CN102228458B - Meropenem sodium/sulbactam sodium medicinal composition - Google Patents
Meropenem sodium/sulbactam sodium medicinal composition Download PDFInfo
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Abstract
The invention provides a combined medicament, in particular a meropenem sodium and sulbactam sodium combined medicine which is used for treating infectious diseases caused by Acinetobacter baumanii. The meropenem sodium and sulbactam sodium combined medicine has synergistic and cumulative antibacterial effects on the infectious diseases caused by the Acinetobacter baumanii, particularly has good synergistic and cumulative antibacterial effects on multiple medicine-resistant Acinetobacter baumanii, and can be used for curing the clinical infection caused by the multiple medicine-resistant Acinetobacter baumanii.
Description
Technical field
The invention provides a kind of combination medicine, specifically, provide a kind of combination medicine that is used for the treatment of Acinetobacter bauamnnii and causes the meropenem/sulbactam sodium of infectious disease.Belong to medical technical field.
Background technology
Antibiotic resistance is not new problem, but it is strengthening the mankind's threat.Although each state is all taking action, must make an effort to avoid being backwards to the epoch that occur before antibiotic, can be used future without medicine.Therefore World Hygiene Day theme in 2011 is orientated as and is resisted drug resistance.
Carbapenem antibiotics is the class antibiotic that antimicrobial spectrum is the widest so far, antibacterial activity is very strong, but along with being widely used of carbapenems, Acinetobacter bauamnnii increases year by year to the antibacterial resistant rate of carbapenems.Once and to Carbapenem-resistant, just mean that existing common broad-spectrum antibacterials are to its many inefficacies.
Acinetobacter bauamnnii (Acinetobacter baumanii) is non-fermentation gram-negative bacteria, is distributed widely in nature and hospital environment, and be conditioned pathogen.In clinical common acinetobacter calcoaceticus, Acinetobacter bauamnnii account for clinical separation acinetobacter antibacterial 70%, the infection that other strain causes is more rare.Identify Acinetobacter bauamnnii: 16sRNA, 23sRNA, 51-like-OXA.Have that grinding traces it to its cause and be and carry multidrug resistant gene and multi-medicament efflux pump gene mdfA is the origin cause of formation of the general drug resistance of Acinetobacter bauamnnii, the multiple Mobile genetic elements of this type of bacterial strain portability, very easily causes the horizontal transfer of drug resistant gene simultaneously.
In recent years, the nosocomial infection of being caused by Acinetobacter bauamnnii increases year by year, and multiple countries have reported a lot of hospital infection outbreak of epidemic by its initiation in succession, cause global extensive concern.There is general drug resistance acinetobacter calcoaceticus outburst in BJ Union Hospital in 2004 of China, involves 74 patients in 18 wards, nearly 59.4% patient infection.In 4796 strain acinetobacters of 14 hospitals in 2009 (Acinetobacter bauamnnii accounts for 86.6%), the resistant rate of meropenem is 52.4%.Acinetobacter bauamnnii can cause breathe pneumonia, septicemia, urinary system infection, meningitis etc. serious, the even infection of lethal, ratio in Nosocomial Infection Pathogens increases very fast, clinically the Acinetobacter bauamnnii of drug resistance is not had to specific treatment medicine.
In to the monitoring of the whole America 2005-2007 bacterial resistance of 3 years, find, gram-negative bacteria is comparatively stable to the sensitivity of each antibacterials in these 3 years, have only the sensitivity of Acinetobacter bauamnnii is had to downward trend year by year, and drug resistance, multidrug resistant rate be constantly to rise, its Acinetobacter bauamnnii ratio that accounts for whole clinical separation rises to 30.8% by 6.3%.Carbapenems medicine is the choice drug for the treatment of Acinetobacter bauamnnii severe infection, but carbapenem multiple antibiotic resistant strain is occurring all over the world successively in recent years, from Spain to Norway, there is alarming multidrug resistant Acinetobacter bauamnnii " invasion " phenomenon, popular in the wound soldier who stays Afghanistan and U.S. army of Iraq and the British army, cause serious public health problem, the Acinetobacter bauamnnii that U.S. army of Iraq takes back is popular in the U.S..
