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

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PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPY Pea F et al. Clin Pharmacokinet 2007 (12) 997-1038. DRUG REMOVAL BY MEANS OF CRRT. Dissemination. CONVECTION. Attributes OF SOME RENAL REPLACEMNT THERAPIES. . . . Adjusted from Joy et al. Ann Pharmacother 1998; 32: 362-375.

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Sedate DOSING IN AKI FEDERICO PEA INSTITUTE OF CLINICAL PHARMACOLOGY AND TOXICOLOGY UNIVERSITY OF UDINE ITALY Disclosure of interests : Consultant : Astellas , Pfizer; Janssen-Cilag Speaker agency: GlaxoSmithKline, Gilead , Janssen Cilag , Merch Sharp & Dohme , Novartis, Pfizer, Sanofi Aventis , Schering-Plow, Wyeth 6° PCRRT, Rome, 08-10 April 2010

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

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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

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PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPY Pea 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

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PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPY Pea 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

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HEMOFILTRATION POST-DILUTION Solute expelled by convection HEMOFILTRATION PRE-DILUTION Solute, weakened with substitution volume, evacuated by convection HEMODIALYSIS Solute expelled by dispersion, molded by sub-atomic weight DRUG CLEARANCE DURING RENAL REPLACEMENT THERAPY (RRT) Pump Substitution liquid Substitution liquid Substitution liquid 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 = molded by MW Bohler J. Kidney Int 1999;Suppl.72:24-28

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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. Part 219 in Critical Care Nephrology, second Ed. Ronco C, Bellum and Bellomo Editors

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

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SURVIVING SEPSIS CAMPAIGN: INTERNATIONAL GUIDELINES FOR MANAGEMENT OF SEVERE SEPSIS AND SEPTIC SHOCK: 2008 Dellinger RP et al. Serious Care Med 2008; 34: 17-60 INITIAL RESUSCITATION AND INFECTION ISSUES: ANTIBIOTIC THERAPY Begin intravenous anti-toxins as ahead of schedule as could reasonably be expected, and dependably inside the main hour of perceiving extreme sepsis (1D) and septic stun (1B). Expansive range: at least one specialists dynamic against likely bacterial/parasitic pathogens and with great infiltration into assumed source (1b) Reassess antimicrobial regimen day by day to streamline adequacy, counteract resistance, keep away from danger & limit costs (1c) Consider mix treatment in pseudomonas diseases (2d) Consider mix empiric treatment in neutropenic patients (2d) Combination treatment close to 3–5 days and deescalation taking after susceptibilities (2d) Duration of treatment ordinarily restricted to 7–10 days; longer if reaction moderate, undrainable foci of contamination, or immunologic lacks (1d) Stop antimicrobial treatment if cause is observed to be non-irresistible (1d)

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SURVIVING SEPSIS CAMPAIGN: INTERNATIONAL GUIDELINES FOR MANAGEMENT OF SEVERE SEPSIS AND SEPTIC SHOCK: 2008 Dellinger RP et al. Serious Care Med 2008; 34: 17-60 INITIAL RESUSCITATION AND INFECTION ISSUES: ANTIBIOTIC THERAPY Begin intravenous anti-infection agents as right on time as could be expected under the circumstances, and dependably inside the principal hour of perceiving extreme sepsis (1D) and septic stun (1B). Expansive range: at least one operators dynamic against likely bacterial/parasitic pathogens and with great infiltration into assumed source (1b) Reassess antimicrobial regimen day by day to advance viability, avert resistance, keep away from poisonous quality & limit costs (1c) Consider blend treatment in pseudomonas diseases (2d) Consider mix empiric treatment in neutropenic patients (2d) Combination treatment close to 3–5 days and deescalation taking after susceptibilities (2d) Duration of treatment normally restricted to 7–10 days; longer if reaction moderate, undrainable foci of contamination, or immunologic lacks (1d) Stop antimicrobial treatment if cause is observed to be non-irresistible (1d)

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ANTIMICROBIAL THERAPY IN THE CRITICALLY ILL PATIENTS: A REVIEW OF THOSE PATHOPHYSIOLOGICAL CONDITIONS RESPONSIBLE FOR HUGE PK VARIABILITY Pea F, Viale P, Furlanut M Clin Pharmacokinet 2005; 44: 1009-1034 Critically sick 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 Reduced antimicrobial renal discharge Antimicrobial weakening or misfortune Enhanced antimicrobial renal discharge Consider DOSAGE INCREASE Consider DOSAGE INCREASE Consider LD DOSAGE INCREASE Consider DOSAGE DECREASE

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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 anti-toxin treatment in patients with extreme sepsis and septic stun ought to mean incite accomplishment and support of ideal introduction at the disease site with wide range antimicrobial operators regulated in an opportune way . Once that causative pathogens have been recognized and tried for their in vitro powerlessness, consequent de-acceleration of antimicrobial treatment ought to be connected at whatever point attainable . The objective of suitable anti-infection treatment must be sought after undauntedly and with progression in the light of the continuous blast of anti-toxin safe contaminations which torment the ICU setting and of the proceed with reduction of anti-toxin pipeline.

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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 anti-microbial treatment in patients with extreme sepsis and septic stun ought to mean incite accomplishment and upkeep of ideal introduction at the contamination site with expansive range antimicrobial specialists managed in a convenient way . Once that causative pathogens have been recognized and tried for their in vitro powerlessness, resulting de-heightening of antimicrobial treatment ought to be connected at whatever point possible. The objective of suitable anti-microbial treatment must be sought after steadfastly and with coherence in the light of the progressing blast of anti-toxin safe diseases which torment the ICU setting and of the proceed with abatement of anti-microbial pipeline.

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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.

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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. Section 219 in Critical Care Nephrology, second Ed. Ronco C, Bellum and Bellomo Editors

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

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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. Section 219 in Critical Care Nephrology, second Ed. Ronco C, Bellum and Bellomo Editors

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

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SIEVING COEFFICIENT DURING CVVH C UF Sc = C P Golper TA & Marx MA. Kidney Int 1998; Suppl.66: 165-168

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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. Section 219 in Critical Care Nephrology, second Ed. Ronco C, Bellum and Bellomo Editors

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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

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MOLECULAR WEIGHT PLASMA PROTEIN BINDING VOLUME OF DISTR

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