CRRT抗生素剂量调整最终版ppt课件(PPT 50页)

1、CRRT抗生素剂量调整1第1页，共50页。contextContinuous 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

2、adult patients receiving CRRT. Doses used in intermittent hemodialysis cannot be directly applied to these patientsantibiotic pharmacokinetics are different than those in patients with normal renal function.2第2页，共50页。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）3第3页，共50页。4第4页，共50页。5第5

3、页，共50页。6第6页，共50页。7第7页，共50页。剂量调整难度大危重患者/ARF：Vd、PBCRRT: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8第8页，共50页。Data Sources 19952004 Data Sources: MEDLINE search from February 1986 to 2008.9第9页，共50页。Data Sources 1995200410第10页，共50页。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）11第11页，共50页。几点说明1.In

4、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 pro

5、perties (timedependent vs. concentration-dependent killing), 3.while minimizing toxicity due to unnecessarily high concentrations.12第12页，共50页。13第13页，共50页。14第14页，共50页。ANTIBIOTICS FOR DRUG-RESISTANT GRAM-POSITIVE BACTERIA VancomycinThe half-life of vancomycin increases significantly in patients with r

6、enal 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 dosag

7、e 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, suchas skin and soft-tissue infections or unc

8、omplicated 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

9、 the treatment of health careassociated pneumonia, because of suboptimal penetration of vancomycin into lung tissue15第15页，共50页。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

10、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

11、 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

12、, 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 CRRT16第16页，

13、共50页。b-LACTAMSCarbapenems.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 p

14、ercentage 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 a

15、ccumulates in patients with hepatic dysfunction, and increasing the dosing interval may be needed to avoid potential unknown adverse effects of cilastatin accumulation.17第17页，共50页。The meropenem MIC for most susceptible bacteria is 4 mg/L. This represents an appropriate trough concentration for criti

16、cally 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 dosag

17、e 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.18第18页，共50页。b-Lactamaseinhibitor combinations.Of the 3 b-lactamaseinhibitor combi

18、nations 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

19、 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

20、 to produce trough concentrationsof 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-resi

21、stant pathogen, such as Pseudomonas aeruginosafor patients with no residual renal functionwho are undergoing CVVH and receiving prolonged therapywith piperacillin-tazobactam, it is not known whether tazobactamaccumulates.Moreover, the toxicities of tazobactam arenot known, and it has been recommende

22、d that alternating dosesof piperacillin alone in these patients may avoid the potentialtoxicity associated with tazobactam accumulation19第19页，共50页。Although few data exist with ampicillin-sulbactam and ticarcillin-clavulanate 35, extrapolations are possible between piperacillin-tazobactam and ampicil

23、lin-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 pai

24、r 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 inte

25、rval 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.20第20页，共50页。Cepha

26、losporins 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

27、 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. 21第21页，共50页。Ceftriaxone is

28、 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 wi

29、th normal renal function, and therefore, no dose adjustment is necessary for patients receiving CRRT。22第22页，共50页。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

30、.If the goal in critically ill patients is to maintain a therapeutic concentration for the entire dosing interval, anormal, unadjusted dose may be required. This is the case with cefepimeOn the basis of 2 well-done studies involving critically ill patients, a cefepime dosage of 1 g q12h is appropria

31、te for most patients receiving CVVH, and up to 2 g q12h is appropriate for patients receiving CVVHD or CVVHDF23第23页，共50页。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 dataIt is no

32、t 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 CV

33、VH.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 2.24第24页，共50页。FLUOROQUINOLONESFe

34、w antibiotic classes have more data supporting the influence of pharmacodynamics on clinical outcomes than fluoroquinolones.AUC/MICevidence exists that manufacturer-recommended dosing for ciprofloxacin will not always achieve a target AUC/MIC ratio in critically ill patientsA ciprofloxacin dosage of

35、 400 mg q.d. is recommended by the manufacturer for patients with a creatinine clearance rate of_30 mL/min In critically ill patientsreceiving 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

36、doses are lesslikely to achieve a target ratio.25第25页，共50页。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 a

37、re not required after hemodialysisLevofloxacin is eliminated by CVVH and CVVHDFA 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

