Cardiobacterium species

Authors: Mitzi Nisbet MBChB, FRACP, Selwyn D R Lang MBChB, FRACP, FRCPA Updated: January, 2008

Monograph
Reference
Tables
What's New
Reviews
History

General Description

Cardiobacterium species are slow-growing, fastidious, capnophilic, Gram-negative bacilli represented by the “C” in HACEK, an acronym for Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium species, Eikenella corrodens and Kingella species (28). All these organisms have the propensity to cause endocarditis, but in the case of Cardiobacterium this disease is, with rare exceptions, its only pathological manifestation (79).

C. hominis was first isolated from four patients with subacute bacterial endocarditis in 1962 and was described as a Pasteurella-like organism, designated “CDC group 11-D”. The patients were middle-aged, from various parts of the United States and presented over a 10 month period (88). The name C. hominis was conferred in 1964 (82) at which time there was only the single species in the genus. In 2001, a distinct Cardiobacterium species was isolated from blood cultures from a patient with a congenital bicuspid aortic valve, insidious endocarditis, and a ruptured cerebral aneurysm (33). The name Cardiobacterium valvarum was proposed and subsequently validated (59). More recently, a case of endocarditis due to a novel Cardiobacterium species, more closely resembling C. valvarum than C. hominis, but distinct from both, has been reported (31,34). Additional isolates of Cardiobacterium, differing in some respects from both the above species, but more closely resembling C. valvarum, have been characterized among oral bacteria in a culture collection (32).

A review in 2001 of endocarditis due to rare and fastidious bacteria (12) noted that C. hominis endocarditis had been recorded in 76 patients. For comparison, numbers due to other HACEK organisms were: Haemophilus species [178], Actinobacillus actinomycetemcomitans [93], Eikenella corrodens [19] and Kingella species [33] (12). To these should be added a case due to Suttonella indologenes (formerly Kingella indologenes) (35). There have been sporadic reports of C. hominis endocarditis since the above review (1, 2, 5,11,30,41,51,55,65,71), some diagnosed by non-culture techniques (26,41,65). Additional cases probably go unreported.

Microbiology Guided Medline Search

Although growth of Cardiobacterium in modern commercial media is usually detectable after 3 to 5 days, incubation for 2 to 3 weeks has been recommended before reporting a culture as negative (91,93). Routine Gram-staining and sub-culturing is essential since there is likely to be no visible change, such as turbidity or haemolysis, in the blood culture medium. On initial isolation the 1-3 µm long bacilli may be Gram-variable. They are frequently bulbous at one or both ends and arranged in short chains or rossettes. When grown in media containing yeast extract, these characteristic features may be lost and the cells appear as regular, regularly staining, Gram-negative bacilli (93). Cardiobacterium grows on blood or chocolate agar at 35oC when there is adequate humidity and an atmosphere enriched by CO2. Cardiobacterium grows poorly or not at all anaerobically. It will seldom grow on MacConkey agar or other enteric media. On blood or chocolate agar, small, glistening, opaque colonies usually become apparent after 2 or 3 days, but occasionally take up to 2 weeks. Colonies, other than those of C. valvarum, may produce slight α-haemolysis. With further incubation, both C. hominis and C. valvarum colonies may pit the agar (32,33,94).

C. hominis is oxidase-positive, catalase-negative, nitrate-negative, urease-negative and indole-positive. These reactions may be weak on initial isolation but become more obvious with subculture (79). C. valvarum is strongly indole-positive but differs from C. hominis in that it does not utilize maltose, sucrose or mannitol (32,33). The positive indole reaction is useful in distinguishing C. hominis and C. valvarum from unspeciated, oral strains of Cardiobacterium including the novel isolate known to have caused endocarditis (34). All these have been indole-negative, as are most other “HACEK” organisms with the exception of C. hominis, C. valvarum and Suttonella indologenes. C. hominis differs from S. indologenes in giving a negative alkaline phosphatase reaction and in utilizing mannitol.

Epidemiology Guided Medline Search

Cardiobacterium species are members of the normal oral and upper respiratory flora in humans and may be found rarely on other mucosal surfaces. Slotnik, using a labeled, hyperimmune, rabbit antiserum and selective culture, was able to detect C. hominis in the upper respiratory flora of 68% of normal subjects. There was no predilection for any particular age or sex (83). C. hominis was also recovered from 2 of 159 cervical and vaginal smears (84). Organisms binding the specific antibody were seen in 70% of stool samples but could not be cultured (83). C. hominis has not been isolated from animals, soil and water or hospital equipment.

