Ceftaroline fosamil doses and breakpoints for Staphylococcus aureus in complicated skin and soft tissue infections

J Antimicrob Chemother. 2019 Feb 1;74(2):425-431. doi: 10.1093/jac/dky439.

Abstract

Objectives: To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600 mg q8h by 2 h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4 mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate = 2 mg/L and resistant >2 mg/L).

Methods: A population PK model for ceftaroline and ceftaroline fosamil was developed using PK data from 21 clinical studies. The final model was used to simulate PTA in patients with cSSTI receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or 600 mg q8h by 2 h iv infusion. PTA was calculated by MIC for S. aureus PK/PD targets derived from preclinical studies (27% fT>MIC for stasis, 31% fT>MIC for 1 log10 kill and 35% fT>MIC for 2 log10 kill) and compared with S. aureus ceftaroline MIC distributions from a 2013 global surveillance study.

Results: The final population PK model based on 951 subjects adequately described ceftaroline and ceftaroline fosamil PK. High PTA (>90%) was predicted for the ceftaroline fosamil 600 mg q12h dosage regimen against S. aureus isolates with ceftaroline MICs ≤2 mg/L. Greater than 90% PTA was predicted for the ceftaroline fosamil 600 mg q8h dosage regimen against S. aureus with ceftaroline MICs ≤4 mg/L.

Conclusions: The approved ceftaroline fosamil dosage regimens for adults and adolescents with cSSTI achieve high PTA against S. aureus at the associated EUCAST breakpoints.

Trial registration: ClinicalTrials.gov NCT01499277 NCT01371838 NCT01458743 NCT01612507 NCT01664065.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Bacterial Agents / pharmacokinetics*
  • Anti-Bacterial Agents / therapeutic use
  • Cephalosporins / pharmacokinetics*
  • Cephalosporins / therapeutic use
  • Child
  • Clinical Trials as Topic
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Soft Tissue Infections / drug therapy*
  • Soft Tissue Infections / microbiology*
  • Staphylococcal Infections / complications
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Skin Infections / drug therapy*
  • Staphylococcus aureus / drug effects
  • Young Adult

Substances

  • Anti-Bacterial Agents
  • Cephalosporins
  • ceftaroline fosamil

Associated data

  • ClinicalTrials.gov/NCT01499277
  • ClinicalTrials.gov/NCT01371838
  • ClinicalTrials.gov/NCT01458743
  • ClinicalTrials.gov/NCT01612507
  • ClinicalTrials.gov/NCT01664065