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For over a decade now, the arrival of any new anti-bacteria drug on the scene has been greeted by so rapturous a press that normal, protective skepticism has been dazzled to death. The public is always eager to believe that an all-conquering panacea is at last within grasp, and the few professional voices that have been raised in protest have been drowned out by the blare of trumpets. The unwelcome truth is, however, that many of yesterday’s miracle drugs have moved quietly backstage.
The layman inquisitive enough to peer behind the scenes is apt to get a shock. First, his optimism is dashed with cold water by the London Lancet: “Scarcely a month passes without the description of one or more antibiotics, most of which are likely to be of little or no practical importance.” He finds another world-famous medical journal calling attention to “The Waning Power of Penicillin.” Sulfathiazole and sulfapyridine, he discovers, have been quietly dropped from the American Medical Association’s list of New and Non-Official Remedies because of the high frequency of serious reactions. In fact, the local application of all sulfonamides has been condemned. Toxic effects on patients, it turns out, far outweigh any benefits. And on the editorial page of the British Medical Journal, a stinging rebuke to streptomycin further jars his complacency: “What are we to think of a chemotherapeutic agent which can become an essential growth factor for a previously susceptible organism?” —one which might, as the New England Journal of Medicine points out, actually aggravate infection by encouraging bacteria to multiply.
Last year, the Veterans Administration had to warn the 400,000 discharged servicemen who had been treated for syphilis to come back for checkups. There was a good likelihood, VA officials announced that the cure had failed in 20 to 30 per cent of these wartime and postwar cases. The old Army treatment (bismuth and arsenic) was time-tested, and the results could be more or less accurately predicted. Not so with the newcomer, penicillin. Even today, when the newer therapy is a medical specialty, its failure rate in early syphilis is 5 to 15 per cent and sometimes higher. The use of penicillin in syphilis is still in the experimental stage, say responsible doctors, who also admit that they aren’t yet exactly sure when syphilis is cured.
Such dilemmas are not new to medical men. A rather spectacular failure helped to usher in the antibiotic age. Twenty years ago, bacteriophage–”phage” for short in ecstatic headlines–was the wonder drug of the hour. This mysterious foe of bacteria had been hailed with all the familiar cliches of medical reporting: “The latest weapon against disease…Gives promise of becoming the world’s greatest disease conqueror…The dawn of a new era in bacteriology…” etc. D’Herelle of the Pasteur Institute, who discovered it, foresaw the day when deadly epidemics would be stopped cold by pouring his bacteria-killer into a city’s water supply.
Unfortunately, the day never came. In any event, phage did not live up to its promise. Almost without exception, phage-treated patients developed fever and nausea. The antibiotic destroyed the enemy in the test tube, but not in the patient. Phage therapy went out.
A cautious surgeon will tell you that an operation cannot definitely be declared successful until five or ten years afterward. Slowly we are learning that conservative physicians are right when they insist that it takes ten to twenty years, or longer, to determine the long-range virtues–and hazards–of any new drug treatment.
The hazards are sometimes slow to reveal themselves, as was demonstrated in the history of agranulocytosis–a fatal malady peculiar to our pharmaceutical times. Dr. Roy R. Kracke, dean and professor of clinical medicine at the University of Alabama Medical College, told the story recently in Hygeia.
The disease, he said, first appeared in Berlin in 1922. There were only five cases to begin with, all women. They had one symptom in common: their white blood cells had in some mysterious way been completely destroyed. Their bodies, disarmed against invaders, became masses of infections. Ulcers multiplied in many parts of the body, especially the mouth. All five died.
Soon the disease spread to the United States. Here it was noticed that females were victims in a ratio of 4 to 1 over men. Many seemed to be women who had difficult menstrual periods. Significantly, agranulocytosis was at first twelve times more prevalent among members of the medical professions and their families than elsewhere. Nearly all of those afflicted died. Meanwhile, the disease spread until, in 1934, several thousand deaths were reported in this country alone. After several more years of sifting, investigators put the finger on a benzine ring drug, amidopyrine, better known as pyramidon. Doctors stopped prescribing it. Hospitals banned it. The Food and Drug Administration and the Federal Trade Commission barred it from over-the-counter sale. By 1938, agranulocytosis had practically disappeared.
