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Effects of Klebsiella pneumoniae carbapenemase subtypes, extended-spectrum β-lactamases, and porin mutations on the in vitro activity of ceftazidime-avibactam against carbapenem-resistant K. pneumoniae.
Antimicrob Agents Chemother. 2015 Sep; 59(9):5793-7.AA

Abstract

Avibactam is a novel β-lactamase inhibitor with affinity for Klebsiella pneumoniae carbapenemases (KPCs). In combination with ceftazidime, the agent demonstrates activity against KPC-producing K. pneumoniae (KPC-Kp). KPC-Kp strains are genetically diverse and harbor multiple resistance determinants, including defects in outer membrane proteins and extended-spectrum β-lactamases (ESBLs). Mutations in porin gene ompK36 confer high-level carbapenem resistance to KPC-Kp strains. Whether specific mechanisms of antimicrobial resistance also influence the activity of ceftazidime-avibactam is unknown. We defined the effects of ceftazidime-avibactam against 72 KPC-Kp strains with diverse mechanisms of resistance, including various combinations of KPC subtypes and ESBL and ompK36 mutations. Ceftazidime MICs ranged from 64 to 4,096 μg/ml and were lowered by a median of 512-fold with the addition of avibactam. All strains exhibited ceftazidime-avibactam MICs at or below the CLSI breakpoint for ceftazidime (≤4 μg/ml; range, 0.25 to 4). However, the MICs were within two 2-fold dilutions of the CLSI breakpoint against 24% of the strains, and those strains would be classified as nonsusceptible to ceftazidime by EUCAST criteria (MIC > 1 μg/ml). Median ceftazidime-avibactam MICs were higher against KPC-3 than KPC-2 variants (P = 0.02). Among KPC-2-Kp strains, the presence of both ESBL and porin mutations was associated with higher drug MICs compared to those seen with either factor alone (P = 0.003 and P = 0.02, respectively). In conclusion, ceftazidime-avibactam displays activity against genetically diverse KPC-Kp strains. Strains with higher-level drug MICs provide a reason for caution. Judicious use of ceftazidime-avibactam alone or in combination with other agents will be important to prevent the emergence of resistance.

Authors+Show Affiliations

Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Antibiotic Management Program, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA cjc76@pitt.edu.XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Department of Medicine, University of Florida, Gainesville, Florida, USA.Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Antibiotic Management Program, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26169413

Citation

Shields, Ryan K., et al. "Effects of Klebsiella Pneumoniae Carbapenemase Subtypes, Extended-spectrum Β-lactamases, and Porin Mutations On the in Vitro Activity of Ceftazidime-avibactam Against Carbapenem-resistant K. Pneumoniae." Antimicrobial Agents and Chemotherapy, vol. 59, no. 9, 2015, pp. 5793-7.
Shields RK, Clancy CJ, Hao B, et al. Effects of Klebsiella pneumoniae carbapenemase subtypes, extended-spectrum β-lactamases, and porin mutations on the in vitro activity of ceftazidime-avibactam against carbapenem-resistant K. pneumoniae. Antimicrob Agents Chemother. 2015;59(9):5793-7.
Shields, R. K., Clancy, C. J., Hao, B., Chen, L., Press, E. G., Iovine, N. M., Kreiswirth, B. N., & Nguyen, M. H. (2015). Effects of Klebsiella pneumoniae carbapenemase subtypes, extended-spectrum β-lactamases, and porin mutations on the in vitro activity of ceftazidime-avibactam against carbapenem-resistant K. pneumoniae. Antimicrobial Agents and Chemotherapy, 59(9), 5793-7. https://doi.org/10.1128/AAC.00548-15
Shields RK, et al. Effects of Klebsiella Pneumoniae Carbapenemase Subtypes, Extended-spectrum Β-lactamases, and Porin Mutations On the in Vitro Activity of Ceftazidime-avibactam Against Carbapenem-resistant K. Pneumoniae. Antimicrob Agents Chemother. 2015;59(9):5793-7. PubMed PMID: 26169413.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of Klebsiella pneumoniae carbapenemase subtypes, extended-spectrum β-lactamases, and porin mutations on the in vitro activity of ceftazidime-avibactam against carbapenem-resistant K. pneumoniae. AU - Shields,Ryan K, AU - Clancy,Cornelius J, AU - Hao,Binghua, AU - Chen,Liang, AU - Press,Ellen G, AU - Iovine,Nicole M, AU - Kreiswirth,Barry N, AU - Nguyen,M Hong, Y1 - 2015/07/13/ PY - 2015/03/05/received PY - 2015/07/08/accepted PY - 2015/7/15/entrez PY - 2015/7/15/pubmed PY - 2016/5/19/medline SP - 5793 EP - 7 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 59 IS - 9 N2 - Avibactam is a novel β-lactamase inhibitor with affinity for Klebsiella pneumoniae carbapenemases (KPCs). In combination with ceftazidime, the agent demonstrates activity against KPC-producing K. pneumoniae (KPC-Kp). KPC-Kp strains are genetically diverse and harbor multiple resistance determinants, including defects in outer membrane proteins and extended-spectrum β-lactamases (ESBLs). Mutations in porin gene ompK36 confer high-level carbapenem resistance to KPC-Kp strains. Whether specific mechanisms of antimicrobial resistance also influence the activity of ceftazidime-avibactam is unknown. We defined the effects of ceftazidime-avibactam against 72 KPC-Kp strains with diverse mechanisms of resistance, including various combinations of KPC subtypes and ESBL and ompK36 mutations. Ceftazidime MICs ranged from 64 to 4,096 μg/ml and were lowered by a median of 512-fold with the addition of avibactam. All strains exhibited ceftazidime-avibactam MICs at or below the CLSI breakpoint for ceftazidime (≤4 μg/ml; range, 0.25 to 4). However, the MICs were within two 2-fold dilutions of the CLSI breakpoint against 24% of the strains, and those strains would be classified as nonsusceptible to ceftazidime by EUCAST criteria (MIC > 1 μg/ml). Median ceftazidime-avibactam MICs were higher against KPC-3 than KPC-2 variants (P = 0.02). Among KPC-2-Kp strains, the presence of both ESBL and porin mutations was associated with higher drug MICs compared to those seen with either factor alone (P = 0.003 and P = 0.02, respectively). In conclusion, ceftazidime-avibactam displays activity against genetically diverse KPC-Kp strains. Strains with higher-level drug MICs provide a reason for caution. Judicious use of ceftazidime-avibactam alone or in combination with other agents will be important to prevent the emergence of resistance. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/26169413/Effects_of_Klebsiella_pneumoniae_carbapenemase_subtypes_extended_spectrum_β_lactamases_and_porin_mutations_on_the_in_vitro_activity_of_ceftazidime_avibactam_against_carbapenem_resistant_K__pneumoniae_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=26169413 DB - PRIME DP - Unbound Medicine ER -