Dataset Information

Multicenter Evaluation of Ceftazidime-Avibactam Susceptibility Testing of Enterobacterales and Pseudomonas aeruginosa on the Vitek 2 System.

ABSTRACT: In this multisite study, Vitek 2 AST-Gram-Negative Ceftazidime/Avibactam test results for 1,073 isolates (866 Enterobacterales and 207 Pseudomonas aeruginosa) were compared to the Clinical and Laboratory Standards Institute (CLSI) broth microdilution (BMD) reference method. The results were analyzed for essential agreement (EA), category agreement (CA), major error rates, and very major error rates following FDA/ISO performance criteria using the FDA-recognized CLSI/EUCAST breakpoints (sensitive [S], ≤8/4 μg/ml; resistant [R], ≥16/4 μg/ml). The overall EA was 94.5% (1,014/1,073) and CA was 98.7% (1,059/1,073). No very major errors were reported. The major error rate was 1.4% (14/998). Out of 14 major errors, 9 were within EA. Based on the EA and lack of an intermediate category for ceftazidime-avibactam (CZA), the adjusted major error rate for FDA criteria was 0.5% (5/998). The performance for ISO criteria after error resolutions included EA of 94.5% (1,014/1,073), CA of 98.9% (1,061/1,073), major error of 1.2% (12/998), and no very major error. Vitek 2 met the ISO and FDA criteria of ≥95% reproducibility and ≥95% quality control (QC) results within acceptable ranges for QC organisms. Vitek 2 overall performance for Enterobacterales and P. aeruginosa met or exceeded the FDA and ISO performance criteria; thus, it is a reliable alternative to the BMD reference method for routine CZA susceptibility testing.

SUBMITTER: Humphries R

PROVIDER: S-EPMC8106713 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Project description:Ceftazidime-avibactam (CZA) is the combination of a third-generation cephalosporin and a new non-β-lactam β-lactamase inhibitor capable of inactivating class A, C, and some D β-lactamases. From a collection of 2,727 clinical isolates of Enterobacterales (n = 2,235) and P. aeruginosa (n = 492) that were collected between 2016 and 2017 from five Latin American countries, we investigated the molecular resistance mechanisms to CZA of 127 (18/2,235 [0.8%] Enterobacterales and 109/492 [22.1%] P. aeruginosa). First, by qPCR for the presence of genes encoding KPC, NDM, VIM, IMP, OXA-48-like, and SPM-1 carbapenemases, and second, by whole-genome sequencing (WGS). From the CZA-resistant isolates, MBL-encoding genes were detected in all 18 Enterobacterales and 42/109 P. aeruginosa isolates, explaining their resistant phenotype. Resistant isolates that yielded a negative qPCR result for any of the MBL encoding genes were subjected to WGS. The WGS analysis of the 67 remaining P. aeruginosa isolates showed mutations in genes previously associated with reduced susceptibility to CZA, such as those involved in the MexAB-OprM efflux pump and AmpC (PDC) hyperproduction, PoxB (blaOXA-50-like), FtsI (PBP3), DacB (PBP4), and OprD. The results presented here offer a snapshot of the molecular epidemiological landscape for CZA resistance before the introduction of this antibiotic into the Latin American market. Therefore, these results serve as a valuable comparison tool to trace the evolution of the resistance to CZA in this carbapenemase-endemic geographical region. IMPORTANCE In this manuscript, we determine the molecular mechanisms of ceftazidime-avibactam resistance in Enterobacterales and P. aeruginosa isolates from five Latin American countries. Our results reveal a low rate of resistance to ceftazidime-avibactam among Enterobacterales; in contrast, resistance in P. aeruginosa has proven to be more complex, as it might involve multiple known and possibly unknown resistance mechanisms.

