Appraisal Edited
and reappraisal
by Arthur
Infective
C. DeGraff
and Julian
endocarditis:
Part
of cardiac
therapy
Frieden
II. Current
therapy
Joan I. Casey, M.D. Michael H. Miller, M.D. Bronx, iv. Y.
Many clinical and experimental studies have been undertaken in the past few years to determine optimal therapy for infectious endocarditis which continues to be one of the most serious infectious diseases of man. The increased prominence of unusual organisms and the changes in sensitivity patterns of the more characteristic organisms is important therapeutically. Therapy often must be started prior to a knowledge of the causative organisms. It is useful to review briefly some of the predisposing conditions associated with this disease. A knowledge of the probable portal of entry enables one to make an educated guessas to the organisms, and therefore, the most useful antibiotic, or combination of antibiotics. In recent years there has been a decrease in rheumatic heart disease and an increase in the number of people surviving with prosthetic valves, congenital heart disease, and arteriosclerotic heart disease. These people are at an increased risk of bacterial endocarditis, so that over-all there has been no decrease in the number of patients with bacterial endocarditis. There has also been a change in the types of organisms causing bacterial endocarditis. Documentation of bacteremias associated with dental procedures has re-affirmed the importance of the mouth flora as a primary source of organisms. These organisms, usually viridans streptococci, have an ability to adhere to heart valves not found in other organisms such as gram-negative From the Division Mont&ore Hospital College of Medicine, Received
for publication
of Infectious Diseases, and Medical Center, Bronx, N. Y. April
Department and the
of Medicine, Albert Einstein
6. 1978.
Reprint requests: Joan I. Casey, M.D., Department of Medicine, Division of Infectious Diseases, Mont&ore Hospital and Medical Center. E. Gunhill and Bainbridge Aves., Bronx. N. Y. 10467.
OOOZ-870:3/78/0296-0263$00.70/O
0 1978 The
C. V. Mosby
Co.
rods. This may be the reason these streptococci remain the leading cause of infective endocarditis. The disease is usually sub-acute although fulminating infection can occur with these organisms. The increased use of intravenous infusions in the hospital and intravenous heroin in the community has increased the incidence of bacteremias which may lead to valvular infections. The organisms involved in these latter infections are usually Staphylococcus aureus, Enterobacteriaceae Sp., Pseudomonas aeruginosa or enterococci. Manipulation or infection of the genitourinary and gastrointestinal tracts may lead to transient bacteremias and valvular infections with Group D streptococci or rarely gram-negative rods. Group D enterococcus endocarditis, rarely seen prior to the introduction of antibiotics,’ is now not uncommon in this setting. The diseasemay be acute or sub-acute. Group D non enterococcus includes Streptococcus bovis, increasingly recognized as a cause of endocarditis,” and Streptococcus equinus only rarely a cause of human disease. Staphylococcus aureus is found on normal human skin, and may enter the blood stream secondarily to intravenous lines, superficial skin infections or wound infections. Staphylococcus aureus endocarditis may be seen in children including those with hematogenous osteomylitis and this association should be recognized. Blood cultures growing Staphylococcus epidermidis, which is also found on normal skin, may represent contamination or infection. Continuous bacteremia must be considered to represent intravascular infection and be treated as such, although true infection with Staphylococcus epidermidis is unusual except in the patients with prosthetic valves.
American
Heart
Journal
263
Casey
and
Therapeutic
Miller
principles
There are certain principles which apply to the treatment of bacterial endocarditis. Adequate concentrations of active drug must be achieved at the site of infection over a defined period of time. Eagle and colleague& demonstrated that even in those lesions where the action of the antibiotic may be augmented by the body’s host defenses, as much as twenty times the minimal inhibitory concentrations (MIC) of antibiotic may be necessary to kill the infecting organism. In endocarditis, the vegetation consists of a fibrin network in which millions of organisms may be entrapped and protected from the body’s host defenses. High concentrations of antibiotic are needed to effect a cure of bacterial endocarditis, and the antibiotics used must kill, and not just inhibit the growth of the organism. Quantitative sensitivity testing by tube dilution is used to ascertain the minimum concentration of antibiotic necessary to inhibit, and to kill (MBC) the patient’s organism. A practical way to obtain some indication of appropriate therapy is the Schlicter test.” This is a measure of the ability of the patient’s serum, which contains the appropriate antibiotics, to inhibit or kill the organism causing the patient’s infection. Two specimens are taken, one representing the peak concentration, taken at the appropriate time after the dose is given, and one representing the nadir, taken just before the next dose is due. A serum bactericidal level of at least 1 to 8 at the nadir is that which has been associated with the best results of antibiotic therapy. To achieve these levels parenteral therapy is usually required. Duration of therapy is usually four weeks for very sensitive organisms, and six weeks for the less sensitive as well as the more virulent pathogens. These recommendations for the duration of therapy are mainly based on the current practice of physicians who have long dealt with this disease. Short courses may lead to relapses, and unusually long courses can lead to suprainfections. The antibiotic chosen should be the one with the narrowest possible spectrum, which has been proven to be effective clinically. Newer antibiotics are not necessarily better. The choice of a drug should include consideration of cost and toxicity. Failure of clinical response to the most appropriate antibiotics may be related to a delay in starting therapy, sub-optimal doses, the wrong
264
route, minimal duration of therapy, the development of local or metastatic abscesses, the presence of a foreign body (e.g., prosthetic valve) or the underlying disease in the host. Streptococcus
viridans
