骨伤患者耐亚胺培南铜绿假单胞菌感染状况及耐药性分析

目的:了解我院骨伤患者耐亚胺培南铜绿假单胞菌的感染狀況及耐药性特点,为临床医师合理用药提供参考方法:回顾性分析2010年1月至2013年12月分离到的250株耐亚胺培南铜绿假单胞菌,其菌种鉴定及药敏采用美国BD Phoenix100結全自动细菌鉴定及药敏分析系统进行。果:四年间我院耐亚胺培南铜绿假单胞菌感染率不断提高,平均占28.5%。主要来源于分泌物标本,占64.0%。耐亚胺培南铜绿假单胞菌对哌拉西林/他唑巴坦、阿米卡星、头孢他啶耐药率较低分别为33.6%、35.2%、48.4%,可作为临床用药的参考。结论我院耐耐亚胺培南铜绿假单胞菌感染情況较严重,应根据药敏试验结果,指导临床合理使用亚胺培南,控制耐亚胺培南铜绿假单胞菌的院內流行传播。     

噬菌体治疗对铜绿假单胞菌诱导的肺炎小鼠细菌负荷和炎症水平的影响

铜绿假单胞菌是医院获得性感染和肺部感染的主要致病菌之一,能够引发患者烧伤部位、呼吸道和泌尿道的慢性和急性感染,导致严重的发病率和死亡率。由于抗生素的滥用,铜绿假单胞菌已经对多种抗生素表现出耐药性,严重限制了可用于治疗感染患者的治疗方案。噬菌体依靠内寄生活的细菌进行生存和繁殖,其结构简单,分布广泛,被发现能够用于治疗人类细菌感染疾病,是治疗由铜绿假单胞菌引发的感染的可能方案之一。本研究构建了铜绿假单胞菌诱导的肺炎小鼠模型,对模型小鼠进行噬菌体和美罗培南的单独和联合给药处理,采用ELISA和Western blotting等方法检测了小鼠血清,支气管肺泡灌洗液和肺组织中的细菌负荷、常规生化指标和炎症因子水平。表明经铜绿假单胞菌感染后的小鼠,肺组织的细菌负荷显著增加,血清CRP和乳酸升高,TNF-α、IL-1β、IL-6和透明质酸水平也都显著上升。噬菌体和美罗培南的单独或联合处理能显著下调这些上升,其中噬菌体单独使用对乳酸的下调作用最为显著,而联合用药则对下调血清IL-1β水平具有协同优势。     

铜绿假单胞菌的分布特点耐药性分析

目的分析3年来我院患者铜绿假单胞菌的耐药特点,为临床合理用药提供依据,并有助于医院感染预防与控制。方法对2010年至2012年我院各类感染患者标本中分离获得的铜绿假单胞菌,采用纸片扩散法（K-B法）检测抗菌药物的敏感性,并用WHONET5．3软件对药敏结果进行统计分析。结果3年分离的铜绿假单胞菌共计369株,其对多黏菌素B无耐药,对亚胺培南、美罗培南、头孢哌酮／舒巴坦、哌拉西彬他唑巴坦和阿米卡星的耐药率较低（6．81％～22．73％）,对其他抗菌药物的耐药率较高（32．47％～73．38％）。结论铜绿假单胞菌对多种抗菌药物均具有较高的耐药性,临床上治疗该菌感染时应根据药敏检测结果选择抗菌药物。     

