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

Abstract

fAvibactam is a novel ␤-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 ␤-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 g/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 g/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 g/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. Avibactam is a non-␤-lactam, ␤-lactamase inhibitor with broad-spectrum activity against Ambler class A, class C, and some class D serine-based ␤-lactamases. Most notably, the agent inhibits class C Klebsiella pneumoniae carbapenemases (KPCs). The addition of avibactam to ceftazidime results in considerably lower ceftazidime MICs (1). As a result, ceftazidime-avibactam may prove to be a valuable addition to the limited antibiotic armamentarium against infections caused by carbapenem-resistant Enterobacteriaceae (CRE) (2, 3). At the University of Pittsburgh Medical Center, sequence type 258 (ST258) international epidemic clone of KPC-producing K. pneumoniae (KPC-Kp) is the predominant CRE; however, outcomes among KPC-Kp-infected patients, and the constellation of resistant determinants among individual strains, are highly variable (2, 4). Carbapenem resistance is mediated through multiple mechanisms, including production of KPCs, defects in outer membrane proteins (OMPs), and expression of other extended-spectrum ␤-lactamases (ESBLs) (2). Therefore, inhibition of ␤-lactamases may not provide a "one-size-fits-all" therapeutic option against CRE.We have recently shown that specific mutations in the ompK36 por...

Detection and Characterization of &lt;i&gt;β&lt;/i&gt;-Lactamase Encoding Genes in Carbapenem Non-Susceptible Gram-Negative Bacteria and Susceptibility of Isolates to Ceftazidime-Avibactam at a New York City Community Hospital

“…Another survey, which also characterized such isolates and their susceptibility to CA, reported MIC 50/90 , of 1/1µg/ml [20]. Although not assessed in our study, elevated MICs have been associated with KPC-3 strains of K. pneumoniae as well as strains with ESBLs and porin mutations and this is an area for future investigation [21].…”

Prevalence of Carbapenem-Resistant Klebsiella Pneumoniae (CRKP) and the Distribution of Class 1 Integron in Their Strains Isolated from a Hospital in Central China

“…10 The mechanism for drug resistance of CRKP is mainly related to two aspects: the excessive expression of Amp Combined with pore protein loss, and the production of carbapenem enzymes. 11 In addition to carbapenem and beta lactam resistance, CRKP was found frequently to carry resistant genes to other antibiotics, and easily develop into multiple-drug resistance bacterium. 12 Although reported CRKP detection rate was variable, it has shown a rapid growth trend worldwide.…”

Impaired Inhibition by Avibactam and Resistance to the Ceftazidime-Avibactam Combination Due to the D 179 Y Substitution in the KPC-2 β-Lactamase

“…The mechanism described in reference 10 is clearly distinct from the impaired carbamylation by avibactam reported for the D 179 Y substitution in the current study. The D 179 Y substitution was recently shown to be responsible for the acquisition of ceftazidime-avibactam resistance under treatment in K. pneumoniae isolates producing the closely related enzyme KPC-3 (8,16). The fact that a single mutation is sufficient for impaired inhibition of KPC ␤-lactamases by avibactam indicates that the emergence of resistance under treatment may jeopardize the efficacy of the ceftazidime-avibactam combination in the future (17).…”