Throughout his career, Paul Ehrlich (1854–1915) struggled to under- stand the body’s immunological defenses and to develop experimentally based therapeutic systems to augment them. Like Pasteur, his theoreti- cal interests were closely linked to practical problems. This interplay between the theoretical and practical resulted in signiﬁcant contributions to immunology, toxicology, pharmacology, and therapeutics. Ehrlich’s achievements include the development of salvarsan and other drugs,
clariﬁcation of the distinction between active and passive immunity, rec- ognition of the latent period in the development of active immunity, and an ingenious conceptual model for antibody production and antigen– antibody recognition. Salvarsan, the ﬁrst chemotherapeutic agent speciﬁcally aimed at the microbe that causes syphilis, provided an effec- tive demonstration for Paul Ehrlich’s belief that it is possible to ﬁght infectious diseases through a systematic search for drugs that kill invad- ing microorganisms without damaging the host. Such drugs have been called ‘‘magic bullets.’’
Ehrlich’s doctoral thesis ‘‘A Contribution towards the Theory and
Practice of Histological Staining,’’ seems to contain the germ of his life’s work: the concept that speciﬁc chemicals can interact with partic- ular tissues, cells, subcellular components, or microbial agents. In 1878,
after studying at the Universities of Breslau, Strasbourg, and Leipzig, Ehrlich graduated and qualiﬁed as a doctor of medicine. As assistant to Friedrich Frerichs at the Berlin Medical Clinic, Ehrlich was allowed to continue his research. But Frerichs committed suicide in 1885, and Ehrlich’s new supervisor expected his senior physicians to devote more time to the clinic than to research. Depressed and somewhat ill, Ehrlich seized the opportunity provided by a positive tuberculin test to leave the hospital and embark on a consumptive’s pilgrimage to Egypt. Return- ing to Berlin with his health restored, Ehrlich was distressed to ﬁnd himself almost totally excluded from the academic community. He was not nominated for a professorship or offered a position in a scientiﬁc institute for 15 years. During this period, he conducted studies of the nervous system that involved testing the effect of methylene blue on neuralgia and malaria.
Selective staining techniques allowed Ehrlich to distinguish differ-
ent types of white blood cells and leukemias. Somewhat later, using bac- teriological techniques and transplantable tumors, Ehrlich initiated a new approach to cancer research in which cancer cells were treated like microbes and the host organism served as the nutrient medium. Finally, in 1896, Ehrlich was appointed director of a new Institute for Serology and Serum Testing. Facilities at the Institute were rather limited, but Ehrlich told friends he could work in a barn, as long as he had test tubes, a Bunsen burner, and blotting paper. Three years later, the Insti- tute was transferred from Berlin to Frankfurt and renamed the Royal Institute for Experimental Therapy. Next to the Royal Institute, thanks to a large bequest from Franziska Speyer, Ehrlich established the Georg Speyer Institute for Chemotherapy.
In 1908, Ehrlich shared the Nobel Prize in Physiology or Medicine with E´ lie Metchnikoff (1845–1916) for their work on immunity. Ehrlich’s Nobel Prize lecture, entitled ‘‘Partial Cell Functions,’’ began
with a tribute to the concept of the cell as the unit of life and ‘‘the axis around which the whole of the modern science of life revolves.’’ He thought, however, that the problem of cell life had reached a stage of investigation in which it was necessary to ‘‘break down the concept of the cell as a unit into that of a great number of individual speciﬁc partial functions.’’ Research programs that analyzed the chemical nature of the many processes occurring within the cell would provide a real understanding of vital functions and lead to the ‘‘rational use of medicinal substances.’’ Progress in this direction, he explained, had come about as a result of attempts to ﬁnd the key to the mysterious processes underlying the discovery of the antitoxins. ‘‘Key’’ was the operative word, because as the great organic chemist Emil Fischer (1852–1919) had said of enzymes and their substrates, antibodies and antigens entered into a chemical bond of such strict speciﬁcity that they inter- acted like lock and key.
