Ceftazidime-Avibactam Susceptibility Breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa.
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ABSTRACT:
SUBMITTER: Nichols WW
PROVIDER: S-EPMC6201065 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
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Project description:We evaluated the correlation between MIC and disk diffusion inhibition zones when testing ceftazidime-avibactam, using the 30/20-?g disk and the disk diffusion and MIC breakpoints established by the U.S. FDA and the Clinical and Laboratory Standards Institute (CLSI). Organisms used included 2 groups of Enterobacteriaceae isolates and 2 groups of Pseudomonas aeruginosa isolates; 1 group of each consisted of randomly selected isolates and the second group consisted of a challenge group from thousands of surveillance isolates with an increased proportion of organisms displaying ceftazidime-avibactam MIC values close to the breakpoints. Broth microdilution, disk diffusion tests, and data analysis were performed according to reference standardized methods. Ceftazidime-avibactam breakpoints of ?8/4 (susceptible) and ?16/4 ?g/ml (resistant) for MIC and ?21/?20 mm for disk diffusion, as established by the U.S. FDA and the CLSI, were applied for Enterobacteriaceae and P. aeruginosa Ceftazidime-avibactam MIC and disk zone (30/20-?g disk) correlation were acceptable when testing Enterobacteriaceae (overall, very major [VM] and major [Ma] error rates of 0.4% and 0.0%, respectively) and nearly so when testing P. aeruginosa (2.3% VM and 2.9% Ma errors). In summary, disk diffusion and broth microdilution testing results demonstrated good categorical agreement for ceftazidime-avibactam against Enterobacteriaceae and P. aeruginosa, using 30/20-?g disks.
| S-EPMC5971542 | biostudies-literature
Project description: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.
| S-EPMC4135815 | biostudies-literature
Project description:The combination of ceftazidime and avibactam possesses potent activity against resistant Gram-negative pathogens, including Pseudomonas aeruginosa. We compared the efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam using a hollow-fiber system and neutropenic and immunocompetent murine thigh infection models. Twenty-seven clinical P. aeruginosa isolates with ceftazidime MICs of 8 to 128 mg/liter and ceftazidime-avibactam MICs of 4 to 32 mg/liter were utilized in neutropenic mouse studies; 15 of the isolates were also evaluated in immunocompetent mice. Six isolates were studied in both the hollow-fiber system and the neutropenic mouse. In both systems, the free drug concentration-time profile seen in humans given 2 g of ceftazidime every 8 h (2-h infusion), with or without avibactam at 500 mg every 8 h (2-h infusion), was evaluated. In vivo activity was pharmacodynamically predictable based on the MIC. Ceftazidime decreased bacterial densities by ?0.5 log unit for 10/27 isolates, while ceftazidime-avibactam did so for 22/27 isolates. In immunocompetent animals, enhancements in activity were seen for both drugs, with ceftazidime achieving reductions of ?0.3 log unit for 10/15 isolates, whereas ceftazidime-avibactam did so against all 15 isolates. In vitro, ceftazidime resulted in regrowth by 24 h against all isolates, while ceftazidime-avibactam achieved stasis or better against 4/7 isolates. Mutants with elevated ceftazidime-avibactam MICs appeared after 24 h from 3/7 isolates studied in vitro; however, no resistant mutants were detected in vivo. Against this highly ceftazidime-nonsusceptible population of P. aeruginosa, treatment with human simulated doses of ceftazidime-avibactam resulted in pharmacodynamically predictable activity, particularly in vivo, against isolates with MICs of ?16 mg/liter, and this represents a potential new option to combat these difficult-to-treat pathogens.
| S-EPMC3497209 | biostudies-literature
Project description:Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to ?-lactam resistance were identified. Moreover, expression of blaPDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicle-treated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactam-fosfomycin was superior to either drug alone. By employing a "mechanism-based approach" to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-?-lactamases.
| S-EPMC6639593 | biostudies-literature
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.
| S-EPMC4958170 | biostudies-literature
Project description: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.
