CN102225062B - Pharmaceutical composition for treating infectious diseases caused by Acinetobacter baumannii - Google Patents
Pharmaceutical composition for treating infectious diseases caused by Acinetobacter baumannii Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition for treating infectious diseases caused by Acinetobacter baumannii, particularly relates to a combined administration medicine of faropenem or pharmaceutical salts thereof and tazobactam or pharmaceutical salts thereof, as well as relates to a medicinal application of the pharmaceutical composition in treating infectious diseases caused by Acinetobacter baumannii. The invention surprisingly finds that faropenem and tazobactam have synergic and accumulative antibacterial actions, and the combination administration of faropenem and tazobactam in a weight ratio of (1:1) to (1-12) has a distinct bactericidal action and is significantly better than single administration of faropenem sodium.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that Acinetobacter bauamnnii causes infectious disease for the treatment of, particularly, relate to faropenem or its pharmaceutical salts and Tazobactam Sodium or its pharmaceutical salts combination medicine, also relate to the medical usage that Acinetobacter bauamnnii causes infectious disease that is used for the treatment of of described pharmaceutical composition.Belong to medical technical field.
Background technology
Acinetobacter bauamnnii (Acinetobacter baumanii) is non-fermentation gram-negative bacteria, is distributed widely in nature and the hospital environment, and be conditioned pathogen.Acinetobacter bauamnnii, Acinetobacter calcoaceticus, unnamed gene kind 3,13TU phenotype are very approaching, so they are referred to as the compound Acinetobacter calcoaceticus of Bao Man.The large absolutely number of the acinetobacter calcoaceticus that is separated in the clinical samples is Acinetobacter bauamnnii, and the infection that other strain causes is more rare.Identify Acinetobacter bauamnnii: 16sRNA, 23sRNA, 51-like-OXA.
In recent years, the increasing sharply of the multiple antibiotic resistant strain of Acinetobacter bauamnnii, the nosocomial infection of initiation increases year by year, and particularly a plurality of countries have reported a lot of hospital infection outbreak of epidemic by its initiation in succession, cause global extensive concern.Acinetobacter bauamnnii can cause serious even infection lethal such as breathing pneumonia, septicemia, urinary system infection, meningitis, ratio in Nosocomial Infection Pathogens increases very fast, clinically the Acinetobacter bauamnnii of drug resistance is not had the specific treatment medicine.Once caused infectious disease with cefoperazone/Tazobactam Sodium treatment by Acinetobacter bauamnnii clinically.But in recent years research finds that cefoperazone/Tazobactam Sodium is more and more to the drug resistance of Acinetobacter bauamnnii, produces cefoperazone/Tazobactam Sodium drug resistance, and multidrug resistant mechanism is complicated, has caused multiple antibiotic resistance.
In to the monitoring of the bacterial resistance in 3 years of the whole America 2005-2007, find, gram-negative bacteria sensitivity to each antibacterials in these 3 years is comparatively stable, the sensitivity that has only Acinetobacter bauamnnii has downward trend year by year, and drug resistance, general resistant rate be constantly to rise, and its Acinetobacter bauamnnii ratio that accounts for whole clinical separation rises to 30.8% by 6.3%.The carbapenems medicine is the choice drug for the treatment of Acinetobacter bauamnnii severe infection, but the general Resistant strain of carbapenem is occurring all over the world successively in recent years, from Spain to Norway, alarming multidrug resistant Acinetobacter bauamnnii " invasion " phenomenon has appearred, popular in the wound soldier who stays Afghanistan and Iraq U.S. army and the British army, cause serious public health problem, the Acinetobacter bauamnnii that Iraq U.S. army takes back is popular in the U.S..
Faropenem sodium, English name: Faropenem sodium, chemical name: (5R, 6S)-6-[(1R)-1-ethoxy]-the 7-oxidation-3-[(2R)-the 2-tetrahydrofuran base]-4-thia-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid list sodium salt.Faropenem is clinical carbapenem antibiotic medicine commonly used.
Sodium-tazobactam, English name Tazobactam Sodium, chemical name: (2S, 3S, 5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazole-1-ylmethyl)-4-sulfo--1-azabicyclo [3.2.0] heptane-2-carboxylic acid 4,4-dioxide.Sodium-tazobactam is a kind of beta-lactamase inhibitor, and it is low to have toxicity, good stability, the advantage such as Inhibiting enzyme activity is strong.Various types of beta-lactamases (particularly ultraphotic spectrum beta-lactamase) all there is irreversible inhibitory action.
