Atb en dialisis[1]

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Atb en dialisis[1]

  1. 1. Clin Pharmacokinet 2007; 46 (12): 997-1038 REVIEW ARTICLE 0312-5963/07/0012-0997/$44.95/0 © 2007 Adis Data Information BV. All rights reserved. Pharmacokinetic Considerations for Antimicrobial Therapy in Patients Receiving Renal Replacement Therapy Federico Pea,1 Pierluigi Viale,2 Federica Pavan1 and Mario Furlanut1 1 Institute of Clinical Pharmacology and Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Udine, Italy 2 Clinic of Infectious Diseases, Department of Medical and Morphological Research, Medical School, University of Udine, Udine, Italy Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997 1. Principles of Drug Removal during Renal Replacement Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999 1.1 Working Differences between Haemodialysis and Haemofiltration . . . . . . . . . . . . . . . . . . . . . . . 999 1.2 Characteristics of Drugs and Continuous Renal Replacement Therapy (CRRT) Devices Affecting Extracorporeal Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001 2. Rationales for Appropriate Dosage Adjustment of Antimicrobials during CRRT: the Importance of Pharmacokinetic-Pharmacodynamic Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004 3. Pharmacokinetics of Antimicrobials during CRRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005 3.1 Hydrophilic Antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005 3.1.1 Carbapenems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005 3.1.2 Penicillins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018 3.1.3 Cephalosporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1020 3.1.4 Aminoglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1025 3.1.5 Glycopeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026 3.2 Lipophilic Antibacterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1028 3.2.1 Fluoroquinolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1028 3.2.2 Oxazolidinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031 3.2.3 Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032 3.3 Antifungal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032 3.3.1 Polyenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032 3.3.2 Triazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1034 Abstract Continuous renal replacement therapy (CRRT), particularly continuous venovenous haemofiltration (CVVH) and continuous venovenous haemodiafiltra- tion (CVVHDF), are gaining increasing relevance in routine clinical management of intensive care unit patients. The application of CRRT, by leading to extracorporeal clearance (CLCRRT), may significantly alter the pharmacokinetic behaviour of some drugs. This may be of particular interest in critically ill patients presenting with life-threatening infections, since the risk of underdosing with antimicrobial agents during this procedure may lead to both therapeutic failure and the spread of breakthrough resistance. The intent of this review is to discuss the pharmacokinetic principles of CLCRRT of antimicrobial agents during the application of CVVH and CVVHDF and to summarise the most recent findings on
  2. 2. 998 Pea et al. this topic (from 1996 to December 2006) in order to understand the basis for optimal dosage adjustments of different antimicrobial agents. Removal of solutes from the blood through semi-permeable membranes during RRT may occur by means of two different physicochemical processes, namely, diffusion or convection. Whereas intermittent haemodialysis (IHD) is essentially a diffusive technique and CVVH is a convective technique, CVVHDF is a combination of both. As a general rule, the efficiency of drug removal by the different techniques is expected to be CVVHDF > CVVH > IHD, but indeed CLCRRT may vary greatly depending mainly on the peculiar physicochemical properties of each single compound and the CRRT device’s characteristics and operating conditions. Considering that RRT substitutes for renal function in clearing plasma, CLCRRT is expected to be clinically relevant for drugs with dominant renal clearance, especially when presenting a limited volume of distri- bution and poor plasma protein binding. Consistently, CLCRRT should be clinical- ly relevant particularly for most hydrophilic antimicrobial agents (e.g. β-lactams, aminoglycosides, glycopeptides), whereas it should assume much lower relevance for lipophilic compounds (e.g. fluoroquinolones, oxazolidinones), which general- ly are nonrenally cleared. However, there are some notable exceptions: ceftriax- one and oxacillin, although hydrophilics, are characterised by primary biliary elimination; levofloxacin and ciprofloxacin, although lipophilics, are renally cleared. As far as CRRT characteristics are concerned, the extent of drug removal is expected to be directly proportional to the device’s surface area and to be dependent on the mode of replacement fluid administration (predilution or postdilution) and on the ultrafiltration and/or dialysate flow rates applied. Conversely, drug removal by means of CVVH or CVVHDF is unaffect- ed by the drug size, considering that almost all antimicrobial agents have molecu- lar weights significantly lower (<2000Da) than the haemofilter cut-off (30 000–50 000Da). Drugs that normally have high renal clearance and that exhibit high CLCRRT during CVVH or CVVHDF may need a significant dosage increase in comparison with renal failure or even IHD. Conversely, drugs that are normally nonrenally cleared and that exhibit very low CLCRRT during CVVH or CVVHDF may need no dosage modification in comparison with normal renal function. Bearing these principles in mind will almost certainly aid the manage- ment of antimicrobial therapy in critically ill patients undergoing CRRT, thus containing the risk of inappropriate exposure. However, some peculiar pathophys- iological conditions occurring in critical illness may significantly contribute to further alteration of the pharmacokinetics of antimicrobial agents during CRRT (i.e. hypoalbuminaemia, expansion of extracellular fluids or presence of residual renal function). Accordingly, therapeutic drug monitoring should be considered a very helpful tool for optimising drug exposure during CRRT. Renal replacement therapy (RRT) is an approach and so some of these techniques, particularly contin- originally employed mainly for blood purification in uous venovenous haemofiltration (CVVH) and con- the presence of chronic renal impairment, as in the tinuous venovenous haemodiafiltration (CVVHDF), case of intermittent haemodialysis (IHD). More re- are gaining increasing relevance in routine clini- cently, continuous RRT (CRRT) has been intro- cal management of intensive care unit (ICU) pa- duced as adjunctive therapy to treat critically ill tients.[1,2] Additionally, some researchers have be- patients in the presence of multiple organ failure, lieved that the excessive production of pro-inflam- © 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
