Culture results of heart valves resected because of streptococcal endocarditis: insights into duration of treatment to achieve valve sterilization

Arlo Upton1, Dragana Drinkovic1, Sudha Pottumarthy1, Teena West2 and Arthur J. Morris1,3,*

Departments of 1 Clinical Microbiology and 2 Biostatistics, Auckland District Health Board, Auckland, and 3 Microbiology Laboratory, Diagnostic Medlab, Panmure, PO Box 14743, Auckland, New Zealand


* Corresponding author. Tel: +649-571-4093; Fax: +649-571-4091; Email: amorris{at}dml.co.nz

Received 15 September 2004; returned 19 October 2004; revised 31 October 2004; accepted 9 November 2004


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives:

To analyse the culture results of heart valves removed following streptococcal endocarditis in order to gain insight into the duration of treatment required for valve sterilization.

Patients and methods:

Retrospective review of 131 episodes of streptococcal endocarditis: 94 due to {alpha}-haemolytic streptococci; 15 due to ß-haemolytic streptococci; 10 due to nutritionally deficient streptococci; eight due to the Streptococcus anginosus group and four due to Streptococcus pneumoniae. Patients had their valves removed during antimicrobial treatment. Culture results were analysed with respect to duration of treatment before surgery.

Results:

For {alpha}-haemolytic streptococci, 17 (18%) valves were culture-positive and 77 (82%) culture-negative after a median (range) of 4 (1–20) and 16 (4–58) days of treatment, respectively, P < 0.001. For ß-haemolytic streptococci, two valves (13%) were culture-positive; both patients had received ≤4 days of treatment. Four patients (40%) with nutritionally deficient streptococci were culture-positive, and had received ≤8 days of treatment. For the S. anginosus group, two valves (25%) were culture-positive; both patients had received ≤4 days of treatment before operation. Overall, only one of 131 (0.8%) valves was culture-positive after 14 days of treatment. All valves infected with ß-haemolytic streptococci, nutritionally deficient streptococci and the S. anginosus group, who were treated for more than 8 days before surgery, were culture-negative.

Conclusions:

Our findings support current treatment guidelines for endocarditis caused by {alpha}-haemolytic streptococci. We suggest that the recommended duration of treatment for endocarditis resulting from other streptococci may be excessive and treatment trials evaluating 2 and 4 week regimens are justified.

Keywords: {alpha}-haemolytic streptococci , ß-haemolytic streptococci , Streptococcus anginosus , Streptococcus pneumoniae , surgery


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Guidelines for the medical treatment of bacterial endocarditis resulting from {alpha}-haemolytic streptococci and Streptococcus bovis are well established. For a fully susceptible isolate—penicillin MIC ≤ 0.125 mg/L—an uncomplicated native valve endocarditis (NVE) can be treated with either 4 weeks of benzylpenicillin or 2 weeks of penicillin and aminoglycoside.1,2 Where there is reduced susceptibility to penicillin (MIC > 0.125 mg/L) British guidelines suggest 4 weeks of penicillin and aminoglycoside,1 whereas the American Heart Association suggests 4 weeks of penicillin with an aminoglycoside for the first 2 weeks of therapy.2 Recommended treatment for prosthetic valve endocarditis (PVE) is 6 weeks of penicillin with an aminoglycoside for the first 2 weeks.1,2

In contrast, there are no specific recommendations for the treatment of endocarditis resulting from ß-haemolytic streptococci, the Streptococcus anginosus (formerly Streptococcus milleri) group or Streptococcus pneumoniae. Most authors recommend 4–6 weeks of penicillin. Some recommend the addition of an aminoglycoside for the first 2 weeks, particularly for Lancefield groups B, C and G, for which the penicillin MICs can be higher than for Streptococcus pyogenes.25 Endocarditis caused by the S. anginosus group is rare and large series are lacking. Most cases reported in the literature have been treated with 4–6 weeks of penicillin with or without an initial 2 weeks with an aminoglycoside.3,6

We have analysed valve culture results of patients undergoing valve-replacement surgery for streptococcal endocarditis, with respect to the duration of pre-operative antibiotic treatment, to gain insight into the duration of antibiotic treatment required for valve sterilization.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients

Green Lane Hospital's cardiothoracic unit serves ~1 million people. All patients undergoing valve-replacement surgery in the period September 1963–December 1999 who had endocarditis recorded as the cause of their valve dysfunction had their charts retrospectively reviewed.7,8 Data pertaining to the number of blood cultures taken, organism(s) isolated, duration and type of antibiotic treatment received before surgery, indication(s) for surgery, operative findings and histopathologic and culture results of the resected valve, were collected. All patients received their first dose of surgical prophylaxis immediately before their operation. For most patients, this was either cefradine, or more recently cefazolin.

