Antifungal Dosing Considerations in Patients Undergoing Continuous Renal Replacement Therapy

Purpose of Review

The incidence of systemic fungal infections is increasing among patients admitted to the intensive care unit (ICU). Acute kidney injury (AKI) occurs in one third of ICU patients and approximately 5% require renal replacement therapy (RRT). Among those requiring RRT, continuous RRT (CRRT) is used in more than 70% of cases. This review aims to summarize antifungal dosing management in ICU patients receiving CRRT.

Recent Findings

For most antifungal agents, including new azoles such as posaconazole and isavuconazole, CRRT does not significantly affect antifungal pharmacokinetics (PK) mainly due to drug liver elimination and high protein binding. For fluconazole, increased dose is recommended during CRRT taking into account the type of CRRT mode (CVVHF or CVVHDF), membrane surface, and effluent and dialysis flow rates. A dose increase for itraconazole seems also necessary during CRRT; a dose decrease for flucytosine is probably necessary but data are too scarce to give a strong recommendation.

Summary

In ICU patients receiving CRRT, no dosing adjustment is required for the majority of antifungal agents commonly used to treat invasive fungal infections (IFIs) excepted for fluconazole, itraconazole, and flucytosine. Due to high PK variability, therapeutic drug monitoring should be considered in ICU patients receiving CRRT.

     

Continuous Renal Replacement Therapy as a Supportive Treatment for Acute Pediatric Necrotizing Fasciitis

Acute necrotizing fasciitis (NF) in children is a dangerous illness characterized by progressive necrosis of the skin and subcutaneous tissue. The present study summarizes our recent experience with the treatment of pediatric patients with severe NF. Between 2000 and 2009, eight children suffering from NF were admitted to our department. Four of the children received an active treatment strategy including continuous renal replacement therapy (CRRT), radical debridement, and broad-spectrum antibiotics. Another four children presented at a late stage of illness, and did not complete treatment. Clinical data for these two patient groups were retrospectively analyzed. The four patients that completed CRRT, radical debridement, and a course of broad-spectrum antibiotics were cured without any significant residual morbidity. The other four infants died shortly after admission. Early diagnosis, timely debridement, and aggressive use of broad-spectrum antibiotics are key factors for achieving a satisfactory outcome for cases of acute NF. Early intervention with CRRT to prevent septic shock may also improve patient outcome.     

连续肾脏替代疗法治疗重症急性胰腺炎时机的探讨

目的:探讨连续肾脏替代疗法(CRRT)治疗重症急性胰腺炎的最佳时机。方法:选取我院收治的30例重症急性胰腺炎(SAP)患者为研究对象,按发病后行CRRT的时间分将患者随机为A、B两组,A组发病后72小时内治疗,B组发病后72小时后治疗,分析和比较两组治疗后的临床转归及生命体征变化、APACHEⅡ评分变化急性生理与慢性健康状况、住院费用、平均住院时间。结果:经CRRT治疗后,A组死亡率(14.3%)低于B组(43.7%),差异有统计学意义(P0.05);A、B两组治疗后体温、心率、呼吸、平均动脉压平稳,A组优于B组,差异有统计学意义(P0.05);A组的平均住院时间(15.7±8.9)d、住院费用(107000±65000)万元均明显优于B组,差异有统计学意义(P0.05);两组患者治疗后APACHEⅡ评分均明显优于治疗前,治疗后A组APACHEⅡ评分明显优于B组,差异显著有统计学意义(P0.05)。结论:早期行CRRT能明显改善重症急性胰腺炎患者的疗效和预后,最佳治疗时机可能为发病后72小时内。     

连续性肾脏替代治疗与间歇性血液透析对急性肾损伤的临床疗效比较

目的:比较连续性肾脏替代治疗与间歇性血液透析对急性肾损伤的临床疗效。方法:回顾性分析从2014年2月到2016年2月来我院治疗的急性肾损伤患者50例,按照治疗方法分为连续性肾脏替代治疗(Continuous renal replacement therapy,CRRT)组与间歇性血液透析(Intermittent hemodialysis,IHD)组,每组各25例。记录两组治疗前的基线数据,治疗前与治疗后的血清C-反应蛋白(C-reactive protein,CRP)、血肌酐(Serum creatinine,SCr)含量以及尿量恢复时间、重症监护室(Intensive care unit,ICU)住院时间、心血管事件发生率。结果:CRRT组与IHD组治疗前的一般资料以及尿量、血清CRP、SCr水平比较差异均无统计学意义(P0.05)。治疗1周后,与IHD组相比,CRRT组血清CRP、SCr水平明显下降,尿量恢复时间、ICU住院时间均明显缩短,心血管发生率(32.0%vs.64.0%)明显下降,差异均具有统计学意义(P0.05)。结论:CRRT治疗急性肾损伤能有效改善患者肾功能,缩短ICU住院时间并提高治疗安全性。     

