恩诺沙星和庆大霉素溶液对假中间型葡萄球菌超过28天的稳定性和体 ...

王帆

The stability and in vitro antibacterial efficacy of enrofloxacin and gentamicin solutions against Staphylococcus pseudintermedius over 28 days

恩诺沙星和庆大霉素溶液对假中间型葡萄球菌超过28天的稳定性和体外抑菌效果

作者：Shin Park | Taeho Oh | Seulgi Bae

 

翻译：王濮嵩

 

Abstract 摘要

Background: Many clinicians prepare compounded otic solutions to treat otitis externa (OE). Research evaluating the stability and antimicrobial efficacy of these solutions is limited.

背景：许多临床医生配制复合耳液治疗外耳炎（OE）。评估这些溶液稳定性和抗菌效果的研究有限。

Hypothesis/Objectives: This study determined the chemical stability and in vitro bactericidal efficacy of compounded solutions of enrofloxacin and gentamicin during storage for 28days.

假设/目标：本研究测定了恩诺沙星和庆大霉素复合溶液保存28天的化学稳定性和体外杀菌效果。

Materials and methods: Solutions of enrofloxacin (10 mg/mL, 1%) and gentamicin (3 mg/mL, 0.3%) were prepared with normal saline and 1 mg/mL dexamethasone. Solutions were stored at room temperature (25°C) for 0, 14 and 28days. The chemical stability of the antibiotics and dexamethasone were determined using liquid chromatography tandem mass spectrometry in triplicate. Efficacy assessment was made with 10 isolates of Staphylococcus pseudintermedius obtained from dogs with OE. Serial 10-fold dilutions of the bacteria with the compounded solutions were prepared and the colony count results were converted into colony-forming units (cfus). The mean cfu/mL and cfu/mL reduction rates were compared between Day (D)0, D14 and D28. All of the antimicrobial testing solutions were performed in triplicate.

材料和方法：用生理盐水和1mg/ml地塞米松与恩诺沙星（10mg/ml，1%）和庆大霉素（3mg/ml,0.3%）配制溶液。溶液在室温（25℃）下保存0，14,28天。采用液相色谱串联质谱法测定抗生素和地塞米松的化学稳定性。从OE患犬上分离10株假中间型葡萄球菌进行疗效评估。配制10倍稀释的细菌和混合溶液，并将菌落计数结果转化为菌落形成单位（cfus）。比较D0,14,28天的平均cfu/ml和cfu/ml下降率。所有的抗生素测试溶液一式三份。

Results: Chromatography showed that both antibiotics and dexamethasone were stable for 28days. No significant differences were observed in the antibiotic bactericidal efficacy of stored solutions at D0, D14 or D28.

结果：色谱分析表明，抗生素和地塞米松在28天内稳定。在D0,D14和D28天的储存溶液的抗菌效果没有显著差异。

Conclusions and clinical relevance: Solutions of 1% enrofloxacin and 0.3% gentamicin in normal saline with 0.1% dexamethasone maintained chemical stability and bactericidal efficacy over 28days. These solutions can be considered as alternatives to commercial preparations for treatment of canine OE when indicated.

结论和临床相关性：1%恩诺沙星和0.3%庆大霉素加0.1%地塞米松的生理盐水溶液保持化学稳定和杀菌效果超过28天。这些溶液被认为是商品化治疗犬OE的代替选择。

KEYWORDS

关键词

dexamethasone, enrofloxacin, gentamicin, off-label use, Staphylococcus pseudintermedius

地塞米松、恩诺沙星、庆大霉素、标签外使用、假中间型葡萄球菌

 

INTRODUCTION

介绍

Otitis externa (OE) is a skin condition commonly encountered in small animal clinics, affecting approximately 5%–20% of dogs. Treatment of infection and inflammation are the main goals. Topical therapy is preferred in most cases because it directly delivers the drug to the affected site, minimising potential systemic adverse effects.