Human infection is endogenously acquired. Almost all cases reported have been endocarditis (1-3,5-16,18-26,28,30,36-40,42,46-63,67-69,72-75,77,79-82,85-90,92-96). Although C. hominis was responsible for only 2 of 1,989 cases of endocarditis accumulated from 13 published series before 1983, it accounted for 14 of 111 cases in case reports of endocarditis due to “unusual organisms” (6). At least 75% of patients have had underlying anatomical cardiac defects such as rheumatic heart disease or congenital abnormalities (12,93). Prosthetic heart valves were infected in 13%, all as late complications of the cardiac surgery (12,93). In 44% of cases of endocarditis due to C. hominis there had been a prior dental procedure or evidence of gingival infection (12). Three reported cases followed gastrointestinal endoscopy (55,74). Most cases have been in middle-aged adults and, in contrast to endocarditis due to other HACEK organisms; the aortic valve is most frequently involved (12). Four cases due to Cardiobacterium non-hominis involved aortic valves (one prosthetic valve infection) in middle-aged men (11,27,33,34). Two of these cases occurred following dental extractions (11,34).

Clinical Manifestations Guided Medline Search

Endocarditis due to Cardiobacterium species tends to be exceptionally low grade and insidious. In one case, systemic symptoms preceded the eventual diagnosis for 12 months (56) and of 34 cases identified up to 1983, the average duration of symptoms preceding diagnosis was 169 days (93). Cardiobacterium forms large friable vegetations associated with frequent embolic complications (33,34,48,63,77,93). The clinical presentation has included low-grade fever [86%], splenomegaly [59%], emboli [44%] and congestive heart failure [44%] (12). Several cases have presented with, or have developed, neurological symptoms and signs (24,25,46,52,63,92). One of these presented with meningitis (25). Intracranial mycotic aneurysm (33,41) and ruptured mycotic aneurysm of the superior mesenteric artery (81) illustrate the propensity for Cardiobacterium endocarditis to embolize. Francioli et al noted that emboli were reported in 13 of 31 cases (25). Vasculitic manifestations such as glomerulonephritis (49), arthralgia and skin rashes, including a bullous eruption (18), may complicate C. hominis endocarditis and false positive tests for syphilis have been reported (93). Severe thrombocytopenia associated with platelet antibodies has been described (1). A patient with C. hominis infection of a bioprosthetic mitral valve, presented with septic arthritis (2). The case due to C. valvarum was afebrile and presented with a ruptured cerebral aneurysm (33). The patient infected by a novel Cardiobacterium was also afebrile and was noted to have large friable vegetations at the time of valve replacement (34).

With appropriate treatment, the outcome is generally good: overall 87% have survived with 30% undergoing valve replacement (12). In a review of 22 cases of infective endocarditis due to C. hominis, Robison et al reported a bacteriological cure in all but one case, and in this patient, Enterococcus species, not C. hominis, was recovered from vegetations on the valve at postmortem (77).

Currie et al have reviewed 10 cases of C. hominis infection involving prosthetic valves to which they add the first reported involvement of an aortic homograft valve (19). In six cases the aortic valve alone was involved, in three the mitral valve alone and in two, both aortic and mitral valves. All were cured, five undergoing valve replacements primarily for haemodynamic reasons (19). Both patients with endocarditis from Cardiobacterium non- hominis survived (33,34). Rare cases of C. hominis focal infection, without endocarditis, include a pacemaker lead infection with vertebral osteomyelitis (66) and an abdominal abscess (76), pericarditis (45) and peritonitis in a patient receiving continuous ambulatory peritoneal dialysis (9). In addition, there are occasional reported cases of sepsis and bacteremia without evidence of endocarditis (22,78).

Laboratory Diagnosis Guided Medline Search

In the clinical laboratory, C. hominis is recovered almost exclusively from blood cultures from patients with endocarditis. Automated blood culture systems generally produce small incremental changes in growth indices after 3 to 5 days, however, incubation in a liquid medium for at least 14 days has been recommended before cultures are presumed to be negative (56). In one report, the organism was recovered only after terminal subculture following 10 days incubation of a BACTEC 6A blood culture bottle (53). Petti et al. reviewed over 59,000 positive blood culture isolates and found 35 HACEK organisms isolated including two Cardiobacterium isolates (70). However of the 407 blood cultures with extended incubation in this series none grew HACEK organisms hence their recommendation of a standard incubation period of 5 days for all blood cultures.

C. hominis has also been cultured from vegetations on a native heart valve following failure of antibiotic treatment (54) and from an infected prosthetic valve in a patient whose blood cultures had remained negative (87). Characteristics that help distinguish C. hominis from other bacteria of the HACEK group are described in the section on microbiology (above). Non-culture techniques, such as polymerase chain reaction, are being increasingly used (26,34,41,63,65,71), obviating the need for such tests as antibody response (93,95).

Pathogenesis Guided Medline Search

C. hominis is of low virulence (79). Using the original clinical isolate, Tucker et al were unable to produce disease in animals. Between 107 and 108 viable organisms were injected intravenously, intraperitoneally or subcutaneously into mice, guinea pigs, rabbits, hamsters and pigeons, but produced no evidence of infection (88). It has been suggested that this is in keeping with the tendency of C. hominis to infect previously damaged or prosthetic valves and to run a relatively insidious course (79).

