Antibiotic associated diarrhea microbial code 10. Antibiotic-associated diarrhea. Risk factors for idiopathic AAD

For citation: Belmer S.V. Antibiotic-associated intestinal dysbacteriosis // BC. 2004. No. 3. S. 148

M The numerous microbiocenosis of the human intestine is represented by more than 500 species of microorganisms, and in various parts of the gastrointestinal tract, their number ranges from 10 3 to 10 12 CFU / ml. The most numerous representatives of the human intestinal microbial community are Bifidobacterium sp., E. coli, Lactobacillus sp., Bacterioides sp., anaerobic streptococci, Clostridium sp. and many others. Microorganisms of the gastrointestinal tract provide the processes of digestion and absorption, intestinal trophism, anti-infective protection, synthesis of vitamins and many others. etc. The most numerous and best studied are the microorganisms of the large intestine, numbering about 10 12 CFU / ml.

Various factors of the external and internal environment can significantly affect the composition of the intestinal microflora, which can not only disrupt the normal course of physiological processes, but even lead to severe pathological conditions. A qualitative and / or quantitative change in the composition of the intestinal microflora is called intestinal dysbacteriosis. . Dysbacteriosis is always secondary. The most common reason for the development of intestinal dysbacteriosis is the use of antibiotics that directly suppress the vital activity of intestinal microorganisms and significantly change the "microbial landscape" of the gastrointestinal tract.

Other causes of dysbacteriosis are inflammatory diseases of the intestinal mucosa of both infectious and non-infectious nature. A significant role among non-infectious factors is played by long-term functional disorders of the gastrointestinal tract, including the biliary system, as well as fermentopathy and allergic lesions of the intestinal mucosa. A significant change in the intestinal microflora occurs under the influence of environmentally unfavorable environmental factors and stressful conditions of the body: physical and mental overload. The influence of the age factor on the intestinal microbiocenosis was noted. In children, dysbacteriosis develops quite quickly, which is associated with enzymatic and immune immaturity of the intestine. In the elderly, there is an age-related weakening of the enzymatic and immunological activity of the intestinal mucosa, as well as a change in lifestyle, a decrease in motor activity and diet. It is important to note that intestinal dysbacteriosis, not being a disease (therefore, it cannot be a diagnosis), is an important pathological process that can lead to severe damage to the gastrointestinal tract, which should be taken into account when determining the tactics of treating a patient. Indeed, a violation of the composition of the intestinal microflora can contribute to damage to enterocytes and disruption of physiological processes in the intestine, lead to an increase in intestinal permeability for macromolecules, change motility, reduce the protective properties of the mucous barrier, creating conditions for the development of pathogenic microorganisms.

A complex of pathological changes in the composition of the intestinal microflora with corresponding clinical manifestations associated with dysbacteriosis developed as a result of the use of antibiotics is often referred to in foreign literature as antibiotic-associated diarrhea ( antibiotic associated diarrhea). Based on our understanding of this process, the term "antibiotic-associated intestinal dysbacteriosis" can be considered more pathogenetically justified. The frequency of this condition, according to various authors, ranges from 5 to 39%. Naturally, in these patients it is almost always possible to detect signs of colitis endoscopically and histologically, which also justifies the term "antibiotic-associated colitis". Risk factors for its development are the age of the patient (under 6 years and over 65 years), concomitant diseases of the digestive system, as well as a decrease in the function of the immune system.

Most modern antibiotics can cause intestinal dysbacteriosis, although the action of each of them has certain characteristics. In particular, ampicillin largely inhibits the growth of both aerobic and anaerobic microflora, while amoxicillin, by only minimally inhibiting the activity of most normal intestinal microorganisms, contributes to some increase in the population of representatives of the genus Enterobacteria caea. Similarly, the combined preparation of amoxicillin and clavulanic acid affects the intestinal microbiocenosis. At the same time, most modern penicillins do not contribute to the reproduction of fungi and C. difficile. Oral cefpodoxime, cefprozil and ceftibuten definitely increase the number of representatives of the genus Enterobacteriacaea in the intestine, while cefaclor and cephradine have almost no effect on the intestinal microflora, and the use of cefixime leads to a significant decrease in anaerobic microorganisms. It is important that most cephalosporins contribute to the growth of the number of enterococci and C. difficile. Fluoroquinolones largely inhibit the growth of microbes of the genus Enterobacteriacaea and, to a lesser extent, enterococci and anaerobic microorganisms, while not promoting the growth of fungi and C. difficile .

The most severe and even life-threatening condition associated with antibiotic-associated intestinal dysbacteriosis is the so-called. C. difficile associated colitis caused by overgrowth in the intestine C. difficile. The latter is normally detected by bacteriological examination in 1-3% of healthy individuals, but in more than 20% of patients receiving antibiotic therapy. In some patients, against the background of inhibition of the normal flora by taking antibiotics, an avalanche-like population growth occurs. C. difficile with a change in its toxigenic properties, incl. an increase in the synthesis of enterotoxin A and cytotoxin B. This results in severe damage to the colon mucosa. Most often, C. difficile-associated colitis develops with the use of clindamycin or lincomycin, semi-synthetic penicillins, less often - cephalosporins with a wide spectrum of antibacterial action. The most severe form C. difficile-associated colitis is pseudomembranous colitis, the lethality in the development of which reaches 30%.

Typical symptoms of pseudomembranous colitis are severe abdominal pain, fever up to 40 ° C, frequent (10-20 times a day) loose stools mixed with mucus and blood. Also, signs of severe endotoxicosis are often observed, and leukocytosis and an increase in ESR are detected in the blood. In the colon, hyperemia of the mucous membrane and fibrinous films formed in the areas of necrosis of the mucous membrane are found in the form of pale grayish-yellow plaques 0.5-2.0 cm in diameter on a slightly elevated base. Histologically, areas of necrosis of the colonic mucosa, edema of the submucosal layer, round cell infiltration of the lamina propria, and focal extravasation of erythrocytes are revealed. The most accessible diagnostic test for pseudomembranous colitis is the determination of toxin A in the feces. C. difficile latex agglutination method.

The first year of a child's life, and especially its first months, are the most vulnerable in terms of the development of any intestinal dysbacteriosis, incl. antibiotic-associated. This is due to the fact that at this time the primary formation of the intestinal microflora occurs, which, combined with the immaturity of the immune system, makes it very unstable in relation to many exogenous factors.

Factors that provide favorable conditions for the formation of normal intestinal microflora contribute to the prevention of antibiotic-associated dysbacteriosis not only in this age period, but, to a greater or lesser extent, throughout the child's later life. Of great importance for the formation of intestinal microflora is natural feeding, both due to the immunological factors present in human milk, and due to the presence of prebiotics in milk. The first circumstance is important in connection with the relative immaturity of the immune system of a newborn child, while colonization of the intestine by certain types of microorganisms must be controlled by both specific and non-specific mechanisms. In particular, a newborn child can only synthesize class M immunoglobulins in sufficient quantities, while class A immunoglobulins are practically not formed during the first month of life and enter the gastrointestinal tract of the infant with mother's milk. Non-specific factors also come with mother's milk, which together provide not only effective anti-infective protection for the child in the most vulnerable period of his life, but also the normal process of colonization of the intestines by microorganisms.

Human milk also contains nutrients that ensure the growth and reproduction of normal intestinal microflora, called "prebiotics". Prebiotics - these are partially or completely indigestible food components that selectively stimulate the growth and / or metabolism of one or more groups of microorganisms living in the large intestine, ensuring the normal composition of the intestinal microbiocenosis. Prebiotics in human milk are lactose and oligosaccharides. Until recently, the latter were absent in formulas for artificial feeding, however, at present, various combinations of galacto- and fructooligosaccharides are actively introduced into them. The mechanism of action of all prebiotics is the same: without splitting in the small intestine by the enzyme systems of the macroorganism, they are utilized by the microflora, mainly bifidobacteria and lactobacilli, ensuring their growth and activity. In addition, as a result of bacterial metabolism of lactose and oligosaccharides in the colon, the optimal content of short-chain fatty acids necessary for the stable functioning of colonocytes is ensured. Thus, to ensure the normal formation of the intestinal microflora, natural feeding is highly desirable, and if it is impossible, the use of mixtures containing prebiotics is recommended.

Thus, it becomes obvious that numerous external factors can disrupt the formation of intestinal microflora in a newborn child. Antibiotic therapy, even justified, in children of the first year of life can lead to severe intestinal dysbacteriosis, however, in older children and even adults, it can seriously disrupt the already formed intestinal biocenosis.

In this regard, one of the problems that have arisen in recent years is the development of intestinal dysbacteriosis against the background of eradication. H. pylori. The anti-Helicobacter regimens in various combinations may include various antibacterial drugs, such as amoxicillin, macrolides (clarithromycin, roxithromycin, azithromycin), metronidazole, furazolidone, bismuth subcitrate, as well as modern drugs that reduce gastric secretion (proton pump blockers or H2 blockers - histamine receptors), which are also capable, albeit indirectly, of reducing the resistance of the natural intestinal microflora. Numerous studies indicate the need to include biological preparations, in particular bifidum-containing, in the complex therapy of Helicobacter-associated diseases of the upper digestive tract, which makes it possible to reduce the incidence and severity of dysbiotic changes and, as a result, reduce the severity and duration of abdominal pain and dyspepsia. syndromes in children.

