Producing Penicillin
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《新英格兰医药杂志》
Although Alexander Fleming discovered penicillin in 1928, the substance was largely ignored until scientists at Oxford University rediscovered it in the early 1940s. Because of World War II, with its air raids and threat of German invasion, the Oxford group sought help in the United States. The meagerness of the supplies of penicillin dictated its slow evolution as a chemotherapeutic agent. Its early history involved attempts to synthesize the chemical structure and to invent ways to produce larger quantities to meet the rapidly growing demand. As more and more types of infections were found to be susceptible to penicillin, it also became evident that military needs would command priority for the insufficient amounts available. In the fall of 1942, Charles Pfizer Company committed its citric acid–production facilities to the production of penicillin (through deep-tank fermentation), and the supply problem was on its way to resolution.
(Figure)
Penicillium notatum.
Hossler/Custom Medical Stock Photo
One type of infection that was conspicuously unresponsive in the initial trials of penicillin was streptococcal subacute bacterial endocarditis, a slowly progressive bacterial infection of heart valves that had been damaged, usually by rheumatic fever. Mortality among patients with this condition was 97 percent. The first trials were not encouraging: 17 patients were treated; 4 died, 10 showed no improvement, and 2 of the 3 who initially seemed a little better had relapses as soon as treatment was stopped.1
The day before the trial report was published, Dr. Leo Loewe and his associates at Brooklyn's Jewish Hospital found themselves at the bedside of a 34-year-old man with streptococcal endocarditis. They had treated him for six months — with huge doses of sulfa drugs, artificial fever therapy, heparin, and moderate doses of penicillin — without benefit. Now, out of sheer desperation, they tried a larger dose of penicillin: 200,000 units per day instead of the standard 40,000 units2 — a dose that is minuscule by today's standards, though it must have seemed enormous to them. The larger dose was given by a continuous intravenous drip, and the alpha-hemolytic streptococcus disappeared from the patient's blood; it reappeared when treatment was stopped, but a second several-week course of 200,000 units per day eliminated the organism permanently.2
After this cure, Loewe and his group saw patient after patient with endocarditis, many of them with advanced disease that had resulted in heart failure, emboli, or bleeding or leaking from ruptured mycotic aneurysms. The physicians turned none away, but all penicillin was now designated for military use. Fortunately, from the beginning of their adventures, the Brooklyn doctors had had the sympathetic ear of John L. Smith, the senior executive of Charles Pfizer, who furnished them with enough penicillin to treat seven additional patients. All seven survived,3 and Smith reportedly visited the bedside of each one.
Once again, the government ordered Pfizer to ship all the penicillin it produced — with the exception of a small allowance for continued research — directly to the military. So Smith supplied Loewe's group with much of the company's research allotment of the drug. Suspecting that Loewe was using penicillin that should have gone to the military, the National Defense Research Council undertook an investigation of him and Smith. There was discussion of bringing charges against Smith, before it was decided that he had acted within the regulations — and on behalf of the common good.
Source Information
From the Division of Infectious Diseases, University Hospitals of Cleveland, Cleveland.
References
Keefer CS, Blake FG, Marshall EK Jr, Lockwood JS, Wood BW. Penicillin and treatment of infections: a report of 500 cases. Statement by the Committee on Chemotherapeutic and Other Agents, Division of Medical Sciences, National Research Council. JAMA 1943;122:1217-1224.
Loewe L, Rosenblatt P, Greene HJ, Russell M. Combined penicillin and heparin therapy of subacute bacterial endocarditis: report of seven consecutive successfully treated patients. JAMA 1944;124:144-149.
Dowling HF. Fighting infection: conquests of the twentieth century. Cambridge, Mass.: Harvard University Press, 1977.
Related Letters:
Production of Penicillin
Tishler P. V., Lerner P. I.(Phillip I. Lerner, M.D.)
(Figure)
Penicillium notatum.
Hossler/Custom Medical Stock Photo
One type of infection that was conspicuously unresponsive in the initial trials of penicillin was streptococcal subacute bacterial endocarditis, a slowly progressive bacterial infection of heart valves that had been damaged, usually by rheumatic fever. Mortality among patients with this condition was 97 percent. The first trials were not encouraging: 17 patients were treated; 4 died, 10 showed no improvement, and 2 of the 3 who initially seemed a little better had relapses as soon as treatment was stopped.1
The day before the trial report was published, Dr. Leo Loewe and his associates at Brooklyn's Jewish Hospital found themselves at the bedside of a 34-year-old man with streptococcal endocarditis. They had treated him for six months — with huge doses of sulfa drugs, artificial fever therapy, heparin, and moderate doses of penicillin — without benefit. Now, out of sheer desperation, they tried a larger dose of penicillin: 200,000 units per day instead of the standard 40,000 units2 — a dose that is minuscule by today's standards, though it must have seemed enormous to them. The larger dose was given by a continuous intravenous drip, and the alpha-hemolytic streptococcus disappeared from the patient's blood; it reappeared when treatment was stopped, but a second several-week course of 200,000 units per day eliminated the organism permanently.2
After this cure, Loewe and his group saw patient after patient with endocarditis, many of them with advanced disease that had resulted in heart failure, emboli, or bleeding or leaking from ruptured mycotic aneurysms. The physicians turned none away, but all penicillin was now designated for military use. Fortunately, from the beginning of their adventures, the Brooklyn doctors had had the sympathetic ear of John L. Smith, the senior executive of Charles Pfizer, who furnished them with enough penicillin to treat seven additional patients. All seven survived,3 and Smith reportedly visited the bedside of each one.
Once again, the government ordered Pfizer to ship all the penicillin it produced — with the exception of a small allowance for continued research — directly to the military. So Smith supplied Loewe's group with much of the company's research allotment of the drug. Suspecting that Loewe was using penicillin that should have gone to the military, the National Defense Research Council undertook an investigation of him and Smith. There was discussion of bringing charges against Smith, before it was decided that he had acted within the regulations — and on behalf of the common good.
Source Information
From the Division of Infectious Diseases, University Hospitals of Cleveland, Cleveland.
References
Keefer CS, Blake FG, Marshall EK Jr, Lockwood JS, Wood BW. Penicillin and treatment of infections: a report of 500 cases. Statement by the Committee on Chemotherapeutic and Other Agents, Division of Medical Sciences, National Research Council. JAMA 1943;122:1217-1224.
Loewe L, Rosenblatt P, Greene HJ, Russell M. Combined penicillin and heparin therapy of subacute bacterial endocarditis: report of seven consecutive successfully treated patients. JAMA 1944;124:144-149.
Dowling HF. Fighting infection: conquests of the twentieth century. Cambridge, Mass.: Harvard University Press, 1977.
Related Letters:
Production of Penicillin
Tishler P. V., Lerner P. I.(Phillip I. Lerner, M.D.)