Antimicrobial agents. Classification of antimicrobial drugs

Antimicrobial agents. Classification of antimicrobial drugs

According to the spectrum of activity, antimicrobial drugs are divided into: antibacterial, antifungal and antiprotozoal. In addition, all antimicrobial agents are divided into drugs with a narrow and wide spectrum of action.

Narrow-spectrum drugs primarily targeting gram-positive microorganisms include, for example, natural penicillins, macrolides, lincomycin, fusidine, oxacillin, vancomycin, and first-generation cephalosporins. Narrow-spectrum drugs primarily targeting gram-negative bacilli include polymyxins and monobactams. Broad-spectrum drugs include tetracyclines, chloramphenicol, aminoglycosides, most semisynthetic penicillins, cephalosporins starting from the 2nd generation, carbopenems, fluoroquinolones. The antifungal drugs nystatin and levorin (only against candida) have a narrow spectrum, and clotrimazole, miconazole, amphotericin B have a wide spectrum.

According to the type of interaction with the microbial cell, antimicrobial drugs are divided into:

· bactericidal – irreversibly disrupt the functions of the microbial cell or its integrity, causing immediate death of the microorganism, used for severe infections and in weakened patients,

· bacteriostatic – reversibly block cell replication or division, used for mild infections in non-weakened patients.

According to acid resistance, antimicrobial drugs are classified into:

acid-resistant - can be used orally, for example, phenoxymethylpenicillin,

· acid-labile – intended only for parenteral use, for example, benzylpenicillin.

Currently, the following main groups of antimicrobial drugs are used for systemic use.

¨ Lactam antibiotics

Lactam antibiotics ( Table 9.2) of all antimicrobial drugs are the least toxic, since, by disrupting the synthesis of the bacterial cell wall, they have no target in the human body. Their use in cases where pathogens are sensitive to them is preferable. Carbapenems have the widest spectrum of action among lactam antibiotics; they are used as reserve drugs - only for infections resistant to penicillins and cephalosporins, as well as for hospital-acquired and polymicrobial infections.

¨ Antibiotics of other groups

Antibiotics of other groups ( Table 9.3) have different mechanisms of action. Bacteriostatic drugs disrupt the stages of protein synthesis on ribosomes, while bactericidal drugs disrupt either the integrity of the cytoplasmic membrane or the process of DNA and RNA synthesis. In any case, they have a target in the human body, therefore, compared to lactam drugs, they are more toxic, and should be used only when it is impossible to use the latter.

¨ Synthetic antibacterial drugs

Synthetic antibacterial drugs ( Table 9.4 ) also have different mechanisms of action: inhibition of DNA gyrase, disruption of the incorporation of PABA into DHPA, etc. Also recommended for use when it is impossible to use lactam antibiotics.

¨ Side effects of antimicrobial drugs,

their prevention and treatment

Antimicrobial drugs have a wide variety of side effects, some of which can lead to serious complications and even death.

Allergic reactions

Allergic reactions can occur when using any antimicrobial drug. Allergic dermatitis, bronchospasm, rhinitis, arthritis, Quincke's edema, anaphylactic shock, vasculitis, nephritis, lupus-like syndrome may develop. Most often they are observed with the use of penicillins and sulfonamides. Some patients develop cross-allergy to penicillins and cephalosporins. Allergies to vancomycin and sulfonamides are often observed. Very rarely, aminoglycosides and chloramphenicol cause allergic reactions.

Prevention is facilitated by a thorough collection of allergy history. If the patient cannot indicate which antibacterial drugs he had allergic reactions to, tests must be performed before administering antibiotics. The development of an allergy, regardless of the severity of the reaction, requires immediate discontinuation of the drug that caused it. Subsequently, the introduction of even antibiotics with a similar chemical structure (for example, cephalosporins for allergies to penicillin) is allowed only in cases of extreme necessity. Treatment of infection should be continued with drugs from other groups. In case of severe allergic reactions, intravenous administration of prednisolone and sympathomimetics and infusion therapy are required. In mild cases, antihistamines are prescribed.

Irritant effect on routes of administration

When administered orally, the irritant effect can be expressed in dyspepsia, and when administered intravenously, it can result in the development of phlebitis. Thrombophlebitis is most often caused by cephalosporins and glycopeptides.

Superinfection, including dysbacteriosis

The likelihood of dysbacteriosis depends on the breadth of the spectrum of action of the drug. The most common candidomycosis develops when using narrow-spectrum drugs after a week, when using broad-spectrum drugs - already from one tablet. However, cephalosporins cause fungal superinfection relatively rarely. Lincomycin ranks first in the frequency and severity of dysbiosis caused. Disorders of the flora during its use can take the form of pseudomembranous colitis - a severe intestinal disease caused by clostridia, accompanied by diarrhea, dehydration, electrolyte disturbances, and in some cases complicated by perforation of the colon. Glycopeptides can also cause pseudomembranous colitis. Tetracyclines, fluoroquinolones, and chloramphenicol often cause dysbacteriosis.

Dysbacteriosis requires discontinuation of the drug used and long-term treatment with eubiotics after preliminary antimicrobial therapy, which is carried out based on the sensitivity of the microorganism that caused the inflammatory process in the intestine. Antibiotics used to treat dysbiosis should not affect the normal intestinal autoflora - bifidobacteria and lactobacilli. However, the treatment of pseudomembranous colitis uses metronidazole or, alternatively, vancomycin. Correction of water and electrolyte imbalances is also necessary.

