RU2710252C1 - Method of bone cavities replacement in treatment of patients with chronic osteomyelitis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely traumatology and orthopedics, and discloses a method for bone cavity replacement in treating the patients with chronic osteomyelitis by filling the cavities with bone-substituting material. Method is characterized by that the bone cavities in chronic osteomyelitis are replaced with an antimicrobial composition of bone cement with an antibiotic gentamycin and antiseptics poviargol and dioxydine, as well as high-molecular medical polyvinylpyrrolidone with molecular weight of 1000000 D, with a certain ratio of components.

EFFECT: invention prolongs the antimicrobial action of the antimicrobial composition, which is filled with a bone cavity in treating the patients with chronic osteomyelitis, as well as providing the above composition with antimicrobial action against antibiotic-resistant microorganisms, which reduces the risk of recurrent chronic osteomyelitis and can be used in the rapid replacement of bone cavities in treating the patients with chronic osteomyelitis.

1 cl, 2 dwg, 1 tbl, 3 ex

Description

The invention relates to medicine, namely to traumatology and orthopedics, and can be used for surgical replacement of bone cavities in the treatment of patients with chronic osteomyelitis.

It is known that in the general structure of diseases of the musculoskeletal system chronic osteomyelitis is 12-25% [Stolyarov EA et al. Replacement of residual bone cavities after necrosecestrectomy in chronic osteomyelitis // Genius Orthopedics. - 2009. - No. 4. - from. 11-16; Linnik S.A. and other results of the use of different types of bone cavity replacement in the surgical treatment of patients with chronic osteomyelitis // Honey. science. Basic research. - 2012. - No. 7. - from. 100].

Known methods for replacing a defect in bone tissue using alloplastic material. In this case, allografts are used, the preservation of which is carried out by freezing or processing with various preservatives [Volkov M.V., Berezhnoy A.L., Virabov S.V. Replacing bone defects with alloplastic material according to the method of "brushwood brushing" // Orthopedics, traumatology and prosthetics: Rep. inter. Sat, Kiev, 1983, Issue 13, S. 10-14].

The disadvantage of this method is the fact that the cellular elements of allografts during transplantation always die. The dead bone actually becomes a foreign body, the processes of reconstruction of allografts are accompanied by invasion of blood vessels and the formation of a new bone, but only due to the cells of the surrounding tissues. The disadvantages should also include a high risk of immune rejection and the risk of virus transfer to the recipient.

Known methods for filling bone deficiency with crushed bone graft. In clinical practice, such biomaterials can be used in the form of large fragments, crumbs, powder, paste [Bone grafting in dentistry and maxillofacial surgery. Osteoplastic materials / Ed. A.S. Pankratova. - M .: BINOM Publishing House, 2011 .-- p. 86-92].

The disadvantages of such methods are:

- the need to combine large fragments of a bone allograft with finely divided biomaterials for better adaptation to the shape of the tissue bed and to prevent the traumatic effect of the edges and surfaces of bone fragments on the soft tissues surrounding the transplantation area;

- replacement of the bone graft occurs according to the peripheral type, which implies the initial resorption of the transplanted biomaterial with the subsequent gradual formation of bone regenerate.

Bone tissue defect is also replaced by autologous bone [Belousov A.E. Plastic, reconstructive and aesthetic surgery. - St. Petersburg: Hippocrates, 1998.p. 590-603]. The most commonly used autografts: ribs, diaphysis of the tibia, metaphysis of the radius and tibia, ilium, joints of the toes, etc. However, autograft is always associated with additional surgical trauma and complications associated with taking the material, prolonging the duration of the operation and possible lysis autotissue, as well as with extensive bone defects, it is quite difficult to use autologous bone tissue due to its deficiency in the donor zone.

Known methods for replacing defects in bone tissue using compositions containing drugs. So, for example, in chronic osteomyelitis of long tubular bones [RU 2137428, 1999], the bone defect is filled with a composition consisting of a liquid part - a 15% solution of Sulfacrylate glue in acetone and a dry powder mixture - methyluracil and antibiotic taken in a two-day old dosage. The disadvantages of this method of treatment include a short (within 12-15 days) antibacterial effect of the composition, as well as the inability to choose an antibiotic in the presence of microflora resistant to antibiotics.

Widespread methods for the replacement of defects in bone tissue using compositions based on bone-substitute cement, in particular, cements based on phosphoric acid calcium as a filling and bonding material with increased biocompatibility with bone tissue and bioactivity [RU 2236215, 2004]. This material is filled into voids and holes of various nature in living bone, after which they provide the body with building material and a matrix for regenerating bone tissue.

