Reply to “Successful Target Attainment of Telavancin at Elevated MICs: Fact or Fiction?”

In reading Dr. Farkas’ letter, he cites two concerns with the exposure target (AUC/MIC of 219) employed in our probability of target attainment (PTA) analyses (6). First, he indicates that the AUC value linked to 1-log10-unit reduction in the bacterial burden in the neutropenic mouse thigh MRSA infection model was rather conservative (7). Second, he indicates that the MIC value employed in the PTA analyses may be 1-log2 dilution too high (5–7). Because of these two concerns, he indicates that the results of our PTA analyses should be interpreted very conservatively and should not be readily applied to complicated skin and skin structure infections (cSSSIs) due to MRSA with MIC values in excess of 1 mg/liter. Furthermore, he suggests that additional multistrain neutropenic murine-thigh infection model experiments are needed to refine the pharmacodynamic target for telavancin. In regard to his first point, we were purposefully conservative in our approach in identifying the AUC target (7). Data demonstrate that use of human dosing schemes associated with stasis in neutropenic murine-thigh infection models have a high likelihood of clinical success in phase III cSSSI trials (1). Given that only one parent dosing scheme is typically evaluated in phase III cSSSI trials, the FDA now strongly encourages companies to use neutropenic murine-thigh infection model data to inform the dose selection process (1). Rather than selecting the pharmacodynamic target associated with stasis, a conservative approach was taken, and the exposure target linked to a 1-log-unit reduction in bacterial burden was selected. While neutropenic murine-thigh infection model data were available for several MRSA strains, MRSA ATCC strain 33591 was selected to quantify the dosing regimen needed for a 1-log-unit reduction, since its MIC value was 1 mg/liter on initial testing and this was at the higher end of the MRSA MIC distribution (5). Furthermore, the total daily dose (in milligrams per kilogram of body weight) required for a 1-log10-unit reduction in CFU/g against this MRSA strain in neutropenic mouse thigh studies was also consistent with the other MRSA strains at the upper end of the 1-log10-unit CFU/g reduction total daily dose distribution (5). Since there was variability in response among tested MRSA isolates, we felt that it was best to be extremely conservative when selecting the exposure target (1-log10-unit reduction from baseline) and strain (5). As for his second point, we confirm that the MIC value was 1 mg/liter in the original experiments by Hegde et al. (5). In a separate study by Hegde and colleagues within the same article, the influence of protein binding was studied by determining the effect of 95% mouse serum or mouse albumin (40 mg/ml) on the MIC of telavancin. These experiments were conducted using arithmetic dilutions of the drug to improve accuracy. In this separate study, the MIC value of telavancin in broth was reported to be 0.4 mg/liter. We acknowledge that other authors have also reported the telavancin MIC value for MRSA (ATCC strain 33591) to be 0.5 mg/liter (2, 4, 8–10). Please note that 0.4, 0.5, and 1 mg/liter are within the acceptable variability of the MIC testing methodology ( 1-log2 dilution) (3). Because the acceptable variability for MIC methods is 1 doubling dilution, we do not view this as a major concern. On the basis of the conservative approach employed, we believe the AUC/MIC target of 219 is a reasonable estimate of the exposure required for a 1-log10-unit reduction in CFU/g against the majority of MRSA isolates encountered in clinical practice. Furthermore, the comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III cSSSI trials were appropriate from a PTA standpoint and support their usage in clinical practice (6). Although our results indicate that PTA is highly acceptable at 2 mg/liter, we do not support use of telavancin for cSSSIs due to Staphylococcus aureus with MIC values in excess of 1 mg/liter, since the FDA and CLSI susceptibility breakpoint is 1 mg/liter (3, 6). Last, while we agree with Dr. Farkas that additional multistrain neutropenic murine-thigh infection model experiments may enhance our understanding of the pharmacodynamics of telavancin, we do not believe these studies are necessary. The goal of the original neutropenic murine-thigh MRSA infection model studies was to identify a dosing scheme for phase III cSSSI drug studies. Since the drug is now approved, the utility of the FDA-approved dosing scheme should be revisited as more clinical derived PK/PD data become available. In particular, human data, rather than animal data, should be used to refine our understanding of the telavancin exposure-response relationships.