Abstract
Bacterial resistance to antibiotic treatment is a huge concern: introduction of any new antibiotic is shortly followed by the emergence of resistant bacterial isolates in the clinic. This issue is compounded by a severe lack of new antibiotics reaching the market. The significant rise in clinical resistance to antibiotics is especially problematic in nosocomial infections, where already vulnerable patients may fail to respond to treatment, causing even greater health concern. A recent focus has been on the development of anti-virulence drugs as a second line of defence in the treatment of antibiotic-resistant infections. This treatment, which weakens bacteria by reducing their virulence rather than killing them, should allow infections to be cleared through the body׳s natural defence mechanisms. In this way there should be little to no selective pressure exerted on the organism and, as such, a predominantly resistant population should be less likely to emerge. However, before the likelihood of resistance to these novel drugs emerging can be predicted, we must first establish whether such drugs can actually be effective. Many believe that anti-virulence drugs would not be powerful enough to clear existing infections, restricting their potential application to prophylaxis. We have developed a mathematical model that provides a theoretical framework to reveal the circumstances under which anti-virulence drugs may or may not be successful. We demonstrate that by harnessing and combining the advantages of antibiotics with those provided by anti-virulence drugs, given infection-specific parameters, it is possible to identify treatment strategies that would efficiently clear bacterial infections, while preventing the emergence of antibiotic-resistant subpopulations. Our findings strongly support the continuation of research into anti-virulence drugs and demonstrate that their applicability may reach beyond infection prevention.
Highlights
Bacterial resistance to antibiotic agents is an increasing problem in modern society
Antibiotic treatment (A(0) = 4 μg/ml, A∗(0) = 0 μg/ml) We consider a scenario where the bacterial population at the site of infection is composed predominantly of an antibiotic-susceptible subpopulation and a minor, resistant subpopulation which has arisen through cross-contamination of the site with a resistant population introduced from an environmental source [27, 28]
We establish that our parameter set predicts the emergence of antibiotic-resistant bacteria in an infection when initially they exist in far smaller numbers than susceptible bacteria (Figure 2a) but dominate the infection as a result of conjugation
Summary
Bacterial resistance to antibiotic agents is an increasing problem in modern society. Horizontal resistance can lead to multidrug resistance and is a major concern in hospitals, where resistant bacteria are able to remain viable despite antibiotic use, and are the cause of many serious nosocomial infections in already vulnerable patients [7, 6]. Anti-virulence drugs would minimize any harm caused by bacteria while they remain in the host until they can be cleared by natural defences. This can occur either by being flushed out of the system or by being eradicated by the host’s immune response. In combination with antibiotics and under specific treatment strategies, anti-virulence drugs can be effective in treating bacterial infections where antibiotic resistance is a concern. We exploit parameter surveys to ascertain under what conditions certain behaviour will occur
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