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DRUG DOSING IN AKI FEDERICO PEA INSTITUTE OF CLINICAL PHARMACOLOGY AND TOXICOLOGY UNIVERSITY OF UDINE ITALY

DRUG DOSING IN AKI FEDERICO PEA INSTITUTE OF CLINICAL PHARMACOLOGY AND TOXICOLOGY UNIVERSITY OF UDINE ITALY. Disclosure of interests : Consultant : Astellas , Pfizer; Janssen-Cilag

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DRUG DOSING IN AKI FEDERICO PEA INSTITUTE OF CLINICAL PHARMACOLOGY AND TOXICOLOGY UNIVERSITY OF UDINE ITALY

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  1. DRUG DOSING IN AKIFEDERICO PEAINSTITUTE OF CLINICAL PHARMACOLOGY AND TOXICOLOGYUNIVERSITY OF UDINEITALY Disclosureofinterests: Consultant: Astellas, Pfizer; Janssen-Cilag Speaker bureau: GlaxoSmithKline, Gilead, JanssenCilag, Merch Sharp & Dohme, Novartis, Pfizer, SanofiAventis, Schering-Plough, Wyeth 6° PCRRT, Rome, 08-10 April 2010

  2. PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPYPea F et al. Clin Pharmacokinet 2007 (12) 997-1038 DRUG REMOVAL BY MEANS OF CRRT DIFFUSION CONVECTION

  3. PROCEDURE DIFFUSION CONVECTION VASCULAR ACCESS ++++ + Fistula or Veno - Venous IHD +++ ++ Fistula o Veno - Venous IHDF ++++ + None CAPD 0 ++++ Arterio - Venous CAVH 0 ++++ Veno - Venous CVVH ++++ + Arterio - Venous CAVHD ++++ + Veno - Venous CVVHD +++ +++ Arteri o - Venous CAVHDF +++ +++ Veno - Venous CVVHDF CHARACTERISTICS OF SOME RENAL REPLACEMNT THERAPIES Adapted from Joy et al. Ann Pharmacother 1998; 32: 362-375

  4. PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPYPea F et al.Clin Pharmacokinet 2007 (12) 997-1038 CHARACTERISTICS OF DRUG REMOVAL DURING HEMODIALYSIS • DRUG REMOVAL BY DIFFUSION • PASSIVE PROCESS • IN COUNTERCORRENT • CONDITIONED BY MW • LONG-TIME FOR EQUILIBRIUM • NO REPLACEMENT FLUID NEEDED DIALYSATE BFR

  5. PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPYPea F et al.Clin Pharmacokinet 2007 (12) 997-1038 CHARACTERISTICS OF DRUG REMOVAL DURING HEMOFILTRATION • DRUG REMOVAL BY CONVECTION • ACTIVE PROCESS • PUMP DRIVEN PRESSURE GRADIENT • UNCONDITIONED BY MW • RAPID EQUILIBRIUM • REPLACEMENT FLUID NEEDED REPLACEMENT FLUID PRE POST BFR UF

  6. HEMOFILTRATION POST-DILUTION Solute removed by convection HEMOFILTRATION PRE-DILUTION Solute, diluted with substitution volume, removed by convection HEMODIALYSIS Solute removed by diffusion, conditioned by molecular weight DRUG CLEARANCE DURING RENAL REPLACEMENT THERAPY (RRT) Pump Pump Pump Substitution fluid Substitution fluid Substitution fluid Hemofilter Hemofilter Hemodialyzer Saturation e.g. 80% Saturation e.g. 40-90% Saturation 100% Drug Clearance = UFR Drug Clearance = (UFR x BFR) / (BFR + SFR) Drug Clearance = conditioned by MW Bohler J. Kidney Int 1999;Suppl.72:24-28

  7. FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE DURING RENAL REPLACEMENT THERAPY • COMPOSITION • SURFACE AREA • PORE SIZE • ADSORPTION DEVICE PROPERTIES DRUG PROPERTIES • MOLECULAR WEIGHT • PLASMA PROTEIN BINDING • VOLUME OF DISTRIBUTION • PROPORTION OF RENAL CLEARANCE Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors

