clue t o the etiology of his illness was missed early i n the patient's disease when a report was made of Ρ aerugi nosa on culture, w h i c h on disk testing showed sensitivity to tetracycline and kanamycin, w i t h resistance t o gentamicin. This unusual data on sensitivity should sug gest infection w i t h Ρ pseudomallei. T h e combination of t r â n e t h o p r i m and sulfamethoxazole should be considered a primary d r u g i n the treatment of pulmonary melioidosis, particularly i n those whose condition shows in vitro resistance to treatment w i t h tetracycline or fails to improve on a trial of therapy w i t h this drug. Studies of sensitivity should be obtained initially and should be repeated at intervals d u r i n g therapy. Dosage may be adjusted on the basis of bactericidal levels. A C K N O W L E D G M E N T : We wish to thank Dr. Jay Sanford of the School of Medicine, Uniformed Services University of the Health Sciences, for his advice in the management of this patient and the Center for Disease Control, Atlanta, for providing the data on minimum inhibitory concentrations. REFERENCES 1 Everett ED, Nelson RA: Pulmonary melioidosis. Am Rev Respir Dis 112:331-340, 1975 2 Everett ED, Kishimoto RX: In vitro sensitivity of 33 strains of Pseudomonas pseudomallei to trimethoprim and sulfamethoxazole. J Infect Dis 128 (suppl):539, 1973 3 John JF Jr: Trimethoprim-sulfamethoxazole therapy i n pulmonary melioidosis. Am Rev Respir Dis 114:1021-1025, 1976 4 Eickhoff TC, Bennett JV, Haynes PS, et al: Pseudomonas pseudomallei: Susceptibility to chemotherapeutic agents. J Infect Dis 121:95-102, 1970 5 Green RN, Tuffnell PG: Laboratory acquired melioidosis. Am J Med 44:599-605, 1968
Bacterial Endocarditis on a Prosthetic Valve* Oral Treatment with Amoxicillin Moshe Lidji, Μ.Ό.; Ethan Rubinstein, M.D.; and Heskel Samra, M.D. A patient with endocarditis due to Streptococcus fae calis on an aortic valvular prosthesis was successfully treated using large oral doses of amoxicillin concurrently with intramuscular administration of streptomycin. Oral therapy was employed because of a persistent reaction to intravenously administered antibiotics. Oral therapy for bacterial endocarditis occurring on an artificial valve may be attempted as a last resort when all other accepted therapeutic measures have failed.
rrihe current recommended treatment for patients w i t h endocarditis due to Streptococcus faecalis o n •From the Infectious Diseases Unit and the Department of Medicine, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
224 LIDJI, RUBINSTEIN, SAMRA
prosthetic cardiac valves is intravenous therapy w i t h high doses of penicillin or ampicillin, w i t h the addition of an aminoglycoside. Surgical replacement of the infected prosthesis is recommended when medical ther apy fails. ' Despite these measures, a high mortality has been noted for prosthetic valvular endocarditis. " Whereas endocarditis o œ u n i n g on a natural valve has been successfully treated w i t h oral therapy, ' no such information is available œ n c e r n i n g the therapy for bacterial endocarditis on a prosthetic valve. A patient w i t h endocarditis due to S faecalis on an artificial aortic valve w h o was unable to tolerate any intravenous therapy was treated successfully w i t h large oral doses of amoxicillin and intramuscular administration of streptomycin. This combination of drugs yielded a satisfactory bactericidal effect on the serum, w h i c h correlated w i t h the recovery of the patient. 1-7
5
6
4
8
7
9
