ANTIBIOTIC DOSE AND DOSE INTERVALS IN RRT and ECMO

ANTIBIOTIC DOSE AND DOSE INTERVALS IN RRT and ECMO Professor Jeffrey Lipman Department of Intensive Care Medicine Royal Brisbane Hospital University of Queensland

NO CONFLICT OF INTERESTS

Important concept Recommended dosages are obtained from healthy volunteers and possibly (ward) sick patients

Clinical pharmacology: drug development Antibiotic regimens are derived from noncritically ill volunteers. Their haemodynamic system is normal, as is their liver and kidney blood flow. They have not leaky capillaries nor have they drips and pipes in every orifice.

The kidney and antibiotics Blot S et al. Diagnostic Microbiology and Infectious Disease 2014;79:77 84

Antibiotic related IMPORTANT pharmacokinetic parameters Cmax Peak Concentration Cmin t 1/2 V AUC Cl Trough Concentration Half-life (or V D ) Volume of distribution Area under curve Clearance Protein binding

Capillary lead and fluid administration

Marik PE Anaesthesia and Intensive Care 1993;21:172-3.

.we have found that higher-thanrecommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations. 35mg/kg loading 35mg/kg/day

VOLUME OF DISTRIBUTION ALTERATIONS IN ICU Antibiotics that stay in extravascular and extracellular space ie that don t penetrate solid organs, (hydrophilic tendencies) namely AMINOGLYCOSIDES GLYCOPEPTIDES β-lactams (to a lesser extent) COLISTIN

LOADING DOSE vs CLEARANCES Fundamental concept Loading dose is INDEPENDENT of clearances EVEN IN RENAL FAILURE (without clearance) YOU MUST GIVE LOADING DOSE

LOW EXPOSURE TO ANTIBIOTICS ENABLES DEVELOPMENT OF RESISTANCE Critical Care Medicine August 2008;36:2433-40

Sepsis changes PK Extracorporeal circuits Altered CL and Increased Vd cf AKI? Plasma concentrations

(C)RRT (Continuous) Renal Replacement Therapy Kidney Filter FLOW Semi-permeable Membrane FLOW Ultrafiltrate Dialysate

CRRT Effects on Electrolytes and Water.. and Drugs. FLOW K K Ca Ca PO4 H2O Cr Cr Cr Cr Ur Semi-permeable Membrane FLOW Ultrafiltrate +/- Dialysate

DRUG CLEARANCE If you know 1. Membrane Pore Size 2. Drug Size 3. Sieving Coefficient Then it s easy!

DRUG CLEARANCE If you know 1. Membrane Pore Size 2. Drug Size 3. Sieving Coefficient Then it s easy!

CRRT Continuous Renal Replacement Therapy Kidney Filter Access (Pre- Filter) From Patient Return (Post Filter) To Patient FLOW Semi-permeable Membrane FLOW Ultrafiltrate Dialysate

CVVHD Continuous Veno-Venous HeamoDialysis NO Replacement Fluid. Access (Pre- Filter) From Patient FLOW Kidney Filter Return (Post Filter) To Patient Semi-permeable Membrane FLOW Ultrafiltrate Dialysate

CVVHD Removal of urea, toxins, electrolytes & DRUGS (small molecules) FLOW K K Ca Ca PO4 Cr Cr Cr Cr Ur Semi-permeable Membrane FLOW Effluent Dialysate

CVVHD Sd = [Antibiotic] dialysate [Antibiotic] plasma

CVVHD Cl CVVHD Qd x Sd

CVVH Removal of H 2 O, urea, toxins, electrolytes & DRUGS (small + middle molecules) FLOW H2O K K Ca Ca PO4 H2O H2O H2O H2O H2O Cr Cr Cr Cr H2O Ur H2O Semi-permeable Membrane Ultrafiltrate

CVVH Continuous Veno-Venous Heamofiltration Replacement Fluid can be either Pre- Filter or Post Filter. Access (Pre- Filter) From Patient FLOW Kidney Filter Return (Post Filter) To Patient Semi-permeable Membrane FLOW Ultrafiltrate NO Dialysate

CVVH Sc = [Antibiotic] ultrafiltrate [Antibiotic] plasma

CVVH Cl CVVH(pre) = Qf x Sc x CF where CF = Qb Qb + Q pre

CVVHDF Continuous Veno-Venous HeamoDiaFiltration Replacement Fluid can be either Pre- Filter or Post Filter. Access (Pre- Filter) From Patient Kidney Filter Return (Post Filter) To Patient FLOW Semi-permeable Membrane FLOW Ultrafiltrate Dialysate

