Swiss
Drug resistance is a major problem for the treatment of many bacterial diseases, in particular tuberculosis. Social aspects have been shown to be important, and the quality of individual TB control programmes and patient adherence to treatment are both known to contribute to the emergence and spread of drug-resistant strains
Combatting drug resistant tuberculosis
Very little is known about the bacterial characteristics which predispose certain drug-resistant strains to be more successful than others. Until fairly recently, a concept that was almost universally accepted was that of ‘fitness-cost’, which stated that drug resistant pathogens were less evolutionarily fit
than drug susceptible strains. In the
past, this led to government policies that denied treatment to those with multi drug- resistant strains, as not only was their treatment far more complicated and expensive, but the likelihood of passing on the multi drug-resistant strains would be decreased. Since then, numerous epidemics of multi
drug-resistant tuberculosis have occurred in areas across the globe. “The fact that it is now totally unacceptable to deny certain patients treatment has led us to question the policy previously held by the World Health Organisation (WHO)
that it was
best not to treat those with multi drug- resistant strains of TB,” says Sebastien Gagneux, “and it is these recent epidemics that have led to us ditching the ‘fitness- cost’ dogma that brought about this policy.
What we don’t know, however, is why the dogma was wrong. “As it turns out, there are many factors that
will decide how fit a drug-resistant strain will be, and so everything is much more complicated than was originally thought – as is almost always the case in biology!” It is these factors affecting the fitness of drug-resistant strains of TB that have been
developed drug resistance over time during treatment. “What we found was that, at least as far as rifampicin is concerned, all of the lab-generated drug-resistant strains had reduced levels of fitness compared to their susceptible counterparts,” says Gagneux. “However, there was also a huge range of effects
that these mutations
incurred, so although all of them caused resistance to rifampicin, the side effects on the fitness of the strain were greatly varied. “What was really interesting, however,
“These compensatory mutations do indeed contribute to the
success of multi drug- resistant strains”
the main focus of Gagneux and his
colleagues’ work. Starting out with a simple assay in the lab,
they used competition
experiments to compare strains that had been generated in the lab to have resistance with clinical isolates from patients who had
was when we then moved on to look at the clinical strains. We took initial isolates from patients who had drug-susceptible strains of TB. Then after several months, when for whatever reasons these patients had developed resistance to the drug, we took a second isolate and compared these two samples. Although it was
true that
some of the second isolates had some sort of fitness defect compared to the drug- susceptible counterparts, in some cases the drug-resistant strain would have an equal or even higher fitness level. At this time, the hypothesis was that during the time in which the patient developed resistance,
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