CONCISE COMMUNICATION

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1 CONCISE COMMUNICATION Rothia dentocariosa, endocarditis and mycotic aneurysms: case report and review of the literature M. Boudewijns 1, K. Magerman 1, J. Verhaegen 2, G. Debrock 3, W. E. Peetermans 3, P. Donkersloot 4, A. Mewis 1, V. Peeters 1, J. L. Rummens 1 and R. Cartuyvels 1 1 Clinical Laboratory, Virga Jesse Hospital, Stadsomvaart 11, B-3500 Hasselt, 2 Department of Microbiology and 3 Department of Internal Medicine, University Hospital Leuven and 4 Department of Neurosurgery, Virga Jesse Hospital, Hasselt, Belgium Tel: þ Fax: þ reinoud.cartuyvels@virgajesse.be Rothia dentocariosa is a rare cause of endocarditis. It occurs most frequently in patients with prior heart conditions. Although the clinical course is typically subacute, it has a high rate of complications. In particular, the reported incidence of mycotic aneurysms is as high as 25%. Penicillin is the treatment of choice, but additional complications may necessitate prompt surgical intervention. As far as we know, this paper reports the first case of repeated subarachnoid hemorrhages due to R. dentocariosa endocarditis. Keywords Rothia dentocariosa, endocarditis, mycotic aneurysm Accepted 16 January 2002 Clin Microbiol Infect 2003; 9: INTRODUCTION In 1967, the genus Rothia was created to classify the bacterium until then known as Actinomyces dentocariosus, Nocardia dentocariosus or Nocardia salivae [1]. Rothia dentocariosa is a common inhabitant of the cavities of the human mouth and throat [2,3]. The bacterium was first isolated from carious lesions [4]. However, since 1975 there have been several reports of serious infections due to R. dentocariosa [5]. The most serious infection associated with R. dentocariosa is infectious endocarditis (IE), although R. dentocariosa is a rare cause of IE [6 21]. We report a case of IE caused by R. dentocariosa with an unusual presentation and a complicated course. Nineteen previously reported cases are reviewed. CASE REPORT A 17-year-old girl was admitted to the hospital because of severe frontal headache of sudden onset. She was known to have impaired function of the as a consequence of a congenital bicuspid valve, for which she had undergone open valvotomy at the age of 4 and percutaneous dilatation at the age of 13. Two months before admission, the patient developed a low-grade fever, malaise, and an erysipeloid lesion on her leg. At first she was treated by her general practitioner with clometocillin, an oral penicillin, and subsequently with amoxicillin clavulanic acid. Both treatments failed to resolve the symptoms definitively, after an initial response. On admission, the patient was pale and somnolent. She showed meningeal irritation but no focal neurologic deficits. A grade 4/6 systolic murmur at the left sternal border and a grade 2/6 diastolic murmur at the apex were noted. The temperature was C, the blood pressure was 140/ 60 mmhg, the pulse was 64/min, and the respiratory rate was 16/min. The results of skin, abdominal and lung examination were unremarkable. A contrast-enhanced computed tomographic (CT) scan of the brain revealed a subarachnoid hemorrhage localized in the right temporoparietal region. Four-vessel cerebral angiography demonstrated the presence of an aneurysm at the right communicans posterior artery. The results of an ß 2003 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

2 Concise Communication 223 electrocardiogram and a chest roentgenogram were interpreted as being normal. Transthoracic echocardiography (TTE) documented moderate insufficiency and severe stenosis. No vegetations were seen. Laboratory tests were notable for a hemoglobin concentration of 11.5 g/dl, a leukocyte count of /mm 3,a sedimentation rate of 41 mm/h, and a c-reative protein concentration (CRP) of 2.3 mg/dl. Liver and renal function tests were normal, as was the urinalysis. The patient underwent neurosurgical trepanation and clipping of the intracranial aneurysm. The postoperative course was uncomplicated, apart from the development of a subconjunctival hemorrhage. On day 20 of