Chemotherapy of Tuberculosis--Part II

Hart, P. D.

doi:10.1136/bmj.2.4483.849

Cited by 8 publications

(3 citation statements)

References 8 publications

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“…Certainly, if Hinshaw and Feldman had not been already conducting their work in the guinea pig model of tuberculosis, the translation of streptomycin to the clinic might have been delayed substantially. The use of multiple preclinical species such as mice, rats, rabbits, and guinea pigs in those historical studies is also worthy of remark, with certain antimicrobial agents showing variable exposure and efficacy in different species even then ( 29 , 75 – 77 ). While analysis of parameters of new drugs in at least two preclinical species is standard in the field of pharmacokinetics, efficacy is often validated in only one, perhaps as a result of the difficulties, expense, and effort of recapitulating disease in multiple species.…”

Section: Lessons From the History Of Combination Therapymentioning

confidence: 99%

Origins of Combination Therapy for Tuberculosis: Lessons for Future Antimicrobial Development and Application

Kerantzas

Jacobs

2017

mBio

154

102

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Tuberculosis is a global health problem that causes the death of approximately 1.5 million people worldwide each year (WHO, p. 1–126, Global Tuberculosis Report, 2015). Treatment of drug-susceptible tuberculosis requires combination antimicrobial therapy with a minimum of four antimicrobial agents applied over the course of 6 months. The first instance of combination antimicrobial therapy applied to tuberculosis was the joint use of streptomycin and para-aminosalicylic acid as documented by the Medical Research Council of the United Kingdom in 1950. These antimicrobial drugs were the product of many decades of investigation into both organism-derived antibiotics and synthetic chemotherapy and were the first agents in those respective categories to show substantial clinical efficacy and widespread use for tuberculosis. The events leading to the discovery and application of these two agents demonstrate that investments in all aspects of research, from basic science to clinical application, are necessary for the continued success of science in finding treatments for human disease. This observation is especially worth considering given the expanded role that combination therapy may play in combating the current rise in resistance to antimicrobial drugs.

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Section: Lessons From the History Of Combination Therapymentioning

confidence: 99%

Origins of Combination Therapy for Tuberculosis: Lessons for Future Antimicrobial Development and Application

Kerantzas

Jacobs

2017

mBio

154

102

View full text Add to dashboard Cite

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“…Similarly, treatment of tuberculosis in experimental animals (mice, guinea pigs, and rabbits) gave various results depending primarily on the sulfonamide used and whether the drug was administered prior to or simultaneously with infection or after infection had occurred (9,12,13,18,19,30). Sulfadiazine improved animal survival significantly more than did other old sulfonamides (13,19,30).…”

