Reference: March 2025 | Issue 3 | Vol 11 | Page 56
Infective endocarditis (IE) is a complex, multisystemic condition resulting from infection of the endocardial surface of the heart, native or prosthetic heart valves, or infection of implantable intracardiac devices. Clinical presentation of IE varies widely. It can present with acute, rapidly progressive symptoms, or may have a more chronic onset, and is classified as ‘definite’, ‘possible’, or ‘rejected’ IE, according to the Modified Duke Criteria. IE is a very serious disease and can be fatal if left untreated.
Rising incidence of IE
The development of IE requires a predisposing condition, pathogens entering the bloodstream, and a poor host immune response for effective clearance of the pathogen. Several studies have noted an increased incidence in IE, with several factors contributing to this including the older age of the population, increasing availability of interventional and surgical treatment options for disease (not only limited to cardiovascular ones), increasing antibiotic resistance, and growing use of diagnostic tools for the diagnosis of IE.
Following the 2015 European Society of Cardiology (ESC) guidelines, there has been a reduced emphasis on antibiotic prophylaxis, but it is unknown if this has significantly contributed to the increased incidence of IE.
Several studies have demonstrated an increased incidence of IE-related hospitalisations/deaths, while others do not illustrate this trend since the reduced use of antibiotic prophylaxis. However, in high-risk individuals, antibiotic prophylaxis was associated with significant reduction of IE after invasive dental procedures, mostly extractions and oral surgical procedures.
In view of this, the most recent guidelines (2023 ESC guidelines) have subdivided the population into high, intermediate, and low risk – with antibiotic prophylaxis being guided according to the population risk. Table 1 depicts the stratification of patients into their respective risk category.
| High risk |
Patients with previous IE Patients with surgically-implanted prosthetic valve and any material used for cardiac valve repair Patients with untreated congenital heart disease and those treated with prosthetic material Patients with ventricular assist devices as destination therapy |
| Intermediate risk |
Patients with rheumatic heart diseases Patients with non-rheumatic degenerative valve disease Patients with congenital valve abnormalities, including bicuspid aortic valve Patients with implanted electronic devices Patients with hypertrophic cardiomyopathy |
| Low risk | All other patients |
TABLE 1: Populations at risk of IE
High risk patients for IE must receive antibiotic prophylaxis before at-risk dental procedures including dental extractions, oral surgery procedures, and dental procedures involving manipulation of the gingival and periapical region of the teeth.
Moreover, the latest guidelines have suggested the use of antibiotic prophylaxis in high-risk patients for invasive diagnostic or therapeutic non-dental procedures, such as those on the respiratory, gastrointestinal, genitourinary tract, skin, and musculoskeletal systems. Antibiotic prophylaxis is also recommended before transcatheter aortic valve implantation and other transcatheter valvular procedures.
Apart from antibiotic prophylaxis, several general prevention measures are strongly recommended for patients at high or moderate risk of IE including:
- Strict dental hygiene;
- Strict cutaneous hygiene;
- Disinfection of wounds;
- Curative antibiotic therapy for any focus of bacterial infection, but with avoidance of self-medication
with antibiotics; - Strict infection control measures for any at-risk procedure;
- Discouragement of piercing and tattooing;
- Limitation of infusion catheters and invasive procedures whenever possible and strict care bundles for central and peripheral intravenous infusions.
| Setting | Recommendation |
|---|---|
| Community-acquired NVE or late PVE (≥12 months post cardiac surgery) |
Targeted at staphylococci, streptococci, and enterococci: Ampicillin with ceftriaxone or flucloxacillin and gentamicin ► Ampicillin 12g/day IV in 4-6 doses ► Ceftriaxone 4g/day IV or intramuscularly (IM) in 2 doses ► Flucloxacillin 12g per day IV in 4-6 doses ► Gentamicin 3mg/kg/day IV once daily |
| Early PVE (<12 months post cardiac surgery) or healthcare-associated |
Targeted at methicillin-resistant staphylococci, enterococci, and non-HACEK gram-negative pathogens: Vancomycin or daptomycin combined with gentamicin and rifampicin ► Vancomycin 30mg/kg/day IV in 2 doses ► Daptomycin 10mg/kg/day IV once daily ► Gentamicin 3mg/kg/day IV or IM once daily ► Rifampicin 900-1200mg IV or orally in 2-3 doses |
| Allergy to beta-lactams. Community-acquired NVE or late PVE |
Targeted at staphylococci, streptococci, and enterococci: Cefazolin or vancomycin in combination with gentamicin ► Cefazolin 6g/day IV in 3 doses ► Vancomycin 30mg/kg/day IV in 2 doses ► Gentamicin 3mg/kg/day IV or IM once daily |
TABLE 2: Empiric antibiotic therapy recommendations for IE in adults
Management
The management of IE, based on the 2023 ESC guidelines, includes timely diagnosis, treatment with antimicrobials for eradication of causative microorganisms, and in cases of complicated IE, surgical intervention to remove any infected material. Multidisciplinary care should be provided to the patient including input from infectious disease, cardiology, and cardiac surgery specialists in order to optimise clinical evaluation along with guidance in terms of antibiotic and surgical treatment (if required).
