CRRT抗生素剂量调整.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系本人改正。,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系本人改正。,context,Continuous renal replacement therapy(CRRT)is now commonly used as a means of support for critically ill patients with renal failure.,acute renal failure or chronic renal failure.,No recent comprehensive guidelines exist that provide antibiotic dosing recommendations for adult patients receiving CRRT.,Doses used in intermittent hemodialysis cannot be directly applied to these patients,antibiotic pharmacokinetics are different than those in patients with normal renal function.,目前现状,CRRT,广泛用于,重症病人,肾脏衰竭,治疗,缺乏此类人群,抗生素,剂量调整的指导,（传统的剂量调整方案不适用于CRRT患者）,剂量调整难度大,危重患者/ARF：Vd、PB,CRRT:肾脏排泄率25%有意义,不同抗生素具有不同药代、药动学,患者抗生素-,CRRT,三者关系,Data Sources 19952004,Data Sources:,MEDLINE search from February 1986 to 2008.,Data Sources 19952004,推荐依据,1.有相关报道,2.没有相关报道：a化学性质,b其它临床数据（分子量、蛋白结合率PB、间断透析的清除率）,几点说明,1.In most cases,the recommended“target”drug concentration corresponds to the upper limit of the MIC range for susceptibility.,2.The goal of our dosing recommendations is to keep the concentration above the target MIC for an optimal proportion of the dosing interval,reflecting known pharmacodynamic properties(timedependent vs.concentration-dependent killing),3.while minimizing toxicity due to unnecessarily high concentrations.,ANTIBIOTICS FOR DRUG-RESISTANT GRAM-POSITIVE BACTERIA,Vancomycin,The half-life of vancomycin increases significantly in patients with renal insufficiency.,CVVH,CVVHD,and CVVHDF all effectively remove vancomycin.,a vancomycin loading dose of 1520 mg/kg is warranted.,Vancomycin,maintenance dosing,for patients receiving CVVH varies from 500 mg q24h to 1500 mg q48h receiving CVVHD or CVVHDF,we recommend a vancomycin maintenance dosage of 11.5 g q24h.Monitoring of plasma vancomycin concentrations and subsequent dose adjustments are recommended to achieve desired trough concentrations.,A trough concentration of 510 mg/L is adequate for infections in which drug penetration is optimal,such,as skin and soft-tissue infections or uncomplicated bacteremia.,However,higher troughs(1015 mg/L)are indicated for infections in which penetration is dependent on passive diffusion of drug into an avascular part of the body,such as osteomyelitis,endocarditis,or meningitis.,Recent guidelines also recommend higher troughs(1520 mg/L)in the treatment of health careassociated pneumonia,because of suboptimal penetration of vancomycin into lung tissue,Linezolid.,Fifty percent of a linezolid dose is metabolized in the liver to 2 inactive metabolites,and 30%of the dose is excreted in the urine as unchanged drug.,There is no adjustment recommended for patients with renal failure;,however,linezolid clearance is increased by 80%during intermittent hemodialysis.,There are very few data on linezolid clearance during CRRT.,On the basis of studies,a linezolid dosage of 600 mg q12h provides a serum trough concentration,of 4mg/L,which is the upper limit of the MIC range for drugs-susceptible,Staphylococcus,species.,The upper limit of the MIC range for drug-susceptible,Enterococcus,and,Streptococcus,species is,2 mg/L.,Thus,no linezolid dosage adjustment is recommended for patients receiving any form of CRRT,;,however,in such patients,neither the disposition nor the clinical relevance of inactive linezolid metabolites are known.Therefore,the reader is cautioned to pay attention to hematopoietic and neuropathic adverse effects when administering linezolid for extended periods to patients receiving CRRT,b,-LACTAMS,Carbapenems.,Imipenem,and,cilastatin,have similar pharmacokinetic properties in patients with normal renal function;,both drugs accumulate in patients with renal insufficiency.,Cilastatin,may accumulate to a greater extent,because nonrenal clearance of cilastatin accounts for a lower percentage of its total clearance,compared with imipenem.,To maintain an,imipenem,trough concentration of 2 mg/L during CRRT,a dosage of 250 mg q6h or 500mg q8h is recommended.,A higher dosage(500 mg q6h)may be warranted in cases of relative resistance to imipenem(MIC,_4 mg/L).Cilastatin also accumulates in patients with hepatic dysfunction,and increasing the dosing interval may be needed to avoid potential unknown adverse effects of cilastatin accumulation.,The,meropenem,MIC for most susceptible bacteria is 4 mg/L.,This represents an appropriate trough concentration for critically ill patients,especially when the pathogen and MIC are not yet known.,Many studies have analyzed the pharmacokinetics of meropenem in patients receiving CRRT.,There is significant variability in the data,owing to different equipment,flow rates,and treatment goals.,However,a meropenem dosage of 1 g q12h will produce a trough concentration of 4 mg/L in most patients,regardless of CRRT modality.,If the organism is found to be highly susceptible to meropenem,a lower dosage(500 mg q12h)may be appropriate.,b,-Lactamaseinhibitor combinations.,Of the 3 