Microencapsulation of a cyclodextrin complex of the UV filter, butyl methoxydibenzoylmethane: in vivo skin penetration studies

Lipid microparticles loaded with the complex between hydroxypropyl-β-cyclodextrin (HP-β-CD) and the sunscreen agent, butyl methoxydibenzoylmethane (BMDBM) were evaluated for their effect on the UV filter percutaneous penetration. The microparticles were prepared by the melt emulsification technique using tristearin as lipidic material and hydrogenate phosphatidylcholine as the surfactant. Human skin penetration was investigated in vivo by the tape stripping technique, a minimal invasive procedure based on the progressive removal of the upper cutaneous layers (stratum corneum) with adhesive tape strips. The amount of sunscreen fixed to each strip was determined by HPLC after solvent extraction. The recovery of the UV filter from spiked adhesive tapes was >94.4% and the precision of the method was better than 7.6% relative standard deviation. Non-encapsulated BMDBM, its complex with HP-β-CD, the lipid microparticles loaded with the sunscreen alone or the BMDBM/HP-β-CD complex were introduced into oil-in-water emulsions and applied to human volunteers. Compared to the cream with the non-encapsulated sunscreen agent (percentage of the applied dose penetrated, 9.7%±2.5), the amount of BMDBM diffusing into the stratum corneum was increased by the formulations containing the BMDBM/HP-β-CD complex (17.1%±3.2 of the applied dose) or the microparticles loaded with BMDBM only (15.1%±2.7 of the applied dose). On the contrary, a significant decrease in the level of UV filter penetrated into the stratum corneum was achieved by the cream containing the microencapsulated BMDBM/HP-β-CD complex (percentage of the applied dose penetrated, 6.0%±1.5). The reduced BMDBM percutaneous penetration attained by the latter system should enhance the UV filter efficacy and limit potential toxicological risks.     

In vivo and in vitro skin permeation of butyl methoxydibenzoylmethane from lipospheres

Lipid microparticles (lipospheres) loaded with butyl methoxydibenzoylmethane (BMDBM), a widely used UV-A sunscreen agent, were prepared by melt technique and evaluated for skin permeation both in vivo, by tape stripping method, and in vitro, by a flow-through diffusion chamber. Following in vivo human skin application of an O/W emulsion containing 2% of BMDBM loaded in lipospheres, 15% of the applied sunscreen accumulated in the uppermost layers of the stratum corneum without remarkably modifying the skin permeation of the unencapsulated sunscreen. These results were found to be predicted by an in vitro methodology involving the diffusion of BMDBM through a lipophilized synthetic membrane into a hydrophilic receptor phase, simulating the viable epidermis better than an ethanolic receptor phase.     

Formulation and in vitro evaluation of a PEGylated microscopic lipospheres delivery system for ceftriaxone sodium

The aim of this study was to formulate and evaluate in vitro, ceftriaxone sodium lipospheres dispersions for oral administration. Ceftriaxone sodium lipospheres were prepared by melt-emulsification using 30%w/w Phospholipon^® 90H in Softisan^® 154 as the lipid matrix containing increasing quantities of PEG 4000 (10, 20, 30, and 40%w/w). Characterization based on particle size, particle morphology, encapsulation efficiency, loading capacity and pH were carried out on the lipospheres. Microbiological studies of the ceftriaxone sodium-loaded lipospheres were performed using Escherichia coli as the model organism. In vitro permeation of ceftriaxone sodium from the lipospheres through artificial membrane (0.22?μm pore size) was carried out using Franz cell and simulated intestinal fluid (SIF) without pancreatin as acceptor medium. Photomicrographs revealed spherical particles within a micrometer range with minimal growth after 1 month (Maximum size?=?64.76?±?3.81?μm). Microbiological studies indicated that lipospheres formulated with 20%w/w of PEG 4000 containing 2%w/w or 3%w/w of ceftriaxone sodium gave significantly (p?<?0.05) higher inhibition zone diameter than those with 30%w/w or 40%w/w of PEG 4000. The result also indicated that lipospheres with 10%w/w PEG 4000 resulted in significantly higher encapsulation efficiency (p?<?0.05) while those with 30%w/w gave the least, while the loading capacity values ranged from 3.22?mg of ceftriaxone sodium/100?mg of lipid to 6.36?mg of ceftriaxone sodium/100?mg of lipid. Permeation coefficient values varied and ranged from 8.55?×?10^?7 cm/s to 2.08?×?10^?6 cm/s depending on the concentration of PEG 4000. The result of this study gave insight that the issue of ceftriaxone stability in oral formulation could be adequately addressed by tactical engineering of lipid drug delivery systems such as lipospheres.     

