Pharmacological properties of the drug Metronidazole
A nitroimidazole derivative that has antiprotozoal and bactericidal effects. Active against Trichomonas vaginalis, Entamoeba histolytica , Giardia Lamblia , as well as against obligate anaerobes, including anaerobic gram-negative bacteria ( Bacteroides spp. , including the Bacteroides fragilis group , Fusobacterium spp. ), anaerobic gram-positive bacteria ( Clostridium spp. and sensitive strains Eubacterium ), anaerobic gram-positive cocci (including Peptococcus spp. and Peptostreptoccus spp. ). Not active against aerobic bacteria. The formation of resistance of infectious agents to metronidazole has not been observed. Metronidazole penetrates into microorganisms, and its nitro group is probably converted into hydroxylamine, which contributes to the effect on the DNA of microorganisms, leading to their death. Almost completely absorbed after oral administration. Concomitant food intake does not affect the absorption of metronidazole. After oral administration at a dose of 200 mg, the maximum plasma concentration (about 5 mcg/ml) is achieved in approximately 1–2 hours. Less than 10% of metronidazole is bound to plasma proteins. Quickly distributed in the body. It enters the liver and is excreted in high concentrations in bile. Partially excreted in urine unchanged and in the form of metabolites.
Indications for use of the drug Metronidazole
Acute and chronic trichomoniasis, giardiasis, amebiasis, cutaneous leishmaniasis, acute ulcerative gingivitis, peptic ulcer of the stomach or duodenum. Infections caused by anaerobic pathogens sensitive to metronidazole: infections of the central nervous system (brain abscess, meningitis), lungs and pleura (abscess pneumonia, aspiration pneumonia, lung abscess), abdominal organs and peritoneum (peritonitis, liver abscess, infectious complications after direct surgery and colon), pelvic organs (endometritis, infectious complications after hysterectomy), ENT organs (including Simanovsky-Plaut-Vincent angina), bones and joints (including osteomyelitis), endocarditis, gas gangrene, oral infections , teeth, jaws, septicemia with thrombophlebitis, for prophylactic purposes during surgical interventions with an increased risk of anaerobic infection (gynecological operations, operations on the abdominal organs). Intravaginal administration: bacterial vaginosis of various etiologies. External use: papular-pustular rash, rosacea and vulgar acne.
Indications
- Treatment of protozoal infections: intestinal and extraintestinal amebiasis, trichomoniasis.
- Infections caused by gram-negative anaerobes of the Bacteroidaceae family: brain and lung abscesses, necrotizing pneumonia, infections of the osteoarticular system, bacterial endocarditis and sepsis.
- The drug is effective against clostridial flora, which causes infections of the genitourinary system and infections of the abdominal organs.
- Metronidazole is used in gastroenterology for the treatment of gastritis, gastric and duodenal ulcers associated with H. pylori.
- Prophylactic use during operations on the colon and gynecological interventions.
