- Email: [email protected]
Infective Endocarditis Caused by Nutritionally Variant Streptococci
Infective Endocarditis Caused by Nutritionally Variant Streptococci CHENG-HSIN LIN, MD; RON-BIN HSU, MD
ABSTRACT: Background: Infective endocarditis caused by nutritionally variant streptococci (NVS) has a higher rate of complications than endocarditis caused by other streptococci. The bacteriologic failure rate and the mortality rate are high. However, current knowledge on this disease derives from previous patient data from 1987. Recent case reports showed successful antibiotic treatment in the absence of surgery. Here, we report the clinical outcome of infective endocarditis caused by NVS in our hospital. Methods: Data were collected by retrospective case note review. Results: Between 1996 and 2006, there were 8 cases of NVS endocarditis: 4 patients had infection caused by Abiotrophia defectiva and 4 patients had infection caused by Granulicatella adiacens. Vegetation size on echocardiography was large (10 mm) in 7 patients, and embolization occurred in 3 patients. Patients were treated with penicillin and
gentamicin initially, and 3 of them were successfully treated. The regimens were shifted to vancomycin, teicoplanin, or cefotaxime in 2 cases because of poor therapeutic responses. A total of 4 patients underwent early valve replacement successfully because of severe heart failure. Three patients underwent mitral valve repair successfully at the time of 2, 4, and 7 months after the diagnosis of endocarditis. The valve cultures at surgery were negative. There was no mortality or relapse. The bacteriologic failure rate was zero. Conclusions: Antibiotic treatment with penicillin and gentamicin had a high rate of success in patients with infective endocarditis caused by NVS. Early surgical intervention should be considered in those patients with deteriorating heart failure due to valve destruction. KEY INDEXING TERMS: Infective endocarditis; Nutritionally variant streptococci. [Am J Med Sci 2007;334(4):235–239.]
N
the absence of surgery.7–9 However, certain bias existed and only patients with successful treatment were reported. Here, we report the clinical outcome of infective endocarditis caused by NVS in our hospital.
utritionally variant streptococci (NVS) cause approximately 3% to 5% of cases of streptococcal infective endocarditis.1–7 Infective endocarditis caused by NVS has a higher rate of complications than endocarditis caused by other streptococci. Previous case studies and literature reviews have reported significant mortality and morbidity associated with this infection.1– 6 Embolization occurred in 27%, and the bacteriologic failure rate was up to 40% of patients with NVS endocarditis.1 The mortality rate was 17% to 20% because of severe heart failure.1– 6 NVS endocarditis has remained very difficult to treat medically with antibiotics alone, and surgical intervention has been required to effect cure in a lot of patients with complicated course. However, current knowledge on this disease mostly derives from studies with literature review.1 The included patients were reported in 1987. Recent case reports showed successful antibiotic treatment in
From the Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China. Submitted November 23, 2006; accepted in revised form March 19, 2007. Corresponding author: Dr. Ron-Bin Hsu, National Taiwan University Hospital, No.7, Chung-Shan S. Road, Taipei, Taiwan 100, ROC (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Patients and Methods Setting National Taiwan University Hospital (Taipei, Taiwan) is a 2000-bed tertiary care hospital. It serves an urban population of 2 million persons as both first-line and tertiary facilities. It serves also as a referral center for other hospitals in the country with a population of 22 million persons. Patients The study patient cohort was obtained from a retrospective analysis of the clinical data for patients with NVS infective endocarditis. Modified Duke criteria10 were applied for the diagnosis of infective endocarditis. To meet qualification for definite infective endocarditis, patients had to have 2 major, 1 major, and 3 minor, or 5 minor clinical criteria. Only definite cases of infective endocarditis were included. After the identification of streptococci from blood cultures and cardiac vegetation from echocardiogram, treatment with intravenous antibiotic was started in all patients. If penicillin sensitive streptococcus was isolated, combined antibiotic treatment with high-dose penicillin G sodium (2 to 5 million Units q 4 hours) and gentamicin were given. Gentamicin was continued for at least 2 weeks. If high-level penicillin resistant streptococcus was isolated or the fever persisted after the use of penicillin and gentamicin, ceftriaxone (1 g q 12 hours), vancomycin (1 g q 12 hours), or
235
NVS Endocarditis
Table 1. Patient Demographics of Infective Endocarditis Caused by NVS
Pathogen
Penicillin Susceptibility
51
A. defectiva
Sensitive
NA
None
F
12
A. defectiva
Sensitive
None
3
M
65
A. defectiva
Resistant
4
M
49
A. defectiva
Sensitive
5
F
18
G. adiacens
Sensitive
Ampicillin 0.19 g/mL Penicillin 0.125 g/mL Penicillin 0.032 g/mL NA
6
M
61
G. adiacens
Sensitive
NA
7 8
M F
30 28
G. adiacens G. adiacens
Sensitive Sensitive
NA NA
Diabetes mellitus None Nephrotic syndrome
No.