Meropenem Meropenem or its trihydrate are a kind of penems antibiotics clinically.
Sulbactam (sulbactam), sulbactam sodium is irreversible competitive beta-lactamase inhibitor, the beta-lactamase that Grain-positive and negative bacterium (except bacillus pyocyaneus) are produced all has inhibitory action, after there is irreversible reaction with enzyme, make enzyme deactivation, inhibitor can not make the activity of enzyme be restored after removing.There is very strong irreversible competitive inhibition with produced beta-lactamase.
Summary of the invention
One of the object of the invention is to provide a kind of combination medicine of meropenem sulbactam.Technical solution of the present invention is as follows:
A kind of pharmaceutical composition, is made up of active constituents of medicine and pharmaceutically acceptable adjuvant, it is characterized in that described active constituents of medicine is meropenem or its hydrate and sulbactam or its pharmaceutical salts.
Described meropenem hydrate can be for example Meropenem trihydrate etc.Described sulbactam pharmaceutical salts, is preferably sulbactam sodium.
Preferably, pharmaceutical composition described above, wherein said active component is meropenem and sulbactam sodium.
Pharmaceutical composition described above, wherein the weight ratio of meropenem and sulbactam sodium is 2: 1～1: 3, preferably 1: 1～1: 3 is more preferably 1: 1～1: 2.
Preferably, the invention provides a kind of pharmaceutical composition that causes infectious disease for medicine treatment Acinetobacter bauamnnii, formed by active constituents of medicine and pharmaceutically acceptable adjuvant, it is characterized in that described active constituents of medicine is meropenem and sulbactam sodium, wherein the weight ratio of meropenem and sulbactam sodium is 2: 1～1: 3, preferably 1: 1～1: 3 is more preferably 1: 1～1: 2.
As another goal of the invention of the present invention, provide the application of a kind of pharmaceutical composition described above in the medicine that causes infectious disease for the preparation for the treatment of Acinetobacter bauamnnii.
Preferably, meropenem or its hydrate cause the application in the medicine of infectious disease at preparation and sulbactam or its pharmaceutical salts drug combination treatment Acinetobacter bauamnnii.
Preferably, sulbactam or its pharmaceutical salts cause the application in the medicine of infectious disease at preparation and meropenem or its hydrate drug combination treatment Acinetobacter bauamnnii.
Wherein, application described above, wherein the weight ratio of meropenem and sulbactam sodium is 2: 1～1: 3, preferably 1: 1～1: 3 is more preferably 1: 1～1: 2.
Acinetobacter bauamnnii described above causes infectious disease, can be selected from and breathe pneumonia, septicemia, urinary system infection, meningitis etc.
The present invention also provides a kind of patient pack of the apparatus that comprises the unit dose for measuring, and this patient pack comprises meropenem and sulbactam sodium and helps patient to use the apparatus of combination medicine of the present invention.
Pharmaceutical composition of the present invention, wherein can comprise one or more pharmaceutically acceptable auxiliaries or carrier, and it is not particularly limited, and can be pharmaceutic adjuvant or adjuvant conventional in this area.Those skilled in the art can require to select suitable pharmacy adjuvant according to pharmaceutical dosage form.
The present invention studies unexpectedly discovery, the infectious disease that meropenem and sulbactam combination medicine cause Acinetobacter bauamnnii has collaborative and cumulative antibacterial action, particularly to multidrug resistant Acinetobacter bauamnnii, strain also has well collaborative and cumulative antibacterial action, can be used to cure the clinical infection causing due to multidrug resistant Acinetobacter bauamnnii clinically.
