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Ceftazidime-avibactam activity against a challenge set of carbapenem-resistant Enterobacterales: Ompk36 L3 alterations and β-lactamases with ceftazidime hydrolytic activity lead to elevated MIC values.
Int J Antimicrob Agents. 2020 Jul; 56(1):106011.IJ

Abstract

INTRODUCTION

This study examined ceftazidime-avibactam activity against carbapenem-resistant Enterobacterales (CRE) clinical isolates and resistance mechanisms among non-metallo β-lactamase (MBL) producers displaying ceftazidime-avibactam MIC values at 4 mg/L.

METHODS

CRE isolates (286 of 8161 Enterobacterales) collected in Asia-Pacific, Europe and Latin America during 2016 were screened for carbapenemase genes. Selected isolates were susceptibility tested for ceftazidime-avibactam in the presence or absence of phenylalanine-arginyl β-naphthylamide (PAβN) and polymyxin B nonapeptide (PMBN). Genome sequences were investigated for the integrity of outer membrane protein (OMP) genes and multilocus sequence typing. qRT-PCR assays were conducted to determine expression of acrA, ampC, and OMP genes.

RESULTS

Ceftazidime-avibactam inhibited 99.2% of the Enterobacterales, 22 (78.7%) of the 286 CRE and 226 (100%) non-MBL producers. Among carbapenemase producers (85.3%; 244 of 286), the most common gene was blaKPC (76 blaKPC-3 and 46 blaKPC-2), followed by blaOXA-48-like (60 isolates) and blaNDM (37). Ceftazidime-avibactam MIC values at 4 mg/L were noted among 14 Klebsiella pneumoniae (13 carrying blaKPC and 1 blaCTX-M-15) mostly from Italy and Brazil and 1 Klebsiella aerogenes overexpressing ampC. PAβN did not significantly decrease ceftazidime-avibactam results, but adding PMBN did significantly decrease the MIC results for the combination. All K. pneumoniae isolates had a premature stop codon at OmpK35 and most isolates had L3 alterations of OmpK36, low expression of this gene, or OmpC disruption (K. aerogenes). Nine K. pneumoniae isolates belonged to clonal complex 258 and displayed intrahospital clonality.

CONCLUSION

Ceftazidime-avibactam is an important addition to the armamentarium against multidrug-resistant organisms, and elevated MIC results for this combination seem to be associated with L3 OmpK36 alterations and β-lactamases able to hydrolyze ceftazidime.

Authors+Show Affiliations

JMI Laboratories, North Liberty, IA 52317, USA. Electronic address: mariana-castanheira@jmilabs.com.JMI Laboratories, North Liberty, IA 52317, USA.JMI Laboratories, North Liberty, IA 52317, USA.JMI Laboratories, North Liberty, IA 52317, USA.JMI Laboratories, North Liberty, IA 52317, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32417206

