Ceftaroline versus Ceftriaxone in a Highly Penicillin-Resistant Pneumococcal Pneumonia Rabbit Model Using Simulated Human Dosing

Abstract

ABSTRACTCeftaroline (CPT) is a new cephalosporin exhibiting bactericidal activity against Gram-positive organisms, including methicillin-resistantStaphylococcus aureus(MRSA) and multidrug-resistantStreptococcus pneumoniae(MDRSP), as well as common Gram-negative pathogens. This study investigated thein vivoefficacy of a 48-hour simulated human dose regimen of CPT compared with ceftriaxone (CRO) against isolates ofS. pneumoniaewith different susceptibilities to penicillin in a rabbit pneumonia model. ThreeS. pneumoniaestrains were used: CRO-susceptible penicillin-susceptibleS. pneumoniae(CRO-S PSSP), CRO-susceptible penicillin-intermediateS. pneumoniae(CRO-S PISP), and CRO-resistant penicillin-resistantS. 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 (AUC0–24s) were 155 and 938 mg · h/liter, respectively, the maximum concentrations in serum (Cmaxs) were 20 and 158 mg/liter, respectively, and the minimum concentrations in serum (Cmins) 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 thein vivobactericidal activity of CPT against pneumococci.