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Effects of KPC Variant and Porin Genotype on the In Vitro Activity of Meropenem-Vaborbactam against Carbapenem-Resistant Enterobacteriaceae.
Antimicrob Agents Chemother. 2019 03; 63(3)AA

Abstract

Meropenem-vaborbactam is a new agent with the potential to treat carbapenem-resistant Enterobacteriaceae (CRE) infections. We describe the in vitro activity of meropenem-vaborbactam against representative CRE genotypes and laboratory-engineered Escherichia coli isolates harboring mutant bla KPC genes associated with ceftazidime-avibactam resistance. We also compared disk diffusion and gradient strip testing methods to standard broth microdilution methods. Against 120 CRE isolates, median ceftazidime-avibactam and meropenem-vaborbactam MICs were 1 and 0.03 µg/ml, respectively. Ninety-eight percent (117/120) of isolates were susceptible to meropenem-vaborbactam (MICs ≤ 4 µg/ml). Against Klebsiella pneumoniae isolates harboring mutant bla KPC, the addition of vaborbactam lowered the meropenem MICs in 78% of isolates (14/18); 100% were susceptible to meropenem-vaborbactam. Median meropenem-vaborbactam MICs were higher against K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae isolates with mutant ompK36 porin genes (n = 26) than against those with wild-type ompK36 porin genes (n = 54) (0.25 versus 0.03 µg/ml; P < 0.0001). Against E. coli TOP10 isolates with plasmid constructs containing wild-type bla KPC or mutant bla KPC, the addition of vaborbactam at 8 µg/ml lowered the meropenem MICs 2- to 512-fold, resulting in meropenem-vaborbactam MICs of 0.03 µg/ml. The rates of categorical agreement with broth microdilution for disk diffusion or gradient strips ranged from 90 to 95%. Essential agreement rates were higher for research-use-only (RUO) gradient strips manufactured by bioMérieux (82%) than for those manufactured by Liofilchem (48%) (P < 0.0001). Taken together, our data highlight the potent in vitro activity of meropenem-vaborbactam against CRE, including isolates resistant to ceftazidime-avibactam. Vaborbactam inhibited both wild-type and variant KPC enzymes. On the other hand, KPC-producing K. pneumoniae isolates with ompK36 mutations displayed higher meropenem-vaborbactam MICs than isolates with wild-type ompK36 The results of susceptibility testing with RUO bioMérieux gradient strips most closely aligned with those of broth microdilution methods.

Authors+Show Affiliations

Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA shieldsrk@upmc.edu. XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30617090

Citation

Wilson, William R., et al. "Effects of KPC Variant and Porin Genotype On the in Vitro Activity of Meropenem-Vaborbactam Against Carbapenem-Resistant Enterobacteriaceae." Antimicrobial Agents and Chemotherapy, vol. 63, no. 3, 2019.
Wilson WR, Kline EG, Jones CE, et al. Effects of KPC Variant and Porin Genotype on the In Vitro Activity of Meropenem-Vaborbactam against Carbapenem-Resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2019;63(3).
Wilson, W. R., Kline, E. G., Jones, C. E., Morder, K. T., Mettus, R. T., Doi, Y., Nguyen, M. H., Clancy, C. J., & Shields, R. K. (2019). Effects of KPC Variant and Porin Genotype on the In Vitro Activity of Meropenem-Vaborbactam against Carbapenem-Resistant Enterobacteriaceae. Antimicrobial Agents and Chemotherapy, 63(3). https://doi.org/10.1128/AAC.02048-18
Wilson WR, et al. Effects of KPC Variant and Porin Genotype On the in Vitro Activity of Meropenem-Vaborbactam Against Carbapenem-Resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2019;63(3) PubMed PMID: 30617090.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of KPC Variant and Porin Genotype on the In Vitro Activity of Meropenem-Vaborbactam against Carbapenem-Resistant Enterobacteriaceae. AU - Wilson,William R, AU - Kline,Ellen G, AU - Jones,Chelsea E, AU - Morder,Kristin T, AU - Mettus,Roberta T, AU - Doi,Yohei, AU - Nguyen,M Hong, AU - Clancy,Cornelius J, AU - Shields,Ryan K, Y1 - 2019/02/26/ PY - 2018/09/24/received PY - 2018/12/23/accepted PY - 2019/1/9/pubmed PY - 2020/2/19/medline PY - 2019/1/9/entrez KW - CRE KW - KPC KW - ceftazidime-avibactam KW - disk diffusion KW - gradient strip KW - meropenem-vaborbactam KW - porin JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 63 IS - 3 N2 - Meropenem-vaborbactam is a new agent with the potential to treat carbapenem-resistant Enterobacteriaceae (CRE) infections. We describe the in vitro activity of meropenem-vaborbactam against representative CRE genotypes and laboratory-engineered Escherichia coli isolates harboring mutant bla KPC genes associated with ceftazidime-avibactam resistance. We also compared disk diffusion and gradient strip testing methods to standard broth microdilution methods. Against 120 CRE isolates, median ceftazidime-avibactam and meropenem-vaborbactam MICs were 1 and 0.03 µg/ml, respectively. Ninety-eight percent (117/120) of isolates were susceptible to meropenem-vaborbactam (MICs ≤ 4 µg/ml). Against Klebsiella pneumoniae isolates harboring mutant bla KPC, the addition of vaborbactam lowered the meropenem MICs in 78% of isolates (14/18); 100% were susceptible to meropenem-vaborbactam. Median meropenem-vaborbactam MICs were higher against K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae isolates with mutant ompK36 porin genes (n = 26) than against those with wild-type ompK36 porin genes (n = 54) (0.25 versus 0.03 µg/ml; P < 0.0001). Against E. coli TOP10 isolates with plasmid constructs containing wild-type bla KPC or mutant bla KPC, the addition of vaborbactam at 8 µg/ml lowered the meropenem MICs 2- to 512-fold, resulting in meropenem-vaborbactam MICs of 0.03 µg/ml. The rates of categorical agreement with broth microdilution for disk diffusion or gradient strips ranged from 90 to 95%. Essential agreement rates were higher for research-use-only (RUO) gradient strips manufactured by bioMérieux (82%) than for those manufactured by Liofilchem (48%) (P < 0.0001). Taken together, our data highlight the potent in vitro activity of meropenem-vaborbactam against CRE, including isolates resistant to ceftazidime-avibactam. Vaborbactam inhibited both wild-type and variant KPC enzymes. On the other hand, KPC-producing K. pneumoniae isolates with ompK36 mutations displayed higher meropenem-vaborbactam MICs than isolates with wild-type ompK36 The results of susceptibility testing with RUO bioMérieux gradient strips most closely aligned with those of broth microdilution methods. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/30617090/Effects_of_KPC_Variant_and_Porin_Genotype_on_the_In_Vitro_Activity_of_Meropenem_Vaborbactam_against_Carbapenem_Resistant_Enterobacteriaceae_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&amp;pmid=30617090 DB - PRIME DP - Unbound Medicine ER -