THE SPECIES OF VIRIDANS STREPTOCOCCI ASSOCIATED WITH MICROBIAL ENDOCARDITIS: INCIDENCE AND ANTIMICROBIAL SUSCEPTIBILITY RICHARD B. ROBERTS, M.D. AND (BY INVITATION) ARLENE G. KRIEGER, B.A. AND KATHARINE C. GROSS, M.S. NEW YORK
Since 1932, when The New York Hospital moved to its present site at York Avenue and 68th Street, 728 patients with microbial endocarditis have been seen at this institution. Streptococcal endocarditis has been observed in 536 or 74% of these patients. This clinical experience over the past 45 years has provided a basis for over thirty physicians to investigate various clinical and therapeutic modalities in this disease. The viridans streptococci, a heterogeneous group of organisms, are the most frequent cause of microbial endocarditis. Six species of human viridans streptococci were characterized by Colman and Williams in 1972.' These species include S. mitior, S. sanguis, S. milleri, S. salivarius, S. mutans and S. pneumoniae. Excluding S. pneumoniae, the other five species are considered oral streptococci because they normally inhabit the human oral cavity.2 Although S. bovis is a nonenterococcal group D streptococcus, it may be classified as a viridans streptococcus.3'4 This latter species is more commonly isolated from the gastrointestinal tract than from the oral cavity.5 Recently, the incidence of the various viridans streptococcal species in microbial endocarditis has been reported by two streptococcal reference laboratories.6'7 However, these frequencies may not be representative since the most difficult species such as S. mutans are usually referred to reference laboratories for identification.7 The studies reported herein describe the speciation of viridans streptococci isolated from consecutive patients with microbial endocarditis seen during 19441955 and 1970-1977 at The New York Hospital and compare the incidence and antimicrobial susceptibility patterns of these organisms. MATERIALS AND METHODS The criteria for selection of patients with microbial endocarditis were similar to those previously employed at this institution8 and include: (1) isolation of the same microorganism from two separate blood specimens From the Department of Medicine, Cornell University Medical College and the Laboratory of Microbiology, The New York Hospital-Cornell Medical Center, New York, New York. 36
SPECIES OF VIRIDANS STREPTOCOCCI
37
from a patient with a syndrome consistent with microbial endocarditis, (2) isolation of a microorganism from a single blood culture during life, in addition to autopsy confirmation of the diagnosis, or (3) isolation of a microorganism from vegetations at autopsy in addition to presence of microorganisms on microscopic examination of the vegetation. Isolates from patients with microbial endocarditis were identified as streptococci on the basis of gram stain, colonial morphology and catalase reaction. Initial classification was based on hemolysis on sheep blood agar plate (SBAP, 5% sheep blood in Trypticase-Soy agar base, BBL) and esculin hydrolysis in the presence of 40% bile (bile-esculin agar slant [BE, Difco], without horse serum.9). Viridans streptococcal isolates were then speciated by a modification of the battery of tests described by Colman and Williams' (Table I). These tests include: (1) hemolysis on sheep blood agar, (2) hydrolysis of bile-esculin, esculin, arginine and starch, (3) growth in 6.5% NaCl broth and at 45°C, (4) fermentation patterns employing eleven sugars, (5) the production of acetoin from glucose, and (6) the production of polysaccharide (either dextran or levan) from 5% sucrose. To prepare inocula for differential media, growth from an 18 hour SBAP culture was removed with a sterile cotton swab and transferred to a tube containing 3 ml sterile saline. Turbidity was approximately equal to that of an overnight broth culture in Todd-Hewitt broth (THB, Difco) or approximately 109 colony forming units per ml. One tenth ml was added to all test media as well as SBAP to verify purity and incubated aerobically at 35°C. Preparation of certain differential media has been described previously.10 In addition, ability to hydrolyse esculin was determined on a Trypicase Soy Agar (BBL) slant containing 0.1% Esculin (Difco) and 0.05% ferric citrate. Arginine hydrolysis was tested in decarboxylase base Moeller (Difco) broth with 0.5% L-arginine hydroxide (Sigma) and overlaid with sterile mineral oil. Production of acetoin (acetyl-methylcarbinol) from glucose was detected by testing for the Voges-Proskauer reaction after 24 to 48 hours incubation in broth containing 1% Tryptone, 0.5% yeast extract, 0.5% K2HPO4, 0.5% NaCl and 0.2% glucose to which an additional 0.5% glucose was added aseptically after autoclaving. The 5% sucrose broth for determining the production of dextran was prepared according to Carlsson" and the production of levan was demonstrated on Mitis-Salivarius Agar (Difco). Preparation of media supplemented with 0.001% pyridoxal hydrochloride for the isolation and identification of vitamin B6-dependent streptococci has been described previously.12 Methods for the identification of S. bovis isolates have been reported previously.10 The minimum inhibitory concentration (MIC) of penicillin G and streptomycin was determined
38
ROBERTS ET AL.
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by the standard two-fold broth dilution technique. Antimicrobial susceptibility to erythromycin was determined by the standard disc diffusion method.'3 RESULTS AND DISCUSSION Yearly Incidence of Microbial Endocarditis. Previous studies from this institution suggested that the incidence of microbial endocarditis was declining during the time period 1944-1960 when compared to 19331944 due in part to the use of antibiotics.8 However, as shown in Figure 1, the incidence during the past eight years, i.e. 1970-1977, parallels that between 1932-1944 and appears to be increasing. Indeed, we now see approximately 27 patients with microbial endocarditis yearly compared to 12-14 patients in previous years. This apparent increase in incidence is due in part to the relative new entities of microbial endocarditis in heroin addicts and patients with prosthetic valves in which staphylococci and fungi are frequently seen (see below). Incidence of Etiologic Organisms in Microbial Endocarditis. The causative organisms in 216 patients with 219 episodes of microbial endocarditis at The New York Hospital from 1970-1977 are listed in Table II. Streptococci and staphylococci have accounted for 83% of cases; the remaining are caused by various microorganisms. S. epidermidis 1.2
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Year FIG. 1. The incidence of microbial endocarditis expressed as the number of cases per 1,000 admissions to The New York Hospital for the time periods 1933-1944, 1945-1960 and 1970-1977. The lines shown pass through the mean year and mean case rate for each period. The former two periods were previously reported by Kaye et al.8
40
ROBERTS ET AL.
TABLE II
Causative Organisms in 216 Patients with 219 Episodes of Microbial Endocarditis. The New York Hospital, 1970-1977 Organisn
Number
128 Streptococci Viridans streptococci 108 S. faecalis*t 15 2 ,8 hemolytic streptococci 2 S. pneumoniae Staphylococci 56 32 S. aureus 24 S. epidermidis Diphtheroids 7 Hemophilus species 5 (H. parainfluenzae, H. aphrophilus, Actinobacillus) 4 Gram negative bacilli (E. coli, P. vulgaris, S. marcescens, S. cholerae-suis) Fungi 9 5 Candida species 3 Aspergillus species** 1 Scopulariopsis 4 Miscellaneous (B. cereus, N. sicca, Citrobacter,* Micrococcus**) 7 Culture-negative *' ** Both organisms isolated from the same patient. t Organisms associated with repeated episodes of endocarditis.
