Resistance

Microbial resistance was first recognized in the late nineteenth century, when students from the laboratories of Robert Koch in Germany and Louis Pasteur in France tested agents to disinfect germs contaminating hospital environments. ^{Reference Kossiakoff1} In 1887, Pasteur’s student M.G. Kossiakoff unexpectedly found that bacteria initially killed by the antiseptics boric acid and bichloride mercury became “tolerant” to them. ^{Reference Kossiakoff1} He used the term “resistance” to describe microbes that required increasing concentrations of antiseptics to destroy them. ^{Reference Kossiakoff1} In the following decades, researchers noticed resistance in other experimental settings. In 1906, Paul Ehrlich, a Koch student, observed that trypanosomes became resistant to the azo and trypan blue dyes he was using to kill the microbe in his murine model. ^{Reference Ehrlich2} In 1910, Julius Morganroth, another Koch student, described resistance in mice infected with Pneumococcus spp that were treated with a quinine derivative, optochin. ^{Reference Morgenroth and Levy3}

By the early twentieth century, physicians noted that bacterial resistance occurred not only in experimental settings but also in clinical practice. In 1917, Rockefeller Institute researchers Henry Moore and Alan Chesney noticed that pneumococci isolated from respiratory specimens of humans treated with optochin required increasing amounts in vitro to inhibit growth. ^{Reference Moore and Chesney4} The drug was never widely used in medical practice, however, because of prohibitive toxicities (eg, deafness and blindness). ^{Reference Moore and Chesney4} Physicians continued the search for an effective, nontoxic drug during a time when they relied on antisera in clinical settings. In 1937, they encountered resistance to a modified azo dye, prontosil, developed by the German researcher Gerhard Domagk, in streptococci recovered from sputum of patients receiving therapy. ^{Reference MacLean, Rogers and Fleming5} Enthusiasm for using sulfa clinically, however, was tempered by concerning, albeit not life-threatening, toxicities (eg, rash and gastrointestinal intolerance). By 1941, a new, less toxic antimicrobial, penicillin garnered immediate favor among physicians when it was used to treat infected battle wounds during World War II. ^{Reference Abraham, Chain and Fletcher6} Resistance among staphylococci was observed immediately following penicillin use in humans. ^{Reference Rammelkamp and Maxon7} By the 1940s, a pattern had emerged—resistance developed soon after antibiotics (a term coined in 1943 by medical researcher Selman Waksman) were used in clinical settings.

Misuse of antibiotics

Most physicians at the time, however, overlooked resistance as a matter of clinical concern. ^{Reference Abraham, Gale and Davies8} They were captivated by the powers of antibiotics to cure infections that had previously been serious or lethal. ^{Reference Rouche9} Furthermore, technological advancements during the 1950s enabled mass production to overcome a major shortcoming of antibiotics—their limited supply. ^{Reference Rouche9} Now that drugs like penicillin were available in surplus, physicians and the lay public became attracted to the idea that potent antibiotics would someday render all infectious diseases obsolete. ^{Reference Rouche9}

Physicians became so confident in the powers of antibiotics that they sometimes prescribed them without restraint. Their habit was fueled by aggressive promotional activities of pharmaceutical companies during the 1950s. ^{Reference Gradmann10} By the 1960s, studies estimated that physicians frequently used antibiotics inappropriately—in 60% of cases—including times when the diagnosis was uncertain or viral infections were more likely to be present. ^{Reference Scheckler and Bennett11} As antimicrobials could potentially be beneficial, it appeared to physicians that there was no downside of liberally prescribing nontoxic and potentially effective drugs that were now available in surplus.

Medical reformers

In the 1950s, a group of university-based physicians recognized that physicians’ casual use of antibiotics posed a grave problem. Led by Maxwell Finland (Harvard), and including Louis Weinstein (Tufts), Harry Dowling and Mark Lepper (Illinois), Ernest Jawetz (San Francisco), and Hobard Reimann (Jefferson), these physicians had begun their careers in the 1930s before the availability of antibiotics. ^{Reference Finland and Weinstein12–Reference Dowling, Lepper and Jackson14} Although they acknowledged the success of antibiotics, they focused their investigative careers on exposing the hazardous complications of antibiotic overuse they had witnessed firsthand, including hastening resistance. ^{Reference Lepper15}