Embodiment of the present invention experiment has been used from 102 strain imipenem-resistant bacterial strains of outpatient service isolation identification all carries bla
oXA-51gene, blaoxa-
51group gene is the natural intrinsic gene of Acinetobacter bauamnnii chromosome, and antibacterial shows as the sensitivity to beta-lactam antibiotic.The Acinetobacter bauamnnii of experiment is not only to imipenem-resistant, also selected simultaneously, to meropenem, piperacillin, piperacillin/Tazobactam Sodium (1: 1), cefoperazone, Sulbactam/Cefoperazone (1: 1), ciprofloxacin resistance, in these Resistant strains, to use meropenem/sulbactam sodium composition simultaneously.By the in vitro activity of 4 kinds of variable concentrations mass ratioes (2: 1,1: 1,1: 2,1: 3) is shown, meropenem/sulbactam sodium drug combination can significantly improve imipenem-resistant bacterial strain is all carried to bla
oXA-51the sensitivity of the Acinetobacter bauamnnii of gene, has clear and definite and strong antibacterial activity.Meropenem all has stronger bactericidal action from the different proportionings of sulbactam sodium, and the proportioning of 2: 1 to 1: 3 is all significantly better than the independent medication of meropenem to the bactericidal action of Acinetobacter bauamnnii.In vitro tests result shows, meropenem/sulbactam sodium 2: 1-1: 3 all have stronger vitro antibacterial activity than meropenem list medicine.
The specific embodiment
Further set forth the present invention below by embodiment, but and in the present invention is protected perhaps scope be construed as limiting.
Embodiment 1: meropenem/sulbactam sodium in vitro activity
One, materials and methods
1. test drug:
(1) meropenem (Meropenem), chemical name 3-[[5-[(dimethylamino) carbonyl]-3-pyrrolidinyl] sulfo-]-6-(1-ethoxy)-4-methyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid lot number 0430-200002, purchased from Nat'l Pharmaceutical & Biological Products Control Institute.
(2) sulbactam sodium (Sulbactam sodium SBT): lot number 0430-200002, purchased from Nat'l Pharmaceutical & Biological Products Control Institute.
By weight, wherein meropenem weight is with the meropenem pure calculating of giving money as a gift for following ratio proportioning, and sulbactam sodium weight is given money as a gift and purely calculated by sulbactam with sulbactam sodium.
2. test proportioning:
(1) meropenem
(2) sulbactam sodium
(3) meropenem+sulbactam sodium (2: 1)
(4) meropenem+sulbactam sodium (1: 1)
(5) meropenem+sulbactam sodium (1: 2)
(6) meropenem+sulbactam sodium (1: 3)
3. test strain:
This experiment has been used from 102 strain imipenem-resistant bacterial strains of outpatient service isolation identification and has all carried bla
oXA-51gene, blaoxa-
51group gene is the natural intrinsic gene of Acinetobacter bauamnnii chromosome, and antibacterial shows as the sensitivity to beta-lactam antibiotic.The Bao Man bacillus of this 102 strain is simultaneously to meropenem, piperacillin, piperacillin/Tazobactam Sodium (1: 1), cefoperazone, Sulbactam/Cefoperazone (1: 1), ciprofloxacin also while drug resistance, belong to multidrug resistant Acinetobacter bauamnnii, Quality Control bacterium is escherichia coli ATCC25922 and Pseudomonas aeruginosa ATCC27853.The known bacterial strain of above-mentioned prior art, all purchased from attached Shengjing city hospital of Chinese Medical Sciences University.
4. reagent and instrument
M-H meat soup and M-H agar (French Biomerieux SA); Taq archaeal dna polymerase, dNTPs, DNA Maker DL2000, ApaI enzyme (TaKaRa company); Calorstat (Chongqing Si Da company), pulsed field gel electrophoresis instrument (Biorad company); Gel imaging system (genome company), than turbid instrument (French Biomerieux SA), PCR instrument (Eppendorf company of the U.S.).