  3. 3. Disposition of Antimicrobials during CRRT 999 matory cytokines as a host response to infection 1. Principles of Drug Removal during during sepsis may be responsible for the cascade of Renal Replacement Therapies events leading to multiple organ failure.[3] Consist- ently, removal of such cytokines by means of CRRT 1.1 Working Differences between has been proposed as powerfully effective pathoge- Haemodialysis and Haemofiltration netic treatment of sepsis to protect patients from unfavourable outcomes.[4] Removal of solutes from blood through semi- Regardless of opinion on the role of CRRT, it permeable membranes during RRT may occur by has been proven that the growing confidence in means of two different physicochemical processes: namely, diffusion or convection (table I). CRRTs has resulted in improved survival of critical- Diffusion, which represents the typical working ly ill patients with acute renal failure.[5] However, principle of haemodialysis (figure 1), occurs pas- it should not be overlooked that the application sively in counter-current with respect to blood flow of CRRT, by leading to extracorporeal clearance and is driven by the gradient of concentration. Addi- (CLCRRT), may significantly alter the pharmacokin- tionally, the clearance efficiency during IHD is etic behaviour of some drugs. greater for small drugs (figure 2). However, the cut- Of note, the extent of CLCRRT may be of particu- off of modern synthetic dialyser membranes (the so- lar interest in critically ill patients presenting with called high-flux membranes) is significantly larger than that of the old cuprophane dialyser membranes life-threatening infections, since the risk of un- (<1000Da). This means that although high molecu- derdosing with antimicrobial agents during this pro- lar weight may protect some large molecules (name- cedure may lead to both therapeutic failure and the ly, the glycopeptides vancomycin and teicoplanin, spread of resistance. the streptogramin combination of quinupristin/dal- It is now widely accepted that the definition of fopristin, and the polimixin colistin) from removal ‘inappropriate antimicrobial therapy’ in the treat- when using old cuprophane membranes, this no ment of critically ill patients refers not only to an longer occurs when using modern high-flux mem- unsuitable drug choice in terms of the spectrum of branes. Conversely, convection, which represents the activity, but also to potential underexposure at the typical working process of haemofiltration (figure infection site as a consequence of an inadequate 3), occurs actively and more rapidly thanks to a dosing regimen due to the patient’s particular patho- pump-driven pressure gradient. Interestingly, drug physiological status and/or iatrogenic conditions.[6,7] removal by means of haemofiltration is independent The aim of this review is to discuss the pharma- from drug molecule size, considering that almost cokinetic principles of CLCRRT of antimicrobial Table I. Comparison of characteristics of drug removal during agents during the application of CVVH and CV- haemodialysis vs haemofiltration VHDF and to summarise the most recent findings Characteristic Haemodialysis Haemofiltration on this topic in order to understand the basis for Drug removal By diffusion across By convection across a semi-permeable a semi-permeable optimal dosage adjustments of different antimicro- membrane membrane bial agents. The literature search was done through Process Passive Active MEDLINE and refers to articles published from Principle Counter current flow Pump-driven pressure gradient 1996 to December 2006. Conditioning Conditioned by drug Unconditioned by drug In order to better understand the rationales for molecular weight molecular weight dosage adjustments of antimicrobials during RRT, it Equilibrium Long Rapid time may be useful to describe the working principles of Replacement Not needed Needed to reconstitute the most frequently applied techniques and to define fluid blood volume (pre- or postdilution mode) which factors may affect drug removal. © 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
  4. 4. 1000 Pea et al. Dialysate On the basis of the type of body access and the relative role of diffusion and/or convection, RRTs may be classified into several different types (table BFR BFR II). The most frequently applied techniques are sure- ly represented by IHD on the one hand and CVVH Dialysate or CVVHDF on the other hand. Whereas IHD is Dialysis fluid in Dialysate out essentially a diffusive technique, CVVH is a con- Fig. 1. Schematic representation of intermittent haemodialysis. vective technique and CVVHDF is a combination of BFR = blood flow rate. both. Interestingly, CVVHDF is sometimes applied in very critically ill patients presenting with sepsis all antimicrobial agents have molecular weights sig- and acute renal failure, with the intent of enabling nificantly lower than the haemofilter cut-off sufficient removal of metabolites through perfusion (30 000–50 000Da), whose high value has the intent of the haemofilter with the dialysate.