CASE REPORT A 63-year-old man was admitted to the Chaim Sheba Medical Center, Tel-Hashomer, Israel, because of the recent onset of left hemiparesis following one month of fever and malaise. The patient had undergone an aortic valvular replacement and aneurysmectomy of the ascending aorta for syphilitic cardiovascular disease three years prior to this admission. His postoperative course had been uneventful, and he remained in good health until the present illness. The patient denied any dental or genitourinary manipulations. On admission the patient appeared to be in no acute distress. His temperature was 38.4°C ( 1 0 1 . 1 F ) , the blood pressure was 180/80 mm Hg, and the pulse rate was 68 beats per minute. A grade 3/6 systolic murmur was heard over the aortic area; the murmur did not radiate. A small petechia was observed on the patient's left thumb. Neurologic examination revealed mild paresis of the left arm and leg. The findings from the rest of the physical examination were normal. No other signs of endocarditis were observed. The results of laboratory tests were as follows: hemoglobin level, 8.7 gm/100 m l ; hematocrit reading, 23 percent; white blood cell count, 9,600/cu mm, with a shift to the left; erythrocyte sedimentation rate, 25 mm in the first hour; V D R L test, negative; and Treponema pallidum immobilization test, positive. The rest of the chemical findings on the blood and cerebrospinal fluid were normal. Six consecutive cultures of blood grew S faecalis, and the minimum inhibitory concentration of ampicillin was 1.75¿tg/ml and of amoxicillin 0.5/ag/ml. The minimum inhibitory concentration of streptomycin was lOO^g/ml. Synergism was demonstrated both for the combination of ampicillin and streptomycin and for amoxicillin and streptomycin. The patient was started on therapy with 12 gm of ampicillin intravenously daily and 1 gm of streptomycin intramuscularly. Very severe thrombophlebitis developed rapidly in all of the veins into which ampicillin was introduced. Intravenous therapy with ampicillin was therefore changed to oral administration of 24 gm of ampicillin daily, and therapy with streptomycin was continued; however, the bactericidal effect in the serum varied between 1:2 and 1:16 on various occasions. Repeated attempts to administer medication intravenously failed because of immediately recurring grave thrombophlebitis. While the patient was receiving oral therapy with ampicillin (total, ten days), atrial fibrillation appeared, and his fever persisted. Therefore, oral administrae
CHEST, 74: 2, AUGUST, 1978
bon of 24 gm of amoxicillin daily was started, and therapy with streptomycin was continued for six weeks. The patient tolerated this regimen well. During therapy with amoxicillin, the bactericidal effect in the serum on repeated occasions varied between 1:32 and 1:64, and serum levels of amoxicillin varied between 37¿¿g/ml and 51/Ag/ml. During this treatment the fever returned to normal. Five months later, a diastolic murmur developed, and the patient underwent an aortic valvular replacement. At surgery, the valvular prosthesis was attached to the aortic annulus along only one-third of its circumference. No ulcerations, aneurysms, granulations, or vegetations were found; and multiple cultures taken from the prosthetic valve, sutures, and endocardium were sterile. A new prosthetic valve was inserted, and the patient made an uneventful recovery.
of oral therapy w i t h amoxicillin and intramuscular administration of streptomycin. W e believe that for the occasional patient w i t h a prosthetic valve w h o has late o œ u r r i n g subacute bacterial endocarditis caused b y a highly sensitive pathogen and w h o is unable to receive intravenous therapy, a trial of oral antibiotic such as amoxicillin i n combination w i t h parenteral therapy w i t h
aminoglycosides is justified.
This mode of therapy should only be employed as a last therapeutic resort and should be accompanied b y careful clinical and laboratory evaluation.
REFERENCES MATERIALS AND METHODS
1 Weinstein L , Schlesinger J: Treatment of infective endo-
Streptococcus faecalis (Enterococcus) was characterized according to standard criteria. Minimum inhibitory concentrations were determined by the standard broth dilution technique in trypticase soy broth. Synergism was determined by the checkerboard technique. Bactericidal levels i n the serum were measured by the tube dilution method. Levels of antibiotics in the blood were determined by the disk-diffusion test against Bacillus subtüis (ATCC 6633). 10
11