Sex
1
M
2
Age (yr)
Medical Diseases
MIC
None Diabetes mellitus None
Previous Heart Disease
Valve Lesion and Vegetation Size
Mitral valve prolapse None
Mitral ⬍10 mm
Mitral regurgitation None
Mitral 11 ⫻ 10 mm
Rheumatic heart disease None None None
Mitral 11 ⫻ 3 mm
Aortic 15 ⫻ 16 mm Mitral 16 ⫻ 8 mm Mitral and tricuspid 20 ⫻ 12 mm Mitral 11 ⫻ 11 mm Mitral and aortic 12 ⫻ 13 mm
NVS, Nutritionally variant streptococci; MIC, minimal inhibitory concentration; A., Abiotrophia; G., Granulicatella.
teicoplanin (6 to 12 mg/kg per day) was given. Antibiotics were administered intravenously in hospital and continued for at least 4 to 8 weeks or until the clinical and laboratory parameters of infection returned to normal. The bacteriologic failure rate was defined as positive blood cultures after 7 days of antibiotic therapy, relapse after a course of therapy with appropriate antibiotics, or a positive valve culture after therapy.1 Indications of Operation The indications for surgery in our patients were refractory heart failure secondary to valve destruction, severe paravalvular abscess, and uncontrolled infection with persistent fever and leukocytosis. Laboratory Methods Isolates of NVS were identified to the species level using the standard conventional biochemical methods and the Rapid ID32 STREP systems (bioMe´rieux Vitek).11,12 Sequencing of 16S rRNA genes was performed for further confirmation, as described elsewhere.13 The sequence of the PCR products was compared with known 16S rRNA gene sequences in the GenBank. Minimal inhibitory concentrations (MIC) of antimicrobial agents for the isolates of NVS were determined by the broth microdilution method and interpreted according to the guidelines established by the Clinical Laboratory Standard Institute (CLSI) for streptococci other than Streptococcus pneumoniae.14,15 For the susceptibility testing of these isolates, the standard cation-adjusted Mueller-Hinton broth (BBL Microbiology Systems) supplemented with 3% lysed horse blood was used, and the inoculated microtiter plates were incubated at 37°C in ambient air; S. pneumoniae ATCC 49619 was included as the control strain. In this study, strains for penicillin resistance were defined as follows: susceptible, MIC ⬍0.125 g/mL; intermediately resistant, MIC ⫽ 0.125 to 2.0 g/mL; high-level resistant, MIC ⱖ2 g/mL.
Results Patient Characteristics Between 1996 and 2006, 428 cases of definite infective endocarditis were identified. Among them, 35 cases (8%) were culture-negative and 8 cases were infections caused by NVS. Clinical characteristics of the 8 patients were summarized in Table 1. 236
Of these 8 patients, 5 were male, and the median age was 39.5 years (range, 12 to 65). Two patients had diabetes mellitus, and 1 patient had chronic steroid therapy because of nephrotic syndrome. Three of the 8 cases had previous heart diseases with mitral valve prolapse, rheumatic heart disease, and mitral regurgitation due to chordal rupture each in 1 patient. The vegetation size on echocardiography was large (10 mm) in 7 patients (Table 1), and embolization occurred in 3 patients (spleen, brain, and lower limbs each in 1 patient). Bacteriology and Antimicrobial Resistance Testing Data are shown in Table 1. Four patients had infection caused by Abiotrophia defectiva and 4 patients had infection caused by Granulicatella adiacens. Seven isolates were sensitive to penicillin and one isolate was intermediately resistant to penicillin. Medical Treatment All cases were treated with penicillin and gentamicin initially, and only 3 of them (patients 1, 3, and 7) were successfully treated (Table 2). One 30-yearold male patient (patient 7) had infective endocarditis caused by G. adiacen, which was complicated by a ruptured mycotic cerebral aneurysm with an intracerebral hemorrhage at the left fronto-parietal region. Antibiotic treatment was shifted to ceftriaxone because of skin allergy. He underwent mitral valve repair for severe mitral regurgitation 2 months later. Surgery was delayed because of cerebral hemorrhage. Antibiotic regimens were shifted to vancomycin, teicoplanin, or cefotaxime in 2 cases because of poor therapeutic responses. One 12-year-old girl (patient 2) with no underlying heart disease had mitral infective endocarditis caused by A. defectiva. This orOctober 2007 Volume 334 Number 4
Lin and Hsu
Table 2. Clinical Outcomes of Infective Endocarditis Caused by NVS Time of Surgery
Indication of Surgery
P, G
Late 7 months
None None
V, G, T, R, Cefo P, G
None Late 2 months
4
Heart failure
P, G, Ceft
Early 1 day
Sever mitral regurgitation None Severe mitral regurgitation Heart failure
5
Heart failure
P, G
Early 7 days
Heart failure
6
Heart failure
P, G
Early 44 days
Heart failure
7
Ruptured cerebral mycotic aneurysms Heart failure, limb embolization
P, G, Ceft
Late 4 months
Severe mitral regurgitation
P, G, V, T
Early 21 days
Heart failure
No.
Complications
1
Splenic infarction
2 3
8
Medical Treatment
Operative Procedure
Outcome
Mitral valve repair
No relapse
None Mitral valve repair
No relapse No relapse
Aortic valve replacement with mechanical valve Mitral valve replacement with mechanical valve Mitral and tricuspid valve replacement with bioprosthesis Mitral valve repair
No relapse
Aortic and mitral valve replacement with bioprosthesis
No relapse No relapse No relapse No relapse
NVS, Nutritionally variant streptococci; P, Penicillin; G, Gentamicin; V, Vancomycin; T, Teicoplanin; R, Rifampin; Cefo, cefotaxime; Ceft, ceftriaxone.