There the story might have ended if at about that time the sulfa drugs had not appeared. Sulfa compounds can cause the disease and soon agranulocytosis was again a medical problem. “Some patients,” reported Dr. Kracke, “have lost their lives in this way from the administration of sulfa drugs. Indeed, it has been shown that sulfa drugs are capable of producing severe effects not only on white cells but also on red; they can cause the most severe types of anemia. Even a normal dose of sulfa drug within a few days can destroy the red cells in such numbers that they are cut in half. Furthermore, they can cause marked depletion of the blood platelets (a coagulant), producing severe hemorrhages from which the patient may die of uncontrollable bleeding. Fortunately, these results happen in only an occasional patient.”
It is a disquieting paradox to find ourselves fighting disease germs with a drug which simultaneously destroys the body’s own natural mechanism for doing the same job. But Dr. Kracke did introduce “a cheering note.” Penicillin, he observed, was a sort of godsend to sulfa therapy. It can be used to control most of the secondary infections which develop in the absence of white blood cells caused by the sulfonamides. Thus, the patient can be kept alive long enough for the bone marrow to manufacture more white cells.
Somewhere along the line, though, Dr. Kracke became noticeably disconcerted. “The safest rule,” he concluded thoughtfully, “is to remember that what you don’t take won’t hurt you.” This is a useful thought, but not popular, since, as Sir William Osler once remarked, “the desire to take medicine is perhaps the greatest feature which distinguishes man from animals.”
Once a patient and his advising physician have started going around in modern drug cycles, they may find it difficult to stop. Mr. Ecks, for example, has been given penicillin. It can cause severe skin reactions in the form of giant hives. These usually start on the scalp, the palms and the soles, and later may involve the whole body. The debilitating itch can be controlled to some extent by the brand new anti-histamine drugs, though these are too new for anyone to know precisely what they do, or why. But many of the anti-histamine drugs themselves bring about what physicians warily term “unpleasant side effects.”
Penicillin, at least too much of it, does something else to that once delicately balanced organism, the human body. Like the old-fashioned sulfa drugs and the infant prodigy, aureomycin, penicillin may interfere with the growth of the intestinal organisms which synthesize the B vitamins. Then, unless vitamin supplements are given, the patient may find himself with odd-sounding deficiency diseases such as glassitis and angular stomatitis.
The hypothetical end is not yet. Skin specialists remind us that vitamin B complex, in turn, often causes a diffuse, itchy skin eruption on the arms, torso and thighs. “The benefits of thiamine chloride,” they say, “are nullified by the inconvenience, insomnia and nervousness caused by vitamin itch.”
The allergists, another group of specialists whose business is prospering in the rash of new drugs, have admitted for some time that asthma and rhinitis (with symptoms like hay fever) resulting from drug allergy are not at all unusual. Penicillin and the sulfas are among the chief suspects. Recently, a worried Florida doctor queried his colleagues as follows in the Journal of the American Medical Association: “I have under observation a group of patients who have been sensitized by the sulfonamide drugs, penicillin and some of the antihistaminics…Could this not be the reason why one sees more allergic persons today who have asthma, rhinitis or other allergies which may have been initiated by the various drugs in question?”
To be fair, however, it should be stressed that such a sorry sequence of cause and effect rarely runs the full theoretical course. The risks cannot all be calculated, but most physicians are alert to the dangers–at least those reported so far. Doctors know, for instance, when directing the use of sulfanilamide, that nausea, headache, fever, jaundice, pallor and shock, in that order, indicate acute haemolytic anemia, and that immediate blood transfusions are imperative, since the red cells are destroyed so fast that the hemoglobin in the blood may fall to 30 per cent over night. Once this condition develops, mortality is high.
Sulfonamide therapy is never without risk, warns Dr. J. Stewart Lawrence in his book, The Sulfonamides in Theory and Practice. It has cured many, or at least helped nature to cure (the action is not completely understood). It has also killed. Serious and sometimes fatal kidney damage is perhaps the commonest of the undesirable by-products. Some sulfas are unquestionably less toxic than others, but kidney trouble has been estimated to occur in as many as 70 per cent of the cases treated with sulfapyridine and sulfathiazole.
