CN116327764B - High-efficiency broad-spectrum drug-resistant bacteria resistant pharmaceutical composition, preparation method and application thereof - Google Patents
High-efficiency broad-spectrum drug-resistant bacteria resistant pharmaceutical composition, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a broad-spectrum drug-resistant bacteria resistant pharmaceutical composition, which contains any one of aztreonam or pharmaceutically acceptable salts thereof and any one of zidasbactam or pharmaceutically acceptable salts thereof, wherein the mass ratio of the aztreonam or the pharmaceutically acceptable salts thereof to the zidasbactam or the pharmaceutically acceptable salts thereof in the composition is 2:1-1:280, the growth of drug-resistant bacteria is effectively inhibited, the activity of the aztreonam for resisting the drug-resistant bacteria, particularly the therapeutic activity of the multi-drug-resistant bacteria is obviously improved, the dosage of the aztreonam is obviously reduced, the drug resistance of beta-lactamase antibiotics is reduced or even reversed, the recurrence rate and the serious adverse reaction incidence rate of the drug-resistant bacteria and the multi-drug-resistant bacteria are obviously reduced, and the technical problems of broad-spectrum, safe and efficient inhibition of the activity of the super bacteria and the multi-drug-resistant bacteria are effectively solved.
Description
Technical Field
The invention relates to the field of medicines, in particular to a high-efficiency broad-spectrum drug-resistant bacteria resistant pharmaceutical composition, a preparation method and application thereof.
Background
The abuse of antibacterial drugs causes the types and the number of drug-resistant bacteria to be more and more, so that the super drug-resistant pathogenic bacteria with complexity and multiple resistance to the antibacterial drugs appear, and the infectious diseases caused by the infection of the super drug-resistant pathogenic bacteria show a rising trend year by year, and seriously threaten the health of human beings. Twelve "superbacteria" that are most resistant worldwide and threatening human health were published by the World Health Organization (WHO) 2017, including three severe deadly bacteria [ c.carbapenemase-resistant acinetobacter baumannii (CRAB), c.carbapenemase-resistant pseudomonas aeruginosa (CRPA) and c.carbapenemase-resistant enterobacteriales (CRE) ], six highly deadly bacteria (enterococcus faecium, staphylococcus aureus, helicobacter pylori, salmonella, neisseria gonorrhoeae, campylobacter) and three moderately deadly bacteria (streptococcus pneumoniae, haemophilus influenzae and shigella). The main drug resistance mechanisms of severely deadly bacteria include the production of class a carbapenemases (KPC), class B metalloenzymes (e.g., NDM, IMP, VIM, SPM, etc.), class D enzymes (e.g., OXA-type), etc., while drug resistant bacteria produce ultra-broad spectrum β -lactamases (ESBLs, e.g., SHV, CTX-M, TEM, etc.) and cephalosporinases (e.g., CMY, etc.) associated with drug resistance of penicillins, cephalosporins, etc.
Klebsiella pneumoniae (Klebsiella pneumoniae, KP) is one of the important pathogenic bacteria for clinical isolation and nosocomial infection. Klebsiella pneumoniae infection is commonly seen in aged people, malnutrition, chronic alcoholism, chronic obstructive pulmonary disease patients and the like, and can lead to acute pulmonary inflammation, severe pneumonia (diffuse lesions and extensive lung injury appear in the lung, and damage to multiple organ functions of human bodies), septicemia, suppurative meningitis, severe toxemia and the like, and has the symptoms of emergency onset, serious illness, high fever, chills and sweating 、 Cough, expectoration, severe chest pain, skin and digestive tract bleeding, and bleeding at the venipuncture site, severe poisoning symptoms such as disturbance of consciousness, dysphoria, delirium and the like occur, and even infectious shock (such as cold limbs, thin pulse, skin bloody, blood pressure drop and the like) is manifested, the shock occurrence rate is sometimes up to 63%, the death rate is 37-50%, and the life safety of patients is seriously endangered.
