Penicillin for Pneumococcal Pneumonia.

“In the Mortality Bills,” wrote William Osler in 1905, “pneumonia is an easy second, to tuberculosis; indeed in many cities the death-rate is now higher and it has become, to use the phrase of Bunyan, the captain of the men of death. ” The statement remained true for another four decades. Yet, in only a few years, in the 1940s, a new treatment for this frequently fatal disease changed its outcome in a profound and lasting way. The standard of care for pneumococcal pneumonia in the United States in 1943, as defined by Russell Cecil in that year’s edition of his Textbook of Medicine by American Authors, focused on the general care of the patient, relief of symptoms, and specific measures for the treatment of infection. The introduction of sulfonamides was still considered revolutionary on the basis of a report from Birmingham, England, which had indicated a fatality rate of 8% in 100 cases treated with sulfapyridine and 27% in a control group in 1938. The oral administration of the drug was frequently associated with severe nausea, followed sometimes by intractable vomiting. Intravenous dosing did not prove effective, and the concentration of the drug for intramuscular route had not been established. A second molecule, sulfathiazole, had become available in 1939 and produced a significantly lower incidence of nausea. Just 1 year later, trials indicated that a third sulfonamide derivative, sulfadiazine, was just as effective, but less toxic than its predecessors. In the practice of Cecil on the wards of New York Hospital and Bellevue Hospital, the initial oral dose of sulfadiazine ranged from 2 to 4 gm and therapy continued with 1 gm every 4 hours until the patient remained afebrile for 24–72 hours. A soluble form of the drug was also available for “emergency” intravenous administration, usually as a single dose of 5 gm. Sodium bicarbonate was added to the regimen in dosages sufficient to maintain the urine alkaline and thus prevent crystalluria, a common adverse effect of sulfonamides. Cecil described in detail the potential for serious and potentially fatal toxic effects of sulfonamides, such as acute renal failure, leukopenia, hemolytic anemia, hepatitis, and peripheral neuropathy and outlined the principle for their recognition and prevention. He also mentioned his own observations with regard to acquired hypersensitivity, characterized by fever, morbilliform or urticarial rash, angioneurotic edema, and systemic reactions. “Sulfonamide-fast” pneumococci were first identified in the Alexander Fleming’s laboratory in 1939. Of great concern was the demonstration that pneumococci could change from susceptible to resistant during the course of treatment, a phenomenon that contributed to the mortality rate in patients with pneumonia. In the case of a 62year-old patient admitted gravely ill to Bellevue Hospital in New York City with pneumonic consolidations of the right middle and lower lobes and type 1 pneumococcus in blood culture, the fever decreased by the third day during treatment with sulfadiazine intravenously and orally but rose again 1 day later. A blood culture obtained on the eighth hospital day indicated persistent bacteremia despite therapeutic plasma levels of sulfadiazine. The patient remained acutely ill until she was injected with type 1 antipneumococcal rabbit serum. A search for an alternative form of chemotherapy was immediately started, and pioneering animal experiments performed by William Tillett’s group at Bellevue in 1942 indicated that all sulfadiazine-resistant strains of pneumococci were sensitive to penicillin. Systematic laboratory investigations of bacterial inhibition by penicillin were started by Howard Florey in 1929 and concluded successfully at Oxford after Ernst Chain joined this effort in 1938. A small number of victims of the German bombing of England were treated with penicillin in London in the winter of 1940– 1941. As the existing supply was almost immediately exhausted, Florey came to the United States in July 1941 to look for ways of starting large-scale production of the drug. He met with officials from the Department of Agriculture who understood the importance of the project. An agreement was reached with the US Office of Scientific Research and Development to start production of naturally fermented penicillin at the Northern Regional Research Laboratory in Peoria, IL. The facility had already been involved in fermentation experiments using corn-steep liquid, a by-product of corn starch manufacture, which proved to be an adequate medium for the culture of penicillin-producing molds. The results of the first clinical trial of penicillin for pneumococcal pneumonia in the United States were communicated on November 4, 1943 at a meeting of the New York Academy of Medicine. The 46 patients described in the report had been treated with penicillin at Bellevue in the 1942–1943 season. A second group of 61 patients was treated in the 1943–1944 season, and the effect of penicillin in the entire sample (N 5 110) was submitted for publication to the Journal of Clinical American Journal of Therapeutics 23, e326–e327 (2016)