Between Donor Interest, Global Models and Local Conditions: Treatment and Decision-Making in the Somalia-Finland Tuberculosis Control Project, 1981-3.

Despite numerous global health initiatives after World War II, tuberculosis still poses a major threat in sub-Saharan Africa. This article examines one attempt to tackle this problem: the Somalia-Finland Tuberculosis Control Project. Conducted in the 1980s as a bilateral development aid project between the two countries, it became the most extensive - and expensive - tuberculosis initiative in Somalia in that decade. An interesting feature of the project is that, despite a lack of previous experience in tuberculosis work in developing countries, the Finnish partner decided not to follow the WHO global guidelines designed to standardise tuberculosis activities across the developing world. Instead, Finns established their own treatment programme based on X-ray and short-course chemotherapy - otherwise rarely used in clinical practice in Africa. Through a close reading and comparison of the correspondence, project plans, memos and minutes, the article analyses the formation of this strategy. Focusing on ground-level decision-making, it argues that the decisions were based not only on a belief in the superior clinical effectiveness of these methods, but also on the fact that they better suited Finnish ambitions and project logic. Thus, the article supports the notion that donor perspectives on resources and project objectives determined what was seen as feasible treatment in a developing country. By shedding light on the debate between the supporters of short-course chemotherapy and the WHO standard treatment strategy, it also contributes to the early history of DOTS (directly observed treatment, short course).

Regimens to treat multidrug-resistant tuberculosis: past, present and future perspectives.

Over the past few decades, treatment of multidrug-resistant (MDR)/extensively drug-resistant (XDR) tuberculosis (TB) has been challenging because of its prolonged duration (up to 20-24 months), toxicity, costs and sub-optimal outcomes.After over 40 years of neglect, two new drugs (bedaquiline and delamanid) have been made available to manage difficult-to-treat MDR-/XDR-TB cases. World Health Organization (WHO) guidelines published in March 2019 endorsed the possibility of treating MDR-TB patients with a full oral regimen, following previous guidelines published in 2016 which launched a shorter regimen lasting 9-10 months.The objectives of this article are to review the main achievements in MDR-TB treatment through the description of the existing WHO strategies, to discuss the main ongoing trials and to shed light on potential future scenarios and revised definitions necessary to manage drug-resistant TB.

History of Pulmonary Tuberculosis.

Tuberculosis (TB) parallels the history of human development from the Stone Age to the present. TB continues to be in the top 10 causes of global human mortality over that period. This article highlights the history of pulmonary TB from the onset of human existence to the present. Despite its long history, TB was slowly identified as a major cause of disease, and defined causation and significant treatment strategies advances over the past 150 years. TB remains a major challenge for definitive global prevention and cure. This article gives a brief overview of the history of TB.

[Inicio del tratamiento farmacológico de la tuberculosis].

The appearance of new anti-tuberculosis drugs such as bedaquiline and delamanid makes it impossible not to remember that the first strictly controlled medical trials of tuberculosis treatment were published in two rigorously researched outstanding articles that can be qualified as historical. In 1948, streptomycin was formally studied as an efficacious anti-tuberculosis drug. In 1952, another trial compared streptomycin-paramino salicylic acid with isoniazid, by means of which the first bases of pharmacological tuberculosis treatment were established.

La aparición de nuevos fármacos antituberculosos, como la bedaquilina y el delaminid, hace inevitable recordar que los primeros ensayos estrictamente controlados del tratamiento médico de la tuberculosis se publicaron en dos artículos de excelente y rigurosa investigación científica que pueden calificarse como históricos. En 1948 se estudió formalmente la estreptomicina como medicamento antituberculoso eficaz. En 1952, en otro ensayo se comparó estreptomicina-ácido paraaminosalicílico con isoniacida, con lo que se establecieron las primeras bases del tratamiento farmacológico de la tuberculosis.

Evidence of mechanism in the evaluation of streptomycin and thalidomide.

