ceftobiprole and Enterobacteriaceae-Infections

This study aimed to evaluate in vitro susceptibility to ceftobiprole of clinical strains identified from prosthetic joint infections (PJIs) compared to that of the associations currently recommended for post-operative empirical antibiotic therapy (PEAT) (vancomycin with either cefepime, third-generation cephalosporin or piperacillin-tazobactam).. We performed a 1-year retrospective study on all the surgical procedures performed in our hospital for PJI. Susceptibility profiles of all the strains cultured from surgical samples were reviewed to compare ceftobiprole to current used associations.. During the study period (from January 2018 to December 2018), we identified 106 patients managed for PJI and a total of 216 surgical interventions. One hundred-fifty strains were identified from intraoperative samples, excluding redundant strains. Staphylococcus spp. represented 52.7% of all strains and Enterobacteriales 13.3%. Twenty-three patients had polymicrobial infection (22%). Among 149 surgical procedures with positive culture results, ceftobiprole covered the bacterial strains in 138 (92.6%) cases. In comparison, this percentage was 94.6% for vancomycin plus cefepime (p = 0.64), 92.6% for vancomycin plus a third-generation cephalosporin in 138 cases (p = 1) and 94.6% for vancomycin plus piperacillin-tazobactam) (p = 0.64).. Based on antimicrobial susceptibility testing, our results suggest that ceftobiprole could be an interesting option for PEAT in PJIs, allowing the use of a single agent.

Topics: Anti-Bacterial Agents; Cephalosporins; Coinfection; Enterobacteriaceae Infections; Female; Humans; Male; Microbial Sensitivity Tests; Prosthesis-Related Infections; Retrospective Studies; Staphylococcal Infections

Ceftobiprole medocaril is the parenteral prodrug of ceftobiprole, a novel pyrrolidinone broad-spectrum cephalosporin with in vitro and in vivo bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). We have used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic (PK)-pharmacodynamic (PD) activities of ceftobiprole against multiple strains of S. aureus (including MRSA), S. pneumoniae (including PRSP), and gram-negative bacilli. Serum levels of ceftobiprole following the administration of multiple doses were determined by a microbiological assay. In vivo bactericidal activities and postantibiotic effects (PAEs) of ceftobiprole against MRSA and PRSP strains were determined from serial CFU/thigh values following single doses of ceftobiprole (40 and 160 mg/kg of body weight). Dose fractionation studies were used to determine which PK-PD index correlated best with activity. Magnitudes of the PK-PD indices were calculated from MICs and PK parameters. A sigmoid dose-response model was used to estimate the dose (mg/kg/24 h) required to achieve a static and 2-log(10) kill effects over 24 h. PK results showed area under the concentration-time curve/dose values of 1.8 to 2.8 and half-lives of 0.29 to 0.51 h. MICs ranged from 0.015 to 2 microg/ml. Ceftobiprole demonstrated time-dependent killing; its in vivo PAEs varied from 3.8 h to 4.8 h for MRSA and from 0 to 0.8 h for PRSP. The time above MIC (T > MIC) correlated best with efficacy for both MRSA and PRSP. The T > MIC values required for the static doses were significantly longer (P < 0.001) for Enterobacteriaceae (36 to 45%) than for S. aureus (14 to 28%) and S. pneumoniae (15 to 22%). The drug showed activities in the lung model similar to those in the thigh model. The presence of neutrophils significantly enhanced the activity of ceftobiprole against S. pneumoniae but only slightly against Klebsiella pneumoniae. Based on its PD profile, ceftobiprole is a promising new beta-lactam agent with activity against gram-negative and gram-positive organisms including MRSA and PRSP.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Cephalosporin Resistance; Cephalosporins; Disease Models, Animal; Dose-Response Relationship, Drug; Enterobacteriaceae Infections; Extremities; Female; Gram-Negative Bacterial Infections; Lung Diseases; Methicillin Resistance; Mice; Mice, Inbred ICR; Neutropenia; Penicillin Resistance; Pneumococcal Infections; Staphylococcal Infections; Staphylococcus aureus