外耳炎（OE）是小动物诊所常见的一种皮肤疾病，约5%-20%的犬患病。治疗感染和炎症是主要目标。大部分病例首选外部治疗，因为其直接将药物用于患病部位，全身性不良反应最低。

 

The most commonly used topical agents consist of a combination of glucocorticoids, antimicrobials, and antifungals.Common antibiotics include gentamicin or enrofloxacin which are effective against several infectious organisms associated with canine OE.Topical glucocorticoids reduce pain and swelling of the otic canal.Commercially licensed products are not always available or appropriate for all patients or all conditions. Gentamicin and enrofloxacin can easily be obtained as injectable solutions, and practitioners can use compounded combinations of these solutions for the treatment of OE. Sometimes, veterinary practices use or recommend off-label combinations for the treatment of OE.However, very few studies have investigated the stability and efficacy of these off-label compounded solutions.Generally, these studies compared the efficacy of the combinations of various injectable antibiotics or glucocorticoids with that of commercial ear cleaners.

最常用的外部药物是包括糖皮质激素，抗细菌药和抗真菌药物的组合。常见的抗生素包括庆大霉素或恩诺沙星，他们对于犬OE相关的几种感染性微生物有效。外部糖皮质激素降低耳道疼痛和肿胀。商业许可的产品并不总是适用于所有患病动物或所有疾病。庆大霉素和恩诺沙星作为注射液容易获得，从业者可以使用这些溶液的混合制品来治疗OE。有时，兽医使用或推荐标签外制品来治疗OE。然而，非常少的研究来调查这些标签外混合溶液的稳定性和效果。通常，这些研究比较各种抗生素注射液和糖皮质激素组合与商业化洗耳液的效果。

 

The aim of this study was to determine the chemical stability and antibacterial effects of two antibiotic solutions, combined with injectable dexamethasone, and to investigate if these formulations could be used to treat canine OE associated with Staphylococcus pseudintermedius.

本研究的目的是确定两种抗生素溶液与可注射的地塞米松混合后的化学稳定性和抗菌效果，并且研究这些配方是否可以用于治疗与假中间型葡萄球菌有关的犬OE。

 

MATERIALS AND METHODS

材料和方法

Bacterial isolates

细菌菌株

Ten S. pseudintermedius isolates were obtained from client-owned dogs that visited the Kyungpook University Veterinary Medical Teaching Hospital for the evaluation of OE. Written consent for sample collection was obtained from the dog owners. Before sample collection, clinicians evaluated ear cytological results of dogs with OE. After confirming the presence of cocci, swabs were obtained from the dogs' ear canals using sterile cotton swabs. These samples were cultivated in sheep blood agar and incubated aerobically at 37°C for 18–24h. A conventional Vitek system (bioMérieux) was used to identify the bacteria. Staphylococcus pseudintermedius was confirmed using the 16S rRNA gene sequencing method using 27F and 1492R primers. Bacterial DNA nucleotide sequences that matched those of the isolated microorganisms were identified using NCBI Blast.

从韩国庆北大学兽医教学医院就诊的OE患犬中分离10株假中间型葡萄球菌。样本收集已获得犬主的书面同意。在收集样本前，临床医生评估患有OE犬的耳道细胞学结果。在确认存在球菌后，使用无菌棉签从犬耳道中采集拭子。这些样本在羊血琼脂培养，37℃有氧培养18-24小时。采用常规Vitek系统来鉴定细菌。假中间型葡萄球菌采用16S rRNA基因测序法，引物为27F和1492R。细菌DNA核苷酸序列与分离的微生物相匹配，使用NCBI Blast进行鉴定。

 

Topical solutions

外部溶液

Commercially available injectable enrofloxacin (50mg/mL, Baytril, Elanco), gentamicin sulfate injection (40mg/mL, Shin Poong Pharmaceutical) and dexamethasone injection (5 mg/mL, Jeil Pharmaceutical) were used to prepare the test solutions. Normal saline (0.9% NaCl, JW Pharmaceutical) was used as the diluent. The final concentrations for enrofloxacin, gentamicin and dexamethasone were 1%, 0.3% and 0.1%, respectively. The solutions used were as follows: enrofloxacin solution (ED) – 1% enrofloxacin, 0.1% dexamethasone and normal saline; gentamicin solution (GD) – 0.3% gentamicin, 0.1% dexamethasone and normal saline.