Studies have shown that the global klebsiella pneumoniae has 20% -70% of resistance to carbapenem antibiotics, 20% -30% of susceptibility to carbapenemase (KPC) and 40% -70% of susceptibility to carbapenemase. With the widespread popularity of producing ultra-broad spectrum beta lactamase beta-lactamases (ESBLs) enterobacteria, carbapenem antibacterial agents become the last drug to control their infection. With the great application of carbapenem antibacterial agents, carbapenem-resistant enterobacteria (carbapenem-resistant enterobacteriaceae, CRE) are becoming widely popular, and carbapenem-resistant klebsiella pneumoniae (carbapenem-resistantKlebsiella pneumoniae, CRKP) is becoming the most dominant pathogenic bacteria. The drug resistance mechanism of klebsiella pneumoniae mainly comprises beta-lactamase production, biofilm formation, outer membrane porin deletion, active excretion of antibacterial drugs and the like, and the drug resistance is related to the production of carbapenem hydrolytic lactamase (comprising klebsiella pneumoniae carbapenemase KPC type, OXA type, B type lactamase and the like). The rate of nosocomial infections caused by klebsiella pneumoniae has increased year by year, and the increasing number of multi-drug resistant strains often results in failure of clinical antimicrobial treatment and prolonged course of disease. Data in CHINET-2019 show that klebsiella pneumoniae (kpn) is the second in clinical isolated strains, and becomes the first big pathogenic bacteria after exceeding Acinetobacter baumannii in respiratory tract specimens in 2017, the resistance rate of kpn to carbapenem antibacterial drugs in China is 15% -20%, and the resistance rates of kpn to imipenem and meropenem are 25.3% and 26.8%, respectively, which brings great challenges to clinical treatment.
Clinically common drug-resistant enzymes include sensitive bacterial enzyme production, ultra-broad spectrum beta-lactamases (ESBLs), cephalosporinases (AmpC class enzymes), aminoglycoside Modifying Enzymes (AMEs), and carbapenemases. Antibacterial agents against infections with ultra-broad spectrum beta-lactamase (ESBLs) positive bacteria may be selected from carbapenems, cephalosporins, ceftazidime abamectin, beta-lactam plus enzyme inhibitors (containing tazobactam, sulbactam and clavulanic acid), light and medium infections caused by ultra-broad spectrum beta-lactamase (ESBLs) positive bacteria may be treated with cephalosporins (e.g. cefmetazole, cefoxitin, cefminox), beta-lactamase inhibitor cocktails (e.g. cefoperazone/sulbactam, piperacillin/tazobactam), oxacephem (e.g. floxaban, laxocephem), and severe infections caused by resistance to ultra-broad spectrum beta-lactamase are treated with carbapenems (e.g. meropenem, imipenem), or in combination with other antibiotics. The cephalosporin enzyme (AmpC enzyme) can resist beta lactam antibiotics except fourth generation cephalosporin and carbapenem, and can not be inhibited by clavulanic acid, and the antibacterial agent can be carbapenem or fourth generation cephalosporin. Carbapenemases are resistant to broad spectrum cephalosporins, fluoroquinolones, aminoglycosides, etc., the penicillinase producing klebsiella pneumoniae (CRKP) hydrolyzes almost all lactam antibiotics, the antibacterial agent may be selected from tigecycline-based combined aminoglycosides (such as amikacin)/carbapenems (such as meropenem, imipenem)/phosphomycins/polymyxins (such as polymyxin E, polymyxin B), or selected from polymyxin (such as polymyxin E, polymyxin B) -based combined carbapenems (such as meropenem, imipenem)/tigecycline/phosphomycins/aminoglycosides (such as amikacin), or selected from ceftazidime/abamectin.