Use of the drug Metronidazole
Orally For the treatment of trichomoniasis, 0.25 g is prescribed orally 2 times a day for 7–10 days. Sometimes in the first 3-4 days 0.25 g is prescribed 3 times a day. The total dose per course of treatment is 5 g. Children are prescribed in smaller doses according to age. For giardiasis, the dose for adults is 0.25 g 2 times a day for 5 days, for amebiasis - 0.25 g 2-3 times a day, for children aged 2 to 5 years - 0.25 g per day, from 5 to 10 years - 0.375 g, from 10 to 15 years - 0.5 g per day with meals in 1-2 doses. Treatment of amebiasis usually lasts 10 days. When treating cutaneous leishmaniasis, adults are prescribed 0.2 g 4 times a day for 7 days, children 0.1 g 3 times a day, then after a 7-day break for 14 days, adults 0.2 g 3 times per day, for children - 0.1 g 2 times a day. For anaerobic infections, therapeutic doses for oral administration for adults and children over 13 years of age are usually 0.4–0.5 g 3 times a day (during or after meals) for 7 days or more. Children under 13 years of age - at the rate of 7.5 mg/kg 3 times a day. IV Administer intravenously. Before administration, you can additionally dilute the required volume with 0.9% sodium chloride solution, dextrose or potassium chloride solution for infusion. For therapeutic purposes, adults and children over 12 years of age are given 0.5–1 g of metronidazole intravenously at the beginning of treatment, then 0.5 g every 8 hours. Metronidazole can be used as monotherapy or in combination with other antibacterial agents (do not mix in one bottle). As a rule, parenteral administration of metronidazole is continued for 7 days, then the patient is prescribed metronidazole for oral administration at a dose of 400 mg 3 times a day. If necessary (depending on clinical and bacteriological data), intravenous administration of metronidazole is continued for a longer time. The daily dose of metronidazole should not exceed 4 g. For preventive purposes, adults and children over 12 years of age are administered 500–1000 mg of metronidazole on the eve of surgery, on the day of surgery and the day after it - 1500 mg/day (500 mg every 8 hours). After 1–2 days (or after a longer period) they switch to the use of metronidazole orally (200–400 mg/day); the general course of prophylactic use of metronidazole is usually 7 days. For the treatment of children under 12 years of age, a single dose of metronidazole administered intravenously for therapeutic purposes is 7.5 mg/kg (and the dose of metronidazole for subsequent oral administration is 3.7–7.5 mg/kg). In severe liver diseases, it is recommended to administer a reduced dose of metronidazole, since in these cases the metabolism and elimination of metronidazole slows down. Intravaginally Used in gel form. The dose of metronidazole for intravaginal administration is 50 mg 2 times a day (morning and evening). The course of treatment is 5 days. Externally A thin layer of 1% gel is applied to a previously cleansed affected area of skin 2 times a day (morning and evening) and lightly rubbed. A pronounced clinical effect is observed after 3 weeks of therapy.
The use of a combination of metronidazole and miconazole in the correction of vaginal dysbiosis
Introduction
One of the most common complaints when women visit a gynecologist is pathological discharge from the genital tract (leucorrhoea). The cause of pathological vaginal discharge can be a number of diseases and conditions [1]. According to various researchers, in 22–50% of cases, leucorrhoea is a symptom of bacterial vaginosis (BV) [2]. BV is a non-inflammatory disease of the vagina associated with changes in its microflora. This condition is extremely widespread among women of fertile age (20–45 years), its incidence in this group reaches 80%, i.e., out of 10 women, 8 experience BV at least once in their life. The disease does not pose a danger to the patient herself, but can negatively affect her reproductive function. BV often causes miscarriages, intrauterine fetal infections, complications after childbirth, abortions, and invasive interventions on the genitals. It has now become known that the vaginal microbiocenosis is a dynamic and much more complex ecosystem than previously thought. The state of the microflora of the genital area most seriously affects the health of women as a whole [2]. For the first time in 1892, Doderlein presented descriptions and images of the vaginal bacillus, subsequently named after him, and divided the bacterial communities of the female genital tract into “normal” (with a predominance of vaginal lactic acid bacilli) and “abnormal” (containing other numerous organisms, often streptococci or staphylococci ) [2]. It is known that the vagina is normally populated by lactobacilli, which break down glycogen, which is rich in vaginal epithelial cells, to form lactic acid. Thus, an acidic environment is constantly maintained in the woman’s lower genital tract, which prevents the establishment and growth of pathogenic microflora. To maintain normal conditions and the protective function of the vagina, a large number of lactobacilli are necessary, so their share in its biocenosis is 95–98%. For various reasons listed below, lactic acid bacilli are displaced and replaced by other microorganisms. This situation facilitates the colonization of the vagina by pathogenic microorganisms - causative agents of sexually transmitted infections, but in most cases there