使用商品化恩诺沙星注射液（50mg/ml）、硫酸庆大霉素注射液（40mg/ml）和地塞米松注射液（5mg/ml）配置测试溶液。稀释剂使用生理盐水（0.9% NaCl）。恩诺沙星、庆大霉素和地塞米松的最终浓度分别为1%、0.3%和0.1%。使用的溶液为：恩诺沙星溶液（ED）-1%恩诺沙星、0.1%地塞米松和生理盐水；庆大霉素溶液（GD）-0.3%庆大霉素、0.1%地塞米松和生理盐水。

 

Each solution was prepared using a 23 gauge needle and 1 mL syringe, and was stored in 15mL conical tubes (SPL Life Science) at room temperature (25°C) for 0, 14 and 28days. The tubes were wrapped in aluminium foil during storage to protect the solutions from ambient light.

每种溶液用23号针头和1ml注射器配制，保存于15ml锥形瓶中，并置于室温（25℃）中，0天、14天和28天。在储存过程中用铝箔包裹瓶子，以保护溶液不受光的影响。

 

Chemical stability

化学稳定性

Chemical stability was determined using liquid chromatography--tandem mass spectrometry (LC–MS/MS) which is a sensitive and specific method for analysing the concentration of drugs in a liquid suspension without the use of natural chromatophores or fluorophores.Subsequently, the concentration of antibiotics was quantified using an API 4000 LC–MS/MS system (AB Sciex LLC) equipped with an electrospray ionisation interface.

使用液相色谱-串联质谱法（LC–MS/MS）测定化学稳定性，这是一种不使用天然色谱团或荧光团分析悬浊液中药物浓度的敏感和特异的方法。随后，使用配备电喷雾电离界面的API 4000 LC-MS /MS系统(AB Sciex LLC)对抗生素浓度进行定量。

 

The ED solution was diluted 1000-fold using acetonitrile, while GD was diluted 10-fold using distilled water. Differences in the elution mode and conditions account for these dilution differences. Ten microlitres of diluted ED and GD were dissolved in 90μl of CGK-012 (internal standard, IS). Operating conditions were optimised as follows: curtain gas flow 5 L/min; nebuliser and heater gas flow 17L/min; source exhaust flow 6 L/min; turbo heater temperature 450°C; turbo ion-spray interface voltage 5.5kV; collision gas pressure 3.5×10−5 Torr. Next, substances in mixed drug solutions were separated using a reversed-phase column (Poroshell EC-C18, Agilent) (internal diameter 50×2.1mm, particle size 2.7μm). Distilled water and acetonitrile (3:7 v/v, including 0.1% formic acid) was used as the mobile phase. The column was heated to 30°C, and the mobile phase was eluted at 0.2mL/min using an HP 1100 series pump (Agilent).

ED溶液用乙腈稀释1000倍，GD溶液用蒸馏水稀释10倍。洗脱方式和条件的不同造成了这些稀释的差异。10微升稀释的ED和GD溶液溶入90微升CGK-012中（内部标准，IS）。优化操作条件如下：幕气流量5L/分钟 ；喷雾器和加热器气流量17L/分钟；源排气流6L/分钟；涡轮加热器温度450℃；涡轮离子喷雾界面电压5.5KV；碰撞气体压力3.5×10−5 托。然后，采用反相色谱柱（内径50×2.1mm，粒径2.7um）分离混合溶液中的物质。蒸馏水和乙腈（3:7，v/v，含0.1%甲酸）为流动相。将圆柱加热至30℃，使用HP 1100系列泵以0.2ml/分钟洗脱流动相。

 