ganism was susceptible to ampicillin with an MIC of 0.19 g/mL by E-test. The MICs of vancomycin, cefotaxime and rifampin were 1.5, 1 and 0.016 g/ mL, respectively. Vancomycin and gentamicin were used, and the fever subsided gradually. The follow-up echocardiography 1 week later showed a decrease in the size of the vegetation. However, fever flared up on the 10th day, and the antibiotics were changed to ampicillin and teicoplanin because of the suspicion of drug fever. Five blood cultures taken 5 days later were sterile. Blood examination revealed eosinophilia. The vegetation size steadily decreased. The antibiotic regimen was shifted to ampicillin and gentamicin for 2 weeks and finally to cefotaxime and rifampin for another 4 weeks. She was discharged after an 8-week course of treatment in stable condition. Echocardiography at discharge showed only small vegetation on the anterior leaflet of the mitral valve. She remained well on outpatient follow-up for 69 months. One 28-year-old woman (patient 8) with nephrotic syndrome had mitral and aortic valve infective endocarditis caused by G. adiacens. Penicillin and gentamicin were used initially, and the fever subsided gradually. However, fever flared up on the 11th day, and the antibiotics were shifted to vancomycin and then teicoplanin because of persistent fever. Blood cultures taken then were sterile. The follow-up echocardiography showed an increase in the size of the vegetation and severe valve regurgitation. She underwent aortic and mitral valve replacement on the 21st day because of severe heart failure. The valve culture was negative. She remained well on outpatient follow-up for 130 months. Surgical Treatment As shown in Table 2, a total of 7 patients underwent surgery. Four patients (patients 4, 5, 8, and 6) THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
underwent early surgery because of severe heart failure at the time of 1, 7, 21, and 44 days after the diagnosis of infective endocarditis. One 49-yearold diabetic male (patient 4) with no underlying heart disease had aortic infective endocarditis and severe aortic regurgitation. He was treated as respiratory tract infection with oral antibiotic at outpatient clinic. He was brought to emergency department because of severe heart failure. Penicillin and gentamicin were used empirically. He underwent emergency aortic valve replacement on the first day. Blood culture was A. defectiva. This organism was penicillin resistant and with a penicillin MIC of 0.032 g/mL by E-test. The antibiotic regimen was shifted to ceftriaxone for 6 weeks after operation. The valve culture was negative. He remained well on outpatient follow-up for 5 months. All of 4 patients with early surgery underwent valve replacement because of large vegetations and extensive valve destruction. Two patients had mechanical heart valves, and 2 patients had bioprosthesis. The valve cultures were negative in these 4 patients. Among 4 patients with successful antibiotic treatment, 3 patients underwent mitral valve repair successfully at the time of 2, 4, and 7 months after the diagnosis of infective endocarditis because of severe mitral regurgitation. Operation consisted of quadrangular resection of torn leaflets and annular plication. In summary, 7 of these 8 patients underwent surgical intervention because of complications caused by infective endocarditis. There was no mortality or morbidity. Overall, all of our patients were treated successfully with penicillin or other beta-lactams plus gentamicin or a glycopeptide for 4 to 8 weeks, and there was no relapse. A total of 7 patients underwent 237
NVS Endocarditis
surgery and the valve cultures were negative. The bacteriologic failure rate was zero in our series. The median follow-up duration was 63 months (range, 4 to 130). Discussion Nutritionally Variant Streptococci NVS were originally described in 1961 by Frenkle and Hirsch16 as a new type of viridans group streptococci because of a characteristic growth requirement, prolonged incubation period, satellite-promoting phenomenon, pleomorphic morphotypes, and variable Gram stain findings. In 1989, Bouvet et al17 performed a DNA-DNA hybridization that divided the NVS into 2 species, Streptococcus adjacens and Streptococcus defectiva. In 1995, using the 16S rRNA gene sequencing NVS, Kawamura et al18 proposed a new genus, Abiotrophia, for the NVS and included 4 species (A. defectiva, A. adiacens, A. balaenopterae, and A. elegans). In 2000, on the basis of 16S rRNA tree topology and sequence divergence considerations, Collins and Lawson11 further proposed a new genus, Granulicatella, to reclassify A. adiacens, A. balaenopterae, and A. elegans as G. adiacens, G. balaenopterae, and G. elegans, respectively. In Taiwan, the first case of human NVS infection occurred in 1996.19 The increasing awareness of laboratory staff members to these organisms and improved laboratory procedures permit more accurate identification of NVS.19 In this series of 8 endocarditis caused by NVS, 4 patients had infection caused by A. defectiva and 4 patients had infection caused by G. adiacens. No patient had infection caused by other NVS. Endocarditis More than 100 cases of NVS endocarditis have been reported in the literature.1–9 NVS strains are part of the normal oral, intestinal and genitourinary flora. The portal of entry in most cases of endocarditis is via the mouth, teeth or throat. NVS cause approximately 3% to 5% of cases of streptococcal infective endocarditis. However, this figure is probably an underestimation, because NVS is a fastidious organism and might fail to grow on the initial subculture. Identification based on phenotypic method scan result in misidentification of the pathogen. They are likely to be responsible for some culture-negative infective endocarditis.20 Molecular methods were used to improve the detection and facilitate the identification.18 In our previous report,21 3% of cases of streptococcal endocarditis were caused by NVS in our hospital. NVS endocarditis is associated with significantly higher morbidity and mortality than that caused by viridans streptococci or enterococci.1– 6 Multiple factors contribute to the virulence of NVS. First, NVS produce exopolysaccharide and have high binding capacity for fibronectin and extracellular matrix 238
