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Keywords:

  • Infective endocarditis;
  • Streptococcus bovis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Objective  To determine the specific characteristics of Streptococcus bovis infective endocarditis (IE) by reviewing our own experience of S. bovis IE.

Methods  Twenty episodes of definite S. bovis IE were reviewed in 20 patients hospitalized from 1980 to 1996.

Results  The mean age was 62 ± 14 years, and 14 (70%) patients had no known predisposing cardiac condition. The principal antimicrobials used were penicillin G (N = 10) and amoxycillin (N = 8). Surgery was required in four (20%) patients. Neurologic complications occurred in eight (40%) patients, after initiation of therapy in six (75%) (mean time: 14 days). An unfavorable outcome was observed in four of 20 patients and tended to be more frequent in patients who had had neurologic complications (P = 0.10). Colonic tumors were present in 11 of 16 (69%) patients.

Conclusions  Advanced age, occurrence of IE on presumably normal valves, high rate of neurologic complications, associated gastrointestinal diseases and low mortality rate during initial follow-up are characteristic features of S. bovis IE observed in this study.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Infective endocarditis (IE) remains a severe disease with a high rate of mortality worldwide despite recommendations for prophylaxis and effective treatment. Streptococcus bovis is the causative agent in 5–14% cases of IE with positive blood cultures [1,2]. It is the third most common microorganism responsible for IE, following viridans streptococci and staphylococci, and is even more frequent than Enterococcus species in some series [2,3]. S. bovis belongs to group D of the Lancefield classification and was separated from Enterococcus species in 1984 [4]. Although, in 1974, Moellering drew attention to the distinction between S. bovis IE and enterococcus IE, the clinical and microbiological characteristics and the outcome of S. bovis IE were generally grouped with those of IE due to Enterococcus species until 1984. Since 1984, S. bovis IE has been considered equivalent to S. viridans IE, and antibiotics have been more or less interchangeable, because the antibiotic susceptibility patterns of these two species are considered to be similar [5–7].

To identify the specific characteristics of S. bovis IE and the factors associated with an unfavorable outcome, we retrospectively evaluated the clinical course of 20 patients with definite IE caused by S. bovis.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Clinical characteristics of the patients

The charts of the patients with definite S. bovis IE hospitalized in the department from 1980 to 1996 were reviewed. IE was defined according to Duke University [8]. Two-dimensional transthoracic echocardiograms were performed using standard techniques before initiation of therapy, and were combined with transesophageal echocardiograms when this technique became available. The following information was obtained from each chart: age, sex, history of known pre-existing cardiac disease, clinical symptoms and physical findings, identification of valves involved, bacteriologic data, antimicrobial agents, dose and route of administration, duration of therapy, clinical outcome, complications and cause of death in fatal cases. After the infection was controlled with appropriate therapy, patients had an exploration of the colon by colonoscopy and/or barium enema because of the known association between S. bovis IE and gastrointestinal tumors.

Microbiological methods

S. bovis was isolated in at least two sets of blood cultures and identified as previously described [9]. The antimicrobial sensitivity of strains was tested using the disk diffusion method on Mueller–Hinton blood agar plates. The minimal inhibitory concentrations (MICs) and, since 1990, the minimal bactericidal concentrations (MBCs) were measured according to standard methods. The MBC was defined as the concentration of antibiotic allowing fewer than 0.01% surviving organisms. The streptococci were considered to be tolerant if the MBC/MIC ratio was ≥ 32 [10].

Assessment of outcome and prognostic factors

Complications of IE were classified into heart failure, peripheral emboli, spondylodiskitis, and neurologic events. Neurologic events were defined as the occurrence of acute neurologic abnormalities, with or without CT scan abnormalities and/or abnormal cerebrospinal fluid. The patients were considered to be cured when they had disappearance of fever, clinical signs and biological abnormalities, and sterilization of blood cultures after a complete course of antimicrobial therapy. Failure was defined as death due to S. bovis IE during hospitalization or relapse of infection. Prognostic evaluation was done by comparing the characteristics of the patients with a favorable outcome to those of the patients with failure. Comparisons were made using the chi-square test or Fischer exact test. Statistical significance was defined as a P-value less than 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Clinical characteristics

The study population consisted of 18 men and two women with a mean age of 62 years (range 35–82). On admission, all patients but one were febrile; this patient had been taking antibiotics during the 15 days prior to admission. The mean duration of illness from the first symptoms to the initiation of antibiotic therapy was 48 ± 24 days. It was 17.5 days for the patients with unfavorable outcome versus 55.5 days for the other patients. The first manifestations were prolonged fever in 12 (60%) patients, spondylodiskitis in two patients, meningitis in one patient, decompensation of cirrhosis with ascites in two patients, cutaneous vasculitis in one patient, encephalopathy in one patient, and pulmonary septic embolism in one patient. A heart murmur was present in 85% of patients. IE involved the mitral valve in nine (45%) patients, the aortic valve in eight (40%) patients, and the tricuspid valve in one patient. Several valves were involved in two (10%) patients.