Aztreonam is an antibacterial drug for inhibiting cell wall synthesis, has the characteristics of weak immunogenicity, little cross allergy with penicillins and cephalosporins, and the like, is clinically used for replacing aminoglycoside drugs to treat aerobic gram-negative bacterial infection of patients with renal function impairment, is used for treating patients allergic to penicillins and cephalosporins under the condition of close observation, and is used for treating the following infection symptoms: 1) Urinary tract infection: escherichia coli, proteus mirabilis, pseudomonas aeruginosa, enterobacter cloacae, klebsiella en-smelling, citrobacter, and Serratia mucilaginosa, and recurrent cystitis; 2) Lower respiratory tract infection: escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, haemophilus influenzae, proteus mirabilis, enterobacter and Serratia viscosa caused pneumonia and bronchitis; 3) Blood flow infection: blood flow infections caused by escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, proteus mirabilis, serratia viscosa and enterobacteria; 4) Skin soft tissue infection: skin soft tissue infections (including surgical wound infections, ulcers and burn wound infections) caused by escherichia coli, proteus mirabilis, serratia viscosa, enterobacter, pseudomonas aeruginosa, klebsiella pneumoniae, and citrobacter; 5) Peritonitis and abdominal infection: comprises abdominal cavity infection caused by Escherichia coli, klebsiella on nose, klebsiella pneumoniae, enterobacter cloacae, pseudomonas aeruginosa, citrobacter, and Serratia viscosa, and is often combined with anti-anaerobic medicines such as metronidazole; 6) Genital tract infection: gynecological infections such as endometritis and pelvic inflammation caused by Escherichia coli, klebsiella pneumoniae, enterobacter (including Enterobacter cloacae), pseudomonas aeruginosa and Proteus mirabilis are often combined with anti-anaerobic medicines such as metronidazole. However, aztreonam has mild liver toxicity and affects human nerves, if the dosage is improper, the hepatic cell injury and the human gustatory nerves are damaged, so that the patient has serious adverse effects such as drug-induced hepatic injury, gustatory disappearance, shock or anaphylactic shock, granulocytopenia, thrombocytopenia, gastrointestinal bleeding, exfoliative dermatitis, hypotension, central nervous system reaction, muscle pain, hypodynamia, nausea, abdominal pain, coagulation dysfunction and the like, and the symptoms are shown, especially, when the dosage of the patient is excessive or the patient is used together with other drugs, the serious adverse effects are more obvious. Therefore, the broad-spectrum high-efficiency drug-resistant bacteria resistant pharmaceutical composition is developed to meet the clinical unmet demand and ensure the life health of the masses.
Disclosure of Invention
The invention aims to provide a broad-spectrum drug-resistant bacteria resistant pharmaceutical composition, which contains any one of aztreonam or pharmaceutically acceptable salt thereof and any one of zidasbactam or pharmaceutically acceptable salt thereof, wherein the mass ratio of the aztreonam or pharmaceutically acceptable salt thereof to the zidasbactam or pharmaceutically acceptable salt thereof in the composition is 2:1-1:280, said resistant bacteria being selected from any one or combination of klebsiella pneumoniae, enterobacter cloacae, citrobacter freundii, klebsiella aerogenes, klebsiella acidogenes, carbapenemase Resistant Acinetobacter Baumannii (CRAB), carbapenemase Resistant Pseudomonas Aeruginosa (CRPA), carbapenemase Resistant Enterobacteriales (CRE), enterococcus faecium, staphylococcus aureus, helicobacter pylori, salmonella, neisseria gonorrhoeae, campylobacter, streptococcus pneumoniae, haemophilus influenzae, shigella, said pharmaceutically acceptable salts being selected from any one of hydrochloride, hydrobromide, phosphate, hydrogen phosphate, sulfate, bisulfate, acetate, malonate, valerate, glutamate, oleate, p-toluenesulfonate, methanesulfonate, isethionate, fumarate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanilla, mandelate, succinate, gluconate, lactose.
In a preferred technical scheme of the invention, the drug-resistant bacteria are selected from any one of Klebsiella pneumoniae producing KPC, klebsiella pneumoniae producing KPC+NDM, klebsiella pneumoniae producing NDM, klebsiella pneumoniae producing OXA, enterobacter cloacae producing NDM, fuusi citrate producing NDM, klebsiella aerogenes producing NDM, klebsiella oxytoca producing KPC+NDM+IMP and Pseudomonas aeruginosa producing CRPA.
In a preferred embodiment of the present invention, the drug-resistant bacteria produce a drug-resistant bacteria enzyme selected from any one of class a enzymes, class B metalloenzymes, serine carbapenemases, penicillinase, cephalosporinase, OXA enzymes, and ultra-broad-spectrum beta-lactamase (ESBL), or a combination thereof.
In a preferred embodiment of the present invention, the drug-resistant bacteria enzyme produced by the drug-resistant bacteria is selected from any one or a combination of KPC, NDM, IMP, OXA-48 and SHV, TEM, CMY, CTX-M-15.
In a preferred embodiment of the invention, the mass ratio of aztreonam to zidasbactam in the composition is 1:8-1:268, preferably 1:16-1:256.
