RU2377985C2 - Preparation for treating infectious diseases caused by multiresistant bacteria - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to antibacterial therapy, namely to medications for infectious diseases caused by multiresistant bacteria. The invention can be used for treatment of hospital mainly, and also severe heavy and extremely severe infectious diseases. The preparation represents mixed cephalosporin antibiotic Cefepime and beta-lactamase inhibitor Sulbactam in the ratio 1:1 to 1:2, respectively.

EFFECT: application of the preparation allows improving clinical effectiveness for infectious diseases essentially.

4 tbl, 2 dwg

Description

The invention relates to medicine, in particular to antibacterial therapy, and in particular to agents for the treatment of infectious diseases caused by multi-resistant bacteria. The invention can be used to treat mainly hospital, as well as severe and extremely serious infectious diseases.

Hospital (nosocomial) infections and infectious complications in the resuscitation and intensive care units (ICU) remain one of the significant causes of adverse outcomes, prolonged hospitalization and increased financial costs for treatment. According to a multicenter cohort study, the incidence of infections of different localization in ICU was 18.9%, while 65% of infections were hospitalized (Alberti C., Brun-Buisson C., Burchardi H., et al. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med 2002; 28: 108-21). Mortality among patients without signs of infection in the study was 16.9%, and among patients with infections reached 53.6%.

Among hospital infections, bloodstream, respiratory, and wound infections pose the greatest threat. Urinary tract infections in the vast majority of cases do not pose a serious threat to the lives of patients, but may require additional antibacterial therapy and lead to an extension of hospitalization. According to the EPIC study, 58.7% of all hospital infections in ICU accounted for respiratory tract infections, 12% for bloodstream infections, 6.9% for wound infections, 4.8% for skin and soft tissue infections, and 17.6% for urinary tract infections , other sources were noted in 13.7% of cases, in several patients several foci of infection were simultaneously detected (Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA 1995; 274: 639-44).

Given the limited capabilities of modern microbiology for the rapid diagnosis and assessment of the antibiotic sensitivity of hospital infection pathogens, the appointment of antibacterial drugs to treat the corresponding infections can only be empirical. Moreover, the choice of drugs for empirical therapy should be based on the probable etiology of the infectious process and the spectrum of antibiotic sensitivity of possible pathogens.

Depending on the localization, infections of the bloodstream, respiratory tract, urinary tract, skin and soft tissues, as well as intra-abdominal infections are distinguished among hospital infections. According to long-term observations within the framework of the National Nosocomial Infections Control System, bloodstream infections were caused by coagulase-negative staphylococci in 39% of cases, S. aureus in 12% of cases, Enterococcus spp. In 11%, Enterobacteriaceae in 8.3%, P. aeruginosa - in 3.7%, Candida spp. - in 11.5%. In infections of a different location, the role of gram-negative bacteria significantly increases (Richards M.J., Edwards J.R., Culver D.H., Gaynes RP. Nosocomial infections in combined medical-surgical intensive care units in the United States. Infect Control Hosp Epidemiol 2000; 21: 510-5). According to a study of the etiology of nosocomial infections in the intensive care and resuscitation departments of Moscow, the leading causative agents of severe infections of the respiratory tract in the intensive care and resuscitation departments were bacteria of the Enterobacteriaceae family (33.8%), Pseudomonas spp. (24.9%), Acinetobacter spp. (18.1% ), Staphylococcus aureus (16.0%); bloodstream infections - coagulase-negative staphylococci (33.6%), S. aureus (26.1%), Enterobacteriaceae (17.6%); wound infections - Enterobacteriaceae (35.7%), coagulase-negative staphylococci (17.8%), Pseudomonas spp. (14.3%) (Sidorenko S.V., Rezvan S.P., Eremina L.V et al. Etiology and antibiotic sensitivity of causative agents of severe hospital infections in intensive care units. Antibiotics and chemotherapy, 2005; 33-41).

Thus, gram-negative bacteria account for more than half of all cases of severe and extremely severe infections in the intensive care and resuscitation departments. According to existing practice, antibacterial drugs of the following groups are used to treat these infections - beta-lactams, aminoglycosides and fluoroquinolones. Moreover, at present, the basis for the treatment of severe infections is one of the subgroups of beta-lactam antibiotics - cephalosporins III-IV generations. However, the effectiveness of the use of all these drugs is significantly limited by the formation and widespread resistance to them among the bacteria - causative agents of infectious diseases.

