不同碳青霉烯类抗生素对丙戊酸血浆药物浓度的影响

<正>丙戊酸(valproic acid)为临床常用的广谱抗癫痫药,与其他药物联合应用可能出现药物相互作用,导致抗癫痫治疗失败,其中碳青霉烯类抗生素对丙戊酸血浆药物浓度(血药浓度)的影响已引起临床关注。1997年,Nagia等[1]首次报道帕尼培南显著降低丙戊酸的血药浓度。继后发现美罗培南与丙戊酸合用导致后者血药浓度降低[2],从而人们逐渐认识到碳青霉烯类抗生素与丙戊酸之间可能存在药物相互作用。截止2013年,已有158起关于碳青霉烯类抗生素与丙戊酸相互作用的报道。本文通过对相关     

碳青霉烯类抗生素与丙戊酸相互作用的特点、机制及临床意义

目的简述碳青霉烯类抗生素与丙戊酸相互作用的特点与机制,为临床合理用药提供参考。方法检索国内外医药数据库,下载有关碳青霉烯类抗生素与丙戊酸相互作用的文献,进行文献综述。结果碳青霉烯类抗生素可大幅度迅速降低丙戊酸的血药浓度,因而导致患者癫痫再发作或发作频率增加。美罗培南的报道最多,影响最为严重。相互作用的主要机制是抑制丙戊酸葡萄糖醛酸结合物的水解。结论碳青霉烯类抗生素与丙戊酸不宜合用。     

丙戊酸钠血药浓度与抗癫痫作用的相关性

目的:分析丙戊酸钠防治癫痫的血药浓度监测结果,探讨其临床合理用药方法.方法:采用药物浓度自动分析仪(TDX)测定丙戊酸钠血药浓度,并分析其与抗癫痫的疗效关系.结果:丙戊酸钠血药浓度在50～100 mg/L时的抗癫痫作用好,不良反应少;<50 mg/L时抗癫痫作用差,而>100 mg/L时的不良反应多.结论:丙戊酸钠的血药浓度与疗效有较好的相关性,应加强对丙戊酸钠的血药浓度监测,提高临床合理用药.     

838例(次)丙戊酸钠血药浓度测定结果分析

目的 通过测定丙戊酸钠血药浓度,为临床合理用药提供药学技术服务.方法 采用荧光偏振免疫法(FPIA)测定838例次患者丙戊酸钠血药浓度,将测定结果进行比较分析.结果 838例次丙戊酸钠测定值在治疗浓度50～100μg/ml范围内421例次(占50.2%),低于治疗浓度范围下限(<50μg/ml)385例次(占45.9%),高于治疗浓度范围上限(>100μg/ml)32例次(占3.8%).结论 丙戊酸钠体内代谢个体差异大,影响其血药浓度及其疗效的因素众多,因此临床使用丙戊酸钠应充分考虑患者的生理、病理和药物相互作用复杂的特点,及时测定血药浓度并根据测定数据综合考虑各方面因素,调整给药方案,以实现较合理的个体化用药.     

重症感染患者美罗培南血药浓度达标情况及影响因素分析

目的 分析美罗培南血药浓度达标情况及可能的影响因素,为优化重症感染患者美罗培南的给药方案提供依据。方法 采用回顾性研究方法,收集广西南宁市第一人民医院2020年5月至2022年2月使用美罗培南并进行血药浓度监测的重症感染病例资料185例,以谷浓度2μg/ml为靶值,将患者分为达标组113例和未达标组72例,统计美罗培南谷浓度的达标情况并分析其影响因素。结果 185例重症感染患者美罗培南的谷浓度中位数为3.41μg/ml,血药浓度达标率为60.44%,单因素分析显示,达标组和未达标组患者的年龄、给药剂量、肌酐清除率差异有显著性（P<0.05）。多因素logistic回归分析显示,肌酐清除率是美罗培南血药浓度达标率的影响因素。结论 重症感染患者美罗培南血药浓度达标率较低,建议加强血药浓度监测,以优化美罗培南的给药方案,提高临床疗效,减少不良反应及耐药菌的产生。     

影响城乡活动性癫痫患者丙戊酸钠治疗效果的相关因素及护理干预措施分析

目的:探讨影响活动性癫痫患者丙戊酸钠治疗效果的相关因素及护理干预措施。方法:回顾性分析2013年11月~2015年12月口服丙戊酸钠单药治疗且均随访满1年的195例活动性癫痫患者,观察随访1年癫痫发作与否,单因素及Logistic多因素回归分析影响丙戊酸钠疗效的相关因素。结果:单因素分析结果显示,癫痫发作组与癫痫未发作患者在病程(10与≥10年)、入组前1年癫痫发作频率(≥1次/日、≥1次/月且1次/日与1次/月)、患者依从性(好与差)、丙戊酸钠血药浓度(低于有效浓度、有效浓度与中毒浓度)等方面比较差异均有统计学意义(P0.05);Logistic多因素分析发现影响丙戊酸钠治疗效果独立因子包括病程、入组前癫痫发作频率、依从性及丙戊酸钠血药浓度。结论:护理干预实施过程中需注意提高癫痫患者依从性,加强丙戊酸钠血药浓度监测,同时重点关注病程长、入组前癫痫发作较频繁患者。     