Susceptibility In Vitro and In Vivo Guided Medline Search In Vitro, Guided Medline Search In Vivo

Susceptibility testing of C. hominis can be difficult owing to the fastidious nature and slow growth rate of the organism. Non-hominis species appear to be even more fastidious and troublesome in this regard (33,34). It is important, however, to perform susceptibility testing because the result is never entirely predictable.

Table 1 summarizes representative susceptibilities of several strains to a range of antibiotics (2). Notably, all 22 isolates tested against penicillin were susceptible; however, one isolate developed resistance to ampicillin during treatment (75). Kugler et al tested 29 antimicrobials against HACEK organisms, including five isolates of C. hominis, using the Etest method. None were β-lactamase producers. MIC50 values were < 0.016 µg/ml in the case of penicillin, ampicillin, ampicillin/sulbactam, ticarcillin, piperacillin/tazobactam, cefixime, ceftibuten, cefpodoxime, cefdinir, cefuroxime, cefoxitin, imipenem and meropenem and < 0.2 µg/ml in the case of cefprozil, cefotaxime, ceftriaxone, ceftazidime, cefepime, cefpirome, ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, sparfloxacin, trovafloxacin and rifampicin. Carbapenems were the most active of all the agents tested. Oxacillin was the least active β-lactam (range MIC 0.5-4 µg/ml), and ofloxacin the least active fluoroquinolone (range MIC 0.032-8 µg/ml). The MIC range of trimethoprim/sulphamethoxazole was 0.5-1.5 µg/ml (44). The MICs of DX-619, a new des-F(6)-quinolone, against 5 Cardiobacterium hominis strains have been reported to be between 0.016 to 0.03 µg/ml with an MIC50 of 0.016 (43).

There are very few published data on the bactericidal activity of antibiotics for C. hominis. Chloramphenicol has been noted to achieve bactericidal titers in serum of 1:32 in a patient with C. hominis infection successfully treated with this drug (75). Vogt et al reported MIC/MBC (µg/ml) for a single isolate: penicillin 0.06/0.06, mezlocillin 0.5/0.5, tobramycin 1/2, imipenem 0.06/0.25, and ciprofloxacin 0.06/0.06 (89). Their patient developed renal toxicity while receiving treatment with mezlocillin and gentamicin, relapsed on mezlocillin alone, and was cured with ciprofloxacin. Both peak and trough sera were rapidly bactericidal while the patient received ciprofloxacin.

Although ampicillin resistance was reported to have emerged during treatment of a case of C. hominis endocarditis in 1977 (75), there have been only two case reports of C. hominis endocarditis due to β-lactamase producing strains (50,53). In each case β-lactamase production was confirmed using a chromogenic cephalosporin test and susceptibility to amoxicillin was restored in the presence of clavulanic acid. Since different susceptibility testing methods were used, direct comparison of the susceptibilities of the two isolates is difficult. The French isolate (50) was tested using a disc diffusion method and was noted to be susceptible to tetracycline, rifampicin, vancomycin, and imipenem but resistant to cefotaxime, erythromycin, cotrimoxazole and gentamicin. The Taiwan isolate (53) was tested using a broth dilution method and the breakpoints for Streptococcus pneumoniae (64). Minimum inhibitory concentrations (µg/ml) of penicillin and ampicillin were >256 and that of amoxycillin/clavulanate 0.5; cephalothin 4.0; cefotaxime and ceftriaxone 1.0; tetracycline 4.0; gentamicin 0.5; ciprofloxacin 0.5 trimethoprim/sulphamethoxazole 0.25 and vancomycin 8.0. C. valvarum was shown by Etest to be susceptible at the following concentrations (MIC, µg/ml) to amikacin (1.5), cefepime (0.38), ceftazidime (0.064), ciprofloxacin (0.016), imipenem (0.032), ticarcillin-clavulanate (0.03), and trimethoprim-sulphamethoxazole (0.03) (33).

Recent guidelines recommend routinely testing susceptibility of all clinically significant HACEK isolates to ceftriaxone or cefotaxime, ampicillin, amoxicillin/clavulanic acid and imipenem using cation adjunct Mueller-Hinton broth with lysed horse blood (17). Table 2 summarizes interpretative criteria for susceptibility testing for HACEK organisms including Cardiobacterium. β-lactamase producing Cardiobacterium can readily be detected by testing colonies with nitrocefin (17). It is important that susceptibility testing for isolates causing serious infection is performed in conjunction with clinical assessment (39).

