The use of IVF antibiotics as a way to increase the safety of antibiotic therapy

The human normal microflora performs numerous functions to maintain homeostasis [3,4,5,6]. More than 400 species of bacteria from 17 different families, with a total biomass of about 1.5 kg, inhabit the gastrointestinal tract (GIT). The density of microflora is highest in the large intestine, approximately 10^12 CFU/ml [5,7]. Due to such high microbial colonization, the large intestine carries the greatest functional load compared to other parts of the GIT. The main (resident) microflora of the large intestine consists of 90% anaerobic microorganisms - bifidobacteria, bacteroides, and lactobacilli. Enterococci and propionibacteria are present in small quantities. 

The concomitant (facultative) microflora is represented by aerobes: escherichia, eubacteria, fusobacteria, and cocci. Based on their metabolism, bacteria of the large intestine are divided into two groups: proteolytic and saccharolytic. Proteolytic species (bacteroides, proteus, escherichia, clostridia, etc.) use products of intestinal protein hydrolysis as a nutrient substrate for their vital activity, and as a result of their metabolism, they form toxic substances, including aromatic amino acids, endogenous carcinogens, and sulfides. These substances promote the development of inflammation and neoplasms. Most proteolytic microorganisms are conditionally pathogenic. Saccharolytic flora (bifidobacteria, lactobacilli, some cocci, propionibacteria) use carbohydrate substrates entering the large intestine and polysaccharides from intestinal mucus.

The metabolic functions performed by saccharolytic microbes maintain homeostasis and neutralize the negative influences of proteolytic flora.

The normal microflora of the GIT carries out metabolic and protective functions. Within the framework of metabolic functions, the GIT microflora synthesizes a number of amino acids, vitamins, short-chain fatty acids (SCFAs), and a whole range of other biologically active substances. The protective and immune functions of the microflora are aimed at maintaining colonization resistance and antagonism against pathogenic and conditionally pathogenic microorganisms. Bifidobacteria and lactobacilli of the normal intestinal microflora regulate non-specific and specific cellular and humoral immunity, induce the synthesis of immunoglobulins, lysozyme, and interferon [7,8,9,10]. Various factors of the external and internal environment can significantly influence the composition of the intestinal microflora, which can not only disrupt the normal course of physiological processes but also lead to severe pathological conditions. A qualitative and/or quantitative change in the composition of the intestinal microflora is called intestinal dysbiosis. One of the most common causes of intestinal dysbiosis is the use of antibiotics, which, due to their spectrum of antibacterial action, can suppress the vital activity of intestinal microorganisms and significantly alter the "microbial landscape" of the GIT. The negative impact of antibiotics on the intestinal microflora can occur through several components. An adverse effect can be caused by the part of the drug that is not absorbed in the intestine or re-enters it due to enterohepatic circulation. Also, the fraction of the antibiotic that enters the systemic bloodstream and exerts an antibacterial effect on various organs and tissues of the body, including the GIT, can suppress the saprophytic bacteria of the GIT (Figure 1).

Figure 1

 

Pathological changes in the composition of the intestinal microflora can contribute to damage to enterocytes and disruption of physiological processes in the intestine, lead to increased intestinal permeability for macromolecules, alter motility, reduce the protective properties of the mucosal barrier, and create conditions for the development of pathogenic microorganisms. The clinical manifestations of impaired intestinal microbiocenosis can vary in severity from mild diarrhea to severe colitis with a fatal outcome. The complex of pathological changes in the composition of the intestinal microflora with corresponding clinical manifestations, developed as a result of antibiotic use, is designated as antibiotic-associated diarrhea (AAD). In patients with this pathology, signs of colitis can almost always be detected endoscopically and histologically, which also makes the term "antibiotic-associated colitis" justified. The frequency of this condition, according to various authors, ranges from 5 to 39%. The most severe and even life-threatening condition associated with antibiotic-associated intestinal dysbiosis is C. difficile-associated colitis, caused by the overgrowth of C. difficile in the intestine.