| S-EPMC8106713 | biostudies-literature
Project description:Ceftazidime-avibactam is a combination of ?-lactam/?-lactamase inhibitor, the use of which is restricted to some clinical cases, including cystic fibrosis patients infected with multidrug-resistant Pseudomonas aeruginosa, in which mutation is the main driver of resistance. This study aims to predict the mechanisms of mutation-driven resistance that are selected for when P. aeruginosa is challenged with either ceftazidime or ceftazidime-avibactam. For this purpose, P. aeruginosa PA14 was submitted to experimental evolution in the absence of antibiotics and in the presence of increasing concentrations of ceftazidime or ceftazidime-avibactam for 30 consecutive days. Final populations were analyzed by whole-genome sequencing. All evolved populations reached similar levels of ceftazidime resistance. In addition, they were more susceptible to amikacin and produced pyomelanin. A first event in this evolution was the selection of large chromosomal deletions containing hmgA (involved in pyomelanin production), galU (involved in ?-lactams resistance), and mexXY-oprM (involved in aminoglycoside resistance). Besides mutations in mpl and dacB that regulate ?-lactamase expression, mutations related to MexAB-OprM overexpression were prevalent. Ceftazidime-avibactam challenge selected mutants in the putative efflux pump PA14_45890 and PA14_45910 and in a two-component system (PA14_45870 and PA14_45880), likely regulating its expression. All populations produced pyomelanin and were more susceptible to aminoglycosides, likely due to the selection of large chromosomal deletions. Since pyomelanin-producing mutants presenting similar deletions are regularly isolated from infections, the potential aminoglycoside hypersusceptiblity and reduced ?-lactam susceptibility of pyomelanin-producing P. aeruginosa should be taken into consideration for treating infections caused by these isolates.
| S-EPMC6153820 | biostudies-literature
Project description:BACKGROUND:Detection of ceftazidime/avibactam (CAZ/AVI) antibacterial activity is absolutely vital with the rapid growth of carbapenem resistant Enterobacteriaceae (CRE). But now, there is no available automated antimicrobial susceptibility testing card for CAZ/AVI, so Kirby-Bauer has become an economical and practical method for detecting CAZ/AVI antibacterial activity against Enterobacteriaceae. RESULT:In this study, antimicrobial susceptibility testing of CAZ/AVI against 386 Enterobacteriaceae (188 Klebsiella pneumoniae, 122 Escherichia coli, 76 Enterobacter cloacae) isolated from clinical patients was performed by broth microdilution. Of the 386 strains, 54 extended spectrum β lactamases negative (ESBL(-)), 104 extended spectrum β lactamases positive (ESBL(+)), 228 CRE. 287 isolates were susceptible to CAZ/AVI and 99 isolates were resistant to CAZ/AVI. At the same time, to obtain optimal content avibactam (AVI) disk containing ceftazidime (30 μg), inhibition zone diameter of four kinds of ceftazidime (30 μg) disk containing different AVI content (0 μg, 10 μg, 25 μg, 50 μg) were tested by Kirby-Bauer method. The microdilution broth method interpretation was used as the standard to estimate susceptible or resistance and then coherence analysis was carried out between Kirby-Bauer and broth microdilution. The result shows the inhibition zone diameter of 30 μg/50 μg disk, susceptible isolates: 20.5 mm-31.5 mm, resistance isolates: 8.25 mm-21.5 mm. The inhibition zone diameter of 30 μg/25 μg disk, susceptible isolates: 19.7 mm-31.3 mm, resistance isolates: 6.5 mm-19.2 mm. The inhibition zone diameter of 30 μg/10 μg disk, susceptible isolates: 19.5 mm-31 mm, resistance isolates: 6.5 mm-11 mm. The inhibition zone diameter of ceftazidime (30 μg), susceptible isolates: 6.5 mm-27.5 mm, resistance isolates 6.5 mm. CONCLUSION:Our results show that 30 μg/50 μg, 30 μg/25 μg, 30 μg/10 μg CAZ/AVI disk have significant statistical differences to determinate CAZ/AVI antibacterial activity, but for 30 μg/50 μg disk, there has a cross section between susceptible isolates (minimum 20.5 mm) and resistance isolates (maximum 21.5 mm). For 30 μg/25 μg disk, it is hard to distinguish the difference between susceptible isolates (minimum 19.7 mm) and resistance isolates (maximum 19.2 mm), so 30 μg/10 μg CAZ/AVI disk is more conducive to determinate antibacterial activity.