Known cement for bone replacement containing amorphous calcium phosphate, an additional source of calcium, selected from the group: calcium oxide, calcium hydroxide, calcium phosphate and physiological saline [US Patent 5782971, 1992]. Such compositions of non-absorbable bone cement do not have an antimicrobial effect, since they do not contain antimicrobial components, and therefore cannot be used to fill bone cavities in chronic osteomyelitis.

There is evidence that non-absorbable bone cement may be the site of adhesion of microorganisms, their growth and, as a result, the formation of antibiotic resistance [Gitelis S., Brebach G.T. The treatment of chronic osteomyelitis with abiodegradable antibiotic-impregnated implant. J. Orthopedic. Surg. (Hong-Kong) 2002; 10: 53-60].

In the available literature, there are few descriptions of studies devoted to assessing the duration and effectiveness of the antimicrobial effect of bone cement with antibiotics, which is used, inter alia, to fill bone cavities in the treatment of patients with chronic osteomyelitis. For example, a team of Canadian researchers studied the time of depletion of antibiotics from bone cement extracts with vancomycin and tobramycin by the method of polarization fluorescence immunoassay, which was 67 days [Penner M.J., Duncan SR, Marsi V.A. The in vitro elution characteristics of antibiotic-loaded CMS and Palacos-R bone cements // J. Arthroplasty. - 1999 .-- 14 (2). - P. 209-214]. In his study, G.G. Dziuba chromatographically evaluated the elimination level of vancomycin, additionally added to bone cement with gentamicin. Moreover, the elution time of gentamicin itself was not evaluated. It was shown that by the 30th day of the experiment, the concentration of vancomycin in the solution was not determined or was lower than its minimum inhibitory concentration in relation to staphylococcal isolates sensitive to this antibiotic [G. Dzyuba Orthopedic surgery of osteomyelitis coxitis: Abstract. diss ... doctor of medical science. - Omsk, 2018. - 44 p.].

Bacterial colonization of the implant can be accomplished through two alternative mechanisms. The first is through direct non-specific interaction between the bacterium and the artificial surface of the “host” not coated with proteins, due to the electrostatic field, surface tension, Van der Waals forces, hydrophobicity and hydrogen bonds. It has been shown that there is selective adhesion of microbes to the implant depending on the material from which it is made. For example, the adhesion of Staphylococcus epidermidis strains occurs better to the polymer parts of the implant, and S. aureus strains to metal parts [T. Kilmetov, I. Akhtyamov. and others. Local antibiotic therapy for infection of the joint endoprosthesis area. Kazan medical journal. 2014; 3 (95): 405-411]. In this regard, in the future, when evaluating the antimicrobial effect of the proposed bone-replacing material, Staphylococcus epidermidis is used as a test strain.

As a prototype for the closest technical essence, we have chosen a method for replacing bone cavities in the treatment of patients with chronic osteomyelitis with non-absorbable materials - bone cement (polymethyl methacrylate) containing gentamicin, which is successfully used in Europe for the treatment of chronic osteomyelitis, while the duration of the antimicrobial effect of bone cement with gentamicin , selected as a prototype, is 56 days [Local use of antibiotics in the treatment of bone infections. V.V. Privolnev, A.V. Rodin, E.V. Karakulina. Clinical Microbiology and Antimicrobial Chemotherapy, 2012, Volume 14, No. 2, p. 118-131; Mendel V., Simanowski H.J., Scholz N.S., Heymman H. Therapy with gentamicin-PMMA beads, gentamicin-collagen sponge, and cefazolin for experimental osteomyelitis due to Staphylococcus aureus in rats. Arch Orthopedic Trauma Surg. 2005; 125: 363-8].

The disadvantages of the above analogues, and the prototype are:

Недостаточно длительный срок антимикробного действия костно-замещающих материалов - 56 дней - для полноценной санации замещаемых костных полостей при лечении больных хроническим остеомиелитом, что существенно влияет на риск развития рецидива хронического остеомиелита.

The insufficiently long period of antimicrobial action of bone-substituting materials - 56 days - for the full rehabilitation of replaced bone cavities in the treatment of patients with chronic osteomyelitis, which significantly affects the risk of recurrence of chronic osteomyelitis.

Отсутствие в доступной литературе, посвященной аналогам и прототипу, данных о наличии антимикробного действия костно-замещающих материалов при лечении больных хроническим остеомиелитом в отношении устойчивых к антибиотикам микроорганизмов.

The lack of available literature on analogues and prototype data on the presence of antimicrobial action of bone-replacing materials in the treatment of patients with chronic osteomyelitis in relation to antibiotic-resistant microorganisms.

The objective of the invention is to reduce the risk of recurrence of chronic osteomyelitis in the replacement of bone cavities in the treatment of patients with chronic osteomyelitis.

