International Journal of Infectious Diseases 31 (2015) 56–58

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Case Report

Case series of infective endocarditis caused by Granulicatella species Eduardo Leal Adam *, Rinaldo Focaccia Siciliano, Danielle Menosi Gualandro, Daniela Calderaro, Victor Sarli Issa, Flavia Rossi, Bruno Caramelli, Alfredo Jose Mansur, Tania Mara Varejao Strabelli Heart Institute (InCor), University of Sao Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44, Bloco 1, sala CCIH, Cerqueira Cesar–SP, Sao Paulo, 05403-000, Brazil

A R T I C L E I N F O

Article history: Received 23 July 2014 Received in revised form 27 September 2014 Accepted 6 October 2014 Corresponding Editor: Eskild Petersen, Aarhus, Denmark Keywords: Granulicatella spp Endocarditis Nutritionally variant streptococci

S U M M A R Y

Background: Nutritionally variant streptococci (NVS) are Gram-positive cocci characterized by their dependence on pyridoxal or cysteine supplementation for growth in standard blood culture media. They are responsible for severe infections in immunocompetent and immunosuppressed hosts, including infective endocarditis (IE). NVS have been divided into two different genera, Granulicatella and Abiotrophia. Methods: We report four cases of IE caused by Granulicatella species, including clinical presentation, echocardiographic characteristics, treatments received, and outcomes. We also performed a literature search for previously reported cases of IE caused by Granulicatella species to better characterize this condition. Results: A total of 29 cases of Granulicatella endocarditis were analyzed, including the four newly reported cases. The aortic (44%) and mitral (38%) valves were those most commonly affected. Multivalvular involvement was observed in 13% of cases. The mean vegetation length was 16 mm. Complications were frequent, including heart failure (30%), embolism (30%), and perivalvular abscess (11%). The most frequent antibiotic regimen (85%) was penicillin or one of its derivatives plus gentamicin. The mortality rate was 17%. Conclusions: Endocarditis due to Granulicatella species is a rare and severe condition. Complications are frequent despite the use of appropriate antibiotic regimens. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).

1. Introduction Nutritionally variant streptococci (NVS) were first described in 1961 by Frenkel and Hirsch as fastidious organisms that showed satellitism around colonies of other bacteria.1 These Gram-positive cocci were characterized by their dependence on pyridoxal or cysteine supplementation for growth in standard blood culture media. Although part of the normal oral, gastrointestinal, and genitourinary microbiota, NVS can cause severe infections in both immunocompetent and immunosuppressed hosts. NVS are also described as a cause of culture-negative infective endocarditis (IE), due to their slow growth and requirement for special media for identification. Other conditions related to NVS include primary bloodstream infections in neutropenic patients, central nervous system infections, osteomyelitis, septic arthritis, chronic sinusitis, and endophthalmitis.

After the subsequent division of the NVS into different genera, their most recent classification was proposed by Collins and Lawson in 2000 based on 16S rRNA gene sequencing, as follows: Granulicatella genus, comprising Granulicatella adiacens, Granulicatella elegans, and Granulicatella balaenopterae; and Abiotrophia genus, comprising solely Abiotrophia defectiva.2 Although more than 100 cases of IE caused by NVS have been reported to date, we found only 25 cases of IE caused specifically by Granulicatella sp since their division into the different genera and species (Table 1).3–21 In the present article, we report four cases of IE caused by Granulicatella species from our institution and provide a brief review of the literature.

2. Case reports 2.1. Case 1

* Corresponding author. Tel.: +55 11 982283377; fax: +55 11 26615538. E-mail address: [email protected] (E.L. Adam).

A 31-year-old male presented with a history of fever, fatigue, and lower extremity edema of 15 days duration. The patient

http://dx.doi.org/10.1016/j.ijid.2014.10.023 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

E.L. Adam et al. / International Journal of Infectious Diseases 31 (2015) 56–58

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Table 1 Cases of Granulicatella spp endocarditis reported to date Reference

Age, years

Sex

Valve

Vegetation size (mm)

Complications

Antibiotics

Valve surgery

Outcome

[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [13] [13] [13] [14] [15] [16] [17] [18] [18] [18] [18] [19] [20] [21] This This This This

38 71 29 68 57 85 53 18 77 43 18 61 30 28 47 31 71 81 58 63 38 63 40 32 86 31 64 75 59

