Combination treatment of liposomal amphotericin B and isavuconazole is synergistic in treating experimental mucormycosis

Abstract

Objectives Liposomal amphotericin B (L-AMB) and isavuconazonium sulphate are commonly used antifungal drugs to treat mucormycosis. However, the efficacy of combination therapy of L-AMB/isavuconazonium sulphate versus monotherapy is unknown. We used an immunosuppressed mouse model of pulmonary mucormycosis to compare the efficacy of L-AMB/isavuconazonium sulphate versus either drug alone. Methods Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with L-AMB, isavuconazonium sulphate, or a combination of both started 8 h post-infection and continued through to Day +4. Placebo mice received vehicle control. Survival to Day +21 and tissue fungal burden (by conidial equivalent using quantitative PCR) on Day +4, served as primary and secondary endpoints, respectively. Results For mice infected with R. delemar, L-AMB and isavuconazonium sulphate equally prolonged median survival time and enhanced survival versus placebo (an overall survival of 50% for either drug alone, versus 5% for placebo). Importantly, combination treatment resulted in an overall survival of 80%. Both antifungal drugs reduced tissue fungal burden of lungs and brain by ∼1.0–2.0 log versus placebo-treated mice. Treatment with combination therapy resulted in 2.0–3.5 log reduction in fungal burden of either organ versus placebo and 1.0 log reduction versus either drug alone. Similar treatment outcomes were obtained using mice infected with M. circinelloides. Conclusions The L-AMB/isavuconazonium sulphate combination demonstrated greater activity versus monotherapy in immunosuppressed mice infected with either of the two most common causes of mucormycosis. These studies warrant further investigation of L-AMB/isavuconazonium sulphate combination therapy as an optimal therapy of human mucormycosis.

Successful treatment of rhino-cerebral mucormycosis with dual antifungal therapy and minimal surgical debridement

“…Of note, isavuconazole has good central nervous system penetration [31] . A study by Gebremariam et al, 2021 found combination therapy of liposomal amphotericin B and isavuconazole, the dual antifungal treatment used in this report, had greater reduction in fungal burden of mucormycosis compared to monotherapy [49] . The patient presented here was able to tolerate dual-antifungal treatment and could not undergo surgical debridement.…”

Rhino-Orbital Cerebral Mucormycosis in a Patient With Diabetic Ketoacidosis: A Case Report and Literature Review

“…Azoles like isavuconazole and posaconazole oral suspensions are also used in first-line treatment, while terbinafine and echinocandins are not effective against mucormycosis ( 4 ). Ibrahim et al demonstrated the superiority of L-AMB/isavuconazonium sulfate combination over either drug alone in treating murine mucormycosis, however, whether this finding could be transformed into humans warrants further investigation ( 39 ).…”

Combination therapy in Mucormycosis: Current evidence from the world literature, a mini review

“…Furthermore, the combination is at least expected to reduce the therapeutic doses so that adverse events can be minimized. Some recent animal models have described the synergistic role of triazoles and polyenes [ 36 , 37 ]. The first murine model that described a better survival rate with low dose AMB (0.3 mg/kg/day) and posaconazole combination compared to monotherapy in immunosuppressed mice with disseminated disease.…”