[2] Indeed, al- of enabling removal of inflammatory cytokines. Ad- though this approach is currently still a very ques- ditionally, since (similarly to the glomerular filtra- tionable issue, what should be mentioned is the fact tion in the kidney) the haemofiltration process pro- that in these circumstances, very high flow rates of duces an ultrafiltrate, refilling with a substitution up to 6 L/h may be applied. fluid is required in order to preserve an adequate As a general rule, the efficiency of drug re- circulatory volume. Of note, replacement may be moval by the different techniques is expected to be applied before or after blood filtration, that is in CVVHDF > CVVH > IHD, but indeed CLCRRT may predilution or in postdilution mode, and this may vary greatly, mainly depending on the peculiar obviously affect the entity of drug clearance to a physicochemical properties and pharmacokinetic different extent. behaviour of each single compound. Teicoplanin Q/D Vancomycin Colistin Rifampicin Ceftriaxone Ceftazidime Piperacillin Cefpirome Cefepime Cefotaxime Moxifloxacin Meropenem Aztreonam Clindamycin Gatifloxacin Levofloxacin Amoxicillin Ampicillin Linezolid Ciprofloxacin Imipenem Metronidazole 0 500 1000 1500 2000 Molecular weight (Da) Fig. 2. Molecular weight of some antimicrobial agents. Q/D = quinupristin/dalfopristin. © 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
  5. 5. Disposition of Antimicrobials during CRRT 1001 Replacement fluid Post-dilution Pre-dilution BFR BFR UF Fig. 3. Schematic representation of continuous venovenous haemofiltration. BFR = blood flow rate; UF = ultrafiltrate. 1.2 Characteristics of Drugs and Continuous According to this distinction, it seems clear Renal Replacement Therapy (CRRT) Devices that CLCRRT should be clinically relevant for Affecting Extracorporeal Clearance most hydrophilic agents, whereas it should assume much lower relevance for the lipophilic compounds Considering that RRT substitutes for renal func- which, in general, are nonrenally cleared. Obvi- tion in clearing plasma, CLCRRT is expected to be ously, some notably exceptions to this general rule clinically relevant for drugs with dominant renal may exist. Ceftriaxone and oxacillin, although hy- clearance (CLR), especially when presenting a limit- drophilics, are characterised by primary biliary ed volume of distribution (Vd) and poor plasma elimination, and so they are not expected to be protein binding. significantly removed by CRRT; on the other hand, The pharmacokinetic parameters of the most rel- levofloxacin and ciprofloxacin, although lipophilics, evant antimicrobial agents assessed in healthy vol- are renally cleared, and so they might be removed by unteers are shown in table III. Comparison of these data with those observed during the application of CRRT. CRRT enhances understanding of the relevance that Table II. Characteristics of some renal replacement therapies CRRT may have for extracorporeal removal of each (adapted from Joy et al.,[8] with permission) single drug. Procedure Removal by Removal by Vascular In this respect, it may be useful to split an- diffusion convection access timicrobials, according to their solubility, into hy- IHD ++++ + Fistula or VV drophilic or lipophilic compounds (figure 4).[6,7] Hy- IHDF ++++ ++ Fistula or VV drophilic compounds, which include β-lactams, gly- CAPD ++++ + None CAVH – ++++ AV copeptides and aminoglycosides, are unable to – CVVH ++++ VV passively cross the plasmatic membrane of the CAVHD ++++ + AV eukaryotic cell, and so their distribution is limited CVVHD ++++ + VV only to the plasma and to the extracellular space, and CAVHDF +++ +++ AV they are usually excreted via the renal route as CVVHDF +++ +++ VV unchanged drug. On the contrary, lipophilic agents, AV = artery and vein; CAPD = continuous ambulatory peritoneal which include macrolides, fluoroquinolones, tetra- dialysis; CAVH = continuous arteriovenous haemofiltration; CAVHD = continuous arteriovenous haemodialysis; CAVHDF = cyclines, chloramphenicol, rifampicin (rifampin) continuous arteriovenous haemodiafiltration; CVVH = continuous and linezolid, may freely cross the plasmatic mem- venovenous haemofiltration; CVVHD = continuous venovenous haemodialysis; CVVHDF = continuous venovenous brane of the eukaryotic cells, and so they are widely haemodiafiltration; IHD = intermittent haemodialysis; IHDF = distributed into the intracellular compartment and intermittent haemodiafiltration; VV = vein and vein; – indicates not must often be metabolised through different path- occurring; + indicates mild; + + indicates moderate; + + + indicates marked; + + + + indicates intense. ways before elimination. © 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
  6. 6. Table III. Overview of the pharmacokinetic (PK) parameters of some antimicrobial agents in healthy volunteersa 1002 Drug MW (Da) t1/2 (h) Vss (L) CL (mL/min) CLR (mL/min) CLR : CL ratio PB (%) Antibacterials Carbapenems meropenem[9] 383.47 1.0 14–21b 186.67 140 0.75 9 imipenem[9] 317.37 0.9–1.11b 14–21b 250.0 112.5–125.0b 0.45–0.50b 9 Penicillins flucloxacillin[10] 453.88 2.1 20.6 122.5 88 0.72 96 piperacillin[11] 517.56 0.75 10.64 181.72 102.58 0.56 30 tazobactam[11] 300.29 0.89 11.9 184.87 125.44 0.68 30 Cephalosporins cefepime[12] 480.57 2.32 18.4 143 132 0.92 16–19b cefpirome[13] 514.59 1.76 18.1 142 113.6 0.80 10 © 2007 Adis Data Information BV. All rights reserved. ceftazidime[14] 546.58 1.58 12.46 131.83 122.5 0.93 18.7 ceftriaxone[15,16] 554.59 8.8 10.7 14.2 8.6 0.61 90 Aminoglycosides netilmicin[17,18] 475.58 2 47.6 91 67 0.74 0 Glycopeptides vancomycin[19,20] 1449.27 8.1 41.16 84.8 0.70 37 teicoplanin[21,22] 1877.66 92.3 47.6 14.70 14 0.95 96 Fluoroquinolones ciprofloxacin[23] 331.34 4 137.9 448.33 318.33 0.71 20–40b levofloxacin[24,25] 370.38 6–8b 77 133 106.4 0.80 24–38b moxifloxacin[26,27] 401.43 13 222 248.33 50.5 0.20 30–50b ofloxacin[28,29] 361.37 6.67 134.4 227.5 190 0.74 15 Oxazolidinones linezolid[30,31] 337.35 4.8 30–50b 97.3 25.9 0.27 31 Antifungals Polyenes amphotericin B[32,33] 924.08 357 15.3 4.78 0.32 90–95b amphotericin B lipid complex[33] 924.08 9170 436 liposomal amphotericin B[32,33] 924.08 7.7 11.3 0.58 0.05 Azoles fluconazole[34] 306.27 29.7 52 21.03 12.91 0.61 11–12b a The values are expressed as means unless specified otherwise. b Range. CLR = renal clearance; CL = total body clearance; MW = molecular weight; PB = plasma protein binding; t1/2 = elimination half-life; Vss = volume of distribution at steady state. Clin Pharmacokinet 2007; 46 (12) Pea et al.