Cases of pseudomembranous colitis developing up to two months after completion of a course of antibacterial therapy have been recorded [11,12,13]. In some patients, antibiotic intake causes an avalanche-like growth of the C. difficile population. This is accompanied by changes in the toxigenic properties of the microorganism, increasing the synthesis of enterotoxin A and cytotoxin B. The result is severe damage to the colonic mucosa. A severe form of C. difficile-associated colitis is pseudomembranous colitis, the mortality rate of which reaches 30% [14,15,16]. 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. Signs of severe endotoxemia are also often observed, and leukocytosis and increased ESR are detected in the blood. Hyperemia of the mucous membrane and fibrinous films formed on areas of mucosal necrosis, appearing as pale grayish-yellow plaques 0.5-2.0 cm in diameter on a slightly raised base, are found in the colon. Histological examination reveals areas of necrosis of the colonic mucosa, edema of the submucosal layer, round-cell infiltration of the lamina propria, and focal extravasates of erythrocytes. The most accessible diagnostic test for pseudomembranous colitis is the detection of C. difficile toxin A in feces by the latex agglutination method.

Most modern antibiotics can cause intestinal dysbiosis. However, the effects of different groups and individual drugs have certain specificities. In particular, ampicillin suppresses the growth of intestinal microflora to a greater extent than amoxicillin, which only promotes a slight increase in the population of representatives of the Enterobacteriaceae family. This is determined by the significantly lower enteral bioavailability of ampicillin compared to amoxicillin and a fairly large fraction of the drug that remains and acts in the lumen of the large intestine. Antibiotics from the cephalosporin group promote an increase in the number of enterococci and C. difficile. Fluoroquinolones significantly suppress the growth of microbes of the Enterobacteriaceae family and to a lesser extent - enterococci and anaerobic microorganisms, while not promoting the growth of fungi and C. difficile [17].

Three groups of agents are used to restore microflora: probiotics, prebiotics, and synbiotics. Probiotics are food products, medicines, or dietary supplements in the form of monocultures or combined cultures based on live representatives of the resident microflora (bifidobacteria, lactobacilli, enterococci) or non-pathogenic spore-forming microorganisms and saccharomycetes.

Prebiotics are not absorbed in the small intestine and undergo bacterial fermentation in the large intestine. Most prebiotics belong to oligo- or polysaccharides (fiber). Synbiotics are a combination of probiotics and prebiotics. The main group of prebiotics consists of oligosaccharides with 2-10 carbon atoms. Oligosaccharides are not hydrolyzed and are not absorbed in the small intestine because the brush border lacks enzymes for their breakdown. They enter the large intestine unchanged, where they undergo bacterial fermentation. This group of prebiotics includes lactulose - a synthetic disaccharide consisting of fructose and galactose. Lactulose exerts its action only in the large intestine. It is hydrolyzed mainly by bifidobacteria and lactobacilli, for which lactulose serves as a nutrient substrate, leading to an increase in their biomass. Thus, this disaccharide is a bifidogenic and lactogenic prebiotic that normalizes the balance and restores the functions of the microflora [19,20,21]. The final products of lactulose metabolism are formic acid and short-chain fatty acids (SCFAs). The antagonism of bifidobacteria and lactobacilli and the decrease in pH (acidification of the environment) in the intestinal cavity due to acidic metabolites leads to the suppression of the growth of conditionally pathogenic proteolytic microflora. The enhancement of bifidobacteria growth under the influence of lactulose was proven in a study conducted by Bouchnic Y. [22].

Another trial on healthy volunteers showed that while taking lactulose, the population density of bifidobacteria increased by 1.5 times compared to the baseline level, while the population density of clostridia decreased almost 3-fold in parallel. A pronounced effect of lactulose on stimulating the growth and enzymatic activity of bifidobacteria has been demonstrated [23]. An important advantage of lactulose over probiotics is the possibility of its use together with antibacterial drugs in patients undergoing repeated courses of antibiotic therapy for chronic diseases (such as chronic non-specific lung diseases, chronic pyelonephritis, etc.). The prebiotic action of lactulose restores the disturbed microbiocenosis of the large intestine and prevents the suppression of normal microflora. The effectiveness of probiotics in such cases is significantly lower, as the live bacterial strains they contain are adversely affected by the antibiotics. The strains of microorganisms in probiotics are not always compatible with the representatives of the individual's own microflora. Because of this, they can modulate immune inflammation. Furthermore, probiotics can transfer antibiotic resistance to strains of the human microflora. Any probiotic strain is potentially dangerous as a donor and recipient of antibiotic resistance genes. It has been shown that lactulose restores cellular and humoral immunity [8]. As it turns out, its 2-week intake leads to a significant increase or complete normalization of IgA levels, T-helpers, and T-suppressors in different categories of patients.

Lactulose potentiates the positive effects of probiotic lacto- and bifidobacteria. Based on this potentiating combination, dietary supplements and medicinal products classified as synbiotics are formulated.

