Amphotericin Bin vitroresistance is associated with fatalAspergillus flavusinfection

Abstract

Whether in vitro antifungal susceptibility findings correlate with the outcome of patients with invasive aspergillosis (IA) remains debated. This study aimed to test whether IA patients' outcomes were associated with in vitro susceptibility results. To do so, we determined the in vitro susceptibility to amphotericin B (AMB) of 37 Aspergillus flavus isolates from 14 patients with haematological malignancies diagnosed with proven or probable IA, of which 13 were treated with AMB deoxycholate. Minimal inhibitory concentrations (MICs) were determined by Etest with the isolates classified as in vitro sensitive (AMB-S) or resistant (AMB-R) if their MICs were < 2 or ≥ 2 mg/l, respectively. The association of the patients' death with primary disease, administered antifungal treatment, and infection with AMB-R A. flavus was tested using generalized estimating equations logistic regression. We assessed AMB-R in 31/37 (84%) isolates. In the patients treated with AMB, the survival rate was 2/3 (67%) and 2/9 (22%) for those infected with AMB-S or AMB-R A. flavus, respectively. Both infection with AMB-R A. flavus (P = 0.014) strain and acute myelocytic leukaemia as the underlying primary disease (P = 0.036) were independent predictors of death. Our findings indicate that in vitro resistance predicts a poor outcome in patients with A. flavus invasive disease treated with AMB. Recent advances in non-culture-based microbiological methods should not discourage efforts to obtain in vitro antifungal susceptibility results, which are critical for the choice of antifungal therapy in patients with IA.

Susceptibility Breakpoints for Amphotericin B and Aspergillus Species in an In Vitro Pharmacokinetic-Pharmacodynamic Model Simulating Free-Drug Concentrations in Human Serum

“…Furthermore, in a review paper of 60 clinical cases of invasive A. terreus infections published from 1966 to 2003, 28 cases were treated with conventional amphotericin B, and the mortality rate was 96% (27/28), which is also in agreement with the 98% of A. terreus isolates estimated in the present study being nonsusceptible (39). Finally, in a cohort study of 11 cases of invasive A. flavus infections treated only with conventional amphotericin B, the mortality rate was 81% (9/11), in agreement with the 90% of A. flavus isolates estimated in the present study being nonsusceptible (16). Interestingly, in the latter study, all patients with A. flavus isolate MICs of Ն1 mg/liter died.…”

“…Therefore, the majority of the isolates would be considered wild-type susceptible based on the 1-mg/liter cutoff, while conventional amphotericin B therapy has been associated with Ͻ60% of survival in all clinical trials (3,4,14). Furthermore, treatment failure was observed in patients infected with A. fumigatus and A. flavus isolates with CLSI MICs of 0.25 to 0.5 mg/liter and 1 mg/liter, respectively, when treated with the standard dose of 1 mg/kg of conventional amphotericin B (15,16). Thus, a clinically relevant and useful susceptibility breakpoint for amphotericin B and Aspergillus spp.…”

Phase II Study on Voriconazole for Treatment of Chinese Patients with Malignant Hematological Disorders and Invasive Aspergillosis

“…Commonly recommended medications for aspergillosis include itraconazole, amphotericin B, caspofungin and voriconazole,etc, and the efficiency various in different reports (Wingard et al, 2011;Egerer et al, 2012;Hadrich et al, 2012;Yuan et al, 2012). Voriconazole is a second-generation synthetic triazole antifungal drug, a derivatives of fluconazole.…”

Aspergillus Collagen-Like Genes ( acl ): Identification, Sequence Polymorphism, and Assessment for PCR-Based Pathogen Detection

“…Although the assay is capable of detecting 15 different Aspergillus spp. according to the manufacturer product insert, it does not discriminate between the species, which can be a crucial determinant for selection of appropriate antifungal treatment (62)(63)(64)(65)(66). A similar ITS1-based qPCR assay for detection of the four medically most important Aspergillus species, i.e., A. fumigatus, A. flavus, A. niger, and A. terreus, has been successfully developed and tested in the United States (67).…”