Malek et al. BMC Infectious Diseases (2019) 19:301 https://doi.org/10.1186/s12879-019-3912-8

CASEREPORT Open Access garvieae, an unusual in : case report and review of the literature Alexandre Malek1†, Alejandro De la Hoz2†, Sara Isabel Gomez-Villegas3, Cima Nowbakht1 and Cesar A. Arias1,4,5,6,7*

Abstract Background: Lactococcus garvieae is an unusual cause of infective endocarditis (IE). No current diagnostic and therapeutic guidelines are available to treat IE caused by these organisms. Based on a case report, we provide a review of the literature of IE caused by L. garvieae and highlight diagnostic and treatment challenges of these and implications for management. Case presentation: A 50-year-old Asian male with mitral prosthetic valve presented to the hospital with intracranial haemorrhage, which was successfully treated. Three weeks later, he complained of generalized malaise. Further work up revealed cultures positive for Gram-positive cocci identified as L. garvieae by MALDI-TOF. An echocardiogram confirmed the diagnosis of IE. Susceptibility testing showed resistance only to clindamycin. Vancomycin plus were started as empirical therapy and, subsequently, the combination of ceftriaxone plus gentamicin was used after susceptibility studies were available. After two weeks of combination therapy, ceftriaxone was continued as monotherapy for six additional weeks with good outcome. Conclusions: Twenty-five cases of IE by Lactococcus garvieae have been reported in the literature. Compared to other Gram-positive cocci, L. garvieae affects more frequently patients with prosthetic valves. IE presents in a subacute manner and the case fatality rate can be as high as 16%, comparable to that of streptococcal IE (15.7%). Reliable methods for identification of L. garvieae include MALDI-TOF, 16S RNA PCR, API 32 strep kit and BD Automated Phoenix System. Recommended antimicrobials for L. garvieae IE are , , ceftriaxone or vancomycin in monotherapy or in combination with gentamicin. Keywords: Lactococcus, Case report, Gram positive cocci, Infective endocarditis, Diagnosis, Treatment, Risk factors

Background isolated from raw cow milk, goat cheese, fish, beef meat, Lactococcus garvieae are Gram-positive cocci previously poultry and pork meat [6]. Human infections caused by L. considered part of the genus Streptococcus. In 1985, these garvieae have been reported in different countries and organisms were classified within the genus lactococci due have been associated to ingestion of raw seafood. Indeed, to DNA-DNA hybridization studies and fatty acid profiles a study by Wang et al. found that among four patients [1–3]. Currently, the genus Lactococcus contains 11 spe- with invasive L. garvieae , three had ingested sea cies [4]. L. garvieae is associated with fish infections in food contaminated by these organisms [7]. Infective endo- warm water causing outbreaks of haemorrhagic sepsis in carditis (IE) is a known disease caused by L. garvieae, [2, 5]. These organisms have also been however, the true incidence of disease is difficult to assess since misidentification with other Gram-positive cocci like spp. and streptococci (employing different * Correspondence: [email protected]; [email protected] †Alexandre Malek and Alejandro De la Hoz contributed equally to this work. automatized diagnostic tools) has commonly been re- 1Department of Internal Medicine, Division of Infectious Diseases, UTHealth - ported [8, 9]. Here, we report a case of L. garvieae IE and McGovern Medical School, Houston, TX, USA describe the risk factors associated with this disease, the 4Center for Antimicrobial Resistance and Microbial Genomics (CARMiG), UTHealth - McGovern Medical School, Houston, TX, USA diagnostic challenges to identify these organisms and Full list of author information is available at the end of the article therapeutic approaches used to treat these infections. We