Finland showed that infections caused by antibiotic-resistant organisms were not only inevitable, they were also lethal. ^{Reference Finland16} He was not the first, however, to argue that antibiotic resistance was a medical concern. Alexander Fleming acknowledged the problem of penicillin resistance in 1945. ^{Reference Fleming17} Furthermore, Rene Dubos, a plant biologist, predicted that drug-resistant organisms could threaten the antibiotic model itself. ^{Reference Dubos18} The theoretical risk of resistance raised by Fleming and Dubos, however, was overshadowed by physicians’ enthusiasm for antibiotics. During this time, Finland was the first to actually demonstrate that antimicrobial overuse correlated with increased resistance and hospital mortality in his hospital setting. ^{Reference Finland16} He showed that mortality from infections at the hospital where he worked, Boston City Hospital, only temporarily declined following penicillin before reverting to pre-antibiotic rates. Patients in the 1950s, Finland concluded, continued to die of infections just as they had done before antibiotics were available. But this time, infections were due to drug-resistant organisms.

Finland and his colleagues illustrated how resistance was not solely due to imprudent prescribing habits. The changing hospital environment of the 1950s also fueled the emergence of resistance. ^{Reference Lepper15,Reference Finland19,Reference Moser20} The introduction of intensive care units designed to provide life support for patients who had complicated heart attacks or respiratory paralysis due to poliomyelitis provided an ideal milieu for the spread of resistant organisms. ^{Reference Dowling, Lepper and Jackson14} These units were equipped with new devices to prolong lives—mechanical ventilators to assist breathing through an endotracheal tube, cardiac monitors including those with telemetry, external pacemakers, defibrillators, dialysis equipment for renal problems, and equipment for constant monitoring and maintaining bodily functions, including intravenous catheters, feeding tubes, suction pumps, and drains. ^{Reference Reimann13} Finland worried that the changing hospital environment was enabling antibiotic-resistant organisms to develop so rapidly in hospitals that it might offset any benefit that antimicrobials provided.

Physician education and persuasion

In the 1950s, Finland and his colleagues decided to take action. They trusted that they could persuade physicians who had unwavering faith in antibiotics to curb their indiscriminant and dangerous habits by educating them about the harms of resistance. Finland and the reformers taught physicians to relinquish their habit of overusing antibiotics that enabled the emergence of resistant infections. ^{Reference Finland and Weinstein12–Reference Finland16} They also used the increasingly apparent toxicity profiles of antibiotics used at the time—penicillin, streptomycin, and aureomycin—to bolster their argument. ^{Reference Finland and Weinstein12} They told physicians they had paid too much attention to the accomplishments of antibiotics while downplaying their dangers—resistance and toxicities. ^{Reference Finland and Weinstein12} They relied upon education as their tool to persuade physicians to voluntarily restrain their harmful habit of overprescribing antibiotics while simultaneously advocating for hospital infection control practices—handwashing and wearing gloves—to curtail the spread of resistant microbes.

Over the following decades, Finland elaborated on the harms of antibiotic overuse in the hospital. From the 1950s to 1970, Finland collected longitudinal data again from Boston City Hospital demonstrating that the overall incidence of hospital infections did not diminish in the antibiotic era. ^{Reference Finland21} Rather, antibiotics had simply shifted the bacteriologic patterns of serious infections. The widespread use of antibiotics at Boston City Hospital during this period was accompanied by a decline in bacteremia due to Staphylococcus aureus and an increase in bacteremia due to Enterobacterales and fungi. Finland concluded that the major factor responsible for the changing ecology of serious bacterial infections was the selective pressure of antibiotics that were “so widely used and overused.” ^{Reference Finland21} He showed that infections continued to pose as much of a threat in the antibiotic era as they had before antibiotics were available. Only now infections had become more varied and complex due to injudicious prescribing patterns.

Finland grew increasingly alarmed about the changing spectrum of infections. He recognized that physicians did not have safe and effective drugs at hand to treat the new patterns of hospital infections and that patients were dying of infections just as they had done in the pre-antibiotic era. He maintained that the increases in these bacteremias had “much more than compensated for the difference in number of cases and numbers of deaths.” ^{Reference Finland21} He lamented that “the picture of serious bacterial infections, as reflected in blood stream invasion, is not a pleasant one to contemplate.” ^{Reference Finland21} He scolded physicians for their recklessness. He said, “The blame for this bad situation is largely due to [physician’s] excessive and universal resort to antimicrobials.” ^{Reference Finland21} Finland warned physicians that they were losing ground in combating hospital infections because they misused antibiotics.