Impaired tolerance to alcohol is common to all lactam antibiotics, metronidazole, and chloramphenicol. It is manifested by the appearance of nausea, vomiting, dizziness, tremor, sweating and a drop in blood pressure when drinking alcohol simultaneously. Patients should be warned not to drink alcohol during the entire period of treatment with an antimicrobial drug.

Organ-specific side effects for various groups of drugs:

· Damage to the blood system and hematopoiesis - inherent in chloramphenicol, less commonly lincosomides, 1st generation cephalosporins, sulfonamides, nitrofuran derivatives, fluoroquinolones, glycopeptides. Manifested by aplastic anemia, leukopenia, thrombytopenia. It is necessary to discontinue the drug, in severe cases, replacement therapy. Hemorrhagic syndrome can develop with the use of 2-3 generation cephalosporins, which impair the absorption of vitamin K in the intestine, antipseudomonal penicillins, which impair platelet function, and metronidazole, which displaces coumarin anticoagulants from bonds with albumin. Vitamin K preparations are used for treatment and prevention.

· Liver damage – inherent in tetracyclines, which block the enzyme system of hepatocytes, as well as oxacillin, aztreonam, lincosamines and sulfonamides. Macrolides and ceftriaxone can cause cholestasis and cholestatic hepatitis. Clinical manifestations are an increase in liver enzymes and bilirubin in the blood serum. If it is necessary to use hepatotoxic antimicrobial agents for more than a week, laboratory monitoring of the listed indicators is necessary. In case of an increase in AST, ALT, bilirubin, alkaline phosphatase or glutamyl transpeptidase, treatment should be continued with drugs of other groups.

· Damage to bones and teeth is typical for tetracyclines, growing cartilage – for fluoroquinolones.

· Kidney damage is inherent in aminoglycosides and polymyxins that disrupt tubular function, sulfonamides that cause crystalluria, generation cephalosporins that cause albuminuria, and vancomycin. Predisposing factors are old age, kidney disease, hypovolemia and hypotension. Therefore, when treating with these drugs, preliminary correction of hypovolemia, control of diuresis, and selection of doses taking into account renal function and body mass are necessary. The course of treatment should be short.

· Myocarditis is a side effect of chloramphenicol.

· Dyspepsia, which is not a consequence of dysbacteriosis, is typical when using macrolides that have prokinetic properties.

· Various lesions of the central nervous system develop from many antimicrobial drugs. Observed:

- psychoses during treatment with chloramphenicol,

- paresis and peripheral paralysis when using aminoglycosides and polymyxins due to their curare-like action (therefore they cannot be used simultaneously with muscle relaxants),

- headache and central vomiting when using sulfonamides and nitrofurans,

- convulsions and hallucinations when using aminopenicillins and cephalosporins in high doses, resulting from the antagonism of these drugs with GABA,

- convulsions when using imipenem,

- agitation when using fluoroquinolones,

- meningism when treated with tetracyclines due to their increase in cerebrospinal fluid production,

- visual impairment during treatment with aztreonam and chloramphenicol,

- peripheral neuropathy when using isoniazid, metronidazole, chloramphenicol.

· Hearing damage and vestibular disorders are a side effect of aminoglycosides, more characteristic of the 1st generation. Since this effect is associated with the accumulation of drugs, the duration of their use should not exceed 7 days. Additional risk factors include old age, renal failure and concomitant use of loop diuretics. Vancomycin causes reversible changes in hearing. If there are complaints of hearing loss, dizziness, nausea, or unsteadiness when walking, it is necessary to replace the antibiotic with drugs from other groups.

· Skin lesions in the form of dermatitis are characteristic of chloramphenicol. Tetracyclines and fluoroquinolones cause photosensitivity. Physiotherapeutic procedures are not prescribed during treatment with these drugs, and exposure to the sun should be avoided.

· Hypofunction of the thyroid gland is caused by sulfonamides.

· Teratogenicity is inherent in tetracyclines, fluoroquinolones, and sulfonamides.

· Paralysis of the respiratory muscles is possible with rapid intravenous administration of lincomycin and cardiodepression with rapid intravenous administration of tetracyclines.

· Electrolyte disturbances are caused by antipseudomonal penicillins. The development of hypokalemia is especially dangerous in the presence of diseases of the cardiovascular system. When prescribing these drugs, monitoring of ECG and blood electrolytes is necessary. In treatment, infusion-corrective therapy and diuretics are used.

Microbiological diagnostics

The effectiveness of microbiological diagnostics, which is absolutely necessary for the rational selection of antimicrobial therapy, depends on compliance with the rules for collection, transportation and storage of the test material. Rules for collecting biological material include:

- taking material from the area as close as possible to the source of infection,

— prevention of contamination by other microflora.

Transportation of the material must, on the one hand, ensure the viability of bacteria, and on the other hand, prevent their reproduction. It is advisable that the material be stored at room temperature before the start of the study and for no more than 2 hours. Currently, special tightly closed sterile containers and transport media are used for collecting and transporting material.

