Infective endocarditis (ΙΕ) is a potentially lethal disease and it has become more complex when it iscaused by multidrug-resistant(MDR) pathogens difficult to treat, such as MDR enterococci. Endocarditis due to multidrug-resistant enterococci and specifically MDR Enterococcus faecium is rare as most of the reports of these strains are single case reports. Vancomycin-resistant E.faecium IE is an uncommon nosocomial infection that can affect patients who have significant comorbidities. Optimal antimicrobial therapy is still not defined and remains a challenging issue, but an attempt should be made to identify a bactericidal combination therapy.

We report a case of native valve endocarditis due to vancomycin-resistant E. faecium (VRE) that was paired with a clinical history of recent non-ST elevation myocardial infarction (N-STEMI) and previous surgical manipulations in the biliary tract.

Case report

A 65-year-old man presented to the Emergency Department (ED) the previous year, with a 24-hour history of repeated epigastric pain reflected to his back that was resolving with isosorbide dinitrate intake. Upon presentation in the ED, the patient denied fever, chills, cough, headache, sick contacts and recent travel.

His past medical history was significant for coronary artery disease, diabetes mellitus, hypertension and dyslipidemia. His coronary artery disease had begun twenty years previously. He had been submitted to a percutaneous coronary intervention angioplasty(PCI) in the left anterior descending artery – LAD(2014) and a coronary artery bypass graft (CABG) for left main coronary artery and three vessel disease (2017). Furthermore, he stated an episode of acute pancreatitis that led to cholecystectomy and insertion of biliary drainage catheter via percutaneous transhepatic cholangiography (PTC), which had been removed 2 months previously. The tissue biopsy for possible existence of cholangiocarcinomatosis was negative at that time, although a 4 cm mass was found anteriorly of the pancreatic head on abdomen CT scan. In addition, he stated an 18 kg body weight loss during the past 7 months and that he was on ciprofloxacin (500 mg orally q12h) and metronidazole (500 mg orally q8h) treatment the week before admission, due to the previous episode of biliary occlusion.

A thorough physical examination was conducted and yielded the following results: vital signs are given below: the patient was afebrile; pulse was 95 beats per minute (bpm); blood pressure (BP) 115/60 mmHg; oxygen saturation (SatO₂) 99% in ambient air. There was no peripheral edema. Cardiovascular system: included first sound (S1), second sound (S2) with regular rhythm and diastolic murmur in the heart base.Lungs: clear lungs with no wheezes or cough; mild dyspnea on exertion was present. Abdomen: soft and non-tender; bowel sounds were present.

An ambulatory electrocardiogram (ECG) upon arrival exhibited sinus rhythm, mild tachycardia, presence of q wave on III and avF, and ST-wave segment depression with T-wave inversion on V3-V6. A transthoracic echocardiogram (TTE) was completed, which revealed ejection fraction (EF) 50%, mild dilated left atrium, the presence of a flail aortic valve leaflet and moderate to severe aortic regurgitation.

The current diagnosis on admission was non-ST elevation myocardial infarction (N-STEMI) and the patient started taking metoprolol (50 mg orally q12h), rosuvastatin (40 mg orally q24h), aspirin (100 mg orally q24h), clopidogrel (75 mg orally q24h), ramipril (2.5 mg orally q24h), ezetimibe (10 mg orally q24h) and glyceryl trinitrate (TTS 5 mg q24h). Coronary angiography was conducted, which revealed coronary disease in three coronary arteries and well-functioning grafts. The left descending coronary artery (LAD) had a severe stenosis 95% (culprit lesion) very distally beyond the left internal mammary artery (LIMA) connection with LAD.

On day 9, the patient spiked a fever of 38.9°C with chills, blood cultures were taken and piperacillin/tazobactam was started. Physical examination revealed the same diastolic murmur. There were no peripheral stigmata of endocarditis like Osler’s nodes, Janeway lesions or Roth’s spots.

Laboratory results showed the following: white blood count (WBC) was 10.5 ×10³/µL with 76.2% neutrophils (NEU); hemoglobin (Hb):10.3 g/dL; hematocrit (Hct): 31%; platelets (PLT): 443×10³/µL; procalcitonin (PCT): 1.2 ng/mL; C-reactive protein (CRP): 2.56 mg/dL (normal range: 0-0,5 mg/dL); creatinine (Cr):1.1 mg/dL, SGOT: 52 IU/L; SGPT: 24 IU/L; total bilirubin was 1.6 mg/dL; and rheumatoid factor (RF): 563 IU/mL (normal range <15). A new transthoracic echocardiogram showed the same flail aortic valve leaflet along with a second one, a finding compatible with infectious endocarditis.