In a preferred technical scheme of the invention, the mass ratio of the aztreonam to the zidamantan in the composition is 2:1, 1:1, 1:2, 1:4, 1: 6. 1:8, 1:16, 1:32, 1:64, 1:128, 1:256, 1:10, 1:12, 1:14, 1:18, 1:20, 1:22, 1:24, 1:28, 1:30, 1:34, 1:36, 1:38, 1:40, 1:42, 1: 44. 1:46, 1:48, 1:50, 1:52, 1:54, 1:56, 1:58, 1:60, 1:62, 1:66, 1:68, 1:70, 1:80, 1:90, 1:100, 1:110, 1:133, 1:150, 1: 200. 1:250, 1:265, 1:280.
In a preferred technical scheme of the invention, the active ingredients of the pharmaceutical composition consist of aztreonam and zidasbactam.
In a preferred embodiment of the present invention, the pharmaceutical composition consists of a first composition comprising aztreonam and a second composition comprising zidovetaine.
In a preferred embodiment of the present invention, the first composition and the second composition are administered simultaneously or sequentially.
In a preferred embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
In the preferred technical scheme of the invention, the dosage of the pharmaceutically acceptable carrier in the pharmaceutical composition or the type of the pharmaceutically acceptable carrier depends on the physicochemical properties and the content of the effective components in the composition, the type of the preparation, the dissolution of the preparation, the bioavailability and other factors.
In a preferred embodiment of the present invention, the pharmaceutical composition is in a form selected from any one of an oral preparation, an injection and an external preparation.
In a preferred embodiment of the present invention, the oral preparation is selected from any one of oral liquid preparation, tablet, capsule, granule, syrup, powder, dew, effervescent, suspension, pill, dripping pill, mixture, paste, emulsion, and liniment.
In a preferred embodiment of the present invention, the external preparation is selected from any one of a gel, a paste, a patch, a cream, an ointment, a liniment, a lotion, a suppository, a smear, a cream, an ointment, an aerosol, a dry powder inhalant, a spray, and an aerosol.
In a preferred technical scheme of the invention, the injection is selected from any one of solution type injection, emulsion type injection, suspension type injection, sterile powder for injection and large transfusion.
In a preferred embodiment of the present invention, the pharmaceutically acceptable carrier of the present invention is a common excipient or adjuvant used in the art to prepare a desired formulation, including fillers (diluents), disintegrants, binders, lubricants (glidants or anti-adherents), dispersants, wetting agents, pH adjusters (acid-base adjusters), osmotic pressure adjusters, pore-forming agents, solubilizing agents, antioxidants, bacteriostats (bactericides), analgesics (anesthetics), suspending agents, emulsifiers, co-emulsifiers, lyoprotectants, flavoring agents, perfuming agents, and the like.
In a preferred embodiment of the present invention, the filler is selected from lactose, powdered sugar, dextrin, starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch, cellulose, inorganic calcium salt, calcium chloride, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, sorbitol, mannitol, microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, and hydroxypropyl methylcellulose, or a combination thereof.
In a preferred embodiment of the present invention, the disintegrating agent is selected from any one of starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch or derivatives thereof, crosslinked polyvinylpyrrolidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, or combinations thereof.
In a preferred embodiment of the present invention, the binder is selected from any one of syrup, acacia, gelatin, sorbitol, tragacanth, cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gelatin slurry, starch slurry, polyvinylpyrrolidone, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch, or a combination thereof.
In a preferred embodiment of the present invention, the lubricant is selected from any one of or a combination of silica fume, magnesium stearate, talc, colloidal silica, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, and sodium lauryl sulfate.
In a preferred embodiment of the present invention, the wetting agent is selected from any one of sodium dodecyl sulfate, polysorbate (tween), water, alcohol, ester, or a combination thereof.
In a preferred embodiment of the present invention, the antioxidant is selected from any one of sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, vitamin C, vitamin E, dibutyl benzoic acid, butyl Hydroxy Anisole (BHA), dibutyl hydroxy toluene (BHT), propyl Gallate (PG), nicotinamide, acetylcysteine, tert-butyl hydroquinone (TBHQ), or a combination thereof.
In a preferred embodiment of the present invention, the bacteriostatic agent (bactericide) is selected from any one of phenol, cresol, chlorobutanol, benzyl alcohol or a combination thereof.
