What is the significance of high carbapenem resistance in Klebsiella (K.) pneumoniae and Escherichia (E.) coli?

From the Guidelines

Carbapenem-resistant Klebsiella pneumoniae and Escherichia coli infections should be treated with novel β-lactam agents such as ceftazidime/avibactam or meropenem/vaborbactam as first-line options. These infections pose a significant clinical concern due to high carbapenem resistance rates, which can lead to increased morbidity, mortality, and compromised quality of life 1. The treatment approach has evolved with the introduction of new antibiotics, which have shown improved clinical outcomes compared to traditional antibiotic regimens.

Key Considerations

• Ceftazidime/avibactam and meropenem/vaborbactam have been shown to be effective in treating KPC-producing CRE infections, with ceftazidime/avibactam demonstrating a higher clinical cure rate and lower nephrotoxicity compared to colistin 1.
• Meropenem/vaborbactam may be considered as the first choice for specific types of infections, such as pneumonia, due to its high epithelial lining fluid (ELF) concentrations 1.
• Local epidemiology and the emergence of ceftazidime/avibactam resistance in KPC-producing isolates should be considered when selecting a treatment option 1.
• Imipenem/relebactam and cefiderocol may also be considered as potential alternatives for the treatment of infections involving KPC-producing CRE, although clinical studies of their efficacy in these patients are limited 1.

Treatment Approach

• Ceftazidime/avibactam (2.5 g every 8 hours) or meropenem/vaborbactam (4 g every 8 hours) should be used as first-line treatment options for KPC-producing CRE infections 1.
• Treatment duration typically ranges from 7-14 days, depending on the infection site and severity.
• Antimicrobial susceptibility testing is essential before initiating therapy to guide appropriate treatment.
• Infection control measures, including contact precautions, hand hygiene, and environmental cleaning, are crucial to prevent the spread of carbapenem-resistant organisms in healthcare settings 1.

From the FDA Drug Label

VABOMERE demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: KPC, SME, TEM, SHV, CTX-M, CMY, and ACT. Some isolates of E. coli, K. pneumoniae, E. cloacae, C. freundii, P. mirabilis, P. stuartii that produced beta-lactamases, were susceptible to VABOMERE (minimum inhibitory concentration ≤4 mcg /mL). These isolates produced one or more beta-lactamases of the following enzyme groups: OXA (non-carbapenemases), KPC, CTX-M, TEM, SHV, CMY, and ACT

• Carbapenem resistance is a concern in K. pneumoniae and E. coli, with some isolates producing carbapenem-hydrolyzing beta-lactamases such as KPC.
• VABOMERE has been shown to be active against some K. pneumoniae and E. coli isolates that produce beta-lactamases, including KPC.
• However, VABOMERE is not active against bacteria that produce metallo-beta lactamases or oxacillinases with carbapenemase activity.
• The FDA drug label does provide some information on the activity of VABOMERE against K. pneumoniae and E. coli isolates with beta-lactamase production, including carbapenem-hydrolyzing beta-lactamases 2.

From the Research

Carbapenem Resistance in K. pneumoniae and E. coli

• Carbapenem resistance is a significant concern in the treatment of infections caused by Gram-negative bacteria, including K. pneumoniae and E. coli 3.
• The production of class B metallo-beta-lactamases, such as VIM1, is a common mechanism of carbapenem resistance in K. pneumoniae 3.
• Carbapenem-resistant K. pneumoniae and E. coli infections are difficult to treat and require alternative therapeutic options, such as combination therapy with meropenem and vaborbactam or colistin 4, 5.

Therapeutic Options for Carbapenem-Resistant Infections

• Meropenem-vaborbactam has shown potent in vitro activity against carbapenem-resistant Enterobacteriaceae, including K. pneumoniae and E. coli 6.
• Aztreonam-avibactam is another therapeutic option that has demonstrated activity against carbapenem-resistant Enterobacterales, including those with class A, B, and D carbapenemases 7.
• Combination therapy with ceftazidime-avibactam, meropenem-vaborbactam, or imipenem/cilastatin-relebactam may be effective against KPC-producing Enterobacterales 5.

Mechanisms of Resistance and Detection

• The presence of carbapenemase genes, such as KPC-encoding genes, is a common mechanism of carbapenem resistance in K. pneumoniae and E. coli 7.
• Whole-genome sequencing and antimicrobial susceptibility testing can be used to detect and characterize carbapenem-resistant isolates 6, 7.
• The use of disk diffusion and gradient strip testing methods can also be used to detect carbapenem resistance, although the results may vary depending on the method used 6.