Mechanisms of resistance and clinical relevance of resistance to β-lactams, glycopeptides, and fluoroquinolones

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.

FIGURE 1

Time line showing the use of different classes of antibiotics and the publication of the first article describing resistance (or a new class of β-lactamases conferring resistance) to that class of antibiotics in a previously susceptible organism. It can be seen that emergence of resistance generally follows closely on the heels of clinical introduction of antibiotics. ESBL = extended-spectrum β-lactamase.

FIGURE 2

Representative graph (not based on actual data) of the individual and combined contributions of various fluoroquinolone resistance mechanisms to clinical resistance to fluoroquinolones. In this case, the baseline susceptible species (Escherichia coli, for example) would have a minimum inhibitory concentration (MIC) in the absence of any resistance mechanism of 0.06 μg/mL. In vitro experiments performed during the development of a fluoroquinolone, for example, would determine the mutant prevention concentration (MPC) (the concentration of antimicrobial agent that will suppress the emergence of single-step mutants) to be 1 μg/mL, or one doubling dilution above the MIC that would result from a single gyrA amino acid substitution (which confers a 3-fold increase in resistance). With clinical use of the agent, auxiliary mechanisms of resistance, such as activation of intrinsic efflux pumps or acquisition of qnr genes or modifying enzyme gene aac(6′)-Ib-cr, are acquired by strains and increase the MIC but not to a level that would be considered clinically resistant. With one or more of these auxiliary genes present, the 8-fold increase in MIC associated with a single amino acid change in gyrA results in a strain that has an MIC above the previously defined MPC (ie, 1 μg/mL is no longer the MPC). Under these circumstances, a previously defined MPC is inaccurate and misleading and may result in selection of resistant mutants.