title: Ceftaroline versus ceftriaxone in a highly penicillin-resistant pneumococcal pneumonia rabbit model using simulated human dosing.
abstract: Ceftaroline (CPT) is a new cephalosporin exhibiting bactericidal activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), as well as common Gram-negative pathogens. This study investigated the in vivo efficacy of a 48-hour simulated human dose regimen of CPT compared with ceftriaxone (CRO) against isolates of S. pneumoniae with different susceptibilities to penicillin in a rabbit pneumonia model. Three S. pneumoniae strains were used: CRO-susceptible penicillin-susceptible S. pneumoniae (CRO-S PSSP), CRO-susceptible penicillin-intermediate S. pneumoniae (CRO-S PISP), and CRO-resistant penicillin-resistant S. pneumoniae (CRO-R PRSP). Animals were randomized to the control group (no treatment) (n = 22) or to a group given intravenous (IV) CPT human equivalent (HE) dosage (600 mg/12 h; n = 19) or IV CRO HE dosage (1 g/24 h; n = 19). The total doses needed to achieve the HE dosage were 71 and 82 mg/kg of body weight/24 h for CRO and CPT, respectively. One group of rabbits infected with the CRO-R PRSP strain received intramuscular (IM) administration of CPT (5 or 20 mg/kg twice daily; n = 5 for each). Evaluation of efficacy was based on bacterial counts in the lungs and spleen. For IV CPT and IV CRO, the mean areas under the concentration-time curves from 0 to 24 h (AUC(0-24)s) were 155 and 938 mg · h/liter, respectively, the maximum concentrations in serum (C(max)s) were 20 and 158 mg/liter, respectively, and the minimum concentrations in serum (C(min)s) were 1.3 and 6 mg/liter, respectively. Both agents effectively treated pulmonary infections caused by CRO-S PSSP or CRO-S PISP with complete bacterial eradication in the lungs and spleen after 2 days of treatment. Against PRSP, CPT demonstrated excellent bactericidal activity, reducing bacterial counts in the lungs and spleen by approximately 8 and 4 log units, respectively (P < 0.001); CRO treatment resulted in a 2-log-unit reduction in the bacterial counts in lungs that did not reach statistical significance. Twice-daily IM CPT (5 mg/kg) reduced the bacterial burden by approximately 6 log units in the lungs and 3 log units in the spleen, and the 20-mg/kg dosage effectively eradicated PRSP infection. These findings further validate the in vivo bactericidal activity of CPT against pneumococci.
authors.affiliation: Infectious Diseases Laboratory, University Hospital, Dijon, France. delphine.croisier@chu-dijon.fr
authors.forename: Delphine
authors.initials: D
authors.lastname: Croisier-Bertin
authors.forename: Lionel
authors.initials: L
authors.lastname: Piroth
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Charles
authors.forename: Aurélie
authors.initials: A
authors.lastname: Larribeau
authors.forename: Donald
authors.initials: D
authors.lastname: Biek
authors.forename: Yigong
authors.initials: Y
authors.lastname: Ge
authors.forename: Pascal
authors.initials: P
authors.lastname: Chavanet
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D002443:Ceftriaxone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002511:Cephalosporins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D010403:Penicillin Resistance / Q000187:drug effects*; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy*; D011817:Rabbits; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000472:pathogenicity*; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D002511:Cephalosporins; D000097583:Ceftaroline