Structure elucidation of the tetrahydrocannabinol complex with randomly methylated β-cyclodextrin

The low aqueous solubility of the bioactive cannabinoid tetrahydrocannabinol (THC) is a serious obstacle for the development of more efficient administration forms. In this study the aqueous solubility of THC was tested in the presence of -, β- and γ-CD, and randomly methylated β-CD (RAMEB). It was found that only RAMEB was able to increase the aqueous solubility of THC to a significant level. A THC concentration of about 14 mg/ml was reached by using a 24% (187 mM) RAMEB solution, which means an increase in solubility of four orders of magnitude. The resulting THC/RAMEB complex was investigated through phase-solubility analysis, complemented by ¹H NMR, NOESY- and UV-studies in order to obtain details on the stoichiometry, geometry and thermodynamics of the complexation. The binding ratio of THC to CD was found to be 2:1, with the second THC molecule bound by non-inclusion interactions. Based on the obtained results a model for the complex structure is presented. Stability of the complex under laboratory room conditions was tested up to 8 weeks. Results show that complexation with RAMEB seems to be promising for the development of water-based THC formulations.     

Implication of inclusion complexation of glimepiride in cyclodextrin-polymer systems on its dissolution, stability and therapeutic efficacy

The effect of complexation of glimepiride, a poorly water-soluble antidiabetic drug, with β-cyclodextrin and its derivatives (HP-β-CyD and SBE-β-CyD) in presence of different concentrations of water-soluble polymers (HPMC, PVP, PEG 4000 and PEG 6000) on the dissolution rate of the drug has been investigated. The results revealed that the dissolution rate of the drug from these ternary systems is highly dependent on polymer type and concentration. The dissolution rate of the drug from ternary systems containing PEG 4000 or PEG 6000 seems to be generally higher than from systems containing HPMC or PVP. An optimum increase in the dissolution rate of the drug was observed at a polymer concentration of 5% for PEG 4000 or PEG 6000 and at 20% concentration of HPMC or PVP. The dissolution rate of the drug from the ternary system glimepiride–HP-β-CyD–5% PEG 4000 was high compared to the other systems. Tablets containing the drug or its equivalent amount of this ternary system were prepared and subjected to accelerated stability testing at 40 °C/75% R.H. to investigate the effect of storage on the chemical stability as well as therapeutic efficacy of the tablets. The results revealed stability of the tablets and consistent therapeutic efficacy on storage.     

Influence of cyclodextrins on in vitro human skin absorption of the sunscreen, butyl-methoxydibenzoylmethane

The effects of hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-CD (SBE7-β-CD) on in vitro human skin penetration and retention of the sunscreen agent butyl-methoxydibenzoylmethane (BM-DBM) were investigated. The interaction between the UV filter and the cyclodextrins was studied in water by phase-solubility analysis. Solid complexes were prepared by the co-evaporation method and characterized by ¹H NMR spectroscopy, thermal analysis and powder X-ray diffraction. Solutions containing BM-DBM free or complexed with cyclodextrins were applied to excised human skin in Franz diffusion cells and the amount of sunscreen permeated after 6 h into the stratum corneum, viable epidermis, dermis and receptor fluid was assessed by HPLC. As much as 14.10–16.78% of the applied dose of BM-DBM penetrated within the skin tissue. No sunscreen was detected in the dermis and in the receiver phase. The greater proportion (84.6–95.5%) of the absorbed UV filter was localized in the stratum corneum with no significant differences between uncomplexed or complexed BM-DBM. Notable levels (2.29% of the applied dose) of the sunscreen agent accumulated in the epidermis from the preparation containing free BM-DBM. The epidermal concentration of the UV filter was markedly reduced (0.66% of the applied dose) by complexation with SBE7-β-CD, whereas HP-β-CD had no effect. The decreased BM-DBM retention in the epidermal region achieved by SBE7-β-CD limits direct contact of the sunscreen and of its reactive photolytic products with the skin viable tissues.     

