Investigation of in vitro activity of the ceftazidime-avibactam-aztreonam, meropenem-colistin combinations and cefiderocol monotherapy against new delhi̇ metallo-beta-lactamase (NDM) positive klebsiella pneumoniae strai̇ns

The increasing isolation rates of New Delhi Metallo-beta-lactamase (NDM) positive Klebsiella pneumoniae and the lack of a standardized algorithm for treating infections caused by these isolates have created a need to investigate effective therapeutic options. A total of 63 K. pneumoniae isolates, identified as NDM positive by real-time polymerase chain reaction (PCR), isolated from various clinical samples in the Bacteriology Laboratory of the Department of Medical Microbiology at Süleyman Demirel University Faculty of Medicine, were included in the study. The susceptibilities of isolates to ceftazidime-avibactam, aztreonam, meropenem, and colistin were tested by the broth microdilution method, and evaluated according to the current breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). The efficacy of ceftazidime-avibactam-aztreonam and meropenem-colistin combinations against NDM positive K. pneumoniae isolates was tested using the checkerboard method. Time-kill assays were conducted to investigate the bactericidal activity of ceftazidime-avibactam-aztreonam and meropenem-colistin combinations against 5 isolates harboring different carbapenemase genes, evaluated in concentration-and time-dependent manners. All NDM positive K. pneumoniae isolates in our study (100%) were resistant to ceftazidime-avibactam, aztreonam, and meropenem, while 77.8% were resistant to ceftiderocol and 54% were resistant to colistin. According to the checkerboard test results, the ceftazidime-avibactam-aztreonam combination showed synergistic interaction against all isolates (100%), whereas the meropenem-colistin combination exhibited synergistic interaction against 57.1% of isolates, additive interaction against 25.4%, and undefined interaction against 17.5%. Time-kill assays demonstrated synergistic activity with the ceftazidime-avibactam-aztreonam combination against all isolates and bactericidal effects were observed at certain time points. With the meropenem-colistin combination, synergistic activity was observed against 4 isolates and bactericidal effects were determined at certain time points. Although an undefined interaction was determined in the checkerboard test against 1 isolate (NDM+OXA-48 positive) with the MEM-COL combination; synergistic activity and bactericidal effects were observed at the 12th and 24th hours with the 1xMIC MEM + 1xMIC COL combination in the time-kill assay against the same isolate. In conclusion, the combination of ceftazidime-avibactam-aztreonam seems to be a promising treatment option in infections caused by NDM positive K. pneumoniae isolates. In cases where ceftazidime-avibactam-aztreonam combination therapy cannot be applied, meropenem-colistin combination therapy or cefiderocol monotherapy may be considered as alternative treatment options.