Patients received standard doses of intravenous antibiotics, with appropriate adjustments for renal impairment. Doses and combination treatment followed those recommended in commonly used guidelines, e.g. 1.2–1.8 g penicillin G every 4 h, amoxicillin 2 g every 4 h, gentamicin 1 mg/kg every 8 h.1,2 Blood cultures and resected valves were processed in the microbiology and histopathology laboratories, as previously described.7,8 Briefly, vegetations were ground up in 0.5 mL of broth, and both solid and liquid media inoculated. Four liquid media (20 mL each) were used: Sabouraud dextrose broth; biphasic brain heart infusion broth with a nutrient agar slope; hypertonic blood culture media containing 10% sucrose; and anaerobic thioglycollate broth. Broths were inspected daily for 7 days, and then subcultured when growth was suspected, or routinely subcultured after 7 days. This extensive culture procedure was used to provide a range of conditions to recover infecting organisms and provide a dilution effect to counter any antibiotic in the specimen. Penicillin MIC determinations were performed by either broth dilutions following NCCLS methodology, or the Etest (AB Biodisk, Sweden) and interpreted according to NCCLS criteria. {alpha}-Haemolytic streptococci breakpoints were used for {alpha}-haemolytic streptococci, ß-haemolytic streptococci and the S. anginosus group (MIC ≤ 0.125 mg/L=susceptible, > 0.125 mg/L=non-susceptible), and S. pneumoniae breakpoints for S. pneumoniae (MIC ≤ 0.06 mg/L=susceptible, 0.12–1.0 mg/L=intermediate, > 1.0 mg/L=resistant).9

Definitions

The modified Duke criteria10 were used to define cases of endocarditis. In addition, a positive microbiology Gram stain was taken as definitive evidence of endocarditis.7 Combination antibiotic therapy was defined as the receipt of two or more antibiotics active against the streptococcal isolates, and as having the potential to act synergistically, simultaneously for at least 1 day.11 Continuous combination therapy was defined as receipt of two or more active antibiotics for the entire pre-operative period, and partial combination therapy was defined as receipt of two or more active antibiotics for a part of the pre-operative period. Combination therapy usually consisted of a ß-lactam with an aminoglycoside. Invasive disease was defined at operation by the presence of infection extending beyond the valve leaflets into the valve ring, or involvement of the sewing ring of a prosthetic valve.

Statistics

Data are presented as counts (percentages) and medians (ranges) unless otherwise stated. Differences across groups were compared using the Mann–Whitney U-test. Associations between a positive valve culture result and other baseline characteristics were examined with logistic regression (with positive/negative culture as the outcome measure). The results are reported as odds ratios and 95% confidence intervals. For ease of interpretation, continuous risk factors in the final models were expressed using categorical classifications, since it had been established that the results were not sensitive to continuous or categorical expression. Where an established cut-point was not available, the upper quartile has been used. All analysis was performed using SAS statistical software, and a P value of 0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
One hundred and thirty-eight patients had streptococcal endocarditis. Seven patients were excluded because the excised valve was not cultured. Of the remaining 131 patients, 87 (66%) had NVE and 44 (34%) had PVE; 125 met the criteria for definite endocarditis, 122 (93%) by pathological criteria and three (2%) by clinical criteria, and six (5%) met the clinical criteria for possible endocarditis (Table 1). Sixty-nine percent of patients were male and the median age was 43 years (5–76).


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Table 1. Features of patients undergoing valve surgery for streptococcal endocarditis

 
When all patients were analysed together by univariate logistic regression analysis, invasive disease and duration of antibiotic therapy before surgery were found to be associated with a positive valve culture (Table 2).


