Review
The biological cost of antibiotic resistance

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Abstract

The frequency and rates of ascent and dissemination of antibiotic resistance in bacterial populations are anticipated to be directly related to the volume of antibiotic use and inversely related to the cost that resistance imposes on the fitness of bacteria. The data available from recent laboratory studies suggest that most, but not all, resistance-determining mutations and accessory elements engender some fitness cost, but those costs are likely to be ameliorated by subsequent evolution.

Introduction

The use of antibiotics by humans can be seen as an evolutionary experiment of enormous magnitude, a window from which to view not-quite-natural selection operating in real time. Within 50 years, the number of species and strains of pathogenic and commensal bacteria resistant to antibiotics and the number of antibiotics to which they are resistant has increased virtually monotonically world-wide. Infections that had been readily treatable by chemotherapy may no longer be 1, 2, 3, 4. It is clear that the evolution and spread of resistance can be attributed to the use and overuse of antibiotics (also see Guillemot’s review on antibiotic usage, this issue, pp 494–498). Not so clear is whether this situation can be reversed in a reasonable amount of time. That depends on factors which we may be able to control, such as the rate and pattern of antibiotic use, but also on factors over which we have no control, the biological cost resistance imposes on the fitness of bacteria 5•, 6•, and the rate and degree to which natural selection will ameliorate these costs.

Section snippets

Measuring the biological costs of resistance

The fitness of the pathogens that are the targets of antibiotic therapy is a complex character with a number of interrelated elements. The most important of these are the relative rates at which antibiotic-sensitive and -resistant bacteria firstly, reproduce and die (compete) in infected hosts and the environment, secondly, are transmitted between hosts, and thirdly, are cleared from infected hosts 5•, 6•. At any given time, the magnitude of these elements will depend on the extent and pattern

Experimentally estimating the costs of resistance and studying the adaptation to those costs

Experimental studies of the biological cost of resistance have focused almost exclusively on the relative rates of growth, survival and competitive performance of antibiotic-sensitive and -resistant bacteria. In some studies, the costs of resistance were estimated from the exponential growth rates of sensitive and resistant bacteria in monocultures 7••, 8• but more commonly they have been measured by pairwise competition experiments. Mixtures of otherwise isogenic sensitive and resistant

Is there a cost to resistance?

It is convenient to separately consider the costs of resistance encoded by chromosomal mutations, where resistance is achieved primarily by the modification of target molecules 17, 18, 19, 20, 21, and that determined by accessory elements, where resistance is generally due to enzymes that inactivate the antibiotic or pumps that remove it from the cell 17, 18, 19, 20, 21, 22, 23. Resistance encoded by accessory elements may also give rise to costs associated with the replication and maintenance

Reversion, compensatory evolution and amelioration of fitness costs

Although occasionally, in the absence of antibiotics, drug-sensitive revertants have evolved in most cases, adaptation to the costs of chromosomal resistance in vitro and in vivo has been through compensatory mutations (Table 2). In the majority, but not all cases, the second site mutations compensating for the cost of resistance have been identified. These occur by additional (or alternative) mutations at the same locus as the resistance gene, intragenic suppression, or at other loci,

Reality

Experimental studies of the costs of resistance, and adaptation to those costs make a number of predictions that can be tested (and rejected) by examining the resistance genes and accessory elements found in bacteria isolated from humans and domestic animals to see if the same mutations ascend. The results of the few tests of this type done to date suggest that chromosomal mutations responsible for acquired resistance in pathogenic bacteria are likely to be the same as those mutations observed

Implications

Although it has been long thought that antibiotic-resistance genes and accessory elements would engender a cost in the fitness of bacteria, the actual evidence for this being the case is, at best, modest and that which has been gathered recently does not paint a rosy picture for the future of the resistance problem. Resistance mutations, such as those found in the bacteria from patients treated with antibiotics, have virtually no cost when measured by competition experiments in vitro or in

Acknowledgements

This endeavor was supported by the Swedish Natural Sciences and Medical Research Councils, Swedish Institute for Infectious Disease Control, Lovens Pharmaceutical Products (DI Andersson), the US National Institutes of Health, GM3372 and AI40662, and the Swedish National Science Foundation — NFR, (BR Levin). We wish to thank Anders Håkansson for reading this manuscript and useful comments and suggestions.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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