%
58
25
3 2 2 4
2
3
and diphtheroids are most frequently seen in prosthetic valve patients." Fungi have been observed in these patients as well as in heroin addicts. Polymicrobial endocarditis and recurrent episodes of endocarditis have been relatively uncommon, the former seen only in patients with prosthetic valves or in heroin addicts. Culture-negative endocarditis accounted for only 3% of endocarditis. This low incidence when compared to other reports 5 16 is due in large part to the media and isolation procedures employed in our diagnostic laboratory. Indeed, some bacteria, i.e. Hemophilus species, have grown only in beef heart infusion broth which is prepared weekly at The New York Hospital.17 Incidence of Streptococcal Endocarditis. The incidence and relative frequency of streptococcal endocarditis at The New York Hospital since 1932 are shown in Table III. Whereas in prior years, streptococci were responsible for 84-88% of microbial endocarditis, these organisms have been isolated from 58% of patients since 1970. Although the relative frequency of streptococcal endocarditis has declined in recent years, the yearly incidence has increased; 16 patients have been seen annually
SPECIES OF VIRIDANS STREPTOCOCCI
41
since 1970 compared to a yearly incidence of 10 patients during the two previous time periods. Viridans streptococci have accounted for 49% of recent microbial endocarditis compared to 70-73% (including the lactis group) prior to 1970. This relative frequency has also been noted by others. 15, 16. 18 19 Although a significant increase in enterococcal endocarditis had been noted previously (2 to 10% from 1932-1943 to 1944-1960), enterococci have been responsible for only 7% of cases in recent years. The question occurs, however, whether previous isolates may have included both S. faecalis and S. bovis. Speciation of Viridans Streptococci. In the past, the viridans streptococci have been identified in many diagnostic laboratories by the type of hemolysis they produce on blood agar. Since these organisms are most commonly associated with microbial endocarditis, speciation of the viridans streptococci was performed in order to determine the relative frequency, antimicrobial susceptibility and clinical characteristics that might be associated with each species. Ninety-eight of the 108 isolates from endocarditis patients seen from 1970-1977 were speciated. In addition, through the foresight and interest of Drs. Ralph Tompsett and Walsh McDermott, viridans streptococcal isolates from 105 consecutive patients with endocarditis seen between 1944 and 1955 had been freezedried; 92 or 88% of these isolates were reconstituted and available for speciation. As shown in Table I, the six species (excluding S. pneumoniae) have, except for rare exceptions, the following characteristics in common: no growth in 6.5% NaCl and the ability to ferment lactose and sucrose but not pyruvate, arabinose or sorbose. With the exception of the strong positive reaction of S. bovis and the variable positive reactions of S. milleri and S. mutans, bile esculin medium is usually negative after overnight incubation because of the failure of the other species to grow TABLE III The Incidence and Relative Frequency of Streptococcal Endocarditis at The New York Hospital 1932-1943 1944-1960 1970-1977 Organism (210 patients) (216 patients) (173 patients) Streptococci 88% 84% 58% Viridans streptococci 73% 70% 49% S. faecalis 10 2 7 5 ,8 hemolytic streptococci 3 1 S. pneumoniae 8 1 1 Staphylococci 7 10 25 S. aureus 5 9 14 S. epidermidis 2 1 11 Miscellaneous 6 6 14 Culture-negative 3
42
ROBERTS ET AL.
in 40% bile. Each species, however, has certain distinctive characteristics. The two alpha hemolytic species (S. mitior and S. sanguis) differ in that S. sanguis hydrolyses esculin and arginine whereas S. mitior does not. In addition, S. sanguis ferments inulin and salicin while S. mitior is usually negative. The other species are usually non-hemolytic. S. milleri (synonyms include Streptococcus MG, S. anginosus, Peptostreptococcus intermedius) which may also produce alpha or beta hemolysis, is considered microaerophilic in that growth is enhanced by carbon dioxide or in some instances by anaerobiosis. Although its biochemical reactions resemble S. sanguis, S. milleri does not ferment inulin and produces acetoin from glucose. S. salivarius and S. mutans hydrolyse esculin but not arginine. They may be differentiated by their colonial morphology on agar (S. mutans produces a pinpoint adherent colony) and the ability of S. mutans to ferment mannitol and sorbitol. S. mutans is also microaerophilic. S. salivarius produces levan whereas S. mutans produces dextran which is deposited on the wall of the tube containing 5% sucrose broth. S. bovis may be differentiated from the other species by its strong bile-esculin reaction, and its ability to hydrolyse starch and grow at 45°C. Endocarditis isolates of this species usually ferment mannitol.'0 Using these tests, only 4 of 190 isolates (2%) could not be classified into one of the six species. The relative frequency of the viridans streptococcal species in microbial endocarditis during the different time periods is shown in Table IV. S. mitior and S. sanguis were most frequently observed in both study periods, a finding also reported by both reference laboratories.6'7 S. milleri, S. salivarius and S. mutans were infrequently associated with endocarditis. The first organism, however, (S. milleri) has been associated with a high incidence of suppurative complications.20 Recently, we have described viridans streptococci which require an excess of pyridoxal hydrochloride for growth. 2 17 These pyridoxal-dependent streptococci are probably similar to the satelliting streptococci reported by others.21'22 In our hands, these nutritional variants most closely resemble S. mitior, although they do ferment inulin. Definitive identification, however, will depend on the failure of detecting rhamnose in the cell walls of these organisms.3 Pyridoxal-dependent streptococci, which do not grow in many of the commercial media employed for blood cultures, were responsible for 5-6% of viridans streptococcal isolates in both series. Two additional isolates which satellited other organisms were not speciated because they could not be reconstituted from stock cultures. S. bovis accounted for only 5% of viridans streptococcal isolates during 1944-1955 but for 28% in recent years. This significant increase in incidence may be due in part to the difference in age of patients who
43
SPECIES OF VIRIDANS STREPTOCOCCI
TABLE IV Species of Viridans Streptococci Associated with Microbial Endocarditis 1970-1977**
1944-1955*
Species
S. mitior Vitamin B6 dependent S. sanguis S. milleri S. salivarius S. mutans S. bovis Unclassified * 92 of 105 isolates were speciated. ** 98 of 108 isolates were speciated.
