Ceftolozane-Tazobactam in the Treatment of Experimental Pseudomonas aeruginosa Pneumonia in Persistently Neutropenic Rabbits: Impact on Strains with Genetically Defined Mechanisms of Resistance

Abstract

Ceftolozane-tazobactam (C/T) is a novel cephalosporin with in vitro activity against Pseudomonas aeruginosa that is resistant to extended-spectrum penicillins and antipseudomonal cephalosporins. In order to assess the antimicrobial effect of C/T in treatment of Pseudomonas pneumonia, we investigated the pharmacokinetics and efficacy of C/T in persistently neutropenic rabbits. Pseudomonas pneumonia was established by direct endotracheal inoculation. Treatment groups consisted of C/T, ceftazidime (CAZ), piperacillin-tazobactam (TZP), and untreated controls (UC). Rabbits received a dosage of C/T of 80 mg/kg every 4 h (q4h) intravenously (i.v.) (53 mg/kg ceftolozane/26 mg/kg tazobactam) to match the free drug time above the MIC as well as a comparable plasma area under the concentration-time curve (AUC) (humanized doses of ceftolozane-tazobactam of 3 g [2 g/1 g]) q8h, due to the more rapid elimination of ceftolozane in rabbits (0.75 h) than in humans (2.5 h). Four molecularly characterized clinical P. aeruginosa isolates from patients with pneumonia were studied, including one isolate from each classification group: pan-susceptible (PS), outer membrane porin D (OPRD) porin loss (OPRDPL), efflux pump expression (EPE), and AmpC hyperexpression (ACHE). Treatment was continued for 12 days. Treatment with ceftolozane-tazobactam resulted in a ≥105 reduction in residual pulmonary and bronchoalveolar lavage (BAL) fluid bacterial burdens caused by all 4 strains (P ≤ 0.01). This antibacterial activity coincided with reduction of lung weight (an organism-mediated pulmonary injury marker) (P < 0.05). CAZ was less active in ACHE-infected rabbits, and TZP had less activity against EPE, ACHE, and OPRDPL strains. Survival was prolonged in the C/T and CAZ treatment groups in comparison to the TZP and UC groups (P < 0.001). Ceftolozane-tazobactam is highly active in treatment of experimental P. aeruginosa pneumonia in persistently neutropenic rabbits, including infections caused by strains with the most common resistance mechanisms.

Keywords: Pseudomonas aeruginosa; ceftolozane-tazobactam; pneumonia; rabbits.

Copyright © 2019 American Society for Microbiology.

Figures

FIG 1

Plasma pharmacokinetics of ceftolozane on day 6 after intravenous administration of ceftolozane-tazobactam at 40 (26.3 mg/kg ceftolozane), 80 (53.3 mg/kg ceftolozane), and 160 (106.6 mg/kg ceftolozane) mg/kg every 8 h to healthy New Zealand White rabbits. All values are presented as means from samples of four animals each ± SEM.

FIG 2

Dose proportionality of ceftolozane administered as ceftolozane-tazobactam across dosages of 26 and 106 mg/kg i.v.

FIG 3

Pulmonary bacterial burden (log CFU/g) in rabbits with experimental Pseudomonas aeruginosa pneumonia treated with ceftolozane-tazobactam (C/T), ceftazidime (CAZ), and piperacillin-tazobactam (TZP) according to mechanism of resistance. †, P < 0.01 (decreased residual bacterial burden in treatment groups in comparison to that in untreated controls). All values are expressed as mean ± SEM.

FIG 4

Bronchoalveolar lavage (BAL) fluid bacterial burden (log CFU/ml) in rabbits with experimental Pseudomonas aeruginosa pneumonia treated with ceftolozane-tazobactam (C/T), ceftazidime (CAZ), and piperacillin-tazobactam (TZP) according to mechanism of resistance. *, P < 0.05; †, P < 0.01 (decreased residual bacterial burden in treatment groups in comparison to that in untreated controls). All values are expressed as mean ± SEM.

FIG 5

Lung weights (g) (marker of organism-mediated pulmonary injury) in rabbits with experimental Pseudomonas aeruginosa pneumonia treated with ceftolozane-tazobactam (C/T), ceftazidime (CAZ), and piperacillin-tazobactam (TZP) according to mechanism of resistance. *, P < 0.05; †, P < 0.01 (decreased lung weights in treatment groups in comparison to that of untreated controls). All values are expressed as mean ± SEM. The normal lung weight for the rabbits used in this study is approximately 15 g.

FIG 6

Cumulative survival probability in rabbits with experimental Pseudomonas aeruginosa pneumonia treated with ceftolozane-tazobactam (C/T), ceftazidime (CAZ), and piperacillin-tazobactam (TZP) according to mechanism of resistance. *, P < 0.05; †, P < 0.01; ¶, P < 0.01 (prolonged survival in treatment groups). All values are expressed as percentage of cumulative survival probability.

FIG 7

Hematoxylin and eosin (upper panel) and tissue Gram (lower panel) stains of P. aeruginosa-infected neutropenic rabbit lung tissue in a rabbit with experimental Pseudomonas aeruginosa pneumonia, showing severe, multifocal to coalescing, subacute, necrotizing pneumonia (upper panel) with thrombosis, pleuritis, marked edema, hemorrhage, and intralesional Gram-negative bacilli (lower panel). Large numbers of intra- and extracellular Gram-negative bacilli are present within most lesions (lower panel).