  8. WHY DRUG REMOVAL BY RENAL REPLACEMENT THERAPY IS ESPECIALLY RELEVANT FOR ANTIMICROBIAL DRUGS?

  9. SURVIVING SEPSIS CAMPAIGN: INTERNATIONAL GUIDELINES FOR MANAGEMENT OF SEVERE SEPSIS AND SEPTIC SHOCK: 2008Dellinger RP et al. Intensive Care Med 2008; 34: 17-60 INITIAL RESUSCITATION AND INFECTION ISSUES: ANTIBIOTIC THERAPY • Begin intravenous antibiotics as early as possible, and always within the first hour of recognizing severe sepsis (1D) and septic shock (1B). • Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with good penetration into presumed source (1b) • Reassess antimicrobial regimen daily to optimise efficacy, prevent resistance, avoid toxicity & minimise costs (1c) • Consider combination therapy in pseudomonas infections (2d) • Consider combination empiric therapy in neutropenic patients (2d) • Combination therapy no more than 3–5 days and deescalation following susceptibilities (2d) • Duration of therapy typically limited to 7–10 days; longer if response slow, undrainable foci of infection, or immunologic deficiencies (1d) • Stop antimicrobial therapy if cause is found to be non-infectious (1d)

  10. SURVIVING SEPSIS CAMPAIGN: INTERNATIONAL GUIDELINES FOR MANAGEMENT OF SEVERE SEPSIS AND SEPTIC SHOCK: 2008Dellinger RP et al. Intensive Care Med 2008; 34: 17-60 INITIAL RESUSCITATION AND INFECTION ISSUES: ANTIBIOTIC THERAPY • Begin intravenous antibiotics as early as possible, and always within the first hour of recognizing severe sepsis (1D) and septic shock (1B). • Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with good penetration into presumed source (1b) • Reassess antimicrobial regimen daily to optimise efficacy, prevent resistance, avoid toxicity & minimise costs (1c) • Consider combination therapy in pseudomonas infections (2d) • Consider combination empiric therapy in neutropenic patients (2d) • Combination therapy no more than 3–5 days and deescalation following susceptibilities (2d) • Duration of therapy typically limited to 7–10 days; longer if response slow, undrainable foci of infection, or immunologic deficiencies (1d) • Stop antimicrobial therapy if cause is found to be non-infectious (1d)

  11. ANTIMICROBIAL THERAPY IN THE CRITICALLY ILL PATIENTS:A REVIEW OF THOSE PATHOPHYSIOLOGICAL CONDITIONS RESPONSIBLE FOR HUGE PK VARIABILITYPea F, Viale P, Furlanut MClin Pharmacokinet 2005; 44: 1009-1034 Critically ill patients RENAL CL  MD VARIATIONS IN RENAL CLEARANCE VARIATIONS IN EXTRACELLULAR FLUID Vd  LD SEVERE SEPSIS AND CAPILLARY LEAKAGE Increased if Increased if Decreased if HYPERDYNAMICS DRUG ABUSE BURNS PLEURAL EFFUSION ASCITES MEDIASTINITIS RENAL IMPAIRMENT POST-SURGICAL DRAINAGES FLUID THERAPY FLUID THERAPY OEDEMA HAEMODINAMICALLY ACTIVE DRUGS LEUKEMIA OEDEMA DIALYSIS HYPOALBUMINAEMIA HYPOALBUMINAEMIA HYPOALBUMINAEMIA Reduced antimicrobial renal excretion Antimicrobial dilution or loss Enhanced antimicrobial renal excretion Consider DOSAGE INCREASE Consider DOSAGE INCREASE Consider LD DOSAGE INCREASE Consider DOSAGE DECREASE

  12. APPROPRIATE ANTIBIOTIC THERAPY IN SEVERE SEPSIS AND SEPTIC SHOCK: DOES THE DOSE MATTER ?Pea F and Viale P. Crit Care 2009; 13 (3) 214 CRITICAL ISSUES • Appropriate antibiotic therapy in patients with severe sepsis and septic shock should mean prompt achievement and maintenance of optimal exposure at the infection site with broad-spectrum antimicrobial agents administered in a timely manner. • Once that causative pathogens have been identified and tested for their in vitro susceptibility, subsequent de-escalation of antimicrobial therapy should be applied whenever feasible. • The goal of appropriate antibiotic therapy must be pursued resolutely and with continuity in the light of the ongoing explosion of antibiotic-resistant infections which plague the ICU setting and of the continue decrease of antibiotic pipeline.

  13. APPROPRIATE ANTIBIOTIC THERAPY IN SEVERE SEPSIS AND SEPTIC SHOCK: DOES THE DOSE MATTER ?Pea F and Viale P. Crit Care 2009; 13 (3) 214 CRITICAL ISSUES • Appropriate antibiotic therapy in patients with severe sepsis and septic shock should mean prompt achievement and maintenance of optimal exposure at the infection site with broad-spectrum antimicrobial agents administered in a timely manner. • Once that causative pathogens have been identified and tested for their in vitro susceptibility, subsequent de-escalation of antimicrobial therapy should be applied whenever feasible. • The goal of appropriate antibiotic therapy must be pursued resolutely and with continuity in the light of the ongoing explosion of antibiotic-resistant infections which plague the ICU setting and of the continue decrease of antibiotic pipeline.

