Monte Carlo simulation for dosage optimization of the best available therapy for bloodstream infections secondary to carbapenemase-producing Klebsiella pneumoniae in critically ill patients

Abstract

Objective: We aimed to use Monte Carlo simulation, based on pharmacokinetic/pharmacodynamic targets, to investigate and determine the optimal dosage of the available combination therapies for carbapenem-resistant Klebsiella pneumoniae (CRKP) in critically ill patients. Methods: We collected CRKP clinical isolates from Phramongkutklao Hospital between October 2020 and June 2022. A molecular study of resistant genes was performed using polymerase chain reaction. Broth microdilution checkerboards were used to evaluate the mono- and synergistic antibiotic activities. Monte Carlo simulation was used to determine the optimal antibiotic regimens, based on the probability of target attainment (PTA) and cumulative fraction of response. Results: The 54 CRKP isolates were resistant to tigecycline (100%), colistin (75.9%), amikacin (70.4%), and gentamicin (63.0%). The most common carbapenemase genotype was blaoxacillinases (OXA)-48-like (42.6%), followed by blaNew Delhi metallo beta-lactamase (NDM) (29.6%) and coexistence of blaOXA-48-like and blaNDM (22.2%). Based on the PTA, synergistic and additive activities against CRKP isolates were observed with appropriate dosages of tigecycline–colistin (67.9%), tigecycline–gentamicin (62.2%), and tigecycline–amikacin (51.4%). Conclusions: Tigecycline–colistin was the best available combination therapy for critically ill patients with CRKP, especially NDM. When used in combination with tigecycline, a colistin creatinine clearance of <90 mL/min can raise the cumulative fraction of response target and less nephrotoxicity.

Keywords

• Carbapenem-resistant enterobacterales
• Metallo-beta-lactamase
• Oxacillinases
• Tigecycline
• Colistin
• Aminoglycoside