美罗培南对1139株革兰阴性杆菌抗菌活性研究

目的分析美罗培南对革兰阴性杆菌的抗菌活性,为临床合理使用美罗培南提供正确依据。方法将宁波市第一医院2004年6月至2005年8月的临床各种标本分离获得的革兰阴性杆菌在VITEK-32微生物自动鉴定分析仪中进行鉴定和药敏试验。用双纸片法及2-巯基丙酸抑制试验进行ESBLs、AmpC和金属酶的检测。结果共检出临床常见的革兰阴性杆菌1139株,其中肠杆菌科559株（大肠埃希菌309株,肺炎克雷伯菌186株,阴沟肠杆菌64株）,非发酵菌580株（铜绿假单胞菌227株,嗜麦芽窄食单胞菌72株,脑膜脓毒黄杆菌44株．鲍曼不动杆菌178株．洋葱伯克霍尔德菌30株,荧光假单胞菌29株）。美罗培南对大肠埃希菌、肺炎克雷伯菌、阴沟肠杆菌、铜绿假单胞菌、鲍曼不动杆菌、嗜麦芽窄食单胞菌、脑膜脓毒黄杆菌、荧光假单胞菌的耐药率分别为0．0％、0．0％、0．0％、22．9％、23．6％、90．3％、100．0、63．3％和3．4％。结论美罗培南对革兰阴性杆菌有很强的抗菌活性,其抗菌活性要强于亚胺培南,是目前治疗肠杆菌科细菌特别是产ESBLs、AmpC酶细菌感染的危重患者的最理想用药。美罗培南耐药率呈逐年增加趋势,应引起重视。美罗培南对嗜麦芽窄食单胞菌、脑膜脓毒黄杆菌、洋葱伯克霍尔德菌活性很低,临床对于上述细菌感染不应选用美罗培南。     

老年气管插管患者下呼吸道感染细菌分布及 耐药性分析

目的研究老年气管插管患者下呼吸道感染的病原菌分布及耐药情况,为临床插管前预防性经验用药提供参考。方法回顾性分析2014-2016年上海市虹口区江湾医院老年气管插管患者的病原菌分布及耐药性情况。结果 560例标本中共检出177株致病菌,其中革兰阴性杆菌121株(68.36%),以肺炎克雷伯菌、铜绿假单胞菌为主;除鲍曼不动杆菌/溶血不动杆菌外,其他革兰阴性杆菌对亚胺培南、美罗培南敏感性均较高。革兰阳性球菌检出52株(29.38%),以金黄色葡萄球菌为主(其中MRSA 37株),对万古霉素敏感性较高。另外分离到真菌4株。结论气管插管患者下呼吸道感染致病菌以肺炎克雷伯菌、铜绿假单胞菌、金黄色葡萄球菌为主。在临床应用中,应根据本地区、本医院的病原菌分布状况和细菌耐药情况,给予适当药物,预防感染。     

临床分离铜绿假单胞菌对氟喹诺酮类抗菌药物的耐药性检测

目的了解临床分离铜绿假单胞菌对喹诺酮类等抗菌药物的耐药性。方法琼脂稀释法测定86株铜绿假单胞菌对5种氟喹诺酮类抗菌药物以及头孢吡肟、美罗培南的耐药性。结果铜绿假单胞菌对诺氟沙星、氧氟沙星、左氧氟沙星、环丙沙星、加替沙星的耐药率分别为50%、61.6%、51.2%、48.8%、51.2%;对头孢吡肟和美罗培南的耐药率分别为30.2%、23.2%。结论铜绿假单胞菌对氟喹诺酮类抗菌药物耐药显著,临床应加强检测和监测。     

2010年宜昌市铜绿假单胞菌的耐药性分析

了解宜昌市铜绿假单胞菌（Pseudomonas aeruginosa）临床分离株的耐药现状。宜昌市城区5所医院临床分离的铜绿假单胞菌菌株,用K-B法作药敏试验,并根据统计其耐药情况及耐药表型（模式）分析可能存在的耐药机制。临床分离的铜绿假单胞菌共1 575株,耐药率依次为阿米卡星7.1%、美罗培南17.2%、头孢吡肟20.4%、头孢哌酮/舒巴坦21.0%、哌拉西林/他唑巴坦22.5%、环丙沙星23.1%、庆大霉素23.4%、头孢他啶25.0%、亚胺培南25.2%、哌拉西林30.4%、氨曲南34.5%、复方新诺明59.0%、米诺环素75.6%。多重耐药（MDR）和泛耐药（PDR）株分别占41.5%和0.17%。对各种抗假单胞菌药物分别耐药的菌株仍有13%～25.7%对阿米卡星敏感,提示在严重铜绿假单胞菌感染患者的治疗中,β内酰胺类抗假单胞菌药加氨基糖苷类仍是一个很好的联合用药组合。细菌耐药性仍呈增长趋势,临床上感染多重耐药和泛耐药的铜绿假单胞菌的治疗仍很棘手,应合理使用抗生素,尽量延缓耐药菌株的出现。     