Finland acknowledged that he had previously overestimated the willingness of physicians to reform voluntarily. He recognized that physicians armed with knowledge of the dangers of antibiotic overuse he had provided them had not moderated their prescribing excess. ^{Reference Finland22} New estimates showed that antibiotic overuse remained constant at 60%—it had never abated despite his warnings for 20 years. ^{Reference Finland22} Finland bemoaned that his attempts to voluntarily restrain physician habits through education had become nothing more than “another jeremiad from an old and experienced physician, teacher, and clinical investigator reaching the ‘end of his line.’” ^{Reference Finland21} He challenged a new generation of physicians to become “activists [to] reappraise our current efforts and to create novel methods of preventing and coping with the increasingly serious (hospital) infections.” ^{Reference Finland21} Resigned that physicians’ indiscriminate behavior had been refractory to his efforts of reform, Finland called for his trainees to take over the activism that he and his colleagues had begun.

Finland’s trainees accepted his challenge. They, however, adopted the same general approach of attempting to persuade physicians to restrain their excessive antibiotic prescribing behavior through education. Calvin Kunin, Finland’s former student, acknowledged that his mentor’s approach had resulted in “no overall change in prescribing patterns.” ^{Reference Kunin, Tupasi and Craig23} Kunin sought to directly address the motives of physicians whom he believed overprescribe antibiotics when they are uncertain or wish to avoid patient dissatisfaction and the possibility of a lawsuit. He challenged physicians not to succumb to meet the individual patients’ expectations over the long-term interest of microbial species. He concluded, “Overuse is to be condemned because it is wasteful and expensive.” ^{Reference Kunin, Tupasi and Craig23} Moreover, it would hasten the occurrence of the “antibiotic armageddon.” ^{Reference Kunin24} Kunin was stoking the latent fear of the finality of the antibiotic era to coax physicians to alter their habits voluntarily. In the 1970s, the idea of changing behavior to preserve a nonrenewable resource resonated with environmentalist discourses that had gained traction in society at large during the 1970s.

The imperative to reform overprescribing habits would wax and wane over the succeeding decades. It seemed less immediate in the 1980s as the influx of new antibiotics available to physicians for treating resistant organisms seemed plentiful. ^{Reference Powers25} With an abundance of newly marketed and effective drugs (eg, third-generation cephalosporins, quinolones, and β-lactamase inhibitors), anxieties about the end of the antibiotic era had waned. By the 1990s, however, apprehensions about antibiotic overuse resurfaced as an array of microbes (eg, vancomycin-resistant enterococci, methicillin-resistant staphylococci, and extended-spectrum β-lactamase–producing organisms) had developed resistance even to recently licensed antibiotics. ^{Reference Weber and Courvalin26}

The specter of an antibiotic armageddon resurfaced in the 1990s when there was a shortfall of new antibiotics in the pharmaceutical pipeline. Furthermore, increasing federal requirements to license antibiotics at this time became a disincentive for pharmaceutical companies to develop new ones. ^{Reference Rex, Eisenstein and Alder27} Regulations that required expensive development and low tolerance for risk on part of regulatory agencies charged with safety of the public became disincentives for companies to develop new drugs. ^{Reference Laxminarayan and Duse28} As a consequence of expanding resistance and contraction of new drugs, the number of effective antibiotics physicians had to treat resistant infection had dwindled. ^{Reference Weber and Courvalin26} Furthermore, the use of new tools (eg, therapeutic guidelines, cascade reporting of antimicrobial susceptibilities, and antibiotic handbooks) failed to persuade physicians not to use antibiotics unnecessarily. As Kunin alluded, physicians could not voluntarily resist what he termed “the seductive promise … of the drugs of fear,” especially during times when they could not be reassured that a dangerous infection was not present. ^{Reference Ehrlich2} Because physicians could not voluntarily moderate their antibiotic prescribing behavior, regulatory agencies acted to impose externally mandated restrictions on physicians’ liberty to prescribe. Voluntarism yielded to regulation during a time when there was heightened concern about antibiotic overuse.

Regulation

In the early 2000s, many hospitals adopted regulatory programs to control physicians’ antibiotic prescribing habits. Antibiotic restriction, however, was not an altogether new strategy. It had been implemented sporadically since the 1950s. In 1957, Hammersmith Hospital (London) showed a reduction in drug resistant staphylococcal infections after restricting penicillin use according to clearly defined indications. ^{Reference Barber, Dutton, Beard, Elmes and Williams29} Later, in the 1970s, Boston City Hospital placed antibiotics on a restricted list that was dispensed from the pharmacy only if authorized by a member of the infectious disease service. ^{Reference McGowan and Finland30} These hospitals had attempted to restrict antibiotic use well before this was embraced on a widespread scale in the 2000s.

