Mechanisms of Antibiotic Resistance

Abstract

Although antibiotic resistance has come to the fore in the media and clinical practice relatively recently, it is by no means a new issue; Alexander Fleming discussed the risks of penicillin resistance more than sixty years ago, but even he was behind the times. Bacteria have been competing with each other for millions of years, producing compounds which kill or inhibit other species—it is not surprising that bacteria have evolved defence mechanisms. Current major concerns are the rise of pan-drug resistant gram-negative organisms and the spread of multi-drug resistant TB. Bacterial cells turn over rapidly—this rate of reproduction leads to many errors in DNA replication. Many of these mutations are deleterious to the organism, but others confer new properties, such as changing the structure of an enzyme. The application of selection pressure in the form of antimicrobial therapy leads to the survival of mutants that have randomly acquired resistance mechanisms. There are two useful ways to categorize resistance mechanisms: by how bacterial cells acquire them and by the physical mechanism of action. The types of acquisition have important infection control ramifications. Resistance can be subdivided into three separate categories: ● Intrinsic resistance— mechanisms hard coded into all members of a bacterial species at the chromosomal level. If an organism’s antibiogram suggests susceptibility to an agent to which it should be intrinsically resistant, further work should be done to check that the identification is correct. Examples include gram-negative bacteria being resistant to glycopeptides due to the outer cell membrane, anaerobes being resistant to aminoglycosides due to lack of an uptake mechanism, and amoxicillin resistance in Klebsiella due to beta-lactamase production. ● Mutational resistance—resistance that arises randomly due to DNA replication errors in conjunction with selection pressure applied by antimicrobial agents. This is the basis of the majority of the mechanisms detailed in this chapter. ● Transferrable resistance— mutational resistance that is passed horizontally from the bacterium in which it arose to another cell, possibly of a different species entirely. This happens through either transposons (DNA that incorporates into the bacterial chromosome) or plasmids (rings of DNA that replicate independent of the main chromosome).