240例咽部细菌感染患者病原菌分布及耐药分析

目的:探讨咽部细菌感染患者病原菌分布及其耐药情况.方法:收集我院240例咽部细菌感染患者病原菌,采用常规方法进行鉴定,药敏试验采用K-B法.结果:占咽部感染病原菌分布前两位的为链球菌属(30.0％)和奈瑟菌属(18.3％),其次为肺炎克雷伯菌(12.5％)、铜绿假单胞菌(11.3％)和真菌(5.0％).药敏结果显示,致病菌肺炎克雷伯菌对环丙沙星、阿米卡星、头孢吡肟、哌拉西林/他唑巴坦、头孢哌酮/舒巴坦、亚胺培南和美罗培南有较低的耐药率(小于20.0％);铜绿假单胞菌对环丙沙星、阿米卡星和头孢吡肟有较低的耐药率(小于20.0％).结论:咽部细菌感染常见致病菌为肺炎克雷伯菌和铜绿假单胞菌,对喹诺酮类药物、氨基糖苷类药物和第四代头孢菌素都有较低的耐药率,可以做为治疗咽部主要致病菌感染的可选药物.     

仙居县ICU病房铜绿假单胞菌感染调查及耐药性分析

目的了解铜绿假单胞菌在仙居县ICU病房内感染现状及其对临床常用抗菌药物的耐药情况,为铜绿假单胞菌感染的防治提供依据。方法对2011-2013年仙居县人民医院ICU患者下呼吸道感染铜绿假单胞菌药敏情况进行分析,对泛耐药菌株感染危险因素进行单因素分析。结果 622株铜绿假单胞菌对常用的抗生素有不同程度的耐药性,耐药率分别为:哌拉西林28.41%、哌拉西林/他唑巴坦24.84%、阿米卡星8.57%、环丙沙星17.32%、庆大霉素11.23%、左旋氧氟沙星22.36%、妥布霉素3.73%、头孢他啶36.75%、头孢吡肟32.00%、头孢哌酮/舒巴坦15.38%、亚胺培南39.83%、美洛培南37.36%。铜绿假单胞菌是ICU患者下呼吸道感染的主要致病菌,位居第二位,检出率为19.92%。广谱抗生素的应用、气管插管/气管切开、多器官功能障碍综合征是ICU泛耐药铜绿假单胞菌感染主要的危险因素,泛耐药比例为:广谱抗生素的应用78.57%、气管插管/气管切开76.19%、MODS 76.19%。结论铜绿假单胞菌易引发ICU病房下呼吸道感染,且耐药现象严重,易产生泛耐药,临床应根据药敏结果合理用药,控制耐药株的流行。     

鲍曼不动杆菌和铜绿假单胞菌在低碱性氨基酸培养基中对抗菌药物的敏感性

为了探讨鲍曼不动杆菌和铜绿假单胞菌在低碱性氨基酸培养基中对抗菌药物的敏感性,本研究利用常规培养基和低碱性氨基酸培养基,采用琼脂稀释法检测140株鲍曼不动杆菌和60株铜绿假单胞菌对亚胺培南、帕尼培南和罗美培南的最低抑菌浓度,利用K-B纸片扩散法进行药敏实验并计算敏感率。结果显示,在低碱性培养基中,铜绿假单胞菌和鲍曼不动杆菌对三种药物的最低抑菌浓度(MIC)值显著降低,铜绿假单胞菌在低碱性氨基酸培养基中对帕尼培南的敏感率显著上升,而鲍曼不动杆菌对三种药物的敏感性均显著上升。研究表明,在低碱性氨基酸培养基中,鲍曼不动杆菌和铜绿假单胞菌对帕尼培南、亚胺培南和美罗培南的敏感性有所增强,在临床检验中需考虑由培养基导致的敏感性差异。     

