Ceftaroline efficacy against high-MIC clinical Staphylococcus aureus isolates in an in vitro hollow-fibre infection model

The Journal of Antimicrobial Chemotherapy
Renu SinghJane E Ambler

Abstract

The current CLSI and EUCAST clinical susceptible breakpoint for 600 mg q12h dosing of ceftaroline (active metabolite of ceftaroline fosamil) for Staphylococcus aureus is ≤1 mg/L. Efficacy data for S. aureus infections with ceftaroline MIC ≥2 mg/L are limited. This study was designed to generate in-depth pharmacokinetic/pharmacodynamics (PK/PD) understanding of S. aureus isolates inhibited by ≥ 2 mg/L ceftaroline using an in vitro hollow-fibre infection model (HFIM). The PK/PD target of ceftaroline was investigated against 12 diverse characterized clinical MRSA isolates with ceftaroline MICs of 2 or 4 mg/L using q8h dosing for 24 h. These isolates carried substitutions in the penicillin-binding domain (PBD) and/or the non-PBD. Additionally, PD responses of mutants with ceftaroline MICs ranging from 2 to 32 mg/L were evaluated against the mean 600 mg q8h human-simulated dose over 72 h. The mean stasis, 1 log10-kill and 2 log10-kill PK/PD targets were 29%, 32% and 35% f T>MIC, respectively. In addition, these data suggest that the PK/PD target for MRSA is not impacted by the presence of substitutions in the non-PBD commonly found in isolates with ceftaroline MIC values of ≤ 2 mg/L. HFIM studies with 600 mg q8h dosing demonstrated ...Continue Reading

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Citations

Nov 1, 2018·The Journal of Antimicrobial Chemotherapy·Shampa DasDavid Melnick
Apr 22, 2020·Antimicrobial Agents and Chemotherapy·Kyle C MolinaDouglas N Fish
Aug 14, 2019·International Journal of Antimicrobial Agents·Tobias WelteJennifer Hammond
Oct 24, 2020·Communications Biology·Maria Celeste VarelaAdriana E Rosato
Apr 2, 2018·European Journal of Medicinal Chemistry·Ahmed KotbAbdelrahman S Mayhoub

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