In a preferred embodiment of the present invention, the analgesic (anesthetic) is selected from any one of chlorobutanol, benzyl alcohol, lidocaine, procaine, and combinations thereof.
In a preferred embodiment of the present invention, the suspending agent is selected from any one or a combination of microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, syrup, glycerin, gelatin, acacia, tragacanth, sodium alginate, potassium alginate, and pectin.
In a preferred embodiment of the present invention, the acid-base modifier (pH modifier) is selected from any one of hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, sodium citrate, potassium citrate, malic acid, sodium malate, potassium malate, sodium dihydrogen phosphate, disodium hydrogen phosphate, calcium hydroxide, calcium lactate, sodium phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate, sodium carbonate, and combinations thereof.
In a preferred embodiment of the present invention, the osmotic pressure regulator is selected from any one of sodium chloride, potassium chloride, glucose, phosphate, and citrate.
In a preferred embodiment of the present invention, the emulsifier is selected from any one of sodium stearate, potassium stearate, triethanolamine stearate, magnesium stearate, calcium stearate, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, polysorbate (tween), span, mesitylene, benzyl, polyvinyl alcohol, tragacanth, acacia, pluronic F-68, lecithin, and soybean lecithin, or a combination thereof.
In a preferred embodiment of the present invention, the co-emulsifier is selected from any one of n-butanol, ethylene glycol, ethanol, propylene glycol, glycerol, polyglycerol ester or a combination thereof.
In a preferred embodiment of the present invention, the lyoprotectant is selected from any one or a combination of sucrose, lactose, galactose, glucose, trehalose, mannitol, and sorbitol.
In a preferred embodiment of the present invention, the solubilizing agent is selected from any one of tween-80, pluronic F-68, mesitylene, benzyl mesitylene, cholate, deoxycholate, glycerol, propylene glycol, polyethylene glycol, or a combination thereof.
In a preferred embodiment of the present invention, the flavoring agent is selected from any one of honey, syrup, acid, alkali, essence, sweetener, or a combination thereof.
In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention is microencapsulated with any one of aztreonam or a pharmaceutically acceptable salt thereof and any one of zidovetan or a pharmaceutically acceptable salt thereof according to a preparation method of a sustained-release preparation or a controlled-release preparation in the art, such as adding a retarder coating or preparing a matrix preparation, and the like, and then prepared into a sustained-release preparation or a controlled-release preparation.
In a preferred embodiment of the present invention, the sustained-release preparation carrier or the controlled-release preparation carrier is selected from any one of or a combination of oleaginous admixture, a hydrocolloid, a water-insoluble retarder, an enteric retarder, and a biodegradable retarder.
In a preferred embodiment of the present invention, the oleaginous additive is selected from any one of glyceryl monostearate, hydrogenated castor oil, mineral oil, polysiloxane, and dimethylsiloxane, or a combination thereof.
In a preferred embodiment of the present invention, the hydrocolloid is selected from any one of Methylcellulose (MC), sodium carboxymethylcellulose (CMC-Na), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HMPC), polyvinylpyrrolidone (PVP), acacia, tragacanth or carbopol, polyvinyl alcohol (PVA), pectin, alginate, chitosan, xanthan gum, guar gum, carrageenan, gelatin, agar, galactomannan, or a combination thereof.
In a preferred embodiment of the present invention, the water-insoluble retarder is selected from any one of Ethyl Cellulose (EC), cellulose Acetate (CA), polyethylene, polypropylene, polysiloxane, ethylene-vinyl acetate copolymer (EVA), polymethyl methacrylate, or a combination thereof.
In a preferred embodiment of the present invention, the enteric retarder is selected from any one of Cellulose Acetate Phthalate (CAP), hydroxypropyl methylcellulose phthalate (HMPCP), polyvinyl alcohol phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS) acrylic resin or a combination thereof.
In a preferred embodiment of the present invention, the biodegradable retarder is selected from any one of waxy, fatty acid ester, fatty alcohol, carnauba wax, stearic acid, glyceryl monostearate, stearyl alcohol, cetyl alcohol, or a combination thereof.
In a preferred embodiment of the present invention, the administration mode of the pharmaceutical composition is selected from any one of oral administration, injection administration, mucosal administration and dermal administration.
In the preferred technical scheme of the invention, the accumulated antibacterial rate of the pharmaceutical composition on drug-resistant bacteria is more than or equal to 69%, preferably more than or equal to 90%, and more preferably 100%.