Number 29
6 41 4 2 3 4 3
%
Number
%
32 6 44 5 2 3 5 3
28 5 25 3 1 7 28 1
28 5 25 3 1 7 28 1
develop endocarditis. Previous studies from this institution have reported an increase in age of female and male patients with viridans streptococcal endocarditis during 1944-1960 as compared to 19321943.8 The mean age of patients with viridans streptococcal endocarditis from 1970-1977 was 53 years (51 years for females and 54 years for males). However, an even greater discrepancy in age was observed when patients with S. bovis endocarditis were compared to those with other forms of viridans streptococcal endocarditis. The range of ages of patients with S. bovis endocarditis was 47 to 92 years with a mean of 67 years. Indeed, 22 of 28 patients or 79% were over 60 years of age. No difference was noted between males and females (mean of 66 and 68 years respectively). The range of ages for endocarditis patients infected with the other five species was 6-88 years with a mean of 48 years (45 years for females and 50 years for males). Furthermore, only 25 of 77 patients, or 32%, were over 60 years of age. Except for patients with S. milleri endocarditis, no difference was noted in age amongst patients with endocarditis due to the other species of viridans streptococci (mean 46-52 years). The observation that S. bovis endocarditis occurs in the elderly population has also been noted by Parker and Ball.6 This finding may also be related to the high incidence of lower gastrointestinal malignancies in these patients.23' 24 Antimicrobial Susceptibility of Viridans Streptococci and Species. Previous reports from The New York Hospital have shown that, despite the widespread use of antibiotics, penicillin susceptibility of viridans streptococci associated with endocarditis has remained the same.8'25 A comparison of those findings with more recent observations is shown in Figure 2. Of the 98 isolates examined since 1970, only 17% were resistant to penicillin G (MIC > 0.1 unit per ml) compared to 18% resistant from 1944 to 1951 and 20% from 1952 to 1960.
44
ROBERTS ET AL.
The ranges of penicillin suceptibility for each viridans streptococcal species during 1944-1955 and 1970-1977 are shown in Table V. The cumulative percent of strains resistant to penicillin (MIC > 0.1 ,ug per ml) for each species was as follows: S. mitior, 11%, S. sangius, 9%, S. milleri, S. salivarius and S. mutans combined, 5%, and S. bovis, 25%. Whereas all S. mitior isolates were sensitive during the early time period, 21% were resistant in recent years. S. sanguis isolates on the other hand were more resistant during 1944-1955 than 1970-1977 (12% Penclin
Of viridons
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SPECIES OF VIRIDANS STREPTOCOCCI
45
TABLE V Ranges ofPenicillin G Susceptibility of Viridans Streptococcal Species 1944-1955 1970-1977 Species MIC MIC* Number Number S. mitior 0.012-0.10 28 0.012-3.10 29 0.012-0.05 5 0.025-1.60 Vitamin B6f dependent 6 S. sanguis 0.012-0.40 25 0.005-0.40 41 4 0.050-0.10 3 S. milleri 0.025-0.10 S. salivarius 0.100-0.80 1 2 0.050 S. mutans 0.025-0.05 7 0.012-0.10 3 S. bovis 0.025-0.10 28 0.050-0.40 4 * MIC -minimum inhibitory concentration (,ug per ml)
versus 4%). Although the first two vitamin B6-dependent streptococcal strains isolated from our patients with endocarditis were resistant to penicillin,17 examination of additional strains has shown that only 18% (two of eleven isolates) are resistant, an incidence similar to all viridans streptococci. S. bovis has recently been considered a sensitive group D streptococcus.2628 However, 25% of strains were resistant to penicillin, the highest percentage of all the viridans streptococcal species. These findings further emphasize the importance of determining the penicillin susceptibility of all species to ensure the administration of appropriate antimicrobial therapy. During the past year, we have detected three viridans streptococcal isolates from patients with endocarditis that were resistant by disc sensitivity testing to erythromycin. These are the first isolates resistant to erythromycin since 1971 when we initiated sensitivity testing to this antibiotic for all streptococci isolated from blood cultures. Over this period, 3 of 62 viridans streptococci (5%), none of 21 S. bovis isolates and 6 of 9 S. faecalis isolates (66%) have been resistant to erythromycin. The resistant isolates were speciated as S. mitior, S. mitior variant (vitamin B6-dependent streptococcus) and S. sanguis. A review of the clinical histories revealed that in each instance, erythromycin had been administered in the recent past. In one patient, erythromycin had been given both orally and parenterally for eleven weeks for viridans streptococcal endocarditis because the original isolate was sensitive to erythromycin and the patient allergic to penicillin. In the other two patients, erythromycin had been given for 10 to 14 days for upper respiratory tract infections in addition to dental prophylaxis in one of these patients. The development of erythromycin resistance by oral human viridans streptococci in patients receiving clindamycin has been reported previously.29 These preliminary observations suggest that in penicillin-allergic patients with underlying heart disease, erythromycin should be reserved for those situations requiring dental prophylaxis and not be used in other clinical settings.
46
ROBERTS ET AL.
SUMMARY Streptococcal endocarditis has been well recognized for decades and over the years investigators at The New York Hospital have defined many of the diagnostic and therapeutic modalities currently employed in patients with this disease. In this study, speciation of the viridans streptococci has provided new insights into the relative frequency and antimicrobial susceptibility patterns of these organisms. Indeed, recent studies also suggest that S. milleri endocarditis is associated with a high incidence of suppurative complications and that patients with S. bovis endocarditis may have a significant incidence of underlying but asymptomatic lower gastrointestinal malignancies.23 24 Further studies correlating viridans streptococcal species with other clinical and laboratory parameters of endocarditis should provide additional insights into this disease. REFERENCES 1. COLMAN, G., AND WILLIAMS, R. E. O.: Taxonomy of Some Human Viridans Streptococci, in Streptococci and Streptococcal Diseases. Recognition, Understanding and Management. Wannamaker, L. W., and Matsen, J. M., eds., New York, Academic Press, Inc., p. 281, 1972. 2. HARDIE, J. M., AND BOWDEN, G. H.: Physiological Classification of Oral Viridans Streptococci. J. Dent. Res. 55: A166, 1976. 3. COLMAN, G.: The Viridans Streptococci, In Selected Topics in Clinical Bacteriology, de Louvois, J., ed., Baltimore, Williams & Wilkins Company, p. 179, 1976. 4. WANNAMAKER, L. W., ANM PARKER M. T.: Microbiology of Bacteria Often Responsible for Infective Endocarditis, In Infective Endocarditis-An American Heart Association Symposium. Kaplan, E. L., and Taranta, A. V., eds., No. 52, p. 9, 1977. 5. ATTEBERY, H. R., SUTTER, V. L., Arm FINEGOLD, S. M.: Normal Human Intestinal Flora, In Anaerobic Bacteria: Role in Disease, Balows, A., DeHaan, R. M., and Dowell, V. R., eds., Springfield, Illinois, Charles C. Thomas, p. 81, 1974. 6. PARKER, M. T., AND BALL, L. C.: Streptococci und Aerococci Associated with Systemic Infection in Man. J. Med. Microbiol. 9: 275, 1976. 7. FACKLAM, R. R.: Physiological Differentiation of Viridans Streptococci. J. Clin. Microbiol. 5: 184, 1977. 8. KAYE, D., MCCORMACK, R. C., AND HOOK, E. W.: Bacterial Endocarditis: The Changing Pattern Since the Introduction of Penicillin Therapy. Antimicrob. Agents and Chemother. 1961, 37, 1962. 9. FACKLAM, R. R.: Comparison of Several Laboratory Media for Presumptive Identification of Enterococci and Group D Streptococci. Appl. Microbiol. 26: 138, 1973. 10. GRoss, K. C., HOUGHTON, M. P., AND SENTERFIT, L. B.: Presumptive Speciation of Streptococcus bovis and other Group D Streptococci from Human Sources by Using Arginine and Pyruvate Tests. J. Clin. Microbiol. 1: 54, 1975. 11. CARLSSON, J.: A Numerical Taxonomic Study of Human Oral Streptococci. Odont. Rev. 19: 137, 1968. 12. CAREY, R. B., GRoss, K. C., AND ROBERTS, R. B.: Vitamin B6-Dependent Streptococcus mitior (mitis) Isolated from Patients with Systemic Infections. J. Inf. Dis. 131: 722, 1975. 13. BAUER, A. W., KIRBY, W. W. M., SHERRIS, J. C., AND TURCK, M.: Antibiotic
