Resisting Antibiotics

The Antibiotic Era: Reform, Resistance, and the Pursuit of a Rational Therapeutics
Scott H. Podolsky
Johns Hopkins University Press, $34.95 (cloth)

President Obama’s announcement in January that his 2016 budget would double investment to fight antibiotic resistance followed a September 2014 report from his Council of Advisors on Science and Technology (PCAST). “The evolution of antibiotic resistance is now occurring at an alarming rate,” the report warns,

and is outpacing the development of new countermeasures capable of thwarting infections in humans. This situation threatens patient care, economic growth, public health, agriculture, economic security, and national security.

The World Health Organization’s 2014 report likewise cautions that a post-antibiotic era is not an “apocalyptic fantasy” but “a very real possibility.”

One might be surprised to discover that this genre of warning is almost a half-century old. Even Newsweek ran a piece titled “The End of Antibiotics” more than twenty years ago. What has stood in the way of heeding these admonitions?

The PCAST report recommends a sensible consensus of medical and policy expertise: do not waste existing drugs; make it easier to develop new ones; use financial incentives to encourage appropriate behavior. “Antibiotic stewardship” is the term of art, aggregating the responsibilities of quite different groups—doctors, farmers, researchers, hospitals, pharmaceutical companies—and hiding a variety of human conflicts. Yet not a single historical work is cited to analyze the behavior these measures are intended to address, to explain the success of stewardship in the past, to evaluate the response to warnings repeatedly voiced since the 1940s—or to show why we should expect the balance of power today to be different from that of previous crises in antibiotic confidence.

A welcome new book takes a longer view. In The Antibiotic Era: Reform, Resistance, and the Pursuit of a Rational Therapeutics, physician-historian Scott Podolsky examines both the social and scientific forces at work in the history of antibiotic reform in the United States. “Perhaps no domain in conventional medicine has been subjected to such ongoing scrutiny . . . as the development and prescribing of antibiotics,” the book’s introduction says. Podolsky focuses on the scrutiny that emerged among a handful of infectious disease experts in the 1950s. Alarmed by the “irrational” use of certain heavily advertised antibiotics, they helped to reshape conceptions of medical evidence, empower the Food and Drug Administration, and institutionalize the controlled clinical trial as a scientific and regulatory tool.

Yet these changes in turn elicited a backlash against regulation that has made it difficult to secure centralized oversight of antibiotic prescription practices. Following the legacy of these reforms over several decades, Podolsky shows how arguments incited by antibiotics took on broader significance in contests between therapeutic enthusiasm and skepticism, science and business, free enterprise and regulation, doctor and patient. These problems remain with us today, and the resistance these reformers faced was more than microbial.

Alexander Fleming fortuitously observed the antibiotic effect of penicillin in 1928, but it was not used to treat a large number of civilians until Boston’s massive Cocoanut Grove fire in 1942. Among the physicians tending to the wounded was Maxwell Finland, who over a long career at Harvard and Boston City Hospital became one of the country’s leading infectious disease experts. Drawing on Finland’s previously unstudied archive, and synthesizing decades of scholarship by a scattered but growing community of historians, Podolsky takes Finland and likeminded researchers as focal points in a larger study of conflicting conceptions of therapeutic rationality: debates about what drugs are appropriate to use and when it is appropriate to use them.

Researchers had been aware of the phenomenon of resistance from the beginning—Fleming even mentioned it in his 1945 Nobel Prize lecture—but the earliest systematic efforts at antibiotic reform were sparked by the rise of large marketing-oriented pharmaceutical companies and the influence they were perceived to exert on medical decision-making.

The sulfa drugs of the 1930s, followed by penicillin and its great success in World War II, had ushered in an age of therapeutic confidence. Streptomycin cured tuberculosis; actinomycin even attacked large viruses blamed for cancer. But by midcentury, it looked as if scientific boom might be followed by commercial bust. The price of penicillin had plummeted, as worldwide production outpaced consumption. The new industry, having benefited from the rhetoric of the wonder drug, now needed a continuous supply of patentable products. Podolsky quotes Pfizer president John McKeen telling the New York Society of Security Analysts in March 1950 that “if you want to lose your shirt in a hurry, start making penicillin and streptomycin”—and that “from a profit point of view, the only realistic solution to this (antibiotic) problem lies in the development of new and exclusive antibiotic specialties.”

The profit problem was solved, at least temporarily, by the discovery of the tetracycline group of drugs. These compounds killed a broad spectrum of bacteria, including some penicillin couldn’t. Blitz marketing campaigns rapidly persuaded doctors and built a great new American industry. McKeen would tell the same security analysts in 1953 that “it has been possible to expand the sales of the Antibiotic Division rapidly only by using vigorous promotional techniques.” In scale, pharmaceutical companies began to resemble their more established and powerful counterparts in the chemical industry.

