Antifungal prophylaxis: Whom, what and when

Professor Yee-Chun Chen
Professor of Medicine
National Taiwan University Hospital and College of Medicine; and
Investigator, National Institute of Infectious Diseases and Vaccinology
National Health Research Institutes
Taiwan

Invasive fungal disease causes substantial morbidity and mortality, largely due to difficulty in obtaining a timely diagnosis that has been attributed to limitations of available diagnostic tests. This further causes delays in treatment initiation, suboptimal response to treatment and the use of substantial resources. These factors form the rationale for antifungal prophylaxis administration. However, debates regarding the universal systemic primary prophylaxis remain due to resistance, toxicity and cost considerations.

Cost-effectiveness

Primary prophylaxis has been proven to be cost-effective in selected high-risk patients with hematologic malignancies. A network meta-analysis and pharmacoeconomic analysis of 21 randomized controlled trials evaluating triazole prophylaxis showed that, overall, posaconazole was superior in reducing invasive fungal infection (IFI) and all-cause deaths among patients receiving chemotherapy for acute myelogenous leukemia (AML) and was considered cost-effective.¹ Itraconazole solution, on the other hand, was least costly, particularly as prophylaxis in the AML cohort; however, this needs to be weighed against the efficacy and tolerability of the agent.

The right patient and right prophylaxis

Prophylactic strategy should be individualized based on risk-benefit assessment at each hospital, or, even for each patient, after considering factors such as, epidemiology, diagnostic tools, therapeutics and cost-effectiveness. Neutropenia remains the most important risk factor for IFI,² while others include underlying conditions such as graft-versus-host disease and progressive cancer, immunogenetic factors and environmental factors.

The selection of a prophylactic agent should be based on knowledge of the host, the antifungal agents and the strategies available (Table).³ Consideration should be given to the efficacy, bioavailability, toxicity, drug-drug interaction, compliance and cost.

Table. Selection of primary antifungal prophylaxis

Diagnosis or status of the hosts	Primary	Alternative	Comments
AML and MDS patients receiving induction chemotherapy	Nystatin (S/L)	Posaconazole (S/H) Itraconazole (W/H) Fluconazole 50–400 mg (W/H) AmB-d (W/H)	Clinical trials for fluconazole showed various results.
Allogeneic HSCT, initial neutropenic phase	Nystatin (S/L) Fluconazole 400 mg IV or po (S/H) Micafungin 50 mg (W/H)	Voriconazole 200 mg (4 mg/kg) bid po (W/H) Itraconazole (W/H) AmB-d (W/H)
Allogeneic HSCT, GVHD phase	Nystatin (S/L) Posaconazole (S/H) Voriconazole (S/H)	Itraconazole (W/H) Fluconazole (W/H) AmB-d (W/H)	Prophylactic use of anti-mold agents is recommended in patients with severe GVHD under treatment with high-dose steroid or equivalent immunosuppressants.

AmB-d, amphotericin B deoxycholate; AML, acute myeloid leukemia; bid, twice a day; IV, intravenous; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome; po, orally

Grading: S/H, strong recommendation, high-quality evidence; S/L, strong recommendation, low-quality evidence; W/H, weak recommendation, high-quality evidence

Highlights of the Medical Mycology Training Network Conference.

References

Zhao YJ, et al. Antimicrob Agents Chemother 2015;60:376-386.
Gerson SL, et al. Ann Intern Med 1984;100:345-351.
Ko BS, et al. J Microbiol Immunol Infect 2018;51:287-301.