Carbapenem-Resistant Klebsiella pneumoniae Strains Exhibit Diversity in Aminoglycoside-Modifying Enzymes, Which Exert Differing Effects on Plazomicin and Other Agents

Abstract

eWe measured in vitro activity of plazomicin, a next-generation aminoglycoside, and other aminoglycosides against 50 carbapenem-resistant Klebsiella pneumoniae strains from two centers and correlated the results with the presence of various aminoglycoside-modifying enzymes (AMEs). Ninety-four percent of strains were sequence type 258 (ST258) clones, which exhibited 5 ompK36 genotypes; 80% and 10% of strains produced Klebsiella pneumoniae carbapenemase 2 (KPC-2) and KPC-3, respectively. Ninety-eight percent of strains possessed AMEs, including AAC(6=)-Ib (98%), APH(3=)-Ia (56%), AAC(3)-IV (38%), and ANT(2؆)-Ia (2%). Gentamicin, tobramycin, and amikacin nonsusceptibility rates were 40, 98, and 16%, respectively. Plazomicin MICs ranged from 0.25 to 1 g/ml. Tobramycin and plazomicin MICs correlated with gentamicin MICs (r ‫؍‬ 0.75 and 0.57, respectively). Plazomicin exerted bactericidal activity against 17% (1؋ MIC) and 94% (4؋ MIC) of strains. All strains with AAC(6=)-Ib were tobramycin-resistant; 16% were nonsusceptible to amikacin. AAC(6=)-Ib combined with another AME was associated with higher gentamicin, tobramycin, and plazomicin MICs than AAC(6=)-Ib alone (P ‫؍‬ 0.01, 0.0008, and 0.046, respectively). The presence of AAC(3)-IV in a strain was also associated with higher gentamicin, tobramycin, and plazomicin MICs (P ‫؍‬ 0.0006, P < 0.0001, and P ‫؍‬ 0.01, respectively). The combination of AAC(6=)-Ib and another AME, the presence of AAC(3)-IV, and the presence of APH(3=)-Ia were each associated with gentamicin resistance (P ‫؍‬ 0.0002, 0.003, and 0.01, respectively). In conclusion, carbapenem-resistant K. pneumoniae strains (including ST258 clones) exhibit highly diverse antimicrobial resistance genotypes and phenotypes. Plazomicin may offer a treatment option against strains resistant to other aminoglycosides. The development of molecular assays that predict antimicrobial responses among carbapenem-resistant K. pneumoniae strains should be a research priority.

Plazomicin Activity against 346 Extended-Spectrum-β-Lactamase/AmpC-Producing Escherichia coli Urinary Isolates in Relation to Aminoglycoside-Modifying Enzymes

“…Only 2 of the 58 isolates that harbored the aac(6=)-Ib gene alone expressed phenotypic resistance to amikacin, although it has been reported that aac(6=)-Ib confers resistance to both antibiotics (3). These observations were consistent with previous studies where, despite the possession of aac(6=)-Ib, low amikacin MICs have been reported for E. coli and K. pneumoniae strains (14,17). In our study, moreover, there was a statistically significant relationship (P Ͻ 0.01) between the presence of an aac(6=)-Ib gene and an amikacin MIC of Ͼ8 mg/liter.…”

“…PCR screening showed that aac(6=)-Ib was the most prevalent gene. Similar results have been reported by other authors (17,18). All strains with aac(6=)-Ib were tobramycin resistant.…”

“…Using EUCAST breakpoints (9), the AME presence was not always correlated with aminoglycoside resistance. Similar results were previously reported both in E. coli isolates and in K. pneumoniae isolates (17,18). PCR screening showed that aac(6=)-Ib was the most prevalent gene.…”

“…The level of correlation between the MICs for plazomicin and amikacin by Spearman's rank test was higher (r ϭ 0.600; P Ͻ 0.001) than the level of correlation between the MICs for plazomicin and tobramycin (r ϭ 0.271; P Ͻ 0.001) and gentamicin (r ϭ 0.112; P ϭ 0.038), respectively. This is the first description of a correlation between the MICs of plazomicin and those of amikacin, tobramycin, and gentamicin in E. coli isolates, although a correlation between the plazomicin MICs and those of gentamicin has been reported in carbapenemase-producing Klebsiella pneumoniae (17).…”

Antibiofilm Peptides Increase the Susceptibility of Carbapenemase-Producing Klebsiella pneumoniae Clinical Isolates to β-Lactam Antibiotics

“…Tigecycline, aminoglycosides, and the polymyxins (polymyxin B and colistin) are currently the best treatment options for carbapenemase-producing strains (13). However, these strains also have the potential to develop resistance to these antibiotics (14)(15)(16).…”