The development and spread of resistance to cephalosporins III-IV generations among representatives of the Enterobacteriaceae family is a serious threat to the existing health care system. The leading mechanism of resistance is the hydrolysis of these drugs with β-lactamase enzymes. Of the more than 500 currently known beta-lactamases, the most common are enzymes belonging to molecular class A, sensitive to the action of inhibitors (clavulanic acid, sulbactam and tazobactam), capable of hydrolyzing I-IV generations of cephalosporins and called broad-spectrum beta-lactamases (BLRS).

BLRS is detected in all representatives of the Enterobacteriaceae family, but most often in Escherichia coli and Klebsiella pneumoniae. The first BLRS, which were derivatives of beta-lactamases of a wide spectrum, were discovered in the mid-80s. Since then, more than 200 different BLRS have been described, and this list is constantly updated (www. Lahey. Org / studies). Historically, the enzymes TEM and SHV groups are the earliest and most common. In recent years, enzymes of the CTX-M group have been widely distributed and become prevalent in a number of geographical regions. Enzymes of the OXA group are rather rare; the enzymes BES-1, FEC-1, GES-1, CME-1, PER-1, PER-2, SFO-1, TLA-1, VEB-1 are even more rare.

According to the SENTRY study, the frequency of isolation of K. pneumoniae strains producing BLRS is: 45% in Latin America, 25% in the West Pacific region, 23% in Europe, 8% in the USA, 5% in Canada (Winokur PL, Canton R., Casellas JM, Legakis N., Variations in prevalence of strains expressing an extended-spectrum in-lactamase phenotype and characterization of isolates from Europe, the Americas, and the Western Pacific region, Clin Infect Dis 2001; 32: S94-S104 ) According to the MYSTIC study, in Europe, the frequency of BLRS among Klebsiella spp. reaches 32.8%, and among Escherichia coli 14.4% (Jones RN, Pfaller MA. Antimicrobial activity against strains of Escherichia coli and Klebsiella spp.with resistance phenotypes consistent with an extended-spectrum "beta" - lactamase in Europe. Clinical Microbiology and Infection 2003 ; 9: 708-12). Moreover, the highest frequency is observed in Eastern Europe, including the Russian Federation. According to the MICROMAX study, the incidence of these enzymes in the hospitals of R.F. among E. coli it reaches 40%, and among K. pneumoniae - 90% (Sidorenko S.V., Strachunsky L.S., Akhmedova L.I. et al. Results of a multicenter study of the comparative activity of cefepime and other antibiotics against pathogens of severe hospital infections (program "Micromax"). Antibiotics and chemotherapy 2005; 44: 7-16).

The second leading mechanism of resistance to cephalosporins of III, but not IV generation is the overproduction of chromosome beta-lactamases of class C. This phenomenon is most often found in Enterobacter spp., Serratia spp., Morganella spp., Providencia spp. and Citrobacter freundii, but it is also possible in E. coli and K. pneumoniae. In addition, the mobilization of class C chromosome beta-lactamases to plasmids is possible. A sign of the likely production of class C beta-lactams is resistance to cefoxitin. This cephalosporin is destroyed by these beta-lactamases, but is resistant to BLRS.

Thus, it is obvious that modern health care urgently needs drugs that overcome the resistance associated with the production of beta-lactamases. The use of antibacterial drugs from groups such as aminoglycosides and fluoroquinolones cannot solve this problem, because as a result of various genetic processes, beta-lactamase producing strains in most cases have associated resistance to the listed antibacterial drugs.

The widespread use for the treatment of severe infections of beta-lactam preparations from the carbapenem group (imipenem, meropenem and others), which are resistant to many beta-lactamases, also does not completely solve the problem, since it leads to the formation of multiple resistant strains of such an important nosocomial pathogen as R. aeruginosa.

One of the ways to overcome the resistance associated with the production of beta-lactamases is the development of combination drugs, including beta-lactam antibiotics and irreversible beta-lactamase inhibitors.