Another object of the present invention is to provide the use of the broad-spectrum anti-drug resistant bacterial pharmaceutical composition of the present invention for the preparation of a medicament for the prevention and treatment of drug resistant bacterial infections.
In a preferred embodiment of the present invention, the drug-resistant bacteria are selected from any one of klebsiella pneumoniae, enterobacter cloacae, citrobacter freundii, klebsiella aerogenes, klebsiella oxytoca, acinetobacter baumannii (CRAB), pseudomonas aeruginosa (CRPA), carbapenem-resistant enterobacteriales (CRE), enterococcus faecium, staphylococcus aureus, helicobacter pylori, salmonella, neisseria gonorrhoeae, campylobacter, streptococcus pneumoniae, haemophilus influenzae, shigella, and combinations thereof.
In a preferred technical scheme of the invention, the drug-resistant bacteria are selected from any one of Klebsiella pneumoniae producing KPC, klebsiella pneumoniae producing KPC+NDM, klebsiella pneumoniae producing NDM, klebsiella pneumoniae producing OXA, enterobacter cloacae producing NDM, fuusi citrate producing NDM, klebsiella aerogenes producing NDM, klebsiella oxytoca producing KPC+NDM+IMP and Pseudomonas aeruginosa producing CRPA.
In a preferred embodiment of the present invention, the drug-resistant bacteria produce a drug-resistant bacteria enzyme selected from any one of class a enzymes, class B metalloenzymes, serine carbapenemases, penicillinase, cephalosporinase, OXA enzymes, and ultra-broad-spectrum- β lactamase (ESBL), or a combination thereof.
In a preferred embodiment of the present invention, the drug-resistant bacteria enzyme produced by the drug-resistant bacteria is selected from any one or a combination of KPC, NDM, IMP, OXA-48 and SHV, TEM, CMY, CTX-M-15.
In a preferred embodiment of the present invention, the infection is selected from any one of urinary tract infection, lower respiratory tract infection, blood flow infection, skin soft tissue infection, peritonitis, abdominal cavity infection, genital tract infection, skin infection, soft tissue infection, granulocytopenic fever, intra-abdominal infection, respiratory tract infection, pneumonia, bacteremia, meningitis, surgical infection, or a combination thereof.
Unless otherwise indicated, when the invention relates to a percentage between liquids, the percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentage between solids and liquids, the percentage being weight/volume percentage; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the invention scientifically screens the composition and the proportion of aztreonam or pharmaceutically acceptable salt thereof and zidambatan or pharmaceutically acceptable salt thereof, and efficiently and widely inhibits the growth activity of drug-resistant bacteria, especially multi-drug-resistant bacteria, by utilizing aztreonam or salt thereof and zidambatan or salt thereof, wherein the drug-resistant bacteria are selected from any one or combination of klebsiella pneumoniae, enterobacter cloacae, strainella furrada, klebsiella oxytoca, acinetobacter baumannii (CRAB), pseudomonas aeruginosa (CRPA), carbapenem drug-resistant enterobacterias (CRE), enterococcus faecium, staphylococcus aureus, helicobacter pylori, salmonella, neisseria gonorrhoeae, campylobacter, streptococcus pneumoniae, haemophilus influenzae and shigella, especially can inhibit the growth of Klebsiella pneumoniae producing KPC, klebsiella pneumoniae producing KPC+NDM, klebsiella pneumoniae producing NDM, klebsiella pneumoniae producing OXA, enterobacter cloacae producing NDM, citrobacter freundii producing NDM, klebsiella aerogenes producing KPC+NDM+IMP, klebsiella oxytoca producing CRPA and Pseudomonas aeruginosa producing CRPA with high efficiency, remarkably improves the drug-resistant bacteria activity of aztreonam, especially the therapeutic activity of multiple drug-resistant bacteria, remarkably reduces the dosage of aztreonam, even reverses the drug resistance of beta-lactamase antibiotics, remarkably reduces the recurrence rate and serious adverse reaction incidence rate of drug-resistant bacteria and multiple drug-resistant bacteria, effectively solves the technical problems of broad spectrum, safety, high efficiency inhibition of 'super bacteria' and multiple drug-resistant bacteria activity, has the advantages of high efficiency, broad spectrum, safety, high efficiency, good stability, high bioavailability and the like, provides a new treatment means for effectively preventing and treating the infection of super bacteria and multi-drug resistant bacteria clinically, and leads patients to benefit directly.
