RU2345784C1 - Method of treatment of chronic purulent rhinosinusitis - Google Patents

Abstract

FIELD: medicine; otorhinolaryngology.

SUBSTANCE: preparation pyobacteriophage polyvalent purified liquid is injected in maxillary sinus in amount 5-10 ml twice a day, every 12 hours within 6 days. Besides, from the first day of treatment, the preparation is introduced intranasal dosed 3 ml twice a day within 21 days.

EFFECT: long remission of disease resulted from restored adequate immune response and absence of depressed condition of cellular representation of nasal and sinus mucous membrane, stable synthesis of secretory immunoglobulin class A, normalised indicators of phagocytosis completeness, maximal pathogen elimination from nasal and sinus mucous membranes.

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Description

The invention relates to medicine, namely to otorhinolaryngology, and can be used to treat chronic purulent rhinosinusitis.

According to modern views, the treatment of sinusitis should comply with the following principles of etiopathogenetic therapy: unloading therapy (means to reduce swelling of the nasal mucosa), puncture treatment, the possibility of quick and targeted evacuation of purulent discharge from the paranasal sinus cavity, local antibacterial and systemic antibiotic therapy [S.V. Ryazantsev. The principles of etiopathogenetic therapy of acute sinusitis. SPb., 2005. S.12-33].

The lack of effectiveness of the traditional treatment of chronic purulent rhinosinusitis is the high resistance of microorganisms to antibacterial drugs, the lack of restoration of the sinus sterility and the change in the immune response of the mucous membranes of the nose and sinuses.

With local treatment, antimicrobial agents act on the pathogen directly in the focus of inflammation, in the sinuses, they can be prescribed in combination with the systemic use of antibiotics, and in some cases as monotherapy of chronic purulent rhinosinusitis.

For Russia, the first-line tool in the treatment of the disease is puncture of the maxillary sinus with washing and the introduction of antiseptic drugs. Systemic antibiotic therapy is used, as a rule, as an additional treatment. During puncture, the sinuses are usually washed with physiological saline or furatsillin solution at a dilution of 1: 5000 followed by the introduction of a 1% solution of dioxidine (derivative of a wide spectrum of di-N-quinoxaline oxide). The drug "Dioxidin" has been used for more than 25 years in clinics in Russia to treat various forms of purulent infection, including the treatment of purulent rhinosinusitis by introducing into the sinuses [LB Dainyak, L.G. Tsyrulnikova, M.E. Zagoryanskaya. Wounds and wound infection. Int. conf. M., 1998; S.108-130]. The basis of the mechanism of action of dioxidine is damage to the biosynthesis of DNA of a microbial cell with profound impairment of the nucleotide structure. Despite the obvious positive clinical experience in the treatment of various forms of purulent infection, the toxicological features of dioxidine require it to be considered as a reserve drug. The small therapeutic latitude of dioxidine (a narrow range between tolerated and toxic doses) dictates strict adherence to dosages, not only when administered intravenously, but also locally, especially when introduced into the cavity, continuous long-term irrigation. A significant drawback of the drug, limiting its widespread use, are mutagenic activity, embryotoxicity and damage to the cortical layer of the adrenal gland [E.N. Padeiskaya. Infections and antimicrobial therapy. M., 2001; T.3 / No.5. S.8-17]. The lack of dioxidine is also the inhibition of local protective immune responses and general immunity [V.E. Tseilikman, S.V. Sibiryak, O.B. Tseilikman, I.I. Grigoriev, D.Z. Shibkova. Immunology of the Urals. Materials of the IV conference of immunologists of the Urals, Ufa, 2005; No. 1 (4). P.28].