5. method
The 5.1 in-vitro antibacterial medicine drug sensitive detections plate doubling dilution of adopting international standards.Measure the minimum inhibitory concentration (M IC) of each antibacterials to various pathogenic bacterium.By the critical concentration of U.S.'s laboratory and clinical criteria institute (CILS) regulation in 2009, judge the sensitivity of every strain bacterium to antibacterials, obtain antibacterial responsive rate (S%), the intermediary of measured various antibacterials are led to (I%) and resistant rate (R%).Wherein antibacterial is judged to be drug resistance to imipenum MIC >=16.
5.2 pulsed field gel electrophoresiss (pulsed-field gel electrophoresis, PFGE) boiling method extracts bacteria total DNA.Genomic DNA uses after ApaI enzyme action, inserts in 1% agarose gel in 0.5mol/L tromethane-ethylenediaminetetraacetic acid (Tris-EDTA), uses 6V/cm pulsed field gel electrophoresis instrument to detect.Burst length scope, at 5.0-8.0s, continues 24h.Then gel ethidium bromide staining is observed under uviol lamp and film making is retained.
5.3 OXA enzyme gene tests: detect 4 groups of OXA enzyme genes with PCR method.PCR reaction system volume 20 μ L, PCR condition: 94 ℃ of denaturation 5min, 94 ℃ of degeneration 25s, 56 ℃ of annealing 40s, 72 ℃ are extended 50s, and after 30 circulations, 72 ℃ are extended 6min again.PCR product is made Preliminary Identification with 1.5% agarose gel electrophoresis and Ethidum Eremide dyeing.PCR primer is synthetic by Shanghai Sheng Gong engineering company.PCR product electrophoresis is cut glue and is carried out checking order after purification.Sequence in sequencing result and GenBank is compared, determine product type.
6. the influence factor of pair vitro antibacterial activity
(1) bacterial load impact
Different bacterium amounts (10 with four kinds of proportioning meropenem/sulbactam sodium of plate doubling dilution mensuration to test bacterium
4, 10
5, 10
6, 10
7cFU/ml) impact on MIC value (MIC 6mg/L).
(2) impact of Medium's PH Value
Measure 6 kinds of proportioning meropenem/sulbactam sodium to the impact on MIC value under different pH condition of test bacterium with plate doubling dilution.
(3) impact of serum albumin content
Measure 6 kinds of proportioning meropenem/sulbactam sodium with plate doubling dilution test bacterium is observed to the impact of serum albumin content on MIC value in different serum-concentration (25%, 50%, 75%) and the culture medium that does not contain serum.
Two, result
1. the antibacterial activity in vitro of meropenem/sulbactam sodium to Acinetobacter bauamnnii
The results are shown in Table 1.
Table 1. antibacterial activity in vitro
As seen from Table 1, in MIC90, meropenem is to Acinetobacter bauamnnii antibacterial activity drug resistance (break of drug resistance is 16), the antibacterial activity of sulbactam sodium is higher 4 times than meropenem separately, but also belonging to drug resistance. the antibacterial activity of meropenem/sulbactam sodium (2: 1) is 4 times of meropenem and suitable with the antibacterial activity of independent sulbactam sodium, being 8 times of single medicine meropenems and being 2 times of independent sulbactam sodium of meropenem/sulbactam 1: 1, and meropenem/sulbactam 1: 2nd, 32 times of single medicine meropenems and be independent the more than 8 times of sulbactam sodium.
2. the influence factor of pair vitro antibacterial activity:
(1) as shown in table 2, the meropenem/sulbactam sodium of different proportionings is respectively 10 at bacterial load
4, 10
5, 10
6with 10
7when CFU/ml, to Acinetobacter bauamnnii MIC value.Illustrate that bacterial load is 10
4～10
7the MIC value of the meropenem/sulbactam sodium anti-Acinetobacter bauamnnii of CFU/ml to different proportionings has no significant effect.
