What are the types of Antimicrobial Resistance (AMR), particularly the importance of Carbapenem resistance and Colistin resistance?

From the Guidelines

Carbapenem and colistin resistance are critical concerns in the treatment of infections caused by multidrug-resistant Gram-negative bacteria, and combination therapy approaches, such as colistin-meropenem, should be considered to address these resistance mechanisms. The emergence of carbapenem resistance, primarily through carbapenemase production, porin mutations, and efflux pumps, severely limits treatment options for serious infections caused by Gram-negative bacteria like Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii 1. Colistin resistance, which has emerged more recently, typically develops through modifications to bacterial lipopolysaccharides, preventing colistin from binding to bacterial membranes, and is particularly alarming as colistin serves as a last-resort antibiotic for multidrug-resistant infections 1.

Some key points to consider in addressing carbapenem and colistin resistance include:

• Implementing combination therapy approaches, such as ceftazidime-avibactam plus aztreonam for NDM-producing organisms, to optimize treatment outcomes 1
• Optimizing dosing through therapeutic drug monitoring to ensure effective drug concentrations and minimize toxicity 1
• Strictly adhering to antimicrobial stewardship principles to preserve the effectiveness of remaining antimicrobial options 1
• Enhancing infection control measures, surveillance of resistance patterns, and judicious antibiotic use across healthcare and agricultural settings to prevent the spread of resistant organisms 1

The use of colistin-meropenem combination therapy has been shown to be effective in treating infections caused by carbapenem-resistant Gram-negative bacteria, with some studies suggesting improved outcomes compared to monotherapy 1. However, the evidence is not uniform, and the choice of treatment should be individualized based on the specific clinical scenario and susceptibility patterns 1. The most recent and highest-quality study suggests that combination therapy with colistin and meropenem may be associated with improved outcomes, including reduced mortality and improved microbiological eradication rates 1.

From the FDA Drug Label

There are several mechanisms of resistance to carbapenems: 1) decreased permeability of the outer membrane of gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake, 2) reduced affinity of the target PBPs, 3) increased expression of efflux pump components, and 4) production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases).

The types of Antimicrobial Resistance (AMR), particularly stressing the importance of Carbapenem resistance and Colistin resistance, are not directly addressed in the provided drug label. However, the label does mention the mechanisms of resistance to carbapenems, which include:

• Decreased permeability of the outer membrane of gram-negative bacteria
• Reduced affinity of the target PBPs
• Increased expression of efflux pump components
• Production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases) 2

From the Research

Types of AMR Resistance

• Carbapenem resistance is a significant concern, as carbapenems are often considered the last line of defense against resistant bacteria 3, 4, 5, 6.
• Colistin resistance is also a major issue, as colistin is often used as a treatment for carbapenem-resistant infections 3, 4, 5, 6.

Importance of Carbapenem Resistance

• Carbapenem-resistant Enterobacteriaceae (CRE) infections are associated with high mortality rates and limited treatment options 3, 4, 5, 6.
• The emergence of carbapenemase-producing bacteria has made carbapenem resistance a major public health concern 3, 4, 5, 6.

Importance of Colistin Resistance

• Colistin is often used as a last-resort treatment for carbapenem-resistant infections, making colistin resistance a significant concern 3, 4, 5, 6.
• The development of colistin resistance can leave few treatment options for patients with resistant infections 3, 4, 5, 6.

Treatment Options for Carbapenem-Resistant Infections

• Ceftazidime-avibactam and meropenem-vaborbactam are emerging treatments for carbapenem-resistant infections 3, 4, 5, 6.
• Combination therapy with aztreonam, ceftazidime-avibactam, and colistin may be effective for treating carbapenemase-producing infections 5.

Global Burden of AMR

• The burden of antimicrobial resistance is significant, with over 2.8 million antimicrobial-resistant infections occurring every year in the United States alone 7.
• Mitigation efforts, such as infection prevention and control, data tracking, and antimicrobial stewardship, are necessary to decrease AMR threats 7.