Comparative "real world" in vitro activity of two new antimicrobials (ceftolozane-tazobactam and ceftazidime-avibactam) against ceftazidime non-susceptible Pseudomonas aeruginosa and resistant Enterobacteriaceae from california long term acute care hospitals

Abstract Background Meropenem/vaborbactam (MV) is a carbapenem and boronic acid–based β-lactamase inhibitor combination product with potent in vitro activity against Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae. As carbapenem resistance in Pseudomonas aeruginosa (PSA) is primarily driven by porin mutations, efflux pumps, or infrequently by metallo-β-lactamases, vaborbactam is not expected to improve the in vitro activity of meropenem (MEM) against this pathogen. However, limited data currently exists assessing the comparative in vitro activity of MEM and MV. The purpose of this study was to compare the in vitro activity of MV and MEM against a large real-world sample of clinical isolates of PSA where both MV and MEM are routinely tested on all isolates. Methods All cultures from patient infections with PSA from May 2018 to February 2019 at Michigan Medicine were included. Minimum inhibitory concentrations (MICs) were determined using TREK broth microdilution panels and isolates were considered susceptible to MV if the MIC was ≤4 mg/L and MEM if the MIC was ≤2 mg/L. Results A total of 2,967 isolates of PSA from clinical specimens were included. 80.5% of isolates were susceptible to MEM (MIC50 ≤1 mg/L and MIC90 8 mg/L, range ≤1 to >32 mg/L) at a breakpoint of ≤2 mg/L and 86.3% at a breakpoint of ≤4 mg/L; whereas 90.8% of isolates were susceptible to MV (MIC50 ≤1 mg/L and MIC90 4 mg/L, range ≤1 to >8 mg/L). Of those displaying MEM MIC >2 mg/L, 53% (n = 308) were susceptible to MV. Of those displaying MEM MIC >4 mg/L, 33.7% (n = 137) were susceptible to MV. Although the majority of MIC discordances in MEM-R/MV-S isolates were 1–2 doubling dilutions, 52 (38%) isolates had their meropenem MIC decreased ≥3 doubling dilutions by the addition of vaborbactam suggesting significant inhibitory activity (Table 1). Conclusion We found a surprising number of PSA isolates with discordant MV and MEM susceptibility at Michigan Medicine. Further exploration of mechanisms of meropenem resistance in these isolates is warranted. Disclosures All authors: No reported disclosures.

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522. In Vitro Antimicrobial Activity of Ceftazidime/Avibactam Compared with Ceftolozane/Tazobactam Against Real-world Clinical Isolates of Pseudomonas aeruginosa at a Large Academic Tertiary Care Hospital

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.591 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S251-S252

Author(s):

Twisha S Patel ◽

Keith S Kaye ◽

Vince Marshall ◽

Jay Krishnan ◽

John Mills ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Real World ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Vitro Activity ◽

Clinical Isolates ◽

Care Hospital ◽

In Vitro Activity ◽

Routine Testing

Abstract Background Ceftazidime/avibactam (CZA) and ceftolozane-tazobactam (CT) are new additions to the antibiotic armamentarium with activity against gram-negative pathogens, most notably drug-resistant Pseudomonas aeruginosa (PSA). The purpose of this study was to compare the in vitro activity of CZA and CT against a large real-world sample of clinical isolates of PSA displaying different phenotypes of resistance to conventional β-lactams at an institution where both CZA and CT are routinely tested on all isolates. Methods All cultures from patient infections with PSA from May 2018 to February 2019 at Michigan Medicine were included. Minimum inhibitory concentrations (MICs) for all β-lactams were determined using TREK broth microdilution panels and isolates were considered susceptible to CZA if the MIC was ≤8 mg/L and CT if the MIC was ≤4 mg/L. Results A total of 2,972 isolates of PSA from clinical specimens were included. Table 1 compares CZA and CT susceptibility, MIC50, MIC90, and MIC range for all isolates including those displaying resistance to various β-lactams. Among all isolates of PSA, CZA (96.2% susceptible) was slightly more active than CT (94.2%) and both agents were ~10% more active than the closest comparator (ceftazidime, 86.6%). In vitro activity of cefepime, piperacillin/tazobactam, and meropenem were 84.8%, 78%, and 80.3%, respectively. The activity of both CZA and CT dropped significantly among isolates with pan-β-lactam resistance (i.e., resistance to all conventional anti-pseudomonal β lactams, PBR) but CZA remained more active than CT (59.4% vs. 41.5%, P < 0.001). Of isolates displaying resistance to CT, 84 (48.6%) were susceptible to CZA. However, of those with resistance to CZA, only 24 (21.2%) were susceptible to CT (Table 2). Conclusion CZA was the most active β-lactam against PSA isolates at Michigan Medicine. Among PSA with PBR, CZA demonstrated superior activity compared with CT. Additionally, a significant number of isolates with resistance to CT were susceptible to CZA. Our findings are unique compared with other published reports where CT has consistently demonstrated greater activity than CZA against resistant P. aeruginosa and suggest routine testing of both CT and CZA should occur. Disclosures All authors: No reported disclosures.

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In vitro activity of ceftazidime-avibactam and comparators against Pseudomonas aeruginosa from Europe 2012–2014

10.26226/morressier.56d6be77d462b80296c9797b ◽

2016 ◽

Author(s):

Meredith Hackel

Keyword(s):

Pseudomonas Aeruginosa ◽

Vitro Activity ◽

In Vitro Activity

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Murepavadin antimicrobial activity against and resistance development in cystic fibrosis Pseudomonas aeruginosa isolates

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa529 ◽

2020 ◽

Author(s):

María Díez-Aguilar ◽

Marta Hernández-García ◽

María-Isabel Morosini ◽

Ad Fluit ◽

Michael M Tunney ◽

...

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Antimicrobial Activity ◽

Spontaneous Mutation ◽

Lung Surfactant ◽

Vitro Activity ◽

In Vitro Activity ◽

Broth Microdilution ◽

Agar Dilution

Abstract Background Murepavadin, a novel peptidomimetic antibiotic, is being developed as an inhalation therapy for treatment of Pseudomonas aeruginosa respiratory infection in people with cystic fibrosis (CF). It blocks the activity of the LptD protein in P. aeruginosa causing outer membrane alterations. Objectives To determine the in vitro activity of murepavadin against CF P. aeruginosa isolates and to investigate potential mechanisms of resistance. Methods MIC values were determined by both broth microdilution and agar dilution and results compared. The effect of artificial sputum and lung surfactant on in vitro activity was also measured. Spontaneous mutation frequency was estimated. Bactericidal activity was investigated using time–kill assays. Resistant mutants were studied by WGS. Results The murepavadin MIC50 was 0.125 versus 4 mg/L and the MIC90 was 2 versus 32 mg/L by broth microdilution and agar dilution, respectively. Essential agreement was >90% when determining in vitro activity with artificial sputum or lung surfactant. It was bactericidal at a concentration of 32 mg/L against 95.4% of the strains within 1–5 h. Murepavadin MICs were 2–9 two-fold dilutions higher for the mutant derivatives (0.5 to >16 mg/L) than for the parental strains. Second-step mutants were obtained for the PAO mutS reference strain with an 8×MIC increase. WGS showed mutations in genes involved in LPS biosynthesis (lpxL1, lpxL2, bamA2, lptD, lpxT and msbA). Conclusions Murepavadin characteristics, such as its specific activity against P. aeruginosa, its unique mechanism of action and its strong antimicrobial activity, encourage the further clinical evaluation of this drug.

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