## Abstract

Purpose Invasive fungal infection (IFI) is one of the leading causes of mortality and morbidity in neutropenic patients with hematological malignancies (HM). Randomized studies and followed by metanalysis suggest the prophylactic effects of antifungal agents for chemotherapy-induced neutropenia. The purpose of this study is to estimate the medical costs on each antifungal agent for prophylaxis of antifungal infection in neutropenic patients in Japan.

Method PubMed was searched for articles, which reported antifungal prophylaxis in neutropenic patients with HM, published after 1999, using 3 keywords; ’prophylaxis ’, ’hematological malignancy’ and ’fungal infection’. Fifteen articles that met the criteria were selected;

1. randomized controlled trial,

2. more than 100 cases overall,

3. prospective study, and

4. single agent used in each study arm.

Antifungal agents were limited to the 4 drugs; fluconazole (FLCZ) capsules or tablets, itraconazole (ITCZ) capsules or oral solution, micafungin (MCFG), and liposomal amphotericin B (L-AMB). We assumed 3-week-prophylaxis after chemotherapy and 2-week-target therapy for the occurrence of the breakthrough infection, and designed the decision tree models in which a breakthrough fungal infection occurred in certain incidence of proven and probable IFI. The incidences of IFI from the 15 studies were applied to our model. MCFG, voriconazole (VRCZ) and L-AMB were applied as target therapies to the assumed Candida spp., Aspergillus spp., and other fungal infections, respectively. An average expected cost for prophylaxis on each antifungal agent was calculated and compared. Sensitive analysis was performed for the parameter of the incidence of breakthrough IFI.

Results In each prophylaxis agent, the collected study population was 1061 cases in FLCZ, 1510 in ITCZ, 425 in MCFG, and 219 in L-AMB. The incidence of proven and probable IFI was 4.3% (46/1061) in FLCZ, 2.7% (41/1510) in ITCZ, 1.6% (7/425) in MCFG, and 3.7% (8/219) in L-AMB. Causative fungi were revealed in table 1 below. The mean duration to the breakthrough fungal infection was 20 days (95CI, 13–26) after chemotherapy. The average expected cost for prophylaxis in each drug was $1,098 for FLCZ,$532 for ITCZ, $1,313 for MCFG, and$2297 for L-AMB.

Conclusion In our review, the prophylactic failure seems be comparable in the 4 antifungal agents. However, cost-effectiveness was the superior in the prophylaxis by ITCZ than the other agents in neutropenic patients with HM in Japan.

The incidence of proven and probable IFI and its causes.

Agents for prophylaxisProven and probable IFIProphylactic success (%) (95% CI)Candida spp. (%)Aspergillus spp. (%)Other fungus (%)
Number of the causative fungus is indicated as the proportion among prophylactic failure cases.
FLCZ 4.3% (46/1061) 95.7 (94.3–96.7) 23.7 63.2 13.2
ITCZ 2.7% (41/1510) 97.3 (96.3–98.0) 23.5 58.8 17.6
MCFG 1.6% (7/425) 98.4 (96.6–99.2) 57.1 14.3 28.6
L-AMB 3.7% (8/219) 96.3 (93.0–98.1) 75.0 25.0 0.0
Agents for prophylaxisProven and probable IFIProphylactic success (%) (95% CI)Candida spp. (%)Aspergillus spp. (%)Other fungus (%)
Number of the causative fungus is indicated as the proportion among prophylactic failure cases.
FLCZ 4.3% (46/1061) 95.7 (94.3–96.7) 23.7 63.2 13.2
ITCZ 2.7% (41/1510) 97.3 (96.3–98.0) 23.5 58.8 17.6
MCFG 1.6% (7/425) 98.4 (96.6–99.2) 57.1 14.3 28.6
L-AMB 3.7% (8/219) 96.3 (93.0–98.1) 75.0 25.0 0.0

## Author notes

Disclosure: No relevant conflicts of interest to declare.