NR F M M M M F M F M F M M F M M M M M M F F M F M M M M F

Aortic Aortic (prosthetic) Aortic Pacemaker lead No vegetation NR NR Pulmonic (prosthetic) Aortic Aortic (prosthetic) Mitral Mitral and tricuspid Mitral Mitral and aortic Mitral Mitral Mitral Mitral Mitral Mitral and aortic Tricuspid Mitral and tricuspid Aortic Tricuspid Aortic (prosthetic) Aortic Aortic Aortic Aortic

NR NR 14 NR No vegetation NR NR NR NR NR 16 20 11 13 15 10 20 18 NR NR NR NR 15 NR NR 21 26 19 8

NR None Heart failure Osteomyelitis CNS embolism NR NR None None Abscess Heart failure Heart failure CNS embolism Heart failure, peripheral embolism CNS embolism CNS embolism Peripheral embolism Heart failure None Heart failure None None Abscess, heart failure None None Abscess, fistula Heart failure CNS and spleen embolism Kidney and spleen embolism

PT, VAN, GEN PEN, GEN AMOX, GEN PEN, GEN, RIF AMP, GEN NR PEN, GEN VAN, GEN, RIF VAN, AMP, GEN PEN, GEN PEN, GEN PEN, GEN PEN, GEN, CEF PEN, GEN, TEI, VAN NR OXA, GEN AMP, GEN AMP, GEN VAN, GEN AMOX, GEN AMOX, GEN AMOX, GEN VAN, AMP, GEN LEV, PEN DAP, CEF CEF, OXA, GEN, TEI CEF, OXA, GEN, TEI, VAN CEF, PEN, GEN CEF, GEN, VAN

Yes Yes Yes No No NR Yes No No No Yes Yes Yes Yes Yes Yes No No No Yes No No Yes No No Yes Yes No Yes

Survived Survived Survived Survived Survived Died Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Died Survived Survived Died Survived Died Died Survived

report report report report

F, female; M, male; NR, not reported; CNS, central nervous system; PT, piperacillin–tazobactam; VAN, vancomycin; GEN, gentamicin; PEN, penicillin; AMOX, amoxicillin; RIF, rifampin; AMP, ampicillin; CEF, ceftriaxone; TEI, teicoplanin; OXA, oxacillin; LEV, levofloxacin; DAP, daptomycin.

2.3. Case 3

reported an unintentional 6-kg weight loss in the preceding months. An echocardiogram showed a bicuspid aortic valve with severe regurgitation and a 21-mm mobile vegetation. There was a cavity suggestive of abscess formation in the mitro-aortic region and a fistula from the aorta to the left ventricle. Ceftriaxone, oxacillin, and gentamicin were started. Surgery was performed for correction of the local complications and valve replacement. After identification of Granulicatella sp in blood cultures, the antibiotic regimen was changed to teicoplanin and gentamicin. The patient was discharged home after 4 weeks of combined antibiotic therapy.

A previously hypertensive 75-year-old male was admitted for investigation of weight loss and fatigue that had started after an ischemic stroke 3 months before. His laboratory examinations showed anemia, acute renal failure, and hematuria with dysmorphic features. An echocardiogram showed severe aortic regurgitation along with a 19-mm vegetation, and blood cultures were positive for G. adiacens in two samples. Penicillin and gentamicin were initiated. The patient developed embolization to the spleen, seizures, and hemodynamic instability, leading to death 3 weeks later.

2.2. Case 2

2.4. Case 4

A 64-year-old male with a past medical history of diabetes, obesity, and two coronary artery bypass surgeries was admitted for evaluation of effort-induced dyspnea in the 30 days prior to hospital presentation. The patient reported a weight loss of 25 kg in the past 6 months. Physical examination showed signs of pulmonary edema and poor dental hygiene. An echocardiogram revealed two vegetations in the aortic valve and moderate valve regurgitation. The initial empiric treatment for the IE was ceftriaxone, oxacillin, and gentamicin. On the seventh day of antibiotic therapy, the patient developed cardiogenic shock, requiring emergency valve replacement surgery. G. adiacens was identified in six blood cultures. Postoperatively, the antibiotic regimen was changed to teicoplanin and maintained for 6 weeks. The patient developed acute renal failure requiring hemodialysis and multiple hospital-acquired infections, which were treated with vancomycin, meropenem, polymyxin, and fluconazole. He progressed to refractory septic shock and died 5 months after the surgery.