is a change to nonspecific microflora. It includes bacteria that live on the skin of the perineum, perianal folds, and in the lower part of the urethra. They freely occupy a new habitat, multiply intensively, but cannot perform the functions of normal microflora. Their enzyme system is different from that of lactobacilli and does not break down glycogen to form lactic acid. Nonspecific microflora causes a number of disturbances in the metabolic and immune processes of the vagina as a whole. The level of production of protective immunoglobulin A decreases, which prevents pathogenic agents from attaching to the vaginal epithelium. Epithelial cells partially adsorb opportunistic bacteria on their surface and are intensively desquamated, which is associated with the appearance of discharge in BV. Lactobacilli are replaced mainly by anaerobes - bacteria that function without access to oxygen. Some of the products of their metabolism - volatile fatty acids and amino acids - are broken down in the vagina into volatile amines, which have a characteristic fishy odor. The described changes lead to a shift in vaginal pH from acidic to alkaline values. This entails progressive changes in the protein, carbohydrate, mineral and lipid metabolism of epithelial cells. Their production and mucus production increase, which clinically manifests itself as heavy discharge - the main symptom of BV. It should be noted that there is no inflammatory reaction in the walls of the vagina, and all changes are only functional in nature. Currently, a detailed study of the cultural and biochemical properties of representatives of vaginal biopsy specimens has led to the transformation of knowledge about the types of disorders of vaginal normocenosis and its infectious pathology [3]. So, BV is not a sexually transmitted infection
and does not have a single pathogen, which is why it is otherwise called “nonspecific vaginosis.” The root cause is a change in the vaginal environment, which entails disturbances in microbiocenosis. The microflora that replaces lactobacilli can be different and is most often represented by associations of opportunistic bacteria. Among them, the following groups are distinguished: bacteroids; peptococci; peptostreptococci; megaspheres; leptotrichia; atopobium; gardnerella; mycoplasma. It is also worth noting that disturbances of the vaginal microcenosis occur in 45–86% of patients in gynecological hospitals and lead to infectious complications after surgical interventions on the pelvic organs and contribute to the occurrence of diseases of the internal organs. By damaging the biological barrier, they increase several times the likelihood of infection with sexually transmitted pathogens. The growth of lactobacilli, as a rule, is excessive - their number in vaginal secretions reaches 1010 per 1 ml. However, comfortable conditions for their reproduction arise only after the influence of certain factors of the external or internal environment of the body [4].
The main causes of BV can be divided into 2 large groups.
Internal (endogenous): hormonal imbalance with a predominance of progesterone; atrophy of the vaginal mucosa; intestinal dysbiosis; immune disorders in the body. External (exogenous): long-term treatment with antibiotics; drug immunosuppression (taking cytostatics, glucocorticoids); radiation therapy of tumors; foreign objects in the vagina (hygienic tampons, pessaries, contraceptive diaphragms, rings); use of spermicides, frequent douching; failure to comply with personal hygiene rules. All of these factors in one way or another disrupt the normal functioning of the vaginal mucosa or cause the death of a large number of lactobacilli. Thus, a niche is freed up for opportunistic microflora, and it immediately occupies it. Despite the fact that the disease is not a sexually transmitted infection, its occurrence is often associated with sexual intercourse, especially when changing partners. Signs of BV in women develop on average one day after sexual intercourse without a barrier method of contraception. If the cause of the disease was the use of antibiotics and other medications, changes in hormonal levels (menopause), then the symptoms of BV develop regardless of sexual activity. According to modern concepts, one of the key links in the pathogenesis of BV is the ability of etiologically significant bacteria to form biofilms [2]. A biofilm is a microbial community in which cells are attached to any surface and/or to each other and are enclosed in an interbacterial matrix of extracellular polymeric substances synthesized by them; bacteria in biofilms have altered physiological properties [5]. Biofilm microflora is more resistant to adverse factors of a physical, chemical and biological nature compared to free-floating (planktonic) bacteria. Under such conditions, bacteria are resistant to ultraviolet radiation, dehydration, viruses, antibiotics and immune defense factors. The stability factor of biofilms is the mucus-polymer layer produced immediately after adhesion and including lipopolysaccharides, proteoglycans, glycoproteins, endopolysaccharides, similar to the substance of the cell wall, glycocalyx and bacterial capsules [5]. Recent studies indicate that BV exists as a polymicrobial biofilm infection [6, 7]. It is believed that Gardnerella vaginalis
is the first to attach to the vaginal epithelium and then serves as a “scaffold” for the attachment of other bacteria.