Viridans streptococci, also reported as alpha streptococcus, are organisms which do not fit well into other classifications of streptococci. Organisms now reported as Streptococcus mitis, Streptococcus sanguis, and Streptococcus mutans may also be reported by some laboratories simply as Streptococcus uiridans. Authors differ on the terms “penicillin sensitive” and “relatively resistant” with reference to these particular organisms. Blount’s classification of an organism with an MBC of less than 0.1 unit per ml. as sensitive, 0.1 to 1.0 unit/ml. as moderately sensitive, and greater than 1.0 unit/ml. as relatively resistant would seem to be adequate for therapeutic purposes.5 Standard therapy for the sensitive organisms would be one million units intravenously every two hours, or two million units intravenously every four hours for a period of four weeks. For the moderately sensitive the dose may be raised to three million units every four hours. Those organisms which are relatively resistant may require the addition of streptomycin 500 mg. intramuscularly every twelve hours. Although some authors use this combination for all casesof viridans streptococci endocarditis,” the results with penicillin alone are very good, especially when the organism is very sensitive. The possibility of shortening the course of therapy for viridans streptococci endocarditis to two weeks has been investigated.’ Results with penicillin alone were poor, two patients relapsed of 13 so treated. Patients treated with penicillin plus streptomycin for two weeks appeared to respond well whether the penicillin was given by mouth or parenterally. There were no relapses in these latter two groups. One hundred patients treated by Cox and colleagues” with penicillin V by mouth and streptomycin intramuscularly for two weeks had a very good recovery rate. However, some patients, in particular the elderly and the ill, absorb oral drugs poorly, and compliance with oral medications is poor. The addition of streptomycin may result in ototoxicity and pain or even abscess formation at the injection site. Blood levels of antibiotic and serum bactericidal levels
August,
1978, Vol. 96, No. 2
Infective enhcnditis. would have to be carefully monitored during these regimens. For these reasons the shortened course of therapy could only be recommended for patients in whom four weeks of hospitalization would create severe economic hardships. These patients would have to be followed very closely for relapse or complications. If the patient gives a history of penicillin allergy a cephalosporin is sometimes suggested, such as cephalothin 2 grams intravenously every four hours. If the patient has given a clear history of anaphylaxis or exfoliative dermatis, cephalosporins should not be used as there may be cross reactions to these drugs in penicillin allergic patients. Unfortunately, reliable skin test antigens are not commercially available and desensitization is not universally recommended. An additional problem with cephalothin exists if there is a lesion in the central nervous system. Cephalosporin antibiotics may not cross the blood brain barrier and, therefore, may be ineffective in the presence of complications such as an infected cerebral infarct, or brain abscess. If cephalothin cannot be given for these reasons, vancomycin 500 mg. intravenously every six hours should be used. Rarely, vancomycin may not be bacteriocida1 for the viridans streptococci. Group
D Streptococci
This group includes enterococci and non-enterococci. Enterococci are resistant to penicillin and ampicillin, and the treatment of valvular infections with these organisms requires the use of penicillin plus an aminoglycoside. The combination of penicillin plus streptomycin has been used most extensively. Standiford and colleagues” and Moellering and co-workers’” have reported large numbers of strains of enterococci from two hospitals resistant to this combination. Synergy studies using different combinations of antibiotics may be helpful. Unfortunately, these are usually available only in the laboratories of the larger teaching hospitals. Standiford and associates” suggested that synergy does not occur if the MIC of streptomycin is 2000 pg/ml. or greater, but even this may not be completely reliable as an indicator of which strains will show synergy.” Since these studies are usually not available until several days after therapy is started, we would suggest that penicillin 1.5 million units intravenously every two hours and streptomycin 500 mg.
American
Heart
Journal
Part II
intramuscularly every twelve hours be initiated. If the sensitivity data indicates high level streptomycin resistance (i.e., MIC > 2000 ,ug/ml.), gentamicin, 1 mg./kilogram of body weight every eight hours is used in place of streptomycin. Combined therapy is continued for four to six weeks. In view of the toxicity of aminoglycosides, especially if used for long periods of time, it is very important to measure the blood ul.ea nitrogen and creatinine levels and adjust the dose of the aminoglycosides if indicated. Measurement of serum aminoglycoside levels should be carried out during the course of therapy if possible. Enterococcal endocarditis in the penicillin allergic patient presents special problems since alternative drugs are ototoxic and nephrotoxic and any combination of these may have additive toxicity. In such a case, therefore. we would attempt to desensitize the patient to penicillin and use penicillin and streptomycin as above. Methods are described for this procedure” in which small amounts of penicillin are given over time until the required dose is reached. This procedure requires that the patient 1sconstantly attended, and that equipment and personnel are available at the bedside for the management of an anaphylactic reaction should it occur. Desensitization is not recommended for patients who have had an exfoliative reaction to penicillin. If penicillin cannot be tolerated, vancomycin alone or with an aminoglycoside is used. Geracie’ has recently stated that vancomycin should not be used alone for enterococcal endocarditis since bactericidal levels are rarely achieved. Vancomyczin and streptomycin are synergistic for about one half to two thirds of strains of enterococci.’ ’ The combination of vancomycin and gentamicin is synergistic for almost all strains.14Since the former combination is probably less toxic than the latter, we would recommend the vancomycin and .*treptomycin combination in penicillin allergic patients who have enterococcal strains which cannot be treated with vancomycin alone. In a life-threatening situation, the more toxic combination of o vancomycin and gentamicin should probably be instituted until all of the necessary laborat,ory data are available. Other
Group
D Streptococci
Streptococcus bouis and Streptococcus equinus are similar to the viridans streptococci in that
265
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and
Miller
they may be very sensitive or relatively resistant to penicillin.‘5 They are treated in the same way as described for viridans streptococci. Staphylococcus
aureus
If the organism is known to be sensitive to penicillin, that antibiotic is the drug of choice. Few strains of Staphylococcus aureus are sensitive, however, and for this reason initial therapy of staphylococcal infections is with a penicillinase resistant penicillin such as nafcillin or oxacillin. The dose of penicillin is similar to that for sensitive viridans streptococci, the dose of nafcillin is 1 gram intravenously every 2 hours, or 2 grams intravenously every four hours. Patients occasionally complain of pain when these antibiotics are given intravenously and the infusion may be given more slowly in these situations. Recent data, both in vitro and in animals suggest that the combination of nafcillin and gentamicin results in more rapid killing of Staphylococcus aureus than nafcillin alone. The advantage of rapid killing is that destruction of the valve which may be seen with Staphylococcus aureus infections in particular may be prevented. Controlled clinical trials are currently underway to test this combination of drugs in large numbers of patients with Staphylococcus aureus endocarditis. In a small study by Watanakunakorn and Baird’” there appeared to be little difference between patients treated with the combination and those treated with nafcillin alone. For the penicillin allergic patient in whom cephalosporins may be considered, we prefer cephalothin, since all cephalosporins may not be equally effective in therapy of staphylococcal infections. If the risk of hypersensitivity reactions is considered prohibitive to the use of cephalosporins, vancomycin 500 mg. intravenously every six hours, or one gram every twelve hours may be used. A recently recognized problem with the penicillinase resistant penicillins, cephalosporins and vancomycin is the socalled tolerance of certain strains of Staphylococcus aureus to these antibiotics. In these strains the difference between the MIC and the MBC is thirty-two fold or higher. This contrasts with the usual two to fourfold differences seen in most strains. These tolerant strains are resistant to the action of these drugs although they are reported as sensitive by the Kirby-Bauer disc assay which co-relates with the MIC only. The clinical significance of this phenomenon is not known. Howev-
