First Danish case of infective endocarditis caused by Enterococcus hirae

Abstract

Enterococcus hirae, a member of the Enterococcus genus, is known to cause infections, including infective endocarditis (IE), in animal species. In humans, E. hirae is an uncommon pathogen, but has been associated with severe and recurrent disease. Here, we report the first Danish case of E. hirae native aortic valve IE in a 62-year-old woman with no history of heart disease. She presented to the hospital with symptoms of gastroenteritis but no signs of heart disease. Nevertheless, blood culture revealed growth of E. hirae, and a transoesophageal echocardiography demonstrated a mobile mass adherent to the aortic valve, compatible with a vegetation. The patient was successfully treated for E. hirae native aortic valve IE with 4 weeks of intravenous benzylpenicillin in combination with gentamicin for the initial 2 weeks. To the best of our knowledge, this is the first documented case of E. hirae IE in Denmark and the sixth documented case worldwide.

Background

Enterococci are Gram-positive, facultative anaerobic cocci that are members of the intestinal microbiome of nearly all land animals, including humans.¹ In humans, they are associated with a variety of infections, such as urinary tract infections, intra-abdominal infections and infective endocarditis (IE).² The Enterococcus genus currently comprises 59 validated taxa (https://lpsn.dsmz.de/), as of June 2020, of which Enterococcus faecalis and E. faecium historically represent the majority of identified species in humans, accounting for 80%–90% and 5%–10% of all enterococcal infections, respectively.¹

IE is a life-threatening disease, and despite improvements in its management it remains associated with severe complications and high mortality.³ Streptococci, enterococci and staphylococci are altogether responsible for the majority of all IE cases.³ A recent Danish study identified patients from 2010 to 2017 with E. faecalis, Staphylococcus aureus, Streptococcus species and coagulase-negative staphylococci (CoNS) bacteraemia and examined the prevalence of IE. The study found that patients with E. faecalis bacteraemia had the highest prevalence of IE (16.7%), followed by S. aureus (10.1%), Streptococcus species (7.3%) and CoNS (1.6%).⁴

E. hirae, first described as a new species in 1985 by Farrow and Collins,⁵ is another member of the Enterococcus genus and is known as an opportunistic pathogen in psittacine birds and rats.^{6 7} E. hirae has also been associated with high mortality in broiler flocks due to septicaemia and endocarditis.⁸ To date, only a limited number of human cases of E. hirae infection have been described.⁹ Here, we present the first Danish patient with E. hirae IE and to our knowledge the sixth case detailed in the literature.

Case presentation

A 62-year-old woman presented to the hospital with a 2-week history of diarrhoea, vomiting and a 10 kg weight loss. In addition, she had been experiencing headache and dizziness over the past few weeks. The patient had a 6-year-old history of curative laparoscopic surgery for colorectal cancer without any sequelae. She was on daily use of paracetamol and non-steroidal anti-inflammatory drugs coadministered with proton-pump inhibitors for chronic hip pain. On admission, physical examination disclosed no heart murmurs or other abnormalities except for epigastric pain. The patient was afebrile, with normal vital parameters. Laboratory investigation revealed white cell count of 11.1×10⁹/L and C- reactive protein (CRP) of 18 mg/L. In addition, electrolyte disturbances were observed with hyponatraemia (123 mmol/L) and hypokalaemia (2.7 mmol/L). Arterial blood gas showed compensated metabolic acidosis with pH of 7.39, partial pressure of carbon dioxide of 2.3 kPa and base excess of −14 mmol/L. Treatment with intravenous rehydration and correction of the electrolyte imbalance were initiated.

Two days after admission, the patient had a body temperature of 38°C and an increasing level of CRP to 90 mg/L. A blood culture was performed, but antibiotic treatment was not initiated until the following day when the blood culture revealed growth of Gram-positive cocci in short chains, subsequently identified as E. hirae. The focus of infection from where E. hirae may have entered the bloodstream was not known; however, a second blood culture was performed, and immediately thereafter intravenous piperacillin-tazobactam 4.5 g 6-hourly was administered on suspicion of an intra-abdominal infection. The next day the patient had become afebrile. A contrast CT scan of the chest, abdomen and pelvis demonstrated wall thickening of the duodenum, representative of a well-known duodenal diverticulum, but was otherwise normal. Stool samples were negative for norovirus, toxin-producing Clostridioides difficile, Campylobacter, Salmonella, Shigella, Yersinia enterocolitica and Vibrio. The patient had no symptoms of urinary tract infection, and a urine culture revealed no growth of E. hirae.

