用药咨询

两性霉素B对全身性霉菌感染很有临床价值,但不良反应较多,特别是肾毒性。动物试验和临床研究指出,甘露醇可防止这种肾毒性。机理是它扩张肾小管,保持肾小球滤过率,促进肾小管的清除,从而缩短药物与肾小管的接触时间。参考用法:患者数年前有两性霉素B肾毒性反应史,再次接受该药治疗,剂量     

氨基糖苷类抗生素与其他药物间的相互作用

氨基糖苷类抗生素与其他抗生素间的相互作用氨基糖苷类 两性霉素4例归因于艮他霉素和两性霉素联合应用而引起肾毒性的病例,其相互作用、机制、重要性和处理:4个病人应用中等剂量的艮他霉素和两性霉素 B 治疗,呈现出归因于两种药物合并使用的肾损害。已知这两种抗生素在足够高的剂量时都有肾毒性,而各自的低剂量合用,其肾毒性呈相加作用。如合用这两种抗生素,在没有更多的了解之前,必须仔细、慎重地检查肾功能。     

两性霉素B脂质体致急性肾损伤相关危险因素分析

目的统计分析两性霉素B脂质体致急性肾损伤(AKI)的发生率及相关危险因素。方法回顾性分析某三甲医院2016年1月—2018年12月使用两性霉素B脂质体患者的病历资料,记录患者基本资料和相关用药情况,采用单因素与多因素逐步logistic回归分析两性霉素B脂质体相关AKI危险因素。结果272例使用两性霉素B脂质体的患者,24例发生两性霉素B脂质体相关AKI,发生率8.8%;单因素分析显示,女性、联用环孢素、造血干细胞移植和两性霉素B脂质体累计使用量≥450 mg与AKI发生有关(P<0.1);多因素分析显示,女性和两性霉素B脂质体累计使用量≥450 mg是AKI独立危险因素(P<0.05);13例发生AKI患者停药1周后肌酐值较用药期间最高值下降(P<0.05)。结论两性霉素B脂质体致AKI较常见,用药期间应加强女性患者及累计使用剂量≥450 mg患者发生AKI的风险评估,密切监测给药期间尤其是约2周患者肌酐水平。大部分患者AKI可逆。     

两性霉素B相关肝损伤发生情况及其影响因素分析

目的:探讨两性霉素B相关肝损伤的发生情况并分析其影响因素。方法:通过医院信息系统收集2013年1月至2017年12月在复旦大学附属中山医院住院期间应用两性霉素B且用药前后肝功能检查结果记录完整患者的病历资料进行回顾性分析。根据《药物性肝损伤诊治指南》进行肝损伤分型与诊断,计算两性霉素B致肝损伤发生率,并将患者按年龄(≤45、>45岁),入院前3个月内有无肝损伤/肝病史,所用两性霉素B剂型(非脂质体、脂质体)、最大日剂量(<30、≥30 mg)、最大日剂量/体重(<0.5、≥0.5 mg/kg),是否阶梯加量用药、疗程(≤21、>21 d)、累积剂量(<600、≥600 mg)、累积剂量/体重(<10、≥10 mg/kg),是否联用保肝药物,以及是否联用其他有肝毒性的药物,各分为2组,分别比较上述11项临床特征不同的2组患者应用两性霉素B后血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、总胆红素(TBil)、碱性磷酸酶(ALP)和γ-谷氨酰转移酶(γ-GT)水平,应用多因素Logistic回归分析和多重线性回归分析方法分析两性霉素B致肝损伤的影响因素,前者效应值为比值比( OR)及其95%置信区间( CI),后者效应值为标准化回归系数及其95 %CI和 R 2值。 结果:纳入分析的患者共42例,男性31例,女性11例;年龄13~92岁;体重(65.0±12.3)kg。42例患者中,>45岁者26例;既往有肝损伤/肝病史者15例;应用两性霉素B者30例,应用两性霉素B脂质体者10例,2种剂型均应用者2例;两性霉素B最大日剂量<30 mg、最大日剂量/体重<0.5 mg/kg者25例,≥30 mg、≥0.5 mg/kg者17例;阶梯加量用药者28例,初始剂量即为最大日剂量者14例;累积剂量<600 mg、累积剂量/体重<10 mg/kg者24例,≥600 mg、≥10 mg/kg者18例;联用保肝药物者29例;联用其他有肝毒性的药物者33例。应用两性霉素B后,42例患者TBil、ALT水平均高于用药前( P=0.019;P=0.017),诊断为两性霉素B相关肝损伤者7例,肝损伤发生率为16.7%。Logistic回归分析结果显示,入院前3个月内肝损伤/肝病史是用药后γ-GT水平升高的独立危险因素( OR=2.029,95 %CI:1.037~3.970, P=0.039);多重线性回归分析结果显示,两性霉素B最大日剂量≥30 mg、累积剂量≥600 mg是用药后TBil水平升高的独立危险因素(标准化回归系数:0.59,95 %CI:0.28~0.90, P=0.001;标准化回归系数:1.61,95 %CI:0.14~3.07, P=0.033;R 2=0.524),入院前3个月内肝损伤/肝病史是用药后ALP和γ-GT升高的独立危险因素(标准化回归系数:0.85,95 %CI:0.25~1.45, P=0.006, R2=0.205;标准化系数:0.89,95 %CI:0.29~1.50, P=0.005, R2=0.206)。 结论:复旦大学附属中山医院两性霉素B致肝损伤的发生率为16.7%。两性霉素B最大日剂量≥30 mg、累积剂量≥600 mg是用药后TBil水平升高的独立危险因素,入院前3个月内肝损伤/肝病史是用药后ALP和γ-GT升高的独立危险因素。     

