Introduction

Klebsiella pneumoniae is the primary opportunistic pathogen of healthcare-associated carbapenem-resistant Enterobacterales (CRE) infections. Carbapenem-resistant Klebsiella pneumoniae (CPKP) infections seriously threaten global public health. Ceftazidime–avibactam exhibits a broad spectrum of activity against a variety of β-lactamases expressed by Enterobacterales, however, it does not inhibit the activity of metallo-β-lactamases (MBLs). Further, non-MBLs mediated ceftazidime–avibactam resistance in CRE is rising. Studies have shown no mortality difference between patients who manage infections caused by CRE with ceftazidime–avibactam alone and those treated with combination regimens. However, ceftazidime–avibactam resistance emergence was reported at 3.0% in the combination group and 4.1% in the monotherapy group; it is even seen in KP carbapenemase (KPC)-positive isolates.

Aim

To assess the in-vitro synergistic activity of ceftazidime–avibactam in combination with colistin, amikacin, gentamicin, and fosfomycin against CRKP isolates

Patient Profile

• 55 isolates of CRKP were collected from hospitalized adult inpatients; each patient was represented by only one isolate

Method

Study Design

• The minimum inhibitory concentrations (MICs) of ceftazidime–avibactam, colistin, amikacin, and gentamicin were determined by broth microdilution method and that of fosfomycin were determined by agar dilution method
• A checkerboard assay was done to examine the antibacterial activity of ceftazidime–avibactam with colistin, amikacin, gentamicin, and fosfomycin against CRKP isolates

Endpoint

• Synergy testing

Results

Efficacy

• CRKP isolates were 89.1% susceptible to ceftazidime-avibactam, 16.4% to colistin, 21.8% to gentamicin, and 29.1% to amikacin and, 47.3% to fosfomycin
• The most synergistic effects were observed in the combination of ceftazidime-avibactam-colistin (78.2%) and ceftazidime-avibactam-fosfomycin (63.6%) against CRKP isolates (Figure 1)
• Synergistic effects were seen in 33.3% of strains were resistant to ceftazidime-avibactam and colistin; while no effects were seen in ceftazidime-avibactam-susceptible and colistin-resistant strains and synergistic effects were observed in 95.3%
• Synergistic results were found in 10.5% of ceftazidime–avibactam-susceptible and gentamicin-resistant strains and 19.4% of ceftazidime–avibactam-susceptible and amikacin-resistant strains
• Synergistic results were found in 66.7% of ceftazidime–avibactam-resistant and fosfomycin-susceptible strains and 42.3% of ceftazidime–avibactam-susceptible and fosfomycin-resistant strains
• In combinations of ceftazidime-avibactam with gentamicin, amikacin, and fosfomycin, synergistic effects were not observed when strains were resistant to both antibiotics 
• No synergistic effect was observed in cases where isolates were susceptible to aminoglycosides but resistant to ceftazidime–avibactam
• Only the KPC-positive strain showed synergistic effects with the combination of ceftazidime–avibactam and gentamicin

Figure 1: In vitro synergistic effect of antibiotic combinations against Klebsiella pneumoniae isolates

Conclusion

Combining ceftazidime–avibactam with colistin and fosfomycin improved in-vitro activity against clinical CRKP isolates.

Sci Rep 2024; 14: 17567