Descripción diagrama “Sumarios del SCADA HMI”

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Taubman Center, University of Michigan Health System, Ann Arbor, Michigan, US

*E-mail: [email protected]

activity of a variety of factory-obtained dyes in his trypanosomal mouse model (Ehrlich, 1909). Using a laborious trial and error method, Ehrlich identified both azo and trypan blue dyes that killed the trypa-nosomes (Ehrlich, 1909), but he also described that the microbes concomitantly developed resistance to one or the other dye in a specific fashion. Noting that mice with dye-resistant strains did not survive treat-ment, he postulated that specific resistance would be lethal unless the mice were treated with an alter-nate agent (Ehrlich, 1909). Later, another student of Koch, Julius Morgenroth, described resistance in a different setting. He showed in 1910 that resistance to the bacterium pneumococcus developed when infected mice were being treated with a derivative of quinine, ethylhydrocupreine (optochin) (Morgenroth and Levy, 1911). Thus, by 1910, German researchers had iden-tified fundamental issues about resistance—its rapid onset, its ability to compromise antimicrobial effi-cacy, and its specificity, which could be averted by using an alternate drug.

Researchers also identified resistance as soon as antimicrobials were first used in humans. Optochin was licensed for use in humans in 1913, shortly after Morgenroth’s animal experiments (Bulloch, 1938). Physicians immediately observed that not all humans receiving the drug responded to therapy.

Seeking an explanation, Henry Moore and Alan Chesney, researchers at the Rockefeller Institute in New York, turned their attention to pneumococcal microbes recovered from respiratory specimens from humans who had failed therapy. They showed that these microbes required larger amounts of optochin than previously employed to inhibit growth in vitro, a phenomenon they called “fastness” (Moore and Chesney, 1917). They speculated that the pneu-mococcus organism could be “educated” to grow in the presence of a particular drug to which it had been exposed (Moore and Chesney, 1917). Optochin never gained widespread traction for use in humans, not because of resistance, but because it gave rise to troubling toxicities—including tinnitus, deafness, and blindness. In the absence of a safe alternate drug, physicians opted to use antisera to treat pneumo-coccal infections (Kazanjian, 2004). Although serum therapy was effective, it also had its own set of problems. Allergic reactions developed in response to horse sera and delays resulted from a need to identify a particular strain of pneumococcus and then match it with the strain of the pneumococcal isolate (Finland and Sutliff, 1933). Meanwhile, to circumvent these problems, investigators continued

a vigilant search for an effective, nontoxic chemo-therapeutic agent to treat human infections.

It was not until two decades later that newly discovered antimicrobial agents became available for use in humans. In 1936, Gerhard Domagk, a German pathologist, developed a chemically modi-fied azo dye, prontosil—the first sulfa drug—which was effective when given to animals infected with streptococci (Domagk, 1935). Shortly thereafter, prontosil was shown to be effective in humans with pneumonia and urinary infections. Concomitant with its use in humans, resistance to prontosil was demonstrated in bacteria isolated from the sputum and urine of patients who failed therapy (MacLean et al., 1939). As was the case for optochin, enthusi-asm for using this sulfa drug was tempered not by the development of resistance, but by its array of toxic side effects, including rash and gastrointesti-nal intolerance. By 1941, however, a new antibi-otic, penicillin, garnered immediate favor among physicians when it was first used to treat infections in soldiers wounded in battle during World War II (Abraham et al., 1941). Unlike the earlier antimi-crobials, enthusiasm for penicillin soared, in part because of its comparatively low toxicity profile.

As had been the case with the earlier drugs, resist-ance among some bacteria, especially staphylo-cocci, was described immediately following use of penicillin in humans (Rammelkamp and Maxon, 1942). Investigators in the 1940s noted a pattern—

it seemed almost inevitable that a pathogen devel-oped resistance soon after antibacterial drugs had been used in humans.

Is Resistance a Problem?

Did physicians view resistance as a clinical concern, or merely an insignificant by-product of antibiotic therapy? The dominant view among physicians up to the mid-20th century was that resistance was a trivial occurrence that could be overlooked (Abraham, 1953). This attitude, which may seem cavalier today, becomes comprehensible when it is considered in its historical context. Resistance emerged during the progressive era in the late 19th century, a time when belief in science as a means to deliver certain, dependable medical therapies was at its apogee (Diner, 1998). Anti-infective therapies were the most noteworthy achievement of scientific medicine at the time, and acknowledging resistance as a prob-lem could only tarnish the luster of the triumphant narrative of scientific medicine (Kazanjian, 2004).