Improved photostability indicating ion-pair chromatography method for pergolide analysis in tablets and in the presence of cyclodextrins

Pergolide (PG) a semi-synthetic ergot alkaloid derivative used mainly for the treatment of Parkinson's disease is known to be a photosensitive drug substance. The major photodegradation products are PG sulphoxide (SX) and PG sulphone (SN), which are also the main impurities of the bulk drug substance. It is widely metabolized to more than 10 metabolites including SX and SN. In this work an improved photostability indicating ion-pair chromatography method for PG mesilate was developed. The method can be applied in the determination of PG and impurities in aqueous solutions and in tablets for routine analysis. This new method is appropriate for the quantitative determination of PG in the presence of its impurities and photodegradation products and can also be used for PG complexes with cyclodextrins (commonly used as photostabilizing agents). Furthermore it is suitable for the quantitation of its impurities and its thermal or photo-induced decomposition products. Separation was achieved on a ThermoQuest C(18) BDS column and Sodium octanosulphonate was used as ion-pairing agent. Analysis was performed at 223 nm. Validation parameters included: specificity, linearity, precision and accuracy, limit of quantitation and suitability. The method was found to be specific and linear for PG, as well as for SX and, SN impurities. The recovery was 100.83+/-0.46% for PG, 99.86+/-0.33% for SX and 99.77+/-1.84% for SN. Finally the photodegradation profile of PG mesilate was studied in different initial sample concentration. The obtained result revealed that: PG photolysis is catalyzed by its degradation products and that decrease of initial sample concentration reduces the rate of PG photoinduced degradation.     

Study of ascorbic acid interaction with hydroxypropyl-beta-cyclodextrin and triethanolamine, separately and in combination

Complexation between ascorbic acid, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and triethanolamine (TEA), separately and in combination, was studied in solution and solid state. The freeze-drying method was used to prepare solid complexes, while physical mixtures being obtained by simple blending. These complexes were characterized in the solid state using differential scanning calorimetry (DSC) and infrared spectroscopy (IR). Nuclear magnetic resonance spectroscopy ((1)H and (13)C NMR) was used in aqueous solutions to obtain information about the mode of interaction. The degradation rate of each complex in solution was determined, and the stability constant of the complexes and the degradation rate of the ascorbic acid within the complexes were obtained. NMR studies provided clear evidence of partial inclusion into the HP-beta-CD cavity, but the stability constant value was very small indicating a weak host-guest interaction. The influence of complexation on the degradation rate of ascorbic acid was evaluated, and the data obtained showed a pronounced enhancement of aqueous stability with the TEA association complex, while this effect was lower with the HP-beta-CD inclusion complex. NMR experiments showed evidence of the formation of aggregates.     

丁苯酞治疗急性脑梗死的临床价值分析

目的对丁苯酞治疗急性脑梗死的临床价值进行研究。方法选取2011年8月～2013年8月急性脑梗死患者172例,随机分为对照组和研究组,在给予两组患者改善血液循环药物及抗血小板药物的治疗的基础上,对照组患者采取胞二磷胆碱静脉注射治疗,研究组采取丁苯酞治疗,对两组患者临床治疗效果进行比较。结果研究组中急性脑梗死患者临床治疗总有效率95．35％,明显高于对照组患者临床治疗总有效率82．56％（P〈0．05）。结论对急性脑梗死患者采取丁苯酞药物治疗能有效改善患者血液流变学及临床疗效,值得积极推广。     

Encapsulation of babchi essential oil into microsponges: Physicochemical properties,cytotoxic evaluation and anti-microbial activity

