Carbapenemase-directed therapy: optimizing antibiotic combinations against carbapenem-resistant Klebsiella pneumoniae.

OBJECTIVE

Given the limited therapeutic options for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) due to multidrug resistance, this study aimed to evaluate combination therapeutic strategies based on carbapenemase profiles and resistance phenotypes.

METHODS

The in vitro activities of ceftazidime-avibactam (CZA) and polymyxin B (PMB)-based combinations was systematically evaluated against 139 CRKP isolates, including K. pneumoniae carbapenemase (KPC) producing strains, New Delhi metallo-β-lactamase (NDM), and KPC and NDM co-producing carbapenem-resistant K. pneumoniae strains (KN-CRKP). The combination effects of these antimicrobial combinations were assessed using the fractional inhibitory concentration index (FICI) and susceptibility breakpoint index (SBPI).

RESULTS

Among CZA-resistant KPC-CRKP isolates, combinations of CZA with β-lactams exhibited high synergy rates (79.7-86.5%). In PMB-resistant KPC-CRKP, PMB + CZA demonstrated substantially higher synergy rates (53.2%) than conventional PMB-carbapenem combinations (≤3.8%). Against NDM-CRKP, CZA + aztreonam (ATM) showed synergistic activity in 83.3% of isolates. Notably, in KN-CRKP, CZA + ATM produced synergistic or additive effects in all isolates, despite resistance to the individual agents. SBPI analysis further suggested substantial antimicrobial enhancement in some combinations classified as indifferent by FICI, including PMB + tigecycline (TGC).

CONCLUSIONS

Carbapenemase profiles substantially influence the efficacy of combination therapies against CRKP. CZA-based combinations, particularly those combined with β-lactams or ATM, demonstrated favorable in vitro activity against KPC and NDM-producing CRKP, while PMB in combination with CZA partially restored activity in PMB-resistance isolates. Notably, the CZA-ATM regimen showed consistently favorable activity against both NDM-CRKP and KPC-NDM co-producing isolates. These findings support the potential value of carbapenemase profile-guided combination therapy for optimizing treatment of highly resistant CRKP infections.