The initial blood cultures revealed bacteremia due to Enterococcus faecium that was resistant to vancomycin (minimum inhibitory concentration – MIC ≥256mg/L), teicoplanin (MIC ≥32 mg/L), levofloxacin (MIC ≥8 mg/L), chloramphenicol (MIC ≥16 mg/L), imipenem (MIC ≥16 mg/L), gentamicin (HL)SYN-R, streptomycin (HL)SYN-R and susceptible to ceftaroline (MIC 2 mg/L), linezolid (MIC 2 mg/L), daptomycin (MIC 1.5 mg/L) and tigecycline (MIC ≤0.12 mg/L). The used MIC determination methods were the VITEK 2 automated system and the gradient concentration of antibiotic in impregnated strips. For the results interpretation EUCAST guidelines were used. In total, four set of blood cultures were taken, (two were drawn on the first occurrence of fever and the other two were drawn during fever the next day), all of them positive to vancomycin-resistant E.faecium. As a consequence, piperacillin/tazobactam was discontinued and daptomycin (12 mg/kg iv qd), linezolid (600 mg iv q12h) and tigecycline (150 mg iv loading dose, then 75 mg iv q12h) were started.

The patient was afebrile 4 days after the new antibiotic regimen initiation, and the blood cultures became negative 3 days after his apyrexia. After the first few days of administration of antibiotics, the patient complained about headache, anorexia, nausea, dyspepsia, constipation and inability. Additionally, a gradual decrease in the procalcitonin (PCT): 0.35 ng/mL and C-reactive protein (CRP):0.57 mg/dL levels were observed. However, we faced a significant reduction of platelets (PLT): 18×10³/µL, after 14 days of administration of linezolid due to myelotoxicity. Hyperventilation and lactic acidosis (Lac): 12 mmol/L were further complications caused by linezolid. Moreover, an increase in the liver enzymes (SGOT: 75 IU/L, SGPT: 89 IU/L) and international normalized ratio (INR): 1.92 (normal range: 0.9-1.1) parallel with fibrinogen reduction to 1.0 g/L (normal range: 1.8-3.5 g/L),were observed probably due to tigecycline administration.

Having taken all the above into account, we decided to discontinue linezolid and tigecycline 2 weeks after their initiation and add ceftaroline (600 mg iv q8h), to daptomycin.

In the same period, a transesophageal echocardiogram (TEE) showed an aggravation of the findings with the aortic valve having three vegetations: on the right coronary cusp (RCC), on the left coronary cusp (LCC) and on the non-coronary cusp (NCC). Moderate-to-severe aortic valve regurgitation was noted. There was mild mitral valve regurgitation, free from any vegetation. There was no thrombus noted (Figure 1).

 

 

On day 28 of admission, the patient exhibited dyspnea, hypoxemia with peripheral edema. A chest X-ray showed mild pulmonary edema with small bilateral pleural effusions, for which furosemide was given.

On day 35,which was the ninth day after the discontinuation of linezolid and tigecycline, a mild rise in platelets (PLT) to 43.2×10³/µL, a reduction of SGOT/SGPT to normal levels, and a fibrinogen and INR ratio normalization were noted. In the same evening, the patient’s status became worse with chest tightness, dyspnea, and acute respiratory insufficiency. The arterial blood gas (ABG) test was: arterial blood pH: 7.34, bicarbonate: 9.7 meq/L, partial pressure of oxygen: 67 mmHg, partial pressure of carbon dioxide: 18 mmHg and lactic acid: 17.9 mmol/L. The patient was intubated, and during the intubation, he had an episode of cardiac arrest. A cardiopulmonary resuscitation (CPR) was followed by administration of adrenaline, atropine, and vasoconstrictors. The echocardiogram showed injection fraction (EF): 40%, pulmonary artery systolic pressure (PASP): 60 mmHg, posterior wall immobility, and diffuse dysimmobility. The patient was hemodynamically unstable and oliguric.

He was transferred to intensive care unit (ICU) after a negative RNA-PCR test for SARS-CoV-2. He was set on continuous veno-venous hemodiafiltration (CVVHDF). The patient’s medical status complicated with hepatic ischemia, increase of INR and the necessity of blood and plasma transfusions. In the midst of polyorganic insufficiency, the patient died 4 days later.

Enterococci are gram-positive constituents of the normal gastrointestinal flora. However, they can also be nosocomial pathogens resistant to many antimicrobials.¹ Moreover, enterococci represent the second leading cause of nosocomial infection after staphylococci, producing also catheter-associated bacteremias.² The main sources of enterococcal bacteremia are the gastrointestinal and the urinary tract, particularly in case of associated invasive procedures, indwelling catheters, the presence of malignant or inflammatory lesions and anatomical abnormalities.

