Resistance in People and Populations
Ehrlich's advice that treatment of infections should "hit hard and hit early," formulated in the earliest days of antimicrobial chemotherapy, presciently summarized the principles of treatment for infections such as tuberculosis (TB) . These principles are embodied in modern protocols of directly observed, short-course chemotherapy, where the goal is to treat with adequate concentrations of multiple drugs and maintain treatment until the bacterial population is extinct.Resistance to each of the major antituberculosis drugs is mediated by single point mutation; therefore tuberculosis treatment is designed to prevent the ascent of subpopulations of mutant bacilli that are resistant to any one of the drugs. Similar principles have been suggested for other infections in which resistance can arise by simple mutation, most notably HIV , although there has been some controversy on this topic . In these infections, the relationship between treatment, resistance in the treated person, and resistance in the community at large is relatively clear. Inadequate therapy (owing to subtherapeutic drug concentrations, too few drugs, or poor adherence to therapy) results in the emergence of resistance, and possibly treatment failure, in the treated host. Following the emergence of resistance in the treated host, resistant infections may be transmitted to others (Figure, A; Table).
Four mechanisms by which antibiotic treatment can create selection for resistance in the population, showing direct effectsincreased resistance in treated (yellow) vs. untreated (white) hosts, and indirect effectsincreased resistance in others (turquoise) due to treatment of specific hosts. (A) Subpopulations (usually mutants) of resistant (red) bacteria are present in a host infected with a predominantly susceptible (green) strain; treatment fails, resulting in outgrowth of the resistant subpopulation, which can then be transmitted to other, susceptible hosts (turquoise).
(B) Successful treatment of an individual infected with a susceptible strain reduces the ability of that host to transmit the infection to other susceptible hosts, making those hosts more likely to be infected by resistant pathogens than they would otherwise have been, and shifting the competitive balance toward resistant infections.
(C) Treatment of an infection eradicates a population of susceptible bacteria carried (often commensally) by the host, making that host more susceptible to acquisition of a new strain. If the newly acquired strain has a high probability of being resistant (as in the context of an outbreak of a resistant strain), this can significantly increase the treated individuals risk of carrying a resistant strain, relative to an untreated one.
(D) Treatment of an infection in an individual who is already colonized (commensally) with resistant organisms may result in increased load of those organisms if competing flora (perhaps of another species) are inhibitedleading to increased shedding of the resistant organism and possibly to increased individual risk of infection with the resistant organism.
For many pathogens, both the genetics and the epidemiology of resistance differ from those of TB in important ways. For example, methicillin resistance in S. aureus and vancomycin resistance in Enterococcus are mediated by the acquisition of one or several new genes, rather than by point mutations in existing genes. In Streptococcus pneumoniae, penicillin resistance occurs when segments of wild-type penicillin-binding protein genes are replaced with alleles whose sequences differ from the wild-type at multiple positions. These new resistance mechanisms arose and spread in large populations under conditions of antibiotic selection pressure, but they are unlikely to occur de novo in any single person because of the multiple changes involved. Organisms (or plasmids) bearing these types of resistance must be acquired, generally as a consequence of cross-transmission. Furthermore, most of these organisms are not obligate pathogens such as HIV or TB; as a result, much of their exposure to antibiotics occurs during treatment directed at infections caused by other, unrelated organisms.
Because of these genetic and epidemiologic differences, the paradigm for tuberculosis treatment, minimizing resistance in the treated host and the community by preventing the emergence of resistant subpopulations during treatment, is often inapplicable to these organisms . Antibiotic treatment promotes the spread of these organisms, as suggested by the rapid increases in resistance in many of the organisms after the new drug classes are introduced. However, the effects of treatment in promoting resistance occur by less direct mechanisms, which depend on competitive interactions between drug-resistant and drug-susceptible strains.
Emerging Infectious Diseases. 2002;8(4) © 2002 Centers for Disease Control and Prevention (CDC)
Cite this: Antimicrobial Use and Antimicrobial Resistance: A Population Perspective - Medscape - Apr 01, 2002.