In the late 70s, among the products of the biosynthesis of Streptomyces clavuligerus, a beta-lactam structure compound was found that has insignificant intrinsic antibacterial activity, but is capable of irreversibly inhibiting beta-lactamases - clavulanic acid (Brown AG, Butterworth D., Cole M., Naturally occurring beta -lactamase inhibitors with antibacterial activity. Journal of Antibiotics 1979; 29: 668-9). Almost simultaneously, a message appeared on the synthesis of penicillinate sulfone, later called sulbactam (English AR, Retsema JA, Girard AE, Lynch JE, Barth WE, CP-45, 899, a Beta-Lactamase Inhibitor That Extends the Antibacterial Spectrum of Beta-Lactams: Initial Bacteriological Characterization. Antimicrob Agents Chemother 1978; 14: 414-9). Later, another penicillin sulfone was synthesized - tazobactam (Aronoff SC, Jacobs MR, Johenning S., Yamabe S., Comparative activities of the beta-lactamase inhibitors YTR 830, sodium clavulanate, and sulbactam combined with amoxicillin or ampicillin. Antimicrob Agents Chemother 1984 ; 26: 580-2).

The listed inhibitors have common features of interaction with beta-lactamases that distinguish them from other beta-lactam antibiotics. At the first stage of interaction (common to all compounds), the beta-lactam ring is destroyed and the enzyme - antibiotic complex is formed. However, in the future the reaction paths differ: for ordinary antibiotics, the formed complex almost immediately decomposes with the release of the destroyed antibiotic molecule and the active enzyme molecule; in the case of inhibitors, the complex is stable and the enzyme molecule is "excluded" from the process of further hydrolysis of antibiotics. Due to the described features of interaction with beta-lactamases, clavulanic acid, sulbactam and tazobactam are called "suicidal" inhibitors.

Currently, in practice, a number of combinations of semisynthetic penicillins with beta-lactamase inhibitors (“inhibitor-protected” penicillins - amoxicillin / clavulanic acid, amoxicillin / sulbactam, ampicillin / sulbactam, ticarcillin / clavulanic acid, and piperazcil also) are widely used in practice. cephalosporin III generation cefoperazone with sulbactam.

However, for all of the listed combination preparations, certain disadvantages are characteristic. So, combination preparations based on aminopenicillins are suitable only for the treatment of relatively mild community-acquired infections, since these antibiotics have a relatively narrow spectrum of action that does not include many hospital pathogens, and their activity level is low. The combined preparations based on carboxypenicillins (ticarcillin / clavulanate) and ureidopenicillins (piperacillin / tazobactam), despite the wide spectrum of action of these antibiotics, also proved to be insufficiently effective due to the high sensitivity to beta-lactamases hydrolysis and the high level of production of these enzymes, the inhibitors cannot completely protect antibiotics from destruction. In addition, clavulanic acid, which is part of the drug ticarcillin / clavulanate, has the ability to induce the synthesis of chromosome beta-lactamases of class C bacteria of the Enterobacter - Serratia - Citrobacter - Morganella group, which reduces the activity of the drug against these bacteria.

The combination of cephalosporin of the third generation of cefoperazone and an irreversible sulbactam inhibitor (sulperazone) turned out to be more promising. The specified drug is considered as an analogue of the claimed drug in terms of antimicrobial activity and clinical efficacy. Its disadvantages include the greatest sensitivity among all cephalosporins of the 3rd-4th generations to the action of not only extended-spectrum beta-lactamases, but also broad-spectrum enzymes. In addition, the drug, like other III generation cephalosporins, is destroyed by class C chromosome beta-lactamases.

The technical result is the creation of a drug that has therapeutic efficacy in severe hospital (nosocomial) infections caused by multiple resistant gram-negative bacteria of the Enterobacteriaceae family, the genera Pseudomonas, Acinetobacter by overcoming the resistance of these bacteria due to the production of chromosome and plasmid beta-lactamases of class C, as well as Class A beta-lactamase wide and extended spectra. The drug should be able to be used as a means of empirical treatment of severe infections before isolating pathogens and obtaining results of an assessment of their antibiotic sensitivity. The use of the drug should significantly increase the effectiveness of the treatment of infectious diseases.

The achievement of these technical results is provided by a means for the treatment of infectious diseases caused by multi-resistant bacteria, which is a mixture of cephalosporin antibiotic cefepime and beta-lactamase inhibitor sulbactam with a ratio of 1: 1 to 1: 2, respectively.

The choice of the optimal ratio of the antibacterial drug, the inhibitor, the activity of various combinations of ingredients was carried out and evaluated in relation to the collection of microorganisms with genetically established resistance mechanisms, as well as in relation to gram-negative bacteria circulating in Moscow hospitals during 2005-2006. The study and comparison of the antimicrobial activity of the claimed drug with other combined drugs was carried out using bacterial strains with known resistance mechanisms.