Prevention and correction of antibiotic-associated intestinal dysbacteriosis is a rather difficult task, especially in children of the first year of life, especially if antibiotic therapy should be continued for health reasons. The basis for the prevention of intestinal dysbacteriosis is rational antibiotic therapy and the exclusion of unreasonable cases of prescribing antibacterial agents. . In children of the first year of life, an important factor in prevention is the preservation of breastfeeding or, if not possible, the use of mixtures with prebiotics. Typically, treatment includes the following areas: reducing excessive microbial contamination of the small intestine and restoring normal microflora.

To reduce microbial contamination of the small intestine in adult practice, it is customary to use antibiotics and other antiseptics (nitrofurans, nalidixic acid). But in young children, in the absence of clinical and laboratory signs of enterocolitis, it is preferable to use not antibiotics, but drugs belonging to the group of probiotics. These are primarily spore monocomponent probiotics. For children older than 2 years, the most preferred monocomponent probiotic containing yeast fungi - enterol.

At the second stage of therapy, the main attention is paid to the restoration of normal microflora. For this purpose, both widely known monocomponent (bifidumbacterin, etc.), and polycomponent (primadofilus, etc.) and combined probiotics are used. Some polyvalent preparations, along with strains of bifido- and lactobacilli, include strains of enterococci with high antagonistic activity against opportunistic and pathogenic pathogens (Linex). This significantly increases the activity of drugs compared to monocomponent probiotics.

In the treatment of antibiotic-associated intestinal dysbacteriosis, probiotics currently occupy a key position - preparations containing microorganisms that have a positive effect on intestinal microbiocenosis. The founder of the concept of probiotics was I.I. Mechnikov, who was awarded the Nobel Prize in Medicine in 1908 for a series of works in this direction. In particular, he showed that certain microorganisms can inhibit the growth of Vibrio cholerae, while others, on the contrary, stimulate. Since then, a large number of microorganisms have been studied that could be used in everyday medical practice in the composition of probiotic preparations and food, but only a few of them are officially recognized as such today. The main criterion for this is the probiotic effect, proven in double-blind placebo-controlled studies. This "exam" passed B. bifidum, Lactobacillus acidophilus, Lactobacillus GG, Lactobacillus fermentum, Strepto (Entero) coccus faecium SF68, S. termophilus, Saccharomyces boulardii. These microorganisms are part of numerous preparations, both monobacterial and combined. On the other hand, the microorganism must overcome the upper parts of the digestive tract with minimal losses, and therefore it becomes necessary to place it in a pH-sensitive capsule. Finally, long-term preservation of microorganisms during storage is ensured by their lyophilization.

A drug that meets the requirements listed above is Linex , which is a complex of 3 live lyophilized bacteria Bifidobacterium infantis v.liberorum, Lactobacillus acidophilus and Streptococcus faecium in an amount of at least 1.2x10 7 . An important feature of the microorganisms that make up Linex is their resistance to antibiotics and chemotherapeutic agents, resistance to penicillins, incl. semi-synthetic, macrolides, cephalosporins, fluoroquinolones and tetracyclines. This circumstance allows the use of Linex, if necessary, in combination with antibiotics in order to prevent dysbacteriosis. These features make it possible to single out Linex in a number of drugs for the correction of intestinal dysbacteriosis of various origins.

We analyzed the results of correction of antibiotic-associated intestinal dysbacteriosis with Linex in 8 children aged 6 to 12 months (Group 1) and 19 children aged 1 to 5 years (Group 2), who developed intestinal dysbacteriosis could be associated with the use of oral antibiotics from the group of penicillins and cephalosporins in age dosages. The purpose of these drugs was associated with the treatment of acute respiratory diseases. In all cases, against the background of taking an antibiotic at the end of the course, there was an increase in stools (up to 8 times a day), which had a mushy or liquid character and contained impurities of mucus and greenery. The general condition of the child in all cases was determined by the nature of the underlying pathological process, and the unstable stool persisted even after its relief. In connection with the violation of the stool, the children were examined within a period of several days to 2 weeks from the onset of intestinal disorders. Bacteriological examination of faeces revealed intestinal dysbacteriosis in all of them, the general characteristic of which was a significant decrease in bifido- and lactoflora. In order to correct it, the children received 1 capsule of Linex 2 times a day. Clinical improvement (normalization of stool) was observed in 6 children from the 1st group and 14 children from the 2nd group within 7 days, in 7 children from the 1st group and 16 children from the 2nd group within 14 days, in 17 children from the 2nd group for 21 days. During the specified period, in 1 child from the 1st group and in 2 children from the 2nd group, the stool did not normalize completely, remaining mushy, although the impurities of mucus and greenery disappeared. After 21 days, microbiological improvement was noted in all children, although the normalization of the indicators of the number of bifidus and lactobacilli was noted only in half of the cases (in 5 children from the 1st group and 10 children from the 2nd group). The effect of the treatment did not depend on the duration and nature of the ongoing antibiotic therapy, which caused intestinal dysbacteriosis. The data obtained allow us to conclude that the correction of antibiotic-associated dysbacteriosis in children with Linex containing live lyfilized lactobacilli, bifidobacteria and enterococcus is effective. The combined use of Linex and the adsorbent-mucocytoprotector diosmectite increased the effectiveness of therapy: the symptoms stopped in 8 out of 10 children aged 4-7 years. The appointment of the drug Linex during a course of antibiotics excluded the development of clinically obvious intestinal dysbacteriosis in about half of the cases (in 6 out of 11 children).

Thus, even reasonable use of antibiotics can lead to the development of serious intestinal dysbacteriosis, which may result in colitis. The combined use of probiotics with antibiotics can reduce the risk of antibiotic-associated dysbacteriosis or reduce its severity. In the case of the development of antibiotic-associated intestinal dysbacteriosis in children, the appointment of biological preparations is indicated, the effect of which can be enhanced by enterosorbents. Development C. difficile-associated colitis requires special therapeutic tactics, including the use of specific antibacterial drugs, but also not excluding probiotics.

Epidemiology. In the general population, the appearance of symptoms of antibiotic-associated diarrhea, both during antibiotic therapy and within two months after its completion, occurs in 5–62% patients.

Risk factors for antibiotic-associated diarrhea include:
the age of the patient is younger than 6 years or older than 65 years;
the presence of a previous chronic gastroenterological pathology;
previous antibiotic-associated diarrhea;
severe chronic disease and immunodeficiency;
long-term stay of the patient in the hospital (the frequency of infection with Clostridium difficile (the etiological factor of infectious antibiotic-associated diarrhea) is 13% with hospitalization up to 2 weeks and 50% with a hospitalization period of more than 4 weeks);
performing surgical and endoscopic manipulations;
the use of antibacterial drugs with a wide spectrum of action (clindamycin, aminopenicillins, cephalosporins II and III generation, etc.);
increasing the duration of antibiotic therapy;
conducting repeated courses of antibiotic therapy;
a combination of several antibacterial drugs;
the use of antibacterial drugs excreted in the bile.

!!! in patients with immunosuppression, after surgical interventions and who have had previous episodes of diarrhea associated with Clostridium difficile, there is a high risk of developing a fulminant form of the disease (an important sign of threatening fulminant colitis is a sharp rise in the number of leukocytes to 30 10 9 / l and above, often in combination with a pronounced shift in leukocyte formulas to the left)

Classification of antibiotic-associated diarrhea:
antibiotic-associated non-infectious diarrhea(up to 80% of cases):
- the influence of a number of antibiotics on the motility and function of the digestive tract (almost all drugs of the group of fourteen-membered macrolides);
- the presence in the preparation of an additional component with a diarrheal effect (for example, clavulanic acid) or the presence of a direct laxative effect in the preparation (parenteral cephalosporins - cefoperazone, ceftriaxone and oral cephalosporin - cefixime);
- direct toxic effect on the intestinal mucosa (chloramphenicol, tetracycline);
- hidden induction of malabsorption, suppression of the metabolism of carbohydrates, short-chain fatty acids and bile acids;
- violations of the composition of the normal intestinal microflora;
antibiotic-associated infectious diarrhea(idiopathic, 15-20% of cases) - due to colonization of the intestine by opportunistic strains of bacteria and develops after 1-3 days from the start of the use of antibacterial drugs; possible etiological factors are Clostridium difficili, Clostridium perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida spp., Salmonella, etc.

!!! to date, it has been established that antibiotic-associated diarrhea is caused only by toxigenic strains of Clostridium difficili (the strain was named "difficile", since it was difficult to cultivate it at the initial stages of its study), the involvement of other microorganisms in the development of antibiotic-associated diarrhea remains a controversial issue, since most of these bacteria belong to the normal flora of the gastrointestinal tract

Clostridium difficile infection occurs initially in a hospital (the microorganism is sown from the surfaces of beds, floors, window sills, medical equipment, hands of medical and attendants). Clostridium difficile enters the intestine in the form of spores resistant to external influences, which are already converted into vegetative forms in the large intestine. Depending on the state of the patient's body, either a state of asymptomatic carriage or a clinical picture of colitis is formed; an adequate immune response does not prevent infection but reduces morbidity, mortality, and relapse rates. Clostridium difficile produces two protein toxins (A and B) that damage the mucosa and cause inflammation.

