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Four Antibiotic Resistance Mechanisms of Clinical Importance

With rising numbers of patients infected by multidrug resistant organisms (MDROs), hospitals and federal agencies have increased their focus on implementing effective antimicrobial stewardship programs. At the same time, researchers have gained a deeper understanding of the mechanisms by which bacteria develop resistance and the impact of prolonged therapy with antibiotics on patient and community health.

Bacteria may develop resistance by acquiring genes from other bacteria in the environment or by mutations of their own genes. Certain genetic components, such as phages, plasmids and transposons, may facilitate the transfer of resistant genes.1 Sharing of genes that provide resistance may be promoted by the presence of low levels of antibiotics in the environment.2

As bacteria acquire resistance to an antibiotic or multiple antibiotics, they typically do so in one of four ways:3

  • Inactivation: Three enzymes effectively inactivate antibiotics, beta-lactamases, aminoglycoside-modifying enzymes and chloramphenicol actyltransferases. About 300 beta-lactamases have been identified. The most clinically significant of these are associated with gram-negative bacteria and provide resistance to third-generation cephalosporins, most penicillins, aztreonam, cefamandole and cefoperazone in Enterobacteriaceae. This, in turn, has led to increased use of carbapenem and driven development of carbapenem-resistant Enterobacteriaceae (CRE). First detected in India, CRE are now rated an “urgent concern” in the United States by the Centers for Disease Control and Prevention. Other varieties of beta-lactamases are also found in Enterobacter spp., Psudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis.The aminoglycoside-modifying enzymes confer extended-spectrum resistance to aminoglycosides and fluoroquinolones to strains of a number of pathogens, including S. aureus, E. Faecalis and S. pneumoniae. Some H. influenzae strains have the enzyme chloramphenicol transacetylase which increase enzymatic degradation of hydroxyl groups of chloramphenicol.

  • Changes in target site: Modifications in the molecules targeted by the antibiotic can reduce its ability to bind to the pathogen. Common changes include peptidoglycan structure reduce the ability of beta-lactams such as penicillins, cephalosporins, carbapenems and others to inhibit cell wall synthesis. In E. faecium, this alteration provides resistance to ampicillin and in S. pneumoniae, it increases resistance to penicillin.

Mutations in RNA can create resistance to drugs that target specific ribosomal subunits in gram negative bacteria. These can reduce the effectiveness of macrolides, lincosmaides and streptogramin B.

  • Development of alternative targets: Some bacteria develop a second enzyme that performs the same function as the one targeted by an antibiotic. While the initial enzyme may be inactivated by the drug, the alternate enables the organisms continued survival. In methicillin-resistant S. aureus, a new penicillin-binding protein (PBP2a) ensures cell wall synthesis even in the presence of high beta-lactamase concentrations, providing resistance to all beta-lactam antibiotics as well as streptomycin, tetracycline and, in some instances, erythromycin.

  • Reduced permeability/increased effluxion: Cells can reduce an antibiotic’s concentration–and effectiveness–by allowing less in through reduced membrane permeability or pushing more out more quickly via enhance efflux systems. Some efflux pumps can promote multidrug resistance by quickly eliminating a wide variety of therapeutic agents. P. aeruginosa uses at least four efflux pumps which effectively expel a number of drugs. Enhance effluxion contribute to resistance to fluoroquinolones, tetracyclines, chloramphenicol, erythromycin, penicillins, cephalosporins, macrolides, sulfonamides and other agents.

How has your hospital attempted to reduce the development of multidrug resistant organisms?


  1. Giedraitien? A, Vitkauskien? A, Naginien? R, Pavilonis A. Antibiotic
    resistance mechanisms of clinically important bacteria. Medicina (Kaunas).
    2011;47(3):137-46. Review. English, Lithuanian.

  2. Davies J, Davies D. Origins and Evolution of Antibiotic Resistance. Microbiol Mol Biol Rev. 2010 Sept;74(3):417-433.

  3. Schmieder R, Edwards R. Insights into Antibiotic Resistance Through Metagenomic Approaches. Future Microbiology. 2012;7(1):73-89.

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