Historical and hygienic aspects on roles of quality requirements for antibiotic products in Japan: Part 5 - Introduction of technology and knowledge on streptomycin production from the United States of Americat.

In order to investigate the roles of quality requirements for antibiotics products in Japan, from historical and hygienic aspects, we examined how technology and knowledge in the production and quality control of streptomycin were introduced from the United States of America. In this study, through detailed investigations and analyses, it was confirmed that the introduction of technology and knowledge on streptomycin was strongly supported by Brigadier General CRAWFORD SAms, the chief of the Public Health and Welfare Section (PHW) of the Supreme Commander for Allied Powers/General Headquarters, via the Ministry of Welfare in Japan. Dr. SELMAN WAKSMAN, the discoverer of streptomycin, along with scientists of Merck & Co., also helped Japanese industries extensively, via PHW, by providing the original streptomycin-producing strains and transferring expertise in streptomycin production. With the technology and knowledge being introduced from the USA, domestic production of streptomycin preparations increased very rapidly. As noted in our previous report, domestic production reached amounts enough to satisfy national demand within three years. Japanese people have a racial tendency to be highly susceptible to tuberculosis known as an incurable national disease. Thanks to streptomycin therapy, the tuberculosis mortality rate (per 100,000 population) had fallen dramatically within only five years from 187.2 in 1947 to 82.2 in 1952.

[Contribution of microbiologists of Kirov City to development of penicillin and streptomycin production processes (70 years since development of technology for submerged production of first domestic antibiotics)].

The publication is concerned with development of the technological processes for submered production of the first domestic antibiotics 70 years age. The literature data on the contribution of the microbiologists of the Kirov City and mainly the workers of the Red Army Research Institute of Epidemiology and Hygiene (nowadays Central Research Institute No. 48 of the Ministry of Defense of the Russian Federation, Kirov), to development of the manufacture processes for production of penicillin and streptomycin are reviewed.

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.

The history of tuberculosis.

Tuberculosis has claimed its victims throughout much of known human history. It reached epidemic proportions in Europe and North America during the 18th and 19th centuries, earning the sobriquet, "Captain Among these Men of Death." Then it began to decline. Understanding of the pathogenesis of tuberculosis began with the work of Théophile Laennec at the beginning of the 19th century and was further advanced by the demonstration of the transmissibility of Mycobacterium tuberculosis infection by Jean-Antoine Villemin in 1865 and the identification of the tubercle bacillus as the etiologic agent by Robert Koch in 1882. Clemens von Pirquet developed the tuberculin skin test in 1907 and 3 years later used it to demonstrate latent tuberculous infection in asymptomatic children. In the late 19th and early 20th centuries sanatoria developed for the treatment of patients with tuberculosis. The rest provided there was supplemented with pulmonary collapse procedures designed to rest infected parts of lungs and to close cavities. Public Health measures to combat the spread of tuberculosis emerged following the discovery of its bacterial cause. BCG vaccination was widely employed following World War I. The modern era of tuberculosis treatment and control was heralded by the discovery of streptomycin in 1944 and isoniazid in 1952.

[20th century at a glance: the streptomycin story]. / Police épistémologique: l'enquête "streptomycine".

The discovery of streptomycin is attributed to a microbiologist, Selman Waksman, Nobel Prize 1952, a paternity that was disputed by his collaborator Albert Schatz, who was the first author of the princeps article. Two pioneering clinical studies involved streptomycin, both of which have been widely used as reference works. The first one was English, under the name of Austin Bradford Hill. It inaugurated a randomization in medicine. The second trial was American, and carried out by the Veteran Administration. It made use for the first time of the "control group". The present article analyses the genesis of clinical trials and illustrates the recurrent difficulties encountered in their implementation.

Re-Inventing Infectious Disease: Antibiotic Resistance and Drug Development at the Bayer Company 1945-80.

This paper analyses how research on antibiotic resistance has been a driving force in the development of new antibiotics. Drug resistance, while being a problem for physicians and patients, offers attractive perspectives for those who research and develop new medicines. It imposes limits on the usability of older medicines and simultaneously modifies pathologies in a way that opens markets for new treatments. Studying resistance can thus be an important part of developing and marketing antibiotics. The chosen example is that of the German pharmaceutical company Bayer. Before World War Two, Bayer had pioneered the development of anti-infective chemotherapy, sulpha drugs in particular, but had missed the boat when it came to fungal antibiotics. Exacerbated by the effects of war, Bayer's world market presence, which had been considerable prior to the war, had plummeted. In this critical situation, the company opted for a development strategy that tried to capitalise on the problems created by the use of first-generation antibiotics. Part and parcel of this strategy was monitoring what can be called the structural change of infectious disease. In practice, this meant to focus on pathologies resulting from resistance and hospital infections. In addition, Bayer also focused on lifestyle pathologies such as athlete's foot. This paper will follow drug development and marketing at Bayer from 1945 to about 1980. In this period, Bayer managed to regain some of its previous standing in markets but could not escape from the overall crisis of anti-infective drug development from the 1970s on.

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.