Enrofloxacin, gentamicin, dexamethasone and the IS were identified mainly as protonated ions [M+H]+at m/z 360.3, 478.4, 393.3 and 358.1, respectively. Subsequently, product ions were scanned in Q3 after collision with nitrogen in Q2 at m/z 316.1 for enrofloxacin (declustering potential 106eV; collision energy 35eV; dwell time 18ms), 322.1 for gentamicin (declustering potential 271eV; collision energy 21eV; dwell time 10ms), 355.2 for dexamethasone (declustering potential 46eV; collision energy 19eV; dwell time 20ms) and 229.3 for IS (declustering potential 111eV; collision energy 39eV; dwell time 16ms). Quantification was finally achieved through selective reaction monitoring of the protonated precursor and derived product ions, after which analytical data were processed using Analyst software (v1.5.2, Applied Biosystems/Thermo Fisher Scientific).16 Stability was considered acceptable if the percentage difference in the area ratio was <15% in accordance with the US Food and Drug Administration (FDA) guidelines.17 The area ratio was calculated by dividing the analyte peak area by the IS peak area. Samples from each of the three time points [Day (D)0, D14 and D28] were analysed in triplicate.

恩诺沙星、庆大霉素、地塞米松和IS主要为质子化离子[M+H]，m/z分别为360.3,478.4,393.3和358.1。随后，在Q2中与氮气碰撞后在Q3中扫描产物离子，恩诺沙星的m/z为316.1（聚簇电压 106eV；碰撞能量35eV；停留时间18ms），庆大霉素的m/z为322.1（聚簇电压 271eV；碰撞能量21eV；停留时间10ms），地塞米松的m/z为355.2（聚簇电压 46eV；碰撞能量19eV；停留时间20ms）；IS的m/z为229.3（聚簇电压 111eV；碰撞能量39eV；停留时间16ms）。最终通过对质子化前体和衍生产物离子的选择反应监测实现量化，之后使用分析软件对分析数据进行处理。16 根据美国食品和药物管理局(FDA)的指南，如果面积比的百分比差异<15%，则稳定性被认为是可接受的。17 面积比的计算方法是用分析物峰面积除以IS峰面积。从三个时间点[第(D)0天，第14天和第28天]的每个样本进行三次重复分析。

 

Antimicrobial efficacy

抗菌效果

The bactericidal efficacy of the solutions was determined using the modified colony count method.Ten microlitres of S.  pseudintermedius, corresponding to a 0.5 McFarland standard solution, was inoculated into 240μL of ED and GD, and incubated in a 96 well flatbottomed plate (SPL Life Science) at approximately 25°C for 30min. As each S. pseudintermedius isolate had a different growth rate and antimicrobial susceptibility, each inoculated test solution was diluted to an appropriate concentration that allowed for manual bacterial colony counting (colony number between 100 and 300) after subsequent experiments. Five 10-fold serial dilutions of the test solutions with bacteria were prepared using tryptic soy broth (Kisanbio) as the diluent. Twenty test solutions were prepared by mixing two topical solutions (ED and GD) with 10 bacterial isolates. Ten microlitres of each test solution was inoculated into tryptic soy agar (Kisanbio) and incubated at 37°C. After 24h of incubation, a manual colony count was performed, and the number of colonies counted was converted into colony-forming units (cfu)/mL. The ED and GD were stored at room temperature (25°C), and antimicrobial tests were conducted again on D14 and D28 in the same manner. All of the subsequent antimicrobial tests for the combined test solutions were conducted in triplicate.

