Introduction
Infective endocarditis (ΙΕ) is a potentially lethal disease and it has
become more complex when it is caused by multidrug-resistant pathogens
difficult to treat, such as
multidrug-resistant Enterococci. Endocarditis due to
multidrug-resistant Enterococci and specifically
multidrug-resistant Enterococcus faecium (E. fαecium) is
rare as most of the reports of these strains are single case
reports. VRE. faecium IE is an uncommon nosocomial infection that
affect patients with significant comorbid conditions. Optimal
antimicrobial therapy remains undefined and a challenging issue, but an
attempt to identify bactericidal combination therapy should be sought.
We report a case of native valve endocarditis due
to vancomycin-resistant E. faecium (VRE) that was paired with a
clinical history of recent N-STEMI and previous surgical manipulations
in the biliary tract.
Case history
A 65-year-old man presented to the emergency department with a 24h
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 dislipidemia. His coronary artery
disease had beguntwenty years ago. He had been submitted in a
percutaneous coronary intervention angioplasty (PCI) in the LAD (2014)
and a coronary artery bypass graft (CABG) for Left Main 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 ago. The tissue biopsy for possible existence
of cholangiocarcinomatosis was negative at that time, although
a 4cm mass was found anteriorly of the pancreatic head in abdomen CT. In
addition, he stated a 18kgr body weight loss during the last 7
months and that he was on ciprofloxacin and metronidazole treatment the
last week before admission, due to the previous episode
of billiary occlusion.
A thorough physical examination was conducted and yielded the following
results:
Vital signs: the patient was afebrile; pulse was 95 beats per
minute (bpm); blood pressure 115/60mmHg (BP); oxygen saturation 99%
(Sat02). There was no peripheral edema.
CVS: included S1, S2 with regular rhythm and diastolic murmur in the
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,
rosuvastatin, aspirin, clopidogrel, ramipril, ezetimibe and glyceryl
trinitrate. Coronary angiography was conducted which revealed coronary
disease in three coronary arteries and well-functioning grafts. Left
descending Coronary artery (LAD) had a severe stenosis 95% (culprit
lesion) very distally beyond 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 x103 /uL with 76,2%
neutrophils (NEU); hemoglobin (Hb): 10,3g/dL; hematocrit (Hct): 31%;
platelets (PLT): 443x10³/uL; procalcitonin (PCT): 1,2ng/mL; C-reactive
protein (CRP): 2,56mg/dL (0-0,5); creatinine (Cr): 1,1mg/dL, SGOT:
52IU/L; SGPT: 24IU/L; total bilirubin was 1,6mg/dL; and rheumatoid
factor (RF): 563IU/ml (<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 (MIC, ≥256 mg/L), teicoplanin
(MIC, ≥32mg/L), levofloxacin (MIC, ≥8mg/L), chloramphenicol (MIC,
≥16mg/L), imipenem (MIC, ≥16mg/L), gentamycin (HL)SYN-R,
streptomycin (HL)SYN-R and susceptible to ceftaroline (MIC, 2mg/L),
linezolid (MIC, 2mg/L), daptomycin (MIC, 1,5mg/L) and tigecycline (MIC,
≤0,12mg/L). In total, there had been taken four set of blood
cultures, all of them positive
to vancomycin-resistant E. faecium (VRE). As a consequence,
piperacillin/tazobactam was discontinued and daptomycin
(12mg/Kgr iv q.d), linezolid (600mg iv q12h) and tigecycline (150mg iv
loading dose, 75mg iv q12h) were started.
After the new antibiotic regimen initiation, the patient was afebrile
and the blood cultures became negative 4 days and 3 days respectively
later. During the administration of antibiotics, the patient complained
about headache, anorexia, nausea, dyspepsia, constipation and inability.
Additionally, a gradual decrease in the procalcitonin (PCT):0,35ng/mL
and C-reactive protein (CRP): 0,57mg/dL levels were observed. However,
we faced a significant reduction of platelets (PLT): 18x10³/uL, due to
myelotoxicity of linezolid. Hyperventilation and lactic acidosis (Lac):
12mmol/L were further complications caused by the drug. Moreover, an
increase in the liver enzymes
(SGOT: 75IU/L, SGPT: 89IU/L) and international normalization
ratio (INR): 1,92 (0,9-1,1) parallel with fibrinogen reduction to 1,0g/L
(1,8-3,5), were observed propably due to tigecycline administration.
Having taken all the above into account, we decided to discontinue
linezolid and tigecycline two weeks after their initiation and
add ceftaroline (600mg iv q8h), to daptomycin.
In the same period, a transesophageal
echocardiogram (TEE) showed the aortic valve having three (3)
vegetations: on the right coronary cusp (RCC), on the left coronary cusp
(LCC) and on the non-coronary cusp (NCC). It was noted moderate to
severe aortic valve regurgitation. 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 rising in platelets (PLT) to
43,2x10³/uL, a reduction of SGOT/SGPT in normal
levels, and a fibrinogen and INR ratio normalization was 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: 9,7meq/L, partial
pressure of oxygen: 67mmHg, partial pressure of carbon dioxide: 18mmHg
and lactic acid: 17,9mmol/L. The patient was intubated, and during the
process 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):
60mmHg, posterior wall immobility, and diffuse disimmobility. The
patient was hemodynamically unstable and oligouric.
He was transmitted to ICU after anegative RNA-PCR test for COVID-19. He
was set on continuous veno-venous hemodiafiltration (CVVHDF). The
patient’s medical status complicated with hepatic ischemia, increase of
INR ratio and the necessity of blood and plasma transfusions. In the
midst of polyorganic insufficiency, the patient died 4 days later.
