Antimicrobial agent for preventing implant-associated infection and method for using it

FIELD: medicine.

SUBSTANCE: invention represents an antimicrobial agent for preventing an implant-associated infection containing gentamicin sulphate 0.96 g, dioxidine 1.0 g, medium-molecular-weight medical collidone (molecular weight 30000D) 10.0 g, distilled water up to 100.0 ml.

EFFECT: extending the range of products preventing the developing implant-associated infection and prevents preserving the antimicrobial activity of the tissues surrounding the implantation area.

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The invention relates to medicine and can be used for the prevention of implant-associated infection. Most reconstructive surgeries in orthopedics and traumatology, including hip and knee joint arthroplasty, involves the use of implants (components of the endoprosthesis, plates, screws, intramedullary rods, and other metal structures). Deep infection of the surgical intervention after this type of operation is a special case of implant-associated infection. Treatment of this complication includes the complex of therapeutic measures: revision and reorganization of purulent lesion, usually with the removal of an existing implant due to long-term systemic antibiotic therapy. In most cases, especially when infection of prosthetic joints of the patient during the subsidence of the infectious process is waiting for the second surgical intervention, the frequency of recurrence of infection is increased tenfold compared with the frequency of infectious complications after primary surgery. Typically, the ineffectiveness of the treatment of implant-associated infection even when well executed rehabilitation purulent and removing the metal due to the ineffectiveness of the antibiotic therapy. This can be caused by inadequate blood supply to the area osteosclerosis or presence of pronounced scarring in the area of surgical intervention, especially after repeated operations. In addition, in the modern view, microbial biofilm in implant-associated infections are one of the main reasons for the failure of antibiotic therapy because of the increased stability of microbial cells in the composition of the films [El-Husseini, M., Patel, S., MacFarlane R. J., Haddad F. S. Biodegradable antibiotic delivery systems. J Bone Joint Surgery 2011; 93 (Part 2): 151-7]. Treatment of implant-associated infection in traumatology and orthopedics is a lengthy, costly and not always effective, and the chronic infection in the majority of cases leads to the development of osteomyelitis and disability of the patient. Thus, in traumatology-Orthopaedics acquires special importance is the prevention of implant-associated infection.

One way to reduce the risk of implant-associated infection in traumatology and orthopedics is antimicrobial prophylaxis, which consists in the use of cephalosporins 1-2 generation (Cefazolin or cefuroxime) [Federal guidance on the use of medicines. Issue XI. M., "Echo" 2010. - 944 S.]. The disadvantage of this method is the lack of activity of these antibiotics against most nosocomial strains: methicillinresistant staphylococci, Enterobacteriaceae and Pseudomonas aeruginosa, agents who purchase the special significance when repeated and multiple surgeries.

Another way to prevent implant-associated infection, for example after replacement of large joints, is the use of bone cement containing antibiotics (eg, gentamicin) [Langlais F. 2003. Can we improve he results of revision arthroplasty for infected total hip replacement? J Bone Joint Surg Br 85: 637-640]. The disadvantages of this method is the limited list of operations that shows the use of bone cement, and slow release of antibiotic, which does not allow to achieve the effective concentration of the antibiotic in the area of surgical intervention and does not contribute to prevent the formation of microbial biofilms in cement [Tunney, M. M., N. Dunne, G. Einarsson, et al. Biofilm formation by bacteria isolated from retrieved failed prosthetic hip implants in an in vitro model of hip arthroplasty antibiotic prophylaxis. Journal of a French Brasserie Research 2007; vol.25, N 1: 2-10].

The prototype of the present invention is a method for the prevention of implant-associated infection using biodegradable compositions, such as a collagen sponge containing gentamicin. Using this method allows you to exceed the minimum inhibitory concentration (MIC) of gentamicin against Staphylococcus 600 times and to achieve eradication of the pathogen even in the composition of the microbial film [http://www.collatamp.ru; Fux, C. A., J. W. Costerton, P. S. Stewart, P. Stoodley Survival strategies of biofilm infections. Trends In Microbiology 2005; 13: 34-40]. The disadvantages of the this method is the high cost of collagen sponges, containing the antibiotic and dose gentamicin introduced into the wound, the patient is 3-5 times higher than the permitted daily dosage.

The invention was the creation of tools for the prevention of implant-associated infection, devoid of these shortcomings.

The technical result of the invention is the prevention of implant-associated infection and preservation of the antimicrobial activity of the tissues surrounding the implant installation area.

The result of the invention is achieved through the creation of antimicrobial drugs based on polyvinylpyrrolidone (kollidon) containing combinations of antimicrobial drugs: antibiotic (gentamicin) and antiseptic (dioxidine) in the permitted doses, which is active against the majority of pathogens bone, is a water-soluble, and application of this tool by intraoperative irrigation of the implant and the tissue in the area of installation.

