Faculty Opinions recommendation of Structure of the monomeric outer-membrane porin OmpG in the open and closed conformation.

Abstract Background Vaborbactam is a cyclic boronic acid β-lactamase inhibitor (BLI) developed to potently inhibit Ambler class A&C enzymes, including KPC carbapenemases. Metallo-β-lactamases (MBL) and some Class D oxacillinases (OXA) are not inactivated by vaborbactam. Meropenem-vaborbactam (MV) was recently approved for the treatment of carbapenem-resistant Enterobacteriaceae complicated urinary tract infections. Recent studies have identified outer membrane porin (Ompk35 and -36) mutations in Klebsiella pneumoniae (KP) as a mechanism of decreased susceptibility to MV. We evaluated the activity of MV against a historical cohort of KP clinical isolates with these porin gene mutations. Methods WGS of carbapenem-resistant KP clinical isolates was performed and those harboring mutations in Ompk35 or Ompk36 were selected for testing. Strain KP ATCC BAA-1705 was used as a positive control. Meropenem and MV minimum inhibitory concentrations (MIC) were determined by broth microdilution (BMD) in custom 96-well plates (ThermoFisher Scientific) with a constant 8 µg/mL vaborbactam concentration. The MIC of ceftazidime–avibactam (CZA) was determined by standard BMD reference methods and interpreted according to CLSI criteria. Results A total of 105 KP isolates with either partial or complete mutations in outer membrane porin genes were included in the analysis. All isolates were resistant to Meropenem. The median MV MIC was 0.03 µg/mL (range, 0.015 to >16 µg/mL). Eleven isolates (10.4%) were resistant to MV. Sixteen additional isolates (16.1%) demonstrated higher than expected MV MICs ranging from 1 to 4 µg/mL. Only 1/11 resistant isolates harbored a gene for MBL production. Gene mutations in blaKPC were not detected. See Table 1 for characteristics of resistant isolates. Conclusion Resistance and decreased susceptibility to MV is demonstrated in a historical cohort of KP clinical isolates dating back to 2013. WGS reliably identifies porin variants secondary to gene mutations in Ompk35 and Ompk36 as the underlying mechanism of decreased susceptibility. CZA appears to retain activity against these isolates. Caution should be exercised regarding the empiric use of MV against increasingly resistant KP as a result of non-β-lactamase-mediated mechanisms. Disclosures All authors: No reported disclosures.

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In Vitro Activity of Imipenem and Colistin against a Carbapenem-ResistantKlebsiella pneumoniaeIsolate Coproducing SHV-31, CMY-2, and DHA-1

BioMed Research International ◽

10.1155/2015/568079 ◽

2015 ◽

Vol 2015 ◽

pp. 1-5 ◽

Cited By ~ 4

Author(s):

Hung-Jen Tang ◽

Yee-Huang Ku ◽

Mei-Feng Lee ◽

Yin-Ching Chuang ◽

Wen-Liang Yu

Keyword(s):

Outer Membrane ◽

Multidrug Resistant ◽

In Vitro Activity ◽

Carbapenem Resistant ◽

Hip Infection ◽

Outer Membrane Porin ◽

The Common ◽

Inoculum Effect ◽

Time Kill

We investigated the synergism of colistin and imipenem against a multidrug-resistantK. pneumoniaeisolate which was recovered from a severe hip infection. PCR and DNA sequencing were used to characterize the outer membrane porin genes and the resistance genes mediating the commonβ-lactamases and carbapenemases. Synergism was evaluated by time-kill studies. TheblaSHV-31,blaCMY-2, andblaDHA-1were detected. Outer membrane porin genes analysis revealed loss ofompK36and frame-shift mutation ofompK35. The common carbapenemase genes were not found. Time-kill studies demonstrated that a combination of 1x MIC of colistin (2 mg/L) and 1x MIC of imipenem (8 mg/L) was synergistic and bactericidal but with inoculum effect. Bactericidal activity without inoculum effect was observed by concentration of 2x MIC of colistin alone or plus 2x MIC of imipenem. In conclusion, colistin plus imipenem could be an alternative option to treat carbapenem-resistantK. pneumoniaeinfections.

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