Short-term effects of appropriate empirical antimicrobial treatment with ceftolozane/tazobactam in a swine model of nosocomial pneumonia

A. Motos, G. Li Bassi, F. Pagliara, L. Fernandez-Barat, H. Yang, E.A. Xiol, T. Senussi, F.A. Idone, C. Travierso, C. Chiurazzi, R. Amaro, M. Yang, J. Bobi, M. Rigol, D.P. Nicolau, G. Frigola, R. Cabrera, J. Ramirez, P. Pelosi, F. BlasiM. Antonelli, A. Artigas, J. Vila, M. Kollef, A. Torres

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The rising frequency of multidrug-resistant and extensively drug-resistant (MDR/XDR) pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with ceftolozane/tazobactam (C/T) compared with IEAT with piperacillin/tazobactam (TZP) in MDR Pseudomonas aeruginosa pneumonia. Twenty-one pigs with pneumonia caused by an XDR P. aeruginosa strain (susceptible to C/T but resistant to TZP) were ventilated for up to 72 h. Twenty-four hours after bacterial challenge, animals were randomized to receive 2-day treatment with either intravenous saline (untreated) or 25 to 50 mg of C/T per kg body weight (AEAT) or 200 to 225 mg of TZP per kg (IEAT) every 8 h. The primary outcome was the P. aeruginosa burden in lung tissue and the histopathology injury. P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage (BAL) fluid, the development of antibiotic resistance, and inflammatory markers were secondary outcomes. Overall, P. aeruginosa lung burden was 5.30 (range, 4.00 to 6.30), 4.04 (3.64 to 4.51), and 4.04 (3.05 to 4.88) log10CFU/g in the untreated, AEAT, and IEAT groups, respectively (P = 0.299), without histopathological differences (P = 0.556). In contrast, in tracheal secretions (P < 0.001) and BAL fluid (P = 0.002), bactericidal efficacy was higher in the AEAT group. An increased MIC to TZP was found in 3 animals, while resistance to C/T did not develop. Interleukin-1β (IL-1β) was significantly downregulated by AEAT in comparison to other groups (P = 0.031). In a mechanically ventilated swine model of XDR P. aeruginosa pneumonia, appropriate initial treatment with C/T decreased respiratory secretions' bacterial burden, prevented development of resistance, achieved the pharmacodynamic target, and may have reduced systemic inflammation. However, after only 2 days of treatment, P. aeruginosa tissue concentrations were moderately affected.

Original languageEnglish
Article numbere01899-20
JournalAntimicrobial Agents and Chemotherapy
Issue number2
Publication statusPublished - 2021


  • Animal models
  • Appropriate empirical antimicrobial treatment
  • Mechanical ventilation
  • Pneumonia
  • Pseudomonas aeruginosa
  • ceftolozane plus tazobactam
  • interleukin 1beta
  • interleukin 8
  • oxygen
  • piperacillin plus tazobactam
  • sodium chloride
  • antiinfective agent
  • ceftolozane
  • cephalosporin derivative
  • penicillanic acid
  • tazobactam
  • animal experiment
  • animal model
  • animal tissue
  • antibiotic resistance
  • antibiotic sensitivity
  • antibiotic therapy
  • antimicrobial therapy
  • area under the curve
  • Article
  • bacterial load
  • bactericidal activity
  • bronchoalveolar lavage fluid
  • clinical feature
  • colony forming unit
  • comparative study
  • controlled study
  • disease severity
  • down regulation
  • epithelial lining fluid
  • female
  • histopathology
  • hospital infection
  • lung burden
  • lung gas exchange
  • lung lavage fluid
  • lung lobe
  • lung mechanics
  • lung parenchyma
  • lung ventilation
  • microbiological examination
  • minimum inhibitory concentration
  • nonhuman
  • outcome assessment
  • oxygenation
  • plasma concentration-time curve
  • porcine model
  • priority journal
  • Pseudomonas pneumonia
  • qualitative analysis
  • quantitative analysis
  • volume of distribution
  • animal
  • cross infection
  • microbial sensitivity test
  • multidrug resistance
  • pig
  • Pseudomonas infection
  • Animals
  • Anti-Bacterial Agents
  • Anti-Infective Agents
  • Cephalosporins
  • Cross Infection
  • Drug Resistance, Multiple, Bacterial
  • Healthcare-Associated Pneumonia
  • Microbial Sensitivity Tests
  • Penicillanic Acid
  • Pseudomonas Infections
  • Swine
  • Tazobactam


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