Gonzalez, A.V., Ullmann, A.J., Almyroudis, N.G., & Segal, B.H. (2008). Broad-spectrum antifungal prophylaxis in patients with cancer at high risk for invasive mold infections: point. Journal of the National Comprehensive Cancer Network, 6, 175–182.

To determine if there is sufficient evidence that pre-emptive antifungal treatment is as effective as antifungal prophylaxis with posaconazole. The patient populations addressed included patients with acute myelogenous leukemia or myelodysplastic syndrome with prolonged chemotherapy-induced neutropenia and allogeneic hematopoietic stem cell transplantation (HSCT) recipients with significant graft-versus-host disease.

Prophylactic antifungal therapy is defined as the initiation of an antifungal agent to high-risk patients to prevent a fungal infection. Pre-emptive antifungal therapy is defined as the initiation of antifungal therapy in high-risk patients based on laboratory markers, radiologic monitoring, or both to identify early ​invasive fungal infections (IFIs) before clinically overt disease develops. The authors based their evaluation on the principle that prophylaxis of fungal infections is important due to the significant morbidity and mortality associated with fungal infections, the incidence in high-risk patients, the safety of available antifungal agents, and the lack of sensitive methods of early detection. A pre-emptive approach is limited by the sensitivity and specificity of available detection methods. The authors reviewed the current literature on posaconazole prophylaxis and pre-emptive antifungal therapy.

No databases used for a search were listed, nor were any inclusion or exclusion criteria mentioned. However, keywords searched were invasive fungal infection, prophylaxis, pre-emptive therapy, and aspergillosis.

One prospective, randomized trial compared posaconazole with fluconazole or itraconazole as a primary antifungal prophylaxis in patients with acute myelogenous leukemia or myelodysplastic syndrome with prolonged chemotherapy-induced neutropenia. Proven or probable IFIs occurred in seven (2%) patients in the posaconazole group and 25 (8%) patients in the fluconazole or itraconazole group (p < 0.001). Significantly fewer patients in the posaconazole group had invasive aspergillosis. Survival was improved in posaconazole recipients (p = 0.04). Serious adverse events possibly related to treatment occurred in 6% of patients in the posaconazole group and in 2% in the fluconazole or itraconazole group (p = 0.01).

One prospective, randomized trial compared primary antifungal prophylaxis with posaconazole versus fluconazole in allogeneic HSCT recipients with significant graft-versus-host disease on immunosuppression. Posaconazole was at least as effective as fluconazole in preventing IFIs during the prespecified period of observation (incidence, 5.3% versus 9%, respectively; p = 0.07) but was superior in preventing invasive aspergillosis and deaths caused by IFIs. If the analysis was restricted to the period in which patients received the study drug, posaconazole was considered superior to fluconazole in preventing IFIs (incidence, 2.4% versus 7.6%; p = 0.004), particularly invasive aspergillosis (incidence, 1% versus 5.9%; p = 0.001). Treatment-related adverse events were similar between the groups. One peer-reviewed publication reported pre-emptive antifungal therapy. The study was a feasibility study in which a total of 136 treatment episodes for patients with neutropenia at high risk for IFI were screened with daily serum galactomannan testing. There was a diagnostic algorithm that included chest computed tomography (CT) scans and bronchoalveolar lavage. Patients who met prespecified criteria for probable or proven invasive fungal infection received pre-emptive therapy with liposomal amphotericin B; neutropenic fever alone did not trigger modification in the antifungal regimen. Although this approach was successful in identifying early invasive aspergillosis and avoiding amphotericin B use in most patients with persistent neutropenic fever of unknown origin, invasive aspergillosis developed in 17 patients and zygomycosis in one patient among 136 chemotherapy treatment episodes. All cases of invasive aspergillosis were identified through positive antigenemia results. Seven (41%) deaths occurred in patients with positive serum galactomannan results; of these, six had autopsy-proven invasive aspergillosis. However, only two patients were considered to have died directly because of invasive aspergillosis.

The authors believe that insufficient evidence exists to recommend a pre-emptive antifungal therapy approach in place of posaconazole prophylaxis in patients with acute myelogenous leukemia or myelodysplastic syndrome with prolonged chemotherapy-induced neutropenia and allogeneic hematopoietic cell transplantation (HCT) recipients with significant graft-versus-host disease.

No conflict of interest was stated.

Posaconazole is recommended as a primary antifungal prophylaxis in patients with acute myelogenous leukemia or myelodysplastic syndrome with prolonged chemotherapy-induced neutropenia and in allogeneic HCT recipients with significant graft-versus-host disease. Pre-emptive treatment is not recommended in these patient populations.