Ehrlich used the term ‘‘immunotherapy’’ as early as 1906 in a period of great hope that many diseases would be prevented or cured by serum therapy. As the limitations of serum therapy became more apparent, especially in the case of cancer, Ehrlich eventually shifted his focus from immunology to experimental pharmacology and chemotherapy. Further progress, Ehrlich concluded, would have to come from synthetic drugs rather than natural antibodies. In the mid-nineteenth century, many researchers had questioned the value of all remedies, but Ehrlich saw experimental pharmacology as a science with great promise and potential.
In studying the marvelous speciﬁcity of the antibodies generated
in response to the challenge of poisons, toxins, and other foreign invaders, Ehrlich became convinced that it should be possible to design chemotherapeutic substances by exploiting speciﬁc interactions between synthetic chemicals and biological materials. Because the body did not produce effective antibodies for every challenge, Ehrlich considered it the task of medical science to provide chemical agents that would substitute for or augment the body’s natural defenses. Antibodies were nature’s own magic bullets; chemotherapy was an attempt to imitate nature by creating drugs lethal to pathogenic microbes, but harmless to the patient.
Using the ‘‘disinfection’’ produced by quinine for malaria as a
model, Ehrlich planned an extensive series of tests of potential drugs and their derivatives. Despite the ambitious scope of his research pro- gram, he encouraged his associates to take time for reﬂection. Ehrlich believed that the keys to success in research were ‘‘Gelt, Geduld, and Gluck’’ (money, patience, and luck), and that spending too much time in the laboratory meant wasteful use of supplies and experimental ani- mals. Ehrlich closely supervised the work of all his collaborators, to the point that senior associates working in his laboratory complained about the lack of independence. Each day he gave even the most senior researcher little notes (Blo¨ ke), which might be considered the precursors of ‘‘post-it’’ notes, that told them what they should be doing.
The ﬁrst targets for Ehrlich’s new chemotherapy were the trypano-
somes, the causative agents of African sleeping sickness, Gambia fever, and nagana. Following his ‘‘chemical intuition’’ along a path that had begun with his early studies of dye substances, Ehrlich began an investigation of a drug called atoxyl and related arsenic compounds. Atoxyl was quite effective in the test tube, but was not a suitable thera- peutic agent because it caused neurological damage and blindness. The distinction between killing microbes in the test tube and killing them in a living being, without causing damage to the patient, is often forgotten. Ehrlich’s test tube experiments proved that the accepted chemical formula for atoxyl was incorrect. It was, therefore, possible to create myriads of derivatives, many of which proved to be safer and more effective than atoxyl.
Because spirochetes were thought to be similar to trypanosomes, Ehrlich’s group also conducted tests on spirochetal diseases. Fritz Schaudinn (1871–1906) and Erich Hoffmann (1868–1959) had discov- ered the causative agent for syphilis in 1905. Within a year, scientists succeeded in establishing syphilitic infections in rabbits. Sahachiro Hata (1873–1938), an expert in the use of this model system, conducted sys- tematic tests of Ehrlich’s arsenical compounds on the microbes that cause syphilis, chicken spirillosis, and relapsing fever. Some of the atoxyl derivatives were quite toxic, but birds infected with chicken spi- rillosis were cured by one injection of Preparation 606. This chemical also cured relapsing fever in rats and syphilis in rabbits.
After two physicians offered to be guinea pigs, Ehrlich’s collabora-
tors began a series of intramuscular injections of 606 on certain patients with progressive paralysis, an invariably fatal condition thought to be of syphilitic origin. Expecting at most a slight increase in survival, they were surprised at the improvements caused by a single injection of the drug. The possibility that toxic effects might be delayed remained unre- solved. Moreover, the remissions, relapses, and complications that were part of the natural history of syphilis made evaluating remedies extremely difﬁcult. Preparation 606, which was given the name salvar- san, underwent testing that was quite extensive compared to the usual practices of the time. After the drug had been tested on almost thirty thousand patients, salvarsan was made available to the medical commu- nity at large. When congratulated on this remarkable achievement, Ehrlich often replied that salvarsan accounted for one moment of good luck after seven years of misfortune. With tens of thousands successfully treated for syphilis he could not anticipate the misfortunes still to come.