266
er, if the patient is not responding well on the usual antibiotic regimen, and the spread in MIC/ MBC is demonstrated, several antibiotic combinations, such as nafcillin/gentamicin should be tested and the optimal one chosen. Intrinsic resistance to methicillin and other penicillinase resistant penicillins which may be recognized by the Kirby-Bauer disc assay has not been a major problem in this country, although it may be seen occasionally. Disc sensitivities which suggest that an organism is resistant to methicillin and sensitive to cephalosporin are probably inaccurate. These latter strains of Staphylococcus aureus are resistant usually to cephalosporins also, but unlike the tolerant organisms are frequently sensitive to vancomycin. At least six weeks of intravenous therapy is most commonly used for Staphylococcus aureus endocarditis. There is some uncertainty about duration of therapy for patients who have one or possible two blood cultures positive for Staphylococcus aureus secondary to removable foci of infection. Commonly a four to six week course has been recommended, but therapy in these cases must be individualized. Iannini and Crossley17 suggest that a ten day course of antistaphylococcal antibiotics is sufficient, but Watanakunakorn and Baird’” reiterate that in their experience endocarditis is commonly seen in such patients. It is essential in these situations that at least three to five blood cultures be obtained over several hours and if these are positive for Staphylococcus aureus the patient should be treated as if he or she has endocarditis. Staphylococcus
epidermidis
Staphylococcus epidermidis may be sensitive to penicillin or the penicillinase resistant penicillins, in which case therapy is similar to that of Staphylococcus aureus. Some strains of Staphylococcus epidermidis are resistant by tube dilution assays to these antibiotics, even when disc tests indicate sensitivity to the cephalosporins. Recent animal data indicate that a combination of vancomycin and gentamicin may be the most active combination for nafcillin resistant Staphylococcus epidermidis.‘” Anaerobic
organisms
Anaerobic organisms are rare causes of infective endocarditis. The gram-positive cocci such as peptostreptococcus and peptococcus are usually
August,
1978, Vol. 96, No. 2
sensitive to penicillin. These infections can be treated with high doses of penicillin such as 24 millions units per day. Patients who are allergic to penicillin, or patients who have Bacteroides fragilis (an anaerobic gram-negative rod) infections present problems. For the allergic patient, desensitization and treatment with penicillin may be the therapeutic regimen of choice. For the patient with Bacteroides fragilis infective endocarditis, the choice of drugs is limited as these organisms are commonly resistant to penicillin and sensitive only to drugs considered to be bacteriostatic and not bacteriocidal. Clindamycin has been reported to be bacteriocidal for some strains of Bacteroides fragilis,“” and if this is demonstrated for a particular organism this drug could be used in doses of 300 mg. intravenously every four to six hours, Serum bactericidal levels must be monitored, and the patient carefully observed for evidence of toxic side effects. The most common side effect is diarrhea which can lead to pseudomembranous colitis. This serious effect is not common, especially if the drug is stopped as soon as diarrhea begins. The process may be reversible with cholestyramine.” Cardiac arrythmias and liver function abnormalities are occasionally observed. The only bacteriocidal drug for treating Bacteroides fragilis endocarditis at the present time is metronidazole. Although this drug has recently been shown to be carcinogenic in mice, in this serious situation it may be the best drug. Cephoxitin, a new cephalosporin, may prove to be useful in treating infections with Bacteroides fragilis. Preliminary data indicates that cephoxitin has activity against these organisms and it is a relatively non-toxic drug. Currently, it is available only for research purposes. Aerobic
gram-negative
rods
Aerobic gram-negative rods rarely cause infective endocarditis, except in unusual circumstances such as in post-valvular replacement infections and in drug addicted persons. Some of these organisms such as Escherichia coli and Proteus mirabilis may be sensitive to ampicillin and cephalothin, other such as Klebsiella pneumoniae are resistant to ampicillin, but may be sensitive to cephalothin, and others such as Pseudomonas aeruginosa are resistant to ampicillin and cephalothin but are usually sensitive to gentamicin. Some hospitals are now
American
Heart
Journal
reporting gram-negative rods which are resistant to gentamicin and sensitive only to amikacin. The least toxic bactericidal drug should be used and therapy should continue for four and possibly six weeks. Combination of drugs such as cephalothin and gentamicin may be synergistic against Klebsiella and are suggested in those infections with organisms sensitive to both drugs. If the organism is Pseudomonas aeruginosa and it 1ssensitive to both carbenicillin and tobramycin, the combination should be used. Ticarcillin may be used in place of carbenicillin and gentamicin in place of tobramycin. The dose of tobramycin for pseudomonas infections is 1.5 mg./Kg. intramuscularly every eight hours and carbenicillin is given in dose of 4 to 6 grams intravenously every four hours. Carbenicillin may cause hypokalemic alkalosis and/or a bleeding diathesis, the latter especially in patients with impaired renal function. Fungal
Endocarditis
Fungal endocarditis is rare, and occurs almost exclusively in patients who have prosthetic valves, prolonged intravenous infusions or heroin addiction. Several reports of candida bacteremia following gastrectomies suggest that the risk of this infection may be increased in these patients. Rubinstein and colleagues”Z found that the heroin addicted persons were likely to have unusual species of candida, such as parapsilosis and tropicalis, while the patients who had had cardiac surgery were infected with candida albicans or aspergillus. It is difficult to differentiate transient fungemia from actual infection. Endocarditis has been documented in patients several months after so called transient fungemia.2’ Medoff and colleagues”:’suggests a short course of amphotericin for patients with transient fungemia. This might apply to those individuals who are at increased risk of fungal infections. However, since most individuals who develop transient candida fungemia respond to simple maneuvers such as discontinuation of intravenous or bladder catheters, we would recommend these procedures for the majority of patients. If blood cultures are positive following discontinuation of the catheters, antifungal therapy should be instituted. In patients with aspergillus endocarditis, blood cultures are rarely positive. Once the decision is made that t.he patient has