b-lactamaseinhibitor combinations available commercially,only piperacillin-tazobactam has been extensively studied in patients receiving CRRT.,On the basis of published data,piperacillin is cleared by all modalities of CRRT.,The tazobactam concentration has been shown to accumulate relative to the piperacillin concentration during CVVH.,Thus,piperacillinis the limiting factor to consider when choosing an optimal dose.On the basis of results of 4 studies evaluating piperacillin or the fixed combination of piperacillin-tazobactam in patients receiving CRRT,a dosage of 2 g/0.25 g q6h piperacillin-tazobactam is expected to produce trough concentrations,of these agents in excess of the MIC for most drugsusceptible bacteria during the majority of the dosing interval.,For patients receiving CVVHD or CVVHDF,one should consider increasing the dose to 3 g/0.375 g piperacillin-tazobactam if treating a relatively drug-resistant pathogen,such as Pseudomonas aeruginosa,for patients with no residual renal function,who are undergoing CVVH and receiving prolonged therapy,with piperacillin-tazobactam,it is not known whether tazobactam,accumulates.,Moreover,the toxicities of tazobactam are,not known,and it has been recommended that alternating doses,of piperacillin alone in these patients may avoid the potential,toxicity associated with tazobactam accumulation,Although few data exist with ampicillin-sulbactam and ticarcillin-clavulanate 35,extrapolations are possible between piperacillin-tazobactam and ampicillin-sulbactam.Piperacillin,tazobactam,ampicillin,and sulbactam primarily are excreted by the kidneys,and all 4 drugs accumulate in persons with renal dysfunction.,the ratio of b-lactam to b-lactamase inhibitor is preserved in persons with varying degrees of renal insufficiency,because each pair has similar pharmacokinetics.This is not true for ticarcillin-clavulanate.,Although ticarcillin will also accumulate with renal dysfunction,clavulanate is not affected;it is metabolized by the liver.If the dosing interval is extended,only ticarcillin will remain in plasma at the end of the interval For this reason,an interval 18 h is not recommended with ticarcillin-clavulanate during CRRT.Because CVVHD and CVVHDF are more efficient at removing b-lactams such as ticarcillin,the dosing interval with these CRRTmodalities should not exceed 6 h for ticarcillin-clavulanate.,Cephalosporins and aztreonam.,With,the exception of ceftriaxone,these b-lactams are renally excreted and accumulate in persons with renal dysfunction.,the rate of elimination is directly proportional to renal function,patients requiring intermittent hemodialysis may receive doses much less often.,In some instances,3 times weekly dosing after,hemodialysis,is adequate.,However,clearance by,CRRT,is greater for most of these agents,necessitating more-frequent dosing to maintain therapeutic concentrations greater than the MIC for an optimal proportion of the dosing interval.,Ceftriaxone is the exception in this group of b-lactams,primarily because of its extensive protein-binding capacity,which prevents it from being filtered,and its hepatic metabolism and biliary excretion.,Ceftriaxone clearance in patients receiving CVVH has been shown to be equivalent to clearance in subjects with normal renal function,and therefore,no dose adjustment is necessary for patients receiving CRRT。,The other cephalosporins,and,aztreonam,are cleared at a rate equivalent to a creatinine clearance rate of,3050,mL/min during CVVHD or CVVHDF,whereas the rate of clearance by CVVH is lower.,If the goal in critically ill patients is to maintain a therapeutic concentration for the entire dosing interval,a,normal,unadjusted dose may be required.This is the case with cefepime,On the basis of 2 well-done studies involving critically ill patients,a cefepime dosage of 1 g q12h is appropriate for most patients receiving CVVH,and up to 2 g q12h is appropriate for patients receiving CVVHD or CVVHDF,Cefepime and,ceftazidime,pharmacokinetics are almost identical,and similar doses are advocated.,Older recommendations for CVVH dosing(12 g q2448 h)are based on CAVH data,It is not clear whether CAVH data can be extrapolated to CVVH,CVVHD,and CVVHDF.,A ceftazidime dosage of 2 g q12h is needed to maintain concentrations above the MIC for most nosocomial gram-negative bacteria in critically ill patients receiving CVVHD and CVVHDF.,Ceftazidime 1 g q12h is appropriate during CVVH,.,Studies have not been performed with cefazolin,cefotaxime,or aztreonam during CRRT.However,their pharmacokinetic and molecular properties are similar enough such that extrapolations are appropriate,.,Dosing recommendations for these b-lactams are listed in table 2.,FLUOROQUINOLONES,Few antibiotic classes have more data supporting the influence of pharmacodynamics on clinical outcomes than fluoroquinolones.,AUC/MIC,evidence exists,that manufacturer-recommended dosing for ciprofloxacin will not always achieve a target AUC/MIC ratio