Clinical Use of Streptomycin in the Treatment of Tuberculosis

Pfuetze, Karl H.; Glover, Robert P.; White, Ellison F.; Feldman, William H.; Hinshaw, H. Corwin

doi:10.1378/chest.12.6.515

Cited by 18 publications

(11 citation statements)

References 4 publications

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“…In 1943, David Schatz discovered streptomycin, a natural product that could actually kill tubercle bacilli [18]. Unfortunately, 85% of the patients treated with streptomycin developed streptomycin-resistant TB in the first clinical trial of streptomycin [19,20]. The addition of paraaminosalicylic acid (PAS), discovered by Domagk [16], could reduce the emergence of streptomycin resistance [21,22], establishing the first multidrug therapy [19].…”

Section: The Origins Of Chemotherapy and Antibiotics And The Need Formentioning

confidence: 99%

The Isoniazid Paradigm of Killing, Resistance, and Persistence in Mycobacterium tuberculosis

Vilchèze

Jacobs

2019

Journal of Molecular Biology

111

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Isoniazid (INH) was the first synthesized drug that mediated bactericidal killing of the bacterium Mycobacterium tuberculosis, a major clinical breakthrough. To this day, INH remains a cornerstone of modern tuberculosis (TB) chemotherapy. This review describes the serendipitous discovery of INH, its effectiveness on TB patients, and early studies to discover its mechanisms of bacteriocidal activity. Forty years after its introduction as a TB drug, the development of gene transfer in mycobacteria enabled the discovery of the genes encoding INH resistance, namely, the activator (katG) and the target (inhA) of INH. Further biochemical and x-ray crystallography studies on KatG and InhA proteins and mutants provided comprehensive understanding of INH mode of action and resistance mechanisms. Bacterial cultures can harbor subpopulations that are genetically or phenotypically resistant cells, the latter known as persisters. Treatment of exponentially growing cultures of M. tuberculosis with INH reproducibly kills 99% to 99.9% of cells in 3 days. Importantly, the surviving cells are slowly replicating or non-replicating cells expressing a unique stress response signature: these are the persisters. These persisters can be visualized using dual-reporter mycobacteriophages and their formation prevented using reducing compounds, such as N-acetylcysteine or vitamin C, that enhance M. tuberculosis’ respiration. Altogether, this review portrays a detailed molecular analysis of INH killing and resistance mechanisms including persistence. The phenomenon of persistence is clearly the single greatest impediment to TB control, and research aimed at understanding persistence will provide new strategies to improve TB chemotherapy.

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Section: The Origins Of Chemotherapy and Antibiotics And The Need Formentioning

confidence: 99%

The Isoniazid Paradigm of Killing, Resistance, and Persistence in Mycobacterium tuberculosis

Vilchèze

Jacobs

2019

Journal of Molecular Biology

111

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“…It is important to note that even before the active component had been identified, indeed within weeks of its discovery, streptomycin was evaluated in a chicken embryo model of infection with Salmonella gallinarum and within 6 months of its discovery streptomycin was being evaluated for efficacy in guinea pigs infected with M. tuberculosis [8]. Even more amazingly, within 1 year of its discovery, streptomycin was used for the first time to treat a pulmonary TB patient [9]. Eight years later, in 1952, Selman Waksman was awarded the Nobel Prize for medicine for discovering the first highly effective anti-TB agent.…”

Section: Streptomycinmentioning

confidence: 99%

Modern Drug Development

Barry¹

2002

Issues in Infectious Diseases

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Current recommended drug therapy for tuberculosis (TB) consists of 2 months of daily treatment with isoniazid, rifampicin, and pyrazinamide, often with the inclusion of ethambutol in areas where drug resistance is common. This 2-month course of therapy is usually sufficient to render all patients sputum culture negative but an additional 4 months of therapy is required to guarantee that patients will not relapse with disease following completion of their regimen [1]. This optimum 'short-course' chemotherapy was determined to be effective through an extraordinary series of field trials conducted in TB patients globally from 1946 to 1976 and it is highly effective -if the entire 6-month course is completed, 95% or more of patients can be cured of their disease [2].The reality of the situation is that TB control programs now focus their resources on increasingly complex logistical solutions to the problem of ensuring that patients complete this extensive chemotherapy rather than on drugs per se or ancillary activities such as surveillance and detection of new cases. Direct supervision of therapy by a health care provider (originally implemented by the British Medical Research Council in 1958 in Hong Kong and Madras but then later re-marketed as ' DOT' or Directly Observed Therapy [3]) is now considered standard despite that this requires the vast majority of the resources for TB 'chemotherapy' go not to pay for the drugs, but for the support infrastructure necessary to deliver them effectively [4]. Despite heroic efforts by the international community, in many regions of the world TB control programs either do not exist or are loosely organized coalitions with little understanding of the principles of TB therapy and with little access to high-quality drugs or a stable system through which to supervise their administration for such an extensive time period.A major contributing factor, therefore, to the difficulty of achieving worldwide success with TB eradication stems from the fundamental limitation

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“…Combination chemotherapy was pioneered in a series of landmark trials conducted by the United Kingdom Medical Research Council and the Mayo Clinic in the United States. 29,30,31 Subsequently, 421 in the 1970s, with the introduction of rifampin in clinical practice and the renewed interest in pyrazinamide, the duration of therapy could be reduced to 6 to 9 months; such modern regimens can cure virtually all cases infected with drug-susceptible isolates. [32][33][34][35][36][37][38] Despite the availability of highly effective therapeutic regimens, mortality can remain high when case management is poor, even in the developed world.…”

Section: Mortality From Tuberculosismentioning

confidence: 99%