  14. DEVELOPMENTAL CHANGES IN PHYSIOLOGIC FACTORS THAT INFLUENCE DRUG DISPOSITION IN INFANTS, CHILDREN, AND ADOLESCENTS Kearns GL et al. N Engl J Med 2003;349:1157-67.

  15. MOLECULAR WEIGHT PLASMA PROTEIN BINDING VOLUME OF DISTRIBUTION PROPORTION OF RENAL CLEARANCE FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE DURING RENAL REPLACEMENT THERAPY • COMPOSITION • SURFACE AREA • PORE SIZE • ADSORPTION DEVICE PROPERTIES DRUG PROPERTIES Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors

  16. MOLECULAR WEIGHT Pea F et al.Clin Pharmacokinet 2007 (12) 997-1038

  17. MOLECULAR WEIGHT PLASMA PROTEIN BINDING VOLUME OF DISTRIBUTION PROPORTION OF RENAL CLEARANCE FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE DURING RENAL REPLACEMENT THERAPY • COMPOSITION • SURFACE AREA • PORE SIZE • ADSORPTION DEVICE PROPERTIES DRUG PROPERTIES Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors

  18. PLASMA PROTEIN BINDING Pea F et al.Clin Pharmacokinet 2007 (12) 997-1038

  19. SIEVING COEFFICIENT DURING CVVH CUF Sc = CP Golper TA & Marx MA. Kidney Int 1998; Suppl.66: 165-168

  20. MOLECULAR WEIGHT PLASMA PROTEIN BINDING VOLUME OF DISTRIBUTION PROPORTION OF RENAL CLEARANCE FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE DURING RENAL REPLACEMENT THERAPY • COMPOSITION • SURFACE AREA • PORE SIZE • ADSORPTION DEVICE PROPERTIES DRUG PROPERTIES Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors

  21. HYDROPHILIC ANTIBIOTICS BETA-LACTAMS PENICILLINS CEPHALOSPORINS CARBAPENEMS MONOBACTAMS GLYCOPEPTIDES AMINOGLYCOSIDES LIPOPHILIC ANTIBIOTICS • MACROLIDES • FLUOROQUINOLONES • TETRACYCLINES • CHLORAMPHENICOL • RIFAMPICIN • LINEZOLID • LOW VOLUME OF DISTRIBUTION • INABILITY OF DIFFUSING THROUGH MEMBRANES • INACTIVITY AGAINST INTRACELLULAR PATHOGENS • RENAL ELIMINATION AS UNCHANGED DRUG • HIGH VOLUME OF DISTRIBUTION • ABILITY OF DIFFUSING THROUGH MEMBRANES • ACTIVITY AGAINST INTRACELLULAR PATHOGENS • ELIMINATION AFTER LIVER METABOLIZATION Pea F, Viale P, Furlanut M. Clin Pharmacokinet 2005; 44: 1009-1034 Pea F & Viale P. Clin Infect Dis 2006; 42: 1764-1771

  22. MOLECULAR WEIGHT PLASMA PROTEIN BINDING VOLUME OF DISTRIBUTION PROPORTION OF RENAL CLEARANCE FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE DURING RENAL REPLACEMENT THERAPY • COMPOSITION • SURFACE AREA • PORE SIZE • ADSORPTION DEVICE PROPERTIES DRUG PROPERTIES Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors

  23. HYDROPHILIC ANTIBIOTICS BETA-LACTAMS PENICILLINS CEPHALOSPORINS CARBAPENEMS MONOBACTAMS GLYCOPEPTIDES AMINOGLYCOSIDES LIPOPHILIC ANTIBIOTICS • MACROLIDES • FLUOROQUINOLONES • TETRACYCLINES • CHLORAMPHENICOL • RIFAMPICIN • LINEZOLID • LOW VOLUME OF DISTRIBUTION • INABILITY OF DIFFUSING THROUGH MEMBRANES • INACTIVITY AGAINST INTRACELLULAR PATHOGENS • RENAL ELIMINATION AS UNCHANGED DRUG • HIGH VOLUME OF DISTRIBUTION • ABILITY OF DIFFUSING THROUGH MEMBRANES • ACTIVITY AGAINST INTRACELLULAR PATHOGENS • ELIMINATION AFTER LIVER METABOLIZATION Pea F, Viale P, Furlanut M. Clin Pharmacokinet 2005; 44: 1009-1034 Pea F & Viale P. Clin Infect Dis 2006; 42: 1764-1771

