Carbapenemase producing Klebsiella pneumoniae: implication on future therapeutic strategies

ABSTRACT

Introduction

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.

Areas covered

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.

Expert opinion

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.

KEYWORDS:

• KPC
• carbapenemase
• Klebsiella pneumoniae
• cefiderocol
• metallo-β-lactamases
• eravacycline
• apramycin
• novel β-lactamase inhibitors

Article highlights

• Carbapenemase producing Klebsiella pneumoniae is considered as one of the most critical threats to global health.

• The most relevant mechanism of resistance in Klebsiella pneumoniae is the presence of a β-lactamase.

• KPC-producing K. pneumoniae is the most prevalent carbapenemase identified globally and is associated with high mortality. Countries such as USA, China, Greece and Italy are considered endemic.

• Ceftazidime-avibactam, meropenem-vaborbactam and imipenem-cilastatin-relebactam are promising therapeutic options for treating KPC-producing K. pneumoniae, as all are active in vitroagainst Amber class A (including KPC) and class C.

• Novel β-lactam/β-lactamase inhibitors in clinical development (i.e. aztreonam-avibactam, cefepime-zidebactam, cefepime-taniborbactam and meropenem-nacubactam) are forthcoming with promising efficacy against Amber class A and C, as well as class B.

• Cefiderocol, characterized as the ‘Trojan horse’ antimicrobial agent, is a potent in vitro against all Amber group β-lactamases, including metallo-β-lactamases. Approval has been registered only for complicated urinary tract infections since treatment with cefiderocol has been linked with increased in all-cause mortality in patients with carbapenem-resistant Gram-negative bacterial infections.

• Eravacycline, a novel synthetic tetracycline analogue overcoming the primary mechanism of tetracycline resistance has in vitroactivity against KPC producing K. pneumoniae. However, clinical data regarding treatment of KPC producing K. pneumoniae are lacking.

• Apramycin is an aminoglycoside that has been traditionally used in veterinary medicine. However, has promising activity against carbapenemase producing K. pneumoniae.

Declaration of interest

H Giamarellou has received speaker honoraria from Pfizer and MSD. I Karaiskos has received speaker honoraria from Pfizer. The author(s) have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors have substantially contributed to the conception and design of the review article and interpreting the relevant literature and been involved in writing the review article or revised it for intellectual content.

Additional information

Funding

This paper was not funded.