SPECIES OF VIRIDANS STREPTOCOCCI
47
Susceptibility Testing by Standardized Single Disc Method. Amer. J. Clin. Path. 45: 493, 1966. 14. MASUR, H., AND JOHNSON, W. D.: Prosthetic Valve Endocarditis: Institutional Variation and Some New Aspects. Submitted for publication. 15. BLOUNT, J. G.: Bacterial Endocarditis. Am. J. Med. 38: 909, 1965. 16. LERNER, P. I., AND WEINSTEIN, L.: Infective Endocarditis in the Antibiotic Era. N. Engl. J. Med. 274: 323, 1966. 17. CAREY, R. B., BRAUSE, B. D., AND ROBERTS, R. B.: Antimicrobial Therapy of Vitamin B6-Dependent Streptococcal Endocarditis. Annals Int. Med. 87: 150, 1977. 18. GERACI, J. E.: The Antibiotic Therapy of Bacterial Endocarditis. Med. Clin. N. Amer. 42: 1101, 1958. 19. TOMPsETT, R.: Bacterial Endocarditis: Changes in the Clinical Spectrum. Arch. Int. Med. 119: 329, 1967. 20. MURRAY, H. W., GROSS, K. C., MASUR, H., AND ROBERTS, R. B. Serious Infections Caused by Streptococcus milleri. Amer. J. Med. In press. 21. CAYEUX, P., ACAR, J. F., AND CHABBERT, Y. A.: Bacterial Persistence in Streptococcal Endocarditis Due to Thiol-Requiring Mutants. J. Inf. Dis. 124: 247, 1971. 22. MCCARTHY, L. R., AND BoTrONE, E. J.: Bacteremia and Endocarditis Caused by Satelliting Streptococci. Am. J. Clin. Path. 61: 585, 1974. 23. MURRAY, H. W., AND ROBERTS, R. B.: Streptococcus bovis Bacteremia and Underlying Gastrointestinal Disease. Arch. Int. Med. In press. 24. KLEIN, R. S., RECCO, R. A., CATALANO, H. T., EDBERG, S. C., CASEY, J. I., AND STEIGBIGEL, N. H.: Association of Streptococcus bovis with Carcinoma of the Colon. N. Engl. J. Med. 297: 800, 1977. 25. BERNTSEN, C. A.: Unaltered Pencillin Susceptibility of Streptococci. J. Am. Med. Assoc. 157: 331, 1955. 26. RAVERBY, W. D., BoTrONE, E. J., AND KEUSCH, G. T.: Group D Streptococcal Bacteremia with Emphasis on the Incidence and Presentation of Infections due to Streptococcus bovis. N. Engl. J. Med. 289: 1400, 1973. 27. MOELLERING, R. C., WATSON, B. K., AND KUNZ, L. J.: Endocarditis Due to Group D Streptococci. Amer. J. Med. 57: 239, 1974. 28. HOPPEs, W. L., AND LERNER, P. I.: Nonenterococcal Group D Streptococcal Endocarditis Caused by Streptococcus bovis. Annals Int. Med. 81: 588, 1974. 29. PHILLIPS, I., WARREN, C., HARRISON, J. M., SHARPLES, P., BALL, L. C., AND PARKER, M. T.: Antibiotic Susceptibilities of Streptococci from the Mouth and Blood of Patients Treated with Penicillin or Lincomycin and Clindamycin. Med. Microbiol. 9: 393, 1976. DISCUSSION DR. EDWARD W. HOOK (Charlottesville): I think it's interesting that you have evidence of an apparent increase in the incidence of bacterial endocarditis at the New York Hospital in the last seven years. Can you identify any of the factors that might account for this? Does this relate to an increase in the number of post-surgical cases? I would also be interested in your comments about the preventability of these infections. How many of the patients had identifiable events that might be associated with bacteremia and how many of them actually had adequate antimicrobial prophylaxis? DR. RICHARD B. ROBERTS (New York): I don't have any answers to the last questions, since we did not review that data. Furthermore, it is a retrospective study and depends upon what has been recorded in the patient's chart. For the first question, we are now seeing between 25 and 30 patients with microbial endocarditis per year and as I had mentioned, I think this is in part due to the fact of cardiac surgery and that we are seeing a number of heroin addicts admitted with S. aureus endocarditis. But, in addition
48
ROBERTS ET AL.
to those patients, we are seeing approximately 16 patients per year with streptococcal endocarditis. I believe during the late 50's and early 60's, the time period that you and Don Kaye reported your experience, approximately nine to ten patients were seen annually. Thus, I think we are seeing more streprococcal endocarditis not associated with open-heart surgery as well as other forms of microbial endocarditis. DR. JAMES ALLEN (Buffalo): Dick, since Dr. Keefer defined abacteremic endocarditis as a presumably unique and specific type of that disease, its percentage occurrence reported in most series has ranged anywhere from 10-20%. I think Dr. Weinstein reported about 16%, and our own percentage is running around 12. I know there have been multiple reasons offered for the occurrence of abacteremia-such as failure to recognize the existence of prior antibiotic therapy. The New York series has stood out and I noticed in your first slide it continues to do so - as having one of the lowest percentages of abacteremic endocarditis reported. Are you guys just a lot better than the rest of us in the bacteriologic diagnosis of this disease? DR. RICHARD B. ROBERTS (New York): No, it's not the guys, it is the diagnostic microbiology laboratory. We use three culture media. One is trypticase soy broth which is commercially available. The second is thioglycollate broth and the third is the one that I mentioned which is beef heart infusion broth which is made fresh at The New York Hospital. Over 5% of organisms in patients with endocarditis have grown only in heart infusion broth and not in trypticase soy broth or thioglycollate broth. So I think one factor is the type of media you use, especially for the growth of fastidious or>anisms. The other point I think is that the laboratory does subculture blindly from those bottles at day one, four and seven, onto blood agar and keeps blood cultures for a total of 14 days; I think this procedure also increases our batting average. I think it's probably more a direct reflection again of the expertise of the diagnostic microbiology laboratory than it is really a difference in geographic area or clinical experience. DR. THOMAS H. HUNTER (Charlottesville): I wish you would take me through the disappearance of these other enterococci that used to be on our list, particularly, I forget the name of the one that's a beta hemolytic bug that used to be found now and again in enterococcal endocarditis. What's happened to it? DR. RICHARD B. ROBERTS (New York): Maybe Ralph Tompsett will discuss that in the next presentation. We are seeing less enterococcal endocarditis at The New York Hospital. However, the numbers are very small and I am really not quite sure how significant it is. I don't believe that Streptococcus bovis was usually considered an enterococcus in previous years. Because most of these strains, as you know, are sensitive to penicillin, I think they probably were reported as viridans streptococci. Thank you very much.
