M any clinical and laboratory studies reported in

Endocarditis after Cardiac Valvular Replacement* ]. E. Okies, M.D.,]. Viroslav, M.D., and T. W. Williams, ]r., M.D. In men and seven women infectious endocarditis developed on their prostheses following valve replacement. ylococcus dermiclis was the most common etiologic agent. Four survivors were treated medically with antibiotics and supportive cardiac drugs. Two required re-replacement of the prosthetic valve in order to remove the source of unremitting infection and mechanical mahunction of the valve. Twelve deaths resulted from persistent infection, systemic embolization, and unresponsive congestive heart failure. Some of the deaths might have been prevented by earher replacement of the prosthetic valve. This should be done early in any patient with persistent sepsis, multiple systemic emboh, or a malfunctioning valve. M any clinical and laboratory studies reported in the past decade suggest that foreign bodies in the cardiovascular system predispose to infection. Bahnson and associates in 95 reported a patient with endocarditis following open heart surgery whose infection responded to removal of an infected silk suture. Elek and Coven noted that the presence of a silk suture increased by a factor of 0,000 the susceptibility to local infection in dogs. Barney and c o l l e a gproduced u e s = ~ infection in all dogs with damaged or prosthetic valves when given bacteria intravenously, while no infections were noted in a group of control animals with normal heart valves given comparable numbers of organisms. Geraci and co-workers 4 were among the first to describe infection on prosthetic valves in human beings and to recommend prophylactic antibiotics to diminish the incidence of infection. In 965 Nelson and associates 5 proved the effectiveness of prophylactic antibiotics in cardiac surgery by lowering a 4. percent incidence of bacterial endocarditis to. From the Cora and Webb Mading Department of Surgery, the Departments of Medicine and Microbiology, Baylor College of Medicine, and the Methodist Hospital, Houston, Texas. Supported by grant RR-0050 from the Clinical Research Centers Branch, National Institutes of Health, Bethesda, Maryland. percent. Amoury and co-workers6 ( 965) and Stein and colleagues ( 966) demonstrated that the incidence of bacterial endocarditis due to ylococcus sp could be lowered to 0 percent if the patients were given specific antistaphylococcic prophylaxis (methicillin, oxacillin, and/ or cloxacillin). Since the great majority of postvalvular replacement endocarditis is caused by staphylococci, the overall incidence has been reduced to less than percent with widespread appropriate use of these antibiotics. SuMMARY OF CASES Since 96, 8 patients who received a single (ten aortic, seven mitral) or double (one aortic and mitral) valve replacement for luetic and rheumatic heart disease have acquired endocarditis on their prostheses. There were men and women ranging in age from 6 to 6 years, Table ). The source of infection was unknown in eight patients. The remainder had these sources of infection: the GU tract ( 5), dental manipulation ( ), surgical wound ( ), gastrointestinal tract ( ) and skin ( ). The organisms were cultured from the blood in all but one case and from the valve at autopsy in one. The organisms recovered were ywcoccus dermidis ( ), ywcoccus aureus ( ), Streptococcus ( ), Klebsiella ( ), Serratia (l ), and Candida albicans (l ). Thirteen patients received prophylactic antibiotics consisting of combinations of penicillin, ampicllin, chloramphenicol, tetracycline, and/ or streptomycin prior to, during, and after valve replacement. Five patients received methicillin- 98

ENDOCARDITIS AFTER VALVE REPLACEMENT 99 Table I Case 4 5 6 8 9 0 4 5 6 8 Race Organism Age Sex Valve Prophylaxis Recovered Cultures 66 WF Serratia marcescens 6 WM 4 WM 54 WM WM 8 WF 48 WF 55 WF 5 WM 4 WM 9 WM 60 WM 49 WF 4 WM 0 WF 8 WF WM 55 NM Tetracycline aureus KlebsieUa sp Candida albicans Source of Cause of Group Antibiotic Rx Death Surgery Dental Work Wound Skin ttnknown Gentamicin Vancomycin Colistin Gentamicin ne oxacillin prophylaxis. Upon establishment of a diagnosis of endocarditis the patients were treated with appropriate antibiotics achieving bactericidal levels of :6 dilutions or greater in all but one patient in whom the diagnosis was made at postmortem examination. Clinical diagnosis was based upon the findings of fever and four or more positive blood cultures in all patients and splenomegaly, systemic emboli and hemodynamic abnormalities from valve malfunction in most patients. RESULTS Six of the 8 patients are alive at this time, five more than one year after the course of antibiotic therapy. Medical treatment was the sole form of therapy for four of the six survivors. There were two patients with early infection ( < two weeks) and two with late infections (four months and two years) after surgery. The early infections were caused by dermidis and y Streptococcus while the late were caused by y streptococci (Table ). The other two survivors required replacement of the prosthetic valve because of persistent sepsis and a malfunctioning valve (Table ). Causes of the deaths were analyzed and divided into three major groups: Group!