Ceftolozane-Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections: Clinical Effectiveness and Evolution of Resistance

Abstract

Background: Data on the use of ceftolozane-tazobactam and emergence of ceftolozane-tazobactam resistance during multidrug resistant (MDR)-Pseudomonas aeruginosa infections are limited.

Methods: We performed a retrospective study of 21 patients treated with ceftolozane-tazobactam for MDR-P. aeruginosa infections. Whole genome sequencing and quantitative real-time polymerase chain reaction were performed on longitudinal isolates.

Results: Median age was 58 years; 9 patients (43%) were transplant recipients. Median simplified acute physiology score-II (SAPS-II) was 26. Eighteen (86%) patients were treated for respiratory tract infections; others were treated for bloodstream, complicated intraabdominal infections, or complicated urinary tract infections. Ceftolozane-tazobactam was discontinued in 1 patient (rash). Thirty-day all-cause and attributable mortality rates were 10% (2/21) and 5% (1/21), respectively; corresponding 90-day mortality rates were 48% (10/21) and 19% (4/21). The ceftolozane-tazobactam failure rate was 29% (6/21). SAPS-II score was the sole predictor of failure. Ceftolozane-tazobactam resistance emerged in 3 (14%) patients. Resistance was associated with de novo mutations, rather than acquisition of resistant nosocomial isolates. ampC overexpression and mutations were identified as potential resistance determinants.

Conclusions: In this small study, ceftolozane-tazobactam was successful in treating 71% of patients with MDR-P. aeruginosa infections, most of whom had pneumonia. The emergence of ceftolozane-tazobactam resistance in 3 patients is worrisome and may be mediated in part by AmpC-related mechanisms. More research on treatment responses and resistance during various types of MDR-P. aeruginosa infections is needed to define ceftolozane-tazobactam's place in the armamentarium.

Keywords: AmpC beta-lactamase; MDR Pseudomonas; ceftolozane-tazobactam; omega loop; resistance mechanisms.

Figure 1.

Whole genome phylogeny of isolates from patients treated with ceftolozane-tazobactam and isolates with preexisting ceftolozane-tazobactam resistance from a control patient who was not treated with the drug (patient 22 [P22]) [41]. The phylogeny was inferred from all informative single nucleotide polymorphisms in the core genome with FastTree, using the most closely related available reference genome, strain PA_BWHPSA022. All isolates definitively cluster by patient (P). Sensitivity or resistance to ceftolozane-tazobactam is denoted as S or R and timing of isolation is denoted by numbering (eg, for patient 7: P7-S, P7-R1, P7-R2, P7-R3, P7-R4). Distance bar = 0.2 nucleotide differences per phylogenetically informative site.

Figure 2.

Diagram of mutations occurring in the ampR-ampC genomic region among resistant isolates. Mutation location, type, and proximity to the Ω-loop, known to confer resistance when mutated, is denoted. Orange box: nucleotides deleted in isolates from patient 7. Yellow box: domain encoding the Ω-loop. Abbreviation: bp, basepair.