38、, after a 500mg loading dose, are appropriate for patients receiving CVVH,CVVHD, or CVVHDF26第26页，共50页。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 mox

39、ifloxacin dosage for patients receiving CRRT 27第27页，共50页。AMINOGLYCOSIDES Todays filters are capable of removing aminoglycosides at a rate equivalent to a creatinine clearance rate of 1040 mL/minThis equates to an aminoglycoside half-life of 620 h.The typical dosing interval with aminoglycosides will

40、 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.28第28页，共50页。29第29页，共50页。ANTIFUNGALS 80% of the fluconazole dose is eliminated unchanged via the kidneys.azole-resistant Candida a daily

41、dose of 800 mg for critically ill patients receiving CVVHD or CVVHDF with a combined ultrafiltration and dialysate flow rate of 2 L/ha daily dose of 400 mg for patients receiving CVVH400 mg (CVVHD and CVVHDF) or to 200 mg (CVVH) if the species is not Candida krusei or Candida glabrata and the flucon

42、azole MIC is _8 mg/L.30第30页，共50页。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 insufficiencyUse of intravenous itraconazole and voriconazole is not recommended for pat

43、ients with creatinine clearance rates of 30 and 50 mL/minAlthough oral formulations are not contraindicated（禁忌）, there are few data about triazole dosing for patients receiving CRRTOn the basis of pharmacokinetics data, no dose reduction is recommended for patients receiving CRRT. 31第31页，共50页。Amphot

44、ericin B.dose adjustments for CRRT are not recommended.32第32页，共50页。Data Sources: MEDLINE search from February 1986 to 2008.33第33页，共50页。Pharmacokinetic Factors Influencing Initial Doses of AntibacterialsVolume of distributionAlthough both critical illness and acute renal failure may affect volume of

45、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.34第34页，共50页。Pharmacokinetic Factors Influencing Maintenance DosesMaintenance

46、doses are determined by antibacterial clearance.Total clearance=non-CRRT clearance (renal clearance due to residual renal function plus nonrenal clearance) and CRRT clearance35第35页，共50页。Nonrenal clearance may be affected by critical illness, for example, because of hepatic dysfunction.It may also be

47、 increased in the presence of acute renal failureCRRT clearance is affected by PB, adsorption, and Gibbs-Donnan effectPB影响因素Disease states, such as uremia, cirrhosis, nephrotic syndrome, epilepsy, hepatitis, pregnancy, and severe burnssystemic pH, heparin, free fatty acids, and drugs such as salicyl

48、ate and sulfonamide36第36页，共50页。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

49、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 s

50、aturation coefficient of the drug. Both sieving and saturation coefficient are related to the plasma protein binding and thus may be altered in renal failure.37第37页，共50页。Conclusions:Appropriate dose calculation requires knowledge of the pharmacokinetic target and the usual minimum inhibitory concent

51、ration of the suspected organism in the patients locality(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 thos

52、e without renal failure), the sieving or saturation coefficient of the relevant drug in critically ill patients, the dose and mode of CRRT being used, and the actual dose of CRRT that is delivered. This large number of variables results in considerable inter- and intrapatient heterogeneity in dose r

53、equirements. 38第38页，共50页。The ability of a drug to pass through the membrane is expressed as the sieving coefficient (Sc):the ratio of drug concentration in the ultrafiltrate to plasma.Sc=1-PBPB in the critically ill is variable and for some drugs (e.g., levofloxacin) Sc varies widely 39第39页，共50页。CIC

54、VVH(pre)= Qf Sc CF,where CF =Qb/(Qb +Qrep)40第40页，共50页。In postdilution modeCICVVH(post) = Qf Sc41第41页，共50页。Several aspects of this recommendation require elaboration.需要说明的几个问题：1. First, for the sake of simplicity, the formula recommended for calculation of half-life is based on a single compartment a

55、nd is therefore not strictly accurate.2. intravenous infusion of antibacterials with time-dependent killing characteristics is recommended because dose estimation is much simpler42第42页，共50页。2.intermittent bolus doseswhere k =CL/Vd T =dosing interval(mins) and Cth_ target threshold concentration.43第43页，共50页。3. for patients with residual renal function, total clearance needs to be adjusted for renal clearance.In this context, it is important to understand that adju