Babchi essential oil (BEO) is a valuable essential oil reported to possess a variety of biological activities such as antitumor, anti inflammatory, immunomodulatory, antioxidant, antifungal and antibacterial properties. Due to its anti-microbial properties, this oil possesses an immense potential for the treatment of dermatological disorders. Further, it has minimal tendency to develop resistance, a common issue with most of the antibiotics. However, its highly viscous nature and poor stability in the presence of light, air and high temperature, limits its practical applications. To surmount these issues, this research aims to encapsulate BEO in ethyl cellulose (EC) microsponges for enhanced stability, antibacterial effect and decreased dermal toxicity. The quasi emulsion solvent evaporation technique was used for fabrication of the BEO microsponges employing EC as polymer, polyvinyl alcohol (PVA) as stabilizer and dichloro methane (DCM) as solvent. The effect of formulation variables such as the amount of EC and PVA were also investigated. The prepared microformulations were evaluated for production yield, encapsulation efficiency, particle size and in vitro release. In vitro cytotoxicity was also checked to assess dermal safety of BEO microsponges. Results revealed that all the dispersions were in micro size range (20.44 ± 3.13 μm to 41.75 ± 3.65 μm), with good encapsulation efficiency (87.70 ± 1.20% of F2) and controlled release profile (cumulative drug release 73.34 ± 1.76%). Field emission scanning electron microscopy results showed that the microsponges possessed a spherical uniform shape with a spongy structure. Results of cytotoxicity study indicated that the prepared microsponges were safer on dermal cells in comparison to pure BEO. The optimized formulation was also evaluated for in vitro antimicrobial assay against dermal bacteria like Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli, which confirmed their enhanced antibacterial activity. Furthermore, the results of photostability and stability analysis indicated improved stability of BEO loaded microsponges. Hence, encapsulation of BEO in microsponges resulted in efficacious carrier system in terms of stability as well as safety of this essential oil alongwith handling benefits.     

Characterization and in vitro evaluation of the formoterol/cyclodextrin complex for pulmonary administration by nebulization

The aim of this work is to investigate the effect of cyclodextrin complexation on the pulmonary deposition of formoterol, a drug with a very poor aqueous solubility, after jet nebulization. Two types of cyclodextrins, a hydroxypropyl β cyclodextrin (Kleptose HP) and a polydispersed methyl β cyclodextrin (Crysmeb) were used. The interactions of formoterol with the cyclodextrins were studied by NMR. The aqueous cyclodextrin solutions containing formoterol were defined by their physicochemical properties in relation to nebulization capacity: density, surface tension and viscosity. Nebulization efficiency was evaluated by measuring droplet size, nebulization rate, quantity nebulized and nebulization time. The NMR ROESY spectra suggest that formoterol or a part of it is included inside the cyclodextrins. Densities and viscosities of the solutions tested are close to those of water; the lower surface tensions compared to water (53.7 and 56.7 vs 70 mN/m) favour the formation of small droplets. The aqueous solutions of cyclodextrins and formoterol studied can generate aerosols with a particle size that is compatible with pulmonary deposition. Respirable fraction values between 57.5% and 88 % were obtained when nebulizing the solutions with four nebulizers that differ geometrically. Nebulization rates varied from 0.19 to 0.47 g/min. Large quantities of drug nebulized over acceptable delivery times were observed. β-cyclodextrin derivatives can be used to formulate nebulizable solutions of formoterol. It is indispensable to define the appropriate nebulizers and operating conditions associated with the solutions to obtain adapted and reproducible activity.     

Determination of the molecular complexation constant between alprostadil and alpha-cyclodextrin by conductometry: implications for a freeze-dried formulation

The binding constant between alprostadil (PGE₁) and -cyclodextrin (-CD) was determined at four temperatures using conductance measurements. Alpha-cyclodextrin is an excipient material in Caverject dual chamber syringe (DCS) that was added to enhance stability. The binding constant was used to calculate the amount of PGE₁ free upon reconstitution and injection, since only the free drug is clinically active. The conductivity measurement is based on a decrease in specific conductance as alprostadil is titrated with -CD. The change in conductivity was plotted versus free ligand concentration (-CD) to generate a binding curve. As the value of the binding constant proved to be dependent on substrate concentration, it is really a pseudo binding constant. A value of 742 ± 60 M⁻¹ was obtained for a 0.5 mM solution of alprostadil at 27 °C and a value of 550 ± 52 M⁻¹ at 37 °C. These results compare favorably to values previously obtained by NMR and capillary electrophoresis. Calculation of the fraction PGE₁ free upon reconstitution and injection show it to approach the desired outcome of one. Hence, the amount of drug delivered by Caverject DCS is nominally equivalent to that delivered by Caverject S. Po., a predecessor product that contains no alpha-cyclodextrin.     

