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The advent of antibiotics: Episodes from the early days of the “miracle drugs”

1999; Elsevier BV; Volume: 126; Issue: 1 Linguagem: Inglês

10.1067/msy.1999.98701

1532-7361

Francis D. Moore,

Bacterial Identification and Susceptibility Testing

Although the sulfonamides had arrived piecemeal in the late 1930s, with sulfanilamide leading the list followed by many others including sulfathiazole, sulfadiazine, and the widely heralded “sulfamiracle,” we were largely unprepared for the reality of penicillin. We had heard about the work of Florey and Fleming before any of the remarkable new substance arrived in the early months of 1943. The story of Fleming's bacterial culture plates and his serendipitous observation that those plates contaminated with a common bread mold, penicillium, showed signs of growth inhibition, was told and retold both by bacteriologists and in the newspapers. But none of this prepared us for the reality of penicillin, its remarkable clinical effects, and its almost total lack of toxicity. Less often analyzed was the passage of almost 10 years between Fleming's first observations and its recognition, refinement, and development for clinical use, done in collaboration with Florey. When the first small batches of rather impure penicillin became available during the war years, I was finishing my residency and starting out as assistant to Leland McKittrick, whose practice included many diabetics with gangrene, often requiring amputation. During that same period (1939-1947) I was also working with Oliver Cope in the care of burns. We had an active burn treatment unit at Massachusetts General Hospital, with the patients largely concentrated on the 12th floor of the newly completed George Robert White Building. The recent Cocoanut Grove fire (November 1942) had thrust on us a massive experience with the treatment of burns, demonstrating a few strengths in the treatment programs then in use and many severe weaknesses, especially in the pulmonary injury of burns, an area in which Cope's work broke new ground and I was privileged to take part. As tiny doses of penicillin became available, they were administered with great caution and close attention to the results. Although we were not yet afflicted with human use committees, there was plenty of motivation to use the materials carefully and sparingly and to document the results. There was a desire to avoid the incautious excesses that had characterized the introduction of sulfanilamide only a few years before. At that time, for example, an orthopedic surgeon ground up some sulfanilamide pills into a sort of fine powder that was then placed in a sugar shaker and “powdered” throughout the dissection area of orthopedic operations. No one ever measured the blood levels that resulted from this sudden massive dose, and I do not recall any cases of renal failure resulting from them. As one critic wryly observed, “If he just scattered the powder a little further, it would sterilize the entire county.” Possibly hopes were highest for its use in severe burns, and we felt that some of the most spectacular opportunities for the saving of life were evident in burns. Occasionally, remarkable results were observed. I remember in particular a severely burned patient who seemed to have a spreading systemic infection, the sort of spreading cellulitis that was often lethal. At that time I was working under the guidance of Oliver Cope. He instructed me to determine whether this patient might possibly receive some penicillin as soon as we received our weekly batch that afternoon. I visited the patient several times that evening, hesitating to spend our precious penicillin if it was not needed. Sometime around midnight the patient underwent a sort of “crisis” and was suddenly and hugely better. The crisis was possibly engendered by a sudden increase in immunocompetence or the sudden release of antibodies or immune lymphocytes. But to us it just looked like a sort of “crisis” (as often observed in pneumonia) occurring in a burned patient. This was not the first time that such a sudden turn had been observed. We could save the precious penicillin for someone else. Because we had only a small amount of penicillin, it was obvious that it was unwise to waste this precious material on a patient who was getting better anyway. Because I was in the operating room the next morning at the time of rounds, I was not in attendance when Oliver Cope came to see the patients with his students. In any event, Dr Cope, arriving on the ward immediately asked to see the patient who presumably had received the penicillin. The patient was hugely better. There was elation. Dr Cope told the students about the remarkable effect of penicillin. The nurses in attendance were very tactful and did not mention that in point of fact the patient had received no penicillin whatsoever. Enthusiasm carried the day. Those students were given a mental picture of the wonderful effects of this new miracle drug that, although totally erroneous regarding that patient, might have served some worthy end. Several hours later I told Dr Cope that we still had quite a bit of penicillin if any was needed. He asked, rather critically, “Didn't you give it to that patient with the spreading cellulitis?” I replied in the negative, indicating that the patient had been through a sort of”crisis” and suddenly got much better sometime around midnight, without any new drugs. I am not sure he perceived the irony of his enthusiasm with the students on the effect of penicillin. In any event, this is not a story on Oliver Cope, on the nurses, or on myself but merely an indication of the unbridled enthusiasm that surrounded the introduction of penicillin. The principal effect of penicillin in burns was to avoid or abate the early invasive infections that were sometimes fatal and to improve the success of skin grafts. Wound closure was essential for recovery. The most spectacular case of penicillin response that I can recall was in a patient of Dr Edward Churchill who had undergone a thoracoplasty. Dr Churchill had for many years carried out surgery in the treatment of pulmonary tuberculosis. He did many thoracoplasties to assist in collapse therapy, and in cases of bronchostenosis he occasionally did a lobectomy or even a pneumonectomy. Some of these provided spectacularly good results. One of these patients who had undergone a thoracoplasty a day or 2 before (with its attendant massive tissue dissection of the chest wall) was suddenly afflicted with a widespread, massive, virulent, and spreading cellulitis with bright pink coloration. It did not take a great deal of diagnostic acumen to make a diagnosis of “surgical scarlet fever,” a disorder always caused by β-hemolytic streptococci and usually fatal within a few days. The patient had a high fever and became toxic and disoriented and then comatose, and his blood pressure began to fall. The sulfonamides were helpful in such cases, but effects were rarely dramatic. The drugs were given by mouth to very sick patients whose gastrointestinal absorption might have been impaired. I suggested the use of some of our small supply of penicillin for this patient. Here indeed penicillin was at its best—a sensitive organism and spreading cellulitis. The patient had high fever and disorientation and was soon threatened with shock and death. It is difficult to describe the change that resulted from giving penicillin to this patient. The patient woke up, felt much better, and asked for food; his temperature came down; he began to make urine; and the storm was quickly over. Looking back on the introduction of antibiotics, there were few more spectacular patients than this, the right drug, the right micro-organism, and a huge “blood-bug interface.” The violent differences of opinion on penicillin (and soon thereafter on streptomycin) among the staff and between the medical department and the surgical department (only rarely based on quantitative knowledge) made this era one of great controversy but considerable patient benefit. The lack of toxicity of both penicillin and streptomycin was a providential dispensation that saved many of our patients from harm and helped many through this dark period. We soon learned that one of the beer companies was brewing the penicillium mold in huge vats, just the way beer was made. Penicillin soon became widely available in more adequate quantities. Now, 50 years later, there is still difference of opinion on the use of penicillin and other antibiotics in surgery. Although such differences of opinion are inevitable, the lack of toxicity of penicillin will remain one of the outstanding blessings of this century.