Risk factors for diarrhea caused by Clostridium difficile:
long stay in the hospital;
stay in the intensive care unit;
staying in the same room with a patient suffering from diarrhea caused by Clostridium difficile (the microbe persists in the wards for more than 40 days after the discharge of the infected patient);
antibacterial therapy;
immunosuppressive therapy;
elderly age;
use of a nasogastric tube;
recent surgery;
the use of antacids;

Clinical picture. The symptom complex that develops on the background of antibiotic therapy can vary from minor transient intestinal discomfort to severe forms of diarrhea and pseudomembranous colitis, which is characterized by watery diarrhea, fever, leukocytosis, and the formation of pseudomembranes found in feces and colonoscopy. In severe cases, pseudomembranous colitis is complicated by toxic megacolon, perforation, and shock.

Diagnostics: history, fecal analysis (for severe or persistent diarrhea in order to detect toxins A or B), cytotoxin method("gold standard", disadvantage - a long period of waiting for the results of the study), linked immunosorbent assay(has high specificity, false-negative results are recorded in 10–20% of cases), inoculation of Clostridium difficile (the disadvantage is that this method does not allow differentiating non-pathogenic and pathogenic strains).

Treatment. For mild to moderate antibiotic-associated diarrhea: rehydration is applied, the prescribed antibiotic(s) are withdrawn, or the antibiotic is changed. In some cases, when the antibiotic is discontinued within 3 days, a complete regression of symptoms is noted if its development was associated with Clostridium difficile infection. For antibiotic-associated diarrhea caused by Clostridium difficile, severe take oral metronidazole 250 mg 4 times a day or vancomycin 125 mg 4 times a day for 10 days. As a rule, diarrhea disappears after 2-3 days. In general, metranidazole is used as the first line drug, and vancomycin remains as a reserve for cases of severe diarrhea, metronidazole intolerance, metronidazole failure, or pregnancy. For any severity of antibiotic-associated diarrhea it is possible to use probiotics (linex, bifiform).

Prevention. Prevention of nosocomial infection is based on compliance with isolation and barrier measures, disinfection of wards throughout the course of the disease, as well as thorough hand washing (during an outbreak of infection associated with Clostridium difficile, it is recommended to wash hands with soap and water before and after removing gloves), the use of probiotics. For the prevention of antibiotic-associated diarrhea, it is possible to use (mentioned when considering treatment) probiotics (linex, bifiform), as well as the use of prebiotics (lactulose, hilak-forte). In addition, one of the approaches to the prevention of antibiotic-associated diarrhea may be the use of drugs that have cytomucoprotective effects, such as smecta.

Yu.O. Shulpekova
MMA named after I.M. Sechenov

Modern medicine is unthinkable without the use of various antibacterial agents. However, the appointment of antibiotics must be approached carefully, keeping in mind the possibility of developing numerous adverse reactions, one of which is antibiotic-associated diarrhea.

Already in the 1950s, with the beginning of the widespread use of antibiotics, a causal relationship was established between the use of antibacterial agents and the development of diarrhea. And today, intestinal damage is considered as one of the most frequent undesirable effects of antibiotic therapy, which most often develops in debilitated patients.

The concept of antibiotic-associated diarrhea includes cases of loose stools in the period after the start of antibiotic therapy and up to 4 weeks after antibiotic withdrawal (in cases where other causes of its development are excluded). In foreign literature, the terms "nosocomial colitis", "antibiotic-associated colitis" are also used as synonyms.

• 10-25% - when prescribing amoxicillin / clavulanate;
• 15-20% - when prescribing cefixime;
• 5-10% - when prescribing ampicillin or clindamycin;
• 2-5% - when prescribing cephalosporins (except cefixime) or macrolides (erythromycin, clarithromycin), tetracyclines;
• 1-2% - when prescribing fluoroquinolones;
• less than 1% - when prescribing trimethoprim - sulfamethoxazole.

As the causes of the development of antibiotic-associated diarrhea in developed countries, penicillin derivatives and cephalosporins are leading, due to their widespread use. Diarrhea occurs more often with oral antibiotics, but it can also develop with parenteral and even transvaginal use.

Pathogenesis

Antibacterial drugs are able to suppress the growth of not only pathogenic microorganisms, but also the symbiotic microflora inhabiting the gastrointestinal tract.

The symbiotic microflora that inhabits the lumen of the gastrointestinal tract produces substances with antibacterial activity (in particular, bacteriocins and short-chain fatty acids - lactic, acetic, butyric), which prevent the introduction of pathogenic microorganisms and overgrowth, the development of opportunistic flora. Bifidobacteria and lactobacilli, enterococci, Escherichia coli have the most pronounced antagonistic properties. In case of violation of the natural protection of the intestine, conditions arise for the reproduction of conditionally pathogenic flora.

When talking about antibiotic-associated diarrhea, from a practical point of view, it is important to distinguish between its idiopathic variant and diarrhea caused by the microorganism Clostridium difficile.

Idiopathic antibiotic-associated diarrhea. Pathogenetic mechanisms for the development of idiopathic antibiotic-associated diarrhea remain poorly understood. It is assumed that various factors are involved in its development.

When prescribing antibiotics containing clavulanic acid, diarrhea can develop due to stimulation of intestinal motility (that is, in such cases, diarrhea is hyperkinetic in nature).

When prescribing cefoperazone and cefixime, diarrhea is likely to develop, which is hyperosmolar in nature, due to incomplete absorption of these antibiotics from the intestinal lumen.

Nevertheless, the most likely universal pathogenetic mechanism for the development of idiopathic antibiotic-associated diarrhea is the negative impact of antibacterial agents on the microflora that inhabits the lumen of the gastrointestinal tract. Violation of the composition of the intestinal microflora is accompanied by a chain of pathogenetic events leading to impaired bowel function. The name "idiopathic" emphasizes that in this condition, in most cases, it is not possible to identify the specific pathogen that causes the development of diarrhea. Clostridium perfrigens, bacteria of the genus Salmonella, which can be isolated in 2–3% of cases, staphylococcus aureus, Proteus, enterococcus, and yeasts are considered as possible etiological factors. However, the pathogenic role of fungi in antibiotic-associated diarrhea remains a matter of debate.

Another important consequence of the violation of the composition of the intestinal microflora is a change in the enterohepatic circulation of bile acids. Normally, primary (conjugated) bile acids enter the lumen of the small intestine, where they undergo excessive deconjugation under the influence of altered microflora. An increased amount of deconjugated bile acids enters the lumen of the colon and stimulates the secretion of chlorides and water (secretory diarrhea develops).

Clinical picture

The risk of developing idiopathic antibiotic-associated diarrhea depends on the dose of the drug used. Symptoms are not specific. As a rule, there is a mildly pronounced loosening of the stool.

The disease, as a rule, proceeds without an increase in body temperature and leukocytosis in the blood and is not accompanied by the appearance of pathological impurities in the feces (blood and leukocytes). In endoscopic examination, inflammatory changes in the mucous membrane of the colon are not detected. As a rule, idiopathic antibiotic-associated diarrhea does not lead to the development of complications.

Treatment

The main principle of treatment of idiopathic antibiotic-associated diarrhea is the abolition of the antibacterial drug or a decrease in its dose (if necessary, continue treatment). If necessary, prescribe antidiarrheal agents (loperamide, diosmectite, aluminum-containing antacids), as well as agents for the correction of dehydration.

It is advisable to prescribe probiotic preparations that help restore normal intestinal microflora (see below).

Diarrhea due to Clostridium difficile

The isolation of this form of antibiotic-associated diarrhea is justified by its special clinical significance.

The most severe acute inflammatory bowel disease caused by the microorganism Clostridium difficile and usually associated with the use of antibiotics is called pseudomembranous colitis. The cause of pseudomembranous colitis in almost 100% of cases is Clostridium difficile infection.

Clostridium difficile is an obligate anaerobic Gram-positive spore-forming bacterium that is naturally resistant to most antibiotics. Clostridium difficile is able to persist in the environment for a long time. Its spores are resistant to heat treatment. This microorganism was first described in 1935 by the American microbiologists Hall and O'Tool in the study of the intestinal microflora of newborns and was not initially considered as a pathogenic microorganism. The specific name "difficile" ("difficult") emphasizes the difficulty of isolating this microorganism by the cultural method.

In 1977 Larson et al. isolated from the feces of patients with a severe form of antibiotic-associated diarrhea - pseudomembranous colitis - a toxin that has a cytopathic effect in tissue culture. Somewhat later, the pathogen producing this toxin was established: it turned out to be Clostridium difficile.

The frequency of asymptomatic carriage of Clostridium difficile in newborns is 50%, among the adult population - 3–15%, while its population in the normal intestinal microflora of a healthy adult does not exceed 0.01–0.001%. It increases significantly (up to 15–40%) when taking antibiotics that inhibit the growth of intestinal flora strains that normally suppress the vital activity of Clostridium difficile (primarily clindamycin, ampicillin, cephalosporins).

Clostridium difficile produces 4 toxins in the intestinal lumen. Invasion of the microorganism into the intestinal mucosa is not observed.

Enterotoxins A and B play a major role in the development of intestinal changes. Toxin A has a pro-secretory and pro-inflammatory effect; it is able to activate cells participating in inflammation, cause the release of inflammatory mediators and substance P, degranulation of mast cells, and stimulate chemotaxis of polymorphonuclear leukocytes. Toxin B exhibits the properties of a cytotoxin and has a damaging effect on colonocytes and mesenchymal cells. This is accompanied by actin disaggregation and disruption of intercellular contacts.

The pro-inflammatory and decontaminating action of toxins A and B leads to a significant increase in the permeability of the intestinal mucosa.