Study of the photostability of 18 sunscreens in creams by measuring the SPF in vitro

The target of this research was to evaluate the photostability of various sunscreen agents incorporated into an O/W emulsion. The concept of photostability is very important in the field of solar protection. The effectiveness of the anti-solar products is quantified using a universal indicator: the sun protection factor (SPF). This number which can be found on packaging can be given in two different ways: by methods in vivo (Colipa method) and in vitro. It is this last method which was adopted for this study. According to selected filter UVB (currently directive 76/768/EEC modified authorized 18 filters UVB), we can obtain more or less effective creams. We chose the irradiation of sun lotions formulated using the authorized filters, used with their maximum amount of employment, in a Suntest, with an irradiance of 650 W/m(2) throughout variable time. With interval of regular time, one carries out a measurement of SPF in order to establish for each filter the kinetics SPF=f(time). An indicator of stability (t(90)) is then given. In this way, we could classify the filters by order of increasing photostability.     

Delay in ICR/f rat lens opacification by the instillation of eye drops containing disulfiram and hydroxypropyl-beta-cyclodextrin inclusion complex

In this study, we attempted to enhance disulfiram (DSF) solubility using a 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and hydroxypropylmethylcellulose (HPMC). We also investigated the effect of an HPbetaCD solution containing DSF and HPMC (DSF eye drops) on cataract development in ICR/f rat. The solubility of DSF increased with increasing HPbetaCD concentration, and the solubility of DSF in HPbetaCD solution containing 0.1% HPMC was approximately 20% greater than that of DSF in HPbetaCD solution without HPMC. In in vivo transcorneal penetration experiments using rabbits, only diethyldithiocarbamate (DDC) was detected (DSF was not detected) in the aqueous humor. This DSF-DDC conversion in the cornea was inhibited by treatment with a sulfhydryl (SH) inhibitor, p-mercuribenzoate and N-ethylmaleimide, in in vitro transcorneal penetration experiments using rabbit corneas. On the other hand, the instillation of 0.25% and 0.5% DSF eye drops delayed cataract development in ICR/f rats, a recessive-type hereditary cataractous strain. The present study demonstrates that DSF in HPbetaCD solution with HPMC is converted to DDC by the catalysis of proteins containing SH residues in the cornea, and this DDC may cause the delay in cataract development in ICR/f rats.     

Interaction between curcumin and human serum albumin in the presence of excipients and the effect of binding on curcumin photostability

Curcumin (Cur) is known to bind to human serum albumin (HSA) which may lead to a reduced phototoxic effect of the compound in the presence of serum or saliva. The influence of excipients on the Cur–HSA binding was studied by HSA florescence quenching and Cur absorption and emission spectroscopy in the presence and absence of the selected excipients. Photostabilty of Cur in the presence of HSA was evaluated, as well as the effect of excipients on HSA bound Cur photodegradation. Cyclodextrins (CDs) (2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin) and polymers (polyethylene glycol 400, PEG 400 and Pluronic F-127, PF-127) were selected for the study. CDs and PF-127 seem to decrease Cur binding to HSA, probably through competitive binding. Cur was still bound to HSA in polyethylene glycol (PEG) solutions at the highest investigated concentration (5% w/v). However, high PEG concentration appears to have effect on the protein conformation, as shown by the fluorescence quenching study. Low Cur photostability in the presence of HSA could be improved by the addition of hydroxylpropyl-γ-cyclodextrin (HPγCD) to the samples, whereas PEG and PF-127 showed no effect.     

The expulsion of lipophilic drugs from the cores of solid lipid microspheres in diluted suspensions and in concentrates

The aim of the study was to compare incorporation of bupivacaine base, bupivacaine stearate and indomethacin in diluted suspensions of lipospheres (10%, w/w of lipid) and in concentrates (50%, w/w of lipid). The lipid cores were composed of a mixture of solid and liquid triglycerides (Precirol and Miglyol 4:1). The lipospheres sizing between 0.5–10 μm (suspensions) and 0.5–20 μm (concentrates) were prepared using a hot emulsification with high-shear mixing and cold resolidification method. None of the studied drugs was successfully incorporated in the lipid core. The increased incorporation of drugs determined in the concentrated lipospheres was only apparent, since in fact all the dose was only attached to the surface of the lipid particles and was transferred to the aqueous phase in the course of an intensive agitation. The presence of hydrophilic polymers in the aqueous phase did not prevent the expulsion effect although drug precipitation was retarded. The expulsion effect did not correlate with the solubility of drugs determined in the bulk lipids.     