苯巴比妥、丙戊酸钠的血药浓度监测对外伤性颞叶性癫痫治疗的临床观察

选取2006年8月~2009年5月3年南通大学附属医院收治的88例患者分成颞叶性癫痫发作手术组和颞叶性癫痫发作非手术组,每组分别随机给予苯巴比妥和丙戊酸钠,监测各组血药浓度,在有效血药浓度下观察治疗有效率,将增加给药剂量仍效差或无效的患者,给予苯巴比妥和丙戊酸钠联合治疗,观察有效血药浓度下的治疗有效率。苯巴比妥和丙戊酸钠在有效血药浓度范围内的对外伤性颞叶性癫痫的治疗有效率比低于有效血药浓度时的治疗有效率明显增高(P0.05),而在高于效血药浓度时其治疗有效率无明显增高(P0.05)。若单种药物在增大血药浓度时还治疗无效的患者,其在两种药物联合运用后在有效血药浓度范围之内治疗有效率明显增加(P0.05)。苯巴比妥和丙戊酸钠联用时可使后者血药浓度下降,使前者血药浓度升高,因此临床需要监测血药浓度。在有效血药浓度范围内仍控制不好的外伤性颞叶性癫痫,即使增加其血药浓度也不能增强抗癫痫作用,通过血药浓度的监测能及时更换或加用药物。     

6例开颅术后丙戊酸钠相关性高血氨脑病患者的护理

目的 总结开颅术后丙戊酸钠相关性高血氨脑病的特点及护理经验.方法 分析和总结6例开颅术后丙戊酸钠相关性高血氨脑病患者在病情变化观察、用药、安全和心理等方面的护理要点.结果 6例患者血浆氨恢复正常时间为1~3 d,5例临床症状消失,消失时间为1~3 d,4例出现迟发性肝功能损伤.结论 丙戊酸钠相关性高血氨脑病是严重的并发症.及时发现和正确判断患者是否出现丙戊酸钠相关性高血氨脑病,是护理工作难点.护士需严密观察患者的意识动态变化及精神症状的发生,配合医生及时检测丙戊酸钠血药浓度、血氨浓度,早期识别丙戊酸钠相关性高血氨脑病,做好用药、安全及心理护理.     

不同血药浓度丙戊酸钠治疗儿童癫痫疗效观察

丙戊酸钠（VPA）是儿科常用的抗癫痫药物（AEDS）。本文通过对不同血药浓度丙戊酸钠治疗疗效观察，分析药物剂量、血药浓度与临床疗效的关系，为临床个体化应用丙戊酸钠提供依据。     

冰片对丙戊酸钠透过血脑屏障的影响

目的探讨冰片对丙戊酸钠在家兔体内透过血脑屏障的影响。方法12只家兔随机分为对照组和冰片组，每组6只。两组动物均静脉滴注丙戊酸钠达稳态，之后冰片组予冰片灌胃给药。采用荧光偏振免疫分析法检测家兔血浆和脑脊液丙戊酸钠的浓度，计算药代动力学参数。结果与对照组相比，冰片组家兔脑脊液平均药物浓度升高，曲线下面积增加（P〈0．05），稳态脑脊液药物浓度出现峰值时间为6h，脑血浓度比亦升高（P〈0．05），但血药浓度并未升高。结论冰片可提高血脑屏障对丙戊酸钠的通透性，但对血药浓度影响较小。     

Epileptic seizures caused by low valproic acid levels from an interaction with meropenem

A 55-year-old woman was diagnosed with pneumonia and was treated with meropenem; 5 days later she developed epileptic seizures. She had been treated with valproic acid for 16 years to control her epileptic seizures. Her serum valproic acid concentration was low during treatment with meropenem than previously recorded despite an increase of valproic dose. As soon as administration of meropenem was withdrawn, valproic acid concentration increased to previous levels and her seizures stopped. Meropenem decreases valproic acid concentration, and may promote the development of epileptic seizures in previously controlled epileptic patients. The acute lowering of serum valproate produced by meropenem probably precludes their concomitant use.     