-Patients dying with unremitting infection ( one case ). CHEST, VOL 59, NO., FEBRUARY 9

00 OKIES, VIROSLAV AND WILLIAMS Table ---Summary of MedicaUy Cured Parienl lfilh Pro.lhetic Y a l ~ Endocarditi ~ e Onset after Valve Source Serum Race Replace- of MIC/MBC Daily Dose Level Case Age Sex ment Organism pg/ml Antibiotic Rx Duration Peak/Low Remarks 6 8 WF 4 months GU tract -r strep.9/.8 6gm IV :8/6 Renal failure 6weeks present before antibiotic therapy. 49 WF years -r strep 6.5/50 mil U IV :64/6 + 4 weeks.0 gm IM weeks 4 WM weeks GU tract -r strep.8/.56 0gm IV :56/6 Residual aortic 4 weeks insufficiency requiring corrective surgery four monthsl&ter. lo 4 WM weeks 50/00 8 mil U IV Renal failure 5/50 gm IV present before./6.5.5 gm IM antibiotic 6.5/.5 Vancomycin 4gms IV- :/6 therapy. 4 weeks * was used for the first four days. * was used for the next three days. " was used for the next five days. Group II-Patients dying of multiple systemic emboli (four cases). Group III-( a) Patients dying with intractable heart failure without replacement of the prosthetic valve ( three cases ). (b) Patients dying with intractable heart failure with replacement of the prosthetic valve (four cases). All but one patient in Group III had clinical or bacteriologic evidence of infection at the time of death. DISCUSSION When the historic background of the insertion of foreign materials into the heart is reviewed, several interesting facts are noted. First, there is a high incidence of infection surrounding the prosthesis in the absence of prophylactic antibiotics. Barney and co-workers found a 00 percent infection rate in dogs with damaged or prosthetic valves given intravenous bacteria, while no infections could be induced in dogs with normal valves. When bacteria were infused six weeks following valve replacement, no infections were produced. These experiments indicate that the valves can become inoculated during the operative procedure or in the immediate postoperative period. Geraci and associates4 ( 96) reviewed the Mayo Clinic experience with postprosthetic endocarditis and found approximately a 0 percent incidence of staphylococcic infection. In 4 cases of prosthetic valve endocarditis reviewed they noted a mortality of. percent. They were the first to recommend antistaphylococcic prophylaxis in order to prevent this infection. Second, the incidence of infection can be lowered to less than percent when appropriate bactericidal prophylactic antibiotics are used. Nelson and colleagues5 ( 965) in a prospective study of 50 cases of open heart surgery found a 4. percent incidence of endocarditis when no prophylactic antibiotics were used. The incidence was lowered to. percent when prophylactic penicillin and streptomycin were given. The addition of methicillin for one week in the immediate postoperative period lowered the incidence to 0 percent. Amoury and coworkers 6 ( 965) reported cases of prosthetic valve endocarditis (.6 percent incidence in 5 cases), of which were due to dermidis. The mortality in the entire series was 0 percent. In 98 patients who received specific antistaphylococcic prophylaxis, no endocarditis was found during an 8 month follow-up period. Stein and associates ( 966) found an incidence of endocarditis on valvular prostheses of. percent compared to an incidence of less than percent for other open and closed heart operative procedures. When no prophylaxis was given, endocarditis was CHEST, VOL 59, NO., FEBRUARY 9