The early faith in biomedicine was later reinforced when penicillin was introduced during World War II. At the time, a belief in advanced technology, including new weapons to defeat the enemy or anti-biotics to keep the troops healthy after sustaining battle wounds, was viewed a key factor responsible for America’s victory (Kazanjian, 2004). The meta-phor of penicillin as a miracle drug that could van-quish microbial enemies was carried over to the postwar civilian period. During the 1950s, techno-logic advancements enabled mass production to overcome what was perceived to be penicillin’s one limitation—its limited supply (Roueché, 1953).

Now that the drug was available in surplus, people became captivated by the hope that potent antibiot-ics, together with effective vaccines, would someday render infectious diseases obsolete (Winslow, 1943).

If physicians were to acknowledge resistance as a problem, it would only deter this confidence in bio-medicine. Moreover, physicians could now witness firsthand the drama of restoring health to humans who had infections that would have previously been lethal. This memory would strengthen their already unwavering faith in penicillin.

Physicians became so confident in the powers of penicillin and the antibiotics that were to follow that they were willing to prescribe them without restraint. How often did physicians actually use antibiotics in circumstances where they had no demonstrated benefit? By the 1960s, a group of medical researchers studied physician prescribing habits and showed that physicians used antibiotics inappropriately in 60% of cases, including circum-stances when the diagnosis was uncertain, or in situations where viral infections were more likely to be present (Scheckler and Bennett, 1970). As antimicrobials could potentially be beneficial, what was the downside of overprescribing drugs that physicians believed had magical powers and were now available in surplus?

In the 1950s, when optimism about the miracle drugs was at its pinnacle, a cadre of academic medi-cal investigators in the US argued that physicians’

casual use of antibiotics posed a grave problem. These physicians, led by Maxwell Finland at Harvard, Louis Weinstein at Tufts, Harry Dowling and Mark Lepper at Illinois, Ernest Jawetz at San Francisco, and Hobard Reimann at Jefferson, had begun their careers in the 1930s before antibiotic availability (Finland and Weinstein, 1953; Dowling et al., 1955;

Reimann, 1961). Acknowledging the success of anti-biotics, they nonetheless focused their investigations

on antibiotic misuse, which they witnessed firsthand, and the effects of resistance on populations. They linked antibiotic overuse with the hastening of resistance, which by then had accompanied aureo-mycin in the 1950s (Lepper, 1955). Finland (1960) showed that infections caused by the antibiotic-resist-ant organisms in the 1950s were not only inevitable, they were as lethal as those anteceding antibiotics.

He was not the first to argue that antibiotic resist-ance was a medical concern; this had previously been noted following the use of optochin and sulfa drugs (Moore and Chesney, 1917; MacLean et al., 1939). In addition, Alexander Fleming acknowledged that resistance to penicillin posed a problem in his Nobel Prize acceptance speech in 1945 (Fleming, 1999). Later, Rene Dubos, a plant biologist, pre-dicted that drug-resistant organisms could threaten the antibiotic model itself (Dubos, 1959). However, Finland was the first investigator to use large-scale numbers to demonstrate that the increasing rates of resistance were associated with increased mortality (Finland, 1960). He showed that mortality from these infections, which had declined following the discovery and use of penicillin, had reverted in the 1950s to rates that preceded the introduction of antibiotics in the 1930s. Patients died of infections from drug-resistant microbes just as they had done before antibiotics were available.

The physician investigators argued that the unse-lected use of antibiotics in the new hospital environ-ment of the 1950s facilitated the developenviron-ment of harmful resistance. New hospital structures, together with antibiotic overuse, compounded the acceleration of resistance (Finland, 1955). Changes in the hospi-tal environment, the physicians showed, encour-aged the rapid spread of resistant organisms among patients in intensive care units (ICUs) designed to provide life support for patients who had complica-tions from heart attacks and to house ventilation systems for polio patients whose respiratory mus-cles were paralyzed (Dowling et al., 1955). These units were equipped with devices that were used 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, equipment for constant monitoring of bodily functions, and an array of intravenous catheters, feeding tubes, suction pumps, and drains (Reimann, 1961). Physicians realized that the new hospital setting provided an environment that per-mitted the rapid transmission of bacteria from one

person to another. Together, combination of the new nosocomial structures and imprudent physician pre-scribing habits fueled the increase in antibiotic resist-ance (Moser, 1956). The physician investigators argued in the 1950s that the problem of antibiotic-resistant organisms was developing so rapidly in hospitals that it offset any benefit that antimicrobi-als provided.