The technical result of the invention is:

увеличение срока антимикробного действия антимикробной композиции, которой заполняют костную полость при лечении больных хроническим остеомиелитом;

prolongation of the antimicrobial effect of the antimicrobial composition, which fill the bone cavity in the treatment of patients with chronic osteomyelitis;

обеспечение вышеуказанной композиции антимикробным действием в отношении устойчивых к антибиотикам микроорганизмов.

providing the above composition with antimicrobial activity against antibiotic-resistant microorganisms.

The technical result of the invention is achieved in that, bone cavities in chronic osteomyelitis are replaced with an antimicrobial composition of bone cement with an antibiotic gentamicin and antiseptics poviargolum and dioxidine, as well as high molecular weight polyvinylpyrrolidone medical with a molecular weight of 1,000,000 D, with a ratio of components, mass. %:

Bone cement 63.92-63.0 Gentamicin 0.81-0.79 Plasticizer 32.36-31.89 Poviargol 0.97-1.44 Dioxidine 0.97-1.44 Polyvinylpyrrolidone high molecular weight medical 0.97-1.44

The inventive method of replacing bone cavities in the treatment of patients with chronic osteomyelitis is as follows:

Sequestrnecrectomy is performed for a patient under general anesthesia. The bone cavity is thoroughly washed with a solution of antiseptics using pulse lavage. The resulting bone cavity is filled with an antimicrobial composition, which is prepared as follows:

A bone cement powder of 39.5 g with gentamicin 0.5 g, poviargol powder 0.62 g, dioxidine powder 0.62 g, PVP powder 0.62 g is placed in a sterile mortar, mixed with a sterile spatula, 20 ml liquid plasticizer is added and thoroughly mix in accordance with the manufacturer's instructions.

When adding a liquid plasticizer to the cement mixture in accordance with the manufacturer's instructions, a plastic mass is obtained, which tightly fills the formed bone cavity. After polymerization of the introduced plastic mass, the wound is sutured in layers tightly.

The essential distinguishing features of the invention and the causal relationship between them and the achieved result:

An antimicrobial composition based on bone cement with gentamicin is used as a bone replacement material for bone replacement in the treatment of patients with chronic osteomyelitis. Unlike the prototype, the antimicrobial composition additionally contains the antiseptics poviargolum, dioxidine, as well as high molecular weight polyvinylpyrrolidone medical with a molecular weight of 1,000,000 D, with a ratio of components, mass. %:

Bone cement 63.92-63.0 Gentamicin 0.81-0.79 Plasticizer 32.36-31.89 Poviargol 0.97-1.44 Dioxidine 0.97-1.44 Polyvinylpyrrolidone high molecular weight medical 0.97-1.44

Poviargol is a highly dispersed metallic silver stabilized by low molecular weight medical polyvinylpyrrolidone; It is a light powder from greenish gray to greenish brown. In medical practice, poviargol is used as an aqueous solution for external use, which is prepared immediately before use. Poviargol is an antimicrobial agent with a wide spectrum of action, active against aerobic and anaerobic microflora, including antibiotic-resistant. At concentrations up to 100 μg / ml, it inhibits the growth of most bacteria (staphylococci, streptococci, Pseudomonas aeruginosa and Escherichia coli, Proteus, Shigella, Salmonella, etc.).

The antimicrobial effect of poviargol is sharply weakened in sodium chloride solutions; therefore, the use of poviargol in physiological saline is not recommended. The drug has an anti-inflammatory effect and stimulates reparative processes in the wound at the epithelialization stage at concentrations of 1-3%. Low toxicity, does not have an irritating effect on the skin and mucous membranes, does not cause allergic reactions and dermatitis. Poviargol is used as an antimicrobial (bactericidal) agent for the prevention and treatment of purulent-septic complications of wounds, ulcers, burns and pressure sores, including those that do not heal for a long time during antibiotic treatment; with infectious diseases of the upper respiratory tract, ear, throat, nose, eyes and oral cavity; for diseases of the genitourinary system and musculoskeletal system (http://sktb-technolog.ru/poviargolum2; “Poviargol: a new bactericidal agent for treating infected wounds [Clinical experience in traumatology, purulent surgery, burn therapy, gynecology, urology and ophthalmology A reference guide for doctors / Edited by Corresponding Member of the Russian Academy of Sciences Panarina EF, MD, Professor Blagitko EM Novosibirsk: Publishing House 1998. - 66 pp.].

