title: Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function.
abstract: In this study, the probability of pharmacokinetic/pharmacodynamic target attainment (PTA) of ceftaroline against clinical isolates causing community-acquired bacterial pneumonia (CABP) and complicated skin and skin-structure infection (cSSSI) in Europe was evaluated. Three dosing regimens were assessed: 600 mg every 12 h (q12 h) as a 1-h infusion (standard dose) or 600 mg every 8 h (q8 h) as a 2-h infusion in virtual patients with normal renal function; and 400 mg q12 h as a 1-h infusion in patients with moderate renal impairment. Pharmacokinetic and microbiological data were obtained from the literature. The PTA and the cumulative fraction of response (CFR) were calculated by Monte Carlo simulation. In patients with normal renal function, the ceftaroline standard dose (600 mg q12 h as a 1-h infusion) can be sufficient to treat CABP due to ceftazidime-susceptible (CAZ-S) Escherichia coli, CAZ-S Klebsiella pneumoniae, meticillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis (CFR>90%). However, against meticillin-resistant S. aureus (MRSA), the CFR was 72%. In cSSSI, the CFR was also <80% for MRSA. Administration of ceftaroline 600 mg q8 h as a 2-h infusion or 400 mg q12 h as a 1-h infusion in patients with moderate renal insufficiency provided a high probability of treatment success (CFR ca. 100%) for most micro-organisms causing CABP and cSSSI, including MRSA and penicillin-non-susceptible S. pneumoniae. These results suggest that in patients with normal renal function, ceftaroline 600 mg q8 h as a 2-h infusion may be a better option than the standard dose, especially if the MRSA rate is high.
authors.affiliation: Microbiology Service, Hospital Universitario de Álava, Servicio Vasco de Salud Osakidetza, Vitoria-Gasteiz, Spain; Instituto de Investigación Sanitaria de Álava (BIOARABA), Servicio Vasco de Salud Osakidetza, Vitoria-Gasteiz, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Canut
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain; Centro de Investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Isla
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain; Centro de Investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain. Electronic address: alicia.rodriguez@ehu.es.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-Gascón
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002511:Cephalosporins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D017714:Community-Acquired Infections / Q000188:drug therapy*; D005060:Europe; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000502:physiology; D007677:Kidney Function Tests; D009010:Monte Carlo Method; D018410:Pneumonia, Bacterial / Q000188:drug therapy*; D017192:Skin Diseases, Bacterial / Q000188:drug therapy*; D016896:Treatment Outcome; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000097583:Ceftaroline
keywords: Antimicrobial therapy; Ceftaroline fosamil; Community-acquired pneumonia; PK/PD; Skin and soft-tissue infection