Since 1932, when The New York Hospital moved to its present site at York Avenue and 68th Street, 728 patients with microbial endocarditis have been seen at this institution. Streptococcal endocarditis has been observed in 536 or 74% of these patients. This clinical experience over the past 45 years has provided a basis for over thirty physicians to investigate various clinical and therapeutic modalities in this disease. The viridans streptococci, a heterogeneous group of organisms, are the most frequent cause of microbial endocarditis. Six species of human viridans streptococci were characterized by Colman and Williams in 1972.' These species include S. mitior, S. sanguis, S. milleri, S. salivarius, S. mutans and S. pneumoniae. Excluding S. pneumoniae, the other five species are considered oral streptococci because they normally inhabit the human oral cavity.2 Although S. bovis is a nonenterococcal group D streptococcus, it may be classified as a viridans streptococcus.3'4 This latter species is more commonly isolated from the gastrointestinal tract than from the oral cavity.5 Recently, the incidence of the various viridans streptococcal species in microbial endocarditis has been reported by two streptococcal reference laboratories.6'7 However, these frequencies may not be representative since the most difficult species such as S. mutans are usually referred to reference laboratories for identification.7 The studies reported herein describe the speciation of viridans streptococci isolated from consecutive patients with microbial endocarditis seen during 19441955 and 1970-1977 at The New York Hospital and compare the incidence and antimicrobial susceptibility patterns of these organisms. MATERIALS AND METHODS The criteria for selection of patients with microbial endocarditis were similar to those previously employed at this institution8 and include: (1) isolation of the same microorganism from two separate blood specimens From the Department of Medicine, Cornell University Medical College and the Laboratory of Microbiology, The New York Hospital-Cornell Medical Center, New York, New York. 36
SPECIES OF VIRIDANS STREPTOCOCCI
37
from a patient with a syndrome consistent with microbial endocarditis, (2) isolation of a microorganism from a single blood culture during life, in addition to autopsy confirmation of the diagnosis, or (3) isolation of a microorganism from vegetations at autopsy in addition to presence of microorganisms on microscopic examination of the vegetation. Isolates from patients with microbial endocarditis were identified as streptococci on the basis of gram stain, colonial morphology and catalase reaction. Initial classification was based on hemolysis on sheep blood agar plate (SBAP, 5% sheep blood in Trypticase-Soy agar base, BBL) and esculin hydrolysis in the presence of 40% bile (bile-esculin agar slant [BE, Difco], without horse serum.9). Viridans streptococcal isolates were then speciated by a modification of the battery of tests described by Colman and Williams' (Table I). These tests include: (1) hemolysis on sheep blood agar, (2) hydrolysis of bile-esculin, esculin, arginine and starch, (3) growth in 6.5% NaCl broth and at 45°C, (4) fermentation patterns employing eleven sugars, (5) the production of acetoin from glucose, and (6) the production of polysaccharide (either dextran or levan) from 5% sucrose. To prepare inocula for differential media, growth from an 18 hour SBAP culture was removed with a sterile cotton swab and transferred to a tube containing 3 ml sterile saline. Turbidity was approximately equal to that of an overnight broth culture in Todd-Hewitt broth (THB, Difco) or approximately 109 colony forming units per ml. One tenth ml was added to all test media as well as SBAP to verify purity and incubated aerobically at 35°C. Preparation of certain differential media has been described previously.10 In addition, ability to hydrolyse esculin was determined on a Trypicase Soy Agar (BBL) slant containing 0.1% Esculin (Difco) and 0.05% ferric citrate. Arginine hydrolysis was tested in decarboxylase base Moeller (Difco) broth with 0.5% L-arginine hydroxide (Sigma) and overlaid with sterile mineral oil. Production of acetoin (acetyl-methylcarbinol) from glucose was detected by testing for the Voges-Proskauer reaction after 24 to 48 hours incubation in broth containing 1% Tryptone, 0.5% yeast extract, 0.5% K2HPO4, 0.5% NaCl and 0.2% glucose to which an additional 0.5% glucose was added aseptically after autoclaving. The 5% sucrose broth for determining the production of dextran was prepared according to Carlsson" and the production of levan was demonstrated on Mitis-Salivarius Agar (Difco). Preparation of media supplemented with 0.001% pyridoxal hydrochloride for the isolation and identification of vitamin B6-dependent streptococci has been described previously.12 Methods for the identification of S. bovis isolates have been reported previously.10 The minimum inhibitory concentration (MIC) of penicillin G and streptomycin was determined
38
ROBERTS ET AL.
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by the standard two-fold broth dilution technique. Antimicrobial susceptibility to erythromycin was determined by the standard disc diffusion method.'3 RESULTS AND DISCUSSION Yearly Incidence of Microbial Endocarditis. Previous studies from this institution suggested that the incidence of microbial endocarditis was declining during the time period 1944-1960 when compared to 19331944 due in part to the use of antibiotics.8 However, as shown in Figure 1, the incidence during the past eight years, i.e. 1970-1977, parallels that between 1932-1944 and appears to be increasing. Indeed, we now see approximately 27 patients with microbial endocarditis yearly compared to 12-14 patients in previous years. This apparent increase in incidence is due in part to the relative new entities of microbial endocarditis in heroin addicts and patients with prosthetic valves in which staphylococci and fungi are frequently seen (see below). Incidence of Etiologic Organisms in Microbial Endocarditis. The causative organisms in 216 patients with 219 episodes of microbial endocarditis at The New York Hospital from 1970-1977 are listed in Table II. Streptococci and staphylococci have accounted for 83% of cases; the remaining are caused by various microorganisms. S. epidermidis 1.2
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Year FIG. 1. The incidence of microbial endocarditis expressed as the number of cases per 1,000 admissions to The New York Hospital for the time periods 1933-1944, 1945-1960 and 1970-1977. The lines shown pass through the mean year and mean case rate for each period. The former two periods were previously reported by Kaye et al.8
40
ROBERTS ET AL.
TABLE II
Causative Organisms in 216 Patients with 219 Episodes of Microbial Endocarditis. The New York Hospital, 1970-1977 Organisn
Number
128 Streptococci Viridans streptococci 108 S. faecalis*t 15 2 ,8 hemolytic streptococci 2 S. pneumoniae Staphylococci 56 32 S. aureus 24 S. epidermidis Diphtheroids 7 Hemophilus species 5 (H. parainfluenzae, H. aphrophilus, Actinobacillus) 4 Gram negative bacilli (E. coli, P. vulgaris, S. marcescens, S. cholerae-suis) Fungi 9 5 Candida species 3 Aspergillus species** 1 Scopulariopsis 4 Miscellaneous (B. cereus, N. sicca, Citrobacter,* Micrococcus**) 7 Culture-negative *' ** Both organisms isolated from the same patient. t Organisms associated with repeated episodes of endocarditis.