in critically ill patients,A ciprofloxacin dosage of 400 mg q.d.is recommended by the manufacturer for patients with a creatinine clearance rate of_30 mL/min In critically ill patients,receiving,CRRT,a dosage of 600800 mg per day may be more likely to achieve an optimal AUC/MIC ratio,and for organisms with a ciprofloxacin MIC of _1 mg/mL,standard doses are lesslikely to achieve a target ratio.,Levofloxacin,is excreted largely unchanged in the urine,and significant dosage adjustments are necessary for patients with renal failure.,Intermittent hemodialysis,does not effectively remove levofloxacin,and therefore,supplemental doses are not required after hemodialysis,Levofloxacin is eliminated by,CVVH,and CVVHDF,A levofloxacin dosage of 250 mg q24h provided Cmax/MIC and AUC24/MIC values that were comparable to the values found in patients with normal renal function after a dosage of 500 mg q24h.,Levofloxacin dosages of 250 mg q24h,after a 500mg loading dose,are appropriate for patients receiving CVVH,CVVHD,or CVVHDF,The pharmacokinetics of,moxifloxacin,have been recently studied in critically ill patients receiving CVVHDF 50.These data,as well as known pharmacokinetics data,indicate no need to adjust the moxifloxacin dosage for patients receiving CRRT,AMINOGLYCOSIDES,Todays filters are capable of removing aminoglycosides at a rate equivalent to a creatinine clearance rate of 1040 mL/min,This equates to an aminoglycoside half-life of 620 h.,The typical dosing interval with aminoglycosides will be 3 halflives;,therefore,the typical dosing interval during CRRT will be 1860 h.,Indeed,most patients undergoing CRRT will require an interval of 24,36,or 48 h.,ANTIFUNGALS,80%of the,fluconazole,dose is eliminated unchanged via the kidneys.,azole-resistant,Candida,a daily dose of 800 mg for critically ill patients receiving CVVHD or CVVHDF with a combined ultrafiltration and dialysate flow rate of 2 L/h,a daily dose of 400 mg for patients receiving,CVVH,400 mg(CVVHD and CVVHDF)or to 200 mg(CVVH)if the species is not,Candida krusei,or,Candida glabrata,and the fluconazole MIC is _8 mg/L.,Itraconazole and voriconazole,The parenteral formulations are solubilized in a cyclodextrin diluent,which is eliminated by the kidneys and will accumulate in patients with renal insufficiency,Use of intravenous itraconazole and voriconazole is not recommended for patients with creatinine clearance rates of 30 and 50 mL/min,Although oral formulations are not contraindicated（禁忌）,there are few data about triazole dosing for patients receiving CRRT,On the basis of pharmacokinetics data,no dose reduction is recommended for patients receiving CRRT.,Amphotericin B.,dose adjustments for CRRT are not recommended.,Data Sources:,MEDLINE search from February 1986 to 2008.,Pharmacokinetic Factors Influencing Initial Doses of Antibacterials,Volume of distribution,Although both critical illness and acute renal failure may affect volume of distribution,CRRT itself generally has no effect.,Although antibacterial volume of distribution would be expected to increase in the critically il and those with acute renal failure,this is only the case for certain agents.,Pharmacokinetic Factors Influencing Maintenance Doses,Maintenance doses,are determined by antibacterial clearance.,Total clearance=,non,-,CRRT,clearance,(renal clearance due to,residual renal function,plus,nonrenal clearance,)and,CRRT clearance,Nonrenal clearance,may be affected by critical illness,for example,because of hepatic dysfunction.,It may also be increased in the presence of acute renal failure,CRRT clearance,is affected by,PB,adsorption,and Gibbs-Donnan effect,PB影响因素,Disease states,such as uremia,cirrhosis,nephrotic syndrome,epilepsy,hepatitis,pregnancy,and severe burns,systemic pH,heparin,free fatty acids,and drugs such as salicylate and sulfonamide,Optimal dosing,of antibacterials is dependent on achieving pharmacokinetic targets associated with maximal killing of bacteria and improved outcomes.,The initial dose,is dependent on the volume of distribution.,Maintenance doses,are dependent on clearance.,Both should be adjusted according to the pharmacokinetic target associated with optimal bacterial killing,when known.,The volume of distribution,of some antibacterials is altered by critical illness or acute renal failure or both.,Clearance,by CRRT is dependent on the dose and mode of CRRT and the sieving or saturation coefficient of the drug.,Both,sieving,and,saturation coefficient,are related to the plasma protein binding and thus may be altered in renal failure.,Conclusions:,Appropriate dose calculation requires knowledge of the,pharmacokinetic target,and the usual,minimum inhibitory concentration,of the suspected organism in the,patients,l,ocality,(or if unavailable,the break point for the organism),published pharmacokinetic data(volume of distribution,non-CRRT clearance)on critically ill patients receiving CRRT(which may differ substantially from noncritically ill patients or tho