Interestingly, the severity of the course of infection is not directly related to the toxigenicity of various strains of the pathogen. Carriers of C. difficile may have a significant amount of toxins in the feces without the development of clinical symptoms. Some antibiotics, especially lincomycin, clindamycin, and ampicillin, in asymptomatic carriers of C. difficile stimulate the production of toxins A and B without increasing the overall population of the microorganism.

For the development of diarrhea due to C. difficile infection, the presence of so-called predisposing or trigger factors is necessary. In the vast majority of cases, such a factor is antibiotics (primarily lincomycin and clindamycin). The role of antibiotics in the pathogenesis of diarrhea is reduced to the suppression of the normal intestinal microflora, in particular, a sharp decrease in the number of non-toxigenic clostridia, and the creation of conditions for the reproduction of the opportunistic microorganism Clostridium difficile. It has been reported that even a single dose of an antibiotic can trigger the development of this disease.

However, diarrhea caused by C. difficile infection can also develop in the absence of antibiotic therapy, under other conditions in which there is a violation of the normal microbial biocenosis of the intestine:

• in old age;
• with uremia;
• with congenital and acquired immunodeficiencies (including against the background of hematological diseases, the use of cytostatic drugs and immunosuppressants);
• with intestinal obstruction;
• against the background of chronic inflammatory bowel diseases (nonspecific ulcerative colitis and Crohn's disease);
• against the background of ischemic colitis;
• against the background of heart failure, with violations of the blood supply to the intestines (including in shock conditions);
• on the background of a staphylococcal infection.

The risk of developing pseudomembranous colitis after operations on the abdominal organs is especially great. It was reported about the development of pseudomembranous colitis against the background of the active use of laxatives.

The place of predisposing factors in the pathogenesis of C. difficile infection, apparently, can be defined as follows: “exposure to predisposing factors → inhibition of normal microflora → growth of the C. difficile population → production of toxins A and B → damage to the colonic mucosa.”

The bulk of cases of diarrhea due to C. difficile are cases of nosocomial diarrhea. Additional factors of nosocomial spread of C. difficile infection are fecal-oral infection (transfer by medical personnel or through contact between patients). It is also possible infection during endoscopic examination.

Manifestations of C. difficile infection range from asymptomatic carriage to severe forms of enterocolitis, which is referred to as "pseudomembranous colitis". The prevalence of C. difficile infection, according to different authors, ranges from 2.7 to 10% among hospital patients.(depending on the nature of background diseases).

In 35% of patients with pseudomembranous colitis, the localization of inflammatory changes is limited to the large intestine, in other cases, the small intestine is also involved in the pathological process. The predominant lesion of the colon, apparently, can be explained by the fact that this is the predominant habitat of anaerobic clostridia.

Clinical manifestations can develop both against the background of taking an antibiotic (usually from the 4th to the 9th day, the minimum period is after a few hours), and after a considerable period (up to 6-10 weeks) after stopping its administration. Unlike idiopathic antibiotic-associated diarrhea, the risk of developing pseudomembranous colitis does not depend on the dose of antibiotic.

The onset of pseudomembranous colitis is characterized by the development of profuse watery diarrhea (with a frequency of stools up to 15–30 times a day), often with an admixture of blood, mucus, and pus. As a rule, there is a fever (reaching up to 38.5–40 ° C), moderate or intense pain in the abdomen of a cramping or constant nature. Neutrophilic leukocytosis (10–20 x 10 9 /l) is observed in the blood, in some cases a leukemoid reaction is observed. With severe exudation and a significant loss of protein in the feces, hypoalbuminemia and edema develop.

Cases of the development of reactive polyarthritis involving large joints are described.

Complications of pseudomembranous colitis include dehydration and electrolyte disturbances, development of hypovolemic shock, toxic megacolon, hypoalbuminemia, and edema up to anasarca. Rare complications include perforation of the colon, intestinal bleeding, development of peritonitis, sepsis. For the diagnosis of sepsis, a prerequisite is the identification of stable bacteremia in the presence of clinical signs of a systemic inflammatory reaction: body temperature above 38°C or below 36°C; heart rate over 90 beats. per minute; respiratory rate over 20 per minute or PaCO 2 less than 32 mm Hg; the number of leukocytes in the blood is over 12x10 9 /l or less than 4x10 9 /l or the number of immature forms exceeds 10%. It is extremely rare to observe a lightning-fast course of pseudomembranous colitis, resembling cholera, in these cases, severe dehydration develops within a few hours.

If untreated, mortality in pseudomembranous colitis reaches 15-30%.

In patients who need to continue antibiotic therapy to treat the underlying disease, recurrences of diarrhea are observed in 5–50% of cases, and with repeated use of the “guilty” antibiotic, the frequency of recurrent attacks increases to 80%.

Diagnosis of pseudomembranous colitis Based on 4 main features:

• diarrhea after taking antibiotics;
• identification of characteristic macroscopic changes in the colon;
• a kind of microscopic picture;
• proof of the etiological role of C. difficile.

Imaging techniques include colonoscopy and computed tomography. Colonoscopy reveals quite specific macroscopic changes in the colon (primarily the rectum and sigmoid colon): the presence of pseudomembranes consisting of necrotic epithelium impregnated with fibrin. Pseudomembranes on the intestinal mucosa are found in moderate and severe forms of pseudomembranous colitis and look like yellowish-greenish plaques, soft but tightly connected to the underlying tissues, with a diameter of several mm to several cm, on a slightly elevated base. Ulcers may be found in place of the sloughing membranes. The mucous membrane between the membranes looks unchanged. The formation of such pseudomembranes is a fairly specific sign of pseudomembranous colitis and can serve as a differential diagnostic difference from ulcerative colitis, Crohn's disease, ischemic colitis.

Microscopic examination determines that the pseudomembrane contains necrotic epithelium, abundant cellular infiltrate and mucus. Microbial growth takes place in the membrane. Full-blooded vessels are seen in the underlying intact mucosa and submucosa.

In milder forms of the disease, mucosal changes may be limited only by the development of catarrhal changes in the form of plethora and edema of the mucous membrane, its granularity.

Computed tomography can reveal thickening of the colon wall and the presence of an inflammatory effusion in the abdominal cavity.

The use of methods to prove the etiological role of C. difficile seems to be the most rigorous and accurate approach in the diagnosis of antibiotic-associated diarrhea caused by this microorganism.

Bacteriological study of the anaerobic portion of fecal microorganisms is inaccessible, expensive and does not meet clinical needs, because takes several days. In addition, the specificity of the culture method is low due to the high prevalence of asymptomatic carriage of this microorganism among hospital patients and patients taking antibiotics.

Therefore, the detection of toxins produced by C. difficile in the feces of patients is recognized as the method of choice. A highly sensitive and specific method for detecting toxin B using tissue culture has been proposed. In this case, it is possible to quantify the cytotoxic effect of the patient's fecal filtrate on tissue culture. However, the use of this method is economically unprofitable, it is used only in a few laboratories.

The C. difficile toxin A latex agglutination test can detect the presence of toxin A in faeces in less than 1 hour. The sensitivity of the method is about 80%, the specificity is more than 86%.

Since the early 1990s, most laboratories have used enzyme immunoassay to detect toxin A or toxins A and B, which increases the diagnostic value. The advantages of the method are simplicity and speed of execution. Sensitivity is 63-89%, specificity is 95-100%.

Treatment of antibiotic-associated diarrhea due to infection Clostridium difficile

Since antibiotic-associated diarrhea due to C. difficile can be classified as infectious diarrhea, it is advisable to isolate the patient when establishing this diagnosis in order to prevent infection of others.

A prerequisite is the abolition of the antibacterial agent that caused the appearance of diarrhea. In many cases, this measure already leads to relief of the symptoms of the disease.

In the absence of effect and in the presence of a severe course of clostridial colitis, active treatment tactics are necessary.

Antibacterial drugs (vancomycin or metronidazole) are prescribed to suppress the growth of the C. difficile population.

Vancomycin is poorly absorbed from the intestinal lumen, and here its antibacterial action is carried out with maximum efficiency. The drug is prescribed at 0.125-0.5 g 4 times a day. Treatment is continued for 7-14 days. The effectiveness of vancomycin is 95-100%: in most cases of C. difficile infection, when vancomycin is prescribed, the fever disappears after 24-48 hours, and diarrhea stops by the end of 4-5 days. If vancomycin is ineffective, one should think about another possible cause of diarrhea, in particular, the onset of non-specific ulcerative colitis.

As an alternative to vancomycin, metronidazole can be used, which has a comparable efficacy to vancomycin. The advantages of metronidazole are significantly lower cost, no risk of selection of vancomycin-resistant enterococci. Metronidazole is administered orally at 0.25 g 4 times a day or 0.5 mg 2-3 times a day for 7-14 days.

Another antibiotic effective for pseudomembranous colitis is bacitracin, which belongs to the class of polypeptide antibiotics. He is prescribed 25,000 IU orally 4 times a day. Bacitracin is practically not absorbed from the gastrointestinal tract, and therefore a high concentration of the drug is created in the colon. The high cost of this drug, the frequency of side effects limit its use.

If oral administration of these antibacterial agents is impossible (in an extremely serious condition of the patient, dynamic intestinal obstruction), metronidazole is used intravenously at 500 mg every 6 hours; Vancomycin is administered up to 2 g per day through a small bowel or rectal tube.

If there are signs of dehydration, infusion therapy is prescribed to correct the water and electrolyte balance.

For the purpose of sorption and removal of clostridial toxins and microbial bodies from the intestinal lumen, it is recommended to prescribe enterosorbents and drugs that reduce the adhesion of microorganisms on colonocytes (diosmectite).