%
58
25
3 2 2 4
2
3
and diphtheroids are most frequently seen in prosthetic valve patients." Fungi have been observed in these patients as well as in heroin addicts. Polymicrobial endocarditis and recurrent episodes of endocarditis have been relatively uncommon, the former seen only in patients with prosthetic valves or in heroin addicts. Culture-negative endocarditis accounted for only 3% of endocarditis. This low incidence when compared to other reports 5 16 is due in large part to the media and isolation procedures employed in our diagnostic laboratory. Indeed, some bacteria, i.e. Hemophilus species, have grown only in beef heart infusion broth which is prepared weekly at The New York Hospital.17 Incidence of Streptococcal Endocarditis. The incidence and relative frequency of streptococcal endocarditis at The New York Hospital since 1932 are shown in Table III. Whereas in prior years, streptococci were responsible for 84-88% of microbial endocarditis, these organisms have been isolated from 58% of patients since 1970. Although the relative frequency of streptococcal endocarditis has declined in recent years, the yearly incidence has increased; 16 patients have been seen annually
SPECIES OF VIRIDANS STREPTOCOCCI
41
since 1970 compared to a yearly incidence of 10 patients during the two previous time periods. Viridans streptococci have accounted for 49% of recent microbial endocarditis compared to 70-73% (including the lactis group) prior to 1970. This relative frequency has also been noted by others. 15, 16. 18 19 Although a significant increase in enterococcal endocarditis had been noted previously (2 to 10% from 1932-1943 to 1944-1960), enterococci have been responsible for only 7% of cases in recent years. The question occurs, however, whether previous isolates may have included both S. faecalis and S. bovis. Speciation of Viridans Streptococci. In the past, the viridans streptococci have been identified in many diagnostic laboratories by the type of hemolysis they produce on blood agar. Since these organisms are most commonly associated with microbial endocarditis, speciation of the viridans streptococci was performed in order to determine the relative frequency, antimicrobial susceptibility and clinical characteristics that might be associated with each species. Ninety-eight of the 108 isolates from endocarditis patients seen from 1970-1977 were speciated. In addition, through the foresight and interest of Drs. Ralph Tompsett and Walsh McDermott, viridans streptococcal isolates from 105 consecutive patients with endocarditis seen between 1944 and 1955 had been freezedried; 92 or 88% of these isolates were reconstituted and available for speciation. As shown in Table I, the six species (excluding S. pneumoniae) have, except for rare exceptions, the following characteristics in common: no growth in 6.5% NaCl and the ability to ferment lactose and sucrose but not pyruvate, arabinose or sorbose. With the exception of the strong positive reaction of S. bovis and the variable positive reactions of S. milleri and S. mutans, bile esculin medium is usually negative after overnight incubation because of the failure of the other species to grow TABLE III The Incidence and Relative Frequency of Streptococcal Endocarditis at The New York Hospital 1932-1943 1944-1960 1970-1977 Organism (210 patients) (216 patients) (173 patients) Streptococci 88% 84% 58% Viridans streptococci 73% 70% 49% S. faecalis 10 2 7 5 ,8 hemolytic streptococci 3 1 S. pneumoniae 8 1 1 Staphylococci 7 10 25 S. aureus 5 9 14 S. epidermidis 2 1 11 Miscellaneous 6 6 14 Culture-negative 3
42
ROBERTS ET AL.
in 40% bile. Each species, however, has certain distinctive characteristics. The two alpha hemolytic species (S. mitior and S. sanguis) differ in that S. sanguis hydrolyses esculin and arginine whereas S. mitior does not. In addition, S. sanguis ferments inulin and salicin while S. mitior is usually negative. The other species are usually non-hemolytic. S. milleri (synonyms include Streptococcus MG, S. anginosus, Peptostreptococcus intermedius) which may also produce alpha or beta hemolysis, is considered microaerophilic in that growth is enhanced by carbon dioxide or in some instances by anaerobiosis. Although its biochemical reactions resemble S. sanguis, S. milleri does not ferment inulin and produces acetoin from glucose. S. salivarius and S. mutans hydrolyse esculin but not arginine. They may be differentiated by their colonial morphology on agar (S. mutans produces a pinpoint adherent colony) and the ability of S. mutans to ferment mannitol and sorbitol. S. mutans is also microaerophilic. S. salivarius produces levan whereas S. mutans produces dextran which is deposited on the wall of the tube containing 5% sucrose broth. S. bovis may be differentiated from the other species by its strong bile-esculin reaction, and its ability to hydrolyse starch and grow at 45°C. Endocarditis isolates of this species usually ferment mannitol.'0 Using these tests, only 4 of 190 isolates (2%) could not be classified into one of the six species. The relative frequency of the viridans streptococcal species in microbial endocarditis during the different time periods is shown in Table IV. S. mitior and S. sanguis were most frequently observed in both study periods, a finding also reported by both reference laboratories.6'7 S. milleri, S. salivarius and S. mutans were infrequently associated with endocarditis. The first organism, however, (S. milleri) has been associated with a high incidence of suppurative complications.20 Recently, we have described viridans streptococci which require an excess of pyridoxal hydrochloride for growth. 2 17 These pyridoxal-dependent streptococci are probably similar to the satelliting streptococci reported by others.21'22 In our hands, these nutritional variants most closely resemble S. mitior, although they do ferment inulin. Definitive identification, however, will depend on the failure of detecting rhamnose in the cell walls of these organisms.3 Pyridoxal-dependent streptococci, which do not grow in many of the commercial media employed for blood cultures, were responsible for 5-6% of viridans streptococcal isolates in both series. Two additional isolates which satellited other organisms were not speciated because they could not be reconstituted from stock cultures. S. bovis accounted for only 5% of viridans streptococcal isolates during 1944-1955 but for 28% in recent years. This significant increase in incidence may be due in part to the difference in age of patients who
43
SPECIES OF VIRIDANS STREPTOCOCCI
TABLE IV Species of Viridans Streptococci Associated with Microbial Endocarditis 1970-1977**
1944-1955*
Species
S. mitior Vitamin B6 dependent S. sanguis S. milleri S. salivarius S. mutans S. bovis Unclassified * 92 of 105 isolates were speciated. ** 98 of 108 isolates were speciated.
Number 29
6 41 4 2 3 4 3
%
Number
%
32 6 44 5 2 3 5 3
28 5 25 3 1 7 28 1
28 5 25 3 1 7 28 1
develop endocarditis. Previous studies from this institution have reported an increase in age of female and male patients with viridans streptococcal endocarditis during 1944-1960 as compared to 19321943.8 The mean age of patients with viridans streptococcal endocarditis from 1970-1977 was 53 years (51 years for females and 54 years for males). However, an even greater discrepancy in age was observed when patients with S. bovis endocarditis were compared to those with other forms of viridans streptococcal endocarditis. The range of ages of patients with S. bovis endocarditis was 47 to 92 years with a mean of 67 years. Indeed, 22 of 28 patients or 79% were over 60 years of age. No difference was noted between males and females (mean of 66 and 68 years respectively). The range of ages for endocarditis patients infected with the other five species was 6-88 years with a mean of 48 years (45 years for females and 50 years for males). Furthermore, only 25 of 77 patients, or 32%, were over 60 years of age. Except for patients with S. milleri endocarditis, no difference was noted in age amongst patients with endocarditis due to the other species of viridans streptococci (mean 46-52 years). The observation that S. bovis endocarditis occurs in the elderly population has also been noted by Parker and Ball.6 This finding may also be related to the high incidence of lower gastrointestinal malignancies in these patients.23' 24 Antimicrobial Susceptibility of Viridans Streptococci and Species. Previous reports from The New York Hospital have shown that, despite the widespread use of antibiotics, penicillin susceptibility of viridans streptococci associated with endocarditis has remained the same.8'25 A comparison of those findings with more recent observations is shown in Figure 2. Of the 98 isolates examined since 1970, only 17% were resistant to penicillin G (MIC > 0.1 unit per ml) compared to 18% resistant from 1944 to 1951 and 20% from 1952 to 1960.