“Quite apart from the fatal complications,” says Dr. Lawrence, “some degree of visceral damage is nearly always produced.” Doctors at the University of Michigan Hospital in Ann Arbor, during a four-year period, performed autopsies on 283 patients who had received sulfa-drug treatment shortly before they died. More than half were found to have myocarditis (inflammation of the heart’s muscular wall) for which there was apparently no explanation other than the drug. As a check, the doctors injected rats and mice with doses of sulfa comparatively smaller than are used in human treatment. The animals developed myocarditis.
Since the fact is well known that sulfa and the antibiotic drugs often give quick relief, it is natural for a patient to be willing to take his chances on possible long-term effects. The trouble is–and this he usually does not know–the oftener we take sulfa, the more sensitive to it we tend to become, and the earlier and more severe the toxic reactions. Sulfa medication for mild disorders may prohibit its use later in serious illness. Drug fever, for example, which can result from dosage with penicillin and streptomycin (but is more common after sulfa treatment), seldom occurs the first time the drug is used. But the second time, sulfa fever, as high as 106° F., may appear within an hour or two. Although not necessarily fatal or even serious, the fever has misled some physicians into diagnosing a spread of the infection. The dosage would then be increased and deaths would result.
Far more disturbing in its long term implications is the drug resistance put up by the embattled bugs themselves. The battle against bacteria, like that against insects, is a two-sided contest. Certain types of flies used to die like flies when they encountered DDT in the heyday of that spray. Their descendents, as most of us now know, resist up to 50 times that original dosage. Nature, apparently rejecting man’s prejudice in favor of his own survival at the expense of her other creatures, is also fighting back at the antibiotics with her usual ingenuity. In the case of sulfa drugs, medical men were slow to recognize the phenomenon. Today they keep a vigilant watch for the warning signs–and worry.
Nine years ago, in the bright morning of the sulfa era, laboratory workers found that streptococci, grown in broth which contained a low concentration of sulfanilamide, became drug resistant in sixteen hours. They could develop and thrive as happily in broth, whether the drug was present or not. Presently, scattered evidence turned up here and there to indicate that what could happen in a test tube could happen inside the body. Patients being treated for endocarditis, pneumonia and gonorrhea were found to have drug-resistant bacteria.
“Bugs” that develop immunity are a menace to any community as well as to the patient, as Dr. Lawrence, among others, has pointed out. “Such resistant organisms may apparently be disseminated by carriers, so that eventually the development of drug resistance on a large scale might render all sulfonamide therapy valueless. Resistance to one sulfonamide, unfortunately, usually means resistance to the others.”
In 1946, Army and Navy doctors had some alarming experiences which duly found their way into the pages of the Journal of the American Medical Association. In several Army and Navy units, mass prophylaxis of the men had been undertaken with sulfadiazine to prevent respiratory infections. The streptococci, after an initial Dunkirk, returned to the fray, rearmed against the drug, and produced extensive outbreaks of haemolytic strep infections that could not be controlled by any of the sulfa drugs.
This was troublesome news for the medical profession both here and abroad. “Drug-resistant bacteria might become highly pathogenic, be seated in populations, and result in wide-spread diseases refractory to treatment by sulfonamides,” said New York State Journal of Medicine editors. “Indiscriminate chemotherapy constitutes a real hazard.” In England the independent medical journal, Lancet, was moved to comment that “The possibility of the epidemic spread of a strain of pneumococcus or streptococcus which is both virulent and drug-resistant is not to be regarded lightly…”
By this time, luckily, penicillin was in the saddle, riding to the rescue. Far less poisonous than anything on the sulfa drug shelf, it was effective, for the time being at least, against many of those bacteria that had toughened themselves against sulfa.
The reprieve was dramatic but probably temporary. A. new note of dismay may now be detected in the intramural talk of doctors and scientists. In 1948, Sir Lionel Whitby, president of the British Medical Association, told his colleagues that a large proportion of gonorrhea cases are now sulfonamide-resistant, and that the outlook for penicillin and streptomycin in many infections which they once cured is not much brighter.
There was a good reason for Sir Lionel’s pessimism. Among patients at London’s Hammersmith Hospital in 1947, the incidence of penicillin proof strains of staphylococcus had increased in less than a year from 12.5 per cent to 3 8 per cent. A year later, the figure had reached 59 per cent. Moreover, the new-style bugs had been found in patients never treated with penicillin. They were being carried by nurses and doctors.
