Antimicrobial Use and Antimicrobial Resistance: A Population Perspective

Marc Lipsitch, Matthew H. Samore


Emerging Infectious Diseases. 2002;8(4) 

In This Article

Combinations of Direct and Indirect Effects on Resistance

A third mechanism by which antimicrobial use increases the number of patients colonized or infected with resistant organisms is by modifying the treated host’s colonization resistance (Figure, C; Table). Eradication or reduction of drug-susceptible normal flora by antibiotic treatment may increase vulnerability to acquisition of new strains. This effect will increase the patient’s probability of being colonized with a resistant organism if, during or shortly after treatment, he or she is exposed to others with resistant organisms. This mechanism is direct in the sense that it increases the treated patient’s risk of colonization with resistant organisms but is also associated with indirect effects because of the requirement for transmission. An index host given antibiotics is placed at greater risk for colonization with resistant organisms (direct effect), but this risk is amplified by his or her exposure to other patients harboring resistant organisms, which is in turn enhanced by their use of antibiotics (indirect effect).

A fourth mechanism by which antimicrobial use increases antimicrobial resistance is by increasing the density of resistant organisms within a patient who already harbors such organisms at a lower density (Figure, D; Table). Enhanced shedding of these organisms, resulting in an increased risk to other patients (an indirect effect), has been documented (i.e., in the case of anti-anaerobic agents that increase shedding of vancomycin-resistant Enterococci (VRE) [24]. An increased risk of resistant infection to the treated patient (a direct effect) may occur if a higher density of resistant organisms places the patient at higher risk of infection with his or her own flora. Unlike the other three ways by which antimicrobial use promotes resistance, this mechanism is mediated through antimicrobial treatment of patients already colonized with the resistant organism.

There are a number of other cases in which direct and indirect effects of antibiotic treatment are combined. Due to the diversity of genetic mechanisms of resistance, the risk of emergence of resistance during treatment represents a continuum, with TB at one end and VRE (or MRSA) at the other. Fluoroquinolone resistance in S. pneumoniae mediated by the accumulation of mutations in the DNA gyrase and topoisomerase IV genes [25], or resistance to third-generation cephalosporins in Enterobacteriaceae mediated by mutations in TEM and SHV beta-lactamases located on plasmids [26], lie between these two extremes. In these cases, multiple mutations are required to turn a fully susceptible strain into a clinically resistant one. For a patient colonized or infected with a fully susceptible strain, emergence of resistance during treatment may be highly unlikely because of the requirement for selecting multiple mutations. However, in such cases, there may be selection in consecutive hosts for small increases in levels of resistance to a particular compound, resulting eventually in the emergence of clinical resistance [27]. Patients may be colonized with a mixed flora of resistant and susceptible organisms, and eradication of the drug-susceptible flora may permit outgrowth of the resistant subpopulation [28]. This mechanism has some formal similarity to what occurs in TB, except that for a colonizing bacterium such as the pneumococcus or the enteric colonizers, outgrowth of resistant organisms in the site of colonization need not be associated with treatment failure. In these cases, the treated patient is at increased risk of carrying resistant organisms (direct effect), but an indirect effect on the population occurs because the treated patient no longer carries susceptible organisms and is, therefore, unable to transmit them.

Treatment with one antimicrobial drug can select for resistance to a number of other, unrelated agents, by several means. If individual organisms are resistant to multiple drugs, then use of any one of these may promote resistance to others [29]. Additionally, by altering the balance of different components of the indigenous microbial flora, treatment with one agent may increase the load of a pathogen resistant to another agent, simply by killing off competing flora of different species; this has been observed, for example, with anti-anaerobic treatments that increase the load of VRE [24]. These complexities increase the number of relationships that need to be studied in assessing the effects of antimicrobial use on resistance and also the number of potential confounders in any study.


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