title: Low Frequency of Ceftazidime-Avibactam Resistance among Enterobacteriaceae Isolates CarryingblaKPCCollected in U.S. Hospitals from 2012 to 2015.
abstract: Klebsiella pneumoniaecarbapenemase (KPC)-producingEnterobacteriaceaeisolates have been increasingly reported worldwide, and therapeutic options to treat infections caused by these organisms are limited. We evaluated the activity of ceftazidime-avibactam and comparators against 456Enterobacteriaceaeisolates carryingblaKPCcollected from 79 U.S. hospitals during 2012 to 2015. Overall, ceftazidime-avibactam (MIC50/90, 0.5/2 μg/ml; 99.3% susceptible) and tigecycline (MIC50/90, 0.5/1 μg/ml; 98.9% susceptible at ≤2 μg/ml) were the most active agents. Only 80.5% and 59.0% of isolates were susceptible to colistin and amikacin, respectively. All three isolates (0.7%) displaying resistance to ceftazidime-avibactam (K. pneumoniae; MICs, ≥16 μg/ml) were evaluated using whole-genome sequencing analysis and relative quantification of expression levels of porins and efflux pump. Two isolates carried metallo-β-lactamase genes,blaNDM-1orblaVIM-4, among other β-lactam resistance mechanisms, and one displayed a premature stop codon inompK35and decreased expression ofompK36Ceftazidime-avibactam was active against 100.0 and 99.3% of isolates carryingblaKPC-3(n= 221) andblaKPC-2(n= 145), respectively. Isolates carryingblaKPCwere more commonly recovered from pneumonia (n= 155), urinary tract (n= 93), and skin/soft tissue (n= 74) infections. Ceftazidime-avibactam (97.8 to 100.0% susceptible) was consistently active against isolates from all infection sites.K. pneumoniae(83.3% of the collection) susceptibility rates were 99.2% for ceftazidime-avibactam, 98.9% for tigecycline, and 80.1% for colistin. Ceftazidime-avibactam susceptibility did not vary substantially when comparing isolates from intensive care unit (ICU) patients to those from non-ICU patients. Ceftazidime-avibactam was active against this large collection of isolates carryingblaKPCand represents a valuable addition to the armamentarium currently available for the treatment of infections caused by KPC-producingEnterobacteriaceae.
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA Mariana-castanheira@jmilabs.com.
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Rodrigo E
authors.initials: RE
authors.lastname: Mendes
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Helio S
authors.initials: HS
authors.lastname: Sader
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D002442:Ceftazidime / Q000494:pharmacology*; D003091:Colistin / Q000494:pharmacology; D004338:Drug Combinations; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D004756:Enterobacteriaceae Infections / Q000188:drug therapy / Q000453:epidemiology* / Q000382:microbiology; D015870:Gene Expression; D006761:Hospitals; D006801:Humans; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives / Q000494:pharmacology; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D018461:Soft Tissue Infections / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D000078304:Tigecycline; D014481:United States / Q000453:epidemiology; D014552:Urinary Tract Infections / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D018440:beta-Lactam Resistance / Q000235:genetics*; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; D000078304:Tigecycline; D002442:Ceftazidime; D001618:beta-Lactamases; D008911:Minocycline; D003091:Colistin
keywords: KPC; ceftazidime-avibactam; permeability