Drug-resistant TB in South Africa
mutants (10–7 x 109 = 102). To fight them, a combination – or cocktail – of different anti-TB drugs is administered together. The principle underlying such ‘combination therapy’ is that the probability of a single bacterium simultaneously carrying mutations that can confer resistance to two or more drugs is extremely low (much less than one in a trillion; 10–7 x 10–7 = 10–14). The emergence of MDR and XDR strains of MTB that carry multiple resistance-conferring mutations betrays failure to adhere to fundamental tenets of antibacterial therapy; each public-health factor mentioned above (poor compliance, inappropriate therapy, prolonged infectiousness, and insufficiently rapid detection of resistance strains) undermines the effectiveness of combination therapy. The severely compromised immune response of HIV-infected patients also alters progression of TB disease, which could affect drug resistance3.
Above: Drug resistance develops when the bacteria that cause TB are not exposed to the correct concentrations of drugs for the prescribed amount of time. If a patient presents to a clinic with active TB, and the infecting strain (represented as black spots) displays no pre-existing drug resistance, antibiotics will normally clear the bacteria and make the disease symptoms disappear after initial treatment (A). If the patient complies with the treatment, almost all the bacteria will eventually be killed and the symptoms of disease eradicated; the patient is cured. In many cases, however, not all the bacteria are killed and a small sub-population of them remains behind. These have the capacity to resume active replication and cause disease if the patient becomes immunecompromised through, for example, advancing age, diabetes, or HIV infection (B). Where the prescribed treatment is not followed for the full length of time, concentrations of antibiotics in the blood and lungs fall below the range needed to kill the bacteria. Bacteria exposed to this sub-optimal concentration of antibiotics can adapt, survive, and, ultimately, become drug-resistant. The first and most likely case is the evolution of single (mono) drug resistance (C, where red spots represent mono-resistant bacilli). These mono-resistant bacteria can multiply again, amplifying the resistant population and leading to disease requiring re-treatment (D). A patient’s non-compliance can cause resistance to a second drug to evolve (E), giving rise to multi-drug-resistant (MDR) strains (blue spots). Alternatively, MDR can evolve in a single step as a result of noncompliance during the initial round of treatment (F). Patients carrying MDR-TB can transmit this form of the disease to others (G). Many people can be infected with drug-resistant strains, which makes treatment difficult, even if newly infected patients comply with the treatment regimen. Further mismanagement of MDR-TB by the prescription of inappropriate or ineffective anti-TB drugs (particularly in the absence of effective drug susceptibility testing), or by non-compliance, can ultimately lead to the development of resistance to second-line antibiotics (H), and to extensively drug-resistant (XDR) TB.
TB only after they fail to respond to standard treatment. Furthermore, even where testing has taken place, several months can pass before the diagnosis is confirmed, resulting in dangerous delays in administering second-line drugs. During this period, the risk of transmitting MDR strains to others is high and, where patients are co-infected with HIV, there is a strong likelihood of death. New tests, however, will enable the rapid determination of a drug-resistance profile, which should result in the prescription of appropriate drugs, rather than drugs that will be ineffective and, more worryingly, amplify resistance. ▲ ▲
Fighting resistance Given the relatively few anti-TB drugs available, prudent use of the drugs that we know is crucial and the subject of active research. Considerable efforts are also being directed towards the development of novel antibacterial agents to inhibit bacterial components not previously considered for antibiotic targeting. Whereas most current antibiotics target processes that are essential for the growth of bacteria, new strategies have been proposed to target alternative processes – those required for the bacterium to cause disease, but not essential for its survival. Such targets include factors required for virulence, as well as the very processes implicated in the generation of mutations. In this way, the usefulness of antibiotics can be prolonged. Perhaps the greatest single problem for TB control in high-burden countries is the time it takes to reach a positive diagnosis of drug-resistant TB – compounded by HIV co-infection, which can mask factors that routine TB diagnosis takes into account. Molecular diagnostic tests now available can distinguish certain drug-resistant strains by assessing the target gene mutations most commonly associated with drug resistance. Most TB patients in developing countries, however, are tested for drug-resistant
How drug-resistant TB can evolve
3. The effect of HIV infection on the emergence of drug resistance is unknown. On the one hand, the bacterial numbers are elevated, therefore increasing the likelihood of resistance. This could be countered by a compromised immune system, which might affect the emergence of resistance. Additional questions include the diffusion of drugs (TB in HIV patients affects numerous areas of the body), as well as the possibility that less ‘fit’ resistant mutants could survive in an immunecompromised host (but would be eliminated in immune-competent hosts).
Above: Rifampicin-resistant isolates of a non-pathogenic mycobacterium, M. smegmatis. This strain is used routinely as a surrogate in drug-resistance studies of M. tuberculosis in analyses that provide insight into the mutation rates of these organisms.
Quest 4(3) 2008 35