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seek to provide clinicians with relevant and updated infor- (MIC 1.5 μg/ml) and (MIC 2 μg/ml). With mation on the diagnosis and management of IE caused by these results, vancomycin was switched to ceftriaxone the genus L. garvieae. 2 g IV twice daily plus gentamicin as combination We searched MEDLINE, EMBASE and LILACS using therapy for the first 2 weeks. This regimen was chosen the following MeSH, major and free terms: “endocarditis”, basedonpreviouscasessincenospecificguidelines “endocarditis, bacterial”, “endocarditis, subacute bacterial”, exist on how to treat these organisms. Gentamicin was “endocarditis bacteriana”, “endocarditis bacteriana suba- stopped after two weeks and ceftriaxone was contin- guda” and “lactococo”, “lactococcus”, “lactococcus lactis”, ued for 4 additional weeks pending a surgical decision. “lactococcus garvieae”, “lactococcus garvieae endocardi- In the setting of intracranial bleed and IE, rupture of a tis”. We selected all the articles in Spanish, English and mycotic aneurysm was highly suspected and the pa- French published before March 2018 that included case tient was considered a possible surgical candidate for reports of endocarditis and Lactococcus in the titles. aortic valve replacement. CT angiography of the brain (5 weeks after the initial episode of intracranial bleed) Case presentation showed encephalomalacia in the left parietal and oc- A 50-year-old Asian man with history of rheumatic cipital lobes with subacute to chronic haemorrhage, disease (without hypertension) and mechanical pros- with no mycotic aneurysms. After several discussions, thetic mitral valve replacement 5 years before admission, the stroke team agreed on resuming anticoagulation dyslipidaemia and reflux esophagitis presented to the with heparin IV drip (considering that the patient had emergency room with severe bilateral occipital headache. a “chronic” bleed without active haemorrhage and that He was diagnosed with an intracranial haemorrhage the risk of embolism was high due to the presence of a confirmed by CT brain. At the time of admission, his mechanical heart valve and IE). It was also suggested INR was within therapeutic range (2.35). After initial postponing aortic valve replacement for at least 4 work up, the patient was hospitalized for 10 days and weeks after effective antimicrobial therapy. After 4 discharged without any residual neurologic sequelae. weeks of therapy, decrease of inflammatory markers Atorvastatin was prescribed. No fever or elevation of the (CRP to 8.5 mg/dl and ESR to 40 mm/h) was observed C reactive protein (CRP) or erythrocyte sedimentation and repeat blood cultures were negative. rate (ESR) were identified during the admission. He Upon further questioning, the patient admitted that worked as an accountant and had been living in the US his diet was rich in grilled fish. Additionally, he reported for the past 30 years with no recent travel outside the a long history of chronic epigastric pain for 5 years, for US. Three weeks later, he complained of flu-like symp- which he had been taking over the counter medicines. toms and oseltamivir was prescribed. A week later, the An esophagogastroduodenoscopy showed severe gastritis patient returned to the hospital with epistaxis, haema- and reflux esophagitis. After 6 weeks of treatment for IE, turia, and malaise without fever. Physical examination the patient had clinical improvement with no recurrence was unremarkable with normal neurologic exam, except of infection but repeat TEE revealed severe aortic valve for a pansystolic heart murmur. Blood tests showed ele- insufficiency. He underwent mechanical aortic valve re- vated white blood count (14.5 × 109/L) and serum cre- placement without complications and cultures from the atinine of 1.54 mg/dl (Normal value: 0.8–1.2 mg/dl). excised valve were sterile. CRP and ESR were also elevated (34.5 mg/dl and 75 mm/h, respectively). A Chest X ray was found without Discussion and conclusion acute abnormalities and the urine analysis showed no Different clinical presentations of subacute IE make it abnormalities. Three days after admission, blood cul- challenging to make an early diagnosis of infection and tures were positive for Gram-positive cocci in chains in can cause delays in appropriate treatment. In our case, 4 out of 4 