Prophylaxis of endocarditis: current views and indications in children and young adults

Keywords

infective endocarditis, paediatric, prevention, prophylaxis, young adults

Background

Prophylaxis and treatment of infective endocarditis in neonates, children, and in young adults requires special expertise and an experienced endocarditis team. In these age groups, epidemiology, pathophysiology, diagnostics, severity, and outcome of the disease have specificities different from those in adults [1].

Infective endocarditis in childhood has a significant, high mortality rate (around 5-10%), which can be even higher in a more vulnerable patient population.

Furthermore, special clinical scenarios, e.g., patients with congenital structural heart defects, cyanotic heart diseases, and patients with repaired congenital defects require individual management. Tailored antibiotic therapy in childhood must be in keeping with age, and local corresponding microbiomes and resistance profile.

Prevention and prophylaxis of infective endocarditis is the cornerstone to avoid severe consequences, and warrants individual decision making in all paediatric patients. For instance, pathomechanisms, risk stratification and scoring assessment is essential in a suspected infective endocarditis in paediatric patients. Those at high risk of developing infective endocarditis must receive antibiotic prophylaxis. The antimicrobial prophylaxis itself has to be individually tailored to paediatric needs, e.g., compliance with taking tablets vs. liquid medication in an otherwise generally well child may have an impact on the success of prophylaxis. Antibiotic prophylaxis of infective endocarditis has always been a debated issue and stands in a grey zone. The American Heart Association modified their guidelines on childhood infective endocarditis significantly in 2007 and declined antibiotic prophylaxis, reserving it for high-risk groups only. Following this change, serial reports and reviews have indicated non-significant changes in the prevalence of infective endocarditis. In keeping with these reports, it was also concluded that before 2007 antibiotic medications had been overused [2]. Additionally, non-pharmacological preventive steps, most importantly oral hygiene, must be advised in all patients at risk of infective endocarditis.

This short paper focuses on the prevention and prophylaxis of childhood infective endocarditis. We are not proposing to provide a detailed description of special diagnostic and treatment steps in the paediatric population.

Unique features of infective endocarditis in paediatrics

Epidemiology

The overall presentation of infective endocarditis in childhood is less frequent than in the adult population; however, hospital admissions and the severity of the disease carry a higher burden. The annual incidence of infective endocarditis in children (under 18 years old) is around 90/100,000 children. The vast majority of these patients suffer from congenital heart diseases and have undergone a reparative surgical or device procedure in the postnatal period. One other group with an increased incidence of infective endocarditis is paediatric oncology patients who are prone to recurrent bacteraemia due to long-standing central venous catheters and medication ports [3].

Aetiology

The aetiology of childhood infective endocarditis usually differs from that in adults. Artificial valves are the predominant cause of infective endocarditis in adulthood, while mainly congenital structural abnormalities are responsible in childhood. Grown-up congenital heart diseases (GUCH) are responsible for a small proportion of infective endocarditis patients in adulthood. High-risk patients in the perinatal and childhood population are those who suffer from congenital heart disease. In detail, common predisposing conditions are congenital valve abnormalities, ventricular and atrial septal defects, and cyanotic heart diseases including tetralogy of Fallot. Furthermore, these patients are vulnerable in the postoperative theatre. For instance, central lines present a huge risk for developing infective endocarditis. Interestingly, infective endocarditis in the neonate occurs mainly in healthy hearts; only one third of them happen in congenital heart defects. Furthermore, a huge number of these cases involve right-sided endocarditis and could have been prevented with reasonable use of asepsis and antisepsis measures.

Infective endocarditis has a high mortality in the paediatric population. Vulnerable hospital-bound neonates and toddlers have a high risk of developing bacteraemia from routine procedures and thus they are at higher risk of infective endocarditis. Bacteraemia and endothelial damage are cornerstone pathologic steps for infective endocarditis. The perinatal population also tends to develop non-bacterial endocarditis, referring to non-significant or not-quantifiable systemic bacteraemia. Given that these patients have major structural abnormalities, implanted devices, artificial valves, and implanted conduits, they tend to develop fibrinous tissue overgrowth and biofilm on these surfaces. Endothelial damage – a key step in the development of infective vegetation on the endocardial membranes – occurs more frequently and early in the vulnerable perinatal and childhood population. Turbulent blood flow and high-velocity jets, which are both common in congenital heart disease and in repaired structural abnormalities, eliminate laminal blood flow, which significantly increases the risk of development of endocardial endothelial damage. In developed industrial countries, a huge decline has been observed in the incidence of rheumatic heart disease among the paediatric population. However, in developing countries it still occurs at a high rate and is responsible for a reasonable number of infective endocarditis cases. In the European population, rheumatic heart disease-associated infective endocarditis is rare nowadays. Vaccinations, diagnostics and antimicrobial therapy have largely decreased the prevalence of rheumatic heart disease. In parallel with the decrease in rheumatic cases, an increase in the number of neonatal/childhood survivors of severe congenital heart defects has been observed. These patients may face multiple surgical or device procedures throughout their lives.

In the young adult population, infective endocarditis has a low incidence in healthy hearts. A small proportion of these subjects (teenage young adults in underprivileged social circumstances) tend to be intravenous drug users and have an increased risk for the development of right heart infective endocarditis. Additionally, long-term use of inserted central catheters for any reason increases the risk of right-sided infective endocarditis in young adults.

Apart from aetiology, the characteristics of infective endocarditis are mainly the same in childhood as in adulthood. The three major pathogen groups are the viridans streptococci, Staphylococcus aureus and enterococcus species. Caries in early childhood is common in young schoolchildren. It has been proved that early childhood caries has a correlation with the prevalence of infective endocarditis in the population at risk. Furthermore, in-depth studies have shown that the educational level of the parents and their attitude towards prevention are key factors to avoid oral pathogen-related infective endocarditis. For this reason, parental awareness of these risk factors and their informed acts towards prevention are imperative [4]. Enterococcal endocarditis is less common in children than in adults. Organisms of the HACEK group occur even more rarely. Kingella kingae is a rare pathogen, which tends to have more contagious effects in neonates and in small children. It can be endemically isolated from the oropharynx in children’s communities. If the Kingella kingae infection is related to infective endocarditis that mirrors a severe infection and bacteraemia, it is usually accompanied by infectious osteomyelitis or osteoarthritis and, in some cases, immunosuppression [5].

Endothelial injury, which is a predominant step in the development of infective endocarditis, happens earlier and with less manipulation than in adults. Non-bacterial infective endocarditis is more frequent in childhood than in adults. Culture-negative endocarditis occurs in around 5% of paediatric cases. The three main pathogenic populations all have a strong virulence factor via adhesions, which have been widely investigated in preclinical in vivo models and tend to have major importance in the childhood pathogenesis of infective endocarditis.

Furthermore, in the case of an implanted device, an endothelialised layer or antithrombotic surface compound on them are key to preventing device-related infections. Mechanical circulatory support devices, mainly for bridging to heart transplant or to recovery, are more frequently used in a childhood population. Thus, antithrombotic and anti-infective attempts are of key importance when engineering these biomechanical artificial support devices. Additionally, biofilm formation may occur on these surfaces, tentatively on long-term mechanical circulatory support, resulting in significantly increased risk of infective endocarditis.

Symptoms and diagnoses

Diagnoses of infective endocarditis in the paediatric population rely on the same diagnostics tools as in adults; the modified Duke Criteria can, in general, be used for paediatric patients as well. Imaging may include echocardiography, positron emission tomography (PET)/computed tomography (CT) and nuclear cardiology. However, in the paediatric population, investigation with radiation must be avoided as much as possible. Transoesophageal echocardiography (TEE) is rarely needed in children, as transthoracic anatomy usually allows thorough investigation. However, diagnosis of childhood endocarditis may be very difficult and requires huge awareness on the part of all staff. Neonates and small children may have non-specific symptoms, which may be accidentally linked to other, more specific clinical conditions. Thus, the diagnosis and treatment of infective endocarditis may be delayed. Surprisingly, the number of peripheral microembolic and vascular complications decreases in parallel with younger age. In neonates and small children, the symptoms of infective endocarditis are not evident and may have huge variation, thus making early diagnoses critical. These comprise neurological symptoms (altered consciousness, seizures), gastrointestinal dysfunction and, more commonly, heart failure, which itself also requires great awareness on the part of physicians in order to diagnose early. Interestingly, the minor criteria of the Duke score system are rarely identified in small children, e.g., Osler nodes, Roth’s spots, and Janeway lesions are rarely mentioned in paediatric infective endocarditis papers and case reports [3]. In young adults, extracardiac manifestation, e.g., thromboembolic complications and septic embolisation are common. Culture-negative infective endocarditis should be considered carefully, as there may be a failure in sampling techniques or sampling parallel with antibiotics or after the start of an antibiotic course. In children, sometimes it is even more difficult to identify underlying pathogens or the first culture samples may have negative results [6].

Prevention and prophylaxis in the paediatric and neonatal population

Antimicrobial use for prevention of infective endocarditis remains a widely debated area of paediatric cardiology. A randomised clinical trial has never ever been performed, not even in adult patients, and there is no reasonable prospect of one in the paediatric population. Interestingly, only a small proportion (~20%) of paediatric infective endocarditis cases are related to any kind of invasive procedure, e.g., dental procedures. Importantly, European and American guidelines strongly recommend oral hygiene as a key preventive step. The NICE guidelines only recommend antibiotic prophylaxis if the patient is in the high-risk group for developing infective endocarditis. High-risk paediatric patients are listed in Table 1.

Table 1. Paediatric patients at high risk for infective endocarditis.

AHA guidelines group paediatric patients in accordance with their surgical conditions: repaired, unrepaired and palliated patients. Knirsch and Nadal reported a calculated lifetime risk ratio for repaired and unrepaired congenital heart disease patients. According to their studies, non-repaired congenital heart disease has a 59% risk, while repaired ones have a 41% risk of developing infective endocarditis [7]. Additionally, the prevalence of infective endocarditis differed in these subgroups in an American population. Unrepaired congenital heart disease carries the highest risk for developing infective endocarditis. It is even more increased in the case of cyanotic heart diseases. The next highest risk population are neonates with significant outflow tract obstruction diseases. Surgical or transcatheter repair is technically doable in almost all congenital defects; thus, the lifetime survival rate rapidly increases, resulting in an increased number of GUCH patients. Given that they need special care and understanding of complex pathologies and repair status, each GUCH patient requires individual assessment for infective endocarditis risk and antibiotic prophylaxis needs to be determined.

Preventive steps in the vulnerable, high-risk population are key to protecting this patient group from developing a disease which is especially life-threatening and has poor prognosis. In general, oral bacteraemia is responsible for 20% of infective endocarditis cases. Dental procedures are not common in the paediatric population; however, focus has to be placed on oral hygiene. Intensive care unit (ICU) treatment, oral or airway suction may easily cause mucosal membrane injury. Additionally, dental growth can also result in significant bacteraemia, which should be avoided, especially after major surgery.

Furthermore, skin hygiene also has an impact on prevention. Meticulous handling and disinfection of any wound are strongly recommended, as is eradication or decrease of any chronic bacterial carriage: skin, urine, nasal. The use of any kind of invasive procedure and curative treatment of any bacterial focus should be limited (referring to ESC IE guideline Table 4) [8].

Other general recommendations for cardiac and vascular procedures are similar in the paediatric population to those in adults. Any carriage of nasal Staphylococcus must be eradicated before any planned invasive procedure. In case of pacemaker or ICD implantation, a perioperative single-dose antibiotic prophylaxis is recommended. Antimicrobial prophylaxis is generally recommended in patients who are at high risk of developing infective endocarditis parallel with any procedure supposedly resulting in bacteraemia. However, recent debate has shown concern in this field and assumes that bacteraemia can occur via simple everyday activities, e.g., toothbrushing and chewing may cause undetectable bacteraemia. In the case of gastrointestinal or genitourinary procedures, prevention is no longer recommended. Some other conditions, such as bicuspid aortic valve with stenosis and patent ductus arteriosus, were previously recommended to receive antibiotic prophylaxis via certain procedures. Current guidelines do not recommend prophylaxis in these patients; however, other special clinical conditions may influence this decision making. Routine prophylaxis is not recommended in this patient population [8].

A small study in the UK evaluated the efficacy of antimicrobial prophylaxis before and after NICE guideline recommendations with neutral results in terms of antimicrobial use. This means that increased utilisation of antibiotic prophylaxis does not prevent a significant number of infective endocarditis cases. That investigation rather underpins the importance of oral hygiene and the prevention of oral diseases in childhood rather than the key role of antimicrobial prophylaxis [9]. 2007 was the year of modifying antibiotic prophylaxis recommendations in the AHA guidelines. Therefore, it may be argued that strict antibiotic prophylaxis for infective endocarditis did not prevent a significant number of cases. On the other hand, one publication found a significant inverse correlation between the cessation of antibiotics for prophylaxis and the rising incidence of infective endocarditis in the UK after the NICE guidelines were modified in 2008 [10]. Similar trends were observed in The Netherlands after the adoption of the 2009 ESC Guideline [11]. These controversial facts should warrant caution and the use of common sense in the practice of antibiotic prophylaxis.

The cornerstones of safe and feasible antimicrobial therapy in children are: body surface area (BSA), (weight), age-adjusted doses. Always consider and adjust for kidney function as well. Furthermore, thorough compliance is imperative and adherence to guidelines is key for prevention and for curative treatment as well. Local antibiotic guidance, e.g., local frequent strains, resistance, and sensitivity data must be kept in mind.

Vaccines to prevent microbial infections in a high-risk paediatric population

Arguments were established that active or passive immunisation techniques would be extremely efficient in a high-risk neonatal or paediatric population. Recently, vaccines for viridans streptococci, Candida albicans, and Staphylococci species have been developed and are at the preclinical phase. Some of these have also been tested in clinical trials, e.g., two compounds of passive immunisation for Staphylococcal infections have been tested in clinical studies in a neonatal population.

Passive immunisation strategies were recently included in a randomised, phase II clinical trial investigating the effects of a monoclonal antibody, called 514G3, in order to acquire passive immunisation in Staphylococcus aureus infection and bacteraemia. According to clinicaltrials.gov, the trial was recently completed; however, no results have been published as yet. The monoclonal antibody was applied in a single dose, parallel with the standard of evidence-based antibiotic treatment on both arms. The trial was investigating adult subjects. Paediatric relevance is questionable and, once these novel approaches have been approved, paediatric use may still be off-label. All of the clinical trials with passive immunisation techniques have been neutral so far and did not meet the endpoint for efficacy in terms of decreasing bacteraemia and eradicating sepsis.

Further clinical investigations are going on in an adult population to study active immunisation and its relevance to preventing infective endocarditis. These are investigating active immunisation against Staphylococcus aureus in haemodialysis patients, and in a cardiac and spinal surgery population. Other vaccines are also under development, mainly against Staphylococcus aureus, with some others against Candida albicans. Vaccines have not yet brought a breakthrough in the prevention of infective endocarditis although they may have a significant role in a specific, targeted patient population [12].

Conclusions and outlook

Infective endocarditis is a less frequent but more severe condition in children than in adults. Antibiotic prophylaxis is strongly recommended in high-risk patients undergoing medical procedures with bacteraemia. Intermediate- and low-risk patients should probably avoid antibiotic prophylaxis according to the current guidelines. However, recent analyses are rather controversial concerning the advantages of lenient antibiotic prophylaxis. Amoxicillin and ampicillin are the mainstay of prophylaxis in weight- and renal function-adjusted doses, and clindamycin and cephalosporines are the alternatives in patients with a known penicillin allergy. Individualised risk assessment and decision-making ought to be performed in every child at risk of infective endocarditis.