Management of infectious endocarditis from the perspective of the Infectious Diseases specialist – a 2023 update

An increase in the number and the complexity of cardiac surgery has brought on a rise in the proportion of health-care-associated Infectious Endocarditis (IE), and as a result, today S. aureus is the most common causative patho-gen for this condition. Clinical suspicion for IE should be raised in front of a patient with predisposing risk factors, a new heart murmur and/or vasculitic/embolic events. The Duke Criteria have been long used to diagnose IE. However, they underwent several changes in order to improve their sensitivity in the diagnosis of Q-fever IE and to decrease the size of the possible IE group. Our primary goal is to enhance the knowledge regarding the diagnosis and treatment of infective endocarditis. In acute IE, prior to beginning antibiotic therapy, at least three sets of blood cultures must be taken, ideally from three distinct sites, as determining the etiologic agent is of highest importance. The diagnosis of IE cannot be made based just on a single positive blood culture. To diagnose subacute IE, three to five sets of blood cultures must be drawn over the course of 24 hours.


INTRODUCTION. DEFINITIONS
Infection of the cardiac endothelium, known as infective endocarditis (IE), has an annual incidence of up to 12.7/100 000 and a mortality rate of up to 30% at 30 days. Over time, the epidemiology of IE has altered progressively, with a rise in the proportion of healthcare-associated IE (which now accounts for 25-30% of IE in recent studies). This is brought on by an increase in the number of cardiac surgeries and greater use of intravenous lines and intracardiac devices. Furthermore, in industrialized countries, we witness a drop in the number of postrheumatic valvulopathies, so IE affects mainly young adults (IV drug abuse patients  IVDA IE) and older patients (maximum incidence between 70 and 80 years of age -mean age of patients -60.8 years). More than half of the patients are above 50 [1,2,3].
Our primary goal is to enhance the knowledge regarding the diagnosis and treatment of IE. Additionally, we sought to compare the AHA (American Heart Association) and ESC (European Society of Cardiology) guidelines, which are the two major guidelines regarding the treatment of this condition.

ETIOLOGY OF INFECTIVE ENDOCARDITIS
Each type of IE has a different etiologic agent. The responsible microorganism relies on the entry site -dental (oral streptococci), cutaneous (staphylococci), urinary (enterococci) etc. Overall, today S. aureus infection is the most common cause of IE -IE complicates between 35.6 and 60.5% of staphylococcal bacteremia.

Native Valve Infective Endocarditis (NVE)
Streptococcus species, such as S. viridans, Streptococcus gallolyticus (ex. S. bovis), and enterococci, are responsible for over 70% of NVE cases. 25% of cases are brought on by Staphylococcus species, which typically have an acute course that is more aggressive [2].

Prosthetic Valve Endocarditis (PVE)
Early prosthetic valve endocarditis, which occurs during the first year after cardiac surgery, shows differently than late PVE, which manifests as a subacute condition comparable to NVE.
The organisms that are typically inferred when discussing early PVE are S. aureus and S. epidermidis, both of which are frequently methicillin-resistant (e.g., MRSA). Streptococci are the most frequent cause of late illness. In general, CoNS account for 30% of PVE cases [2].

Intravenous Drug Abuse Infective Endocarditis (IVDA IE)
In individuals with IVDA IE, Staphylococcus aureus is the most frequent etiologic organism (MRSA accounting for many of the cases, mainly in patients with prior hospitalizations, long-term use of IVD, and non-prescribed antibiotic use. Groups A, C, and G streptococci and enterococci also are recovered from patients with IVDA IE.
Gram-negative organisms are rarely implicated -members of the HACEK family and Pseudomonas aeruginosa are the most often isolated etiologic agents [2].

Nosocomial/healthcare-associated infective endocarditis
Endocarditis can occur because of medical procedures involving intravascular devices, including hemodialysis shunts and catheters, chemotherapeutic and hyperalimentation lines, central or peripheral intravenous catheters, and rhythm control devices implantation, such as pacemakers and defibrillators. The most prevalent pathogens are gram-positive cocci, such as S. aureus, CoNS, enterococci, and non enterococcal streptococci [2].

