Resolution of the Interdisciplinary Council of Experts devoted to the problem of diagnosis and treatment of vaginitis of various etiologies in real clinical practice. Use of a new combined topical drug for the treatment of vaginitis of various etiologies. Educational project "ORIGINAL"

On October 16, 2020, the Council of Experts was held at V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow.

The meeting was attended by G.T. Sukhikh, V.N. Serov, I.I. Baranov, I.A. Apolikhina, M.R. Rakhmatulina, T.V. Priputnevich, S.V. Pavlovich, S.K. Zyryanov, N.N. Klimko, O.I. Butranova.

The participants of the meeting noted that vaginitis is the most common inflammatory diseases of the lower part of the female genital tract, and it is often associated with vaginal dysbiosis. Among outpatients, every third or fourth patient sees a gynecologist because of vulvovaginal infections.

Vaginitis, especially in the case of its complicated course, can cause not only a decrease in the quality of life, but also a negative impact on a woman's reproductive function. There is evidence of a negative effect of vaginitis on fertility and a correlation with miscarriage [1].

Biocenosis is a unique ecosystem that protects the female genital tract from causative agents of genital infections. Normal vaginal microbiota containing lactobacilli that produce lactic acid (pH 3.8–4.5) is a key factor of local immunity [2]. A balanced biocenosis stimulates immune mechanisms and the formation of H2O2; it protects the mucous membranes of the vagina preventing the development of bacterial vaginosis and aerobic (non-specific) vaginitis in most cases. The impairment of normocenosis can result from a number of causes, including trauma during childbirth, improper intimate hygiene, menopause, pharmacological aggression, etc. It is known that every Russian woman experiences at least one episode of bacterial vaginosis (BV) during her life, and every third has vaginitis. There are different species and a wide range of infections that can cause inflammatory diseases of the female genitals. The causative agents are bacteria (40–50% of cases), Candida fungi (20–25%), trichomonads and viruses (10%). Among the pathogens of non-specific (aerobic) vaginitis there are Esherichia spp., Enterococcus spp., Corynebacterium spp., Streptococcus spp., Staphylococcus spp. and others, as well as their combinations, including Candida spp., Trichomonas vaginalis. At the same time, there is an increase in the frequency of vaginal infections caused by microorganisms from the normal vaginal microflora.

In a general population of women, the incidence of BV may be 15–50%, vulvovaginal candidiasis (VVC) is 16–30%, Trichomonas vaginitis is 5–25%, and aerobic vaginitis is 2–8% [3, 4]. One third of all types of vaginitis has mixed forms, their clinical picture is often characterized by a decrease in the number and severity of symptoms which makes it difficult to diagnose and contributes to the prolonged course of the disease [5]. This problem is an interdisciplinary one, since women with vaginitis symptoms may be the patients of a gynecologist, dermatologist, venereologist or urologist.

The treatment of mixed infections requires a comprehensive approach and exposure to all etiological agents [5]. Unsatisfactory results of therapy and chronic inflammatory processes in some cases are due to imperfect treatment regimens where complex interactions of all constituents of the microflora are not taken into account. Mixed infections often require the use of several medications, which leads to polypharmacy and low compliance [6]. Higher incidence of mixed infections increases the role of differential diagnosis. However, the actual clinical practice of an obstetrician-gynecologist in the treatment of vulvovaginal infections shows that therapy is often prescribed empirically before receiving the results of a microscopic smear analysis or due to the fact that such a study is impossible.

Modern approaches to the diagnosis of lower urinary tract infections have significantly changed the view of their etiology. Thus, until the middle of the XX century, the vaginal microcenosis was considered homogeneous and represented mainly by Lactobacillus acidophilus («Doderlein bacillus»). Further studies have shown that the vaginal microcenosis of reproductive-aged women is represented by Lactobacillus spp. and a large group of opportunistic microorganisms.

In the modern methodology, there is a more precise approach to such concepts as normocenosis, BV, aerobic vaginitis, and VVC. In particular, Lactobacillus acidophilus has been proven to be responsible for the normal state. But the study of the vaginal microbiota made it possible to identify other types of lactobacilli. The spectrum of yeast fungi that cause the development of VVC is also diverse, and their species identification is very important for determining their sensitivity to antimycotic drugs. The necessity of differential diagnosis has also been proved by the results of studies showing that the sensitivity of the main pathogens of aerobic vaginitis (Escherichia coli, Streptococcus agalactiae) has decreased significantly.

