RU2505296C1 - Method for empiric treatment of females with inflammatory small pelvis diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: azithromycin infusions are combined with the daily administration of metronidazole. Azithromycin is administered in a single dose of 1.0 g on the 5th post-infusion day. The treatment is combined with the daily administration from the first day of the metronidazole therapy twice a day in a dose of 500 mg for 14 days.

EFFECT: effective treatment ensured by reducing a dose and risk of side effects.

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Description

The invention relates to dermatovenerology and obstetrics-gynecology, namely to the treatment of inflammatory diseases of the pelvic organs.

Inflammatory diseases of the pelvic organs (PID) are the most common pathology in the modern world. This term refers to the spectrum of inflammatory diseases of the upper part of the female reproductive tract, combining various combinations of endometritis, salpingitis, tubo-ovarian abscess and pelvic peritonitis [1, 2].

Women with PID make up 60-65% of outpatient gynecological patients and up to 30% hospitalized [3].

VZOMT has a polymicrobial etiology, the structure of which is dominated by sexually transmitted pathogens (STIs), Neisseria gonorrhoeae (25-50%) and Chlamydia trachomatis (25-30%) [4, 5], as well as anaerobes. In Russia, especially among adolescents and young women, among the etiological factors, the leading role is played by C.trachomatis (UXI) [6]. In the absence of timely treatment, 40% of women with UCI develop PID [7, 8], which are associated with a 4–6-fold increase in the risk of irreversible damage to the fallopian tubes. Many authors in the study of tube aspirates, biopsy samples from fibria found in 30-80% of patients with C. trachomatis [9, 10].

To prevent the long-term effects of PID, affecting the reproductive function of women, treatment should be started as early as possible [11].

Most patients with PID can be treated on an outpatient basis or in day care hospitals (at dermatovenerologists, obstetrician-gynecologists), for a mild and moderate course of the disease is observed in 36%, subclinical in 60%, and in severe cases they are subject to hospitalization.

Preparations for the treatment of PID should lead to the elimination of, first of all, N. gonorrhoeae and C.trachomatis. Step-by-step therapy is preferred: intravenous (iv) administration of the drug for two days with subsequent transition to oral administration [12].

One of the schemes recommended by the US Sexually Transmitted Disease Control and Prevention Center (CDC) is the administration of ofloxacin (Ofloxin®-200) 400 mg 2 times a day iv for two days, then its oral administration in 2 tablets. (400 mg) 2 times a day for 12 days [13]. For the purpose of influencing anaerobes, metronidazole inside 2 tablets was prescribed simultaneously (from the first day). (500 mg) 2 times a day for 14 days. The course of treatment took 14 days.

But, both abroad and in Russia, an increase in the resistance of N. gonorrhoeae and C.trachomatis to fluoroquinolones was noted [14, 15].

Azithromycin (Sumamed®) has pharmacokinetics and pharmacodynamics, which allows creating a concentration of the drug in tissues significantly higher than the minimum inhibitory concentration (MIC) for C. trachomatis, N. gonorrhoeae, forming therapeutic concentrations in phagolysosomes and cytoplasm - in the environment of chlamydia, mycoplasma [16 ]. The effectiveness of treatment of women with PID has been proved to be a tablet form of azithromycin according to the regimen of 1.0 g once a day for 1-7-14 days [17].

Since 2004, the infusion form of azithromycin (Sumamed®), intended for the empirical treatment of women with VZOMT, has appeared on the Russian market. The instructions indicate the indications for its use - infectious and inflammatory diseases of the pelvic organs [18].

The treatment regimen is as follows: azithromycin 500 mg iv once a day for two days, then taking 250 mg capsules once a day for 5 days. Thus, the course of treatment takes 7 days [17, 19].

In connection with the above, empirical treatment was performed for 54 women with PID.

Ofloxacin in combination with metronidazole was administered to 26 patients of the comparison group (HS); the main group (OG) of 28 women - azithromycin in combination with metronidazole according to the above schemes.

The dynamics of subjective disorders and clinical signs of PID in OH and HS on the first day after the end of therapy is shown in Figure 1, and the comparative results of therapy for women with PID in one month after the end of therapy in OH and HS in Figure 2.

As can be seen from the figures, both on the first day after the end of therapy, and after 2 months, the higher clinical efficacy of treatment in OG was statistically significant.

