DEFINITION OF RESISTANCE
The action of antimicrobial agents on a range of targets within the bacterial cell can result in inhibition of bacterial growth or in killing of the bacterial cell (Chap. 139). Reduction in or loss of an agent’s antibacterial effect is referred to as resistance, and the properties of or alterations in the bacterium that result in reduced antimicrobial activity are termed resistance mechanisms. Bacteria can be resistant to single or multiple antimicrobials, as detailed in the sections that follow. The occurrence and magnitude of resistance are often assessed in clinical microbiology laboratories by measurement of the lowest drug concentration that inhibits growth of a bacterium (minimal inhibitory concentration, or MIC) with a standardized inoculum and growth conditions. MIC values are generally interpreted as representing bacterial susceptibility, intermediate susceptibility, or resistance; the interpretation is based on correlations of the MIC values with the pharmacokinetics and delivery of a drug to the site of infection in the body as well as with data from clinical trials. Thus, a clinical laboratory result of “susceptible” for a bacterium predicts a likely clinical response to an appropriately dosed antimicrobial drug by a patient infected with that organism, whereas a result of “resistant” predicts poor or no clinical response to that drug. Breakpoint MIC values for categorization of bacteria as susceptible, intermediate, or resistant are generally developed by regulatory and advisory groups and are often based on the distribution of MIC values from a large collection of recent clinical bacterial isolates. Research studies on the mechanisms and epidemiology of resistance may in some cases use different and less rigid definitions of resistance based on determination of a reproducible increase in an MIC value relative to a baseline reference MIC, independent of clinical breakpoints.
Mechanisms of resistance to antibacterial agents, as illustrated in a gram-negative bacterium. Similar mechanisms are found in gram-positive bacteria, but their lack of an outer membrane causes β-lactamases to be excreted outside the cell, rather than into the periplasmic space between the inner and outer membranes, and reduces the efficiency of efflux pumps because exported drugs can re-enter the cell after crossing a single membrane, rather than the two membranes in gram-negative bacteria. Red spheres indicate antibiotics. (From Peleg AY, Hooper DC: Hospital-acquired infections due to gram-negative bacteria. N Engl J Med 362:1084, 2010. © 2010 Massachusetts Medical Society. Reprinted with permission.)
MECHANISMS OF RESISTANCE
Bacteria use a wide variety of mechanisms to block or circumvent the activity of antibacterial agents (Table 140-1 and Fig. 140-1). Although myriad, these mechanisms can generally be grouped into three categories: (1) alteration or bypassing of targets that exhibit reduced binding of the drug, (2) altered access of the drug to its target by reductions in uptake or increases in active efflux, and (3) a modification of ...