Chloramphenicol was the first antibiotic discovered to be effective in treating a broad range of bacterial and rickettsial diseases, though its use was later restricted because of toxic side effects in some individuals.
In November, 1947, scientists from Parke, Davis and Company
While screening soil isolates for possible antibacterial substances, Paul Burkholder, working in the Osborn Botanical Laboratory at Yale, tested a culture of the new species of streptomyces for its ability to inhibit the growth of bacteria. Cultures of streptomyces were seen to inhibit a wide variety of bacteria, including strains of Staphylococcus, Streptococcus, Salmonella, and Shigella. A research team at Parke, Davis tested liquid filtrates obtained from streptomyces cultures and found that these too possessed antibacterial properties. Once Parke, Davis had isolated the new antibiotic and subjected it to thorough testing, the company published its work jointly with Burkholder and others involved in the research in the journal Science. The same antibiotic was also found that same year by a group at the University of Illinois; the Illinois group subsequently allowed Parke, Davis to claim precedence.
The first of the broad-spectrum antibiotics, chloramphenicol was unique for a number of reasons. Its relatively simple structure was found to contain both an organically bound chlorine and a nitro-benzene group, which is unusual among natural compounds. It became the first antibiotic to be synthesized in the laboratory, a project headed by Mildred Rebstock at Parke, Davis. Rebstock also discovered that chloramphenicol was derived from dichloroacetic acid, another toxic chemical (previously used in the treatment of warts) not at the time known to occur as a natural product. The chemical name given to the drug was D-threo-1-paranitrophenyl-2-dichloroacetamide-1,3-propanediol, abbreviated as chloramphenicol; the drug was marketed under the trade name chloromycetin. Rebstock’s synthesis remained the basis for mass-producing an effective antibacterial cheaply. Although the substance contained several toxic components, toxicity was not initially found associated with its use.
Chloramphenicol appeared to be the ideal antibacterial drug. It was rapidly absorbed through the gastrointestinal tract and could reach a therapeutic concentration in the blood quickly. It was also found to be capable of penetrating body cells while continuing its antibacterial activity, a property that made it useful in the treatment of rickettsial disease
Rickettsia bacteria are “energy parasites”: That is, though they are bacteria, most rickettsia are incapable of independent growth and replicate only within living cells. Among the diseases associated with rickettsial infection are various forms of typhus and spotted fevers. No effective treatment was known for rickettsial disease in the 1940’s, and few vaccines were available as preventive measures. Chloramphenicol appeared to be ideal for testing as a treatment.
During World War II, scrub typhus (caused by what was then called Rickettsia orientalis) was a particular problem to soldiers and civilians in Southeast Asia. Joseph Smadel, the scientific director of the Walter Reed Army Institute for Research
Smadel also arranged a field test of the efficacy of chloramphenicol as an anti-rickettsial in Kuala Lumpur, Malaya (now Malaysia), in March, 1948. By the completion of the mission in June, dozens of patients had been successfully treated and the effectiveness of the antibiotic established. Chloramphenicol was released for public use in 1949.
Chloramphenicol was widely used for a decade before any significant evidence of toxicity became known. Between 1949 and 1951, there had been reports of several adults having died following the treatment of typhoid fever with chloramphenicol, but at the time, these deaths had been ascribed to the severity of the illness. In 1959, however, James Sutherland
Chloramphenicol was subsequently found to interfere with the energy-producing capacity of mitochondria in those organs with a high rate of oxygen consumption; the heart, liver, and kidneys were at particular risk. Persons, particularly infants, who were unable to detoxify the drug efficiently were particularly susceptible to the accumulation of toxic levels in the blood.
Chloramphenicol was also found to be linked to two forms of bone-marrow toxicity in adults. The first, a dose-related cell depression, can result in depressed levels of production of any or all of the three major forms of blood cells: erythrocytes (red cells), leukocytes (white cells), and platelets. This condition, which is generally reversible, results from the combination of the drug’s antimitochondrial properties and its ability to inhibit hemoglobin synthesis in developing red cells. The other form of toxicity, an irreversible aplastic anemia resulting in discontinuation of cell production, is generally fatal; the precise cause is unknown, but there may be a genetic component to its development. Although these serious side effects are rare, a study by the California Medical Association in 1967 found the occurrence of cases to be as high as one per twenty-four thousand applications, depending on dose. The accumulation of such data was sufficient for the use of chloramphenicol to be restricted, in the 1960’s, to cases for which there is little alternative treatment.