Associated conditions

At initial presentation, six (30%) patients had a known pre-existing cardiac disease: one patient had a previous IE, and five had a history of valvular disease, including one patient with a mitral valve prolapse. Two other patients had coronary disease, and 12 (60%) patients had no known previous predisposing cardiac condition (Table 1). No additional unknown pre-existing cardiac condition was discovered by echocardiographic examination at the time of IE. Cirrhosis was present in four (20%) patients. One patient had HIV infection. A previous diagnosis of colon carcinoma had been made in one patient, 2 years before the episode of S. bovis IE. The patient was considered to be cured of cancer. Sixteen patients underwent a gastrointestinal evaluation after the episode of IE, one with barium enema examination alone and 15 with colonoscopy. Three of the four patients without colonic examination died before exploration of the colon could be done. Colonic tumors were present in 11 of 16 (69%) patients; eight patients had benign polyps and three had biopsy-proven carcinoma, including the patient with previous colon carcinoma. Five patients had dental disease, and two of these patients had both dental and colonic disease.

Table 1.   Characteristics of definite Streptococcus bovis endocarditis in 20 patients
Patient N (age (years))SexSiteKnown predisposing cardiac conditionEchocardiographic results Vegetation–regurgitationInitial regimena dosagec/durationSecondary regimenbExtracardiac complications, time to occurrence compared to initiation of therapy (days)Outcome (days)
  1. a Associated with an aminoglycoside in all patients. b Monotherapy except for patients 8,12,13 and 14 (associated with an aminoglycoside). c Respective daily doses of amoxycillin, penicillin and teicoplanin are expressed in grams, 106 units and milligrams. dPatients with coronary disease. ePatients with a tolerant strain (see Table 2). fValve surgery (days after initiation of therapy) for heart failure in patients 8, 14 and 19, or for peripheral emboli in patient 9. T, tricuspid; A, aortic; M, mitral; V, vegetation; R, regurgitation; classified from mild (I) to severe (IV).

Patients with favorable outcome
 1 (63)MTricuspidPrevious IETV–TR (II)Amoxycillin 12/28 daysAmoxycillinPulmonary embolus (− 8)Cure
 3 (59)MMitralNoned–MR (I)Teicoplanin 400/28 daysNo changeNoneCure
 4 (53)FAorticNoneAV–AR (I)Penicillin G 20/14 daysAmoxycillinPeripheral embolus (+ 18)Cure
 5 (82)eMAorticNoneAV–AR (II)Amoxycillin 8/21 daysAmoxycillinCerebral ischemia (+ 26)Cure
 6 (78)FMitralMitral regurgitationMV–MR (II)Amoxycillin 9/15 daysAmoxycillinNoneCure
 7 (81)eMMitralMitral regurgitationMV–MR (III)Amoxycillin 12/21 daysImipenemNoneCure
 8 (67)eMAorticNoneAV–AR (II)Amoxycillin 12/15 daysVancomycin, valve surgeryf (43)Cerebral ischemia (+ 10)Cure
 10 (36)MAorticAortic regurgitationAV–AR (I)Amoxycillin 12/30 daysAmoxycillinMeningitis (− 3)Cure
 11 (77)MAorticAortic regurgitationAV–AR (I)Penicillin G 40/45 daysAmoxycillinNoneCure
 12 (72)MAorticNonedAV–AR (I)Penicillin G 40/13 daysPristinamycinNoneCure
 13 (58)MMitralNone–MR (I)Penicillin G 30/24 daysAmoxycillinNoneCure
 14 (50)  MAorticNoneAV–AR (III)Penicillin G 20/26 days, Valve surgeryf (17)AmoxycillinCerebral ischemia (+ 8)Cure
 15 (56)MMitralNone–MR (II)Penicillin G 30/30 daysAmoxycillinNoneCure
 17 (71)  MMitralNoneMV–MR (II)Penicillin G 40/21 daysAmoxycillinSpondylodiskitis (− 10) Cerebral ischemia (− 10)Cure
 18 (47)MMitralNone–MR (II)Penicillin G 30/38 daysNo changeNoneCure
 20 (64)MMitralNoneMV–MR (I)Penicillin G 30/30 daysAmoxycillinSpondylodiskitis (− 60)Cure
Patients with failure
 2 (35)MAorticNoneAV–AR (II)Teicoplanin 400/10 daysNo changeBrain hemorrhage (+ 9)Death (10)
 9 (69)  MAortic, mitralNoneAV, MV-AR (I), MR (I)Penicillin G 40/22 days, Valve surgeryf (7)No changePeripheral emboli (+ 10)Death (22)
 16 (74)  MMitralNoneMV–MR (II)Amoxycillin 8/26 daysNo changeSeizures (+ 5), Cerebral ischemia (27)Death (27)
 19 (48)  MAortic, mitralMitral regurgitation– AR (III–IV), MR (I)Amoxycillin 12/26 days, Valve surgeryf (5)No changeSeizures (+ 15)Death (26)