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Table 2. Association between endocarditis, treatment type and positive valve culture result

 
{alpha}-Haemolytic streptococci

Ninety-four patients had endocarditis due to {alpha}-haemolytic streptococci, 59 (63%) had NVE, 19 had infected allografts, three had infected stented allografts, nine had infected mechanical and four had infected bio-prostheses. Sixty-six (70%) were male and the median age was 43 years (13–75). A penicillin MIC was available for 53 isolates; 48 (91%) were ≤ 0.125 mg/L. Forty-nine patients (52%) were treated with combination therapy (48 with a ß-lactam and an aminoglycoside and one with vancomycin and rifampicin), 14 (15%) with ß-lactam monotherapy, and 31 (33%) with partial combination therapy (29 with ß-lactam and aminoglycoside, and two with ß-lactam, aminoglycoside and vancomycin). Seventeen (18%) valves were culture-positive and 77 (82%) were culture-negative after a median of 4 (1–20) and 16 (4–58) days of antibiotic therapy, respectively (P < 0.001). Four of the culture-positive valves were native and had received between 10–20 days of combination therapy. By univariate logistic regression analysis, only antibiotic duration was associated with a positive valve culture (Table 3).


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Table 3. Association between endocarditis, treatment type and positive valve culture for {alpha}-haemolytic streptococci

 
ß-Haemolytic streptococci

Fifteen patients had endocarditis due to ß-haemolytic streptococci (Lancefield group A five; B four; G six). Twelve (80%) patients were male and the median age was 59 (8–76). Penicillin MICs were available for eight isolates and all were ≤ 0.016 mg/L. Twelve cases were NVE and three were PVE (mechanical two, porcine one). At excision, two valves were culture-positive (one each of group A and G) after 2 and 4 days of continuous combination antibiotic therapy with penicillin and gentamicin. Both were found to have extensive disease (intracardiac fistulae) at operation. The remaining 13 valves were culture-negative after a median of 15 (4–62) days treatment. Nine of the 13 (69%) culture-negative cases had received antibiotic treatment for < 28 days. Seven of 13 (54%) culture-negative patients had extensive disease seen intra-operatively. Of the 13 culture-negative patients, five were treated with monotherapy (ß-lactam, vancomycin and clindamycin) and the remaining eight were treated with partial combination (four) or continuous combination (four) therapy with a ß-lactam and aminoglycoside.

Nutritionally deficient streptococci

Ten patients had endocarditis due to nutritionally deficient streptococci (also known as nutritionally variant streptococci and currently named Abiotrophia and Granulicatella spp.). Seven patients were male (70%) and the median age was 33 years (18–71). Penicillin MICs were available for six isolates; two ≥ 0.25 mg/L and four ≤ 0.05 mg/L. Two isolates had penicillin MBCs recorded and both were 0.05 mg/L. Seven patients had NVE and three had PVE (one on a porcine valve and two on allograft valves). All patients were treated with combination therapy of penicillin or ampicillin/amoxicillin and an aminoglycoside for a median of 10 (1–17) days. Extensive infection was seen intra-operatively in three cases, and these three and one other were culture-positive after 1, 6, 7 and 8 days of combination treatment. Culture-negative cases had 9–17 days of pre-operative combination treatment.

S. anginosus group

Eight patients had endocarditis resulting from the S. anginosus group. Six patients were male (75%) and the median age was 45 years (18–76). Penicillin MICs were available for six isolates and all were ≤ 0.125 mg/L. All but one had native valve infection. Two of eight (25%) patients had culture-positive valves. One with PVE received 3 days of pre-operative penicillin; the other with NVE received 4 days of penicillin and gentamicin pre-operatively. Both had operative findings of infection beyond the valve (intracardiac fistulae). The remaining six patients had their valves excised between days 8 and 20 of antibiotic therapy and the valves were culture-negative. One had extensive disease seen intra-operatively. Three of the six were excised on days 8, 12 and 13. Six patients were treated pre-operatively with gentamicin (at least initially) in addition to penicillin and ceftriaxone in five cases and one case, respectively. One patient was treated with penicillin and another with cefuroxime monotherapy.

