Le Infezioni in Medicina, n. 2, 67-74, 2012 Rassegna Endocarditis caused Review by nutritionally variant streptococci: a case report and literature review Endocardite da varianti nutrizionali streptococciche: descrizione di un caso e revisione della letteratura

Simone Giuliano1, Roberta Caccese2, Paolo Carfagna2, Antonio Vena1, Marco Falcone1, Mario Venditti1 1Department of Public Health and Infectious Diseases, “La Sapienza” University of Rome, Rome, Italy; 2Hospital San Giovanni, Rome, Italy

n INTRODUCTION oedema and a holosystolic murmur of moder- ate intensity heard best at the cardiac apex and n the present study we investigated a case of irradiating to the axilla. IE caused by a fastidious bacterium, Granuli- Leukocyte count on admission was 8.360 per µl, Icatella adiacens, previously grouped with the the hemoglobin level was 12.0 g/dl. Multipla- nutritionally variant streptococci (NVS). nar transesophageal echocardiography showed and are found as part erosion of both cusps of the aortic valve and a of the normal flora colonizing oral, genitouri- 15 mm vegetation on the noncoronary cusp; a nary, and intestinal tracts and can be responsi- periannular abscess with suspect perivalvular ble of infections such as endocarditis, conjunc- pseudoaneurysm was seen; severe aortic regur- tivitis, endophthalmitis, infectious keratopaty, gitation, left ventricle enlargement with re- otitis, pancreatic abscesses and post-partum duced ejection fraction were also observed. sepsis [1, 2]. Pending the availability of diagnostic data, the Since we have found relatively few cases of en- patient was empirically treated with intra- docarditis caused by NVS described in litera- venous ampicillin (2 g q4h) plus gentamicin (80 ture in the past 10 years, this case report and the mg q8h) and vancomycin (500 mg q6h). Van- accompanying review may be of some interest comycin was withdrawn on day 4, after blood for clinical practice. culture results. Two sets of blood cultures yielded a slow grow- ing Gram-positive catalase-negative streptococ- n CASE REPORT cus, subsequently identified as Granulicatella adiacens by Vitek GPI card (bioMerieux Vitek). A 40-year-old man presenting with malaise, Antimicrobial susceptibility was performed us- worsening dyspnea, palpitation and acute heart ing Kirby-Bauer disc diffusion method accord- failure was admitted to the Emergency Depart- ing to standard guidelines [1, 3]. Isolates were ment at University “La Sapienza” of Rome. One susceptible to , ampicillin, linezolid month before presentation, patient had suf- and vancomycin and resistant to ceftriaxone. fered an episode of bronchitis treated with an- Susceptibility to gentamicin was not assessed. tibiotics (ceftriaxone, azithromycin and amoxi- On day 2 the patient underwent to aortic valve cillin in sequence) and he had had no dental or replacement. On day 7 he was discharged from surgical procedures. the ICU, fever subsided and general condition Physical examination revealed no fever, normal improved allowing the patient to be transferred blood pressure, sinus tachycardia, peripheral to a cardiac rehabilitation center on day 14.

