ANTIBIOTICS AND IMMUNOLOGY

12 May

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,

Paul Ehrlich

Paul Ehrlich.

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

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.

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