In a foreign publication, a comparative analysis of the effectiveness of VZOMT treatment by administering azithromycin in the form of monotherapy (500 mg iv, once a day for two days, then 250 mg orally for 5 days) in combination with metronidazole (500 mg 2 times a day for 14 days) was carried out ) and standard therapy regimens (metronidazole + doxycycline + cefocam + probenicide and doxycycline + amoxicillin / clavulanate) [20].

Clinical efficacy in the azithromycin monotherapy group was 97.1% and was comparable to that in the combination of azithromycin with metronidazole (98.1%) and with two comparison groups (94.6%). The pharmacokinetics of the tablet form of azithromycin in tissues (uterus, prostate, cervical canal) was studied [21, 22]. The concentration of azithromycin is maintained in the tissues after a single dose of 1.0 g for 7-14 days, exceeding the MPC for C. trachomatis many times, which allows elimination of the pathogen. It was this that served as the basis for the development of a pulse therapy regimen for complicated chlamydial processes: 1.0 g on days 1–7–14 [23].

However, studies to determine the concentration of the infusion form of azithromycin in the tissues have not been conducted.

The task was to develop a regimen of stepwise therapy with azithromycin in women with PID based on pharmacological studies.

The task was achieved by determining the concentration of azithromycin in uterine tissue in 39 women. Intravenous azithromycin was administered for preoperative preparation. Uterine tissue was obtained during surgery in women for uterine fibroids and fibroids.

The concentration of azithromycin in uterine tissue was studied by the microbiological method. As a test microbe used a billionth suspension of St. aureus strain 209 P [24].

Under observation were women who made up 4 groups.

The first group included 20 patients who underwent surgery with the removal of uterine tissue on average one day after the infusion of azithromycin in a dose of 500 mg once.

The average concentration of azithromycin in the uterine tissue was 1.63 ± 0.12 μg / g. In this case, individual differences in tissue levels of azithromycin were revealed. Antibiotic concentrations ranged from 0.45 μg / g to 2.5 μg / g. However, only 2 (10.0%) of 20 women (0.45 and 0.55 μg / g) had the lowest concentrations. and high (2.0-2.5 μg / g) - in 4 (20.0%) patients. The remaining 14 women (70.0%) ranged from 1.0-1.9 μg / g. In most women, the concentration of azithromycin was in the middle range.

The excess of the minimum, maximum and average concentrations (MPC) of azithromycin in the uterine tissue in relation to C.trachomatis after a single infusion of 500 mg in Figure 3. As can be seen from the figure, the average concentration of azithromycin exceeded the MPC for C.trachomatis by 13 times, which is sufficient for pathogen elimination.

The second group consisted of 12 women who were prescribed 2 infusions of azithromycin 500 mg once a day for two days, and then on the third day they underwent surgery with a fence of uterine tissue.

The average concentration of azithromycin in the whole group in the uterine tissue was 3.99 ± 0.63 μg / g. In one patient, a low individual concentration of azithromycin in the uterine tissue was recorded - 0.4 μg / g. In 3 (25.0%) women, the concentration of the drug was high (6.4-6.5-7.5 μg / g) and in 8 (66.7%) - average (within 1.7-5.0 μg / g). The summary data is shown in Figure 4. As can be seen from the figure, a double administration of azithromycin significantly increased the antibiotic content in the uterine tissue: the minimum concentration of azithromycin was 3.8 times, the maximum concentration 3 times, the average 3.99 times.

Figure 4 shows the multiplicity of exceeding the concentration of azithromycin in the uterine tissue in relation to the MPC for C.trachomatis (IPC 0.125 μg / ml) one day after two infusions of the drug (500 mg / day).

As can be seen from the figure, the minimum concentration of azithromycin in the uterine tissue exceeded the MPC for C.trachomatis by 13.6 times, the maximum - by 60 times, the average - by 31.9 times. The above indicates that even the lowest individual concentration of the drug is able to eliminate the pathogen.

The third group consisted of 7 women in whom the concentration of azithromycin in the uterine tissue was studied on the 4th day after a single infusion of 500 mg of the drug.

The average concentration of azithromycin in the uterine tissue for the whole group was 1.22 ± 0.17 μg / g. Individual concentrations of azithromycin in uterine tissue ranged from 0.55 μg / g to 1.6 μg / g. Concentration up to 1.0 μg / g was observed only in 2 (28.6%) patients, in the remaining 5 (71.4%) it was in the range 1.2-1.8 μg / g.

