CLINICAL-PHARMACOLOGICAL APPROACH TO THE CLINICAL USE OF BACTERIOPHAGE DRUGS IN ACUTE INTESTINAL INFECTIONS

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CLINICAL-PHARMACOLOGICAL APPROACH TO THE CLINICAL USE OF

BACTERIOPHAGE DRUGS IN ACUTE INTESTINAL INFECTIONS

Abdukodirova Shakhnoza

Assistant, Department of Clinical Pharmacology, Samarkand State Medical University

Subhonov Umar Umedovich

Student of group 613, Faculty of Medicine, Samarkand State Medical University

Mukhtorov Amirjon Shokirjonovich

Student of group 511, Faculty of Pharmacy, Samarkand State Medical University

https://doi.org/10.5281/zenodo.14766706

Abstract. Acute intestinal infections (AI) are a large group of infectious diseases caused

by pathogenic, opportunistic bacteria, viruses, protozoa, transmitted through household, water or

food, characterized by inflammatory lesions of the gastrointestinal tract. (GIT) of varying degrees,

the development of vomiting, diarrhea, intoxication and dehydration. The main causative agents

of acute intestinal infections in young children are viruses. In children under one year of age, the

etiological agent of acute intestinal infections in 90% of cases is various viruses, in children 1-4

years old - 75%, in children over 5 years old - 40%. The most common cause of diarrhea in

children is rotavirus. By the age of 3-5, every child experiences it at least once. Rotaviruses cause

30-50% of cases of gastroenteritis requiring hospitalization and parenteral rehydration.

According to various sources, up to 440,000 children die from rotavirus gastroenteritis worldwide

each year (1). In addition to rotavirus, the causative agents of viral diarrhea are RNA-containing

astroviruses, Norfolk virus, and similar agents belonging to the group of unclassified viruses,

which received their names from the places where they were found - Norfolk (Ohio, USA), Hawaii

virus, Mount Snow virus, etc. In addition, caliciviruses, adenoviruses, enteroviruses,

coronaviruses, and cytomegalovirus are also responsible for viral diarrhea (2).

Key words: Salmonella spp., Shigella spp., Escherichia coli, Clostridium botulinum,

Yersinia enterocolitica, Yersinia pseudotuberculosis, Vibrio cholerae, Campylobacter spp.,

Staphylococcus spp.

Introduction

The share of bacterial infectious agents in the etiology of acute intestinal infections

increases with the age of the child - from 10% in infants to 60% in children aged 5-14 years.

Bacterial pathogens of acute intestinal infections are divided into two groups: pathogenic and

opportunistic. The first group includes

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Opportunistic pathogens that can cause ACI are represented by a wide range of bacteria

and include Proteus spp., Klebsiella spp., Pseudomonas spp., Providencia spp., Clostridium

perfringens, Clostridium difficile, Citrobacter spp., Morganirat sp, Enterobacter. spp., Hafnia

alvei, Edwardsiella tarda, Vibrio spp. (cholera and non-cholera groups O1 and O139).

Pathogenic bacteria cause acute intestinal infections that are specific nosological entities,

while the clinical signs of intestinal infections caused by opportunistic bacteria are less specific.

Exceptions are pseudomembranous colitis caused by Clostridium difficile and necrotic

enteritis of swine caused by strains of Clostridium perfringens, the causative agent of gas gangrene

that produce β-toxin. The development of necrotic enterocolitis in newborns is also associated with

the latter pathogen (3). Opportunistic pathogens are so called because they cause infectious

diseases under certain conditions (reduced immunity, infancy, and other modifying risk factors for

severe disease).

ACI still occupies a leading position in the infectious pathology of childhood, second only

to ARVI in terms of incidence. Up to 1.2 billion cases of diarrheal diseases are recorded worldwide

annually. Every year, 5 to 8 million children under 5 years of age die from acute respiratory

infections in the world. Mortality rates are especially high in developing countries, where acute

intestinal infections are the most common cause of dehydration and malnutrition. The incidence

and mortality from acute intestinal infections are highest in children under 5 years of age. Natural

feeding eliminates infection through food and water and protects the child from intestinal

infections. When a child begins to receive complementary foods, the risk of intestinal infections

increases sharply. Compared with adults, enterotoxigenic and enteropathogenic escherichiosis and

campylobacteriosis are more common in children. Salmonellosis is most common in infants, and

dysentery is most common in children over 6 months of age. Up to 4 years (2).