The prototype of the invention is a method of treatment by introducing a polyvalent purified pyobacteriophage into the sinuses punctured by catheterization or by the method of movement for 6 days [Stratieva O.V. et al. “The Use of the Multivalent Combined Pyobacteriophage in Acute and Recurrent Paranasal Sinusitis in Children”, XV Congress of Otorhinolaryngologists of Russia, September 25-29. 1995, St. Petersburg, 1995, t.2., S.32-35]. It should be noted that a positive clinical effect was obtained only in patients without impaired patency of natural anastomoses (in 30 of 45 patients (66.7%)). In addition, the author provides data on the immediate results of treatment and it is not possible to judge the distant ones.

The technical result is a long-term remission as a result of restoration of an adequate immune response and the absence of inhibition of the state of cellular representation of the nasal mucosa and sinuses, the stability of the synthesis of secretory immunoglobulin class A, normalization of the completeness of phagocytosis (according to immuno-cytograms), the maximum elimination of the pathogen from the mucous membranes of the nose and sinuses.

The proposed method is as follows: after puncture and catheterization of the maxillary sinus, it is washed with sterile physiological saline to clean wash water, then 5-10 ml of the polyvalent purified pyobacteriophage is introduced into the sinus, the external end of the catheter is closed. Sinus emptying occurs through the natural anastomosis. The procedure is carried out 2 times a day with an interval of 12 hours. The course of treatment is 6 days. At the same time, the patient injected a polyvalent purified pyobacteriophage of 5 drops (3 ml) into the general nasal passage or insert turundas moistened with a pyobacteriophage into the general nasal passage from the 1st to the 21st day of treatment 2 times a day.

They use the drug Pyobacteriophage purified polyvalent liquid produced by the FSUE NPO Mikrogen of the Ministry of Health of the Russian Federation, a branch in Ufa Immunopreparat (registration number R.92.203.22, FS-42-3898-99), which is a mixture of bacteriophages of staphylococci, streptococci, protea , Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli.

The proposed method of treatment differs from the prototype in the mode of administration of the drug, namely in the maxillary sinus for 6 days and intranasally for 21 days; administered dose of the drug, namely 5-10 ml of phage in the sinus (120 ml of phage) and 3 ml on the mucous membrane of the common nasal passage (126 ml of phage), the course dose of 246 ml of phage. Thus, the claimed invention meets the criterion of "novelty."

To assess the effectiveness of the therapy, patients were divided into three groups, depending on the choice of drug. In the first group (n = 52), patients were washed with an inflamed sinus followed by the introduction of a polyvalent purified pyobacteriophage in the form of monotherapy. In the second group (n = 34), patients received purified polyvalent pyobacteriophage in combination with intramuscular antibiotic administration. In the treatment of patients of the third group (n = 50), the traditional method was used - washing the affected sinus with a solution of furacilin at a dilution of 1: 5000 and intramuscular administration of an antibiotic. The cephalosporin antibiotic of the cefotaxime series was administered to patients of the second and third groups by 1.0 gram intramuscularly 2 times a day for 7 days. The effectiveness of various methods of etiotropic therapy and microbial representation on the mucous membranes of the maxillary sinuses in dynamics in patients with chronic purulent rhinosinusitis was evaluated on the 7th and 21st days of treatment.

The application of the proposed method of treatment in 52 patients with chronic purulent rhinosinusitis contributed to the rapid relief of the inflammatory process of the affected sinuses, which is confirmed by bacteriological (table 1) and immunological studies (table 2) and long-term results.

A comparative study of the spectrum of antibacterial activity of antibiotics and the polyvalent purified pyobacteriophage showed (Table 1) that, against bacteria of the genus Staphylococcus, the most active polyvalent purified pyobacteriophage was 88.2% and cefotaxime 90.8%.

The antibacterial activity of rifampicin was 79.1%, ampicillin - 70.1%, lincomycin - 57.5%, vancomycin - 55.1%. The differences found in the antibacterial activity of the polyvalent purified pyobacteriophage, cefotaxime, rifampicin, ampicillin were not statistically significant (p> 0.05).

