LITERATURE REVIEW FOR ANTIBIOTIC RESISTANCE EPIDEMIOLOGY Brenda Rashleigh 3/16/95 Although antibiotic resistance appeared shortly after the development of antibiotics, the magnitude of the problem is presently increasing as both the formation and the transmission of antibiotic-resistant strains escalate. Antibiotics act by inhibiting either protein synthesis, cell wall construction, or DNA replication (Pharmaceutical Information Associated, Ltd., 1994). A pathogen becomes resistant to an antibiotic used to treat it either through mutation or through the acquisition of a plasmid for resistance from another strain of bacteria (Neu, 1992). Resistant pathogens render an antibiotic ineffective by either destroying or modifying the antibiotic or preventing the antibiotic from recognizing or accessing its target. For instance, microbes treated with the beta-lactam family of antibiotics (i.e., penicillins) have developed enzymes to destroy the beta-lactams, and as researchers alter the structure of the beta-lactams slightly, the bacterial enzyme mutates to match the altered antibiotic structure (Travis, 1994). The development of resistance is correlated with the level of antibiotic use (Cohen, 1992). Therefore, overuse of antibiotics in hospitals and in the community has increased the number of resistance-conferring mutations. The problem of antibiotic resistance is further complicated by an increasing transmission rate and the lack of simple solutions for control. The hospital and the community can be considered as separate systems that interact with each other in the epidemiology of antibiotic resistance, and a resistant strain can arise in either system (Cohen, 1992). In hospitals, particularly, there has been an increased use of broad spectrum antibiotics which have contributed to the problem of resistance. Also in hospitals, prophylactic use of antibiotics, such as before surgery, is a major contributor to increased resistance (Jernigan, pers. comm.). In the community, the generous use of antibiotics for even mild cases of disease has contributed to the resistance problem. Also, development of resistance in bacterial strains can occur when a patient does not complete a cycle of antibiotics: this has been a problem particularly in the treatment of tuberculosis patients, where the treatment regime must be conducted over a duration of several months. The incidence of antibiotic treatment in the community has recently multiplied due to a growth in the segment of the population most susceptible to infection: the elderly and the immuno-compromised. Major transmission routes of antibiotic resistant bacteria are the same as for non-resistant bacterial pathogens: fecal-oral transmission, foodborne transmission, sexual transmission, and respiratory transmission (Cohen, 1992). In hospitals, attendants and contaminated equipment are significant modes of transmission (Harris, pers. comm., Ewald, 1988). There is no difference between transmission rates of sensitive and resistant strains (Holtzman et al., 1980). In recent years, several factors have increased transmission of both types of these bacterial pathogens: increased travel, especially international travel; and a decline in living conditions--overcrowding, poor nutrition, and poor sanitation--in inner cities and developing countries (Cohen, 1992). Local community transmission has increased in areas which have high contact and relatively high proportion of immuno-compromised individuals, such as child day-care facilities, nursing homes, and correctional facilities. No simple solutions are in sight. In the past, the strategy to combat resistance has been to administer a different antibiotic. In some cases this may still work: in Hungary, the level of penicillin resistant pneumococcus infections dropped from a high of 50% in the 1980s to 34% in 1992, possibly due to a decrease in penicillin use and a switch to other antibiotics (Nowak, 1994). However, resistant organisms at present include penicillin-resistant and methicillin- resistant staphylococci, vancomycin-resistant enterococci, and multidrug-resistant tuberculosis (Cohen, 1992), and few new antibiotics are on the horizon (Travis, 1994). Another possible avenue for control is the selective use of antibiotics for more serious infections, in order to discourage the development of resistant strains (Ewald, 1994). A different type of strategy to combat antibiotic resistance is to fight the mutations of bacteria by "poisoning" the resistance mechanism (Page, 1994). For example, in the case of beta-lactams, where the antibiotic is destroyed by an enzyme (beta-lactamase) produced by the bacteria, researchers have developed a beta-lactamase inhibitor which is given to the patient in combination with the antibiotic. In another case, a group of researchers at Emory University concerned with the treatment of antibiotic-resistant tuberculosis are developing a surfactant drug that, when given in combination with antibiotics, acts in part by making tuberculosis bacteria more permeable to antibiotics (Hunter, pers. comm.). A final possible strategy, termed "Darwinian reversal," an individual infected with a resistant pathogen is inoculated with the unmutated (sensitive) pathogen in hopes that the sensitive pathogen will out-compete the resistant pathogen (Goldhaber, 1994). It is assumed that there is a cost of resistance to the bacteria carrying the plasmid, therefore in an untreated case the unmutated strain would be more successful (Jernigan, pers. comm.). Once the unmutated pathogen has won the competition, it can be treated with antibiotic. A problem with this strategy, as well as others, is that bacteria can exchange genetic material, and resistance can be transferred among strains and/or between species (Travis, 1994; Davies, 1994), however, the rate of transfer is not well understood. Clearly, a better understanding of the biology and epidemiology are needed as we face the prospect of the post-antimicrobial era. REFERENCES Cohen, M.L., 1992. Epidemiology of drug resistance: Implications for a post- antimicrobial era. Science 257:1050-1055. Ewald, P.W., 1988. Cultural vectors, virulence, and the emergence of evolutionary epidemiology. Oxford Survey of Evolutionary Biology 5:215-45. Ewald, P.W., 1994. Evolution of infectious disease. 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