To further investigate the source of infection, a transoesophageal echocardiography (TEE) was performed on day 6 of hospitalisation, which demonstrated thickening of the left-sided coronary cusp of the aortic valve and a mobile mass of 0.4 cm adherent to the cusp, compatible with a vegetation (see figure 1). Aortic valve IE was diagnosed, and antibiotic treatment was changed to intravenous benzylpenicillin 3 g every 6 hours for 4 weeks in combination with intravenous gentamicin 3 mg/kg once daily for 2 weeks. Furthermore, a positron emission tomography-CT showed a significantly increased uptake of fluorodeoxyglucose (¹⁸F) in the stomach, and a subsequent gastroscopy revealed a hiatal hernia and a duodenal diverticulum, but otherwise no abnormalities. A surgeon performed a check of the patient’s oral status, and the first and second molars were extracted due to suspicion of periodontitis.

Figure 1.

Transoesophageal echocardiography long-axis view shows thickening of the left-sided coronary cusp of the aortic valve and a vegetation attached (arrow) that prolapses into the left ventricle during diastole. AO, aorta; LV, left ventricle; RV, right ventricle.

Investigations

A standard blood culture set (two bottles, BD BACTEC Plus Aerobic medium; one bottle, BD BACTEC Lytic Anaerobic medium) was obtained 40 hours after admission. After 12-hour incubation in a BD BACTEC FX instrument (Becton, Dickinson and Company, Franklin Lakes, USA), one aerobic and the anaerobic bottle revealed growth of Gram-positive cocci in short chains. Using MALDI Biotyper (Bruker Daltonics, Bremen, Germany), the bacterium was identified as E. hirae (log score 2.510). A repeat blood culture taken 20 hours after the first blood culture remained culture-negative during 14 days of incubation.

Antimicrobial susceptibility testing was performed using ETEST (bioMérieux, Marcy l’Etoile, France) and the minimum inhibitory concentrations (MICs) were as follows: benzylpenicillin: 1 mg/L; ampicillin: 0.5 mg/L; gentamicin: 3 mg/L; and vancomycin: 0.38 mg/L. Susceptibility to vancomycin was further analysed using disc diffusion (Neo-Sensitabs, Rosco Diagnostica A/S, Høje-Taastrup, Denmark). The zone to vancomycin was 16 mm, with a sharp zone edge after 24 hours of incubation. MICs for ampicillin and vancomycin were interpreted as susceptible (S) using EUCAST breakpoint table V.8.1 for Enterococcus species. MICs for benzylpenicillin and gentamicin were also reported to the clinicians but without interpretation of S. The MIC for benzylpenicillin was low, and according to the 2015 European Society of Cardiology (ESC) guidelines for the management of IE³ the strain was fully penicillin-susceptible due to MIC ≤8 mg/L, whereas the strain had wildtype low-level intrinsic resistance to gentamicin due to MIC well below ≤128 mg/L.

To confirm the strain (AAUH 185363) to species level, we performed sequencing of the isolate using the Illumina MiSeq instrument, producing 2×300 bp paired-end reads using Nextera XT Library Preparation Kit (Illumina Denmark ApS, Copenhagen, Denmark). Reads were assembled using CLC Genomics Workbench V.11 (QIAGEN Bioinformatics, Aarhus, Denmark) to a total sequence length of 3 361 702 bp, with a G+C content of 38.3%. Finally, we made a simple phylogenetic tree using the UPGMA (unweighted pair group method with arithmetic mean) method (see figure 2).

Figure 2.

UPGMA dendrogram showing the Enterococcus hirae strain (AAUH 185363) and other enterococcal reference strains. The dendrogram was based on a distance matrix of pairwise differences based on whole genome sequence analysis using CLC Genomics Workbench V.11 software.

Outcome and follow-up

After 4 weeks of antibiotic treatment, a control TEE demonstrated no reduction in the size of the vegetation. However, as the patient has fully recovered and all blood parameters were normal, including CRP, she was discharged. Unfortunately, the patient did not comply with planned follow-up visits; however, 20 months after hospital discharge, the patient has not been rehospitalised and is still alive.

Discussion

To the best of our knowledge, this is the first case of native valve E. hirae IE in Denmark and the sixth documented case of E. hirae IE in world literature. Enterococci are well-known nosocomial pathogens causing infections that include, among others, bacteraemia, urinary tract infections, intra-abdominal infections and IE. A recent Danish study described a prevalence of IE of 16.7% among patients with E. faecalis bacteraemia.⁴

E. hirae is a commensal of the microbiota of psittacine birds, poultry and rats, and causes infections including IE and colonic pathology in various animal species.^{6 8 10} The present case had no close contact with birds or other animals, and whether E. hirae is domestic in humans is unknown. The MALDI Biotyper seems to be a reliable method for species identification of Enterococcus species.¹¹ However, identification of E. hirae in clinical samples is rare, and the prevalence of E. hirae infection is estimated to account for 0.4%–3.03% of all human enterococcal infections.^12–14 To date, various human infections with E. hirae have been described, including bacteraemia, spondylodiscitis, urinary tract infection, bacterial peritonitis, cholangitis and IE.9 13 15–23 Like infections caused by E. faecalis, infection due to E. hirae seems mainly community-acquired, in contrast to infections caused by E. faecium, which are predominantly nosocomial infections.