ENDOCARDITIS AFTER VALVE REPLACEMENT Early <0 Days Post Op Cultured in Table ~ r «a n i " m " Earlr and Late ln/ecliom. of Prophylaxis Patients Other Total early infections Late >0 l Days Post Op* Other Total late infections 6 4 Organism SerraJ.ia marcescens Klebsiella sp 'Y Streptococcus dermidis aureus Candida sp dermidis 'Y Streptococcus dermidis 'YStreptococcus *ne of these occurred in less than four months. found in nine of 4 cases (. percent). Various prophylactic antibiotics reduced the incidence to only. percent ( of 4 cases), and methicillin prophylaxis allowed only one infection in 69 cases, for an incidence of 0. percent. Windsor et al 8 ( 968) noted no prosthetic valve endocarditis in 0 patients treated with prophylactic penicillin, streptomycin and methicillin. Of his seven patients who were unable to receive penicillin and methicillin due to drug allergies, ylococcus albus endocarditis developed in one patient. In this series of 8 cases of postoperative prosthetic valve endocarditis, developed early and seven developed late infections. The incidence of staphylococcic infection in the early ( 64 percent) and late ( 0 percent) postoperative period is nearly identical. Five of the patients herein reported received adequate prophylaxis with methicillin-oxacillin. In this small group three developed endocarditis in the early postoperative period from G U tract infections with bacteremia, but none was due to staphylococci. The remaining two patients developed endocarditis late in the postoperative period and were related to urinary tract infection or dental manipulation with bacteremia (Table ). One of these was caused by a methicillin sensitive dermidis (case 5). This emphasizes the importance of proper antibiotic coverage for patients with prosthetic valves undergoing procedures that are likely to cause bacteremia. Third, in some cases of prosthetic valve endocarditis the infection has been cured by excision of the infected prosthesis. Geraci and co-workers9 ( 96) reported one case of Corynebacterium xerosis endocarditis successfully treated with penicillin and valve re-replacement. Walker and associateso 0 ( 969) reported three cases of prosthetic valve endocarditis treated successfully with antibiotics and surgery. One patient died six weeks postoperation of unknown causes. One was alive 0 months and another 5 months following re-replacement of the prosthetic valves and both were doing well. Fourth, there is no evidence of increased incidence of prosthetic valve endocarditis in patients who have received prostheses for the treatment of acute bacterial endocarditis, suggesting that valvular replacement does not increase the chances of persistence or recurrence of the infection in patients treated with adequate antibiotics. Braniff and colleagues ( 96), Okies et al ( 90) as well as other writers have reported series of patients with acute bacterial endocarditis treated by excision and prosthetic valve replacement in the early stages of antibiotic therapy without evidence of prosthetic endocarditis on long-term follow-up. In the majority of patients with infected prostheses some hemodynamic abnormalities ultimately will develop if not treated. This can be due to direct involvement of the annular tissue causing disruption of the suture line of the valve at the annulus with paraprosthetic leakage, or due to mechanical failure of the poppet from an encroaching vegetation. Although sterilization of the valve may be accomplished, the hemodynamic abnormalities persist and can result in intractable heart failure or multiple systemic emboli. Twelve of our 8 patients died with a resulting mortality rate of ffl percent. It was apparent from review of these cases that surgery was not seriously considered in eight patients and was performed only after the patients were moribund in four. We think that some of these patients could have been salvaged if surgical therapy had been undertaken at an earlier stage of their disease process. It is important, therefore, to establish criteria that will allow selection of patients to be reoperated on early in the course of treatment. It is clear that prosthetic valve endocarditis that responds to antibiotic and supportive medical therapy should be treated conservatively so long as no hemodynamic abnormality exists. With signs and symptoms of unremittant infection, systemic embolization, or abnormal hemodynamics, the patient should have surgery promptly in order to remove the source of infection or emboli or to correct the hemodynamic abnormality. Catheterization data has helped to determine the hemodynamic status of some of the patients, but the patient's clinical picture is much more important, since patients with low cardiac output may not show abnormal gradients across CHEST, VOL 59, NO., FEBRUARY 9

