Molecular Mechanisms Mediating Ceftazidime/Avibactam Resistance Amongst Carbapenem-Resistant Klebsiella pneumoniae Isolates from Cancer Patients

BACKGROUND: A growing body of evidence suggests that ceftazidime/avibactam (CZA) is a potential therapeutic option for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections; however, resistant strains are increasingly emerged worldwide. Herein, we deemed to investigate the susceptibility profile of CRKP isolates from cancer patients to CZA and to identify the underlying resistance mechanisms. METHODS: Clinical samples were obtained from adult patients admitted to the Oncology Center of Mansoura University, Mansoura, Egypt. The antibiotic susceptibility pattern of K. pneumoniae isolates to different antibiotics was tested by the modified Kirby Bauer’s disc diffusion method. Minimum inhibitory concentrations of CZA were assessed using broth microdilution method. Screening for carbapenemase-producing strains was achieved by the modified Hodge test. Multiplex polymerase chain reactions (PCRs) were conducted for uncovering of carbapenemase-encoding genes (bla(KPC), bla(VIM), bla(IMP), bla(NDM-1), and bla(OXA-48)), and outer membrane porin genes (ompK35 and ompK36). RESULTS: A total of 12 CZA-resistant isolates were identified out of 47 CRKP isolates (25.5%). The MIC(50) and MIC(90) of CZA against CRKP were 1 and 64 µg/mL, respectively. Risk factors for CZA resistance included chronic kidney disease, mechanical ventilation, longer length of hospital stay, and ICU admission. The multivariate logistic regression demonstrated that longer length of hospital stay (P=0.03) was the only independent predictor for acquisition of CZA-resistant isolates. The leading mechanism for CZA resistance was sustained by bla(KPC) (50%), meanwhile 16.7% and 8.3% of the CZA-resistant isolates harbored bla(OXA-48) and bla(OXA-48)/bla(NDM-1), respectively. The MBL-encoding genes bla(NDM-1) and bla(IMP) were detected in 16.7% and 8.3% of the isolates, respectively. Absence of both ompK35 and ompK36 was observed in 58.3% of the CZA-resistant isolates. CONCLUSION: CZA has displayed superior in vitro activity against CRKP isolates in comparison to other antibiotics; however, thorough molecular characterization of resistant strains is highly recommended in future studies to detect and monitor the emergence of further tackling strains.