Alchemists often began the search for their elixirs of life with poi-
sons, because the fact that a substance was a known poison proved that it was powerful. As this ancient approach suggests, it is unreasonable to expect any drug to be both effective and completely harmless. Neverthe- less, some of Ehrlich’s supporters argued that salvarsan was nontoxic, while his critics accused the drug of causing a wide range of adverse reactions. A dermatologist named Richard Dreuw made one of the ﬁrst attacks on salvarsan. Although most doctors were complaining that Ehrlich had been too cautious, Dreuw accused Ehrlich of releasing salvarsan without sufﬁcient testing. When medical journals rejected his papers, Dreuw became obsessed with the idea that a ‘‘salvarsan syn- dicate’’ was controlling the Germany medical community and suppress- ing all criticism of salvarsan. Joined by some members of the Reichstag and anti-Semitic newspapers, Dreuw attacked Ehrlich personally and demanded that the Imperial Health Ofﬁce establish a national ban on salvarsan.
Anti-salvarsan crusaders claimed that the drug caused deafness,
blindness, nerve damage, and death, but ignored the fact that one million
people had been successfully treated. Moreover, deafness, blindness, nerve damage, and death were also caused by syphilis. Compared to the deaths caused by syphilis, and the suffering of its victims, salvarsan was relatively benign, although prolonged treatment involved real dan- gers of adverse effects in some patients. Another problem was that patients who had been cured often returned to the behaviors that caused them to contract syphilis in the ﬁrst place; they blamed the ‘‘relapse’’ not on themselves, but on salvarsan.
The most bizarre member of the anti-salvarsan crusade was Karl Wassmann, a writer who habitually dressed as a monk. Hearing prosti- tutes complain that salvarsan was being forced on them at the Frankfurt Hospital, Wassmann concluded that Prof. Herxheimer, director of the Dermatology Department, was an agent of the ‘‘salvarsan syndicate.’’ From 1913 on, Wassmann made the battle between prostitutes and the medical authorities a major theme of his magazine, The Freethinker. According to Wassmann, the government was suppressing the truth about the salvarsan syndicate and the appalling effects caused by the drug. Proclaiming himself champion of the abused underclass, Wassmann courted controversy to call attention to himself and his writ- ings. Unwilling to accept these attacks on his professional behavior, Herxheimer sued Wassmann for slander. Salvarsan was so completely vindicated by the evidence brought out at the trial that when the prose- cution requested a six-month prison term for Wassmann the court doubled the sentence. Despite this outcome, Ehrlich was extremely dis- tressed by the trial and the futility of trying to present complex scientiﬁc and medical issues in the hostile, adversarial environment of the court- room. Salvarsan, with the addition of mercury and bismuth, remained the standard remedy for syphilis until it was replaced by penicillin after World War II.
Attempts to create an arsenal of magic bullets were largely unsuc-
cessful until the 1930s when Gerhard Domagk (1895–1964) found that a sulfur-containing red dye called prontosil protected mice from strepto- coccal infections. This led to the synthesis of a series of related drugs called the sulfonamides or ‘‘sulfa drugs,’’ which were highly effective against certain bacteria. Domagk was the director of research in experi- mental pathology and bacteriology at the German chemical ﬁrm I. G. Farben. Like Ehrlich, Domagk turned to the study of dyes as a means of understanding pathogenic microorganisms. Preliminary studies of bacterial staining led to a systematic survey of the aniline dyes in hopes of ﬁnding chemicals that would kill bacteria.
