Correlation of MIC with Outcome for Candida Species Tested against Voriconazole: Analysis and Proposal for Interpretive Breakpoints

Abstract

Developing interpretive breakpoints for any given organism-drug combination requires integration of the MIC distribution, pharmacokinetic and pharmacodynamic parameters, and the relationship between the in vitro activity and outcome from both in vivo and clinical studies. Using data generated by standardized broth microdilution and disk diffusion test methods, the Antifungal Susceptibility Subcommittee of the Clinical and Laboratory Standards Institute has now proposed interpretive breakpoints for voriconazole and Candida species. The MIC distribution for voriconazole was determined using a collection of 8,702 clinical isolates. The overall MIC 90 was 0.25 g/ml and 99% of the isolates were inhibited at <1 g/ml of voriconazole. Similar results were obtained for 1,681 Candida isolates (16 species) from the phase III clinical trials. Analysis of the available data for 249 patients from six phase III voriconazole clinical trials demonstrated a statistically significant correlation (P ‫؍‬ 0.021) between MIC and investigator end-of-treatment assessment of outcome. Consistent with parallel pharmacodynamic analyses, these data support the following MIC breakpoints for voriconazole and Candida species: susceptible (S), <1 g/ml; susceptible dose dependent (SDD), 2 g/ml; and resistant (R), >4 g/ml. The corresponding disk test breakpoints are as follows: S, >17 mm; SDD, 14 to 16 mm; and R, <13 mm.

Selection of a Surrogate Agent (Fluconazole or Voriconazole) for Initial Susceptibility Testing of Posaconazole against Candida spp.: Results from a Global Antifungal Surveillance Program

“…Furthermore, we have shown that the availability of posaconazole susceptibility testing results for Candida spp., in any medical center currently performing antifungal susceptibility testing of either fluconazole or voriconazole, can be accomplished by using the fluconazole or voriconazole result as a surrogate marker for posaconazole susceptibility and resistance. Arguably, the most important role of in vitro susceptibility testing is to predict the resistance of the infecting organism to the agent under consideration for use in the patient (32,33,37). The occurrence of false-resistance errors with this application of the "class representative" concept to the available triazoles was very low and was acceptable for surrogate marker testing.…”

“…The facts that both fluconazole and voriconazole are in the same triazole class as posaconazole, have Clinical and Laboratory Standards Institute (CLSI)-approved MIC interpretive breakpoints (32,33), and are available on some commercially available MIC panels (10,19,29,34,38) suggest that one or both of these agents may be useful as a surrogate marker for posaconazole susceptibility.…”

“…MIC interpretive criteria for fluconazole and voriconazole were those published by Pfaller et al (32,33) and the CLSI (20). Breakpoints were as follows: susceptible (S), Յ8 g/ml (fluconazole) and Յ1 g/ml (voriconazole); susceptible dose dependent (SDD), 16 to 32 g/ml (fluconazole) and 2 g/ml (voriconazole); resistant (R), Ն64 g/ml (fluconazole) and Ն4 g/ml (voriconazole).…”

Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole

“…21 Using MIC data for voriconazole in over 8000 clinical isolates, the Antifungal Susceptibility Subcommittee of the Clinical and Laboratory Standards Institute has now proposed interpretive breakpoints for voriconazole and Candida species. 22 These are as follows: o1 mg/ml susceptible, 2 mg/ml susceptible dose dependent, and 44 mg/ml resistant. Although the majority of C glabrata isolates were susceptible to voriconazole, among the fluconazole-resistant isolates, 44% were susceptible to voriconazole in a dose-dependent manner (MIC 2 mg/ml).…”

Fluconazole resistance in Candida glabrata is associated with increased bud formation and metallothionein production

“…However, reports of FL failure in similar groups of patients have also been documented (Marr et al, 2002;Saiman et al, 2000). Additionally, on exposure to FL, the levels of resistance can increase dramatically, which selects for drug-resistant subpopulations, leading to clinically significant FL resistance (Pfaller et al, 2006). C. glabrata is thought to acquire drug resistance as a result of its haploid nature and its ability to mutate rapidly following exposure to triazole-derived agents (Safdar et al, 2002).…”