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Antimicrobial activity of ceftazidime-avibactam against Gram-negative organisms collected from U.S. medical centers in 2012.

ABSTRACT: The activities of the novel ?-lactam-?-lactamase inhibitor combination ceftazidime-avibactam and comparator agents were evaluated against a contemporary collection of clinically significant Gram-negative bacilli. Avibactam is a novel non-?-lactam ?-lactamase inhibitor that inhibits Ambler class A, C, and some D enzymes. A total of 10,928 Gram-negative bacilli-8,640 Enterobacteriaceae, 1,967 Pseudomonas aeruginosa, and 321 Acinetobacter sp. isolates-were collected from 73 U.S. hospitals and tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Ceftazidime was combined with avibactam at a fixed concentration of 4 ?g/ml. Overall, 99.8% of Enterobacteriaceae strains were inhibited at a ceftazidime-avibactam MIC of ?4 ?g/ml. Ceftazidime-avibactam was active against extended-spectrum ?-lactamase (ESBL)-phenotype Escherichia coli and Klebsiella pneumoniae, meropenem-nonsusceptible (MIC?2 ?g/ml) K. pneumoniae, and ceftazidime-nonsusceptible Enterobacter cloacae. Among ESBL-phenotype K. pneumoniae strains, 61.1% were meropenem susceptible and 99.3% were inhibited at a ceftazidime-avibactam MIC of ?4 ?g/ml. Among P. aeruginosa strains, 96.9% were inhibited at a ceftazidime-avibactam MIC of ?8 ?g/ml, and susceptibility rates for meropenem, ceftazidime, and piperacillin-tazobactam were 82.0, 83.2, and 78.3%, respectively. Ceftazidime-avibactam was the most active compound tested against meropenem-nonsusceptible P. aeruginosa (MIC50/MIC90, 4/16 ?g/ml; 87.3% inhibited at ?8 ?g/ml). Acinetobacter spp. (ceftazidime-avibactam MIC50/MIC90, 16/>32 ?g/ml) showed high rates of resistance to most tested agents. In summary, ceftazidime-avibactam demonstrated potent activity against a large collection of contemporary Gram-negative bacilli isolated from patients in U.S. hospitals in 2012, including organisms that are resistant to most currently available agents, such as K. pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae and meropenem-nonsusceptible P. aeruginosa.

SUBMITTER: Sader HS

PROVIDER: S-EPMC3957905 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Antimicrobial activity of ceftazidime-avibactam against Gram-negative organisms collected from U.S. medical centers in 2012.

Sader Helio S HS Castanheira Mariana M Flamm Robert K RK Farrell David J DJ Jones Ronald N RN

Antimicrobial agents and chemotherapy 20131230 3

The activities of the novel β-lactam-β-lactamase inhibitor combination ceftazidime-avibactam and comparator agents were evaluated against a contemporary collection of clinically significant Gram-negative bacilli. Avibactam is a novel non-β-lactam β-lactamase inhibitor that inhibits Ambler class A, C, and some D enzymes. A total of 10,928 Gram-negative bacilli-8,640 Enterobacteriaceae, 1,967 Pseudomonas aeruginosa, and 321 Acinetobacter sp. isolates-were collected from 73 U.S. hospitals and teste ...[more]

