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Comparative Evaluation of the In Vitro Activities of WCK 5222 (Cefepime-Zidebactam) and Combination Antibiotic Therapies against Carbapenem-Resistant Pseudomonas aeruginosa.

ABSTRACT: The in vitro activity of WCK 5222 (cefepime-zidebactam) was compared to that of several available combination therapies among 30 clinical carbapenem-resistant Pseudomonas aeruginosa (CRP) strains using gradient diffusion strips. The combinations included nonsusceptible ?-lactams (cefepime, ceftolozane-tazobactam, and meropenem) with amikacin and fosfomycin. WCK 5222 MICs ranged from 2 to 32?mg/liter, and 97% were ?16?mg/liter, while 105/146 (72%) combinations demonstrated inhibition below established susceptibility breakpoints. WCK 5222 monotherapy may be preferred over the combinations assessed for CRP infections.

SUBMITTER: Mullane EM

PROVIDER: S-EPMC7038276 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Comparative Evaluation of the In Vitro Activities of WCK 5222 (Cefepime-Zidebactam) and Combination Antibiotic Therapies against Carbapenem-Resistant Pseudomonas aeruginosa.

Mullane Elias M EM Avery Lindsay M LM Nicolau David P DP

Antimicrobial agents and chemotherapy 20200221 3

The in vitro activity of WCK 5222 (cefepime-zidebactam) was compared to that of several available combination therapies among 30 clinical carbapenem-resistant Pseudomonas aeruginosa (CRP) strains using gradient diffusion strips. The combinations included nonsusceptible β-lactams (cefepime, ceftolozane-tazobactam, and meropenem) with amikacin and fosfomycin. WCK 5222 MICs ranged from 2 to 32 mg/liter, and 97% were ≤16 mg/liter, while 105/146 (72%) combinations demonstrated inhibitio ...[more]

PMID: 31844009

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Project description:WCK 5222 (cefepime/zidebactam) is a β-lactam/β-lactamase inhibitor combination that is effective against a broad range of highly drug-resistant bacterial pathogens, including those producing metallo-β-lactamase. In this study, we isolated a multidrug-resistant Pseudomonas aeruginosa clinical strain that is resistant to a variety of β-lactam antibiotics and the ceftazidime-avibactam combination. A metallo-β-lactamase gene blaDIM-2 was identified on a self-transmissible megaplasmid in the strain, which confers the resistance to β-lactam antibiotics, leaving WCK 5222 potentially one of the last treatment resorts. In vitro passaging assay combined with whole-genome sequencing revealed mutations in the pbpA gene (encoding the zidebactam target protein PBP2) in the evolved resistant mutants. Among the mutations, a V516M mutation increased the bacterial virulence in a murine acute pneumonia model. Reconstitution of the mutations in the reference strain PAO1 verified their roles in the resistance to zidebactam and revealed their influences on cell morphology in the absence and presence of zidebactam. Microscale thermophoresis (MST) assays demonstrated that the mutations reduced the affinity between PBP2 and zidebactam to various extents. Overall, our results revealed that mutations in the pbpA gene might be a major cause of evolved resistance to WCK 5222 in clinical settings. IMPORTANCE Antibiotic resistance imposes a severe threat on human health. WCK 5222 is a β-lactam/β-lactamase inhibitor combination that is composed of cefepime and zidebactam. It is one of the few antibiotics in clinical trials that are effective against multidrug-resistant Pseudomonas aeruginosa, including those producing metallo-β-lactamases. Understanding the mechanisms and development of bacterial resistance to WCK 5222 may provide clues for the development of strategies to suppress resistant evolvement. In this study, we performed an in vitro passaging assay by using a multidrug-resistant P. aeruginosa clinical isolate. Our results revealed that mutations in the zidebactam target protein PBP2 play a major role in the bacterial resistance to WCK 5222. We further demonstrated that the mutations reduced the affinities between PBP2 and zidebactam and resulted in functional resistance of PBP2 to zidebactam.

Project description:WCK 5222 (cefepime-zidebactam, 2 g + 1g, every 8 h [q8h]) is in clinical development for the treatment of infections caused by carbapenem-resistant and multidrug-resistant (MDR) Gram-negative bacilli. We determined the in vitro susceptibility of 1,385 clinical isolates of non-carbapenem-susceptible Enterobacterales, MDR Pseudomonas aeruginosa (also non-carbapenem susceptible), Stenotrophomonas maltophilia, and Burkholderia spp. collected worldwide (49 countries) from 2014 to 2016 to cefepime-zidebactam (1:1 ratio), ceftazidime-avibactam, imipenem-relebactam, ceftolozane-tazobactam, and colistin using the CLSI broth microdilution method. Cefepime-zidebactam inhibited 98.5% of non-carbapenem-susceptible Enterobacterales (n = 1,018) at ≤8 μg/ml (provisional cefepime-zidebactam-susceptible MIC breakpoint). Against the subset of metallo-β-lactamase (MBL)-positive Enterobacterales (n = 214), cefepime-zidebactam inhibited 94.9% of isolates at ≤8 μg/ml. Further, it inhibited 99.6% of MDR P. aeruginosa (n = 262) isolates at ≤32 μg/ml (proposed cefepime-zidebactam-susceptible pharmacokinetic/pharmacodynamic MIC breakpoint), including all MBL-positive isolates (n = 94). Moreover, cefepime-zidebactam was active against the majority of isolates of Enterobacterales (≥95%) and P. aeruginosa (99%) that were not susceptible to ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and colistin. Most isolates (99%) of S. maltophilia (n = 101; MIC50, 8 μg/ml; MIC90, 32 μg/ml) and Burkholderia spp. (n = 4; MIC range, 16 to 32 μg/ml) were also inhibited by cefepime-zidebactam at ≤32 μg/ml. The activity of cefepime-zidebactam against carbapenem-resistant Gram-negative bacteria is ascribed to its β-lactam enhancer mechanism of action (i.e., zidebactam binding to penicillin binding protein 2 [PBP2] and its universal stability to both serine β-lactamases and MBLs). The results from this study support the continued development of cefepime-zidebactam as a potential therapy for infections caused by Enterobacterales, P. aeruginosa, and other nonfermentative Gram-negative bacilli where resistance to marketed antimicrobial agents is a limiting factor.