Antimicrobial Therapy Guided Medline Search

General

For many years, penicillin or ampicillin, alone, or in combination with an aminoglycoside, were regarded as the standard treatment for endocarditis due to HACEK organisms (29). Serum bactericidal titres for C. hominis in patients given penicillin alone have ranged from 1:256 to 1:2560 and the average duration of treatment for cured patients was 37 days with a range of 12 to 49 days (94). Twenty-seven (87%) of 31 patients with C. hominis endocarditis, including all 4 patients with prosthetic heart valve involvement, were cured (94). However, with the emergence of β-lactamase producing strains within the HACEK group of organisms the American Heart Association (4) recommends ceftriaxone or ampicillin-sulbactam as the drugs of choice for treatment of HACEK endocarditis, an approach endorsed by others (8). The recommended dose of ceftriaxone is 2g once daily intravenously or intramuscularly. The recommended duration of treatment is 4 weeks for native valve disease and 6 weeks when a prosthetic valve is involved (Table 3) (4). A successful outcome has been reported in 11 patients with C. hominis infection of prosthetic valves (19). Treatment regimens included ampicillin or ceftriaxone alone for 4 weeks, and penicillin or ampicillin, plus gentamicin for almost 6 weeks. Three cases of successful treatment of aortic homograft valve infection have been reported (55). Treatment regimens included ceftriaxone and gentamicin for 18 days followed by oral amoxicillin, 6 weeks of ceftriaxone followed by 6 months of oral amoxicillin and 6 weeks of ceftriaxone alone.

Although third generation cephalosporins have been recommended because of the occurrence of β-lactamase-producing HACEK organisms (4), this might be questioned for C. hominis infection since ceftriaxone was seemingly ineffective in both cases due to β-lactamase-producing strains. The one patient, whose organism was resistant to cefotaxime in vitro, remained febrile after receiving ceftriaxone for 6 days, and was cured using a combination of vancomycin and rifampicin followed by amoxycillin/clavulanate and rifampicin (50). The other patient received ampicillin and gentamicin for two weeks, then ceftriaxone (MIC 1.0 µg/ml) 2 g 12 hourly for a further three weeks. At this time she developed a skin rash and was changed to intravenous ciprofloxacin 400 mg 12 hourly, before undergoing aortic valve replacement for progressive heart failure (53). Although neither patient was proven to have bacteriological failure following the recommended course of ceftriaxone, they illustrate the importance of determining susceptibilities in each case and the occasional need for alternative treatment options. Based on limited data, it would seem reasonable to treat infection due to β-lactamase producing strains of C. hominis with a carbapenem, a β-lactam/β-lactamase-inhibitor combination or a fluoroquinolone. It should, however, be noted that the fluoroquinolones have variable activity e.g. ofloxacin MIC is as high as 8.0 µg/ml (44). One patient with C. valvarum infection was treated successfully with piperacillin/tazobactam despite susceptibility to cephalosporins (33) another was treated successfully with amoxicillin and gentamicin in combination with surgical excision (11)

Alternative Regimens

The American Heart Association’s preferred alternative to a third generation cephalosporin treatment with ampicillin-sulbactam (4). There are few precedents for managing infection due to isolates resistant to penicillins or cephalosporins, or for treating patients unable to tolerate these antibiotics. Gentamicin alone for 6 weeks has been reported to be successful (10). However, the suggested treatment for those with β-lactam allergies is a fluoroquinolone, provided susceptibility is confirmed (4). This recommendation is necessarily made on the basis of scanty published data. While combination treatment with a β-lactam plus an aminoglycoside is commonly used, there is no evidence that it is superior to monotherapy for C. hominis endocarditis. Current guidelines no longer recommend gentamicin because of its nephrotoxicity (4).

Adjunctive Treatment and Prevention

Adjunctive treatment is primarily valve replacement when required. Steroid treatment has been used for glomerulonephritis complicating C. hominis endocarditis (49).

As in the prevention of any endocarditis due to normal oral flora, prevention entails good dental hygiene. Prophylactic regimens recommended to prevent viridans streptococcal endocarditis are likely to be as effective – if effective at all – in preventing Cardiobacterium endocarditis. However, exceptions are inevitable: one case report documents C. hominis endocarditis due to a strain resistant to erythromycin (MIC 12.5 µg/ml) and vancomycin (MIC 25 µg/ml) in a penicillin allergic patient who had received prophylactic erythromycin for a dental extraction (73). No vaccine is available.

References

1. Arnold DM, Smaill F, Warkentin TE, Christjanson L, Walker I. Cardiobacterium hominis endocarditis associated with very severe thrombocytopenia and platelet antibodies. Am J Hematol 2004; 76:373-77. [PubMed]

2. Apisarnthanarak A, Johnson RM, Braverman AC, Dunne WM, Little JR. Cardiobacterium hominis bioprosthetic valve endocarditis presenting as septic arthritis. Diagn Microbiol Infect Dis 2002; 42:79-81. [PubMed]

3. Arrizabalaga P, Botey A, Darnell A, Marin P, Cavalle F, Pumarola A, Revert L. Generalized fibromuscular dysplasia and calcified aneurysm. Sepsis caused by Cardiobacterium hominis. Med Clin (Barc) 1983; 80:537-540. [PubMed]

4. Baddour L, Wilson W, Bayer A et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complication: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circ 2005; 111: e394-434. [PubMed]

5. Balcou-Leroy E, Bera J, Fugere AS, Gabez B, Boldron-Ghaddar A, Werquin S. Cardiobacterium hominis endocarditis. A case report. Arch Mal Coeur Vaiss 2003; 96:923-26. [PubMed]

