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Abstract

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.

1. The End of Antibiotics

In August 1992, Science, not usually a journal that specialises in historical research, had some sad news from recent history to deliver to its readers: the end of the antibiotic era had come. Fifty years after that class of medicines had been invented, a wave of drug resistant strains of microbes was about to frustrate decades of progress in infection medicine. Hospitals, where, if we follow the perspective of the paper in Science, patients suffering from infections had become a rare sight in preceding decades, had turned into places where the most dangerous microbes preyed on inmates. ‘When these new drug-resistant strains become endemic in hospitals, you will be safer staying home than going to a hospital’¹ an aghast doctor was quoted as saying. The editorial bore the title The Microbial Wars and left little room for doubt that, for the time being, it was the microbes who had won this war. As Mitchell Cohen wrote in another paper in the same Science issue, if there was one lesson that antimicrobial resistance taught it was the promise that a ‘post-antimicrobial era’ was about to unfold.²Science was, of course, not the only purveyor of such news. During the late 1980s and early 1990s, we find the air humming with stories about the return of old and the arrival of new diseases – of superbugs that had outsmarted the former super drugs.³ The 1990s were, as the editor of the journal Infection, Genetics and Evolution put it, the ‘golden age of genetics and the dark age of infectious diseases’.⁴

While authors of such gloomy prophecies could differ in their wording, they usually pointed to one and the same reason for why the antibiotic age had come to an end: the seemingly unstoppable rise of antibiotic resistance.⁵ The same class of medicines that for Frank M. Burnet in the 1950s had promised ‘the virtual elimination of infectious diseases as a significant factor in social life’⁶ had now been rendered useless by an increase in antibiotic resistance that went unchecked by pharmacological innovation. We might be tempted to discard such statements as yet another case of a typical 1980s doomsday prophecy, yet they seemed to correspond to reality:⁷ around 1990, the pharmaceutical industry experienced an innovation crisis that included anti-infective medicines but was not limited to them.⁸ Awareness of what has become known as the empty pipeline syndrome seems to have originated in those days.⁹ Ever, the empty pipeline syndrome has proven to be a remarkably stable framing. When the director of the Centers for Disease Control and Prevention (CDC) presented a report on antimicrobial resistance to the public on 18 September 2013, he reiterated the warning that ‘we risk entering a post antibiotic era where even a simple infection can be deadly.’¹⁰ With 20 years of hindsight, it seems reasonable to say that the age of the therapeutic revolution that had characterised mid-twentieth-century medicine and pharmacology had come to an end by that time.¹¹

At the same time, the notion of the end of antibiotics that became so popular around 1990 presupposes an explanation of how this situation had come about. Often invoked, this narrative ascribed the end of the therapeutic revolution to an arms race between biology and technology that industry had lost to more ingenious microbes.¹² It is precisely this notion that the paper would like to question and it will do so along two lines: first, it will challenge the idea that the pharmaceutical industry reacted defensively to resistance. Instead, industry embraced the phenomenon, not least since resistance seemed to create exciting new markets for antibiotics. Secondly, the paper will challenge the notion that it was the rise of resistance alone that caused the 1980s innovation crisis. Instead, the paper claims that the situation resulted from consciously pursued strategies of research and marketing. In a wider sense, the innovation crisis will be discussed against the backdrop of the so-called eclipse of the therapeutic revolution, which was making itself felt towards the end of the twentieth century.

Focusing on the development of anti-infective medicines at the German pharmaceutical company Bayer, the paper is structured in four parts. Opening with a few general considerations on what developing and marketing anti-infective drugs in the twentieth century entailed, it explains why studying antibiotic resistance was part of Bayer’s research from the very outset. In a second step, the paper analyses Bayer’s work on anti-tubercular drugs around 1950, where monitoring resistance became a crucial part of drug development. The third part shows how the company’s decision to specialise in antibiotics for the hospital market in the early 1960s resulted from its focus on bacterial resistance. In addition, the paper looks at Bayer’s related investment into what can be called lifestyle infections. After analysing the state of antibiotics development around 1980, the paper finally returns to the initial hypothesis that the end of antibiotics, as was proclaimed around 1990, was not caused by a high tide of resistance alone, but also reflected a low tide of industrial investments that had begun a decade earlier.

2. Understanding Drug Action and Studying Resistance

When it comes to producing anti-infective medicines, Bayer had been one of the pioneers of that field around 1900. However, the approach was not based on searching for therapeutic molecules amongst microscopic fungi, which became the source of modern antibiotics. Instead, Bayer’s research reflected the company’s origins in producing synthetic dyestuffs.¹³ When developing medicines, researchers at Bayer usually relied on synthetic organic chemistry rather than microbiological screening. Such an approach was widespread in German pharmaceutical industry where important companies had a legacy of being producers of synthetic dyestuffs.¹⁴ In 1910, Hoechst, a company with a comparable profile and later Bayer’s partner in IG Farben during the inter-war years, pioneered modern anti-infective chemotherapy with the development of a treatment for syphilis, Salvarsan.¹⁵ This medicine had been developed in cooperation with the immunologist Paul Ehrlich and it was through Ehrlich’s work on experimental chemotherapy that studying antibiotic resistance became part of drug development in the company’s research department. As early as 1907, Ehrlich observed the occurrence of resistance while testing arsenicals in relation to parasitic infections and described it as a stable, inheritable and specific trait of certain microbes, which could, for instance, be bred into strains. The phenomenon seemed to be of little clinical relevance, since it was not observed when the drug in question, atoxyl, was applied on a large scale in Africa.¹⁶ Ehrlich assumed that resistance could be employed as a model of parasite–drug interaction. After all, it provided some – alas, negative – proof for the existence of pathways into parasite cells, so-called chemo receptors.¹⁷ When, in 1910, one of Ehrlich’s pupils, Wilhelm Röhl, became head of Bayer’s pathological laboratory, he would employ induced resistance as an ex-negativo model of drug action on the cellular level.¹⁸ Probably reflecting Bayer’s strong commitment to antiparasitics, the drugs that came out of Röhl’s laboratory in the following decades were effective against tropical parasitic infections such as sleeping sickness or malaria.¹⁹ The company’s pre-World War Two career as a producer of anti-infectives peaked in the 1930s when, while technically being part of the conglomerate IG Farben, Bayer launched the first sulpha drug, Prontosil.²⁰ This medicine was the hallmark of Bayer’s inter-war strategy regarding anti-infective drug development that was based on the chemical synthesis of effective molecules.²¹ At the brink of the Second World War, Bayer was indeed a major pharmaceutical company, holding a seventeen per cent share of the world market in 1938.²² Bayer was also a pioneer in so-called ethical drug marketing that was based on addressing physicians rather than their patients and providing information in the form of scientifically grounded claims rather than blunt advertisement.²³ When it comes to anti-infectives, the company’s portfolio boasted medicines addressing such conditions as malaria, sleeping sickness, pneumonia or sepsis. Taken in their entirety, such medicines also provide some insight into how the market for anti-infective medicines was framed in those days: commercial attention focused on infectious diseases with a high prevalence and high death rate; in other words on those conditions that had been defined as common infectious diseases by late nineteenth century medical bacteriology.²⁴ Paul Ehrlich’s grand design for anti-infective chemotherapy had aimed to target such conditions²⁵ and Bayer’s targeting of the anti-infectives market was similar.²⁶ Tackling infectious disease was essentially framed as a conquest of common infectious disease – of nature itself, in fact. In the 1930s, this conquest seemed well under way.²⁷

3. In the Shadow of Streptomycin

Now part of the conglomerate IG Farben, the Second World War created a host of challenges for Bayer and diminished the company’s standing as a major producer of anti-infective medicines. As we all know, the Second World War saw the arrival of mass antibiotic therapy with sulphas and fungal antibiotics and the resulting arrival of resistant pathogens as a clinical phenomenon.²⁸ The war also brought about changes to the German pharmaceutical industry that are of specific relevance to our story: most importantly, when it came to new developments, the boat of fungal antibiotics had been missed.²⁹ The German pharmaceutical industry was practically not involved in the development of first-generation antibiotics such as penicillin or streptomycin. At the same time, American and British antibiotic producers now entered a greatly expanded a market that had previously been dominated by German companies.³⁰ The challenges were substantial. In Bayer’s case, this meant that a formerly innovative, major producer of medicines now had to rebuild a portfolio that, for the time being, was heavily reliant on licensed molecules. By the mid-1950s, Bayer’s world market share had dropped like a stone. Interestingly, Bayer’s production itself had not collapsed; by 1951, the company’s pharmaceutical turnover had already regained the level it had had before the war. Yet, the world market had grown eightfold in that same period and Bayer had not participated in that growth. In 1938, turnover on the international market had been three times higher than that on the domestic market. In 1955, this proportion was reversed. The company was now a regional producer.³¹

How Bayer tried to tackle such a situation can be shown by the example of antitubercular drugs. Prior to the war, the head of development, inventor of sulphas and Nobel Prize laureate Gerhard Domagk,³² had even advised to stay out of this field. Domagk’s argument had been that tuberculosis represented a diminishing market because of its declining prevalence. What historians and epidemiologists have came to call the epidemiologic transition later on was beginning to make itself felt.³³ After decades of more or less steady decline of tuberculosis’ prevalence, Domagk noted that there was ‘no vital necessity’ for a medicine on the eve of the Second World War.³⁴ During the war, however, that decision seems to have been reconsidered and Bayer’s research on potential tuberculosis medications in preparation for the post-war economy actually started before the war ended.³⁵ In 1943, when a molecule with good antitubercular properties was under investigation, work was suspended and a patent was registered, but knowledge was shelved before it had reached the stage of clinical development. This decision presumably reflected experiences from the aftermath of the First World War, when patents for marketed drugs had been violated but allied control had not penetrated the company’s developmental pipeline any deeper.³⁶ When the war ended in 1945, Bayer’s tentative wartime tuberculosis research suddenly seemed justified, when tuberculosis dramatically returned to the country: ‘Suddenly, the creation of an effective therapy of tuberculosis for an impoverished and starving population became a pressing problem.’³⁷

However, the post-war world market was no longer a market in which Bayer held a dominant position. In part, this was due to political reasons, since, under occupying rule, access to foreign markets remained limited for decades to come.³⁸ What was decisive, however, was that Bayer lacked innovative products and thus became a producer reliant on in-licensed medicines. As already mentioned, the success of fungal antibiotics had shifted power relations and previously smaller Anglo-American companies now outranked their German counterparts on the worldwide drug market. One consequence of this development was that German companies found themselves excluded from lucrative markets. When Bayer purchased a licence for the production of first-generation antibiotics from an American company, it was forced to restrain from selling these antibiotics on the large American market.³⁹ While abstaining from cooperation in research and development in which it would have been a junior partner, like Spanish or Italian producers did,⁴⁰ the international profile that the company had had before the war was beginning to feel like a dim memory. In terms of anti-tubercular medicines, the arrival of the potent antituberculosis antibiotic, streptomycin, in 1947 initially meant that Bayer’s 1943 substance could have been shelved for good.

The company, however, refused to be relegated to the status of a regional producer and its first attempt to re-enter the market of antitubercular medicines was an attempt to challenge streptomycin head on. Development of the 1943 molecule, a thiosemicarbazone, was reinstated in 1946 and the medicine was marketed under the brand name Conteben from 1949.⁴¹ However, Conteben did not fare well in direct comparison with streptomycin: it was less effective, more toxic and could thus not be applied in high doses.⁴² Being classified as a third class drug by the American Veterans Organization did not help either, and Bayer seems to have silently withdrawn it from the market in the 1950s.⁴³

Despite streptomycin’s therapeutic efficacy, a chink in its armour seemed to open a path for marketing other medicines: when applied alone, streptomycin produced resistant bacteria at a high rate.⁴⁴ This unwelcome development could, however, be checked by combining it with another drug. The possibility of this approach was shown in 1948 when streptomycin and para aminosalicylic acid, known as PAS, were combined. The contemporary scientific explanation for the phenomenon was that the different drugs were effective against each other’s resistant strains and thus checked the process of selection of resistant strains that mono-therapy brought about in a patient.⁴⁵ Research on drug combination therapy was occurring in a situation where antimicrobial resistance was about to become a more widespread phenomenon. What had started with resistant gonococci during the war was, as a review paper noted, now also the case for tuberculosis:

As a result of too much dissemination bacteria are bred that are resistant to individual medicines. We have experienced this in gonococci: 10 to 15 years ago gonococci were much more sensitive to sulphonamides than today, where resistant strains have been bred. It is a generally known that under the application of streptomycin over 2-6 month some bacteria will remain, which are no longer susceptible to streptomycin.⁴⁶

Conteben, however, due to its relative toxicity, could not be administered in higher doses and over prolonged periods. Thus a combination therapy with streptomycin, modelled on the example of the latter’s combination with PAS, was not an option for Bayer for the time being.⁴⁷ Still, with streptomycin resistance on the increase, combination therapy appeared to open the door for other medicines. In order to market another one of its molecules, isonicotinylhydrazine, better known as isoniazid, Bayer decided that they should first learn more about resistance produced by streptomycin. Developing Bayer’s brand of isoniazid, Neoteben, thus involved a large clinical development programme, which focused on the diagnosis and control of antibacterial resistance.⁴⁸

A look at the actual process of Bayer’s work on drug development is illuminating. Diagnosing resistance as a cause of failing therapies was not a simple undertaking in those days. Instead of simply identifying a species by cultivation, one had to determine specific strains of resistant microbes. It required the application of serological or phage testing that few hospitals, let alone practitioners, were able to do.⁴⁹ Exploiting this situation, Bayer spread the word that they would do such testing in their laboratories. From the files in Bayer’s archives, it becomes clear that within a short time this strategy resulted in a rather impressive library of resistant tuberculosis. That library was then used to design a therapeutic protocol on the combined application of streptomycin, isoniazid and PAS.

The illustration (figure 1) shows a patient file from the clinical development programme of what became known as combination therapy. From the date, it is obvious that the programme was continued well beyond the marketing of Neoteben and Pasalon, Bayer’s own brand of PAS, in 1951 and 1953 respectively. It was indeed difficult to say where research ended and marketing began. Resistance assays had been crucial in the entire process since they simultaneously served to establish and advertise the proposed effect. Resistance to streptomycin had created an opening for the marketing of a medicine for which there would have been no need otherwise. As mentioned, Bayer had, before the war, been a pioneer in ethical drug marketing. Basing advertisements on the statements of a trustworthy professional remained a common approach in post-war Germany.⁵¹ Consistently, Bayer’s clinical development programme was accompanied by affirmative publications. As Ludwig Heilmeyer, Bayer’s most important collaborator in clinical development, noted, ‘Experiments undertaken with the aim of producing resistance, have shown that INH produces resistance at much slower rates.’⁵² While isoniazid indeed proved to be a medicine of high efficacy and could be combined with streptomycin, Ludwig Heilmeyer’s statement was still affirmative in character. In fact, that medicine became notorious for the high rate of resistance it produced and was thus best used in combination therapy.⁵³

A tuberculosis culture sent from a hospital in February 1954 is checked for susceptibility against available medicines.