The appointment of antidiarrheal agents and antispasmodics is contraindicated because of the risk of developing a formidable complication - toxic megacolon.

In 0.4% of patients with the most severe forms of pseudomembranous colitis, despite ongoing etiotropic and pathogenetic therapy, the condition progressively worsens and there is a need for colectomy.

Treatment of relapses of Clostridium difficile infection is carried out according to the scheme of vancomycin or metronidazole per os for 10-14 days, then: cholestyramine 4 g 3 times a day in combination with lactobacterin 1 g 4 times a day for 3-4 weeks. and vancomycin 125 mg every other day for 3 weeks.

For the prevention of relapses, the appointment of medicinal yeast Saccharomyces boulardii 250 mg 2 times a day for 4 weeks is indicated.

Comparative characteristics of the clinical features of idiopathic antibiotic-associated diarrhea and antibiotic-associated diarrhea due to C. difficile infection and treatment approaches are presented in Table 1.

Table 1.
Comparative characteristics of idiopathic antibiotic-associated diarrhea and diarrhea associated with infection C. difficile

The possibility of using probiotics in the prevention and treatment of antibiotic-associated diarrhea

Currently, much attention is paid to the study of the effectiveness of various preparations of the probiotic class, which include representatives of the main intestinal microflora.

The therapeutic effect of probiotics is explained by the fact that the microorganisms that make up them replace the functions of their own normal intestinal microflora in the intestine:

• create unfavorable conditions for the reproduction and vital activity of pathogenic microorganisms due to the production of lactic acid, bacteriocins;
• participate in the synthesis of vitamins B 1, B 2, B 3, B 6, B 12, H (biotin), PP, folic acid, vitamins K and E, ascorbic acid;
• create favorable conditions for the absorption of iron, calcium, vitamin D (due to the production of lactic acid and lowering the pH);
• lactobacilli and enterococcus in the small intestine carry out the enzymatic breakdown of proteins, fats and complex carbohydrates (including with lactase deficiency);
• secrete enzymes that facilitate the digestion of proteins in infants (phosphoprotein phosphatase of bifidobacteria is involved in the metabolism of milk casein);
• bifidum bacteria in the colon break down non-absorbed food components (carbohydrates and proteins);
• participate in the metabolism of bilirubin and bile acids (the formation of stercobilin, coprosterol, deoxycholic and lithocholic acids; promote the reabsorption of bile acids).

The complexity of organizing the assessment of the effect and comparison of the actions of various probiotics lies in the fact that at present there are no pharmacokinetic models for the study in humans of complex biological substances consisting of components with different molecular weights and not entering the systemic circulation.

Yet, for some therapeutic organisms, there is compelling evidence for the prevention and treatment of antibiotic-associated diarrhoea.

1. Saccharomyces boulardii at a dose of 1 g / day. prevents the development of antibiotic-associated diarrhea in patients on artificial nutrition through a catheter; they also prevent recurrences of Clostridium difficile infection.
2. The appointment of Lactobacillus GG leads to a significant reduction in the severity of diarrhea.
3. Saccharomyces boulardii in combination with Enterococcus faecium or Enterococcus faecium SF68 have been shown to be effective agents in the prevention of antibiotic associated diarrhea.
4. Enterococcus faecium (10 9 CFU/day) reduces the incidence of antibiotic-associated diarrhea from 27% to 9%.
5. Bifidobacterium longum (10 9 CFU/day) prevents erythromycin-associated disorders of the gastrointestinal tract.
6. In a comparative evaluation of the effectiveness of Lactobacillus GG, Saccharomyces boulardii, Lactobacillus acidophilus, Bifidobacterium lactis: all probiotics were more effective than placebo in the prevention of antibiotic-associated diarrhea.

As a probiotic for preventing the development of antibiotic-associated diarrhea and restoring bowel function after discontinuation of an antibacterial agent, Linex can be recommended. The composition of the drug includes a combination of live lyophilized lactic acid bacteria - representatives of the natural microflora from different parts of the intestine: Bifidobacterium infantis v. liberorum, Lactobacillus acidophilus, Enterococcus faecium. For inclusion in the preparation, strains were selected that are resistant to most antibiotics and chemotherapeutic agents and capable of further reproduction over several generations, even under conditions of antibiotic therapy. Special studies have shown that there is no transfer of resistance from these microbes to other intestinal inhabitants. The composition of Linex can be described as “physiological”, since the composition of the combination includes microbial species belonging to the classes of the main inhabitants of the intestine and playing the most important role in the production of short-chain fatty acids, ensuring epithelial trophism, antagonism against opportunistic and pathogenic microflora. Due to the inclusion in the composition of Linex lactic streptococcus (Enterococcus faecium), which has a high enzymatic activity, the effect of the drug also extends to the upper intestines.

Linex is available in the form of capsules containing at least 1.2x10 7 CFU of live lyophilized bacteria. All three strains of Linex bacteria are resistant to the aggressive environment of the stomach, which allows them to freely reach all sections of the intestine without losing their biological activity. When used in young children, the contents of the capsule can be diluted in a small amount of milk or other liquid.

A contraindication to the appointment of Linex is hypersensitivity to the components of the drug. There are no reports of an overdose of Linex. Side effects are not registered. The conducted studies have shown the absence of a teratogenic effect of lyophilized bacteria. There are no reports of side effects of using Linex during pregnancy and lactation.

Undesirable drug interactions of Linex are not marked. The drug can be used simultaneously with antibiotics and chemotherapeutic agents.

References can be found on the site rmj.ru

The study of the intestinal microflora began in 1886, when F. Escherich described Escherichia coli ( Bacterium coli communae). In 1908, Nobel laureate Russian scientist Ilya Ilyich Mechnikov proved the need for intestinal bacteria for health and longevity. To date, the presence of 500 types of microbes has been established in the intestines of a healthy person. The normal microbial flora is one of the barriers to bacteria entering the intestines. It stimulates the immune defense, increases the secretion of IgA into the intestinal lumen. Escherichia coli, enterococci, bifidobacteria, acidophilus bacilli have antagonistic properties and are able to suppress the growth of pathogenic microorganisms. Violation of the composition of the microflora leads to a decrease in the body's resistance to intestinal infections.

There are mucoid microflora (M-microflora) - microorganisms associated with the intestinal mucosa, and cavity microflora (P-microflora) - microorganisms localized in the intestinal lumen.

In relation to the macroorganism, representatives of the intestinal biocenosis are divided into 4 groups:

obligate microflora (the main intestinal microflora is bifidobacteria, lactobacilli, normal E. coli, propionobacteria, peptostreptococci, enterococci);

optional (conditionally pathogenic and saprophytic microorganisms - bacteroids, staphylococci, streptococci, peptococci, yeast-like fungi, veyonella, fusobacteria, bacilli);

transient (random microorganisms that are not capable of a long stay in the body - flavobacteria, pseudomonads);

pathogenic (causative agents of infectious diseases - shigella, salmonella, yersinia, etc.).

When microbes utilize indigestible carbohydrates (fiber), short-chain fatty acids are formed. They provide the cells of the intestine with energy carriers, improving the trophism of the mucous membrane. An insufficient amount of fiber in the diet leads to a decrease in the synthesis of short-chain fatty acids. As a result, dystrophic changes in the epithelium occur and the permeability of the intestinal barrier for antigens of food and microbial origin increases.

Under the influence of microbial enzymes in the ileum, bile acids (FA) are deconjugated and primary FAs are converted into secondary FAs. Under physiological conditions, 80-95% of the fatty acids are reabsorbed, the rest are excreted in the feces as metabolites. The latter contribute to the formation of fecal masses, inhibit the absorption of water, preventing excessive dehydration of feces. Excessive bacterial colonization of the small intestine leads to premature FA deconjugation and secretory diarrhea.

Thus, the morphological and functional state of the intestine depends on the composition of its microflora.

In the jejunum of healthy people, there are up to 100,000 bacteria per 1 ml of contents. The main part of them are streptococci, staphylococci, lactic acid bacilli. In the distal ileum, the number of microbes increases due to enterococci, Escherichia coli, bacteroides and anaerobic bacteria.

The microbial composition of feces does not reflect the complete picture of the intestinal biocenosis, does not provide operational information about the composition of microorganisms in the intestine. In practice, data on only 15-20 types of microbes contained in feces are taken into account. Usually examine the number of bifidobacteria, lactobacilli, enterobacteria, Escherichia coli, Proteus, Enterococcus, Staphylococcus aureus, Pseudomonas aeruginosa and Candida.

Intestinal dysbiosis - violation of the ecological balance of microorganisms, characterized by a change in the quantitative ratio and qualitative composition of the indigenous microflora in the microbiocenosis. The term "dysbacteriosis" was first introduced by A. Nissle in 1916.

The severity of dysbiosis is determined by the degree of decrease in bifidobacteria and other obligate microorganisms and the increase in the number of opportunistic and pathogenic species.

I degree - decrease in the number of obligate representatives (bifidobacteria and / or lactobacilli) by 1-2 orders of magnitude, without an increase in opportunistic microflora (OPM), an increase in the number of OPM with a normal number of bifidobacteria. II degree - moderate or significant decrease in the number of bifidobacteria, combined with pronounced changes in the aerobic microflora (reduction of lactobacilli, the appearance of altered forms of Escherichia coli, UPM in high quantities). III degree - a large number of UPM, both of the same species and in associations, the isolation of pathogenic microorganisms (Mekhtiev S. N., Grinevich V. B., Zakharenko S. M.).