components.20 Second, the generation time for NVS (2 to 3 hours) being slower than that of viridans streptococci (40 to 50 minutes) may attenuate the effect of the beta-lactam antibiotics.20 In a literature review of 30 cases of infective endocarditis caused by NVS strains, Stein and Nelson1 reported that this infection was difficult to treat and had a poor outcome. Embolization occurred in 27%, relapse after therapy occurred in 17%, and death occurred in 17% of these patients. In addition, bacteriologic failure occurred in 41% of cases, despite sensitivity of the organisms to the antibiotics used in the majority of these cases. Surgery was required in 38% of the cases reviewed. In this current series, NVS endocarditis was associated with high rate of complications and operation was indicated in the majority of cases. However, in contrast to previous reports in old times,1– 6 there was no mortality and no relapse in our patients and this result was similar to the more recent case reports.7–9 Because there was no relapse and the valve culture was negative at surgery, the bacteriologic failure rate in this series was zero. Combined medical and surgical treatment in infective endocarditis caused by NVS had a favorable outcome in this study. Antibiotic treatment with penicillin and gentamicin had a high rate of success. Early surgical intervention should be considered in those patients with deteriorating heart failure due to valve destruction.22 This study was limited by small case number and retrospective study. However, this study is a singlecenter experience and one of the largest series of NVS infective endocarditis ever reported in the literature. In conclusion, antibiotic treatment with penicillin and gentamicin had a high rate of success in patients with infective endocarditis caused by NVS. Early surgical intervention should be considered in those patients with deteriorating heart failure due to valve destruction. References 1. Stein DS, Nelson KE. Endocarditis due to nutritionally deficient streptococci: therapeutic dilemma. Rev Infect Dis 1987;9:908–16. 2. Bouvet A. Human endocarditis due to nutritionally variant streptococci: streptococcus adjacens and Streptococcus defectivus. Eur Heart J 1995;16:S24–7. 3. Christensen JJ, Gruhn N, Facklam RR. Endocarditis caused by Abiotrophia species. Scand J Infect Dis 1999;31: 210–2. 4. Wijetunga M, Bello E, Schatz I. Abiotrophia endocarditis: a case report and review of literature. Hawaii Med J 2002; 61:10–2. 5. Chang HH, Lu CY, Hsueh PR, et al. Endocarditis caused by Abiotrophia defectiva in children. Pediatr Infect Dis J 2002;21:697–700. 6. Sharaf MA, Shaikh N. Abiotrophia endocarditis: case report and review of the literature. Can J Cardiol 2005;21:1309–11.
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7. Lainscak M, Lejko-Zupanc T, Strumblj I, et al. Infective endocarditis due to Abiotrophia defectiva: a report of two cases. J Heart Valve Dis 2005;14:33–6. 8. Jeng A, Chen J, Katsivas T. Prosthetic valve endocarditis from Granulicatella adiacens (nutritionally variant streptococcus). J Infect 2005;51:125–9. 9. Yemisen M, Koksal F, Mete B, et al. Abiotrophia defectiva: a rare cause of infective endocarditis. Scan J Infect Dis 2006;38:939–41. 10. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633–8. 11. Collins MD, Lawson PA. The genus Abiotrophia (Kawamura et al) is not monophyletic: proposal of Granulicatella gen. nov., Granulicatella adiacens comb. nov., Granulicatella elegans comb. nov. and Granulicatella balaenopterae comb. nov. Int J Syst Evol Microbiol 2000;50:365–9. 12. Christensen JJ, Facklam RR. Granulicatella and Abiotrophia species from human clinical specimens. J Clin Microbiol 2001;39:3520–3. 13. Roggenkamp A, Leitritz L, Baus K, et al. PCR for detection and identification of Abiotrophia spp. J Clin Microbiol 1998;36:2844–6. 14. National Committee for Clinical Laboratory Standards (NCCLS). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standardsfifth edition. M7-A5. Wayne, PA; NCCLS, 2003.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
15. National Committee for Clinical Laboratory Standards (NCCLS). Performance standards for antimicrobial susceptibility testing: thirteenth informational supplement. M100S13. Wayne, PA: NCCLS, 2003. 16. Frenkel A, Hirsch W. Spontaneous development of L forms of streptococci requiring secretions of other bacteria or sulfhydryl compounds for normal growth. Nature 1961;191:728–30. 17. Bouvet A, Grimont F, Grimont PAD. Streptococcus defectivus sp. nov. and Streptococcus adjacens sp. nov., nutritionally variant streptococci from human clinical specimens. Int J Syst Bacteriol 1989;39:290–4. 18. Kawamura Y, Hou XG, Sultana F, et al. Transfer of Streptococcus adjacens and Streptococcus defectivus to Abiotrophia gen. nov. as Abiotrophia adiacens comb. nov. and Abiotrophia defectiva comb. nov., respectively. Int J Syst Bacteriol 1995;45: 798–803. 19. Liao CH, Teng LJ, Hsueh PR, et al. Nutritionally variant streptococcal infections at a University Hospital in Taiwan: disease emergence and high prevalence of beta-lactam and macrolide resistance. Clin Infect Dis 2004;38:452–5. 20. Rouff KL. Nutritionally variant streptococci. Clin Microbiol Rev 1991;4:184–90. 21. Hsu RB, Lin FY. Effect of penicillin resistance on presentation and outcome of nonenterococcal streptococcal infective endocarditis. Cardiology 2006;105:234–9. 22. Al-Jasser AM, Enani MA. Al-Faqih. Endocarditis caused by Abiotrophia defectiva. Libyan J Med, AOP: 061223.