Gerhard Domagk was enthusiastic about the potential that resistance research and the marketing of combination therapies harboured. In 1958, he envisioned a bright future in which resistant tuberculosis was controlled for good – thanks to Bayer: ‘Preparations, which will render the issue of resistance, which is so overrated today, irrelevant, could help to secure a unique position of pre-eminence in the field of antitubercular drugs to Bayer.’⁵⁴ In his annual report for 1958, Domagk also insisted that tuberculosis was an important market segment – with 260 000 cases of pulmonary tuberculosis in West Germany alone, it must not be ignored.⁵⁵ Managing tuberculosis in patients was all about preventing resistance from arising and in the 1950s, Domagk clearly aimed to command a portfolio of medicines that addressed this task. By combining their own developments like Neoteben with other drugs, Bayer launched several preparations that essentially packaged combination therapy in one pill. Significantly, one of these, Orthomycin, a combination of isoniazid and a streptomycin derivative, launched in 1953, was advertised (see figure 2) as ‘[] delaying the onset of chemo-resistance to single components and also [exerting] effects on germs resistant to Streptomycin and Neoteben’.⁵⁶

Advertisement for Orthomycin, mid-1950s, BAL, 166/8.

Combining two of Bayer’s own molecules, Nicoteben, a combination of Neoteben and the revitalised Conteben, was launched in 1956 and followed the same rationale. In 1962, Domagk’s successor as head of the pathological laboratory, Albert Michael Walter, maintained that Nicoteben had a better capability of controlling resistance than the common combination of streptomycin and PAS (for none of which Bayer held patents).⁵⁷ While working on developing yet another antitubercular medicine in 1960, the strategy to be followed at Bayer’s R&D laboratories in Elberfeld was almost the same as in the early 1950s. Only this time, isoniazid, which Bayer had marketed as the answer to streptomycin resistance earlier on, became the target of that strategy: ‘All the efforts at our laboratories in Elberfeld in creating a new tuberculostatic are focused on substances with efficacy against INH-resistant strains.’⁵⁸

4. Reinventing Infectious Disease

Rather than illustrating Bayer’s comeback as a producer of anti-infectives, Domagk’s statements, however, indicate the problems that the company was facing. To start with, earnings from tuberculosis combination therapy were not impressive.⁵⁹ The reasons for this lay less in the protocol itself than in the chosen target for drug development. Following a short spike of new infections in the immediate post-war years, tuberculosis quickly returned to the path of decline that had characterised its pre-war history. To give an example, new infections for the large German state of North-Rhine Westphalia rose from 14.5 per 10 000 inhabitants in 1938 to 41.7 in 1945, sliding to 32.9 in 1949 and dropping to 9.3 per 10 000 in 1965.⁶⁰

Furthermore, the style of development practised under Domagk seemed outdated in two respects: firstly, it focused on major common infectious diseases, whose impact was diminishing. Secondly, it consciously avoided microbiological approaches and held on to synthetic chemistry that had paved the way to the sulpha drugs. Something that could not be expressed in a structural chemical formula had little chance of getting past the so-called department for chemical analysis that had a gatekeeper function in Bayer’s research pipeline. In a consistent manner, Domagk’s institute for pathology – in effect, Bayer’s drug development department – did not employ a single microbiologist in the 1950s. Even in relation to the sulphas, Domagk’s approach of prioritising potent medicines in favour of those which offered ease of use was out of date. While proposing the use of sulphas in many fields, Domagk failed to realise the attractions that so-called long-lasting preparations offered.

Curiously, Domagk seemed to be aware of the market opportunities created by resistant microbes. In his correspondence with a lung specialist in 1951, he stressed that resistant tuberculosis could become as prevalent as resistant gonococcus during the war (when sulphas had been mass-applied against them). Domagk’s views also echoed calls for so-called rational application of antibiotics, which were becoming prevalent in those years:⁶¹

Regarding the application of sulphonamides, of penicillin and other antibiotics, a frequent misuse has crept in to apply these medicines quite indiscriminately and in high doses even in the case of light infections. This has to be avoided regarding tuberculosis at all costs. If we let it happen, like with gonorrhoea, these resistant strains are propagated in the future, the result will be an endless race between chemotherapy and new infections. Nobody knows what the outcome will be.⁶²

As early as 1953, he even identified resistant bacteria as a possible future market. Commenting on the increasing presence of resistant Staphylococcus in hospitals, he saw a bright future for Bayer’s chemicals: ‘Until now, the medicine of choice in staphylococcal infections was penicillin. The increasing presence of resistant strains of Staphylococcus (in some hospitals up to 50 and 60%) creates yet another opening for chemotherapy.’⁶³ Yet, Domagk, it seems, also stubbornly clung to his greatest lifetime achievement, the sulphas, thereby perpetuating Bayer’s isolation in terms of its chemical research focus. When approached repeatedly by the company’s director of pharmaceutical development, Bunge, to come up with some new medicine that could tackle resistant Staphylococcus, Domagk insisted that this medicine had been invented long ago – and referred Bunge to one of Domagk’s sulphonamides, Debenal.⁶⁴ However, while future sales of sulphonamides such as Durenat (launched in 1960), did indeed profit from the declining applicability of first-generation antibiotics,⁶⁵ there was little hope for the long-term success of a purely chemical-focused development strategy in the late 1950s. Even in this field, where Bayer was still strong, sales were sliding. This was, in part, due to a steadily declining popularity of sulphas as such. However, as the sales department dryly summarised in 1958, Bayer had done little to amend the situation: ‘The group of sulphonamides is in a continuous decline; it fell by 15% in relation to the previous years. We have not participated in the modern development of sulphonamides.’⁶⁶

It was only in 1960 that a sweeping rearrangement of research and development came under way and it was bound up with some important changes in the history of antibiotic resistance that we briefly need to consider. Previously having being considered rare phenomena, antibiotic resistance gained increasing recognition from 1953 onwards, when an epidemic of penicillin resistant Staphylococcus literally swept around the planet. The spread of so-called Staph 80/81, named after the phages employed for its identification, brought the epidemic character of antibiotic resistance to researchers’ attention and greatly boosted the field of clinical microbiology.⁶⁷ At the same time, the obviously widespread presence of microbes no longer responding to penicillin initiated the development of penicillinase-resistant, semi-synthetic antibiotics that would live up to the challenge.⁶⁸ Simultaneously, and to the dismay of therapeutic rationalists in internal medicine, combination antibiotics and so-called broad-spectrum antibiotics were becoming highly popular.⁶⁹

Shortly after Domagk’s mildly enforced retirement in 1960, Bayer seized the occasion to redefine its antibiotic development strategy in relation to such challenges. Domagk had been firmly rooted in a non-clinical research tradition – he held a chair in pathology. By contrast, Albert Michael Walter, Domagk’s successor, had a background in internal medicine. He had been trained at one of Bayer’s most important collaborating hospitals, the university clinic in Freiburg, where he had headed the clinical microbiology laboratory. Walter’s thesis, written for his Habilitation – the German post-PhD exam that qualifies for a university chair – had dealt with the question of how to delay the onset of antimicrobial resistance by applying combination therapy. Being a pupil of Domagk’s most important clinical collaborator in tuberculosis, Ludwig Heilmeyer, who was director of Freiburg University clinic of internal medicine, Walter had been investigating how to transpose what had become established for tuberculosis to other infections, notably, those caused by Staphylococcus aureus.⁷⁰ With his former superior Heilmeyer, Walter had co-authored a popular textbook on antibiotic therapy.⁷¹ Before starting in his new position, Walter was sent on a training tour of US laboratories. According to Domagk, Walter was being hired to ride his hobby horse tuberculosis – that is to ‘familiarize himself with experimental work on tuberculosis with the aim of taking over this field one day’,⁷² and to take over Bayer’s work on sulphonamides. However, once in office, Walter showed little interest in tuberculosis and instead expanded Bayer’s portfolio in the direction of semi-synthetic antibiotics effective for a multiplicity of conditions.

There is evidence that the style of research in what used to be Domagk’s laboratory changed substantially around his retirement. Focusing foremost on what can be called the structural change of infections, Walter directed drug development to where new and transformed pathologies were to be found: ie. to hospital medicine. This resulted in an intensification of the style of clinical development that Domagk had practised when isoniazid was developed. Probably also reflecting the now widespread laboratory capacities in many hospitals, Bayer’s approach came to rely less on broadcasting their laboratory services in a rather random fashion, as had been the case in the early 1950s, but on collaborating closely with a limited number of hospitals.⁷³ These hospitals turned into more than just providers of probes but functioned as collaborators. As Walter insisted, what mattered was to involve clinical expertise in pre- and post-marketing development of medicines. Competent collaborators would help with the development of those medicines and in turn their standing in the field would help to market those drugs.⁷⁴ During the early 1960s, Bayer also tried to modify its purely chemical research approach. From 1961, the idea was formed to employ a microbiologist in drug development rather than relying exclusively on chemists, as the company had done so far. As a result, Karl Metzger, a specialist in microbiology, was hired in 1963. Bayer’s turn to microbiology would later become the basis of Metzger’s mycological work.⁷⁵ In their entirety, all of these developments meant that pharmaceutical development in the early 1960s looked different from what it had been before. What had been an approach to market medicines for classical common infectious diseases like tuberculosis was about to be changed into a pipeline capable of identifying new targets of intervention, for example in relation to resistant Staphylococcus. At the same time Bayer, like other producers of medicines, changed its evaluation of clinicians and of their expertise in the research and development process. Slowly moving from advertising to marketing, clinicians came to be viewed as more than mere targets for information and instead came to be appreciated as providers of information on which drug researchers relied.⁷⁶ As analysed for the example of research of cancer drugs, the later twentieth century saw the evolution of a situation in which basic science would not simply be informed by clinical medicine, but, instead, both spheres came to the entangled.⁷⁷

The first visible result of this type of development and Bayer’s first success with antibiotics was Binotal, Bayer’s brand of the broad-spectrum antibiotic ampicillin. The semi-synthetic molecule as such was not Bayer’s; it had been discovered by Beecham in the UK. Yet Bayer, capitalising on its traditional strength in chemical synthesis, found a more cost efficient way of mass producing the molecule and reached an agreement to divide markets with Beecham.⁷⁸ The move towards semi-synthetic penicillins, so called 6-APA penicillins, was common amongst producers of antibiotics. It has been attributed to a situation where profits from first-generation antibiotics had been sliding substantially. One reason for this was that neither penicillin nor streptomycin were protected by patents and that the technology needed for their production had been actively disseminated by the WHO.⁷⁹ As a consequence, the occurrence of resistance against penicillin and streptomycin was not entirely bad news for the pharmaceutical companies: resistance made less profitable antibiotics less useful and created a market for new generation antibiotics. Around 1960, penicillinase-resistant antibiotics seemed able to revive the antibiotic miracle.⁸⁰ Presumably, like many other producers, Bayer seized the opportunity of launching medicines that would answer the problems created by the excessive application of first-generation antibiotics. While exploring the capabilities of ampicillin, Walter employed and developed Domagk’s clinical development network and protocol for a new purpose.

During a press conference held at a medical congress in the summer of 1962, Walter presented three new semi-synthetic penicillins.⁸¹ The presentation seems to have highlighted an ongoing revival of the antibiotic miracle that was based on being able to tackle antibiotic resistance. Since the introduction of the original penicillin, nature had ‘so-to-speak gone to counter attack’. Resistant bacteria capable of inactivating antibiotics with the enzyme penicillinase had created an ‘apparently hopeless situation’ – out of which semi-synthetic penicillins offered a way out. Such medicines offered several advantages, two of which are of particular importance to our story:

3. One of these new penicillins, namely Baycillin [Bayer’s brand of propicillin], has an enormous spectrum of activity that elsewhere is only found in so-called broad-spectrum antibiotics.

4. Another semisynthetic penicillin, Stapenor [Bayer’s brand of oxacillin] furthermore has the advantage that penicillinase, which is the defensive ferments of the bacteria, can no longer destroy it.

Even germs which have proven to be resistant so far fall prey to the deadly action of these substances that have resulted from German-English collaboration.

In fact, the article points to a form of collaboration that allowed Bayer to increase its international standing. While none of the three antibiotics were Bayer’s own molecules and the drugs’ profitability thus lagged behind Bayers’s pre-war sulphas,⁸² the company’s strength in chemical synthesis played out in the mass production of semi-synthetic penicillins. While still lacking a substantial invention, this was, nonetheless, a step forward: Beecham and Bayer divided markets between them and, in addition to selling its own brand of the ampicillin, Bayer became a company active in refining crude semi-synthetic penicillins for others.⁸³ As a broad-spectrum antibiotic, ampicillin also indicates a shift in Bayer’s development strategy away from medicines that were magic bullets directed against specific pathologies towards a medicine, whose quality lay in the opposite, namely, in delivering a shotgun reply to a host of infections. When discussing the market introduction of Propicillin in late 1961, Walter proposed to base the advertising of this medicine on its efficacy against a host of infections and specifically on its efficacy against resistant Staphylococcus:

Arguments for advertising

The following arguments for sales are to be accepted:

• Swift absorption and higher serum concentration, for that reason high titre and superior effect in streptococcal, pneumococcal and sensitive staphylococcal infections.

