1. Introduction

The advent of antibiotics has made it possible to cope with many severe life-threatening infections and save a large number of human lives. The widespread and uncontrolled use of various groups of antibacterial drugs, especially in outpatient settings, has led to the development of many undesirable effects. In ten years, the frequency of antibiotic use worldwide has increased by 36%. Due to antibiotic resistance, reserve antibiotics are increasingly used, for example, the use of carbopenems has increased by 45%, polymyxins by 13% [1]. Imbalance of the symbiotic microbiota against the background of antibiotic therapy affects the development of not only acute allergic reactions and antibiotic resistance, but also type II diabetes mellitus, metabolic syndrome, atopic dermatitis, bronchial asthma, irritable bowel syndrome, oncological diseases and even myocardial infarction [2-3]. One of the frequent complications of antibiotic therapy may be the development of antibiotic-associated diarrhea (AAD). According to the WHO definition, AAD is characterized by increased stool frequency (more than 3 times a day), occurring against the background of antibiotic therapy or within 8 weeks after its end, and is accompanied by an increase in its volume, a change in consistency, the appearance of pathological impurities in the form of mucus, greens and blood. According to various epidemiological observations, on average, AAD develops in 5-30% of people receiving an antibiotic [4]. In children, the incidence of antibiotic-associated complications is more than 11% after the use of broad-spectrum antibiotics, and in immunocompromised patients it increases to 42% [5].

In hospitals, the incidence of AAD reaches 20-25%, but in recent years, the free release of medicines, including antibiotics, has led to an increase in the number of AAD in outpatient patients. In some patients, AAD may have a mild course, and when the antibiotic is discontinued, the symptoms disappear. Clinical symptoms may appear even 8 weeks after the end of the course of antibiotic therapy and have an erased course, which significantly complicates the interpretation of the diagnosis. However, there are severe life-threatening forms of AAD, manifested by pseudomembranous colitis (PMK). Taking absolutely any antibacterial drug can have an impact on the development of AAD, with an even greater probability with its high activity against anaerobes. The greatest risk of developing AAD is when using clindamycin, lincomycin, aminopenicillins, cephalosporins of the II and III generations. In the works of L. Mc Farland (1993), it was noted that 5-10% of cases of AAD develop when exposed to ampicillin, 10-25% – cephalosporins of the second generation and only 2-5% of cases – when using other antibiotics (tetracycline, macrolides, nitrofurantoin, co-trimoxazole, fluoroquinolones, aminoglycosides). It is important to note that the dose, method and frequency of administration of the antibiotic do not affect the risk of antibiotic-associated complications. Special attention should be paid to the use of broad-spectrum antibiotics with the lowest absorption in the intestinal lumen or secreted by bile into the intestinal lumen (for example, ceftriaxone). Diarrhea that occurs against the background of antibacterial therapy may be infectious and non-infectious in nature. The non-infectious genesis of AAD is associated with impaired motility, toxic effects on the intestinal epithelium, impaired metabolism of bile acids and carbohydrates in the intestine, etc. For example, macrolides stimulate motilin receptors, which causes a contraction of the smooth muscles of the antrum of the stomach and duodenum, leading to the development of diarrhea [6]. The toxic effect of tetracycline and neomycin on the mucous membrane of the gastrointestinal tract is manifested by the direct destruction of epithelial cells, shortening of intestinal villi, infiltration of its own plate by plasma cells, eosinophils and macrophages, which is accompanied by a decrease in the absorption of water and electrolytes. Penicillin causes acute hemorrhagic colitis, which is based on the development of allergic vasculitis in the mucous membrane of the colon [7]. The infectious nature of AAD may etiologically be associated with various pathogens - Clostridium perfringens, Salmonella species, Clostridium difficil, which are able to colonize the intestine against the background of suppression of normal microflora. Most researchers believe that one of the most significant infectious agents is Clostridium difficile (C. difficile), which is associated with up to 10-25% of all AAD and up to 90-100% of cases of pseudomembranous colitis. However, for the development of manifest forms of infections caused by C. difficile, it is necessary not only colonization of the intestine with toxigenic strains of the pathogen, but also the presence of risk factors: taking antibiotics of certain groups, age of children, features of the main and concomitant diseases, duration of hospital stay, the state of the intestinal microflora, etc. The combination of risk factors in infectious pathology in children creates prerequisites for the activation of Clostridium difficile infection, characterized by polymorphism of clinical manifestations from the gastrointestinal tract, and timely diagnosis of which is of great importance for adequate therapy. Basically, few works are devoted to the study of Clostridium difficile infection in adults, [8.9] whereas in pediatrics many aspects of this problem have not been solved to date, the issues of differential diagnosis of Clostridium difficile infection with AAD of non-infectious genesis and infectious genesis have not been sufficiently studied. Criteria for early diagnosis have not been developed, taking into account the risk factors for Clostridium difficile infection, the informative value of markers of inflammation in the colon has not been established to determine the nature and topic of gastrointestinal tract damage, and the choice of tactics for managing patients with AAD.