  7. 7. Disposition of Antimicrobials during CRRT 1003 Hydrophilic Lipophilic As far as the Vd is concerned, the larger it is, the less likely it is that the drug will be removed by • β-lactams • Macrolides • penicillins • Fluoroquinolones RRT, considering that the Vd reflects where a given • cephalosporins • Tetracyclines drug is compartmentalised in the body. According- • carbapenems • Chloramphenicol • monobactams • Rifampicin ly, during RRT, extracellularly located hydrophilic • Glycopeptides • Linezolid agents will be much more promptly removable from • Aminoglycosides the body than intracellularly accumulated lipophilic ones. This means that although for most hydrophilic • Limited volume of distribution • Large volume of distribution compounds, supplemental dosing may often be ne- • Inability to passively diffuse • Freely diffuse through through plasmatic membrane plasmatic membrane of cessary during CRRT in comparison with anephric of eukariotic cells eukariotic cells patients, for most lipophilic drugs with a wide Vd, • Inactive against intracellular • Active against intracellular even if the extraction across the RRT filter is 100%, pathogens pathogens • Eliminated renally as the • Eliminated often after hepatic only a small fraction of the drug present in the body unchanged drug metabolism will be removed, thus rendering supplemental dos- Fig. 4. Classification of antimicrobials according to their physico- ing unnecessary. chemical properties. Finally, considering that because of the haemofil- ter’s cut-off, only the unbound moiety of a given membrane, a process whose extent is expected to be drug is available for extracorporeal elimination, the maximal immediately after starting RRT and then to higher the plasma protein binding is (figure 5), the progressively decrease over time until filter exhaus- lower the drug clearance will be. This concept is tion. exemplified by the sieving coefficient (Sc), which is Accordingly, caution was expressed regarding the ratio between the drug concentrations in the calculation of the supplemental dose of a given drug ultrafiltrate and in plasma, and may be defined by during haemofiltration only on the basis of the theo- equation 1: retical unbound fraction instead of the Sc.[39] CUF Sc = As far as the CRRT device characteristics are CP concerned, the extent of drug removal is expected to (Eq. 1) be directly proportional to the device’s surface area where CUF is the drug concentration in the ultrafil- and to be dependent on the mode of replacement trate and Cp is the drug concentration in the plasma. fluid administration and on the ultrafiltration and/or The Sc values of some antimicrobials are shown in dialysate rates applied. figure 6. When the replacement fluid to reconstitute blood Interestingly, whereas in most cases the Sc during volume is added in the postdilution mode, name- CVVH in humans should equate to the unbound ly after haemofiltration, drug clearance during moiety of the drug[35] (as documented, for example, haemofiltration (CLHF) will equate to the ultrafiltra- for 66 different compounds by Golper)[36] it may, tion rate (QUF) [equation 2]: however, sometimes be significantly different. CLHF(postdilution) = QUF × Sc Indeed, some factors might explain this finding. First, in critically ill patients presenting with hy- (Eq. 2) poalbuminaemia, the unbound fraction of normally Conversely, in the predilution mode, considering moderately to highly bound drugs may vary, and that plasma has been diluted by the substitution fluid so drug clearance may be increased in these circum- before entering the haemofilter, drug clearance will stances.[36,37] Interestingly, it has recently been be lower due to a dilution factor (DF; equation 3): shown that this may be clinically relevant especial- QBF ly for the glycopeptides teicoplanin[38] and van- DF = QBF + QRF comycin.[35] Additionally, drug extraction may be further increased by adsorption to the haemofilter (Eq. 3) © 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