In vitro synergy test of meropenem and sulbactam against clinical isolates of Acinetobacter baumannii

Meropenem and imipenem are often the drugs of choice for the treatment of infections due to multidrug-resistant Acinetobacter baumannii. The present study aimed at evaluating the interaction between meropenem and sulbactam through microdilution and checkerboard methods against 48 clinical isolates of A. baumannii collected from Brazilian hospitals. All the isolates presented elevated minimum inhibitory concentration (>or=2 microg/mL) to either meropenem or sulbactam. The checkerboard method with the combination of meropenem and sulbactam demonstrated 29.2% (14/48) synergism, 47.9% (23/48) partial synergism, 10.5% (5/48) additive, 6.2% (3/48) indifference, and 6.2% (3/48) antagonism (SigmaFIC(min)=0.09 and SigmaFIC(max)=8). Thus, combinations of meropenem and sulbactam may show synergism or partial synergism for most A. baumannii isolates. Further studies may help identify treatment options for patients with infections caused by these organisms, particularly with this combination, where both drugs have time-dependent activities and might be suitable for therapy optimization studies.     

Effect of concomitant administration of meropenem and valproic acid in an elderly chinese patient

Background: Meropenem is a carbapenem with a broad spectrum of activity against β-lactamase-producing organisms. Valproic acid is widely used in the treatment of generalized tonic-clonic and partial seizures. Concomitant administration of meropenem and valproic acid reportedly leads to a rapid decline in serum concentrations of valproic acid, which is sometimes associated with seizures.Case summary: This report describes an 85-year-old Chinese male inpatient who twice received concomitant administration of meropenem and valproic acid for the treatment of pneumonia and poststroke epilepsy, respectively. Rapid declines in valproic acid concentrations were observed both times after meropenem administration. No seizures occurred in the first treatment period; however, when the patient suffered pneumonia again 3 months later, the same concomitant therapy was prescribed, and seizures occurred. It is difficult to identify a single etiology of the seizures. Based on a score of 7 on the Naranjo adverse drug reaction probability scale, the seizures were considered to be probably related to the concomitant administration of meropenem and valproic acid.Conclusions: Various factors make the effect of concomitant administration of meropenem and valproic acid unpredictable, even in the same patient. Caution should be used when administering meropenem and valproic acid concomitantly, especially in elderly patients with central nervous system disorders, even if the patient has had a successful prior experience with these 2 drugs. If concomitant administration is essential, very close serum concentration monitoring and clinical observation are necessary.     

Pharmacokinetics and total elimination of meropenem and vancomycin in intensive care unit patients undergoing extended daily dialysis

OBJECTIVE: Extended daily dialysis (EDD) combines the advantage of both intermittent hemodialysis and continuous renal replacement therapy: excellent detoxification accompanied by cardiovascular tolerability. The aim of this study was to evaluate pharmacokinetics of meropenem and vancomycin in critically ill patients with renal failure undergoing EDD. DESIGN: Prospective clinical study. SETTING: Surgical intensive care unit in a tertiary care center. PATIENTS: We studied intensive care patients with anuric acute renal failure being treated with EDD and receiving meropenem (n = 10) or vancomycin (n = 10) therapy. INTERVENTIONS: The antibiotics were administered 6 hrs (1.0 g meropenem) or 12 hrs (1.0 g vancomycin) before EDD was started in order to study the pharmacokinetics before and during EDD. In addition to the application of different methods to calculate pharmacokinetic parameters, the total dialysate concentration of both drugs was measured. RESULTS: Based on the amount of the drug recovered from the collected spent dialysate, the fraction of drug removed by one dialysis treatment was 18% for meropenem and 26% for vancomycin. Dosing regimes for intermittent hemodialysis and continuous renal replacement therapy cannot be used for critically ill patients treated with EDD. CONCLUSION: Our data suggest that patients treated with EDD by means of a high-flux dialyzer (polysulphone; surface area, 1.3 m; blood and dialysate flow, 160 mL/min; EDD time, 480 mins) and current dosing regimens run the risk of being significantly underdosed, which may have detrimental effects on critically ill patients with life-threatening infections. The exact dose has to be tailored according to weight and severity of illness as well as the current minimal inhibitory concentration against the incriminated bacteria. Whenever possible, therapeutic drug monitoring should be performed.     

Antimicrobial-induced release of endotoxin from Pseudomonas aeruginosa: comparison of in vitro and animal models