• (2)

  Relative resistance to staphylococcal penicillinase. For that reason effective in moderately resistant (or partially resistant) resistant Staphylococci. Increased safety in all – sensitive or resistant – staphylococcal infections. It should be the oral penicillin of choice in all Streptococcus, Pneumococcus and Staphylococcus infections.⁸⁴

A related marketing strategy was pursued with the sulpha drug Durenat, a joint development with Schering that became available from 1960. In his market analysis for this year, Walter came to the conclusion that Durenat had clearly profited from the diminishing market share of first-generation antibiotics and had become Germany’s best selling anti-infective chemotherapy, claiming a thirty per cent share of the market – even though that needed to be shared with the partner Schering. When it came to advertising, Walter said ‘it was time to emphasize the scientific arguments in favour of Durenat in a fashion comparable to the way it was practised with Baycillin.’⁸⁵

We need not go into more detail, but we should be aware of the consequences. Bayer had traditionally been strong in the hospital market and it tried to reaffirm its position in this market segment by employing a new strategy. It was based on closely integrating laboratory and clinical research in the fashion described above for the tuberculostatics. This entailed both broad-spectrum preparations and medicines that were specifically designed to tackle resistant bacteria. When it came to the latter, Bayer still had to rely on buying licenses in the 1960s but was increasingly able to deliver some in-house development in the 1970s.⁸⁶

If we step back for a moment and reflect on the type of pathologies that were targeted, we become aware that a fundamental change had occurred. It can be understood against the backdrop of a process in which, as already mentioned, pharmaceutical companies were slowly moving from advertising to marketing. This gave the researchers involved a heightened awareness of changes in their markets. Domagk, like presumably many other researchers of his generation, had aimed at a fairly static panorama of preferably common and serious infectious diseases like tuberculosis or pneumonia. Such orientation was based on the dominant philosophy of early twentieth-century public health expertise. By contrast, in the 1960s, Walter had realised that, in modern infection medicine, both pathologies and drugs were evolving quickly.⁸⁷ Disease was no longer considered a static entity. Bayer’s research pipeline was now guided by the search for transformed or new pathologies, such as those created by resistant staphylococcus. As a memorandum noted in the mid-1960s,

when it comes to developing new antibiotics the question of efficacy should not only be discussed in relation to [antibiotics’] good effect on sensitive germs. [Development] needs to focus on novel traits that would increase therapeutic safety which goes to say [antibiotics’] effectiveness in penicillin resistant staphylococci.⁸⁸

It is the new emphasis on antibiotic resistance – for which, ironically, second-generation antibiotics like methicillin seemed the ultimate answer – that is most striking here at first sight. However, the focus on broad-spectrum antibiotics, which Bayer shared with many other companies, also deserves closer inspection. We should be aware that the popularity of such medicines rose at a time when infection medicine was undergoing important changes. Challenges lay, not least, in the rising tide of hospital infections, often caused by so-called non-classical microbes.⁸⁹ This reflected changes in the composition of hospital populations: with the mass arrival of the elderly, of those who had undergone cancer chemotherapy, and of patients who received organ transplants in increasing numbers, hospitals increasingly sheltered people with weakened immune systems. As a result, these patients were vulnerable to microbial infections, such as Pseudomonas or Klebsiella, which would not cause clinical symptoms in healthy people. While, biologically speaking, such pathologies had little in common with those caused by resistant microbes, they were connected nonetheless: both were tied to the hospital environment outside of which they would not normally be found. Both were perceived as being new, and both would profit from appropriate antibiotic therapy. Seen from the perspective of the producers of medicines – that is to say as a market segment – these types of infection differed little. At Bayer, microbes of both sorts were even referred to by the same term. The term ‘problematic germs’ (Problemkeime), however, leaves entirely open the question of whether a germ is problematic as a result of its resistance or as a result of the impaired immunity of the host. A memorandum from 1981 identifies immune-compromised patients as a highly important market segment:

In human medicine, patients with impaired bodily immune response form a relevant part of the patient population. The causes for this are manifold and they reside on the one hand in severe basic condition (eg. tumors, accidents, cardiac conditions) on the other hand in therapy (cytostatics-immunosuppressants, radiation, antibiotics therapy). The approach of the team therefore resides in exploring new paths of anti-infective therapy for patients with impaired immunities.⁹⁰

As a consequence, the development of anti-infective medicines showed signs of change and stagnation at the same time. While being innovative in identifying new targets for intervention beyond classic, life-threatening infections, the notion that the answer to the challenges of hospital medicine lay in new drugs was upheld.⁹¹ What was crucial in understanding resistance and presumably also in new markets, as Walter put it in a memorandum in 1960, was clinical expertise. It required cooperation of microbiologists and clinicians – with the latter taking the lead. In an internal manual on resistance diagnostics, Walter explained whose knowledge counted most when it came to evaluating a test result: ‘Any schematic evaluation of results is to be objected to. It results in discrepancies and quite often in fatal misjudgements. What is decisive for evaluating the determination of resistance is clinical experience and reflection.’⁹² This certainly stood in contrast to Domagk’s approach, who had viewed clinicians as people who were in need of advice rather than providing it. Clinicians for him had been ‘helpless practitioners’⁹³ to be enlightened by laboratory researchers about drugs in general – and presumably also about resistance. Both Domagk and Walter were indebted to a tradition of ethical pharmaceutical marketing. The change from one to the other was about shifting focus when it came to identifying markets. Domagk focused on conditions that were part of the slowly developing landscape of common infectious disease; instead, Walter tried to monitor ongoing change. In 1973, the objectives of the ß-lactam antibiotics team were defined in a manner that was suited to identifying change as it happened: ‘What our investigations of ß lactam antibiotics aim for is to find preparations with better curative effects for conditions caused by so-called problematic germs.’⁹⁴

5. Lifestyle Infections

In the 1960s, apart from intensifying collaboration with clinicians, Bayer also began to soften their exclusively chemical research tradition. In about 1963, as already mentioned, a medical mycology laboratory was installed and a microbiologist, Karl Metzger, was hired.⁹⁵ Not much later, the old pathological institute was split in two with the infections department now being called the Institute for Medical Microbiology (while cancers and chronic conditions became allocated to a department of their own). From the 1970s onwards, Bayer, like other pharmaceutical companies, embarked on microbiological screening programmes – for example, for actinomycetes. However, when it came to envisioning new markets and drugs, focusing on the dynamic change of infections involved more than studying hospital related pathologies. It also facilitated a fresh view on infectious processes at large – providing the insight that earning serious money was by no means dependant on treating serious conditions. Instead, the medicalisation of lifestyle-related conditions would actually create new diseases – and markets.⁹⁶ From the sulphas to penicillin, drug development for infectious diseases had focused on life-threatening conditions. While being highly ethical, it was also a self-limiting marketing strategy.⁹⁷ During the 1950s, the search for therapeutic targets was widened to non-life-threatening conditions.⁹⁸ Bronchitis, to name a well-researched example, was transformed from an irritation that would only be treated in cases of complication into a condition that would profit from early intervention with antibiotics.⁹⁹ What was needed were infectious processes that were widespread but which had been given little attention so far. Chronicity, which had come to be the prime focus of modern drug development,¹⁰⁰ would be an added advantage. It was Bayer’s new mycology laboratory that, in 1967, answered the call for a new kind of drug. Clotrimazole, better known under its brand name Canesten, was a treatment for fungal infections such as athlete’s foot. Such conditions had been around for a long time. Of course, there were all kinds of treatments, but they were usually of poor efficacy. Given the widespread character of the condition, an effective molecule promised enormous income.¹⁰¹ Furthermore, the association between the infection’s epidemiology and lifestyle factors, such as wearing sneakers and rubber boots or using indoor swimming pools, meant that repeated or even preventive application promised even better sales. In the words of Bayer’s chronicler Hermann Baum, clotrimazole became a lottery winner, ‘the first substance that offered real therapeutic progress’¹⁰² that had come out of Bayer’s development during the post-war period. An advertisement for it from the early 1970s (see figure 3) presents a medicine that supports a hygienic family life rather than fighting a dangerous infection.

Canesten, supporting a healthy family life. Advertisement from the 1970s. BAL, 166/8.

Canesten was Bayer’s own patent and could be marketed worldwide. Put on the market from 1973 and becoming an over-the-counter medicine later on, it became a real cash cow. It seems to have sidelined any other antifungal medicine.¹⁰³ If we take a look at Bayer’s turnover in pharmaceuticals for the year 1980, Canesten (179 million marks) was only surpassed by Adalat (223), an antihypertension drug, and Aspirin (214). Unlike the antibiotic Binotal (130), for which Bayer had acquired a licence from Beecham, which came rather close to Canesten in terms of turnover, Canesten also was Bayer’s own molecule.¹⁰⁴ Significantly, the two most successful preparations, Canesten and Adalat, targeted chronic conditions – despite the many differences that exist between angina pectoris and athlete’s foot.¹⁰⁵

Unfortunately, little information on the research and marketing strategy of Canesten has survived. However, a situation in 1975, when researchers were contemplating to repeat Canesten’s success by focusing on herpes as a comparable condition, gives us a glimpse of how this might have been approached (see figure 4).

Brainstorming the market potential of a medicine for herpes, BAL, 327/87.

Note that the exploration of market potential is really what the brainstorming was about. The first three of the four bullet points concern analysis of market potential, while the science of the condition is discussed as ‘Background’ and is in fourth position. Presumably, it would have figured prominently in Domagk’s days. Profit could now be viewed independently from the seriousness of the condition in question and even from therapeutic efficacy. Commenting on a competitor’s product (Viru-Merz), the authors stated that it has ‘no effect, but turnover.’

In the 1970s, the development of antibiotic medicines looked very different from what it had been 30 years before. First of all, Bayer now had three large screening programmes for antifungals, ß-lactam antibiotics and actinomycetes – thereby finally employing on large scale a tool in drug development that had moved central to the work of the company’s American competitors since the 1950s.¹⁰⁷ What the company was trying to target in the late 1970s was nicely put by Karl Metzger during a meeting of the research committee in October 1977. Starting with a critical evaluation of what Bayer could offer, Metzger mentioned that Bayer’s antibiotics were either broad in spectrum like Mezlocillin but sensitive to ß-lactamase or, like Oxacillin, narrow-spectrum but resistant to ß-lactamase. The ideal antibiotic would thus be a broad-spectrum preparation with two added capacities: ‘What we are searching for is an antibiotic that can be applied without risk, to which as many as possible different bacteria are sensitive but should be resistant to ß-lactamase so that all strains of the different species will be checked.’¹⁰⁸

Simultaneously, other work had been discontinued and this is most obvious in the case of tuberculosis, which also dropped off the radar of other drug companies and public health organisations in the period.¹⁰⁹ In 1974, Bayer’s high-ranking research committee decided that ‘our envisioned extension in relation to bacteriostatic medicines should be partly balanced by cutting back on the tuberculosis sector.’¹¹⁰ Two years later, that same committee sealed the coffin on the development of medicines for that condition stating ‘that there is no therapeutic need for a new tuberculosis medicine in industrialised countries (tb-treatment is merely a management problem)’.¹¹¹ In fact, the crisis of Bayer’s tuberculostatics was indicative of a structural problem that Bayer’s traditional stronghold in medicines for common infections and tropical diseases entailed: having been inventions in their day, these medications now corresponded to an epidemiological landscape of the past – or of low income countries that could not afford them. In 1977, the research committee was informed about what the company’s branch management for pharmaceuticals thought were ‘Problemgebiete der Forschung’ [problematic areas of research]:

(a) the area of malaria/trypanosomes is abandoned

(b) the areas bilharziosis, fasciolosis, filariasis are integrated together with the nematodes into the new area nematodes

(c) Research on tuberculosis is reduced to an in-vitro screening.¹¹²

6. Infection and Innovation

Bayer’s strategy in relation to developing anti-infective medicines had been thoroughly modernised from about 1960 onwards. In marketing, chronic non-life-threatening conditions were targeted and new antibiotics for the hospital market were developed; in research, the exclusively chemical tradition was softened and microbiological screening programmes started. This happened against the backdrop of a successful international cooperation in the development of semi-synthetic antibiotics. It looked as though the company was finally able to escape from the strategic isolation into which its reliance on the sulphas had led it.¹¹³ However, costly as they were, screening programmes did not really deliver the blockbuster medicines that had been hoped for. Despite a few new antibiotics, clotrimazole was not a prelude to further successful developments. This meant that Bayer only partially escaped the fate of being a rather small producer, who was therefore heavily reliant on in-licensing medicines in order to appear as something it no longer was but still aspired to be: a global player. In 1968 for instance, Bayer would even take a licence for a medicine it believed had no market potential. The reason was that the company wanted to appear as a comprehensive producer to its clinical collaborators.

All in all what I have heard about Carbenicillin does not speak in favour of it being a smashing success and generating lots of turnover. To incorporate it into our portfolio has indeed been proposed by you for another reason, namely so that [our department for] Clinical Research would still be able to offer a substance to its clinical collaborators and will not be pushed out of contacts with clinics by other companies.¹¹⁴

The optimism around the screening programmes that had prevailed in the early 1970s gave way to scepticism towards the end of the decade. As far as we know, this was becoming widespread in the pharmaceutical industry in those days: it was dawning on companies that compared to other types of conditions, treating infections was – financially speaking – not rewarding.

Desperation was in the air and in this situation researchers were cautiously trying to think beyond the magic-bullet approach, which they had been following for almost eighty years. So far, their work had built on the assumption that curing infections was all about attacking the responsible pathogen. Held in 1980, a high profile workshop had the revealing title ‘new approaches in infection control’ and it illustrates the atmosphere of perplexity that was prevalent those days (see figure 5).

Result of a brainstorming session in 1980. Produced for the workshop ‘new approaches in infection control’, BAL, 323/150.

It is not so much the somewhat holistic rhetoric about strengthening host immunity as an approach that is telling here – the author, Bartmann, obviously feels uneasy about using the term immunology and places it in quotation marks – but the explicit statement that classical chemotherapy directed against the pathogen no longer held innovative potential. As the author maintained, the objective of therapy was to sustain the host, not, primarily, to kill the pathogen. In fact, researchers at Bayer were by no means alone in making this observation and we have good reason to assume that the frustration that Science reported in 1992 had prevailed in industry at least a decade earlier.¹¹⁶

Turning back to Bayer, an irony of our story lies in the fact that in the early 1980s another blockbuster antibiotic was just around the corner: in 1983 Bayer filed its patent for ciprofloxacin, yet another broad-spectrum antibiotic that was marketed from 1986.¹¹⁷ Cipro was aggressively advertised as a medicine to tackle resistance. The medicine was praised as ‘Intelligent, fast, bactericidal’ and, in an imagined autobiographical statement, a microbe would come to the sad conclusion: ‘I was one of the resistant ones. Then I met with the unexpected.’¹¹⁸ However, since the historian’s insight is traditionally limited by archival laws that prohibit access to material more recent than thirty years, we cannot really comment further on this. Two observations, however, can be made: ciprofloxacin was not a molecule identified in one of the screening programmes; it was a chance discovery in a service laboratory. Also, it seems that this invention had no influence on the long-term strategy of the company, which, in fact, discontinued all research into infectious diseases and antibiotics in 2003.¹¹⁹

When it comes to Bayer’s post-war history, we see two challenges, which the company shared with other producers of anti-infective medicine. Rather than focusing on molecular innovation, most companies’ drug development, following the 1970s, was characterised by declining invention and revamping existing portfolios to keep profits flowing. In Bayer’s case, this tendency was aggravated by being a comparatively small producer of anti-infectives and sitting on a relatively outdated product portfolio. It was this challenge which other German drug producers faced also and it limited their capacity to grow in a period of rapid internationalisation of drug companies.¹²⁰ Having studied Bayer’s pharmaceutical marketing during the 1960s, Heiko Braun has come to the conclusion that the company experienced an existential crisis in the years following World War Two.¹²¹ The look that we have taken at the development of anti-infective developments modifies this picture to some extent: we see a process that was initiated by the investment into semi-synthetic antibiotics around 1960 and by a modification in the research style. Innovation cycles in the pharmaceutical industry are usually long term and thus Bayer’s comeback in the 1960s, in part, resulted from its traditional strength in synthetic organic chemistry that paid off when semi-synthetic antibiotics became fashionable.¹²² However, the revival can not be reduced to that and the reliance on traditional strengths was accompanied by a broadening of technological resources through microbiological screening and, most of all, a research and development focus that embraced the evolution of infectious disease. It entailed focusing on the hospital market and exploring the novel market segment of lifestyle infectious disease. As a result, in the 1970s, we see a company about to escape from the hard haul that had resulted from its previous framing of markets and lack of molecular invention that had resulted from not participating in the development of first-generation antibiotics. All this seemed to culminate in the discovery of another blockbuster antibiotic around 1980. If, however, cipro made a difference, it did so only for Bayer. Internationally, antibiotics development continued to slide all the way to the end of the century.

Let us conclude with a few words on stories beyond the scope of a single company. To the historian, it seems that the therapeutic revolution, which, as far as antibiotics are concerned, began in the 1930s, was quite limited in time and was more or less over a generation later. Investigating the causes of why it was short lived, this paper opened by questioning the simple notion of an empty drug development pipeline in which ingenious resistant bacteria outsmarted an aspiring pharmaceutical industry. In fact, the pharmaceutical industry – if the example of Bayer allows for some generalisation – initially embraced the phenomenon of antibiotic resistance since it seemed to offer exciting new markets. When strategies to profitably exploit this segment came into crisis, scepticism as to whether anti-infective medicines could be profitable in the first place was ensuing. The pipeline, it seems, did not run dry. It looks more like it was abandoned.