267
Casey
and
Miller
in fact fungal infection, antifungal therapy is instituted. Amphotericin intravenously is started, usually at a dose of 1 mg. of amphotericin B in 500 ml. of 5 per cent dextrose in water. The infusion is given over a time period of three to four hours. The initial infusion may cause severe reactions such as fever, shaking chills, headaches, nausea and vomiting, and even hypotension. Aspirin and benedryl by mouth and hydrocortisone given in doses of 25 to 50 mg. in the infusion bottle may be useful if the reactions are poorly tolerated. The dose of amphotericin is increased in increments of 5 mg. per day to a total dose of 0.5 to 0.6 mg. per kilogram of body weight. It is usual for the BUN and creatinine to rise. Renal function should be closely monitored until these parameters stabilize. Bennett?’ prefers to keep the BUN below 50 mg. per cent and the creatinine below 3.5 mg. per cent. If these parameters do stabilize, the dose may be gradually changed to 1.0 to 1.2 mg. per kilogram given every other day. Hypokalemia may require potassium therapy. The hematocrit may fall secondary to decreased production of erythrocytes. The toxic side effects of the drug usually resolve after therapy is discontinued although subtle renal impairment may persist. Since fungal endocarditis rarely, if ever, responds to medical therapy alone, replacement of the infected valve is usually undertaken after a week or 10 days of therapy from the time the optimal dose is achieved. Chemotherapy is continued for at least 4 to 6 weeks after surgery. Some species of fungi may be sensitive to five fluorocytosine. There is very little data regarding the effectiveness of this drug in endocarditis, although the combination with amphotericin B may be additive or minimally synergistic.“” The dose of drug is 30 mg. per kilogram by mouth, every six hours in patients with normal renal function. Because of the leukopenia and thrombocytopenia associated with this drug, and because its use in endocarditis has been minimal, we do not recommend it in patients with decreased renal function. Abacteremic
endocarditis
For patients in whom the clinical suspicion of endocarditis is very high, but blood cultures are negative, penicillin one million units intravenously every two hours and streptomycin 500 mg. intramuscularly every 12 hours is a rational regimen. This combination treats viridans strep-
268
tococci, enterococcus, and some of the unusual pathogens mentioned. Penicillin alone may result in a clinical response but not a microbiological cure. If the patient does not respond to this regimen, nafcillin 1 gram every two hours may be added although Staphylococcus aureus is such an invasive organism, it is unlikely that abacteremic endocarditis is seen in Staphylococcus aureus infections, unless the patient has had antibiotics prior to blood culturing. REFERENCES Finland, M., and Barnes, M. W.: Changing etiology of bacterial endocarditis in the antibacterial era: Experiences of the Boston City Hospital 1933-65, Ann. Intern. Med. 77:341, 1970. C.: Streptococcus bovis endocarditis, 2. Watanakunakorn, Am. J. Med. 56:256, 1974. 3. Eagle, H., Fleishman, R., and Musselman, A. D.: Effect of schedule of administration on therapeutic efficacy of penicillin: importance of aggregate time penicillin remains at effectively bactericidal levels, Am. J. Med. 9:280, 1950. J. G., and MacLean, H. A.: A method of 4. Schlicter, determining the effective therapeutic level in the treatment of subacute endocarditis with penicillin: a preliminary report, AM. HEART J. 34:209, 1947. 5. Blount, J. G.: Bacterial endocarditis, Am. J. Med. 38:909, 1965. 6. Wolfe, J. C., and Johnson, W. D.: Penicillin-sensitive streptococcal endocarditis. In vitro and clinical observations on penicillin-streptomycin therapy, Ann. Intern. Med. 81:178, 1974. 7. Tan, J. S., Terhune, C. A., Kaplan, S., and Hamburger, M.: Successful two-week treatment schedule for penicillin-susceptible streptococcus viridans endocarditis, Lancet 2:1340, 1971. 8. Cox, F., Quinn, E., Madhavan, T., and Fisher, E.: Oral treatment of bacterial endocarditis: Results in 100 cases. Abstract No. 208, 13th Interscience Conference on Antimicrobial Agents and Chemotherapy, September, 1973. 9. Standiford, H. D., DeMaine, H. B., and Kirby, W. M. M.: Antibiotic synergism of enterocicci, Arch. Intern. Med. 126:255, 1970. 10. Moellering, R. C., Wennersten, C., Medrek, T., and Weinberg, A.: Prevalence of high level resistance to aminoglycosides in clinical isolates of enterococci, Antimicrob. Agents Chemother. 10:335, 1970. 11. Watanakunakorn, C.: Penicillin combined with gentamitin or streptomycin: synergism against enterococci, J. Infect. Dis. 124:581, 1971. 12. Fellner, M., VanHecke, E., Rozan, M., and Baer, R.: Mechanisms of clinical desensitization in urticarial hvuersensitivitv to nenicillin. J. Allergv 46:55, 1970. 13. Geracie, J. E.:” Vancomycin; Mayo Ciin. Proc. 52:631, 1977. 14. Watanakunakorn, C., and Babie, C.: Synergism of vancomycin-gentamicin and vancomycin-streptomycin against enterococci, Antimicrob. Agents Chemother. 4:120, 1973. 15. Thornesberry, C., Baker, C. N., and Facklam, R. R.: Antibiotic susceptibility of Streptococcus bovis and other group D streptococci causing endocarditis, Antimicrob. Agents Chemother. 5:228, 1974. 1.
August, 1978, Vol. 96, No. 2
Infective
16.
17.
18.
19.
20.
Watanakunakorn, C., and Baird, I. M.: Prognostic factors in Staphylococcus aureus endocarditis and results of therapy with penicillin and gentamicin, Am. J. Med. Sci. 273:133, 1977. Iannini, P. B., and Crossley, K.: Therapy of Staphylococcus uureus bacteremia associated with a removable focus of infection, Ann. Intern. Med. 84:558, 1976. Watanakunakorn, C., and Baird, I. M.: Staphylococcus bacteremia and endocarditis associated with a removable infected intravenous device, Am. J. Med. 63:253, 1977. Lowy, F.. Walsh, J., Mayers, M., and Steigbigel, N.: Therapy of experimental methicillin-resistant staphylococcus epidermidis infection. Abstract No. 234, 17th Interscience Conference on Antimicrobial Agents and Chemotherapy, October, 1977. Nastro, L. J., and Finegold, S. M.: Bactericidal activity of five antimicrobial agents against Bacteroides fragilis, J. Infect. Dis. 126:104, 1972.
American
Heart
Journal
21.
22.
23.
24. 25.
fvzdocnrditis.
Part
II
Burbige, E., and Milligan, F. D.: Pseudomembranous colitis. Association with antibiotics and therapy with cholestyramine, J.A.M.A. 231:1157, 197.5. Rubinstein, E., Noriega, E., Simberkoff. M., Holzman. R., and Rahal, J. J.: Fungal Endocarditis: Analysis of 24 cases and review of the literature, Medicine 54:331, 1975. Medoff, G., Dismukes, W. E., Meade, H. 2-i.. and Moses. J.: A new therapeutic approach to candida infections. Arch. Intern. Med. 130:241, 1972. Bennett, 6. E.: Chemotherapy of systemi
and reappraisal
by Arthur
Infective
C. DeGraff
and Julian
endocarditis:
Part
of cardiac
therapy
Frieden
II. Current
therapy
Joan I. Casey, M.D. Michael H. Miller, M.D. Bronx, iv. Y.