To no less an extent, the effectiveness of microbiological diagnostics depends on the competent interpretation of the results. It is believed that the isolation of pathogenic microorganisms, even in small quantities, always allows them to be classified as the true causative agents of the disease. A conditionally pathogenic microorganism is considered a pathogen if it is isolated from normally sterile environments of the body or in large quantities from environments not typical for its habitat. Otherwise, it is a representative of normal autoflora or contaminates the test material during collection or research. Isolation of low-pathogenic bacteria from areas uncharacteristic of their habitat in moderate quantities indicates the translocation of microorganisms, but does not allow them to be classified as the true causative agents of the disease.

It can be much more difficult to interpret the results of a microbiological study when culturing several types of microorganisms. In such cases, they focus on the quantitative ratio of potential pathogens. More often, 1-2 of them are significant in the etiology of this disease. It should be borne in mind that the likelihood of equal etiological significance of more than 3 different types of microorganisms is negligible.

Laboratory tests for the production of ESBLs by Gram-negative microorganisms are based on the sensitivity of ESBLs to beta-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam. Moreover, if a microorganism of the Enterobacteriaceae family is resistant to 3rd generation cephalosporins, and when beta-lactamase inhibitors are added to these drugs, it demonstrates sensitivity, then this strain is identified as ESBL-producing.

Antibiotic therapy should be aimed only at the true causative agent of the infection! However, in most hospitals, microbiological laboratories cannot establish the etiology of infection and the sensitivity of pathogens to antimicrobial drugs on the day of admission of the patient, so the initial empirical prescription of antibiotics is inevitable. At the same time, the peculiarities of the etiology of infections of various localizations characteristic of a given medical institution are taken into account. In this connection, regular microbiological studies of the structure of infectious diseases and the sensitivity of their pathogens to antibacterial drugs are necessary in each hospital. Analysis of the results of such microbiological monitoring must be carried out monthly.

Table 9.2.

Lactam antibiotics.

Table 9.3.

Antibiotics of other groups.

Table 9.4.

Synthetic antibacterial drugs.

Rational antibacterial therapy of intestinal infections

00:00

Oksana Mikhailovna Drapkina , professor, doctor of medical sciences:

– In this section we have direct coverage from St. Petersburg. Professor Zakharenko Sergei Mikhailovich.

"Rational antibacterial therapy of intestinal infections."

Sergey Mikhailovich Zakharenko , professor, doctor of medical sciences:

– Good afternoon, dear colleagues! It's warm here in St. Petersburg. Intestinal infections are not yet rampant. But we must be mentally prepared for the fact that the problem, no matter how it was solved before we came into the world, will probably not be solved in the near future.

If you look at the estimates of the World Health Organization (WHO), intestinal infections occupy a fairly high place as a cause of death in the world. Fourth place in low-income countries. Sixth place overall in countries around the world.

(Slide show).

The most interesting is probably the very bottom line on this slide. The proportion of the population dying due to intestinal infections in developed countries and throughout the world differs by literally 0.001%. If compared with countries that are considered highly developed, the difference will be only 0.006%.

Both for Russia and for the United States or some countries of the African continent, the problem remains relevant for many years.

It is generally accepted that infections caused by viruses are of greatest relevance today. But if we look at the results of a European study on the effectiveness of diagnosing bacterial enteric agents, we see that for every case of campylobacteriosis that is diagnosed in Europe, there are on average 274 undiagnosed cases.

This applies to salmonellosis, shigelliosis and escherichiosis. We must be aware that about half of the cases may be due to viruses. But about half of the cases are bacterial agents that require specific attention.

(Slide show).

This house of health and the path to recovery for a patient with an intestinal infection is based on the diet. 4 pillars in the form of etiotropic therapy, rehydration, pathogenetic therapy and symptomatic therapy must be fully presented, but competently and balanced for each patient.

Today we are talking about only one extreme pillar - etiotropic therapy, which has its own problems. There is no single scheme that can be learned to cure every patient. There is no drug that can be given a 100% advantage in all cases. The problem of antibiotic resistance has not yet been solved for any pathogen or antibiotic.

02:45

A particular nuisance is due to the fact that resistance is initially formed as multi-resistance.

In conditions where patients and doctors have recommendations that equally position both first-line drugs (2-3 drugs) and second-line drugs (3-4 drugs), we must have some basis for an additional positive or negative decision in favor of one drug or another.

In addition to the antimicrobial effect, it makes sense to take into account other effects, which we will now try to talk about.

It is of fundamental importance to separate diarrhea into cases that occur in residents (those who live in the region) and non-residents (or traveler's diarrhea). It is important to identify groups of patients in whom the disease occurs with or without hemocolitis.

Speaking of traveler's diarrhea, here are some things to consider. The main etiological agents that interfere with the lives of our travelers are E. coli. The main pathogen is enterotoxigenic bacilli. Please note the dependence on studies of the host country and time of year. The proportion of enteroaggregative and enterohemorrhagic strains varies.

WHO and classicists involved in the treatment of traveler's diarrhea previously recommended 4 groups of drugs with varying degrees of evidence. Today it is Trimethoprim, Sulfamethoxazole due to the increase in global resistance. With a good level of evidence, we can operate with three groups of drugs: fluoroquinolones, Rifaximin (a non-absorbable drug) and Azithromycin.