The treatment is based on its two-stage approach which implies action on the pathogen and obligatory reconstitution of the local immune status.

The clinicians agree on the opinion that the treatment of acute and chronic vaginitis requires drugs that would affect pathogenic microorganisms with minimal impact on the normal microflora.

Metronidazole which is a 5-nitroimidazole derivative meets these requirements among antimicrobial and antiprotozoal drugs. Preparations of this group interact with the DNA of microbial cells inhibiting the synthesis of their nucleic acids and producing a bactericidal effect [7–9].

Available data indicate that metronidazole does not affect normal microflora, but it remains active against anaerobic bacteria, and also has an anti-Trichomonas effect. Metronidazole is characterized by a minimal increase in resistance levels, despite long-term experience of use [10].

Chloramphenicol is an antibacterial drug with a bacteriostatic effect that has a wide range of activity (Gram-positive and Gram-negative bacteria, including those typical of the intestinal flora, as well as chlamydia, rickettsia, spirochetes, etc.). The drug suppresses the synthesis of microbial proteins by binding the 50S ribosome subunit and stops the formation of the peptide chain [11].

Topical use of chloramphenicol in gynecology is characterized by a high safety profile which is confirmed by the data of studies that included pregnant women [12, 13]. Chloramphenicol is practically not absorbed when used intravaginally. Systemic side effects in intravaginal use are not described.

Natamycin is a polyene antimycotic from the group of macrolides that has a fungicidal (dose-dependent) effect. The spectrum of activity of this drug includes most yeast-like fungi Candida spp., Rhodotorula spp., etc., dermatomycetes (Trichophyton, Microsporum, Epidermophyton), mycelial fungi (Aspergillus spp., Fusanium spp.), protozoa (trichomonads, acanthamoeba, etc.) [14, 15].

Natamycin binds sterols of fungal cell membranes, impairing their integrity and function. This impairment leads to changes in cell permeability and cell death; it has a fungistatic effect and does not have a systemic effect.

Resistance to natamycin is not found in clinical practice. Moreover, topical polyenes, which include natamycin, in contrast to other groups of antimycotics, are safe for pregnant women and the fetus [16].

Hydrocortisone acetate is a glucocorticosteroid (GCS) that has anti-inflammatory properties: analgesic, antiexudative, decongestant, and antipruritic [17]. Unlike the above-mentioned drugs, hydrocortisone is responsible not for the etiological, but for the symptomatic and pathogenetic component of therapy.

The clinical experience of intravaginal use of hydrocortisone drugs shows the safety of topical use of the drug in gynecology, which is confirmed by the results of published scientific papers [18, 19].

Hydrocortisone acetate has moderate glucocorticoid activity and is practically not absorbed during topical application. In comparison with synthetic GCS (including more active prednisone compounds), hydrocortisone acetate can act as an optimal drug for intravaginal use [20].

In general, local therapy with combined drugs demonstrates its advantages in the treatment of vaginal infections and provides:

• the possibility of using small doses of antimicrobial drug;
• the concentration of the drug in the focus of infection;
• wide range of actions;
• low risk of systemic exposure and optimal use for patients with extragenital diseases.

The choice of combined intravaginal medications is also reflected in the draft of new clinical guidelines for the management of patients with vaginitis.

The basis of intravaginal preparations is of great importance, therefore, semi-synthetic glycerides (Suppocire AM) are optimal. The substance melts under the influence of body temperature and contributes to the uniform distribution of the active components of the drug on the mucosa. The convenience of using suppositories on this basis increases patients’ adherence to the treatment [21, 22].

In 2020, a new Russian drug «Targifort», developed by the company Avexima, was registered. It is intended for intravaginal treatment of vaginitis and its prevention. Its action is due to the total effect of its components: metronidazole (500 mg), chloramphenicol (200 mg), natamycin (150 mg), hydrocortisone acetate (15 mg).

The company Avexima initiated an open comparative randomized multicenter clinical trial «Use of a new combination medication for topical application (metronidazole + chloramphenicol + natamycin + hydrocortisone acetate) in the treatment of vaginitis of various etiologies». The scientific coordinator of the study was the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia [23].

The aim of the phase III study was to determine the efficacy and safety of the medication «Targifort» in two groups of 360 women aged 18–45 years with acute vaginitis. According to the study design, patients of one group received the drug «Targifort», vaginal suppositories (JSC «Avexima», Russia); patients of the other group received vaginal tablets containing neomycin sulfate, ternidazole, nystatin, and prednisolone sodium metasulfobenzoate. The treatment lasted for 10 days in both groups.