The activity of the remaining 6 studied antibiotics was in the range of 6.1-35.4%. Kanamycin and benzylpenicillin were not active in 100% of cases. In terms of its antibacterial activity, purified pyobacteriophage was superior to kanamycin, benzylpenicillin, oxacillin, gentamicin, tetracycline, streptomycin. The differences found are statistically significant (p <0.001).

Isolated bacteria of the genus Streptococcus had maximum sensitivity to purified polyvalent pyobacteriophage and antibiotics cefotaxime, ampicillin, rifampicin, lincomycin, oxacillin - 100%. 66.7% of Streptococcus strains were sensitive to streptomycin, while only 33.3% were sensitive to vancomycin, and all strains of the Streptococcus genus were resistant to gentamicin, tetracycline, kanamycin and benzylpenicillin. The differences found in the degree of activity of the polyvalent purified pebacteriophage and the indicated antibiotics are statistically significant (p <0.001).

Bacteria Ps. aeruginosa was characterized by 100% resistance to almost all the antibiotics studied, with the exception of cefotaxime, active against only 50.0% of the strains, and ampicillin, an activity of 33.3%. The maximum antibacterial activity (100%) was detected in the purified polyvalent bacteriophage. The differences found in the degree of activity of pyobacteriophage and these antibiotics are statistically significant (p <0.001).

With respect to E. coli bacteria, the maximum antibacterial activity (100%) was detected in purified pyobacteriophage. The sensitivity of E. coli to gentamicin was 50.0%, to vancomycin - 25.0%. The bacteria E. coli were resistant to other antibacterial drugs in 100% of cases. The differences found in the degree of activity of pyobacteriophage and these antibiotics are statistically significant (p <0.001).

Bacteria Kl. pneumoniae were equally sensitive (p> 0.05) to the purified polyvalent pyobacteriophage (100%) and cefotaxime (100%). Sensitivity to gentamicin was 75.0%, and Kl bacteria to the rest of the studied antibiotics. pneumoniae were completely (100%) resistant. The differences found in the degree of activity of pyobacteriophage and these antibiotics are statistically significant (p <0.001).

Thus, it was found that the polyvalent purified pyobacteriophage by antibacterial activity was more active than cefotaxime against Kl bacteria. pneumoniae, E. coli, Ps.aeruginosa (p <0.05) and had equal (p> 0.05) activity against bacteria of the genera Staphylococcus and Streptococcus.

It was noted that in all groups, regardless of the type of antibiotic therapy, sterile sinuses were identified after treatment: 76.94% in the first, 82.34% in the second, 79.0% in the third group. Moreover, on the seventh day of treatment in all groups, significant differences in the number of sterile crops were not detected (p> 0.05). In the treatment with polyvalent purified pyobacteriophage in monotherapy in the first group on the 7th day, microorganisms were isolated, represented by the bacteria St.aureus - 15.38%, St.epidermidis - 3.84%, E. coli - 3.84%. No inoculation of fungal flora was noted.

In the second and third groups, after antibiotic therapy, there was an increase in Candida albicans (in 17.7% and 16.0% of patients, respectively), and in the third group there was also an increase in St.aureus (5.0% of cases).

The highest degree of elimination of pathogens from the mucous membranes of the maxillary sinuses of patients with chronic purulent rhinosinusitis on the 21st day of treatment was noted in the first group of patients treated with purified polyvalent phobacteriophage - 94.3%. In the second group of patients (bacteriophage and antibiotic), the degree of elimination was 73.5%, and in the third group of patients treated with antibiotics, 76.0%. The differences found are statistically significant (p <0.01; p <0.001).

In 5.7% of cases in the first group, the growth of gram-positive microflora - Micrococcus pyogenes continued. In the second group, the number of sterile crops decreased from 82.3 to 73.5%, in the third - from 79.0 to 76.0%. In addition, in patients treated with antibiotics, the sowing rate of Candida albicans increased: from 17.7 to 26.4% in the second and from 16.0 to 24.0% in the third group, respectively.