04:28

(Slide show).

If they are comparable in terms of the level of evidence, then you see in the comments that for fluoroquinolones one should not forget about side effects and the formation of extraintestinal resistance. For Rifaximin, with a good level of safety, the question of therapy with hemocolitis is not removed. Azithromycin, despite all its charm, still cannot be used for absolutely all infections and infections occurring with hemocolitis. There are problems with the formation of resistance.

(Slide show).

This is what the current recommendations for the treatment of traveler's diarrhea look like. Antibiotics are not recommended for treating mild cases. Even Loperamide, which is actively proposed in these cases, is not necessary.

The middle part of the slide is devoted to four drugs that cost sequentially and equally. The question arises: how to choose them.

Comparing the effectiveness, we see that Rifaximin is not inferior in its effectiveness to fluoroquinolones, both in terms of choice of dosage (can be used twice) and in terms of obtaining the final result in the form of cessation of diarrhea.

What factors can be taken into account? If we look at the first line, we see that fluoroquinolones cannot escape photodermatitis in a number of cases. There is no escape from restrictions on age, pregnancy and the problem of the formation of extraintestinal resistance.

For macrolides, most restrictions have been lifted, except that resistant strains form quite quickly in adults. They register.

Rifaximin occupies a position that is quite favorable from a comparison point of view based on these restrictions. At the same time, there is a certain wariness regarding resistance, which can be overcome by the data we receive on the survival of mutants resistant to Rifaximin.

When discussing the problem of resistance of emerging mutant strains to Rifaximin, several factors should be taken into account. The first is the frequency of formation of this resistance. The second is the consequences. Ciprofloxacin gives a resistance of 10-8 against E. coli. Rifaximin differs by approximately one order of magnitude from the test drug.

06:41

It is quite rare that resistance develops in clastridians, anaerobic or aerobic cocci and bacteria. But the most interesting thing is that the formation of resistance to Rifaximin is not accompanied by the formation of resistance to other antibacterial drugs. Multidrug resistance in a complex is not typical.

The formation of chromosomal type resistance reduces the viability of strains and reduces the likelihood of horizontal transmission of resistance genes to other related microorganisms.

A wide range of inhibitory agents allows us to combat the vast majority of enteropathogens that we may encounter when discussing the problem of diarrhea. High concentration in a relatively small biovolume, distribution of the drug in the wall layer of mucus creates increased local concentrations. They persist for 3-4 days, even after discontinuation of the drug, accompanying the drug with mucus along the intestinal wall.

(Slide show).

An additional advantage of Rifaximin, used in doses from 600 mg to 1200 mg, is its activity against protozoal agents. This American study presents the treatment of patients who had mixed infections.

Antiparasitic activity is quite noticeable and interesting. Traveler's diarrhea is, of course, a wonderful event. But it is advisable not to get sick. From the point of view of prevention, antibacterial drugs have been, are being used, and will probably be used for a long time.

In the 1970s, absorbable drugs with systemic effects were actively used. But since the mid-1980s, it has been recommended to limit the use of drugs, moving to non-absorbable drugs on the market. Since 1992, the use of non-absorbable drugs has been considered quite promising, except in cases where there is reason to use drugs with a systemic effect when traveling to regions where infections susceptible to them are common or, possibly, there is a high risk of infection.

08:41

Comparing the effectiveness of Rifaximin with placebo shows, of course, several times greater effectiveness. We are not talking about randomness here. We are talking about fairly good quality and performance of the drug. Dosages that can be used in practical use are only 200 mg per day.

One to two weeks of use does not lead to catastrophic changes in the composition of either the microflora of the colon or the microflora of the small intestine.

A special property of Rifaximin is its solubility depending on the volume of bile present. High solubility in the small intestine provides both a high preventive effect and high efficiency in the presence of bacterial overgrowth syndrome in the small intestine.

A rather smoothly decreasing concentration of the drug along the colon provides a microbiocyte-preserving effect and the ability to preserve normal microflora. Or, as will be shown below, use with probiotics.

Speaking about diarrhea of ​​residents, that is, those who are sick in their territory, you should draw your attention to several fundamental points related, first of all, to Escherichiosis.

Escherichiosis showed how severe it can be last year with an outbreak in Germany. I will now try to demonstrate the lessons of this outbreak to you. Enterotoxigenic escherichiosis, travelers' diarrhea and residents' diarrhea are treated in approximately the same way. There are no special features here.

These regimens are also used to treat diarrhea caused by enteropathogenic and E. coli. Difficulties arise with respect to enteroaggregative strains and enterohemorrhagic strains.

Considering the effectiveness of "Rifaximin", in relation to this group of pathogens, it has been reasonably shown that within 4-8 hours the degree of activity of production of both heat-labile and heat-stable toxin by enterotoxigenic Escherichia coli decreases.

(Unintelligible, 10:35) and enteroaggregative strains produce pathogenicity factors to a lesser extent. At the same time, with the use of Rifaximin, lower production of interleukin-8, which plays a role in the pathogenesis of these conditions, was noted.

10:48

The use of Rifaximin makes it possible to control the viability and population of enteroaggregative Escherichia coli. The entire group of escherichiosis falls under the more effective influence of an absorbed drug than the use of systemic drugs.