Discussion
Enterococci are gram-positive bacteria that are part of the normal
gastrointestinal flora. They have become
increasingly nosocomial pathogens resistant to many antimicrobials and
they can survive in the environment for prolonged periods of time (1).
Moreover, enterococci are considered the second leading cause of
nosocomial infections (after staphylococci), including
catheter-associated bacteremias. The more commonly described sources of
enterococcal bacteremia are gastrointestinal and urinary tracts (with an
important association with invasive procedures),indwelling catheters and
anatomical abnormalities including the presence of malignant or
inflammatory lesions.
The frequency of enterococcal bacteremia which results in IE varies
widely. Risk factors for the development of IE in patients with
enterococcal bacteremia include a history of pre-existing valvular heart
disease, prosthetic valve, and older age with underlying diseases (2).
The first case of vancomycin-resistant enterococci endocarditis
that met the Duke criteria was reported in 1996 (3). Risk factors for
the development VRE IE possibly are a history of livertransplantation,
hemodialysis, prior long-term antibiotic use, increased severity of
illness and corticosteroid treatment (4). An important issue in the
epidemiology of enterococcal IE is the increase of infection caused by
multidrug-resistant E. faecium .
The clinical presentation of enterococcal IE is usually subacute, with
fever and the presence of a cardiac murmur as the most common findings
in the physical examination. Classical signs of IE such as Osler’s nodes
or Roth’s spots are less frequently found. The main complication of
enterococcal IE is heart failure, which occurs in almost half of the
patients and has an important impact on outcome.
Enterococci possess both intrinsic and acquired resistance
properties. Their penicillin binding proteins allow them to resist
beta-lactam antibiotics (5). Another problem correlates with the
emergence and widespread dissemination of
multidrug-resistant E. faecium isolates belonging to a
hospital-associated (HA) genetic subclade that is responsible for most
of the infections caused by this species (6). Genomic analyses have
shown that the allelic variant of the gene encoding the
penicillin-binding protein 5 (associated with high-level resistance to
ampicillin) and genes coding for aminoglycoside modifying enzymes are
frequently found in E. faecium isolates belonging to this genetic
lineage (clade A) (7). Tranditionally, vancomycin was the antibiotic of
choice for treatment of
ampicillin-resistant E. faecium infections;
however E. faecium isolates are often resistant to vancomycin,
making this antibiotic useless for the majority of E. faecium IE
patients.
Unfortunatelly, there are no data available from randomized, controlled
trials to determine optimal therapy. Treatment of enterococcal
endocarditis necessitates a bactericidal synergistic combination of
antimicrobials. Enterococci are considered to be resistant to vancomycin
if MICs are >4mg/L. For strains of enterococci resistant
to β-lactams, vancomycin, or aminoglycosides, it is reasonable to test
for susceptibility in vitro to daptomycin and linezolid according
to the American Heart Association (AHA) guidelines (8). Linezolid is
bacteriostatic in vitro against enterococci, whereas daptomycin is
bactericidal in vitro in susceptible
strains. Quinupristin-dalfopristin may be active in vitro but it is
rarely used because of side effects, including intractable muscle pain.
Tigecycline is active in vitro against some strains of
multidrug-resistant enterococci, but there are minimal published
data on its use.Furthermore, on the context of the current treatment
guidelines there is an argument that VRE endocarditis is an indication
for valve replacement on the basis of lack of effective antimicrobial
therapy (9).
Because our patient was not a candidate for an operation due to
underlying increased severity of illness, our goal was to identify a
regimen that we believed would offer maximal bactericidal activity. We
chose to treat him with daptomycin, linezolid and tigecycline
according to the AHA guidelines (8). 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 afrebrile 4 days after
the begining of antibiotics, he exhibited common and even more
challenging side effects due to linezolid andtigecycline intake. We
decided to change them to daptomycin/ceftaroline according
the available sensitivity test and the AHA guidelines: Combination
therapy with daptomycin and ampicillin or ceftaroline may be considered,
especially in patients with persistent bacteremia or enterococcal
strains with high MIC’s to daptomycin within the susceptible
range (Class IIb;Level of Evidence C ) (8).
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 billiary tract obstruction. Although the
hypothesis of possible cholangiocarcinomatosis had never
been confirmed, we reasonably accept that our patient was a
candidate for GI colonization and infection
of vancomycin-resistant E. faecium . His already
critical medical situation complicated with 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 enterococci infections and particularly the severity
of vancomycin-resistant E. faecium IE in a critically ill
patient. At the present time, there are no data available on
the management of vancomycin-resistant E. faecium , and the
optimal therapy of these species remains unknown.
Georgousi Kleoniki, M.D., Ph.D.¹˟, Floros George, M.D.²,Kachrimanidis
Ioannis, M.D.¹, Liodi Aikaterini, M.D.¹, Tsantoulas Alexandros,M.D.¹,
Tzaki Maria,M.D.¹, Velisaris George,M.D.², Agora Olga, M.D.², Tsiplakou
Sofia, M.D., Ph.D.³, Kyriazis Ioannis, M.D., Ph.D.¹, Kafkas Nikolaos,
M.D., Ph.D.²
˟Corresonding author
Corresponding: Georgousi Kleoniki, M.D., Ph.D., Infectious Diseases
Consultant, Internal Medicine Department, KAT General Hospital, Nikis
Street 2, Kifissia, Attica, 14561, Greece. Tel:, +302132086338. Email:methexiskleri@gmail.com