S. pneumoniae

Four patients had endocarditis due to S. pneumoniae; two on native valves. The median patient age was 29 years (5–51) and three were female. Penicillin MICs were available for two isolates and both were ≤ 0.01 mg/L. All valves were culture-negative after 3, 7, 10 and 23 days of treatment. Two patients were treated with continuous combination (3 and 10 days), one with partial combination therapy of a ß-lactam and aminoglycoside, and one with penicillin monotherapy. Invasive disease was seen on the two prosthetic valves but not on either native valve.

All episodes

For the 131 valves in our study, only one (0.8%) was culture-positive when excised after 14 days of antibiotic treatment. The patient had NVE due to S. sanguis (an {alpha}-haemolytic streptococcus), penicillin MIC = 0.03 mg/L, and was treated for 20 days with a combination therapy of penicillin and gentamicin. At operation, the infection was found to be extensive, involving both the mitral and aortic valves. Where endocarditis resulted from either ß-haemolytic streptococci, the S. anginosus group, S. pneumoniae or nutritionally deficient streptococci all valves removed after 8 days of antibiotic treatment were culture-negative (Figure 1).



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Figure 1. Duration of treatment before surgery and valve culture results for patients with streptococcal endocarditis. Crosses, culture-positive; open circles, culture-negative.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
{alpha}-Haemolytic streptococci account for 30%–40% of all infective endocarditis.7,12 In uncomplicated infection caused by penicillin-susceptible isolates, 2 weeks of continuous combination or 4 weeks of penicillin therapy has been shown to cure patients in > 95% of cases.13 Our data support these recommendations. Unfortunately, we do not have MIC data for all isolates and have not been able to assess the influence of penicillin non-susceptibility (MIC > 0.125 mg/L) on valve sterilization.

Endocarditis due to ß-haemolytic streptococci, particularly Lancefield groups B and G, is increasingly seen in the elderly where treatment is often medical only.35 These organisms appear to be more virulent than {alpha}-haemolytic streptococci and have an associated mortality of 21%–56%.35 We report on 15 patients with endocarditis due to ß-haemolytic streptococci. Only two valves were culture-positive, both were excised after less than a week of antibiotic therapy. The culture-negative valves were excised after 4–62 days of antibiotics and 69% of these were excised after receiving < 4 weeks of therapy. Unfortunately, we cannot know whether the four valves receiving 31–62 days treatment would have been culture-negative if excised after 4 weeks only. Lefort et al.3 report on 56 patients with endocarditis due to ß-haemolytic streptococci. They were treated with a median of 42 (3, 120) days of treatment (mostly a combination of ß-lactam and aminoglycoside) and 5% relapsed. The details of their treatment and whether or not they had NVE or PVE is not discussed. In contrast, other authors have reported short case series of S. pyogenes (Lancefield group A) endocarditis, where patients have been cured with between 2–6 weeks of antibiotic treatment.14,15 Studies of Streptococcus agalactiae (Lancefield group B) endocarditis report mortality to be ~50%, but do not mention relapse, presumably because it was not observed.4,5 In a more recent study of 31 cases of endocarditis caused by ß-haemolytic streptococci treated for at least 4 weeks (mean 5.9 weeks), no relapse was seen in the 16 patients for whom there were follow-up records available.16 We believe our data suggest that 4 weeks of ß-lactam with or without aminoglycoside for the first 2 weeks may be sufficient to cure uncomplicated NVE due to ß-haemolytic streptococci and we believe that a clinical trial of this is warranted.

