In Vivo Efficacy of Ceftaroline Fosamil in a Methicillin-Resistant Panton-Valentine Leukocidin-Producing Staphylococcus aureus Rabbit Pneumonia Model

• Published in: Antimicrobial agents and chemotherapy 2014-04, Vol.58 (4), p.1855-1861
• Main Authors: CROISIER-BERTIN, Delphine, HAYEZ, Davy, LINA, Gerard, VANDENESCH, Francois, CHAVANET, Pascal, DA SILVA, Sonia, LABROUSSE, Delphine, BIEK, Donald, BADIOU, Cedric, DUMITRESCU, Oana, GUERARD, Pascal, CHARLES, Pierre-Emmanuel, PIROTH, Lionel
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial diseases; Bacterial Toxins; Bacterial Toxins - metabolism; Biological and medical sciences; Ceftaroline; Cephalosporins; Cephalosporins - therapeutic use; Exotoxins; Exotoxins - metabolism; Experimental Therapeutics; Human bacterial diseases; Infectious diseases; Leukocidins; Leukocidins - metabolism; Life Sciences; Male; Medical sciences; Methicillin-Resistant Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - metabolism; Pharmacology. Drug treatments; Pneumonia; Pneumonia - drug therapy; Rabbits; Staphylococcal Infections; Staphylococcal Infections - drug therapy; Staphylococcal infections, streptococcal infections, pneumococcal infections; Staphylococcus aureus; Streptococcus pneumoniae
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01707-13

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with broad-spectrum in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), and common Gram-negative pathogens. This study investigated the in vivo activity of ceftaroline fosamil compared with clindamycin, linezolid, and vancomycin in a severe pneumonia model due to MRSA-producing Panton-Valentine leukocidin (PVL). A USA300 PVL-positive clone was used to induce pneumonia in rabbits. Infected rabbits were randomly assigned to no treatment or simulated human-equivalent dosing with ceftaroline fosamil, clindamycin, linezolid, or vancomycin. Residual bacterial concentrations in the lungs and spleen were assessed after 48 h of treatment. PVL expression was measured using a specific enzyme-linked immunosorbent assay (ELISA). Ceftaroline, clindamycin, and linezolid considerably reduced mortality rates compared with the control, whereas vancomycin did not. Pulmonary and splenic bacterial titers and PVL concentrations were greatly reduced by ceftaroline, clindamycin, and linezolid. Ceftaroline, clindamycin, and linezolid were associated with reduced pulmonary tissue damage based on significantly lower macroscopic scores. Ceftaroline fosamil, clindamycin, and, to a lesser extent, linezolid were efficient in reducing bacterial titers in both the lungs and spleen and decreasing macroscopic scores and PVL production compared with the control.