Summary of the invention
Be the infectious disease of effectively treating Acinetobacter bauamnnii, particularly causing for general drug resistance or multidrug resistant Acinetobacter bauamnnii, the invention provides a kind of combination medicine of faropenem/Tazobactam Sodium.For achieving the above object, technical solution of the present invention is as follows:
The invention provides the application in the medicine that causes infectious disease for the preparation of the treatment Acinetobacter bauamnnii of a kind of faropenem or its pharmaceutical salts and Tazobactam Sodium or its pharmaceutical salts.
Preferably, application described above is characterized in that the application in the medicine that causes infectious disease for the preparation of the treatment Acinetobacter bauamnnii of Faropenem sodium and sodium-tazobactam.
Application described above, wherein said Acinetobacter bauamnnii comprise the Acinetobacter bauamnnii to carbapenem antibiotic and/or beta-lactam antibiotic drug resistance.For example, Faropenem sodium, piperacillin, piperacillin/Tazobactam Sodium (1: 1), cefoperazone, cefoperazone/Tazobactam Sodium (1: 1) had drug resistance or multidrug resistant Acinetobacter bauamnnii strain.
The application that the present invention is described above, wherein said infectious disease is breathed pneumonia, septicemia, urinary system infection, meningitis etc. such as being selected from, or even infection serious, lethal.
Preferably, the application that the present invention is described above, wherein the weight ratio of faropenem and Tazobactam Sodium is 1: 1～1: 12, and the weight ratio of optimal seeking method faropenem and sodium-tazobactam is 1: 1～1: 12, more preferably 1: 1,1: 3,1: 5,1: 8 or 1: 12.
The present invention also provides a kind of medicine that Acinetobacter bauamnnii causes infectious disease that is used for the treatment of, and it comprises faropenem or its officinal salt and Tazobactam Sodium or its officinal salt and optional one or more pharmaceutically acceptable carriers that exist.
As the preferred described medicine that Acinetobacter bauamnnii causes infectious disease that is used for the treatment of, it is characterized in that it comprises Faropenem sodium and sodium-tazobactam and optional one or more pharmaceutically acceptable carriers that exist.
Wherein, described pharmaceutically acceptable carrier is not particularly limited, and can be usual pharmaceutical adjuvant or adjuvant in the pharmaceuticals industry, to prepare suitable medicament.
The medicine that the present invention is described above is not particularly limited, and can be the preparation of suitable various route of administration, such as oral Preparation such as capsule, tablet, granule etc., also can be injecting and administering preparations, such as aqueous injection, lyophilized injectable powder, infusion solution etc.
Preferably, described above be used for the treatment of the medicine that Acinetobacter bauamnnii causes infectious disease, wherein the weight ratio of faropenem and Tazobactam Sodium is 1: 1～1: 12, the weight ratio of optimal seeking method faropenem and sodium-tazobactam is 1: 1～1: 12, more preferably 1: 1,1: 3,1: 5,1: 8 or 1: 12.
The present invention also provides Faropenem sodium for the preparation of the purposes in the medicament that causes infectious disease with the sodium-tazobactam administration with the treatment Acinetobacter bauamnnii.
The present invention also provides sodium-tazobactam for the preparation of the purposes in the medicament that causes infectious disease with the Faropenem sodium administration with the treatment Acinetobacter bauamnnii.
The present invention is surprisingly found out that Faropenem sodium and sodium-tazobactam drug combination compositions have collaborative and cumulative antibacterial action to general drug resistance Bao Man bacterial strain, can cure clinically because the clinical infection that general drug resistance Acinetobacter bauamnnii causes.The present invention tests and has used the imipenem-resistant bacterial strain all to carry the natural intrinsic blaOXA-51 gene of Acinetobacter bauamnnii chromosome, and the imipenem-resistant bacterial strain Acinetobacter bauamnnii that all carries blaOXA-51 shows as the sensitivity to the faropenem sodium/tazobactam sodium as a result.
The Acinetobacter bauamnnii of this experiment is not only to imipenem-resistant, also selected simultaneously simultaneously to Faropenem sodium, piperacillin, piperacillin/Tazobactam Sodium (1: 1), cefoperazone, cefoperazone/Tazobactam Sodium (1: 1) drug resistance, in these Resistant strains use faropenem sodium/tazobactam sodium compositionss.By to 5 kinds of variable concentrations mass ratioes (1: 1,1: 3,1: 5,1: 8,1: 12) in vitro activity show, faropenem sodium/tazobactam sodium associating can significantly improve the sensitivity of the imipenem-resistant bacterial strain all being carried the Acinetobacter bauamnnii of blaOXA-51 gene, has clear and definite and strong antibacterial activity.