重症急性肾损伤患者经连续性肾脏替代治疗后肾功能恢复的影响因素

目的：通过研究重症急性肾损伤患者经连续性’肾脏替代治疗后肾功能恢复的影响因素,为重症急性肾损伤患者的诊治及预后提供科学依据。方法：选取2009年7月至2013年10月本院住院且采用CRRT治疗的284例重症急性肾损伤患者,记录患者的一般资料、APACHEII评分、血液生化指标、伴随症状及肾功能预后情况,将预后情况和各影响因素进行Logistic回归分析得出影响。肾功能恢复的影响因素。结果：284例重症急性肾损伤患者中,肾功能恢复有89例（31．33％）;肾功能恢复组的年龄、衰竭器官数、APACHEⅡ评分、动脉血二氧化碳分压、合并慢性肾脏病率及合并严重基础疾病率均低于肾功能未恢复组,而平均动脉压和血小板计数高于肾功能未恢复组（P〈0．05）,两组间合并机械通气率和合并少／无尿率无统计学差异（P〉0．05）;衰竭器官数、APAC—HEⅡ评分、合并严重基础疾病及AKl分期为CRRT治疗重症急性肾损伤患者肾功能恢复的危险因素。结论：CRRT治疗重症急性肾损伤的主要危险因素为衰竭器官数、APACHEⅡ评分、合并严重基础疾病及AKl分期。在临床治疗中,应正确评估病情,早期及时采取CRRT治疗,以提高生存率,促进肾脏功能恢复。     

Antifungal Dosing in Critically Ill Patients

This article reviews appropriate dosing for antifungals and emphasizes factors specific to the critically ill patient, along with drug pharmacokinetics and pharmacodynamics. The rationale for doses of the echinocandins (caspofungin, micafungin, anidulafungin), triazoles (fluconazole, voriconazole, itraconazole, posaconazole), amphotericin B (including lipid formulations), and flucytosine are discussed.     

连续肾脏替代治疗对脓毒症患者血清中TNF-alpha、IL-6 和IL-8 表达的影响

目的：探讨连续肾脏替代治疗（CRRT）对脓毒症患者血清中肿瘤坏死因子alpha（TNF-alpha）、白介素-6（IL-6）和白介素-8（IL-8）的 影响。方法：将我院2013 年1 月-2014 年6 月间收治的80 例脓毒症患者随机分为观察组与对照组各40 例,两组患者均给予脓毒 症常规治疗,观察组另给予CRRT 治疗。观察比较两组患者治疗前1 天,治疗后24 h,72 h空腹静脉血TNF-alpha、IL-6、IL-8 水平。结 果：观察组治愈率为85.0%（34/40）,明显高于对照组的55.0%（22/40）,差异有统计学意义（P<0.05）;治疗24h、72h 后两组患者 TNF-alpha、IL-6和IL-8 水平均明显下降,其中观察组下降更显著,差异均有统计学意义（P<0.05）。结论：CRRT 能有效降低脓毒症患 者血清中TNF-alpha、IL-6 和IL-8 水平,有助于对炎症反应的正向调节。     

不同CRRT治疗时机对脓毒症合并急性肾功能不全患者疗效及预后的影响

目的:探讨不同持续性肾脏替代治疗(CRRT)治疗时机对脓毒症合并急性肾功能不全患者的临床疗效及预后的影响。方法:将我院ICU收治的60例脓毒症合并急性肾功能不全患者,按照CRRT治疗时机分为早期组(1-2期,n=30)和晚期组(3期,n=30)。比较两组患者治疗前后不同时点平均动脉压(MAP)、白细胞(WBC)计数、血红蛋白(HB)、血小板(PLT)计数、急性生理学与慢性健康状况(APACHE)Ⅱ评分等临床资料的变化,机械通气时间,肾功能恢复率及28 d病死率等。结果:与早期组比较,晚期组治疗后WBC计数明显升高(P0.05)。治疗后12 h、24 h、72 h,早期组ACHEⅡ评分较晚期组显著降低(P0.05)。与晚期组比较,早期组机械通气时间显著缩短,肾功能恢复明显升高,28d内病死率也明显降低(P0.05)。结论:脓毒症合并急性肾功能不全患者应早期启动CRRT治疗,最佳介入时间是KDIGO-AKI 3期之前,有助于改善患者预后。     

