What are the types of Carbapenem-Resistant Enterobacteriaceae (CRE), including Carbapenemase-producing CRE and non-Carbapenemase-producing CRE, and their mechanisms?

From the Guidelines

Carbapenem-resistant Enterobacteriaceae (CRE) are primarily classified into two types: carbapenemase-producing CRE (CP-CRE) and non-carbapenemase-producing CRE (non-CP-CRE), with CP-CRE being further subdivided based on the type of carbapenemase they produce, such as KPC, NDM, VIM, IMP, and OXA-48-like enzymes, as identified in a recent study 1. The main difference between these types lies in their resistance mechanisms. CP-CRE produce carbapenemases that directly inactivate carbapenem antibiotics, whereas non-CP-CRE achieve resistance through a combination of mechanisms including the production of extended-spectrum β-lactamases (ESBLs) or AmpC β-lactamases, along with decreased membrane permeability due to porin mutations or efflux pump overexpression, as discussed in a guideline endorsed by the Italian Society of Infection and Tropical Diseases 1.

Key Mechanisms and Types of CRE

• Carbapenemase-producing CRE (CP-CRE): These produce enzymes like KPC, NDM, VIM, IMP, and OXA-48-like, which directly hydrolyze carbapenems. The Ambler classification system categorizes these carbapenemases into classes A, B, and D, with KPC belonging to Class A, MBLs (NDM, VIM, IMP) to Class B, and OXA-48-like to Class D 1.
• Non-carbapenemase-producing CRE (non-CP-CRE): These achieve carbapenem resistance through mechanisms such as the production of ESBLs or AmpC β-lactamases combined with decreased membrane permeability or efflux pump overexpression.

Clinical Importance and Treatment

The distinction between CP-CRE and non-CP-CRE is crucial because CP-CRE generally exhibit higher resistance levels, are associated with higher treatment failure rates, and necessitate more aggressive infection control measures due to their ability to spread resistance genes horizontally to other bacteria, as emphasized in a study on the diagnosis and management of infections caused by multidrug-resistant bacteria 1. For the treatment of infections caused by KPC-producing CRE, novel β-lactam agents such as ceftazidime/avibactam and meropenem/vaborbactam are strongly recommended as first-line treatment options, based on their efficacy and safety profiles demonstrated in recent studies 1. Imipenem/relebactam and cefiderocol may also be considered as potential alternatives, although the evidence for their use in KPC-producing CRE infections is currently limited to in vitro studies and requires further clinical validation. The choice between these agents should consider factors such as the site of infection, local epidemiology, and the emergence of resistance, highlighting the need for rapid testing to identify specific carbapenemases and guide antibiotic therapy, as recommended in guidelines endorsed by the Italian Society of Infection and Tropical Diseases 1.

From the Research

Types of Carbapenem-Resistant Enterobacteriaceae (CRE)

• Carbapenemase-producing CRE (CP-CRE): These bacteria produce enzymes called carbapenemases that deactivate carbapenems and most other β-lactam antibiotics 2, 3, 4, 5, 6.
• Non-carbapenemase-producing CRE (non-CP-CRE): These bacteria are resistant to carbapenems but do not produce carbapenemases 2, 3, 4, 5, 6.

Mechanisms of Resistance

• Carbapenemase production: CP-CRE produce enzymes that hydrolyze carbapenems, rendering them ineffective 2, 3, 4, 5, 6.
• Other mechanisms: Non-CP-CRE may exhibit resistance through other mechanisms, such as porin loss or efflux pump overexpression 5.

Comparison of CP-CRE and Non-CP-CRE

• Mortality: CP-CRE are associated with higher mortality rates compared to non-CP-CRE 6.
• Antibiotic resistance: CP-CRE tend to have higher minimum inhibitory concentrations (MICs) to meropenem compared to non-CP-CRE 6.
• Treatment outcomes: The odds of dying within 14 days are more than 4 times greater for CP-CRE compared to non-CP-CRE bacteremic patients 6.

Treatment Options

• Older agents: Polymyxins, fosfomycin, and aminoglycosides are used to treat CRE infections, although their efficacy and toxicity are concerns 2, 3, 5.
• Newer agents: Ceftazidime/avibactam, meropenem/vaborbactam, plazomicin, and eravacycline are newer antibiotics with potential for treating CRE infections 3, 4.
• Combination therapy: High-dose and combination strategies, including the use of new β-lactam/β-lactamase inhibitors, may be considered for severe CRE infections 3, 5.