6. Ben-Chetrit E, Nashif M, Levo Y. Infective endocarditis caused by uncommon bacteria. Scand J Infect Dis 1983; 15:179-183. [PubMed]

7. Bellorini M, Makhoul N, Loiret J, Poulain JM, Guyon P, Granier J. Cardiobacterium hominis on a aortic valve prosthesis. Arch Mal Coeur Vaiss 1987; 80:663-665. [PubMed]

8. Berbari EF, Cockerill FR, Steckelberg JM. Infective endocarditis due to unusual or fastidious microrganisms. Mayo Clin Proc 1997; 72:532-542. [PubMed]

9. Bhan I, Java Chen E, Bazari H. Isolation of Cardiobacterium hominis from the peritoneal fluid of a patient on continous ambulatory peritoneal dialsysis. Scand J Infect Dis 2006; 38: 301-3. [PubMed]

10. Botha P, Venter M, Cardiobacterium hominis as a cause of bacterial endocarditis [Letter]. S Afr Med J 1996; 86:91. [PubMed]

11. Bothelo E, Gouriet F, Fournier P, Roux V, Habib G, Thuny F, Metras D, Roult D, Casalta J. Endocarditis caused by Cardiobacterium valvarum. J Clin Microbiol 2006; 44: 657-8. [PubMed]

12. Brouqui P, Raoult D. Endocarditis due to rare and fastidious bacteria. Clin Micro Rev 2001; 14:177-207. [PubMed]

13. Brunn B, Buch J, Kirkegaard E, Bjaelder P. Endocarditis caused by Cardiobacterium hominis – two case reports. Acta Path Microbiol Immunol Scand 1983; 91:325-328. [PubMed]

14. Carasusan MJ, Marco MC, Aisa ML, Canas JM. Subacute infectious endocarditis caused by Cardiobacterium hominis. Presentation of a case. Enferm Infecc Microbiol Clin 1995; 13:496. [PubMed]

15. ChongY, Kim TS, Lee SY, Shim WH, Choo BK. Cardiobacterium hominis endocarditis - a case report. Yonsei Med J 1985; 26:78-81. [PubMed]

16. Christen RD. Cardiobacterium hominis endocarditis in a patient with a hypersensitivity reaction to penicillin. Successful treatment with partial resection of the posterior mitral valve leaflet and antibiotic therapy with cefazolin. Infection 1990; 18:291-293. [PubMed]

17. Clinical and Laboratory Standards Institute. Methods for antimicrobial dilution and disk susceptibility testing of infrequently isolated or fastidious bacteria. Approved standard M45-A. Wayne, PA: Clinical and Laboratory Standards Institute, 2006.

18. Colebunders R, Mertens A, Mahler CH, Parizal G. Cardiobacterium hominis endocarditis. Acta Clinica Belgica 1982; 37:158-161. [PubMed]

19. Currie PF, Codispoti M, Mankad PS, Godman MJ. Late aortic homograft endocarditis caused by Cardiobacterium hominis: a case report and review of the literature. Heart 2000; 83:579-581. [PubMed]

20. DeGuise M, Lalonde G, Girouard Y. Cardiobacterium hominis endocarditis. Can J Cardiol 1990; 6:461-462. [PubMed]

21. De Resende MV, Mansur AJ, Tarasoutchi F, Tavelin W, Grinberg M. Endocarditis in heart valve bioprosthesis caused by Cardiobacterium hominis. Arq Bras Cardiol 1990; 55:117-119. [PubMed]

22. Detton E, Glikmanas M. Cardiobacterium hominis septicaemia. Sem Hop 1981; 18:178-180. [PubMed]

23. El Khizzi N, Kasab SA, Osobo AO. HACEK group endocarditis at the Riyadh Armed Forces Hospital. J Infect 1997; 34:69-74. [PubMed]

24. Ellner JJ, Rosenthal MS, Lerner PI, McHenry MC. Infective endocarditis caused by slow-growing, fastidious, Gram-negative bacteria. Medicine 1979; 58:145-158. [PubMed]

25. Francioli PB, Roussianos D, Glauser MP. Cardiobacterium hominis endocarditis manifesting as bacterial meningitis. Arch Intern Med 1983; 143:1483-1484. [PubMed]

26. Gatselis N, Malli E, Papadamou G, Petinaki E, Dalekos G. Direct detection of Cardiobacterium hominis in serum from a patient with infective endocarditis by broad-range PCR. J Clin Microbiol 2006; 44: 669-72. [PubMed]

27. Geissdorfer W, Tandler R, Schlundt C, Weyand M, Daniel W, Schoerner C. Fatal bioprosthetic aortic valve endocarditis due to Cardiobacterium valvarum. J Clin Microbiol 2007; 45:2324-6. [PubMed]

28. Geraci JE, Wilson WR. Endocarditis due to gram-negative bacteria: Report of 56 cases. Mayo Clin Proc 1982; 57:145-148. [PubMed]