Thus, the use of a polyvalent pyobacteriophage purified in the treatment of chronic purulent rhinosinusitis allows eliminating pathogens from the focus of inflammation in 94.3% of cases. When using antibiotics, the degree of elimination is 76.0%, and with the combination of an antibiotic and pyobacteriophage, a polyvalent purified one is 73.5%. The use of antibiotic therapy in the treatment of chronic purulent rhinosinusitis in 24.0-26.4% of cases is characterized by secondary infection of the nasal mucosa and sinuses of Candida albicans, which may lead to chronic inflammation and the occurrence of secondary infections.

According to table 2, the local immunity of the nasal mucous membranes in patients with chronic purulent rhinosinusitis was characterized by increased cytosis mainly due to neutrophils with a low degree of destruction and an increase in the number of lymphocytes. The phagocytic activity of neutrophils in patients with chronic purulent rhinosinusitis did not differ from its activity in practically healthy individuals, however, the number of destroyed phagocytes with incomplete phagocytosis in patients with chronic purulent rhinosinusitis was higher than in practically healthy individuals (p <0.001). Changes in mucociliary clearance were also detected in the form of slowing down the movement of the cilia of the ciliated epithelium of the nasal mucous membranes. According to the content of secretory immunoglobulin class A, no significant differences were detected. An increase in the level of extracellular peroxidase activity occurred in patients with chronic purulent rhinosinusitis in comparison with practically healthy individuals (p <0.001). This fact characterizes the intensity of inflammation of the mucous membrane of the maxillary sinuses and nose.

Traditional therapy, including antibiotics, contributed to the inhibition of the phagocytic link of local immunity, and the state of the cellular and humoral links indicated the presence of persistent inflammation, which was manifested in high cytosis due to neutrophils with reduced phagocytic properties and high values of extracellular peroxidase activity and a decrease in secretory levels class A immunoglobulin

The use of a polyvalent purified pyobacteriophage in monotherapy stimulated the ability of neutrophils to complete phagocytosis and normalized the level of extracellular peroxidase activity (a marker of inflammation). Monotherapy with purified polyvalent pyobacteriophage was not accompanied by a decrease in the phagocytic properties of neutrophils, and the values of local immunity indicators corresponded to their values in practically healthy individuals and indicated the completion of the inflammatory process. Class A secretory immunoglobulin values remained stable.

Thus, it was found that the purified polyvalent pyobacteriophage, along with a wide spectrum of antibacterial activity, also has anti-inflammatory and immunotropic properties.

An analysis of the survey questionnaire data showed that the highest relapse rate was observed in the third group - in 14 out of 50 (28%) of the patients surveyed, in the second group - in 8 out of 34 (23.5%) and in the first group - in 6 of 52 ( 11.5%). The differences found in the frequency of disease recurrence in patients of the first and second; the first and third groups are statistically significant (p <0.05).

Thus, when studying the clinical efficacy of various methods of treatment of chronic purulent rhinosinusitis according to the immediate results of clinical differences, it was not revealed. At the same time, an analysis of the long-term results of treatment indicates that the relapse rate in the first group, where purified polyvalent pyobacteriophage was used in the treatment, was 2.4 times lower compared with the relapse rate in the traditional antibiotic treatment group (p <0.05), which makes it possible to recommend this treatment method to widespread use in clinical practice.

The data obtained characterize the polyvalent purified pyobacteriophage as a drug with a wide spectrum of antibacterial activity, immunotropic effect and high clinical efficacy in the treatment of patients with chronic purulent rhinosinusitis.