Finland and his colleagues were not content to simply observe this alarming trend. They decided to take action. How, they wondered, could physicians who had such unwavering faith in the miraculous drugs be persuaded to curb their indiscriminant and dangerous prescribing habits? The physician inves-tigators resorted to the method they were most familiar with—education. They had faith that knowledge of the potential harm in encouraging resistance would be a sufficient deterrent for physi-cians to overuse antibiotics. The medical researcher–

educators relied on the belief that knowledge would change physician behavior—but, as it would turn out, they underestimated the unwillingness of physi-cians to relinquish their habits of using antibiotics in circumstances where they were not absolutely necessary. The task of persuading physicians to vol-untarily moderate their unrestrained antibiotic- prescribing behavior would prove daunting.

Physician Education

Finland and others told physicians in widely read jour-nals in the 1950s that they had become too compla-cent and must correct their habit of giving antibiotics casually. The physician researcher–educators were telling physicians that they had been too optimistic about antibiotics (Reimann, 1961). They acknowl-edged that antibiotics definitely had favorable accom-plishments in saving lives of people who would have otherwise died, but noted that they also created a problem of their own by enabling resistant infec-tions (Finland, 1960). They also used the array of newly recognized side effects of the drugs, which became apparent by the 1950s following the licens-ing of penicillin, streptomycin, and aureomycin, to bolster their argument (Finland and Weinstein, 1953).

They asserted that too much attention had been paid to the accomplishments of antibiotics as opposed to their dangers, which also included resistance and toxicities (Finland and Weinstein, 1953). In other words, they were using education as a method to persuade physicians to restrain their harmful habit of overprescribing antibiotics.

By the 1970s, the medical researchers elaborated on the previously recognized harms caused by anti-biotic overuse. Clearly, antianti-biotics had not eliminated infections, as some had earlier predicted. Finland showed that overall incidence of hospital infections did not diminish in the antibiotic era (Finland, 1970).

Rather, antibiotics simply shifted the bacteriologic patterns of serious infections. Finland noted that the widespread use of antibiotics at Boston City Hospital (Massachusetts) over the years was accompanied by a decline in bacteremias due to Staphylococcus aureus and an increase in much less frequent causes of bac-teremias due to enterobacteriaceae and fungi. Finland concluded that the major factor responsible for the changing ecology of serious bacterial infections was the selective pressure of antibiotics that he claimed were “so widely used and overused” (Finland, 1970).

Thus, infections continued to pose as much of a threat three decades into the antibiotic era as they had before antibiotics were available, but the problems that physicians had previously encountered had now become more varied and complex.

Finland grew anxious about this changing spec-trum of infections that had emerged by the 1970s. He recognized that the problem with the new infections was that physicians did not have safe and effective drugs at hand to treat them. Consequently, patients were dying of infections just as they had done before the antibiotic era. He said that the increases in these bacteremias, then uninfluenced by licensed drugs, had “much more than compensated for the difference in number of cases and numbers of deaths”

(Finland, 1970). He lamented that “the picture of serious bacterial infections, as reflected in blood stream invasion, is not a pleasant one to contemplate”

(Finland, 1970). He admonished physicians for their recklessness. He said the “blame” for this “bad situ-ation” is largely due to [physicians’] excessive and universal resort to antimicrobials” (Finland, 1970).

That is, physicians, through their widespread use of antibiotics, had created a problem that was worse than the one they had started with.

By the 1970s, Finland was disconsolate that his attempts to change physician behavior through edu-cation had been ineffectual. He admitted that despite his fervent efforts, his educational tactic had had no impact whatsoever on reducing the emergence of resistant bacteria. Physicians, armed with knowledge of the dangers of antibiotic overuse, had, he acknowl-edged, not moderated their uncontrolled habits (Finland, 1979). Furthermore, antibiotic overuse had not abated at all over the past two decades despite

his warnings, as physicians misused antibiotics at the same rate, 60%, as they had done earlier (Kunin et al., 1973). Finland became resigned that promis-cuous antibiotic use was an incorrigible habit which was not subject to voluntary restraint through edu-cation. He lamented that his attempts were becom-ing nothbecom-ing more than “another jeremiad from an old and experienced physician, teacher, and clinical investigator reaching the ‘end of his line’” (Finland, 1970). He then threw down the gauntlet to a new generation of physicians to become what he called

“activists” to “reappraise our current efforts and to create novel methods of preventing and coping with the increasingly serious (hospital) infections”

(Finland, 1970). The old guard of physician educa-tors admitted that their tactics to resolve the problem of antibiotic overuse through education had failed.