Table 1 presents the dynamics of clinical indicators in animals with experimental implant-associated infection in the early postoperative period, where the sign "*" denotes performance that is significantly different from baseline (p<0,05).

Table 2 presents the dynamics of clinical and biochemical parameters in animals with experimental implant-associated Jn is the under in the early postoperative period, where the sign "1" denotes the performance, significantly different from baseline (p<0,05); mark "2"is a rate significantly different from those in group III (p<0,05); mark "3"is the indicator that is significantly different from those in group III (p<0,01).

Table 3 presents the results of the bacteriological examination of tissue biopsies and remote spokes Kirchner to 14 days after placement of experimental animals, where the sign "1" denotes the performance, significantly different from baseline (p<0,05); mark "2"is a rate significantly different from those in group III (p<0,05); mark "3"is the indicator that is significantly different from those in group III (p<0,01);

The invention is carried out as follows.

Based on the weight of kollidon under sterile conditions to prepare antimicrobial agent containing:

- gentamicin sulphate - 0.96 g;

- dioxidine - 1.0 g;

- collide (molecular weight 30000D) - 10.0 g;

- distilled water to 100.0 ml

The way to prevent implant-associated infection is to intraoperative irrigation of the implant before installing it into the bone and for irrigation of the tissues in the area of surgical antimicrobial agent, followed eshiwani the m postoperative wounds, which leads to the eradication of the existing wound microflora and wound healing by first intention.

EXAMPLE 1.

To evaluate the effectiveness of the proposed method in the experiment were used in 13 rabbits of both sexes breed Chinchilla weight 3-3 .5 kg, who underwent surgery for the implantation of the spokes of Kirchner in the bone-marrow channel of the femur. For simulation of implant-associated infection, the implant and the surrounding tissue infected two milliliters (2.0 ml) daily broth culture of the strain S. aureus ATCC 6538, containing 1×108CFU/ml

Animals I (main) group (5 rabbits) under intravenous anesthesia (propofol, fentanyl) in aseptic conditions recorded hind limbs. A longitudinal incision was exposed thigh. Through the spit of the femur pin Kirchner with a diameter of 1.5 mm was performable bone marrow channel and then was bored out then channel the needle length 30 mm larger diameter (2.5 mm), later in the cavity of the channel was administered 0.5 ml of the microbial suspension and irrigated the wound with 1.5 ml of microbial suspension, then after 1-2 minutes have established needle Kirchner (30 mm diameter 2.5 mm), pre-treated antimicrobial polymer composition, addition of 2.0 ml of the composition was applied from a syringe on the soft tissue in the wound, after which the wound is sutured and treated with a solution of iodine.

Animals of group II (4 CR the face) was also simulated implant-associated infection, but 30 minutes before the start of the operation was injected intravenous Ceftriaxone at a dose of 50 mg/kg of body weight, and after infection, washed the wound with chlorhexidine solution.

Animals III (control) group (4 rabbit) was also simulated implant-associated infection (see the above diagram), but did not prevention preoperative injection of Ceftriaxone or intraoperative introduction antimicrobial composition.

All animals in the experiment were evaluated by changes of temperature and body mass, the circumference of the operated hip in the dynamics on the 5th, 7th and 14th day, and also performed the clinical analysis of blood and was determined by C-reactive protein (SRV) in the serum before the operation and in the dynamics on the 7th and 14th day. Daily assessed the General condition of the animal behavior, food consumption and water; noted the presence of clinical signs of inflammation (swelling, redness, impaired function), measured rectal temperature. The animals were taken out of their experience at 14 days after surgery for the analysis of microbial contamination of remote structures (spokes Kirchner) and tissue biopsies from the area of surgery, and antimicrobial activity of the muscle tissue.

Statistical analysis was performed using nonparametric methods for small samples: U-criterion Mana Whitney, reliability is of associ at P< 0,05. The research results are presented in tables 1-3.

In the postoperative period has not been established significant difference in the temperature response in animals of different groups. While animals in the control group showed a significant reduction of body weight 575 g (p<0,05) for 14 days compared with baseline (table.1). The estimation of local signs of inflammation showed that all animals in the postoperative period in varying degrees had signs of inflammation (swelling of the operated limb, blood and hyperthermia), but in the I and II groups, these effects were cropped to the 5th day, and the animals of the control group survived until the end of the observation period, in addition, two animals from the control group to the 14th day on the background of infiltrative changes formed sections of abstsedirovaniya.