R. Alveset al. [8] identified 30 species of bacteria associated with BV and, in model experiments, characterized their virulence, defined as high adhesion, cytotoxicity, and a predisposition to form biofilms. It was shown that most bacteria associated with BV tended to grow as biofilms, but G. vaginalis had the highest virulence (60–90%), and Atopobium vaginae had the lowest.
The diagnosis of BV is established after collecting the patient’s medical history, studying her complaints, examining her in a gynecological chair and obtaining laboratory data.
In favor of BV, they say: age - sexually active women of reproductive age are most often affected; relationship with a change of partner, treatment of other diseases, surgical intervention; moderate or mild severity of clinical signs of the disease. During the examination, the doctor assesses the condition of the vagina, cervix, and external genitalia. With nonspecific changes, the mucous membrane is pink, not inflamed, and unevenly covered with secretions. In acute BV they are white-gray, with an unpleasant odor. If the disease has become chronic and lasts for several years, the discharge changes its color to yellowish-green, becomes thicker, more viscous, resembles cottage cheese or has a foamy appearance. During the examination, the gynecologist measures the vaginal pH with an indicator strip: with BV, its value is above 4.8–5.0. It is also worth noting the Nugent criteria - one of the main diagnostic systems for BV, which, however, in the light of new data on the “lactobacillary-free” type of vaginal microflora has shortcomings. Thus, to characterize the microbiota, the number of lactobacilli relative to BV, the associated bacterial morphotypes, is assessed. Indeed, women with a predominance of Lactobacillus spp
. they do not have BV in the vaginal biopsy. However, the conclusion that a small number of lactobacilli or their absence clearly confirms the presence of BV is incorrect [2]. Laboratory diagnosis of BV involves microscopy of stained vaginal smears. Key cells are found in them - epithelial cells of the mucous membrane with microbial bodies adhered to their surface. The cell takes on a granular appearance, its boundaries become fuzzy and dotted. Also, microscopy reveals a sharp decrease in the number of lactobacilli, up to complete disappearance from the population [2, 9, 10]. Instead, nonspecific microflora is found: single cocci, streptococci, small bacilli. Bacteriological seeding of secretions is carried out in rare cases when it is necessary to accurately determine the composition of the altered microflora. Currently, the gold standard for diagnosing BV is real-time polymerase chain reaction.
Treatment of BV
It is known that bacteria in biofilms respond to antibiotic therapy differently than planktonic bacteria, since the intercellular matrix of the biofilm can bind or not allow and/or inactivate antibiotics [7, 8]. In this regard, the formation of biofilms in BV is considered one of the main causes of persistent and recurrent BV [7, 8]. The search for drugs capable of penetrating biofilms and destroying them seems to be an urgent task. In vitro
data indicate the ability of lactobacilli to effectively destroy biofilms [7], which allows us to consider the combination of antibacterial drugs with probiotics as a promising approach to the treatment of BV.
The following regimens are recommended for the treatment of BV: European recommendations for the management of patients with pathological vaginal discharge, published by the International Union against Sexually Transmitted Infections - IUSTI (International Union against Sexually Transmitted Infections)/WHO in 2011: metronidazole (gel 0.75%) 5 g intravaginally for 5 days or clindamycin (2% cream) 5 g intravaginally at bedtime for 7 days, or clindamycin per os 300 mg twice a day for 7 days [11]. 2010 Centers for Disease Control and Prevention (CDC) recommendations: metronidazole 500 mg orally bid for 7 days or metronidazole (0.75% gel) 5 g vaginally at night for 5 days, or clindamycin (2% cream) 5 g vaginally at night for 7 days [12]. We carried out a study, the purpose
of which was to compare subjective and laboratory parameters before the study and 14 days after using the drug metronidazole and miconazole (combined drug Metromicon-Neo® (JSC Avexima, Russia) in the treatment of BV.