Dioxidine - 2,3-bis- (oxymethyl) quinoxaline 1,4-di-N-oxide. Broad-spectrum antibacterial bactericidal drug. It is active against Proteus vulgaris, Pseudomonas aeruginosa, Friedlander bacilli, Escherichia coli, Shigella dysenteria, Shigella flexneri, Shigella boydii, Shigella sonnei, Salmonella spp., Staphylococcus spp., Streptococcus spp., Pathogenic perfen. Dioxidin has a detrimental effect on pathogenic cells by inhibiting the formation of DNA, while it does not affect the production of RNA and protein. Also, the main active substance destroys the microbiological structure (the membrane and nucleotides, which play an important role in the formation of intracellular energy). The drug is widely used in medicine due to its effective suppression of pathogenic flora in anoxic conditions. It acts on strains of bacteria resistant to other antimicrobial drugs, including antibiotics. It does not have a local irritant effect. With the on / in the introduction is characterized by low therapeutic breadth, and therefore strict adherence to the recommended doses is necessary. The treatment of burns and purulent-necrotic wounds promotes faster cleaning of the wound surface, stimulates reparative regeneration and marginal epithelization, and favorably affects the course of the wound process. After iv administration, the therapeutic concentration in the blood remains for 4-6 hours. The time to reach C _max in the blood is 1-2 hours after a single injection. It penetrates well and quickly into all organs and tissues, excreted by the kidneys. With repeated injections does not cumulate. External use of dioxidine is advisable in the following cases: infected burns; soft tissue phlegmon; deep or superficial wounds on the body; trophic ulcers and long healing wounds; purulent wounds with osteomyelitis. Intracavitary administration of dioxidine is indicated in the following cases: peritonitis; abscesses; purulent pleurisy; purulent processes in the abdominal or chest cavity; wounds of the biliary and urinary tract; pleural empyema; wounds and phlegmons with deep purulent cavities (pelvic fiber phlegmons, soft tissue abscesses, purulent mastitis, postoperative biliary and urinary tract wounds) ("Local treatment of infected wounds, purulent-necrotic processes in the abdominal cavity and retroperitoneal space with an antimicrobial preparation - dioxide. manual for surgeons / Edited by Galimzyanova F.V., Prudkova M.I. Ekaterinburg: UGMA, 2012 .-- 20 p.).

High-molecular-weight polyvinylpyrrolidone medical - is registered in the Register of Medicines as a binding agent. PVP is produced in the form of a pharmaceutically pure powder, free-flowing white or yellowish-white powder with particles of various sizes, a specific smell. The mass-average molecular weight of PVP is 1,000,000– 1,500,000 Da (Volker Buhler. Kollidon® Polyvinylpyrrolidone for the pharmaceutical industry / Translated from English under the editorship of Ph.D. K.V. Alekseev. BASF: 2001. - 310 s). An aqueous solution of PVP is a sterile, viscous, clear, slightly colored liquid with a specific faint odor. The weight average molecular weight depends on the resulting viscosity of the solution and ranges from 500,000 to 2,000,000 Da. PVP has sorbing and antitoxic properties.

Bone replacement material for bone replacement in chronic osteomyelitis based on bone cement with gentamicin for the study of antimicrobial activity was obtained as follows:

A bone cement powder of 39.5 g with a gentamicin content of 0.5 g was placed in a sterile mortar (1).

A bone cement powder of 39.5 g with a gentamicin content of 0.5 g, vancomycin powder (Edicin) 4 g was placed in a sterile mortar (2).

Bone cement powder of 39.5 g with a gentamicin content of 0.5 g and poviargol powder 0.61 g (1%) were placed in a sterile mortar (3).

A bone cement powder of 39.5 g with a gentamicin content of 0.5 g and dioxidine powder of 0.61 g (1%) was placed in a sterile mortar (4).

Bone cement powder of 39.5 g with a content of gentamicin of 0.5 g, poviargol powder of 0.62 g (1%), dioxidine powder of 0.62 g (1%) was placed in a sterile mortar (5).

Bone cement powder of 39.5 g with 0.5 g of gentamicin, poviargol powder of 0.62 g (1%), dioxidine powder of 0.62 g (1%), PVP powder of 0.62 g was placed in a sterile mortar (6) (1%).

By adding 20 ml of liquid plasticizer to the corresponding mixture in each mortar, in accordance with the manufacturer's instructions, a plastic mass was obtained with thorough mixing, during the polymerization of which hemispheres 1 g in weight were formed on 96-well polystyrene plates.

Further in the work we used extracts from prepared cement compositions. Hoods were obtained by the standard method according to the requirements set forth in [A collection of guidelines for toxicological and hygienic studies of polymer materials and medical products based on them for medical purposes, Ministry of Health of the USSR, Moscow, 1987. - 98 p .; Mader J.T., Calhoun J., Cobos J. In vitro evaluation of antibiotic diffusion from antibiotic-impregnated biodegradable beads and polymethylmethacrylate beads // Antimicrob Agents and Chemother. - 1997 .-- vol. 47, no. 2. - p. 415-418].

Hoods were prepared from cement hemispheres, keeping them for 24 hours in sterile phosphate buffer (pH 7.2-7.4) at a temperature of 37 ° C in a thermostat.