67 2012 Combination therapy with ampicillin 12 g/die Granulicatella spp.) and 1 proved to be resistant and gentamicin 80 mg q8h lasted for 4 weeks (Abiotrophia spp.). In two cases the penicillin and then the patient was given an additional susceptibility was not reported. two-week treatment regimen with ampicillin Sites of infection: Endocarditis involved native alone same dosage as above. mitral valve in 10 patients (44%), native aortic No evidences of relapse were detected after a valve in 7 (26%), prosthetic valve in 2 (9%), six month follow-up. pacemaker lead in 1 (4%). No site of infection was reported in 4 cases. Analysis of the literature Therapy: All patients were treated with appro- Up until 2001 more than 100 cases of endo- priate antimicrobial combination chemothera- carditis caused by NVS were reported in litera- py (antibiotic regimen not reported in 3 cases); ture [2, 4-6]. These microorganisms have been heart valve replacement was performed in 11 responsible for 5-6% of all cases of streptococcal patients (48%). endocarditis; preexisting heart disease was doc- Mortality: Overall mortality was 9% meaning 2 umented in up to 90% of patients and prosthet- patients died out of 23. For both, no data about ic heart valve involvement was found in 10% of either antibiotic therapy administered or possi- patients [2, 3, 6, 7]. ble hearth valve surgery were reported. One of Systemic embolization occurred in one-third of them had Abiotrophia defectiva isolated from patients, aortic and mitral valves were reported blood cultures and the other one Granulicatella to be affected with similar frequency (13% and adiacens. Both isolates were susceptible to peni- 11%, respectively) 7. Morbidity and mortality cillin. proved higher than those associated with other forms of viridans streptococcal and enterococ- cal endocarditis [2, 4]. Although a bactericidal n DISCUSSION effect was demonstrated in vitro, therapy turned out to be unsuccessful in 41% of pa- Abiotrophia and Granulicatella, previously tients. About 27% of patients required heart known as NVS, are considered etiologic agents valve replacement surgery and mortality was of 5% of streptococcal endocarditis [6, 8]. These approximately 20%. More than 30% of strains of fastidious have been reported to be a NVS showed resistance to penicillin concentra- common cause of culture-negative bacterial en- tions of 0.12 mg/l [2, 5]. docarditis and their role in this infectious dis- After an extensive search in MEDLINE over the ease could be underestimated [6]. past 10 years, we found 22 well documented Streptococcus adiacens and Streptococcus defec- cases of endocarditis caused by NVS with iden- tivus were first recognized by Woo and Bouvet tification of bacterial species. [9, 10]. As a result of 16S rRNA gene sequence We have analyzed patient risk factors, bacterial data and other phylogenetic analysis, the species involved, penicillin susceptibility, sites names Abiotrophia adiacens and Abiotrophia defec- of infection, therapy administered and mortali- tiva were proposed in 1995 [9, 11]. Abiotrophia ty rates (Table 1). adiacens was subsequently transferred to Gran- We have examined 6 female patients (26%) and ulicatella adiacens by Collins and Lawson in 2000 17 male patients (74%), with a mean age of 47 [9, 12]. years (range 12-85). The identification, epidemiology and the spec- Risk factors: Fourteen patients (61%) showed un- trum of clinical diseases caused by G. adiacens derlying valvular heart predisposing condi- and A. defectiva have always been dependent tions, such as congenital valvular heart disease upon phenotypic characterization, but unusual (28%) or heart valve prosthesis (9%) and 9 pa- phenotypic characteristics that do not correlate tients (39%) had no risk factors for endocarditis. with the species descriptions in the literature Bacterial species: Abiotrophia spp. was isolated in are not uncommon and the gold standard of 10 (43%) cases of endocarditis, while Granuli- identification is considered 16S rRNA gene se- catella spp. was found in 13 (57%) cases. quencing [9, 13]. Penicillin susceptibility: Eighteen (78%) strains Such organisms may require broth supple- were reported to be susceptible to penicillin, 3 mented with pyridoxal hydrochloride or cys- strains (12%) were variably resistant to peni- teine and may exhibit a laboratory phenome- cillin; among them, 2 showed a reduced sus- non of “penicillin tolerance”. For tolerant ceptibility to penicillin (1 Abiotrophia spp. and 1 strains, the minimum bactericidal concentra-