Note on archival sources:

All quotes from the archives of Bayer AG (BAL) are translations from German by the author.

Footnotes

^1.Daniel E. Koshland, ‘The Microbial Wars’, Science, 257, (1992), 1021. A scholarly monograph on the history of hospital infections Graham A.J. Ayliffe and Mary P. English, Hospital Infection From Miasmas to MRSA (Cambridge: Cambridge University Press, 2003), 134–70 seems to confirm the lines of development presented by Koshland: it describes a substantial improvement in relation to hospital infections occurring in the early twentieth century which was threatened by consequences of widespread antibiotic use after World War Two.

^2.Cohen Mitchell L., ‘Epidemiology of Drug Resistance: Implications for a Post-Antimicrobial Era’, Science, 257 (1992), 1050–1055. [PubMed] [Google Scholar]

^3.L.A. Reyolds and E.M. Tansey (eds), Superbugs and Superdrugs: A History of MRSA, (London: Wellcome Trust Centre for the History of Medicine at UCL 2008); Robert Bud, Penicillin: Triumph and Tragedy (Oxford: Oxford University Press, 2007); Nicholas B. King, ‘The Scale Politics of Emerging Diseases’, Osiris, 19, (2004), 62–76; David Satcher, ‘Emerging Infections: Getting Ahead of the Curve’, Emerging Infectious Diseases, 1, (1995), 6; Joshua Lederberg, Robert E. Shope and Stanley C. Oaks (eds), Emerging Infections. Microbial Threats to Health in the United States (Washington, DC: National Academic Press, 1992).

^4.Tibayrenc Michel, ‘The Golden Age of Genetics and the Dark Age of Infectious Diseases’, Infection, Genetics and Evolution, 1 (2001), 1–2. [PubMed] [Google Scholar]

^5.William C. Summers, ‘Microbial drug resistance: a historical perspective’, in R.G. Wax et al. (eds), Bacterial Resistance to Antimicrobials (Boca Raton, FL: CRC Press, 2008), 1–9; Frank Ryan, The Forgotten Plague: How the Battle Against Tuberculosis Was Won – and Lost (Boston: Little, Brown, 1993); Claudia Eberhardt-Metzger and Renate Ries, Verkannt und heimtükisch – Die ungebrochene Macht der Seuchen (Basel: Birkhäuser, 1996); H. Schadewaldt (ed.) Die Rückkehr der Seuchen (Köln: vgs, 1994).

^6.Burnet Frank Macfarlane, The Natural History of Infectious Disease (Cambridge: Cambridge University Press, 1953), 1940 ix. [Google Scholar]

^7.Hünemörder Kai F., ‘Kassandra im modernen Gewand. Die umweltapokalyptischen Mahnrufe der frühen 1970er Jahre’, in Uekötter F. and Hohensee J. (eds), Wird Kassandra heiser? Die Geschichte falscher Ökoalarme (Stuttgart: Steiner, 2004), 78–97. [Google Scholar]

^8.Greenwood David, Antimicrobial Drugs. Chronicle of a Twentieth Century Triumph (Oxford: Oxford University Press, 2008) 262–3. [Google Scholar]

^9.Ibid.: 262/3; Humphrey P. Rang, ‘The development of the pharmaceutical industry’, in H.P. Rang (ed.), Drug Discovery and Development: Technology in Transition (London: Churchill Livingstone, 2005), 3–18, here 16/7; Brad Spellberg et al., ‘Trends in Antimicrobial Drug Development: Implications for the Future’, Clinical Infectious Diseases, 38, (2004), 1279–86. Cf. Maryn McKenna’s blog on the empty pipeline: http://www.superbugtheblog.com/2009/11/antibiotics-eu-pipeline-is-empty-too.html See Maryn McKenna, Suberbug: The Fatal Menace of MRSA (New York: Free Press, 2010), ch. 12 on the end of antibiotics.

^10.Author’s transcription from http://www.youtube.com/watch?v=uZt6q2uwM2g Cf. Centers for Disease Control and Prevention (CDC) (ed.) Antibiotic Resistance Threats in the United States, 2013 (CDC, 2013).

^11.Bonah Christianet al., ‘Standard drugs and drug standards. A comparative historical study of pharmaceuticals in the 20th-century’, in Bonah C.et al. (ed.), Harmonizing Drugs. Standards in 20th-Century Pharmaceutical History (Paris: Editions Glyphe, 2009), 17–27. [Google Scholar]

^12.Eberhardt-Metzger and Ries, op. cit. (note 5); Schadewaldt, op. cit. (note 5); Ryan, op. cit. (note 5).

^13.Plumpe Gottfried, Die I.G. Farbenindustrie AG: Wirtschaft, Technik und Politik 1904–45 (Berlin: Dunker & Humblodt, 1990). [Google Scholar]

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^16.Gradmann Christoph, Laboratory Disease: Robert Koch’s Medical Bacteriology (Baltimore, MD: Johns Hopkins University Press, 2009), 213–225. [Google Scholar]

^17.Christoph Gradmann, ‘Magic Bullets and Moving Targets: Antibiotic Resistance and Experimental Chemotherapy 1900–40’, Dynamis, 31, (2011), 305–21. Cf. Ehrlich’s side chain theory: Cay-Rüdiger Prüll, Andreas-Holger Maehle and Robert Francis Halliwell, A Short History of the Drug Receptor Concept (Basingstoke: Palgrave, 2009); John Parascandola, ‘The Theoretical Basis of Paul Ehrlich’s Chemotherapy’, Journal for the History of Medicine and Allied Sciences, 36, (1981), 19–43; Arthur Silverstein, Paul Ehrlich’s Receptor Immunology: The Magnificent Obsession (San Diego, CA: Academic Press, 2003).

^18.Gradmann 2011, op. cit. (note 17).

^19.Horst Bernd Dünschede, Tropenmedizinische Forschung bei Bayer (Düsseldorf: Trilsch, 1971). Bayer Leverkusen Tropenabteilung, Die Chemotherapie der Schlafkrankheit (Leverkusen: Bayer, 1938).

^20.John E. Lesch, The First Miracle Drugs: How the Sulfa Drugs Transformed Medicine (Oxford: Oxford University Press, 2007); Cf. Axel A.H. Dalhoff, ‘Discovery and Development of Anti-infectives at Bayer: A Personal View. Part I: Antiparasitics, Sulfonamides, and Antitubercular drugs’, Sim News, 57, (2007), 135–50, here 135–42.

^21.Wilhelm Bartmann, Zwischen Tradition und Fortschritt. Aus der Geschichte der Pharmabereiche von Bayer, Hoechst und Schering von 1935–75 (Stuttgart: Steiner, 2003), 106–12. Cf. John E. Lesch, ‘Chemistry and biomedicine in an industrial setting: the invention of the sulfa drugs’, in S.H. Mauskopf (ed.), Chemical Sciences in the Modern World (Philadelphia, PA, University of Pennsylvania Press, 1993), 158–215.

^22.Baum Hermann A., Geschichte der Pharma nach dem Zweiten Weltkrieg (Leverkusen: Bayer AG Leverkusen, 1983). [Google Scholar]

^23.Jean-Paul Gaudillière and Ulrike Thoms, ‘Pharmaceutical Firms and the Construction of Drug Markets: from Branding to Scientific Marketing’, History and Technology, 29, (2013), 105–15; Ulrike Thoms, ‘Standardizing Selling. Pharmaceutical marketing, the Pharmaceutical Company and the Marketing Expert (1900–80)’, History and Technology, 29, (2013), 169–87.

^24.Berger Silvia, Bakterien in Krieg und Frieden: eine Geschichte der medizinischen Bakteriologie in Deutschland 1890–933 (Göttingen: Wallstein, 2009), 27–90. [Google Scholar]

^25.Parascandola, op. cit. (note 17); Prüll, Maehle and Halliwell, op. cit. (note 17).

^26.Dalhoff 2007, op. cit. (note 20); Axel A.H. Dalhoff, ‘Discovery and Development of Anti-infectives at Bayer: A Personal View. Part II: ß-lactam antibiotics’, Sim News, 58, (2008), 6–18; Cf. Heiko Braun, ‘Von der Vertriebs- und “Propagandapolitik” zum Pharmamarketing? Eine Marketinggeschichte des deutschen Pharmabereichs der Farbenfrabriken Bayer AG 1957–71’ (Unpublished M.A. thesis: University of Bonn, 2009).

^27.Charles-Edward Emory Winslow, The Conquest of Epidemic Disease: A Chapter in the History of Ideas (Princeton, NJ: Princeton University Press, 1987 (1967)).

^28.Bud, op. cit. (note 3): 116–8; Lesch, op. cit. (note 20); For a contemporary account see John A. Kolmer, Penicillin Therapy. Including Streptomycin, Tyrothricin And Other Antibiotic Therapy 2nd ed. (New York; London: Appleton-Century, 1947 (1945)): 54–56.

^29.Gaudillière Jean-Paul and Gausemeier Bernd, ‘Molding National Research Systems: the Introduction of Penicillin to Germany and France’, Osiris, 20 (2005), 180–202. [PubMed] [Google Scholar]

^30.Bud, op. cit. (note 3): 23–53.

^31.Bartmann, op. cit. (note 21), 301–3. Cf. Patrick Kleedehn, Die Rückkehr auf den Weltmarkt. Die Internationalisierung der Bayer AG Leverkusen nach dem Zweiten Weltkrieg bis zum Jahre 1961 (Stuttgart: Franz Steiner Verlag, 2007), 151–63.

^32.Ekkehard Grundmann, Gerhard Domagk – der erste Sieger über die Infektionskrankheiten (Münster: Lit, 2001).

^33.Francis Barrymore Smith, The Retreat of Tuberculosis 1850–950 (London: Croom Helm, 1987). For a contemporary account see V.C. Barry, The Chemotherapy of Tuberculosis (London: Butterworth, 1964). Cf. George Weisz and Jesse Olszynko-Gryn, ‘The Theory of Epidemiologic Transition: The Origin of a Citation Classic’, Journal for the History of Medicine and Allied Sciences, 65, (2009), 287–326.

^34.Domagk, unpublished memories, quoted in Dietrich Redeker, Zur Entwicklungsgeschichte der Tuberkulostatika und Antituberkulotika (Stuttgart: Deutscher Apotheker Verlag, 1990), 100.

^35.Background: Dalhoff, op. cit. (note 20), 143–4; Redeker, op. cit. (note 34), 84–104.

^36.Wimmer, op. cit. (note 14). According to Redeker, op. cit. (note 34), 90, a patent was registered in 1943.

^37.Domagk, quoted in Redeker, op. cit. (note 34), 100.

^38.Bartmann, op. cit. (note 21), 301–29.

^39.That company was Schenley. It took Bayer almost 30 years before substantial turnover could be achieved in the US market. Ibid., 318–19. Cf. Kleedehn, op. cit. (note 31), 152–3.

^40.Mauro Capocci, ‘ “A Chain is Gonna Come”. Building a Penicillin Production Plant in Post-war Italy’, Dynamis, 31, (2011), 343–62; Maria Jesús Santemases, ‘Screening Antibiotics: Industrial Research by CEPA and Merck in the 1950s’, Dynamis, 31, (2011), 407–27. [PubMed]

^41.Redeker, op. cit. (note 34), 91, Dalhoff, op. cit. (note 20), 144, 146.

^42.Redeker, op. cit. (note 34), 93.

^43.Ibid, 98, 104, Barry, op. cit. (note 33), 49.

^44.Kolmer, op. cit. (note 28): 54–6, H.W. Florey et al.Antibiotics: A Survey of Penicillin, Streptomycin, and other Antimicrobial Substances from Fungi, Actinomycetes, Bacteria, and Plants (Oxford: Oxford University Press, 1949), 1365–400.

^45.On this and the following, see Barry, op. cit. (note 33): 192–202. Cf. Redeker, op. cit. (note 34), 123.

^46.H. Dennig and H. Hangleiter, ‘Der heutige Stand der Chemotherapie bakterieller Erkrankungen und der Infektionskrankheiten’, Deutsche medizinische Wochenschrift, 76, (1951), 647–9; 680–2: here 647. [PubMed]

^47.Redeker, op. cit. (note 34), 104.

^48.Archive of the Bayer AG, Leverkusen (BAL), 316/3.

^49.Christoph Gradmann, ‘Sensitive Matters. The World Health Organisation and Antibiotics Resistance Testing, 1945–75’, Social History of Medicine, 26, (2013), 555–74. Cf. Kathryn Hillier, ‘Babies and Bacteria: Phage Typing, Bacteriologists, and the Birth of Infection Control’, Bulletin of the History of Medicine, 80, (2006), 733–61. [PubMed]

^50.BAL, 316/3.82.

^51.Arthur Daemmrich, Pharmacopolitics: Drug Regulation in the United States and Germany (Chapel Hill, NC: University of North Carolina Press, 2004), 77–8.

^52.Ludwig Heilmeyer, ‘Vorläufiger Bericht über Isonikotinsäurehydrazid (Rimifon, Neoteben) auf Grund experimenteller und klinischer Untersuchungen’, Deutsche medizinische Wochenschrift, 94, (1952), 1303–8. [PubMed]

^53.Barry, op. cit. (note 33), 194–8. Redeker, op. cit. (note 34), 180–97 points to the affirmative character of Domagk’s and his collaborators’ statements.

^54.BAL 103/11.2. Annual report [Jahresbericht] for 1958.

^55.Ibid., 1957.

^56.From Orthomycin advert of 1955, BAL 166/8.

^57.BAL, 363/101, of 5.11.62.

^58.Bunge to Hansen, 2.11.1960, BAL, 367/626.

^59.Bartmann, op. cit. (note 21), 320.

^60.Ulrike Lindner, Gesundheitspolitik in der Nachkriegszeit: Grossbritannien und die Bundesrepublik Deutschland im Vergleich (München R. Oldenbourg 2004), 127–59. Cf. Smith, op. cit. (note 33).

^61.Podolsky Scott H., ‘Antibiotics and the Social History of the Controlled Clinical Trial’, Journal for the History of Medicine and Allied Sciences, 65 (2010), 327–367. [PubMed] [Google Scholar]

^62.Domagk to Kreutzer, 10.3.1951, BAL, 372/016.

^63.Domagk, Annual report [Jahresbericht] 1953, BAL, 103/11.2, p. 23.

^64.Domagk to Bunge, 10.11.1958, BAL, 372/24.

^65.Memorandum on the meeting of the “working group [Arbeitsgruppe] chemotherapeutics: antibiotics, sulphonamides, tubculostatics”, 5.11.1962, BAL, 363/101.

^66.Annual Report 1958 of pharmaceutical sales department [Jahresbericht für 1958 der Pharmazeutischen Verkaufsabteilung], BAL, 103/11.2. Cf. Bartmann, op. cit. (note 21), 321.

^67.Hillier, op. cit. (note 49).