This paper considers what evidence is needed to establish the effectiveness and safety of a drug therapy. The claim that A cures D is a particular case of a causal claim in medicine. So the paper begins with a general analysis of the evidence for causal claims in medicine. Such evidence is divided into two types: statistical evidence and evidence of mechanism. These are further divided into observational and interventional, producing a 2x2 classification. It is shown that historically there have different assessments of the importance of these different types of evidence. Evidence-based medicine (EBM) puts forward the thesis that claims of the form 'A cures D without harming the patient' can be established using only randomized controlled trials or RCTs. This thesis of EBM is criticized by considering two historical examples: streptomycin and thalidomide. Generalizing from these, it is claimed that the effectiveness and safety of a drug therapy can only be established by using both statistical evidence and evidence of mechanism. This is a specific instance of the Russo-Williamson thesis.

Colworth prize lecture 2016: exploiting new biological targets from a whole-cell phenotypic screening campaign for TB drug discovery.

Mycobacterium tuberculosis is the aetiological agent of tuberculosis (TB) and is the leading bacterial cause of mortality and morbidity in the world. One third of the world's population is infected with TB, and in conjunction with HIV represents a serious problem that urgently needs addressing. TB is a disease of poverty and mostly affects young adults in their productive years, primarily in the developing world. The most recent report from the World Health Organisation states that 8 million new cases of TB were reported and that ~1.5 million people died from TB. The efficacy of treatment is threatened by the emergence of multi-drug and extensively drug-resistant strains of M. tuberculosis. It can be argued that, globally, M. tuberculosis is the single most important infectious agent affecting mankind. Our research aims to establish an academic-industrial partnership with the goal of discovering new drug targets and hit-to-lead new chemical entities for TB drug discovery.

Drug-resistant tuberculosis in Zhejiang Province, China: an updated analysis of time trends, 1999-2013.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) hinder the progress of TB control. OBJECTIVE: To track the trend of drug-resistant tuberculosis (DR-TB) prevalence in Zhejiang Province from 1999 to 2013, and identify risk factors of resistance to second-line drugs among MDR-TB patients. DESIGN: Four DR-TB surveys had been done in Zhejiang Province in 1999, 2004, 2008 and 2013 through questionnaires, in which demographic and epidemiological items were included. After questionnaires, drug susceptibility testing (DST) targeted at four first-line drugs was done for all TB patients and DST targeted at six second-line drugs (only in 2008 and 2013) for MDR-TB patients. The drug resistance trend over time was analyzed using the Cochran-Armitage test. The factors associated with resistance to second-line drugs among MDR-TB patients were examined by a multivariate logistic regression model. RESULTS: Of 936 patients enrolled, 27 (3.21%) and 20 (21.28%) MDR-TB cases were registered as new and previously treated cases, respectively. MDR-TB showed a decreasing trend (Z = -3.31, p < 0.01) while resistance to any first-line drugs showed an increasing trend (Z = 5.22, p < 0.001), from 1999 to 2013. The highest resistance rate was shown to ofloxacin among MDR-TB patients both in 2008 (28.8%) and in 2013 (27.7%), while resistance to para-aminosalicylate decreased significantly (Z = -2.06, p = 0.04) between 2008 and 2013. MDR-TB patients aged 45-65 years (OR = 5.00, p = 0.02) were more likely to be resistant to any second-line drugs. CONCLUSIONS: DR-TB including MDR-TB remains a major public health problem in Zhejiang Province. Further efforts on MDR-TB control should be conducted to hinder drug resistance, including critical clinical use of anti-TB antibiotics and preventing transmission.

The history of tuberculosis: from the first historical records to the isolation of Koch's bacillus.

Tuberculosis (TB) is a contagious, infectious disease, due to Mycobacterium tuberculosis (MT) that has always been a permanent challenge over the course of human history, because of its severe social implications. It has been hypothesized that the genus Mycobacterium originated more than 150 million years ago. In the Middle Ages, scrofula, a disease affecting cervical lymph nodes, was described as a new clinical form of TB. The illness was known in England and France as "king's evil", and it was widely believed that persons affected could heal after a royal touch. In 1720, for the first time, the infectious origin of TB was conjectured by the English physician Benjamin Marten, while the first successful remedy against TB was the introduction of the sanatorium cure. The famous scientist Robert Koch was able to isolate the tubercle bacillus and presented this extraordinary result to the society of Physiology in Berlin on 24 March 1882. In the decades following this discovery, the Pirquet and Mantoux tuberculin skin tests, Albert Calmette and Camille Guérin BCG vaccine, Selman Waksman streptomycin and other anti-tuberculous drugs were developed.