Many clinical and experimental studies have been undertaken in the past few years to determine optimal therapy for infectious endocarditis which continues to be one of the most serious infectious diseases of man. The increased prominence of unusual organisms and the changes in sensitivity patterns of the more characteristic organisms is important therapeutically. Therapy often must be started prior to a knowledge of the causative organisms. It is useful to review briefly some of the predisposing conditions associated with this disease. A knowledge of the probable portal of entry enables one to make an educated guessas to the organisms, and therefore, the most useful antibiotic, or combination of antibiotics. In recent years there has been a decrease in rheumatic heart disease and an increase in the number of people surviving with prosthetic valves, congenital heart disease, and arteriosclerotic heart disease. These people are at an increased risk of bacterial endocarditis, so that over-all there has been no decrease in the number of patients with bacterial endocarditis. There has also been a change in the types of organisms causing bacterial endocarditis. Documentation of bacteremias associated with dental procedures has re-affirmed the importance of the mouth flora as a primary source of organisms. These organisms, usually viridans streptococci, have an ability to adhere to heart valves not found in other organisms such as gram-negative From the Division Mont&ore Hospital College of Medicine, Received
for publication
of Infectious Diseases, and Medical Center, Bronx, N. Y. April
Department and the
of Medicine, Albert Einstein
6. 1978.
Reprint requests: Joan I. Casey, M.D., Department of Medicine, Division of Infectious Diseases, Mont&ore Hospital and Medical Center. E. Gunhill and Bainbridge Aves., Bronx. N. Y. 10467.
OOOZ-870:3/78/0296-0263$00.70/O
0 1978 The
C. V. Mosby
Co.
rods. This may be the reason these streptococci remain the leading cause of infective endocarditis. The disease is usually sub-acute although fulminating infection can occur with these organisms. The increased use of intravenous infusions in the hospital and intravenous heroin in the community has increased the incidence of bacteremias which may lead to valvular infections. The organisms involved in these latter infections are usually Staphylococcus aureus, Enterobacteriaceae Sp., Pseudomonas aeruginosa or enterococci. Manipulation or infection of the genitourinary and gastrointestinal tracts may lead to transient bacteremias and valvular infections with Group D streptococci or rarely gram-negative rods. Group D enterococcus endocarditis, rarely seen prior to the introduction of antibiotics,’ is now not uncommon in this setting. The diseasemay be acute or sub-acute. Group D non enterococcus includes Streptococcus bovis, increasingly recognized as a cause of endocarditis,” and Streptococcus equinus only rarely a cause of human disease. Staphylococcus aureus is found on normal human skin, and may enter the blood stream secondarily to intravenous lines, superficial skin infections or wound infections. Staphylococcus aureus endocarditis may be seen in children including those with hematogenous osteomylitis and this association should be recognized. Blood cultures growing Staphylococcus epidermidis, which is also found on normal skin, may represent contamination or infection. Continuous bacteremia must be considered to represent intravascular infection and be treated as such, although true infection with Staphylococcus epidermidis is unusual except in the patients with prosthetic valves.
American
Heart
Journal
263
Casey
and
Therapeutic
Miller
principles
There are certain principles which apply to the treatment of bacterial endocarditis. Adequate concentrations of active drug must be achieved at the site of infection over a defined period of time. Eagle and colleague& demonstrated that even in those lesions where the action of the antibiotic may be augmented by the body’s host defenses, as much as twenty times the minimal inhibitory concentrations (MIC) of antibiotic may be necessary to kill the infecting organism. In endocarditis, the vegetation consists of a fibrin network in which millions of organisms may be entrapped and protected from the body’s host defenses. High concentrations of antibiotic are needed to effect a cure of bacterial endocarditis, and the antibiotics used must kill, and not just inhibit the growth of the organism. Quantitative sensitivity testing by tube dilution is used to ascertain the minimum concentration of antibiotic necessary to inhibit, and to kill (MBC) the patient’s organism. A practical way to obtain some indication of appropriate therapy is the Schlicter test.” This is a measure of the ability of the patient’s serum, which contains the appropriate antibiotics, to inhibit or kill the organism causing the patient’s infection. Two specimens are taken, one representing the peak concentration, taken at the appropriate time after the dose is given, and one representing the nadir, taken just before the next dose is due. A serum bactericidal level of at least 1 to 8 at the nadir is that which has been associated with the best results of antibiotic therapy. To achieve these levels parenteral therapy is usually required. Duration of therapy is usually four weeks for very sensitive organisms, and six weeks for the less sensitive as well as the more virulent pathogens. These recommendations for the duration of therapy are mainly based on the current practice of physicians who have long dealt with this disease. Short courses may lead to relapses, and unusually long courses can lead to suprainfections. The antibiotic chosen should be the one with the narrowest possible spectrum, which has been proven to be effective clinically. Newer antibiotics are not necessarily better. The choice of a drug should include consideration of cost and toxicity. Failure of clinical response to the most appropriate antibiotics may be related to a delay in starting therapy, sub-optimal doses, the wrong
264
route, minimal duration of therapy, the development of local or metastatic abscesses, the presence of a foreign body (e.g., prosthetic valve) or the underlying disease in the host. Streptococcus
viridans
Viridans streptococci, also reported as alpha streptococcus, are organisms which do not fit well into other classifications of streptococci. Organisms now reported as Streptococcus mitis, Streptococcus sanguis, and Streptococcus mutans may also be reported by some laboratories simply as Streptococcus uiridans. Authors differ on the terms “penicillin sensitive” and “relatively resistant” with reference to these particular organisms. Blount’s classification of an organism with an MBC of less than 0.1 unit per ml. as sensitive, 0.1 to 1.0 unit/ml. as moderately sensitive, and greater than 1.0 unit/ml. as relatively resistant would seem to be adequate for therapeutic purposes.5 Standard therapy for the sensitive organisms would be one million units intravenously every two hours, or two million units intravenously every four hours for a period of four weeks. For the moderately sensitive the dose may be raised to three million units every four hours. Those organisms which are relatively resistant may require the addition of streptomycin 500 mg. intramuscularly every twelve hours. Although some authors use this combination for all casesof viridans streptococci endocarditis,” the results with penicillin alone are very good, especially when the organism is very sensitive. The possibility of shortening the course of therapy for viridans streptococci endocarditis to two weeks has been investigated.’ Results with penicillin alone were poor, two patients relapsed of 13 so treated. Patients treated with penicillin plus streptomycin for two weeks appeared to respond well whether the penicillin was given by mouth or parenterally. There were no relapses in these latter two groups. One hundred patients treated by Cox and colleagues” with penicillin V by mouth and streptomycin intramuscularly for two weeks had a very good recovery rate. However, some patients, in particular the elderly and the ill, absorb oral drugs poorly, and compliance with oral medications is poor. The addition of streptomycin may result in ototoxicity and pain or even abscess formation at the injection site. Blood levels of antibiotic and serum bactericidal levels
