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Bactericidal activity, absence of serum effect, and time-kill kinetics of ceftazidime-avibactam against ?-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa.

ABSTRACT: Avibactam, a non-?-lactam ?-lactamase inhibitor with activity against extended-spectrum ?-lactamases (ESBLs), KPC, AmpC, and some OXA enzymes, extends the antibacterial activity of ceftazidime against most ceftazidime-resistant organisms producing these enzymes. In this study, the bactericidal activity of ceftazidime-avibactam against 18 Pseudomonas aeruginosa isolates and 15 Enterobacteriaceae isolates, including wild-type isolates and ESBL, KPC, and/or AmpC producers, was evaluated. Ceftazidime-avibactam MICs (0.016 to 32 ?g/ml) were lower than those for ceftazidime alone (0.06 to ?256 ?g/ml) against all isolates except for 2 P. aeruginosa isolates (1 blaVIM-positive isolate and 1 blaOXA-23-positive isolate). The minimum bactericidal concentration/MIC ratios of ceftazidime-avibactam were ?4 for all isolates, indicating bactericidal activity. Human serum and human serum albumin had a minimal effect on ceftazidime-avibactam MICs. Ceftazidime-avibactam time-kill kinetics were evaluated at low MIC multiples and showed time-dependent reductions in the number of CFU/ml from 0 to 6 h for all strains tested. A ?3-log10 decrease in the number of CFU/ml was observed at 6 h for all Enterobacteriaceae, and a 2-log10 reduction in the number of CFU/ml was observed at 6 h for 3 of the 6 P. aeruginosa isolates. Regrowth was noted at 24 h for some of the isolates tested in time-kill assays. These data demonstrate the potent bactericidal activity of ceftazidime-avibactam and support the continued clinical development of ceftazidime-avibactam as a new treatment option for infections caused by Enterobacteriaceae and P. aeruginosa, including isolates resistant to ceftazidime by mechanisms dependent on avibactam-sensitive ?-lactamases.

SUBMITTER: Keepers TR

PROVIDER: S-EPMC4135815 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Bactericidal activity, absence of serum effect, and time-kill kinetics of ceftazidime-avibactam against β-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa.

Keepers Tiffany R TR Gomez Marcela M Celeri Chris C Nichols Wright W WW Krause Kevin M KM

Antimicrobial agents and chemotherapy 20140623 9

Avibactam, a non-β-lactam β-lactamase inhibitor with activity against extended-spectrum β-lactamases (ESBLs), KPC, AmpC, and some OXA enzymes, extends the antibacterial activity of ceftazidime against most ceftazidime-resistant organisms producing these enzymes. In this study, the bactericidal activity of ceftazidime-avibactam against 18 Pseudomonas aeruginosa isolates and 15 Enterobacteriaceae isolates, including wild-type isolates and ESBL, KPC, and/or AmpC producers, was evaluated. Ceftazidim ...[more]

PMID: 24957838

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Project description:Klebsiella pneumoniae carbapenemase (KPC)-producing Pseudomonas aeruginosa (KPC-PA) has been reported sporadically. However, epidemiological and antimicrobial susceptibility data specific for KPC-PA are lacking. We collected 374 carbapenem-resistant P. aeruginosa (CRPA) isolates from seven hospitals in China from June 2016 to February 2019 and identified the blaKPC-2 gene in 40.4% (n = 151/374) of the isolates. Approximately one-half of all KPC-PA isolates (n = 76/151; 50.3%) were resistant to ceftazidime-avibactam (CAZ-AVI). Combining Kraken2 taxonomy identification and Nanopore sequencing, we identified eight plasmid types, five of which carried blaKPC-2, and 13 combination patterns of these plasmid types. In addition, we identified IS26-ΔTn6296 and Tn1403-like-ΔTn6296 as the two mobile genetic elements that mediated blaKPC-2 transmission. blaKPC-2 plasmid curing in 28 strains restored CAZ-AVI susceptibility, suggesting that blaKPC-2 was the mediator of CAZ-AVI resistance. Furthermore, the blaKPC-2 copy number was found to correlate with KPC expression and, therefore, CAZ-AVI resistance. Taken together, our results suggest that KPC-PA is becoming a clinical threat and that using CAZ-AVI to treat this specific pathogen should be done with caution. IMPORTANCE Previous research has reported several cases of KPC-PA strains and three KPC-encoding P. aeruginosa plasmid types in China. However, the prevalence and clinical significance of KPC-PA are not available. In addition, the susceptibility of the strains to CAZ-AVI remains unknown. Samples in this study were collected from seven tertiary hospitals prior to CAZ-AVI clinical approval in China. Therefore, our results represent a retrospective study establishing the baseline efficacy of the novel β-lactam/β-lactamase combination agent for treating KPC-PA infections. The observed correlation between the blaKPC copy number and CAZ-AVI resistance suggests that close monitoring of the susceptibility of the strain during treatment is required. It would also be beneficial to screen for the blaKPC gene in CRPA strains for antimicrobial surveillance purposes.