Analysis of laboratory data showed (table.2) that animals of groups I and II leukocyte counts and CRP levels to 14 days did not differ from baseline, while the animals of group II at the end of the observation period continued increase in the number of neutrophils in 1,5 times in comparison with the original, and in group I, which was introduced polymer composition, the number of neutrophils returned to the original. In rabbits of the control group manifestations of infectious-inflammatory process were more pronounced during all periods n is the observation: on the 7th and 14th day level leukocytosis was significantly higher than in both groups of mapping, in addition, the number of neutrophils at 14 days was significantly higher than in the group of animals which were injected antibacterial polymer composition (table.2).

To determine the antimicrobial activity generated in the muscle tissue in the proposed method, on the 14th day after the implants take tissue biopsies from the area of surgical intervention (3 samples from each experimental animal). Samples of muscle tissue homogenized and were prepared dilution 1:10 in saline. Next, 10 μl of the prepared solution was applied on sterile paper discs of 6 mm in diameter (similar to the disks to determine the antibiotic sensitivity, but not loaded with antibiotics), which were placed on plates with agar Baird-Parker, pre-seeded with a lawn of the test-culture of S. aureus (100 μl bacterial suspension of 1·108CFU/ml). Seeded cups with disks thermostatically for 24 h at 37°C, after which the estimated zone of inhibition of growth of Staphylococcus. The results are presented in table 3.

To assess microbial contamination of infected tissues was carried out by quantitative seeding source homogenizate and breeding of the Cup with blood agar, 100 ál. Incubated for 24 h at 37°C, and then counted the number of colonies on the Cup is x and estimated the number of microbial cells in 1 g of tissue. The results are shown in table 3.

For the study of microbial biofilms formed on the implants removed the needles were placed in sterile containers with saline solution of 10:1 relative to the mass of the fragment and treated with ultrasound for 5 minutes at a power of 300 W and a nominal frequency of 40 kHz. Then sown in 100 μl of the suspension to plates with agar Baird-Parker. Incubated for 24 h at 37°C, and then counted the number of colonies on plates and assessed the microbial colonization of needles.

Found that in animals of group I muscle tissue from the area of application of a polymeric antibacterial compositions possessed antimicrobial activity on the 14th day after its introduction (PL.3). It is shown that the use of the claimed method of tissue surrounding the wound, acquire antimicrobial properties that prevent the development of infectious process in the locus infected with a suspension of Staphylococcus. The content of bacterial cells in 1 g of tissue did not exceed 0-0,48 in the logarithmic representation (Lg CFU/g), in contrast to similar indicators for the comparison 0,19-1,93 and compared with control 3,34-to 4.52.

When applying the proposed method of tissue preservation wound, acquire and retain antimicrobial properties up to 14 days and show antimicrobial activity that is otverzhdaetsya method of diffusion in agar: zone of growth inhibition of the test culture in the study of tissue samples from experimental animals ranged from 6 to 30 mm, unlike similar performance when using the method of comparison (0 mm) and compared with the control (0 mm).

The effectiveness of the proposed method is confirmed also by the results of bacteriological studies of remote spokes, after ultrasonic treatment. Microbial colonization of remote implants in the main group was 0-2,4 CFU/cm2the surface, in contrast to similar figures 1,2-7,3 CFU/cm2when using the method of comparison and in contrast to a 13.9-408,2 CFU/cm2in the control group.

The analysis of the presented data shows that intraoperative use of the inventive antimicrobial drugs during orthopedic operations can prevent the development of implant-associated infection in the postoperative period, which is manifested early normalization of clinical and clinical and laboratory findings and is confirmed by the results of bacteriological research.

Thus, as can be seen from the above example, we declare our antimicrobial agent containing antibacterial drugs in the permitted doses, unlike the prototype, and a method for its use can prevent the development of implant-associated infection in the setting of orthopedic structures by maintaining antimicrobial activity of the tissues surrounding the x wound, up to 14 days after surgery.

Literature

1. El-Husseini, M., Patel, S., MacFarlane R. J., Haddad F. S. Biodegradable antibiotic delivery systems. // J Bone Joint Surgery 2011; 93 (Part 2): 151-7.

2. Federal guidance on the use of medicines. Issue XI. M., "Echo", 2010. - 944 S.

3. Langlais F. Can we improve he results of revision arthroplasty for infected total hip replacement? // J Bone Joint Surg Br 2003; 85: 637-640.

4. Tunney, M. M., N. Dunne, G. Einarsson, et al Biofilm formation by bacteria isolated from retrieved failed prosthetic hip implants in an in vitro model of hip arthroplasty antibiotic prophylaxis. // The Journal of a French Brasserie Research 2007; vol.25, N 1: 2-10.

5. http://www.collatamp.ru

6. Fux, C. A., J. W. Costerton, P. S. Stewart, P. Stoodley Survival strategies of biofilm infections. // Trends Microbiology 2005; 13: 34-40.