Thus, a look into the period of the 1940s through 1970s from the perspective of antibiotic resistance shows that it was not the “golden era” antibiotic arcadia that current physicians view it as being. We have romanticized this era as being something that it never was. There was gold, Finland admitted—in curing infections in individual patients that had once been lethal—a dramatic and powerful experi-ence for patients and doctors at their bedsides, but the gold had always been tarnished by the recogni-tion that antibiotics had never diminished fatalities on a population level. Rather, antibiotics shifted the infections that were responsible for death in hospi-tals. Throughout this time we now view as golden, we hear the voices of physicians who were alarmed by the problems caused by antibiotic overuse and dismayed by their feckless attempts to reverse it.

Resigned that physicians’ behavior had been refrac-tory to their outspokenness, they called for their trainees to take over the cause that they had begun.

Finland’s trainees indeed dutifully accepted the invi-tation to become the activists that their mentor had requested, but like Finland, they too were researcher–

educators who used the same tools of their mentors—education—to moderate excessive anti-biotic prescribing. Operating under the same belief that education would favorably change physician behavior, the new breed of activists recast the argu-ment to resonate with arguargu-ments made in other spheres at the time. They emphasized that antibiot-ics would be become a lost resource unless physi-cians learned to use them more cautiously. In the 1970s, they had aligned their argument of preserving a nonrenewable resource with discourses in other spheres that were garnering credibility and government

action. At this time, environmentalists argued to reduce the consumption of fossil fuel use in order to preserve nonrenewable resources (A+E Networks, 2010). The environmentalist movement became mainstream in America in the 1970s when the gov-ernment created the United States Environmental Protection Agency (US EPA), a body that was granted lawmaking powers, and America designated an annual Earth Day dedicated to conserving resources (US EPA, 2016). The new generation of antibiotic activists both reinforced and heightened their argu-ment by aligning it with arguargu-ments made by envi-ronmentalists to conserve nonrenewable resources.

In addition to echoing themes of the environ-mentalists, the new generation of medical investiga-tors sought an explanation for the ineffectualness of its forbear’s arguments. Calvin Kunin, a trainee of Finland’s, acknowledged “since the beginning of the antibiotic era,” educational efforts had resulted in “no overall change in prescribing patterns”

(Kunin et al., 1973). Seeking to understand the reluctance to change habits from the perspective of the prescribing physician, Kunin speculated that physicians prescribe antibiotics during periods of uncertainty to avoid disastrous outcomes or out of fear of patient dissatisfaction and possibility of a lawsuit. He argued that clinicians had succumbed to perceived pressure to give priority in clinical set-tings to the immediate risk of individual patients over the long-term interest of microbial species to meet patients’ expectations. Perhaps aware that he could not alter these factors, Kunin resorted to the same assertions of his predecessors, but delivered them more trenchantly. He stated acerbically, “over-use is to be condemned beca“over-use it is wasteful and expensive” (Kunin et al., 1973). Next, he warned that the problem increased the cost of medical care, and that one person’s overuse affected all physicians (Dowling et al., 1955). Finally, he asserted that antibiotic overuse would hasten the occurrence of the “antibiotic Armageddon” (Kunin, 1997). Kunin was stoking the latent fear of the finality of the antibi-otic era as a deterrent to overuse, even though warn-ings of hastening the end of the antibiotic era had previously been insufficient to coax physicians to alter their habits.

Throughout the antibiotic era, the anxieties that physicians expressed about the ending of the anti-biotic model have fluctuated in response to changing social and biological circumstances. The optimistic mood in the powers of biomedicine to terminate the world’s epidemics in the 1950s overshadowed

any consideration of resistance as a problem. This confidence had cooled by the 1980s, when AIDS shattered the false belief that infectious diseases would succumb to the laboratory’s insights (Kazanjian, 2014). With a deluge of new antibiotics available for physicians to treat infections in the 1980s, the imperative to reduce overprescribing habits seemed less immediate as the number of agents available

any consideration of resistance as a problem. This confidence had cooled by the 1980s, when AIDS shattered the false belief that infectious diseases would succumb to the laboratory’s insights (Kazanjian, 2014). With a deluge of new antibiotics available for physicians to treat infections in the 1980s, the imperative to reduce overprescribing habits seemed less immediate as the number of agents available