万古霉素治疗葡萄球菌肺炎的疗效与肾毒性评价

目的:评价万古霉素治疗葡萄球菌肺炎的疗效及肾毒性。方法:回顾性分析浙江省中医院加强监护病房(ICU)应用万古霉素治疗 67例葡萄球菌感染病人的临床资料。根据病人肌酐清除率,决定每日万古霉素剂量,每日剂量 (30±s10 )mg·kg-1,疗程 7~14d,疗程剂量(22±13)g。结果:临床有效率为 88 %,细菌清除率 88 % (59 /67),毒性发生率为 16 % (11 /67 ),在发生肾毒性的病人中,23 %肾功能可以恢复正常。Logistic回归分析表明APACHEⅡ评分及万古霉素治疗前感染持续时间是临床疗效相关因素,肾毒性的发生与APACHEⅡ评分、万古霉素剂量及其他药物密切相关。结论:万古霉素治疗葡萄球菌肺炎疗效明显,肾毒性低,是安全可靠的抗生素。     

常用抗菌药的肾损害及其防治

许多抗菌药具有潜在的肾毒性,主要以原型药经肾排泄。水溶性高的药物易引起肾损害,其严重程度一般随剂量增大或疗程延长而增加。由药物引起的变态反应致肾损害与剂量关系不明显。临床上必须对各种抗菌药的肾毒性有深刻的了解和认识,防止医源性药物肾损害。1易引起肾损害的抗菌药1.1 氨基糖苷类抗生素此类药物均有不同程度的肾毒性,主要是抑制细胞溶酶体,直接损害肾小管上皮细胞,早期表现为肾脏浓缩功能减退及轻度蛋白尿,可伴有血尿、管型尿,晚期出现肾小球滤过率下降和氮质代谢废物潴留,一般于用药后5～7日起病,7～10日毒性最强,及时停药后可恢复。     

肾小管性酸中毒15例临床分析

肾小管性酸中毒(RTA)是一组临床综合征,是由近端及/或远端肾小管功能障碍所引起的代谢性酸中毒,而肾小球功能则正常或损害较轻。现将我院近5年来收治的15例RTA分析如下: 临床资料一般资料:男3例,女12例,年龄20～69岁,病程多数在2年内。全组患者均无阳性家族史,其中继发于慢性肾盂肾炎6例,海绵肾2例,慢性活动性肝炎、肝硬化2例,重叠综合征1例,梗阻性肾病1例,原因不明3例。     

