ppi-0903 and Pseudomonas-Infections

Current antibiotics available for the treatment of healthcare-associated pneumonia (HCAP) may result in clinical failure due to resistance development, side effect intolerance, or poor pharmacokinetic-pharmacodynamic profiles. New agents active against common HCAP pathogens are needed. The mechanism of action, spectrum of activity, pharmacokinetics, adverse effects, and clinical efficacy of seven new agents in clinical development or recently approved with either methicillin-resistant Staphylococcus aureus (MRSA) or pseudomonal activity are reviewed. They include doripenem, a new antipseudomonal carbapenem; ceftobiprole and ceftaroline, two anti-MRSA cephalosporins; iclaprim, a selective dihydrofolate reductase antagonist; and three glycopeptides, dalbavancin, telavancin, and oritavancin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Ceftaroline; Cephalosporins; Cross Infection; Doripenem; Glycopeptides; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pseudomonas Infections; Pyrimidines; Staphylococcal Infections; Teicoplanin

Previous in vivo studies using a human-simulated regimen of ceftaroline/avibactam 600/600mg every 8h (q8h) showed activity against extended-spectrum β-lactamase-, AmpC- and KPC-producing Enterobacteriaceae with minimum inhibitory concentrations (MICs) ≤ 1 μg/mL. Here we sought to determine the efficacy of this human-simulated regimen against organisms with MICs ≥ 1 μg/mL to help determine a breakpoint value that would reliability predict efficacy in humans. In total, 31 isolates (1 Escherichia coli, 9 Klebsiella pneumoniae, 9 Enterobacter cloacae, 1 Citrobacter koseri, 2 Serratia marcescens, 1 Klebsiella oxytoca and 8 Pseudomonas aeruginosa) with ceftaroline/avibactam MICs of 1 to 16 μg/mL were tested in a murine immunocompromised thigh infection model; 15 isolates were also tested in an immunocompetent model. Doses were given to simulate human free drug exposures of ceftaroline fosamil/avibactam 600/600 mg q8h over 24h as a 1-h infusion by targeting the fT>MIC profile. Efficacy was evaluated as the change in log10 CFU compared with 0-h controls after 24h. Reductions in bacterial CFU in the neutropenic model were seen against a majority of isolates tested with MICs ≤ 4 μg/mL, where fT>MIC was >55%. More variable efficacy was seen in isolates with MICs ≥ 8 μg/mL, where fT>MIC drops below 40%. Overall activity was enhanced in the immunocompetent model. The humanised regimen of ceftaroline fosamil/avibactam 600/600 mg q8h as a 1-h infusion showed predictable efficacy against isolates with various genotypic and phenotypic profiles and MICs ≤ 4 μg/mL. These data provide valuable information to help determine a ceftaroline/avibactam breakpoint for Enterobacteriaceae.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Ceftaroline; Cephalosporins; Disease Models, Animal; Enterobacter cloacae; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Reproducibility of Results; Thigh