In the clinic of dysbiosis, the following key syndromes are distinguished:

Dyspeptic (decreased appetite, regurgitation, belching, nausea, vomiting);

Intestinal syndrome (bloating, rumbling of the intestines, a tendency to constipation or loose stools with undigested food residues);

Secondary malabsorption syndrome (persistent diarrhea with malabsorption of monosaccharides, electrolytes),

Polyhypovitaminosis (dry skin, hair loss, brittle nails, cheilitis, stomatitis).

New approaches in the diagnosis of dysbiosis

An alternative to routine bacteriological studies is the chemical methods of differentiation of microorganisms and, in particular, gas chromatography (GC) in combination with mass spectrometry (GC-MS). The method is based on the determination of the components of bacterial cells that appear as a result of their natural death or attack by the immune system. Minor lipid components of microbial membranes are used as markers. According to their content, up to 170 species of bacteria and fungi in various biological media can be determined within a few hours.

Almost 50% of the biomass of the parietal microflora are actinomycetes, which occupy an intermediate position between bacteria and fungi. About 25% of the microbial flora is represented by aerobic cocci (staphylococci, streptococci, enterococci and coryneform bacteria). The number of bifido- and lactobacilli ranges from 20 to 30%. Other anaerobes (Peptostreptococci, Bacteroids, Clostridia, Propionobacteria) make up about 10% in the small intestine and up to 20% in the large intestine. The share of enterobacteria accounts for 1% of the total number of microflora of the mucous membrane.

Up to 90-95% of colon microbes are anaerobes (bifidobacteria and bacteroids) and only 5-10% of all bacteria are strict aerobic and facultative flora (lactic acid and Escherichia coli, enterococci, staphylococci, fungi, proteus).

Dysbiosis is not an independent disease. Its appearance is promoted by disorders of intestinal digestion, motility, local immunity, antibiotics, antacids and other drugs. It is necessary to establish the cause that caused dysbiosis, and not try to "cure" the intestinal microflora, based on its bacteriological analysis of feces.

The properties of the microbes that inhabit the intestines are not always taken into account when prescribing antibiotics. Antibacterial drugs inhibit the growth of not only pathogenic microorganisms, but also normal microflora. As a result, saprophytic microbes with high resistance to drugs multiply, acquiring pathogenic properties.

Diarrhea associated with antibiotic use

Patients receiving antibiotic therapy may develop diarrhea caused by intestinal dysbiosis (AAD - antibiotic-associated diarrhea). The frequency of such diarrhea ranges from 5-25%. The reason for it is a decrease in the number of microbes sensitive to the antibiotic, and the emergence of resistant strains that are absent in the norm. The most famous representative of such microorganisms is the pathogenic strain Clostridium difficile (Cl. difficile), but other microbes that can increase the secretion of ions and water and damage the intestinal wall can also be the cause of antibiotic-associated diarrhea. These are staphylococci, proteus, yeast fungi, enterococci, Pseudomonas aeruginosa, Klebsiella. According to the type of diarrhea, AAD is usually referred to as secretory and inflammatory types.

Antibiotic-associated diarrhea is most commonly caused by lincomycin, ampicillin, clindamycin, benzylpenicillin, cephalosporins, tetracyclines, and erythromycin. The route of administration of the antibiotic is not of great importance. When taken orally, in addition to the eradication of microorganisms, the effect of the antibiotic on the mucous membrane of the small intestine occurs. When administered parenterally, antibiotics affect the intestinal biocenosis, excreted with saliva, bile, secretions of the small and large intestines.

Symptoms of AAD in most patients usually appear during treatment, and in 30% - within 7-10 days after its termination.

Most researchers consider clostridia to be the etiological factor of AAD, in particular Cl. difficile. Among the adult population, the level of its carriage is low and is equal to 2-3%. breeding conditions Cl. difficile are an anaerobic environment and inhibition of normal intestinal microflora.

Clinical manifestations of AAD range from mild diarrhea to severe pseudomembranous colitis (PMC). MVP is an acute bowel disease that is a complication of antibiotic therapy. Found to cause it Cl. difficile.

Symptoms

The main symptom of AAD is profuse watery diarrhea, preceded by the administration of antibiotics for several days or more. Then there are cramping pains in the abdomen, subsiding after a stool. In cases where fever occurs, leukocytosis increases in the blood, and leukocytes appear in the feces, MVP should be suspected.

After discontinuation of the antibiotic in a number of patients, the symptoms quickly disappear. With MVP, despite the cessation of antibiotic therapy, in most cases the frequency of stool increases, dehydration and hypoproteinemia appear. In severe cases, dehydration quickly sets in, toxic expansion and perforation of the colon develop, and death is possible.

Diagnosis

The diagnosis of AAD is based on the association of diarrhea with antibiotic use. The diagnosis of MVP is confirmed by bacteriological examination of feces and the determination of the toxin in it. Cl. difficile. The frequency of detection of toxin in the feces of patients with AAD does not exceed 15%.

In patients with diarrhea associated with Cl. difficile significant leukocytosis. There is evidence that in patients with leukocytosis 15800 and above, there is a high probability of developing MVP caused by Cl. difficile. This is because toxin A, secreted by Cl. difficile causes inflammation, fluid secretion, fever and convulsions. Therefore, in all patients with AAD occurring with intoxication and leukocytosis of 15800 and above, it should be considered the cause of diarrhea Cl. difficile.

Parfenov A. I., Osipov G. A., Bogomolov P. O. used the GC-MS method to assess the composition of the microbial flora of the small intestine in 30 patients with AAD and found that diarrhea can be associated not only with an infectious agent ( Cl. difficile), but with a significant change in the normal microflora towards an increase in numbers from 7 to 30 out of 50 controlled microorganisms. At the same time, the overall colonization of the small intestine increases by 2-5 times compared with the norm.

In patients with AAD, morphological changes in the large intestine are most often absent. In severe cases, endoscopy reveals 3 types of changes: 1) catarrhal inflammation (edema and hyperemia) of the mucous membrane; 2) erosive-hemorrhagic lesion; 3) pseudomembranous lesion.

The endoscopic picture of PMK is characterized by the presence of plaque-like, ribbon-like and solid "membranes", soft, but tightly soldered to the mucous membrane. Changes are most pronounced in the distal colon and rectum. The mucous membrane is edematous, but not ulcerated. Histological examination revealed subepithelial edema with round cell infiltration of the lamina propria, capillary stasis with erythrocytes escaping beyond the vessels. At the stage of formation of pseudomembranes, infiltrates form under the surface epithelium of the mucous membrane. The epithelial layer rises and is absent in some places: the exposed places of the mucous membrane are covered only by desquamated epithelium. In the later stages of the disease, these areas may occupy large segments of the intestine.

Differential Diagnosis

Association of diarrhea with antibiotic therapy usually does not create difficulties in the diagnosis of AAD. In severe cases, the picture of MVP may resemble cholera or the fulminant form of ulcerative colitis, Crohn's disease. However, the latter are characterized by more or less pronounced bloody diarrhea, uncharacteristic of MVP. Nevertheless, the possibility of developing erosive-hemorrhagic changes in the mucous membrane in AAD does not exclude the appearance of bloody discharge from the rectum in some patients.

AAD treatment

Etiotropic therapy of AAD and MVP caused by Cl. difficile, most authors consider the appointment of vancomycin and metronidazole (trichopolum, metrogil).

Immediately cancel the antibiotic that caused diarrhea. Assign vancomycin at an initial dose of 125 mg orally 4 times a day, if necessary, the dose is increased to 500 mg 4 times a day. Treatment is continued for 7-10 days. Metronidazole is given at 0.5 g orally 2 times a day (or 0.25 g 4 times a day).

Bacitracin is also used at 25 thousand IU orally 4 times a day. Treatment is carried out within 7-10 days. Bacitracin is almost not absorbed, and therefore a high concentration of the drug is created in the colon. With dehydration, infusion therapy and oral rehydration are used (Regidron, Citroglucosolan). Cholestyramine is prescribed to bind toxin A.

There are reports of the possibility of treating AAD with high doses of probiotics as well. S. Perskyp and L. Brandt (2000) found that the normal human microflora is able to eliminate diarrhea caused by Cl. difficile. The bactericidal action of normal microflora ensures the recovery of more than 95% of patients with AAD associated with Cl. difficile. It prevents the occurrence of chronic clostridial and other infections, which can cause chronic gastrointestinal disorders in some patients. Probiotic therapy for AAD and MVP should be started as early as possible, without waiting for confirmation of the diagnosis.

Since the number of microbes that provide a therapeutic effect is several orders of magnitude higher than the doses of conventional bacterial preparations, the issue of local delivery of probiotics to the intestine is being discussed. This can be done with saline enemas, through a nasoduodenal tube, or through a colonoscope. The latter method attracts attention, because in this case probiotics are injected directly into the proximal colon.

One of the main probiotic preparations used for the treatment of AAD is Linex. This is a combined preparation containing components of the natural microflora from different parts of the intestine. The bifidobacteria, lactobacilli and non-toxigenic lactic enterococcus that are part of the composition maintain the balance of the intestinal microflora and ensure its physiological functions: create unfavorable conditions for the reproduction and vital activity of pathogenic microorganisms; participate in the synthesis of vitamins B 1, B 2, PP, folic acid, vitamins K and E, ascorbic acid, provide the body's need for vitamins B 6, B 12 and biotin; producing lactic acid and lowering the pH of the intestinal contents, they create favorable conditions for the absorption of iron, calcium, vitamin D. Lactic acid bacteria carry out the enzymatic breakdown of proteins, fats and complex carbohydrates, carbohydrates and proteins that are not absorbed in the small intestine undergo deeper cleavage in the large intestine by anaerobes ( including bifidobacteria). The bacteria that make up the drug are involved in the metabolism of bile acids.