^68.Bud, op. cit. (note 3), 116–39; Greenwood, op. cit. (note 8); E.M. Tansey (ed.) Post Penicillin Antibiotics: from Acceptance to Resistance. A Witness Seminar, held at the Wellcome Institute for the History of Medicine, London, 12 May 1998 (London: Wellcome Trust, 2000).

^69.Podolsky, op. cit. (note 61).

^70.Albert Michael Walter, ‘Experimentelle Grundlagen und klinische Erfahrungen zur Antibiotika-Resistenz der Bakterien und der Resistenzverzögerung durch eine Kombinationstherapie’, Habilitation: University of Freiburg, 1957.

^71.Ludwig Heilmeyer and Albert Michael Walter, Antibiotika-Fibel. Indikation und Anwendung der Chemotherapeutika und Antibiotika (Stuttgart: Thieme, 1954). In later editions, he co-authored the book with his co-researchers at Bayer: Albert Michael Walter et al., Antibiotika-Fibel. Antibiotika und Chemotherapie (Stuttgart: Thieme, 1969).

^72.Domagk, Jahresbericht für 1958, BAL, 103/11.2.

^73.BAL 316/3.82 and 316/3.85 where the delivery of suspected resistant samples is documented. While in the early 1950 we see lots of spontaneous delivery with requests for determination of strains, the laboratory showed little interest in such activity after about 1955 and instead relied on collaboration with established partners.

^74.Minutes of a meeting 5.11.62 of the working group [Arbeitsgruppe] on antibiotics, sulphonamides and tuberculostatics, BAL, 372/29, 4: ‘For preparations that are traded already it is impossible to employ excellent testers’.

^75.BAL, 363/101; Baum, op. cit. (note 22): 253. Plans to employ a mycologist go back to 1961. Once hired, Metzger was sent on the customary training tour (Marget and Liebermeister, which were collaborating clinicians; Chabbert, a researcher at the Institut Pasteur). A short biography of Metzger is to be found in Axel A.H. Dalhoff, ‘Discovery and Development of Anti-infectives at Bayer: A Personal View. Part III. Fluorquinolones’, Sim News, 58, (2008), 89–105.

^76.Jean-Paul Gaudillière and Ulrike Thoms, ‘Introduction’, in J.-P. Gaudillière and U Thoms (eds), Research for Sales: The Development of Scientific Marketing in the 20th Century Pharmaceutical Industry (London: Pickering and Chatto, forthcoming), 1–17. I thank the authors for sharing their unpublished work with me.

^77.Ilana Löwy, Between Bench and Bedside: Science, Healing and Interleukin-2 in a Cancer Ward (Cambridge, MA; London: Harvard University Press, 1996); Alberto Cambrosio and Peter Keating, Biomedical Platforms. Realigning the Normal and the Pathological in Late-Twentieth-Century Medicine (Cambridge, MA: MIT Press, 2003), 50.

^78.Baum, op. cit. (note 22), 131–3; H.G. Lazell, From Pills to Penicillin: The Beecham Story: A Personal Account (London: Heinemann, 1975), 177–9.

^79.Bud, op. cit. (note 3), 75–96; Greenwood, op. cit. (note 8), 122–6.

^80.Bud, op. cit. (note 3), 116–39.

^81.Kassler Post No. 230/Vol.80, 1.9.1962, ‘Sieg über die Resistenz der Bakterien‘, in BAL, 363/101. The substances were Binotal (ampicillin), Stapenor (oxacillin) and Baycillin (propicillin). Cf. Dalhoff, op. cit. (note 26): 13. Cf. BAL, 363/101, 1.6.1962, Walter’s memorandum on the coordinated introduction of the three medicines.

^82.Bartmann, op. cit. (note 21), 309.

^83.Dalhoff, op. cit. (note 26), 10.

^84.Walter’s memorandum on the introduction of Bayer 5393 [propicillin]. 12.12.1961, BAL, 363/101. The memorandum is reporting a discussion in Walter’s team on the marketing of the antibiotic and was addressed to employees in pharmaceutical marketing and development.

^85.BAL, 363/101. Memorandum on the meeting of the ‘working group [Arbeitsgruppe] chemotherapeutics: antibiotics, sulphonamides, tubculostatics’, 5.11.1962. It reports on very good sales of Baycillin, while Stapenor is doing less well. Binotal only became marketed from 1.11.1961.

^86.Dalhoff, op. cit. (note 26) for an overview. The brand names with years of marketing and effective substances are: Stapenor (1962) Oxacillin; Resitopen (1972) Carbenicillin Oxacillin; Microcillin (1973) Carbenicillin; Securopen (1977) Azlocillin; Baypen (1977) Mezlocillin. Azlocillin and Mezlocillin were own developments.

^87.Cf. letter by Walter to Bunge, 20.7.1960 (BAL, 372/27) where he states, on the example of the new antibiotic chloramphenicol, his opinion that any new antibiotic would be devalued by resistant bacteria over time.

^88.Undated memorandum, Bayer archives, BAL, 372/28. Judging from its positioning in the archive it should be from the mid-1960s.

^89.Flurin Condrau and Robert Kirk, ‘Negotiating Hospital Infections: The Debate between Ecological Balance and Eradication Strategies in British Hospitals, 1947–69’, Dynamis, 31, (2011), 385–405; Ayliffe and English, op. cit. (note 1). [PMC free article] [PubMed]

^90.State of the art report [Statusbericht] for 1980, working group immune defence, BAL, 323/104, of 28.1.1981.

^91.Bud, op. cit. (note 3), 116–39.

^92.Memorandum on resistance determination, Walter, 30.9.1960, BAL, 372/27.

^93.Quoted in Redeker, op. cit. (note 34), 100.

^94.State of the art report [Statusbericht] for 1973, AK ß-lactam-Antibiotika, BAL 323/99. Cf. Baum, op. cit. (note 22): 263–6 on Bayer’s new antibiotics in the 1970s.

^95.Ibid.

^96.Jeremy Greene, Prescribing by Numbers: Drugs and the Definition of Disease (Baltimore, MD: Johns Hopkins University Press, 2007).

^97.Bartmann, op. cit. (note 21), 320.

^98.Ibid., 339.

^99.John T. MacFarlane and Michael Worboys, ‘The Changing Management of Acute Bronchitis in Britain, 1940–70: The Impact of Antibiotics’, Medical History, 52, (2008), 47–72. [PMC free article] [PubMed]

^100.Greene, op. cit. (note 96).

^101.Greenwood, op. cit. (note 8), 345–92. Aya Homei and Michael Worboys, Pathologies of Progress: Fungal Disease in Britain and the United States, 1850–2000 (Basingstoke: Palgrave, 2013).

^102.Baum, op. cit. (note 22), 253.

^103.Greenwood, op. cit. (note 8), 358.

^104.Baum, op. cit. (note 22): 356. The numbers are in millions of Deutsche Mark.

^105.Bartmann, op. cit. (note 21), 350 mentions that Adalat and Canesten in 1975 created three times as much turnover than ten other newly marketed preparations in those years.

^106.BAL, 327/87.

^107.Daemmrich, op. cit. (note 51), 55.

^108.Research commission [Forschungskomission] pharma, minutes of the meeting 7.10.1977, 21.10.1977. BAL, 323/86. Cf. Research commission [Forschungskomission] pharma, minutes of the meeting 1.2.1974 (8.2.74), ‘Target of Bayer’s research is to find new ß-lactam antibiotics, which combine the advantages of currently traded products (effectiveness in small quantities and concurrent low toxicity) but do not possess their disadvantages (limited antibacterial spectrum, sensitivity to pencillinase, triggering allergies, swift discharge, sometime a necessity to apply by drips)’.

^109.Greenwood, op. cit. (note 8), 187/8. Cf. Linda Bryder, Flurin Condrau and Michael Worboys, ‘Tuberculosis and its histories: then and now’, in F Condrau and M Worboys (eds), Tuberculosis Then and Now: Perspectives on the History of an Infectious Disease, (Montreal: McGill-Queens University Press, 2010), 3–23.

^110.Research committee [Forschungskommittee] 1974, BAL 323/87.

^111.Research committee [Forschungskommittee] 1976, BAL 323/87.

^112.BAL 323/156, Department research [Ressort Forschung], minutes of a meeting held 10.1.77 (of 14.1.77).

^113.Cf. Bartmann, op. cit. (note 21), 363.

^114.BAL, 372/87, Letter Bartmann to Bunge, 29.8.1968.

^115.BAL, 323/150.

^116.Charles H. Stuart-Harris and David M. Harris (eds), The Control of Antibiotic-resistant Bacteria, (London; New York: Academic Press, 1982); John Mann, The Elusive Magic Bullet: The search for the Perfect Drug (Oxford: Oxford University Press, 1999); J. Parascandola (ed.) The History of Antibiotics: Symposium, (Madison, WI: American Institute of the History of Pharmacy, 1980). Greenwood, op. cit. (note 8), 262–3. Rang, op. cit. (note 9), 16–17; Spellberg et al., op. cit. (note 9).

^117.Work had started in 1981. On ciprofloxacin: Dalhoff, op. cit. (note 75), 92–6.

^118.Quotes from an advertising poster campaign for Ciprofloxacin, BAL, 166/8.

^119.Dalhoff, op. cit. (note 75), 100.

^120.Viviane Quirke and Jean-Paul Gaudillière, ‘The Era of Biomedicine: Science, Medicine, and Public Health in Britain and France after the Second World War’, Medical History, 52, (2008), 441–52, here 451. [PMC free article] [PubMed]

^121.Braun, op. cit. (note 26), 140.

^122.Louis Galambos and Jane Eliot Sewell, Networks of Innovation: Vaccine Development at Merck, Sharp and Dohme, and Mulford, 1895–1995 (Cambridge: Cambridge University Press, 1996), 241–3 have emphasised a similar pattern in their study of Merck, Sharp & Dome’s vaccine business.

John Henry 'Doc' Holliday (August 14, 1851 – November 8, 1887) was an Americangambler, gunfighter, and dentist. A close friend and associate of lawmanWyatt Earp, Holliday is best known for his role in the events leading up to and following the Gunfight at the O.K. Corral. He developed a reputation as having killed more than a dozen men in various altercations, but modern researchers have concluded that, contrary to popular myth-making, Holliday killed only one or two men. Holliday's colorful life and character have been depicted in many books and portrayed by well-known actors in numerous movies and television series.^[1]:415

At age 21, Holliday earned a degree in dentistry from the Pennsylvania College of Dental Surgery. He set up practice in Atlanta, Georgia, but he was soon diagnosed with tuberculosis, the same disease that had claimed his mother when he was 15, having acquired it while tending to her needs while she was still in the contagious phase of the illness. Hoping the climate in the American Southwest would ease his symptoms, he moved to that region and became a gambler, a reputable profession in Arizona in that day.^[2] Over the next few years, he reportedly had several confrontations. While in Texas, he saved Wyatt Earp's life and they became friends. In 1879, he joined Earp in Las Vegas, New Mexico and then rode with him to Prescott, Arizona,^[3] and then Tombstone. In Tombstone, local members of the outlaw Cochise County Cowboys repeatedly threatened him and spread rumors that he had robbed a stage. On October 26, 1881, Holliday was deputized by Tombstone city marshal Virgil Earp. The lawmen attempted to disarm five members of the Cowboys near the O.K. Corral on the west side of town, which resulted in the 30-second shootout.

Following the Tombstone shootout, Virgil Earp was maimed by hidden assailants while Morgan Earp was murdered. Unable to obtain justice in the courts, Wyatt Earp took matters into his own hands. As the recently appointed deputy U.S. marshal, Earp formally deputized Holliday, among others. As a federal posse, they pursued the outlaw Cowboys they believed were responsible. They found Frank Stilwelllying in wait as Virgil boarded a train for California and killed him. The local sheriff issued a warrant for the arrest of five members of the federal posse, including Holliday. The federal posse killed three other Cowboys during late March and early April 1882, before they rode to the New Mexico Territory. Wyatt Earp learned of an extradition request for Holliday and arranged for Colorado Governor Frederick Walker Pitkin to deny Holliday's extradition. Holliday spent the few remaining years of his life in Colorado, and died of tuberculosis in his bed at the Hotel Glenwood at age 36.^[4]

• 2Begins dental practice
• 5Move to New Mexico
• 6Move to Arizona Territory
• 7Arrives in Colorado
• 8Death and burial
• 9Public reputation
• 12In popular culture

Early life and education[edit]

Holliday was born in Griffin, Georgia, to Henry Burroughs Holliday and Alice Jane (McKey) Holliday.^[5] He was of English and Scottish ancestry.^{[6]: 236} His father served in the Mexican–American War and the Civil War (as a Confederate). When the Mexican–American War ended, Henry brought home an adopted son named Francisco and taught Holliday to shoot.^[7] Holliday was baptized at the First Presbyterian Church of Griffin in 1852.^[8] In 1864, his family moved to Valdosta, Georgia,^[8] where his mother died of tuberculosis on September 16, 1866.^[5] The same disease killed his adopted brother. Three months after his wife's death, his father married Rachel Martin.

Holliday attended the Valdosta Institute,^[8] where he received a classical education in rhetoric, grammar, mathematics, history, and languages—principally Latin, but some French and Ancient Greek.^[8]

In 1870, 19-year-old Holliday left home for Philadelphia. On March 1, 1872, at age 20, he received his Doctor of Dental Surgery degree from the Pennsylvania College of Dental Surgery (now part of the University of Pennsylvania School of Dental Medicine).^[5] Holliday graduated five months before his 21st birthday, so the school held his degree until he turned 21, the minimum age required to practice dentistry.^[9]:50

Begins dental practice[edit]

Holliday moved to St. Louis, Missouri, so he could work as an assistant for a classmate, A. Jameson Fuches, Jr.^[1]:51 Less than four months later, at the end of July, he relocated to Atlanta, where he joined a dental practice. He lived with his uncle and his family so he could begin to build up his dental practice.^[10] A few weeks before Holliday's birthday, dentist Arthur C. Ford advertised in the Atlanta papers that Holliday would substitute for him while he was attending dental meetings.

Fight in Georgia[edit]

There are some reports that Holliday was involved in a shooting on the Withlacoochee River, Georgia, in 1873. The earliest mention is by Bat Masterson in a profile of Doc he wrote in 1907. According to that story, when Holliday was 22, he went with some friends to a swimming hole on his uncles' land, where they discovered it was occupied by a group of African-American youth.^[1]:64–67

Susan McKey Thomas, the daughter of Doc's uncle Thomas S. McKey, said her father told her: 'They rode in on the Negroes in swimming in a part of the Withlacoochee River that 'Doc' and his friends had cleared to be used as their swimming hole. The presence of the Negroes in their swimming hole enraged 'Doc,' and he drew his pistol, shooting over their heads to scare them off.' Papa said, 'He shot over their heads!'^[11]

According to Masterson's story, Holliday leveled a double-barreled shotgun at them, and when they exited the swimming hole, killed two of the youths. Some family members thought it best that Holliday leave the state, but other members of Holliday's family dispute those accounts.^[1]:64–67 Researcher and historian Gary Roberts searched for contemporary evidence of the event for many months without success. Earp author Allen Barra also searched for evidence corroborating the incident and found no credibility in Masterson's story.^[12]

Diagnosed with tuberculosis[edit]

Catholic Pilgrimages 2019 To Rome

Shortly after beginning his dental practice, Holliday was diagnosed with tuberculosis.^[13] He was given only a few months to live, but was told that a drier and warmer climate might slow the deterioration of his health.^[5][14] After Dr. Ford's return in September, Holliday left for Dallas, Texas, the 'last big city before the uncivilized Western Frontier.'^{[1]:53, 55}

Move to Dallas[edit]

When he arrived in Dallas, Holliday partnered with a friend of his father's, Dr. John A. Seegar.^[15] They won awards for their dental work at the Annual Fair of the North Texas Agricultural, Mechanical, and Blood Stock Association at the Dallas County Fair. They received all three awards: 'Best set of teeth in gold', 'Best in vulcanized rubber', and 'Best set of artificial teeth and dental ware.'^[16] Their office was located along Elm Street, between Market and Austin Streets.^[17] They dissolved the practice on March 2, 1874, and Holliday opened his own practice over the Dallas County Bank at the corner of Main and Lamar Streets.