From the 1950s to 1990s, efforts to control antibiotic prescribing were centered within infection control programs. In 1958, the American Hospital Association’s Advisory Committee on Infection required that all hospitals conduct surveillance for hospital-associated infections and establish an infection control program. ³¹ These programs formed the Comprehensive Hospital Infections Project (CHIP) network that tracked the widespread nature of hospital-acquired resistant organisms. In response to the findings from CHIP, the Centers for Disease Control recommended in 1970 that hospitals staff their programs with an infection control nurse and a hospital epidemiologist. ^{Reference Scheckler, Garner and Kaiser32} By 1976, the Joint Commission on Accreditation of Hospitals (JCAH) created infection control standards for these committees and they recommended surveillance personnel for each hospital. ^{Reference Hughes33,Reference Klapp and Ramphal34} But these committees were ineffectual because they lacked specific expertise and a specific strategy to limit unnecessary antibiotics. ^{Reference Dowling35} To address these shortcomings, the Infectious Disease Society of America (IDSA) issued specific recommendations on how to adopt restriction policies for the use of selected antimicrobials in 1988. ^{Reference Marr, Moffet and Kunin36} They recommended that all hospitals assemble an infection control committee composed of individuals who had expertise to construct antibiotic restriction lists—an infectious disease physician, infection control practitioner, a microbiologist and a pharmacist. ^{Reference Marr, Moffet and Kunin36} The IDSA gave guidance on how to release restricted agents when predetermined protocols are followed, and provide direction in developing policies and guidelines to survey antibiotic use. IDSA, however, stopped short of recommending that the committee be granted the authority to stop antibiotics in situations where they were given without meeting specified indications and these programs failed to reduce the spread of resistant organisms.

The imperative to salvage the threatened antibiotic model in the 1990s was followed by a call for more stringent regulatory programs. The multidisciplinary antibiotic stewardship programs created in the early 2000s enabled physicians to deny antibiotics that were prescribed without meeting an accepted indication. These programs required that restricted antibiotics must first be approved by a team of experts before they could be released for use. As early as 1997, some hospitals had reported that prior authorization programs resulted in a shift from expensive broad-spectrum antibiotics to narrower agents, saved costs, and increased susceptibilities to several drugs. ^{Reference White, Atmar, Wilson, Cate, Stager and Greenberg37} Furthermore, these programs did not compromise patient care or result in suboptimal antibiotic use, which had been a reservation of some infectious disease physicians. ^{Reference Dunagan and Medoff38} In addition to reducing antibiotic expenditures, prior approval significantly lowered rates of infection caused by drug-resistant bacteria. ^{Reference Frank, Batteiger and Sorensen39} Stewardship programs sought to improve antibiotic usage by adopting a model where experts were granted the authority to control physicians’ antibiotic choices by placing limits on them. With the authorization to discontinue an antibiotic chosen by a physician, through the mechanisms of automatic stop orders, therapeutic interchanges, or mandatory infectious diseases consultations for use, stewardship programs now had the teeth to restrict overuse that previous programs lacked.

In addition to possessing regulatory authority, stewardship programs represented a multidisciplinary, comprehensive enterprise that encompassed multifaceted elements of their antecedent antibiotic control programs. They incorporated conventional approaches of educating healthcare workers about the virtues of antibiotic restraint. But they also added new programmatic elements: a restricted formulary, a link to improved diagnostics to help identify the etiology of infections and direct therapy, and coordination with infection control measures to prevent transmission of resistant species. ^{Reference Fishman40} Although stewardship programs intended to standardize these tasks, there was ample flexibility built into the actual mechanics of restricting antibiotics to ensure the program could be tailored to the specific needs of hospitals. These methods included telephone approval, antibiotic order forms (written justification), automatic stop orders, direct interactions, implementation of control categories, and simple chart entry. Thus, stewardship programs systematized and integrated ad hoc activities of previous programs and empowered the discontinuation of unnecessary antibiotics through mechanisms that could be customized to individual hospital environments. In this sense, current antibiotic stewardship programs are essentially an outgrowth of earlier educational and restriction programs except they are more comprehensive, integrative, and they are empowered with the authority to place limitations on physicians’ prescribing habits.

In conclusion, reformers who recognized excessive antibiotic use as a problem in the 1950s learned that physicians would not voluntarily restrain their indiscriminate antibiotic prescribing habits. By the 1970s, hospitals resorted to implementing programs designed to limit antibiotic use through externally imposed restrictions. But these programs were ineffective as they lacked the authority to enforce antibiotic restrictions. When these efforts failed to modify physician behavior, programs designed to curtail antibiotic overuse by vesting infectious disease physicians with the authority to deny inappropriately prescribed antibiotics were adopted to prevent antibiotic resistant organisms from arising and spreading in the hospital.