  8. 8. 1004 Pea et al. where QBF is the blood flow rate and QRF is the ing which concentrations are maintained above the replacement flow rate. Therefore, drug clearance minimum inhibitory concentration of the aetiologi- will be (equation 4): cal agent (T>MIC) is considered the most rele- QUF × Sc × QBF vant pharmacodynamic parameter. In this regard, CLHF(predilution) = QBF + QRF exposure may be optimised by maintaining the mini- (Eq. 4) mum plasma concentration above the MIC (Cmin>MIC),[7] maximal efficacy being ensured in 2. Rationales for Appropriate Dosage the presence of a Cmin four to five times the MIC. Adjustment of Antimicrobials Accordingly, for these agents, the most suitable during CRRT: the Importance of approach to preserve efficacy during CRRT is to Pharmacokinetic-Pharmacodynamic maintain the frequency of drug administration while Relationships modifying the amount of each single dose. Drugs that are significantly cleared during CV- Conversely, for concentration-dependent antimi- VH or CVVHDF may need significant dosage in- crobials, namely aminoglycosides and fluoroquino- creases in comparison with renal failure or even lones, the most important pharmacodynamic para- IHD. This may be performed by increasing the meters are represented by the ratios between the amount of each single dose, or conversely by short- peak plasma concentration (Cmax) and the MIC, ening the dosing interval. The approach taken will with optimal exposure in the presence of a Cmax/ differ according to the type of antimicrobial activi- MIC ratio of >8–10, and between the area under the ty, which may be time dependent or concentra- plasma concentration-time curve (AUC) and the tion dependent. For time-dependent antimicrobials, MIC, with optimal exposure in the presence of an namely β-lactams, macrolides, glycopeptides, ox- AUC/MIC ratio of >100. Accordingly, to optimise azolidinones and azole antifungals, the time dur- efficacy with these agents during CRRT, it may be Clindamycin Teicoplanin Ceftriaxone Aztreonam Vancomycin Moxifloxacin Cefotaxime Linezolid Levofloxacin Ciprofloxacin Piperacillin Ampicillin Gatifloxacin Imipenem Amoxicillin Cefepime Ceftazidime Metronidazole Meropenem 0 20 40 60 80 100 Plasma protein binding (%) Fig. 5. Plasma protein binding of some antimicrobial agents. © 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
  9. 9. Disposition of Antimicrobials during CRRT 1005 Cefotaxime Amikacin Netilmicin Tobramycin Imipenem Ceftazidime Metronidazole Piperacillin Gentamicin Vancomycin Ampicillin Penicillin Ciprofloxacin Clindamycin Ceftriaxone Teicoplanin Oxacillin 0.0 0.2 0.4 0.6 0.8 1.0 1.2 Sieving coefficient Fig. 6. Sieving coefficients of some antimicrobial agents. more useful to extend the dosing interval while sible in the presence of multiple references, some maintaining a fixed dosage. suggestions on how to interpret the data and how to Bearing these principles in mind will almost cer- proceed with dosage adjustments are provided. For tainly aid the management of antimicrobial therapy clarity, it should be considered that in the descrip- in critically ill patients undergoing CRRT, thus con- tion of the different studies, the various flow rates taining the risk of inappropriate exposure. (QUF and/or the dialysate flow rate [QD]) in condi- Finally, it is worth noting that in critically ill tioning CLCRRT have been qualitatively defined as patients, it is mandatory to consider the severity of follows: low when <0.5 L/h, moderate when approx- the infection and the susceptibility pattern of patho- imately 1.0 L/h, high when approximately 1.5–2 L/h gens involved in the infections in order to contain and very high when >2.5–3.0 L/h. the mortality risk of infection. Accordingly, in the presence of a severe life-threatening infection po- 3.1 Hydrophilic Antimicrobials tentially caused by less