enterococcal endocarditis. Ν Engl J Med 274:710-715, 1966 3 Mandell GL, Kaye D, Levison M E , et al: Enterococcal endocarditis: An analysis of 38 patients observed at the New York Hospital Cornell Medical Center. Arch Intern 4 Dismukes W E , Karchmer A W , Buckley M J, et al: Pros
The history, physical signs, and positive cultures of blood leave litde doubt that our patient suffered from bacterial endocarditis occurring on a prosthetic aortic valve. The fact that no signs of active disease were seen at the time of repeat surgery and that all cultures were sterile points to the success of the pharmacologic regimen used. Our patient demonstrates that under special circumstances and when all other therapeutic measures have failed, successful oral therapy for bacterial endocarditis of a prosthetic valve is possible. Certain requirements fulfilled i n our patient are mandatory, ie: ( 1 ) the pathogen responsible for the infection must be highly sensitive to the d r u g employed; and ( 2 ) absorption of the drug from the gastrointestinal tract must be adequate to produce a strong bactericidal effect i n the serum. For S faecalis, the m i n i m u m inhibitory concentration of amoxicillin was 0.5/xg/ml and of ampicillin was 1.75/¿g/ml. Absorption of amoxicillin from the gastrointestinal tract has been reported to be higher than that of a m p i c i l l i n , ' as was the case i n our patient. The bactericidal effect i n the serum of the patient while he was receiving therapy w i t h amoxicillin was significantly higher than while receiving equal doses of ampicillin; i t was higher than 1:8, the minimal dilution required for the treatment of bacterial endocarditis. Amoxicillin administered orally has previously been reported to be effective i n the treatment of enterococcal endocarditis occurring on a natural v a l v e ; however, to our knowledge, this is the first case report of a patient w i t h enterococcal endocarditis occurring on a prosthetic valve w h o was treated successfully w i t h the combination 13
14
15
CHEST, 74: 2, AUGUST, 1978
2 Jawetz E, Sonne M : Penicillin-streptomycin treatment of
Med 125:258-264, 1970
DISCUSSION
12
carditis. Prog Cardiovasc Dis 16:275-302, 1973
thetic valve endocarditis. Circulation 48:365-377, 1973 5 Wilson WR, Javmin PR, Danielson GK, et al: Prosthetic valve endocarditis. Ann Intern Med 82:751-756, 1975 6 Shaffer RB, Hall W H : Bacterial endocarditis following open heart surgery. Am J Cardiol 25:602-607, 1970 7 Moellering RC, Watson BK, Kunz L J : Endocarditis due to group D streptococci. Am J Med 57:239-250,1974 8 Gray IR, Tai AR, Wallace JG, et al: Oral treatment of bacterial endocarditis with penicillin. Lancet 2:110-114, 1964 9 Gray IR: The choice of antibiotic for treating infective endocarditis. Q J Med 44:449-458, 1975 10 Baily WR, Scott EG: Diagnostic Microbiology (3rd ed). St. Louis, CV Mosby Co, 1970, pp 120-128 11 Sabath L D : Synergy of antimicrobial substances. Antimicrob Agents Chemother 1968:210-217, 1967 12 Neu H C : Antimicrobial activity and human pharmacol ogy of amoxycillin. J Infect Dis 129 (suppl) :S123-S131, 1974 13 Lode H , Janisch P, Wevta Η : Comparative pharmacology of three ampicillins and amoxycillin administered orally. J Infect Dis 129 (suppl) :S156-S168, 1974 14 Lerner P I , Weinstein L : Infective endocarditis. Ν Engl J Med 274:323-331, 1966 15 Seligman SI: Treatment of enterococcal endocarditis with oral amoxycillin and intramuscular gentamicin. J Infect Dis 129 (suppl).S213-S215, 1974
BACTERIAL ENDOCARDITIS ON A PROSTHETIC VALVE 225
Bacterial Endocarditis on a Prosthetic Valve* Oral Treatment with Amoxicillin Moshe Lidji, Μ.Ό.; Ethan Rubinstein, M.D.; and Heskel Samra, M.D. A patient with endocarditis due to Streptococcus fae calis on an aortic valvular prosthesis was successfully treated using large oral doses of amoxicillin concurrently with intramuscular administration of streptomycin. Oral therapy was employed because of a persistent reaction to intravenously administered antibiotics. Oral therapy for bacterial endocarditis occurring on an artificial valve may be attempted as a last resort when all other accepted therapeutic measures have failed.