Citation

Castanheira, Mariana, et al. "Ceftazidime-avibactam Activity Against a Challenge Set of Carbapenem-resistant Enterobacterales: Ompk36 L3 Alterations and Β-lactamases With Ceftazidime Hydrolytic Activity Lead to Elevated MIC Values." International Journal of Antimicrobial Agents, vol. 56, no. 1, 2020, p. 106011.
Castanheira M, Doyle TB, Hubler C, et al. Ceftazidime-avibactam activity against a challenge set of carbapenem-resistant Enterobacterales: Ompk36 L3 alterations and β-lactamases with ceftazidime hydrolytic activity lead to elevated MIC values. Int J Antimicrob Agents. 2020;56(1):106011.
Castanheira, M., Doyle, T. B., Hubler, C., Sader, H. S., & Mendes, R. E. (2020). Ceftazidime-avibactam activity against a challenge set of carbapenem-resistant Enterobacterales: Ompk36 L3 alterations and β-lactamases with ceftazidime hydrolytic activity lead to elevated MIC values. International Journal of Antimicrobial Agents, 56(1), 106011. https://doi.org/10.1016/j.ijantimicag.2020.106011
Castanheira M, et al. Ceftazidime-avibactam Activity Against a Challenge Set of Carbapenem-resistant Enterobacterales: Ompk36 L3 Alterations and Β-lactamases With Ceftazidime Hydrolytic Activity Lead to Elevated MIC Values. Int J Antimicrob Agents. 2020;56(1):106011. PubMed PMID: 32417206.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ceftazidime-avibactam activity against a challenge set of carbapenem-resistant Enterobacterales: Ompk36 L3 alterations and β-lactamases with ceftazidime hydrolytic activity lead to elevated MIC values. AU - Castanheira,Mariana, AU - Doyle,Timothy B, AU - Hubler,Cory, AU - Sader,Helio S, AU - Mendes,Rodrigo E, Y1 - 2020/05/15/ PY - 2019/10/28/received PY - 2020/02/24/revised PY - 2020/05/01/accepted PY - 2020/5/18/pubmed PY - 2021/4/20/medline PY - 2020/5/18/entrez KW - Beta-lactam/beta-lactamase inhibitor combinations KW - Carbapenemases KW - Outer membrane proteins SP - 106011 EP - 106011 JF - International journal of antimicrobial agents JO - Int J Antimicrob Agents VL - 56 IS - 1 N2 - INTRODUCTION: This study examined ceftazidime-avibactam activity against carbapenem-resistant Enterobacterales (CRE) clinical isolates and resistance mechanisms among non-metallo β-lactamase (MBL) producers displaying ceftazidime-avibactam MIC values at 4 mg/L. METHODS: CRE isolates (286 of 8161 Enterobacterales) collected in Asia-Pacific, Europe and Latin America during 2016 were screened for carbapenemase genes. Selected isolates were susceptibility tested for ceftazidime-avibactam in the presence or absence of phenylalanine-arginyl β-naphthylamide (PAβN) and polymyxin B nonapeptide (PMBN). Genome sequences were investigated for the integrity of outer membrane protein (OMP) genes and multilocus sequence typing. qRT-PCR assays were conducted to determine expression of acrA, ampC, and OMP genes. RESULTS: Ceftazidime-avibactam inhibited 99.2% of the Enterobacterales, 22 (78.7%) of the 286 CRE and 226 (100%) non-MBL producers. Among carbapenemase producers (85.3%; 244 of 286), the most common gene was blaKPC (76 blaKPC-3 and 46 blaKPC-2), followed by blaOXA-48-like (60 isolates) and blaNDM (37). Ceftazidime-avibactam MIC values at 4 mg/L were noted among 14 Klebsiella pneumoniae (13 carrying blaKPC and 1 blaCTX-M-15) mostly from Italy and Brazil and 1 Klebsiella aerogenes overexpressing ampC. PAβN did not significantly decrease ceftazidime-avibactam results, but adding PMBN did significantly decrease the MIC results for the combination. All K. pneumoniae isolates had a premature stop codon at OmpK35 and most isolates had L3 alterations of OmpK36, low expression of this gene, or OmpC disruption (K. aerogenes). Nine K. pneumoniae isolates belonged to clonal complex 258 and displayed intrahospital clonality. CONCLUSION: Ceftazidime-avibactam is an important addition to the armamentarium against multidrug-resistant organisms, and elevated MIC results for this combination seem to be associated with L3 OmpK36 alterations and β-lactamases able to hydrolyze ceftazidime. SN - 1872-7913 UR - https://www.unboundmedicine.com/medline/citation/32417206/Ceftazidime_avibactam_activity_against_a_challenge_set_of_carbapenem_resistant_Enterobacterales:_Ompk36_L3_alterations_and_β_lactamases_with_ceftazidime_hydrolytic_activity_lead_to_elevated_MIC_values_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0924-8579(20)30169-2 DB - PRIME DP - Unbound Medicine ER -