bottles. Transthoracic echocardiography was treatment of IE was delayed due to low suspicion of the inconclusive, but a transoesophageal echocardiography disease at presentation and the occurrence of the intra- (TEE) revealed a 0.8 cm vegetation on the ventricular cranial haemorrhage. Importantly, collection of blood side of the native aortic valve without valve dysfunction, cultures as soon as infection was suspected, led to isola- confirming the diagnosis of IE. Empirical intravenous tion of L. garvieae and identification using MALDI-TOF. antibiotic therapy was started with vancomycin 30 mg/ A total of 25 cases of IE caused by L. garvieae were kg/day in divided doses and gentamicin 3 mg/kg/day. identified in the literature review [8–30]. Among the 25 The organism was recovered on blood agar and was cases of IE caused by L. garvieae (Table 1), 58% were identified by MALDI-TOF as Lactococcus garvieae. reported in men and the median age of presentation was Susceptibility testing showed resistance to clindamy- 68 years. Median duration of symptoms before consult- cin, whereas it was susceptible to penicillin (MIC ing was 14 days (IQR = 6.2–21). The most common re- 0.25 μg/ml), ceftriaxone (MIC 0.25 μg/ml), vancomycin ported symptoms were fever (68%) and chills (28%). Table 1 Clinical, microbiological and management characteristics of IE by L. garvieae Malek Reference Country Age Sex Associated Symptoms Physical Laboratories and Identification Susceptibility Therapy and Complications factors for IE and duration examination Echocardiography days of and Outcome Diseases Infectious BMC al. et by L. (days) (Vegetation size) treatment garvieae and comorbidities Clavero Chile 72 F AV fistulas, Chills, fever Fever, systolic TEE: mitral vegetation LG: Vitek 2¥,MS MIC: VAN: 2 μg/ml, Empiric: CLO Shock, et al. 2017 Diverticulosis, (1) murmur, (4 mm) Labs: and 16S rRNA CTX 0.25 µg/ml + AMK respiratory CKD, DM 2 and pulmonary Leucocytosis elevated PCR. PEN: 0.5 µg/ml. Directed: VAN failure (Died) HTN, colonic crackles CRP Colonoscopy: Kirby Bauer: + GEN µg (NI) polyps Colonic polyps Sensitive: ERY, CIP, SXT, AMC Resistant: CLI. Applying the criteria for B- (2019)19:301 haemolytic streptococci Lim and UK 57 M Cooked fish, Fever weight Pansystolic TEE: mitral valve LG: MS PEN MIC: 1 mg/L AMX + GEN No Jenkins gallstones, renal loss (60) murmur vegetation (NI) and Etest BioMérieux, S: (42d) Valve complications, 2017 stones, Colonic regurgitation. GEN 200 µg Oxoid replacement (Alive) polyps Colonoscopy: by diffusion disc Duodenal polyps testing. Landeloos Belgium 82 F Prosthetic mitral Fever, Bradycardia, TEE: mitral vegetation LG: MS, 16S rRNA NI Empiric: CRO No et al. 2017 valve, previous hyporexia, Basal lung (10x5mm) Labs: PCR. Directed: MXF complications endocarditis, dyspnoea (14) crepitations, Elevated CRP no Changed: PEN (Alive) Cooked fish, reinforce leucocytosis. Colonoscopy: + GEN colonic polyps, caused S2 Colonic polyps. Ambulatory: FA, HTN, AMX Osteoporosis. monotherapy (42d) No valve replacement Bazemore USA 45 M Multiple substance Malaise, Fever, systolic No Echo reported. LG: MS E-test: sensitive to Empiric: TZP Aortic valve et al. 2016 abuse. weakness (60) murmur Leucocytosis, Elevated CRO and VAN Cut-off + VAN dehiscence Repair of aortic CRP and ESR. values for S. bovis Directed: CRO + GEN (NI) + Valve (Alive) root repair aneurysm, Hepatitis C and Suh et al. South 75 F Mitral valve Dyspnoea (3) Holosystolic TTE: mitral vegetation (16 LG: Vitek 2¥, 16S MicroScan MICroSTREP Empiric: CRO Heart failure 2016 Korea prosthesis, murmur mm) Labs: leucocytosis, rRNA PCR. plus panel: PEN + GEN + RIF (Alive) eats Elevated CRP 0.12 µg/ml, AMC: Directed: TEC sea fresh food. 0.5/0.25 µg/ml, Changed: CRO monotherapy CRO 0.25 µg/ml, (40d) CTX 0.25 µg/ml, Aortic and MEM 0.06 µg/ml, mitral replacement VAN 1 µg/ml, LVX 1 µg/ml, CLI > 0.5 mcg/ml (only R to CLI). 10 of 3 Page E test (bioMérieux, Marcy lEtoile, France) PEN 0.75 mg/L, CRO 0.38 mg/L, Table 1 Clinical, microbiological and management characteristics of IE by L. garvieae (Continued) Malek Reference Country Age Sex Associated Symptoms Physical Laboratories and Identification Susceptibility Therapy and Complications factors for IE and duration examination Echocardiography days of and Outcome Diseases Infectious BMC al. et by L. (days) (Vegetation size) treatment garvieae and comorbidities TEC 0.125 mg/L. Susceptibility CLSI for viridans streptococci. Heras Spain 68 M Prosthetic aortic Fever, NI TTE: mitral vegetations LG: MS and 16S Streptococci Empiric: DAP + AMP + CRO AKI, Aortic Cañas et al. valve, Dyspnoea (10) (NI). rRNA PCR breakpoints: Directed: DAP+AMP + CRO + valve