The present invention tests and has used from 74 strain imipenem-resistant bacterial strains of outpatient service isolation identification 53 strains to carry the blaOXA-51 gene, the 23sRNA gene is carried in 21 strains, blaOXA-51,23sRNA group gene is the natural intrinsic gene of Acinetobacter bauamnnii chromosome, and antibacterial shows as the sensitivity to beta-lactam antibiotic.
Faropenem sodium all has stronger bactericidal action from the different proportionings of sodium-tazobactam, and 1: 1 to 1: 12 proportioning all is better than the independent medication of Faropenem sodium to the bactericidal action of Bao Man bacterium.
The specific embodiment
Further set forth the present invention below by embodiment, but purport of the present invention and protection domain are not construed as limiting.
Embodiment 1: faropenem sodium/tazobactam sodium in vitro activity
One, materials and methods
1. test drug:
(1) Faropenem sodium (Faropenem): the new Pharmaceutical production in capital, Zhejiang, lot number DK67-1012281, content 91.6%.
(2) sodium-tazobactam (Tazobactam Sodium): lot number 0481-9801, tire: 93.7%., available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Following ratio proportioning by weight, wherein Faropenem sodium weight is with the Faropenem sodium pure calculating of giving money as a gift, Tazobactam Sodium weight is given money as a gift with sodium-tazobactam and is purely calculated by Tazobactam Sodium.
2. test proportioning:
(1) Faropenem sodium
(2) sodium-tazobactam
(3) faropenem sodium-tazobactam sodium (1: 1);
(4) Faropenem sodium+sodium-tazobactam (1: 3);
(5) Faropenem sodium+sodium-tazobactam (1: 5);
(6) Faropenem sodium+sodium-tazobactam (1: 8);
(7) Faropenem sodium+sodium-tazobactam (1: 12).
3. test strain:
This experiment has used from 74 strain imipenem-resistant bacterial strains of outpatient service isolation identification 53 strains to carry bla
OXA-51Gene, the 23sRNA gene is carried in 21 strains, and blaOXA-51,23sRNA group 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 74 strain is simultaneously to Faropenem sodium, piperacillin, piperacillin/Tazobactam Sodium (1: 1), cefoperazone, cefoperazone/Tazobactam Sodium (1: 1) also drug resistance, belong to the multidrug resistant Acinetobacter bauamnnii, the Quality Control bacterium is escherichia coli ATCC25922 and Pseudomonas aeruginosa ATCC27853.Bacterial strain is available 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 four reaches company), pulsed field gel electrophoresis instrument (Biorad company); Gel imaging system (genome company), than turbid instrument (French Biomerieux SA), PCR instrument (U.S. Eppendorf company).
5. method
The plate doubling dilution 5.1 in-vitro antibacterial medicine drug sensitive detection is adopted international standards.Measure each antibacterials to the minimum inhibitory concentration (M IC) of various pathogenic bacterium.Critical concentration by U.S.'s laboratory and clinical criteria institute (CILS) regulation in 2009, judge every strain bacterium to the sensitivity of antibacterials, obtain antibacterial responsive rate (S%), the intermediary of the various antibacterials measured led (I%) and resistant rate (R%).Wherein antibacterial is judged to be drug resistance to imipenum MIC 〉=16.
5.2 pulsed field gel electrophoresis (pulsed-field gel electrophoresis, PFGE) boiling method extracts bacteria total DNA.Genomic DNA is inserted in 1% agarose gel in 0.5mol/L tromethane-ethylenediaminetetraacetic acid (Tris-EDTA) after using the ApaI enzyme action, uses 6V/cm pulsed field gel electrophoresis instrument to detect.The burst length scope continues 24h at 5.0-8.0s.Then the gel ethidium bromide staining is observed under uviol lamp and the film making retention.
5.3OXA enzyme gene test: detect 4 groups of OXA enzyme genes with the PCR method.PCR reaction system volume 20 μ L, the 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.The PCR product is made Preliminary Identification with 1.5% agarose gel electrophoresis and Ethidum Eremide dyeing.The PCR primer is given birth to worker engineering company by Shanghai and is synthesized.PCR product electrophoresis is cut glue and is carried out checking order behind the purification.Sequence among sequencing result and the GenBank is compared, determine the product type.
6. to the influence factor of vitro antibacterial activity
(1) bacterial load impact
Measure 5 kinds of matching method faropenem/sodium-tazobactams to the different bacterium amounts (10 of test bacterium with the plate doubling dilution
4, 10
5, 10
6, 10
7CFU/ml) on the impact of MIC value.