(Slide show).

Slide dedicated to the results of the epidemic caused by E. coli O104 in Germany. On the right you see good drugs that are effectively used to treat salmonellosis, dysentery or some other infections. We did not work on this group of patients.

Today, the treatment tactics for escherichiosis caused by enterohemorrhagic Escherichia coli with a high risk of developing hemolytic-uremic syndrome are based on the use of carbopenems in cases where systemic therapy is required. "Rifaximin" as a non-absorbable drug in cases where local therapy is indicated and there is no need for systemic action.

Recommended doses are controversial - from 600 mg to 1200 mg. They do not exceed average therapeutic recommendations.

(Slide show).

It is difficult to make a diagnosis from the first meeting with the patient. But patients can be divided into at least 2 groups: patients with hemocolitis and without hemocolitis. Here are the treatment regimens for patients without hemocolitis. The effective use of Rifaximin is possible if we look at the limited trials we have done comparing Alfa Normix with Ciprofloxacin.

It can be seen that the differences in the duration of diarrhea in the key syndrome in this disease are less than half a day. The drugs are again equally effective for both traveler's diarrhea and resident diarrhea.

A huge problem that has come to a head in recent years. Flashes with. difficile-associated diseases in Canada with thirty deaths suggests that today we, unfortunately, know little about this disease and are poorly diagnosed. But we clearly understand the therapeutic tactics both from foreign publications and from our own clinical experience.

Metronidazole is positioned as the drug of choice for many reasons. First of all, the cost. It is used to treat mild to severe primary episodes. If there is no effect within three days of therapy, we switch to the use of Vancomycin.

Vancomycin is the “gold standard” in the treatment of this disease. But it is quite expensive, so it is primarily recommended for severe disease or relapses.

13:15

What to do if the patient cannot be cured with these two drugs. Today, there is “Fidaksomicin” abroad, which is included in the recommendations. We only have Rifaximin.

Rifaximin can be used to treat this group of patients in doses of 400 mg to 800 mg per day for 10 to 14 days. It has a particular advantage in patients with liver damage. To date, unfortunately, we have not yet received immunoglobulins that can be used to treat this group of patients. We don't have bacteriophages.

An interesting and fundamentally important for the positioning of Rifaximin, at least the third anti-clastridial agent, is the very high level of bacteriological effectiveness, reaching 73%. While for Metronidazole and Vancomycin this figure is about 65%.

In this study, antibiotics were prescribed for 14 days. A shorter course has a greater chance of relapse.

One more circumstance. Today it is extremely difficult to find patients who do not have any problems with metabolic disorders or liver disease.

How do antibiotics interact with the liver, and are there any risks? Disulfiram-like reactions, well known, include Metronidazole, Furazolidone, and Cefoperazone. There is a fairly wide range of drugs falling into this zone.

14:41

(Slide show).

A number of drugs are frankly not recommended for liver diseases. The entire range of antimicrobial agents is presented on this slide. Do we always remember that these drugs have limited permission.

The risk of hepatotoxicity also increases with fluoroquinolones. In particular, Moxifloxacin is present here with a risk of 4.3 against the background of liver disease.

Drug interactions are an important problem, both at the intestinal level and extraintestinal interactions. "Rifaximin", having other metabolic mechanisms and being absorbed in an extremely small volume, is still capable of stimulating cytochrome P450. This promotes the metabolism of other xenobiotics.

This is not enough. As it turned out, the use of this drug in patients with damaged liver not only contributes to the level of circulating endotoxin and proinflammatory cytokines, but also has certain vaso- and cardiotropic effects. Of course, they are not direct, but indirect. However, this is an additional “bonus” that these severe patients receive.

Today, it is quite actively proposed to use antibiotics together with probiotics. How effective and safe is this therapy for probiotics? These two studies presented on the slide show the possibility of using, at a minimum, bifid-containing drugs together with Rifaximin.

The strains do not lose their probiotic properties in the presence of Rifaximin. This combination therapy appears to be quite feasible.

More interesting data was obtained literally over the last 5-7 years. They relate to the affinity of Rifaximin with the pregnane X receptor, which is involved in the regulation of an adequate nonspecific and immunological response. These properties are interesting and important from the point of view of using the drug in the treatment of not only intestinal infections, but also inflammatory bowel diseases.

Thus, today there is no doubt that our ideas about the frequency and detection of intestinal infections are somewhat underestimated. In fact, there are more of these patients. But we should not consider every patient with diarrhea as infectious. It is necessary to look for other factors and causes and fully examine patients.

We must remain alert to the possible cause of intestinal infection caused by bacterial agents and appropriately select antibacterial therapy. Far underestimated today are travelers' diarrhea and nosocomial diarrhea, including those caused by. difficile.

Therapy for diarrhea and intestinal infections cannot be without alternative. A competent assessment of the severity of symptoms and fever allows you to choose drugs with systemic or local action. Among drugs with systemic action, there is no alternative to fluoroquinolone. And among non-absorbable drugs on our market there is no alternative to Rifaximin.

C. Difficile-associated diseases should be the second target for the use of this group of drugs. In particular, Rifaximina.

(Slide show).