susceptible pathogens with Generally speaking, most hydrophilic antimicro- higher MICs (e.g. Pseudomonas aeruginosa), a bials exhibit a low Vd and high CLR in healthy higher starting dose would probably be prudent. volunteers, and so they are expected to be highly CRRT removable. Interestingly, given their low Vd, 3. Pharmacokinetics of Antimicrobials the application of high CRRT flow rates may mark- during CRRT edly increase the extent of elimination since the drug is essentially confined in the plasma and in the tissue The most recent and relevant studies on the interstitium. pharmacokinetics of antimicrobials during the appli- cation of CVVH or CVVHDF since 1996 are listed 3.1.1 Carbapenems in table IV. In this review, the studies have been The carbapenems imipenem/cilastatin and mer- summarised for each compound and, whenever fea- openem exhibit low Vd, low plasma protein binding © 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (12)
  10. 10. Table IV. Overview of the pharmacokinetics (PK) of some antimicrobial agents during continuous renal replacement therapy (CRRT) and dosage recommendations 1006 Drug; Residual CRRT RFa Membrane/ QBF QUF QD CL Sca CLCRRT CLCRRT t1/2 Comment and dosage dosagea CLCR surface (mL/ (mL/h)a (mL/h)a (mL/ (mL/min)a (% of (h)a recommendation (mL/min) areaa min)a min)a CL)a Antibacterials Carbapenems meropenem; NS CVVH Post PS/ 150 2748 143.7 NS 49.7 34.6 2.33 1g q8h appropriate for 1g SD (9)[40] (ARF) 0.43m2 infections caused by susceptible bacteria (plasma concentration 4.3 mg/L after 6h) meropenem; 1.3 CVVH NS AN69 160 1100 52.0 1.17 22.0 42.3 8.7 Observed Cmin 7.3 mg/L; 0.5g q8h 0.5g q12h appropriate or q12h (9)[41] © 2007 Adis Data Information BV. All rights reserved. meropenem; NS CVVH NS AN69 200 1650 76.2 0.63 17.2 22.5 6.37 0.5g q12h appropriate 0.5g q12h (5)[42] (ARF) for infections caused by susceptible bacteria (Cmin 3.0 mg/L) meropenem; NS CVVH Pre (1), AN69/ 10 1600 82.9 NS 24.4 29.4 3.63 Observed T>4 mg/L 0.5g q12h (8)[43] (ARF) post (7) 0.9m2 = 8.22h Observed T>8 mg/L = 4.72h 0.5g q12h appropriate for infections caused by susceptible bacteria meropenem; NS CVVH Post AN69/ 150 1700 60.5 0.95 25.0 41.3 5.89 1.0g q12h appropriate 1.0g q12h (10)[44] (ARF) (5) 0.9m2 for infections caused by susceptible bacteria (T>4 mg/L = 8h) NS CVVHDF Post AN69/ 150 1200 1200 74.9 0.92 38.9 49.4 4.44 1.0g q12h appropriate (ARF) (5) 0.9m2 for infections caused by susceptible bacteria (T>4 mg/L = 8h) meropenem; NS CVVHDF Pre AN69/ 119 500 600 74.7 0.65 27.0 36.2 5.13 Predicted Cmin >4 mg/L 1.0g q12h (9), (ARF) 0.9m2 for >8h with 0.75g q8h; 0.5g q12h (4), for >12h with 1.5g q12h 1.0g q8h (1), 0.5g q8h (1)[45] meropenem; NS CVVH NS PS/ 100 400 54.5 NS NS NS 7.5 CVVH accounted for 1g (6)[46] (ARF) (6) 0.7m2 13% of elimination in 12h; 0.5g q8h appropriate Continued next page Clin Pharmacokinet 2007; 46 (12) Pea et al.
  11. 11. Table IV. Contd Drug; Residual CRRT RFa Membrane/ QBF QUF QD CL Sca CLCRRT CLCRRT t1/2 Comment and dosage dosagea CLCR surface (mL/ (mL/h)a (mL/h)a (mL/ (mL/min)a (% of (h)a recommendation (mL/min) areaa min)a min)a CL)a NS CVVHDF NS PS/ 100 400 1000 78.7 NS NS NS 5.6 CVVHDF 1 L/h (ARF) (6) 0.7m2 accounted for 33% of elimination in 12h; 1.0g q12h appropriate NS CVVHDF NS PS/ 100 400 2000 95.2 NS NS NS 4.8 CVVHDF 2 L/h (ARF) (6) 0.7m2 accounted for 40% of elimination in 12h; 1.0g q12h appropriate meropenem; 1.1 CVVHDF Pre AN69/ 150 1057 928.6 150.3 0.76 27.0 22.7 3.72 Observed Cmin >4 mg/L 0.5 q6h (5), 1.4m2 (4), except for 0.5g q8h 0.5 q8h (1), PS/ © 2007 Adis Data Information BV. All rights reserved. 