hospitalization, the patient was discharged. However, 1 week later, she was readmitted because of recurrence of severe headache, followed by an epileptic insult with postictal right hemiparesis and dysphasia. Physical examination revealed a pale and agitated girl. She was hemodynamically stable. The temperature was C. The heart murmur was unchanged. A skin rash and mild clubbing were present. She showed good dental hygiene. She was being treated by an orthodontist, but denied recent invasive dental procedures. Compared with her first admission, no other abnormalities were noted. A repeat CT of the brain confirmed the presence of a new subarachnoid hemorrhage localized at the left parietal region. Four-vessel cerebral angiography revealed at least three bilateral intracranial aneurysms (Figure 1). A repeat TTE showed similar findings as the first time. The hemoglobin concentration was 9.2 g/dl, the leukocyte count /mm 3, and the CRP 13.4 mg/dl. The diagnosis of intracranial mycotic aneurysms was made, presumably related to an episode of IE. Four sets of blood cultures were taken over a 2-h period. The blood cultures were incubated at 35 8C using the Bactec 9240 system (Becton Dickinson, Sparks, MD, USA) in aerobic and anaerobic bottles (Bactec Plus Aerobic/F and Anaerobic/F, Becton Dickinson). After 3 days of incubation, all of the aerobic bottles became positive. Gram staining revealed Gram-positive filamentous rods with occasional branching. The bacterium was nonmotile and non-acid-fast. Subcultures on 5% sheep blood agar yielded non-hemolytic, small, adherent, dry white colonies after 24 h of aerobic incubation at 35 8C. After prolonged incubation, the colony surface became rough, with several colonies showing a spoked-wheel morphology. No aerial mycelium was produced. On Triple Sugar Iron agar, the bacterium had a mucoid appearance and showed acidification of both butt and slant. The following biochemical reactions were positive: catalase production, esculin hydrolysis, and nitrate reduction. Oxidase, urease, indol, lysine and ornithine decarboxylase and gelatinase production were negative. Carbohydrate-fermentation reactions were positive for glucose, sucrose and maltose, but negative for lactose, mannitol and xylose. Use of API CORYNE test strips (Biomérieux, Marcy l Etoile, France) yielded code , compatible with identification of R. dentocariosa. Analysis of the cellular fatty acid (CFA) composition (Microbial ID, Newark, NY, USA) revealed that the majority of the CFAs comprised one of two types: anteisopentadecanoic acid (C a15 : 0 ) and anteisoheptadecanoic acid (C a17 : 0 ). Based on the above described characteristics, the Laboratory of Microbiology of the University Hospital Leuven confirmed the identification of the bacterium as R. dentocariosa. The minimal inhibitory concentrations (MICs) for antimicrobial agents, measured on horse blood agar using the gradient diffusion method (E test, AB Biodisk, Solna, Sweden), were: penicillin mg/l, cefotaxime mg/ L, clindamycin 0.75 mg/l, vancomycin 1.5 mg/l, teicoplanin 0.75 mg/l, and gentamicin 1.5 mg/l. Meanwhile, the patient was transferred to the University Hospital Leuven, where transesophageal echocardiography (TEE) demonstrated the presence of a vegetation on the right leaflet of the bicuspid. An orthopantomogram showed no dental decay. Treatment with intravenous penicillin (24 million U/day) was started, combined with amikacin (1 g/day) after a few days. During this treatment, the patient developed fever and some Janeway lesions on the forearms. Fourteen sets of blood cultures were taken over a 20-day period, but yielded no growth of bacteria. Because a routinely performed repeat TEE showed the presence of an aortic root abscess after 1 week of treatment, the patient underwent replacement. The valve was cultured and yielded growth of coagulase-negative Staphylococcus, probably due to contamination. One month after treatment, the patient was doing well. Repeat fourvessel cerebral angiography showed that the intracranial mycotic aneurysms had resolved. Nine months after treatment, the patient still is doing well.