Linex contains lactic acid bacteria that are resistant to antibiotics. Adults and children over 12 years of age are prescribed 2 capsules 3 times / day after meals with a small amount of liquid. The duration of treatment is on average 1-2 months. When using the drug in recommended doses, no side effects were noted. Contraindications - hypersensitivity to the components of the drug or dairy products. The conducted studies did not reveal the presence of a teratogenic effect in Linex, there were no reports of a negative effect of the drug during pregnancy and lactation. To preserve the viability of the components of the drug, it is not recommended to drink Linex with hot drinks, you should refrain from drinking alcohol.

The clinical manifestations of an allergy to lactic acid bacteria are similar to those of an allergy to dairy products, therefore, if symptoms of an allergy appear, the drug should be discontinued to determine its causes. No cases of Linex overdose have been reported. Its undesirable interaction with other drugs was not noted. The composition of the drug Linex allows you to take it simultaneously with antibacterial agents.

For the symptomatic treatment of diarrhea, the following are also used: adsorbent attapulgite, 1.2-1.5 g after each liquid stool; loperamide, 2-4 mg orally after each bowel movement (no more than 8 mg / day); diphenoxylate/atropine (Lomotil) 5 mg orally 4 times a day until diarrhea stops; belladonna tincture, 5-10 drops inside 3 times a day before meals; hyoscyamine (Levsin) 0.125 mg sublingually as needed or 0.375 mg orally 2 times a day; antispasmodic dicycloverine, 20 mg orally 4 times a day; codeine, 30 mg orally 2-4 times a day; octreotide (100-600 mg / day s / c in 2-4 doses) - a synthetic analogue of somatostatin; enterosorbents (Smecta, Espumizan).

Treatment of dysbiosis itself

Standard therapy for dysbiosis is aimed at eliminating excessive bacterial colonization of the small intestine, restoring normal microflora, improving intestinal digestion and absorption, restoring intestinal motility and increasing the body's immunoreactivity.

Antibacterial drugs are used according to indications to suppress the growth of pathogenic microflora in the small intestine. Usually prescribed antibiotics from the group of fluoroquinolones, penicillins, cephalosporins, tetracyclines or metronidazole. The drugs are taken orally in usual doses for 7-10 days.

It is optimal to use agents that have a minimal effect on the symbiotic microflora and inhibit the growth of Proteus, staphylococci, yeast fungi and other aggressive strains. These include antiseptics: Intetrix, Enterol, Bactisubtil, Nifuroxazide, etc. In severe forms of staphylococcal dysbiosis, antibiotics are used: ofloxacin, oxacillin, amoxicillin. They are prescribed for a period of 10-14 days. In the case of the appearance of fungi in the feces or intestinal juice, the use of natamycin, fluconazole and other mycostatics is indicated.

Bacterial preparations (probiotics) can be prescribed without prior antibiotic therapy or after it. Bifidumbacterin, Probifor, Bifikol, Lactobacterin, Linex, Bifiform, Normoflorins L, D, B, Polibakterin, Narine, Acipol, Nutrolin B, Travis are used.

Another way to treat dysbiosis is to influence the pathogenic microbial flora with metabolic products of normal microorganisms (prebiotics). One of these drugs is Hilak-forte, a sterile concentrate of metabolic products of normal microflora: lactic acid, lactose, amino acids and fatty acids. These substances contribute to the restoration of the biological environment in the intestine, necessary for the existence of normal microflora, inhibit the growth of pathogenic bacteria, improve trophism and function of epitheliocytes and colonocytes. One milliliter of the drug contains the biologically active substances of 100 billion normal microorganisms. Hilak-forte is prescribed 60 drops 3 times a day for a period of 4 weeks in combination with antibacterial drugs or after their use.

In addition, lactulose syrup (Duphalac, Portalac) is used, which acidifies intestinal juice and inhibits the growth of pathogenic microflora. The active substance is a synthetic disaccharide that is not hydrolyzed in the small intestine and enters the colon unchanged, where it is cleaved under the action of the colon flora with the formation of low molecular weight organic acids, which leads to a decrease in the pH of the intestinal contents.

Under the action of the drug, the absorption of ammonia by the colon and its excretion from the body increases, the growth of acidophilic bacteria (including lactobacilli) is stimulated, the reproduction of proteolytic bacteria is suppressed and the formation of nitrogen-containing toxic substances is reduced. The clinical effect occurs after 2 days of treatment. The drug in the form of a syrup for oral administration is prescribed to adults at a dose of 15-45 ml / day, the maintenance dose is 10-25 ml / day. The drug should be taken 1 time / day in the morning with food, with water, any other liquid or food.

Side effects from the digestive system: in the first days - flatulence (passing on its own after 2 days); with prolonged use in high doses, abdominal pain, diarrhea are possible. Contraindications: galactosemia; intestinal obstruction; hypersensitivity to the components of the drug. Lactulose can be used during pregnancy and lactation according to indications. The drug should be used with caution in diabetic patients.

Of the other prebiotics, calcium pantothenate should be noted (participates in the processes of acetylation and oxidation in cells, carbohydrate and fat metabolism, the synthesis of acetylcholine, is utilized by bifidobacteria and contributes to an increase in their mass), aminomethylbenzoic acid (Pamba, Amben) is an inhibitor of fibrinolysis, inhibits proteolytic enzymes conditionally pathogenic bacteria, stimulating the growth of normal microflora, lysozyme (has a bifidogenic, immunomodulatory, anti-inflammatory effect, improves digestion, suppresses pathogenic flora).

In the treatment of dysbiosis, it is recommended to use herbal remedies. They are intestinal antiseptics, suppress pathogenic and preserve saprophytic microflora. Herbal teas normalize appetite, improve digestion, intestinal motility, have antimicrobial and immunomodulatory effects, and promote mucosal regeneration. St. John's wort, calendula, eucalyptus, yarrow, cinquefoil, sage, oregano, cowberry, plantain give a pronounced bactericidal effect. Nettle, lemon balm, coltsfoot, plantain, tricolor violet, string have an immunocorrective effect. Cowberries, nettles, raspberries, currants, mountain ash, rose hips are rich in vitamins.

Patients with impaired abdominal digestion are prescribed pancreatic enzymes (Creon, Pancitrate). In order to improve the absorption function, Essentiale forte H, loperamide (Imodium) and trimebutine are used.

To increase the reactivity of the organism in debilitated patients with severe dysbiosis, it is advisable to prescribe Anaferon, Immunal, Likopid and other immunomodulators. The course of treatment should last an average of 4 weeks. At the same time, vitamin-mineral complexes are prescribed (Vitamineral, Alphabet, etc.).

For literature inquiries, please contact the editor.

V. V. Skvortsov, Doctor of Medical Sciences
VolGMU, Volgograd

This is a disease that is characterized by the appearance of unformed stools during or after taking antibacterial drugs. The disease is accompanied by dyspeptic symptoms (loose stools, gas formation). In severe cases, intense abdominal pain, weakness, fever appear. Diagnosis is based on the establishment of a connection between the intake of antibiotics and the development of diarrhea. Additionally, fecal analysis, endoscopic examination of the intestine are carried out. Treatment involves the abolition of AB, the appointment of probiotics and detoxification drugs. If the causative agent of the disease is detected, etiotropic antibiotic therapy is carried out.

ICD-10

K91.8 Other disorders of the digestive system following medical procedures, not elsewhere classified

General information

Antibiotic-associated diarrhea (AAD, nosocomial colitis) - three or more episodes of loose stools, recurring for at least two days and associated with taking antibacterial drugs (AB). The disorder can manifest itself within 4 weeks after the abolition of AB. In developed countries, bowel disease is the most common response to antibiotic therapy, with AAD occurring in 5-30% of cases in people taking antibiotics. Pathology proceeds both in a mild self-limiting form and in the form of severe protracted colitis. In modern gastroenterology, at least 70% of cases are due to idiopathic AAD, 30% - to Clostridium difficile-associated diarrhea. The disease affects men and women equally.

Causes of AAD

Antibiotic-associated diarrhea often develops after the appointment of penicillin antibiotics, tetracyclines, cephalosporins. The route of drug administration has little to no effect on the likelihood of diarrhea. When taken orally, medications affect the mucous layer of the gastrointestinal tract. When administered parenterally, AB metabolites are excreted in bile and saliva, affecting the obligate microflora. Taking into account the causes of the disease, there are 2 forms of AAD:

1. idiopathic(IAAD). It develops as a result of the negative impact of AB on the eubiosis of the gastrointestinal tract. The influence of pathogenic microorganisms on the gastrointestinal tract is one of the possible causes of the development of this disease. Among the variety of pathogens, staphylococci, proteus, enterococci, clostridia, fungi are often found. The risk of AAD increases with prolonged (more than 10 days), frequent and incorrect intake of AB (exceeding the dose).
2. Clostridium difficile-associated diarrhea(C. difficile-AD). Etiologically associated with a violation of the microflora and excessive colonization of the gastrointestinal tract by opportunistic bacteria Clostridium difficile. Dysbacteriosis occurs as a result of taking antibiotics from the group of cephalosporins, amoxicillin, lincomycin. There are known cases of the development of an intrahospital antibiotic-associated infection by transmitting the pathogen through personal hygiene products (towels, soap, dishes), medical instruments with poor-quality processing.

