1、CRRT抗生素剂量调整1context 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 p
2、atients 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.2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）34567剂量调整难度大 危重患者/ARF：Vd、PB CRRT:肾脏排
3、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 Data Sources 19952004 Data Sources: MEDLINE search from February 1986 to 2008.9 Data Sources 1995200410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几点说明 1.In most cases,the recommended “target” drug concentration corresponds to the upper limit o
4、f 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 toxicit
5、y due to unnecessarily high concentrations.121314ANTIBIOTICS FOR DRUG-RESISTANT GRAM-POSITIVE BACTERIA VancomycinThe 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
6、 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 a
7、chieve 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 uncomplicated bacteremia.However, higher troughs (1015 mg/L) are indicated for infections in which penetration is depend
8、ent 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 tissue15
9、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
10、 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 rang
11、e 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,
12、the reader is cautioned to pay attention to hematopoietic and neuropathic adverse effects when administering linezolid for extended periods to patients receiving CRRT16b-LACTAMSCarbapenems.Imipenem and cilastatin have similar pharmacokinetic properties in patients with normal renal function; both dr
13、ugs 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
14、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 effe
15、cts of cilastatin accumulation.17The 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 patient
16、s 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 su
17、sceptible to meropenem, a lower dosage (500 mg q12h) may be appropriate.18b-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, piperac
18、illin 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
19、 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 concentrationsof these agents in excess of the MIC for most drugsusceptible bacteria during the majority of the dosing interval.For patien
20、ts 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 aeruginosafor patients with no residual renal functionwho are undergoing CVVH and receiving prolonged therapywith piperac
21、illin-tazobactam, it is not known whether tazobactamaccumulates.Moreover, the toxicities of tazobactam arenot known, and it has been recommended that alternating dosesof piperacillin alone in these patients may avoid the potentialtoxicity associated with tazobactam accumulation19Although few data ex
22、ist 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.
23、 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 affect
24、ed; 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 s
25、uch as ticarcillin, the dosing interval with these CRRTmodalities should not exceed 6 h for ticarcillin-clavulanate.20 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 di
26、rectly 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 mainta
27、in therapeutic concentrations greater than the MIC for an optimal proportion of the dosing interval. 21 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
28、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。22 The other cephalosporins and aztreonam are cleared at a rate equivalent to a
29、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, anormal, unadjusted dose may be required. This is the case with cefepime
30、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 CVVHDF23Cefepime and ceftazidime pharmacokinetics are almost identical, and similar
31、doses are advocated.Older recommendations for CVVH dosing (12 g q2448 h) are based on CAVH dataIt 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 bacter
32、ia 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 appr
33、opriate.Dosing recommendations for these b-lactams are listed in table 2.24FLUOROQUINOLONES 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 wi
34、ll 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 a
35、chieve 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.25 Levofloxacin is excreted largely unchanged in the urine, and significant dosage adjustments are necessary for patients with renal failure. Intermittent
36、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
37、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 CVVHDF26 The pharmacokinetics of moxifloxacin have been recently studied in critically ill patients receiving CVVHDF 50. Th
38、ese data, as well as known pharmacokinetics data, indicate no need to adjust the moxifloxacin dosage for patients receiving CRRT 27AMINOGLYCOSIDES Todays filters are capable of removing aminoglycosides at a rate equivalent to a creatinine clearance rate of 1040 mL/min This equates to an aminoglycosi
39、de 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.2829ANTIFUNGALS 80% of the fluconazole dose is eliminated
40、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 spe
41、cies is not Candida krusei or Candida glabrata and the fluconazole MIC is _8 mg/L.30 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 itr
42、aconazole 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 reco
43、mmended for patients receiving CRRT. 31 Amphotericin B. dose adjustments for CRRT are not recommended.32 Data Sources: MEDLINE search from February 1986 to 2008.33Pharmacokinetic Factors Influencing Initial Doses of Antibacterials Volume of distribution Although both critical illness and acute renal
44、 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.34Pharmacokinetic Factors Influencing Mainten
45、ance 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 clearance35 Nonrenal clearance may be affected by critical illness, for example, because of hepatic dysfunction.
46、 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 dr
47、ugs such as salicylate and sulfonamide36Optimal 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. Bot
48、h 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 sie
49、ving 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.37Conclusions:Appropriate dose calculation requires knowledge of the pharmacokinetic target and the usual minimum inhibitory concentr
50、ation 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 those