44
ROBERTS ET AL.
The ranges of penicillin suceptibility for each viridans streptococcal species during 1944-1955 and 1970-1977 are shown in Table V. The cumulative percent of strains resistant to penicillin (MIC > 0.1 ,ug per ml) for each species was as follows: S. mitior, 11%, S. sangius, 9%, S. milleri, S. salivarius and S. mutans combined, 5%, and S. bovis, 25%. Whereas all S. mitior isolates were sensitive during the early time period, 21% were resistant in recent years. S. sanguis isolates on the other hand were more resistant during 1944-1955 than 1970-1977 (12% Penclin
Of viridons
30
2a
4-SI, 79 stmins
IC
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!-60, 45 sraIn
I
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S
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-
*; .@.
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40 30
20
-
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1970-77, 98 strains IC
a
Units of penicillin FIG. 2. The penicillin susceptibility of 98 strains of viridans streptococci isolated from patients with microbial endocarditis from 1970-1977. These results are compared to those previously reported by Kaye et al.8
SPECIES OF VIRIDANS STREPTOCOCCI
45
TABLE V Ranges ofPenicillin G Susceptibility of Viridans Streptococcal Species 1944-1955 1970-1977 Species MIC MIC* Number Number S. mitior 0.012-0.10 28 0.012-3.10 29 0.012-0.05 5 0.025-1.60 Vitamin B6f dependent 6 S. sanguis 0.012-0.40 25 0.005-0.40 41 4 0.050-0.10 3 S. milleri 0.025-0.10 S. salivarius 0.100-0.80 1 2 0.050 S. mutans 0.025-0.05 7 0.012-0.10 3 S. bovis 0.025-0.10 28 0.050-0.40 4 * MIC -minimum inhibitory concentration (,ug per ml)
versus 4%). Although the first two vitamin B6-dependent streptococcal strains isolated from our patients with endocarditis were resistant to penicillin,17 examination of additional strains has shown that only 18% (two of eleven isolates) are resistant, an incidence similar to all viridans streptococci. S. bovis has recently been considered a sensitive group D streptococcus.2628 However, 25% of strains were resistant to penicillin, the highest percentage of all the viridans streptococcal species. These findings further emphasize the importance of determining the penicillin susceptibility of all species to ensure the administration of appropriate antimicrobial therapy. During the past year, we have detected three viridans streptococcal isolates from patients with endocarditis that were resistant by disc sensitivity testing to erythromycin. These are the first isolates resistant to erythromycin since 1971 when we initiated sensitivity testing to this antibiotic for all streptococci isolated from blood cultures. Over this period, 3 of 62 viridans streptococci (5%), none of 21 S. bovis isolates and 6 of 9 S. faecalis isolates (66%) have been resistant to erythromycin. The resistant isolates were speciated as S. mitior, S. mitior variant (vitamin B6-dependent streptococcus) and S. sanguis. A review of the clinical histories revealed that in each instance, erythromycin had been administered in the recent past. In one patient, erythromycin had been given both orally and parenterally for eleven weeks for viridans streptococcal endocarditis because the original isolate was sensitive to erythromycin and the patient allergic to penicillin. In the other two patients, erythromycin had been given for 10 to 14 days for upper respiratory tract infections in addition to dental prophylaxis in one of these patients. The development of erythromycin resistance by oral human viridans streptococci in patients receiving clindamycin has been reported previously.29 These preliminary observations suggest that in penicillin-allergic patients with underlying heart disease, erythromycin should be reserved for those situations requiring dental prophylaxis and not be used in other clinical settings.
46
ROBERTS ET AL.
SUMMARY Streptococcal endocarditis has been well recognized for decades and over the years investigators at The New York Hospital have defined many of the diagnostic and therapeutic modalities currently employed in patients with this disease. In this study, speciation of the viridans streptococci has provided new insights into the relative frequency and antimicrobial susceptibility patterns of these organisms. Indeed, recent studies also suggest that S. milleri endocarditis is associated with a high incidence of suppurative complications and that patients with S. bovis endocarditis may have a significant incidence of underlying but asymptomatic lower gastrointestinal malignancies.23 24 Further studies correlating viridans streptococcal species with other clinical and laboratory parameters of endocarditis should provide additional insights into this disease. REFERENCES 1. COLMAN, G., AND WILLIAMS, R. E. O.: Taxonomy of Some Human Viridans Streptococci, in Streptococci and Streptococcal Diseases. Recognition, Understanding and Management. Wannamaker, L. W., and Matsen, J. M., eds., New York, Academic Press, Inc., p. 281, 1972. 2. HARDIE, J. M., AND BOWDEN, G. H.: Physiological Classification of Oral Viridans Streptococci. J. Dent. Res. 55: A166, 1976. 3. COLMAN, G.: The Viridans Streptococci, In Selected Topics in Clinical Bacteriology, de Louvois, J., ed., Baltimore, Williams & Wilkins Company, p. 179, 1976. 4. WANNAMAKER, L. W., ANM PARKER M. T.: Microbiology of Bacteria Often Responsible for Infective Endocarditis, In Infective Endocarditis-An American Heart Association Symposium. Kaplan, E. L., and Taranta, A. V., eds., No. 52, p. 9, 1977. 5. ATTEBERY, H. R., SUTTER, V. L., Arm FINEGOLD, S. M.: Normal Human Intestinal Flora, In Anaerobic Bacteria: Role in Disease, Balows, A., DeHaan, R. M., and Dowell, V. R., eds., Springfield, Illinois, Charles C. Thomas, p. 81, 1974. 6. PARKER, M. T., AND BALL, L. C.: Streptococci und Aerococci Associated with Systemic Infection in Man. J. Med. Microbiol. 9: 275, 1976. 7. FACKLAM, R. R.: Physiological Differentiation of Viridans Streptococci. J. Clin. Microbiol. 5: 184, 1977. 8. KAYE, D., MCCORMACK, R. C., AND HOOK, E. W.: Bacterial Endocarditis: The Changing Pattern Since the Introduction of Penicillin Therapy. Antimicrob. Agents and Chemother. 1961, 37, 1962. 9. FACKLAM, R. R.: Comparison of Several Laboratory Media for Presumptive Identification of Enterococci and Group D Streptococci. Appl. Microbiol. 26: 138, 1973. 10. GRoss, K. C., HOUGHTON, M. P., AND SENTERFIT, L. B.: Presumptive Speciation of Streptococcus bovis and other Group D Streptococci from Human Sources by Using Arginine and Pyruvate Tests. J. Clin. Microbiol. 1: 54, 1975. 11. CARLSSON, J.: A Numerical Taxonomic Study of Human Oral Streptococci. Odont. Rev. 19: 137, 1968. 12. CAREY, R. B., GRoss, K. C., AND ROBERTS, R. B.: Vitamin B6-Dependent Streptococcus mitior (mitis) Isolated from Patients with Systemic Infections. J. Inf. Dis. 131: 722, 1975. 13. BAUER, A. W., KIRBY, W. W. M., SHERRIS, J. C., AND TURCK, M.: Antibiotic
