Unlocking potentials: the impact of meropenem, meropenem-vaborbactam, and ceftazidime-avibactam in combating carbapenem-resistant Enterobacter cloacae

Carbapenem-resistant Enterobacterales (CREs) are recognized as an urgent public threat by the Centers for Disease Control and Prevention. This study assesses the activity of humanized serum concentrations for meropenem (2 g Q8h), meropenem-vaborbactam (4 g Q8h), and ceftazidime-avibactam (2.5 g Q8h) against carbapenemase-producing (CP) (AR-1046 bla KPC-3 ) and non-CP (AR-8 bla ACT-15 ) Enterobacter cloacae isolates in a 120 h in vitro pharmacodynamic model. Additionally, we compared antimicrobial administration as a bolus or extended infusion for each isolate and treatment. For the CP strain, all treatments with meropenem-vaborbactam and ceftazidime-avibactam were bacteriostatic through 24 h. Extended-infusion meropenem-vaborbactam exhibited the most prolonged bacteriostatic activity and was significantly more effective than ceftazidime-avibactam at 120 h (0.92 log 10 lower mean colony count compared to extended-infusion ceftazidime-avibactam, P < 0.001). For the non-CP strain, all simulated treatments demonstrated initial bactericidal activity through 24 h, except for ceftazidime-avibactam bolus administration. Meropenem and meropenem-vaborbactam, administered as bolus dosing, each maintained significantly greater bacterial colony count reductions compared to extended infusion through 120 h against non-CP CRE ( P < 0.01). No significant differences were found between bolus and extended infusion for ceftazidime-avibactam ( P = 0.08). Resistance development was observed following treatment with meropenem monotherapy (minimum inhibitory concentrations increasing to >32 µg/mL for the non-CP isolate with extended infusion and to >32 µg/mL for the CP isolate with bolus and extended-infusion treatments) and ceftazidime-avibactam (minimum inhibitory concentration increase from 2 to 16 μg/mL with bolus dosing against the CP isolate). Meropenem-vaborbactam exposure did not result in the emergence of antimicrobial resistance in any of the tested models.