Table 1
Groups of animalsBody temperature, °C(Mcp+m_)Body weight, g(Mcp+m_)The volume of the operated hip, cm(Mcp +m_)
The follow-up period, days
Ex.5714Ex.5714Ex.5714
I38,7±1,538,7±1,738,5±2,038,6±1,83300±1503200±1163200±1153370±16025±1,226,2±1,325,5±1,225,2±1,1
II38,7±1,938,9±2,439,0±1,938,9±1,83275±1203000±1022870±1123000±110 24,4±1,425,8±1,325,6±1,225,5±1,2
III38,6±1,939,2±1,839,0±2,438,9±1,53250±1173130±1302850±1282675*±13024,9±1,827,9±1,428,9±1,429,1*±1,4

Table 2
The group of animalsIndicators, Mcp±Art. error /timeframe of the study day
Leukocytes, 109/lNeutrophils, 109/lC-reactive protein, mg/l
071407140714
I10,1±0,611,03±0,310,53±0,74,9±0,45,0±0,64,42±0,40,19±0,040,202±0,050,123±0,04
II10,1±1,112,91,2±0,811,63±0,64,3±0,66,6±1,66,6±1,20,25±0,040,32±0,030,233±0,06
III10,9±0,716,31±1,016,41±1,04,8±0,67,3±1,08,21±1,00,20±0,071,021±0,271,211±0,20

Table 3
Groups of animalsNo. rabbitMicrobial altamente the th strain of S. aureus Antimicrobial activity of the muscle tissue
remote implantmuscle tissue
CFU/cm2CFU/gLgKOE/gThe zone of growth inhibition of S. aureus (mm)
I group96000,009/7/9
116000,0010/12/6
1152,42,00,3030/13/12
1251,23,00,488/10/6
12400,30,007/13/10
Group II1231,21,53 0,190/0/0
1227,38,60·1011,930/0/0
1183,3was 9.330,970/0/0
1172,44,330,640/0/0
Group III12713,92,61·1033,420/0/0
12622,9with 3.27·1044,510/0/0
9719,62,20·1033,340/0/0
98408,23,30·104to 4.520/0/0

1. Of antimicrobial agent for the prevention of implant-associated infection, containing the anti-Christ. nfektsionnye drugs characterized in that a represents a polymer composition and has the following composition: gentamicin sulfate 0.96 g, dioxidine 1.0 g, the weight kollidon medical (molecular weight of 30000 D) 10.0 g distilled water to 100.0 ml

2. The method of application of antimicrobials for the prevention of implant-associated infection, containing anti-infective drugs, characterized in that the antimicrobial agent under item 1 intraoperative irrigate the implant, place it in the bone, then irrigate the tissue in the region of surgical intervention, then postoperative wound is sutured.



 

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2 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a polymer conjugate of an indolocarbazole compound of formula (I), where R1, R2, R3, W1 and W2 represent hydrogen, X represents methoxy-polyethyleneglycol. The method includes the interaction of a polymer compound of formula (II) with an indolocarbazole compound of formula (III), where Y stands for a methoxygroup. The nvention also relates to a polymer conjugate of formula (I), a pharmaceutical composition, containing the conjugate of formula (I) as an active ingredient, and to the application of the polymer conjugate of formula (I).

EFFECT: obtaining the polymer conjugate of the formula with a high output, the polymer conjugate of the formula for treatment of skin pathologies and HMGB1-associated pathologies.

48 cl, 7 dwg, 7 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to polypeptides having hydrolysable covalent bonds with therapeutic agents for drug delivery. The invention also refers to pharmaceutical compositions which contain the compounds according to the invention, to using them in methods of treating cancer.

EFFECT: polypeptide conjugates can be used as vectors for a therapeutic agent transport through the blood-brain barrier (BBB) and for delivery into specific types of cells, such as the ovaries, liver, lungs or kidneys.

6 cl, 16 dwg, 8 tbl, 6 ex

FIELD: veterinary medicine.

SUBSTANCE: agent for treatment of inflammation of udder of cows comprises 10-12 g of crystalline iodine, 100-102 g of polyvinylpyrrolidone and additionally in 1000 g/ml: emulsion wax 10-12; glycerol monostearate 50-52; beewax 10-12; refined sunflower oil 77-78; medical vaseline oil 28-29; glycerol 35-37; purified water - the rest to 1000 ml.

EFFECT: agent enables to carry out for short term the effective treatment of fibrinous, serous and suppurative mastitis and avoid the use of antibiotics and their derivatives, sulphanilamides and nitrofurans and thus to eliminate the negative side effect of the agent on animal body, as well as to reduce the economic cost more than 3 times.

1 tbl, 3 ex

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