[The leprosy "drama": Governador Valadares, public health policies, and their territorial implications in the 1980s]. / O "drama" da hanseníase: Governador Valadares, as políticas públicas de saúde e suas implicações territoriais na década de 1980.

The incidence of leprosy in Governador Valadares, Brazil, in the 1980s spurred this town to pioneer the introduction of polychemotherapy. The aim of this research was to understand how the different actors involved in this context interacted, especially the employees and patients at the Special Public Health Service. To identify the territories that these interactions inevitably constituted, a variety of theoretical instruments were used, including dramatism (Burke) and performance (Turner). By taking a theatrical metaphor, we sought to find out the dynamics by which the different actors took the stage and established their most significant relationships in a dynamic process of constituted and reconstituted territories.

Beyond Biomedicine: Relationships and Care in Tuberculosis Prevention.

With attention to the experiences, agency, and rights of tuberculosis (TB) patients, this symposium on TB and ethics brings together a range of different voices from the social sciences and humanities. To develop fresh insights and new approaches to TB care and prevention, it is important to incorporate diverse perspectives from outside the strictly biomedical model. In the articles presented in this issue of the Journal of Bioethical Inquiry, clinical experience is married with historical and cultural context, ethical concerns are brought to bear on global health, and structural analyses shed light upon the lived experience of people living with TB. The relational and reciprocal dimensions of care feature strongly in these discussions, which serve as a poignant reminder that behind each of the yearly deaths from TB is a deeply personal story. No single discipline holds a monopoly on how to care for each of these people, but strong cases are made for support from mental health and social workers in addressing the kaleidoscope of needs in TB prevention. As the World Health Organization moves towards the goal of eliminating TB globally by 2050, attending to the needs of TB patients serves global interests to lower disease burden and to develop better integrated communities worldwide.

Treatment of Tuberculosis. A Historical Perspective.

Of all achievements in medicine, the successful treatment of tuberculosis has had one of the greatest impacts on society. Tuberculosis was a leading cause of disease and a mortal enemy of humanity for millennia. The first step in finding a cure was the discovery of the cause of tuberculosis by Robert Koch in 1882. The sanatorium movement that began shortly afterward in Europe, and soon spread to the United States, brought attention to the plight of afflicted persons, and catalyzed public health action. The antituberculosis benefit of streptomycin was announced in 1945, although application was limited by the rapid development of resistance. para-Aminosalicylic acid, also discovered in 1945, when combined with streptomycin was found to greatly reduce the occurrence of drug resistance. In 1952, isoniazid opened the modern era of treatment; it was inexpensive, well tolerated, and safe. In the early 1960s, ethambutol was shown to be effective and better tolerated than para-aminosalicylic acid, which it replaced. In the 1970s, rifampin found its place as a keystone in the therapy of tuberculosis. The use of rifampin enabled the course of treatment to be reduced to nine months. Incorporation of pyrazinamide into the first-line regimen led to a further reduction of treatment duration to six months. Treatment of multiple drug-resistant tuberculosis remains a difficult problem requiring lengthy treatment with toxic drugs. However, shortened regimens show promise, and two new drugs, bedaquiline and delamanid, have demonstrated effectiveness in preliminary studies and are being used for extensively drug-resistant tuberculosis.

Cooperative development of antimicrobials: looking back to look ahead.

As foundations and governments mobilize to tackle antimicrobial resistance (AMR), several experiments in academic-industrial collaboration have emerged. Here, I examine two historical precedents, the Penicillin Project and the Malaria Project of the Second World War, and two contemporary examples, the Tuberculosis Drug Accelerator programme and the Tres Cantos Open Lab. These and related experiments suggest that different strategies can be effective in managing academic-industrial collaborations, and that such joint projects can prosper in both multisite and single-site forms, depending on the specific challenges and goals of each project. The success of these strategies and the crisis of AMR warrant additional investment in similar projects.