(2) impact of Medium's PH Value
Measure 5 kinds of matching method faropenem/sodium-tazobactams to the impact on the MIC value under different pH condition of test bacterium with the plate doubling dilution.
(3) impact of serum albumin content
Measure 5 kinds of matching method faropenem/sodium-tazobactams with the plate doubling dilution test bacterium is observed serum albumin content to the impact of MIC value in different serum-concentration (25%, 50%, 75%) and the culture medium that does not contain serum.
Two, result
1. the faropenem sodium/tazobactam sodium is to the antibacterial activity in vitro of 53 strain Acinetobacter bauamnniis (blaOXA-51)
The results are shown in Table 1.
Table 1. medicine is to Acinetobacter bauamnnii (blaOXA-51) antibacterial activity in vitro
*More than the Acinetobacter bauamnnii of 53 strains simultaneously to Faropenem sodium, piperacillin, piperacillin/Tazobactam Sodium (1: 1), cefoperazone, cefoperazone/Tazobactam Sodium (1: 1) also drug resistance, belong to the multidrug resistant Acinetobacter bauamnnii.
2. the faropenem sodium/tazobactam sodium is to the antibacterial activity in vitro of Acinetobacter bauamnnii (23sRNA)
The results are shown in Table 2.
Table 2. medicine is to 21 strain Acinetobacter bauamnnii (23sRNA) antibacterial activity in vitro
*More than the Acinetobacter bauamnnii of 21 strains simultaneously to Faropenem sodium, piperacillin, piperacillin/Tazobactam Sodium (1: 1), cefoperazone, cefoperazone/Tazobactam Sodium (1: 1) drug resistance, belong to the multidrug resistant Acinetobacter bauamnnii.
3. to the influence factor of vitro antibacterial activity:
(1) as shown in table 3, the faropenem sodium/tazobactam sodium of different proportionings is respectively 10 at bacterial load
4, 10
5, 10
6With 10
7During CFU/ml, to Acinetobacter bauamnnii MIC value.Illustrate that bacterial load is 10
4-10
7CFU/ml has no significant effect the MIC value of the anti-Acinetobacter bauamnnii of faropenem sodium/tazobactam sodium of different proportionings.
Table 3. Faropenem sodium+sodium-tazobactam is on the impact of Acinetobacter bauamnnii (blaOXA-51) inoculum concentration
(2) as seen from Table 4, the MIC value to Acinetobacter bauamnnii of 5 kinds of matching method faropenem+Tazobactam Sodiums has no significant effect in pH 5.0～pH 8.0 scopes.
Table 4 Faropenem sodium+sodium-tazobactam under different pH MIC on the impact of Acinetobacter bauamnnii (blaOXA-51)
(3) as seen from Table 5, human albumin's content in the culture medium, anti-Acinetobacter bauamnnii effect has no significant effect to the Faropenem sodium+sodium-tazobactam of 5 kinds of proportionings.
Table 5. Faropenem sodium+sodium-tazobactam human albumin content is on the impact of Acinetobacter bauamnnii (blaOXA-51) MIC
Embodiment 2: the vivo bacteria corrosion action of injection faropenem sodium/tazobactam sodium
Faropenem sodium and sodium-tazobactam be (1: 1) by weight, and (1: 2), (1: 4), (1: 8), the compositions of (1: 12) has significant antibiotic pool treatment effect to the mice that infects.
1. tested medicine
Faropenem sodium content 90.6%, lot number: 081212; Xintai City, Shenzhen medicine company limited provides the new Pharmaceutical production in capital, Zhejiang, lot number DK67-1012281, content 91.6%.
Sodium-tazobactam: lot number 0481-9801, tire: 93.7%.Available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
The preparation of 2 medicines
Be mixed with desired concn with 0.9% sodium chloride fluid injection.
(1), Faropenem sodium (single dose)
(2), sodium-tazobactam (single dose)
(3), Faropenem sodium+sodium-tazobactam (1: 1)
(4), Faropenem sodium+sodium-tazobactam (1: 3)
(5), Faropenem sodium+sodium-tazobactam (1: 5)
(6), Faropenem sodium+sodium-tazobactam (1: 8)
(7), Faropenem sodium+sodium-tazobactam (1: 12)
3 infectious bacterias and bacterium amount
Be Acinetobacter bauamnnii: establish 7 dosage groups, the equal Intraperitoneal injection 1 * 10 of each Mus
-5MLD bacterium liquid 0.5ml.Calculate ED with bacteriumization probit
50(each medicine) in M-H meat soup, cultivates 18h with incubated overnight bacterium liquid transferred species for 35 ℃, is 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 awarded medicinal liquid (0.5ml/ gavage) in 1 hour behind every mouse infection 0.5ml MLD bacterium liquid.