By Directive of the Government of the Russian Federation No. 2135-r dated December 30, 2009, lactulose is included in the List of Vital and Essential Drugs. Thus, the use of the prebiotic lactulose allows for a significant reduction in risks to the GIT microbiocenosis and increases the effectiveness of antibacterial treatment by potentiating the patient's immune system.

Combined medicinal products have become firmly established in physicians' arsenals. These are products where, alongside the drug exerting the main pharmacodynamic effect on the body, a second drug is included – a corrector for the potential side effects of the first component. Examples of such drugs include: combined diuretics containing hydrochlorothiazide and a potassium-sparing diuretic in one tablet; antiplatelet agents containing low doses of acetylsalicylic acid and an antacid; anti-inflammatory drugs containing an NSAID and a proton pump inhibitor, and a number of other combinations. To reduce the damaging impact of antibiotics on the intestinal biocenosis, "eco-friendly antibiotics" (ECO antibiotics) were developed. The tablets of these antibiotics contain both the antibacterial component and the prebiotic lactulose. One of the important technological features in the manufacture of these drugs is the inclusion of a special form of lactulose – anhydrous lactulose – in the tablet composition. This is highly purified lactulose obtained from a solution by crystallization. The amount of impurities in such lactulose does not exceed 3%, whereas in regular lactulose, impurities can constitute 30-35%. The lactulose crystals undergo prolonged drying, are ground into a powder, and are incorporated into the tablet together with the antibacterial drug from a particular group. This allows for the inclusion of amounts of lactulose sufficient for a prebiotic effect into the relatively small volume of a tablet of a given ECO antibiotic (Figure 2).

Figure 2

The pharmacokinetics of ECO antibiotics are completely analogous to drugs containing only the substance with antibacterial action. That is, ECO antibiotics are fully bioequivalent to "simple" antibacterial agents. Anhydrous lactulose does not interact with the antibiotic molecule, does not affect its chemical structure, pharmacokinetics, or the clinical efficacy of the drug.

Anhydrous lactulose, included in ECO antibiotics in an amount of 300 mg per tablet, provides an adequate prebiotic effect but does not cause changes in osmotic pressure in the intestine, does not affect its motility (no laxative effect), unlike conventional lactulose-containing drugs, and prevents the negative impact of the antibiotic on the body's microbiocenosis (Figure 3).

The ECO antibiotics developed to date are listed in Table 1. The composition and production technology for this group of drugs are patented in more than 30 countries worldwide.

Table 1

ECO Antibiotic	Dosage Form
ECOBOL (Amoxicillin)	Tablets 250 mg, #14 Tablets 500 mg, #14
ECOKLAV (Amoxicillin + Clavulanic Acid)	Tablets 375 mg, #15 Tablets 625 mg, #15 Tablets 1000 mg, #15 Powder for suspension 156.25 mg and 312.5 mg per 5 ml
ECOMED (Azithromycin)	Capsules 500 mg, #3 Tablets 250 mg, #6 Powder for suspension 100 mg and 200 mg per 5 ml
EKOZITRIN (Clarithromycin)	Tablets 250 mg, #14 Tablets 500 mg, #14
EKOTSIFOL (Ciprofloxacin)	Tablets 250 mg, #10 Tablets 500 mg, #10
EKOLEVID (Levofloxacin)	Tablets 250 mg, #5 Tablets 500 mg, #5

As can be seen from Table 1, the list of ECO antibiotics includes the most in-demand and widely used drugs in clinical practice. These are the semi-synthetic aminopenicillin amoxicillin (ECOBOL) and the protected semi-synthetic aminopenicillin co-amoxiclav (ECOKLAV). These drugs are included as first-line agents for treating infections of the upper and lower respiratory tracts and urinary tract infections. Amoxicillin (ECOBOL) is also part of the H. pylori eradication regimens recommended by the fourth Maastricht Consensus. Co-amoxiclav (ECOKLAV), due to the inclusion of clavulanic acid alongside amoxicillin, is resistant to the action of beta-lactamases from staphylococci and many gram-negative aerobic and anaerobic bacteria, which determines its sufficiently broad spectrum of antimicrobial action. Besides treating respiratory infections, the drug is widely used for treating abdominal and pelvic organ infections.