These changes took place in a social environment in which neither the relationships between companies and doctors nor those between companies and the state were well regulated. The American Medical Association even reduced its level of oversight, bringing to an end in February 1955 its Seal of Acceptance program, which had limited what could be advertised on the pages of its journal. In the wake of these developments, suspicions arose about the new forms of branding and advertising and their unchecked power over clinical practice. And Congress began to worry about price fixing. While drug prices from different suppliers looked alarmingly similar to some observers, doctors were exuberant about buying their products. “In the view of a key cohort of infectious disease experts,” Podolsky explains, “the traditional agencies relied on at least to examine, if not to curtail, such exuberance appeared to have neglected or abdicated their traditional responsibilities.”

Despite such misgivings among some experts, a narrative of therapeutic revolution through drug development had captured the public imagination. The fortunes of pharmaceutical manufacturers were tied to this rhetoric. Treatments of all kinds of illness were promised to come from so-called “fixed-dose combinations,” which combined in pre-specified ratios broad-spectrum antibiotics already on the market. It was the marketing of these drugs, in particular—the corporate bombardments of doctors with testimonials and mass mailings—that elicited the strongest criticism from Finland and others, igniting a debate that, Podolsky argues, would “irreversibly alter both antimicrobial therapeutics and the broader course of drug regulation in the United States.”

Suspicion crystallized around sales of Sigmamycin, a fixed-dose combination of tetracycline and oleandomycin. Among those supporting the drug’s vigorous promotion was the head of the FDA’s Division of Antibiotics, Henry Welch, who trumpeted it as inaugurating a third generation of “combined therapy” antibiotics, after the “narrow-spectrum” drugs penicillin and streptomycin and their broader spectrum successors.

Podolsky shows the dispute between fixed-dose enthusiasts and skeptics taking shape partly over the course of several annual antibiotics symposia Welch organized in Washington. At the first, in 1953, Welch’s colleague and business partner Félix Martí-Ibañez included in the meeting’s opening speech a colorful explanation of the fixed-dose rationale:

In the struggle between man and microbes, the latter defend themselves—as we do in war—by developing a growing resistance to the weapons which were lethal at the beginning but to which they may eventually become accustomed. The goal of the researchman, therefore, is to change weapons, to forge a new sword against each new shield used by the bacteria, to create antibiotic agents that, like modern Attilas, will destroy everything they encounter in their paths inside the last strongholds of the microbes.

Resistance, from this point of view, was cause not for caution but aggression. Three years later, after hearing papers espousing the clinical benefits of Sigmamycin at Welch’s fourth symposium, Finland authored an unsigned editorial in the New England Journal of Medicine warning physicians who “readily fall prey to the psychologic warfare embodied in the high-powered technics of modern sales promotion.” Following this up a few months later, Finland sounded a sharp criticism of the fixed-dose drugs in a telling article, “The New Antibiotic Era: For Better or For Worse?”:

Much of the clinical information presented [at the 1956 symposium] had the sound of testimonials rather than carefully collected and adequately documented scientific data. To be sure, properly conducted clinical studies may, in the future, support the claims and justify the enthusiasm for these or other combinations of antimicrobial agents, but it is incumbent upon those of us who are intimately concerned with the welfare of our patients to wait until such data are presented before we accept and acclaim any new agents or special formulations and recommend them for general use, particularly in view of their great potential for harm when they are used extensively and indiscriminately.

Voicing what would become a powerful town-versus-gown counterargument, Welch replied that for the majority of practicing physicians, who lacked laboratory support and had to rely on practical judgment and clinical experience, Finland’s concerns risked being “entirely academic.” Podolsky suggests that in these exchanges “an emerging hierarchy of medical knowledge was being formulated, with the ‘testimonial’ at one end and the controlled clinical trial at the other.”

A regulatory hierarchy was being formulated, too. In the post-war era, the Great Depression was still a close memory, and concerns about monopoly and popular access to new technology were widespread. It was not hard to see the growing drug industry as a successor to the car industry, making available essential consumer products at prices that excluded the poor in order to maximize profits. Incited by senators and congressmen—who the pharmaceutical trade journal F-D-C Reports alleged “simply don’t like the prices they have to pay for drugs”—the Federal Trade Commission initiated a major inquiry in 1956. The investigation was carried out by a staff that had been closely involved with the Temporary National Economic Committee’s pre-war scrutiny of big business; in attacking the institutional structure of the new pharmaceutical industry, they were continuing essentially the same fight. In 1958 the FTC published its findings, and the report’s authors moved to the Senate Subcommittee on Antitrust and Monopoly, known for its criticism of the automobile, steel, and bread industries.