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Infective enhcnditis. would have to be carefully monitored during these regimens. For these reasons the shortened course of therapy could only be recommended for patients in whom four weeks of hospitalization would create severe economic hardships. These patients would have to be followed very closely for relapse or complications. If the patient gives a history of penicillin allergy a cephalosporin is sometimes suggested, such as cephalothin 2 grams intravenously every four hours. If the patient has given a clear history of anaphylaxis or exfoliative dermatis, cephalosporins should not be used as there may be cross reactions to these drugs in penicillin allergic patients. Unfortunately, reliable skin test antigens are not commercially available and desensitization is not universally recommended. An additional problem with cephalothin exists if there is a lesion in the central nervous system. Cephalosporin antibiotics may not cross the blood brain barrier and, therefore, may be ineffective in the presence of complications such as an infected cerebral infarct, or brain abscess. If cephalothin cannot be given for these reasons, vancomycin 500 mg. intravenously every six hours should be used. Rarely, vancomycin may not be bacteriocida1 for the viridans streptococci. Group
D Streptococci
This group includes enterococci and non-enterococci. Enterococci are resistant to penicillin and ampicillin, and the treatment of valvular infections with these organisms requires the use of penicillin plus an aminoglycoside. The combination of penicillin plus streptomycin has been used most extensively. Standiford and colleagues” and Moellering and co-workers’” have reported large numbers of strains of enterococci from two hospitals resistant to this combination. Synergy studies using different combinations of antibiotics may be helpful. Unfortunately, these are usually available only in the laboratories of the larger teaching hospitals. Standiford and associates” suggested that synergy does not occur if the MIC of streptomycin is 2000 pg/ml. or greater, but even this may not be completely reliable as an indicator of which strains will show synergy.” Since these studies are usually not available until several days after therapy is started, we would suggest that penicillin 1.5 million units intravenously every two hours and streptomycin 500 mg.
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intramuscularly every twelve hours be initiated. If the sensitivity data indicates high level streptomycin resistance (i.e., MIC > 2000 ,ug/ml.), gentamicin, 1 mg./kilogram of body weight every eight hours is used in place of streptomycin. Combined therapy is continued for four to six weeks. In view of the toxicity of aminoglycosides, especially if used for long periods of time, it is very important to measure the blood ul.ea nitrogen and creatinine levels and adjust the dose of the aminoglycosides if indicated. Measurement of serum aminoglycoside levels should be carried out during the course of therapy if possible. Enterococcal endocarditis in the penicillin allergic patient presents special problems since alternative drugs are ototoxic and nephrotoxic and any combination of these may have additive toxicity. In such a case, therefore. we would attempt to desensitize the patient to penicillin and use penicillin and streptomycin as above. Methods are described for this procedure” in which small amounts of penicillin are given over time until the required dose is reached. This procedure requires that the patient 1sconstantly attended, and that equipment and personnel are available at the bedside for the management of an anaphylactic reaction should it occur. Desensitization is not recommended for patients who have had an exfoliative reaction to penicillin. If penicillin cannot be tolerated, vancomycin alone or with an aminoglycoside is used. Geracie’ has recently stated that vancomycin should not be used alone for enterococcal endocarditis since bactericidal levels are rarely achieved. Vancomyczin and streptomycin are synergistic for about one half to two thirds of strains of enterococci.’ ’ The combination of vancomycin and gentamicin is synergistic for almost all strains.14Since the former combination is probably less toxic than the latter, we would recommend the vancomycin and .*treptomycin combination in penicillin allergic patients who have enterococcal strains which cannot be treated with vancomycin alone. In a life-threatening situation, the more toxic combination of o vancomycin and gentamicin should probably be instituted until all of the necessary laborat,ory data are available. Other
Group
D Streptococci
Streptococcus bouis and Streptococcus equinus are similar to the viridans streptococci in that
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they may be very sensitive or relatively resistant to penicillin.‘5 They are treated in the same way as described for viridans streptococci. Staphylococcus
aureus
If the organism is known to be sensitive to penicillin, that antibiotic is the drug of choice. Few strains of Staphylococcus aureus are sensitive, however, and for this reason initial therapy of staphylococcal infections is with a penicillinase resistant penicillin such as nafcillin or oxacillin. The dose of penicillin is similar to that for sensitive viridans streptococci, the dose of nafcillin is 1 gram intravenously every 2 hours, or 2 grams intravenously every four hours. Patients occasionally complain of pain when these antibiotics are given intravenously and the infusion may be given more slowly in these situations. Recent data, both in vitro and in animals suggest that the combination of nafcillin and gentamicin results in more rapid killing of Staphylococcus aureus than nafcillin alone. The advantage of rapid killing is that destruction of the valve which may be seen with Staphylococcus aureus infections in particular may be prevented. Controlled clinical trials are currently underway to test this combination of drugs in large numbers of patients with Staphylococcus aureus endocarditis. In a small study by Watanakunakorn and Baird’” there appeared to be little difference between patients treated with the combination and those treated with nafcillin alone. For the penicillin allergic patient in whom cephalosporins may be considered, we prefer cephalothin, since all cephalosporins may not be equally effective in therapy of staphylococcal infections. If the risk of hypersensitivity reactions is considered prohibitive to the use of cephalosporins, vancomycin 500 mg. intravenously every six hours, or one gram every twelve hours may be used. A recently recognized problem with the penicillinase resistant penicillins, cephalosporins and vancomycin is the socalled tolerance of certain strains of Staphylococcus aureus to these antibiotics. In these strains the difference between the MIC and the MBC is thirty-two fold or higher. This contrasts with the usual two to fourfold differences seen in most strains. These tolerant strains are resistant to the action of these drugs although they are reported as sensitive by the Kirby-Bauer disc assay which co-relates with the MIC only. The clinical significance of this phenomenon is not known. Howev-