Echocardiographic findings

Transthoracic echocardiograms were performed in all patients and revealed oscillating intracardiac mass on the valve in 14 of the 20 (70%) patients. Six patients had transesophageal echocardiograms, which showed vegetations in all cases; one of these patients had no vegetation on the previous transthoracic echocardiogram. No valvular abscess was observed. The vegetation size was less than 10 mm in three patients, between 10 and 20 mm in nine patients, and more than 20 mm in two patients. For the patient with multiple IE, the vegetation was smaller than 10 mm on one valve, and between 10 and 20 mm for the other valve. Regurgitation was considered as mild in 16 patients and severe in two. For the last two patients, it was mild for the two involved valves for one patient, and mild for one valve and severe for the other for the other patient (Table 1).

Microbiological findings and treatment

All strains were susceptible to penicillin by the disk diffusion method. In three patients, the strain had high levels of resistance to kanamycin (N = 2) and gentamicin (N = 1), respectively. The MICs obtained for penicillin G were less than 0.1 mg/L for the six isolates studied. In three patients, the strain of S. bovis was considered to be tolerant to penicillin, ampicillin, and, in two patients, vancomycin, with a low level of resistance to aminoglycoside (Table 2). The initial antimicrobial treatment used was penicillin G at a mean daily dose of 32 ± 10 million units in 10 (50%) patients, ampicillin or amoxycillin at a mean daily dose of 10.8 ± 1.8 g in eight (40%) patients, and teicoplanin at a mean daily dose of 400 mg in two patients. For the initial treatment, aminoglycosides were given to all patients. The mean duration of the initial treatment was 24 days (10–45).

Table 2.  Bacteriologic data and antimicrobial regimens in the three patients with Streptococcus bovis endocarditis due to a tolerant strain
PatientMIC/MBC (mg/L)Treatment
Penicillin GVancomycinAntibioticDaily doseaTotal duration
  • a

    For the non-aminoglycoside antimicrobial; the aminoglycoside was used at standard doses, e.g. 3 mg/kg/day gentamicin.

50.06/160.25/32Amoxycillin–aminoglycoside, then amoxycillin8 g 8 g 9 weeks
70.03/160.25/4Amoxycillin–aminoglycoside, then tienam12 g 3 g 6 weeks
80.03/160.25/32Amoxycillin–aminoglycoside, then vancomycin–aminoglycoside 12 g 2 g 6 weeks

The initial antimicrobial treatment was changed in 14 (70%) patients. It was changed to monotherapy or to oral administration in 10 patients (penicillin G or ampicillin). One patient was switched to imipenem (patient 7) and another to vancomycin (patient 8) because of low bactericidal activity of penicillin G in vitro. Treatment was changed in two other patients because of penicillin-related adverse events: one patient received pristinamycin because of development of rash and fever (patient 12), and one patient received ampicillin because of colonic hemorrhage requiring colectomy secondary to polypectomy and increased bleeding time related to penicillin (patient 20).

The mean total duration of treatment was 43 days (10–60), and the mean duration of the use of a combination of antibiotics was 33 days (10–60). Surgery was required in four (20%) patients, after a mean duration of antimicrobial therapy of 18 days (5–43), for heart failure in three patients and for recurrent emboli in one patient. Culture of the involved valves was negative in all four patients. The presence of IE was confirmed in all cases by microscopic examination during histologic examination.

Outcome and complications

Apyrexia was achieved at 7 ± 7 days after initiation of therapy. Complications associated with S. bovis IE occurred in 12 (60%) patients, before the initiation of treatment in four (20%) patients, and after a mean duration of therapy of 14 days (10–27) in eight (40%) patients. Three (15%) patients had congestive heart failure as a cardiac complication. Twelve patients, including the three previous patients, had one extracardiac complication: two (12%) patients had spondylodiskitis, three (15%) had extraneurologic peripheral emboli with two recurrences in one patient, and eight (40%) had neurologic manifestations (Table 1, Table 3). One patient had two extracardiac complications. Neurologic complications occurred after the initiation of treatment among six patients, after a mean duration of 14 days (5–27) of therapy.