Section: Vol 53 2009 Tuberculosis and Trimethoprim-sulfamethoxazolementioning

confidence: 99%

Tuberculosis and Trimethoprim-Sulfamethoxazole

Forgács¹,

Wengenack

Hall

et al. 2009

Antimicrob Agents Chemother

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The sulfonamides were the first drugs with antituberculous effects. Their use was abandoned and basically forgotten with the advent of streptomycin and isoniazid combination treatment. There is a widespread belief, apparently based on testing a single isolate on questionable media, that Mycobacterium tuberculosis is resistant to trimethoprim-sulfamethoxazole (TMP-SMX). We saw a complex immunocompromised patient with tuberculosis who was initially treated with TMP-SMX without antituberculous drugs and defervesced on this treatment. An isolate of M. tuberculosis from this patient was found to be sensitive to TMP-SMX. We examined how frequently M. tuberculosis is sensitive to TMP-SMX. Isolates were tested for susceptibility to TMP-SMX on supplemented Middlebrook 7H10 plates. We found that 43 of 44 (98%) isolates of M. tuberculosis were susceptible to the combination of <1 g/ml of TMP and 19 g/ml of SMX (<1/19 g/ml). Thus, the vast majority of our M. tuberculosis isolates were susceptible to TMP-SMX at an MIC similar to that for Mycobacterium kansasii, Mycobacterium marinum, and sensitive rapidly growing mycobacteria, organisms successfully treated with TMP-SMX as part of the treatment regimen. It is possible that TMP-SMX may be useful in treating patients with multiple-drug-resistant and extended drug-resistant tuberculosis. We feel that a clinical trial looking at the effectiveness of TMP-SMX as an antituberculous drug is worthwhile.Between the late 1930s and the early 1950s, sulfonamides (10,14,24,32,33,40) and sulfones (31) were used, usually as monotherapy, for the treatment of tuberculosis; the early preparations of sulfonamides other than sulfanilamide were in general found to have some efficacy. Because of the toxicity of the sulfones and the early sulfonamides (36), and because isoniazid (INH) and streptomycin were stronger antituberculous drugs (31), both groups of drugs were abandoned for the treatment of tuberculosis in the early 1950s, and their use was basically forgotten.We saw a complex immunocompromised patient with fever and pulmonary infiltrates who was initially thought to have possible nocardiosis. He was treated with trimethoprim-sulfamethoxazole (TMP-SMX) for 2 1/2 weeks and defervesced on this treatment. He was found to have tuberculosis without nocardiosis or any other significant infection. Because of his clinical response (defervescence), testing of the susceptibility of his isolate of M. tuberculosis to TMP-SMX was performed, and it was found to be susceptible. It is widely thought that M. tuberculosis is resistant to TMP-SMX (2,29,37,40). After looking at the basis for this belief, we decided to proceed with testing a large number of M. tuberculosis isolates for susceptibility to TMP-SMX. CASE REPORTAn 81-year-old man was admitted to the Lahey Clinic Medical Center because of fever, chills, cough, and dyspnea for 1 day; he had noted fatigue without sweating or weight loss for 2 to 3 weeks. He had undergone a porcine aortic valve replacement 3 years previously. He was receiving prednisone...

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“…In this way the effective concentration of the drug might be increased, for the surface-active molecules instead of being spread evenly throughout the solution would adlineate about the periphery of the bacteria. Many compounds have been shown to be effective in vitro against the tubercle bacillus (14). Of these, among the best known and most thoroughly investigated are the diaminodiphenyl sulfone derivatives.…”

Section: Hypothethical Effect Of Surface-active Substances Upon Mycobmentioning

confidence: 99%

A Means of Increasing the Tuberculostatic Effect of Known Chemotherapeutic Agents

Eiseman

1948

Journal of Experimental Medicine

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Dubos and his coworkers recently have shown the profound influence that certain surface-active oleates have on the in vitro growth of the tubercle bacillus (1-3). Their work suggests that by the addition of these fatty acid in a highly surface-active form a great enhancement of growth can be obtained. The mechanism of action of this surface-active growth-promoting factor has been interpreted according to known physical-chemical principles, which would indicate that the oleate is concentrated at the periphery of, or within the confines of the mycobacterium.In the study here to be reported, 1 several surface-active tuberculostafic substances have been prepared and tested in an effort to determine whether a similar increased effect on the tubercle bacillus would be obtained by concentrating an inhibitory instead of a stimulating substance about the organism.These substances were found to be effective in vitro in relatively low concentrations.The mechanism of such tuberculostatic action was investigated according to physical-chemical principles, by isolating the factor of drug action due to its surface activity from its inherent (non-surface-active) component. This was carried out by introducing a substance antagonistic to the surface-active component of the drug, but in no other way interfering with its antibacterial action. These studies suggest that the property of surface activity may enchance the tuberculostatic action of a given drug. The reason for such action is discussed and correlated with the steric arrangement of the drug molecule in relation to the surface of the mycobacterium. Other previously described surface-active tuberculostafic chemicals and antibiotics have also been studied with this concept in mind, and certain of them are shown to owe a part of their activity to the surface-active character of their molecules. Hypothethical Effect of Surface-Active Substances upon Mycobacteria.--Ingeneral, studies of the effects of surface-active substances upon the growth of bacteria and of acid-fast organisms in particular (4--8) have emphasized the fact that human tubercle bacilli can grow in vitro at a vastly reduced surface

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Chemotherapy of Tuberculosis--Part II

Cited by 8 publications

References 8 publications

Origins of Combination Therapy for Tuberculosis: Lessons for Future Antimicrobial Development and Application

Origins of Combination Therapy for Tuberculosis: Lessons for Future Antimicrobial Development and Application

Tuberculosis and Trimethoprim-Sulfamethoxazole

A Means of Increasing the Tuberculostatic Effect of Known Chemotherapeutic Agents

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