2015 HTN, Laboratories: Leucocytosis, S: CTX: 0.38 µg/ml, ERY: GEN (NI) + Valve replacement dehiscence (2019)19:301 dyslipidaemia, elevate CRP. 0.25 (Alive) Hodgkin mg/dl, VAN 1 µg/ml, lymphoma in LVX 1.5 µg/ml, VAN, remission, AV AMP, CTX, OXA. block. I: PEN-I MIC 0.75 µg/ml, R: CLI 1 µg/ml. Igneri et al. USA 83 M Prosthetic aortic Malaise, fever, NI TTE: Could not exclude NI NI Empiric: AMP + GEN No 2015 valve, vomit, vegetations, Directed: CTX + GEN (42d) complication, Recent dental headache, Labs: Leucocytosis, Valve surgery (Alive) intervention, CHF, cough, Elevated CRP CLL, myalgia, Prostate cancer, diaphoresis Coarctation (7) of aorta, CABG Ortiz et al. Spain 70 F No risk factors or Dyspnoea (NI) Holosystolic TTE: mitral vegetation (NI) NI S: CTX, CIP, ERY, DAP, Empiric: AMC + GEN Directed: No 2014 comorbidities murmur, fever Labs: Leucocytosis and VAN. VAN monotherapy (42d) complications elevated CRP valve surgery (Alive) Spain 77 F Colorectal cancer, Back pain, Purpuric TEE: mitral and aortic NI S: PEN, AMC, CIP, VAN. AMP + GEN (NI) AKI, Heart HTN, CLL fever (2) lesions in vegetation (NI) Labs: NI No valve surgery failure (Died) extremities, fever Tsur et al. Israel 76 M Raw fish, Constipation, Fever, TEE: Vegetation biologic Lactococcus: API S: CRO and GEN. Empiric: CRO No 2014 Prosthetic aortic fever (NI) Tachycardia, prosthetic valve (NI) 32 strep kita, 16S I: PEN Directed: CRO+ GEN (NI) complications valve, CHF, AF, DM Systolic Labs: Leucocytosis rRNA PCR R: CLI No valve replacement (Alive) 2, HTN, murmur. Oesophageal carcinoma. Rasmussen Sweden 81 M Prosthetic aortic Malaise, Fever, systolic TEE: vegetations mitral LG: Vitek 2¥, 16S PEN: 0.5 mg/L, TOB: 2 PEN + TOB (28d) Subdural et al. 2014 valve, headache, murmur. valve and prosthetic valve rRNA PCR mg/L. No valve replacement hematoma rectal dysphasia (NI) (NI) (Alive) diverticulosis, Labs: Elevated CRP CAD, CABG, AF Navas et al. USA 64 M Previous mitral Fatigue, NI Echo not specified: Aortic LG: Vitek 2¥, 16S Streptococcus VAN monotherapy (42d) Intracardiac

2013 valve weight loss, vegetations rRNA PCR and breakpoints: Aortic valve replacement. device 10 of 4 Page repair, Dental hyporexia, MS I: PEN and AMP Removal of pacemaker infection intervention, weakness, Wrong ID: R: CLI (Alive) CAD, Cardiac fever (NI) Microscanb Table 1 Clinical, microbiological and management characteristics of IE by L. garvieae (Continued) Malek Reference Country Age Sex Associated Symptoms Physical Laboratories and Identification Susceptibility Therapy and Complications factors for IE and duration examination Echocardiography days of and Outcome Diseases Infectious BMC al. et by L. (days) (Vegetation size) treatment garvieae and comorbidities defibrillator, DM2, COPD Fleming USA 68 M Prosthetic aortic Migratory Systolic Echo not specified: LG: Vitek 2¥, 16S Breakpoints for VGS: Empiric: AMP + GEN No et al. 2012 valve, arthralgias, ejection Vegetation mitral valve. rRNA PCR S: VAN, SAM, CRO, TZP Directed: VAN monotherapy information of NHL in remission. dyspnoea, murmur. (NI) R: AMP, GEN, CLI. (42d) complications Colonic hyporexia, Splinter Labs: Elevated CRP and No valve replacement (Died)