阿德福韦酯和替诺福韦相关性肾小管病

阿德福韦酯和替诺福韦为核苷酸类似物,用于治疗乙型病毒性肝炎及其他病毒性疾病。近年报道,该两药具有肾毒性。阿德福韦酯和替诺福韦的肾毒性系指连续2次检测的SCr水平比基线水平高≥0.5mg/dl（44.2μmol/L）或血清磷水平〈1.5mg/dl（0.5mmol/L）。阿德福韦酯肾毒性发生率和剂量相关,剂量≥30mg/d时发生率为22%～50%,10mg/d时发生率与安慰剂相似。替诺福韦肾毒性发生率明显低于阿德福韦酯。多数患者的肾毒性反应程度较轻。肾毒性发生的机制可能和药物对线粒体的毒性有关。肾毒性所致病理改变主要为近曲小管上皮细胞广泛水肿、细胞坏死、空泡形成等。预防措施为：用药期间应定期监测肾功能和血磷,避免与其他具有肾毒性的药物联用,药物剂量应按照肌酐清除率进行调整。     

卡泊芬净治疗老年COPD患者侵袭性肺部真菌感染的临床分析

目的研究卡泊芬净在老年COPD患者合并侵袭性肺部真菌感染时抗真菌治疗的有效性和安全性。方法选取老年COPD合并侵袭性肺部真菌感染患者共85例,随机进入观察组和对照组。观察组静脉滴注卡泊芬净,首剂量为70mg／d,之后为50mg／d;对照组静脉滴注两性霉素B脂质体,剂量为3mg／（kg·d）。两组治疗时间持续至症状消失后5d,对比两组患者的临床疗效和不良反应。结果观察组患者42例,总有效率为45．2％,不良反应发生率30．9％;对照组43例,总有效率48．8％,不良反应发生率72．1％。两组患者的总有效率无显著性差异（P〉0．05）,不良反应发生率差异性有统计学意义（P〈0．05）。结论对老年COPD患者发生侵袭性肺部真菌感染后采用卡泊芬净进行治疗,能够获得与两性霉素B脂质体相同的临床疗效,且安全性高,患者耐受性更强,值得在临床上进行推广与应用。     

两性霉素B肾毒性文献计量分析

目的了解和分析国内外两性霉素B肾毒性相关文献的研究现状和方向。方法在Pub Med、SCI、Embase以及CNKI数据库中检索两性霉素B肾毒性方面的文献,进行文献计量学分析。结果纳入国内外研究的相关文献总数为638篇,其中中文31篇,外文607篇;文献从1981年开始逐年增长,2005年达到高峰,当年发表文献127篇。被引频次前10位的文献多为两性霉素B脂质体与其他抗真菌药物或传统两性霉素B在抗真菌感染方面的随机对照临床试验。研究结果表明:两性霉素B为侵袭性曲霉菌感染的一线用药;两性霉素B脂质体与两性霉素B疗效相当,但前者不良反应尤其是肾毒性较小;伏立康唑、伊曲康唑在某些真菌感染方面与两性霉素B疗效相当,安全性各有优劣。结论随着两性霉素B的广泛应用,两性霉素B的肾毒性愈来愈受到重视,相关研究更加深入、广泛。     

Current strategies in the treatment of invasive Aspergillus infections in immunocompromised patients.

Aspergillus infections have a very high mortality rate. Their incidence is growing because of the increasing number of immunocompromised patients. Treatment of Aspergillus infection is difficult, and the agents used have numerous adverse effects and toxicities. Recently, new and less nephrotoxic formulations of amphotericin B have come onto the market and other new drugs, such as voriconazole and terbinafine, are under evaluation for this infection. Restoration of host immune defences by tapering of immunosuppressive therapy in transplant patients or correction of granulocytopenia in haematological disease is the cornerstone of modern treatment of aspergillosis in immunocompromised patients. In patients with invasive aspergillosis it is very important to achieve therapeutic concentrations of antimycotic drugs as quickly as possible. Patients at high risk of developing aspergillosis (e.g. those with granulocytopenia) should be treated on the basis of clinical or radiological criteria alone if microbiological or histological diagnosis would significantly delay treatment. Conventional amphotericin B is still the first-line treatment for patients with invasive aspergillosis. In transplant patients receiving other nephrotoxic drugs, particularly cyclosporin, first-line therapy with one of the new amphotericin B formulations should be considered. If the emergence of renal toxicity in any patient precludes aggressive treatment, the patient should be switched to one of the new formulations of amphotericin B. For patients cured with amphotericin B, secondary prophylaxis is needed at the end of the intravenous therapy. Amphotericin B by aerosol or itraconazole are possible solutions. In non-invasive forms of aspergillosis, such as suppurative bronchitis, patients could be treated either with amphotericin B or itraconazole as first-line therapy.     