In a typical experiment, Domagk determined the quantity of bac-
teria needed to kill inoculated mice (the lethal dose). Then he inoculated mice with 10 times the lethal dose and gave half of the animals a test substance, such as prontosil. By 1932, Domagk had shown that prontosil protected mice against lethal doses of staphylococci and
streptococci. As early as 1933, the drug was secretly used in humans with life-threatening staphylococcal and streptococcal infections. However, Domagk’s report, ‘‘A Contribution to the Chemotherapy of Bacterial Infections,’’ was not published until 1935. Domagk may have delayed publication because of Farben’s interest in securing patent protection, but the delay might also have been caused by some difﬁculties in reproducing the initial results. In 1939, Domagk was awarded the Nobel Prize in Physiology or Medicine ‘‘for the discovery of the antibacterial effects of prontosil,’’ but Nazi ofﬁcials would not allow him to accept it. Germany’s leadership in the development of chemotherapeutic agents was essentially lost during the period from 1933 to 1945, because of National Socialistic policies that isolated Germany from the inter- national research community and forced many Jewish scientists to seek refuge in England and America. Domagk ﬁnally received the Nobel medal in 1947 and delivered a very emotional lecture on progress in chemotherapy.
As soon as Domagk’s results were published, prontosil was tested
in laboratories in France, America, and Britain. Researchers at the Pasteur Institute proved that prontosil was inactive until it was split in the animal body. The antibacterial activity was due to the sulfon- amide portion of the molecule. Not only was sulfanilamide more active than prontosil, it did not have the disadvantage of being a messy red dye. Prontosil was synthesized and patented by I.G. Farben in 1932, but an account of the synthesis of sulfanilamide had been published in 1908. Thus, Farben could not claim patent protection for derivatives of sulfanilamide. With open season on the sulfa drugs, more than ﬁve thousand derivatives were synthesized in the decade after Domagk’s report. In the entire series of sulfonamides, so laboriously synthesized and tested, fewer than 20 clinically useful compounds were identiﬁed. Chemists began to realize that the odds of synthesizing a safe and effective magic bullet were rather like those of winning the lottery.
Nevertheless, studies of the sulfa drugs ﬂooded the literature.
Laboratory tests showed that many of these drugs were effective against various bacteria, at least in the laboratory. Clinical trials in hos- pitals throughout the world provided promising results in the treat- ment of pneumonia, scarlet fever, gonococcal infections, and so forth. Unfortunately, drug-resistant strains of bacteria appeared almost as rapidly as new drugs. The sulfa drugs were indiscriminately prescribed for infections of unknown origin, casually given for suspected gonor- rheal infections, and liberally sprinkled into wounds.
Hailed as ‘‘miracle drugs’’ in the 1930s, by the end of World War
II, the sulfa drugs were considered largely obsolete. Domagk suggested that part of the problem might have been caused by a decrease in natural resistance due to wartime stress and malnutrition, the spread of primary resistant strains enhanced by ‘‘the general upheaval during and
after the war,’’ and the development of resistant strains during the course of treatment. The same disappointments would follow the use of penicillin, Domagk warned, unless physicians learned to appreciate the factors that led to the development and spread of resistant strains.
The next generation of wonder drugs for infectious disease came from a previously obscure corner of nature’s storehouse. By the 1870s, several scientists had called attention to the implications of ‘‘antibiosis’’ (the struggle for existence between different microorganisms), but according to popular mythology, the antibiotic era began in 1928 when Alexander Fleming (1881–1955) discovered penicillin. Of course, the real story is much more complicated. Indeed, in his 1945 Nobel Lecture, Fleming suggested that the discovery of ‘‘natural antiseptics’’ had taken so long because bacteriologists of his generation had taken the fact of microbial antagonisms for granted rather than as a phenom- enon to be explored.
Fleming discovered the effect of the mold Penicillium notatum on bacteria in 1928. Within a year, he demonstrated that crude prepa- rations of penicillin killed certain bacteria but were apparently harmless to higher animals. Penicillin was not the ﬁrst antibacterial agent Flem- ing discovered. In 1922, he found what he called a ‘‘powerful antibacte- rial ferment’’ in nasal secretions, tears, and saliva. Although this enzyme, which was named ‘‘lysozyme,’’ plays a role in the body’s natural defense system, it was not a practical magic bullet. As Fleming often said, he was not a chemist. Howard Florey and Ernst Boris Chain, who later tested and puriﬁed penicillin, worked out the chemical nature and mode of action of lysozyme.