Project description:BackgroundCeftazidime-avibactam was approved in China in 2019 for treating complicated intra-abdominal infections, hospital-acquired pneumonia, ventilator-associated pneumonia, and infections caused by Enterobacterales and Pseudomonas aeruginosa for which treatment options are limited. However, no currently available commercial systems have been approved for antimicrobial susceptibility testing of ceftazidime-avibactam in China. Here, we evaluated the Etest and disk diffusion method for detecting the activity of ceftazidime-avibactam against Enterobacterales and P. aeruginosa in China.ResultsIn total, 194 Enterobacterales and 77 P. aeruginosa isolates, which were divided into a random selection group (140 Enterobacterales and 46 P. aeruginosa isolates) and stock group (54 Enterobacterales and 31 P. aeruginosa isolates), were assessed by the Etest, disk diffusion and broth microdilution methods. Minimum inhibitory concentrations and zone diameters were interpreted according to the CLSI supplement M100 30th edition. For all 271 tested isolates, no very major errors were found by using Etest, whereas the overall major error rate was 2.0% (4/203). The overall categorical agreement rates of Etest for Enterobacterales and P. aeruginosa were 99.5% (193/194) and 96.1% (74/77), respectively, and the essential agreement rates were 95.9% (186/194) and 94.8% (73/77), respectively. The disk diffusion method showed that the very major error and major error rates were 1.5% (3/204) and 2.5% (5/203), respectively. Overall categorical agreement rates values of the disk diffusion method for Enterobacterales and P. aeruginosa were 98.5% (191/194) and 93.5% (72/77) compared with broth microdilution, respectively.ConclusionsFor Enterobacterales and P. aeruginosa, both the Etest and disk diffusion method showed acceptable performance as alternatives to the standard broth microdilution method for clinical treatment interpretation. Application of the disk diffusion method in Enterobacterales was slightly better than that in P. aeruginosa.

Project description:Piperacillin-tazobactam (P/T) is a β-lactam-β-lactamase inhibitor combination frequently used in the hospital setting. Etest is a gradient diffusion method that represents an alternative to broth microdilution (BMD) for performing antimicrobial susceptibility testing. We conducted a multicenter evaluation of the performance of the new P/T Etest compared to that of BMD following U.S. Food and Drug Administration (FDA) and International Standards Organization (ISO) standard ISO 20776-2 criteria using Clinical and Laboratory Standards Institute (CLSI)-FDA and European Committee on Antimicrobial Susceptibility Testing (EUCAST) interpretive breakpoints, respectively. A total of 977 isolates (775 Enterobacterales isolates, 119 Pseudomonas aeruginosa isolates, and 83 Acinetobacter baumannii complex isolates) were tested. Overall essential agreement (EA) was 96.4% and 96.6% for Enterobacterales when FDA and ISO 20776-2 criteria, respectively, were followed. EA was 98.3% for P. aeruginosa and 91.6% for the A. baumannii complex when both the FDA and ISO criteria were followed. Applying CLSI-FDA breakpoints, categorical agreement (CA) reached 93.0%, 93.3%, and 89.2% for the Enterobacterales, P. aeruginosa, and the A. baumannii complex, respectively. Two very major errors (VMEs; 1.1%) were found among the Enterobacterales (for 2 Klebsiella pneumoniae isolates). No additional major errors (MEs) or VMEs were found. Applying EUCAST breakpoints, CA was 94.8% and 95.8% for Enterobacterales and P. aeruginosa, respectively (no breakpoints are currently available for the A. baumannii complex). No VMEs were observed among the Enterobacterales, but 2 (0.4%) MEs were found. Among the P. aeruginosa isolates, 2 (6.9%) VMEs and 3 (3.3%) MEs were observed. These errors resulted when P/T Etest MICs were 1 doubling dilution apart from the BMD MICs. In conclusion, the new P/T Etest represents an accurate tool for performing antimicrobial susceptibility testing of Enterobacterales, P. aeruginosa, and A. baumannii complex isolates with limited category errors.

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.

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Multicenter Evaluation of Ceftazidime-Avibactam Susceptibility Testing of Enterobacterales and Pseudomonas aeruginosa on the Vitek 2 System.

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