PMID: 24379201

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Project description:Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae isolates have been increasingly reported worldwide, and therapeutic options to treat infections caused by these organisms are limited. We evaluated the activity of ceftazidime-avibactam and comparators against 456 Enterobacteriaceae isolates carrying blaKPC collected from 79 U.S. hospitals during 2012 to 2015. Overall, ceftazidime-avibactam (MIC50/90, 0.5/2 μg/ml; 99.3% susceptible) and tigecycline (MIC50/90, 0.5/1 μg/ml; 98.9% susceptible at ≤2 μg/ml) were the most active agents. Only 80.5% and 59.0% of isolates were susceptible to colistin and amikacin, respectively. All three isolates (0.7%) displaying resistance to ceftazidime-avibactam (K. pneumoniae; MICs, ≥16 μg/ml) were evaluated using whole-genome sequencing analysis and relative quantification of expression levels of porins and efflux pump. Two isolates carried metallo-β-lactamase genes, blaNDM-1 or blaVIM-4, among other β-lactam resistance mechanisms, and one displayed a premature stop codon in ompK35 and decreased expression of ompK36 Ceftazidime-avibactam was active against 100.0 and 99.3% of isolates carrying blaKPC-3 (n = 221) and blaKPC-2 (n = 145), respectively. Isolates carrying blaKPC were more commonly recovered from pneumonia (n = 155), urinary tract (n = 93), and skin/soft tissue (n = 74) infections. Ceftazidime-avibactam (97.8 to 100.0% susceptible) was consistently active against isolates from all infection sites. K. pneumoniae (83.3% of the collection) susceptibility rates were 99.2% for ceftazidime-avibactam, 98.9% for tigecycline, and 80.1% for colistin. Ceftazidime-avibactam susceptibility did not vary substantially when comparing isolates from intensive care unit (ICU) patients to those from non-ICU patients. Ceftazidime-avibactam was active against this large collection of isolates carrying blaKPC and represents a valuable addition to the armamentarium currently available for the treatment of infections caused by KPC-producing Enterobacteriaceae.

Project description:BackgroundIncreases in resistance to fluoroquinolones have been correlated with the use of levofloxacin in the treatment of infections caused by Escherichia coli. The analysis presents the in vitro activity of ceftazidime-avibactam and comparator agents against 10,840 levofloxacin-resistant E. coli isolates collected from four geographic regions (Africa/Middle East, Europe, Asia/South Pacific, Latin America) between 2012 and 2018.MethodsNon-duplicate clinical isolates of E. coli were collected from participating centres and shipped to IHMA, Inc., (Schaumburg, IL, USA). Susceptibility testing was performed with frozen broth microdilution panels manufactured by IHMA, according to CLSI guidelines. Levofloxacin-resistance was defined at a minimum inhibitory concentration of ≥ 2 mg/L. Isolates collected between 2012 and 2015 were tested for extended-spectrum β-lactamase (ESBL) activity by determining susceptibility to cefotaxime, cefotaxime-clavulanate, ceftazidime, and ceftazidime-clavulanate as recommended by CLSI guidelines. Isolates collected between 2016 and 2018 were identified as ESBL-positive by genotype using multiplex polymerase chain reaction assays.ResultsA total of 74.8% of levofloxacin-resistant E. coli isolates in the analysis were from three culture sources: urinary tract infections (N = 3229; 29.8%), skin and skin structure infections (N = 2564; 23.7%) and intra-abdominal infections (N = 2313; 21.3%). Susceptibility rates to ceftazidime-avibactam were consistently high in all regions against both ESBL-positive (97.0% in Asia/South Pacific to 99.7% in Africa/Middle East and Latin America) and ESBL-negative isolates (99.4% in Asia/South Pacific to 100% in Latin America). Susceptibility was also high in each region among ESBL-positive and ESBL-negative isolates to colistin (≥ 98.5%), imipenem (≥ 96.5%), meropenem (≥ 96.5%) and tigecycline (≥ 94.1%).ConclusionsAntimicrobial susceptibility to ceftazidime-avibactam among levofloxacin-resistant E. coli isolates, including ESBL-positive isolates, collected from four geographical regions between 2012 and 2018 was consistently high. Susceptibility to the comparator agents colistin, tigecycline, imipenem and meropenem was also high.

