Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To EvaluateIn VitroSusceptibility Test Interpretive Criteria for Ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae

Abstract

cTo 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.

Pharmacokinetics of Ceftaroline in Normal Body Weight and Obese (Classes I, II, and III) Healthy Adult Subjects

“…First, the study here enrolled healthy subjects who typically exhibit decreased pharmacokinetic variability and lower CL T levels compared to infected patients. Previous POP-PK models suggest that subjects in ceftaroline phase 2/3 studies had a 35% higher mean CL T than those in phase 1 studies (27)(28)(29)(30). Given this background, obese class III adults who are acutely infected may theoretically have a higher CL T than that predicted by our model.…”

“…This final POP-PK model was relatively similar to a previously published POP-PK model developed with ceftaroline pharmacokinetic data from clinical trials, albeit with some notable differences (27)(28)(29)(30). The previous model utilized three and two compartments for ceftaroline fosamil and ceftaroline, respectively; parallel linear and Michaelis-Menten elimination pathways for ceftaroline; and additional covariates (age, gender, and phase 2/3 patient status).…”

“…every 12 h as a 1-h infusion should provide adequate target exposure for the majority of clinical isolates of MSSA, S. pneumoniae, and non-ESBL-producing E. coli or Klebsiella spp. encountered in the United States (28)(29)(30). This regimen also appears to be relatively safe with no serious AEs reported in this study.…”

Population pharmacokinetics of ceftaroline in patients with acute bacterial skin and skin structure infections or community‐acquired bacterial pneumonia

“…Simulations were performed using this model to demonstrate that the recommended ceftaroline fosamil dosing regimens provide comparable steady‐state ceftaroline AUC 0–24 in ABSSSI and CABP patients across renal function groups. The simulations were subsequently used to evaluate potential susceptibility test interpretive criteria for S. aureus and S. pneumoniae . Lastly, the population PK model described herein is suitable for use in clinical practice to provide a reasonable approximation of ceftaroline exposure based on knowledge of important subject covariate effects.…”

Reduced In Vitro Activity of Ceftaroline by Etest among Clonal Complex 239 Methicillin-Resistant Staphylococcus aureus Clinical Strains from Australia

“…Suggestions that ceftaroline susceptibility test interpretive criteria could be as high as a MIC of Յ2.0 g/ml (4, 38) are based on achieving an f%T ϾMIC target of 26%, reflecting bacterial stasis, and would be considered the minimum value required when uncomplicated infections in patients with an intact immune system are being treated (39). At a MIC of 2.0 g/ml, standard dosing of ceftaroline with 600 mg twice daily demonstrated lower target attainments, aiming for 1-or 2-log 10 kill (74.5% and 28.8%, respectively, in simulated patients with normal renal function, applying f%T ϾMIC of 36% and 51% for a 1-and 2-log 10 kill, respectively) (38). Monte Carlo simulation with ceftaroline administered 600 mg every 8 hours as a 2-h infusion in patients with normal renal function demonstrated a higher probability of treatment success (from 72% in CABP and 79% in SSTI to Ն99% in both), and the every-8-hour schedule may represent a better option than standard dosing, especially when targeting MRSA (40).…”