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Do antibiotics maintain antibiotic resistance?
Jack A. Heinemann, Robert G. Ankenbauer and Carlos F. Amábile-Cuevas
Important human pathogens resistant to antibiotics result from the human use of antibiotics. Does this imply that reducing their usage or removing antibiotics from medicine and agriculture will restore the effectiveness of these drugs? The authorsargue that resistance evolution and susceptibility evolution are not, in a sense, just different sides of the same coin. Resistance genes acquire new functions and the initial costs of resistance can evolve into advantages. Decreasing drug use might not replace a fundamental change in drug design to avoid the evolution of resistant, and encourage the evolution of susceptible, microorganisms. usedto design desirable evolutionary outcomes rather than to provoke resistance. The reservoir hypothesis The apparently self-evident assumptions of the reservoir hypothesis are rarely stated (Fig. 1). In brief, it assumes that the evolution of resistance is explained by the effect of drugs acting on bacteria. It further assumes that some threshold quantity of antibiotics (used here to refer generallyto antimicrobial agents) is required to both induce and then maintain resistance, because of the corollary that mutations in the genes targeted by drugs are not phenotypically neutral but uncompetitive in the absence of the drug. The threshold is the magic concentration of antibiotics in the environment sufficient to achieve a selection against even those microbes not causing disease. The drugsmust be used on such a scale that very rare microbes, by nature resistant to the drug, begin to prosper and spread on the resources abandoned by their drug-sensitive contemporaries6–14. An emerging reservoir of drug-resistant microbes then adapt to the niche of previous pathogenic species or spread resistance genes to pathogens via the horizontally mobile elements (HMEs), such as viruses, plasmidsand transposons. The clonal spread of resistant microbes and trafficking of resistance genes is consistent with this hypothesis1,4,5,14–21. The stability of resistance in relatively antibiotic-free environments is, however, a challenge to the hypothesis3,13,22–26. What impedes the retreat of resistance genes when antibiotics recede? The first part of this article will describe the mechanisms formaintaining resistance in the absence of overt selection, that is, when the genes are beneficial to the host or vector in other ways. The second part of the review will describe how some combinations of genes syn-

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rug resistance in pathogens is the result of overuse of drugs in medicine and agriculture. A fundamental question is therefore whether prevention of overuse will ensure drugresistance becomes obsolete. That expectation, a prediction of what we call the ‘reservoir hypothesis’, is common in the literature1,2. However, several experimental observations suggest that this expectation might be naive3–6. Many effects of antibiotics on microbial physiology and ecology illustrate how difficult it can be to predict the return of susceptibility. The purpose of this article is not tocatalog every effect of antibiotics, but to inform those who develop or apply new drugs, or those attempting to restore the efficacy of current drugs, about the factors that must be considered if anti-infectives are to be

*1Jack A. Heinemann, 2Robert G. Ankenbauer and 3Carlos F. Amábile-Cuevas, 1Department of Plant and Microbial Sciences, University of Canterbury, Christchurch, New Zealand.2Pfizer Central Research, Box 4962, Eastern Point Road, Groton, CT 06340, USA. 3Fundacion LUSARA para la Investigacion Cientifica, A.C., Apartado Postal 102-006, 08930, Mexico, D.F. *tel: + 643 364 2926; fax: +643 364 2083, e-mail: j.heinemann@pams.canterbury.ac.nz
DDT Vol. 5, No. 5 May 2000
1359-6446/00/$ – see front matter © Elsevier Science Ltd. All rights reserved. PII: S1359-6446(00)01483-5...