3 224 Clinical Microbiology and Infection, Volume 9 Number 3, March 2003 DISCUSSION A MedLine search for R. dentocariosa IE revealed 19 cases [6 21]. These 19 cases and four new cases are summarized in Table 1. In seven cases, no data regarding the identification of the bacterium were shown [2,5 8,15,16]. In fact, in only five cases were the date presented sufficient to meet the minimal microbiological requirements for publication on disease associations of coryneform bacteria, as proposed by Funke [4,10 13,22]. In contrast, all 19 cases met the Duke criteria for the definite or possible diagnosis of IE [23]. Properties allowing presumptive identification of R. dentocariosa are presented in Table 2. R. dentocariosa is a pleomorphic Gram-positive bacterium that varies in form from coccoid to irregular rod-shaped to filamentous with possible branching. Growth is best with aerobic incubation at C. On 5% blood agar, the colonies are white, mostly smooth and about 1 mm in diameter after 24 h of incubation (Figure 2). After prolonged incubation, they become larger and rough, often showing the characteristic spoked-wheel appearance [2,22]. The API CORYNE test strips are useful for identification and typically yield codes or [24]. However, correct identification of R. dentocariosa can be difficult, especially its differentiation from Dermabacter hominis, Actinomyces viscosus, Propionibacterium avidum, and Corynebacterium matruchotii. Chemotaxonomic investigation (e.g. CFA chromatography) is recommended for definite identification of R. dentocariosa [22,24]. If R. dentocariosa is not correctly identified in blood cultures, but regarded as a contaminant coryneform bacterium, delay in diagnosis and appropriate treatment is possible. This has been reported in one case [10]. Various clinical features of R. dentocariosa IE are summarized in Table 3. Of interest are the male predominance (75%), the frequent presence of prior heart conditions (85%), and the high rates of major complications, both cardiac (50%) and non-cardiac (40%). These may be the consequences of a more protracted course of IE caused by this microorganism. Complications reported include cardiac abscess, heart valve insufficiency, congestive heart failure, mycotic aneurysms, brain abscess, intracerebral hemorrhage, subarachnoid hemorrhage, and vertebral osteomyelitis. Nevertheless, only three patients (15%) have died due to complications. Two of these three patients presented with a more acute form of disease. This is illustrated by the reported time between the onset of symptoms and the diagnosis of IE, which was 5 days for these two patients, versus an overall mean of 44 days. The third patient had a protracted disease course, developed cardiac complications, and died because of refusal to undergo cardiac surgery. Our case is remarkable for the occurrence of two subarachnoid hemorrhages within 1 month due to intracranial mycotic aneurysms. To our knowledge, this is the first reported case of R. dentocariosa IE complicated by repeated subarachnoid hemorrhages. Our case brings the total amount of R. dentocariosa IEs complicated by mycotic aneurysms to 25% of reported cases. This is much greater than the reported incidence of mycotic aneurysms as complications of IE (3 5% of cases) [23,25]. Intracranial mycotic aneurysms represent only a fraction of reported mycotic aneurysms, but they are probably underestimated because some remain asymptomatic and resolve with antibiotic therapy. Most intracranial mycotic aneurysms are caused by streptococci and Staphylococcus aureus and are localized to the distal middle cerebral artery branches, as in the present case. Their appearance at this locality is almost pathognomonic for IE, since other cerebral aneurysms are confined to the greater vessels at the skull base. Although most intracranial mycotic aneurysms will heal with antibiotic treatment, some will progress in size and/or number and lead to rupture, causing substantial morbidity or mortality. Treatment decisions concerning medical versus surgical therapy have to be individualized. Frequent serial angiograms are necessary, and prompt excision is indicated upon enlargement or bleeding of a (distal) intracranial mycotic aneurysm [25]. Although antimicrobial