Poor in vivo efficacy of caspofungin, micafungin and amphotericin B against wild-type Candida krusei clinical isolates does not correlate with in vitro susceptibility results

Abstract

We determined micafungin, caspofungin and amphotericin B (AMB) minimum inhibitory concentration (MICs) and killing rates in RPMI-1640 and in RPMI-1640 with 50% serum against three Candida krusei bloodstream isolates. MIC ranges in RPMI-1640 were 0.125-0.25, 0.25 and 0.125-0.5 mg/L, in RPMI-1640 with 50% serum, MICs were 64-128-, 8- and 4-16-fold higher, respectively. In RPMI-1640 micafungin and caspofungin at 1, 4, 16 and 32 mg/L as well as AMB at 2 mg/L were fungicidal against all isolates in ≤3.96, ≤4.42 and 14.96 h, respectively. In RPMI-1640 with 50% serum, caspofungin was fungicidal for all isolates only at 32 mg/L, micafungin and AMB were fungistatic. In neutropenic mice, 5 mg/kg caspofungin and 1 mg/kg AMB were ineffective against two of the three isolates. Thus, in vivo efficacy of echinocandins and AMB is weak or absent against C. krusei. Prescribers treating C. krusei infections with echinocandins should watch out for clinical resistance and therapeutic failure.

In Vitro Pharmacokinetic/Pharmacodynamic Modelling and Simulation of Amphotericin B against Candida auris

“…Similar threshold values for amphotericin B have been reported for other species of Candida and filamentous fungi, such as Aspergillus. In a murine model of invasive candidiasis caused by Candida krusei, a daily dose of 1 mg/kg of amphotericin B was effective in reducing the kidney fungal burden when the MIC of the drug was of 0.125 mg/L, but ineffective when MIC was of 0.5 mg/L [42]. In another murine model study, doses of 1.5 mg/kg/day of amphotericin B resulted in a 15-day survival percentage of >50% for Candida glabrata and <25% for Candida tropicalis, the MIC being 1 mg/L for both species [43].…”

In Vitro Susceptibility Tests in the Context of Antifungal Resistance: Beyond Minimum Inhibitory Concentration in Candida spp.

“…Unfortunately, these studies are mainly related to animal models; human studies consist only of case reports and are still seldomly reported. According to the study conducted by Kardos et al [73], in vitro antifungal susceptibility and fungicidal test results did not correlate with survival of mice models of C. krusei systemic infections. In contrast, in a case of human spondylodiskitis, Pemán et al [74] found a correlation between clinical failure and MFC and time-kill curve results.…”