eravacycline and Klebsiella-Infections

Concerns regarding carbapenem-resistant Klebsiella pneumoniae (CR-Kp), especially in bloodstream infections (BSIs), are continuing to increase worldwide. Several novel agents with activity against BSI CR-Kp have been approved or are in late-stage clinical development. In this study, the antibacterial effects of ceftazidime/avibactam (CZA), aztreonam/avibactam (AZA), meropenem/vaborbactam (MEV), imipenem-cilastatin/relebactam (ICR) and eravacycline (ERV) against three colistin-resistant CR-Kp (COLR-Kp) and four CZA-resistant CR-Kp (CZAR-Kp) were tested by time-kill assay. Klebsiella pneumoniae ATCC® BAA-1705TM was used as a control strain. Two COLR-Kp isolates carried the blaKPC-2 gene and four CAZR-Kp isolates carried metallo-β-lactamase genes. The results revealed that ERV resulted in re-growth of seven tested isolates. CZA and MEV showed a bactericidal effect against isolates harbouring blaKPC-2. ICR reduced the population of six isolates to >5 log10 CFU/mL compared with the initial count. AZA showed a bactericidal effect (>5 log10 CFU/mL) against seven isolates and a bacteriostatic effect (<3 log10 CFU/mL) against one CZAR-Kp isolate. Therefore, AZA and ICR are effective therapeutic candidates for COLR-Kp and CZAR-Kp isolates.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Bacteremia; beta-Lactamase Inhibitors; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Ceftazidime; Cilastatin; Colistin; Drug Combinations; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Tetracyclines

The present study evaluated the carbapenem resistance mechanisms of Klebsiella pneumoniae strains isolated in two Greek tertiary teaching hospitals and their susceptibility to currently used and novel antimicrobial agents.Forty-seven carbapenem resistant K. pneumoniae strains were collected in G. Papanikolaou and Ippokrateio hospital of Thessaloniki between 2016 and 2018. Strain identification and antimicrobial susceptibility was conducted by Vitek 2 system (Biomérieux France). Susceptibility against new antimicrobial agents was examined by disk diffusion method. Polymerase chain reaction (PCR) was used to detect blaKPC, blaVIM, blaNDM and blaOXA-48 genes.The meropenem-EDTA and meropenem-boronic acid synergy test performed on the 24 K. pneumoniae strains demonstrated that 8 (33.3%) yielded positive for metallo-beta-lactamases (MBL) and 16 (66.6%) for K. pneumonia carbapenemases (KPC) production. Colistin demonstrated the highest in vitro activity (87.7%) among the 47 K. pneumoniae strains followed by gentamicin (76.5%) and tigecycline (51%). Among new antibiotics ceftazidime/avibactam showed the highest sensitivity (76.6%) in all strains followed by eravacycline (66.6%). The blaKPC gene was present in 30 strains (63.8%), the blaNDM in 11 (23.4%) and the blaVIM in 6 (12.8%). The blaOXA-48 gene was not detected.Well established antimicrobial agents such as colistin, gentamicin and tigecycline and novel antibiotics like ceftazidime/avibactam and eravacycline can be reliable options for the treatment of invasive infections caused by carbapenem-resistant K. pneumoniae.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Carbapenems; Ceftazidime; Greece; Hospitals, Teaching; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Tetracyclines

This study investigated the characteristics and mechanisms of eravacycline resistance and heteroresistance in clinical Klebsiella pneumoniae isolates. A total of 393 clinical K. pneumoniae isolates were collected and subjected to eravacycline and tigecycline MIC determinations using the agar dilution method. Eravacycline heteroresistance was assessed by a population analysis profile (PAP). The expression levels of efflux pumps and their regulators were determined by quantitative reverse-transcription PCR (qRT-PCR). This study identified 67 eravacycline-nonsusceptible isolates; among the extended-spectrum β-lactamase (ESBL)-positive isolates, eravacycline-nonsusceptible isolates were detected more frequently than tigecycline-nonsusceptible isolates (21.7% vs. 9.4%, p = 0.001). The study sample was observed to include 20 K. pneumoniae isolates with eravacycline heteroresistance. Compared to the reference strain, oqxA or oqxB overexpression was observed in nine eravacycline-nonsusceptible isolates (range, 35.64-309.02-fold) and 13 eravacycline-heteroresistant isolates (8.42-296.34-fold). The overexpression of macA or macB was detected in 12 eravacycline-heteroresistant isolates (3.23-28.35-fold). Overexpression of the efflux pump regulator gene ramA was observed in 11 eravacycline-nonsusceptible isolates (3.33-94.05-fold) and 18 eravacycline-heteroresistant isolates (3.89-571.70-fold). The eravacycline MICs were increased by one-fourfold by overexpression of oqxAB or macAB in three eravacycline-sensitive isolates. In conclusion, the overexpression of OqxAB and MacAB efflux pumps and the transcriptional regulator RamA were suggested to be involved in K. pneumoniae eravacycline resistance and heteroresistance.

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; beta-Lactamases; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Tetracyclines