Prior to the discovery of penicillin
The accidental discovery in 1929 of the antibacterial properties of penicillin represented the first major breakthrough in the practical application of antibiosis. Fleming had been growing staphylococcus in petri dishes in his laboratory. In September, 1928, he noticed that a mold had contaminated one corner of a dish. In a large area around the mold, the staphylococcal colonies had undergone lysis, a phenomenon uncommon with this type of bacteria. As Fleming was unfamiliar with the antibacterial substance, he termed it penicillin, after the name of a common mold suspected to be its source. Fleming went on to demonstrate not only that penicillin exhibited antibacterial properties against a variety of pathogenic organisms but also that some bacteria remained resistant to it.
Penicillin was reported in medical literature in 1929, but it required another decade before the drug’s potential could be realized. It was difficult to purify in therapeutic quantities, and cultures of Penicillium differed widely in how efficiently they could be produced. The work of Howard Florey and Ernst Chain, and the pressure of World War II, eventually led to a solution for these problems.
Realizing that bacteria do not flourish in soil, René Dubos deduced that soil must contain an antibacterial substance. He carefully screened soil and isolated the first antibacterial substance, tyrothricin. Other researchers began a systematic screening of soil samples from all over the world; in 1947, this resulted in Burkholder’s discovery of chloramphenicol.
In its ability to inhibit the growth of a wide range of bacteria, including some that resisted penicillin, chloramphenicol represented the first broad-spectrum antibiotic. Until the 1970’s, it remained the only consistently effective antibiotic in the treatment of Salmonella infections, including typhoid fever. Though chloramphenicol-resistant strains of bacteria have appeared from time to time, this has not been as significant a problem as in the case of other antibiotics.
The recognized toxicity associated with chloramphenicol, first reported in 1959, has resulted in restriction in its use. Nevertheless, chloramphenicol remains an important antibacterial agent in those cases where no alternative treatment exists. Most rickettsia and other bacteria, including chlamydia and spirochetes, both associated with sexually transmitted diseases, remain susceptible to treatment with therapeutic doses easily achieved in the bloodstream. The drug is also active against many penicillin-resistant bacteria and in treatment of patients who may be allergic to penicillin. Further, because of its ability to cross the blood-brain barrier, it remains an option in treating bacterial meningitis.
Less toxic alternatives would continue to be developed. The broad-spectrum antibiotics tetracycline and erythromycin have largely replaced chloramphenicol in common use, such as the treatment of Salmonella or rickettsial diseases. Ironically, its very toxicity, which slowed the drug’s use and may have retarded the development of resistant strains of bacteria, has assured chloramphenicol’s remaining a backup treatment of choice.
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Böttcher, Helmuth. Wonder Drugs: A History of Antibiotics. Translated by Einhart Kawerau. Philadelphia: J. B. Lippincott, 1964. Gives few specifics on chloramphenicol, but presents in an engaging manner the use of therapeutic agents for illness throughout history. -
Brock, Thomas. “Chloramphenicol.” Bacteriological Reviews 25 (1961): 32-48. The first major work on the use of chloramphenicol. Provides a review of the early literature on the clinical use of the antibiotic. No mention of the drug’s toxicity. -
Levy, Stuart B. The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Powers. Cambridge, Mass.: Perseus, 2001. A leading researcher in molecular biology explores a modern-day evolutionary change in bacteria because of misuse of antibiotics. -
Moberg, Carol L., and Zanvil A. Cohn, eds. Launching the Antibiotic Era. New York: Rockefeller University Press, 1990. A collection of first-person accounts on the discovery of antibiotics and their early use. Based on a 1989 symposium honoring René Dubos and his discovery of gramicidin. The chapters on chemotherapy include descriptions of the early field trials of chloramphenicol. -
Parascandola, John, ed. The History of Antibiotics. Madison, Wis.: American Institute of the History of Pharmacy, 1980. Based on a 1979 symposium on the history of antibiotics sponsored by the American Chemical Society. Focuses on the story of penicillin, but includes discussion of the history of bacterial chemotherapy and of the role played by fortuitous discovery. -
Sneader, Walter. Drug Discovery: A History. Hoboken, N.J.: Wiley, 2005. This work provides an interesting narrative of the origins, development, and history of drugs with especially significant social and medical import. Includes discussion of antibiotics. -
Waksman, Selman. The Antibiotic Era. Tokyo: Waksman Foundation of Japan, 1975. Posthumous collection of papers by Waksman on the discovery and use of antibiotics as chemotherapeutic agents. Waksman, who coined the term “antibiotic,” discovered streptomycin; the book provides an excellent history of the field.
Waksman Discovers the Antibiotic Streptomycin
Hodgkin Solves the Structure of Penicillin
Duggar Develops the First Tetracycline Antibiotic
Salk Develops a Polio Vaccine
Isaacs and Lindenmann Discover Interferons
Sabin Develops the Oral Polio Vaccine
World Health Organization Intensifies Its Campaign to Eradicate Smallpox
Scientists Debate the Addition of Antibiotics to Animal Feed
German Measles Vaccine Is Developed