Pathogenesis

The entrance gate and the main target organ for ACI is the gastrointestinal tract. The

essence of the pathogenesis of bacterial acute intestinal infections is the interaction of various

factors of microbial virulence (infectious dose, adhesion, toxin production, invasion) and the host's

defense mechanisms (normal microflora, acidic environment of the gastric contents, intestinal

motor function, vomiting, diarrhea, specific immunity, breastfeeding). According to the results of

electron microscopic studies of the interaction of bacteria with the epithelium of the

gastrointestinal tract, 4 types of this interaction have been identified, characterizing the

mechanisms of pathogenic action of pathogens of acute intestinal infections.

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The pathogenesis of diarrhea due to rotavirus infection is complex and, according to

modern concepts, involves both osmotic and secretory mechanisms.

Rotaviruses infect the epithelial cells of the small intestine (more than the proximal two-

thirds). The virus multiplies in enterocytes located on the tops of the villi and causes their death.

Dead epithelial cells are replaced by differentiated cells that are unable to absorb

carbohydrates, primarily the disaccharide lactose, and other nutrients (amino acids). As a result,

the concentration of these substances in the lumen of the small intestine increases, the reabsorption

of water and electrolytes is impaired, and osmotic watery diarrhea develops. Entering the small

intestine, disaccharides and amino acids become substrates for fermentation by intestinal

microflora with the formation of large amounts of organic acids, hydrogen, carbon dioxide,

methane, and water. As a result, gas formation in the intestines (flatulence) increases and the pH

of the intestinal contents decreases.

The rotavirus-unspecific structural protein NSP4, the first enterotoxin described in viruses,

causes secretory diarrhea similar to bacterial enterotoxins. The mechanism of action of this protein

has two phases: enterotoxigenic and enteroneurogenic. In the enterotoxigenic phase, intestinal

secretion increases, mainly due to the secretion of chlorides, under the influence of NSP4, which

interacts with surface membrane proteins and age-dependent (mainly functioning over 6 months)

calcium-sensitive ion channels. NSP4 does not change the level of cAMP or cGMP in enterocytes.

In the enteroneurogenic phase, as a result of villous ischemia and activation of the enteric nervous

system, the production of nitric oxide (NO) increases, under its influence vascular damage

increases and neurogenic reactive inflammation develops. As a result of vascular damage,

prostaglandin E2 synthesis and cGMP-dependent secretion of anions through adrenergic, non-

cholinergic receptors of the enteric nervous system increase.

In acute intestinal infections, flatulence is associated with increased gas formation due to

bacterial fermentation and indigestion, osmotic diarrhea. The cause of abdominal pain syndrome

is stretching of the intestinal loops and tension of the mesentery, mesenteric inflammation in

infections accompanied by invasive cytotoxic transepithelial interaction, mesenteric adenitis,

inflammation of the intestinal wall. All this is accompanied by stimulation of pain receptors.

Digestive disorders are the result of morphological and functional changes in the

gastrointestinal tract.

Clinical variants of acute intestinal infections

By distribution, OCI is divided into local and generalized, and by severity - mild, moderate

and severe (4, 5, 6).

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With localized infection, the lesion does not extend beyond the gastrointestinal tract and

can be detected at various levels (gastritis, enteritis, colitis, combined lesions), the detection of

which helps scatological examination of feces. According to its results, patients are prescribed

enzyme therapy.

Gastritis - a lesion of the stomach, accompanied by pain and heaviness in the epigastric

region, nausea and repeated vomiting against a background of moderate fever and intoxication.

Short-term liquefaction of stool with an unpleasant odor is possible. Gastritis is the main

manifestation of food poisoning infections. The coprogram reveals a large amount of connective

tissue, coarse plant fiber and unchanged transverse striated muscle fibers.