Nutritionally deficient streptococci account for < 5% of infective endocarditis7,17 and penicillin MICs for these isolates are often > 0.125 mg/L.18 There is a case report of relapse following penicillin monotherapy despite a penicillin-susceptible isolate,19 and relapses following treatment with partial combination therapy (i.e. addition of aminoglycoside to a cell-wall active agent for the first 10–14 days of therapy).20,21 Most authorities recommend treating nutritionally deficient streptococcal endocarditis with 4–6 weeks of ß-lactam and aminoglycoside combination therapy.2 We found that the six patients (60%) treated with 9–17 days of continuous combination antibiotic therapy before valve excision had culture-negative valves and that all culture-positive valves were removed after 8 or fewer days of continuous combination therapy. As nutritionally deficient streptococci often exhibit penicillin tolerance22 penicillin MBCs might be more useful than MIC for predicting bacteriologic outcome and guiding the duration of antibiotic therapy. Unfortunately, MBCs were recorded for only two of our isolates, neither demonstrating penicillin tolerance. We suggest that uncomplicated NVE resulting from nutritionally deficient streptococci with penicillin MICs of ≤ 0.125 mg/L and not exhibiting tolerance (i.e. MBC ≥ 32 x MIC) could be treated with 4 weeks of continuous combination therapy. Clinicians might feel more comfortable with a shorter treatment course if synergy between penicillin and aminoglycoside has been demonstrated for the infecting streptococcal isolate in vitro.

Endocarditis due to the S. anginosus group is rare and clinical trials of length of treatment do not exist. Penicillin MICs are usually between 0.03–0.25 mg/L.2325 The S. anginosus group have a propensity for abscess formation, and limited studies suggest they cause a more aggressive form of endocarditis than other {alpha}-haemolytic streptococci with higher mortality (14%–33% versus 4%–16%).3,6,26 Most cases in the literature have received 4–6 weeks of ß-lactam antibiotic, usually with aminoglycoside for the first 2 weeks. Although our numbers are few, our results suggest that NVE due to the S. anginosus group for which the penicillin MIC is ≤ 0.125 mg/L could be treated with 4 weeks of ß-lactam, with aminoglycoside for the first 2 weeks. However, the largest published series that we are aware of (with 29 patients) of endocarditis due to the S. anginosus group reports a 10% relapse rate after treatment.3 The authors did not compare the treatment of patients who relapsed with those who did not, but do report that patients had a median duration of 50.5 days (21–120) of antibiotic therapy. Ninety-six percent had at least some combination therapy with aminoglycoside and 44% had surgery in the first month of treatment. Also, there is no comment on whether the patients who relapsed had NVE or PVE. All isolates were susceptible to amoxicillin.3 Other case series do not report relapse after 4–6 weeks of ß-lactam treatment with or without aminoglycoside.27,28 Casariego et al.28 report six patients with NVE due to the S. anginosus group. All isolates were penicillin-susceptible and three patients with uncomplicated infection were cured with 14 days of combination therapy. One patient died and the remaining two were cured after 28 and 30 days of penicillin monotherapy, and valvular surgery in one patient. We do not have sufficient data to support 2 weeks of combination therapy as only three of six culture-negative valves were excised after <14 days of therapy. A multicentre prospective study may provide a better indication of whether it is feasible to treat endocarditis due to the S. anginosus group with 4 weeks of partial combination or 2 weeks of continuous combination therapy.

We have too few patients with endocarditis due to S. pneumoniae to draw conclusions about appropriate length of treatment in this infection. S. pneumoniae accounts for 1%–3% of cases of infective endocarditis in the antibiotic era.29 It is typically an aggressive infection; cardiac and extra-cardiac sequelae are common and mortality is reported to be in the range 24%–63%.2931 Most reports in the literature have treated S. pneumoniae endocarditis with 4–6 weeks of a ß-lactam with or without an aminoglycoside for the first 2 weeks.2931

Although our paper is limited by its retrospective nature and the small numbers of patients in the non-{alpha}-haemolytic streptococcal groups, we believe it provides an insight into valve sterilization during antibiotic treatment. Of interest, when patients with endocarditis due to ß-haemolytic streptococci or the S. anginosus group were compared with those with endocarditis due to {alpha}-haemolytic streptococci, the infecting organism was not associated with a positive valve culture. We believe that clinical trials are needed to test our hypothesis that uncomplicated endocarditis due to a penicillin-susceptible strain of either ß-haemolytic streptococci or the S. anginosus group can be cured with 4 weeks of intravenous penicillin or with 2 weeks of combination treatment with penicillin and an aminoglycoside.