用改良的菌落计数方法来测定溶液的杀菌效果。取10微升假中间型葡萄球菌对应0.5McFarland标准溶液，接种到240uL的ED和GD中，在96孔平板25℃培养30分钟。由于每个假中间型葡萄球菌分离株有不同的生长速度和抗菌敏感性，每种接种的测试溶液被稀释至合适的浓度，以便后续试验实验进行人工菌落计数（菌落计数在100-300个）。使用胰蛋白酶大豆肉汤作为稀释剂，制备5个10倍连续稀释的细菌测试溶液。将两种外部溶液（ED和GD）与10种细菌分离株混合，制备20种试验溶液。每种溶液10微升接种至胰蛋白酶大豆琼脂中，在37℃下培养。培养24小时后，进行人工菌落计数，计数的菌落转换为菌落形成单位（cfu）/ml。ED和GD在室温下保持（25℃），D14和D28天以同样的方式再次进行抗菌试验。所有后续的联合试验溶液的抗菌试验一式三份。

 

Statistical methods

统计方法

Statistical analysis was conducted to determine the bactericidal differences in the solutions observed over time. The normality test was performed, and the results were analysed using the Friedman test to compare the mean cfu/mL and repeated measurements ANOVA to compare the cfu/mL reduction rate. Statistical analyses were conducted, using Spss v25.0 (IBM Corp.). A p-value <0.05 was considered significant.

通过统计学方法来确定随着时间推移观察到溶液的杀菌差异。进行正态性试验，结果使用Friedman测试比较平均cfu/mL，和重复测量方差比较cfu/mL降低率。采用Spss v25.0 ( IBM Corp . )进行统计分析。以 p值< 0.05为差异有统计学意义。

 

RESULTS

结果

Chemical stability

化学稳定性

All of the compounds exhibited appropriate peak height at appropriate time points in the chromatogram. The chromatogram area ratios of each component obtained using LC–MS/MS were compared. On the day of preparation (D0), the chromatogram area ratio of each drug was set to 100%. The mean area ratio for enrofloxacin in ED was 99.6% on D14 and 98.4% on D28 compared with that on D0. The mean area ratio for gentamicin in GD was 111.0% on D14 and 103.1% on D28 compared with that on D0. The mean area ratios for dexamethasone in solutions were 92.8% on D14 and 109.6% on D28 compared with that on D0 (Figure 1).

在色谱图中，所有的混合物在适当的时间点都表现出适当的峰值。使用LC–MS/MS对各组分的色谱面积进行比较。在制备当天（D0），设置的每种药物的色谱面积比是100%。与D0相比，恩诺沙星在ED中的平均面积比，D14为99.6%，D28为98.4%。与D0相比，庆大霉素在GD中的平均面积比，D14为111.0%，D28为103.1%。与D0相比，地塞米松在溶液中的平均面积比，D14为92.8%，D28为109.6%。

 

 

FIGURE 1 Mean area ratios for enrofloxacin, gentamicin and dexamethasone compounded samples on day (D)0, D14 and D28

图1，恩诺沙星，庆大霉素和地塞米松的混合样本在D0,D14和D28的平均面积比。

 

 

FIGURE 2 Colony count (cfu/ml) values of the initial bacterial solution and those obtained after applying the enrofloxacin compounded solution. Data are expressed as mean±standard deviation.

图2，最初的细菌溶液和应用恩诺沙星混合溶液后的菌落计数（cfu/ml）值。数据以均数±标准差表示。

 

 

FIGURE 3 Colony count (cfu/ml) values of the initial bacterial solution and those obtained after applying the gentamicin compounded solution. Data are expressed as mean±standard deviation.

图3，最初的细菌溶液和应用庆大霉素混合溶液后的菌落计数（cfu/ml）值。数据以均数±标准差表示

 

In vitro bactericidal efficacy

体外杀菌效果

Control counts for S.  pseudintermedius were 5.79×107 cfu/mL on D0, 5.75×107 cfu/ml on D14 and 5.87×107 cfu/mL on D28. After ED treatment, the mean bacterial counts on D0, D14 and D28 were 0.52×107, 0.5×107 and 0.46×107 cfu/mL, respectively (Figure 2). The cfu/mL reduction rates were 91.3%±3.2% on D0, 91.4%±2.9% on D14 and 92.4%±2.8% on D28. After GD treatment, the mean bacterial counts on D0, D14 and D28 were 0.48×107, 0.52×107 and 0.51×107 cfu/mL, respectively (Figure 3). The cfu/ml reduction rates were 91.2%±3.8% on D0, 90.6%±4.3% on D14 and 90.3%±5.1% on D28. No significant differences were observed between D0, D14 and D28 with respect to the mean bacterial counts (cfu/mL) and reduction rates after treatment with ED (p=0.407 and p=0.06,respectively) and GD (p=0.390 and p=0.330, respectively).