Alexander Fleming was only seven when his elderly father, a Scot- tish farmer died. Because his family’s resources were limited, Fleming worked as a clerk for several years before a small legacy made it pos- sible for him to attend St. Mary’s Medical School in London. More mature than the other students, Fleming excelled at competitive exam- inations, swimming, and shooting. After graduating in 1908, he became assistant to the eminent and eccentric bacteriologist, Sir Almroth Wright (1861–1947). Fleming’s interest in agents that kill bacteria was stimulated by his experience in the Royal Army Medical Corps during the First World War. Attending to the septic wounds that were the com- mon aftermath of battle, Fleming was convinced that chemical antisep- tics were generally more lethal to human tissues than to the invading bacteria.
After the war, Fleming returned to St. Mary’s to continue his research on antibacterial substances. According to what we might call the penicillin myth, a spore drifted through an open window into Fleming’s laboratory and settled in a Petri dish on which he was growing staphylococci. Contamination of bacteriological materials with molds is a common laboratory accident, generally considered a sign of
poor sterile technique and general sloppiness. Acknowledging this cor- relation, Fleming often said that he would have made no discoveries if his laboratory bench had always been neat and tidy. Fortunately, his contaminated plate was left among stacks of dirty Petri dishes when Fleming went off on vacation. On his return, Fleming noticed that staphylococci had been destroyed in the vicinity of a certain mold col- ony and he decided that this case of antibiosis was worth pursuing.
Scientists who tried to recreate this great moment in medical
history suggest an alternative scenario: staphylococci were sown on the famous Petri dish but did not grow because of an unusual cold spell. A spore of the relatively rare P. notatum that had previously fallen onto the plate began to grow during this period. Finally, warmer tempera- tures triggered the growth of the staphylococci and the penicillin that
Alexander Fleming in 1944.
had been released into the medium around the mold colony killed the growing bacteria. Serendipity had to be working overtime in Fleming’s behalf, but it is necessary to propose such a sequence of events in order to explain Fleming’s observation, because penicillin cannot dissolve fully grown colonies of staphylococci. Testing the effects of his mold, Fleming discovered that even in crude, dilute preparations, penicillin stopped the growth of bacteria and caused them to die. It was, however, essentially harmless to white blood cells in the test tube. The active agent in his penicillin preparations was apparently unstable and extremely difﬁcult to purify. Not being an active clinician or a chemist, Fleming rarely managed to have a supply of penicillin and a suitable patient available at the same time. Nor did Fleming perform the animal experiments that would have demonstrated penicillin’s effectiveness in ﬁghting bacteria in infected animals. In 1930, however, one of Fleming’s former students successfully used local applications of crude penicillin in treating eye infections.
In 1928, when Fleming began to work with penicillin, textbooks of
therapeutics and pharmacology were still recommending ancient prep- arations of aromatic substances and heavy metal salts for the treat- ment of infected wounds, along with relatively new disinfectants such as carbolic acid, hydrogen peroxide, iodoform, and the hypochlorites. Chemists had prepared many modiﬁcations of known disinfectants, but physicians generally believed that if any drug were present in the bloodstream in concentrations high enough to kill bacteria, human tissues and organs would be damaged as well. After penicillin had become the new ‘‘wonder drug,’’ Fleming complained that neither bac- teriologists nor physicians paid any attention to penicillin until the introduction of sulfanilamide changed attitudes towards the treatment of bacterial infections.
Although the story of Fleming’s accidental discovery of penicillin
is well known, the fact that penicillin remained a laboratory curiosity until World War II is often forgotten. Both aspects of the penicillin story were recognized in 1945 when the Nobel Prize for Physiology or Medicine was awarded to Alexander Fleming, Howard Walter Florey (1898–1968), and Ernst Boris Chain (1906–1979) ‘‘for the discovery of penicillin and its curative effect in various infectious diseases.’’ Almroth Wright, however, insisted that all the credit for the discovery should go to Fleming and headlines in some prominent newspapers noted that the Nobel Prize had gone to ‘‘Fleming and Two Co-Workers.’’