Efficacy of meropenem in the treatment of severe complicated urinary tract infections]

The clinical and bacteriological efficacies of meropenem in the treatment of 12 patients with urinary tract infection were studied. In 8 patients the drug was administered intravenously in a dose of 1 g every 8 hours and in 4 patients with the creatinine clearance below 50 ml/min it was administered in a dose of 1 g every 12 hours (the treatment course of 7 to 10 days). Meropenem was used in the monotherapy. Severe complicated urinary tract infections were mainly observed in the patients with long-term urolithiasis, subjected to repeated surgical interventions and isolating as a rule polyresistant strains of Pseudomonas aeruginosa and E.agglomerans as the pyelonephritis pathogens at a titre of 5 x 10(5)-5 x 10(8) microbial cells per 1 ml of the urine susceptible to meropenem in 80 to 96 per cent of the cases. The clinical efficacy of the drug was stated in all the patients while the bacteriological efficacy amounted to 88.9 per cent.     

美罗培南联合常规治疗对脓毒症休克合并急性肾功能不全患者炎性因子、肾功能及免疫球蛋白的影响

摘要 目的：探讨脓毒症休克合并急性肾功能不全患者在常规治疗的基础上联合美罗培南治疗后对其肾功能、炎性因子及免疫球蛋白的影响。方法：选取我院80例脓毒症休克合并急性肾功能不全患者,根据随机数字表法分为对照组（n=40）和研究组（n=40）,对照组予以常规治疗,研究组在对照组的基础上联合美罗培南治疗,比较两组患者疗效、炎性因子[降钙素原（PCT）、C反应蛋白（CRP）、白介素-6（IL-6）]、肾功能[尿素氮（BUN）和血肌酐（Scr）]、免疫球蛋白[免疫球蛋白G（IgG）、免疫球蛋白M（IgM）、免疫球蛋白A（IgA）]及不良反应。结果：研究组治疗1个疗程后的临床总有效率为90.00%（36/40）,高于对照组的72.50%（29/40）（P<0.05）。两组不良反应发生率比较无差异（P>0.05）。两组患者治疗1个疗程后BUN、Scr和PCT、CRP、IL-6均下降,且研究组低于对照组（P<0.05）。两组患者治疗1个疗程后IgG、IgM均升高,且研究组高于对照组（P<0.05）;两组患者治疗1个疗程后IgA组间及组内比较无差异（P>0.05）。结论：脓毒症休克合并急性肾功能不全患者在常规治疗的基础上联合美罗培南治疗,疗效显著,可有效改善肾功能及免疫功能,减轻炎性反应,且安全性较好。     

Continuous Infusions of Meropenem in Ambulatory Care: Clinical Efficacy,Safety and Stability

Objectives

Concerns regarding the clinical impact of meropenem instability in continuous infusion (CI) devices may contribute to inconsistent uptake of this method of administration across outpatient parenteral antimicrobial therapy (OPAT) services.

Methods

We retrospectively reviewed the clinical efficacy and safety of CIs of meropenem in two Australian tertiary hospitals and assessed its stability under simulated OPAT conditions including in elastomeric infusion devices containing 1% (2.4 g) or 2% (4.8 g) concentrations at either ‘room temperature’ or ‘cooled’ conditions. Infusate aliquots were assayed at different time-points over 24 hours.

Results

Forty-one (82%) of 50 patients had clinical improvement or were cured. Adverse patient outcomes including hemato-, hepato- and nephrotoxicity were infrequent. Cooled infusers with 1% meropenem had a mean 24-hour recovery of 90.3%. Recoveries of 1% and 2% meropenem at room temperature and 2% under cooled conditions were 88%, 83% and 87%, respectively. Patients receiving 1% meropenem are likely to receive >95% of the maximum deliverable dose (MDD) over a 24-hour period whilst patients receiving 2% meropenem should receive 93% and 87% of the MDD under cooled and room temperature conditions, respectively.

Conclusions

Meropenem infusers are likely to deliver ∼95% MDD and maintain effective plasma concentrations throughout the dosing period. These data reflect our local favourable clinical experience with meropenem CIs.     