In addition to the direct effect of antibacterial agents on the intestinal wall, there are risk factors that increase the likelihood of developing the disease. These include childhood and old age, the presence of severe somatic pathology (heart, kidney failure), uncontrolled intake of antacids, congenital and acquired immunodeficiency states, surgical interventions in the abdominal cavity, tube nutrition. Chronic diseases of the gastrointestinal tract (Crohn's disease, ulcerative colitis) also contribute to the occurrence of antibiotic-associated colitis.

Pathogenesis

Antimicrobial drugs reduce the growth and reproduction of not only pathogenic, but also symbiotic microorganisms. There is a decrease in the obligate intestinal microflora, dysbacteriosis develops. This fact underlies the pathogenesis of both types of antibiotic-associated diarrhea. In the idiopathic form, increased intestinal motility, toxic damage to the mucous membrane, or impaired metabolic processes in the intestine also play a role.

Antibiotic-associated clostridial colitis occurs due to changes in the composition of the endogenous normoflora of the gastrointestinal tract when taking III and IV generation cephalosporins, fluoroquinolones, penicillins. Dysbacteriosis contributes to the reproduction of C. Difficile, which secrete 2 types of toxins (A and B) in large quantities. Being in the lumen of the gastrointestinal tract, enterotoxins destroy epitheliocytes and cause inflammatory changes in the intestinal wall. Colitis mainly affects the large intestine with the formation of diffuse hyperemia and swelling of the mucosa. The wall of the gastrointestinal tract thickens, plaques of fibrin are formed, which look like yellowish plaques (pseudomembranes).

Classification

There are two forms of idiopathic antibiotic-associated diarrhea: infectious and non-infectious. Among the causative agents of the infectious form of AAD, Clostridium perfringens, Staphylococcus aureus, Salmonella, Klebsiella, and fungi of the genus Candida are often found. Non-infectious IAAD is represented by the following types:

• hyperkinetic. Clavulanate and its metabolites increase the motor activity of the gastrointestinal tract, the intake of macrolides causes a contraction of the duodenum and antrum of the stomach. These factors contribute to the appearance of an unformed stool.
• Hyperosmolar. It develops due to partial absorption of AB (cephalosporins) or in violation of carbohydrate metabolism. Carbohydrate metabolites accumulate in the intestinal lumen, causing increased secretion of electrolytes and water.
• Secretory. It is formed due to a violation of intestinal eubiosis and deconjugation of bile acids. Acids stimulate the release of water and chlorine salts into the intestinal lumen, the consequence of these processes is frequent unformed stools.
• toxic. It is formed due to the negative impact of metabolites of penicillins and tetracyclines on the intestinal mucosa. Dysbacteriosis and diarrhea develop.

Manifestations of C. difficile AD can vary from asymptomatic carriage to fulminant and severe forms. Depending on the clinical picture, endoscopy data, the following types of antibiotic-associated clostridial infection are distinguished:

• Diarrhea without colitis. It manifests itself as an unformed stool without intoxication and abdominal syndromes. The intestinal mucosa is not changed.
• Colitis without pseudomembranes. It is characterized by a detailed clinical picture with moderate dehydration and intoxication. In endoscopic examination, catarrhal inflammatory changes in the mucous membrane are observed.
• Pseudomembranous colitis(PMK). This disease is characterized by severe intoxication, dehydration, frequent watery stools and abdominal pain. During colonoscopy, fibrinous plaque and erosive-hemorrhagic changes in the mucosa are determined.
• Fulminant colitis. The most severe form of antibiotic-associated gastrointestinal disorder. It develops at lightning speed (from several hours to a day). Causes serious gastroenterological and septic disorders.

Symptoms of AAD

In idiopathic antibiotic-associated diarrhea, symptoms occur during (in 70% of patients) or after antibiotic treatment is stopped. The main, sometimes the only, manifestation of the disease is unformed stools up to 3-7 times a day without impurities of blood and pus. Pain and a feeling of fullness in the abdomen, flatulence due to increased work of the gastrointestinal tract are rarely noted. The disease proceeds without fever and symptoms of intoxication.

Unlike the idiopathic form, the clinical spectrum of manifestations of Clostridium difficile AD varies from asymptomatic colitis to severe fatal forms of the disease. Bacteriocarrier is expressed by the absence of symptoms and the release of clostridium into the environment with feces. The mild course of the disease is characterized only by loose stools without fever and severe abdominal syndrome. More often observed C. difficile-associated colitis of moderate severity, which is manifested by fever, periodic cramping pain in the umbilical region, repeated diarrhea (10-15 times / day).

The severe course of the disease (PMC) is characterized by frequent (up to 30 times / day) copious watery stools with a fetid odor. Feces may contain impurities of mucus and blood. The disease is accompanied by intense abdominal pain, which disappears after the act of defecation. Patients have a deterioration in their general condition, severe weakness and an increase in temperature up to 38-39°C. In 2-3% of cases, a fulminant form of the disease is recorded, which is manifested by a rapid increase in symptoms, severe intoxication, and the appearance of early severe complications of antibiotic-associated diarrhea.

Complications

Idiopathic AAD responds well to treatment and does not cause complications in patients. Diarrhea caused by C. difficile leads to a persistent decrease in blood pressure, the development of electrolyte disturbances and dehydration. Losses of protein and water contribute to the occurrence of edema of the lower extremities and soft tissues. Further development of the disease provokes the appearance of megacolon, manifestations of the gastrointestinal mucosa up to colon perforation, peritonitis and sepsis. Lack of timely diagnosis and pathogenetic treatment leads to death in 15-30% of cases.

Diagnostics

With the appearance of abundant liquid stools and abdominal discomfort, causing suspicion of the development of antibiotic-associated diarrhea, consultation with a gastroenterologist is required. The specialist, using the study of the anamnesis of life and disease, physical examination, data from laboratory and instrumental examinations, will draw up an appropriate conclusion.

To diagnose idiopathic antibiotic-associated diarrhea, it is sufficient to identify the relationship between taking antibiotics and the onset of diarrhea, and to exclude comorbidities of the gastrointestinal tract. In this case, laboratory parameters remain normal, there are no changes in the intestinal mucosa. If Clostridium difficile-associated diarrhea is suspected, the following methods are used to confirm the diagnosis:

• Laboratory blood tests. In the general blood test, leukocytosis, an increase in ESR, anemia are noted; in biochemical - hypoproteinemia.
• Examination of feces. In the coprogram, leukocytes and erythrocytes are found. The main diagnostic criterion for the disease is the identification of the pathogen in the feces. The diagnostics of choice are the cytopathogenic test (CT) and the toxin neutralization test (RNT), which determine toxin B. The enzyme immunoassay (ELISA) method is sensitive to A and B-endotoxins. Polymerase chain reaction (PCR) is used to identify the genes encoding toxins. The cultural method allows you to detect clostridia in the sowing of feces.
• Colon endoscopy. Colonoscopy is performed to visualize pathological changes in the intestine (pseudomembranes, fibrin films, erosions). Endoscopic diagnosis in severe colitis can be dangerous due to the risk of bowel perforation.

Diagnosis of antibiotic-associated stool disorder is usually not difficult. The idiopathic form of the disease is differentiated from mild food poisoning. Clinic C. difficile-associated diarrhea, namely pseudomembranous colitis, may resemble the course of cholera, Crohn's disease, ulcerative colitis and severe food poisoning. Additionally, a survey radiography of the abdominal cavity, CT scan of the large intestine is performed.

AAD treatment

Treatment of non-clostridial antibiotic-associated diarrhea involves the abolition or reduction of the dose of the antibacterial agent, the appointment of antidiarrheal drugs (loperamide), eubiotics and probiotics (lactobacilli, bifidobacteria). With multiple episodes of loose stools, it is advisable to normalize the water-salt balance.

Identification of Clostridium difficile is an indication for the abolition of antibiotics and the appointment of etiotropic, symptomatic and detoxification therapy. The drug of choice for the treatment of the disease is metronidazole. In severe cases and with intolerance to metronidazole, vancomycin is prescribed. Correction of dehydration and intoxication is carried out by parenteral administration of water-salt solutions (acesol, Ringer's solution, rehydron, etc.).

The complex therapy of clostridial colitis includes the use of enterosorbents, probiotics. The latter are prescribed after etiotropic therapy to restore the normoflora of the intestine in a course of 3-4 months. With complications of MVP (intestinal perforation, megacolon, recurrent progressive course of colitis), surgical treatment is indicated. Perform resection of part or all of the colon (hemicolectomy, colectomy).

Forecast and prevention

The prognosis of idiopathic AAD is favorable. The disease can stop on its own after the abolition of antibiotics and does not require specific treatment. With timely diagnosis and adequate treatment of pseudomembranous colitis, it is possible to achieve a complete recovery. Severe forms of diarrhea, ignoring the symptoms of the disease can lead to complications both from the gastrointestinal tract and the whole body.

Rational antibiotic therapy involves taking medications according to strict indications only when prescribed by a doctor and under his close supervision. Prevention of antibiotic-associated diarrhea includes the use of probiotics to maintain the normal microflora of the gastrointestinal tract, rational nutrition and maintaining an active lifestyle.