Material and methods
A study was conducted at the Medsi CDC on Krasnaya Presnya, in which 40 women aged 20–45 years with disorders of the vaginal microcenosis took part. The diagnosis was established on the basis of complaints, an outpatient test to determine the level of acidity of the vaginal contents and the results of a dynamic microscopic examination. The study drug was Metromicon-Neo®, which is available in the form of vaginal suppositories containing 500 mg of metronidazole and 100 mg of miconazole. Metromicon-Neo® has antibacterial, antiprotozoal and antifungal effects.
Mechanism of action of Metromicon-Neo®:
Metronidazole belongs to the 5-nitroimidazoles and is a drug with a bactericidal type of action that exhibits tropism (the ability to interact) with deoxyribonucleic acid (DNA). The mechanism of action is the biochemical reduction of the 5-nitro group of metronidazole by intracellular transport proteins of anaerobic microorganisms and protozoa. The reduced 5-nitro group of metronidazole interacts with the DNA of microbial cells, inhibiting the synthesis of their nucleic acids, which leads to the death of bacteria. Active against protozoa: Trichomonas vaginalis, Entamoeba histolytica
, as well as obligate anaerobic bacteria: gram-negative -
Bacteroides spp
.
(including Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus), Fusobacterium spp., Veillonella spp., Prevotella spp;
(Prevotella bivia, Prevotella buccae, Prevotella disiens) , gram-positive -
Clostridium spp., Eubacterium spp., Peptococcus spp., Peptostreptococcus spp:, Mobiluncus spp.
and facultative anaerobe -
Gardnerella vaginalis.
Aerobic microorganisms are insensitive to metronidazole, but in the presence of mixed flora (aerobes and anaerobes), metronidazole acts synergistically with antibiotics, with a positive result against ordinary aerobes.
Miconazole is an azole derivative antifungal agent. When used intravaginally, it is active mainly against Candida albicans
. The fungicidal and fungistatic effects of miconazole are caused by inhibition of the biosynthesis of ergosterol in the membrane and plasma membranes of fungi, changes in the lipid composition and permeability of the cell wall, which causes the death of the fungal cell. Indications for use: vaginal candidiasis; trichomonas vaginitis, BV; mixed vaginal infection.
Research results
Before treatment, patients were mainly concerned about the presence of vaginal discharge with an unpleasant odor, and less frequently complained of burning, itching and discomfort in the genital area (Table 1).
Before treatment, all women studied had a vaginal pH of more than 5.0. When microscopy of vaginal smears, the microflora was mainly represented by cocci, a large number of key cells were found, the presence of a large amount of epithelium was detected in 12.5% of cases (Table 2).
All women received Metromicon-Neo® vaginal suppositories, 1 suppository in the morning and at night for 7 days. After 2 weeks Subjective and microscopic findings were assessed. As a result, it was shown that after treatment the patients had a significant reduction in the number of complaints (Table 3).
After treatment, all patients had vaginal pH ≤4.5. According to microscopic examination of vaginal smears, normalization of its microflora was observed (Table 4).
Thus, with the use of the drug Metromicon-Neo®, positive treatment results were noted (clinical picture data, microscopic examination) and good tolerability of the drug.
Conclusion
Based on the data obtained, we can conclude that Metromicon-Neo® can be recommended for the treatment of BV.