美罗培南治疗儿童急性白血病化疗期间合并院内感染的临床分析

目的评价美罗培南治疗儿童急性白血病化疗期间中性粒细胞减少合并院内感染时的临床疗效及安全性。方法52例儿童急性白血病患者强化疗后骨髓抑制期合并院内感染,开始感染时即使用美罗培南28例,在其他广谱抗生素无效的情况下改用美罗培南24例,美罗培南用法每次20mg/kg,每8小时1次,评价治疗效果及不良反应。结果美罗培南在治疗儿童急性白血病中性粒细胞减少合并院内感染的有效率为82.7%（43/52）,且副作用少。开始使用美罗培南组起效时间明显低于更换使用美罗培南组（P〈0.05）,且使用抗生素的时间在开始即使用美罗培南组明显少于更换使用美罗培南组（P〈0.05）。两组的治疗效果差异无显著性。结论美罗培南治疗儿童急性白血病患者化疗后骨髓抑制期合并感染效果明显且较安全,可作为儿童急性白血病患者化疗后骨髓抑制期合并感染的首选药物之一。     

Multicentre study of comparative efficacy of meropenem and combined regimens for empirical antibacterial therapy of severe nosocomial infections: results of clinical and pharmacoeconomic analysis]

Adequacy and effectiveness of empirical antibacterial therapy of severe nosocomial infections with meropenem vs. combined regimens of antibacterial therapy were investigated and the ratio of the cost and effectiveness of the compared regimens was evaluated. A prospective, randomized, open, comparative study of two initiative regimens of empirical antibacterial therapy of severe nosocomial infections was performed: meropenem in a daily dose of 1.5-3 g and the standard regimen with the use of betalactams and fluoroquinolones in combination with aminoglycosides and/or metronidazole. Patients with recorded diagnosis of nosocomial pneumonia (including the ventilator-associated one) or abdominal infection with the signs of severe sepsis and severity of APACHE II > 14 were enrolled. The patients were stratified into 2 groups subject to the disease severity, i.e. APACHE II 15-20 and APACHE II 21-25. One hundred thirty five out of 166 patients with recorded nosocomial infection were included into the final estimate of the therapy adequacy and effectiveness (Protocol Analysis): 62 patients were treated with meropenem and in the treatment of 73 patients the standard antibacterial therapy was used. In the group of the patients treated with meropenem there were stated significantly higher clinical effectiveness (recovery in 80.6% of the patients vs. the control of 46.6%, p < 0.01) and pathogen eradication (89.6 and 48.1% respectively, p < 0.01). The difference in the clinical and bacteriological effectiveness of meropenem and the standard therapy was more evident in the subgroups of more severe patients (APACHE > 20). With the use of meropenem the probability of recovery from nosocomial infection was significantly higher (RR 1.73-1.94, p < 0.001) vs. the control. Meropenem provided significantly higher eradication of the pathogens: P. aeruginosa (88 and 40% respectively, p = 0.007), E. coli (100 and 46.7%, p = 0.003), Acinetobacter spp. (90.9 and 40%, p = 0.02). The antibacterial therapy with the use of meropenem was assessed as adequate in 51 out of 56 patients (91.1%), that was 3 times as frequent as with the use of the standard antibacterial therapy (33.9%). The cost-effectiveness coefficient with the use of meropenem was 2.2 times lower vs. the control. Therefore, the empirical therapy of severe nosocomial infections with meropenem proved to be more adequate and from the economic viewpoint more advantageous vs. the standard combined regimens of antibacterial therapy, that was evident from significantly higher clinical and bacteriological efficacy of the treatment and decrease of the terms of the patients hospitalization in intensive care units (on the average by 5 days).     