Table 3.   Neurologic complications in eight patients with definite Streptococcus bovis endocarditis
Patient No.Length of symptoms (days) before diagnosisEchocardiographic findingsa Regurgitation (grade), Vegetation localizationDays to apyrexiaNeurologic manifestationsCT scan resultsOutcome
TypeDays
  • a

    Grades of regurgitation are classified from minor (I) to serious (IV); the greater size of the vegetation is mentioned. ND, not done; days are indicated as compared to initiation of therapy.

590Aortic regurgitation (II)7Acute horizontal diplopia26NormalCure
Aortic vegetation Oculomotor palsy   
860Aortic regurgitation (II)14Acute left visual acuity decrease10NDCure
Aortic vegetation     
101Aortic regurgitation (I)6Septic meningitis− 3NDCure
Aortic vegetation     
1490Aortic regurgitation (III)17Small stroke8NormalCure
Aortic vegetation Resolvent left hemiparesis   
1760Mitral regurgitation (II)2Amaurosis fugax− 10NormalCure
Mitral vegetation     
290Aortic regurgitation (II)6Deep coma9Massive brainhemorrhageDeath
Aortic vegetation     
1626Mitral regurgitation (II)27Seizure5  
Mitral vegetation Hemiplegia27Sylvian ischemiaDeath
191Aortic (III–IV) and mitral (I) regurgitation6Seizure15NDDeath

The final outcome was considered favorable in 16 (80%) patients. Failure was noted in four patients who died during hospitalization, 10–26 days after the initiation of therapy. One patient died of an early cardiac postoperative complication, two patients died of brain ischemia (one of them after cardiac surgery), and one patient died of brain hemorrhage. Death was associated with neurologic events in three of the four patients (75%).

Prognostic factors

Advanced age, sex, predisposing cardiac condition, the type of valve involved, cirrhosis, mean duration of symptoms before initiation of therapy, surgery and year of hospitalization were not associated with a higher rate of failure. Three of eight patients (37.5%) with neurologic complications died versus one of 12 (8%) patients who had no neurologic complications (P = 0.10).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

This study allowed us to confirm or to identify characteristics of S. bovis IE, which are the advanced age of the patients, the occurrence of IE on presumably normal valves, the high rate of neurologic complications, and the low mortality rate during the initial follow-up. However, the retrospective design of this study, its length of 16 years and the lack of long-term follow-up limit the interpretation of the results.

S. bovis accounts for 5–14% of cases of IE [1–3,11], and its incidence seems to have increased in France in the last 10 years [3,12]. This apparent increase is possibly related to the improved identification techniques for S. bovis and to the increasing age of the population of patients with IE [3]. Like many types of IE, S. bovis IE is more prevalent among men, except in the study of Moellering et al [13–19], and occurred in older individuals than did viridans IE [2,3,11,12,18–23]. It might be related to the associated colonic lesions, more frequent in older patients, which are probably the portal of entry of the microorganism. S. bovis IE develops more often on presumed healthy valves than on previously damaged valves, as opposed to IE caused by other streptococci: only 35% of our patients had a known predisposing cardiac condition, which is comparable to the 38% rate obtained from a cumulative analysis of six series of S. bovis IE [14–16,18–20]. In a recent retrospective comparative study, Kupferwasser also noted these characteristics, which, however, did not reach significant difference as compared to other types of endocarditis [19]. This affinity of S. bovis for normal cardiac valves, if confirmed, is unexplained, and impressed upon us the need to evaluate all patients with S. bovis septicemia for possible or probable IE, even in the absence of a previously known predisposing cardiac condition [24]. Simultaneous involvement of two or three valves reported in 68% of Kupferwasser's patients was observed neither in this series, nor in that of Ballet (36%) [18,19]. This probably explains the extremely high rate of surgery (73%) reported by Kupferwasser, which is much higher than the 20% of this series and might be explained by a referral bias. A colonic tumor was frequently discovered among the patients of this study. This association between S. bovis IE and an underlying intestinal tumor is now well established; these gastrointestinal tumors are found more frequently in S. bovis IE than in enterococcal IE and than in the general population [17,25,26]. Cirrhosis and/or alcoholism comprised the second most frequent predisposing condition, as reported by others, and seem to be more frequent with S. bovis IE than with IE due to other microorganisms [2,14,27]. This may be partly explained by the increased incidence of colonic tumor in the patients with cirrhosis [28]. However, the three patients with cirrhosis who underwent colonic examination had colonic tumors, despite a mean age of 47 years.

