Etiological Structure, Clinical Course and Antibacterial Therapy of Bacterial Infective Endocarditis

The dissertation is devoted to the study of the etiological structure, clinical features and antibacterial therapy of bacterial infective endocarditis. The work examines the changes in the spectrum of causative agents that have occurred over recent decades, in particular the rising share of staphylococci, including community-acquired methicillin-resistant strains (CA-MRSA). The study analyzes the antibiotic resistance of the main pathogens, the clinical course of staphylococcal endocarditis, and the prognostic clinical and anamnestic criteria that may suggest a staphylococcal origin of the disease. On the basis of the obtained data, substantiated regimens of empirical antibacterial therapy are proposed, including consideration of the penetration of vancomycin into heart valves and vegetations.

Relevance of the topic

Over the past 15 years, according to data from developed countries, substantial changes have occurred in the epidemiology and etiology of infectious diseases of the heart and vessels. One of the most dangerous infections of the cardiovascular system is infective endocarditis (IE). This disease is regarded as rare: 1.7 to 6.5 cases per 100,000 population per year [4]. However, despite the advances in cardiac surgery (the possibility of transplantation of artificial heart valves) and the availability of antibacterial agents in the clinician's armamentarium, mortality in IE remains high, at 16–27% [109], and in staphylococcal IE it reaches 65% [120]. The prevalence and incidence of IE have increased. This is associated with an increase in predisposing factors for endocardial damage and infection. Among the main predisposing factors for the development of IE the following should be highlighted. First, this is the emergence and wide spread of various intravascular devices and of diagnostic and therapeutic procedures related to the use of these devices. Such procedures and devices include: peripheral and central venous catheters, intravenous and intra-arterial angiography, defibrillators and artificial pacemakers (implanted inside the heart), vena cava filters, vascular and heart valve prostheses, and arteriovenous fistulas for programmed hemodialysis. Second: this is the increase in the number of intravenous drug users.

The above causes have led to changes in the etiological structure of IE. Prior to the early 1990s, the leading causative agents of IE were streptococci. At present, the periodical literature increasingly contains data indicating the growing relevance of staphylococci in the etiology of IE. According to different data, the proportion of staphylococcal IE ranges from 30 to 50% [87], the proportion of streptococci amounts to only 14% [87], and the rates of enterococcal IE remain stable at 10–15% [18, 109].

Despite the availability of reliable methods of blood culture isolation in the physician's armamentarium, the rate of negative blood cultures in IE is still high, ranging from 10 to 50%. First, this is due to the frequent administration of antibiotics before blood sampling for blood culture [4]; second, it is due to incorrect performance of the bacteriological analysis itself. This results in antibacterial therapy being empirical in approximately half of the cases of IE.

The main causative agents of IE are staphylococci, streptococci and enterococci. However, for the treatment of IE presumably of streptococcal or enterococcal etiology (empirically), preference should be given to penicillins (ampicillin). In the case of staphylococcal IE, these drugs will be ineffective. In this connection, the search for clinical and anamnestic criteria for predicting the staphylococcal etiology of IE appears to be highly relevant. In the periodical literature, the following risk factors for the staphylococcal etiology of IE are distinguished: intravenous drug use, young age, and diabetes mellitus. A detailed comparative analysis of clinical, anamnestic and epidemiological criteria of IE caused by different pathogens is not found in the literature.

In addition to changes in the etiological structure, an increase in the resistance rates of the main causative agents of IE to antibacterial agents has been noted.

Among staphylococci (Staphylococcus aureus, Staphylococcus epidermidis), the proportion of strains resistant to oxacillin (methicillin) has significantly increased. These changes have also affected strains causing IE. Thus, the proportion of IE caused by MRSA has risen from 0% in 1990 to 31% in 2005 [20, 109]. Since 2000, the spread of MRSA strains in the community setting has been noted; these strains are not genetically related to nosocomial MRSA strains and are referred to as Community acquired MRSA (CA-MRSA). Studies by foreign authors have shown that CA-MRSA strains are associated with IE [93].