2. The preparation method has the advantages of simple operation, high yield, better cost, wide applicable crowd, suitability for industrial production and the like.
Detailed Description
The present invention is described below with reference to examples. The invention is not limited to the examples.
In vitro inhibition of drug-resistant bacteria activity study of pharmaceutical compositions:
test strain: the enterobacteriales clinically isolated in the hospital were collected and strain identification was performed using a VITEK MS full-automatic rapid mass spectrometry detection system (purchased from the company Mei Liai, france).
PCR amplification and sequencing: bacterial carbapenemase gene is amplified by PCR amplification technology, bacterial DNA is extracted by heating and boiling method, and primers are synthesized by Shanghai Biotechnology, inc. according to the sequence design provided in GenBank, and the sequences are shown in Table 1.
TABLE 1PCR primer sequences and product Length
PCR reaction system: template DNA 2. Mu.l, 10 XPCR buffer (Mg 2+ plus) 2. Mu.l, 2.5mmol/L dNTP mix 2. Mu.l, 10. Mu.m/. Mu.l sense and antisense primers each 1. Mu.l, 5U/. Mu.l rTaq enzyme 0.3. Mu.l, sterile water 16.7. Mu.l, total volume 25. Mu.l.
PCR reaction conditions: 94℃for 5min,94℃for 30s, annealing temperature for 30s,72℃for 30s,30 cycles, and 72℃for 7min. The amplified products were separated by electrophoresis on 1% agarose (SYBRGreen-containing) and imaged by a gel imaging system to observe the results. The positive amplified products were sequenced by Hangzhou Jie-Biolimited, and the DNA sequencing sequences were aligned on the Gen-Bank network to determine the type and subtype of the gene.
Columbia blood agar medium: purchased from kangtai biotechnology limited, wenzhou city.
Cation-regulated MH broth (CaMHB): purchased from BD company in the united states.
Test drugs (zidasbactam, aztreonam, tigecycline, polymyxin B) were purchased from chinese pharmaceutical biologicals institute.
(1) Zidasbactam stock (640 μg/mL): dissolving the zidamantane with dimethyl sulfoxide (DMSO), and diluting with water.
(2) Aztreonam stock (640 μg/mL): dissolving aztreonam in saturated sodium bicarbonate solution, and diluting with water.
(3) Tigecycline stock solution (640 μg/mL): the tigecycline is prepared by dissolving with sodium bicarbonate solution, and diluting with water.
(4) Polymyxin B stock (640 μg/mL): the polymyxin B is prepared by adding water for dilution after being dissolved in DMSO.
The invention refers to the American society for clinical and laboratory standardization (Clinical and Laboratory Standards Institute, CLSI) M100 guideline file, 2020 edition, and uses broth microdilution to determine the minimum inhibitory concentration (Minimum inhibitory concentration, MIC) of a test substance against a clinically isolated aerobic resistant strain. Test fungus liquidThe bacteria is inoculated after dilution by a 0.5 McO turbidity tube, and the final concentration of the inoculum size of the tested bacteria liquid is 10 5 CFU/mL. Placing the strain in an air state and culturing for 16-20 h at 35+/-2 ℃. The drug sensitive results were read as required by the CLSI M100 file in 2020.
Example 1Research on in-vitro growth activity of drug-resistant bacteria inhibition of pharmaceutical composition
Composition 1: aztreonam: the mass ratio of the zidamantane is 2:1.
Composition 2: aztreonam: the mass ratio of the zidamantane is 1:1.
Composition 3: aztreonam: the mass ratio of the zidamantane is 1:2.
Composition 4: aztreonam: the mass ratio of the zidamantane is 1:4.
Composition 5: aztreonam: the mass ratio of the zidamantane is 1:8.
Composition 6: aztreonam: the mass ratio of the zidamantane is 1:16.
Composition 7: aztreonam: the mass ratio of the zidamantane is 1:32.
Composition 8: aztreonam: the mass ratio of the zidamantane is 1:64.
Composition 9: aztreonam: the mass ratio of the zidamantane is 1:128.
