Short-term effects of appropriate empirical antimicrobial treatment with Ceftolozane/Tazobactam in a swine model of nosocomial Pneumonia

The rising frequency of 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 C/T compared with IEAT with piperacillin/tazobactam(TZP) in MDR Pseudomonas aeruginosa (PA) pneumonia. Twenty-one pigs with pneumonia caused by XDR PA strain (susceptible to C/T but resistant to TZP) were ventilated up to 72h. Twenty-four hours after bacterial challenge, animals were randomized to receive 2-day treatment with either intravenous saline (untreated) or 50-25 mg/kg of C/T (AEAT) or 200-25 mg/kg of TZP (IEAT), every 8h. The primary outcome was the PA burden in lung tissue and the histopathology injury. PA burden in tracheal secretions and bronchoalveolar lavage (BAL) fluid, the development of antibiotic resistance and inflammatory markers were secondary outcomes. Overall PA lung burden was 5.30[4.00-6.30], 4.04[3.64-4.51], and 4.04[3.05-4.88] 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 AEAT group. Increased minimum inhibitory concentration to TZP was found in 3 animals, while resistance to C/T did not develop. 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 pharmacodynamic target and may reduce systemic inflammation. Yet, after only 2 days of treatment, P. aeruginosa tissue concentrations were moderately affected.