    Acknowledgements
 
Financial support for this study was provided by the Auckland Infectious Diseases Education and Research Trust.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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6 . Woo, P., Tse, H., Chan, K. et al. (2004). ‘Streptococcus milleri’ endocarditis caused by Streptococcus anginosus. Diagnostic Microbiology and Infectious Disease 48, 81–8.[CrossRef][ISI][Medline]

7 . Morris, A., Drinkovic, D., Pottumarthy, S. et al. (2003). Gram stain, culture, and histopathological examination findings for heart valves removed because of infective endocarditis. Clinical Infectious Diseases 36, 697–704.[CrossRef][ISI][Medline]

8 . Drinkovic, D., Morris, A., Pottumarthy, S. et al. (2003). Bacteriological outcome of combination versus single-agent treatment for staphylococcal endocarditis. Journal of Antimicrobial Chemotherapy 52, 820–5.[Abstract/Free Full Text]

9 . National Committee for Clinical Laboratory Standards. (2004). Performance Standards for Antimicrobial Susceptibility Testing: Fourteenth Informational Supplement M100-S14. NCCLS, Wayne, PA, USA.

10 . Li, J., Sexton, D., Mick, N. et al. (2000). Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clinical Infectious Diseases 30, 633–8.[CrossRef][ISI][Medline]

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12 . Bayer, A. & Scheld, W. (2000). Endocarditis and intravascular infections. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 5th edn (Mandell, G., Bennett, J. & Dolin, R., Eds), pp. 857–902. Churchill Livingston, Philadelphia, PA, USA.

13 . Wilson, W., Thompson, R., Wilkowske, C. et al. (1981). Short-term therapy for streptococcal infective endocarditis. Combined intramuscular administration of penicillin and streptomycin. Journal of the American Medical Association 245, 360–3.[Abstract]

14 . Burkert, T. & Watanakunakorn, C. (1991). Group A streptococcus endocarditis: report of five cases and review of literature. Journal of Infection 23, 307–16.[ISI][Medline]

15 . Ramirez, C., Naraqi, S. & McCulley, D. (1984). Group A ß-haemolytic streptococcus endocarditis. American Heart Journal 108, 1383–6.[ISI][Medline]

16 . Baddour, L. (1998). Infective endocarditis caused by ß-haemolytic streptococci. Clinical Infectious Diseases 26, 66–71.[ISI][Medline]

17 . Roberts, R., Krieger, A., Schiller, N. et al. (1979). Viridans streptococcal endocarditis: the role of various species, including pyridoxal-dependent streptococci. Reviews of Infectious Diseases 1, 955–66.[ISI][Medline]

18 . Gephart, J. & Washington, J. (1982). Antimicrobial susceptibilities of nutritionally variant streptococci. Journal of Infectious Diseases 146, 536–9.[ISI][Medline]

19 . Levine, J., Hanna, B. & Pollock, A. (1983). Penicillin sensitive nutritionally variant streptococcal endocarditis: relapse after penicillin therapy. American Journal of Medical Science 286, 31–6.

20 . Feder, H. & Olsen, N. (1980). Bacterial endocarditis caused by vitamin B6-dependent viridans group Streptococcus. Paediatrics 66, 309–12.[Abstract]

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23 . Bantar, C., Canigia, L., Relloso, S. et al. (1996). Species belonging to the ‘Streptococcus milleri’ group: antimicrobial susceptibility and comparative prevalence in significant clinical specimens. Journal of Clinical Microbiology 34, 2020–2.[Abstract]

24 . Tracy, M., Wanahita, A., Shuhatovich, Y. et al. (2001). Antibiotic susceptibilities of genetically characterized Streptococcus milleri group strains. Antimicrobial Agents and Chemotherapy 45, 1511–4.[Abstract/Free Full Text]

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27 . Singh, K., Morris, A., Lang, S. et al. (1988). Clinically significant Streptococcus anginosus (Streptococcus milleri) infections: a review of 186 cases. New Zealand Medical Journal 101, 813–6.[ISI][Medline]

28 . Casariego, E., Rodriguez, A., Corredoira, J. et al. (1996). Prospective study of Streptococcus milleri bacteraemia. European Journal of Clinical Microbiology and Infectious Diseases 15, 194–200.[ISI][Medline]

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