Characterizing and predicting amphotericin B-associated nephrotoxicity in bone marrow or peripheral blood stem cell transplant recipients

STUDY OBJECTIVE: To characterize amphotericin B-associated nephrotoxicity and to determine the variables associated with it that can be used to identify, a priori, at-risk patients. DESIGN: Retrospective analysis. SETTING: University hospital. PATIENTS: A homogeneous population of 69 recipients of a bone marrow (BMT) or peripheral blood stem cell transplant (PBSCT) with multiple myeloma and who received at least two doses of amphotericin B deoxycholate from January 1, 1992-January 1, 1995. INTERVENTION: Data on demographics, prior and concomitant nephrotoxic drug therapy, daily laboratory values, and amphotericin B dosing were collected serially from medical and pharmacy records. MEASUREMENTS AND MAIN RESULTS: Forward stepwise logistic regression analysis was performed on the data from the first day of therapy to characterize and determine variables related to amphotericin B-associated nephrotoxicity. Nephrotoxicity occurred in 30 patients (43%) and developed rapidly Patients who developed nephrotoxicity were similar to those who did not in many aspects associated with their treatment. However, baseline estimated creatinine clearance, cyclosporine therapy, nephrotoxic drug therapy within 30 days of starting amphotericin B, and the number of concomitant nephrotoxic drugs were significant predictors of amphotericin B-associated nephrotoxicity. CONCLUSION: Recipients of a BMT or PBSCT who have multiple myeloma and are receiving cyclosporine or multiple nephrotoxic drugs at the start of amphotericin B therapy should be considered at high risk for developing amphotericin B-associated nephrotoxicity. Also, because amphotericin B-associated nephrotoxicity develops rapidly, clinicians should be aware of the rapid changes in serum creatinine and electrolyte levels that can occur.     

Drug-induced nephrotoxicity. Aetiology, clinical features and management

There is a growing number of hospitalised patients who develop a drug-induced renal problem because increasing numbers of potent drugs have been added to the therapeutic arsenal in recent years. The 3 clinical syndromes that can be recognised in drug-induced nephropathy are acute renal failure, chronic interstitial nephritis and the nephrotic syndrome. The first can be caused by prerenal problems, acute interstitial nephritis, acute tubular necrosis and intratubular obstruction. The most important drugs that cause prerenal failure are NSAIDs, captopril and cyclosporin. NSAIDs inhibit the synthesis of prostaglandins, and consequently vasoconstriction of the afferent arteriole leads to lowering of the glomerular filtration rate (GFR); captopril blocks the formation of angiotensin II (which also leads to a lower GFR), and should be used with caution in patients with stenotic renal arteries; cyclosporin causes vasoconstriction of the afferent arteriole, which is probably mediated by the sympathetic system. Combinations of these drugs result in increased nephrotoxicity. The drugs most likely to cause acute interstitial nephritis are antibiotics and NSAIDs. Normally, signs of an allergic reaction are also present. Acute interstitial nephritis is usually self-limiting, but in some studies it is claimed that steroids may promote recovery. Four important causal agents of acute tubular necrosis are aminoglycosides, amphotericin B, radiocontrast agents and cyclosporin. Approximately half of the cases of drug-induced renal failure are related to the use of aminoglycosides: generally, 10 days after start of treatment a nonoliguric renal failure develops, with recovery after withdrawal of the drug in almost all cases. The aminoglycosides are particularly nephrotoxic when combined with other nephrotoxic drugs. 80% of amphotericin B-treated patients develop renal insufficiency, a percentage that increases as the cumulative dose exceeds 5g. It is because of its unique antifungal properties that there are still some indications for the use of this highly nephrotoxic drug; the high percentage of nephrotoxicity can probably be prevented in part by sodium loading. The nephrotoxicity of radiocontrast agents is largely dependent on renal function: from 0.6% in patients with normal renal function to 100% in patients with a serum creatinine above 400 mumol/L. Diabetes mellitus does not add greatly to the risk of radiocontrast nephrotoxicity. The nephrotoxicity of cyclosporin is dose-dependent and reversible, although there are some reports of irreversibility after long term use. Cyclosporin can also result in nephrotoxicity in combination therapy.(ABSTRACT TRUNCATED AT 400 WORDS)     