susceptibility data are rare and no NCCLS protocols exist for testing of susceptibility, the most frequently used antimicrobial therapy for R. dentocariosa IE is the combination of penicillin and gentamicin (45%). Strains of R. dentocariosa tested in nine of 20 cases of IE have shown a universally low penicillin MIC (range mg/l). An elevated gentamicin MIC has been noted in two cases [13,15]. Although no NCCLS susceptibility breakpoints for R. dentocariosa exist, the low penicillin MICs and the favorable outcome with penicillin therapy suggest in vivo susceptibility of R. dentocariosa. Nevertheless, disease progression in patients receiving proper

4 Concise Communication 225 Table 1 Summary of published cases on Rothia dentocariosa endocarditis Case Patient age/sex Symptoms at presentation 1 [6] 58/M Fever b, dyspnea, mental deterioration Risk factors Time to diagnosis a Prior heart condition Other (mg/l) 6 weeks Mitral regurtitation 2 [7] 57/M Fever, myalgia, headache 3 weeks Mitral valve prolapse 3 [8] 53/M Fever 2 weeks Rheumatic mitral valve disease 4 [9] 27/F Fever, fatigue 4 weeks Bicuspid 5 [10] 41/M Fever 2 months Mitral regurgitation 6 [11] 35/M Fever, chills malaise, night sweats headache 7 [12] 40/M Fever, dyspnea, malaise 8 [13] 71/M Fever, chills, malaise 9 [14] 17/M Fever, fatigue, myalgia, abdominal pain 10 [15] 70/M Fever, chills, fatigue, headache, weakness, mental deterioration 11 [15] 67/M Fever, chills, malaise 12 [15] 50/M Fever, malaise, night sweats, arthralgia 5 days Undefined heart murmur 10 days Prosthetic 7 days Prosthetic 6 weeks Rheumatic fever 5 days Mitral regurgitation, aortic insufficiency 1 month Prosthetic 11 months Prosthetic MIC P treatment Antibiotic Complication Outcome None requiring mitral valve replacement <0.01 P þgm Progressive disease Dental 0.01 SM þ P None procedure Dental 0.12 P þgm þ RA None fracture Periodontal <0.06 P þgm Brain abscess abscess None Unknown VA þ GM, then P þ GM Intravenous drug abuse Intracranial mycotic aneurysms with cerebral hemorrhage Unknown VA þ GM Perivalvular abscess acute heart failure requiring replacement Death None Unknown VA þ GM None Dental decay Unknown P þgm, then CRO, back to P None None <0.03 P þgm Mycotic aneurysm artery Alcohol abuse, P þva þ NET Multiple brain Death carious teeth abscesses, mitral Periodontal disease replacement <0.016 RA þ CIP Degenerated aortic prosthetic valve requiring replacement Periodontitis RA þ CRO Aortic root abscess, intracerebral hemorrhage attributed to intracranial mycotic aneurysms

5 226 Clinical Microbiology and Infection, Volume 9 Number 3, March 2003 Table 1 continued Case Patient age/sex Symptoms at presentation 13 [16] 37/M Fever, dyspnea, anorexia 14 [17] 54/M Fever, malaise, dyspnea, dizziness, palpitations Risk factors Time to diagnosis a Prior heart condition Other (mg/l) Unknown None Alcohol abuse, carious teeth, hepatoma 4 weeks Undefined valvular heart disease 15 [18] 6/F Fever 4 weeks Ventricular septum defect 16 [19] 62/M Fever, malaise, weight loss, lumbar pain 17 [20] 57/F Anorexia, weight loss 2 months Unknown Alcohol abuse, carious teeth, periodontitis 6 weeks None Poor dental hygiene 18 [20] 15/M Fever 4 weeks Aortic stenosis and insufficiency 19 [21] 61/F Fever, chest congestion 20 (our 17/F Headache, fever 12 weeks Bicuspid aortic case) valve with stenosis and insufficiency MIC P treatment Unknown AMX þ NET þ MZ Antibiotic Complication Outcome Acute heart failure requiring mitral, aortic and tricuspid valve replacement None abscess, heart failure, refused Unknown P þgm þ VA Aortic root surgery Death None Unknown IPM, then CRO None Diabetes mellitus dental procedure Unknown P þgm, then CRO Vertebral osteomyelitis Unknown failure requiring valve replacement on right deep femoral artery P þgm Acute heart Unknown VA þ GM þ CTX Mycotic aneurysm 17 days Mitral stenosis None Unknown P None Orthodontic treatment P þ AN Intracranial mycotic aneurysms with subarachnoid hemorrhages, aortic root abscess requiring replacement AN, amikacin; AMX, amoxicillin; CRO, ceftriaxone; CTX, cefotaxime; GM, gentamicin; IPM, imipinem; MZ, metronidazole; NET, netilmicin; P, penicillin; RA, rifampin; SM, streptomycin; VA, vancomycin. a Fever >38 8C. b Time from the onset of symptoms to diagnosis.