Fungal endocarditis
Patients using broad-spectrum antibiotics in intensive care units and IV drug users have the greatest risk of fungal endocarditis. Unfortunately, blood cultures typically yield negative results [2].
Blood cultures are negative in 5-10% of IE cases, and the etiologic agent cannot be determined without the use of serologic testing or genetic amplification assays on bioptic tissue (Coxiella burnetii, Bartonella spp.).
The entrance site determines the etiologic agent ( Table 1). The entry point cannot be identified in roughly half of the cases. An infection site, whether active or latent, or an intervention that results in bacteraemia can serve as the entry point [3].

RISK FACTORS FOR INFECTIVE ENDOCARDITIS
Regardless of the type of IE, two conditions must exist for IE to occur: one that allows the microorganism to enter the bloodstream and another that enables the organism to set place in the cardiac endothelium. We already covered the etiologic agents and their different sites of entry, so next we will point out the conditions that predispose the patient to IE.
Remaining endocarditis-related valve damage from an earlier episode is the main risk factor for IE [3].
Almost half of NVE cases occur in apparently healthy individuals, who do not know of any previous heart condition. The most common precursors of NVE are valvulopathies, whether congenital, atheromatous, or degenerative, with valvular regurgitation and mitral valve prolapse with an associated murmur being more frequently implicated than stenosis. Compared to mitral valve disease, aortic valve disease is more prevalent. Other risk factors for IE include congenital heart defects such as tetralogy of Fallot, ventricular septal defect, patent ductus arteriosus, and aortic bicuspid valve. Atrial septal defect is not considered a risk factor IE.
The risk of developing IE in patients with a valvular prosthesis is 1000 times greater than in the general population. Early PVE is more frequently the consequence of perioperative inoculation, especially if it occurs in the first few months after the procedure. However, the risk of developing IE persists for a long time after the intervention [3].
Aging, diabetes mellitus, the use of anticoagulants or steroids, and other risk factors have all been mentioned as potential causes of pacemaker IE. Surgery on any element of the pacemaker system, especially elective battery replacements, is probably the biggest risk factor. Infection rates related to battery replacements are around five times higher than those of initial implantation (6.5% vs. 1.4%).
A postoperative hematoma, an inexperienced surgeon, and a previous temporary transvenous pacing are some other important risk factors for pacemaker IE [2].

CLINICAL PRESENTATION OF INFECTIVE ENDOCARDITIS
Almost all of the patients experience fever, nocturnal diaphoresis, fatigue, loss of weight, and loss of appetite. At presentation, 25% of patients already have an embolic complication.
Clinical suspicion for IE should be raised in front of a patient with predisposing risk factors (listed above), a new heart murmur, and/or vasculitic/embolic events [3].
IE can present as an acute or subacute condition. Acute IE is characterized by rapid (within days) development of symptoms, including high fever, chills, heart failure, splenomegaly, lumbar pains, arthralgias, and systemic complications, including stroke.
With subacute IE, the symptoms develop more slowly (over weeks or months) and include fatigue, difficulty breathing, weight loss, and sometimes fe-ver. On average, six weeks pass between the time of the disease's onset and its diagnosis.
A new heart murmur, although highly suggestive of IE, is present in less than half of the patients [4]. Underlying cardiac disease may present with signs of congestive heart failure brought on by valvular regurgitation. Back pain brought on by spinal osteomyelitis or focal neurologic symptoms from an embolic stroke are examples of secondary phenomena.
People who use intravenous drugs frequently complain of dyspnea, coughing, and chest pain. This is because this group has a high prevalence of tricuspid valve endocarditis with secondary embolic showering of the pulmonary vasculature [2].
Clinical signs and complications of IE will be synthesized in Table 2.  (Table 3) The sensitivity of Duke criteria is typically 80%. Their sensitivity in PVE or implanted device endocarditis is significantly reduced. CT and cerebral MRI may be helpful in such circumstances [3].

