as Malassezia,Trichosporon, Blastoschizomyces, Rhodotorula, Saccharomyces, Clavispora,Hansenula, and Aspergillus.[18,19] Drs. Wingard and Leather downplay thiseffect, and given the infrequent occurrence of these superinfections, theysuggest that empiric antifungal therapy be delayed in a febrile patient onprophylaxis without upper respiratory tract symptoms.
A more conservative approach might also require unremarkabledermatologic and neurologic examinations and chest radiography, in light of thefrequent dissemination of fungi in the neutropenic patient.
The crux of the Wingard and Leather article is found in Table6.Distilled in this one table is a practical, mostly evidence-based approach toempiric antifungal therapy. By taking into account various factors such as thetype of chemotherapy, the use of antifungal prophylaxis, and the presence ofupper respiratory tract symptoms, a clinician can assess the risk for aninvasive fungal infection and decide whether empiric antifungal therapy iswarranted. It lacks a scoring or weighting system, but it does identify theknown risk factors in the neutropenic patient.
The management recommendations in the right column, whilereasonable, are broad guidelines that should be amended based on each center’sunique practice, patient mix, and epidemiology. Currently, antifungal choicesare limited to the triazoles and the various preparations of amphotericin B, soonce the decision to treat a suspected fungal infection is made, the choice ofan antifungal agent is fairly straightforward. However, with the imminentavailability of newer classes of antifungals, treatment options may need to bemodified for the various pathogens, disease states, and risk factors. Frankly,this increased complexity will be most welcome.
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