SLEDD as an alternative And then there is SLEDD Slow Low Efficiency Daily Dialysis, Extended Daily Dialysis A Hybrid of CRRT + IHD Minimal antibiotic clearance data published

Crit Care Med 2011;39:560 70 Nine original research articles plus a few case reports Roberts, Lipman. (Editorial) Crit Care Med 2011;39:602-3

Therapeutic Options of RRT Differ CVVH CVVHD CVVHDF SCUF SLEDD

Tables and equations

If you know 1. Membrane Pore Size 2. Drug Size 3. Sieving Coefficient Then it s easy!

If you know Convection 1. Membrane Pore Size Diffusion 2. Drug Size 3. Sieving Coefficient Protein binding Then Volume of it s distribution easy! Membrane characteristics

HOW DO WE DOSE AT MY HOSPITAL?

Roberts JA, Hope WW, Lipman J. Int J Antimicrob Agents 2010;35:419-20 Roberts JA et al. Int J Antimicrob Agents 2010;36:332-0

BEST WE HAVE Choi et al Crit Care Med 2009;37:2268-82

CRRT and MEROPENEM Jamal et al Crit Care Med 2014:42:1640-50

CRRT and PIPTAZO Jamal et al Crit Care Med 2014:42:1640-50

CRRT and VANC Jamal et al Crit Care Med 2014:42:1640-50

ONE WAY Choi et al Crit Care Med 2009;37:2268-82

Advantages Individualized CRRT MIC Takes PK/PD relationships into account Choi G et al. Crit Care Med 2009; 37: 2268-82 Choi G et al. Blood Purif 2010; 30: 195-212

Alternatively Choose a PK article that most closely resembles the form of CRRT you use Use their clearances see if it seems a reasonable estimate of your clearances Dose accordingly

RECENTLY ACCEPTED REVIEW Jamal JA, Mueller BA, Choi GYS, Lipman J, Roberts JA How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy? Diagnostic Microbiology and Infectious Disease

RECENTLY ACCEPTED REVIEW Jamal JA, Mueller BA, Choi GYS, Lipman J, Roberts JA How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy? Diagnostic Microbiology and Infectious Disease TABLE 1: Pharmacokinetic parameters of different class of antibiotics in critically ill patients receiving variable types of renal replacement therapy modalities

IMPORTANT BEDSIDE PRACTICAL POINT.. You may prescribe Continuous RRT. but is it continuous? How often do you come on morning ward round to here the kidney was off for xxx hours? How often do you do rounds to here Oh we are changing the filter Do you factor in for the down time?

IMPORTANT BEDSIDE PRACTICAL POINT.. What do you do when you want to cease RRT. We say leave the filter off for awhile to see if pt passes urine And often forget to change dose of drugs.. Do you factor in for the down time?

CRITICAL CARE Conclusions: This matched cohort study confirms an increase in Vd and a decrease in CL for meropenem in adult patients receiving ECMO. In patients receiving meropenem on ECMO, standard dosing does not always result in optimal drug concentrations because of the significant PK changes in the setting of critical illness, ECMO and RRT. Therapeutic drug monitoring where possible is recommended until robust dosing guidelines become available. Therapeutic drug monitoring

DEFINITION Therapeutic Drug Monitoring (TDM) refers to analysis and subsequent interpretation of drug concentrations in biological fluids

PLACE TDM should be used to maximise efficacy minimize toxicity To personalise dosing for high probability of therapeutic success, prevent development of resistance, provide low probability of toxicity

BETA-LACTAMS Safe drugs Large therapeutic range TDM should be used to maximise efficacy minimize toxicity

J Chromatogr B 2010;878:2039-2043

CONCLUSION For various reasons therapeutic drug monitoring (TDM) of most antibiotics is difficult if not impossible. We have set up a TDM service for all our beta-lactam use and have (not surprisingly ) shown that in more than half of our ICU patients we are dose adjusting once receiving back a drug level!