Unravelling the 'tangled web': chemotherapy for tuberculosis in Britain, 1940-70 the William Bynum prize essay.

The introduction and assimilation of chemotherapy to treat pulmonary tuberculosis (TB) during the mid-twentieth century appears at first sight to be a success story dominated by the use of streptomycin in a series of randomised clinical trials run under the auspices of the Medical Research Council (MRC). However, what this standard rhetoric overlooks is the complexity of TB chemotherapy, and the relationship between this and two other ways of treating the disease, bed rest and thoracic surgery. During the late 1940s and 1950s, these three treatment strands overlapped one another, and determining best practice from a plethora of prescribing choices was a difficult task. This article focuses on the clinical decision-making underpinning the evolution of successful treatment for TB using drugs alone. Fears over the risk of streptomycin-resistant organisms entering the community meant that, initially, the clinical application of streptomycin was limited. Combining it with other drugs lessened this risk, but even so the potential of chemotherapy as a curative option for TB was not immediately apparent. The MRC ran a series of clinical trials in the post-war period but not all of their recommendations were adopted by clinicians in the field. Rather, a range of different determinants, including the timing of trials, the time taken for results to emerge, and whether these results 'fitted' with individual experience all influenced the translation of trial results into clinical practice.

From milk to rifampicin and back again: history of failures and successes in the treatment for tuberculosis.

The millennial flight against tuberculosis has been characterized by several defeats. Roman physicians suggested to consumptives better nutrition, sea voyages and change of air, while, during the Middle Ages, 'royal touch' were considered as an effective remedy for scrofula. In the following centuries, phthisis was cured using old herbal preparations and new chemical compounds, mainly aimed at soothing symptoms; in addition, harmful approaches (for example, bleeding and purging) were commonly accepted, according to medical theories of that time. In the second part of the nineteenth century, the discovery of the contagious nature of consumption (Villemin, Koch) addressed physicians and scientists toward often-unsuccessful remedies, such as antiparasitic treatment, immunomodulants, vaccination and serum therapy. In that period only sanatorium regimen--based on aerotherapy, bed rest, better nutrition, sunbathing and moderate physical exercise--appeared to provide first partial successes. In these structures, more invasive approaches were also employed, such as lung collapse surgical interventions (for example, phrenicotomy, thoracoplasty) and artificial pneumothorax. Since the second part of the twentieth century, the industrialization of pharmacotherapy, the development of antimicrobial chemotherapy and the introduction of new antibiotics (streptomycin, isoniazid, para-aminosalicylic acid, ethambutol and pyrazinamide) deeply revolutionized treatment for tuberculosis, allowing to achieve important successes. In this same period, the figure of Piero Sensi (1920-2013) deserves to be recalled for his contribution in the development of rifampicin that played a decisive role in the chemical fight against the white plague. Nowadays, antibiotic resistance is an emerging problem, representing a new challenge for physicians and scientists who sometimes re-proposed old 'historical' approaches.

Sera-therapy, exile and Franco's regime. The survival strategy of the Ravetllat-Pla Institute in postwar Spain.

The aim of this paper is to analyse the scientific and commercial survival strategy of the Ravetllat-Pla Institute after the Spanish Civil War. Founded in 1923 by Ramon Pla (1880-1956) and Joaquim Ravetllat (1872-1923), it produced two sera: 'Hemo-antitoxin' and the 'Ravetllat-Pla serum'. When the Civil War ended and Ramon Pla was forced into exile, management of this laboratory was taken over by his daughter, Núia Pla Monseny (1918- 2011) who had to deal with an extremely difficult economic, political and commercial situation. In this paper, I analyse the means by which the Institute survived. These involved the Institute's ability to construct different political symbols from 'Hemo-antitoxin'. I study how Franco's repression influenced this survival strategy and Ramon Pla's role in exile. I also analyse the part played in this scientific and commercial process by the Institute's scientific and commercial network in Chile.