假中间型葡萄球菌的对照计数在D0为5.79×107 cfu/mL，D14为5.75×107 cfu/ml，D28为5.87×107 cfu/mL。在ED治疗后，平均细菌计数在D0,D14和D28分别为 0.52×107, 0.5×107 and 0.46×107 cfu/mL（图2）。cfu/mL的下降率，D0为 91.3%±3.2%，D14为91.4%±2.9%，D28为 92.4%±2.8% 。在GD治疗后，平均细菌计数在D0，D14和D28分别为0.48×107, 0.52×107 and 0.51×107 cfu/mL（图3）。cfu/ml的下降率，D0为91.2%±3.8%，D14为90.6%±4.3% ，D28为90.3%±5.1%。在ED和GD治疗后，在D0，D14和D28之间关于平均细菌计数（cfu/mL）和下降率没有显著差异，ED（分别为p=0.407和p=0.06），GD（分别为p=0.390 和 p=0.330）。

 

DISCUSSION

讨论

This study documented the chemical stability of two antimicrobial solutions in combination with dexamethasone. The stability of both antibiotics was acceptable based on FDA validated bioanalytical criteria throughout the 28day experimental period.

本研究记录了两种抗菌溶液与地塞米松联合使用的化学稳定性。基于FDA验证的生物分析标准，在整个28天试验期间，两种抗生素的稳定性可以接受。

 

The experimental period was set at 28days based on the results of previous studies and taking into consideration the time for which these off-label solutions might be applied in clinical practice. Previous studies have observed the stability and efficacy of compounds for 28days and ≤90days.In most cases, the stability and bactericidal efficacy of these compounds was maintained. One study showed that the concentration of amikacin stored in plastic liquid bottles was significantly increased on D56 and that this was related to evaporation.12 Thus, we considered that if the stability and bactericidal efficacy of these compounds was maintained for 28days, clinicians could use them for that duration and prepare fresh solution if necessary. In addition, we prepared 15mL of solution because this is an amount that could be used for approximately 28days if applied twice daily.

根据之前的研究结果，并考虑到这些标签外溶液可能在临床应用的时间，将试验周期设定为28天。之前的研究观察到混合物的稳定性和有效性为28天，≤90天。在大多数病例中，这些混合物的稳定性和杀菌效果得以保持。一项研究表明，存储在塑料瓶中的阿米卡星浓度在D56显著增加，与蒸发有关。因此，我们认为如果这些混合物的稳定性和杀菌效果能维持28天，临床医生可以在该期限内使用它们，并在必要的时期配制新的溶液。此外，我们准备了15ml溶液，因为，如果一天2次，这是大约可以使用28天的总量。

 

The bactericidal effects of both enrofloxacin and gentamicin were maintained throughout the study period. The concentrations of antibiotics and dexamethasone in the tested solutions were chosen based on commercially licensed products and previous studies.To assess bactericidal efficacy, the mean cfu/mL and cfu/mL reduction rates were compared between D0, D14 and D28. For both antibiotics, cfu/ml reduction rates were>91% and these efficacies were maintained for 28days. While the decrease in mean cfu/mL after applying antibiotics was not significant in our study, this may be due to the differing growth potentials and antimicrobial susceptibility of each S. pseudintermediusstrain used in our study (Table S1). Notwithstanding this, the key finding is that the effects of antibiotics were maintained throughout the experiment.