239
ABSTRACT: Background: Infective endocarditis caused by nutritionally variant streptococci (NVS) has a higher rate of complications than endocarditis caused by other streptococci. The bacteriologic failure rate and the mortality rate are high. However, current knowledge on this disease derives from previous patient data from 1987. Recent case reports showed successful antibiotic treatment in the absence of surgery. Here, we report the clinical outcome of infective endocarditis caused by NVS in our hospital. Methods: Data were collected by retrospective case note review. Results: Between 1996 and 2006, there were 8 cases of NVS endocarditis: 4 patients had infection caused by Abiotrophia defectiva and 4 patients had infection caused by Granulicatella adiacens. Vegetation size on echocardiography was large (10 mm) in 7 patients, and embolization occurred in 3 patients. Patients were treated with penicillin and
gentamicin initially, and 3 of them were successfully treated. The regimens were shifted to vancomycin, teicoplanin, or cefotaxime in 2 cases because of poor therapeutic responses. A total of 4 patients underwent early valve replacement successfully because of severe heart failure. Three patients underwent mitral valve repair successfully at the time of 2, 4, and 7 months after the diagnosis of endocarditis. The valve cultures at surgery were negative. There was no mortality or relapse. The bacteriologic failure rate was zero. Conclusions: Antibiotic treatment with penicillin and gentamicin had a high rate of success in patients with infective endocarditis caused by NVS. Early surgical intervention should be considered in those patients with deteriorating heart failure due to valve destruction. KEY INDEXING TERMS: Infective endocarditis; Nutritionally variant streptococci. [Am J Med Sci 2007;334(4):235–239.]
N
the absence of surgery.7–9 However, certain bias existed and only patients with successful treatment were reported. Here, we report the clinical outcome of infective endocarditis caused by NVS in our hospital.
utritionally variant streptococci (NVS) cause approximately 3% to 5% of cases of streptococcal infective endocarditis.1–7 Infective endocarditis caused by NVS has a higher rate of complications than endocarditis caused by other streptococci. Previous case studies and literature reviews have reported significant mortality and morbidity associated with this infection.1– 6 Embolization occurred in 27%, and the bacteriologic failure rate was up to 40% of patients with NVS endocarditis.1 The mortality rate was 17% to 20% because of severe heart failure.1– 6 NVS endocarditis has remained very difficult to treat medically with antibiotics alone, and surgical intervention has been required to effect cure in a lot of patients with complicated course. However, current knowledge on this disease mostly derives from studies with literature review.1 The included patients were reported in 1987. Recent case reports showed successful antibiotic treatment in
From the Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China. Submitted November 23, 2006; accepted in revised form March 19, 2007. Corresponding author: Dr. Ron-Bin Hsu, National Taiwan University Hospital, No.7, Chung-Shan S. Road, Taipei, Taiwan 100, ROC (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Patients and Methods Setting National Taiwan University Hospital (Taipei, Taiwan) is a 2000-bed tertiary care hospital. It serves an urban population of 2 million persons as both first-line and tertiary facilities. It serves also as a referral center for other hospitals in the country with a population of 22 million persons. Patients The study patient cohort was obtained from a retrospective analysis of the clinical data for patients with NVS infective endocarditis. Modified Duke criteria10 were applied for the diagnosis of infective endocarditis. To meet qualification for definite infective endocarditis, patients had to have 2 major, 1 major, and 3 minor, or 5 minor clinical criteria. Only definite cases of infective endocarditis were included. After the identification of streptococci from blood cultures and cardiac vegetation from echocardiogram, treatment with intravenous antibiotic was started in all patients. If penicillin sensitive streptococcus was isolated, combined antibiotic treatment with high-dose penicillin G sodium (2 to 5 million Units q 4 hours) and gentamicin were given. Gentamicin was continued for at least 2 weeks. If high-level penicillin resistant streptococcus was isolated or the fever persisted after the use of penicillin and gentamicin, ceftriaxone (1 g q 12 hours), vancomycin (1 g q 12 hours), or
235
NVS Endocarditis
Table 1. Patient Demographics of Infective Endocarditis Caused by NVS
Pathogen
Penicillin Susceptibility
51
A. defectiva
Sensitive
NA
None
F
12
A. defectiva
Sensitive
None
3
M
65
A. defectiva
Resistant
4
M
49
A. defectiva
Sensitive
5
F
18
G. adiacens
Sensitive
Ampicillin 0.19 g/mL Penicillin 0.125 g/mL Penicillin 0.032 g/mL NA
6
M
61
G. adiacens
Sensitive
NA
7 8
M F
30 28
G. adiacens G. adiacens
Sensitive Sensitive
NA NA
Diabetes mellitus None Nephrotic syndrome
No.
