Antimicrobial Prophylaxisof Bacterial Endocarditis Prudent Caution or Bacterial Overkill?
ROBERT G. PETERSDORF, M.D. Seattle,
It is accepted medical practice to attempt to prevent bacterial endocarditis in patients with congenital or acquired heart disease who are likely to have bacteremia. This practice is based on the fact that in some patients with certain congenital and some acquired (notably rheumatic) cardiac lesions bacterial endocarditis develops in the wake of bacteremia. Prophylaxis is usually aimed at microorganisms resident in the mouth, nasopharynx and upper respiratory tree, and is usually directed against viridans streptococci. It is generally employed following dental manipulation, including cleaning, tonsillectomy and bronchoscopy with a rigid bronchoscope. Prophylaxis is also indicated in patients who undergo manipulative procedures of the urinary and genital tracts or who have abdominal surgery. Here, prophylaxis is directed primarily against the Enterococcus. Other indications for prophylaxis in susceptible patients include incision and drainage of abscesses, and cardiothoracic surgical procedures. In this situation, the primary aim is to prevent staphylococcal endocarditis. Unfortunately, there are no reliable data that prove conclusively that chemoprophylaxis is effective in preventing endocarditis. In making this statement, several epidemiologic facts that are important in evaluating the efficacy of prophylaxis should be considered: Bacteremia following certain manipulative procedures is very common. For example, its incidence after dental extraction can be as high as 80 per cent in some patients with periodontal disease. Yet, bacterial endocarditis is relatively rare, probably because the bacteremias arising in the oropharynx are transient-usually less than 30 minutes in duration-and low grade-usually with fewer than 10 or 20 organisms/ml of blood. Many patients at risk do not receive prophylaxis because the attending physician or dentist, or the patient himself, is unaware of a cardiac lesion. Bacterial endocarditis develops in relatively few of these patients. In a significant number of patients endocarditis develops in the absence of previously recognized heart disease. These patients, of course, would not he candidates for prophylaxis.
From the Department of Medicine, University of Washington School of Medicine, Seattle, Washington. Requests for reprints should be addressed to Dr. Robert 0. Petersdorf, Department of Medicine, RG 20, University of WashIngton School of Medicine, Seattle, Washington 98195. Manuscript accepted June 13, 1978.
Many cases of endocarditis, however, have followed procedures known to cause bacteremia; prophylaxis might have prevented a significant number of these. For example, of 125 patients with endocarditis at the University of Washington Hospitals [ 11, the infection developed in 13 after such proce-
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OF BACTERIAL. ENDOCARDITIS--PETERSDORF
endocarditis. To substitute for these ineffective regimens, prophylactic programs that were successful in preventing infection in rabbits were proposed. The revised recommendations for prophylaxis following dental manipulation are as follows:
dures. In eight of these, the portal of entry for the organisms was the mouth; two received inadequate prophylaxis whereas six received none at all. In four patients, none of whom received antimicrobial agents, the portal of entry was the genital or urinary tract; in one patient, endocarditis occurred after a hemorrhoidectomy. Since all these patients had previously recognized cardiac disease, it seems reasonable to postulate that in about 10 per cent of these 125 patients bacterial endocarditis was preventable.
Aqueous crystalline penicillin G 1 million U plus procaine penicillin 600,000 U intramuscularly 30 minutes prior to the procedure followed by penicillin V 500 mg orally every 6 hours for eight doses.
The prophylactic regimens in use have been established by the American Heart Association and, until recently, the following recommendations, proposed in 1972, were in force for the prevention of Streptococcus viridans endocarditis  : Procaine penicillin G 600,000 U mixed with crystalline penicillin G 200,000 U given intramuscularly 1 hour before the procedure and once a day for two additional days. Penicillin V 500 mg orally 1 hour before the procedure and then 250 mg every 6 hours for three doses and for an additional two days. Penicillin G 1.2 million U orally 1 hour before dental manipulation and then 600,000 U every six hours for two days after. For patients allergic to penicillin or for those who had been receiving prolonged penicillin prophylaxis for rheumatic fever, some of whom harbor relatively penicillin-resistant streptococci in the mouth, erythromycin 500 mg 1 l/2 to 2 hours before the procedure and then 250 mg every 6 hours for three additional doses the same day and then for two additional days. Recently, the American Heart Association (AHA)  published revised recommendations for prophylaxis of endocarditis. The American Heart Association revision emphasizes the use of parenteral prophylaxis with bactericidal drugs and is based to a large degree on studies of experimental endocarditis in rabbits . The rabbit model entails the placement of a plastic catheter into the right or left side of the heart. Twenty-four hours later, a sterile vegetation has formed at the site of endothelial damage induced by the catheter. Intravenous injection of microorganisms at that time leads to lodgement of bacteria on the sterile vegetation converting it to an infected lesion that closely resembles the vegetations of bacterial endocarditis in man. In this model, it was shown that a number of the regimens proposed by the American Heart Association in 1972 were unsuccessful in preventing experimental bacterial
Aqueous crystalline penicillin G 1 million U plus procaine penicillin 600,000 U intramuscularly plus streptomycin 1 g intramuscularly, 30 minutes to 1 hour before the procedure and then penicillin V 500 mg every 6 hours for eight doses. Penicillin V, 2.0 g orally 30 minutes to 1 hour prior to the procedure and then 500 mg orally every 6 hours for eight doses. Alternate regimens for patients allergic to penicillin are erythromycin 1 g 1 112 to 2 hours prior to the procedure and then 500 mg every 6 hours for eight doses; or Vancomycin 1 g intravenously procedure, then erythromycin hours for eight doses.