His tuberculosis caused coughing spells at inopportune times, and his dental practice slowly declined. Meanwhile, Holliday found he had some skill at gambling, and he soon relied on it as his principal income source.^[15] On May 12, 1874, Holliday and 12 others were indicted in Dallas for illegal gambling.^[17] He was arrested in Dallas in January 1875 after trading gunfire with a saloon keeper, Charles Austin, but no one was injured and he was found not guilty.^[5] He moved his offices to Denison, Texas, but after being fined for gambling in Dallas, he left the state.

Heads farther west[edit]

Holliday headed to Denver, following the stage routes and gambling at towns and army outposts along the way. During the summer of 1875, he settled in Denver under the alias 'Tom Mackey' and found work as a faro dealer for John A. Babb's Theatre Comique at 357 Blake Street. He got in an argument with Bud Ryan, a well-known and tough gambler. Drawing knives, they fought, and Holliday left Ryan seriously wounded.^[18]

Holliday left when he learned about gold being discovered in Wyoming, and on February 5, 1876, he arrived in Cheyenne. He found work as a dealer for Babb's partner, Thomas Miller, who owned the Bella Union Saloon. In the fall of 1876, Miller moved the Bella Union to Deadwood (site of the gold rush in the Dakota Territory), and Holliday went with him.^{[10]:101–103}

In 1877, Holliday returned to Cheyenne, and then Denver, and eventually to Kansas where he visited an aunt. When he left Kansas, he went to Breckenridge, Texas, where he gambled. On July 4, 1877, he had a disagreement with gambler Henry Kahn, and Holliday beat him repeatedly with his walking stick. Both men were arrested and fined, but Kahn was not finished. Later that same day, he shot and seriously wounded the unarmed Holliday.^{[10]:106–109} On July 7, the Dallas Weekly Herald incorrectly reported that Holliday had been killed. His cousin, George Henry Holliday, moved west to help him recover.

Once healed, Holliday relocated to Fort Griffin, Texas. While dealing cards at John Shanssey's saloon, he met Mary Katharine 'Big Nose Kate' Horony, a dance hall woman and occasional prostitute. Her nose was a prominent feature. 'Tough, stubborn and fearless,' she was educated, but chose to work as a prostitute because she liked her independence.^[19] She is the only woman with whom Holliday is known to have had a relationship.^[10]:109[15]

Befriends Wyatt Earp[edit]

In October 1877, outlaws led by 'Dirty' Dave Rudabaugh robbed a Sante Fe Railroad construction camp in Kansas. Rudabaugh fled south into Texas. Wyatt Earp was given a temporary commission as deputy U.S. marshal, and he left Dodge City following Rudabaugh over 400 mi (640 km) to Fort Griffin, a frontier town on the Clear Fork of the Brazos River. Earp went to the Bee Hive Saloon, the largest in town and owned by John Shanssey, whom Earp had met in Wyoming when he was 21.^[10]:113 Shanssey told Earp that Rudabaugh had passed through town earlier in the week, but he did not know where he was headed. Shanssey suggested Earp ask gambler Doc Holliday, who had played cards with Rudabaugh.^[20] Holliday told Earp that he thought Rudabaugh was headed back to Kansas. Earp sent a telegram to Ford County Sheriff Bat Masterson that Rudabaugh might be headed back in his direction.^[21]

After about a month in Fort Griffin, Earp returned to Fort Clark^[22] and in early 1878, he went to Dodge City, where he became the assistant city marshal, serving under Charlie Bassett. During the summer of 1878, Holliday and Horony also arrived in Dodge City, where they stayed at Deacon Cox's boardinghouse as Dr. and Mrs. John H. Holliday. Holliday sought to practice dentistry again, and ran an ad in the local paper:

DENTISTRY

John H. Holliday, Dentist, very respectfully offers his professional services to the citizens of Dodge City and surrounding county during the Summer. Office at Room No. 24 Dodge House. Where satisfaction is not given, money will be refunded.^[23]:11

206 Tours 2018

According to accounts of the following event reported by Glenn Boyer in I Married Wyatt Earp, Earp had run two cowboys, Tobe Driscall and Ed Morrison, out of Wichita earlier in 1878. During the summer, the two cowboys—accompanied by another two dozen men—rode into Dodge and shot up the town while galloping down Front Street. They entered the Long Branch Saloon, vandalized the room, and harassed the customers. Hearing the commotion, Earp burst through the front door, and before he could react, a large number of cowboys were pointing their guns at him. In another version, there were only three to five cowboys. In both stories, Holliday was playing cards in the back of the room and upon seeing the commotion, drew his weapon and put his pistol at Morrison's head, forcing him and his men to disarm, rescuing Earp from a bad situation.^[24][25] No account of any such confrontation was reported by any of the Dodge City newspapers at the time.^[25] Whatever actually happened, Earp credited Holliday with saving his life that day, and the two men became friends.^[24][26]

Other known confrontations[edit]

Holliday was still practicing dentistry from his room in Fort Griffin, Texas, and in Dodge City, Kansas. In an 1878 Dodge newspaper advertisement, he promised money back for less than complete customer satisfaction, but this was the last known time that he worked as a dentist.^[10]:113 He gained the nickname 'Doc' during this period.^[1]:74

Holliday reportedly engaged in a gunfight with a bartender named Charles White. Miguel Otero, who would later become governor of New Mexico Territory, said he was present when Holliday walked into the saloon with a cocked revolver in his hand and challenged White to settle an outstanding argument. White was serving customers at the time and took cover behind a bar, then started shooting at Holliday with his revolver. During the fight, Holliday shot White in the scalp. But there are no contemporaneous newspaper reports of the incident.^[27][1]:120

Bat Masterson reportedly said that Holliday was in Jacksonboro, South Carolina, and got into a gunfight with an unnamed soldier whom Holliday shot and killed. Historian Gary L. Roberts found a record for a Private Robert Smith who had been shot and killed by an 'unknown assailant', but Holliday was never linked to the death.^[1]:78–79

Move to New Mexico[edit]

Holliday developed a reputation for his skill with a gun, as well as with the cards.^[28]:186 A few days before Christmas in 1878, Holliday and Horony arrived in Las Vegas, New Mexico.^{[29]:18[30][31]:30–31} The 22 hot springs near the town were favored by individuals with tuberculosis for their alleged healing properties. Doc opened a dental practice and continued gambling as well, but the winter was unseasonably cold and business was slow. The New Mexico Territorial Legislature passed a bill banning gambling within the territory with surprising ease. On March 8, 1879, Holliday was indicted for 'keeping [a] gaming table' and was fined $25. The ban on gambling combined with extreme low temperatures persuaded him to return to Dodge City for a few months.^[31]

In September 1879, Wyatt Earp resigned as assistant marshal in Dodge City. Accompanied by his common-law wife Mattie Blaylock, his brother Jim, and his wife Bessie, they left for Arizona Territory.^{[29]:18[30][31]:30–31} Holliday and Horony returned to Las Vegas where they rendevouzed with the Earps.^[30] The group arrived in Prescott in November.

Royal Gorge War[edit]

In Dodge City, Holliday joined a team being formed by Deputy U.S. Marshal Bat Masterson. Masterson had been asked to prevent an outbreak of guerrilla warfare between the Atchison, Topeka and Santa Fe Railway and the Denver and Rio Grande Western Railroad (D&RGW), which were vying to be the first to claim a right-of-way across the Royal Gorge, one of the few natural routes through the Rockies that crossed the Continental Divide. Both were striving to be the first to provide rail access to the boom town of Leadville, Colorado.^[32] Royal Gorge was a bottleneck along the Arkansas, too narrow for both railroads to pass through, and with no other reasonable access to the South Park area. Doc remained there for about two and a half months. The federal intervention prompted the so-called 'Treaty of Boston' to end the fighting. The D&RGW completed its line and leased it for use by the Santa Fe.^[33] Holliday took home a share of a $10,000 bribe paid by the D&RGW to Masterson to give up their possession of the Santa Fe roundhouse, and returned to Las Vegas where Horony had remained.

Builds saloon in Las Vegas[edit]

The Santa Fe Railroad built tracks to Las Vegas, New Mexico, but bypassed the city by about a mile. A new town was built up near the tracks and prostitution and gambling flourished there. On July 19, 1879, Holliday and John Joshua Webb, former lawman and gunman, were seated in a saloon. Former U.S. Army scout Mike Gordon tried to persuade one of the saloon girls, a former girlfriend, to leave town with him. She refused and Gordon stormed outside. He began firing into the building,^[34] and a few hours later, Gordon was found mortally wounded outside. Some attribute the shooting to Holliday, but no conclusive evidence of who killed Gordon was ever found.^[34][35] The next day, Holliday paid $372.50 to a carpenter to build a clapboard building to house the Doc Holliday's Saloon with John Webb as his partner. While in town, he was fined twice for keeping a gambling device, and again for carrying a deadly weapon.^[6]:134

Move to Arizona Territory[edit]

It appeared Holliday and Horony were settling into life in Las Vegas when Wyatt Earp arrived on October 18, 1879. He told Holliday he was headed for the silver boom going on in Tombstone, Arizona Territory. Holliday and Horony joined Wyatt and his wife Mattie, as well as Jim Earp and his wife and step daughter, and they left the next day for Prescott, Arizona Territory. They arrived within a few weeks and went straight to the home of Constable Virgil Earp and his wife Allie. Holliday and Horony checked into a hotel and when Wyatt, Virgil, and James Earp with their wives left for Tombstone, Holliday remained in Prescott, where he thought the gambling opportunities were better.^[29][6]:134 Holliday finally joined the Earps in Tombstone in September 1880. Some accounts report that the Earps sent for Holliday for assistance with dealing with the outlaw Cowboys. Holliday quickly became embroiled in the local politics and violence that led up to the Gunfight at the O.K. Corral in October 1881.

Accused in stagecoach robbery[edit]

Holliday and Horony had many fights. After a particularly nasty, drunken argument, Holliday kicked her out. County SheriffJohnny Behan and Milt Joyce saw an opportunity and exploited the situation. They plied Horony with more booze and suggested to her a way to get even with Holliday. She signed an affidavit implicating Holliday in an attempted robbery and murder of passengers aboard a Kinnear and Company stage coach on March 15, 1881, carrying US$26,000 in silver bullion (equivalent to $675,000 in 2018).

Bob Paul, who had run for Pima County sheriff and was contesting the election he lost due to ballot stuffing, was working as the Wells Fargoshotgun messenger. He had taken the reins and driver's seat in Contention City because the usual driver, a well-known and popular man named Eli 'Budd' Philpot, was ill. Philpot was riding in Paul's place as shotgun when three cowboys stopped the stage between Tombstone and Benson, Arizona and tried to rob it.^[36]:180

Paul fired his shotgun and emptied his revolver at the robbers, wounding a cowboy, later identified as Bill Leonard, in the groin. Philpot and passenger Peter Roerig, riding in the rear dickey seat, were both shot and killed.^[37]Holliday was a good friend of Leonard, a former watchmaker from New York.^[38]:181 Based on the affidavit sworn by Horony, Judge Wells Spicer issued an arrest warrant for Holliday.^[39] Rumors flew that Holliday had taken part in the shooting and murders.

Later that day, drunk, Holliday returned to Joyce's saloon. He insulted Joyce and demanded his firearm back. Joyce refused and threw him out, but Holliday came back carrying a revolver and started firing. Joyce pulled out a pistol and Holliday shot the revolver out of Joyce's hand, putting a bullet through his palm. When Joyce's bartender, Parker, tried to grab his gun, Holliday wounded him in the toe. Joyce picked up his pistol and pistol-whipped Holliday, knocking him out. He shot and wounded both men and was convicted of assault.^[40][41][39]

The Earps found witnesses who could attest to Holliday's location elsewhere at the time of the stagecoach murders, and Horony sobered up, revealing that Behan and Joyce had influenced her to sign a document she did not understand. With the cowboy plot revealed, Spicer freed Holliday. The district attorney threw out the charges, labeling them 'ridiculous'. Holliday gave Horony some money and put her on a stage out of town.^[39]

Gunfight at the O.K. Corral[edit]

On October 26, 1881, Virgil Earp was both a deputy U.S. marshal and Tombstone's city police chief. He received reports that cowboys with whom they had had repeated confrontations were armed in violation of the city ordinance that required them to deposit their weapons at a saloon or stable soon after arriving in town. The cowboys had repeatedly threatened the Earps and Holliday. Fearing trouble, Virgil temporarily deputized Holliday and sought backup from his brothers Wyatt and Morgan. Virgil retrieved a short coach gun from the Wells Fargo office and the four men went to find the cowboys.^[42]

On Fremont Street, they ran into Cochise County Sheriff Behan, who told them or implied that he had disarmed the cowboys. To avoid alarming citizens and lessen tension when disarming the cowboys, Virgil gave the coach gun to Holliday so he could conceal it under his long coat. Virgil Earp took Holliday's walking stick.^[43] The lawmen found the cowboys in a narrow 15– to 20-ft-wide lot on Fremont Street, between Fly's boarding house and the Harwood house. Holliday was boarding at Fly's house and he possibly thought they were waiting there to kill him.^[44]

Different witnesses offered varying stories about Holliday's actions. Cowboys witnesses testified that Holliday first pulled out a nickel-plated pistol he was known to carry, while others reported he first fired a longer, bronze-colored gun, possibly the coach gun. Holliday killed Tom McLaury with a shotgun blast in the side of his chest. Holliday was grazed by a bullet possibly fired by Frank McLaury who was on Fremont Street at the time. He supposedly challenged Holliday, yelling, 'I've got you now!' Holliday is reported to have replied, 'Blaze away! You're a daisy if you have.' McLaury died of shots to his stomach and behind his ear. Holliday may have also wounded Billy Clanton.^[45]

One analysis of the fight gives credit to either Holliday or Morgan Earp for firing the fatal shot at McLaury on Fremont Street. Holliday may have been on McLaury's right and Morgan Earp on his left. McLaury was shot in the right side of the head, so Holliday is often given credit for shooting him. However, Wyatt Earp had shot McLaury in his torso earlier, a shot that alone could have killed him. McLaury would have turned away after having been hit and Wyatt could have placed a second shot in his head.^[46][47] A 30-day-long preliminary hearing found that the Earps and Holliday had acted within their duties as lawmen, although this did not pacify Ike Clanton.

