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Breakthrough: Penicillin’s impact on humanity
The discovery of penicillin by Alexander Fleming is arguably the most important discovery in medicine. In 1928, while studying Staphylococcus variants (gram positive bacteria) in the laboratory at St Mary’s Hospital in London, Fleming observed that a mould contaminating one of his cultures caused the bacteria in its vicinity to undergo lysis. The broth in which the fungus was grown was found to be markedly inhibitory for many micro-organisms.
This mould belonged to the genus Penicillium. Fleming named the antibacterial substance penicillin. A decade later, penicillin was developed as a systemic therapeutic agent following concerted research conducted by a group of investigators at the Oxford University, headed by Florey, Chain, and Abraham.
By May 1940, the crude material then available was found to produce dramatic therapeutic effects when administered to mice with experimentally produced streptococcal infection. Despite great obstacles to its laboratory production, enough penicillin was accumulated by 1941 to conduct therapeutic trials in several patients desperately ill with staphylococcal and streptococcal infections refractory to all other therapies.
At this stage, the crude, amorphous penicillin was only about 10 per cent pure and it required nearly 100 litres of the broth in which the mould had been grown to obtain enough of the antibiotic to treat one patient for 24 hours. Records of 1945 show that bedpans were actually used by the Oxford group for growing cultures of Penicillium notatum. Case 1 in the 1941 report from Oxford was that of a policeman who was suffering from a severe mixed staphylococcal and streptococcal infections. He was treated with penicillin, some of which had been recovered from the urine of other patients who had been given the drug. It is said that an Oxford professor referred to penicillin as a remarkable substance, grown in bedpans and purified.
A vast research programme soon was initiated in the United States. During 1942, 122 million units of penicillin were made available, and the first clinical trials were conducted at Yale University and the Mayo Clinic, with dramatic results. By the spring of 1943, 200 patients had been treated using the drug. The results were so impressive that the surgeon general of the US Army authorized a trial of the antibiotic in a military hospital. Soon thereafter, penicillin was adopted throughout the medical services of the US armed forces.
Penicillins constitute one of the most important groups of antibiotics for the treatment of infectious diseases and are widely used today. The new derivatives of the basic penicillin nucleus are still being produced
The deep-fermentation procedure for the biosynthesis of penicillin marked a critical progress in the large-scale production of the antibiotic. From a total production of a few hundred million units a month in the early days, the quantity manufactured rose to over 200 trillion units (nearly 150 tonnes) by 1950. The first marketable penicillin cost several dollars per 100,000 units. Today, the same dose costs only a few cents.
On Sept 1, 1928, Fleming became professor of bacteriology (University of London) at St Mary’s Hospital Medical School. By now he had become an acknowledged authority on staphylococcus and had been invited to write the section on this organism in the projected nine-volume set of Bacteriology in relation to medicine, to be published by the Medical Research Council.
Infectious diseases
Penicillins constitute one of the most important groups of antibiotics for the treatment of infectious diseases and are widely used today. The new derivatives of the basic penicillin nucleus still are being produced. Many of these have unique advantages, making members of this group of antibiotics the drugs of choice for a large number of infections diseases. Such diseases include Pneumococcal infectious, Streptococcal infections, infections with Anaerobes, Staphylococcal infections, Meningococcal infections, Gonococcal infections, Syphilis, Actinomycosis, Diphtheria, Anthrax, Clostridial infections, Rat-Bite fever and Listeria infections.
Demonstration of the effectiveness of penicillin in eradicating micro-organisms was quickly, and quite naturally, followed by attempts to prove that it also was effective in preventing infection in susceptible hosts. As a result, the antibiotic has been administered in almost every situation in which a risk of bacterial invasion has been present. As prophylaxis (prevention) has been investigated under controlled conditions, it has become clear that penicillin is highly effective in some clinical situations, useless and potentially dangerous in others. Combinations of penicillin with inhibitors of ß-lactamase (orbenin and or augmentin) are also available for the treatment of resistant infections.
Streptococcal infections: The administration of penicillin to individuals exposed to Streptococcus bacteria affords them protection from the infection. Twice a day 200,000 units of penicillin G or penicillin V can be given or a single injection of 1.2 million units of benzathine penicillin G can be administered. Indications for this type of prophylaxis include outbreaks of streptococcal disease in closed populations, such as boarding schools or military bases.
Patients with extensive deep burns are at high risk of severe wound infections with S. pyogenes. Several days of “low-dose” prophylaxis (prevention) appear to be effective in reducing the incidence of this complication.
Rheumatic fever: The oral administration of 200,000 units of penicillin G or penicillin V every 12 hours produces a striking decrease in the incidence of recurrences of rheumatic fever in susceptible individuals. Because of the difficulties of compliance, parenteral administration is preferable, especially in children. The intramuscular injection of 1.2 million units of penicillin G benzathine once a month yields excellent results. Prophylaxis must be continued throughout the year.
Syphilis: Prophylaxis for a contact with syphilis consists of a course of therapy as described for primary syphilis. A serological test for syphilis should be performed at monthly intervals for at least four months thereafter.
Valvular heart disease: About 25 per cent of cases of subacute bacterial endocarditis follow dental extractions. This observation, together with the fact that up to 80 per cent of the persons who have had teeth removed experience a transient bacteremia, emphasizes the potential of chemoprophylaxis for those who have congenital or acquired valvular heart disease of any type and need to undergo dental procedures. Since transient bacterial invasion of the bloodstream occurs occasionally after surgical procedures (for instance tonsillectomy and gastrointestinal procedures) and during childbirth, these too are indications for prophylaxis in patients with valvular heart disease.
Whether the incidence of bacterial endocarditis actually is altered by this type of chemoprophylaxis remains to be determined. But detailed recommendations for both adults and children with valvular heart disease have been formulated.
Evaluation of the patient’s history is the most practical way to avoid the use of penicillin in patients who are at the greatest risk of adverse reaction. The majority of patients who give a history of allergy to penicillin should be treated with a different type of antibiotic. Unfortunately there is no available means to confirm a history of penicillin allergy. Skin testing for IgE-mediated immediate-type responses is compromised by the lack of a commercially available minor determinant mixture and the inability of skin tests using major and minor penicillin determinants to predict confidently allergic reactions to synthetic penicillins.
Was Fleming great?
In the final chapter of his book (1984) Macfarlane asks, “If we concede that Fleming had a certain technical genius, can we accept him as a great scientist?” He then spends the rest of the chapter trying to prove that he was not a great scientist!
His main argument is that Fleming’s two great discoveries were results of accidents and not from following a line of research to ultimate triumph. This argument is specious.
It is true that the discovery of both lysozyme and penicillin were, strictly speaking, the result of accidents but the whole thrust of Fleming’s research was to find a substance which would kill bacteria and not harm the patient’s tissues. He carried out many experiments with antiseptics. The discovery of lysozyme in 1921 was the first breakthrough, although it was found to be limited in its effect as an antibiotic.
When he saw the penicillin effect, he instantly recognized that here was something new and promising. He continued to preserve and sub-culture Penicillium notatum throughout the following years and gave a sample to everybody who requested one.
Speaking of Fleming’s discovery of penicillin, Sir Ernest Chain said: “There is no doubt that this discovery, which has changed the history of medicine, has justly earned him a position of immortality.” Who will now dare say that Alexander Flaming was not a great scientist?
The writer, a recipient of the Hilal-i-Imtiaz, works for the Dr Panjwani Centre for Molecular Medicine and Drug Research, International Centre for Chemical Sciences, University of Karachi. Email: arshad.saeed@iccs.edu
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