The task was to assess the full recovery rate determined by clinical and laboratory criteria, including the absence of symptoms such as pain, burning, and itching. All these symptoms were controlled in most of the patients in both groups within the particular time period. There were more asymptomatic patients in the group that received the medication «Targifort», vaginal suppositories, taking into consideration such symptom as itching. In the same group, the symptoms of pain and burning were relieved faster than in the group of patients who received vaginal tablets containing neomycin sulfate, ternidazole, nystatin and prednisolone sodium metasulfobenzoate.

The study demonstrated that the efficacy of the drug «Targifort», vaginal suppositories is not lower in a number of indicators that affect the quality of life of patients (absence of pain in 98.3%, burning in 97.8%, itching in 98.9% in patients of the «Targifort» group and 98.3%, 97.8% and 95.4% in patients of the comparison group); the rate of disappearance of pain and burning (4.3 and 4.8 days) in patients taking «Targifort» is statistically significantly higher than in patients who received vaginal tablets, containing neomycin sulfate, ternidazole, nystatin and prednisolone sodium metasulfobenzoate (5.6 and 5.8 days).

Thus, the symptom of pain was on average controlled faster in patients receiving medication «Targifort», vaginal suppositories, by 1.3 days and the symptom of burning was controlled faster by 1 day. In both cases, the differences were statistically significant.

This drug meets the criteria for modern treatment of non-specific vaginitis. Due to its components (chloramphenicol, metronidazole, natamycin and hydrocortisone acetate), the medication «Targifort», a vaginal suppository, provides a wide range of etiotropic (antimicrobial, antiprotozoal, antifungal) and symptomatic (anti-inflammatory, anesthetic, anti-exudative, decongestant and antipruritic) effects.

Bioavailability and systemic effect of the active components of the medication «Targifort», vaginal suppositories, is much lower than that of oral dosage forms, which favorably affects the safety and tolerability of this therapy.

The results of the study proved the efficacy and safety of a new Russian drug «Targifort», vaginal suppositories and allow the participants of the Council of Experts to recommend the drug «Targifort», vaginal suppositories for the empirical treatment of vaginitis of various etiologies and/or in association with mixed flora in reproductive– aged women, including preventive administration before gynecological and diagnostic operations and intrauterine manipulations.

Participants of the Expert Council and authors of the Resolution

Gennadiy T. Sukhikh, Academician of RAS, MD, Honored Scientist of the Russian Federation, Professor, Director of V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia; Head of the Department of Obstetrics, Gynecology, Perinatology and Reproductive Medicine, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Moscow)

Vladimir N. Serov, Academician of RAS, MD, Professor, President of the Russian Society of Obstetricians and Gynecologists (Moscow)

Igor I. Baranov, MD, Professor, Head of the Department of Scientific and Educational programs, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia (Moscow)

Inna A. Apolikhina, MD, Professor, Head of Department of Aesthetic Gynecology and Rehabilitation, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia; Professor of the Department of Obstetrics, Gynecology, Perinatology, and Reproductive Medicine, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia; President of the Association of Specialists in Aesthetic Gynecology and European Association for Genital Aesthetic Medicine and Plastic Surgery (EAGAMPS) (Moscow)

Margarita R. Rakhmatulina, MD, Professor of the Department of Dermatovenereology and Cosmetology with the Course of Clinical Laboratory Diagnostics, A.I. Burnazyan Federal Medical Biophysical Center, Federal Biomedical Agency of Russia (Moscow)

Tatyana V. Priputnevich, MD, Head of the Department of Microbiology, Clinical Pharmacology and Epidemiology, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia (Moscow)

Stanislav V. Pavlovich, PhD, Associate Professor, Academic Secretary, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia; Professor of the Department of Obstetrics, Gynecology, Perinatology, and Reproductive Medicine, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Moscow)

Sergey K. Zyryanov, MD, Professor, Head of the Department of General and Clinical Pharmacology, Peoples’ Friendship University of Russia; Deputy Chief Physician of City Hospital No. 24 (Moscow)

Nikolay N. Klimko, MD, Professor, Head of the Department of Clinical Mycology, Allergology and Immunology, North-Western State Medical University named after I.I. Mechnikov (Saint-Petersburg)

Olga I. Butranova, PhD, Associate Professor, Director of Studies at the Department of General and Clinical Pharmacology, People’s Friendship University (Moscow)