Only the competent use of all modern capabilities (how this turtle got out of the pen) can probably allow us to get out of the problem of the labyrinth of intestinal infections.

Thank you.

INTESTINAL DYSBACTERIOSIS

What is meant by dysbiosis? What diagnostic methods are modern and reliable? What medications are used for dysbiosis?

The human intestine contains over 500 different types of microbes, the total number of which reaches 1014, which is an order of magnitude higher than the total number of cellular composition of the human body. The number of microorganisms increases in the distal direction, and in the colon 1 g of feces contains 1011 bacteria, which constitutes 30% of the dry residue of the intestinal contents.

Normal intestinal microbial flora

In the jejunum of healthy people there are up to 105 bacteria per 1 ml of intestinal contents. The bulk of these bacteria are streptococci, staphylococci, lactic acid bacilli, other gram-positive aerobic bacteria and fungi. In the distal ileum, the number of microbes increases to 107–108, primarily due to enterococci, Escherichia coli, bacteroides and anaerobic bacteria. We recently found that the concentration of the parietal microflora of the jejunum is 6 orders of magnitude higher than in its cavity, and amounts to 1011 cells/ml. About 50% of the biomass of the parietal microflora are actinomycetes, approximately 25% are aerobic cocci (staphylococci, streptococci, enterococci and coryneform bacteria), from 20 to 30% are bifidobacteria and lactobacilli.

The number of anaerobes (peptostreptococci, bacteroides, clostridia, propionobacteria) is about 10% in the small intestine and up to 20% in the large intestine. Enterobacteriaceae account for 1% of the total microflora of the mucous membrane.

Up to 90-95% of microbes in the large intestine are anaerobes (bifidobacteria and bacteroides), and only 5-10% of all bacteria are strictly aerobic and facultative flora (lactic acid and E. coli, enterococci, staphylococci, fungi, proteus).

Escherichia coli, enterococci, bifidobacteria and acidophilus bacilli have pronounced antagonistic properties. Under conditions of a normally functioning intestine, they are able to suppress the growth of microorganisms unusual for normal microflora.

The internal surface area of ​​the intestine is about 200 m2. It is reliably protected from the penetration of food antigens, microbes and viruses. The body's immune system plays an important role in organizing this defense. About 85% of human lymphatic tissue is concentrated in the intestinal wall, where secretory IgA is produced. Intestinal microflora stimulates immune defense. Intestinal antigens and toxins from intestinal microbes significantly increase the secretion of IgA into the intestinal lumen.

The breakdown of undigested nutrients in the colon is carried out by bacterial enzymes, resulting in the formation of various amines, phenols, organic acids and other compounds. Toxic products of microbial metabolism (cadaverine, histamine and other amines) are excreted in the urine and normally have no effect on the body. When microbes utilize indigestible carbohydrates (fiber), short-chain fatty acids are formed. They provide intestinal cells with energy carriers and, therefore, improve the trophism of the mucous membrane. Fiber deficiency may impair the permeability of the intestinal barrier due to a deficiency of short-chain fatty acids. As a result, intestinal microbes can enter the bloodstream.

Under the influence of microbial enzymes in the distal ileum, bile acids are deconjugated and primary bile acids are converted into secondary ones. Under physiological conditions, 80 to 95% of bile acids are reabsorbed, the rest are excreted in feces in the form of bacterial metabolites. The latter contribute to the normal formation of feces: they inhibit the absorption of water and thereby prevent excessive dehydration of feces.

Dysbacteriosis

The concept of intestinal dysbiosis includes excessive microbial contamination of the small intestine and changes in the microbial composition of the large intestine. Disruption of microbiocenosis occurs to one degree or another in most patients with pathologies of the intestines and other digestive organs. Therefore, dysbiosis is a bacteriological concept. It can be considered as one of the manifestations or complication of the disease, but not an independent nosological form.

The extreme degree of intestinal dysbiosis is the appearance of gastrointestinal bacteria in the blood (bacteremia) or even the development of sepsis.

The composition of the intestinal microflora is disrupted by diseases of the intestines and other digestive organs, treatment with antibiotics and immunosuppressants, and exposure to harmful environmental factors.

Clinical manifestations of dysbiosis depend on the localization of dysbiotic changes.

Dysbacteriosis of the small intestine

With dysbiosis of the small intestine, the number of some microbes in the mucous membrane of the small intestine is increased, while others are decreased. There is an increase in Eubacterium (30 times), α-streptococci (25 times), enterococci (10 times), Candida (15 times), the appearance of bacteria of the genus Acinetobacter and herpes viruses. The number of most anaerobes, actinomycetes, Klebsiella and other microorganisms that are natural inhabitants of the intestines decreases from 2 to 30 times.

The cause of dysbacteriosis can be: a) excessive entry of microorganisms into the small intestine during achylia and dysfunction of the ileocecal valve; b) favorable conditions for the development of pathological microorganisms in cases of impaired intestinal digestion and absorption, development of immunodeficiency and intestinal obstruction.

Increased proliferation of microbes in the small intestine leads to premature deconjugation of bile acids and their loss in feces. An excess of bile acids increases colon motility and causes diarrhea and steatorrhea, and a deficiency of bile acids leads to impaired absorption of fat-soluble vitamins and the development of cholelithiasis.