6 Concise Communication 227 Table 2 Tests for the presumptive identification of Rothia dentocariosa [2,22,24] Biochemical reactions Morphology and colony appearance Enzyme production Carbohydrate fermentation Non-motile Catalase: þ Glucose: þ Gram-positive Esculin hydrolysis: þ Maltose: þ Non-acid fast Nitrate reduction: þ Sucrose: þ Coccoid, irregular rod-shaped or filamentous forms (branching) Urease: Mannitol: Non-hemolytic, white, smooth to rough (spoked-wheel) Indole production: Xylose: Grows best aerobically Alkaline phosphatase: Ribose: b-galactosidase: Lactose: d Pyrrolidonylarylamidase: þ þ, 90% or more of strains positive;, 90% or more of strains negative; d, 11 89% of strains positive. Table 3 Clinical features of patients with Rothia dentocariosa endocarditis (n ¼ 20) Clinical feature Proportion of patients Percentage of patients Mean age in years (range) 44.8 (6 71) Female/male ratio 1 : 3 Prior heart condition 17/20 85% Prior dental procedure/disease 12/20 60% Fever (> 38 8C) 19/20 95% Heart murmur 18/20 90% Peripheral stigmata 10/20 50% Echocardiographic findings consistent with infectious endocarditis 18/20 90% Mean time from the onset of symptoms to diagnosis in days (range) 46 (5 334) Major non-cardiac complication a 8/20 40% Cardiac complication b 10/20 50% Patients requiring cardiac surgery 8/20 40% Death as outcome 3/20 15% a Brain abscess, mycotic aneurysm, intracerebral hemorrhage, subarachnoid hemorrhage, vertebral osteomyelitis. b Cardiac abscess, heart valve insufficiency, congestive heart failure. Figure 1 Four-vessel cerebral angiography showing (arrows) a prominent aneurysm on branches of the left and right arteria cerebri media. antimicrobial therapy has been reported in eight cases (40%). Of these eight patients, seven underwent cardiac surgery; five were cured and two died. This suggests that cardiac surgery has an important place in the treatment of R. dentocariosa IE, when antimicrobial therapy is ineffective. In summary, IE caused by R. dentocariosa is mostly a subacute process with low rates of mortality, but with frequent cardiac and non-cardiac complications. Among the latter, the reported incidence of mycotic aneurysms is high (25%). The universal susceptibility to penicillin makes this

7 228 Clinical Microbiology and Infection, Volume 9 Number 3, March 2003 Figure 2 Appearance of the colonies after 48 h of incubation on sheep blood agar. antibiotic agent first choice for therapy, but additional complications may necessitate prompt surgical intervention. REFERENCES 1. Georg LK, Brown JM. Rothia, General nov., an aerobic genus of the family Actinomycetaceae. Int J Syst Bacteriol 1967; 17: Brown JM, Georg LK, Waters LC. Laboratory identification of Rothia dentocariosa and its occurrence in clinical materials. Appl Microbiol 1969; 17: Von Graevenitz A, Pünter-Streit V, Riegel P, Funke G. Coryneform bacteria in throat cultures of healthy