Macrolide antibiotics hold an important place in antibacterial therapy. Drugs of this group are considered as an alternative to semi-synthetic penicillins in the treatment of bacterial infections of the lower and upper respiratory tracts. This is determined by the relatively high sensitivity of pneumococcus to them. Drugs in this group are effective against intracellular pathogens (chlamydia, mycoplasma, ureaplasma, etc.), which expands their capabilities in treating respiratory infections and makes them one of the primary choices for treating sexually transmitted diseases caused by intracellular pathogens. In addition to their antibacterial effect, macrolides possess anti-inflammatory and immunostimulatory properties.

The most in-demand macrolides today are the semi-synthetic ones: clarithromycin and azithromycin. These drugs are also included in the list of ECO antibiotics under the names ECOMED (azithromycin) and EKOZITRIN (clarithromycin). Some researchers classify azithromycin as an azalide due to the presence of a nitrogen atom in its structure. Azithromycin has the greatest ability among the group's drugs to accumulate in tissues, which allows for its once-daily administration for three days in mild to moderate respiratory infections. The drug is quite effective against Haemophilus influenzae, against which other macrolides are significantly less active. Clarithromycin has a pronounced effect on streptococcus and intracellular pathogens. Its high activity against H. pylori has been noted, leading to its inclusion in eradication regimens for this pathogen in patients with peptic ulcer disease and other conditions.

Alongside the main groups of antibiotics, fluoroquinolones are included in modern antibacterial treatment algorithms. These drugs are synthetic antibacterial agents obtained by incorporating fluorine atoms into the quinolone structure. This significantly expanded the spectrum of antibacterial action and optimized the pharmacokinetics of the group's drugs. Today, "classic" and "respiratory" fluoroquinolones are distinguished. Representatives of both classes are present in the ECO antibiotic "lineup." Ciprofloxacin (EKOTSIFOL) has proven to be the most successful and in-demand among the "classic" fluoroquinolones. It possesses pronounced activity against gram-negative pathogens. The drug is effective against various enterobacteria and Pseudomonas aeruginosa. This allows for its successful use in gastrointestinal tract infections, abdominal infections, urinary tract infections, and nosocomial respiratory infections. Traditionally, the "weak point" in the spectrum of "classic" fluoroquinolones, including ciprofloxacin, is their low antibacterial activity against streptococci, including pneumococci. To overcome this drawback, "respiratory" fluoroquinolones were introduced into clinical practice, whose spectrum of action includes streptococci and pneumococci, including penicillin-resistant strains.

These drugs are active against beta-lactamase-producing strains of Haemophilus influenzae, intracellular pathogens, and gram-negative pathogens. This makes them quite universal in treating respiratory infections caused by pathogens with a high level of resistance to antibiotics (beta-lactams, macrolides), which are often found in patients with significant comorbidities, as well as those suffering from advanced stages of chronic obstructive pulmonary disease (COPD) and having a pronounced decrease in external respiratory function parameters. One of the most common and effective "respiratory" fluoroquinolones is levofloxacin. Levofloxacin is used in combination therapy regimens for tuberculosis and in H. pylori eradication regimens recommended by the IV Maastricht Consensus. It should be noted that for the first time, the IV Maastricht Consensus stated the advisability of using prebiotic therapy to enhance the effect of H. pylori eradication. Levofloxacin is also part of the ECO antibiotic group under the name EKOLEVID. Thus, the list of ECO antibiotics includes the most relevant and modern drugs widely used in clinical practice, both at the outpatient stage and in hospitals.

The efficacy and safety of ECO antibiotics have been evaluated in a number of studies. For instance, a comparative evaluation of the efficacy of EKOZITRIN (clarithromycin) and Klacid (clarithromycin) in outpatients with acute bacterial sinusitis showed their identical bacteriological and clinical efficacy. However, a negative impact on the intestinal microflora was detected with Klacid but was absent with EKOZITRIN [24].

In conclusion, it can be noted that ECO antibiotics are drugs that are bioequivalent to conventional antibiotics containing the same antibacterial substance but significantly superior to them in terms of safety regarding their impact on the patient's microbiocenosis, due to the inclusion of a prebiotic dose of highly purified anhydrous lactulose in their composition. Their use helps maintain the balance of the intestinal microflora and supports the patient's intestinal microecology during treatment. The use of ECO antibiotics significantly reduces the risks of developing candidiasis and C. difficile-associated intestinal damage (antibiotic-associated diarrhea). The positive effect of the prebiotic lactulose enhances the patient's immune status and potentiates the antibacterial effect of the ECO antibiotic.

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