Telavancin Demonstrates Activity against Methicillin-Resistant Staphylococcus aureus Isolates with Reduced Susceptibility to Vancomycin, Daptomycin, and Linezolid in Broth Microdilution MIC and One-Compartment Pharmacokinetic/Pharmacodynamic Models

Methicillin-resistant Staphylococcus aureus (MRSA) isolates have arisen with reduced susceptibility to several anti-MRSA agents. Telavancin (TLV), a novel anti-MRSA agent, retains low MICs against these organisms. Our objective was to determine the MICs for TLV, daptomycin (DAP), vancomycin (VAN), and linezolid (LZD) against daptomycin-nonsusceptible (DNS) S. aureus, vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), and linezolid-resistant (LZDr) S. aureus. We also evaluated these agents against each phenotype in pharmacokinetic/pharmacodynamic (PK/PD) models. Seventy DNS, 100 VISA, 180 hVISA, and 25 LZDr MRSA isolates were randomly selected from our library and tested to determine their MICs against TLV, DAP, VAN, and LZD via broth microdilution and a Trek panel. Four isolates were randomly selected for 168-h in vitro models to evaluate treatment with TLV at 10 mg/kg of body weight/day, DAP at 10 mg/kg/day, VAN at 1 g every 12 h (q12h), and LZD at 600 mg q12h. The MIC50/90 for TLV, DAP, VAN, and LZD against 70 DNS S. aureus isolates were 0.06/0.125 mu g/ml, 2/4 mu g/ml, 1/2 mu g/ml, and 2/2 mu g/ml, respectively. Against 100 VISA isolates, the MIC50/90 were 0.06/0.125 mu g/ml, 1/1 mu g/ml, 4/8 mu g/ml, and 1/2 mu g/ml, respectively. Against 170 hVISA isolates, the MIC50/90 were 0.06/0.125 mu g/ml, 0.5/1 mu g/ml, 1/2 mu g/ml, and 1/2 mu g/ml, respectively. Against 25 LZDr isolates, the MIC50/90 were 0.03/0.06 mu g/ml, 1/1 mu g/ml, 2/2 mu g/ml, and 8/8 mu g/ml, respectively. The TLV MIC was > 0.125 mu g/ml for 10/365 (2.7%) isolates. In PK/PD models, TLV was universally bactericidal at 168 h and statistically superior to all antibiotics against DNS S. aureus strain R2334. These data further establish the potency of TLV against resistant MRSA. The model data demonstrate in vitro bactericidal activity of TLV against hVISA, VISA, DNS S. aureus, and LZDr S. aureus strains. Further clinical research is warranted.