This was very bad news. Said the British Medical Journal:
And so it is turning out. In March 1949, four years after the discovery of streptomycin, the British Ministry of Health issued a statement urging that it be used with extreme caution in view of the severe and sometimes permanent toxic effects. Streptomycin-resistant strains of bacteria must be watched closely, officials emphasized, since they may develop with great rapidity. At the same time, Scotland’s Ministry of Health condemned the tendency to “try” this new antibiotic in every form of tuberculosis.
Although streptomycin is generally acknowledged to be the best drug treatment for tuberculosis, that best is not too good, according to a recent report to the American Medical Association by Drs. H. J. Corper and Maurice L. Cohn of the research department of National Jewish Hospital in Denver. The antibiotic does not destroy the virulent human tubercle bacilli or completely retard their development, and therefore cannot be considered a cure for tuberculosis in man at present.
Resistance of the bacilli develops with such speed that it seems likely the role of streptomycin will be a minor one as an adjunct to surgery and other conventional forms of tuberculosis therapy.
No one yet knows whether bacteria are adapting themselves by mutation or by natural selection, but indiscriminate and/or faulty use of the antibiotic drugs is apparently a potent factor in producing such resistant strains. Both British and American medical journals have called attention to the fact that the enormous consumption of penicillin today can be accounted for only by a great deal of promiscuous dosing.
As a matter of fact, penicillin is now one of the five most commonly prescribed drugs, according to a recent report in Minnesota Medicine. At St. Luke’s Hospital in Duluth during a sample three-weeks period, it was found that approximately half of all patients received penicillin. “The diagnoses ran almost the entire gamut of diseases prevalent in this part of the country.” In addition, the drug was given to forestall infection in a majority of obstetrical, surgical, orthopedic and genito-urinary cases. The study indicated that this wholesale medication was not only excessive but was evidently applied, in most instances, without adequate preliminary analysis of the patient’s bacteria. There is no reason to suppose that a few Duluth doctors are alone in this innocent faith in the cure-all properties of the drug.
Penicillin for self-medication has been available in several forms at drug store counters since 1945. To what extent the uncontrolled use of the drug by laymen is contributing to the resistance movement of the bugs is, of course, impossible to estimate. But medical authorities are concerned about it.
The trouble is becoming more complicated. Inadequate dosage seems to propagate sturdier germs. But massive doses which kill before the bacteria start to fight back, can, theoretically at least, create an even more serious problem for doctors. Chemotherapy could become too successful. The British Medical Journal asks editorially: “May infection be overcome so exclusively by the chemotherapeutic agent alone that the body’s normal defense mechanism may not function, that no immunity results, and a second attack may consequently follow?”
The question is not asked idly. There is already scattered evidence of patients treated with penicillin for streptococcus sore throat who have failed to bring into play their own antibodies (which normally are in there pitching). The penicillin bombs exploded before the leucocytes could get into action. Cases have been reported of post-penicillin recurrence of a disease as severe as the original attack. Nature, if she gets too much outside help, lies down on the job.
“The faculty of disbelief,” said Walter Elliott, former British Minister of Health, “like every other faculty, atrophies from disuse. Yet…it was never more necessary than it is now. The phrase, ‘Science tells us,’ should raise an instant challenge in our minds. Very often, however, it is the prelude to dumb acquiescence.”
Medical science, unharassed by the world’s impatient demands for a catholicon, will in any event make its traditional, cautious, sure-footed way toward the betterment of mankind. But it has been too often betrayed into most unsuitable marriages de convenance by adroit publicity writers and sensational newsmongers. “The pharmaceutical houses in their expensive and well-dressed up publications at times tempt the unwary physician to unsupported conclusions as to the value of newly discovered drugs,” Dr. Ernest P. Boas complained in a recent issue of New York Medicine.
What happens to them? Why do so many of these remedies retire into semi-obscurity or oblivion after the first huzzahs die down? Having asked this question himself, Dr. Austin Smith, director of the A.M.A.’s Division of Therapy and Research, gives one restrained answer:
And now here comes neomycin! Just the thing, it is said, to demolish some of those highly adaptable bugs that have taken streptomycin in their stride. Shall we lay out the red carpet? String the bunting? Or welcome it with the suspended judgment recommended to doctors by the British Medical Journal?
“An attitude of skeptical anticipation is the only possible one, for the drug may possess undesirable qualities not yet apparent.”