Policies aimed at alleviating the growing problem of drug-resistant pathogens by restricting antimicrobial usage implicitly assume that resistance reduces the Darwinian ¢tness of pathogens in the absence of drugs. While ¢tness costs have been demonstrated for bacteria and viruses resistant to some chemotherapeutic agents, these costs are anticipated to decline during subsequent evolution. This has recently been observed in pathogens as diverse as HIVand Escherichia coli. Here we present evidence that these genetic adaptations to the costs of resistance can virtually preclude resistant lineages from reverting to sensitivity. We show that second site mutations which compensate for the substantial (14 and 18% per generation) ¢tness costs of streptomycin resistant (rpsL) mutations in E. coli create a genetic background in which streptomycin sensitive, rpsL alleles have a 4^30% per generation selective disadvantage relative to adapted, resistant strains. We also present evidence that similar compensatory mutations have been ¢xed in long-term streptomycin-resistant laboratory strains of E. coli and may account for the persistence of rpsL streptomycin resistance in populations maintained for more than 10 000 generations in the absence of the antibiotic. We discuss the public health implications of these and other experimental results that question whether the more prudent use of antimicrobial chemotherapy will lead to declines in the incidence of drug-resistant pathogenic microbes.

Mathematical models are used to ascertain the relationship between the incidence of antibiotic treatment and the frequency of resistant bacteria in the commensal flora of human hosts, as well as the rates at which these frequencies would decline following a cessation of antibiotic use. Recent studies of the population biology of plasmid-encoded and chromosomal antibiotic resistance are reviewed for estimates of the parameters of these models and to evaluate other factors contributing to the fate of antibiotic-resistant bacteria in human hosts. The implications of these theoretical and empirical results to the future of antibacterial chemotherapy are discussed.

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As a direct consequence of sex, organisms undergo a haploid and a diploid stage during their life cycle. Although the relative duration of haploid and diploid phases varies greatly among taxa, the diploid phase is more conspicuous in all higher organisms. Therefore it is widely believed that diploidy offers more evolutionary possibilities and is thus nearly always selected for. We have now performed computer simulations to investigate one possible advantage of diploidy, that is, protection against the expression of deleterious mutations. Instead of comparing isolated haploid and diploid populations, we considered interbreeding haploids and diploids. Diploids invaded the population only when the dominance degree of a single deleterious mutation was smaller than about 1/2, and the condition allowing diploidy to invade depended on how harmful the mutation was.