What is the pathology of antimicrobial (antibiotic) resistance?

From the Guidelines

Antibiotic resistance is a mounting public health concern driven by the misuse of antibiotics, leading to increased morbidity, mortality, and healthcare costs, as evidenced by the emergence of resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and extended spectrum beta-lactamase (ESBL) producing organisms 1. The pathology of antimicrobial resistance is complex and multifaceted, involving various mechanisms by which bacteria evolve to survive exposure to antibiotics.

• Bacteria may modify the antibiotic target site, such as altering penicillin-binding proteins, to evade the effects of antibiotics.
• They may produce enzymes that destroy antibiotics, like beta-lactamases that break down penicillins.
• Bacteria can also reduce antibiotic uptake by changing membrane permeability or actively pump antibiotics out of the cell using efflux pumps. The misuse of antibiotics, including unnecessary prescriptions, incorrect dosing, and incomplete treatment courses, accelerates the development of resistance by exerting selective pressure that favors the survival and reproduction of resistant strains 1. This has led to the emergence of multidrug-resistant "superbugs" and increased the burden of infections on healthcare systems, resulting in longer illnesses, higher mortality rates, and increased healthcare costs as infections become harder to treat with standard antibiotics, requiring more expensive and toxic alternatives. Key factors contributing to this issue include estimated rates of inappropriate and unnecessary antibiotic use among office-based practitioners ranging from 25 to 63%, and the significant impact of antimicrobial stewardship programs (ASPs) in reducing overall and inappropriate antimicrobial use, lowering drug costs, decreasing treatment duration, and reducing resistance locally 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 pathology of antimicrobial (antibiotic) resistance involves several key mechanisms, including:

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

From the Research

Mechanisms of Antibiotic Resistance

• Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria 3
• New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis 3
• The molecular pathways behind the emergence of antimicrobial resistance in bacteria were present since ancient times, and some of these mechanisms are the ancestors of current resistance determinants 4
• The presence of inhibitory and sub-inhibitory concentrations of antibiotics in natural habitats can lead to the emergence of novel resistance mechanisms against antimicrobial compounds 4

Horizontal Gene Transfer

• Horizontal gene transfer (HGT) contributes significantly to the rapid spread of resistance, and multiple mechanisms of HGT liberate genes from normal vertical inheritance 5
• Conjugation by plasmids, transduction by bacteriophages, and natural transformation by extracellular DNA each allow genetic material to jump between strains and species 5
• HGT drives the evolution of untreatable "superbugs" by concentrating antibiotic resistance genes (ARGs) together in the same cell 5
• The mechanism of action of plasmid and phage during horizontal gene transfer can lead to the transmission of ARGs 6

Occurrence and Spread of Antibiotic Resistance Genes

• The origin and molecular basis of bacterial resistance is the presence of antibiotic resistance genes (ARGs) 6
• Investigations on ARGs mostly focus on the environments in which antibiotics are frequently used, such as hospitals and farms, but ARGs can also be found in nonclinical environments such as air, aircraft wastewater, migratory bird feces, and sea areas 6
• The spread of ARGs can be facilitated by various factors, including the use and misuse of antibiotics, and the presence of ARGs in the environment 4, 6

Genetic Mechanisms and Control of Antibiotic Resistance

• The expression and interactions of ARGs are important to drug resistance, and comprehension of how bacteria develop and/or acquire ARGs has a critical role in developing propositions to fight against these superbugs 7
• Recent advances involving the use of anti-resistance drugs, such as efflux pump inhibitors, anti-virulence drugs, drugs against quorum sensing, and against type II/III secretion systems, can help combat antibiotic resistance 7
• Antibiotic adjuvants, which help combat antibiotic resistance through deactivation of bacterial mechanisms of action, can restore or prolong the therapeutic activity of known antibiotics 7