Enteritis - a lesion of the small intestine, manifested by non-local (or localized around the

navel), constant (or periodically recurring), independent (or during palpation) abdominal pain;

phenomena of flatulence; liquid, abundant, watery, often foamy, with pieces of undigested food,

yellow or yellow-green in color with a pungent odor and a small amount of transparent mucus

(lumps or flakes). The coprogram contains leukocytes, epithelial cells, a large amount of fatty

acids, starch grains (extracellular and intracellular), muscle fibers and soap (fatty acid salts) and

soluble proteins.

Gastroenteritis is a combination of gastritis with enteritis, often found with escherichiosis

and salmonellosis.

Colitis is an inflammatory lesion of the colon, which is accompanied by independent (or

palpable), constant (or periodically recurring) pain along the entire length of the colon and loose,

light stools with an unpleasant odor and pathological impurities (cloudy mucus, greens, blood). .

The coprogram contains a lot of indigestible fiber, intracellular starch and iodophilic

microflora, leukocytes, erythrocytes.

Enterocolitis - simultaneous damage to the small and large intestine, clinically manifested

by the appearance of a large amount of liquid stool with turbid mucus, sometimes with a large

amount of greens (feces like "swamp mud") and blood, which is characteristic of salmonellosis.

The coprogram contains undigested cellulose, starch grains, and iodophilic flora.

Gastroenterocolitis - damage to all parts of the digestive tract, accompanied by symptoms

of enterocolitis due to repeated vomiting, abdominal pain and intoxication, is more common with

salmonellosis.

Distal colitis is a clinical syndrome characteristic mainly of shigellosis, manifested by

independent (or during palpation) pain in the left iliac region. The pain can be constant, but

intensifies or occurs only before defecation (tenesmus).

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The sigmoid colon is spasmodic, painful during palpation, sphincteritis, flexion or

dilatation of the anus are noted. The stool is loose, frequent, scanty, with a large amount of turbid

mucus, often green and bloody ("hemocolitis"). In severe forms, the stool loses its fecal character

and smell and may consist only of pathological impurities ("rectal spitting"). An analogue of

tenesmus in young children may be restlessness, crying during or before bowel movements. With

distal colitis, the coprogram contains a large number of leukocytes, red blood cells, and mucus.

Common forms of bacterial acute intestinal infections include typhoid-like diseases with

bacteremia (characteristic for salmonellosis, typhoid and paratyphoid fever) and septic (with

septicopyemic foci). Salmonellosis, Grigoriev-Shiga dysentery, campylobacteriosis, intestinal

infections caused by opportunistic microorganisms, often have a generalized course in children

with modifiable risk factors.

The criteria for the severity of AEI are the severity of intoxication, gastrointestinal damage,

and dehydration.

The mild form of the disease is characterized by moderate intoxication (div temperature

not higher than 38-38.5 ° C) and moderate diarrhea (up to 6-7 times a day without significant fluid

loss).

The moderate form of the disease, which occurs most often, is manifested by severe

intoxication (div temperature up to 39-39.5 ° C, headache, dizziness, lethargy) and a pronounced

local syndrome (abdominal pain, flatulence, stool up to 10-12 times a day) , vomiting with fluid

loss in the stool and the development of toxicosis with exicosis of I-II degree.

The severe form of ACI is characterized by a pronounced local syndrome (feces

"uncountable" with a large loss of fluid and electrolytes) and the development of a number of

emergency syndromes (neurotoxicosis, toxicosis with exsicosis of II-III degree , infectious-toxic

shock, hemolytic-uremic syndrome, acute renal failure, sepsis).

Treatment

The main components of the treatment of acute intestinal infections are presented in Table

2.

The most important component of the treatment of acute intestinal infections is rehydration.

Traditionally, the principles of dehydration are discussed separately, the interested reader

will find a detailed description of this method of therapy in the available manuals (6, 7, 8).