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er, if the patient is not responding well on the usual antibiotic regimen, and the spread in MIC/ MBC is demonstrated, several antibiotic combinations, such as nafcillin/gentamicin should be tested and the optimal one chosen. Intrinsic resistance to methicillin and other penicillinase resistant penicillins which may be recognized by the Kirby-Bauer disc assay has not been a major problem in this country, although it may be seen occasionally. Disc sensitivities which suggest that an organism is resistant to methicillin and sensitive to cephalosporin are probably inaccurate. These latter strains of Staphylococcus aureus are resistant usually to cephalosporins also, but unlike the tolerant organisms are frequently sensitive to vancomycin. At least six weeks of intravenous therapy is most commonly used for Staphylococcus aureus endocarditis. There is some uncertainty about duration of therapy for patients who have one or possible two blood cultures positive for Staphylococcus aureus secondary to removable foci of infection. Commonly a four to six week course has been recommended, but therapy in these cases must be individualized. Iannini and Crossley17 suggest that a ten day course of antistaphylococcal antibiotics is sufficient, but Watanakunakorn and Baird’” reiterate that in their experience endocarditis is commonly seen in such patients. It is essential in these situations that at least three to five blood cultures be obtained over several hours and if these are positive for Staphylococcus aureus the patient should be treated as if he or she has endocarditis. Staphylococcus
epidermidis
Staphylococcus epidermidis may be sensitive to penicillin or the penicillinase resistant penicillins, in which case therapy is similar to that of Staphylococcus aureus. Some strains of Staphylococcus epidermidis are resistant by tube dilution assays to these antibiotics, even when disc tests indicate sensitivity to the cephalosporins. Recent animal data indicate that a combination of vancomycin and gentamicin may be the most active combination for nafcillin resistant Staphylococcus epidermidis.‘” Anaerobic
organisms
Anaerobic organisms are rare causes of infective endocarditis. The gram-positive cocci such as peptostreptococcus and peptococcus are usually
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sensitive to penicillin. These infections can be treated with high doses of penicillin such as 24 millions units per day. Patients who are allergic to penicillin, or patients who have Bacteroides fragilis (an anaerobic gram-negative rod) infections present problems. For the allergic patient, desensitization and treatment with penicillin may be the therapeutic regimen of choice. For the patient with Bacteroides fragilis infective endocarditis, the choice of drugs is limited as these organisms are commonly resistant to penicillin and sensitive only to drugs considered to be bacteriostatic and not bacteriocidal. Clindamycin has been reported to be bacteriocidal for some strains of Bacteroides fragilis,“” and if this is demonstrated for a particular organism this drug could be used in doses of 300 mg. intravenously every four to six hours, Serum bactericidal levels must be monitored, and the patient carefully observed for evidence of toxic side effects. The most common side effect is diarrhea which can lead to pseudomembranous colitis. This serious effect is not common, especially if the drug is stopped as soon as diarrhea begins. The process may be reversible with cholestyramine.” Cardiac arrythmias and liver function abnormalities are occasionally observed. The only bacteriocidal drug for treating Bacteroides fragilis endocarditis at the present time is metronidazole. Although this drug has recently been shown to be carcinogenic in mice, in this serious situation it may be the best drug. Cephoxitin, a new cephalosporin, may prove to be useful in treating infections with Bacteroides fragilis. Preliminary data indicates that cephoxitin has activity against these organisms and it is a relatively non-toxic drug. Currently, it is available only for research purposes. Aerobic
gram-negative
rods
Aerobic gram-negative rods rarely cause infective endocarditis, except in unusual circumstances such as in post-valvular replacement infections and in drug addicted persons. Some of these organisms such as Escherichia coli and Proteus mirabilis may be sensitive to ampicillin and cephalothin, other such as Klebsiella pneumoniae are resistant to ampicillin, but may be sensitive to cephalothin, and others such as Pseudomonas aeruginosa are resistant to ampicillin and cephalothin but are usually sensitive to gentamicin. Some hospitals are now
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reporting gram-negative rods which are resistant to gentamicin and sensitive only to amikacin. The least toxic bactericidal drug should be used and therapy should continue for four and possibly six weeks. Combination of drugs such as cephalothin and gentamicin may be synergistic against Klebsiella and are suggested in those infections with organisms sensitive to both drugs. If the organism is Pseudomonas aeruginosa and it 1ssensitive to both carbenicillin and tobramycin, the combination should be used. Ticarcillin may be used in place of carbenicillin and gentamicin in place of tobramycin. The dose of tobramycin for pseudomonas infections is 1.5 mg./Kg. intramuscularly every eight hours and carbenicillin is given in dose of 4 to 6 grams intravenously every four hours. Carbenicillin may cause hypokalemic alkalosis and/or a bleeding diathesis, the latter especially in patients with impaired renal function. Fungal
Endocarditis
Fungal endocarditis is rare, and occurs almost exclusively in patients who have prosthetic valves, prolonged intravenous infusions or heroin addiction. Several reports of candida bacteremia following gastrectomies suggest that the risk of this infection may be increased in these patients. Rubinstein and colleagues”Z found that the heroin addicted persons were likely to have unusual species of candida, such as parapsilosis and tropicalis, while the patients who had had cardiac surgery were infected with candida albicans or aspergillus. It is difficult to differentiate transient fungemia from actual infection. Endocarditis has been documented in patients several months after so called transient fungemia.2’ Medoff and colleagues”:’suggests a short course of amphotericin for patients with transient fungemia. This might apply to those individuals who are at increased risk of fungal infections. However, since most individuals who develop transient candida fungemia respond to simple maneuvers such as discontinuation of intravenous or bladder catheters, we would recommend these procedures for the majority of patients. If blood cultures are positive following discontinuation of the catheters, antifungal therapy should be instituted. In patients with aspergillus endocarditis, blood cultures are rarely positive. Once the decision is made that t.he patient has