Project description:Objective: To systematically review and compare the efficacy and posttreatment resistance of ceftazidime-avibactam therapy and ceftazidime-avibactam-based combination therapy in patients with Gram-negative pathogens. Methods: PubMed, Embase, Web of Science, CNKI, and Wanfang Data databases were searched from their inception up to March 31, 2021, to obtain studies on ceftazidime-avibactam therapy versus ceftazidime-avibactam-based combination therapy in patients with carbapenem-resistant Gram-negative pathogens. The primary outcome was mortality rate, and the second outcomes were microbiologically negative, clinical success, and the development of resistance after ceftazidime-avibactam treatment. Results: Seventeen studies representing 1,435 patients (837 received ceftazidime-avibactam-based combination therapy and 598 received ceftazidime-avibactam therapy) were included in the meta-analysis. The results of the meta-analysis showed that no statistically significant difference was found on mortality rate (Petos odds ratio (OR) = 1.03, 95% confidence interval (CI) 0.79-1.34), microbiologically negative (OR = 0.99, 95% CI 0.54-1.81), and clinical success (OR =0.95, 95% CI 0.64-1.39) between ceftazidime-avibactam-based combination therapy and ceftazidime-avibactam therapy. Although there was no difference in posttreatment resistance of ceftazidime-avibactam (OR = 0.65, 95% CI 0.34-1.26) in all included studies, a trend favoring the combination therapy was found (according to the pooled three studies, OR = 0.18, 95% CI 0.04-0.78). Conclusions: The current evidence suggests that ceftazidime-avibactam-based combination therapy may not have beneficial effects on mortality, microbiologically negative, and clinical success to patients with carbapenem-resistant Gram-negative pathogens. A trend of posttreatment resistance occurred more likely in ceftazidime-avibactam therapy than the combination therapy. Due to the limited number of studies that can be included, additional high-quality studies are needed to verify the above conclusions.

Project description:Broth microdilution antimicrobial susceptibility testing was performed for ceftazidime-avibactam and comparator agents against 7,062 clinical isolates of Pseudomonas aeruginosa collected from 2012 to 2014 in four geographic regions (Europe, Asia/South Pacific, Latin America, Middle East/Africa) as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. The majority of isolates were susceptible to ceftazidime-avibactam, with the proportions susceptible differing marginally across the four regions (MIC90, 8 to 16 ?g/ml; 88.7 to 93.2% susceptible), in contrast to lower susceptibilities to the following comparator ?-lactam agents: ceftazidime (MIC90, 32 to 64 ?g/ml; 71.5 to 80.8% susceptible), meropenem (MIC90, >8 ?g/ml; 64.9 to 77.4% susceptible), and piperacillin-tazobactam (MIC90, >128 ?g/ml; 62.3 to 71.3% susceptible). Compared to the overall population, susceptibility to ceftazidime-avibactam of isolates that were nonsusceptible to ceftazidime (n = 1,627) was reduced to between 56.8% (Middle East/Africa; MIC90, 64 ?g/ml) and 68.9% (Asia/South Pacific; MIC90, 128 ?g/ml), but these percentages were higher than susceptibilities to other ?-lactam agents (0 to 44% susceptible, depending on region and agent; meropenem MIC90, >8 ?g/ml; 26.5 to 43.9% susceptible). For this subset of isolates, susceptibilities to amikacin (MIC90, >32 ?g/ml; 53.2 to 80.0% susceptible) and colistin (MIC90, 1 ?g/ml; 98.5 to 99.5% susceptible) were comparable to or higher than that of ceftazidime-avibactam. A similar observation was made with isolates that were nonsusceptible to meropenem (n = 1,926), with susceptibility to ceftazidime-avibactam between 67.8% (Middle East/Africa; MIC90, 64 ?g/ml) and 74.2% (Europe; MIC90, 32 ?g/ml) but again with reduced susceptibility to comparators except for amikacin (MIC90, >32 ?g/ml; 56.8 to 78.7% susceptible) and colistin (MIC90, 1 ?g/ml; 98.9 to 99.3% susceptible). Of the 8% of isolates not susceptible to ceftazidime-avibactam, the nonsusceptibility of half could be explained by their possession of genes encoding metallo-?-lactamases. The data reported here are consistent with results from other country-specific and regional surveillance studies and show that ceftazidime-avibactam demonstrates in vitro activity against globally collected clinical isolates of P. aeruginosa, including isolates that are resistant to ceftazidime and meropenem.

Dataset Information

Antimicrobial activity of ceftazidime-avibactam against Gram-negative organisms collected from U.S. medical centers in 2012.

Publications

Antimicrobial activity of ceftazidime-avibactam against Gram-negative organisms collected from U.S. medical centers in 2012.

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