S. bovis IE is generally considered to have a favorable outcome: reported mortality rates have varied from 7% to 37%, with an average of 14% [1,13–16,29,30]. The mortality rate in the present study is consistent with those reported above and is comparable with the mortality rate attributed to S. viridans IE [12]. However, two recent series looked at the long-term outcome of S. bovis IE and noted a probability of survival between 60% and 70% at 60 months; this probability is significantly less than for the other types of endocarditis in the comparative study of Kupferwasser [18,19]. This is related to the greater age of the patients, to the colonic lesion sometimes disclosing disseminated carcinoma, and to the liver cirrhosis noted in the patients with S. bovis endocarditis.

In the present study, high doses and prolonged courses of a penicillin combined with an aminoglycoside were used. High doses of penicillin were essentially used for endocarditis in the early 1980s; the prolonged course of antibiotics was related to the high rate of embolic events and to the associated spondylodiskitis. Such a regimen differs from current recommendations for uncomplicated S. bovis endocarditis, which propose a similar regimen with a lower dose of penicillin for S. bovis and S. viridans IE, the dose of penicillin depending mainly on the susceptibility of the strain to penicillin [5–7]. However, the susceptibility to penicillin of S. bovis is similar to that of viridans streptococci, and there are no substantial clinical and microbiological data in support of the high doses of penicillin used in this study.

At least three patients were found to have an S. bovis strain tolerant to penicillin and two to vancomycin; this finding has been reported in 5–20% of S. bovis strains responsible for IE [5–7,11]. Results from experimental endocarditis caused by a penicillin-tolerant strain suggest that an aminoglycoside should be added to penicillin to achieve cure in these situations [31]. However, the clinical significance of this in vitro phenomenon is still uncertain, and its implications for the use of an aminoglycoside have been controversial [6,7,11]. In the present study, a favorable outcome was achieved with prolonged use of a penicillin–aminoglycoside combination in one patient, the use of vancomycin and surgery in a second patient, and the replacement of penicillin by imipenem in the third patient. This aggressive treatment might be partly due to the knowledge of the tolerance of the strains. Prospective evaluation of this phenomenon is warranted in order to search for a relationship between tolerance and prognosis.

The frequency of neurologic complications in patients with IE ranges from 12% to 39% in the literature, and seems to be higher with prosthetic valves; it varies widely with the type of the causative organism [32–35]. This frequency is 12–30% for streptococcal IE, 28–39% for enterococcal IE, and 53–67% for staphylococcal IE [32–35]. It is intermediate for S. bovis IE in this study and in the series of Wang, who also reported a 40% frequency of neurologic complications [24]. Furthermore, the prognostic significance of neurologic complications in the course of S. bovis IE in this series is concordant with the prognostic significance in other series of IE, regardless of the type of the causative organism. Pruitt et al and Jones et al found that the mortality rates in their patients with neurologic complications were higher, 58% and 50% respectively, than in patients without neurologic complications, 20% and 14% respectively [35,36]. In the present study, the prognosis of S. bovis IE appeared to be more related to the occurrence of neurologic complications than to the cardiac factors. These results differed from those of Ballet and Kupferwasser, who related S. bovis IE prognosis to cardiac failure [18,19]. However, referral bias explained the high rate of surgery, the high rate of valvular damage and the lower rate of neurologic events that generally contraindicated surgery.

Our findings, like those of Kupferwasser, provide further evidence that S. bovis IE is not totally similar to S. viridans IE in several aspects. It shares some characteristics with enterococcal IE, such as the age of the patients, the rate of complications, especially neurologic events, and the intestinal reservoir of the bacteria. The occurrence of S. bovis IE on presumed normal valves seems to be a characteristic feature which remains unexplained. The higher rate of valvular damage resulting in a higher percentage of surgical treatment in S. bovis IE reported by some authors has to be confirmed by other large comparative studies [18,19]. There have been recent data supporting ceftriaxone outpatient treatment of uncomplicated IE due to strains of streptococci with high susceptibility to penicillin [37–39]. The high rate of neurologic complications, their occurrence during the first 3 weeks of treatment, their prognostic significance in this series and the high rate of valvular damage noted by others make early outpatient treatment of S. bovis IE questionable; if performed, it must be done with caution in the case of initially uncomplicated S. bovis IE.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
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