This study was designed to compare the amount of lipopolysaccharide (LPS) induced following exposure to doripenem, imipenem/cilastatin, meropenem and ceftazidime in an in vitro computerized-simulation system (simulating the drug concentration pattern in human plasma after administration of a drug), with that induced by exposure to a drug at a constant concentration. When Pseudomonas aeruginosa was exposed to the test drugs at constant concentrations of 0.1 x, 1 x and 10 x MIC, differential relative induction of LPS was observed as follows: ceftazidime > meropenem, doripenem > imipenem/cilastatin. In the computerized-simulation system, however, the amount of LPS induced by treatment with ceftazidime (1 g) was similar to that by doripenem (250 mg), imipenem/cilastatin (500 mg) and meropenem (500 mg). In a rat model of P. aeruginosa bacteraemia, rates of eradication of bacteria from the blood were similar for carbapenems and ceftazidime except for 1 h post-administration of ceftazidime. Serum LPS levels induced by treatment with doripenem (30 mg/kg), imipenem/cilastatin (30 mg/kg), meropenem/cilastatin (30 mg/kg) and ceftazidime (50 mg/kg) were almost the same at 3 h after administration of each drug. Data obtained from computerized-simulation systems might be more applicable than those obtained from organisms exposed to constant drug concentrations for estimating the amount of LPS in the plasma of human patients infected with Gram-negative bacteria.     

急性白血病患者粒细胞缺乏时发热的经验治疗

目的：研究急性白血病患者粒细胞缺乏出现发热时，使用第三代头孢菌素头孢他啶加阿米卡星、碳青霉烯类抗生素亚胺培南或美罗培南治疗的临床疗效的比较。方法：应用回顾性分析方法，观察了106例急性白血病患者在造血干细胞移植预处理或化疗后粒细胞缺乏期出现发热时，对3种治疗方案的反应。结果：碳青霉烯类抗生素亚胺培南或美罗培南单药治疗中性粒细胞缺乏时严重感染的疗效较第三代头孢菌素头孢他啶加阿米卡星好。而美罗培南的不良反应较亚胺培南少。结论：碳青霉烯类抗生素是经验治疗中性粒细胞缺乏时发热的首选药物之一。     

Concentrations of tenofovir and emtricitabine in saliva: implications for preexposure prophylaxis of oral HIV acquisition

To prevent acquisition of HIV through oral sex, drugs used for preexposure prophylaxis (Prep) need to diffuse in saliva. We measured tenofovir (TFV) and emtricitabine (FTC) concentrations simultaneously in the plasma and saliva of 41 HIV-infected patients under stable antiretroviral treatment. Mean ratios of saliva/plasma concentration were 3% (±4%) and 86.9% (±124%) for TFV and FTC, respectively. Tenofovir disoproxil fumarate (TDF) should be used in combination with FTC to prevent oral acquisition of HIV.     

Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration

OBJECTIVE: To study the pharmacokinetics of meropenem in critically ill patients with acute renal failure receiving continuous venovenous hemofiltration (CWHF). DESIGN: Prospective, open-labeled study. SETTING: Medical intensive care unit of the University Medical Center Utrecht. PATIENTS: Five critically ill patients receiving CWHF for acute renal failure treated with meropenem for documented or suspected bacterial infection. INTERVENTION: All patients received meropenem (500 mg) administered intravenously every 12 hrs. Plasma samples and ultrafiltrate aliquots were collected during one dosing interval. MEASUREMENTS AND RESULTS: Mean age and body weight of the patients studied were 46.6 yrs (range, 28-61 yrs) and 85.8 kg (range, 70-100 kg), respectively. The following pharmacokinetic variables for meropenem were obtained: mean peak plasma concentration was 24.5 +/- 7.2 mg/L, mean trough plasma concentration was 3.0 +/- 0.9 mg/L, mean terminal elimination half-life was 6.37 +/- 1.96 hrs, mean total plasma clearance was 4.57 +/- 0.89 L/hr, mean CWHF clearance was 1.03 +/- 0.42 L/hr, mean nonrenal clearance was 3.54 +/- 1.06 L/hr, and mean volume of distribution was 0.37 +/- 0.15 L/kg. CONCLUSION: In critically ill patients with acute renal failure, nonrenal clearance became the main elimination route. CWHF substantially contributed to the clearance of meropenem (23% of mean total plasma clearance). We recommend meropenem to be dosed at 500 mg intravenously every 12 hrs in patients receiving CWHF, according to our operational characteristics. This dosing regimen resulted in adequate trough plasma levels for susceptible microorganisms.     

Reversible parkinsonism and cognitive decline due to a possible interaction of valproic acid and quetiapine

What is known and Objective: Combination therapy with valproic acid plus quetiapine is recommended as one of the first‐line approaches to treatment of manic or mixed episodes in patients with bipolar disorder. Case summary: A 66‐year‐old patient with this psychiatric disease developed parkinsonism and cognitive decline during concomitant treatment with both drugs. The rapid onset of symptoms soon after use of the combination suggested an interaction/using the Karch‐Lasagna criteria, the interaction was judged to be definite. What is new and Conclusion: Their evidence on a pharmacokinetic drug interaction between the two drugs is conflicting but possible underlying mechanisms proposed include CYP3A4 inhibition. As concomitant use of valproate and quetiapine is now quite frequent in bipolar disorder, this potential interaction should be closely monitored, especially in the elderly.