68 2012 Table 1 - Data from case reports of Abiotrophia and Granulicatella spp. endocarditis in the last 10 years. References Patient Related Risk factors Identified Site of Therapy Penicillin MIC Outcome no./age procedures for species infection/ Susceptibility (y)/sex endocarditis Surgery Rosenthal O. 1/68/M None Pacemaker Granulicatella Pacemaker Penicillin Sensitive NR healed et al., 2002 adiacens lead + 30x106U [26] vertebral + rifampin osteomyelitis/ 600 mg + None gentamicin 260 mg (duration not specified) Casalta J.P. 2/29/M Dental Bicuspid Granulicatella Aortic valve/ amoxicillin NR NR healed et al., 2002 procedures aortic elegans Replacement 2g q6h + [27] 3M before valve (negative blood gentamicin IE, pneumonia cultures, positive 3 mg/Kg 1M before IE valve cultures) q24 x 4W Perkins A. 3/57/M Dental Mitral Granulicatella Mitral valve/ ampicillin 2g Sensitive NR healed et al., 2003 procedures regurgitation adiacens None q6h x 4W and [20] 4 and 5M caused by gentamicin before IE myxomatous 80 mg q8h degeneration x 2W Woo P.C. 4/15/M NR Congenital Abiotrophia NR NR Sensitive NR healed et al., 2003 [9] heart disease defectiva 5/74/F NR Chronic Abiotrophia NR NR Sensitive NR Dead rheumatic defectiva heart disease 6/85/M NR Aortic Granulicatella NR NR Sensitive NR Dead regurgitation adiacens Lainscak M. 7/62/M Dental Aortic valve Abiotrophia Prosthetic penicillin Sensitive 0.064 healed et al., 2005 [28] procedures prosthesis defectiva valve/ (5×106 U q.i.d.) µg/ml 4M before IE, None x 6W + pneumonia gentamicin (120 mg b.i.d.) x 2W* 8/26/M Inflamation Marfan Abiotrophia Aortic penicillin Sensitive 0.016 healed of foot toe syndrome defectiva valve/ (6×106 U q.i.d.) µg/ml and tonsillitis None x 6W + 2W before gentamicin (240 mg q.d.) x 2W Ohara- 9/53/F Dental None Granulicatella NR/ penicillin Sensitive 0.06 healed Nemoto Y. procedures elegans Surgery (30 x104 µg/ml et al., 2005 [29] 3M before IE U/kg once a day) + gentamicin (3 mg/kg once a day) + surgery continue 69 2012 Follow References Patient Related Risk factors Identified Site of Therapy Penicillin MIC Outcome no./age procedures for species infection/ Susceptibility (y)/sex endocarditis Surgery Jeng A. et al., 10/18/M Dental Pulmonary Granulicatella Prosthetic vancomycin NR NR healed 2005 [16] procedures valve adiacens valve/ + gentamicin 3-4W before IE prosthesis None + rifampin x 6W Senn L. et al., 11/58/F None Rheumatic Abiotrophia Mitral valve/ amoxicillin/ Sensitive NR healed 2006 [30] fever during defectiva NR clavulanate childhood + amikacin for 1w, then ceftriaxone for 3W*** 12/55/M None None Abiotrophia Aortic ceftriaxone Reduced 0.25 healed defectiva valve/NR for 6w + susceptibility µg/ml amikacin for 4W*** Hernando 13/77/M Dental None Granulicatella Aortic valve/ ampicillin Reduced NR healed Real S. et al., procedures spp None 2g q4h susceptibility 2007 [31] 4M before + gentamicin 80mg q8h x 4W Lin C.H., 14/51/M NR Mitral Abiotrophia Mitral valve/ penicillin, Sensitive NR healed Hsu R.B. 2007 valve defectiva Repair gentamicin° [32] prolapse 15/12/F NR None Abiotrophia Mitral valve/ vancomycin, Sensitive Ampi- healed defectiva None gentamicin, cillin teicoplanin, 0.19 rifampin, µg/ml cefotaxime° 16/65/M NR Mitral Abiotrophia Mitral valve/ penicillin, Resistant penicillin healed regurgitation defectiva Repair gentamicin° 0.125 µg/ml 17/49/M NR None Abiotrophia Aortic valve/ penicillin, Sensitive penicillin healed defectiva Replacement gentamicin, 0.032 ceftriaxone° µg/ml 18/18/F NR Rheumatic Granulicatella Mitral valve/ penicillin, Sensitive NR healed heart adiacens Replacement gentamicin° disease 19/61/M NR None Granulicatella Mitral valve/ penicillin, Sensitive NR healed adiacens Replacement gentamicin° 20/30/M NR None Granulicatella Mitral valve/ penicillin, Sensitive NR healed adiacens Repair gentamicin, ceftriaxone° 21/28/F NR None Granulicatella Mitral valve/ penicillin, Sensitive NR healed adiacens Replacement gentamicin vancomycin, teicoplanin° continue 70 2012 Follow References Patient Related Risk factors Identified Site of Therapy Penicillin MIC Outcome no./age procedures for species infection/ Susceptibility (y)/sex endocarditis Surgery Al Tawfiq J.A. 22/45/M Dental Mitral Granulicatella Mitral non specified Sensitive Penicillin healed et al., 2007 procedures valve elegans valve/Repair 6W antibiotic 0.06 [33] 3M before prolapse treatment µg/ml PR 23/40/M None None Granulicatella Aortic valve/ ampicillin Sensitive NR Healed adiacens Replacement 2g q4h for 6W + gentamicin 80mg q8h for 2W