1.0g q8h (1)[47] 0.9m2 (3) Disposition of Antimicrobials during CRRT meropenem; 23.5 CVVH Pre AN69/ 182.1 1843 0 134.4 0.85 32.2 29.3 2.73 Observed Cmin >2 mg/L 0.5g q6h (6), (4), 1.4m2 (5), (4), except for 1.0g q8h 1.0g q8h (1)[47] CVVHDF PS/ 1000 (3) 0.9m2 (2) (3) meropenem; 95.9 CVVH Pre AN69/ 140 1250 1064.8 0.72 16.4 3.6 1.51 2g q8h did not ensure 2.0g q8h (5), 1.4m2 (6) adequate T>MIC 1.0g q6h (1)[47] (Cmin 0.98 mg/L) imipenem; 0 (10), CVVH NS AN69/ 160 1115 122.2 1.20 22.9 19.7 2.87 Observed Cmin 0.5g q6h (NS), 61 (2) NS 4.1 mg/L for 0.5g q6h; 0.5g q8h (NS)[48] 2.34 mg/L for 0.5g q8h; 0.5g q6h needed imipenem; NS CVVH Post AN69/ 150 1130 145.0 1.21 36.0 24.8 2.71 Observed Cmin 1.4 mg/L; 0.5g q12h (4), (ARF) 0.6m2 0.5g q8–12h appropriate 0.5g q8h (2)[49] only if MIC ≤2 mg/L; 0.5g q6h needed in most critically ill pts imipenem; NS CVVHDF Post AN69/ 158.3 1160 973 178.0 1.28 57.0 32.0 2.56 Observed Cmin 1.1 mg/L; 0.5g q12h (3), (ARF) 0.6m2 0.5g q8–12h appropriate 0.5g q8h (3)[49] only if MIC ≤2 mg/L; 0.5g q6h needed in most critically ill pts Penicillins flucloxacillin; NS CVVH Post PAM/ 169 3420 117.2 0.21 10.3 8.8 4.9 4.0g q8h adequate for MS 4g q8h (10)[50] (ARF) 0.7m2 staphylococcal infections Continued next page Clin Pharmacokinet 2007; 46 (12) 1007
  12. 12. Table IV. Contd 1008 Drug; Residual CRRT RFa Membrane/ QBF QUF QD CL Sca CLCRRT CLCRRT t1/2 Comment and dosage dosagea CLCR surface (mL/ (mL/h)a (mL/h)a (mL/ (mL/min)a (% of (h)a recommendation (mL/min) areaa min)a min)a CL)a piperacillin; NS CVVH NS PS/ 150 816 79.2 NS NS NS 5.1 Very small amount 4.0g first (ARF) 0.5m2 of piperacillin in dose (6)[51] ultrafiltrate (0–8 mg/L); 4.0g q12h recommended piperacillin; NS CVVH NS PS/ 150 612 24.8 NS NS NS 4.8 4.0g q8h (4)[51] (ARF) 0.5m2 piperacillin/ NS CVVH Pre NS NS 1554 42.0/ NS NS NS 5.9/ Risk of accumulation of tazobactam; (ARF) 74.0 8.1 tazobactam; piperacillin 4.0g/0.5g alone should be given q8h (9)[52] intermittently with the piperacillin/tazobactam © 2007 Adis Data Information BV. All rights reserved. combination piperacillin/ NS CVVH Post PS/ 100 800 64.8/ NS NS NS 7.7/ Mean elimination in tazobactam; (ARF) 0.7m2 40.3 13.9 12h = 29%/37%; 4.0g/0.5g (6)[53] 4.0g/0.5g q8h recommended NS CVVHDF Post PS/ 100 800 1000 84.3/ NS NS NS 6.7/ Mean elimination in (ARF) 0.7m2 52.2 11.6 12h = 42%/57%; 4.0g/0.5g q8h recommended NS CVVHDF Post PS/ 100 800 2000 91.3/ NS NS NS 6.1/ Mean elimination in (ARF) 0.7m2 62.5 9.4 12h = 46%/69%; 4.0g/0.5g q8h recommended piperacillin/ NS CVVHD NS AN69 150 140 1500 72.0/ 0.84/ 22.0/ 43.1/ 4.3/ 4.0g/0.5g q12h should tazobactam; (ARF) 38.0 0.64 17.0 47.5 5.6 result in T>MIC of 50% 4.0g/0.5g vs susceptible pathogens q8h (3), with MIC ≤16 mg/L; 4.0g/0.5g TDM should be used to q12h (4), individualise treatment 4.0g/0.5g q24h (1)[54] piperacillin/ 8.67 (4) CVVH Pre AN69/ 185 1626 50.0/ 0.42/ 11.5/ 37.0/ 7.8/ 100% T>MIC vs all tazobactam; 0.9m2 50.4 0.76 20.9 62.5 7.9 susceptible pathogens 4.0g/0.5g q6h (7), 4.0g/0.5g q8h (7)[39] Continued next page Clin Pharmacokinet 2007; 46 (12) Pea et al.
  13. 13. Table IV. Contd Drug; Residual CRRT RFa Membrane/ QBF QUF QD CL Sca CLCRRT CLCRRT t1/2 Comment and dosage dosagea CLCR surface (mL/ (mL/h)a (mL/h)a (mL/ (mL/min)a (% of (h)a recommendation (mL/min) areaa min)a min)a CL)a 25.20 (5) CVVH Pre AN69/ 185 1818 90.6/ 0.38/ 12.2/ 12.7/ 4.2/ 100% T>MIC vs 0.9m2 68.2 0.73 21.9 35.4 4.1 pathogens with MIC ≤32 mg/L; 55% T>MIC vs pathogens with MIC 64 mg/L 82.40 (5) CVVH Pre AN69/ 185 1200 265.2/ 0.23/ 4.8/ 2.8/ 4.2/ 55% T>MIC vs pathogens 0.9m2 180.1 0.86 19.6 13.1 4.1 with MIC 32 mg/L; 17% T>MIC vs pathogens with MIC 64 mg/L; 4.0g/0.5g q4h needed in pts with CLCR >50 mL/min © 2007 Adis Data Information BV. All rights reserved. Cephalosporins Disposition of Antimicrobials during CRRT cefepime; NS CVVHDF Post AN69/ 150 576 1000 23.8 0.72 60.98 258 13.9 2g q12h appropriate for 2g q12h (6)[55] (ARF) 0.6m2 (4), Cmin >5 × MIC (20 mg/L) 57.8 (2) cefepime; CVVH Post AN69/ 150 960 36 0.86 13 40 12.9 2g q24h or 1g q12h 2g 12h (1), (5) 0.6m2 appropriate for pathogens 2g q24h (3), with MIC ≤8 mg/L 1g q12h (1)[56] cefepime; CVVHDF Post AN69/ 150 1020 957 47 0.78 26 59 8.6 2g q24h or 1g q12h 2g q24h (4), (7) 0.6m2 appropriate for pathogens 1g q12h (1), with MIC ≤8 mg/L 1g q24h (2)[56] cefepime; 24.7 (3) CVVU Pre AN69/ 195 1560 0 121.3 0.62 18.5 15.3 4.1 2g q8h appropriate for 2g q8h (4)[57] (2), 0.9m2 (3), (4) (2), (2), (2), (2), (2), (2), Cmin >10 mg/L CVVHDF PS (1) 750 101.8 0.90 35.9 35.3 5.2 (2) (2) (2) (2) (2) (2) (2) cefpirome; NS CVVH Post? PAM/ 150– 1620– 32 0.64 17 53.1 8.8 2g LD then 1g q12h offers 1g q12h (6)[58] (ARF) 0.6m2 200 2040 appropriate coverage cefpirome; NS CVVH Post PS/ 150 2820 589.1 0.78 43.3 7.4 2.36 2g q8h appropriate for 2g q8h (8)[59] (ARF) 0.7m2 susceptible pathogens ceftazidime; NS CVVHDF NS PAN/ 100 1050 500 NS NS NS NS 6.8 CL 19.0 mg/L at 6h and 1g (3)[60] (ARF) 0.6m2 11.9 mg/L at 12h; 1g q24h appropriate Continued next page Clin Pharmacokinet 2007; 46 (12) 1009
  14. 14. Table IV. Contd 1010 Drug; Residual CRRT RFa Membrane/ QBF QUF QD CL Sca CLCRRT CLCRRT t1/2 Comment and dosage dosagea CLCR surface (mL/ (mL/h)a (mL/h)a (mL/ (mL/min)a (% of (h)a recommendation (mL/min) areaa min)a min)a CL)a ceftazidime; NS CVVH No AN69/ 100 500/ 0 NS 0.91 7.5/ CL increased with QUF; no 1g (8)[61] (ESRD) 0.6m2 1000 15.3b significant difference in CL was attributed to the type of membrane utilised; different dosages according to QUF and residual renal function CVVH No PMMA/ 100 500/ 0 NS 0.91 6.3/ 2.1m2 1000 12.5b CVVH No PS/ 100 500/ 0 NS 0.91 9.0/ 0.65m2 1000 16.5b © 2007 Adis Data Information BV. All rights reserved. ceftazidime; NS CVVHD No AN69/ 100 0 500/ NS 8.4/ CL increased with QD; no 1g (8)[61] (ESRD) 0.6m2 1000/ 13.5/ significant difference in CL 1500/ 18.3/ was attributed to the type 2000 21.6 of membrane utilised; different dosages according to QD and residual renal function CVVHD No PMMA/ 100 0 500/ NS 7.3/ 2.1m2 1000/ 14.5/ 1500/ 20.1/ 2000 24.2 CVVHD No PS/ 100 0 500/ NS 8.6/ 0.65m2 1000/ 16.6/ 1500/ 23.2/ 2000 27.5 ceftazidime; NS CVVH Post PS/ 143 2820 98.7 0.69 32.1 32.5 4.3 Cmin 14.0 mg/L – i.e. 2g q8h (12)[62] (ARF) 0.7m2 >MIC of susceptible pathogens (4 mg/L); 2g q8h appropriate; 3g q8h suggested for intermediately resistant pathogen with MIC 8 mg/L ceftazidime; <1 (6), CVVHDF Pre AN69/ 150 1500 1000 62.4 0.81 33.6 53.8 3.6 Css 33.5 mg/L – i.e. 3g q24h CI (7)[63] 5 (1) 0.6m2 4 × MIC of susceptible pathogens; 3g q24 CI after 2g LD appropriate Continued next page Clin Pharmacokinet 2007; 46 (12) Pea et al.
  15. 15. Table IV. Contd Drug; Residual CRRT RFa Membrane/ QBF QUF QD CL Sca CLCRRT CLCRRT t1/2 Comment and dosage dosagea CLCR surface (mL/ (mL/h)a (mL/h)a (mL/ (mL/min)a (% of (h)a recommendation (mL/min) areaa min)a min)a CL)a ceftriaxone; 2 CVVH Post PAM 125 1500 39.3 0.69 16.6 42.2 10.8 No dosage reduction 2g q24h (5), needed; 2g q24h 4g q24h (1)[64] appropriate ceftriaxone; NS CVVH No AN69/ 100 500/ 0 NS 0.48 3.9/ CL increased with QUF 1g (8)[65] (ESRD) 0.6m2 1000 7.2b and was significantly lower with AN69 than with PMMA and PS filters; different dosages according to QUF and residual renal function CVVH No PMMA/ 100 500/ 0 NS 0.86 6/ © 2007 Adis Data Information BV. All rights reserved. 2.1m2 1000 11.8b Disposition of Antimicrobials during CRRT CVVH No PS/ 100 500/ 0 NS 0.82 5.8/ 0.65m2 1000 11.0b ceftriaxone; NS CVVHD No AN69/ 100 0 500/ NS 1.5/ CL increased with QD and 1g (8)[65] (ESRD) 0.6m2 1000/ 2.3/ was significantly lower 1500/ 3.1/ with AN69 than with 2000 3.3 PMMA and PS filters; different dosages according to QD and residual renal function CVVHD No PMMA/ 100 0 500/ NS 1.5/ 2.1m2 1000/ 2.7/ 1500/ 3.8/ 2000 4.4 CVVHD No PS/ 100 0 500/ NS 2.2/ 0.65m2 1000/ 4.0/ 1500/ 5.6/ 2000 6.1 Aminoglycosides netilmicin; 22.3 CVVHDF NS AN69/ 130 150 875 44.03 6.83 150mg q12h does not 150mg q12h 0.6m2 provide effective peak (6)[66] concentrations Glycopeptides teicoplanin; 35 CVVH Pre AN69/ 150 2000 0.17 Drug removal dependent 5.71–11.42 0.9m2 on QUF and fu; mg/kg/day (1)[38] TDM recommended Continued next page Clin Pharmacokinet 2007; 46 (12) 1011

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