In 1938, Florey, Director of the Sir William Dunn School of Pathology at Oxford University, Chain, and Norman Heatley, began a systematic study of naturally occurring antibacterial agents, including lysozyme and substances produced by various microbes. Within two years, partially puriﬁed penicillin was tested in mice infected with viru- lent streptococci. Further experiments proved that penicillin was active
against streptococci, staphylococci, and several other pathogens. With penicillin performing as an ideal magic bullet in mice, the Oxford group quickly moved on to human experiments. The ﬁrst patient was a 43- year-old man who had contracted a mixed infection of staphylococci and streptococci. Although the patient was close to death when treat- ment began, penicillin produced a remarkable improvement. Unfortu- nately, even though the drug was recovered from the patient’s urine, the supply was soon exhausted and the patient died. An account of the ﬁrst successful clinical trial was published in the British medical journal, the Lancet, but further studies became part of the secret war effort.
With Britain’s resources strained by the war, it was obvious that
British pharmaceutical companies could not develop a new drug. Florey was forced to seek American support. The path from laboratory curiosity to the industrial production of penicillin was full of obstacles, not all of them technical and scientiﬁc. Research on penicillin was closely associated with military needs and goals. Inevitably, the secrecy that surrounded the initial trials attracted reporters and generated wild rumors. Within two years of Florey’s visit to the United States, about 16 companies were producing penicillin and major clinical trials were under way. As hundreds of patients were treated with penicillin, researchers became more optimistic about its therapeutic potential. Penicillin was effective in the treatment of syphilis, gonorrhea, and infections caused by pneumococci, staphylococci, and streptococci. Penicillin was hailed as a panacea that would deliver armies from both venereal diseases and battle injuries. Where supplies were limited, military authorities had to decide whether to use it on those wounded in battle, or those
‘‘wounded’’ in the brothels.
In his delayed Nobel Prize Lecture in 1947, Domagk attributed differences in mortality rates for American soldiers in the two world wars to the sulfonamides and penicillin. Of course many other aspects of battleﬁeld conditions, weaponry, military medicine, surgery, and hygiene had changed during the years between the wars, but differences between the nations that had access to penicillin and those that did not reﬂected, at least in part, the role played by antibiotics. Paradoxically, Florey was more cautious in evaluating the impact of penicillin on battle casualties than Domagk. Direct comparisons of raw mortality ﬁgures can be misleading, Florey warned, because in many cases, new therapies and battleﬁeld evacuation techniques extended lives that would have ended abruptly in previous wars. This created increasingly intricate and intractable problems of repair and recovery.
When the war ended, although American and British pharmaceu- tical ﬁrms were selling millions of units of penicillin, there was still a ﬂourishing black market where penicillin bottles were reﬁlled with worth- less chemicals and sold for hundreds of dollars. By 1948, pharmaceutical
plants all over the world were producing penicillin. When penicillin became readily available, many physicians adopted treatment regimens reminiscent of the era of so-called heroic medicine. Penicillin was combined with bismuth, arsenicals, sulfonamides, and other drugs, and injected at frequent intervals. Further work proved that a single dose of penicillin was effective in treating certain diseases. The promise of a simple cure for the major sexually transmitted diseases drove moralists to denounce penicillin as a stimulus to promiscuity.
During the war, some scientists insisted that chemical synthesis of the penicillin molecule would be more productive than further modiﬁ- cations of fermentation techniques. By the late 1940s, chemists had decided that the synthesis of penicillin was impractical, if not impossible. In commercial terms, this was essentially true, but the total synthesis of penicillin was ﬁnally achieved in 1957 by organic chemist John C. Sheehan. Reﬂecting on the problems that followed his synthesis of penicillin, Sheehan noted that it had taken 23 years to clear up patent disputes.
Inspired by lessons learned and proﬁts earned with penicillin,
researchers sifted through samples of dirt from every corner of the world in search of new miracle molds. Quoting Ecclesiastes in his
1952 Nobel Prize Lecture, Selman A. Waksman (1888–1973) reminded his audience: ‘‘The Lord hath created medicines out of the earth; and he that is wise will not abhor them.’’ During his search for such medicines, Waksman, a biochemist and pioneer in soil microbiology, discovered streptomycin, neomycin, and many other antibiotics, most of which were too weak or too toxic for human use. Waksman coined the term ‘‘antibiotic’’ to refer to a group of compounds produced by microorganisms that can inhibit the growth of other microorganisms or even destroy them.