4. experimental technique
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.
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 the low ratio serial dilution, two are faced mutually dosage group dose-difference i value and are 0.1-0.15.The maximum dose level of the title dose=medicinal liquid of giving * mice average weight ÷ administration volume * volumetric flask volume ÷ tires. and observe dead mouse number after 7 days, draw the upper limit and the lower limit of trial drug dosage.
5. experimental result
The results are shown in Table 6.
The different matching method faropenem/sodium-tazobactams of table 6. are to the protective effect of Acinetobacter bauamnnii infecting mouse
Compare with the Faropenem sodium single dose ※ ※ P＜0.001
As shown in table 6, faropenem sodium/tazobactam sodium (1: 2,1: 3,1: 5,1: 8 and 1: 12) obviously is better than the Faropenem sodium single dose to the protective effect of klebsiella pneumoniae abdominal cavity infection mice.
Embodiment 3: the comparative study to the Acinetobacter bauamnnii antibacterial action of faropenem/Tazobactam Sodium and cefoperazone/Tazobactam Sodium
Faropenem sodium and sodium-tazobactam be (1: 1) by weight, and (1: 2), (1: 4), the combination medicine of (1: 8) or (1: 12) has significant antibacterial therapy effect to the mice that infects.
1. tested medicine
Faropenem sodium (Faropenem): the new Pharmaceutical production in capital, Zhejiang, lot number DK67-1012281, content 91.6%.Cefoperazone+sulbactam sodium (1: 1), Xintai City, Shenzhen medicine company limited provides.
Sodium-tazobactam: lot number 0481-9801, tire: 93.7%.Available 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 2 dosage groups, the equal Intraperitoneal injection 1 * 10 of each Mus
-5MLD bacterium liquid 0.5ml.Calculate ED with bacteriumization probit
50(each medicine)
2. medicine preparation
Faropenem sodium+sodium-tazobactam (1: 1); Cefoperazone+sulbactam 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 the low ratio serial dilution, two are faced mutually dosage group dose-difference i value and are 0.1-0.15.The maximum dose level of the title dose=medicinal liquid of giving * mice average weight ÷ administration volume * volumetric flask volume ÷ tires. and 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 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 awarded medicinal liquid (0.5ml/ gavage) in 1 hour behind every mouse infection 0.5ml MLD bacterium liquid.
4 experimental results
See Table 7.
The different matching method faropenem/sodium-tazobactams of table 7. are to the protective effect of Bao acinetobacter mice
※P＜0.001
As shown in table 7, faropenem sodium/tazobactam sodium (1: 1) obviously is better than Sulbactam/Cefoperazone sodium (1: 1) dosage to the protective effect of Acinetobacter bauamnnii abdominal cavity infection mice.
Claims (6)
1. Faropenem sodium and sodium-tazobactam are for the preparation of the application in the medicine of anti-Acinetobacter bauamnnii, and wherein the weight ratio of Faropenem sodium and sodium-tazobactam is 1: 1～1: 12.
2. application according to claim 1, wherein said Acinetobacter bauamnnii comprise the Acinetobacter bauamnnii to carbapenem antibiotic and/or beta-lactam antibiotic drug resistance.
3. application according to claim 1, wherein said medicine are used for breathing pneumonia, septicemia, urinary system infection or meningitis.
4. according to claim 1-3 each described application, wherein the weight ratio of Faropenem sodium and sodium-tazobactam is 1: 1,1: 3,1: 5,1: 8 or 1: 12.
5. medicine that is used for anti-Acinetobacter bauamnnii, it comprises Faropenem sodium and sodium-tazobactam and optional one or more pharmaceutically acceptable carriers that exist, wherein the weight ratio of Faropenem sodium and sodium-tazobactam is 1: 1～1: 12.
6. medicine according to claim 5, wherein the weight ratio of Faropenem sodium and sodium-tazobactam is 1: 1,1: 3,1: 5,1: 8 or 1: 12.
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| Title |
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| 徐浩等.法罗培南钠片治疗细菌性呼吸道感染疗效及体外抗菌活性研究.《淮海医药》.2009,第27卷(第5期),p.396表2. * |
| 果茵茵等.鲍氏不动杆菌的药物治疗进展.《中华医院感染学杂志》.2010,第20 卷(第17期),p.2717左栏第4段. * |
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