polyps fatigue, haemorrhage ESR Colonoscopy: Colonic (2019)19:301 weight loss, in nails of left polyps fever (21) hand Russo et al. Italy 63 M Ascending aorta Fever, chills, Systolic TEE: mitral vegetation (NI) LG: API 32b, Vitek EUCAST Streptococci Empiric: VAN + GEN No 2012 and aortic Pharyngodini, murmur, Labs: Elevated CRP 2¥, 16S rRNA PCR breakpoint: Directed: AMP monotherapy complications valve replacement, weakness. (7) hepatomegaly S: ERY/S: 0.125 μg/ml, (14d) (Alive) previous CTX 0.5 μg/ml No valve replacement endocarditis, HTN. LVX: 0.5 μg/ml, AMP: 0.25 μg/ml, AMC: 0.5 μg/ml, CIP: 0.75 μg/ml, DAP: 0.125 μg/ml, GEN: 2 μg/ml VAN: 2 μg/ml TEC: 0.5 μg/ml I: PEN: 2 μg/ml R: CLI: > 64 μg/ml, RIF > 64 µg/ml Watanabe Japan 55 F No risk factors or Malaise, Systolic TEE: Mitral vegetation (10 LG: Rapid ID32 E test: (AB Biodisk, Empiric: PEN + GEN. Directed: Septic et al. 2011 comorbidities myalgia, fever murmur, mm) Labs: No Strep. a, 16S rRNA Dalvagen, Solna, CRO + GEN (63d) No valve embolism, (60) painful black leucocytosis Elevated CRP Sweden): ERY 0.25 surgery stroke, induration in mg/L, aspirative finger. CLI: > 256, pneumonia VAN: 0.38 mg/L, LZD: (Alive) 2 mg/L, PEN 0.5 mg/L, CRO 0.38 1mg/L, GEN: 1.5 mg/L, STR: 64 mg/L Zuily et al. France 64 F Mitral valve Fever (NI) Fever, Murmur. TEE: Mitral vegetations (NI) LG: PCR NI AMX + GEN (42d) No 2011 prosthesis, fresh Labs: Elevated CRP and no surgery complications seafood, ESR. Leucocytosis (Alive) Pacemaker, Hepatitis C cirrhosis, Wilbring Germany 55 M Fish farmer, Chills, fever, Murmur TEE: Mechanical prosthetic NI NI Inpatient: GEN + VAN + RIF No

et al. 2011 mechanical dyspnoea (14) valve vegetation (7x9mm) ambulatory: LVX + AMC (56d) complications 10 of 5 Page tricuspid Labs: Leucocytosis and No valve replacement (Alive) valve prosthesis, elevated CRP periodontitis Hirakawa Brazil 58 F Mitral prosthetic Fever, chills, Fever, Osler TEE: No vegetations Labs: LG: Not specified S: PEN, GEN, VAN. VAN monotherapy (28d) No Table 1 Clinical, microbiological and management characteristics of IE by L. garvieae (Continued) Malek Reference Country Age Sex Associated Symptoms Physical Laboratories and Identification Susceptibility Therapy and Complications factors for IE and duration examination Echocardiography days of and Outcome Diseases Infectious BMC al. et by L. (days) (Vegetation size) treatment garvieae and comorbidities et al. 2011 valve, fish and diaphoresis, nodes on left Elevated CRP and ESR no biochemical tests. R CLI No valve surgery complications cheese often. erythematous hand and legs. leucocytosis. PCR. (Alive) Dental prosthesis nodules in and recent hands and gingival legs, myalgia, perforation. weakness. (6) DM 2, HTN, Dyslipidaemia (2019)19:301 Li et al. Taiwan 41 M No risk factors or Slurred Right TEE: Mitral vegetation and LG: Vitek 2¥, I: PEN: 0.75 µg/ml. PEN + GEN (30d) Septic emboli, 2008 comorbidities speech (1) hemiplegia rupture of chordae Automated Valve replacement stroke, shock loss of right tendineae (NI) Pheonixc, 16S (Alive) body Labs: Leucocytosis and rRNA PCRe sensation, elevated CRP right positive Babinski sign, murmur, fever Yiu et al. China 67 M Heart rheumatic Chills, fever Fever, mitral TEE: Mitral vegetation NI NI AMP monotherapy (42d) Partial rupture 2007 disease, (21) regurgitation (10x1mm) Labs: Elevated Valve replacement of mitral valve previous murmur ESR Neutrophilia (Alive) endocarditis, eats fresh fish, AF Wang et al. Taiwan 72 M stones, Fever, Systolic Echo not specified: Severe LG: ID32 STREP; NI PEN + GEN (42d) No 2006 mitral purpuric leg murmur. mitral regurgitation, BioMérieux, complications valve prolapse. lesions (14) prolapse of posterior Hazelwood, MO, (Alive) Raw mitral valve, echogenic USA, 16S rRNA fish consumption, mass on the posterior PCR gastric ulcer mitral valve Labs: No leucocytosis. Endoscopy: Gastric ulcer Vinh et al. Canada 80 M DM2, Dyspnoea, Midsystolic TEE: Aortic vegetations Wrong ID: API CLSI Enterococcus Empiric inpatient: AMP No 2006 Hyperlipidaemia, epigastric murmur (24 mm) Labs: NI 20d (L. lactis), spp. breakpoints: Ambulatory: PEN and then complications CAD, CHF discomfort. Vitek S: PEN, CIP, OFX, switched to AMP again. (Alive) (NI) 2¥(Enterococcus), LVX, TET, VAN. Monotherapy (56d) 16S rRNA PCR CLSI Streptococcus Valve replacement spp. breakpoints: S: AMP, VAN, GEN I: PEN R: CLI Fihman France 86 M Prosthetic aortic Fever, right Fever, TEE: Aortic vegetation (10 LG: API 32a, 16S E test: MIC: PEN: Inpatient: AMX + GEN No et al. 2005 valve, hip pain (21) respiratory mm) Labs: Leucocytosis rRNA PCR 0.75 μg/ml, AMX: 0.5 Ambulatory: AMX monotherapy complications Cholecystectomy. distress and elevated CRP. μg/ml CTX: 0.38 μg (49d) (Alive) μ /ml, VAN: 1.5 g/ml, Valve repair 10 of 6 Page TEC: 0.38 μg/ml, CLI > 8 µg/ml James et al. UK 56 F Aortic valve Low back Low back TTE: No vegetations Labs: LG: API Strep f With streptococci Empiric: VAN Directed: TEC Osteomyelitis 2000 prosthesis pain, chills, tenderness, Elevated ESR and CRP. No reference laboratory monotherapy (56d) (Alive) Table 1 Clinical, microbiological and management characteristics of IE by L. garvieae (Continued) Malek Reference Country Age Sex Associated Symptoms Physical Laboratories and Identification Susceptibility Therapy and Complications factors for IE and duration examination Echocardiography days of and Outcome Diseases Infectious BMC al. et by L. (days) (Vegetation size) treatment garvieae and comorbidities night sweat, splinter leucocytosis (Respiratory and weight loss, haemorrhages systemic reference hyporexia (63) In nails, laboratory London UK). murmur Fefer et al. USA 84 F Pacemaker for Hyporexia, Holosystolic TEE: Ruptured chordae LG: Biochemical NCCLS Staphylococcus Empiric: AMP + GEN Directed: Intracranial 1998 heart weakness, murmur, tendineae. Labs: tests. spp. breakpoints: CRO monotherapy (NI) haemorrhage,

block, Aortic valve dyspnoea (NI) bilateral Leucocytosis. Negative S: VAN, AMP, CRO Rupture of (2019)19:301 prosthesis, pulmonary colonoscopy. chordae omeprazole, rales tendineae hypertrophic (Died) cardiomyopathy, ITP, hypothyroidism. NI No information, AMK amikacin, AMX amoxicillin, AMC amoxicillin-, AMP ampicillin, CFZ cefazolin, CDN cefditoren, CTX cefotaxime, CRO ceftriaxone, CEF cephalothin, CHL chloramphenicol, CIP ciprofloxacin, CLR clarithromycin, CLI clindamycin, DAP daptomycin, ERY erythromycin, GEN gentamicin, LVX levofloxacin, LZD linezolid, MEM meropenem, MXF moxifloxacin, OFX ofloxacin, PEN penicillin, TZP piperacillin-tazobactam, RIF rifampin, STR streptomycin, TEC teicoplanin, TET tetracycline, TOB tobramycin, SXT trimethoprim-sulfamethoxazole, VAN vancomycin, MIC Minimal inhibitory concentration, S Sensitive, I Intermediate, R resistant, VGS Viridans Group Streptococci, CKD Chronic kidney disease, AKI Acute kidney injury, DM2 Diabetes mellitus type 2, AF Atrial fibrillation, CHF Cardiac heart failure, NHL Non-Hodgkin Lymphoma, COPD Chronic obstructive pulmonary disease, CLL Chronic lymphocytic leukaemia, CAD Coronary artery disease, CABG Coronary artery bypass graft, LG Lactococcus garvieae a Manual API 32 strep kit, automated Vitek 2 kit with GP identification card (BioMérieux Marcy l’etoile, france), b Microscan walk away system (dade behring, inc., Sacramento, CA), c:Automated Phoenix system (Becton Dickinson Diagnostic systems, Franklin Lakes, NJ), d: API 20strep kit (BioMérieux), e: 500 16S ribosomal rRNA bacterial sequencing kit (PE applied Biosystems, Foster city, CA, USA) ABI PRISM 310 Genetic Analyzer (PE applied biosystems), f: API Strep (BioMérieux, Basngstoke, Hants, UK) ae7o 10 of 7 Page Malek et al. BMC Infectious Diseases (2019) 19:301 Page 8 of 10

Presence of heart murmurs was the most common find- Enterococcus spp. or Staphylococcus spp. With these ing in the physical examination (72%). Laboratory tests breakpoints, most L. garvieae isolates show intermedi- usually showed leucocytosis, elevated CRP and ESR. ate resistance to penicillin and resistance to clindamy- Echocardiogram was reported in 24 out of 25 cases and cin [8, 9, 13, 22]. vegetations were identified in 83.3%. The mitral valve In summary, IE caused by L. garvieae may be a was the most frequently involved valve. Colonoscopy life-threatening infection. The most important predis- was performed in 5 cases, all of which reported colonic posing factor is previous valvular disease. An associ- polyps. The median duration of antimicrobial therapy ation with gastrointestinal disease and consumption of was 42 days (IQR 41–45.5). fish has been established. Reliable methods for identifi- When compared to other Gram-positive microorgan- cation of L. garvieae include MALDI-TOF, 16S RNA