Sex
1
M
2
Age (yr)
Medical Diseases
MIC
None Diabetes mellitus None
Previous Heart Disease
Valve Lesion and Vegetation Size
Mitral valve prolapse None
Mitral ⬍10 mm
Mitral regurgitation None
Mitral 11 ⫻ 10 mm
Rheumatic heart disease None None None
Mitral 11 ⫻ 3 mm
Aortic 15 ⫻ 16 mm Mitral 16 ⫻ 8 mm Mitral and tricuspid 20 ⫻ 12 mm Mitral 11 ⫻ 11 mm Mitral and aortic 12 ⫻ 13 mm
NVS, Nutritionally variant streptococci; MIC, minimal inhibitory concentration; A., Abiotrophia; G., Granulicatella.
teicoplanin (6 to 12 mg/kg per day) was given. Antibiotics were administered intravenously in hospital and continued for at least 4 to 8 weeks or until the clinical and laboratory parameters of infection returned to normal. The bacteriologic failure rate was defined as positive blood cultures after 7 days of antibiotic therapy, relapse after a course of therapy with appropriate antibiotics, or a positive valve culture after therapy.1 Indications of Operation The indications for surgery in our patients were refractory heart failure secondary to valve destruction, severe paravalvular abscess, and uncontrolled infection with persistent fever and leukocytosis. Laboratory Methods Isolates of NVS were identified to the species level using the standard conventional biochemical methods and the Rapid ID32 STREP systems (bioMe´rieux Vitek).11,12 Sequencing of 16S rRNA genes was performed for further confirmation, as described elsewhere.13 The sequence of the PCR products was compared with known 16S rRNA gene sequences in the GenBank. Minimal inhibitory concentrations (MIC) of antimicrobial agents for the isolates of NVS were determined by the broth microdilution method and interpreted according to the guidelines established by the Clinical Laboratory Standard Institute (CLSI) for streptococci other than Streptococcus pneumoniae.14,15 For the susceptibility testing of these isolates, the standard cation-adjusted Mueller-Hinton broth (BBL Microbiology Systems) supplemented with 3% lysed horse blood was used, and the inoculated microtiter plates were incubated at 37°C in ambient air; S. pneumoniae ATCC 49619 was included as the control strain. In this study, strains for penicillin resistance were defined as follows: susceptible, MIC ⬍0.125 g/mL; intermediately resistant, MIC ⫽ 0.125 to 2.0 g/mL; high-level resistant, MIC ⱖ2 g/mL.
Results Patient Characteristics Between 1996 and 2006, 428 cases of definite infective endocarditis were identified. Among them, 35 cases (8%) were culture-negative and 8 cases were infections caused by NVS. Clinical characteristics of the 8 patients were summarized in Table 1. 236
Of these 8 patients, 5 were male, and the median age was 39.5 years (range, 12 to 65). Two patients had diabetes mellitus, and 1 patient had chronic steroid therapy because of nephrotic syndrome. Three of the 8 cases had previous heart diseases with mitral valve prolapse, rheumatic heart disease, and mitral regurgitation due to chordal rupture each in 1 patient. The vegetation size on echocardiography was large (10 mm) in 7 patients (Table 1), and embolization occurred in 3 patients (spleen, brain, and lower limbs each in 1 patient). Bacteriology and Antimicrobial Resistance Testing Data are shown in Table 1. Four patients had infection caused by Abiotrophia defectiva and 4 patients had infection caused by Granulicatella adiacens. Seven isolates were sensitive to penicillin and one isolate was intermediately resistant to penicillin. Medical Treatment All cases were treated with penicillin and gentamicin initially, and only 3 of them (patients 1, 3, and 7) were successfully treated (Table 2). One 30-yearold male patient (patient 7) had infective endocarditis caused by G. adiacen, which was complicated by a ruptured mycotic cerebral aneurysm with an intracerebral hemorrhage at the left fronto-parietal region. Antibiotic treatment was shifted to ceftriaxone because of skin allergy. He underwent mitral valve repair for severe mitral regurgitation 2 months later. Surgery was delayed because of cerebral hemorrhage. Antibiotic regimens were shifted to vancomycin, teicoplanin, or cefotaxime in 2 cases because of poor therapeutic responses. One 12-year-old girl (patient 2) with no underlying heart disease had mitral infective endocarditis caused by A. defectiva. This orOctober 2007 Volume 334 Number 4
Lin and Hsu
Table 2. Clinical Outcomes of Infective Endocarditis Caused by NVS Time of Surgery
Indication of Surgery
P, G
Late 7 months
None None
V, G, T, R, Cefo P, G
None Late 2 months
4
Heart failure
P, G, Ceft
Early 1 day
Sever mitral regurgitation None Severe mitral regurgitation Heart failure
5
Heart failure
P, G
Early 7 days
Heart failure
6
Heart failure
P, G
Early 44 days
Heart failure
7
Ruptured cerebral mycotic aneurysms Heart failure, limb embolization
P, G, Ceft
Late 4 months
Severe mitral regurgitation
P, G, V, T
Early 21 days
Heart failure
No.
Complications
1
Splenic infarction
2 3
8
Medical Treatment
Operative Procedure
Outcome
Mitral valve repair
No relapse
None Mitral valve repair
No relapse No relapse
Aortic valve replacement with mechanical valve Mitral valve replacement with mechanical valve Mitral and tricuspid valve replacement with bioprosthesis Mitral valve repair
No relapse
Aortic and mitral valve replacement with bioprosthesis
No relapse No relapse No relapse No relapse
NVS, Nutritionally variant streptococci; P, Penicillin; G, Gentamicin; V, Vancomycin; T, Teicoplanin; R, Rifampin; Cefo, cefotaxime; Ceft, ceftriaxone.