A study of the activity of the claimed drug in relation to gram-negative bacteria producing extended spectrum beta-lactamases of the TEM, SHV and CTX groups showed its significant advantage over other cephalosporins and combination drugs in terms of the value of the minimum inhibitory concentration (MIC). The results of the study are shown in the diagrams - figure 1 (Escherichia coli) and figure 2 (Klebsiella pneumoniae).

As follows from the data presented, the addition of sulbactam to cefepime (in a 1: 1 ratio) leads to a significant shift of the cefepime MIC in relation to strains of Escherichia coli, Klebsiella pneumoniae towards lower values. The effect of increasing the activity of cefepime with an antibiotic / inhibitor ratio of 2: 1 is significantly lower, and with a ratio of 1: 2 higher. A similar effect of reducing cefepime MIC was obtained with respect to other gram-negative bacteria, such as Serratia marcescens, Enterobacter aerogenes, Citrobacter spp., Morganella spp., Providencia spp. Of particular note is the high activity of the inventive combination drug in relation to pathogens such as Acinetobacter spp.

The effect of decreasing BMD values is also known in the combination of sulbactam with other cephalosporin antibiotics: cefotaxime, ceftriaxone, ceftazidime and cefoperazone. For a quantitative comparison of the activity of various combinations of cephalosporin antibiotics and the claimed drug, it is advisable to use an indicator such as the geometric mean value of the IPC. The geometric mean values of the MPC of the claimed drug in relation to gram-negative bacteria producing beta-lactamases of an extended spectrum of the TEM, SHV and CTX groups are shown in table 1.

As follows from the data obtained, the combination of cefepime and sulbactam, in comparison with other combined preparations, shows significantly greater activity against all the bacteria studied using equal ratios of the antibiotic and inhibitor.

Table 1 A drug E.coli Klebsiella spp. Enterobacter Group P. aeruginosa Acinetobacter spp. Cefepim 17.4 15.3 21.4 29.8 35.3 Cepepime + Sulb (2: 1) 10.4 8.9 13.8 14.5 9.2 Cefepim + sulb (1: 1) 3.1 2.7 4.5 6.4 3.2 Cepepim + sulb (1: 2) 1.3 1.1 2.8 3.5 1.7 Cefotaxime 29.3 27.6 33.4 85.7 93.8 Cefotaxime + Sulb (2: 1) 21.4 23.6 28.7 76.8 84.4 Cefotaxime + Sulb (1: 1) 9.4 8.5 13.4 58.1 32.5 Cefotaxime + Sulb (1: 2) 6.3 5.9 8.6 43.5 29.3 Ceftriaxone 29.3 27.6 33.4 85.7 93.8 Cephrthiaxon + Sulb (2: 1) 28.9 27.1 32.4 86.5 91.9 Cephrthiaxon + Sulb (1: 1) 9.4 8.5 13.4 58.1 32.5 Cephrthiaxon + Sulb (1: 2) 6.9 5.8 8.9 47.8 31.4 Cefoperazone 36.4 31.5 45.7 98.5 112.7 Cefoperazone + Sulb (2: 1) 31.6 27.8 40.5 87.4 90.4 Cefoperazone + sulb (1: 1) 14.5 13.3 19.5 34.6 41.3 Cefoperazone + sulb (1: 2) 9.2 8.1 14.4 28.7 32.4 Ceftazidime 22.4 19.3 25.4 34.8 49.3 Ceftazidime + Sulb (2: 1) 15.4 12.9 18.8 26.5 33.2 Ceftazidime + Sulb (1: 1) 8.1 9.7 8.5 9.4 10.2 Ceftazidime + Sulb (1: 2) 5.3 6.1 5.8 7.5 8.7

A comparative evaluation of the antimicrobial activity of various combinations of antibacterial drugs and beta-lactamase inhibitors against gram-negative bacteria circulating in the intensive care and resuscitation departments of Moscow was carried out using practical criteria of sensitivity to predict the clinical efficacy of antibiotics and their combinations. In all cases, the ratio of antibiotic and inhibitor was 1: 1. At present, such criteria use BMD values that make it possible to classify an infectious microorganism pathogen into one of the following sensitivity categories: “sensitive”, “intermediate”, or “stable” (Methodological guidelines for determining the sensitivity of microorganisms to antibacterial drugs. Methodical instructions 4.2.1890-04 Edn. Moscow, 2004). If the pathogen belongs to the category of “sensitive”, the most likely outcome of the disease is recovery, if to the category of “stable”, then the most likely outcome is failure of treatment, if to the category of “intermediate”, then the outcome of the treatment is not determined.

