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      Emergence of Ceftolozane-Tazobactam-Resistant Pseudomonas aeruginosa during Treatment Is Mediated by a Single AmpC Structural Mutation

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      Antimicrobial Agents and Chemotherapy
      American Society for Microbiology

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          ABSTRACT

          Ceftolozane-tazobactam is a cephalosporin-β-lactamase inhibitor combination that exhibits potent in vitro activity against Pseudomonas aeruginosa , including strains that are resistant to other β-lactams. The emergence of ceftolozane-tazobactam resistance among clinical isolates of P. aeruginosa has rarely been described. Here we characterized ceftolozane-tazobactam-resistant P. aeruginosa strains recovered from a patient who was treated with this agent for 6 weeks for a recurrent wound infection. The results showed that the resistance was mediated by a single AmpC structural mutation.

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          Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations.

          Ceftolozane/tazobactam and ceftazidime/avibactam are 2 novel β-lactam/β-lactamase combination antibiotics. The antimicrobial spectrum of activity of these antibiotics includes multidrug-resistant (MDR) gram-negative bacteria (GNB), including Pseudomonas aeruginosa. Ceftazidime/avibactam is also active against carbapenem-resistant Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases. However, avibactam does not inactivate metallo-β-lactamases such as New Delhi metallo-β-lactamases. Both ceftolozane/tazobactam and ceftazidime/avibactam are only available as intravenous formulations and are dosed 3 times daily in patients with normal renal function. Clinical trials showed noninferiority to comparators of both agents when used in the treatment of complicated urinary tract infections and complicated intra-abdominal infections (when used with metronidazole). Results from pneumonia studies have not yet been reported. In summary, ceftolozane/tazobactam and ceftazidime/avibactam are 2 new second-generation cephalosporin/β-lactamase inhibitor combinations. After appropriate trials are conducted, they may prove useful in the treatment of MDR GNB infections. Antimicrobial stewardship will be essential to preserve the activity of these agents.
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            Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections.

            Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Klebsiella pneumoniae carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant K. pneumoniae emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Whole-genome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant K. pneumoniae isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne blaKPC-3, which were not present in baseline isolates. blaKPC-3 mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in K. pneumoniae, plasmid transfer, and blaKPC cloning into competent Escherichia coli In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y/T243M double substitution > D179Y > V240G. Remarkably, mutations reduced meropenem MICs ≥4-fold from baseline, restoring susceptibility in K. pneumoniae from two patients. Cefepime and ceftriaxone MICs were also reduced ≥4-fold against D179Y/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of blaKPC-3 encoding D179Y/T243M and D179Y variants was diminished compared to blaKPC-3 expression in baseline isolates. In conclusion, the development of resistance-conferring blaKPC-3 mutations in K. pneumoniae within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates.
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              Ceftolozane-Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections: Clinical Effectiveness and Evolution of Resistance

              Twenty-one patients were treated with ceftolozane-tazobactam for multidrug-resistant Pseudomonas aeruginosa infections, predominantly pneumonia. Thirty- and 90-day mortality rates were 10% and 48%, respectively. Resistance emerged in 3 patients, which was associated with mutations in and/or increased expression of ampC β-lactamase. 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.
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                Author and article information

                Journal
                Antimicrobial Agents and Chemotherapy
                Antimicrob. Agents Chemother.
                American Society for Microbiology
                0066-4804
                1098-6596
                November 22 2017
                December 2017
                December 2017
                September 25 2017
                : 61
                : 12
                Article
                10.1128/AAC.01183-17
                5700322
                28052850
                12a0f3ae-4c41-4507-b4f3-ba662f7e7a9d
                © 2017
                History

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