To study the antimicrobial action, the agar diffusion method was used [MUK 4.2.1890-04 “Determination of the sensitivity of microorganisms to antibacterial drugs”. State sanitary and epidemiological regulation of the Russian Federation. M., 2004], evaluating the size of the growth retardation zone of the corresponding test strain. Staphylococcus epidermidis ATCC 14990 / S / (sensitive to gentamicin) and the clinical isolate S. epidermidis 102/18 / R / (resistant to gentamicin, MIC - 30 μg / ml [MUK 4.2.1890-04]) were tested as test strains. . The microbial load was 0.5 according to the McFarland turbidity standard (10 ⁸ CFU / ml). Crops were incubated at 37 ° C for 24 hours.

Hoods were sowed every 3 days for 3 months, and then every 14 days for 8 months. After the next sowing, the sterile phosphate buffer in the tanks with cement was changed to obtain the next hood.

The obtained values of the growth inhibition zones of the gentamicin-sensitive strain of staphylococcus were compared with the requirements of EUCAST-2018 in terms of sensitivity to gentamicin (the growth inhibition zone of the gentamicin-sensitive test strain of the coagulase-negative S. epidermidis should be ≥22 mm).

When evaluating the effectiveness of an antimicrobial composition containing antiseptics, the requirements of EUCAST-2018 are not applicable. We believe that the presence of any zone of growth inhibition of the test microorganism indicates the manifestation of the antimicrobial activity of the composition against it. However, effective antiseptics should reduce the level of the microbial population by at least 2 log ₁₀ [Kramer A., et al. Octenidine, Chlorhexidine, Iodine and lodophores. Preprint, 2008 .-- Georg Thieme Verlag KG. - 85 p.].

During the experiment, when the growth retardation zones of both test strains were obtained by diffusion into agar below the level of sensitivity to gentamicin according to EUCAST-2018 (<22 mm), an additional quantitative test was performed by the cup-suspension method [Afinogenov G.E., Krasnova M .IN. Cup method for evaluating the effectiveness of disinfectants and antiseptics. Methodological recommendations of the Ministry of Health of the Russian Federation No. 2003/17, 2004 - 13 pp.] In order to confirm the antimicrobial effect of extracts from bone cement samples with antiseptics and PVP in relation to any S. epidermidis isolate with a microbial load of 10 ⁸ CFU / ml. When 0.1 ml of inoculum was plated on a Petri dish, the final microbial load was 10 ⁷ CFU / ml.

All studies were carried out in replicates of at least 3 and processed using Student's t-test with determination of the arithmetic mean value and the mean square error of the mean within each group.

The results of a comparative assessment of the antimicrobial activity of extracts from various samples of bone cement are presented in table 1.

From the data of table 1 it can be seen that, in relation to the sensitive strain S. epidermidisATCC 14990, the antimicrobial effect of the control extract (1) remained at the level of EUCAST-2018 requirements in terms of the sensitivity level of S. epidermidis to gentamicin (delay zone ≥ 22 mm) for 42 days. Thus, the effectiveness of gentamicin in bone cement was determined at a point transitional from its bactericidal action to its absence (the point of violation of the sensitivity limit).

An extract with vancomycin (2) had an effect at the control extract level only with gentamicin up to 42 days (the growth inhibition zone was 22.67 ± 0.34 mm).

Under the action of a hood (3) with poviargol 0.61 g (1%), hood (4) with dioxidine 0.61 g (1%) and hood (5) with a combination of poviargol 1% and dioxidine 1%, a growth inhibition zone was observed sensitive test strain for 212 days.

An extract (6) with poviargol 1%, dioxidine 1%, and PVP 1% exerted an antimicrobial effect for up to 348 days, while the zone of growth inhibition of the test strain was 12.33 ± 0.68 mm.

In cases where under the action of extracts with antiseptics (3-4) the growth retardation zones of the sensitive test strain were less than 22 mm, a decrease in the level of the microbial population of staphylococcus by 3 log _{10 was} shown in the cup-suspension test. Under the action of an extract (5) with a combination of 1% povargol and 1% dioxidine, a decrease in the level of the microbial population of staphylococcus by 4 log _{10 is} shown. The action of extracting (6) from a bone cement sample with gentamicin, 1% poviargol, 1% dioxidine, and 1% PVP in this test reduced the level of staphylococcus microbial population by 7 log ₁₀ .

