Abstract
Background Pseudomonas pneumonia is a life-threatening infection with high mortality, particularly in neutropenic patients. The efficacy of current antimicrobial therapy with extended spectrum penicillins (ESPs) and anti-pseudomonal cephalosporins (ASCs) is limited by emergence of resistance. Ceftolozane/tazobactam is a novel cephalosporin with in vitro activity against isolates of Pseudomonas aeruginosa that are resistant to ESPs and ASCs. In order to assess the antimicrobial effect of ceftolozane/tazobactam in treatment of Pseudomonas pneumonia, we investigated this new agent in the treatment of experimental Pseudomonas pneumonia in persistently neutropenic rabbits infected with different strains of genetically defined mechanisms of resistance.Methods Pseudomonas pneumonia was established in a rabbit model by direct endotracheal inoculation of P. aeruginosa 1 × 108–109 CFUs for tracheobronchial colonization that evolves into bronchopneumonia. Four treatment groups were studied: ceftolozane/tazobactam, ceftazidime (CTZ), piperacillin/tazobactam (TZP), and untreated controls (UC). Rabbits were dosed IV to achieve humanized doses of ceftolozane/tazobactam 3g (2g/1g) Q8h, CTZ 2g Q8h, and TZP 4.5g Q8h. Four isolates of P. aeruginosa were studied: pan-susceptible (PS), OPRD porin loss (OPRDPL), efflux pump expression (EPE), and AmpC hyperexpression (ACHE). Profound, persistent neutropenia was maintained with cytosine arabinoside and methylprednisolone. Treatment was continued for 12 days.ResultsTreatment with ceftolozane/tazobactam resulted in ≥105 reduction in residual pulmonary bacterial burden caused by all 4 strains (P ≤ 0.01). This antibacterial activity coincided with reduction of lung weight (P < 0.05), which is a marker of organism-mediated pulmonary injury. CTZ was less active in ACHE-infected rabbits, while TZP had less activity in EPE, ACHE, and OPRDPL strains. Survival was prolonged in ceftolozane/tazobactam and CTZ treatment groups in comparison to that of TZP and UC (P < 0.001).ConclusionCeftolozane/tazobactam is highly active in treatment of experimental P. aeruginosa pneumonia in persistently neutropenic rabbits, including infections caused by strains with the most common resistant mechanisms.Disclosures C. A. DeRyke, Merck: Employee, Salary. D. L. Culshaw, Merck: Employee, Salary. L. Caro, Merck: Employee and Shareholder, Salary and stock options. M. J. Satlin, Hardy Diagnostics: Grant Investigator, Research support. Allergan: Grant Investigator, Grant recipient. Merck: Grant Investigator, Grant recipient. Biomerieux: Grant Investigator, Grant recipient. Achaogen: Consultant, Consulting fee. T. J. Walsh, Merck: Grant Investigator, Research grant. Atellas: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Gilead: Scientific Advisor, Consulting fee. Allergan: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Scynexis: Grant Investigator, Research grant. Amplyx: Grant Investigator, Research grant. Shionogi: Scientific Advisor, Consulting fee.
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