ganism was susceptible to ampicillin with an MIC of 0.19 g/mL by E-test. The MICs of vancomycin, cefotaxime and rifampin were 1.5, 1 and 0.016 g/ mL, respectively. Vancomycin and gentamicin were used, and the fever subsided gradually. The follow-up echocardiography 1 week later showed a decrease in the size of the vegetation. However, fever flared up on the 10th day, and the antibiotics were changed to ampicillin and teicoplanin because of the suspicion of drug fever. Five blood cultures taken 5 days later were sterile. Blood examination revealed eosinophilia. The vegetation size steadily decreased. The antibiotic regimen was shifted to ampicillin and gentamicin for 2 weeks and finally to cefotaxime and rifampin for another 4 weeks. She was discharged after an 8-week course of treatment in stable condition. Echocardiography at discharge showed only small vegetation on the anterior leaflet of the mitral valve. She remained well on outpatient follow-up for 69 months. One 28-year-old woman (patient 8) with nephrotic syndrome had mitral and aortic valve infective endocarditis caused by G. adiacens. Penicillin and gentamicin were used initially, and the fever subsided gradually. However, fever flared up on the 11th day, and the antibiotics were shifted to vancomycin and then teicoplanin because of persistent fever. Blood cultures taken then were sterile. The follow-up echocardiography showed an increase in the size of the vegetation and severe valve regurgitation. She underwent aortic and mitral valve replacement on the 21st day because of severe heart failure. The valve culture was negative. She remained well on outpatient follow-up for 130 months. Surgical Treatment As shown in Table 2, a total of 7 patients underwent surgery. Four patients (patients 4, 5, 8, and 6) THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
underwent early surgery because of severe heart failure at the time of 1, 7, 21, and 44 days after the diagnosis of infective endocarditis. One 49-yearold diabetic male (patient 4) with no underlying heart disease had aortic infective endocarditis and severe aortic regurgitation. He was treated as respiratory tract infection with oral antibiotic at outpatient clinic. He was brought to emergency department because of severe heart failure. Penicillin and gentamicin were used empirically. He underwent emergency aortic valve replacement on the first day. Blood culture was A. defectiva. This organism was penicillin resistant and with a penicillin MIC of 0.032 g/mL by E-test. The antibiotic regimen was shifted to ceftriaxone for 6 weeks after operation. The valve culture was negative. He remained well on outpatient follow-up for 5 months. All of 4 patients with early surgery underwent valve replacement because of large vegetations and extensive valve destruction. Two patients had mechanical heart valves, and 2 patients had bioprosthesis. The valve cultures were negative in these 4 patients. Among 4 patients with successful antibiotic treatment, 3 patients underwent mitral valve repair successfully at the time of 2, 4, and 7 months after the diagnosis of infective endocarditis because of severe mitral regurgitation. Operation consisted of quadrangular resection of torn leaflets and annular plication. In summary, 7 of these 8 patients underwent surgical intervention because of complications caused by infective endocarditis. There was no mortality or morbidity. Overall, all of our patients were treated successfully with penicillin or other beta-lactams plus gentamicin or a glycopeptide for 4 to 8 weeks, and there was no relapse. A total of 7 patients underwent 237
NVS Endocarditis
surgery and the valve cultures were negative. The bacteriologic failure rate was zero in our series. The median follow-up duration was 63 months (range, 4 to 130). Discussion Nutritionally Variant Streptococci NVS were originally described in 1961 by Frenkle and Hirsch16 as a new type of viridans group streptococci because of a characteristic growth requirement, prolonged incubation period, satellite-promoting phenomenon, pleomorphic morphotypes, and variable Gram stain findings. In 1989, Bouvet et al17 performed a DNA-DNA hybridization that divided the NVS into 2 species, Streptococcus adjacens and Streptococcus defectiva. In 1995, using the 16S rRNA gene sequencing NVS, Kawamura et al18 proposed a new genus, Abiotrophia, for the NVS and included 4 species (A. defectiva, A. adiacens, A. balaenopterae, and A. elegans). In 2000, on the basis of 16S rRNA tree topology and sequence divergence considerations, Collins and Lawson11 further proposed a new genus, Granulicatella, to reclassify A. adiacens, A. balaenopterae, and A. elegans as G. adiacens, G. balaenopterae, and G. elegans, respectively. In Taiwan, the first case of human NVS infection occurred in 1996.19 The increasing awareness of laboratory staff members to these organisms and improved laboratory procedures permit more accurate identification of NVS.19 In this series of 8 endocarditis caused by NVS, 4 patients had infection caused by A. defectiva and 4 patients had infection caused by G. adiacens. No patient had infection caused by other NVS. Endocarditis More than 100 cases of NVS endocarditis have been reported in the literature.1–9 NVS strains are part of the normal oral, intestinal and genitourinary flora. The portal of entry in most cases of endocarditis is via the mouth, teeth or throat. NVS cause approximately 3% to 5% of cases of streptococcal infective endocarditis. However, this figure is probably an underestimation, because NVS is a fastidious organism and might fail to grow on the initial subculture. Identification based on phenotypic method scan result in misidentification of the pathogen. They are likely to be responsible for some culture-negative infective endocarditis.20 Molecular methods were used to improve the detection and facilitate the identification.18 In our previous report,21 3% of cases of streptococcal endocarditis were caused by NVS in our hospital. NVS endocarditis is associated with significantly higher morbidity and mortality than that caused by viridans streptococci or enterococci.1– 6 Multiple factors contribute to the virulence of NVS. First, NVS produce exopolysaccharide and have high binding capacity for fibronectin and extracellular matrix 238