isms, L. garvieae seems to affect more frequently pa- PCR, API 32 strep kit (BioMérieux, Marcy l’Etoile, tients with prosthetic valves. In our review, 52% (n = 13) France) and BD Automated Phoenix System. Based on patients with L garvieae IE had prosthetic valves, while prior case reports and our own patient case, the recom- large cohorts of endocarditis caused by Enterococcus mended antimicrobials for L. garvieae are ampicillin (2 spp., Streptococcus spp., Coagulase negative Staphylo- g every 4 h), amoxicillin (200 mg/kg/day divided in 4–6 cocci (CoNS) and S. aureus, report prosthetic valve in- doses), ceftriaxone (2 g every 12–24 h) or vancomycin volvement in 15.3–35%, 16.3–17.2%, 28–32.2% and (30 mg/kg/day divided in 2–3 doses) as monotherapy or 15.3–16% of cases, respectively [31–33]. Complications in combination with gentamicin (3 mg/kg/day). Doses of IE such as valve dehiscence or rupture, septic emboli, were defined using the recommendations for the treat- renal failure, shock, stroke and heart failure were re- ment of VGS and enterococcal IE published by the ported in 50% (n = 12) of cases. Surgery for valve repair American Heart Association/Infectious Diseases Society or replacement was performed in 48% of cases. The case of America (AHA-IDSA) and European Society of Car- fatality rate of L. garvieae IE was 16% (n: 4), which is diology guidelines [34, 35]. It is unclear if combination low compared to that of other GPC such as S. aureus therapy is needed (in cases where aminoglycoside tox- (44.4%), Enterococcus spp. (23%) and CoNS (33.4%), but icity is an issue), given that 5 out of 25 patients with L. comparable to that of streptococci IE (15.7%) [32]. garvieae IE were treated with vancomycin [9, 15, 17], The ingestion of raw sea food or exposure to fish, the teicoplanin [17 ] or ampicillin [8] monotherapy with presence of colonic polyps and the repeated exposure to good outcomes. Further, the majority of patients in the dairy products have been postulated to be risk factors for L. garvieae group who died were treated at some point infection by L. garvieae [7]. Less than half of patients with with monotherapy and combination therapy. IE caused by L. garvieae reported ingestion of fish (includ- ing raw or cooked) [7, 15, 19, 23, 24, 26–28, 30]orweredi- Abbreviations – AF: Atrial fibrillation; AKI: Acute kidney injury,; AMC: Amoxicillin-clavulanic agnosed with a concomitant GI disorder [10, 13, 19 21, 24, acid; AMK: Amikacin; AMP: Ampicillin; AMX: Amoxicillin; BD: Becton 28–30]. Our patient reported both conditions. The most Dickinson; CABG: Coronary artery bypass graft; CAD: Coronary artery disease; important predisposing factor in these patients appears to CDN: Cefditoren; CEF: Cephalothin; CFZ: Cefazolin; CHF: Cardiac heart failure; CHL: Chloramphenicol; CIP: Ciprofloxacin; CKD: Chronic kidney disease; be the presence of previous valvular disease. Of note, colon- CLI: Clindamycin; CLL: Chronic lymphocytic leukaemia; CLR: Clarithromycin; oscopy may be considered in patients with L. garvieae IE to CLSI: Clinical and laboratory standards institute; CLSI: Clinical and Laboratory rule out colonic polyps. Standards Institute; CONS: Coagulase negative staphylococci; COPD: Chronic obstructive pulmonary disease; CRO: Ceftriaxone; CRP: C Reactive Protein; For species identification, MALDI-TOF, 16S RNA PCR, CT: Computed Tomography; CTX: Cefotaxime; DAP: Daptomycin; API 32 strep kit (BioMérieux, Marcy l’Etoile, France), Vitek DM2: Diabetes mellitus type 2; DNA: Deoxyribonucleic acid; 2 kit with GP identification card (BioMérieux) and BD Au- ERY: Erythromycin; ESR: Erythrocyte Sedimentation Rate; EUCAST: European Committee on Antimicrobial Susceptibility Testing; GEN: Gentamicin; tomated Phoenix System seem to be reliable techniques for GI: Gastrointestinal; GP: Gram positive; GPC: Gram positive cocci; the identification of L. garvieae in our series. However, the I: Intermediate; IE: Infective Endocarditis; INR: International Normalized Ratio; Vitek 2 reported misidentification of Enterococcus spp.asL. IQR: Interquartile range; IV: Intravenous; LG: Lactococcus garvieae; LVX: Levofloxacin; LZD: Linezolid; MALDI-TOF: Matrix-Assisted Laser garvieae in one case [8]. In contrast, the API 20 Strep (Bio- Desorption/Ionization Time of Flight; MEM: Meropenem; MIC: Minimum Mérieux, Marcy-l’Etoile, France) and Microscan walk away Inhibitory Concentration; MXF: Moxifloxacin; NHL: Non-Hodgkin Lymphoma; system (Dade Behring, inc., Sacramento, CA) often mis- NI: No information; OFX: Ofloxacin; PCR: Polymerase Chain Reaction; PEN: Penicillin; R: Resistant; RIF: Rifampin; RNA: Ribonucleic acid; S: Sensitive; identified the genus L. garvieae [8, 9]. Since the therapeutic STR: Streptomycin; SXT: Trimethoprim-sulfamethoxazole; TEC: Teicoplanin; approach for enterococci may be different to that used for TEE: Transoesophageal Echocardiography; TET: Tetracyclin; TOB: Tobramycin; Lactococcus, confirmation of identification should be per- TZP: Piperacillin-tazobactam; VAN: Vancomycin formed with a reliable method. As no breakpoints for anti- biotic susceptibility have been determined for Lactococcus Funding This work supported by NIH-National Institute of Allergy and Infectious Dis- spp. by the CLSI or EUCAST, most authors used those for eases grant number K24-AI114818 to CAA. This grant serves for undertaking viridans-group streptococci (VGS), group B streptococci, research performed in CAA lab and for publication. Malek et al. BMC Infectious Diseases (2019) 19:301 Page 9 of 10

The funders of the study had no role in the study design, data collection, 10. Clavero R, Escobar J, Ramos-Avasola S, Merello L, Álvarez F. Lactococcus data analysis, data interpretation, or writing of the manuscript. garvieae endocarditis in a patient undergoing chronic hemodialysis. First case report in Chile and review of the literature. Rev Chil Infectol. 2017;34(4): Availability of data and materials 397–403. No data or materials are available. 11. Fefer JJ, Ratzan KR, Sharp SE, Saiz E. Lactococcus garvieae endocarditis: report of a case and review of the literature. Diagn Microbiol Infect Dis. Authors’ contributions 1998;32(2):127–30. AM, AD and CAA wrote the manuscript and structured the literature review. 12. Fihman V, Raskine L, Barrou Z, Kiffel C, Riahi J, Berçot B, et al. Lactococcus CAA, AM, SG and CN took care of the patient and collected clinical data. All garvieae endocarditis: identification by 16S rRNA and sodA sequence authors reviewed and approved the final version of the manuscript. analysis. J Inf Secur. 2006;52(1):e3–6. 13. Fleming H, Fowler SV, Nguyen L, Hofinger DM. Lactococcus garvieae multi- Ethics approval and consent to participate valve infective endocarditis in a traveler returning from South Korea. Travel Does not apply. Med Infect Dis. 2012;10(2):101–4. 14. Heras Cañas V, Pérez Ramirez MD, Bermudez Jiménez F, Rojo Martin MD, Consent for publication Miranda Casas C, Marin Arriaza M, et al. Lactococcus garvieae endocarditis Written informed consent was given by the patient to publish the in a native valve identified by MALDI-TOF MS and PCR-based 16s rRNA in information in this case report. Spain: a case report. New Microbes New Infect. 2015;5:13–5. 15. Hirakawa TF, da Costa FAA, Vilela MC, Rigon M, Abensur H. Araújo MRE de. Competing interests Lactococcus garvieae endocarditis: first case report in Latin America. Arq CAA has received grant support from Merck, Entasis and MeMed diagnostics. Bras Cardiol. 2011;97(5):e108–10. The other authors have no competing interests to declare. 16. Igneri L, Eltoukhy N, Shaffer A, Goren R. 1200: a rare case of lactococcus garvieae endocarditis in a critically ill patient. Crit Care Med. 2015;43:302. Publisher’sNote 17. James PR, Hardman SM, Patterson DL. Osteomyelitis and possible endocarditis secondary to Lactococcus garvieae: a first case report. Postgrad Springer Nature remains neutral with regard to jurisdictional claims in Med J. 2000;76(895):301–3. published maps and institutional affiliations. 18. Li W-K, Chen Y-S, Wann S-R, Liu Y-C, Tsai H-C. Lactococcus garvieae endocarditis with initial presentation of acute cerebral infarction in a Author details healthy immunocompetent man. 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