The clinical significance of VISA strains (vancomycin intermediate Staphylococcus aureus) increases every year — cases of IE caused by these pathogens have been described. In 2002, a report appeared on the isolation of a Staphylococcus aureus strain resistant to linezolid, an antibiotic of the oxazolidinone group, which today is one of the few reserve agents for the treatment of infections caused by multidrug-resistant Gram-positive microflora.

Among enterococci, relevant causative agents of angiogenic infections, the problem of antibiotic resistance also exists. In particular, among Enterococcus faecium strains resistant to ampicillin, resistance to vancomycin constitutes a serious problem, which limits the use of vancomycin for the treatment of IE.

The aforementioned changes in the etiology of IE and in the resistance rates of the main causative agents of this disease are naturally reflected in the regimens of empirical and etiotropic antibacterial therapy. At present, the drug of choice for the empirical therapy of subacute IE is penicillin (ampicillin). The spectrum of activity of this drug includes streptococci and enterococci sensitive to penicillin (ampicillin). Agents active against staphylococci — oxacillin and vancomycin — are recommended only for the treatment of the acute form of IE. Such recommendations do not fully correspond to the contemporary etiological structure of IE.

Thus, despite the existence of international recommendations on antibacterial therapy of IE, it is necessary to clarify the contemporary etiological structure of IE, to assess the resistance to antibacterial agents of the main causative agents of IE, and to identify anamnestic and clinical factors associated with the staphylococcal etiology of IE, with the aim of developing substantiated recommendations on antibacterial therapy of IE.

Aim and objectives of the study

Aim: to develop regimens of empirical antibacterial therapy of bacterial endocarditis.

Objectives:

1. To study the etiological structure of contemporary infective endocarditis and to assess the antibiotic resistance of the prevailing causative agent;

2. To study the features of the clinical course of infective endocarditis caused by the prevailing causative agent;

3. To evaluate the effectiveness of different regimens of antibacterial therapy of bacterial endocarditis;

4. To study the penetration of vancomycin into heart valves and/or vegetations;

5. To present optimal regimens of empirical antibacterial therapy of bacterial endocarditis.

Scientific novelty

1. For the first time, the dominance of staphylococci in the etiological structure of bacterial endocarditis has been demonstrated;

2. For the first time, it has been revealed that community-acquired methicillin-resistant staphylococcal strains are of substantial significance in the etiology of bacterial endocarditis;

3. For the first time, prognostic factors of the staphylococcal etiology of bacterial endocarditis have been identified: splenomegaly, involvement of the tricuspid valve, and the acute form of infective endocarditis.

4. The results of the analysis of antibacterial therapy of bacterial endocarditis made it possible to substantiate the use of antistaphylococcal agents as the starting empirical antibacterial therapy of infective endocarditis.

Practical significance of the study

The obtained data on the predominance of staphylococci in the etiological structure of infective endocarditis and the resistance rates of these pathogens to antibiotics (oxacillin, vancomycin, rifampicin) have made it possible to formulate recommendations on the rational empirical antibacterial therapy of infective endocarditis.

Clinical-anamnestic and laboratory-instrumental criteria have been identified («splenomegaly», «involvement of the tricuspid valve», «acute form of IE», «number of days from the onset of disease to diagnosis» and «patient's age») that allow predicting the staphylococcal etiology of infective endocarditis with a high probability, which will contribute to the timely administration of adequate empirical antibacterial therapy in cases of negative blood cultures.

Statements defended

1. At present, the leading causative agent of bacterial endocarditis is staphylococcus.

2. Involvement of the tricuspid valve, splenomegaly and the acute form of bacterial endocarditis are prognostic factors of the staphylococcal etiology of infective endocarditis.

3. The drug of choice for the starting empirical antibacterial therapy of infective endocarditis is oxacillin or cefazolin.

4. One quarter of staphylococci are characterized by resistance to oxacillin; therefore, vancomycin and linezolid should be considered as alternative empirical regimens of antibacterial therapy.