Role of humoral mediators in, and influence of a liposomal formulation on, acute amphotericin B nephrotoxicity

The mechanisms responsible for amphotericin B nephrotoxicity remain incompletely understood, but clearly involve reduction in renal blood flow and glomerular filtration rate. Both direct effects of amphotericin B on contractile vascular cells, and indirect effects, due to humoural mediators, have been proposed. This study examines the role of nitric oxide, endothelin and angiotensin II in the acute nephrotoxic effects of amphotericin B in rats, and compares the anti-fungal and nephrotoxic effects of liposomal amphotericin B and amphotericin B-deoxycholate. Anaesthetized rats were given infusions of amphotericin B-deoxycholate in the presence or absence of N-nitro-L-arginine, PD 145065, a non-specific endothelin receptor antagonist, and L-158809, an angiotensin II type I receptor antagonist, or increasing doses of liposomal amphotericin B. Amphotericin B-deoxycholate (0.03 mg/kg/min intravenously) caused a significant 44% reduction in glomerular filtration rate and 65% maximal fall in renal blood flow. N-Nitro-L-arginine-treated rats had a lower renal blood flow and glomerular filtration rate at baseline, but sustained similar reduction of 53% and 75% in these parameters, respectively. PD145065 and L-158809 did not modify these effects either. Increasing doses of liposomal amphotericin B (from 0.01 up to 0.50 mg/kg/min.) induced no change in either glomerular filtration rate or renal blood flow. In vitro susceptibility tests revealed similar potency for liposomal amphotericin B and amphotericin B-deoxycholate in their fungistatic effects and slightly higher potency for amphotericin B-deoxycholate in their fungicidal effect. These results suggest that endogenous endothelin, angiotensin II or nitric oxide systems are not involved in the nephrotoxic effects of amphotericin B. The liposomal amphotericin B results suggest that amphotericin B nephrotoxicity is due to a direct interaction of amphotericin B with renal cells that is prevented by its encapsulation in liposomes.     

A concept for pharmacokinetic-pharmacodynamic dosage adjustment in renal impairment: the case of aminoglycosides

BACKGROUND: For patients with impaired renal function, dosage adjustment is necessary for many drugs. Adjustment with respect only to pharmacokinetic parameters may be insufficient. OBJECTIVE: To apply the theory of pharmacokinetics and pharmacodynamics to derive a mathematical model that links the concentration-time course and the clinical response by means of the pharmacokinetic-pharmacodynamic parameter 'area under the effect-time curve' (AUETC), and to use this analysis and clinical data for aminoglycosides to calculate dosage adjustments in renal impairment. METHODS: Model parameters were estimated for the antimicrobial and nephrotoxic effects of aminoglycosides on the basis of data from the literature. Effect parameters were calculated for various degrees of impaired renal function. RESULTS: Use of the model parameters gave a high correlation between the predicted and the observed (literature) values for antimicrobial efficacy and nephrotoxicity. When calculating dosage adjustments in renal impairment, it was possible to hold only one effect (antimicrobial or nephrotoxic) constant by dosage adjustment, whereas the other changed unfavourably. This was explained by differences between the pharmacodynamic parameters for each effect. For high antimicrobial efficacy, a target peak concentration of 9 mg/L (for gentamicin) should be obtained every 48 hours in advanced renal impairment. For low nephrotoxicity, the peak concentration should not exceed 3 mg/L. CONCLUSIONS: The parameter AUETC could be a useful pharmacokinetic-pharmacodynamic surrogate marker for dosage adjustment in renal impairment. Using the AUETC method, the beneficial effect can be balanced against the adverse effect.     