The impact of table 2. meropenem/sulbactam sodium on Acinetobacter bauamnnii inoculum concentration
(2) as seen from Table 3, the MIC value to Acinetobacter bauamnnii of 4 kinds of proportioning meropenem/sulbactams has no significant effect in pH 5.0～pH 8.0 scopes.
Table 3. meropenem+sulbactam sodium is the impact of MIC on Acinetobacter bauamnnii under different pH
(3) human albumin's content in culture medium, to the meropenem/sulbactam sodium of 4 kinds of proportionings, anti-Acinetobacter bauamnnii effect has no significant effect, and result is as table 4.
The impact of table 4. meropenem/sulbactam sodium human albumin's content on Acinetobacter bauamnnii MIC
Embodiment 2: the vivo bacteria corrosion action research of meropenem/sulbactam sodium
Meropenem and sulbactam sodium be (2: 1) by weight, and (1: 1), (1: 2), the combination medicine of (1: 3), has significant antibacterial therapy effect to the mice infecting.
1 tested medicine
Meropenem (Meropenem, chemical constitution is C17H25N3O5S3H2O) lot number 0430-200002, purchased from Nat'l Pharmaceutical & Biological Products Control Institute.
Sulbactam sodium, lot number: 0430-200002, purchased from Nat'l Pharmaceutical & Biological Products Control Institute.
White mice, Kunming kind, body weight 18～22g, male and female half and half.Chinese Medical Sciences University belongs to the second laboratory animal room of hospital to be provided.The quality certification number, the Liao Dynasty is real moving for word 031.Random packet, 10 every group, male and female half and half.If 7 dosage groups, the equal Intraperitoneal injection 10 of each Mus
-5mLD bacterium liquid 0.5ml.With the calculating ED of Jun Hua probit
50(each medicine)
2 medicine preparations
Be mixed with desired concn with 0.9% sodium chloride fluid injection.
1, meropenem (single dose) 2, sulbactam sodium (single dose)
3, meropenem+sulbactam sodium (2: 1) 4, meropenem+sulbactam sodium (1: 1)
5, meropenem+sulbactam sodium (1: 2) 6, meropenem+sulbactam sodium (1: 3)
Observe dead mouse number after 7 days, draw the upper limit and the lower limit of trial drug dosage, different with bacterial strain, but be the minimum lethal dose (MLD) that causes mice 100% death.Adopt low ratio serial dilution, two are faced dosage group dose-difference i value mutually for 0.1-0.15.Claim maximum dose level × mice average weight ÷ administration volume × volumetric flask volume ÷ of the dose=medicinal liquid of giving to tire. observe dead mouse number after 7 days, draw the upper limit and the lower limit of trial drug dosage.
3 infectious bacterias and bacterium amount
Incubated overnight bacterium liquid transferred species, in M-H meat soup, is cultivated to 18h for 35 ℃, be experiment bacterium stock solution.Bacterium stock solution is suitably diluted, be diluted to the required final concentration of infection animal with 5% high activity dried yeast liquid.This concentration is different according to different strains, but is the minimum lethal dose (MLD. that causes mice 100% death
MLD bacterium liquid processed: total amount=0.5ml × test Mus number; 10 Mus of each dosage group, award medicinal liquid (0.5ml/ gavage) for 1 hour after every mouse infection 0.5ml MLD bacterium liquid.
4 experimental results
In table 5.
The different proportioning meropenem/sulbactam sodium of table 5. are to the protective effect of Acinetobacter bauamnnii infecting mouse
※ ※ P < 0.001 and the comparison of meropenem single dose
As shown in table 5, and meropenem/sulbactam sodium (2: 1,1: 1,1: 2,1: 3) protective effect of Acinetobacter bauamnnii abdominal cavity infection mice is obviously better than to meropenem single dose.