Legend: AE = acute endocarditis; W = week; M = month; NR = not reported; PR = present case-report. *After 25 days of therapy with penicillin the patient developed macular rash and leucopenia; penicillin was substituted by ceftriaxone (2 g q.d.). **The duration of treatment was not reported. ***Doses were not reported. °Penicillin G 2 to 5 million Units q4h (up to 4-8 weeks) + Gentamicin (2 weeks). Ceftriaxone and vancomycin or teicoplanin administration if persistence of fever or high-level penicillin resistant streptococcus isolation. tion (MBC) of penicillin greatly exceeds the of normal heart valves [2, 7]. On the other hand, minimum inhibitory concentration (MIC) (usu- we have confirmed old data regarding pros- ally by 32-fold). These strains are killed more thetic valve involvement (9%) [2, 7]. Unlike slowly by penicillin in animal models of endo- streptococci belonging to the S. bovis group, no carditis [14, 15]. association has been documented between NVS Some authors found a high fibronectin binding and gastrointestinal dis- ability of A. defectiva strains associated with en- eases [18]. docarditis than the Granulicatella spp. isolated Treatment failure have been reported in about from patients with primary bacteremia and 41% of cases of IE caused by NVS, and almost this may be an important factor involved in the 27% of cases required prosthetic valve replace- pathogenesis of A. defectiva endovascular infec- ment, especially due to congestive heart failure tions. Granulicatella spp. bacteremias were ob- or major systemic emboli [3, 19, 20]. Treatment served only when predisposing conditions failure has been ascribed to the delay in begin- such as mucositis and neutropenia were pre- ning antimicrobial therapy attributable to the sent, suggesting a low pathogenicity of the iso- length of time required for isolation and identi- lated strains. fication of these bacteria and for antibiotic sus- Their poor ability to bind to extracellular ma- ceptibility testing. trix components could be correlated with a The slower generation time for NVS (2-3 h) than lower propensity to induce endocarditis [8]. that for (40-50 min), may On the contrary, other studies have demon- attenuate the activity of the beta-lactam antibi- strated that G. adiacens bound fibronectin very otics [16, 21]. In addition, NVS has shown in- avidly in adherence assays and readily caused creased resistance to penicillin, the mainstay of endocarditis on damaged heart tissue in therapy for treatment of streptococcal endo- catheterized rats. A. defectiva also infected dam- carditis, with a recent survey finding that only aged heart tissue significantly, but had moder- 55% of G. adiacens isolates showed penicillin ate levels of binding to fibronectin and other sensitivity, and 8% of A. defectiva isolates exhib- extracellular matrix proteins. Most of the G. ited sensitivity [16, 22]. Of further concern is para-adiacens and G. elegans strains exhibited that NVS have demonstrated significant toler- low binding capacities to any extracellular ma- ance to penicillin, as defined by an MBC/MIC trix proteins and poorly infected heart tissue ratio greater than 32 [16]. Therefore, NVS show [16, 17]. a similar antimicrobial susceptibility profile to Despite of old series showing a very high enterococcal species such as Enterococcus faecalis prevalence (90%) of preexisting heart disease, and unusual enterococci including Enterococcus our case report and review of past 10 year liter- raffinosus [23]. ature seem to show an increased involvement Bouvet has observed that morbidity and mor-