rrihe current recommended treatment for patients w i t h endocarditis due to Streptococcus faecalis o n •From the Infectious Diseases Unit and the Department of Medicine, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
224 LIDJI, RUBINSTEIN, SAMRA
prosthetic cardiac valves is intravenous therapy w i t h high doses of penicillin or ampicillin, w i t h the addition of an aminoglycoside. Surgical replacement of the infected prosthesis is recommended when medical ther apy fails. ' Despite these measures, a high mortality has been noted for prosthetic valvular endocarditis. " Whereas endocarditis o œ u n i n g on a natural valve has been successfully treated w i t h oral therapy, ' no such information is available œ n c e r n i n g the therapy for bacterial endocarditis on a prosthetic valve. A patient w i t h endocarditis due to S faecalis on an artificial aortic valve w h o was unable to tolerate any intravenous therapy was treated successfully w i t h large oral doses of amoxicillin and intramuscular administration of streptomycin. This combination of drugs yielded a satisfactory bactericidal effect on the serum, w h i c h correlated w i t h the recovery of the patient. 1-7
5
6
4
8
7
9
CASE REPORT A 63-year-old man was admitted to the Chaim Sheba Medical Center, Tel-Hashomer, Israel, because of the recent onset of left hemiparesis following one month of fever and malaise. The patient had undergone an aortic valvular replacement and aneurysmectomy of the ascending aorta for syphilitic cardiovascular disease three years prior to this admission. His postoperative course had been uneventful, and he remained in good health until the present illness. The patient denied any dental or genitourinary manipulations. On admission the patient appeared to be in no acute distress. His temperature was 38.4°C ( 1 0 1 . 1 F ) , the blood pressure was 180/80 mm Hg, and the pulse rate was 68 beats per minute. A grade 3/6 systolic murmur was heard over the aortic area; the murmur did not radiate. A small petechia was observed on the patient's left thumb. Neurologic examination revealed mild paresis of the left arm and leg. The findings from the rest of the physical examination were normal. No other signs of endocarditis were observed. The results of laboratory tests were as follows: hemoglobin level, 8.7 gm/100 m l ; hematocrit reading, 23 percent; white blood cell count, 9,600/cu mm, with a shift to the left; erythrocyte sedimentation rate, 25 mm in the first hour; V D R L test, negative; and Treponema pallidum immobilization test, positive. The rest of the chemical findings on the blood and cerebrospinal fluid were normal. Six consecutive cultures of blood grew S faecalis, and the minimum inhibitory concentration of ampicillin was 1.75¿tg/ml and of amoxicillin 0.5/ag/ml. The minimum inhibitory concentration of streptomycin was lOO^g/ml. Synergism was demonstrated both for the combination of ampicillin and streptomycin and for amoxicillin and streptomycin. The patient was started on therapy with 12 gm of ampicillin intravenously daily and 1 gm of streptomycin intramuscularly. Very severe thrombophlebitis developed rapidly in all of the veins into which ampicillin was introduced. Intravenous therapy with ampicillin was therefore changed to oral administration of 24 gm of ampicillin daily, and therapy with streptomycin was continued; however, the bactericidal effect in the serum varied between 1:2 and 1:16 on various occasions. Repeated attempts to administer medication intravenously failed because of immediately recurring grave thrombophlebitis. While the patient was receiving oral therapy with ampicillin (total, ten days), atrial fibrillation appeared, and his fever persisted. Therefore, oral administrae
CHEST, 74: 2, AUGUST, 1978
bon of 24 gm of amoxicillin daily was started, and therapy with streptomycin was continued for six weeks. The patient tolerated this regimen well. During therapy with amoxicillin, the bactericidal effect in the serum on repeated occasions varied between 1:32 and 1:64, and serum levels of amoxicillin varied between 37¿¿g/ml and 51/Ag/ml. During this treatment the fever returned to normal. Five months later, a diastolic murmur developed, and the patient underwent an aortic valvular replacement. At surgery, the valvular prosthesis was attached to the aortic annulus along only one-third of its circumference. No ulcerations, aneurysms, granulations, or vegetations were found; and multiple cultures taken from the prosthetic valve, sutures, and endocardium were sterile. A new prosthetic valve was inserted, and the patient made an uneventful recovery.
of oral therapy w i t h amoxicillin and intramuscular administration of streptomycin. W e believe that for the occasional patient w i t h a prosthetic valve w h o has late o œ u r r i n g subacute bacterial endocarditis caused b y a highly sensitive pathogen and w h o is unable to receive intravenous therapy, a trial of oral antibiotic such as amoxicillin i n combination w i t h parenteral therapy w i t h
aminoglycosides is justified.
This mode of therapy should only be employed as a last therapeutic resort and should be accompanied b y careful clinical and laboratory evaluation.