0 Table 4>--Ciinical Clauifieation of Patienla tdith Pro thetic J' ale Endocardili I Patients who respond to treatment with antibiotics and supportive medical therapv. II Patients who have (a) persistent or recurrent fever and positive blood cultures while receiving adequate antibiotic treatment, (b) systemic-embolization, or (c) mechanical malfunction of the valve or paraprosthetic regurgitation. It is in this group of patients that surgerv should be performed immediately. It is our contention that patients who shift from Group I to Group II should be treated immediately with valvular re-replacement. The decision to remove the infected prosthesis should be made early in this stage of the disease in order to avoid having to perform an emergency procedure. III Moribund patients or patients in whom the annulus has already been destroyed by infection. the affected valves. It was apparent from reviewing our series and from the experience of others, that patients treated for prosthetic valve endocarditis can be separated into three general groups (Table 4). In this series the groupings of patients developing endocarditis in the early and late postoperative periods is as shown in Table 5. All the patients in Group I survived with medical treatment alone. All patients in Group III died with or without surgery. The two patients in Group II survived. Both of these patients were reoperated when they began to deteriorate in spite of adequate medical therapy. The overall mortality for patients with prosthetic valve endocarditis is 0 percent. In the future it should be possible to lower the mortality in Group III by more aggressive early surgical intervention in addition to appropriate antibiotic and medical therapy. Prophylactic antibiotics, particularly methicillin, oxacillin and cloxacillin given prior to and after surgery in appropriate doses will reduce the incidence of prosthetic valve endocarditis to less than percent. It is our policy to administer prophylactic antibiotics to all patients undergoing cardiovascular surgery. ( gm every six hours) is given intramuscularly beginning the night prior to surgery and intravenously ( gm every four hours) Table 5-Cia. ification of the Reported Ca.u a. to Time of On et of Group I Group II Group III Early Late 0 5 OKIES, VIROSLAV AND WILLIAMS following surgery for three to five days until the patient is able to take medications by mouth. Then cloxacillin ( ~ gm every six hours in the fasting state) is given until the sutures are removed and all wounds are well-healed. In patients allergic to penicillin, cephaloridine can be given prior to surgery and cephalothin postoperative in the same dosage and routes as methicillin is used ordinarily. Erythromycin or lincomycin can be used as a substitute for cloxacillin as the oral antibiotic once cephalothin is discontinued. These latter drugs are bacteriostatic and therefore should not be used as the initial prophylactic agents. Prosthetic valve endocarditis is a serious and not uncommon complication in patients undergoing open heart surgery for replacement of diseased valves. Adequate antibiotic prophylaxis will reduce the incidence of endocarditis to < percent. Patients developing prosthetic endocarditis should be treated aggressively medically and surgically in an effort to decrease the 0 percent mortality in this infection. REFERENCES Bahnson HT, Spencer FC, Bennett IL: ylococcal infections of the heart and great vessels, due to silk sutures. Ann Surg 46:99, 95 Elek SD, Coven PE: The virulence of staphylococcus pyogens for man. Brit J Exper Path 8:5, 95 Barney JD, Williams GR, Cayler GG, et al: Influence of intracardiac prosthetic materials on susceptibility to bacterial endocarditis. Circulation 6:684, 96 4 Geraci JE, Dale AJD, McGoon DC: Bacterial endocarditis and endarteritis following cardiac operation. Wis Med J 6:0, 96 5 Nelson RM, Jensen CB, Peterson CA, et al: Effective use of prophylactic antibiotics in open heart surgery. Arch Surg 90:, 965 6 Amoury RA, Bowman FO, Maim JR: Endocarditis associated with intracardiac prostheses. J Thorac Cardiovasc Surg 5 :6, 966 Stein PD, Harken DE, Dexter L: The nature and prevention of prosthetic valve endocarditis. Amer Heart J :9, 966 8 Windsor HM, Fagan P, Shennehan MX: Bacterial endocarditis, mitral regurgitation, and intra-atrial thrombosis following mitral valve replacement. Thorax :, 968 9 Geraci JE, Forth RJ, Ellis FH: Postoperative prosthetic valve bacterial endocarditis due to Corynebacterium xerosis. Mayo Clin Proc 4:6, 96 0 Walter SR, Shumway NE, Merigan TC: Management of infected prostheses. JAMA 08:5, 969 Braniff BA, Shumway NE, Harrison DC: Valve replacement in active bacterial endocarditis. New Eng J Med 6:464, 96 Okies JE, et al: Valvular replacement in bacterial endocarditis. Cardiovas Res Cent Bull 8:6, 90. Reprint requests: Dr. T. Williams, St. Luke's Episcopal Hospital, Houston 05 CHEST, VOL. 59, NO., FEBRUARY 9