Microbiological diagnosis
In acute IE, prior to beginning antibiotic therapy, at least three sets of blood cultures must be taken, ideally from three distinct sites, as determining the etiologic agent is of the highest importance. One set of blood cultures consists of two tubes: one for aerobic and one for anaerobic bacteria. 10 ml of blood should be collected in each tube. The first and third blood cultures must be prelevated one hour apart. The diagnosis of IE cannot be made based just on a single positive blood culture [3].
To diagnose subacute IE, three to five sets of blood cultures must be drawn over the course of 24 hours [2].
If blood cultures show no growth and the clinical suspicion of IE is still high, additional serological, molecular biology, and histopathologic tests should be carried out. This is especially important if the patient hasn't previously been exposed to antibiotics. Since multiplex PCR from blood has limited sensitivity, it is not recommended [3,5].
Diagnostic tests used in culture negative endocarditis are shown in Table 4.

Cardiac imaging
Transthoracic echocardiography (TTE) is essential when the diagnosis of IE is suspected. Transoesophageal echocardiography (TOE) is recommended when TTE is unremarkable but the suspicion is still high. A whole-body CT scan, an MRI, a cardiac CT, PET-CT, or radiolabelled leucocyte single-photon emission computed tomography may be helpful when TTE and TOE are inconclusive [4].
Cardiac CT scans can provide important information about perivalvular lesions, playing an important role in the diagnosis of PVE and intracardiac device endocarditis.
When echocardiography is unclear and there is a high clinical suspicion of PVE, a PET-CT may become useful.
Depending on the clinical presentation, the following tests may help diagnose complications: ECG, thoracic X-ray, serum creatinine levels, whole body CT, and brain MRI. Before cardiovascular surgery, cerebral imaging must be systematically undertaken [4].

TREATMENT OF INFECTIVE ENDOCARDITIS
Antibiotic therapy must be initiated after at least three sets of blood cultures are prelevated. In cases of sepsis or septic shock and when there is an urgent need for cardiac surgery, this restriction is disregarded. In all other situations, microbiological evidence must be provided in order to adjust antibiotic treatment plans following the results [4].

Empirical therapy in Infective Endocarditis
Recommended regimens for NVE and late PVE are IV Amoxicillin plus Oxacillin plus Gentamicin administered until blood culture results are available. If a patient is allergic to penicillin, IV Vancomycin and Gentamicin should be given.
The recommended antibiotic regimen for early PVE includes IV Vancomycin, Gentamicin, and Rifampin [4]. Posology is presented in Table 5.

Pathogen-specific therapy
The isolated bacteria and its susceptibility to antibiotics are key factors in IE treatment. Whether it is NVE or PVE also affects how long the treatment will last. There is little variation in recommended regimens for common organisms in published guidelines [6].

Streptococcal Infective Endocarditis
Both European and American guidelines recommend a beta-lactam antibiotic (Penicillin G/Amoxicillin/Ampicillin/Ceftriaxone) in combination with Gentamicin when treating streptococcal IE caused by S. viridans/gallolyticus (CMI < 0.12 mg/L to Penicillin). It takes two weeks to treat NVE with Gentamycin and a beta-lactam antibiotic, four weeks to treat NVE with a beta-lactam antibiotic alone, and six weeks to treat PVE or complicated NVE. Extracardiac involvement, a diagnosis made > 3 months after the onset, and a need for surgery are all indicators of complicated NVE.
The regimens are the same for S. viridans/gallolyticus with a CMI > 0.12 mg/L to Penicillin; the only differences are in the posology (higher doses of Penicillin/Amoxicillin), and the addition of gentamycin is not optional in this case.
The suggested treatments in cases of beta-lactam allergy include Vancomycin/Teicoplanin with or without Gentamicin. The course of treatment is the same length.  1 alternative: cefazolin 100mg/kg/24h divided in 3 doses or 30mg/kg loading dose with a duration of 1h, then 100mg/kg/24h in continuous infusion 2 will be excluded if the strain is gentamicin resistant 3 if the strain is rifampin resistant, the addition of one or two antibiotics will be taken into consideration, based on the antibiogram results