29. Geraci JE, Greipp PR, Wilkowske CJ, Wilson WR, Washington JA 2nd. Cardiobacterium hominis endocarditis: four cases with clinical and laboratory observations. Mayo Clin Proc 1978; 53: 49-53. [PubMed]

30. Goldberg M, Katz J. Infective endocarditis caused by fastidious oro-pharyngeal HACEK micro-organisms. J Oral Maxillofac Surg 2006; 64: 696-71. [PubMed]

31. Han X. Cardiobacterium valvarum endocarditis. Ann Intern Med 2005; 143: 614. [PubMed]

32. Han XY, Falsen E. Characterization of oral strains of Cardiobacterium valvarum and emended description of the organism. J Clin Microbiol 2005; 43:2370-74. [PubMed]

33. Han XY, Meltzer MC, Woods JT, Fainstein V. Endocarditis with ruptured cerebral aneurysm caused by Cardiobacterium valvarum sp. nov. J Clin Microbiol 2004; 42:1590-95. [PubMed]

34. Hoover SE, Fischer SE, Shaffer R, Steinberg BM, Lucey DR. Endocarditis due to a novel Cardiobacterium species [Letter]. Ann Intern Med 2005; 142:229-30. [PubMed]

35. Jenny DB, Letendre PW, Iverson G. Endocarditis caused by Kingella indologenes. Rev Infect Dis 1987; 9:787-789. [PubMed]

36. Johnson MC, Wasilauskas BL. Cardiobacterium hominis endocarditis. Am J Med Technol 1979; 45:28-30. [PubMed]

37. Jobanputra RS, Moysey J. Endocarditis due to Cardiobacterium hominis. J Clin Pathol 1977; 30:1033-1036. [PubMed]

38. Jolie A, Gnann JW. Cardiobacterium hominis causing late prosthetic valve endocarditis. Southern Med J 1986; 79:1461-1462. [PubMed]

39. Jorgensen J, Hindler J. New consensus guidelines from the Clinical and Laboratory Standards Institute for antimicrobial susceptibility testing of infrequently isolated or fastidious bacteria. Clin Infect Dis 2007; 44: 280-6. [PubMed]

40. Kasper G, Genth KR, Massner B, Wundt W. Endocarditis due to seldom demonstrated bacteria- Cardiobacterium hominis and Actinobacillus actinomycetemcomitans. Med Welt 1983; 34:1212-1216. [PubMed]

41. Khabib ON, Beloborodova NV, Osipov GA. Detection of bacterial molecular markers in the tissue of cardiac valves in normal and pathological states by gas chromatography and mass spectrometry. Zh Mikrobiol Epidemiol Immunobiol 2004; (3):62-8. [PubMed]

42. Kiwan Y, Shubaiber H, Chungh T. Cardiobacterium hominis endocarditis. Report of one case and review of the literature. J Cardiovasc Surg 1989; 30:281-283. [PubMed]

43. Kosowska-Shick K, Smith K, Bogdanovich T, Ednie L, Jones R, Appelbaum P. Activity of DX-619 compared to other agents against viridans group streptococci, Streptococcus bovis, and Cardiobacterium hominis. Antimicrob Agents Chemother 2006; 50 4191-4. [PubMed]

44. Kugler KC, Biedenbach DJ, Jones RN. Determination of the antimicrobial activity of 29 clinically important compounds tested against fastidious HACEK group organisms. Diagn Microbiol Infect Dis 1999; 34:73-76. [PubMed]

45. Kuzucu C, Yetkin G, Kocak G, Nisanoglu V. An unusual case of pericarditis cause by Cardiobacterium hominis. J infect 2005; 50: 346-7. [PubMed]

46. Laguna J, Derby BM, Chase R. Cardiobacterium hominis endocarditis with cerebral mycotic aneurysm. Arch Neurol 1975; 32:438-439. [PubMed]

47. Lane T, MacGregor RR, Wright D, Hollander J. Cardiobacterium hominis: an elusive cause of endocarditis. J Infect 1983; 6:75-80. [PubMed]

48. Lecluse E, Scanu P, Saloux E, Vergnaud M, Valette B, Agostini D. Grard Y, Braud J, Grollier G, Potier JC. Endocarditis caused by Cardiobacterium hominis Presse Med 1994; 23:325-328. [PubMed]

49. Le Moing V, Lacassin F, Delahousse M, Duval X, Longuet P, Leport C, Vilde J-L. Use of corticosteroids in glomerulonephritis related to infective endocarditis: three cases and review. Clin Infect Dis 1998; 28:1057-1061.