Antifungal Pharmacokinetics and Dosing Considerations in Burn Patients

Patients with burn injuries are at high risk of developing invasive fungal infections leading to increased morbidity and mortality. Burn patients undergo major physiologic changes, which produce significant alterations in the pharmacokinetics and pharmacodynamics of antimicrobial agents. These changes result from the breakdown of the body’s natural barriers to infection and the systemic responses that subsequently ensue after burn injury, including systemic inflammatory responses, third spacing, and development of a hypermetabolic state. Severe burn injuries often lead to larger volumes of distribution and increased drug clearance. Limited data are available to guide the clinician in optimizing the dosing regimen of antifungals in patients with burn injuries. We present a review of antifungal pharmacokinetics and describe how these properties can be used to design rational therapeutic regimens tailored to the pharmacodynamic alterations characteristic of burn patients.     

乌司他丁联合连续性肾脏替代治疗对严重脓毒症患者炎症反应和血流动力学的影响

目的:探讨乌司他丁联合连续性肾脏替代(CRRT)治疗对严重脓毒症患者炎症反应和血流动力学的影响。方法:选取2015年5月～2019年4月期间我院收治的严重脓毒症患者119例,将所有患者根据随机数字表法分为对照组(n=59)和研究组(n=60),对照组给予CRRT治疗,研究组在对照组基础上联合乌司他丁治疗,比较两组患者临床疗效、炎症反应指标、血流动力学参数,记录两组患者住院时间及28d内病死率。结果:研究组治疗7 d后的临床总有效率高于对照组(P0.05)。两组治疗7 d后血清白介素-6(IL-6)、降钙素原(PCT)、肿瘤坏死因子-α(TNF-α)水平均下降,且研究组低于对照组(P0.05)。两组患者治疗7 d后心率、平均动脉压(MAP)、血乳酸下降,氧合指数升高(P0.05),研究组治疗7 d后氧合指数高于对照组,血乳酸则低于对照组(P0.05)。研究组住院时间短于对照组(P0.05),两组28d内病死率比较无统计学差异(P0.05)。结论:乌司他丁联合CRRT治疗严重脓毒症患者的疗效确切,可有效抑制机体炎症反应,改善血流动力学,减少住院时间,具有一定的临床应用价值。     

Antifungal Dosing Strategies for Critically Ill Patients

Purpose of review

This article provides updates on antifungals, dosing strategies for safe and effective therapy in the critically ill, including special populations, and the understanding of resistance over the last 5 years.

Recent findings

Reports of adverse effects with echinocandins have risen while antifungal resistance to this class has increased, especially in Candida glabrata. New formulations of posaconazole and isuvaconazole have been developed. Alternative dosing strategies including combination therapy are being evaluated for difficult to treat fungal infections. Other highlights include additional data on dosing patients with severe organ dysfunction, including those on continuous renal replacement therapy, and new breakpoints for individual Candida species being established for the echinocandins and triazole classes.

Summary

Increasing resistance in Candida spp. has made susceptibility testing a standard of care for critically ill patients. New formulations of the triazole antifungals have made prevention and treatment of mold infections more of a reality. There are many implications that must be considered when treating critically ill patients due to alterations in pharmacokinetics and pharmacodynamics in order to ensure adequate treatment. This article exposes the need for further clinical research in treating invasive infections in this patient population.

     

乌司他丁联合连续性肾脏替代疗法对急性重症胰腺炎患者炎症因子及免疫球蛋白的影响

目的:探讨乌司他丁联合连续性肾脏替代疗法(CRRT)对急性重症胰腺炎(SAP)患者炎症因子及免疫球蛋白的影响。方法:选取2013年2月至2017年8月期间我院收治的SAP患者148例为研究对象,根据随机数字表法分为对照组(n=74)与观察组(n=74),两组均给予常规治疗以及乌司他丁药物治疗,观察组则在此基础上联合CRRT治疗,两组均治疗28d后,观察并比较两组患者的临床疗效,治疗前后白细胞介素-6(IL-6)、C-反应蛋白(CRP)、降钙素原(PCT)及IgA、IgG、IgM水平的变化。结果:观察组的总有效率为90.54%(67/74),显著高于对照组的67.57%(50/74)(P0.05)。两组患者治疗28d后血清IL-6、CRP、PCT水平较治疗前均显著降低,且观察组低于对照组(P0.05)。两组患者治疗28d后IgA、IgG、IgM较治疗前均显著升高,且观察组IgG、IgM显著高于对照组(P0.05)。治疗后观察组ICU住院时间短于对照组(P0.05),两组患者病死率比较差异无统计学意义(P0.05)。结论:乌司他丁联合CRRT治疗SAP效果显著,可有效降低患者炎症因子水平,调节免疫系统,改善患者预后,值得临床推广应用。     