Indications for hospitalization of children with acute intestinal infections are as follows:

all severe forms of acute intestinal infections, regardless of the age of the patients;

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moderate forms with symptoms lasting more than 5 days and ineffective therapy in the

outpatient phase;

OCI with severe abdominal pain syndrome, requiring examination and observation by a

surgeon to exclude acute surgical pathology (intussusception, acute appendicitis, etc.);

suspicion of the development of hypo- or hyperosmolar dehydration based on clinical

presentation or previous treatment;

children with modifying risk factors for serious illnesses;

lack of necessary conditions for treatment at home;

all children in closed groups (nursing homes, orphanages, shelters, other hospitals, etc.)

(6).

Diet

Nutrition for children with acute intestinal infections is determined depending on the age

of the patient and the severity of the disease. In children under one year old with mild forms of the

disease, the amount of food is reduced by 15-20% in the first 3-4 days of the disease, the missing

volume is filled with liquid. Optimal nutrition is the use of adapted milk or fermented milk

formulas, if there is no breast milk.

The benefits of continuing breastfeeding during ACI include minimizing the loss of

protein, other nutrients, electrolytes, water, and energy; reducing nutrient losses in the stool and

restoring the intestinal mucosa; providing anti-infective factors and avoiding sensitization to

foreign proteins; and maintaining lactation in mothers who continue breastfeeding (8).

Breastfeeding is the most important protective factor against acute intestinal infections in

children in the first year of life. In developing countries, the risk of death from acute intestinal

infections is 14 times lower for breastfed children than for children who do not receive breast milk.

Breastfeeding is a mechanism that partially compensates for the physiological immune

deficiency of children in the first months of life. Breast milk contains many components of

immunity, the deficiencies of which are noted in newborns: cells (macrophages - 60%, neutrophils

- 25%, lymphocytes, mainly T-lymphocytes - 10%) and soluble components (immunoglobulins,

cytokines, chemokines, receptors, growth factors and innate immunity). However, the main

mechanism by which breastfeeding protects the child from intestinal pathogens in the first months

of life is the presence of a large number of oligosaccharides and glycoconjugates in breast milk.

Breast milk oligosaccharides constitute the third most dense component of breast milk after

lactose and fat. Their mass is greater than that of protein, at 3 g/l. The oligosaccharide composition

of breast milk varies considerably in quantity and quality among nursing mothers.

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Oligosaccharides, glycoconjugates, and glycolipids in breast milk are receptors for

pathogens and their toxins, competing for binding to adhesion receptors on epithelial cells, thereby

inhibiting their pathogenic effects. Table 3 lists the protective factors of breast milk and their

additional pathogens and their toxins.

It is not recommended to include cow's milk, kefir and unadapted milk formulas in the diet

of infants with acute intestinal infections due to the risk of sensitization to cow's milk protein and

the development of diapedetic bleeding in the gastrointestinal tract, osmotic diarrhea and increased

acidosis.

In the diet of children over 6 months, fermented milk mixtures are combined with 5-10%

rice and buckwheat porridge (gluten-free) with water and vegetable puree (puree soup), then the

diet is gradually expanded depending on the age of the child and the nature of the diet before the

disease.

In the first 5 days of the disease, in moderate and severe forms of acute intestinal infections

in infants, the daily amount of food is reduced to 1/2-2/3 of the norm with fractional administration

(8-10 times a day). In severe forms of acute intestinal infections, protein deficiency can occur due

to impaired absorption and loss of amino acids through the intestines during the acute period. This

is typical for children with malnutrition, premature birth, and prolonged starvation diets, especially

for children with acute intestinal infections accompanied by invasive diarrhea. In such cases, from

the 3rd day of the disease, adapted milk formulas enriched with protein are prescribed, used for

feeding premature babies, as well as cottage cheese. The general principle of the diet for infants

with ACI is to “rejuvenate” the diet: reduce the amount of food, increase the frequency of feeding,

and temporarily eliminate complementary foods with gradual expansion.

In children over one year of age with gastroenteritis, foods that increase intestinal motility,

fermentation, contain fiber, have an irritating, sensitizing effect, and are high in fat are excluded

from the diet.

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