| S-EPMC6824082 | biostudies-other
Project description:The in vitro activities of ceftazidime-avibactam and comparators against 9,149 isolates of Enterobacteriaceae and 2,038 isolates of Pseudomonas aeruginosa collected by 42 medical centers in nine countries in the Asia-Pacific region from 2012 to 2015 were determined as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. Antimicrobial susceptibility testing was conducted by Clinical and Laboratory Standards Institute (CLSI) broth microdilution, and isolate subset analysis was performed on the basis of the resistant phenotypes and ?-lactamase content. Ceftazidime-avibactam demonstrated potent in vitro activity (MIC, ?8 ?g/ml) against all Enterobacteriaceae tested (99.0% susceptible) and was the most active against isolates that were metallo-?-lactamase (MBL) negative (99.8% susceptible). Against P. aeruginosa, 92.6% of all isolates and 96.1% of MBL-negative isolates were susceptible to ceftazidime-avibactam (MIC, ?8 ?g/ml). The rates of susceptibility to ceftazidime-avibactam ranged from 97.0% (Philippines) to 100% (Hong Kong, South Korea) for Enterobacteriaceae and from 83.1% (Thailand) to 100% (Hong Kong) among P. aeruginosa isolates, with lower susceptibilities being observed in countries where MBLs were more frequently encountered (Philippines, Thailand). Ceftazidime-avibactam inhibited 97.2 to 100% of Enterobacteriaceae isolates, per country, that carried serine ?-lactamases, including extended-spectrum ?-lactamases, AmpC cephalosporinases, and carbapenemases (KPC, GES, OXA-48-like). It also inhibited 91.3% of P. aeruginosa isolates that were carbapenem nonsusceptible in which no acquired ?-lactamase was detected. Among MBL-negative Enterobacteriaceae isolates that were ceftazidime nonsusceptible, meropenem nonsusceptible, colistin resistant, and multidrug resistant, ceftazidime-avibactam inhibited 96.1, 87.7, 100, and 98.8% of isolates, respectively, and among MBL-negative P. aeruginosa isolates that were ceftazidime nonsusceptible, meropenem nonsusceptible, colistin resistant, and multidrug resistant, ceftazidime-avibactam inhibited 79.6, 83.6, 83.3, and 68.2% of isolates, respectively. Overall, clinical isolates of Enterobacteriaceae and P. aeruginosa collected in nine Asia-Pacific countries from 2012 to 2015 were highly susceptible to ceftazidime-avibactam.
| S-EPMC6021687 | biostudies-other
Project description:ObjectivesTo evaluate the antimicrobial susceptibility patterns of Pseudomonas aeruginosa isolates collected from the lower respiratory tract of cystic fibrosis (CF) patients.MethodsWe susceptibility tested 273 contemporary P. aeruginosa isolates from 39 hospitals worldwide (17 countries) by the reference broth microdilution method.ResultsCeftazidime/avibactam [MIC50/90, 2/8 mg/L; 96.0% susceptible (S)] was the most active agent, followed by ceftolozane/tazobactam (MIC50/90, 1/4 mg/L; 90.5% S), ceftazidime (MIC50/90, 2/>32 mg/L; 80.6% S), piperacillin/tazobactam (MIC50/90, 4/128 mg/L; 80.2% S) and tobramycin (MIC50/90, 2/>16 mg/L; 76.6% S). Ceftazidime/avibactam retained activity against P. aeruginosa isolates non-susceptible to meropenem (86.5% S to ceftazidime/avibactam), piperacillin/tazobactam (85.2% S to ceftazidime/avibactam) or ceftazidime (79.2% S to ceftazidime/avibactam). MDR phenotype was observed among 36.3% of isolates, and 88.9% and 73.7% of MDR isolates were susceptible to ceftazidime/avibactam and ceftolozane/tazobactam, respectively. Against isolates non-susceptible to meropenem, piperacillin/tazobactam and ceftazidime, susceptibility rates were 78.9% for ceftazidime/avibactam and 47.4% for ceftolozane/tazobactam. Ceftazidime/avibactam was active against 65.4% of ceftolozane/tazobactam-non-susceptible isolates and ceftolozane/tazobactam was active against 18.2% of ceftazidime/avibactam-non-susceptible isolates.ConclusionsCeftazidime/avibactam and ceftolozane/tazobactam exhibited potent and broad-spectrum activity against P. aeruginosa isolated from CF patients worldwide, but higher susceptibility rates for ceftazidime/avibactam compared with ceftolozane/tazobactam were observed among the resistant subsets. Ceftazidime/avibactam and ceftolozane/tazobactam represent valuable options to treat CF pulmonary exacerbations caused by P. aeruginosa.
| S-EPMC8417452 | biostudies-literature