The committee was led by Tennessee’s veteran democrat Estes Kefauver, who had developed a significant public profile for his earlier role in exposing the American mafia. Kefauver threw himself into a defense of the little man in a series of hearings on prices and competition in the pharmaceutical industry. A byproduct of the proceedings was the exposure of Welch who, with Martí-Ibañez, co-edited and co-owned both the leading antibiotic journal of the day and the Medical Encyclopedia. The FDA had approved his move into publishing, viewing it as a means of assuring scholarly standards, but Welch learned how to parlay great influence into rich personal advantage. He retired on grounds of ill health on the eve of being summoned to testify before Congress in 1960.

The Kefauver Committee heard testimony from many leading physicians, including Finland, and proposed mechanisms for regulating the rapidly burgeoning industry and mitigating the excessive weight of marketing. This anti–big business report would have been sidelined had not the press just revealed that the United States had only narrowly averted a thalidomide disaster thanks to the keen eyes of a FDA single inspector, Frances Kelsey. In the wake of public outrage, Kennedy’s government speedily supported new regulation, and the Kefauver-Harris amendments to the 1938 Food, Drug, and Cosmetic Act were passed in 1962. Podolsky makes a good case for the importance of this legislation in the FDA’s increasing authority over the efficacy of drugs.

Yet law changed faster than society. The FDA commissioned the National Academy of Sciences (NAS) to perform a retroactive efficacy study of thousands of drugs already on the market. In an illuminating treatment, Podolsky follows this work throughout the 1960s, showing that structural change was long and tortured. The NAS rejected the efficacy of most fixed-dose combinations, but its recommendations took years to be implemented and instigated decade-long challenges in Congress and the courts. Perhaps the highest-profile challenge came from the Upjohn Company, which manufactured one of the industry’s most profitable and heavily prescribed fixed-dose combinations, Panalba. The efforts of fixed-dose critics—and “rational therapeutics” crusaders more generally—were finally vindicated in 1970, when the Sixth Circuit ruled in favor of the FDA, and Panalba was removed from the market.

The most valuable part of Podolsky’s book is his treatment of the ramifications of these changes throughout the 1970s and ’80s. The efficacy review process “had generated a vocal backlash against centralized attempts to further delimit individual antibiotic prescribing behavior . . . resulting in generally failed attempts to control prescribing at local, let alone regional or national, levels in the United States.” Indeed, the institutionalization of the clinical trial had been a “pyrrhic” victory: “while the FDA had been empowered to remove seemingly ‘irrational’ drugs from the marketplace, no one had been empowered to rein in the seemingly inappropriate prescribing of appropriate drugs.” The rights and responsibilities of prescribers is a huge subject, but Podolsky keeps it manageable by focusing on debate among a small number of people. He identifies a town-versus-gown element in which elite physicians, worried about the principles of antibiotic resistance, confronted a mass of practicing doctors who had to contend with patient expectations. Podolsky shifts his attention to such organizations as the Infectious Diseases Society of America (IDSA) as agents of reform and reflects on the criticism the society elicited from doctors and hospitals for its recommendations about prescription practices.

What can historical reflection tell us about our confrontation with resistance today? Podolsky’s work invites at least three lines of thinking.

One is that we should see ourselves in the middle of a decades-old search for rational therapy, evidence-based medicine, and sensible stewardship. But the challenge of resistance is at once biological and social: illnesses themselves, with their various etiologies and cures, cannot be cleanly separated from the authority of doctors, the cost of healthcare, the economic structure of the pharmaceutical industry, the need for cheap food, and the boundaries of the state. What counts as rational depends on how we interpret the problem, and interpretations have varied across both space and time. In the United States the medical profession has resisted external regulation, but in such European countries as Sweden, prescription control has a long tradition.

Second, while the PCAST report is strong on biological challenges and administrative responses, Podolsky’s work highlights the challenge of centralized oversight of prescription practices, in which culture as well as biology plays a significant role. “The regulation of antibiotics in the United States remains decentralized,” Podolsky concludes: “Even the specter of a post-antibiotic era has not overcome resistance to more centralized strategizing regarding this most central component of the therapeutic armamentarium.” The Antibiotic Era is a timely reminder of seven decades of mediation between central intent and local response.

Finally, we must adopt a wider view of what forces and actors are at work: it is not just a matter of doctors and patients. Podolsky’s valuable study draws our attention to many such neglected forces, but it largely leaves out the role of antibiotic usage in agriculture and animal husbandry; that essential dimension must continue to be studied by others. And we must extend our view not just socially and economically but geographically. No longer can we exclude any part of the world from the bacterial ecosystem. Indeed, one of Podolsky’s central themes is the broadening of infectious disease thinking from the local to the global. It is one of the ironies of history that the world’s first antibiotic resistant pneumococcus arose during the 1960s in the Trobriand islands off the eastern coast of New Guinea, which forty years earlier had been studied by the anthropologist Bronisław Malinowski for their remoteness.