Carbapenemase producing Klebsiella pneumoniae: implication on future therapeutic strategies

The emergence of carbapenemase resistant Gram-negative is designated as an 'urgent' priority of public health. Carbapenemase producing Klebsiella pneumoniae (CPKP) is linked with significant mortality. Conventionally used antibiotics (polymyxins, tigecycline, aminoglycosides, etc.) are associated with poor efficacy and toxicity profiles are quite worrisome.

This article reviews mechanism of resistance and evidence regarding novel treatments of infections caused by CPKP, focusing mainly on currently approved new therapies and implications on future therapeutic strategies. A review of novel β-lactam/β-lactamase inhibitors (BLI) recently approved and in clinical development as well as cefiderocol, eravacycline and apramycin are discussed.

Newly approved and forthcoming antimicrobial agents are promising to combat infections caused by CPKP. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are novel agents with favorable outcome and associated with improved mortality in KPC-producing K. pneumoniae infections. However, are inactive against metallo-β-lactamases (MBL). Novel BLI in later stage of development, i.e. aztreonam-avibactam, cefepime-zidebactam, cefepime-taniborbactam, and meropenem-nacubactam as well as cefiderocol are active in vitro against both KPC and MBL. Potential expectations of future therapeutic strategies are improved potency against CPKP, more tolerable safety profile, and capability of overcoming current resistance mechanism of multidrug-resistant K. pneumoniae.