Composition 10: aztreonam: the mass ratio of the zidamantane is 1:256.
Positive control drug: tigecycline and polymyxin B.
The test method comprises the following steps:
1. preparation of test solutions for compositions 1-10: the aztreonam stock solution (640. Mu.g/mL) was taken and added to the first dilution tube, diluted 1:10 gradient with broth, and an equal amount of 8. Mu.g/mL of the solution of zidasbactam was added.
2. Preparation of tigecycline test solution: stock tigecycline (640 μg/mL) was taken and diluted 1:10 gradient with broth.
3. Preparation of polymyxin B test solution: polymyxin B stock (640. Mu.g/mL) was taken and diluted 1:10 in broth.
The minimum inhibitory concentration (Minimum inhibitory concentration, MIC) of the test substance on the clinically isolated aerobic resistant strain was determined by broth microdilution. Cumulative antibacterial rate = number of antibacterial plants/number of cumulative bacterial plants 100%. The results are shown in Table 2.
TABLE 2
The above description of the embodiments of the present invention is not intended to limit the present invention, and those skilled in the art can make various changes or modifications according to the present invention without departing from the spirit of the present invention, and shall fall within the scope of the claims of the present invention.
Claims (8)
1. The application of the broad-spectrum drug-resistant bacteria pharmaceutical composition in preparing drugs for preventing and treating drug-resistant bacteria infection,
the broad-spectrum drug-resistant bacteria pharmaceutical composition contains aztreonam or any one of pharmaceutically acceptable salts thereof and other pharmaceutically acceptable salts of the ambabatam or any one of pharmaceutically acceptable salts thereof, wherein the mass ratio of the aztreonam or the pharmaceutically acceptable salts thereof to the other pharmaceutically acceptable salts of the ambabatam or the pharmaceutically acceptable salts thereof in the composition is 1:8-1:268, the pharmaceutically acceptable salts are selected from any one of hydrochloride, hydrobromide, phosphate, hydrogen phosphate, sulfate, bisulfate, acetate, oxalate, malonate, valerate, glutamate, oleate, p-toluenesulfonate, methanesulfonate, isethionate, fumarate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanilla, mandelate, succinate, gluconate and lactobionate,
the drug-resistant bacteria are selected from any one of Klebsiella pneumoniae producing KPC, klebsiella pneumoniae producing KPC+NDM, klebsiella pneumoniae producing OXA, and Klebsiella oxytoca producing KPC+NDM+IMP.
2. The use of claim 1, wherein the infection is selected from any one of peritonitis, pneumonia, bacteremia, meningitis, or a combination thereof.
3. The use of claim 1, wherein the mass ratio of aztreonam to zidamantan in the composition is 1:8, 1:16, 1:32, 1:64, 1:128, 1:256, 1:10, 1:12, 1:14, 1:18, 1:20, 1:22, 1:24, 1:28, 1:30, 1:34, 1:36, 1:38, 1:40, 1:42, 1: 44. 1:46, 1:48, 1:50, 1:52, 1:54, 1:56, 1:58, 1:60, 1:62, 1:66, 1:68, 1:70, 1:80, 1:90, 1:100, 1:110, 1:133, 1:150, 1: 200. 1:250, 1:265.
4. Use according to any one of claims 1-3, the active ingredient of the pharmaceutical composition consisting of aztreonam and zidasbactam.
5. The use according to any one of claims 1-3, the pharmaceutical composition consisting of a first composition comprising aztreonam and a second composition comprising zidovetan.
6. The use of claim 5, wherein the first composition and the second composition are administered simultaneously or sequentially.
7. The use according to any one of claims 1-3, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
8. The use according to claim 7, wherein the pharmaceutical composition is in a form selected from any of oral preparation, injection and external preparation.
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| CN114531850A (en) * | 2019-10-04 | 2022-05-24 | 富士胶片株式会社 | Pharmaceutical composition and kit characterized by containing novel penicillin derivative or salt thereof and 1 or more compounds selected from beta-lactamase inhibitory compound and antibacterial compound or salt thereof |
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| In vitro activity of aztreonam in combination with newly developedβ-lactamase inhibitors against MDR Enterobacterales and Pseudomonas aeruginosa producing metallo-β-lactamases;Christophe Le Terrier等;Journal of Antimicrobial Chemotherapy;第78卷(第1期);第101-107页 * |
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