In vitro Activity of Ceftolozane/Tazobactam Alone or with an Aminoglycoside Against Multi-Drug-Resistant Pseudomonas aeruginosa from Pediatric Cystic Fibrosis Patients

Introduction: Gram-negative multi-drug resistance is an emerging threat among pediatric patients with cystic fibrosis (CF). Ceftolozane/tazobactam (C/T) is an extended-spectrum cephalosporin/beta-lactamase inhibitor combination that has been shown to maintain activity against MDR P. aeruginosa isolates. The understanding of C/T effectiveness in pediatric patients is extremely limited. Minimum inhibitory concentration (MIC) testing and time-kill analyses were performed to better understand the antimicrobial susceptibility and potential role of C/T.

Methods: Non-duplicate clinical respiratory MDR P. aeruginosa isolates (n = 5) from four pediatric CF patients were identified. MICs were determined for these isolates using CLSI broth microdilution methods. Time-kill analyses were performed using multiples of C/T alone, and combinations of C/T 2× and 8× the MIC with 30 mg/L tobramycin or 80 mg/L amikacin for all isolates. Cell counts were determined by serial dilution plating.

Results: Isolates had variable susceptibilities to C/T (range 0.5-8 mg/L), tobramycin (range 2 to >64 mg/L) and amikacin (range 8 to >256 mg/L). Time-kill analyses revealed an average of 0.71 (range -0.6 to 4.4), 1.50 (range 0.8-2.0) and 2.1 (range 1.2-3.4) log-kill at 4×, 8× and 16× the C/T MIC, respectively. At a tobramycin MIC of 32 mg/L, combination therapy showed synergistic benefit when the isolate was C/T susceptible. C/T and amikacin combination therapy showed synergistic activity at an amikacin MIC >256 mg/L when C/T MIC was 2 mg/L (4.7 log-kill at 2× C/T MIC and 4.0 log-kill at 8× C/T MIC).

Conclusion: C/T appears to be a promising treatment option for treatment of MDR P. aeruginosa in pediatric CF patients, both alone and in combination with tobramycin or amikacin. Interestingly, the benefit of C/T combination therapy with amikacin may be more pronounced than with the addition of tobramycin. Further evaluation of such combination regimens in pediatric CF patients is warranted.