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.

Occurrence of Multiple, Extensive and Pan Drug-Resistant Pseudomonas aeruginosa and Carbapenemase Production from Presumptive Isolates Stored in a Biobank at Ethiopian Public Health Institute

“…23 Experimental research using rabbits demonstrated that ceftolozane-tazobactam was a highly potent antipseudomonal drug that can eradicate genetically distinctive Pseudomonas strains having excellent host survival with effective clearance from tissue. 24 Various surveillance-based studies also showed greater than 90% susceptibility results on this drug, 25 which is in agreement with our finding. Nowadays, this drug is approved by the United States Food and Drug Administration as it is a confirmed novel anti-pseudomonal β-lactam/βlactamase inhibitor combination.…”

New Antibiotics for Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia

“…45 However, to ensure therapeutic drug concentration at the site of the infection and to cover pathogen with higher MICs, the drug is currently approved for the treatment of HAP and VAP at the dosage of 2 g of ceftolozane with 1 g of tazobactam every 8 hours. 46 Since both ceftolozane and tazobactam are primarily eliminated through renal excretion, dosage adjustment is required for patients with acute or chronic kidney injury. 47 The approval of ceftolozane-tazobactam for the treatment of nosocomial pneumonia was based on the ASPECT-NP study, a noninferiority phase 3 trial comparing the efficacy and safety of ceftolozane-tazobactam 3 g every 8 hours with meropenem 1 g every 8 hours for 7 to 14 days of therapy.…”

“…45 However, to ensure therapeutic drug concentration at the site of the infection and to cover pathogen with higher MICs, the drug is currently approved for the treatment of HAP and VAP at the dosage of 2 g of ceftolozane with 1 g of tazobactam every 8 hours. 46 Since both ceftolozane and tazobactam are primarily eliminated through renal excretion, dosage adjustment is required for patients with acute or chronic kidney injury. 47…”

New antibiotics for Gram-negative pneumonia

“…This finding indicates that ELF concentrations of ceftolozane-tazobactam may reach and exceed the MIC of most Gram-negative pathogens causing nosocomial pneumonia [ 32 ]. However, ceftolozane-tazobactam is currently approved for the treatment of nosocomial pneumonia (both HAP and VAP) at a higher dosage (2 g of ceftolozane and 1 g of tazobactam every 8 h) [ 33 ].…”