components.20 Second, the generation time for NVS (2 to 3 hours) being slower than that of viridans streptococci (40 to 50 minutes) may attenuate the effect of the beta-lactam antibiotics.20 In a literature review of 30 cases of infective endocarditis caused by NVS strains, Stein and Nelson1 reported that this infection was difficult to treat and had a poor outcome. Embolization occurred in 27%, relapse after therapy occurred in 17%, and death occurred in 17% of these patients. In addition, bacteriologic failure occurred in 41% of cases, despite sensitivity of the organisms to the antibiotics used in the majority of these cases. Surgery was required in 38% of the cases reviewed. In this current series, NVS endocarditis was associated with high rate of complications and operation was indicated in the majority of cases. However, in contrast to previous reports in old times,1– 6 there was no mortality and no relapse in our patients and this result was similar to the more recent case reports.7–9 Because there was no relapse and the valve culture was negative at surgery, the bacteriologic failure rate in this series was zero. Combined medical and surgical treatment in infective endocarditis caused by NVS had a favorable outcome in this study. Antibiotic treatment with penicillin and gentamicin had a high rate of success. Early surgical intervention should be considered in those patients with deteriorating heart failure due to valve destruction.22 This study was limited by small case number and retrospective study. However, this study is a singlecenter experience and one of the largest series of NVS infective endocarditis ever reported in the literature. In conclusion, antibiotic treatment with penicillin and gentamicin had a high rate of success in patients with infective endocarditis caused by NVS. Early surgical intervention should be considered in those patients with deteriorating heart failure due to valve destruction. References 1. Stein DS, Nelson KE. Endocarditis due to nutritionally deficient streptococci: therapeutic dilemma. Rev Infect Dis 1987;9:908–16. 2. Bouvet A. Human endocarditis due to nutritionally variant streptococci: streptococcus adjacens and Streptococcus defectivus. Eur Heart J 1995;16:S24–7. 3. Christensen JJ, Gruhn N, Facklam RR. Endocarditis caused by Abiotrophia species. Scand J Infect Dis 1999;31: 210–2. 4. Wijetunga M, Bello E, Schatz I. Abiotrophia endocarditis: a case report and review of literature. Hawaii Med J 2002; 61:10–2. 5. Chang HH, Lu CY, Hsueh PR, et al. Endocarditis caused by Abiotrophia defectiva in children. Pediatr Infect Dis J 2002;21:697–700. 6. Sharaf MA, Shaikh N. Abiotrophia endocarditis: case report and review of the literature. Can J Cardiol 2005;21:1309–11.
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7. Lainscak M, Lejko-Zupanc T, Strumblj I, et al. Infective endocarditis due to Abiotrophia defectiva: a report of two cases. J Heart Valve Dis 2005;14:33–6. 8. Jeng A, Chen J, Katsivas T. Prosthetic valve endocarditis from Granulicatella adiacens (nutritionally variant streptococcus). J Infect 2005;51:125–9. 9. Yemisen M, Koksal F, Mete B, et al. Abiotrophia defectiva: a rare cause of infective endocarditis. Scan J Infect Dis 2006;38:939–41. 10. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633–8. 11. Collins MD, Lawson PA. The genus Abiotrophia (Kawamura et al) is not monophyletic: proposal of Granulicatella gen. nov., Granulicatella adiacens comb. nov., Granulicatella elegans comb. nov. and Granulicatella balaenopterae comb. nov. Int J Syst Evol Microbiol 2000;50:365–9. 12. Christensen JJ, Facklam RR. Granulicatella and Abiotrophia species from human clinical specimens. J Clin Microbiol 2001;39:3520–3. 13. Roggenkamp A, Leitritz L, Baus K, et al. PCR for detection and identification of Abiotrophia spp. J Clin Microbiol 1998;36:2844–6. 14. National Committee for Clinical Laboratory Standards (NCCLS). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standardsfifth edition. M7-A5. Wayne, PA; NCCLS, 2003.
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15. National Committee for Clinical Laboratory Standards (NCCLS). Performance standards for antimicrobial susceptibility testing: thirteenth informational supplement. M100S13. Wayne, PA: NCCLS, 2003. 16. Frenkel A, Hirsch W. Spontaneous development of L forms of streptococci requiring secretions of other bacteria or sulfhydryl compounds for normal growth. Nature 1961;191:728–30. 17. Bouvet A, Grimont F, Grimont PAD. Streptococcus defectivus sp. nov. and Streptococcus adjacens sp. nov., nutritionally variant streptococci from human clinical specimens. Int J Syst Bacteriol 1989;39:290–4. 18. Kawamura Y, Hou XG, Sultana F, et al. Transfer of Streptococcus adjacens and Streptococcus defectivus to Abiotrophia gen. nov. as Abiotrophia adiacens comb. nov. and Abiotrophia defectiva comb. nov., respectively. Int J Syst Bacteriol 1995;45: 798–803. 19. Liao CH, Teng LJ, Hsueh PR, et al. Nutritionally variant streptococcal infections at a University Hospital in Taiwan: disease emergence and high prevalence of beta-lactam and macrolide resistance. Clin Infect Dis 2004;38:452–5. 20. Rouff KL. Nutritionally variant streptococci. Clin Microbiol Rev 1991;4:184–90. 21. Hsu RB, Lin FY. Effect of penicillin resistance on presentation and outcome of nonenterococcal streptococcal infective endocarditis. Cardiology 2006;105:234–9. 22. Al-Jasser AM, Enani MA. Al-Faqih. Endocarditis caused by Abiotrophia defectiva. Libyan J Med, AOP: 061223.
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