What is the antibiotic choice for Klebsiella pneumoniae carbapenemase-2 (KPC-2) producing Escherichia coli (E. coli)?

From the Guidelines

For Klebsiella pneumoniae carbapenemase-2 (KPC-2) producing Escherichia coli infections, the first-line treatment options should be novel β-lactam agents such as ceftazidime/avibactam or meropenem/vaborbactam. These recommendations are based on the latest guidelines endorsed by the Italian Society of Infection and Tropical Diseases (SIMIT), the Italian Society of Anti-infective Therapy (SITA), the Italian Group for Antimicrobial Stewardship (GISA), the Italian Association of Clinical Microbiologists (AMCLI), and the Italian Society of Microbiology (SIM) 1.

Key Considerations

• The choice between ceftazidime/avibactam and meropenem/vaborbactam should consider the site of infection, with meropenem/vaborbactam potentially being preferred for infections like pneumonia due to its pharmacokinetic/pharmacodynamic properties 1.
• Local epidemiology and the emergence of resistance to these agents should also be taken into account, with KPC variants conferring resistance to ceftazidime/avibactam being a concern 1.
• Imipenem/relebactam and cefiderocol may be considered as alternative options, although clinical studies supporting their use in KPC-producing CRE infections are limited 1.

Treatment Approach

• Ceftazidime/avibactam and meropenem/vaborbactam are strongly recommended as first-line treatments due to their favorable clinical efficacy and safety profiles compared to traditional antibiotic regimens 1.
• The use of these novel β-lactam agents has been associated with improved clinical outcomes, including higher clinical cure rates and reduced mortality, in patients with CRE infections 1.
• It is essential to consider the potential for nephrotoxicity and adjust dosing accordingly, especially in patients with renal impairment 1.

Infection Control

• Infection control measures, including contact precautions and dedicated equipment, are crucial to prevent the spread of KPC-producing organisms within healthcare settings 1.
• Susceptibility testing is vital before finalizing therapy, as resistance patterns can vary, and the choice of antibiotic should be guided by the results of these tests 1.

From the FDA Drug Label

AVYCAZ demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC, and certain oxacillinases (OXA). AVYCAZ has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections ... Gram-negative Bacteria ... Escherichia coli AVYCAZ is not active against bacteria that produce metallo-beta lactamases and may not have activity against gram-negative bacteria that overexpress efflux pumps or have porin mutations.

Antibiotic choice for Klebsiella pneumoniae carbapenemase-2 producing Escherichia coli:

• AVYCAZ (ceftazidime and avibactam) may be effective against Escherichia coli that produce Klebsiella pneumoniae carbapenemase-2 (KPC-2), as it has demonstrated in vitro activity against KPC-producing organisms 2 2.
• However, it is essential to note that AVYCAZ may not be effective against bacteria that produce metallo-beta-lactamases or have other resistance mechanisms, such as overexpressed efflux pumps or porin mutations.
• Therefore, susceptibility testing should be performed to confirm the effectiveness of AVYCAZ against the specific Escherichia coli isolate.

From the Research

Antibiotic Choice for Klebsiella pneumoniae Carbapenemase-2 Producing Escherichia coli

• The emergence of Klebsiella pneumoniae carbapenemase (KPC)-producing organisms, including Escherichia coli, has increased the challenges in treating infections caused by these organisms 3.
• KPC-2 is a β-lactamase that inactivates carbapenems and β-lactamase inhibitors, and resistance to the new antibiotic ceftazidime-avibactam has already emerged 4.
• Ceftazidime-avibactam-resistant KPC-2-producing Klebsiella pneumoniae strains have been isolated, harboring substitutions in the Ω loop of KPC-2, such as D179Y or D179V 5.
• The combination of ceftazidime and avibactam represents an attempt to overcome the threat of KPCs, but CAZ-AVI-resistant clinical strains expressing KPC variants with substitutions in the Ω-loop are emerging 4.
• Other antibiotic options, such as imipenem, imepenem-relebactam, meropenem-vaborbactam, and aztreonam-avibactam, may be effective against KPC-2-producing Escherichia coli 6.

Mechanisms of Resistance

• The emergence of KPC variants, such as KPC-134, which differs from KPC-2 by a single mutation (D178A) and 8-amino acid insertions, can lead to ceftazidime-avibactam resistance 6.
• The production of KPC variants can result in a concomitant increased susceptibility to broad-spectrum cephalosporins and carbapenems, with the exceptions of ceftazidime and piperacillin-tazobactam 7.
• Enzymatic assays have shown that KPC variants exhibit an increased affinity toward ceftazidime and a slightly decreased sensitivity to avibactam, sustaining their impact on CZA resistance 7.

Treatment Options

• The availability of new beta-lactamase inhibitor combinations, such as ceftazidime-avibactam, represents an advance in safety and efficacy for the treatment of KPC-producing organisms 3.
• Other treatment options, such as polymyxins, tigecycline, fosfomycin, and aminoglycosides, may be effective against KPC-2-producing Escherichia coli, but have pharmacokinetic and toxicity limitations 3.
• Pipeline agents, such as imepenem-relebactam and meropenem-vaborbactam, may represent promising additions to the armamentarium for the treatment of infections caused by KPC-producing isolates 3.