Embodiment 3: meropenem and sulbactam sodium, by weight the combination medicine of (2: 1,1: 1,1: 2,1: 3), have significant antibacterial therapy effect to the mice infecting
1. tested medicine
Meropenem (Meropenem), lot number: 130506-200702, purchased from Nat'l Pharmaceutical & Biological Products Control Institute, medicine company limited of Shenzhen Xintai City provides.
Sulbactam/Cefoperazone sodium (1: 1), pfizer inc produces, lot number, 058354030. medicine company limited of Shenzhen Xintai City provides,
Sulbactam sodium, lot number: 0430-200002, purchased from Nat'l Pharmaceutical & Biological Products Control Institute.
White mice, Kunming kind, body weight 18～24g, male and female half and half.Chinese Medical Sciences University belongs to the second laboratory animal room of hospital to be provided.The quality certification number, the Liao Dynasty is real moving for word 031.Random packet, 10 every group, male and female half and half.If 2 dosage groups, the equal Intraperitoneal injection 10 of each Mus
-5mLD bacterium liquid 0.5ml.With the calculating ED of Jun Hua probit
50(each medicine)
2. medicine preparation
Meropenem/sulbactam sodium (2: 1,1: 1,1: 3); Sulbactam/Cefoperazone sodium (1: 1), is mixed with desired concn with 0.9% sodium chloride fluid injection.
Observe dead mouse number after 7 days, draw the upper limit and the lower limit of trial drug dosage, different with bacterial strain, but be the minimum lethal dose (MLD) that causes mice 100% death.Adopt low ratio serial dilution, two are faced dosage group dose-difference i value mutually for 0.1-0.15.Claim maximum dose level × mice average weight ÷ administration volume × volumetric flask volume ÷ of the dose=medicinal liquid of giving to tire. observe dead mouse number after 7 days, draw the upper limit and the lower limit of trial drug dosage.
3. infectious bacteria and bacterium amount
Incubated overnight bacterium liquid transferred species, in M-H meat soup, is cultivated to 18h for 35 ℃, be experiment bacterium stock solution.Bacterium stock solution is suitably diluted, be diluted to the required final concentration of infection animal with 5% high activity dried yeast liquid.This concentration is different according to different strains, but is the minimum lethal dose (MLD) that causes mice 100% death.
MLD bacterium liquid processed: total amount=0.5ml × test Mus number; 10 Mus of each dosage group, award medicinal liquid (0.5ml/ gavage) for 1 hour after every mouse infection 0.5ml MLD bacterium liquid.
5 experimental results
In table 6.
The different proportioning meropenem/sulbactam sodium of table 6. are to the protective effect of Bao acinetobacter mice
※P＜0.001
As shown in table 6, meropenem/sulbactam sodium (2: 1,1: 1 and 1: 3) is obviously better than cefoperazone+sulbactam sodium (1: 1) dosage to the protective effect of Acinetobacter bauamnnii abdominal cavity infection mice.
Claims (3)
1. one kind is used for the treatment of the pharmaceutical composition of the infectious disease that Acinetobacter bauamnnii causes, formed by active constituents of medicine and pharmaceutically acceptable adjuvant, it is characterized in that described active constituents of medicine is meropenem and sulbactam sodium, wherein the weight ratio of meropenem and sulbactam sodium is 1: 3.
2. the application of pharmaceutical composition claimed in claim 1 in the medicine that causes infectious disease for the preparation for the treatment of Acinetobacter bauamnnii.
3. application according to claim 2, wherein said Acinetobacter bauamnnii causes that infectious disease is selected from breathing pneumonia, septicemia, urinary system infection or meningitis.
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| Carlos R.V. Kiffer, et al..In vitro synergy test of meropenem and sulbactam against clinical isolates of Acinetobacter baumannii.《Diagnostic Microbiology and Infectious Disease》.2005,第52卷317-322. * |
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