50. Le-Quellec A, Bessis D, Perez C, Ciurana AJ. Endocarditis due to ß-lactamase-producing Cardiobacterium hominis [Letter]. Clin Infect Dis 1994; 19:994-995. [PubMed]

51. Lesimple B, Dujardin JJ, Joly P, Hendriex S, Fievert P. A case report of Cardiobacterium hominis endocarditis. Ann Biol Clin (Paris) 2002; 60:468-70. [PubMed]

52. Lin BH, Vieco PT. Intracranial mycotic aneurysm in a patient with endocarditis caused by Cardiobacterium hominis. Can Assoc Radiol J 1995; 46:40-42. [PubMed]

53. Lu P, Hsueh P, Hung C, Teng L, Jang T, Luh K. Infective endocarditis complicated with progressive heart failure due to *-lactamase-producing Cardiobacterium hominis J Clin Micro 2000; 38:2015-2017. [PubMed]

54. Maeland A, Teine AN, Arnesen H, Garborg I. Cardiobacterium hominis endocarditis [Letter]. Eur J Clin Microbiol 1983; 2:216-217. [PubMed]

55. Malani A, Aronoff D, Bradley S, Kauffman C. Cardiobacterium hominis endocarditis: Two cases and a revie of the literature. Eur J Clin Microbiol Infect Dis 2006; 25: 587-95. [PubMed]

56. Manso E, Strusi P, Massacci C, Ferrini L. Endocarditis due to Cardiobacterium hominis. Boll Ist Sieroter Milan 1987; 66:489-90. [PubMed]

57. Marques MT, Barreira R, Almeida M, Gil V. Cardiobacterium hominis prosthetic valve endocarditis diagnosed in Portugal [Letter]. Ann Biol Clin 1995; 53:299-300. [PubMed]

58. Martin-Rico P, Martinez-Rubio C, Perez-Benito L, Sanz-Mareno J. Subacute bacterial endocarditis caused by Cardiobacterium hominis. Enferm Infecc Microbiol Clin 1990; 8:186. [PubMed]

59. Meltzer MC, Woods JT, Fainstein V, Tarrand JJ, Han XY. Endocarditis with a ruptured cerebral aneurysm caused by Cardiobacterium valvarum sp. nov. GenBank direct submission AF506987. Int J Syst Evol Microbiol 2004; 54:1425-26. [PubMed]

60. Meyer DJ, Gering DN. Favorable prognosis of patients with prosthetic valve endocarditis caused by gram-negative bacilli of the HACEK group. Am J Med 1988; 85:104-107. [PubMed]

61. Michel P, Defraigne JO, Carpentier M, Limet R. Valve replacement for endocarditis due to Cardiobacterium hominis. Rev Med Liege 1991; 46:375-377. [PubMed]

62. Midgley J, Lapage SP, Jenkins BA, Barrow GI, Roberts ME, Buck AG. Cardiobacterium hominis endocarditis. J Med Microbiol 1970; 3:91-98. [PubMed]

63. Mueller NJ, Kaplan V, Zbinden R, Altwegg M. Diagnosis of Cardiobacterium hominis endocarditis by broad-range PCR from arterio-embolic tissue. Infection 1999; 27:278-279. [PubMed]

64. National Committee for Clinical Laboratory Standards. 2005. Performance standards for antimicrobial susceptibility testing: fifteenth informational supplement M100-S15. National Committee for Laboratory Standards, Wayne, Pa.

65. Nikkari S, Gotoff R, Bourbeau PP, Brown RE, Kamal NR, Relman DA. Identification of Cardiobacterium hominis by broad-range bacterial polymerase chain reaction analysis in a case of culture–negative endocarditis. Arch Intern Med 2002; 162:477-79. [PubMed]

66. Nurnberger M, Treadwell T, Lin B, Weintraub A. Pacemaker lead infection and vertebral osteomyelitis presumed due to Cardiobacterium hominis [Letter]. Clin Infect Dis 1998; 27:890-891. [PubMed]

67. Pankey GA, Horton JM. Cardiobacterium hominis endocarditis: a case report. J Miss State Med Assoc 1978; 19:107-109. [PubMed]

68. Perdue GD, Dorney ER, Ferrier F. Embolomycotic aneurysm associated with bacterial endocarditis due to Cardiobacterium hominis. Am Surg 1968; 34:901-904. [PubMed]

69. Permanyar-Miralda G, Tornas-Mas MP, Planes-Reig A, Rius-Davi A, Soler-Soler J. Late prosthetic valve endocarditis. Europ Heart J 1984; 5:129-132. [PubMed]

70. Petti C, Bhally H, Weinstein M, Joho K, Wakefield T, Reller L Carrol K. Utility of extended blood culture incubation for isolation of Haemophilus, Actinobacillus, Cardiobacterium, Ekinella and Kingella organisms: a retrospective multicenter evaluation. J Clin Microbiol 2006; 44: 257-9. [PubMed]

71. Petti C, Polage C, Schreckenberger P. The role of 16S rRNA gene sequencing in identification of microorganisms misidentified by conventional methods. J Clin Microbiol 2005; 43: 6123-5. [PubMed]

72. Piot P, Dasnoy J, Eyckmans L Bacterial endocarditis due to Cardiobacterium hominis. Acta Clin Belg 1978; 33:308-312. [PubMed]

73. Prior RB, Spagna VA, Perkins RL. Endocarditis due to strain of Cardiobacterium hominis resistant to erythromycin and vancomycin. Chest 1979; 75:85-86. [PubMed]

74. Pritchard TM, Foust RT, Cantely JR, Leman RB. Prosthetic valve endocarditis due to Cardiobacterium hominis occurring after upper gastrointestinal endoscopy. Am J Med 1991; 90:516-518. [PubMed]

75. Rahal JJ Jr, Simberkoff MS. Bactericidal activity of chloramphenicol in endocarditis and meningitis. In: program and abstracts of the 17th Interscience Conference on Antimicrobial Agents and Chemotherapy (abstract no. 5). Washington, DC: American Society for Microbiology, 1977.

