ReviewAntibiotic resistance in the absence of selective pressure
Introduction
The problem of antibiotic resistance has now gained the attention of the public and of legislators of many countries. In the UK, a Select Committee of the House of Lords held a series of hearings and published a report. The government responded by commissioning a report from its Specialist Medical Advisory Committee (SMAC) making suggestions to tackle the problem [1]. It highlighted the use of antibiotics in the animal feed industry and in the community, especially targeting prescribing for urinary and upper respiratory tract infections. In doing so, it created the impression of the ubiquitous presence of antibiotics in the environment that these were responsible for the continuing problem of antibiotic resistance. Consequently, the conclusions that the SMAC report came to, were based on an number of ideas that are dogmas currently held by many infection practitioners. That is, antibiotic use is responsible for the appearance and maintenance of resistance in the community; organisms that are resistant, are less physiologically fit, a susceptible organism will outgrow resistant ones, if the selective pressure can be removed. From this premise, it becomes obvious that the control of antibiotic use will eradicate the problem of antibiotic resistance. This approach neglects the fact that many of the most important human pathogens have long-term relationship with their hosts whether as commensal organisms in the nasopharynx or hidden in healed tuberculosis lesions and for most their existence they are not exposed antibiotics. The inescapable fact is that many resistant organisms survive well in the environment in the absence of selection pressure. The purpose of this paper is to review the evidence that organisms pay a physiological price for the development of antibiotic resistance and how in the absence of selective pressure they are able to recover physiological fitness and resist eradication by populations of susceptible organisms. In this review, I will consider the way in which organisms become resistant, pay an initial physiological price for this change but are able to survive in compromised human hosts where they can regain fitness and then spread to cause disease in the general population.
Section snippets
Molecular mechanisms of resistance
In recent years, the molecular mechanisms whereby bacteria become resistant to antibiotics have begun to be understood. The rapid spread of resistance mediated by plasmids [2], phages [3], transposons [4] and other mobile genetic elements [5] have been the main focus of attention. Resistance can also develop through changes in the chromosome and these are mechanisms that are important in some primary pathogens such as Mycobacterium tuberculosis (6) and Streptococcus pneumoniae [7]. Much of this
In vitro investigations of physiological price
Several studies have shown that acquisition of plasmid mediated resistance is associated with a decrease in the ‘fitness’ of the organism as measured by its speed of growth [2], [27]. Similarly, E. coli acquire fitness deficits as measured by the peptide chain elongation rate on point mutation to streptomycin resistance [28]. The remainder of this discussion will centre round the primary pathogens S. pneumoniae and M. tuberculosis.
Animal studies
An early study of resistant M. tuberculosis using a guinea pig infection model showed that some isoniazid resistant strains caused much less severe disease than a susceptible strain, H37Rv. Other resistant strains were, however, fully virulent [30]. There was a spectrum of virulence and resistance and the authors concluded that the degree of isoniazid resistance was related to the virulence of the strains — strains with a greater degree of resistance being less virulent. These pioneering
Survival of resistant clones in vivo
If organisms pay a physiological price for resistance how are they to survive in the environment until they recover their fitness by some of the mechanisms described above? If we study the history of the emergence of resistant clones we are able to gain an insight into how this process occurs.
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