71 2012 tality of IE caused by Abiotrophia and Granuli- n CONCLUSION catella spp. exceeded those of the other forms of viridans streptococcal and enterococcal endo- IE caused by NVS exhibits higher relapse, treat- carditis, and patients with endocarditis caused ment failure and mortality rates than those by A. defectiva and Granulicatella species should caused by other oral streptococci. Based on our be treated with a regimen that is recommended literature review, antimicrobial therapy with for enterococcal endocarditis (4, 14). Dapto- penicillin and gentamicin is considered a valu- mycin is a new drug potentially effective able option for the management of patients against Abiotrophia spp. and Granulicatella spp. with this infection. However, early surgical in- [24]. However further studies are required to tervention is often needed in the event of he- evaluate the possible role of this molecule in the modynamic compromise due to extensive valve treatment of endocarditis caused by NVS. destruction. This is consistent with previous ev- Our literature review disclosed a higher peni- idences highlighting the role of surgical inter- cillin sensitivity (78%) compared with old stud- ventions in reducing overall mortality com- ies [2, 7]. This higher in vitro penicillin suscepti- pared with medical treatment alone [25]. bility seems to be concordant with a satisfacto- ry rate of clinical successes. Overall, we have Keywords: Infective Endocarditis (IE), Nutrition- found a very low (9%) mortality rate, with heart ally Variant Streptococci (NVS), Abiotrophia valve surgery carried out in 48% of patients. spp., Granulicatella spp.

SUMMARY

Infective endocarditis (IE) due to Abiotrophia and with high rates of relapse and therapeutic failure Granulicatella species, previously referred to as nu- despite in vitro effective antibiotic treatment regi- tritionally variant streptococci (NVS), occurs rarely mens. Analysis of literature revealed a high preva- and is often associated with negative blood cul- lence (61%) of valvular heart predisposing condi- tures. Rates of treatment failure, infection relapse tions associated with endocarditis caused by NVS, and mortality are higher than those of endocardi- such as congenital valvular heart disease or heart tis caused by other viridans streptococci. valve prosthesis. On the other hand, 39% of cases We report a case of endocarditis caused by Granuli- showed no evidence of risk factors. Combination catella adiacens in a young man with no risk factors, antimicrobial chemotherapy with penicillin and who was successfully treated with surgery and gentamicin represents the antimicrobial treatment combination antimicrobial chemotherapy, and pro- of choice in the management of patients with IE at- vide a literature review of endocarditis attributable tributable to NVS. Heart valve replacement surgery to these rare species of fastidious gram-positive coc- should be considered in cases of hemodynamic de- ci which have proven exceedingly difficult to treat, rangement due to significant valve destruction.

RIASSUNTO

L’endocardite infettiva dovuta a batteri appartenenti ai dovuta a queste rare specie di cocchi Gram-positivi di generi Abiotrophia e Granulicatella, precedentemen- difficile isolamento in laboratorio, il cui isolamento clini- te noti come varianti streptococciche di tipo nutriziona- co risulta associato ad elevata prevalenza di recidive e le (VSN), è un evento raro e spesso associato ad emocol- fallimenti terapeutici, nonostante l’impiego di antibioti- ture negative. I tassi di fallimento terapeutico, recidiva ci attivi in vitro. L’analisi della letteratura ha rivelato di infezione e mortalità sono più elevati rispetto a quel- un’elevata frequenza (61%) di condizioni predisponenti li che si riscontrano nelle endocarditi causate da strep- associate all’insorgenza di endocardite da VSN, come tococchi viridanti. per esempio valvulopatie congenite o valvole protesiche. Riportiamo un caso di endocardite causata da Granuli- D’altra parte il 39% dei pazienti affetti non ha mostrato catella adiacens in un giovane paziente con anamnesi evidenza di condizioni predisponenti. Il trattamento di patologica negativa per fattori di rischio di endocardite, scelta nel trattamento dei pazienti affetti da endocardite trattato con successo mediante l’associazione di un in- causata da VSN è rappresentata dalla combinazione di tervento di sostituzione valvolare e di chemioterapia an- penicillina e gentamicina. L’intervento di sostituzione timicrobica di combinazione. Forniamo, inoltre, una re- valvolare dovrebbe essere considerato in caso di compro- visione della letteratura relativa ai casi di endocardite missione emodinamica dovuta ad esteso danno valvolare.

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