Adverse effects of butyl benzyl phthalate on the reproductive and hematopoietic systems of male rats

A 14-day dietary study was conducted in adult, male, Fischer 344 rats at levels of 0.0, 0.625, 1.25, 2.5 and 5.0% butyl benzyl phthalate (BBP) to evaluate potential effects of this plasticizer on the male reproductive and hematopoietic systems. Total body, thymus, testis, epididymis, prostate and seminal vesicle weights were reduced in the 2.5% and 5% BBP dose groups, while pituitary weight was unaffected. Histological evaluations revealed dose-dependent atrophy of the testis, prostate and seminal vesicles at 2.5% and 5%, atrophy of the thymus and epididymis at 5%, and the presence of immature sperm cells in the tubular lumens and necrosis of the tubular epithelium in the epididymis at 2.5% and 5% BBP. Plasma testosterone concentration was decreased at 5%, while follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations were increased at 2.5% and 5.0% BBP. The circulating components of blood, and clotting times (prothrombin time, activated partial thromboplastin time), were unaffected although bone marrow cellularity was reduced at 2.5% and 5%. Changes in non-reproductive organs included enlargement of liver and kidneys, thymic atrophy and associated morphological abnormalities in these organs. These data indicate a direct toxic effect of BBP on the testis with secondary effects on other reproductive organs. Pituitary and hypothalamic responses did not appear to be affected. The reduced bone marrow cellularities suggest that prolonged exposures to BBP could affect circulating blood components or compromise clotting ability.     

蓝科肤宁联合氟芬那酸丁酯软膏治疗儿童湿疹的疗效和安全性观察

目的观察蓝科肤宁湿敷联合氟芬那酸丁酯软膏治疗儿童湿疹的疗效和安全性。方法将70例儿童湿疹患儿随机分为治疗组和对照组。治疗组36例,对照组34例。治疗组：患儿皮损处用蓝科肤宁溶液湿敷,10～20min/次,2～3次/d;对照组：用生理盐水溶液湿敷,每次10-20min,2～3次/d;湿敷后2组患儿均外涂氟芬那酸丁酯软膏,2次/d,疗程均2周,每周复诊1次,观察患儿主客观症状的改变,治疗第2周结束时观察疗效,并做统计学分析。结果观察结束时,两组患儿治疗后积分均明显降低,前后相比差异有统计学意义（t=41.25,P〈0.01;t=36.29,P〈0.01）;两组间治疗前积分相比差异无统计学意义（t=0.78,P〉0.05）,两组间治疗后积分相比差异有统计学意义（t=-2.06,P〈0.05）;治疗组、对照组的有效率分别为91.67%和73.53%,两者相比差异有统计学意义（χ2=4.05,P〈0.05）。结论蓝科肤宁湿敷联合氟芬那酸丁酯软膏治疗儿童湿疹疗效满意,副作用少见。     

ICU抗菌药物用量与革兰阴性菌耐药的相关性分析

目的 分析我院2013—2018年ICU抗菌药物用量与常见革兰阴性菌耐药率变化的关系,为临床合理使用抗菌药物提供参考。方法 回顾性调查我院ICU病房6年来抗菌药物用量和常见革兰阴性菌的分布情况及耐药率,采用Pearson相关性分析方法分析两者之间的关系。结果 6年来我院ICU病房抗菌药物的总用量逐年上升,碳青霉烯类和β-内酰胺/β-内酰胺酶抑制剂的使用量排在前两位。ICU病房分离的排名前3位的革兰阴性菌为鲍曼不动杆菌、肺炎克雷伯菌和铜绿假单胞菌,2018年3种细菌的耐碳青霉烯菌株分离率分别达到了84.62%、53.54%和66.41%。相关性分析显示碳青霉烯类的用量与鲍曼不动杆菌对替加环素的耐药率(r=0.871, P=0.024)及对左氧氟沙星的耐药率(r=0.900, P=0.015)成正相关,与肺炎克雷伯菌对美罗培南(r=0.852, P=0.031)、头孢吡肟(r=0.817, P=0.047)及左氧氟沙星(r=0.857, P=0.029)的耐药率成正相关。结论 广谱抗菌药物的使用与革兰阴性菌的耐药之间存在复杂的相关性,因此应严格控制并合理使用抗菌药物,以延缓细菌耐药的发展。