The chemotherapy of tuberculosis: past, present and future [State of the art]

Abstract

The history of the development of modern chemotherapy for tuberculosis (TB), largely due to the British Medical Research Council, is first described. There is a current need to shorten the duration of treatment and to prevent and cure drug-resistant disease. These aims will only be achieved if the way in which multidrug treatment prevents resistance from emerging and the reasons for the very slow response to chemotherapy are understood. Consideration of mutation rates to resistance and the size of bacterial populations in lesions makes it very unlikely that resistance would emerge spontaneously, leaving irregularity in drug taking and inadequate dosage as the main reasons for its occurrence. Slow response to treatment seems due to the presence of persister populations whose natural history is only partly known. In the future, we need to explore the persister state in patients and in experimental murine TB, and to take it into account in the design of future mouse experiments. The activity of rifamycins and pyrazinamide is being increased by a rise in rifamycin dosage and the inhalation of pyrazinoic acid. New drugs are gradually being brought into use, initially TMC207 and the nitroimadazoles, PA824 and OPC67683. They will need to be tested in new combination regimens for drug-susceptible and multi- and extensively drug-resistant disease.

Tuberculosis: From an Untreatable Disease in Antiquity to an Untreatable Disease in Modern Times?

“…An outbreak of a highly virulent strain of M. tuberculosis, resistant to multiple drugs in New York City was reported by Steiner et al in 1970, and subsequently other reports followed throughout the 1980s and 1990s [47,69,70]. MDR-TB, defined as resistance to isoniazid and rifampin, has been recognized with increasing frequency, worldwide, since the earliest reports in the 1970s [2, 49,54]. Since the 1990s, MDR-TB has been a significant and growing problem in subSaharan Africa and India.…”

“…To place these treatment goals and guidelines into a more international context, it is necessary to understand the different treatment approaches and implementation in high-incidence, low-income countries. While TB steadily declined during the first half of the 20 th century in Europe and the U.S., the prevalence remained high in many other parts of the world, and by the mid-20 th century, TB outcomes had diverged along the fault lines of the global economy [3,47,49,55]. On September 6 th 1978, perhaps inspired by the eradication of smallpox in the prior year, the delegates of the International Conference on Primary Health Care, convened at Alma-Ata (today's Almaty) in Kazakhstan, and gave their support to the goal of "Health for all by the year 2000"; their commitments and affirmations included a firm statement on combating infectious diseases, perhaps aiming at the possibility to eradicate TB [47,56,57].…”

“…The assessment of "disability-adjusted life-years", a measure of morbidity and mortality by age, was introduced to evaluate the "cost effectiveness" of any given health intervention/ program in order to be deemed worthy of funding. Truly effective treatment of TB in the 1950s and 1960s typically required extensive antimicrobial chemotherapy for 18-24 months, and even with regimens shortened to 9 months, it was quickly evident that a major obstacle to the cure of patients in resource-poor settings and developing countries lay in the patients' compliance with the lengthy treatment regimens, allowing interruptions of drug administration for various reasons [49]. With the intent to maintain the efforts of international TB programs, the WHO recognized this report as an opportunity to develop a new approach to anti-tuberculous therapy: short-course chemotherapy for TB was declared a highly cost effective intervention [47].…”

“…Subsequently, in 1944 the first TB patient was successfully treated with streptomycin and ultimately declared to be cured of the disease [47]. Following this initial success, several other individual and/or anecdotal cases of successful administration of streptomycin followed, until in 1948 the British Medical Research Council (BMRC) conducted the first largescale clinical trial for use of streptomycin in TB patients [48,49]. This trial was the first of its kind and is considered to have set the methodological standard for all modern randomized, controlled clinical trials [47].…”

Mycobacterium tuberculosis adhesins: potential biomarkers as anti-tuberculosis therapeutic and diagnostic targets

“…The synergistic relationship between human immunodeficiency virus (HIV) and M. tuberculosis infection, and the significant increase in the prevalence of multi-, extensively and totally drug-resistant M. tuberculosis strains (Gillespie, 2002;Fauci et al, 2008;Jassal & Bishai, 2009;LoBue, 2009;Velayati et al, 2009;Almeida Da Silva & Palomino, 2011) are largely accountable for the dramatic resurgence of TB as a serious global public health epidemic. This is further complicated by the lack of an effective vaccine (Russell et al, 2010), prolonged chemotherapy regimens (Mitchison & Davies, 2012) and adverse TB/HIV drug interactions (Luetkemeyer et al, 2011). Knowledge on the mechanisms utilized by M. tuberculosis to infect the host would offer novel perspective and define new targets to facilitate the design and development of drugs that are effective against both sensitive and resistant organisms (Ginsberg & Spigelman, 2007), efficacious vaccines (Bermudez et al, 2002), as well as crucially needed rapid, accurate and cheap point-of-care tests (Wallis et al, 2010).…”