The evaluation results of the compared drugs and their combinations are shown in table 2.

table 2 Antibiotics Sustainable,% Intermediate% Sensitive% IPC ₅₀ , μg / ml MIC ₉₀ μg / ml IPC range, μg / ml one 2 3 four 5 6 7 E. coil Ceftazidime 41.7 8 50.3 64 128 0.003-256 Ceftazidime / Sulb 17.9 11.8 60.3 2 16 0.03-16 Ceftriaxone 57.6 13.6 28.8 64 128 0.003-256 Ceftriaxone / Sulb 20.5 12.5 67 8 64 0.03-128 Cefotaxime 47.1 5.8 47.1 16 256 0.03-256 Cefotaxime / sulb 23.5 11.8 64.7 8 256 0.03-64 Cefoperazone 52.9 0 47.1 64 256 0.03-256 Cefoperazone / sulb 18.2 11.8 60 2 16 0.03-16 Cefepim 23.5 11.8 64.7 2 128 0.03-256 Cefepim / sulb 12.1 2.9 85 2 8 03.03-16 K. pneumoniae Ceftazidime 37.5 12.4 50.1 64 128 0.003-256 Ceftazidime / Sulb 10.5 15.6 74.9 8 64 0.03-128 Ceftriaxone 55.6 13.6 30.8 64 128 0.003-256 Ceftriaxone / Sulb 6 22.4 70.1 8 64 0.03-128 Cefotaxime 57.6 13.6 28.8 64 128 0.003-256 Cefotaxime / sulb 6 22.4 70.1 8 64 0.03-128 Cefoperazone 70.1 6 22.4 128 256 0.03-256 Cefoperazone / sulb 1,5 22.1 76.5 8 32 0.03-64 Cefepim 22.1 25 52.9 8 32 0.03-64 Cefepim / sulb 0 13.6 86.4 2 16 0.03-32 R. mirabilis Ceftazidime 57.6 13.6 28.8 64 128 0.003-256 Ceftazidime / Sulb 6 22.4 70.1 8 64 0.03-128 Ceftriaxone 52,2 26.8 21 64 256 0.03-256 Ceftriaxone / Sulb 0 0 one hundred one 2 0.5-4 Cefotaxime 62,2 27 10.8 64 256 0.03-256 Cefotaxime / sulb 0 0 one hundred one 2 0.5-4 Cefoperazone 91.9 0 8.1 256 256 0.12-256 Cefoperazone / sulb 0 0 one hundred one 2 0.5-4 Cefepim 27 21.6 51,4 8 32 0.03-128 Cefepim / sulb 0 0 one hundred one 2 0.5-4 E. cloacae, P. stuartii, S. marcescens Cefotaxime 45.5 18.2 36,4 16 128 0.03-256 Cefotaxime / sulb 36,4 27.3 36,4 16 256 0.03-256 Cefoperazone 54.5 0 45.5 64 256 0.03-256 Cefoperazone / sulb 9.1 18.2 72.7 2 32 0.03-256 Cefepim 36,4 0 63.6 one 256 0.03-256 Cefepim / sulb 0 0 one hundred one 2 0.5-4 R. aeruginosa Ceftazidime 51,2 11.9 36.9 32 128 0.5-256 Ceftazidime / Sulb 6 66.7 27.3 32 32 2-64 Cefoperazone 69 16.7 14.3 64 128 8-256 Cefoperazone / sulb 6 66.7 27.3 32 32 2-64 Cefepim 35.7 40.5 23.8 16 32 1-128 Cefepim / sulb 0 fifteen 85 8 16 1-32 A. baumannii Ceftazidime 75.8 9.7 14.5 64 128 1-128 Ceftazidime / Sulb 0 4.8 95.2 four 16 0.5-32 Cefoperazone 98.4 0 1,6 256 256 16-256 Cefoperazone / sulb 0 4.8 95.2 four 16 0.5-32 Cefepim 55.7 14.8 29.5 32 256 0.12-258 Cefepim / sulb 0 4.8 95.2 four 16 0.5-32

As follows from the data in Table 2, among all tested combinations, the combination of cefepime / sulbactam showed itself in the intensive care and resuscitation departments of Moscow as the most active against pathogens of severe infections. The most demonstrative advantages of cefepime / sulbactam were manifested in relation to P. aeruginosa and bacteria of the E. cloacae group, P. stuartii, S. marcescens. In relation to P. mirabilis, as well as A. baumannii, combinations of all cephalosporins with sulbactam were highly active. The main characteristics (frequency of sensitive and resistant strains, as well as MIC values) of cefotaxime and ceftriaxone, as well as their combination with sulbactam, were similar.