  24. DRUG PROPERTIES CONDITIONING THE HIGHEST POTENTIAL CLEARANCE DURING RRT CVVH-DF • LOW MOLECULAR WEIGHT • LOW PLASMA PROTEIN BINDING • LOW VOLUME OF DISTRIBUTION • HIGH RENAL CLEARANCE Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors

  25. MOLECULAR WEIGHT PLASMA PROTEIN BINDING VOLUME OF DISTRIBUTION PROPORTION OF RENAL CLEARANCE FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE DURING RENAL REPLACEMENT THERAPY • COMPOSITION • SURFACE AREA • PORE SIZE • ADSORPTION DEVICE PROPERTIES DRUG PROPERTIES Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors

  26. CUMULATIVE ADSORPTION OF GENTAMICIN BY HEMOFILTERS AGAINST TIME In Vitro ADSORPTION OF GENTAMICIN AND NETILMICIN BY POLYACRYLONITRILE AND POLYAMIDE HEMOFILTRATION FILTERSLam PKN et al. Antimicrob Agents Chemother 2010 Feb, 54: 963–965

  27. In Vitro ADSORPTION OF GENTAMICIN AND NETILMICIN BY POLYACRYLONITRILE AND POLYAMIDE HEMOFILTRATION FILTERSLam PKN et al. Antimicrob Agents Chemother 2010 Feb, 54: 963–965 CUMULATIVE ADSORPTION OF NETILMICIN BY HEMOFILTERS AGAINST TIME

  28. ALGORITHM FOR INDIVIDUALIZATION OF PHARMACOTHERAPY REGIMENS IN PATIENTS RECEIVING CRRT PATIENT CHARACTERISTICS 1 Residual renal frunction 2 Volume status 3 Other organ function information DRUG-SPECIFIC FACTORS 1 Volume of distribution 2 Protein binding 3 Molecular weight 4 Fraction eliminated unchanged in the urine CALCULATE RESIDUAL RENAL FUNCTION 1 Estimate: residual total body CL from published literature 2 Measure serum concentration-time data prior to CRRT Select CRRT CAVH/CVVH/SCUF 1. Ultrafiltration rate 2. Hemofilter characteristics CAVHDF/CVVHDF 1. Dialysate flow rate 2. Ultrafiltration rate 3. Hemofilter characteristics CAVHD/CVVHD 1. Dialysate flow rate 2. Hemofilter characteristics Estimate SC = literature review for published fup Calculate SC = Cuf/Ca CL CAVH/CVVH 1. Estimate:ClCVVH= Qf•SC ClCVVH= Qf•fu 2. Measure: same as CVVHDF CL CAVHD/CVVHD 1. Estimate: ClCVVHD= fu•Qdial 2.Measure: ClCVVHD= (Cdial•Vdial)/AUC0-t ClCVVHD= (Cdial•Vdial)/Cmidpt CL CAVHDF/CVVHDF 1. Estimate: ClCVVHDF= fu(Qf+Qdial) 2.Measure: ClCVVHDF= (Cdf•Vdf)/AUC0-t ClCVVHDF= (Cdf•Vdf)/Cmidpt Dosage calculation Cltot= ClCRRT+Clresidual Dose= Cp ss•Cltot•t Joy et al. Ann Pharmacother 1998;32:362-375

  29. PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPYPea F et al. Clin Pharmacokinet 2007 (12) 997-1038 GENERAL PRINCIPLES FOR APPROPRIATELY HANDLING RENALLY CLEARED DRUGS DURING CRRT • Drug extraction increases linearly with QUF and/or QD applied • CVVHDF is generally more efficient than CVVH • Post-dilution is more efficient than pre-dilution

  30. PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPYPea F et al. Clin Pharmacokinet 2007 (12) 997-1038 GENERAL PRINCIPLES FOR APPROPRIATELY HANDLING RENALLY CLEARED DRUGS DURING CRRT • Drugs normally at high CLr which exhibit high CLCRRT during CVVH or CVVHDF may need significant dosage increase in comparison with renal failure or even IHD  beta lactams, glycopeptides, aminoglycosides, levofloxacin, ciprofloxacin • Conversely, drugs normally non renally cleared which exhibit very low CLCRRT during CVVH or CVVHDF may need unmodified dosages in comparison with normal renal function  linezolid, moxifloxacin, clindamycin, Q/D, ceftriaxone, oxacillin

