Pharmacodynamic profile of commonly utilised parenteral therapies against meticillin-susceptible and meticillin-resistant Staphylococcus aureus collected from US hospitals

Abstract

Staphylococcus aureus is a well-recognised pathogen with an evolving phenotypic profile often limiting conventional β-lactam use. In vitro potency and pharmacodynamic profile of commonly utilised agents against 1238 meticillin-susceptible S. aureus (MSSA) and 1259 meticillin-resistant S. aureus (MRSA) from clinical specimens at 42 hospitals were assessed. Non-duplicate, non-urine isolates were tested by broth microdilution against cefazolin, ceftaroline, ceftriaxone, daptomycin, linezolid, nafcillin, tigecycline and vancomycin. Monte Carlo simulations were conducted using pharmacokinetic profiles from patients or volunteers to generate the probability of target attainment and determine the cumulative fraction of response (CFR), a modelling-based prediction tool of achieving pharmacokinetic/pharmacodynamic endpoints, for commonly used regimens. Of isolates tested, 62 MSSA (5.0%) were ceftriaxone-non-susceptible and 4 (0.3%) and 2 (0.2%) MRSA were ceftaroline- and daptomycin-non-susceptible, respectively. Against MSSA, cefazolin 1000 mg q8h and nafcillin 2000 mg q4h produced CFRs ≥90%. For ceftriaxone, only 2000 mg q12h produced a CFR ≥90%. Against MSSA and MRSA, ceftaroline, daptomycin, linezolid and tigecycline provided CFRs ≥90%. Vancomycin produced similar CFRs against MSSA and MRSA. Vancomycin 1000 mg and 15 mg/kg q8h produced CFRs of 91% and 93%, respectively, whilst q12h doses were <90%. Against respiratory and blood isolates or ICU isolates, only vancomycin q8h produced desired CFRs, where the MIC90 was 2 μg/mL. These data suggest cefazolin and nafcillin produce high CFRs against MSSA, whilst ceftriaxone at common doses may no longer be suitable. Vancomycin q8h is needed to optimise CFRs. Ceftaroline, daptomycin, tigecycline and linezolid produced sufficiently high CFRs against MSSA and MRSA utilising approved regimens.

Keywords: Meticillin-resistant S. aureus; Meticillin-susceptible S. aureus; Pharmacodynamics; Susceptibility.