It has been demonstrated that bactericidal therapy is superior to bacteriostatic regimens when it comes to eradication of causative organisms. Once the culprit organism is identified, the choice of antibiotic should be targeted to the specific organism, also taking into account its antibiotic susceptibility and sensitivities.
Despite the effectiveness of antibiotics in IE, there are emerging issues such as antibiotic tolerance and resistance. Bacterial tolerance describes bacteria which are still susceptible to a specific antibiotic, but have the ability to escape drug-induced killing and have the ability to resume growth once treatment is withdrawn.
Slow-growing microbes develop tolerance towards most antimicrobials by forming vegetations and biofilms that will, in turn, require extended therapies in order to fully sterilise the affected heart valve(s), which is common in cases of prosthetic valvular endocarditis (PVE).
There is still a preference for bactericidal drug combinations over monotherapy against tolerant microorganisms, and antimicrobial treatment of PVE should last longer, ie, six weeks or more compared with the shorter course of treatment in native valvular endocarditis (NVE) – approximately four to six weeks.
The 2023 ESC guidelines have introduced the possibility of outpatient antibiotic therapy in patients with stable IE following an initial phase of IV antibiotic therapy. This was primarily based on the five-year outcome results of the POET (Partial Oral Treatment of Endocarditis) trial, which confirmed the efficacy of oral antibiotic therapy in patients with left-sided IE related to streptococcus, E faecalis, S aureus or Coagulase-negative staphylococci (CoNS).
Outpatient parenteral antibiotic therapy (OPAT) or oral antimicrobial regimens may be considered if the patient is clinically stable, lives in a stable environment (preferably with a caregiver), is independent or has home help provided. When possible, early discharge from hospital and OPAT help to improve the effects of infection and prevent prolonged hospitalisation, particularly in elderly patients.
Contraindications to OPAT include patients with IE complications such as heart failure (HF); renal failure; severe valvular regurgitation; vegetations larger than 10mm; presence of neurological complications; or those who actively use illicit IV drugs.
In view of this, the 2023 ESC guidelines suggest a first phase of IV antibiotic therapy accompanied by possible surgical removal of infected cardiac tissue or device and draining of any abscesses. In the stable IE patient, a transoesophageal echocardiogram (TOE) should be done at day 10 in order to exclude complications, and then the stable uncomplicated patient can be considered for OPAT, ideally 10 days after starting IV antibiotic therapy or from day seven post-surgical intervention.
Treatment of OPAT patients usually uses the same combinations as those for inpatients, or else a step-down outpatient oral regime. The patients and their relatives/caregivers should be thoroughly educated regarding the disease and how to monitor it. Follow-up by community physicians or nurses is also needed. Complicated cases should remain in hospital and be treated with inpatient IV antibiotic therapy.
PVE
PVE is the most severe form of IE and occurs in 1-6 per cent of patients with valve prostheses. PVE may be more common after biological rather than mechanical valve replacement surgery. Early PVE begins in the peri-operative period and typically involves S aureus, Staphylococcus epidermidis, or nosocomial microorganisms such as gram-negative pathogens or fungi. Late PVE more commonly mimics the pattern of NVE, which is mostly represented by streptococcal and staphylococcal infections.
Diagnosis is more difficult in PVE than in NVE, with clinical presentation being frequently atypical, especially in the early post-operative period where fever is common without macroscopic changes of the prosthesis on cardiac imaging. Nonetheless, persistent fever should trigger the suspicion of PVE, with diagnosis based mainly on the results from echocardiography and blood cultures. Combinations of different imaging techniques such as cardiac CT, nuclear imaging, and TOE improve diagnostic accuracy and provide relevant information in terms of prognosis.
In contrast to NVE, PVE is associated with higher mortality and morbidity and reduced long-term survival. Surgery is recommended for early PVE (within six months of valve surgery) with new valve replacement and complete debridement. Patients with uncomplicated non-staphylococcal late PVE can be managed conservatively.
Complications
Certain complications of IE can only be managed via surgical intervention, with studies showing that surgical management can lead to a survival advantage of up to 20 per cent. There are three main indications for surgery in the setting of IE:
1. HF is the most common indication for surgery. Clinical symptoms can range from mild dyspnoea to pulmonary oedema and cardiogenic shock. HF complicating IE is associated with poorer prognosis, with surgical management the only treatment associated with improved survival.
2. Uncontrolled infection: Surgery is indicated in persistent infection or sepsis despite antibiotic therapy provided that extracardiac abscesses and infected lines have been excluded. Signs of local infection that do not respond to antibiotic therapy, including increasing vegetation size, abscess formation, the creation of pseudoaneurysms and/or fistulae, and new atrioventricular block (AVB) may require surgical intervention, as well as infection with resistant or very virulent organisms.
3. Prevention of septic embolisation (especially to the central nervous system): Risk factors for embolisation include vegetation size >10mm, location of the vegetation on the anterior mitral leaflet, vegetation mobility, previous embolisation and infection with S Aureus, fungus, or Streptococcus bovis. The risk of embolisation falls dramatically after initiation with antibiotics, with serious embolic events being rather uncommon a week after therapy has begun.
Other complications of IE include infective aneurysms, which are rare but life-threatening. Infective cerebral aneurysms may be asymptomatic or cause headaches, seizures, or focal symptoms, and can progress to lethal rupture. They are also associated with subarachnoid, intracerebral, and intracranial haemorrhage, especially when the patient is on anticoagulants.
Digital subtraction angiography is the gold standard diagnostic tests for the detection of infective aneurysms, and has a higher sensitivity in detecting infective aneurysm than CT or magnetic resonance angiography. Patients with unruptured infective cerebral aneurysms can be managed with antibiotic treatment, with interventional treatment considered in cases of ruptured infective aneurysms or unruptured infective aneurysms that do not respond to antibiotics.
Splenic complications of IE range from asymptomatic infarction and abscess formation to splenic rupture and cardiovascular collapse. Splenic infarcts are common and very often asymptomatic. Around 5 per cent of splenic infarcts progress to abscess formation. Splenic complications can present with persistent/recurrent fever, persistent bacteraemia, and abdominal pain, and such patients should under go radiological imaging.
Treatment includes antibiotic therapy for splenic infarction or for small abscesses. When an abscess is large, splenectomy may be considered, usually performed prior to valve surgery. In patients with high surgical risk, percutaneous drainage, and/or laparoscopic surgery may be considered.
Acute renal failure or worsening of kidney function may occur due to renal infarction secondary to septic emboli; haemodynamic impairment in patients with HF; drug toxicity; nephrotoxicity of contrast agents used for diagnostic imaging; or immune complex and vasculitic glomerulonephritis.
IE-related osteoarticular infections are frequent due to the spread of the pathogen through the bloodstream and subsequent tissue implantation, with an incidence of around 6-8 per cent, including infection to the bones, joints, and vertebral discs.
Neurological complications may occur prior to or following the diagnosis of IE and recurrence of events may also occur later on in the course of disease. The possibility of IE should be taken into consideration in patients presenting with meningitis, stroke, or brain abscess.
Silent cerebrovascular complications occur in approximately 80 per cent of patients with IE, while symptomatic cerebrovascular complications occur in up to a third. IE caused by S aureus is more commonly associated with neurological complications compared to IE secondary to other microorganisms.
Other cardiac complications include myocarditis – which will usually present in the form of acute HF and/ or ventricular arrhythmias – and pericarditis. AVB may also develop as the atrioventricular node and His bundle lie close to the tricuspid valve, aortic root, and mitral annulus, with a paravalvular abscess of these valves, especially of the aortic valve, leading to AVB. New-onset AVB caused by abscess is an indication for urgent cardiac surgery. AVB may also develop as a consequence of valve surgery.
Conclusion
In order to prevent serious complications, it is imperative that IE is diagnosed promptly and antibiotic therapy is initiated as soon as possible. In high-risk patients, early cardiac surgery should be considered in order to prevent embolisation of vegetations. Timely, appropriate care is vital for optimal outcomes.
It is also important that patients are followed up and reassessed, especially for the occurrence of complications after discharge such as reinfection, HF, or the need for valve surgery.
Following appropriate treatment for IE, survival rates are 85-90 per cent and 70-80 per cent at one and five years, respectively, with the main predictors of long-term mortality being age, co-morbidities, recurrence of IE, double valve infection, and HF, especially when cardiac surgery cannot be performed.
References available on request