THE END! j.lipman@uq.edu.au www.som.uq.edu.au/btccrc

ONE WAY Choi et al Crit Care Med 2009;37:2268-82

Loading dose=desired concentration x Vd Calculate CRRT clearance based on mode of CRRT, formulae & published values Total clearance (Cl tot ) =calculated CRRT clearance+non-crrt clearance Time above threshold concentration Pharmacokinetic target? C max :MIC ratio C max :MIC & AUC 24 :MIC Calculate elimination rate = concentration x Cl tot Calculate half-life = 0.693 x Vd / Cl tot Calculate target mean concentration = target AUC 24 /24 Maintenance infusion rate= elimination rate Calculate time to reach target trough concentration Repeat loading dose at calculated time Calculate dosing interval = Dose/(Cp x Cl tot ) Repeat loading dose at calculated dosing interval

Loading dose=desired concentration x Vd Loading dose=desired concentration x Vd (28 l) Desired concentration = 5 x MIC = 20 mg/l Calculate CRRT clearance based on mode of CRRT, formulae & published values Loading dose = 20 x 28 500 mg Total clearance (Cl tot ) =calculated CRRT clearance+non-crrt clearance Time above threshold concentration Pharmacokinetic target? C max :MIC ratio C max :MIC & AUC 24 :MIC Calculate elimination rate = concentration x Cl tot Calculate half-life = 0.693 x Vd / Cl tot Calculate target mean concentration = target AUC 24 /24 Maintenance infusion rate= elimination rate Calculate time to reach target trough concentration Repeat loading dose at calculated time Calculate dosing interval = Dose/(Cp x Cl tot ) Repeat loading dose at calculated dosing interval

Loading dose=desired concentration x Vd Calculate CRRT clearance based on mode of CRRT & published Sc or Sd values Cl CVVH (post) = Qf x Sc = 2450 x 0.95 = 2327 ml/h = 39 ml/min Calculate CRRT clearance based on mode of CRRT, formulae & published values Total clearance (Cl tot ) =calculated CRRT clearance+non-crrt clearance Time above threshold concentration Pharmacokinetic target? C max :MIC ratio C max :MIC & AUC 24 :MIC Calculate elimination rate = concentration x Cl tot Calculate half-life = 0.693 x Vd / Cl tot Calculate target mean concentration = target AUC 24 /24 Maintenance infusion rate= elimination rate Calculate time to reach target trough concentration Repeat loading dose at calculated time Calculate dosing interval = Dose/(Cp x Cl tot ) Repeat loading dose at calculated dosing interval

Loading dose=desired concentration x Vd Calculate CRRT clearance based on mode of CRRT, formulae & published values Total clearance Total clearance (Cl tot (Cl ) =calculated tot ) CRRT clearance+non-crrt clearance clearance = 39 + 60 100 ml/min = 0.1 l/min Time above threshold concentration Pharmacokinetic target? C max :MIC ratio C max :MIC & AUC 24 :MIC Calculate elimination rate = concentration x Cl tot Calculate half-life = 0.693 x Vd / Cl tot Calculate target mean concentration = target AUC 24 /24 Maintenance infusion rate= elimination rate Calculate time to reach target trough concentration Repeat loading dose at calculated time Calculate dosing interval = Dose/(Cp x Cl tot ) Repeat loading dose at calculated dosing interval

Loading dose=desired concentration x Vd Calculate CRRT clearance based on mode of CRRT, formulae & published values Total clearance (Cl tot ) =calculated CRRT clearance+non-crrt clearance Time above threshold concentration Calculate elimination rate Pharmacokinetic target? C max :MIC ratio C max :MIC & AUC 24 :MIC = concentration x Cl tot = 20 x 0.1 = 2 mg/min Calculate elimination rate = concentration x Cl tot Calculate half-life = 0.693 x Vd / Cl tot Calculate target mean concentration = target AUC 24 /24 Maintenance infusion rate= elimination rate Calculate time to reach target trough concentration Repeat loading dose at calculated time Calculate dosing interval = Dose/(Cp x Cl tot ) Repeat loading dose at calculated dosing interval

Loading dose=desired concentration x Vd Calculate CRRT clearance based on mode of CRRT, formulae & published values Total clearance (Cl tot ) =calculated CRRT clearance+non-crrt clearance Time above threshold concentration Pharmacokinetic target? C max :MIC ratio C max :MIC & AUC 24 :MIC Calculate elimination rate = concentration x Cl tot Calculate half-life = 0.693 x Vd / Cl tot Calculate target mean concentration = target AUC 24 /24 Maintenance infusion rate = elimination rate = 2 mg/min Maintenance infusion rate= elimination rate Calculate time to reach target trough concentration Repeat loading dose at calculated time Calculate dosing interval = Dose/(Cp x Cl tot ) Repeat loading dose at calculated dosing interval