Figure 5 presents comparative data on the average concentrations of azithromycin in the uterine tissue for groups of patients after a single infusion (500 mg / day) of the drug every other day and on the 4th day and the multiplicity of excess MPC for C.trachomatis.

As can be seen from the figure, on the 5th day after a single infusion of azithromycin (500 mg / day), its high concentration in the uterine tissue remains, which differs from the concentration after 1 day only by 0.41 μg / g, which is only 1.3 times less.

In the uterine tissue, on the 4th day after a single infusion of azithromycin (500 mg / day), the concentration of the drug was found to be 9.8 times higher than the MPC for C.trachomatis, which allows the pathogen to be eradicated.

Data from pharmacological studies indicate that high concentrations of azithromycin in the uterine tissues are maintained on the 4th day after two infusions of azithromycin, which allows you to assign 1.0 g of the drug once on the 5th day after two infusions.

In order to confirm the effectiveness of the proposed scheme, 15 women with PID (OGA) were treated. Comparative data are shown in figures 6 and 7.

As can be seen from the figures, there is no statistically significant difference between stepwise azithromycin therapy: two infusions with a transition to a daily 5-day intake of 250 mg capsules (per 1.5 g course) and the one we offer: two infusions with a switch to a 5 day intake 1 , 0 g of azithromycin).

The proposed scheme has three positive aspects: 1) compliance - a single oral dose; 2) a decrease in the course dose of azithromycin by 0.5 g; 3) reduction of side effects.

All of the above confirms the validity of the developed step therapy, which differs from the scheme reflected in the Instructions.

Examples of specific performance.

Example 1. Patient J., 35 years old, was admitted to the hospital regional clinical Dermatovenerologic Dispensary (KKKVD), Stavropol, with a diagnosis of VZOMT (subacute endometritis).

Prescribed treatment: infusion of azithromycin 500 mg per day once for 2 days, then taking azithromycin capsules of 250 mg once a day for 5 days. From the first day of treatment - metronidazole 500 mg 2 times a day for 14 days.

Subjective disorders in the form of pains in the lower abdomen were not disturbed on the 3rd day from the start of therapy. Vaginal discharge did not bother. On the first day of the end of therapy, the normal number of leukocytes was in the smear from the cervical canal.

2 months after the end of therapy, there were no complaints about the presence of discharge from the cervical canal, the number of leukocytes from the mucous membrane of the cervical canal was normal.

This treatment regimen was effective in the short term and in the long term.

Example 2. Woman S., 41 years old, was admitted to the hospital KKKVD with a diagnosis of PID (subacute endometritis).

Treatment was prescribed: ofloxacin 400 mg iv twice a day for two days, then 400 mg tablets 2 times a day for 12 days + metronidazole 500 mg 2 times a day for 14 days.

Complaints of pain in the lower abdomen persisted for 5 days of therapy. Complaints about the presence of vaginal discharge were noted at the same time. On the first day of the end of therapy during examination, mucosal discharge from the cervical canal was noted in the mirrors and the number of leukocytes in smears with its mucosa was higher than normal.

2 months after the end of therapy, there were no subjective complaints, however, the number of leukocytes in the smear from the mucous membrane of the cervical canal did not return to normal.

Example 3. Patient M., 39 years old, was admitted to the hospital KKKVD with a diagnosis of PID (subacute endometritis).

Prescribed treatment: iv azithromycin in a dose of 500 mg once a day for 2 days. After 4 days, the fifth one is prescribed 1.0 g of the drug once inside. From the first day of therapy received metronidazole 500 mg 2 times a day for 14 days. The treatment was well tolerated. A day after the end of the infusion, pains in the lower abdomen and vaginal discharge were not disturbed.

On the first day of the end of therapy in a smear from the mucous membrane of the cervical canal, the number of leukocytes was normal.

2 months after the end of therapy, she had no complaints, the number of leukocytes from the mucous membrane of the cervical canal was normal.

Thus, the proposed method of empirical treatment of women with inflammatory diseases of the pelvic organs allows a single oral administration of azithromycin, reducing its dose by 0.5 g and reducing the risk of side effects of the drug.

Information sources

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Claims (1)

A method of empirical treatment of women with pelvic inflammatory diseases, including azithromycin infusion, daily metronidazole administration, characterized by a single oral administration of 1.0 g azithromycin on the 5th day after the infusion, in combination with daily administration of metronidazole twice a day 500 mg for 14 days.

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