Changes in the method of administration of the drug, its dose and the duration of the course of treatment are justified by bacteriological studies (94% elimination of pathogens) and immunological studies (normalization of the phagocytic activity of neutrophils, restoration of ability to complete phagocytosis) allowed to obtain high clinical results. The indicated volumes determine not only the bactericidal effect of the phage, but also immunostimulating due to bacterial lysates. The latter seems to be important, since mucosal immunity can give an adequate immuno-rehabilitative effect on a specific dose of the lysate, for example, the bacterial lysates IRS-19 and imudon are administered on the mucous membrane up to 8 times a day. Thus, the claimed invention meets the criterion of "inventive step".

We give an example of clinical use of the proposed method. Patient A., 29 years old, was admitted on the 8th day from the onset of the disease. Clinical diagnosis: bilateral chronic purulent maxillary sinusitis in the acute stage. From the anamnesis it is known that she has been ill for 3 years, 5 times she was treated on an outpatient basis (puncture and systemic antibiotic therapy) at the place of residence. After puncture and removal of free pus in a volume of 4.0 ml from the right sinus and 5.0 ml from the left, both maxillary sinuses were catheterized, after which treatment was carried out according to the proposed scheme. On the first day, smears were taken to determine the flora and sensitivity to antibiotics and for immunological studies. Sowing pus gave the growth of Staphylococcus aureus, sensitive to vancomycin, lincomycin, oxacillin, rifampicin, cefazolin and ciprofloxacin and the preparation of polyvalent purified liquid polyobacteriophage.

In the following days, treatment was carried out according to the above methodology. On the 6th day, purulent discharge from the sinuses is absent, the catheters are removed. The patient was discharged from the clinic on day 9 in satisfactory condition with complete restoration of nasal breathing with continued independent intranasal administration of the pyobacteriophage.

According to immunological tests, the patient had 13.45% of phagocytosis before treatment, of which incomplete autophlora phagocytosis was 60.61%, sIgA level was 63.06 μg / ml. After treatment, phagocytosis is 26.73%, incomplete phagocytosis of autoflora is 38.15%, sIgA is 49.87 μg / ml. At the follow-up examination, after a year, the same indicators were evaluated, phagocytosis - 23.13%, incomplete phagocytosis of autoflora - 31.21%, sIgA - 47.3 μg / ml, which corresponds to the value of healthy individuals and characterizes a stable remission of the inflammatory process.

The proposed method is easily reproducible and when using it, the specified technical result is achieved. Thus, the claimed invention meets the criterion of "industrial applicability".

Table 1
The sensitivity of microorganism strains isolated from the maxillary sinuses to antibiotics and purified polyvalent pyobacteriophage Antibacterial drugs The number of strains sensitive to antibacterial drugs (%) Gram-positive microflora Gram-negative microflora Staphylococcus Streptococcus Ps.aeruginosa E.coli Kl.pneumoniae Pyobacteriophage (1) 88.2 100.0 100.0 100.0 100.0 Cetotaxime (2) 90.8 100.0 50,0 0,0 100.0 Ampicillin (3) 70.1 100.0 33.3 0,0 0,0 Rifampicin (4) 79.1 100.0 0,0 0,0 0,0 Lincomycin (5) 57.5 100.0 0,0 0,0 0,0 Oxacillin (6) 35,4 100.0 0,0 0,0 0,0 Gentamicin (7) 6.1 0,0 0,0 50,0 75.0 Vancomycin (8) 55.1 33.3 0,0 25.0 0,0 Streptomycin (9) 18.1 66.7 0,0 0,0 0,0 Tetracycline (10) 27,2 0,0 0,0 0,0 0,0 Kanamycin (11) 0,0 0,0 0,0 0,0 0,0 Benzylpenicillin (12) 0,0 0,0 0,0 0,0 0,0

Claims (1)

A method of treating chronic purulent rhinosinusitis by puncture of the maxillary sinus of the pyobacteriophage of a polyvalent purified liquid for 6 days, characterized in that it is administered in a volume of 5-10 ml 2 times a day with an interval of 12 hours and additionally, from the first day of treatment, the drug is administered intranasally a volume of 3 ml 2 times a day for 21 days.