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Get the answer of: Why are New TB Drugs Needed?
HIV/AIDS has dramatically increased the risk of developing active TB and HIV co-infection makes TB more difficult to diagnose and treat. The increasing emergence of MDR-TB and the nature of persistent infections pose additional challenges to the treatment with conventional anti-TB drugs.
Although TB can be treated with current drugs, treatment is complex and long involving 4 drugs for 2 months and 2 more drugs for at least another 4 months. Direct Observed Treatment (DOT) as promoted by the WHO to improve compliance for the difficult and long regimen can improve cure rates, but is demanding for patients and labour intensive for health staff.
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In pioneering studies McDermott and colleagues showed that the efficacy of drugs against M. tuberculosis in vitro was not matched by their efficiency in vivo.
The exponentially growing cultures of M. tuberculosis can be sterilised using frontline bactericidal drugs such as INH and RIF, yet the same drug combination requires months to achieve similar effects against bacteria living in host tissues.
This is because of the failure of the drugs to achieve optimal levels within TB lesions, but there is evidence that drug availability is not a limiting factor. It has been proposed that persistence of tubercle bacilli, which consists of 4 different populations, in the chemotherapy treatment might be attributable to physiologic heterogeneity of the bacteria in the tissues.
These populations are:
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1. Bacteria that are actively growing are killed primarily by INH.
2. Bacteria that have spurts of metabolism are killed by RIF.
3. Bacteria that are characterised by low metabolic activity and reside in acid pH environment are killed by PZA.
4. Bacteria that are dormant or per-sisters are not killed by any current TB drug.
This idea was supported by the long established observation that slow and non-growing bacteria are phenotypically resistant or tolerant to killing by antimicrobials. During the initial phase of chemotherapy treatment, which lasts about 2 days, the bacilli are killed exponentially at a rapid rate, followed by a further lengthy period of much slower exponential killing.
It is assumed that those bacilli that are killed in the first 2 days are actively multiplying, while those in the succeeding period are per-sisters killed by the slower sterilising activities of the drugs.
In an in vitro model of drug action, a 30-day static culture has been extensively used for the last 60 years and has been taken to resemble the per-sister population in its response to the drugs.
The drugs added to this static culture have the same slow sterilising actions that are responsible for the prolongation of therapy. This evidence suggests that activity against the population of persistent bacilli ultimately determines the duration of therapy necessary to provide a stable cure of the host.
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Evidently there is an urgent need to develop new and more effective TB drugs that are not only active against MDR-TB but also shorten the length of treatment and target the non-replicating persistent bacilli.