Bacterial toxins and metabolites, such as phenols and biogenic amines, can bind vitamin B12.

Some microorganisms have a cytotoxic effect and damage the epithelium of the small intestine. This leads to a decrease in the height of the villi and deepening of the crypts. Electron microscopy reveals degeneration of microvilli, mitochondria and endoplasmic reticulum.

Colon dysbiosis

The composition of the microflora of the colon can change under the influence of various factors and adverse effects that weaken the body’s defense mechanisms (extreme climatic and geographical conditions, pollution of the biosphere with industrial waste and various chemicals, infectious diseases, diseases of the digestive system, malnutrition, ionizing radiation).

Iatrogenic factors play an important role in the development of colon dysbiosis: the use of antibiotics and sulfonamides, immunosuppressants, steroid hormones, radiotherapy, and surgical interventions. Antibacterial drugs significantly suppress not only pathogenic microbial flora, but also the growth of normal microflora in the colon. As a result, microbes that come from outside or endogenous species that are resistant to drugs (staphylococci, Proteus, yeast, enterococci, Pseudomonas aeruginosa) multiply.

Clinical features of dysbiosis

Clinical manifestations of excessive growth of microorganisms in the small intestine may be completely absent, act as one of the pathogenetic factors of chronic recurrent diarrhea, and in some diseases, for example, diverticulosis of the small intestine, partial intestinal obstruction or after surgical operations on the stomach and intestines, lead to severe diarrhea , steatorrhea and B12-deficiency anemia.

The features of the clinical course of the disease in patients with various variants of colon dysbiosis, according to bacteriological analyzes of stool, in most cases cannot be established. It can be noted that patients with chronic intestinal diseases are more often infected with acute intestinal infections compared to healthy people. This is probably due to a decrease in the antagonistic properties of normal intestinal microflora and, above all, the frequent absence of bifidobacteria.

Particularly dangerous is pseudomembranous colitis, which develops in some patients who have been treated with broad-spectrum antibiotics for a long time. This severe variant of dysbiosis is caused by toxins secreted by Pseudomonas aeruginosa Clostridium difficile, which multiplies in the intestines when the normal microbial flora is suppressed.

The main symptom of pseudomembranous colitis is profuse, watery diarrhea, the onset of which was preceded by the prescription of antibiotics. Then cramping pain in the abdomen appears, body temperature rises, and leukocytosis increases in the blood. The endoscopic picture of pseudomembranous colitis is characterized by the presence of plaque-like, ribbon-like and solid “membranes”, soft but tightly fused to the mucous membrane. The changes are most pronounced in the distal parts of the colon and rectum. The mucous membrane is edematous, but not ulcerated. Histological examination reveals subepithelial edema with round cell infiltration of the lamina propria, capillary stasis with the release of red blood cells outside the vessels. At the stage of formation of pseudomembranes under the surface epithelium of the mucous membrane, exudative infiltrates appear. The epithelial layer is raised and absent in places; bare areas of the mucous membrane are covered only by desquamated epithelium. In later stages of the disease, these areas may occupy large segments of the intestine.

Very rarely, a fulminant course of pseudomembranous colitis, reminiscent of cholera, is observed. Dehydration develops within a few hours and ends in death.

Thus, assessment of the clinical significance of dysbiotic changes should be based primarily on clinical manifestations, and not only on the results of a study of fecal microflora.

Diagnostic methods

Diagnosis of dysbiosis is a complex and time-consuming task. To diagnose small intestinal dysbiosis, culture of small intestinal juice obtained using a sterile probe is used. Dysbacteriosis of the colon is detected using bacteriological studies of stool.

Microbial flora produces a large amount of gases, including hydrogen. This phenomenon is used to diagnose dysbiosis. The concentration of hydrogen in exhaled air on an empty stomach is directly dependent on the severity of bacterial contamination of the small intestine. In patients with intestinal diseases occurring with chronic recurrent diarrhea and bacterial contamination of the small intestine, the concentration of hydrogen in exhaled air significantly exceeds 15 ppm.

To diagnose dysbiosis, a lactulose load is also used. Normally, lactulose is not broken down in the small intestine and is metabolized by the microbial flora of the colon. As a result, the amount of hydrogen in the exhaled air increases (Fig. 1).

The most common bacteriological signs of colon dysbiosis are the absence of the main bacterial symbionts - bifidobacteria and a decrease in the number of lactic acid bacilli. The number of E. coli, enterococci, clostridia, staphylococci, yeast-like fungi and Proteus increases. Some bacterial symbionts develop pathological forms. These include hemolyzing flora, E. coli with weakly expressed enzymatic properties, enteropathogenic E. coli, etc.

An in-depth study of microbiocenosis has shown that traditional methods do not provide true information about the state of the intestinal microflora. Of the 500 known species of microbes, only 10-20 microorganisms are usually studied for diagnostic purposes. It is important in which part - in the jejunum, ileum or colon - the microbial composition is studied. Therefore, the prospects for developing clinical problems of dysbiosis are currently associated with the use of chemical methods for differentiating microorganisms, which make it possible to obtain universal information about the state of microbiocenosis. The most widely used for these purposes are gas chromatography (GC) and gas chromatography coupled with mass spectrometry (GC-MS). This method allows one to obtain unique information about the composition of the monomeric chemical components of the microbial cell and metabolites. Markers of this kind can be determined and used to detect microorganisms. The main advantage and fundamental difference of this method from bacteriological ones is the possibility of quantitative determination of more than 170 taxa of clinically significant microorganisms in various environments of the body. In this case, the results of the study can be obtained within a few hours.