Project description:BACKGROUND: Carbapenemase genes are one of the most frequent mechanisms reported in carbapenem-resistant P. aeruginosa; however, description of P. aeruginosa co-harbouring two or more carbapenemases is unusual. METHODS: In this study we evaluated the presence of carbapenemase genes and the clonality of P. aeruginosa isolates obtained from a hospital over a 12-year period. A total of 127 isolates of carbapenem-resistant P. aeruginosa recovered from 109 patients feces (four samples), rectal swab (three samples), nasal swab (one sample) and anal abscess (one sample), were evaluated. Minimum inhibitory concentrations of the following antibiotics imipenem, meropenem and polymyxin E were determined by broth microdilution. The molecular profile of isolates was evaluated by pulsed field gel electrophoresis (PFGE). PCR for the following carbapenemase genes blaIMP;blaSPM;blaVIM;blaSIM;blaNDM;blaKPC;blaGES and nucleotide sequencing to confirm the enzyme gene types were performed and compared with the database available on the Internet (BLAST-http://www.ncbi.nlm.nhi.gov/blast/). RESULTS: All isolates were carbapenem-resistant, their MIC50 and MIC90 were respectively 64 ?g/mL and 256 ?g/mL to imipenem and 32 ?g/mL and 256 ?g/mL to meropenem, all isolates except one (MIC = 8 mg/L) were susceptible to polymyxin E. The most frequent carbapenemase genes identified were blaSPM identified in 41 isolates (32%), followed by 10 with blakpc and 5 with blaVIM (3.9%). All belonged to the class SPM-1 and VIM-2. In 2011, one isolate harbouring three carbapenemase genes (SPM-1, VIM-2 and KPC-2) that belonged to a new clone was identified in a hematopoietic stem cell transplanted patient. Then, 19 carbapenem-resistant P. aeruginosa were identified in an outbreak that occurred in the bone marrow transplant unit, all positive for SPM-1 gene, and 9 (47.3%) harbored both SPM-1 and KPC. CONCLUSION: Our findings showed that PCR for KPC gene should be performed to evaluate carbapenem resistance in P. aeruginosa and that this agent can harbor more than one carbapenemase gene. Attention should be focused on the possible rapid spread of KPC in P. aeruginosa isolates and for the fact that P. aeruginosa may become a reservoir of this transmissible resistance mechanism.

Project description:This study evaluated the in vitro activity of cefepime-zidebactam in comparison with that of ceftazidime-avibactam and other comparators against clinically significant Gram-negative bacillus isolates. A total of 3,400 nonduplicate Gram-negative clinical isolates were collected from 45 medical centers across China in the CHINET Program in 2018, including Enterobacterales (n = 2,228), Pseudomonas aeruginosa (n = 657), and Acinetobacter baumannii (n = 515). The activities of cefepime-zidebactam and 20 comparators were determined by broth microdilution as recommended by the Clinical and Laboratory Standards Institute. Cefepime-zidebactam demonstrated potent activity against almost all Enterobacterales (MIC50/90, 0.125/1 mg/liter) and good activity against P. aeruginosa (MIC50/90, 2/8 mg/liter). Among the 373 carbapenem-resistant Enterobacteriaceae isolates, 57.3% (213/373) and 15.3% (57/373) were positive for blaKPC-2 and blaNDM, respectively. Cefepime-zidebactam showed a MIC of ≤2 mg/liter for 92.0% (196/213) of blaKPC-2 producers and 79.7% (47/59) of blaNDM producers. Ceftazidime-avibactam showed good in vitro activity against Enterobacterales (MIC50/90, 0.25/2 mg/liter; 94.0% susceptible) and P. aeruginosa (MIC50/90, 4/16 mg/liter; 86.9% susceptible). Ceftazidime-avibactam was active against 9.1% of carbapenem-resistant Escherichia coli isolates (63.6% were blaNDM producers) and 84.6% of Klebsiella pneumoniae isolates (74.3% were blaKPC producers). Most (90.1%) blaKPC-2 producers were susceptible to ceftazidime-avibactam. Cefepime-zidebactam demonstrated limited activity (MIC50/90, 16/32 mg/liter) against the 515 A. baumannii isolates (79.2% were carbapenem resistant), and ceftazidime-avibactam was less active (MIC50/90, 64/>64 mg/liter). Cefepime-zidebactam was highly active against clinical isolates of Enterobacterales and P. aeruginosa, including blaKPC-2-positive Enterobacterales and blaNDM-positive Enterobacterales and carbapenem-resistant P. aeruginosa And ceftazidime-avibactam was highly active against blaKPC-2-positive Enterobacterales and carbapenem-resistant P. aeruginosa.

Dataset Information

Comparative Evaluation of the In Vitro Activities of WCK 5222 (Cefepime-Zidebactam) and Combination Antibiotic Therapies against Carbapenem-Resistant Pseudomonas aeruginosa.

Publications

Comparative Evaluation of the <i>In Vitro</i> Activities of WCK 5222 (Cefepime-Zidebactam) and Combination Antibiotic Therapies against Carbapenem-Resistant <i>Pseudomonas aeruginosa</i>.

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