Empiric Antifungal Therapy for the Neutropenic Patient

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.[1]

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%.[9] 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.

Antifungal Prophylaxis

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.[10]

Furthermore, the University of Washington detected a long-termsurvival advantage in allogeneic BMT recipients who received fluconazole(Diflucan) prophylaxis.[11] 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.[12] In one study, 53% ofparticipants discontinued itraconazole because of gastrointestinal sideeffects.[13] At this point, fluconazole remains the preferred agent forprophylaxis.

Resistant Strains

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.[16] Increased gastrointestinal colonization with theseresistant species can occur during triazole prophylaxis.[17]

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.

Evidence-Based Approach

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.

References:

1. Prentice HG, Kibbler CC, Prentice AG: Towards a targeted,risk-based, antifungal strategy in neutropenic patients. Br J Haematol110:273-284, 2000.

2. Chryssanthou E, Klingspor L, Tollemar J, et al: PCR and othernon-culture methods for diagnosis of invasive Candida infections in allogeneicbone marrow and solid organ transplant recipients. Mycoses 42:239-247, 1999.

3. Denning DW, Evans EG, Kibbler CC, et al: Guidelines for theinvestigation of invasive fungal infections in haematological malignancy andsolid organ transplantation. British Society of Medical Mycology. Eur J ClinMicrobiol Infect Dis 16:424-436, 1997.

4. Goodrich JM, Reed EC, Mori M, et al: Clinical features andanalysis of risk factors for invasive candidal infection after marrowtransplantation. J Infect Dis 164:731-740, 1991.

5. Jantunen E, Ruutu P, Niskanen L, et al: Incidence and riskfactors for invasive fungal infections in allogeneic BMT patients. Bone MarrowTransplant 19:801-808, 1997.

6. Klingspor L, Stintzing G, Fasth A, et al: Deep Candidainfection in children receiving allogeneic bone marrow transplants: Incidence,risk factors, and diagnosis. Bone Marrow Transplant 17:1043-1049, 1996.

7. Rossetti F, Brawner DL, Bowden R, et al: Fungal liverinfection in marrow transplant recipients: Prevalence at autopsy, predisposingfactors, and clinical features. Clin Infect Dis 20:801-811, 1995.

8. Sparrelid E, Hagglund H Remberger M, et al: Bacteraemiaduring the aplastic phase after allogeneic bone marrow transplantation isassociated with early death from invasive fungal infection. Bone MarrowTransplant 22:795-800, 1998.

9. Barnes AJ, Oppenheim BA, Chang J, et al: Early investigationand initiation of therapy for invasive pulmonary aspergillosis in leukaemic andbone marrow transplant patients. Mycoses 42:403-408, 1999.

10. Besnard M, Hartmann O, Valteau-Couanet D, et al: SystemicCandida infection in pediatric bone marrow autotransplantation: Clinical signs,outcome, and prognosis. Bone Marrow Transplant 11:465-470, 1993.

11. Marr KA, Seidel K, Slavin MA, et al: Prolonged fluconazoleprophylaxis is associated with persistent protection against candidiasis-relateddeath in allogeneic marrow transplant recipients: Long-term follow-up of arandomized, placebo-controlled trial. Blood 96:2055-2061, 2000.

12. Huijgens PC, Simoons-Smit AM, van Loenen AC, et al:Fluconazole vs itranconazole for the prevention of fungal infections inhaemato-oncology. J Clin Pathol 52:376-380, 1999.

13. Foot AB, Veys PA, Gibson BE: Itraconazole oral solution asantifungal prophylaxis in children undergoing stem cell transplantation orintensive chemotherapy for haematological disorders. Bone Marrow Transplant24:1089-1093, 1999.

14. Marr KA, White TC, van Burik JA, et al: Development offluconazole resistance in Candida albicans causing disseminated infection in apatient undergoing marrow transplantation. Clin Infect Dis 25:908-910, 1997.

15. Nolte FS, Parkinson T, Falconer DJ, et al: Isolation andcharacterization of fluconazole- and amphotericin B-resistant Candida albicansfrom blood of two patients with leukemia. Antimicrob Agents Chemother41:196-209, 1997.

16. Meis JF, Ruhnke M, de Pauw BE, et al: Candida dubliniensiscandidemia in patients with chemotherapy-induced neutropenia and bone marrowtransplantation. Emerg Infect Dis 5:150-153, 1999.

17. Hoppe JE, Klausner M, Klingebiel T, et al: Retrospectiveanalysis of yeast colonization and infections in paediatric bone marrowtransplant recipients. Mycoses 402:47-54, 1997.

18. Van Burik JH, Leisenring W, Myerson D, et al: The effect ofprophylactic fluconazole on the clinical spectrum of fungal diseases in bonemarrow transplant recipients with special attention to hepatic candidiasis. Anautopsy study of 355 patients. Medicine-Baltimore 77:246-254, 1998.

19. Krcmery V, Krupova I, Denning DW: Invasive yeast infectionsother than Candida spp in acute leukemia. J Hosp Infect 41:181-194, 1999.