Investigation of the In Vitro Synergistic Effect of CeftazidimeAvibactam, Fosfomycin and Meropenem in CarbapenemResistant Klebsiella pneumoniae Isolates

Abstract

It is preferred to use antibiotics in combination because of the difficulties encountered in the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp) isolates. Combination therapies result in a broader antibacterial spectrum, synergistic effects and a reduced risk of resistance during treatment. This study aimed to determine the resistance rates of ceftazidime-avibactam (CZA) and fosfomycin (FOS) in CRKp strains isolated from various clinical samples, to investigate the molecular patterns of carbapenem resistance and to explore the synergistic effect of CZA combined with [OS and meropenem (MEM) in CZA resistant isolates. One hundred carbapenem-resistant K.pneumoniae isolates from various clinical samples sent to Medical Microbiology Laboratory of & Idot;stanbul Medeniyet University G & ouml;ztepe Training and Research Hospital between 2019 and 2023 were included in the study. The carbapenem resistance genes (bla(KPC), bla(NDM), bla(OXA-48), bla(VIM), bla(IMP), bla(OXA-51), bla(OXA-23)/bla(OXA-58)) of the isolates were investigated by multiplex polymerase chain reaction. The agar dilution method was used to determine fosfomycin susceptibility and the broth microdilution method was used for MEM and CZA susceptibility. The checkerboard method was used to study the combinations of CZA with MEM and CZA with FOS in 15 CRKP isolates resistant to CZA. The in vitro synergistic effect of the combinations was analyzed based on the calculated fractional inhibitory concentration index (Sigma FIC). Forty-nine percent of our strains were isolated from patients in the intensive care unit. Fifteen percent of the 100 carbapenem-resistant K.pneumoniae isolates were resistant to CZA and 38% to FOS. According to the resistance patterns, at least one of the carbapenem resistance genes was detected in 85 isolates. Thirty-nine percent of the isolates produced bla(OXA-48), 10% bla(KPC), 2% bla(NDM), and 1% bla(OXA-51), indicating that 52 isolates carried only one resistance gene. Thirty three isolates carried more than one resistance gene which were detected as follows: 17% bla(OXA-48)+bla(KPC, 9)% bla(OXA-48)+bla(NDM, 3)% bla(OXA-48)+bla(NDM)+bla(KPC, 2)% bla(OXA-48)+bla(OXA-51), 1% bla(OXA-48)+bla(OXA-23/58), and 1% bla(OXA-48)+bla(OXA-51)+bla(KPC). No bla(IMP) or bla(VIM) enzymes were detected in any of the isolates. A partial synergistic effect was found in 100% of the CZA and MEM combinations by the checkerboard method in the fifteen CZA resistant isolates, while a partial synergistic effect was found in 33% of the CZA and FOS combinations. The presence of the OXA-48 gene in CRKp isolates in our hospital, the detection of multiple resistance genes in 33% of the isolates and the production of metallo-beta-lactamase (NDM) in 14% of the isolates highlight the importance of determining resistance patterns in resistant strains. CZA, which is a frequently preferred antibiotic in the treatment of CRKp isolates, is not effective against isolates that produce metallo-beta-lactamases. It was concluded that the combination of CZA with MEM, rather than with [OS, may be considered a potential treatment option for serious CRKp infections.