恩诺沙星和庆大霉素的杀菌效果在整个研究期间保持不变。抗生素和地塞米松的浓度在测试溶液中是基于商业化许可的产品和之前研究的选择。为了评估杀菌效果，比较D0，D14，和D28天的平均cfu/mL和cfu/mL减少率。这两种抗生素，cfu/ml减少率>91%，并且这些疗效维持28天。虽然在我们的研究中，平均cfu/mL减少在抗生素后并不显著，这可能是由于在我们的研究中（表S1），每个假中间型葡萄球菌的生长潜力和抗菌敏感性不同。尽管如此，关键是发现抗生素的效果在整个实验过程中保持不变。

 

Countless commercial otic products exist in veterinary medicine, yet some situations necessitate the formulation of off-label otic solutions.For example, certain products include enrofloxacin and silver sulfadiazine as antimicrobials, yet this combination does not contain glucocorticoids; therefore, inflammation control cannot be expected. Other limitations of commercial preparations include systemic adverse effects and the inclusion of potentially irritating substances. Many commercial products contain propylene glycol which can cause contact reactions in some dogs.A combination of topical 0.1% dexamethasone with propylene glycol can increase the potential for adrenal suppression compared with 0.1% dexamethasone with normal saline in healthy dogs.In dogs with OE that have severe ear canal inflammation and for which glucocorticoids or propylene glycol are contraindicated, clinicians can prepare an off-label otic solution that contains dexamethasone at a lower concentration or without propylene glycol as the vehicle.

在兽医学中存在着无数的商业化耳部产品，但有些情况需要制定标签外耳部溶液。例如，某些产品包含恩诺沙星和磺胺嘧啶银作为抗菌剂，但是这个组合不包含糖皮质激素，因此，不能期望其控制炎症。商业化制剂的其他局限性包括全身性不良反应和含有潜在刺激性物质。许多商业化产品包含丙二醇，它可以引起一些犬的接触性反应。在健康犬中，与0.1%地塞米松和生理盐水混合相比，0.1%地塞米松和丙二醇混合可增加潜在的肾上腺抑制。在犬患有严重耳道炎症的外耳炎，糖皮质激素或丙二醇使用禁忌，临床医生可以配置标签外耳部溶液，包含低浓度的地塞米松，或不含有丙二醇作为载体。

 

In order to enhance potency, most commercial products come in the form of a cream suspension, emulsion or ointment, which increase contact time.If a patient has severe ear canal stenosis, these thicker formulations may not adequately contact the ear canal, so a liquid solution might be preferable. Because of this limitation of commercial otic preparations, normal saline was used as a base for the solutions in this study. Off-label otic solutions using normal saline overcome problems related to carrier substance and application caused by commercial products.

为了增强药效，大多数商业化产品，为了增加接触时间，以乳浊液、乳剂或软膏形式出现。如果患病动物伴有严重的耳道狭窄，这些粘稠的配方可能不能充分的接触耳道，所以液体溶液可能更合适。由于商业化耳药的局限性，本研究使用了生理盐水作为基础液。使用生理盐水作为标签外溶液克服了商业化产品带来的载体物质和应用问题。

 

This study had some limitations. The storage conditions for the antibiotic solutions did not vary significantly. Assessment of the chemical stability of the antibiotic solutions after storage at different temperatures, in different containers, with varying UV light exposure, and for longer periods might more accurately reflect real-life conditions. The bactericidal effects of similarly compounded solutions against other microorganisms associated with OE warrant further investigation.

本研究有一些局限性。抗生素溶液的储存条件没有显著变化。评估抗生素溶液在不同的温度，不同的容器，不同的紫外线照射和长时间存储后的化学稳定性，可能更准确的反应真实生活情况。类似的复合溶液对于OE相关的其他微生物的杀菌效果需要进一步研究。

 

CONCLUSIONS

总结

Solutions of enrofloxacin and gentamicin, prepared in saline containing dexamethasone and stored under specific conditions might be an alternative to commercial otic products for the treatment of certain cases of canine OE.

恩诺沙星和庆大霉素溶液，用含地塞米松的生理盐水配制，并在特定条件下储存，可能是治疗某些犬OE的商品化耳部药物的替代品。

 

 

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