Fungal infections in patients with neutropenia: challenges in prophylaxis and treatment

Fungal infections are a leading cause of mortality in patients with neutropenia. Candidiasis and aspergillosis account for most invasive fungal infections. General prophylactic measures include strict hygiene and environmental measures. Haemopoietic growth factors shorten the duration of neutropenia and thus may reduce the incidence of fungal infections. Fluconazole is appropriate for antifungal prophylaxis and should be offered to patients with prolonged neutropenia, such as high-risk patients with leukaemia undergoing remission induction or consolidation therapy and high-risk stem cell transplant recipients. Empirical antifungal therapy is mandatory in patients with persistent febrile neutropenia who fail to respond to broad-spectrum antibacterials. Intravenous amphotericin B at a daily dose of 0.6 to 1 mg/kg is preferred whenever aspergillosis cannot be ruled out. Lipid formulations of amphotericin B have demonstrated similar efficacy and are much better tolerated. Fluconazole is the best choice for acute candidiasis in stable patients; amphotericin B should be used in patients with unstable disease. Use of fluconazole is restricted by the existence of resistant strains (Candida krusei and, to a lesser extent, C. glabrata). Amphotericin B still remains the gold standard for invasive aspergillosis. Lipid formulations of amphotericin B are effective in aspergillosis and because they are less nephrotoxic are indicated in patients with poor renal function. Itraconazole is an alternative in patients who have good intestinal function and are able to eat. Mucormycosis, trichosporonosis, fusariosis and cryptococcosis are less common but require specific management. New antifungal agents, especially new azoles, are under development. Their broad in vitro spectrum and preliminary clinical results are promising.     

Antiretroviral drugs and the kidney: dosage adjustment and renal tolerance

BACKGROUND: Acquired immunodeficiency syndrome (AIDS)-related kidney disorders concern 30% of those patients and can lead to end-stage renal disease (ESRD; 0.6 to 1%). Therefore, administration of antiretroviral drugs in human immunodeficiency virus (HIV) patients with nephropathy is not uncommon. AIM OF THE REVIEW: Since renal insufficiency is not uncommon among HIV-infected patients treated with antiretroviral drugs, guidelines on how to use these drugs in the pattern of an altered renal function are mandatory. This review provides such guidelines established on the basis of pharmacokinetic and clinical studies reported in the international literature. In addition, some of these drugs may be nephrotoxic. Mechanisms and clinical and/or biological manifestations are reviewed to help monitor renal tolerance in patients receiving these drugs. CONCLUSION: Antiretroviral drugs' dosage in HIV-infected patients with altered renal function should be cautiously determined. Drug dosage should not be systematically reduced since dosage adjustment is not mandatory for all therapies (ie. protease inhibitors). Furthermore, when dose reduction is necessary, pharmacokinetic and clinical data from the literature allows to establish practical guidelines on how to use these drugs in such patients.     

Resurgence of colistin use.

PURPOSE: The role of colistin in the treatment of infections caused by multidrug-resistant gram-negative microorganisms is discussed. SUMMARY: Colistin is structurally and pharmacologically related to polymyxin B, the other commercially available drug from the polymyxin class. Colistin is bactericidal in nearly all strains of gram-negative bacilli. As with all antibiotics, resistance is of paramount concern. Resistance to colistin has not been frequently documented. Colistin must be administered parenterally, as it is not absorbed from the gastrointestinal tract, mucous membranes, or intact or denuded skin. Parenteral colistin has been replaced by less-toxic antibiotics and should be reserved for life-threatening infections caused by organisms resistant to preferred drugs. A number of published studies and case reports have reevaluated the safety and efficacy of parenteral colistin use in patients with multidrug-resistant infections. In three case series, 58-74% of patients exhibited a clinical response to colistin. Although colistin was previously viewed as reasonably effective but highly nephrotoxic, recent studies have suggested that nephrotoxicity may not be as severe as once thought. Frequent renal function monitoring is necessary in patients receiving colistin, since adverse renal effect may occur, regardless of the dosage given. The recommended dosage of parenteral colistin for adults and children with normal renal function is 2.5-5 mg/kg/day, administered as two to four divided doses. Doses must be adjusted for renal impairment, and dosing recommendations for patients undergoing renal replacement therapy have not been well established. CONCLUSION: With vigilant monitoring of renal function and the avoidance of concomitant neurotoxic medications, colistin can be used safely and effectively with minimal adverse outcomes.