Earp Vendetta Ride[edit]

The situation in Tombstone soon grew worse when Virgil Earp was ambushed and permanently injured in December 1881. Following that, Morgan Earp was ambushed and killed in March 1882. Several Cowboys were identified by witnesses as suspects in the shooting of Virgil Earp on December 27, 1881, and the assassination of Morgan Earp on March 19, 1882. Additional circumstantial evidence also pointed to their involvement. Wyatt Earp had been appointed deputy U.S. marshal after Virgil was maimed. He deputized Holliday, Warren Earp, Sherman McMaster, and 'Turkey Creek' Jack Johnson.

After Morgan's murder, Wyatt Earp and his deputies guarded Virgil Earp and Allie on their way to the train for Colton, California where his father lived, to recuperate from his serious shotgun wound. In Tucson, on March 20, 1882, the group spotted an armed Frank Stilwell and reportedly Ike Clanton hiding among the railroad cars, apparently lying in wait with the intent to kill Virgil. Frank Stilwell's body was found at dawn alongside the railroad tracks, riddled with buckshot and gunshot wounds.^[48] Wyatt said later in life that he killed Stilwell with a shotgun.^[49]

Tucson Justice of the Peace Charles Meyer issued arrest warrants for five of the Earp party, including Holliday. On March 21, they returned briefly to Tombstone, where they were joined by Texas Jack Vermillion and possibly others. On the morning of March 22, a portion of the Earp posse including Wyatt, Warren, Holliday, Sherman McMaster, and 'Turkey Creek' Johnson rode about 10 mi (16 km) east to Pete Spence's ranch to a wood cutting camp located off the Chiricahua Road, below the South Pass of the Dragoon Mountains.^{[34][50][9]:250} According to Theodore Judah—who witnessed events at the wood camp—the Earp posse arrived around 11:00 am and asked for Spence and Florentino 'Indian Charlie' Cruz. They learned Spence was in jail^[48] and that Cruz was cutting wood nearby. They followed the direction Judah indicated and he soon heard a dozen or so shots. When Cruz did not return the next morning, Judah went looking for him, and found his body full of bullet holes.^[51]

Gunfight at Iron Springs[edit]

Two days later, Earp's posse traveled to Iron Springs located in the Whetstone Mountains, where they expected to meet Charlie Smith, who was supposed to be bringing $1,000 cash from their supporters in Tombstone. With Wyatt and Holliday in the lead, the six lawmen surmounted a small rise overlooking the springs. They surprised eight cowboys camping near the springs. Wyatt Earp and Holliday left the only record of the fight. Curly Bill recognized Wyatt Earp in the lead and immediately grabbed his shotgun and fired at Earp. The other Cowboys also drew their weapons and began firing. Earp dismounted, shotgun in hand. 'Texas Jack' Vermillion's horse was shot and fell on him, pinning his leg and wedging his rifle underneath. Lacking cover, Holliday, Johnson, and McMaster retreated.^[52]

Earp returned Curly Bill's gunfire with his own shotgun and shot him in the chest, nearly cutting him in half according to Earp's later account.^[52] Curly Bill fell into the water by the edge of the spring and lay dead.^[53]

The Cowboys fired a number of shots at the Earp party, but the only casualty was Vermillion's horse, which was killed. Firing his pistol, Wyatt shot Johnny Barnes in the chest and Milt Hicks in the arm. Vermillion tried to retrieve his rifle wedged in the scabbard under his fallen horse, exposing himself to the Cowboys' gunfire. Doc Holliday helped him gain cover. Wyatt had trouble remounting his horse because his cartridge belt had slipped down around his legs.^[52]

Wyatt's long coat was shot through by bullets on both sides. Another bullet struck his boot heel and his saddle horn was hit as well, burning the saddle hide and narrowly missing Wyatt. He was finally able to get on his horse and retreat. McMaster was grazed by a bullet that cut through the straps of his field glasses.^[48]

Earp and Holliday part company[edit]

Holliday and four other members of the posse were still faced with warrants for Stilwell's death. The group elected to leave the Arizona Territory for New Mexico Territory and then on to Colorado. Wyatt and Holliday, who had been fast friends, had a serious disagreement and parted ways in Albuquerque.^[54] According to a letter written by former New Mexico Territory Governor Miguel Otero, Wyatt and Holliday were eating at Fat Charlie's The Retreat Restaurant in Albuquerque 'when Holliday said something about Earp becoming 'a damn Jew-boy.' Earp became angry and left...'

Earp was staying with a prominent businessman, Henry N. Jaffa, who was also president of New Albuquerque's Board of Trade. Jaffa was Jewish, and based on Otero's letter, Earp had, while staying in Jaffa's home, honored Jewish tradition by touching the mezuzah upon entering his home. According to Otero's letter, Jaffa told him, 'Earp's woman was a Jewess.' Earp's anger at Holliday's ethnic slur may indicate that the relationship between Josephine Marcus and Wyatt Earp was more serious at the time than is commonly known.^[55][56] Holliday and Dan Tipton arrived in Pueblo, Colorado in late April 1882.^[1]

Arrives in Colorado[edit]

On May 15, 1882, Holliday was arrested in Denver on the Tucson warrant for murdering Frank Stilwell. When Wyatt Earp learned of the charges, he feared his friend Holliday would not receive a fair trial in Arizona. Earp asked his friend Bat Masterson, then chief of police of Trinidad, Colorado, to help get Holliday released. Masterson drew up bunco charges against Holliday.^[57]

Holliday's extradition hearing was set for May 30. Late in the evening of May 29, Masterson sought help getting an appointment with Colorado Governor Frederick Walker Pitkin. He contacted E.D. Cowen, capital reporter for the Denver Tribune, who held political sway in town. Cowen later wrote, 'He submitted proof of the criminal design upon Holliday's life. Late as the hour was, I called on Pitkin.' His legal reasoning was that the extradition papers for Holliday contained faulty legal language, and that there was already a Colorado warrant out for Holliday—including the bunco charge that Masterson had fabricated. Pitkin was persuaded by the evidence presented by Masterson and refused to honor Arizona's extradition request.^[57]:230

Masterson took Holliday to Pueblo, where he was released on bond two weeks after his arrest.^[58] Holliday and Wyatt met again in June 1882 in Gunnison after Wyatt helped to keep his friend from being convicted on murder charges regarding Frank Stillwell.^[58] Holliday was able to see his old friend Wyatt one last time in the late winter of 1886, where they met in the lobby of the Windsor Hotel. Sadie Marcus described the skeletal Holliday as having a continuous cough and standing on 'unsteady legs.'^[59]

Death of Johnny Ringo[edit]

On July 14, 1882, Holliday's long-time enemy Johnny Ringo was found dead in a low fork of a large tree in West Turkey Creek Valley near Chiricahua Peak, Arizona Territory. He had a bullet hole in his right temple and a revolver was found hanging from a finger of his hand. A coroner's inquest officially ruled his death a suicide;^[60] but according to the book I Married Wyatt Earp, which author and collector Glen Boyer claimed to have assembled from manuscripts written by Earp's third wife, Josephine Marcus Earp, Earp and Holliday traveled to Arizona with some friends in early July, found Ringo in the valley, and killed him.^[61] Boyer refused to produce his source manuscripts, and reporters wrote that his explanations were conflicting and not credible. New York Times contributor Allen Barra wrote that the book 'is now recognized by Earp researchers as a hoax'.^[62]:154[63] A variant of the story, popularized in the movie Tombstone, holds that Holliday stepped in for Earp in response to a gunfight challenge from Ringo, and shot him.^[61]

Evidence is unclear as to Holliday's exact whereabouts on the day of Ringo's death. Records of the District Court of Pueblo County, Colorado indicate that Holliday and his attorney appeared in court in Pueblo on July 11, and again on July 14 to answer charges of 'larceny'; but a writ of capias was issued for him on the 11th, suggesting that he may not have been in court that day.^[64] The Pueblo Daily Chieftain reported that Holliday was seen in Salida, Colorado on July 7, more than 550 miles (890 km) from where Ringo's body was found, and then in Leadville on July 18.^[65] Holliday biographer Karen Holliday Tanner noted that there was still an outstanding murder warrant in Arizona for Holliday's arrest, making it unlikely that he would choose to reenter Arizona at that time.^[66]

Death and burial[edit]

Holliday spent his remaining days in Colorado. After a stay in Leadville, he suffered from the high altitude. He increasingly depended on alcohol and laudanum to ease the symptoms of tuberculosis, and his health and his skills as a gambler began to deteriorate.^[10]:218

Holliday's last known confrontation took place in Hyman's saloon in Leadville. Down to his last dollar, he had pawned his jewelry, and then borrowed $5 (equivalent to $140 in 2018) from Billy Allen, a bartender and special officer at the Monarch Saloon, which enabled Allen to carry a gun and make arrests within the saloon. When Allen demanded he be repaid, Holliday could not comply. He knew Allen was armed, and when Allen appeared ready to attack him, he shot him, wounding him in the arm. Holliday was arrested and put on trial. He claimed self-defense, noting that Allen outweighed him by 50 pounds (23 kg) and he feared for his life. A witness testified that Allen had been armed and in Hyman's earlier in the day apparently looking for Holliday. On March 28, 1885, the jury acquitted Holliday.^[67]

Final days[edit]

In 1887, prematurely gray and badly ailing, Holliday made his way to the Hotel Glenwood, near the hot springs of Glenwood Springs, Colorado.^[68] He hoped to take advantage of the reputed curative power of the waters, but the sulfurous fumes from the spring may have done his lungs more harm than good.^[10]:217 As he lay dying, Holliday is reported to have asked the nurse attending him for a shot of whiskey. When she told him no, he looked at his bootless feet, amused. The nurses said that his last words were, 'This is funny.'^[8] He always figured he would be killed someday with his boots on.^[1]:372 Holliday died at 10am on November 8, 1887. He was 36.^[16] Wyatt Earp did not learn of Holliday's death until two months afterward. Kate Horony later said that she attended to him in his final days, and one contemporary source appears to back her claim.^[69]

Service[edit]

The Glenwood Springs Ute Chief of November 12, 1887, wrote in his obituary that Holliday had been baptized in the Catholic Church. This was based on correspondence written between Holliday and his cousin, Sister Mary Melanie, a Catholic nun. No baptismal record has been found in either St. Stephen's Catholic Church in Glenwood Springs or at the Annunciation Catholic Church in nearby Leadville.^[10]:300 Holliday's mother had been raised a Methodist and later joined a Presbyterian church (her husband's faith), but objected to the Presbyterian doctrine of predestination and reconverted to Methodism publicly before she died, saying that she wanted her son John to know what she believed.^{[1]:14, 41} Holliday himself was later to say that he had joined a Methodist church in Dallas.^[1]:70 At the end of his life, Holliday had struck up friendships with both a Catholic priest, Father E.T. Downey, and a Presbyterian minister, Rev. W.S. Randolph, in Glenwood Springs. When he died, Father Downey was out of town, and so Rev. Randolph presided over the burial at 4pm on the same day that Holliday died. The services were reportedly attended by 'many friends'.^{[1]:370, 372}

Burial[edit]

Holliday is buried in Linwood Cemetery overlooking Glenwood Springs. Since Holliday died in November, the ground may have been frozen. Some modern authors such as Bob Boze Bell^[70] speculate that it would have been impossible to transport him to the cemetery, which was only accessible by a difficult mountain road, or to dig a grave because the ground was frozen. Author Gary Roberts located evidence that other bodies were transported to the Linwood Cemetery at the same time of the month that year. Contemporary newspaper reports explicitly state that Holliday was buried in the Linwood Cemetery, but the exact location of his grave is uncertain.^{[1]:403–404}

206 Tours 2019

Public reputation[edit]

Holliday maintained a fierce persona as was sometimes needed for a gambler to earn respect. He had a contemporary reputation as a skilled gunfighter which modern historians generally regard as accurate.^[1]:410 Tombstone resident George W. Parsons wrote that Holliday confronted Johnny Ringo in January 1882, telling him, 'All I want of you is ten paces out in the street.' Ringo and he were prevented from a gunfight by the Tombstone police, who arrested both. During the Gunfight at the O.K. Corral, Holliday initially carried a shotgun and shot at and may have killed Tom McLaury. Holliday was grazed by a bullet fired by Frank McLaury, and shot back. After Virgil was maimed in a January ambush, Holliday was part of a federal posse led by Deputy U.S. Marshal Earp who guarded him on his way to the railroad in Tucson. There they found Frank Stilwell apparently waiting for the Earps in the rail yard. A warrant for Holliday's arrest was issued after Stilwell was found dead with multiple gunshot wounds. Holliday was part of Earp's federal posse when they killed three other outlaw Cowboys during the Earp Vendetta Ride. Holliday reported that he had been arrested 17 times, four attempts had been made to hang him, and that he survived ambush five times.^[71]

Character[edit]

Throughout his lifetime, Holliday was known by many of his peers as a tempered, calm, Southern gentleman. In an 1896 article, Wyatt Earp said:

I found him a loyal friend and good company. He was a dentist whom necessity had made a gambler; a gentleman whom disease had made a vagabond; a philosopher whom life had made a caustic wit; a long, lean blonde fellow nearly dead with consumption and at the same time the most skillful gambler and nerviest, speediest, deadliest man with a six-gun I ever knew.^[72]

Band Live

In a newspaper interview, Holliday was once asked if his conscience ever troubled him. He is reported to have said, 'I coughed that up with my lungs, years ago.'^[73]:189

Bat Masterson, who had several contacts with Holliday over his lifetime, had a different opinion of Holliday.