76. Rechtman DJ, Nadler JP. Abdominal abscess due to Cardiobacterium hominis and Clostridium bifermentans. Rev Infect Dis 1991; 13:418-419. [PubMed]

77. Robison WJ, Vitelli AS. Infectious endocarditis by Cardiobacterium hominis. South Med J 1985; 78:1020-1021. [PubMed]

78. Ronnevik PK, Neess HC. Septicaemia caused by Cardiobacterium hominis – a case report Acta Path Microbiol Scand 1981; 89:243-244. [PubMed]

79. Savage DD, Kagen RL, Young NA, Horvath AE. Cardiobacterium hominis endocarditis: description of two patients and characterization of the organism. J Clin Microbiol 1977; 5:75-80. [PubMed]

80. Shivaprakasha S, Radhakrishnan K, Kamath P, Karim P. Late prosthetic valve endocarditis due to Cardiobacterium hominis, an unusual complication. Indian J Med Microbiol 2007; 25: 64-6. [PubMed]

81. Silver SE. Ruptured mycotic aneurysm of the superior mesenteric artery that was due to Cardiobacterium endocarditis. Clin Infect Dis 1999; 29:1573-1574. [PubMed]

82. Slotnich IJ, Dougherty M. Further characterization of an unclassified group of bacteria causing endocarditis in man: Cardiobacterium hominis gen. et sp. nov. Antonie von Leeuwenhoek J Microbiol Serol 1964; 30:261-272. [PubMed]

83. Slotnick IJ, Mertz J, Dougherty M. Fluorescent antibody detection of human occurrence of an unclassified bacterial group causing endocarditis. J Infect Dis 1964; 114:503. [PubMed]

84. Slotnick IJ. Cardiobacterium hominis in genitourinary specimens. J Bacteriol 1968; 95:1175. [PubMed]

85. Spernoga JE, Laskowski L, Marr J, Burmeister RJ. Cardiobacterium endocarditis. Southern Med J 1979; 72:85-87. [PubMed]

86. Snyder A, Ellner PD. Cardiobacterium hominis endocarditis. NY State J Med 1969; 69:704-705. [PubMed]

87. Taveras JM III, Campo R, Segal N, Urena PE, Lacayo L. Apparent culture-negative endocarditis of the prosthetic valve caused by Cardiobacterium hominis. South Med J 1993; 86:1439-1440. [PubMed]

88. Tucker DN, Slotnick IJ, King EO, Tynes B, Nicholson J, Crevasse L. Endocarditis caused by a Pasteurella-like organism. Report of four cases. N Engl J Med 1962; 267:913-916. [PubMed]

89. Vogt K, Klefisch F, Hahn H, Schmutzler H. Antibacterial efficacy of ciprofloxacin in a case of endocarditis due to Cardiobacterium hominis. Zbl Bakt 1994; 281:80-84. [PubMed]

90. Weiner M, Werthamer S. Cardiobacterium hominis endocarditis. Characterization of the unusual organisms and review of the literature. Am J Clin Path 1975; 63:131-134. [PubMed]

91. Wilson WR, Karchmer AW, Dajani AS, Taubert KA, Bayer A, Kaye D, Bisno AL, Ferrieri P, Shulman ST, Durack DT. Antibiotic treatment of adults with infective endocarditis due to streptocooci, enterococci, staphylococci, and HACEK organisms. JAMA 1995; 274: 1706-1713. [PubMed]

92. Wong MJ, Chan RM. Atypical presentation of Cardiobacterium hominis endocarditis. Can Med Assoc J 1982; 127:511-512 [PubMed]

93. Wormser GP, Bottone EJ. Cardiobacterium hominis: Review of microbiologic and clinical features. Rev Infect Dis 1983; 5:680-691. [PubMed]

94. Wormser GP, Bottone EJ, Tudy J, Hirschman SZ. Cardiobacterium hominis: review of prior infections and report of endocarditis on a fascia lata prosthetic heart valve. Am J Med Sci 1978; 276:117-126. [PubMed]

95. Zbinden R, Hany A, Luthy R, Conen D, Heinzer I. Antibody response in six HACEK endocarditis cases under therapy. Acta Pathologica Microbiologica et Immunologica Scandinavica 1998; 106:547-52. [PubMed]

96. Zehtner E, Seifert H, Petit M, Plum G, Peters G, Diehl V. A protracted course in Cardiobacterium hominis endocarditis. Dtsch Med Wschr 1991; 116:768-771.[PubMed]