Our studies of microbiocenosis in the blood and biopsy samples of the mucous membrane of the small and large intestines in patients with irritable bowel syndrome allowed us to detect deviations from the norm up to a 30-fold increase or decrease in many components.
It is possible to assess changes in intestinal microflora based on blood analysis data using GC-MS microbial markers. Treatment regimen for intestinal dysbiosis

Treatment

Treatment of dysbacteriosis should be comprehensive (scheme) and include the following measures:

• elimination of excessive bacterial contamination of the small intestine;
• restoration of normal microbial flora of the colon;
• improvement of intestinal digestion and absorption;
• restoration of impaired intestinal motility;
• stimulating the body's reactivity.

Antibacterial drugs

Antibacterial drugs are necessary primarily to suppress the excessive growth of microbial flora in the small intestine. The most widely used antibiotics are from the group of tetracyclines, penicillins, cephalosporins, quinolones (tarivid, nitroxoline) and metronidazole.

However, broad-spectrum antibiotics significantly disrupt eubiosis in the colon. Therefore, they should be used only for diseases accompanied by disorders of absorption and intestinal motility, in which, as a rule, there is a pronounced growth of microbial flora in the lumen of the small intestine.

Antibiotics are prescribed orally in normal doses for 7–10 days.

For diseases accompanied by colon dysbiosis, treatment is best carried out with drugs that have a minimal effect on the symbiont microbial flora and suppress the growth of Proteus, staphylococci, yeast fungi and other aggressive strains of microbes. These include antiseptics: intetrix, ersefuril, nitroxoline, furazolidone, etc.

For severe forms of staphylococcal dysbiosis, antibiotics are used: tarivid, palin, metronidazole (Trichopol), as well as biseptol-480, nevigramon.

Antibacterial drugs are prescribed for 10–14 days. If fungi appear in the stool or intestinal juice, the use of nystatin or levorin is indicated.

In all patients with diarrhea associated with antibiotics, occurring with intoxication and leukocytosis, the occurrence of acute diarrhea should be associated with Cl. difficile.

In this case, an urgent stool culture is done for Cl. difficile and prescribe vancomycin 125 mg orally 4 times a day; if necessary, the dose can be increased to 500 mg 4 times a day. Treatment is continued for 7-10 days. Metronidazole at a dose of 500 mg orally 2 times a day, bacitracin 25,000 IU orally 4 times a day are also effective. Bacitracin is almost not absorbed, and therefore a higher concentration of the drug can be created in the colon. In case of dehydration, adequate infusion therapy is used to correct the water and electrolyte balance. To bind the toxin Cl. difficile use cholestyramine (Questran).

Bacterial preparations

Live cultures of normal microbial flora survive in the human intestine from 1 to 10% of the total dose and are capable, to some extent, of performing the physiological function of normal microbial flora. Bacterial drugs can be prescribed without prior antibacterial therapy or after it. Bifidumbacterin, bificol, lactobacterin, bactisubtil, linex, enterol, etc. are used. The course of treatment lasts 1-2 months.

Another possible way to eliminate dysbiosis is to influence the pathogenic microbial flora with metabolic products of normal microorganisms. Such drugs include Hilak Forte. It was created 50 years ago and is still used to treat patients with intestinal pathologies. Hilak forte is a sterile concentrate of metabolic products of normal intestinal microflora: lactic acid, lactose, amino acids and fatty acids. These substances help restore the biological environment in the intestines necessary for the existence of normal microflora and suppress the growth of pathogenic bacteria. Perhaps metabolic products improve the trophism and function of epithelial cells and colonocytes. 1 ml of the drug corresponds to the biosynthetic active substances of 100 billion normal microorganisms. Hilak forte is prescribed 40–60 drops 3 times a day for up to 4 weeks in combination with antibacterial drugs or after their use.

More recently, there have been reports of the possibility of treating acute diarrhea associated with antibiotic therapy and Cl. difficile, large doses of pre- and probiotics.

Regulators of digestion and intestinal motility

In patients with impaired cavity digestion, Creon, pancitrate and other pancreatic enzymes are used. In order to improve the absorption function, Essentiale, Legalon or Karsil are prescribed, since they stabilize the membranes of the intestinal epithelium. Propulsive bowel function is improved by imodium (loperamide) and trimebutine (debridate).

Stimulants of body reactivity

To increase the reactivity of the body in weakened patients, it is advisable to use taktivin, thymalin, thymogen, immunal, immunofan and other immunostimulating agents. The course of treatment should average 4 weeks. Vitamins are prescribed at the same time.

Prevention of dysbacteriosis

Primary prevention of dysbiosis is a very difficult task. Its solution is associated with general preventive problems: improving the environment, rational nutrition, improving well-being and other numerous factors of the external and internal environment.

Secondary prevention involves the rational use of antibiotics and other medications that disrupt eubiosis, timely and optimal treatment of diseases of the digestive system, accompanied by a violation of microbiocenosis.