  31. DRUG ADMINISTRATION DURING INTERMITTENT HEMODIALYSISAND CONTINUOUS RENAL REPLACEMENT THERAPY:SPECIAL CONSIDERATIONS IN PEDIATRIC PATIENTSVeltri MA et al. Paediatr Drugs. 2004; 6: 45-65 SUGGESTED PEDIATRIC STARTING DOSAGES FOR SELECTED INTRAVENOUS (IV) MEDICATIONS

  32. DRUG ADMINISTRATION DURING INTERMITTENT HEMODIALYSISAND CONTINUOUS RENAL REPLACEMENT THERAPY:SPECIAL CONSIDERATIONS IN PEDIATRIC PATIENTSVeltri MA et al. Paediatr Drugs. 2004; 6: 45-65 SUGGESTED PEDIATRIC STARTING DOSAGES FOR SELECTED INTRAVENOUS (IV) MEDICATIONS

  33. DRUG ADMINISTRATION DURING INTERMITTENT HEMODIALYSISAND CONTINUOUS RENAL REPLACEMENT THERAPY:SPECIAL CONSIDERATIONS IN PEDIATRIC PATIENTSVeltri MA et al. Paediatr Drugs. 2004; 6: 45-65 SUGGESTED PEDIATRIC STARTING DOSAGES FOR SELECTED INTRAVENOUS (IV) MEDICATIONS

  34. PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPYPea F et al. Clin Pharmacokinet 2007 (12) 997-1038 GENERAL PRINCIPLES FOR APPROPRIATELY HANDLING RENALLY CLEARED DRUGS DURING CRRT • Drugs normally at high CLr which exhibit high CLCRRT during CVVH or CVVHDF may need significant dosage increase in comparison with renal failure or even IHD  beta lactams, glycopeptides, aminoglycosides, levofloxacin, ciprofloxacin • Conversely, drugs normally non renally cleared which exhibit very low CLCRRT during CVVH or CVVHDF may need unmodified dosages in comparison with normal renal function  linezolid, moxifloxacin, clindamycin, oxacillin, ceftriaxone

  35. DRUG ADMINISTRATION DURING INTERMITTENT HEMODIALYSISAND CONTINUOUS RENAL REPLACEMENT THERAPY:SPECIAL CONSIDERATIONS IN PEDIATRIC PATIENTSVeltri MA et al. Paediatr Drugs. 2004; 6: 45-65 SUGGESTED PEDIATRIC STARTING DOSAGES FOR SELECTED INTRAVENOUS (IV) MEDICATIONS

  36. WHICH SCHEDULE OF ADMINISTRATION FOR ANTIBIOTICS DURING RENAL REPLACEMENT THERAPY ?

  37. Antibiotic concentration (µg/mL) Optimal exposure: Cmin > MIC MIC (µg/mL) t > MIC Dosing interval (h) PK-PD RELATIONSHIPS • BETA-LACTAMS, GLYCOPEPTIDES, OXAZOLIDINONES • Time-dependent antibacterial activity • TARGET  MAINTENANCE OF CMIN > MIC • t > MIC • t > MIC REFRACT DOSAGES UNTIL TO CONTINUOUS INFUSION Viale P & Pea F in: Nosocomial pneumonia - strategies for management, Ed J. Rello, 2007

  38. Concentration (µg/mL) Cmax AUC MIC (µg/mL) Dosing interval (h) Optimal exposure: Cmax/MIC > 10 AUC/MIC > 40-50 vs G+ AUC/MIC > 125 vs G- PK-PD RELATIONSHIPS • AMINOGLYCOSIDES, FLUOROQUINOLONES • Concentration-dependent antibacterial activity • TARGET  ACHIEVEMENT OF THE HIGHEST CMAX AND/OR AUC • Cmax/MIC > 10 • AUC/MIC > 125 ONCE DAILY DOSING WHENEVER FEASIBLE Viale P & Pea F in: Nosocomial pneumonia - strategies for management, Ed J. Rello, 2007

  39. ANTIBIOTIC DOSING IN CRITICALLY ILL ADULT PATIENTSRECEIVING CONTINUOUS RENAL REPLACEMENT THERAPYTrotman LR et al. Clin Infect Dis (15 October) 2005; 41:1159–66….. patient, drug, and mechanical variables significantly diminishthe utility of routine pharmacokinetic calculations fordetermining antimicrobial dosing during CRRT WHENEVER FEASIBLE DRUG EXPOSURE SHOULD BE OPTIMIZED BY MEANS OF

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