individuals. J Clin Microbiol 1998; 36: Onisi M. Study on the actinomyces from the deeper layers of carious dentine. JDent1949; 6: Scharfen J. Untraditional glucose fermenting actinomycetes as human pathogens. II. Rothia dentocariosa as a cause of abdominal actinomycosis and a pathogen in mice. Zentralbl Bakteriol 1975; 233: Pape J, Singer C, Kiehn TE, Lee BJ, Armstrong D. Infective endocarditis caused by Rothia dentocariosa. Ann Intern Med 1979; 91: Schafer FJ, Wing EJ, Norden CW. Infectious endocarditis caused by Rothia dentocariosa. Ann Intern Med 1979; 91: Broeren SA, Peel MM. Endocarditis caused by Rothia dentocariosa. J Clin Pathol 1984; 37: Isaacson JH, Grenko RT. Rothia dentocariosa endocarditis complicated by brain abscess. Am J Med 1988; 84: Shands JW. Rothia dentocariosa endocarditis. Am J Med 1988; 85: Sudduth EJ, Rozich JD, Farrar WE. Rothia dentocariosa endocarditis complicated by perivalvular abscess. Clin Infect Dis 1993; 17: Anderson MD, Kennedy CA, Walsh TP, Bowler WA. Prosthetic valve endocarditis due to Rothia dentocariosa. Clin Infect Dis 1993; 17: Ruben SJ. Rothia dentocariosa endocarditis. West J Med 1993; 159: Weersink AJL, Rozenberg-Arska M, Westerhof PW, Verhoef J. Rothia dentocariosa endocarditis complicated by an abdominal aneurysm. Clin Infect Dis 1994; 18: Binder D, Zbinden R, Widmer U, Opravil M, Krause M. Native and prosthetic valve endocarditis caused by Rothia dentocariosa: diagnostic and therapeutic considerations. Infection 1997; 25: Kong R, Mebazaa A, Heitz B et al. Case of triple endocarditis caused by Rothia dentocariosa and results of a survey in France. J Clin Microbiol 1998; 36: Ferraz V, McCarthy K, Smith D, Koornhof HJ. Rothia dentocariosa and aortic root abscess. J Infect 1998; 37: Braden DS, Feldman S, Palmer AL. Rothia dentocariosa endocarditis in a child. South Med J 1999; 92: Llopis F, Carratala J. Vertebral osteomyelitis complicating Rothia dentocariosa endocarditis. Eur J Clin Microbiol Infect Dis 2000; 19: Nguyen QV, Kavey RE, Colella C, Weiner LB. Infectious endocarditis caused by Rothia dentocariosa. Infect Med 2000; 17:

8 Concise Communication Larkin J, Montenero J, Targino M, Powers A, Accurso C, Campbell M. Rothia dentocariosa endocarditis. Clin Microbiol Newslet 2001; 23: Funke G, von Graevenitz A, Clarridge JE III, Bernard KA. Clinical microbiology of coryneform bacteria. Clin Microbiol Rev 1997; 10: Bayer AS, Bolger AF, Taubert KA et al. Diagnosis and management of infective endocarditis and its complications. Circulation 1998; 98: Bernard KA, Bellefeuille M, Hollis DG, Daneshvar MI, Moss CW. Cellular fatty acid composition and phenotypic and cultural characterization of CDC fermentative coryneform groups 3 and 5. J Clin Microbiol 1994; 32: Heiro M, Nikoskelainen J, Engblom E et al. Neurologic manifestations of infective endocarditis: a 17-year experience teaching hospital in Finland. Arch Intern Med 2000; 160: