Modern features of infective endocarditis in the Russian Federation

MODERN TREATMENT OF INFECTIOUS ENDOCARDITIS

Criteria for the diagnosis of infective endocarditis are presented, and recommendations for etiotropic antibacterial therapy for this disease are given. The importance of correct blood sampling for microbiological analysis and timely decision on the advisability of surgical treatment is emphasized.

The paper presents diagnostic criteria for infective endocarditis, gives recommendations on the etiotropic antibacterial therapy of the disease. It shows it is important to correctly assay blood for microbiological analysis and to timely decide whether surgical treatment is advisable.

V.B. Beloborodov - Russian Medical Academy of Postgraduate Education, State Clinical Hospital named after. S.P. Botkin, Moscow VB Beloborodov – Russian Medical Academy of Postgraduate Training, SPBotkin City Clinical Hospital, Moscow

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The term “infective endocarditis” (IE) refers to an infection of the heart valves or endocardium caused by bacteria, fungi, rickettsia, chlamydia, and possibly viruses. The etiology of endocarditis is one of the most important characteristics of the disease and, if a pathogen is detected, it is necessarily indicated in the diagnosis. According to the clinical course, acute and subacute IE are distinguished.

Pathogenesis of IE

The pathogenesis of subacute IE is based on primary damage to the valve endothelium. It may be associated with a previous rheumatic lesion, endocardial injury due to turbulent blood flow due to valve prolapse or cardiac malformations. The formation of a platelet thrombus at the site of endocardial damage, the adhesion of pathogenic flora and its subsequent reproduction leads to the development of IE. As a rule, subacute IE is caused by flora with low virulence, which creates conditions for long-term persistence of the pathogen in the affected area until clinical symptoms appear. In contrast, acute IE is usually caused by highly virulent flora, such as Staphylococcus aureus, and in about half of cases there is no previous valvular or endocardial involvement. In recent years, there has been an increase in the number of cases of acute IE, which is one of the manifestations of sepsis. Some authors point to a general trend towards an increase in the incidence of IE due to an increase in the number of patients undergoing prosthetic and vascular graft transplantation, therapy with corticosteroid hormones, cytostatic and other drugs that can potentially cause dysfunction of the immune system or local tissue reactions [1]. Table 1. Duke criteria for diagnosing infective endocarditis

Table 2. Definition of terminology when using Duke criteria

There are certain patterns in the localization of infection. This is associated with the hydrodynamic conditions created in the cavities of the heart: areas of pressure difference and impacts of the blood flow. Such areas for valve insufficiency are the surface of the mitral valve from the atrium, the surface of the aortic valve from the ventricle, chords; in case of a septal defect - the endocardium of the right ventricle in the area of ​​the defect or the opposite wall. An important pathogenetic factor is the ability of microbes to adhere to the endocardium [2]. The experiment showed a higher adhesive ability of staphylococci and streptococci compared to gram-negative bacteria, and noted the important role of fibronectin in binding the peptidoglycan of gram-positive bacteria. Predisposing factors for the development of IE are rheumatic heart valve lesions (about 15%), mitral valve prolapse (10%) and chronic heart disease (20%). In patients with nosocomial infections, the development of IE is associated with bacteremia due to contamination of vascular catheters, hemodialysis shunts, postoperative wound infection, manipulation of the urinary tract, implantation of pacemakers and other reasons [3 – 5].

Clinical diagnosis

Symptoms that occur in patients with IE are initially nonspecific. Fever usually appears first, which may be accompanied by chills. Patients with subacute IE note a gradual increase in malaise, fatigue, sweating, lack of appetite, weight loss, and joint pain. These symptoms can vary in duration, from several weeks to several months. In acute IE, symptoms develop more rapidly than in subacute IE. The diagnosis of IE becomes obvious when a rash appears due to bacterial embolism of the terminal capillaries of the fingers, hemorrhages on the conjunctiva. Typically, the rash and hemorrhages are small (1 - 2 mm in diameter), have clear boundaries and are hemorrhagic in nature. On the fingers, hemorrhages are usually located on the palmar surface in the area of ​​the distal phalanges. Auscultation of the heart is the most important clinical diagnostic technique. The presence of pathological heart murmurs is observed in 85% of patients with IE. The absence of murmurs can be observed at the beginning of the disease, when the anatomical changes in the valves are minor. Other reasons for the absence of murmurs may be damage to the endocardium outside the heart valves, congenital structural features of the valves (bicuspid aortic valve), isolated damage to the tricuspid valve, and elderly patients. Symptoms of heart failure appear with the simultaneous development of myocarditis and endocarditis, and the occurrence of arrhythmia due to damage to the conduction system of the heart. In the acute period of IE, there is a danger of detachment of vegetations and organ embolism. The anatomical location of endocarditis determines possible areas of embolic lesions. Most often they are the vessels of the kidneys, spleen, intestines, and brain. The presence of symptoms of embolism of these organs in combination with fever and abnormal heart murmurs is a reliable criterion for diagnosing IE.

Laboratory diagnostics

Clinical laboratory blood tests do not have specific features: an increase in ESR, anemia, and leukocytosis are noted. Urine examination usually reveals microhematuria and proteinuria. Microbiological blood test data are extremely important. There is evidence of a very high frequency of isolation of microbes from the blood, reaching 85 - 95%. Such results can only be obtained by using modern methods of clinical microbiological research. The first stage of this study is the correct blood sampling, observing the following principles:

• Blood sampling should be done before starting antibiotic therapy.
• The blood sampling technique must exclude accidental contamination of the sample (culture in compliance with the rules of asepsis and antisepsis only by puncture of a vein or artery). • The use of special systems for blood sampling that exclude the content of foreign substances (detergents, sterilants, etc.) that can affect the growth of microflora or cause contamination of the sample. • Immediate transportation of the sample to the laboratory under isothermal conditions, correct labeling of the sample, complete information about the nature of the sample being tested. When collecting blood for sterility, it is necessary to adhere to the rules of asepsis in order to avoid contamination with normal skin flora (coagulase-negative staphylococci, diphtheroids, etc.), especially since these microorganisms can also be the etiological cause of IE. Therefore, the preparation of the patient's skin greatly influences the result of microbiological examination. On the other hand, it is necessary to remember about the possibility of infection of staff from the patient. The use of rubber gloves reduces the risk of infection of personnel with blood-borne infections (viral hepatitis, HIV infection). Method of blood culture for sterility.
The blood collection kit consists of vials of culture media, 2% iodine solution or similar antiseptic, alcohol beads, wipes, syringes, needles, or special blood collection devices.
It is recommended to treat bottle caps for blood collection twice with alcohol. In the area of ​​vessel puncture, the field (10 cm in diameter) is treated twice with an antiseptic using circular movements from the center to the periphery. In case of iodine intolerance, treatment is carried out with a 70% alcohol solution for 2 minutes. For better visualization of the puncture site, iodine is washed off in the projection of the vein using 1 - 2 balls with alcohol, and the movements of the ball should be carried out in the direction “from clean to dirty”. You can palpate the vein at the puncture site only while wearing sterile gloves. Avoid repeated contact of the needle with the skin. To collect blood, 10-20 ml syringes or special devices (vacuum bottles) are used. After drawing blood, the needle is removed from the vein, avoiding repeated contact with the skin. For adults, 5–10 ml of blood is taken in each vial (or the volume of blood recommended by the manufacturer of the relevant equipment). The sample is then labeled with the date and time of collection. If blood culture (for a specific purpose) was performed from a vascular catheter, this should be specifically noted as it is important for the interpretation of the results obtained. Typically, sowing is carried out simultaneously in two bottles: with aerobic and anaerobic conditions. In IE, bacteremia is present in almost all cases, so the advisability of multiple blood cultures and choosing the moment of the patient’s highest body temperature for culture is questionable. Nevertheless, there are certain principles for the frequency of blood cultures. If acute IE is suspected, when it is necessary to immediately begin empirical antibacterial therapy, triple cultures of blood taken by venipuncture from different veins with an interval of 15 - 30 minutes are indicated. This technique provides 70% efficiency and allows adequate assessment of culture results in case of sample contamination. In subacute IE, when etiotropic therapy can be postponed for some time, three blood cultures are also performed within 24 hours. If no growth of flora is obtained from the blood within 48–72 hours, it is recommended to culture another 2–3 times. It is believed that culture of arterial blood and bone marrow does not have any significant advantages over culture of venous blood [6,7]. In the case of etiotropic therapy that is inadequate in terms of spectrum and dose in the acute phase of the disease, blood cultures may be positive within up to 2 weeks of therapy. If antibiotic use can be delayed or discontinued, it is advisable to perform cultures several days after stopping antibiotics. If there is no bacterial growth in a patient with clinical manifestations of IE, consultation with a specialist (clinical microbiologist) is necessary to select an adequate bacteriological examination technique. The pathogen may have biological characteristics (very slow growth, absence of a capsule, etc.) that dictate the need to use special isolation methods. In some cases, to confirm bacteremia, an area of ​​skin with an element of the rash (microbial embolus) is excised, followed by microbiological and histological examination. In acute IE, embolism of the choroid plexuses and brain microvessels may occur, resulting in the development of bacterial meningoencephalitis. In these cases, a diagnostic lumbar puncture is performed with culture and microscopic examination of the cerebrospinal fluid. Echocardiography
is very important for the verification of IE. The use of modern transthoracic echocardiography makes it possible to detect vegetations in approximately 65% ​​of patients. The capabilities of transesophageal echocardiography are somewhat greater and make it possible to detect up to 85-70% of vegetations due to more advanced visualization of the valves of the right half of the heart and artificial valves. The absence of visualization of vegetations on echocardiography does not exclude the diagnosis of IE [8]. This is especially true for patients with clinical manifestations of IE and a culture isolated from the blood. On the contrary, the presence of only fever, without clinical signs of damage to the heart valves, lack of bacteriological confirmation, and negative echocardiography data allow one to exclude IE. EchoCG in combination with Dopplerography, in addition to direct visualization of vegetations, allows one to assess the degree of disturbance of intracardiac hemodynamics, identify pathological changes in the endocardium, the formation of pathological anastomosis, and determine indications for surgical treatment of patients with IE.

Diagnostic criteria

Interest in the use of diagnostic criteria has increased again, since doctors of different specialties are involved in solving the problem of IE: therapists, infectious disease specialists, cardiologists, microbiologists, epidemiologists. It is necessary to achieve mutual understanding and accuracy in the assessment of statistical and epidemiological information, clinical trials of new drugs and the development of preventive measures. The Duke criteria are most often used in modern literature [9,10]. These criteria (“Duke” - after the name of the American university where these criteria were developed) in clinical cases, when carefully applied throughout the disease, are highly sensitive and specific [10]. The criteria are given in table. 1. Use of Duke criteria requires comment. The application of the criteria allows, in the presence of two main signs (repeated isolation of a culture characteristic of IE), to assume a diagnosis of IE without an echocardiogram. Application of the criteria is especially useful in patients with bacteremia. In cases of complex diagnostic situations suspicious for the presence of IE (especially IE of artificial valves), consultation with a specialist with sufficient clinical experience is necessary.

Microbiological characteristics of bacterial IEs

The etiological structure of bacterial IEs in different countries is extremely diverse and dynamic. According to numerous clinical microbiological studies, the most common pathogens are streptococci (55%). Moreover, about 35% of cases of IE are caused by Streptococcus viridans, 10% by enterococci and about 10% by other non-hemolytic streptococci of group D. Staphylococci are the causative agents of IE in approximately 35% of cases, and damage to artificial valves is caused mainly by coagulase-negative staphylococci. Another 10% of cases of IE are caused by other flora; in the literature there are descriptions of IE caused by almost all known bacteria [11,12]. There are known cases of IE caused by Coxiella burnettii and Chlamydia spp. [13]. There are certain clinical and microbiological correlations: low virulent microorganisms usually cause IE of already damaged valves, the disease is characterized by a subacute course; Virulent microorganisms (S. aureus) can infect normal valves, cause their destruction and lead to systemic toxic effects. Currently, S. aureus is the most common cause of acute IE.

Basic principles of treatment for IE

Recommendations for antibiotic therapy for IE vary significantly. However, long-term use of high doses of antibiotics is generally accepted. The rapid clinical effect of antibiotics suitable for the spectrum when choosing an adequate dose can cause a certain euphoria in the patient and the doctor. However, it must be remembered that the elimination of planktonic forms of the pathogen from the bloodstream does not mean eradication of the pathogen from the body. The proliferation of microorganisms inside vegetations and in the fibrin clots covering them creates significant difficulties for the penetration of antibiotics and phagocytosis. Therefore, the duration of use of antibacterial drugs in high doses is determined by the dynamics of vegetation, the dissolution of fibrin deposits and other factors. Laboratory tests that help guide the choice of the dose of the drug and the duration of its use are the determination of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration. In some patients, it is indicated to study the bactericidal activity of serum (BAS). This indicator confirms that the selected dose of antibiotic corresponds to BAS at a dilution of 1:8 and above the peak concentration. However, it must be remembered that data on the correlation between ALS and the outcome of IE were obtained empirically and experimentally. The determination of ALS is useful in patients receiving high doses of penicillin to destroy highly sensitive microorganisms. The effectiveness of ALS research in patients with IE caused by resistant strains is questionable. Although the BAS index is not predictive of disease outcome, there are studies indicating that peak bactericidal titers greater than 1:64 and titers greater than 1:32 accurately predict high bactericidal treatment response. On the other hand, this indicator does not predict an insufficient bacteriological effect [13,14]. It is very important to maintain the isolated strains in the laboratory during treatment and for the next few months. This may be useful if the effectiveness of treatment is insufficient for individual selection of an antibacterial therapy regimen.

Start of antibacterial therapy

If IE is suspected, the moment of starting antibacterial therapy is determined by the severity of the patient's condition. However, in any case, the administration of antibiotics is always preceded by blood sampling for bacteriological examination. In severe patients with acute IE, in whom a delay in the use of antibiotics is undesirable, blood should be taken three times from different veins within 1 hour, and only then the administration of the antibiotic should begin. In patients with subacute IE, with a long history of the disease, and with a questionable clinical picture, it will be more effective to begin antibacterial therapy after receiving the results of a microbiological study. In these cases, there is a high probability of isolating a highly resistant pathogen. Therefore, immediate initiation of antibiotic therapy may make it difficult or impossible to isolate the pathogen and carry out targeted therapy. The timing of initiation of antibiotic therapy in such cases should be decided by an expert with sufficient clinical experience.

Principles for choosing antibacterial therapy

This section discusses the principles of selecting antibacterial drugs in adult patients with normal renal function, without anamnestic data on toxic or allergic reactions to the administration of antibiotics. When choosing antibiotics, one should take into account the results of a clinical microbiological study, the characteristics of the pathogen and its resistance. IE caused by Streptococcus viridans

The MIC of penicillin against this microorganism varies widely, but is usually less than 0.2 μg/ml.
The MIC value of 0.1 - 0.2 μg/ml is the upper limit for strains sensitive to penicillin. Relatively resistant strains are streptococci with an MIC of more than 0.5 μg/ml. Depending on the MIC value, different antibacterial therapy regimens are selected. Treatment of IE caused by susceptible strains of S.viridans is carried out with penicillin, a combination of penicillin and aminoglycosides, or a third generation cephalosporin.
Most studies have shown the high effectiveness of penicillin monotherapy at a dose of 12 - 18 million units / day (with an interval of 4 hours).
The duration of therapy is 4 weeks [15]. However, there are recommendations for increasing the dose of penicillin when S.viridans strains with an MIC of 0.1 - 0.2 μg/ml are detected. The synergistic effect of penicillin and aminoglycoside against S.viridans has been experimentally demonstrated. In combination therapy, the dose of gentamicin is 1 mg/kg at 8-hour intervals for 2 weeks, followed by penicillin monotherapy for another 2 weeks. This regimen of antibacterial therapy was used in patients with IE duration of more than 3 months or with a complicated course of the disease. It is not used if there are contraindications to aminoglycosides in elderly patients, patients with renal failure, or hearing impairment. There is clinical experience with the use of a short (2-week) course of combination therapy with bacteriological effectiveness reaching 98% [15]. However, patients in this group did not have complications of the underlying disease, and the pathogen was highly sensitive to penicillin. This combination therapy option is never used in the presence of shock, intracardiac abscesses, extracardiac foci of infection, if less than 3 months have passed from the moment of illness to the start of antibacterial therapy. The use of ceftriaxone in IE is justified given its suitable antimicrobial spectrum and exceptional pharmacokinetic properties. There are recommendations for a 4-week course of ceftriaxone 2 g/day intravenously or intramuscularly once a day. The possibility of outpatient treatment of patients with IE who do not have complications is attractive. It has recently been shown that once daily administration of ceftriaxone and netilmicin is comparable in effectiveness to the combination of penicillin and aminoglycoside as described above [15, 16]. In the case of relatively resistant strains of S.viridans (MIC 0.2 - 0.4 μg/ml), antibacterial therapy is carried out with penicillin at a dose of 20 million units/day or higher for 4 weeks, often in combination with aminoglycosides at the usual dose. If the MIC turns out to be even higher, then the same regimen is used as for the treatment of IE caused by enterococci. IE caused by group D streptococci
As for Streptococcus bovis, the MICs of penicillin for this microorganism are the same as for other streptococci, therefore the same tactics of antibacterial therapy are used as in the case of IE caused by S.viridans.
Among enterococci there are two clinically significant pathogens: E. faecalis and E. faecium. E.faecalis accounts for more than 70% of cases of enterococcal IE. Enterococci are significantly less sensitive to penicillin and therapeutic doses of gentamicin. The MIC of penicillin against enterococci varies from 1 to 4 μg/ml. Therefore, a dose of 20 - 24 million units of penicillin per day (intravenously) is adequate. To obtain a synergistic effect, the daily dose of gentamicin should be increased to 3 mg/kg. This combination should be used for at least 4 weeks, and in case of late initiation of antibacterial therapy (after the 3rd week of the disease) - 6 weeks [15]. Enterococci with high resistance to gentamicin (MIC 2000 μg/ml) have been described [17], although such cases are few. All of them require the strictest bacteriological control and consultation with specialists, since they do not lend themselves to conventional therapy. Sometimes the only effective treatment is valve transplantation. Some strains of E.faecium are capable of producing penicillinases [18], some of these strains have low sensitivity to gentamicin. In these cases, empirical antibiotic therapy should be carried out taking into account possible multidrug resistance under microbiological control. If empirical therapy with b-lactam antibiotics is insufficiently effective, it is necessary to switch to therapy with drugs of other classes, for example, glycopeptides (vancomycin). However, enterococci have been described that are resistant to almost all known antibiotics, including glycopeptides [19]. Staphylococci
If acute staphylococcal IE is suspected, semisynthetic penicillins should be used at the beginning of treatment, for example, oxacillin at a dose of 12 g/day (2 g IV every 4 hours).
If the sensitivity of staphylococci to penicillin is detected, therapy can be continued with penicillin at a dose of at least 20 million units/day. Numerous experimental studies have proven that the bactericidal effect and valve sterilization occur faster when using a combination of semi-synthetic penicillin and gentamicin. However, the results of clinical trials were not so clear [20]. From a clinical point of view, combination therapy is advisable in the first 3 to 5 days of treatment in order to obtain a faster sterilizing effect and prevent severe damage to the heart valves [15]. Some strains of staphylococci are relatively resistant to penicillins. In these cases, penicillin is combined with gentamicin (1 mg/kg after 8 hours) and rifampicin (300 mg orally after 8 hours) under the control of ALS. In the case of IE caused by methicillin-resistant strain of S. aureus (MRSA), vancomycin is used (1 g at 12-hour intervals intravenously). Treatment of patients with IE caused by coagulase-negative staphylococci should be carried out under microbiological control, taking into account the possible resistance of microorganisms, according to the principles of treatment of IE caused by S.aureus. Therapy for IE caused by staphylococci usually lasts 4–6 weeks. Extending the course to 6 weeks is justified in patients in whom therapy was not sufficiently effective at the onset of the disease. Other pathogens of IE
Endocarditis caused by gram-negative microorganisms is quite difficult to treat due to the presence of various resistance mechanisms in the pathogens.
The effectiveness of treatment of such IE requires mandatory microbiological confirmation. The approximate duration of therapy is 4 - 6 weeks. IE caused by Pseudomonas aeruginosa almost always occurs as a result of nosocomial infection. An aminoglycoside (tobramycin at a dose of 5 - 8 mg/kg per day) in combination with penicillins with antipseudomonal activity (mezlocillin or piperacillin) or ceftazidime or ciprofloxacin for 6 weeks is standard therapy. IE of polymicrobial etiology requires therapy carried out according to general principles. In these cases, it may be necessary to conduct a study of the minimum bactericidal concentration to select the appropriate drugs or their combination in each individual case. IE caused by sensitive microorganisms requires a 4-week course of therapy. In the case of resistant flora, the course of therapy is extended to 6 weeks. Empirical therapy for patients with acute IE until the results of bacteriological examination are obtained.
Therapy should be carried out taking into account the high probability of detection of S.aureus.
The most suitable combination in terms of the spectrum, taking into account the large etiological role of pathogens such as enterococci, is vancomycin (1 g after 12 hours) plus gentamicin (1 mg/kg after 8 hours). Oxacillin or nafcillin (2 g every 4 hours) is used instead of vancomycin in patients with impaired renal function. In very serious conditions of the patient, imipenem, which has a very wide spectrum of action, can be used. Usually, after receiving the results of a microbiological study, correction of etiotropic therapy is carried out. IE not confirmed bacteriologically
In cases where endocarditis does not develop acutely and bacteriological confirmation is not obtained, penicillin or ampicillin is usually used in combination with aminoglycosides.
If the onset of disease is acute, vancomycin may be added [21]. To date, there is no evidence of the benefits of any of these treatment regimens. If the patient's temperature normalizes within a week after the start of therapy, then the total duration of the course is 4 weeks. If a quick effect is not obtained and the diagnosis remains the same, it is necessary to discuss the use of surgical methods for treating endocarditis. Fungi
Fungal IE usually requires combination chemotherapy and surgery [22].
Combination therapy for infection caused by Candida spp. carried out with flucytosine (150 mg/kg per day orally) and amphotericin B (0.5 mg/kg per day intravenously). The best results are described with early surgical interventions and prolonged postoperative therapy with amphotericin B. Insufficient experience with the use of new oral drugs (fluconazole and intraconazole) dictates the need to discuss the indications for their use with specialists. Treatment of patients with a history of an allergic reaction to penicillin
An indication of an allergic reaction to penicillin requires objective confirmation by performing skin tests. If there are no allergic manifestations, the possibility of a severe immediate or delayed anaphylactic reaction is unlikely. Most patients with a history of penicillin intolerance have negative skin tests and can be prescribed penicillin. Cephalosporins can be used as an alternative, but cross-allergic reactions may occur. If S.aureus is sensitive to penicillin, therapy should be carried out in the same way as when Streptococcus viridans is detected (first generation cephalosporins can be used). When penicillin-resistant S. aureus is isolated, most patients can be treated with semisynthetic penicillins (after appropriate skin testing). If it is necessary to select an alternative therapy, then it is necessary to study the tolerability of each first-generation cephalosporin, for example, cephalothin (2 g after 8 hours) [15]. Drugs from other groups can be used, for example vancomycin (0.5 g after 6 hours or 1 g after 12 hours). Clinical observations have shown that vancomycin can be used as an alternative therapy for IE caused by S. aureus [23]. However, in patients with an allergy to penicillin, it is necessary to specifically select an antibiotic. The duration of therapy should be 6 weeks. When enterococci and other resistant streptococci are isolated using skin tests, the tolerability of each antibiotic should be checked. If necessary, appropriate desensitizing therapy can be carried out. If penicillin is intolerant, it is recommended to use vancomycin (0.5 g every 6 hours or 1 g every 12 hours) for 6 weeks. Although the MIC of vancomycin against enterococci is about 3 μg/ml or less, it is usually not bactericidal against enterococci, so its combination with aminoglycosides is recommended. The likelihood of toxic effects from the combination of vancomycin and aminoglycosides is quite high, and patients require laboratory monitoring for timely diagnosis of toxic reactions from the kidneys and nervous system. If they are detected, the use of aminoglycosides should be discontinued.

Application of surgical methods for the treatment of acute IE

The need for surgical intervention for some types of IE is undoubted. However, there are still no generally accepted indications for the use of this type of treatment [24, 25 – 28]. The development and worsening of heart failure, which cannot be prevented by therapeutic methods, is an absolute indication for valve replacement, and this should be done as early as possible [29,30]. In patients with aortic valve disease, a significant reduction in mortality has been shown with a combination of medical and surgical treatment. Severe heart failure leads to high mortality when using only surgical methods. The presence of heart failure during conservative therapy is not an indication for surgical intervention, although it may be a reason to discuss this issue with surgical specialists. Persistent bacteremia (7 - 10 days) against the background of adequate antibacterial therapy is considered a relative indication for surgical treatment. In this case, it is necessary to be sure that other metastatic extracardiac foci of infection are excluded: osteomyelitis, septic pulmonary embolism, intra-abdominal abscesses. To exclude valve ring abscesses and intracardiac abscesses, it is advisable to conduct transesophageal echocardiography [31]. Embolisms often require surgery

Modern features of infective endocarditis in the Russian Federation

The problem of infective endocarditis (IE) is relevant in many countries around the world. According to numerous foreign studies, the incidence of IE is 3–10 cases per 100 thousand people per year. Despite modern diagnostic methods, including transesophageal echocardiography, multislice computed tomography, magnetic resonance imaging, mass spectrometry and polymerase chain reaction, established algorithms for conducting bacteriological blood tests, and the use of rational antimicrobial therapy (AMT) regimens, mortality in IE remains high, amounting to more than 20% [1].

Over the past decades, the number and ratio of the main risk factors for this nosology have increased and changed. The most important role began to be played by injection drug addiction, cardiac surgery and invasive medical procedures (long-term venous catheterization, hemodialysis), which led to a change in the leading pathogen, which currently, according to most studies, is Staphylococcus aureus [6].

In the etiological structure of IE, the leading role is traditionally played by gram-positive microorganisms. Among them, the most commonly isolated are Staphylococcus aureus, Streptococcus viridans, coagulase-negative staphylococcus and Enterococcus spp.

In recent years, there has been an increase in the resistance of most IE pathogens to antimicrobial drugs used in clinical practice. The prevalence of resistance can vary significantly between countries and geographic regions. In the case of IE, the main problem is methicillin-resistant strains of staphylococci and strains of Enterococcus spp. with a high level of resistance to aminoglycosides.

High mortality rates in IE are largely due to the development of potential complications, among which the most common are the development and progression of heart failure, thromboembolic manifestations, the development of infectious aneurysms, as well as damage to internal organs of various locations [2].

Materials and methods

A multicenter study of the etiology, antibiotic resistance and pharmacoepidemiology of infective endocarditis was conducted, consisting of two parts: prospective (September 2011 - December 2021) and retrospective (January 2006 - August 2011).

The study included patients of both sexes of all age groups with definite and probable IE. The diagnosis of IE was made according to Duke criteria. The study included 406 (in the prospective part - 166, in the retrospective part - 240) cases of IE.

The patients were treated as inpatients in 11 medical institutions in 9 cities of the Russian Federation (Arkhangelsk, Kazan, Moscow, Omsk, St. Petersburg, Smolensk, Tyumen, Yakutsk, Yaroslavl). All hospitals that took part in the study are multidisciplinary in nature and have their own microbiological laboratory.

Identification of microorganisms was carried out according to routine local practice. Determination of the sensitivity of the isolated strains of staphylococci and enterococci was carried out using the disk diffusion method.

The criteria for inclusion in the study were: the presence of a diagnosis of definite or probable IE in the hospital patient's chart, the fact that at least one blood sample was taken for bacteriological examination, echocardiography was performed, and the availability of medical documentation.

During the study, anamnestic and clinical data were collected for each patient, which were entered into specially designed individual registration cards and were subsequently entered using the double-entry method into a specialized database developed based on the Microsoft Access data management database for Windows. Statistical data processing was carried out using the statistical package SAS Institute, USA, version 8.02 for Windows XP.

Research results

Currently, the diagnosis of IE is based on the generally accepted Duke criteria, which distinguish major and minor criteria [7, 8].

In the structure of major criteria for IE, in general, the identification of etiologically significant pathogens during bacteriological examination of blood was noted in 35.5%, echocardiographic signs of endocardial damage in 99.5%. In a prospective study, similar figures were 31.5% and 100.0%, in a retrospective study - 38.1% and 99.2%, respectively.

In the structure of minor criteria for IE, in general, immune manifestations were noted in 11.1%, fever in 93.8%, microbiological signs that do not meet the main criterion - in 2.2%, predisposing factors of heart damage and injection drug addiction - in 77.3 %, vascular manifestations - in 38.2%. In a prospective study, similar figures were - 9.6%, 96.4%, 4.2%, 77.1%, 33.1%, in a retrospective study - 12.1%, 92.1%, 0.8% , 77.5%, 41.7% respectively.

Risk factors largely determine the structure of IE pathogens and are important in diagnosis.

In the general structure of the study, among the risk factors for IE in most cases, the following were noted: injection drug addiction - 39.2%, acquired heart disease - 33.2%, previous IE - 18.3% (Fig. 1).

In the prospective part of the study, the most common risk factors were acquired heart disease - 36.1%, injection drug addiction - 30.4%, previous heart surgery - 19.4%, previous IE - 18.8%.

In a retrospective study, the most common risk factors were injection drug addiction - 42.7%, acquired heart disease - 31.3%, previous IE - 18.0%.

Bacteriological blood testing was carried out repeatedly in 52.7% of cases, once in 47.3%. The most significant aspect of this study is the need to conduct it before prescribing AMT. According to the data obtained, the timeliness of bacteriological blood testing was noted in 20.9%, in a prospective study only in 19.3%, in a retrospective study - in 22.1%.

Among imaging diagnostic methods, echocardiography is of greatest importance, allowing in most cases to identify pathological changes in the valvular apparatus of the heart [10].

When conducting echocardiography in the overall structure of the study, only transthoracic echocardiography was used in 84.2%, only transesophageal echocardiography in 3.7%, a combination of transthoracic and transesophageal echocardiography in 12.1%. In a prospective study, similar figures were 75.3%, 4.8%, 19.9%, in a retrospective study - 90.4%, 2.9% and 6.7%.

The most common location of the lesion in the overall structure of the study was the mitral valve - 43.6%, the aortic valve was affected in 37.9%, the tricuspid valve in 34.7%, and the pulmonary valve in 0.5% of cases. In the prospective part of the study, the mitral valve was most often affected - 44.6%, the aortic valve was affected in 39.8%, the tricuspid valve in 34.3%, and the pulmonary valve in 0.6%. In the retrospective part of the study, the mitral valve was most often affected - 42.9%, the aortic valve was affected in 36.7%, the tricuspid valve in 35%, and the pulmonary valve in 0.4% of cases.

The etiotropic focus of AMT in patients with IE is covered in detail in modern foreign recommendations and plays a key role in choosing the most correct treatment [3]. Taking this into account, microbiological identification of the cases included in the study was carried out.

In the overall structure of the study, out of 406 cases, an etiologically significant pathogen was isolated in 144 (35.5%). Gram-positive microorganisms predominated - 130 (90.3%), and among them - Staphylococcus aureus (46.5% of all isolated pathogens) (Fig. 2).

Over the past decades, there has been a global increase in antibiotic resistance among the causative agents of most infections, which largely determines the effectiveness of AMT [9, 11].

In the overall structure of the study, out of 67 identified strains of Staphylococcus aureus, 19 (28.4%) were methicillin-resistant. Of the 23 strains of coagulase-negative staphylococcus, 8 (34.8%) were methicillin-resistant. Among the isolated 23 strains of Enterococcus spp. 13 (56.5%) resistant to gentamicin predominated.

Discussion of the research results

The significance of the problem of IE is confirmed by the absence of a tendency to reduce morbidity and mortality in this pathology [5].

Improving the management of patients with IE is impossible without knowledge of the characteristics of diagnosis and therapy, a clear understanding of the etiological structure, and taking into account global and local data on the antimicrobial resistance of the most common pathogens. In this regard, the effective joint work of clinical microbiological laboratories in order to obtain reliable data on pathogens and their sensitivity to antimicrobial drugs and doctors treating patients with IE is extremely important. One way to obtain such information is to participate in multicenter studies conducted according to a single protocol.

Modern diagnosis of IE is based on the Duke criteria proposed in 1994 and subsequently expanded, according to which the key role in the diagnosis of IE is given to bacteriological blood testing and imaging diagnostic methods [7, 8].

The most commonly used imaging method for diagnosing IE is echocardiography, which makes it possible to determine the location of the lesion, the size of microbial vegetations, the degree and dynamics of compensation of the damaged valve, which in turn determines the further tactics of managing patients with IE [10]. According to the study, 84.2% used exclusively transthoracic echocardiography, the information content of which is significantly lower compared to transesophageal echocardiography. This necessitates optimization of the diagnostic process for patients with IE.

In recent years, there has been an increase in the number of publications demonstrating the potential role of computed tomography and magnetic resonance imaging in the diagnosis of endocardial infections. It should be noted that today these research methods have not entered into routine practice and their use in IE is mainly limited to the diagnosis of thromboembolic complications, as well as the search for a true diagnosis for fever of unknown origin [3].

In this study, the most common site of infection was the mitral valve (43.6%). This is consistent with most modern studies. It should also be noted that the figures for damage to the tricuspid valve are quite high (34.7%), which can be explained by the high frequency of injection drug addiction and other risk factors (catheterization of central veins, invasive manipulations on large vessels and the heart) that contribute to damage to this valve [2].

Characterizing the results of bacteriological blood tests in this study, it should be noted that the level of isolation of etiologically significant pathogens is quite low. In the present study, the etiology was identified in 35.5%. Of key importance in this situation is the fact that in the vast majority of cases, according to the study - in 79.1%, blood samples were taken after the prescription of AMT.

In the structure of risk factors for the study, injection drug addiction and acquired heart disease predominated, 39.2% and 33.2%, respectively. This is confirmed by modern foreign data, according to which there is a tendency to increase the number of cases of IE developing against the background of injection drug addiction and the use of diagnostic invasive manipulations on the heart and large vessels, as well as cases of secondary IE [11].

A fairly significant number of microorganisms, most of which are gram-positive bacteria, can act as causative agents of IE. This is clearly confirmed in modern studies of IE [2].

However, over the past decades, significant changes have occurred in the etiological structure of IE. The main one of these changes is that the leading pathogen has become Staphylococcus aureus, instead of Streptococcus viridans. This trend is observed in most countries, including the Russian Federation. According to the study, the frequency of isolation of Staphylococcus aureus and Streptococcus viridans was 46.5% and 11.8%, respectively. This, in turn, is explained by changes in the ratio of risk factors for this pathology. Among them, injection drug addiction and invasive diagnostic and therapeutic manipulations on the heart and large vessels are currently of paramount importance, while dental procedures and poor oral hygiene are of secondary importance [6].

It should also be noted that changes in the etiological structure of IE and the leading importance of Staphylococcus aureus among pathogens largely explain the high mortality rates in IE. Due to the fact that Staphylococcus aureus produces toxins that cause changes in the blood coagulation system, there is currently a significant number of thromboembolic complications in patients with IE [2].

Noteworthy is the increase in the proportion of MRSA strains both in the general structure of infectious pathology and in IE. According to the present study, among all cases of Staphylococcus aureus isolation, MRSA strains were isolated in 28.4%. At the same time, the proportion of MRSA in the prospective study was 40%, in the retrospective study - 18.9%. Unfortunately, the limited sample size did not allow us to obtain statistically significant differences. At the same time, the trend of increasing methicillin resistance of Staphylococcus aureus raises serious concerns due to the fact that in bacteremia caused by MRSA, there is a decrease in the activity of one of the key drugs in the treatment of IE - vancomycin.

The importance of this problem is confirmed by the fact that, according to numerous literature data, in particular a meta-analysis that included 31 scientific studies with a total number of cases of bacteremia caused by Staphylococcus aureus, 3963, the mortality rate for bacteremia caused by MRSA is significantly higher compared with bacteremia caused by MSSA (p = 0.007) [9].

Along with the increasing role of Staphylococcus aureus in IE, there is a tendency to increase the isolation of Enterococcus spp. The likely reason for this is the high incidence of pathology of the abdominal and pelvic organs and, as a consequence, the fact that today Enterococcus spp. is one of the main causative agents of outpatient and nosocomial cases of bacteremia. In the study, the proportion of isolated strains of Enterococcus spp. amounted to 16.0%. The emerging increase in the number of cases of IE caused by enterococci is of concern due to the fact that these microorganisms have a defective autolysis system, which contributes to the potential development of relapses.

The increase in the number of potential risk factors has led to the fact that over the past decades, the etiological structure of IE includes gram-negative microorganisms, the frequency of isolation of which in most cases is 6–10%. This is confirmed by the results of this study, according to which the proportion of gram-negative bacteria in the etiological structure of IE was 9.7%. Significant attention is paid to a group of slowly growing gram-negative rods that require special cultivation conditions, united by the abbreviation NASEK and being representatives of the microbiota of the oral cavity. Despite the fact that, according to the overwhelming number of studies, gram-negative bacteria are currently not the leading causative agents of IE, it is necessary to take into account the likelihood of these microorganisms in the etiology of IE with the corresponding risk factors due to the fact that in these cases (with the exception of bacteria of the HACEK group) treatment regimens IE will be of a fundamentally different nature [2, 11].

In conclusion, it should be noted that in order to ensure highly effective control measures for IE, it is first of all necessary to know the structural features of risk factors and pathogens of this nosology and regularly monitor the dynamics of their resistance to antimicrobial drugs. Knowledge of these indicators will not only make it possible to more effectively combat IE, but also optimize AMT, which, in turn, will increase the efficiency of patient treatment and reduce the economic losses of medical institutions. At the same time, there is still insufficient data in the Russian Federation characterizing the problems of diagnosis and treatment of IE. It is impossible to rely only on data from foreign studies, due to potential differences in the structure of risk factors and the policy of using antimicrobial drugs in the Russian Federation and abroad.

conclusions

1. Considering the low level of identification of etiologically significant pathogens in IE in the Russian Federation, decoding the risk factors (identification of potential pathogens) of this nosology is important.
2. The structure of risk factors for IE in the Russian Federation is dominated by injection drug addiction and acquired heart disease.
3. The most common causative agent of IE in the Russian Federation is Staphylococcus aureus.
4. To select optimal regimens of empirical and etiotropic therapy, it is extremely important to continue further study of the structure of risk factors and the etiology of IE.

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A. I. Danilov1 T. A. Osipenkova R. S. Kozlov, Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences

Federal State Budgetary Educational Institution of Higher Education SSMU Ministry of Health of the Russian Federation, Smolensk

1 Contact information

Modern features of infective endocarditis in the Russian Federation / A. I. Danilov, T. A. Osipenkova, R. S. Kozlov For citation: Attending physician No. 11/2018; Page numbers in issue: 54-57 Tags: heart, infections, risk factors