Cornely, O.A., Böhme, A., Buchheidt, D., Einsele, H., Heinz, W.J., Karthaus, M., . . . Ullmann, A.J. (2009). Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Haematologica, 94, 113–122.

The purpose of this article was to study the primary prophylaxis of invasive fungal infections (IFI) in patients with hematologic malignancies. Eighty-six trials were reviewed, with a total patient population of 16,922.

In order to compile this resource, data were extracted and a draft manuscript was written by two of the authors and reviewed by a committee of hematologists and infectious disease specialists assigned by the Infectious Diseases Working Party of the German Society for Haematology and Oncology. The consensus draft was secondarily reviewed by the review committee of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. In cases where uniform consensus was not reached, the majority vote was adopted. Treatment recommendations were categorized using the evidence categories of the Infectious Disease Society of America ( IDSA). The categories indicate the strength of evidence and the quality of evidence. 

• A: Good evidence to support  a recommendation for use.
• B: Moderate evidence to support a recommendation for use.
• C: Poor evidence to support a recommendation for use.
• D: Moderate evidence to support a recommendation against use.
• E: Good evidence to support a recommendation against use.

I = evidence from at least one properly randomized, controlled trial; II = evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one center), from multiple time series, or from dramatic results of uncontrolled experiments; III = evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

For the search stragety, the following databases were used: Medline, CancerLit, Embase, Cochrane Library and conference proceedings of Advances Against Aspergillosis, ASH, EBMT, ECCMID, ESMO, Focus on Fungal Infections, and ICAAC/IDSA. Keywords included invasive fungal infection, antifungal prophylaxis, itraconazole, fluconazole, posaconazole, amphotericin B, and liposomal. Inclusion was based on the research being clinical trials on antifungal prophylaxis. Exclusion criteria were trials published as abstracts, only, and meta-analyses.

Active treatment

Fluconazole 400 mg per day was significantly superior to placebo in both the reduction of breakthrough invasive fungal infection and the decrease of IFI attributable mortality; showed a lower incidence of intestinal graft-versus-host disease (GVHD); and is protective against cyclophosphamide toxicity. Doses lower than 400 mg per day failed to show a marked benefit. Also, breakthrough infections are seen with molds and Candida krusei due to their intrinsic resistance to fluconazole. Itraconazole is broader in spectrum than fluconazole, but has a start-up delay; therefore, it is not recommended as a start-up for prophylaxis of invasive fungal infection.

One study found itraconazole suspension at a dose of 2.5 mg/kg bid plus nystatin 500,000 IU qid versus nystatin alone to be a more effective reduction in the rate of fatal candidemia from 2% to 0; however, invasive mold infections and death due to fungal infection were not prevented. Itraconazole was not shown to be more effective than fluconazole in patients with hematologic malignancies and was associated with more adverse outcomes.

At a dose of 600 mg per day, posaconazole resulted in a significant reduction in proven and probable IFIs, mainly by reducing the incidence rate of aspergillosis along with an attributable and overall mortality reduction. Safety, including the overall rate of patients with serious adverse events, was comparable between posaconazole, flucanazole, and itraconazole. The only difference was a higher rate of patients on posaconazole experiencing possibly or probably related serious adverse events than patients on fluconazole or itraconazole prophylaxis. Posaconazole 600 mg per day was associated with decreased mortality associated with GVHD in HCT recipients.

Voriconazole exposure has been associated with a reduction of invasive aspergillosis, but an increase in breakthrough zygomycosis.

Ketoconazole, miconazole, and clotrimazole have not been proven effective.

Amphotericin B, a broad spectrum anti-fungal, does not appear to be significantly effective and is associated with adverse events in all forms (inhalation, deoxycholate infusion, and lipid-based formulations).

Primary prophylaxis with fluconazole 400 mg per day is recommended since it reduces the incidence of invasive candidiasis and mortality after HSCT (AI). The recommended antifungal prophylaxis in patients with neutropenia (ANC < 500 cell/mcl for more than seven days): posaconazole 200 mg PO TID for patients with AML/MDS receiving induction chemotherapy (AI); liposomal amphotericin B 12.5 mg twice a week by inhalation (BII); liposomal amphotericin B 50 mg q 48 hours via IV (CII); itraconazole oral solution 2.5–7.5 mg/kg/d (CI), fluconazole 400 mg per day PO (CI), itraconzole capsules, any dose (CI); caspofungin 50 mg per day IV (CI); conventional amphotericin, any dose IV or 20 mg per day inhalation (EI). 

The recommended antifungal prophylaxis in patients undergoing allogeneic HSCT: fluconazole 400 mg per day PO (until the development of GVHD) (AI); posaconazole 200 mg TID PO (in the setting of GVHD) (AI); itraconazole oral solution 400 mg per day PO (CI); micafungin 50 mg per day IV (CI).

Other recommendations for antifungal prophylaxis: itraconazole, any dose of capsules (CI); voriconazole (CII), fluconazole less than 400 mg per day (EI); ketoconazole, any dose (EII); miconazole, any dose (EII); clotrimazole, any dose (EII); nystatin, any dose (EII).

Fluconazole 400 mg per day is recommended to prevent IFIs in allogeneic stem cell recipients until the development of GVHD. Posaconazole is recommended to prevent IFI in allogeneic stem cell recipients with severe GVHD, and in patients with acute myelogenous leukemia or myelodysplastic syndrome undergoing induction chemotherapy. There is no benefit to the use of  fluconazole in the non-transplantation setting to prevent IFI. Itraconazole, voriconazole, caspofungin, and micafungin are not recommended to prevent IFI since there is limited data. Aerosolized liposomal amphotericin B appears to be effective to reduce the risk of invasive pulmonary aspergillosis in patients with prolonged neutropenia, but it was given with concomitant fluconazole. Conventional amphotericin B is strongly NOT recommended due to toxicity and the availability of other less-toxic effective agents.