The use of combined antimicrobial drugs at the initial stages of the development of BV leads to a reduction in the risk of formation of pathological biofilms, thereby reducing the frequency of disease relapses. Information about the authors:
Yulia Eduardovna Dobrokhotova - Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology, Faculty of Medicine. Federal State Budgetary Educational Institution of Higher Education Russian National Research University named after. N.I. Pirogov of the Russian Ministry of Health. 117997, Russia, Moscow, st. Ostrovityanova, 1. Ivanova Irina Igorevna - obstetrician-gynecologist, gynecologist-endocrinologist. CDC "Medsi" on Krasnaya Presnya. 123242, Russia, Moscow, st. Krasnaya Presnya, 16. Contact information: Ivanova Irina Igorevna, e-mail: [email protected] . Financial transparency: none of the authors has a financial interest in the materials or methods presented. conflict of interest . The article was received on August 23, 2018.
About the authors : Yulia E. Dobrokhotova - Doctor of Medical Science, professor Head of Department of Obstetrics and Gynecology, Medical Faculty, NI Pirogov Russian National Research Medical University.
1, Ostrovityanova str., Moscow, 117997, Russian Federation. Irina I. Ivanova - obstetrician-gynecologist, gynecologist-endocrinologist. CDC “Medsi in Krasnaya Presnya”. 16, Krasnaya Presnya str., Moscow, 123242, Russian Federation. Contact information: Irina I. Ivanova, e-mail: [email protected] . Financial Disclosure: no author has a financial or property interest in any material or method mentioned. There is no conflict of interests. Received 08/23/2018.
Side effects of the drug Metronidazole
Nausea, vomiting, epigastric discomfort, diarrhea, metallic taste in the mouth, candidiasis of the oral and intestinal mucosa, headache, dizziness, drowsiness, lack of coordination, depression; when using high doses - peripheral neuropathy, manifested by myalgia, paresthesia; leukopenia, allergic reactions (skin rash, fever). With intravaginal administration, candidal cervicitis, vaginitis, itching, burning and irritation in the vagina, vulva, swelling of the vulva, vaginal discharge, and frequent urination are possible.
Special instructions for the use of the drug Metronidazole
For organic diseases of the central nervous system and granulocytopenia, metronidazole is prescribed only for health reasons. The use of metronidazole in the first trimester of pregnancy is not recommended; In the second and third trimesters of pregnancy, metronidazole can be used only for health reasons. If it is necessary to prescribe metronidazole, breastfeeding should be temporarily discontinued. Breastfeeding can be resumed 2-3 days after stopping metronidazole. When prescribing a course, systematic monitoring of the peripheral blood picture is necessary. During treatment with metronidazole, you should not drink alcohol due to the possibility of developing a disulfiram-like reaction (dizziness, vomiting). During therapy with metronidazole, it is possible to obtain falsely reduced values of ALT and AST activity in the blood plasma when determined by the spectrometric method. During the use of metronidazole, the urine becomes dark in color.
Drug interactions Metronidazole
With the simultaneous use of metronidazole and indirect anticoagulants, it is possible to increase their concentrations in the blood plasma and increase the risk of bleeding, and therefore regular monitoring of the coagulogram is necessary. With the simultaneous use of metronidazole and lithium salts, an increase in the concentration of lithium in the blood plasma is possible. The simultaneous administration of barbiturates and phenytoin leads to a decrease in the effectiveness of metronidazole. Cimetidine in some cases may slow down the elimination of metronidazole and increase its concentration in the blood serum. When used simultaneously with disulfiram, dizziness and confusion may occur.
List of pharmacies where you can buy Metronidazole:
- Moscow
- Saint Petersburg
Interaction with other medications
Sulfonamides potentiate the main effect of metronidazole.
Simultaneous use with disulfiram increases the risk of developing psychosis. The medications should be taken two to three weeks apart.
During therapy with metronidazole, it is necessary to stop drinking alcohol, including drugs made from ethanol. Neglect will lead to disulfiram-like reactions.
Metranidazole potentiates the activity of indirect anticoagulants, which increases the risk of bleeding. While taking metronidazole, it is necessary to strengthen monitoring of prothrombin time and adjust the dose of anticoagulants.