With respect to the gentamicin-resistant clinical isolate S. epidermidis 102/18, extraction from control bone cement (1) is not effective. When vancomycin was added (extract 2), antimicrobial activity was observed up to 15 days, but at a level lower than the EUCAST-2018 requirements in terms of sensitivity of S. epidermidis to gentamicin (growth retardation zone was 10.33 ± 1.03 mm). Hoods with antiseptics poviargolum 1% or dioxidine 1% (3-4) and hoods (5) with antiseptics poviargolum 1% and dioxidine 1% had an antimicrobial effect for 212 days of observation. An extract (6) with antiseptics poviargol 1%, dioxidine 1% and PVP 1% exerted a prolonged antimicrobial effect for 348 days of observation, while the zone of growth inhibition of the resistant test strain was 12.0 ± 1.03 mm.

In experiments with a gentamicin-resistant test strain S. epidermidis, in all cases when the growth inhibition zones of the test strain were less than 22 mm, under the action of extracts with antiseptics (3-4), a decrease in the level of the microbial population of staphylococcus by 3 log ₁₀ , under the action of hood (5) with a combination of poviargol 1% and dioxidine 1% - by 4 log ₁₀ . The action of extracting (6) from a bone cement sample with gentamicin, povargol 1%, dioxidine 1% and PVP 1% in this test reduced the microbial population of gentamicin-resistant staphylococcus 7 log ₁₀ .

In FIG. 1 presents the results of a quantitative cup-suspension test to evaluate the effect of extract (1) from bone cement with gentamicin against gentamicin-resistant clinical strain S. epidermidis 102/18 at 348 days (initial microbial load of 10 ⁸ CFU / ml), where on the cup Petri shows the continuous growth of the clinical isolate of S. epidermidis 102/18 when exposed to a control extract (1) from bone cement with gentamicin.

In FIG. Figure 2 shows the result of a quantitative cup-suspension test to evaluate the effect of extract (6) from bone cement with gentamicin, 1% poviargol, 1% dioxidine, 1% PVP in relation to the gentamicin-resistant clinical strain S. epidermidis 102/18 on day 348 (initial microbial load 10 ⁸ CFU / ml), where there was no growth of the resistant strain of staphylococcus when exposed to hood (6) with 1% poviargol, 1% dioxidine and 1% PVP, when a growth inhibition zone of 12.0 ± 1 was obtained by agar diffusion 03 mm.

Novotny R.,

Kesselova M. In vitro testing of gentamicin-vancomycin loaded bone cement to prevent prosthetic joint infection // Biomed. Papers. - 2005. -Vol. 149, №1. - P. 153-158; Cui Quanjun, Mihalko William M., Shields John S., Ries Michael, Saleh Khaled J. Antibiotic-Impregnated Cement Spacers for the Treatment of Infection Associated with Total Hip or Knee Arthroplasty // J. Bone Joint Surg. Am. - 2007. - Vol. 89. - P. 871-882]. В единичных публикациях приведены данные по оценке вытяжек из антимикробного костного цемента в отношении полирезистентных микроорганизмов различных видов [Е. Bertazzoni Minelli, Т. Della Bora, A. Benini. Different microbial biofilm formation on polymethylmethacrylate (PMMA) bone cement loaded with gentamicin and vancomycin // Anaerobe. - 2011. - Vol. 17. - P. 380-383]. В этом исследовании авторы показали, что через 24 часа на поверхности костного цемента с гентамицином происходит и рост, и адгезия полирезистентных клинических штаммов: S. aureus ЗА10 MS-GS, S. aureus 5/7 MRSA/VRSA/GRSA, S. epidermidis 137/25 MR/GI, S. hominis126/26 MR/GI, S. epidermidis 8/28 MR/GR, S. haemolyticus 8/28 MR/GR, S. epidermidis 3/2 MR/GR, E.coli 7A27 G-S¹(¹- MS-GS - methicillin-susceptible & gentamicin-susceptible; MR-GR - methicillin-resistant & gentamicin-resistant; MR-GI - methicillin-resistant & gentamicin-intermediate; MRSA/VRSA/GRSA - methicillin-resistant, vancomycin-resistant & gentamicin-resistant; G-S -gentamicin-susceptible).Our data on the activity of gentamicin in bone cement coincide with the data of foreign authors who conducted similar experiments [Privolnev V.V., Rodin A.V., Karakulina E.V. Topical use of antibiotics in the treatment of bone tissue infections // Klin. Microbe. And Antimicro. Chemioter. - 2012. - T. 14, No. 2. - from. 118-131; Gallo J., Kolar M.,