A 59-year-old female, with a prior history of hypothyroidism and dyslipidemia, reported fever and a 5-kg weight loss over a 5month period. Two weeks prior to admission, she had developed left abdominal pain, lower extremity edema, and petechiae. Abdominal computed tomography showed embolization to the spleen and left kidney. An echocardiogram identified a bicuspid aortic valve with severe regurgitation and a vegetation measuring 8 mm in diameter. Six blood cultures revealed Granulicatella spp. After 2 weeks of treatment with ceftriaxone and gentamicin, the fever recurred and an echocardiogram showed an increase in the vegetation size to 12 mm. Valve replacement surgery was performed. The patient received treatment with vancomycin and gentamicin for 30 days and was discharged home asymptomatic. 3. Discussion A subacute or even chronic presentation of IE caused by Granulicatella sp has most often been described in the literature.

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Indeed, all of our patients presented a history of a few months of constitutional symptoms such as weight loss, anorexia, and fever, followed later by heart failure or embolism. When analyzing all cases, we observed that the aortic valve was affected in 44% (13/29) of patients, the mitral valve in 38% (11/29), and the tricuspid valve in 13% (4/29). Prosthetic valve endocarditis accounted for 13% (4/29) of cases. Multivalvular involvement was also observed in 13% (4/29) of patients. Endocarditis caused by Granulicatella sp has been associated with adverse outcomes. Analyzing the 25 previously reported cases together with our four, we found a mortality rate of 17% (5/ 29). When information was available, we found an incidence of heart failure of 30% (8/26). Embolism developed in 30% of patients (8/26) and perivalvular abscess in 11% (3/26). Our four patients developed at least one complication related to IE. A vegetation length greater than 15 mm is recognized as a strong predictor of embolic events and death in patients with IE in the first year after diagnosis.22 At least three of our patients fulfilled this criterion and showed vegetations of 19 to 26 mm. When a vegetation was found, the mean length observed in the literature was 16 mm. At our institution, the Bactec (BD Becton Dickinson) and VITEK 2 (bioMe´rieux) systems were used for culture and identification. A recent review of 23 cases of IE caused by NVS, including Granulicatella species, showed rates of sensitivity to penicillin reaching 78%.19 A phenomenon of penicillin tolerance has been described with NVS, in which the minimum bactericidal concentration (MBC) exceeds the minimum inhibitory concentration (MIC) by over 32-fold, leading to a slower antibiotic effect in vivo and possibly to a worse clinical response.23 Also, the relative difficulty in identification in blood cultures due to their nutritional requirements could possibly lead to delayed initiation of the appropriate antibiotic regimen and treatment failure. In 85% of cases (23/27) the antibiotic regimen included a penicillin or one of its derivatives plus gentamicin. Current guidelines recommend that IE caused by Granulicatella sp should be treated with antibiotics used for enterococcal IE. The American Heart Association guidelines published in 2005 suggest ampicillin or penicillin G plus gentamicin for 4 to 6 weeks or vancomycin as an alternative regimen.24 The European Society of Cardiology 2009 guidelines suggest penicillin G, ceftriaxone, or vancomycin for 6 weeks, combined with an aminoglycoside for at least the first 2 weeks in the treatment of IE caused by NVS.25 In three of the four cases from our institution, the clinical course was unfavorable despite the administration of the recommended antibiotic regimens. The second patient, initially treated with ceftriaxone, gentamicin, and oxacillin, developed cardiogenic shock on the seventh day of treatment, with partial recovery after cardiac surgery and the use of teicoplanin and vancomycin. The third patient was treated with penicillin plus gentamicin and died during treatment. The fourth patient, initially managed with ceftriaxone and gentamicin, showed an increase in vegetation size and fever after 2 weeks of therapy, requiring cardiac surgery and a change of antibiotics to vancomycin and gentamicin. Endocarditis due to Granulicatella spp is a rare and severe condition. Both the difficulty in isolation of the bacteria in blood cultures and the undesirable treatment response highlights the importance of this diagnosis. Considering the rarity of the condition, the analysis of reported cases like ours is of paramount importance.

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