Update on Antifungal Drug Dosing and Therapeutic Drug Monitoring

The prevention and treatment of invasive fungal infections can be compromised by antifungal agents that display unpredictable pharmacokinetics and significant drug interactions and which demonstrate a strong relationship between drug exposure and efficacy and toxicity. Clinical studies have shown that maintaining antifungal drug levels within a targeted range decreases the risk for treatment failure and drug toxicity and thus have established a role for therapeutic drug monitoring with the use of various agents. Evidence from experimental and clinical studies supporting the role of therapeutic drug monitoring and practical applications for attaining targeted levels are reviewed.     

Antifungal Dosing in Obesity: A Review of the Literature

Obesity is becoming a global pandemic that is projected to increase significantly over the next few decades. Unfortunately, studies of drug dosing and pharmacokinetics have largely excluded obese patients. Currently, literature inadequately characterizes drug disposition in these patients. Only a limited selection of literature addresses antibacterial dosing in obesity, and virtually none characterizes antifungal dosing in obesity. This review discusses the changes in pharmacokinetics that occur in obesity and the available in vitro and in vivo data describing the disposition of antifungal agents in obese animals and patients.     

Antifungal Therapy in Pregnancy and Breastfeeding

Antifungal therapy during pregnancy and lactation is challenging because of a lack of data on efficacy and safety, coupled with reports of teratogenicity. Although the Food and Drug Administration pregnancy category provides guidance regarding a drug’s potential fetal risks, limitations such as lack of a specific toxic dose or predisposing pregnancy trimester thwart its application. Central to the selection of optimal antifungal therapy are exploration of the literature and assessment of patient-specific factors, including awareness of effects on the pharmacokinetics of antifungal agents that result from physiologic changes during pregnancy. Topical azoles are favored for superficial fungal infections during pregnancy and lactation, whereas amphotericin B is preferred for invasive fungal infections. Data regarding the use of antifungal agents by breastfeeding women are lacking. More studies are needed, particularly with newer antifungals, to better guide clinicians in selecting optimal antifungal therapy that will provide benefit to the mother without harm to the fetus.     

Clinical Validation of Therapeutic Drug Monitoring of Imipenem in Spent Effluent in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Pilot Study

ObjectivesThe primary objective of this pilot study was to investigate whether the therapeutic drug monitoring of imipenem could be performed with spent effluent instead of blood sampling collected from critically ill patients under continuous renal replacement therapy.MethodsA prospective open-label study was conducted in a real clinical setting. Both blood and effluent samples were collected pairwise before imipenem administration and 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after imipenem administration. Plasma and effluent imipenem concentrations were determined by reversed-phase high-performance liquid chromatography with ultraviolet detection. Pharmacokinetic and pharmacodynamic parameters of blood and effluent samples were calculated.ResultsEighty-three paired plasma and effluent samples were obtained from 10 patients. The Pearson correlation coefficient of the imipenem concentrations in plasma and effluent was 0.950 (P<0.0001). The average plasma-to-effluent imipenem concentration ratio was 1.044 (95% confidence interval, 0.975 to 1.114) with Bland-Altman analysis. No statistically significant difference was found in the pharmacokinetic and pharmacodynamic parameters tested in paired plasma and effluent samples with Wilcoxon test.ConclusionSpent effluent of continuous renal replacement therapy could be used for therapeutic drug monitoring of imipenem instead of blood sampling in critically ill patients.     

Antifungal Therapy in Pediatric Patients

Invasive fungal infections still play a major role in morbidity and mortality in pediatric patients, especially in children undergoing therapy for an underlying malignancy and in preterm infants. Relative to the adult population, pediatric age groups display important differences not only in host biology, predisposing conditions, epidemiology, and presentation of fungal infections, but also in the disposition and clearance of antifungal compounds. During the past decade, several new antifungal agents have been developed. Although not all of these agents are yet approved for children, the pediatric development of antifungal agents has moved forward in an exemplary manner, which is essential for the successful management of the individual patient. This article reviews the current data on pharmacokinetics, safety, and dosing of antifungal agents in pediatric patients.