SPECIES OF VIRIDANS STREPTOCOCCI
47
Susceptibility Testing by Standardized Single Disc Method. Amer. J. Clin. Path. 45: 493, 1966. 14. MASUR, H., AND JOHNSON, W. D.: Prosthetic Valve Endocarditis: Institutional Variation and Some New Aspects. Submitted for publication. 15. BLOUNT, J. G.: Bacterial Endocarditis. Am. J. Med. 38: 909, 1965. 16. LERNER, P. I., AND WEINSTEIN, L.: Infective Endocarditis in the Antibiotic Era. N. Engl. J. Med. 274: 323, 1966. 17. CAREY, R. B., BRAUSE, B. D., AND ROBERTS, R. B.: Antimicrobial Therapy of Vitamin B6-Dependent Streptococcal Endocarditis. Annals Int. Med. 87: 150, 1977. 18. GERACI, J. E.: The Antibiotic Therapy of Bacterial Endocarditis. Med. Clin. N. Amer. 42: 1101, 1958. 19. TOMPsETT, R.: Bacterial Endocarditis: Changes in the Clinical Spectrum. Arch. Int. Med. 119: 329, 1967. 20. MURRAY, H. W., GROSS, K. C., MASUR, H., AND ROBERTS, R. B. Serious Infections Caused by Streptococcus milleri. Amer. J. Med. In press. 21. CAYEUX, P., ACAR, J. F., AND CHABBERT, Y. A.: Bacterial Persistence in Streptococcal Endocarditis Due to Thiol-Requiring Mutants. J. Inf. Dis. 124: 247, 1971. 22. MCCARTHY, L. R., AND BoTrONE, E. J.: Bacteremia and Endocarditis Caused by Satelliting Streptococci. Am. J. Clin. Path. 61: 585, 1974. 23. MURRAY, H. W., AND ROBERTS, R. B.: Streptococcus bovis Bacteremia and Underlying Gastrointestinal Disease. Arch. Int. Med. In press. 24. KLEIN, R. S., RECCO, R. A., CATALANO, H. T., EDBERG, S. C., CASEY, J. I., AND STEIGBIGEL, N. H.: Association of Streptococcus bovis with Carcinoma of the Colon. N. Engl. J. Med. 297: 800, 1977. 25. BERNTSEN, C. A.: Unaltered Pencillin Susceptibility of Streptococci. J. Am. Med. Assoc. 157: 331, 1955. 26. RAVERBY, W. D., BoTrONE, E. J., AND KEUSCH, G. T.: Group D Streptococcal Bacteremia with Emphasis on the Incidence and Presentation of Infections due to Streptococcus bovis. N. Engl. J. Med. 289: 1400, 1973. 27. MOELLERING, R. C., WATSON, B. K., AND KUNZ, L. J.: Endocarditis Due to Group D Streptococci. Amer. J. Med. 57: 239, 1974. 28. HOPPEs, W. L., AND LERNER, P. I.: Nonenterococcal Group D Streptococcal Endocarditis Caused by Streptococcus bovis. Annals Int. Med. 81: 588, 1974. 29. PHILLIPS, I., WARREN, C., HARRISON, J. M., SHARPLES, P., BALL, L. C., AND PARKER, M. T.: Antibiotic Susceptibilities of Streptococci from the Mouth and Blood of Patients Treated with Penicillin or Lincomycin and Clindamycin. Med. Microbiol. 9: 393, 1976. DISCUSSION DR. EDWARD W. HOOK (Charlottesville): I think it's interesting that you have evidence of an apparent increase in the incidence of bacterial endocarditis at the New York Hospital in the last seven years. Can you identify any of the factors that might account for this? Does this relate to an increase in the number of post-surgical cases? I would also be interested in your comments about the preventability of these infections. How many of the patients had identifiable events that might be associated with bacteremia and how many of them actually had adequate antimicrobial prophylaxis? DR. RICHARD B. ROBERTS (New York): I don't have any answers to the last questions, since we did not review that data. Furthermore, it is a retrospective study and depends upon what has been recorded in the patient's chart. For the first question, we are now seeing between 25 and 30 patients with microbial endocarditis per year and as I had mentioned, I think this is in part due to the fact of cardiac surgery and that we are seeing a number of heroin addicts admitted with S. aureus endocarditis. But, in addition
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ROBERTS ET AL.
to those patients, we are seeing approximately 16 patients per year with streptococcal endocarditis. I believe during the late 50's and early 60's, the time period that you and Don Kaye reported your experience, approximately nine to ten patients were seen annually. Thus, I think we are seeing more streprococcal endocarditis not associated with open-heart surgery as well as other forms of microbial endocarditis. DR. JAMES ALLEN (Buffalo): Dick, since Dr. Keefer defined abacteremic endocarditis as a presumably unique and specific type of that disease, its percentage occurrence reported in most series has ranged anywhere from 10-20%. I think Dr. Weinstein reported about 16%, and our own percentage is running around 12. I know there have been multiple reasons offered for the occurrence of abacteremia-such as failure to recognize the existence of prior antibiotic therapy. The New York series has stood out and I noticed in your first slide it continues to do so - as having one of the lowest percentages of abacteremic endocarditis reported. Are you guys just a lot better than the rest of us in the bacteriologic diagnosis of this disease? DR. RICHARD B. ROBERTS (New York): No, it's not the guys, it is the diagnostic microbiology laboratory. We use three culture media. One is trypticase soy broth which is commercially available. The second is thioglycollate broth and the third is the one that I mentioned which is beef heart infusion broth which is made fresh at The New York Hospital. Over 5% of organisms in patients with endocarditis have grown only in heart infusion broth and not in trypticase soy broth or thioglycollate broth. So I think one factor is the type of media you use, especially for the growth of fastidious or>anisms. The other point I think is that the laboratory does subculture blindly from those bottles at day one, four and seven, onto blood agar and keeps blood cultures for a total of 14 days; I think this procedure also increases our batting average. I think it's probably more a direct reflection again of the expertise of the diagnostic microbiology laboratory than it is really a difference in geographic area or clinical experience. DR. THOMAS H. HUNTER (Charlottesville): I wish you would take me through the disappearance of these other enterococci that used to be on our list, particularly, I forget the name of the one that's a beta hemolytic bug that used to be found now and again in enterococcal endocarditis. What's happened to it? DR. RICHARD B. ROBERTS (New York): Maybe Ralph Tompsett will discuss that in the next presentation. We are seeing less enterococcal endocarditis at The New York Hospital. However, the numbers are very small and I am really not quite sure how significant it is. I don't believe that Streptococcus bovis was usually considered an enterococcus in previous years. Because most of these strains, as you know, are sensitive to penicillin, I think they probably were reported as viridans streptococci. Thank you very much.