Enterococcal Infective Endocarditis
As is the case with Streptococcus and Staphylococcus spp, it is important to know whether Enterococci are sensitive or resistant to beta-lactams.
The suggested regimens for beta-lactam-sensitive strains include Amoxicillin (200 mg/kg/24 h) in combination with gentamicin (3 mg/kg/24 h) for 4-6 weeks (gentamicin only for 2 weeks). The recommended antibiotics for individuals who are allergic to beta-lactams are vancomycin (30 mg/kg/24 h) or teicoplanin (6 mg/kg/24 h) in combination with gentamicin, with the same therapy period. For gentamicin resistant, beta-lactam-sensitive strains, amoxicillin is associated with ceftriaxone 2 g bid -for patients who are allergic to penicillins, vancomycin or teicoplanin are preferred, in monotherapy, and the course of treatment is longer than 6 weeks [4].
Culture negative Infective Endocarditis with identification of the etiologic agent (Table 8)

Infective Endocarditis prophylaxis
Today, IE prophylaxis is based on four principles: • Evidence that IE antibiotic prophylaxis is effective is insufficient to account for the widespread use of antibiotics for this purpose; • Antibiotic prophylaxis must be limited only to high-risk patients (patients with a high risk of acquiring iE/post IE complications); • Antibiotic prophylaxis must be limited only to high-risk procedures, that are known to cause bacteremia with germs usually incriminated in IE; • Maintaining good oral hygiene is probably as efficacious as antibiotic prophylaxis. High-risk cardiopathies for which antibiotic prophylaxis is recommended in case of high-risk procedures are the following: • Patients with prosthetic heart valves; • Patients with a history of IE; • Patients with unrepaired cyanogenic congenital heart defects or residual shunt.

CI = contraindicated
For other valve defects or congenital heart defects antibiotic prophylaxis in case of high-risk procedures is not recommended.
High-risk procedures for which antibiotic prophylaxis is recommended in case they are done on IE high-risk patients are the following: dental extractions, subgingival scaling, manipulation of the gingival tissue, periapical region of teeth, or the oral mucosa.
Antibiotic prophylaxis is not recommended in: anesthetic injections in uninfected tissue, suture ablation, retroalveolar X-ray, implantation or adjustment of orthodontic devices or detachable prostheses, or dental or gingival trauma.
Also, antibiotic prophylaxis is not recommended in case of procedures undertaken on the respiratory tract, such as: laryngoscopy, bronchoscopy, endotracheal intubation, nor in case of gastroscopy, TOE, colonoscopy, cystoscopy [4,8].
Recommendations on prophylaxis before abscess incision and drainage are not yet clarified. According to research, simple abscesses seldom cause bacteremia after being punctured and drained. However, MRSA, which is usually implicated in IE, is the pathogen most frequently responsible for oral abscesses. For patients with high-risk conditions undergoing routine incision and drainage of a simple abscess, it is prudent to administer clindamycin (600 mg IM/IV) or vancomycin (20 mg/kg) 30 to 60 minutes before to the procedure [9].

Anticoagulant therapy
Anticoagulant and antiaggregant treatment are contraindicated in IE because they increase the risk of bleeding (particularly in the CNS) while having no effect on stroke risk. If IE affects a person who is currently receiving anticoagulant therapy, the therapy should only be continued if it is absolutely necessary (for example, in the case of patients who have mechanical valvular prostheses). Unfractionated heparin can be used as an alternative to oral anticoagulant treatment for two weeks if necessary [4,10].

CONCLUSIONS
Infective endocarditis, although uncommon, can be a life-threatening illness. The epidemiology and microbiology of this condition have undergone significant changes in recent decades. Despite improvements in diagnosis and treatment, mortality rates remain high. The clinical manifestations of infective endocarditis often involve multiple body systems, leading individuals to seek initial care from various medical professionals who may have varying levels of knowledge about the disease. However, given the prognostic implications, early and accurate diagnosis is crucial. Treatment guidelines have remained relatively stable over the past decade. The issue of antibiotic prophylaxis for high-risk individuals undergoing dental procedures in relation to infective endocarditis is controversial, and further research is needed to establish a consensus.
Conflict of interest disclosure: The authors declare that there are no conflicts of interest.