title: Pharmacokinetic-pharmacodynamic target attainment analyses to evaluate in vitro susceptibility test interpretive criteria for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae.
abstract: To provide support for in vitro susceptibility test interpretive criteria decisions for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae, as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC (f%T>MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achieving f %T>MIC targets for S. aureus and S. pneumoniae based on murine infection models were calculated by MIC. At MICs of 2 mg/liter for S. aureus and 1 mg/liter for S. pneumoniae, the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achieving f %T>MIC targets (≥26 for S. aureus and ≥44 for S. pneumoniae) exceeded 90%. The results of these analyses, which suggested that in vitro susceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline against S. aureus and S. pneumoniae, respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses.
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Van Wart
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rubino
authors.forename: Tatiana
authors.initials: T
authors.lastname: Khariton
authors.forename: Todd A
authors.initials: TA
authors.lastname: Riccobene
authors.forename: H David
authors.initials: HD
authors.lastname: Friedland
authors.forename: Ian A
authors.initials: IA
authors.lastname: Critchley
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D002511:Cephalosporins / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D002986:Clinical Trials as Topic; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D009010:Monte Carlo Method; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D012720:Severity of Illness Index; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000097583:Ceftaroline