1 hour before the 500 mg every 6
Recommendations for the prevention of enterococcal endocarditis are even more stringent, but probably justifiably so. Those proposed by the American Heart Association in 1977 do not differ too radically from those proposed in 1972, and only the 1977 recommendations will be given. They include: Aqueous crystalline penicillin G 2 million U intramuscularly or intravenously, or ampicillin 1.O g intramuscularly or intravenously plus gentamicin 1.5 mg/kg (no more than 80 mg) intramuscularly or intravenously or streptomycin 1.O g intramuscularly at the time of the procedure and for two additional doses (gentamicin every 8 hours or streptomycin every 12 hours). For patients who are allergic to the penicillins, vancomycin 1 g intravenously plus streptomycin 1 g intramuscularly. It is recommended that these drugs be readministered in 12 hours. A major point of contention concerns the revised recommendations for the prevention of endocarditis caused by viridans streptococci. Hook and his colleagues [ 5] have raised two major objections: (1) The rabbit model is not quantitatively applicable to prophylactic regimens in man; and (2) the evidence that previous programs have been ineffective is not convincing.
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It certainly must be admitted that any regimen that was effective in the rabbit model should provide a wide margin of safety in man. In the first place, in order to induce infection in every rabbit (that is, to achieve an IDloo), a large number of organisms, lo0 to 10s colony-forming units, need to be injected. As a consequence, the magnitude of the resulting bacteremia is far greater than occurs in man after dental manipulation. Secondly, the presence of the plastic catheter, which acts as a foreign body, is a deterrent to successful prophylaxis. Although the effect of removing the catheter has not been studied extensively, the catheter seems to delay successful treatment of established infection in rabbits. Thirdly, the pharmacokinetics of antimicrobials in rabbits differ considerably from those in man. In general, the rabbit excretes drugs more rapidly than his human counterpart at comparable doses on a weight basis; this would confer an even greater margin of safety on any prophylactic program in human subjects. It seems clear, then, that prophylaxis in this experimental model provides a more stringent challenge to the drugs than might be expected in man. On the other hand, the argument that the recommendations of 1972 provided adequate prophylaxis is less compelling for at least three reasons: (1) some cases of infection appear to have developed despite apparently adequate prophylaxis following dental manipulation; (2) oral penicillin G is poorly absorbed from the gastrointestinal tract and is unlikely to provide adequate prophylaxis; and (3) a systematic study of prophylaxis failures has not been made, and we do not know in how many patients endocarditis has actually developed after seemingly adequate prophylaxis. There are a number of other problems with the revised recommendations, however. The emphasis on parenteral therapy will make prophylaxis far less acceptable to both patients and dentists. Certainly, given a choice, most patients prefer oral medication to the discomfort of pain in the shoulder or buttock following intramuscular administration of drugs. Moreover, there is a slightly greater likelihood of adverse reactions to parenteral rather than oral penicillins, and intravenous therapy with a drug like vancomycin in the dentist’s office seems totally impractical. What about the cost of these prophylactic programs? Because most of the drugs are inexpensive and the courses of therapy comparatively brief, the cost is relatively modest even if the recent recommendations of the AHA are used. However, drug costs are relatively minor compared to the cost of hospitalization which is entailed in some recommendations for prophylaxis. For example, Kaye  recommends two programs for the prevention of enterococcal endocarditis that require administration of 20 million U of penicillin G intrave-