The frequency of enterococcal bacteremia which results in IE varies widely. Multiple risk factors for the occurrence of IE in patients who have enterococcal bacteremia have been described, such as: history of pre-existing valvular heart disease, prosthetic valve, and older age with underlying diseases.³ The first case of vancomycin-resistant enterococci infective endocarditis (VRE IE) that fulfilled the Duke criteria was reported in 1996.⁴ Risk factors for the development of VREIE possibly are a history of liver transplantation, hemodialysis, prior long-term antibiotic use, increased illness severity and corticosteroid treatment.⁵ According to the epidemiology of enterococcal IE, there is an increasing prevalence of reported cases caused by multidrug-resistant E. faecium.

The clinical presentation of enterococcal IE is in most cases subacute, the physical examination generally revealing fever and a cardiac murmur,^6,7 while classical signs of IE such as Osler’s nodes or Roth’s spots are present less often. Enterococcal IE can be complicated by heart failure, occurring in almost half of the cases, and importantly impacting the outcome.

Enterococci possess both intrinsic and acquired antibiotic resistance determinants. Their penicillin binding proteins (PBP) allow them to resist beta-lactam antibiotics.⁸ Another problem is the emergence and extensive spread of MDR E.faecium isolates belonging to a hospital-associated genetic subclade.⁹ Genomic analyses have shown that the allelic variant of the gene that encodes PBP5, associated with high-level ampicillin resistance, and the genes encoding aminoglycoside-modifying enzymes frequently occur in E.faecium isolates belonging to a particular genetic lineage (clade A).¹⁰ Traditionally, vancomycin was considered the antibiotic of choice for treatment of ampicillin-resistant E. faecium infections. However, E.faecium can often also be resistant to vancomycin, rendering this antibiotic inefficient for most patients with E. faecium IE.¹¹

Unfortunately, no data are available from randomized controlled trials for determining optimal therapy for VRE endocarditis. Treatment of enterococcal endocarditis necessitates a synergistic combination of bactericidal antimicrobials. Enterococci are labelled as resistant to vancomycin if their MICs are >4 mg/L.For enterococcal strains that are resistant to beta-lactams, vancomycin, or aminoglycosides, it is proposed to perform in vitro susceptibility testing to daptomycin and linezolid according totheAmerican Heart Association (AHA) guidelines.¹¹ Quinupristin-dalfopristin may display in vitro activity but is rarely used because of the occurrence of adverse events, including important muscle pain. Tigecycline can also be active in vitro against certain strains of MDR enterococci, but minimal data onits use have been published.¹¹ Furthermore, in the context of the current treatment guidelines there is an argument that VRE endocarditis is an indication for valve replacement, particularly in the context of a lack of effective antibiotic therapy.¹²

Because our patient was not a candidate for surgery due to underlying increased severity of illness, our aim was to choose an antibiotic regimen that we believed would offer the highest bactericidal activity. We treated him with daptomycin, linezolid and tigecycline according to the AHA guidelines.¹¹ We were satisfied by the fact that the blood cultures became negative 7 days after the initiation of therapy.

Despite the fact that our patient was afebrile 4 days after the beginning of antibiotics, he exhibited common and even more challenging side effects due to linezolid and tigecycline intake. We decided to change them to daptomycin/ceftaroline according to the available sensitivity test and the AHA guidelines stating that:"Combination therapy with daptomycin and ampicillin or ceftaroline may be considered, especially in patients with persistent bacteremia or enterococcal strains with high MICs to daptomycin within the susceptible range (Class IIb; Level of Evidence C)”.¹¹

After the discontinuation of linezolid/tigecycline we observed a gradual normalization of the laboratory tests. However, our patient was suffering from critical illnesses. He had a recent episode of N-STEMI and previous hospitalizations with long courses of antibiotics and major surgical manipulations due to biliary tract obstruction. Although the hypothesis of possible cholangiocarcinomatosis had never been confirmed, we reasonably accept that our patient was vulnerable for gastrointestinal colonization and infection with vancomycin-resistant E. faecium. His already critical medical situation was complicated by worsening of coronary artery disease, heart failure, pulmonary edema, pleural effusions and finally respiratory insufficiency.

This case report highlights the lack of published literature on multidrug-resistant enterococcal infections and particularly the severity of vancomycin-resistant E. faecium IE in a critically ill patient. At the present time, no data are available on the management of vancomycin-resistant E. faecium, and the optimal therapy for these bacterial species remains unknown.

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