The data obtained indicate the ability of the drug to overcome most of the most common resistance mechanisms.

The effectiveness of the claimed drug was studied in experimental infections of mice caused by various gram-negative, including multiple-resistant bacteria. The experiments used white outbred male mice weighing 18-20 g. Animals were infected intraperitoneally. In preliminary experiments, for each of the bacterial strains used, the value of the infectious dose was determined, causing the death of 50% of the animals during 96 hours of observation (LD ₅₀ ). Bacterial strains with different levels of sensitivity to beta-lactam antibiotics were used. The value ranged from 10 ^{5 -} 10 ⁷ CFU (colony forming units). In further experiments, an infectious dose of 25-30 LD _{50 was used} . Antibacterial drugs began to be administered 12 hours after infection, the drug was administered 6 times with an interval of 12 hours. The ratio of cefepime / sulbactam was used - 1/1. The data are presented in table 3, where the doses of drugs are given by cefepime.

Table 3 Microorganism Cefepim Cefepime / sulbactam MIC, μg / ml Dose mg / kg Survived / Total MIC, μg / ml Dose mg / kg Survived / Total E.coli 0.12 10 1/6 0.12 10 2/6 twenty 4/6 twenty 5/6 thirty 6/6 thirty 6/6 40 6/6 40 6/6 0 0/6 0 0/6 E.colt 64 10 0/6 2 10 0/6 twenty 0/6 twenty 3/6 thirty 0/6 thirty 6/6 40 0/6 40 5/6 0 0/6 0 0/6 K. pneumoniae 256 10 0/6 2 10 0/6 twenty 0/6 twenty 2/6 thirty 0/6 thirty 5/6 40 0/6 40 5/6 0 0/6 0 0/6 R. aeruginosa 256 10 0/6 four 10 1/6 twenty 0/6 twenty 3/6 thirty 0/6 thirty 4/6 40 0/6 40 4/6 0 0/6 0 0/6

As follows from the materials presented in table 3, when infected animals with a sensitive strain of E. coli, the effectiveness of cefepime and its combination with sulbactam was almost the same. However, with infections caused by resistant bacteria, the effectiveness of the claimed drug was significantly higher.

The study of the pharmacokinetics of the claimed drug was carried out in experiments on rabbits. The main pharmacokinetic parameters of cefepime and sulbactam for both isolated and co-administration are given in table 4.

Table 4 Drug / Dose The maximum concentration in serum, mcg / ml Half-life, h Area according to the pharmacokinetic curve, mcg.h / ml Cefepime 10 mg / kg 19.6 0.5 12.6 Cefepime 20 mg / kg 25.4 0.6 23.4 Sulbactam 10 mg / kg 16.5 0.4 11.4 Sulbactam 20 mg / kg 23.8 0.5 19.5 Cepepime 10 / Sulbactam 10 18.7 / 15.9 0.5 / 0.5 13.7 / 12.6 Cepepim 20 / Sulbactam 20 16.9 / 22.7 0.5 / 0.5

The data presented indicate the absence of interactions of the components of the combined preparation.

Studies of the pharmacokinetics of the claimed drug indicate the possibility of maintaining the necessary concentrations of both components of the drug in the blood during the dosing interval of 8-12 hours

The value of LD ₅₀ in the study of acute toxicity in experiments on outbred mice was higher than 1500 mg / kg

Thus, data on the microbiological activity of the claimed drug, its effectiveness in experimental infections, data on pharmacokinetics and toxicity allow us to conclude that it can be used as a means of empirical treatment of severe infections before isolating pathogens and obtaining the results of evaluating their antibiotic sensitivity.

Claims (1)

The remedy for the treatment of infectious diseases caused by multiple-resistant gram-negative bacteria is a mixture of cefepime and sulbactam in a ratio of 1: 1 to 1: 2, respectively.

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