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nously over a 24 hour period and a third, for penicillinallergic patients, which proposes 2 g of vancomycin intravenously. To each of these is added streptomycin or gentamicin. All programs are continued for three days and require the patient’s hospitalization. And, in this instance, even the drug costs become substantial. In our hospital, a three day penicillin/streptomycin regimen costs $14.70 (not counting the cost of administration), but if gentamicin is substituted for streptomycin the cost rises to $71.07. The vancomycin/streptomycin program costs $102.78 and the vancomycin/gentamicin program $159.15. Moreover, if an average cost of $300/hospital day is assumed, it can be seen that the cost of preventing enterococcal endocarditis could become as high as $1,000 without considering, of course, the cost of the procedure for which prophylaxis was given in the first place. Admittedly, Kaye’s recommendations antedated the regimens suggested by the AHA in 1977. They were based on the newer data obtained in rabbits combined with the 1972 convention of the AHA which called for three days of prophylaxis in every instance. Kaye’s recommendations represent the paradigm of “defensive medicine,” and Kaye himself believes that one day prophylactic regimens suffice for most patients. I believe that there is a middle ground between the recent hyperaggressive recommendations and those in force in the past. My recommendations would combine features of both and may be summarized as follows: The American Heart Association Committee was quite correct in recommending deletion of oral penicillin G as effective prophylaxis. Despite its low cost, the absorption of this drug is too uncertain to justify its continued use. Parenteral prophylaxis against Streptococcus viridans endocarditis should be reserved for high risk patients, such as those with prosthetic heart valves, and need not be used for patients without such intracardiac devices. When parenteral prophylaxis is used a sing/e administration of 1.2 million U of aqueous procaine penicillin plus 1.O g of streptomycin seems adequate. For most other patients, a 2.0 g loading dose of penicillin V followed by 0.5 g for three additional doses should be used. If patients are allergic to penicillin the drug of choice is erythromycin, and a loading dose should be given here as well. In my view, the duration of most of the recommended regimens is too long. In the rabbit model, most successful programs prevented infection after only a single administration of drugs, and there is uniform agreement that this single dose of drug provided a wide margin of safety. It seems incongruous, therefore, to enlarge on this margin of safety even further by adding therapy for at least eight doses. I would think that three doses after
the initial loading dose would suffice. This will decrease cost and will certainly enhance compliance. I also believe that the regimen for the prevention of enterococcal endocarditis must continue to rely on administration of drugs parenterally. However, it should be possible to complete prophylactic therapy within 12 to 24 hours. This would not require prolonged hospitalization for patients undergoing brief procedures, such as cystoscopy. urethral catheterization and dilatation and curettage. If these procedures can be accomplished in a single day, administering prophylaxis during that particular day only would seem adequate. Because 40 per cent of enterococci fail to be inhibited in vitro by the combination of penicillin and streptomycin, we consider penicillin (or ampicillin) and gentamicin as the regimen of choice, admitting that other aminoglycosides may be equally effective under many circumstances.
PROPHYLAXIS OF BACTERIAL ENDOCARDITIS-J’ETERSDDRF
Finally, to come to grips with the efficacy of various prophylactic regimens, the medical and dental professions must keep much better records. Specifically, a cooperative study involving both physicians and dentists should be considered to determine what happens to patients who are given prophylactic chemotherapy. In how many of them does endocardial infection actually develop? Of equal importance is obtaining a careful history from patients with documented endocarditis to ascertain the presence of prior heart disease, events that are associated with baoteremia, and administration of prophylactic drugs during these episodes. Despite the fact that this sequence of historic events should be known by every third year medical student, it is surprising how often these facts, which are so essential to evaluating the efficacy of antimicrobial prophylaxis in bacterial endocarditis, are not obtained.
Pelletier LL Jr, Petersdcrf RG: Infective endocardftis. A review of 125 cases from the University of Washington Hospitals, 1963-72. Medicine (Baltimore) 56: 287, 1977. American Heart Association Committee on Rheumatic Fever and the Committee on Congenital Heart Defects. Prevention of bacterial endocarditis. Circulation: 46 (suppl V): 3, 1972. American Heart Association Committee Report. Prevention of bacterial endocarditis. Circulation 56: 139A. 1977.
Pelletier LL Jr, Durack DT, Petersdorf RG: Chemotherapy of experimental streptococcal endocarditis. IV. Further observations on prophylaxis. J Clin Invest 56: 319, 1975. Sipes JN, Thompson RL. Hook EW: Prophylaxis of infective endocarditis. A m-evaluation. Ann Rev Med 28: 371, 1977. Kaye D: Infective Endocarditis, Baltimore, Baltimore University Press, 1976.
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