REFERENCES MATERIALS AND METHODS
1 Weinstein L , Schlesinger J: Treatment of infective endo-
Streptococcus faecalis (Enterococcus) was characterized according to standard criteria. Minimum inhibitory concentrations were determined by the standard broth dilution technique in trypticase soy broth. Synergism was determined by the checkerboard technique. Bactericidal levels i n the serum were measured by the tube dilution method. Levels of antibiotics in the blood were determined by the disk-diffusion test against Bacillus subtüis (ATCC 6633). 10
11
enterococcal endocarditis. Ν Engl J Med 274:710-715, 1966 3 Mandell GL, Kaye D, Levison M E , et al: Enterococcal endocarditis: An analysis of 38 patients observed at the New York Hospital Cornell Medical Center. Arch Intern 4 Dismukes W E , Karchmer A W , Buckley M J, et al: Pros
The history, physical signs, and positive cultures of blood leave litde doubt that our patient suffered from bacterial endocarditis occurring on a prosthetic aortic valve. The fact that no signs of active disease were seen at the time of repeat surgery and that all cultures were sterile points to the success of the pharmacologic regimen used. Our patient demonstrates that under special circumstances and when all other therapeutic measures have failed, successful oral therapy for bacterial endocarditis of a prosthetic valve is possible. Certain requirements fulfilled i n our patient are mandatory, ie: ( 1 ) the pathogen responsible for the infection must be highly sensitive to the d r u g employed; and ( 2 ) absorption of the drug from the gastrointestinal tract must be adequate to produce a strong bactericidal effect i n the serum. For S faecalis, the m i n i m u m inhibitory concentration of amoxicillin was 0.5/xg/ml and of ampicillin was 1.75/¿g/ml. Absorption of amoxicillin from the gastrointestinal tract has been reported to be higher than that of a m p i c i l l i n , ' as was the case i n our patient. The bactericidal effect i n the serum of the patient while he was receiving therapy w i t h amoxicillin was significantly higher than while receiving equal doses of ampicillin; i t was higher than 1:8, the minimal dilution required for the treatment of bacterial endocarditis. Amoxicillin administered orally has previously been reported to be effective i n the treatment of enterococcal endocarditis occurring on a natural v a l v e ; however, to our knowledge, this is the first case report of a patient w i t h enterococcal endocarditis occurring on a prosthetic valve w h o was treated successfully w i t h the combination 13
14
15
CHEST, 74: 2, AUGUST, 1978
2 Jawetz E, Sonne M : Penicillin-streptomycin treatment of
Med 125:258-264, 1970
DISCUSSION
12
carditis. Prog Cardiovasc Dis 16:275-302, 1973
thetic valve endocarditis. Circulation 48:365-377, 1973 5 Wilson WR, Javmin PR, Danielson GK, et al: Prosthetic valve endocarditis. Ann Intern Med 82:751-756, 1975 6 Shaffer RB, Hall W H : Bacterial endocarditis following open heart surgery. Am J Cardiol 25:602-607, 1970 7 Moellering RC, Watson BK, Kunz L J : Endocarditis due to group D streptococci. Am J Med 57:239-250,1974 8 Gray IR, Tai AR, Wallace JG, et al: Oral treatment of bacterial endocarditis with penicillin. Lancet 2:110-114, 1964 9 Gray IR: The choice of antibiotic for treating infective endocarditis. Q J Med 44:449-458, 1975 10 Baily WR, Scott EG: Diagnostic Microbiology (3rd ed). St. Louis, CV Mosby Co, 1970, pp 120-128 11 Sabath L D : Synergy of antimicrobial substances. Antimicrob Agents Chemother 1968:210-217, 1967 12 Neu H C : Antimicrobial activity and human pharmacol ogy of amoxycillin. J Infect Dis 129 (suppl) :S123-S131, 1974 13 Lode H , Janisch P, Wevta Η : Comparative pharmacology of three ampicillins and amoxycillin administered orally. J Infect Dis 129 (suppl) :S156-S168, 1974 14 Lerner P I , Weinstein L : Infective endocarditis. Ν Engl J Med 274:323-331, 1966 15 Seligman SI: Treatment of enterococcal endocarditis with oral amoxycillin and intramuscular gentamicin. J Infect Dis 129 (suppl).S213-S215, 1974
BACTERIAL ENDOCARDITIS ON A PROSTHETIC VALVE 225
