[Investigation of the In Vitro Activity of Ceftazidime-Avibactam- Aztreonam and Meropenem-Colistin Combinations and Cefiderocol Alone In New Delhi Metallo-β-lactamase Positive and OXA-48, KPC, VIM/IMP Co-producing Klebsiella pneumoniae Isolates].

Currently, the increasing isolation rates of New Delhi metallo-beta-lactamase (NDM) positive Klebsiella pneumoniae and the lack of a standard algorithm for the treatment of infections caused by these isolates necessitate the search for effective treatment options. This study aimed to investigate the efficacy of the combination of ceftazidime-avibactam (CZA), frequently used in the treatment of carbapenem-resistant Enterobacterales (CRE) infections in recent years with aztreonam (AZT), which is expected to become available in our country soon and the combination of meropenem (MEM) with colistin (COL), which is frequently preferred in our hospital against NDM-positive K.pneumoniae isolates using in vitro synergy tests and to determine the susceptibility of these isolates to cefiderocol (FDC), which is recommended as an alternative treatment option in CRE infections. A total of 63 K.pneumoniae isolates, isolated from clinical samples in the Bacteriology Laboratory of the Department of Medical Microbiology at Süleyman Demirel University Faculty of Medicine and identified as NDM positive by real-time polymerase chain reaction, were included in the study. The susceptibility of the isolates to CZA, AZT, MEM and COL was tested by broth microdilution method and FDC susceptibility was tested by Kirby-Bauer disk diffusion method according to the European Committee on Antimicrobial Susceptibility Testing criteria. The efficacy of CZA-AZT and MEM-COL combinations against NDM positive K.pneumoniae isolates was tested using the checkerboard method. Time-kill assays were performed to investigate the bactericidal activity of CZA-AZT and MEM-COL combinations at different concentrations and time points in five isolates harboring different carbapenemase genes (two NDM+OXA-48, one NDM, one NDM+OXA-48+KPC, and one NDM+OXA-48/VIM/IMP). All isolates included in our study were found as resistant to CZA, AZT and MEM, while 77.8% were resistant to FDC and 54% were resistant to COL. According to the checkerboard test results, the CZA-AZT combination showed synergistic interaction against all isolates, while the MEM-COL combination exhibited synergistic interaction against 57.1% of the isolates, additive interaction against 25.4% and undefined interaction against 17.5%. In time-kill assays, synergistic activity was observed at various time points in all isolates with the CZA-AZT combination and in four isolates with the MEM-COL combination, while bactericidal activity was detected at certain time points. Although an undefined interaction was determined in the checkerboard test against one isolate (NDM+OXA-48 positive) with the MEM-COL combination, synergistic activity and bactericidal effect 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 CZA-AZT seems to be a promising treatment option in infections caused by NDM positive K.pneumoniae isolates. In cases where CZA-AZT combination therapy cannot be applied, MEM-COL combination therapy may be considered as an alternative treatment option. In situations where both treatment options cannot be used, cefiderocol monotherapy may be considered as an alternative in selected cases, given the low and heterogeneous susceptibility rates among NDM-positive isolates, provided that close clinical and microbiological monitoring is ensured. However, careful monitoring is required during cefiderocol therapy and treatment modification should be considered in cases of clinical non-response.