Tuberculosis: a long fight against it and its current resurgence.

Unlike the discovery of penicillin in 1928 by A. Fleming, largely due to fortuitous circumstances, the isolation of streptomycin by S.A. Waksman was the result of a systematic research project carried out by a number of workers. In 1952, Waksman received the Nobel Prize in Medicine for having produced the first useful drug against tuberculosis. Before the tubercle bacillus was recognised as the causative agent of the disease, various sanatoria had been set up, as the only remedy for sufferers of tuberculosis. Between 1880 and 1930 sanatoria spread across Europe and North America, and they were partially effective against the ever worsening diffusion of tuberculosis: therefore in the United Kingdom a government-funded agency, the Medical Research Council (MRC), was created in 1913. In 1947 streptomycin was put on the market, opening a new era in the history of modern medicine. Indeed, the first published report of the results of an (individually) randomised clinical trial was the 1948 paper by Bradford Hill and co-workers of the MRC's trial on the use of streptomycin. Streptomycin still represents a first-line agent in the recommended therapy of tuberculosis, whose burden is far higher in low-income countries. The current aim of any global intervention against tuberculosis should be the elimination of the pathology itself, an effort that will need both financial investments in scientific research and the targeted use of the fruits of that research to develop new, effective, preventive and therapeutic tools, such a tool as streptomycin proved to be more than fifty years ago.

[50 years of clinical trials; a new direction in medicine]. / 50 jaar klinische trials; een nieuw kompas in de geneeskunde.

In 1998 the medical community commemorated the completion of the first truly randomised trial, the Medical Research Council Streptomycin Study. This invention is at least as important as Harrison's clocks, which in the 18th century solved the problem of measuring longitude at sea. Naturally the idea of randomised controls had evolved from previous notions. Obtaining informed consent remains essentially a matter between patient and physician, but in the meantime four other interested parties have joined in: governing bodies, the pharmaceutical industry, medical journals, and the mass media. In order to keep all these forces in check, lawmakers should protect the weakest parties against the more powerful ones. There is a great deal to be done in the next 50 years.

[Streptomycin was born fifty years ago]. / Il y a cinquante ans naissait la streptomycine.

The discovery of streptomycin by Waksman in 1943 marked the beginning of true chemotherapy in all forms of tuberculosis. The possibility to reverse the lethal course of tuberculous meningitis in children constituted a hope verged on enthusiasm. But after encouraged results, skepticism arose: cases of resistance of BK to streptomycin were reported and other observations noted severe sequelae when administration had begun too late. Successes due to drug were often weakened by side effects like cochlear and vestibular deficiencies. All those reservations came in addition to the great price of streptomycin, difficulties of its supply and doubts upon long term prognosis for cared patients. Finally streptomycin won. In the following years, new drugs more and more efficient against tuberculosis were used, instead of streptomycin which some enthusiastic people had nevertheless thought only able to eradicate the "white plague". Today, morbidity and mortality from tuberculosis remain dramatic, partly accelerated by the AIDS epidemic and increased by high frequency of cases with BK resistance to all drugs ... except streptomycin. What a long story, full of hopes, for this antibiotic which, during the first clinical trials, saved from certain death ... a child became the author of the present paper!

On the impartiality of early British clinical trials.

Did the impartiality of clinical trials play any role in their acceptance as regulatory standards for the safety and efficacy of drugs? According to the standard account of early British trials in the 1930s and 1940s, their impartiality was just rhetorical: the public demanded fair tests and statistical devices such as randomization created an appearance of neutrality. In fact, the design of the experiment was difficult to understand and the British authorities took advantage of it to promote their own particular interests. I claim that this account is based on a poorly defined concept of experimental fairness (derived from T. Porter's ideas). I present an alternative approach in which a test would be impartial if it incorporates warrants of non-manipulability. With this concept, I reconstruct the history of British trials showing that they were indeed fair and this fairness played a role in their acceptance as regulatory yardsticks.

History of antibiotics. From salvarsan to cephalosporins.

Infections have represented for a long time the leading cause of death in humans. During the 19th century, pneumonia, tuberculosis, diarrhea and diphtheria were considered the main causes of death in children and adults. Only in the late 19th century did it become possible to correlate the existence of microscopic pathogens with the development of various diseases. Within a few years the introduction of antiseptic procedures had begun to reduce mortality due to postsurgical infections. Sanitation and hygiene played a significant role in the reduction of the mortality due to several infectious diseases. The introduction of the first compounds with antimicrobial activity succeeded in conquering many diseases. In this review we analyzed, from a historical perspective, the development of antibiotics and the circumstances that led to their discovery. The first compound with antimicrobial activity was introduced in 1911 by Erlich. He focused his research activity on the discovery of a "magic bullet" to treat syphilis. Afterwards, Foley and colleagues brought penicillin to the forefront. Streptomycin represents the first drug discovered for the treatment of tuberculosis, and its development included the first use of clinical trials. Finally, with the development of cephalosporins, the introduction of new antimicrobial compounds with broad activity against gram-positive and also some gram-negative bacteria began.