Novotny R.,

Kesselova M. In vitro testing of gentamicin-vancomycin loaded bone cement to prevent prosthetic joint infection // Biomed. Papers. - 2005. -Vol. 149, No. 1. - P. 153-158; Cui Quanjun, Mihalko William M., Shields John S., Ries Michael, Saleh Khaled J. Antibiotic-Impregnated Cement Spacers for the Treatment of Infection Associated with Total Hip or Knee Arthroplasty // J. Bone Joint Surg. Am. - 2007. - Vol. 89. - P. 871-882]. Single publications provide data on the assessment of extracts from antimicrobial bone cement in relation to multi-resistant microorganisms of various types [E. Bertazzoni Minelli, T. Della Bora, A. Benini. Different microbial biofilm formation on polymethylmethacrylate (PMMA) bone cement loaded with gentamicin and vancomycin // Anaerobe. - 2011. - Vol. 17. - P. 380-383]. In this study, the authors showed that, after 24 hours, both growth and adhesion of multiresistant clinical strains occur on the surface of bone cement with gentamicin: S. aureus ZA10 MS-GS, S. aureus 5/7 MRSA / VRSA / GRSA, S. epidermidis 137 / 25 MR / GI, S. hominis126 / 26 MR / GI, S. epidermidis 8/28 MR / GR, S. haemolyticus 8/28 MR / GR, S. epidermidis 3/2 MR / GR, E. coli 7A27 GS ¹ ( ¹ - MS-GS - methicillin-susceptible &gentamicin-susceptible; MR-GR - methicillin-resistant &gentamicin-resistant; MR-GI - methicillin-resistant &gentamicin-intermediate; MRSA / VRSA / GRSA - methicillin-resistant, vancomycin-resistant &gentamicin-resistant; GS-agentamicin-susceptible).

Our results on the effectiveness of extraction (2) from bone cement with gentamicin and vancomycin indicate that there is no increased effect due to the second antibiotic, which coincides with the data of other authors who demonstrated complete elimination of vancomycin from polymethyl methacrylate disks by the 12th day by the microbiological method [Mader JT, Calhoun J., Cobos J. In Vitro Evaluation of Antibiotic Diffusion from Antibiotic-Impregnated Biodegradable Beads and Polymethylmethacrylate Beads // Antimicrob. Agents and Chemother. - 1997. - Vol. 41, No. 2. - P. 415-418], as well as by liquid chromatography, showed that the vancomycin content in the hood was below the minimum inhibitory concentration on the 14th day of the experiment [G. Dzyuba Orthopedic surgery of osteomyelitis coxitis: Abstract. diss ... doctor of medical science. - Omsk, 2018. - 44 s].

The introduction of 0.61 g (1%) of poviargol into bone cement, which is silver nanoclusters stabilized with low molecular weight polyvinylpyrrolidone, or 0.61 g (1%) of dioxidine enhances the antimicrobial effect of extracts (3 or 4, respectively) in relation to sensitive and resistant staphylococcus strains up to 212 days. The antimicrobial composition (5), containing poviargol 0.62 g (1%) and dioxidine 0.62 g (1%), also has a bactericidal effect for 212 days against S. epidermidis strains that are sensitive and resistant to gentamicin, while growth retardation of the test strains / S / and / R / was 26.33 ± 1.03 and 25.67 ± 0.34, respectively. The antimicrobial composition (6) with povargol 0.62 g (1%), dioxidine 0.62 g (1%) and high molecular weight PVP 0.62 g (1%) had a prolonged bactericidal effect against both strains of S. epidermidis for 348 days. The zones of growth retardation of the test strains / S / and / R / were 12.33 ± 0.68 and 12.0 ± 1.03, respectively. In addition, hood (6) in the quantitative test in both cases reduced the level of the microbial population by 7 log ₁₀ .

Thus, the optimal ratio of the components of the antimicrobial composition based on bone cement with gentamicin was selected experimentally in the research process. At the same time, the antimicrobial effect of bone cement with gentamicin was enhanced in the presence of poviargol and dioxidine, and the prolongation of this effect in the presence of high molecular weight polyvinylpyrrolidone polymer for 348 days.

The set of essential distinguishing features is new and allows, in comparison with the prototype, to increase the duration of the antimicrobial effect of the antimicrobial composition, which fill the bone cavity in the treatment of chronic osteomyelitis, as well as to provide the above composition with antimicrobial effect against antibiotic-resistant microorganisms, which reduces the risk of chronic relapse osteomyelitis in the replacement of bone cavities in the treatment of patients with chronic osteomyelitis.

We give clinical examples:

Example 1. Patient G., 45 years old.

He entered the clinic SZGMU named after I.I. Mechnikov 04/17/2017 regarding postoperative osteomyelitis of the upper third of the right humerus. Under general anesthesia, sequestrnecrectomy of the upper third of the right humerus was performed. The bone cavity was thoroughly washed with a solution of antiseptics using pulse lavage. The volume of the bone cavity is 32 ml. An antimicrobial composition consisting of bone cement powder 39.5 g with gentamicin 0.5 g, poviargol powder 0.62 g, dioxidine powder 0.62 g, PVP powder 0.62 g, prepared ex tempora, mixed with a sterile spatula, added a liquid spatula plasticizer 20 ml and thoroughly mixed. The bone cavity was densely filled with the bone cement mixture not yet frozen above. After polymerization of the introduced antimicrobial composition, the wound was sutured in layers tightly. They carried out temporary immobilization of the right upper limb with a plaster cast with a bandage for up to 3 weeks. The postoperative wound healed by primary intention. Examined after 1 year. A recurrence of a purulent process was not detected. On radiographs after 12 months, there are no signs of recurrence of osteomyelitis.