While he never did anything to entitle him to a Statue in the Hall of Fame, Doc Holliday was nevertheless a most picturesque character on the western border in those days when the pistol instead of law determined issues.... Holliday had a mean disposition and an ungovernable temper, and under the influence of liquor was a most dangerous man…. Physically, Doc Holliday was a weakling who could not have whipped a healthy fifteen-year-old boy in a go-as-you-please fist fight.^[21]

Stabbings and shootings[edit]

Much of Holliday's violent reputation was nothing but rumors and self promotion. However, he showed great skill in gambling and gunfights. His tuberculosis did not hamper his ability as a gambler and as a marksman. Holliday was ambidextrous.^[44]:96

No contemporaneous newspaper accounts or legal records offer proof of the many unnamed men whom Holliday is credited with killing in popular folklore. The only men he is known to have killed are Mike Gordon in 1879; probably Tom McLaury in Tombstone; and possibly Frank Stilwell in Tucson. Some scholars argue that Holliday may have encouraged the stories about his reputation, although his record never supported those claims.^[1]:410

In a March 1882 interview with the Arizona Daily Star, Virgil Earp told the reporter:

There was something very peculiar about Doc. He was gentlemanly, a good dentist, a friendly man, and yet outside of us boys I don't think he had a friend in the Territory. Tales were told that he had murdered men in different parts of the country; that he had robbed and committed all manner of crimes, and yet when persons were asked how they knew it, they could only admit that it was hearsay, and that nothing of the kind could really be traced up to Doc's account.^[74]

206 Tours Holy Land

Arrests and convictions[edit]

Biographer Karen Holliday Tanner found that Holliday had been arrested 17 times before his 1881 shootout in Tombstone. Only one arrest was for murder, which occurred in an 1879 shootout with Mike Gordon in New Mexico, for which he was acquitted. In the preliminary hearing following the Gunfight at the O.K. Corral, Judge Wells Spicer exonerated Holliday's actions as those of a duly appointed lawman. In Denver, the Arizona warrant against Holliday for Frank Stilwell's murder went unserved when the governor was persuaded by Trinidad Chief of Police Bat Masterson to release Holliday to his custody for bunco charges.^[10]

Among his other arrests, Holliday pleaded guilty to two gambling charges, one charge of carrying a deadly weapon in the city (in connection with the argument with Ringo), and one misdemeanor assault and battery charge (for his shooting of Joyce and Parker). The others were all dismissed or returned as 'not guilty.'^[10]

Alleged murder of Ed Bailey[edit]

Wyatt Earp recounted one event during which Holliday killed a fellow gambler named Ed Bailey. Earp and his common-law wife Mattie Blaylock were in Fort Griffin, Texas, during the winter of 1878, looking for gambling opportunities. Earp visited the saloon of his old friend from Cheyenne, John Shannsey, and met Holliday at the Cattle Exchange.^[75] The story of Holliday killing Bailey first appeared nine years after Holliday's death in an 1896 interview with Wyatt Earp that was published in the San Francisco Enquirer.^[76] According to Earp, Holliday was playing poker with a well-liked local man named Ed Bailey. Holliday caught Bailey 'monkeying with the dead wood' or the discard pile, which was against the rules. According to Earp, Holliday reminded Bailey to 'play poker', which was a polite way to caution him to stop cheating. When Bailey made the same move again, Holliday took the pot without showing his hand, which was his right under the rules. Bailey immediately went for his pistol, but Holliday whipped out a knife from his breast pocket and 'caught Bailey just below the brisket' or upper chest. Bailey died and Holliday, new to town, was detained in his room at the Planter's Hotel.^[10]:115

In Stuart Lake's best-selling biography, Wyatt Earp: Frontier Marshal (1931), Earp added to the story. He is quoted as saying that Holliday's girlfriend, 'Big Nose Kate' Horony, devised a diversion. She procured a second pistol from a friend in town, removed a horse from its shed behind the hotel, and then set fire to the shed. Everyone but Holliday and the lawmen guarding him ran to put out the fire, while she calmly walked in and tossed Holliday the second pistol.^[75] However, no contemporary records have been found of either Bailey's death or of the shed fire. In addition, Horony denied that Holliday killed 'a man named Bailey over a poker game, nor was he arrested and locked up in another hotel room.' She laughed at the idea of 'a 116-pound woman, standing off a deputy, ordering him to throw up his hands, disarming him, rescuing her lover, and hustling him to the waiting ponies.'^[1]:87

Author and Earp expert Ben Traywick doubts that Holliday killed Bailey. He could find no newspaper articles or court records to support the story. He found evidence to support that Holliday was being held in his hotel room under guard, but for 'illegal gambling', and that the story of Horony starting a fire as a diversion to free him was true. The story about Bailey as told in San Francisco Enquirer interview of Earp was likely fabricated by the writer. Years later, Earp wrote:

Of all the nonsensical guff which has been written around my life, there has been none more inaccurate or farfetched than that which has dealt with Doc Holliday. After Holliday died, I gave a San Francisco newspaper reporter a short sketch of his life. Apparently the reporter was not satisfied. The sketch appeared in print with a lot of things added that never existed outside the reporter's imagination ...^[76]

Photos of Holliday[edit]

Three photos of unknown provenance are often reported to be of Holliday, some of them supposedly taken by C.S. Fly in Tombstone, but sometimes reported to have been taken in Dallas. Holliday lived in a rooming house in front of Fly's photography studio. Many individuals share similar facial features, and the faces of people who look radically different can look similar when viewed from certain angles. Because of this, most museum staff, knowledgeable researchers, and collectors require provenance or a documented history for an image to support physical similarities that might exist. Experts rarely offer even a tentative identification of new or unique images of famous people based solely on similarities shared with other known images.^[77]

• Cropped from a larger version, Holliday's graduation photo from the Pennsylvania School of Dental Surgery in March 1872, age 20, known provenance and authenticated as Holliday

• Cropped from a larger version, Holliday in Prescott, Arizona in 1879, age 27, known provenance and authenticated as Holliday

• Uncreased print of supposed 1882 Tombstone photo of Holliday, left side is upturned, detachable shirt collar toward camera, no cowlick, unknown provenance

• Creased and darker version of photo at left, unknown provenance

• Individual most often reported to be Holliday with a cowlick and folded-down collar, heavily retouched, oval, inscribed portrait, unknown provenance

• Individual with a bowler hat and open vest and coat, unknown provenance

Legacy[edit]

Doc Holliday is one of the most recognizable figures in the American Old West, but he is most remembered for his friendship with Wyatt Earp and his role in the Gunfight at the O.K. Corral. Holliday's friendship with the lawman has been a staple of popular sidekicks in American Western culture,^[78] and Holliday himself became a stereotypical image of a deputy and a loyal companion in modern times. He is typically portrayed in films as being loyal to his friend Wyatt, whom he sticks with during the duo's greatest conflicts, such as the Gunfight at the OK Corral and Earp's vendetta, even with the ensuing violence and hardships which they both endured.^[1] Together with Wyatt Earp, Doc Holliday has become a modern symbol of loyalty, brotherhood and friendship.^[79]

The Holliday birth home is marked with an historical marker located in Fayetteville, Georgia.^[80]

A life-sized statue of Holliday and Earp by sculptor Dan Bates was dedicated by the Southern Arizona Transportation Museum at the restored Historic Railroad Depot in Tucson, Arizona, on March 20, 2005, the 122nd anniversary of the killing of Frank Stilwell by Wyatt Earp. The statue stands at the approximate site of the shooting on the train platform.^[81][82]

'Doc Holliday Days' are held yearly in Holliday's birthplace of Griffin, Georgia. Valdosta, Georgia held a Doc Holliday look-alike contest in January 2010, to coincide with its sesquicentennial celebration.^[83]

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Tombstone, Arizona also holds an annual Doc Holli-Days, which started in 2017, and celebrates the gunfighter-dentist on the 2nd weekend of August each year. Events include gunfights, a parade, and a Doc Holliday look-alike contest. Val Kilmer, who played Doc in 1993's Tombstone, was the grand marshal in 2017 and Dennis Quaid, who played Doc in 1994's Wyatt Earp, was the grand marshal in 2018.^[84]

In popular culture[edit]

Holliday was nationally known during his life as a gambler and gunman. The shootout at the O.K. Corral is one of the most famous frontier stories in the American West and numerous Western TV shows and movies have been made about it. Holliday is usually a prominent part of the story.^[6][85]

Documentary[edit]

• In Search of Doc Holliday (2016)

In film and television[edit]

Actors who have portrayed Holliday include:^[86]

• Harvey Clark in Law for Tombstone (1937)
• Cesar Romero in Frontier Marshal (1939)
• Kent Taylor in Tombstone, the Town Too Tough to Die (1942)
• Walter Huston in The Outlaw (1943)
• Victor Mature in My Darling Clementine directed by John Ford, with Henry Fonda as Wyatt Earp (1946)
• Harry Bartell in the 13th episode of the CBS radio program Gunsmoke (July 19, 1952)
• Kim Spalding in the syndicated television series Stories of the Century (1954)
• James Griffith in Masterson of Kansas (1954)
• Barry Atwater in 'The Gunfight at the O.K. Corral', an episode of the CBS TV series 'You Are There', November 6, 1955
• Kirk Douglas in Gunfight at the O.K. Corral (1957) with Burt Lancaster as Wyatt Earp
• Douglas Fowley in The Life and Legend of Wyatt Earp with Hugh O'Brian as Wyatt Earp (1955–1961)^[87]
• Myron Healey in ten episodes of The Life and Legend of Wyatt Earp.^[88]
• Adam West in separate 1959 episodes of Lawman,Sugarfoot (episode: 'Trial of the Canary Kid'), and Colt .45
• Gerald Mohr and Peter Breck each played Holliday in the ABC/WB series Maverick (1957)
• Christopher Dark in an episode of the NBC series Bonanza (1963)
• Martin Landau in the episode 'Doc Holliday' of the TV series Tales of Wells Fargo (1959)
• Anthony Jacobs in the Doctor Who episode 'The Gunfighters' (1966)
• Warren Stevens in the episode 'Doc Holliday's Gold Bars' of the syndicated Western series, Death Valley Days (1966)^[89]
• Jason Robards in Hour of the Gun, James Garner played Wyatt Earp (1967)
• Jack Kelly in The High Chaparral (1967)
• Sam Gilman in the Star Trek episode 'Spectre of the Gun' (1968)
• Stacy Keach in Doc (1971)
• Bill Fletcher in two episodes of the TV series Alias Smith and Jones: 'Which Way to the OK Corral?' (1971) and 'The Ten Days That Shook Kid Curry' (1972)
• John McLiam in Bret Maverick (1981)
• Jeffrey DeMunn in I Married Wyatt Earp (1983)
• Willie Nelson in Stagecoach (1986)^[90]
• Val Kilmer in Tombstone (1993)
• Dennis Quaid in Wyatt Earp (1994)
• Randy Quaid in Purgatory (1999)
• Wilson Bethel in Wyatt Earp's Revenge (2012)
• Ryan Kennedy in Hannah's Law (2012)
• William McNamara in Doc Holliday's Revenge (2014)
• Shane O'Loughlin in Legends and Lies: The Real West on the Fox News Channel series that explores famous figures from the American West
• Tim Rozon in Wynonna Earp (2016) ^[91]
• Edgar Fox in The American West (2016)
• Eric Schumacher in Tombstone Rashomon (2017)
• Jeremy Renner in Untitled Doc Holliday Biopic (TBA) based on Mary Doria Russell's books^[92]

In fiction[edit]

• Epitaph: a Novel of the O.K. Corral by Mary Doria Russell, 2015 ISBN978-0-06-219876-1
• A Wicked Little Town: Book One of The Doc Holliday Series by Elena Sandidge, 2013 ISBN978-0-9928070-0-9
• Southern Son: The Saga of Doc Holliday by Victoria Wilcox, 2013 ISBN978-1-908483-55-3
• Holliday, Nate Bowden and Doug Dabbs, 2012 ISBN978-1-934964-65-1
• Doc: A Novel by Mary Doria Russell, 2011 ISBN978-1-4000-6804-3
• Merkabah Rider: The Mensch With No Name by Edward M. Erdelac, a novel in the Weird West genre, 2010, ISBN978-1-61572-190-0
• The Buntline Special by Mike Resnick, 2010, ISBN978-1-61614-249-0
• Territory by Emma Bull, 2007 ISBN978-0-8125-4836-5
• O.K. Corral, a Lucky Luke comic by artist Morris & writers Eric Adam and Xavier Fauche 1997
• The Last Ride of German Freddie by Walter Jon Williams, a novella in Worlds that Weren't 2005, ISBN978-1-101-21263-9
• Bucking the Tiger: A Novel by Bruce Olds, 2002 ISBN978-0-312-42024-6
• The Fourth Horseman by Randy Lee Eickhoff, 1998 ISBN0-312-85301-7
• Deadlands a tabletop role-playing game produced by Pinnacle Entertainment Group in Law Dogs, 1996, ISBN978-1-889546-26-1
• Wild Times by Brian Garfield, 1978 ISBN978-0-671-24374-6
• The Last Kind Words Saloon by Larry McMurtry, 2014 ISBN978-0-87140-786-3
• At Grave's End by Jeaniene Frost, 2008 ISBN978-0061583070

In song[edit]

• 'Linwood', written and performed by Jon Chandler on The Grand Dame of the Rockies – Songs of the Hotel Colorado and the Roaring Fork Valley; winner of the 2009 Western Writers of AmericaSpur Award for Best Song^[93]
• Danish metal band Volbeat performs the song 'Doc Holliday' on their album Outlaw Gentlemen & Shady Ladies.

References[edit]

1. ^ ^{abcdefghijklmnopqr}Roberts, Gary L. (2006). Doc Holliday: The Life and Legend. John Wiley and Sons, Inc. ISBN0-471-26291-9.^:407–409
2. ^'Gambling in the Old West'. History Net. Wild West Magazine. June 12, 2006. Archived from the original on April 24, 2015. Retrieved April 13, 2015.
3. ^Gary L. Roberts (May 12, 2011). Doc Holliday: The Life and Legend. John Wiley & Sons. p. 29. ISBN978-1-118-13097-1.
4. ^The Associated Press. 'A New Tombstone Sets the Record Straight for Doc Holliday'. The New York Times. NYT. Retrieved August 8, 2019.
5. ^ ^abcde'John Henry Holliday Family History'. Kansas Heritage Group. Archived from the original on May 14, 2015. Retrieved March 30, 2015.
6. ^ ^abcdTanner, Karen Holliday (1998). Doc Holliday: A Family Portrait. Norman, Okla.: University of Oklahoma Press. ISBN0-8061-3036-9.
7. ^'Civil War Soldiers and Sailors'. The National Park Service. Archived from the original on August 14, 2008. Retrieved January 18, 2019.
8. ^ ^abcdePoling, Dean (January 1, 2010). 'Valdosta's Most Infamous Resident – John Henry 'Doc' Holliday'. Valdosta Scene. VI (1): 19–20.
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Further reading[edit]

• Bell, Bob Boze. The Illustrated Life and Times of Doc Holliday, Phoenix: Tri-Star Boze Publications, 1994.
• DeMattos, Jack. 'Gunfighters of the Real West: Doc Holliday,' Real West, January 1982.
• Jahns, Pat. The Frontier World of Doc Holliday: Faro Dealer from Dallas to Deadwood, New York: Hastings House Publishers, Inc. 1957.
• Kirkpatrick, J.R. 'Doc Holliday's Missing Grave.' True West, October 1990.
• Lynch, Sylvia D. (1995). Aristocracy's Outlaw: The Doc Holliday Story. Tennessee Iris Press. ISBN0-9645781-0-7.
• Marks, Paula Mitchell. And Die in the West: The Story of the O.K. Corral Gunfight, New York: William Morrow and Company, Inc., 1989 ISBN0-688-07288-7
• Masterson, W.B. 'Bat. 'Famous Gun Fighters of the Western Frontier: 'Doc' Holliday,' Human Life Magazine, Vol. 5, No. 2, May, 1907.
• Myers, John Myers. Doc Holliday, Boston: Little, Brown and Company, 1955.
• Palmquist, Robert F. 'Good-Bye Old Friend,' Real West, May 1979.
• Roberts, Gary L. 'The Fremont Street Fiasco,' True West, July 1988.
• Roberts, Gary L. (2006). Doc Holliday: The Life and Legend. John Wiley and Sons, Inc. ISBN0-471-26291-9.
• Tanner, Karen Holliday (1998). Doc Holliday: A Family Portrait. University of Oklahoma Press. ISBN978-0-8061-3320-1.

External links[edit]

• Kansasheritage.org, John Henry Holliday family history
• Tombstonetimes.com, 'Where's Doc'