Project description:The activities of ceftazidime-avibactam, ceftolozane-tazobactam, and comparators were evaluated for 733 isolates displaying resistance to broad-spectrum cephalosporins and carrying extended-spectrum β-lactamase (ESBL) genes detected by whole-genome sequencing analysis. Isolates were collected during 2017 in U.S. hospitals. The ESBL producers were 486 Escherichia coli, 190 Klebsiella pneumoniae, and 42 Enterobacter cloacae isolates and isolates from 3 other species. The most common groups of ESBL-encoding genes were blaCTX-M-15-like (n = 491 isolates) and blaCTX-M-15 alone (n = 168) or plus blaOXA-1 (n = 260), followed by blaCTX-M-14-like (n = 162), which included blaCTX-M-27 and blaCTX-M-14 (104 and 51 isolates, respectively), and blaSHV-12 and blaSHV-7 (48 and 22 isolates, respectively). ESBL producers carried other β-lactamases, including 1 E. cloacae harboring blaKPC-3 All ESBL-producing isolates were susceptible to ceftazidime-avibactam, and 90.2/83.9% (CLSI/EUCAST breakpoints) were susceptible to ceftolozane-tazobactam. Tigecycline (98.1/95.8% susceptible) and colistin (99.2%) were comparators that displayed the greatest activity against these isolates. Ceftolozane-tazobactam inhibited 91.4/83.9% of isolates carrying blaCTX-M-15-like and 97.5/95.1% of isolates carrying blaCTX-M-14-like, and its activity was more limited against the 91 isolates carrying blaSHV (66.7/61.1% susceptible). Ceftolozane-tazobactam inhibited 95.5% of the E. coli isolates but only 83.0%, 64.3%, and 80.0% of K. pneumoniae, E. cloacae, and other species harboring ESBL-encoding genes (CLSI breakpoints), respectively. Outer membrane protein sequences for ceftolozane-tazobactam-nonsusceptible isolates did not exhibit significant differences compared to those in genetically related ceftolozane-tazobactam-susceptible isolates. Ceftazidime-avibactam was more active than other agents tested, including ceftolozane-tazobactam, and the activity of this combination was stable regardless of species or ESBL gene carried.

Project description:Background:The efficacy of ceftazidime-avibactam-a cephalosporin-?-lactamase inhibitor combination with in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE)-compared with colistin remains unknown. Methods:Patients initially treated with either ceftazidime-avibactam or colistin for CRE infections were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study. Efficacy, safety, and benefit-risk analyses were performed using intent-to-treat analyses with partial credit and the desirability of outcome ranking approaches. The ordinal efficacy outcome was based on disposition at day 30 after starting treatment (home vs not home but not observed to die in the hospital vs hospital death). All analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW). Results:Thirty-eight patients were treated first with ceftazidime-avibactam and 99 with colistin. Most patients received additional anti-CRE agents as part of their treatment. Bloodstream (n = 63; 46%) and respiratory (n = 30; 22%) infections were most common. In patients treated with ceftazidime-avibactam versus colistin, IPTW-adjusted all-cause hospital mortality 30 days after starting treatment was 9% versus 32%, respectively (difference, 23%; 95% bootstrap confidence interval, 9%-35%; P = .001). In an analysis of disposition at 30 days, patients treated with ceftazidime-avibactam, compared with those treated within colistin, had an IPTW-adjusted probability of a better outcome of 64% (95% confidence interval, 57%-71%). Partial credit analyses indicated uniform superiority of ceftazidime-avibactam to colistin. Conclusions:Ceftazidime-avibactam may be a reasonable alternative to colistin in the treatment of K. pneumoniae carbapenemase-producing CRE infections. These findings require confirmation in a randomized controlled trial.

Dataset Information

Bactericidal activity, absence of serum effect, and time-kill kinetics of ceftazidime-avibactam against ?-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa.

Publications

Bactericidal activity, absence of serum effect, and time-kill kinetics of ceftazidime-avibactam against β-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa.

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