Example 2. Patient A. 52 years.

He entered the clinic SZGMU named after I.I. Mechnikov 06/28/2017 regarding postoperative osteomyelitis of the left calcaneus. Radiography and fistulography of the left calcaneus were performed. Under spinal anesthesia, he performed sequestrnecrectomy. The bone cavity was thoroughly washed with a solution of antiseptics using pulse lavage. The volume of the bone cavity is 6 ml. An antimicrobial composition consisting of bone cement powder 39.5 g with gentamicin 0.5 g, poviargol powder 0.62 g, dioxidine powder 0.62 g, PVP powder 0.62 g, prepared ex tempora, mixed with a sterile spatula, added a liquid spatula plasticizer 20 ml and thoroughly mixed. The bone cavity was densely filled with the bone cement mixture not yet frozen above. After polymerization of the introduced antimicrobial composition, the wound was sutured in layers tightly. The left lower extremity was temporarily immobilized with a plaster cast with a bandage for up to 3-4 weeks. The postoperative wound healed by primary intention. The patient was examined after 1 year. A recurrence of a purulent process was not detected. On radiographs after 12 months, there were no signs of recurrence of osteomyelitis.

Example 3. Patient K., 48 years old.

He entered the clinic SZGMU named after I.I. Mechnikov 09/09/2017 about chronic post-traumatic osteomyelitis of the middle third of the right thigh. Radiographs revealed a purulent foci of the middle third of the right femur containing a bone sequestration of 4.0 × 1.5 × 0.5 cm in size. Under spinal anesthesia, sequestrnecrectomy was performed to healthy bone tissue. The bone cavity was thoroughly washed with a solution of antiseptics using pulse lavage. The volume of the bone cavity is 21 ml. An antimicrobial composition consisting of bone cement powder 39.5 g with gentamicin 0.5 g, poviargol powder 0.62 g, dioxidine powder 0.62 g, PVP powder 0.62 g, prepared ex tempora, mixed with a sterile spatula, added a liquid spatula plasticizer 20 ml and thoroughly mixed. The bone cavity was densely filled with the bone cement mixture not yet frozen above. After polymerization of the introduced antimicrobial composition, the wound was sutured in layers tightly. They carried out temporary immobilization of the right lower limb with a plaster cast with a bandage for up to 3-4 weeks. The postoperative wound healed by primary intention. The patient was examined after 14 months. A recurrence of a purulent process was not detected. On radiographs after 14 months, there were no signs of recurrence of osteomyelitis.

The inventive method was tested in 18 patients with chronic osteomyelitis of long tubular bones and in 3 patients with osteomyelitis of the calcaneus. No postoperative complications were detected.

Thus, the claimed invention allows, in comparison with the prototype:

увеличить срок антимикробного действия костно-замещающего материала на основе антимикробной композиции, состоящей из костного цемента с антибиотиком гентамицином и антисептиками повиарголом и диоксидином, а также высокомолекулярным поливинилпирролидоном медицинским, при замещении костных полостей при лечении больных хроническим остеомиелитом;

to increase the antimicrobial duration of bone substitute material based on an antimicrobial composition consisting of bone cement with antibiotic gentamicin and antiseptics poviargolum and dioxidine, as well as high molecular weight polyvinylpyrrolidone with medical, in the replacement of bone cavities in the treatment of patients with chronic osteomyelitis;

обеспечить антимикробным действием костно-замещающий материал на основе вышеуказанной антимикробной композиции, в отношении устойчивых к антибиотикам микроорганизмов,

to provide an antimicrobial effect with a bone-substitute material based on the above antimicrobial composition, in relation to antibiotic-resistant microorganisms,

which, in turn, reduces the risk of recurrence of chronic osteomyelitis.

Claims (2)

A method for replacing bone cavities in the treatment of patients with chronic osteomyelitis by filling cavities with bone-replacing material, characterized in that an antimicrobial composition consisting of bone cement with antibiotic gentamicin and antiseptics poviargol and dioxidine, as well as high molecular weight polyvinylpyrrolide is used as a bone-replacing material molecular weight of 1,000,000 D, with a ratio of components, mass. %: Bone cement 63.92-63.0 Gentamicin 0.81-0.79 Plasticizer 32.36-31.89 Poviargol 0.97-1.44 Dioxidine 0.97-1.44 Polyvinylpyrrolidone high molecular weight medical 0.97-1.44

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