According to bacteriological folklore, the normally persistent tubercle bacillus could be destroyed in the soil. Waksman, therefore, turned his systematic studies of soil microbes into a search for agents antagonistic to the tubercle bacillus. More than ten thousand different soil microbes were investigated before Waksman, Elizabeth Bugie, and Albert Schatz isolated streptomycin in 1944. One year later, William H. Feldman and H. Corwin Hinshaw of the Mayo Clinic announced that streptomycin was effective against tuberculosis. A major share of credit for recognizing the value of streptomycin belonged to Feldman and Hinshaw. Evaluating remedies for tuberculosis is very difﬁcult because the disease is unpredictable, develops slowly, and is affected by nonspeciﬁc factors, such as diet and rest. The failure of previous miracle cures had left researchers disillusioned and skeptical about the prospects for chemotherapeutic agents. After seeing signs of improve- ment in patients with life-threatening meningeal and miliary tubercu- losis, Feldman and Hinshaw extended their tests to less acute forms of the disease. The early preparations of streptomycin were impure and
caused serious side effects, including fever, chills, muscular pains, and deafness. In some tests, only slightly more than half of the strepto- mycin-treated patients improved after six months. Despite all these problems, in 1948 when eight pharmaceutical companies were producing the drug, demand far exceeded supply. Waksman was awarded the Nobel Prize for the discovery of streptomycin in 1952, two years after the legal settlement of a complex royalty dispute initiated by Schatz. In 1994, Schatz, who insisted that he had not received sufﬁcient credit for the discovery of streptomycin, won the Rutgers University Medal, which is considered a prestigious award, but far short of the Nobel Prize.
Unlike the long barren years between Fleming’s discovery of
penicillin and the exploitation of its therapeutic potential, streptomycin went from laboratory curiosity to major pharmaceutical product within
a few brief years. Indeed, the success of penicillin and streptomycin proved to be a tremendous stimulus to the growth of the pharmaceutical industry and the expansion of research. During the 1940s and 1950s, the golden age of antibiotics, chloramphenicol, neomycin, aureomycin, erythromycin, nystatin, and other valuable antibiotics were discovered. Reﬂecting the optimism of this period, Waksman predicted that future research would lead to the discovery of more active and less toxic agents and to powerful combinations of antibiotics and synthetic compounds. By the 1960s, however, the golden age of discovery of novel antibiotics was essentially over. Most of the antibiotics introduced since then have been slight modiﬁcations of previously known drugs. Moreover, the warnings issued earlier proved to be true. Overuse and misuse of anti- biotics revealed adverse side effects and promoted the development of drug-resistant strains of bacteria.
In many countries, antibiotics are readily available, without pre-
scriptions, and people use them until they feel better. So-called under- ground medical shops help people avoid the expense of consulting a doctor, but antibiotics are ineffective against viruses and usually affect a limited spectrum of bacteria. Some antibiotics are quite dangerous and are only prescribed when no alternatives are available. Moreover, inappropriate use of the drugs contributes to the development of drug-resistant bacteria.
The widespread use of antibiotics to suppress illness and encourage
the growth of animals also poses risks. The risk of creating antibiotic- resistant microbes is well known, but another danger is that antibiotics added to animal feed may appear as contaminants in human foods. The sources of contamination may be convoluted and obscure. A European food scare developed in 2002, for example, because of reports that meat was contaminated with chloramphenicol, a powerful antibiotic that can cause a potentially lethal form of anemia. Chloramphenicol is normally restricted to combating life-threatening diseases such as anthrax and typhoid when other antibiotics are ineffective. Chloramphenicol- contaminated meat was linked to contaminated shrimp that had been mixed with other components of animal feed used in Germany, Austria, Denmark, Poland, and Romania. Some shrimp farmers were apparently using the antibiotic, despite laws banning its use.