In the present case, the patient did not have a predisposing heart condition and symptoms on admission were non-specific for cardiac genesis. Aortic valve IE was diagnosed only after the blood culture turned positive and treatment for E. hirae IE initiated 6 days after hospitalisation. The patient met one major criterion (echocardiography positive for IE) and one minor criterion (one positive blood culture) according to the modified Duke criteria for the diagnosis of IE.³ There was no growth of E. hirae in two separate blood cultures (major criterion), as the repeated blood culture (20 hours apart) taken before antibiotic treatment remained culture-negative during 14 days of incubation.

In the world literature, only five cases of E. hirae IE have been described.^{9 15–18} Involvement of the aortic valve was present in all five cases, in addition to involvement of the mitral valve in one case¹⁵ and development of aortic root abscess in another.¹⁶ The majority of these cases had underlying cardiac diseases, such as coronary artery disease, prosthetic valves, cardiac arrhythmia with prior surgical ablation and bicuspid aortic valve. In the present case, the patient did not undergo valve replacement; however, in four out of the five previous cases of IE caused by E. hirae valve replacement was performed. In one case, the patient was already known with a prosthetic valve and surgery was contraindicated due to the patient’s poor condition.¹⁸

Although none of the previous E. hirae IE cases described a fatal outcome, recurrence of IE was observed in two cases despite appropriate antibiotic treatment.^{17 18} The need for valve replacement and risk of recurrence may indicate that E. hirae IE is difficult to treat. It is well known that treatment of IE due to Enterococcus species is challenging due to high resistance to antibiotic-induced killing and intrinsic mechanisms of resistance to most antibiotics.³ The synergistic effect of penicillin (when susceptible) combined with an aminoglycoside is the preferred treatment in order to obtain sufficient bactericidal effect in severe enterococcal infections.²⁴

According to the 2015 ESC guidelines for the management of IE, the treatment recommendation for Enterococcus species that are fully penicillin-susceptible (penicillin MIC ≤8 mg/L) is penicillin G or ampicillin (or amoxicillin) combined with gentamicin.³ A 4-week therapy is recommended, whereas a 6-week therapy is recommended for patients with >3 months of symptoms or prosthetic valve endocarditis. Antibiotic treatment regimens to the five previous IE cases caused by E. hirae have been extensively reviewed by Pinkes et al.⁹ Three of the five were treated with ampicillin or amoxicillin, plus gentamicin, followed by rifampin,^{15 17 18} and two of the five were treated with ampicillin or penicillin G combined with ceftriaxone.^{9 16} Four of the five received 6-week therapy followed by indefinite chronic suppressive therapy with oral penicillin in a single case.¹⁶ Our case received 4-week therapy with benzylpenicillin and gentamicin (2 weeks) and had no history of relapse. However, as IE caused by E. hirae may present with very different aspects, a collaborative approach from several specialties, including cardiologists, cardiac surgeons, infectious disease specialists, medical microbiologists and others, is needed and treatment (including duration of antimicrobial therapy) should be individualised.

In previous E. hirae IE cases, no documented source of infection was established. In the present case, exposure to animals was not described. However, in two cases a history of gastrointestinal surgery (cholecystectomy⁹ and gastric leiomyoma removal¹⁵) was described, and in one case colonoscopy during hospitalisation with E. hirae IE revealed colonic polyps with adenoma.¹⁸ In our case, the patient had a history of colorectal cancer and presented symptoms of gastroenteritis. In total, four out of six cases of E. hirae IE had a history of gastrointestinal disease. The digestive tract may be the entry of E. hirae bacteraemia and subsequent IE.

In conclusion, E. hirae infections in humans are rare but have been associated with various sites of infection. In addition, severe and recurrent disease with E. hirae has been described. We report the successful management of E. hirae native aortic valve IE. The case was the first Danish case and the first treated successfully with the international recommendation of 4-week therapy with benzylpenicillin and gentamicin.

Learning points.

• Human infection with Enterococcus hirae is rare, but it may cause serious infections such as infectious endocarditis.

• Identification of E. hirae to species level was made using the MALDI Biotyper.

• A 4-week regimen of intravenous benzylpenicillin in combination with gentamicin for the initial 2 weeks was a successful treatment for native valve infective endocarditis due to E. hirae.