纳米银水凝胶涂膜干预气管导管表面铜绿假单胞菌黏附及生物膜形成的实验研究

目的研究纳米银水凝胶涂膜对气管导管（endotracheal tube,ETT）表面铜绿假单胞菌粘附及细菌生物膜（biofilm,BF）形成的干预作用。方法实验共设6组,分别为空白对照组,涂纳米银3．5、7．0、10．5、14．0和17．5μg／cm^2组。参考Brown平板法,制备ETT、表面铜绿假单胞菌BF模型。通过超声振荡-平板菌落计数法检测体外培养6、12、18h时各组ETT表面BF中的活细菌粘附数量。借助激光共聚焦显微镜观察BF中的活死菌分布情况,并测量BF厚度。结果（1）与空白对照组相比,最小量涂膜组（3．5μg／cm^2）体外培养6h时,导管表面活细菌的粘附量显著减少（P〈0．05）,12h时差异无显著性（P〉0．05）;最大量涂膜组（17．5μg／cm^2）体外培养6h时,ETT表面几乎未见细菌粘附（P〈0．05）,18h时BF中的活菌数量及BF厚度均显著减少（P〈0．05）。（2）激光共聚焦显微镜观察可见,培养6h时,空白对照组ETT表面粘附的死活菌呈不规则散点样分布,未见明显的细菌菌落形成,而各实验组ETT表面仅有细菌零星分布,其数量少于空白组。18h时空白对照组表面可见大量活死菌堆积粘连,有小菌落形成并相互交通成地图状,可见典型BF结构,而此时最大量涂膜组（17．5μg／cm^2）表面仅见数量不等的菌落形成,菌落周围可见数量不等的细菌分布。结论纳米银水凝胶涂膜可有效减少ETT表面铜绿假单胞菌的粘附数量,延缓导管表面细菌BF形成,其作用强弱随培养时间及单位面积中的纳米银剂量的变化而变化。     

Off-label biologic regimens in psoriasis: a systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy

Objectives

While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment) with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment.

Data Sources and Study Selection

We searched OVID Medline from January 1, 1990 through August 1, 2011 for prospective clinical trials that studied biologic therapy for psoriasis treatment in adults. Individual articles were screened for studies that examined escalated, reduced, or interrupted therapy with etanercept, adalimumab, infliximab, ustekinumab, or alefacept.

Data Synthesis

A total of 23 articles with 12,617 patients matched the inclusion and exclusion criteria for the systematic review. Data were examined for primary and secondary efficacy outcomes and adverse events including infections, malignancies, cardiovascular events, and anti-drug antibodies. The preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent was necessary for maintenance of disease control. Among non-responders, dose escalation with etanercept, adalimumab, ustekinumab, and alefacept typically resulted in greater efficacy than standard dosing. Dose reduction with etanercept and alefacept resulted in reduced efficacy. Withdrawal of the examined biologics led to an increase in disease activity; efficacy from retreatment did not result in equivalent initial response rates for most biologics. Safety data on off-label dosing regimens are limited.

Conclusion

Dose escalation in non-responders generally resulted in increased efficacy in the examined biologics used to treat moderate-to-severe psoriasis. Continuous treatment with anti-TNF agents and anti-IL12/23 agent results in superior efficacy over interrupted therapy. The decision to use off-label dosing needs to account for both benefits and risks and be individualized to patients'' disease severity, quality of life, and existence of comorbidities.     

Efficacy of monotherapy by meropenem in ventilator-associated pneumonia]

We performed a prospective, open label, randomized study in intensive care unit patients with ventilator-associated pneumonia (VAP) to determine the efficacy and safety of empiric intravenous (i.v.) meropenem monotherapy compared with the combination of ceftazidime plus amikacin. A total of 140 patients receiving mechanical ventilation and diagnosed with pneumonia were included in the study. Patients were randomized to receive either 1 g meropenem i.v. every 8 hours or 2 g ceftazidime i.v. every 8 hours plus 15 mg/kg amikacin daily, administered to patients with normal renal function as two daily doses. Satisfactory clinical responses (cure or improvement) were achieved at the end of treatment in 68.1% of meropenem-treated patients and 54.9% in the ceftazidime/amikacin treated group (relative risk 1.25; 95% confidence interval > 1.00, 1.55). When non-evaluable patients were excluded from the analysis, the satisfactory clinical response was 82.5% and 66.1% for the meropenem and ceftazidime/amikacin patients, respectively (p = 0.044). Logistic regression demonstrated that treatment with meropenem and both the basic traumatic and medical pathologies were significantly associated with a satisfactory response. Adverse events judged to be possible or probably related to treatment were reported by seven (10.1%) patients in the meropenem group and by eight patients (11.3%) in the ceftazidime/amikacin group. The results of this study confirm that monotherapy with meropenem is well tolerated and provides superior efficacy to the conventional combination of ceftazidime and amikacin in combating VAP.     

