Elsevier

Mayo Clinic Proceedings

Volume 87, Issue 2, February 2012, Pages 198-208
Mayo Clinic Proceedings

Symposium on antimicrobial therapy
Mechanisms of Resistance and Clinical Relevance of Resistance to β-Lactams, Glycopeptides, and Fluoroquinolones

https://doi.org/10.1016/j.mayocp.2011.12.003Get rights and content

Abstract

The widespread use of antibiotics has resulted in a growing problem of antimicrobial resistance in the community and hospital settings. Antimicrobial classes for which resistance has become a major problem include the β-lactams, the glycopeptides, and the fluoroquinolones. In gram-positive bacteria, β-lactam resistance most commonly results from expression of intrinsic low-affinity penicillin-binding proteins. In gram-negative bacteria, expression of acquired β-lactamases presents a particular challenge owing to some natural spectra that include virtually all β-lactam classes. Glycopeptide resistance has been largely restricted to nosocomial Enterococcus faecium strains, the spread of which is promoted by ineffective infection control mechanisms for fecal organisms and the widespread use of colonization-promoting antimicrobials (especially cephalosporins and antianaerobic antibiotics). Fluoroquinolone resistance in community-associated strains of Escherichia coli, many of which also express β-lactamases that confer cephalosporin resistance, is increasingly prevalent. Economic and regulatory forces have served to discourage large pharmaceutical companies from developing new antibiotics, suggesting that the antibiotics currently on the market may be all that will be available for the coming decade. As such, it is critical that we devise, test, and implement antimicrobial stewardship strategies that are effective at constraining and, ideally, reducing resistance in human pathogenic bacteria.

Section snippets

Defining Resistance

Antimicrobial resistance and susceptibility in the clinical setting take many forms that are not predictable by in vitro susceptibility testing. For example, susceptible bacteria deep inside an abscess may not be accessible to antibiotics and therefore behave as if they are resistant. A fully susceptible organism may also act resistant if present in a biofilm attached to a foreign body. Conversely, species often considered resistant to specific antibiotics (eg, Pseudomonas aeruginosa and

Resistance to β-Lactams

β-Lactam antibiotics act by binding to cell wall synthesis enzymes known as penicillin-binding proteins (PBPs), thereby inhibiting peptidoglycan synthesis.9 Inhibition of PBPs weakens the cell wall, resulting in inhibition of cell growth and frequently in cell death. The 3 mechanisms of β-lactam resistance are reduced access to the PBPs, reduced PBP binding affinity, and destruction of the antibiotic through the expression of β-lactamase (enzymes that bind and hydrolyze β-lactams) (Table).10 In

Conclusion

Although the emergence of antimicrobial resistance is invariably associated with antimicrobial use, the multiple mechanisms of resistance, the frequency of gene exchange in the natural environment, and the nonspecific nature of many resistance mechanisms make developing resistance-specific strategies to reduce individual resistance phenotypes complicated and fraught with potential deleterious unintended consequences. Efforts to reduce overall antimicrobial exposure, for example, through

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