Evolution of an idea: The case of prophylaxis against infective endocarditis.

The ideas in medicine, many a times, run a parallel course. Although, this allegory is apparent mostly in retrospect, one wonders if the dissection of the trajectory of the ideas could have an educational value. In any case, the remarkable turnaround in therapeutics as we had for many situations, for example in the case of prophylaxis against infective endocarditis more recently, and in antiarrhythmic therapy for VPCs, in B-blockers in heart failure and others in the past, need be examined in the terms of evolution of the idea. It is remarkable that the complete change of stance occurred within a relatively narrow time frame, almost akin to change in fashions, rather than a change of an era. Of course, the changes were necessitated due to parallel progress in many fields and other mounting evidence, but the pattern of the evolution is of concern, since similar things could be happening in contemporary thinking in other areas as well.

The evolution of the treatment of IE, so much taken for granted today, makes an exemplary reading. Much of the early literature has confused rheumatic and infective endocarditis. The bacterial cause of infective endocarditis was not at once apparent. In the pre-antibiotic era, there were numerous different treatments tried, even with a rare report of success. These included intravenous Eusol, intravenous mercury and gentian violet, arsenic, sodium cacodylate, Collargol, blood transfusions, and many others.[1-4] These are enough to give goose bumps to the young graduate reading endocarditis today.

Then, the bacterial causes were discovered, but there were no cures. Vaccine came prior to antibiotics and in desperation, anti-streptococcal serum was injected in patients in the hope of doing good.[5] And patients were vaccinated against the streptococcal recovered from the teeth in graduated dosages in the hope of preventing recurrence.[6] The hopelessness and intense desire for a solution can be felt as one reads through the elaborate clinical descriptions of these cases.

The joy and relief with the discovery of penicillin is palpable by the flurry of the published articles, but it is remarkable that the early result in IE was not successful due to incorrect dosing of penicillin.[7] Surprising it may seem today, but there was not enough penicillin available to treat patients with large dosages, so careful rationing was applied. A dose of 5,00,000 units/day was considered curative in the majority initially, and administration by continuous intramuscular infusion with a soft catheter was considered better than intermittent injections by some. But eventually correct dosages were formulated with much scientifically rigorous studies.[8-11] It was found that longer duration of therapy, rather than the total dose was important, a fact sometimes forgotten even today. Therapy with Penicillin and anticoagulation with heparin was in vogue for sometime[12] in the hope that the bacteria in the thrombus may be attacked better this way, a therapy that is contraindicated today. Some investigators rightly opposed this combination before their peers finally abandoned the concept.[11]

As treatment became effective, the question of prophylaxis arose. The spectre of a serious disease like IE intuitively justifies all efforts at prevention. The oral cavity connection of IE was known and cases of IE were described following extraction, though not always with certainty.[13] The basic tenets of prophylaxis that 1) Bacteria cause IE, 2) Mouth is the source of the causative organism, 3) Dental procedures can cause bacteremia, and 4) Antibiotics kill bacteria are simply true (even today). Antibiotics were used for prophylaxis almost as soon as they were available.[14] This led to systematic recommendation by professional societies like AHA since early 1950s.[15] Initially, antibiotics were prescribed for 2 days before and 2 days after the procedure. Subsequent recommendations identified high and low risks procedures, high and low risk patients, dosages of antibiotics to be used, and held the centre-stage of these endeavors in trying to facilitate the prophylaxis.[16-18] This trend was in full vigor until 1997, but in 2007 as if in volte-face the recommendations were turned topsy-turvy.[19] The patients requiring prophylaxis for dental procedures were significantly pruned and the prophylaxis for gastrointestinal and genitourinary procedures was dropped altogether. Other societies followed the suits, even more vigorously. There are some differences in the recommendations, but mostly the number of patients and procedures requiring prophylaxis has markedly diminished.[2021]

Few things are worth recapitulating. The empiric nature of guidelines was recognized from the beginning in 1950s, but the fervor with which it was revised, expanded and elaborated almost made it appear like a solved case. The 1997 recommendation clearly stated, ‘these are guidelines and not intended to be standard of care or a substitute of clinical judgment’, but in practice, these became the popular opinion. And, as with other popular opinions - ‘The popular opinions always contain broad fallacies, half-truths, and glib generalizations of fifty years before’.[22] Dissenting voices against the role of dental procedures were heard from earlier times, but as so often happens, the voice of sanity is soft.[2324] Further, although all the basic tenets in the arguments for prophylactic treatment of IE are correct as indicated above, a change in the perspective seemingly occurred by realization of additional factors and by putting a sense of quantitation in the simplistic logic of the idea. For example, realization that bacteremia occurring during dental extraction is of similar magnitude like that occurring during daily activities (<10 × 4 colony-forming units),[25] and bacteremia in 1year from daily activities exceed million times more than that occurring during a dental extraction.[25] (IE is not that common so there is yet ill understood relationship of bacteremia and occurrence of IE). And quantitation such as ‘even if the prophylaxis were to be 100% effective, it is likely to prevent exceedingly small number of cases’.[19] Similar quantitation and lack of a-priori evidence underlie the changes in the recommendations for procedures involving gastrointestinal or genitourinary tract. Further, now that the treatment is available, AHA recommends prophylaxis only for those where IE would pose risks of severe adverse outcomes if it occurred, and not for those where lifetime risks of IE are high. This significant departures in perspective occurred in the absence of changes in available hard data, it may indicate progress in the treatment of IE, but is largely driven by the realization of overkill in the previous recommendations. How much role the prevailing medico legal climate in the United States of America played in the changes in the recommendation is difficult to quantitate. It is important to realize, as the committee also recommended, that further studies are required to test the validity and impact of the changes in the recommendations on the occurrence of IE.

A sidelight of viewing this evolution is the change in the underlying cardiac conditions for which the prophylaxis is recommended. While much of the world still struggles with rheumatic heart disease (RHD), it is understandable that recommendations coming from the western world has downplayed RHD, There are no new additional data suggesting that IE in RHD is becoming less serious, but recommendations have taken away RHD patients, based on the better prognosis of native valve IE as compared to prosthetic valve IE, although the life time risks in the two are similar.[19] Prophylaxis was recommended in RHD patients in 1990, RHD was considered a moderate risk lesion in 1997, and is deleted in 2007 as an IE with not that adverse an outcome. The impact of these recommendations in RHD patients remains to be studied. Such studies will have to come from the areas where RHD remains a problem. Thus local adaptation to any global idea remains important. Think globally, but act locally is an inescapable idea.

Thus, in the evolution of this idea we see, first there is a vacuum and intense longing for an idea, then the fateful arrival of the idea, and then the overreach; and finally a correction with a niche for the idea. The prevailing environment can prolong or abbreviate this course of an idea significantly. An agile scientific community should do this job faster, perhaps. Whispers heard in the interim are valuable.

Could any of our current modes of management be in an arena of overreach? At the risks of being the Devil's advocate, could some of our ideas regarding early neonatal surgery, device closures of small defects, early Fontan completion will fall in this trajectory? Keep ideating.