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in fact fungal infection, antifungal therapy is instituted. Amphotericin intravenously is started, usually at a dose of 1 mg. of amphotericin B in 500 ml. of 5 per cent dextrose in water. The infusion is given over a time period of three to four hours. The initial infusion may cause severe reactions such as fever, shaking chills, headaches, nausea and vomiting, and even hypotension. Aspirin and benedryl by mouth and hydrocortisone given in doses of 25 to 50 mg. in the infusion bottle may be useful if the reactions are poorly tolerated. The dose of amphotericin is increased in increments of 5 mg. per day to a total dose of 0.5 to 0.6 mg. per kilogram of body weight. It is usual for the BUN and creatinine to rise. Renal function should be closely monitored until these parameters stabilize. Bennett?’ prefers to keep the BUN below 50 mg. per cent and the creatinine below 3.5 mg. per cent. If these parameters do stabilize, the dose may be gradually changed to 1.0 to 1.2 mg. per kilogram given every other day. Hypokalemia may require potassium therapy. The hematocrit may fall secondary to decreased production of erythrocytes. The toxic side effects of the drug usually resolve after therapy is discontinued although subtle renal impairment may persist. Since fungal endocarditis rarely, if ever, responds to medical therapy alone, replacement of the infected valve is usually undertaken after a week or 10 days of therapy from the time the optimal dose is achieved. Chemotherapy is continued for at least 4 to 6 weeks after surgery. Some species of fungi may be sensitive to five fluorocytosine. There is very little data regarding the effectiveness of this drug in endocarditis, although the combination with amphotericin B may be additive or minimally synergistic.“” The dose of drug is 30 mg. per kilogram by mouth, every six hours in patients with normal renal function. Because of the leukopenia and thrombocytopenia associated with this drug, and because its use in endocarditis has been minimal, we do not recommend it in patients with decreased renal function. Abacteremic
endocarditis
For patients in whom the clinical suspicion of endocarditis is very high, but blood cultures are negative, penicillin one million units intravenously every two hours and streptomycin 500 mg. intramuscularly every 12 hours is a rational regimen. This combination treats viridans strep-
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tococci, enterococcus, and some of the unusual pathogens mentioned. Penicillin alone may result in a clinical response but not a microbiological cure. If the patient does not respond to this regimen, nafcillin 1 gram every two hours may be added although Staphylococcus aureus is such an invasive organism, it is unlikely that abacteremic endocarditis is seen in Staphylococcus aureus infections, unless the patient has had antibiotics prior to blood culturing. REFERENCES Finland, M., and Barnes, M. W.: Changing etiology of bacterial endocarditis in the antibacterial era: Experiences of the Boston City Hospital 1933-65, Ann. Intern. Med. 77:341, 1970. C.: Streptococcus bovis endocarditis, 2. Watanakunakorn, Am. J. Med. 56:256, 1974. 3. Eagle, H., Fleishman, R., and Musselman, A. D.: Effect of schedule of administration on therapeutic efficacy of penicillin: importance of aggregate time penicillin remains at effectively bactericidal levels, Am. J. Med. 9:280, 1950. J. G., and MacLean, H. A.: A method of 4. Schlicter, determining the effective therapeutic level in the treatment of subacute endocarditis with penicillin: a preliminary report, AM. HEART J. 34:209, 1947. 5. Blount, J. G.: Bacterial endocarditis, Am. J. Med. 38:909, 1965. 6. Wolfe, J. C., and Johnson, W. D.: Penicillin-sensitive streptococcal endocarditis. In vitro and clinical observations on penicillin-streptomycin therapy, Ann. Intern. Med. 81:178, 1974. 7. Tan, J. S., Terhune, C. A., Kaplan, S., and Hamburger, M.: Successful two-week treatment schedule for penicillin-susceptible streptococcus viridans endocarditis, Lancet 2:1340, 1971. 8. Cox, F., Quinn, E., Madhavan, T., and Fisher, E.: Oral treatment of bacterial endocarditis: Results in 100 cases. Abstract No. 208, 13th Interscience Conference on Antimicrobial Agents and Chemotherapy, September, 1973. 9. Standiford, H. D., DeMaine, H. B., and Kirby, W. M. M.: Antibiotic synergism of enterocicci, Arch. Intern. Med. 126:255, 1970. 10. Moellering, R. C., Wennersten, C., Medrek, T., and Weinberg, A.: Prevalence of high level resistance to aminoglycosides in clinical isolates of enterococci, Antimicrob. Agents Chemother. 10:335, 1970. 11. Watanakunakorn, C.: Penicillin combined with gentamitin or streptomycin: synergism against enterococci, J. Infect. Dis. 124:581, 1971. 12. Fellner, M., VanHecke, E., Rozan, M., and Baer, R.: Mechanisms of clinical desensitization in urticarial hvuersensitivitv to nenicillin. J. Allergv 46:55, 1970. 13. Geracie, J. E.:” Vancomycin; Mayo Ciin. Proc. 52:631, 1977. 14. Watanakunakorn, C., and Babie, C.: Synergism of vancomycin-gentamicin and vancomycin-streptomycin against enterococci, Antimicrob. Agents Chemother. 4:120, 1973. 15. Thornesberry, C., Baker, C. N., and Facklam, R. R.: Antibiotic susceptibility of Streptococcus bovis and other group D streptococci causing endocarditis, Antimicrob. Agents Chemother. 5:228, 1974. 1.
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17.
18.
19.
20.
Watanakunakorn, C., and Baird, I. M.: Prognostic factors in Staphylococcus aureus endocarditis and results of therapy with penicillin and gentamicin, Am. J. Med. Sci. 273:133, 1977. Iannini, P. B., and Crossley, K.: Therapy of Staphylococcus uureus bacteremia associated with a removable focus of infection, Ann. Intern. Med. 84:558, 1976. Watanakunakorn, C., and Baird, I. M.: Staphylococcus bacteremia and endocarditis associated with a removable infected intravenous device, Am. J. Med. 63:253, 1977. Lowy, F.. Walsh, J., Mayers, M., and Steigbigel, N.: Therapy of experimental methicillin-resistant staphylococcus epidermidis infection. Abstract No. 234, 17th Interscience Conference on Antimicrobial Agents and Chemotherapy, October, 1977. Nastro, L. J., and Finegold, S. M.: Bactericidal activity of five antimicrobial agents against Bacteroides fragilis, J. Infect. Dis. 126:104, 1972.
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22.
23.
24. 25.
fvzdocnrditis.
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Burbige, E., and Milligan, F. D.: Pseudomembranous colitis. Association with antibiotics and therapy with cholestyramine, J.A.M.A. 231:1157, 197.5. Rubinstein, E., Noriega, E., Simberkoff. M., Holzman. R., and Rahal, J. J.: Fungal Endocarditis: Analysis of 24 cases and review of the literature, Medicine 54:331, 1975. Medoff, G., Dismukes, W. E., Meade, H. 2-i.. and Moses. J.: A new therapeutic approach to candida infections. Arch. Intern. Med. 130:241, 1972. Bennett, 6. E.: Chemotherapy of systemi