2. Materials and Methods

The studies were conducted on the basis of the Samarkand Multidisciplinary Medical Center (chief physician — M.K. Azizov), 68 children aged 2 months to 1.5 years with antibiotic-associated diarrhea were under supervision. Antibiotic-associated diarrhea was defined as 3 or more episodes of unformed stool for 2 or more days that occurred against the background of the use of antibacterial agents, unless another cause was identified (WHO, 2002). In the age structure of the examined patients with AAD, children under one year old accounted for 76.5% (52 children). In the age groups older than 1 year – 23.5% (17 patients). Among the examined children, 38 (55.8%) were boys, 30 (44.1%) were girls, no gender differences were found. The study included children with only confirmed antibiotic-associated diarrhea who were treated in gastroenterology and pulmonology departments. The topical characteristics of gastrointestinal tract lesions in AAD revealed 3 main forms: gastroenteritis, enterocolitis and hemocolitis. More than half of the children (57.5%) had AAD with gastroenteritis (39 patients). Enterocolitis was observed in 22 patients (30.1%), hemocolitis in 7 (10.2%). Depending on the severity and duration of toxicosis and exicosis, vomiting and diarrheal syndrome, fever, etc., the moderate form differed in 62 (91.2%) patients, and in 6 (8.8%) - severe form. Laboratory tests included a general blood test, a general urine test, a biochemical blood test, coprology, and bacteriological stool culture. In addition, laboratory studies included the detection of Clostridium difficile by immunochromatographic method c and the determination of its toxins A and B using the Xpect® C. difficile Toxin A^ system, which is an easy-to-use rapid test and provides accurate results within 20 minutes. The specificity of the test is 96.2%. Sensitivity is 95.8%.

3. The Results of the Study

Of the 68 examined patients with antibiotic-associated diarrhea, 32 had Clostridium difficile infection, which was 47%. According to literature sources, the prevalence of this infection in antibiotic-associated diarrhea ranges from 20-25%. Toxins A and B were detected in children in whom AAD developed in a hospital setting and amounted to 18.7% (in 6 patients). When analyzing the incidence of Clostridium difficile infection in various nosologies, it was found that the proportion among children with gastroenterological pathology was higher, which may be due to the depth of damage to the gastrointestinal tract and the severity of dysbiotic disorders occurring against the background of inflammatory bowel disease and the use of antibiotic therapy. When studying the effect of the method of using antibacterial therapy on the detection of Clostridium difficile infection, it was found that the manifestation of clinical manifestations of AAD with the risk of developing this infection with enteral administration was 68%, and when taking antibiotics parenterally was in 31.25% of cases. We have revealed that the risk factor for the development of Clostridium difficile infection is combined antibiotic therapy: the frequency of combined therapy was 65.6% (22 patients). This can be explained by the fact that taking several antibiotics simultaneously enhances their negative effect on microecological relationships in the gastrointestinal tract, expands the range of toxic effects and, as a result, creates additional conditions for the growth and colonization of C. difficile, the formation of toxins and the development of the disease. An antibiotic, in which C. is most often detected. ampicillin (34.4%) and second generation cephalosporin (28.2%) are the most difficult in our studies. A risk factor for the development of C. difficile infection is the combination therapy with antibiotics: the frequency of use of this therapy option in the C.difficile-positive group significantly exceeds the frequency in the C.difficile-negative group (59%) versus 37.70%, respectively, p=0.011). This can be explained by the fact that taking several antibiotics simultaneously enhances their negative effect on the microecological relationships in the gastrointestinal tract, expands the range of toxic effects and, as a result, creates additional conditions for the growth and colonization of C. difficile, the formation of toxins and the development of the disease. Thus, in the etiological structure of AAD in children, the proportion of C. difficile infection was 47%. A risk factor for the development is the combination therapy with antibiotics.