Chronotherapeutic Dose Schedule of Phenytoin and Carbamazepine in Epileptic Patients

The objective of this study was to compare the efficacy and safety of a chronotherapeutic dosing schedule of phenytoin and carbamazepine versus a conventional dosing schedule for the treatment of tonic‐clonic epileptic patients. Of 148 epileptic subjects found to have subtherapeutic trough drug levels (subtherapeutic group, STG), 103 subjects who completed the study were randomized to either STG I (n=51) for treatment by the conventional dosing schedule (tablet phenytoin 100–400 mg/day OD or BD, tablet carbamazepine 200–800 mg BD, or both, equally divided doses with no fixed time of drug intake), with a dose increment but no change in usual time of drug administration allowed; or to STG II (n=52), with no dose increment permitted but a shift in all or most (two‐thirds or three‐fourths) of the daily dose of one or both medications to 20:00 h. The 62 patients who experienced drug toxicity reactions (toxicity group, TG) and who had serum drug levels in the toxic range were assigned to TG I for dose reduction or TG II for dose reduction and drug administration at 20:00 h. Those 16 subjects in STG I and 47 subjects in STG II who initially evidenced subtherapeutic trough drug concentrations exhibited therapeutic drug levels by the end of four weeks of treatment (p<0.01). A significantly greater number of TG II, as compared to TG I, subjects who experienced toxic reactions showed improved drug tolerance. There were no poor responders and more good responders (control of epilepsy for one year) in STG II compared to STG I subjects. The findings of this study indicate that a chronotherapeutic dosing schedule of phenytoin and carbamazepine involving the administration of most or all the daily dose of medication(s) at 20:00 h can improve the response of diurnally active epileptic patients not responding to standard doses, achieve therapeutic drug levels, and reduce toxic manifestations in subjects having drug concentrations beyond the therapeutic range.     

Chronotherapeutic dose schedule of phenytoin and carbamazepine in epileptic patients

The objective of this study was to compare the efficacy and safety of a chronotherapeutic dosing schedule of phenytoin and carbamazepine versus a conventional dosing schedule for the treatment of tonic-clonic epileptic patients. Of 148 epileptic subjects found to have subtherapeutic trough drug levels (subtherapeutic group, STG), 103 subjects who completed the study were randomized to either STG I (n=51) for treatment by the conventional dosing schedule (tablet phenytoin 100-400 mg/day OD or BD, tablet carbamazepine 200-800 mg BD, or both, equally divided doses with no fixed time of drug intake), with a dose increment but no change in usual time of drug administration allowed; or to STG II (n=52), with no dose increment permitted but a shift in all or most (two-thirds or three-fourths) of the daily dose of one or both medications to 20:00 h. The 62 patients who experienced drug toxicity reactions (toxicity group, TG) and who had serum drug levels in the toxic range were assigned to TG I for dose reduction or TG II for dose reduction and drug administration at 20:00 h. Those 16 subjects in STG I and 47 subjects in STG II who initially evidenced subtherapeutic trough drug concentrations exhibited therapeutic drug levels by the end of four weeks of treatment (p<0.01). A significantly greater number of TG II, as compared to TG I, subjects who experienced toxic reactions showed improved drug tolerance. There were no poor responders and more good responders (control of epilepsy for one year) in STG II compared to STG I subjects. The findings of this study indicate that a chronotherapeutic dosing schedule of phenytoin and carbamazepine involving the administration of most or all the daily dose of medication(s) at 20:00 h can improve the response of diurnally active epileptic patients not responding to standard doses, achieve therapeutic drug levels, and reduce toxic manifestations in subjects having drug concentrations beyond the therapeutic range.