ANTIBIOTIC DOSE AND DOSE INTERVALS IN RRT and ECMO

Department of

Intensive Care Medicine

Royal Brisbane Hospital

University of Queensland

Professor Jeffrey Lipman

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 non-critically 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.

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

The kidney and antibiotics

Cmax Peak Concentration

Cmin Trough Concentration

t1/2 Half-life

V (or VD) Volume of distribution

AUC Area under curve

Cl Clearance

Protein binding

Antibiotic related IMPORTANT

pharmacokinetic parameters

Capillary lead and fluid administration

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

….we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations.

35mg/kg loading 35mg/kg/day

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

VOLUME OF DISTRIBUTION

ALTERATIONS IN ICU

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

Kidney Filter

Ultrafiltrate Dialysate

Semi-permeable Membrane

(C)RRT

(Continuous) Renal

Replacement Therapy

Ultrafiltrate

Semi-permeable

Membrane

CRRT Effects on Electrolytes and Water

..…and Drugs.

+/- Dialysate

K Ca PO4

Ur Cr Cr

K Ca PO4

H2O H2O

Then it’s easy!

If you know

1. Membrane Pore Size

2. Drug Size

3. Sieving Coefficient

DRUG CLEARANCE

Then it’s easy!

If you know

2. Drug Size

DRUG CLEARANCE

CRRT Continuous Renal Replacement Therapy

Access (Pre- Filter)

From Patient

Return (Post Filter)

To Patient

Kidney Filter

From Patient

To Patient

Kidney Filter

CVVHD Continuous Veno-Venous HeamoDialysis

NO Replacement Fluid.

Effluent

Semi-permeable

Membrane

CVVHD Removal of urea, toxins, electrolytes

& DRUGS (small molecules)

Dialysate

K Ca PO4

Ur Cr Cr

K Ca PO4

Sd = [Antibiotic] dialysate

[Antibiotic] plasma

ClCVVHD ≈ Qd x Sd

Ultrafiltrate

Semi-permeable

Membrane

K Ca PO4

Ur Cr Cr

K Ca PO4

H2O H2O

CVVH Removal of H2O, urea, toxins, electrolytes

& DRUGS (small + middle molecules)

H2O H2O

From Patient

To Patient

Kidney Filter

Ultrafiltrate

CVVH Continuous Veno-Venous Heamofiltration

Replacement Fluid can be either

Pre- Filter or Post Filter.

NO Dialysate

[Antibiotic] ultrafiltrate

[Antibiotic] plasma Sc =

Cl CVVH(pre) = Qf x Sc x CF

where CF = Qb

Qb + Q pre

From Patient

To Patient Kidney Filter

Ultrafiltrate

CVVHDF Continuous Veno-Venous HeamoDiaFiltration

Dialysate

Replacement Fluid can be either

Pre- Filter or Post Filter.

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

Roberts, Lipman. (Editorial) Crit Care Med 2011;39:602-3

Crit Care Med 2011;39:560–70

Nine original research articles plus a few case reports

Therapeutic Options of

RRT Differ

CVVHDF

Tables and equations

Then it’s easy!

If you know

2. Drug Size

Then it’s easy!

If you know

2. Drug Size

Convection

Diffusion

Protein binding

Volume of distribution

Membrane characteristics

HOW DO WE DOSE

AT MY HOSPITAL?

Roberts JA et al. Int J Antimicrob Agents 2010;36:332-0

Roberts JA, Hope WW, Lipman J. Int J Antimicrob Agents 2010;35:419-20

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

CRRT and VANC

ONE WAY

Advantages

Individualized

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”?

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.

CRITICAL CARE

Therapeutic drug monitoring

DEFINITION

Therapeutic Drug Monitoring (TDM)

refers to analysis and subsequent

interpretation of drug concentrations in biological fluids

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

Time above threshold

concentration Cmax:MIC & AUC24:MIC

Cmax:MIC ratio

Loading dose=Desired concentration x Vd

Calculate CRRT clearance based on mode of CRRT, formulae & published values

Pharmacokinetic

target?

Calculate elimination rate

= concentration x Cltot

Total clearance (Cltot) =calculated CRRT clearance+non-CRRT clearance

Maintenance infusion rate=

elimination rate

Calculate half-life

= 0.693 x Vd / Cltot

Calculate time to reach

target trough concentration

Repeat loading dose at

calculated time

Calculate target mean

concentration

= target AUC24/24

Calculate dosing interval

= Dose/(Cp x Cltot )

calculated dosing interval

Cmax:MIC ratio

Pharmacokinetic

target?

elimination rate

Calculate half-life

calculated time

concentration

= target AUC24/24

Loading dose=Desired concentration x Vd (28 l)

Desired concentration = 5 x MIC = 20 mg/l

Loading dose = 20 x 28 500 mg

Cmax:MIC ratio

Pharmacokinetic

target?

elimination rate

Calculate half-life

calculated time

concentration

= target AUC24/24

Calculate CRRT clearance based on mode of CRRT

& published Sc or Sd values

ClCVVH (post) = Qf x Sc

= 2450 x 0.95 = 2327 ml/h = 39 ml/min

Cmax:MIC ratio

Pharmacokinetic

target?

elimination rate

Calculate half-life

calculated time

concentration

= target AUC24/24

= 39 + 60 100 ml/min = 0.1 l/min

Cmax:MIC ratio

Pharmacokinetic

target?

elimination rate

Calculate half-life

calculated time

concentration

= target AUC24/24

= 20 x 0.1 = 2 mg/min

Cmax:MIC ratio

Pharmacokinetic

target?

elimination rate

Calculate half-life

calculated time

concentration

= target AUC24/24

Maintenance infusion rate

= elimination rate

= 2 mg/min

ANTIBIOTIC DOSE AND DOSE INTERVALS IN RRT and ECMO

Documents

The SPE Foundation through member donations and a … · 2020. 5. 7. · –Visualisation Grötsch, 2016 4. Integrated Reservoir Modelling ... RRT-1 RRT-2 RRT-3 RRT-4 RRT-5 Example:

Dialysis Dose Prescription and Delivery - … Dose Prescription and Delivery . Dose in RRT: ... 618 patients enrolled in a ... O overload combined with loss of lean

Neurologic Complications in Adult ECMO...Neurologic Complications in Adult ECMO Joseph B. Zwischenberger MD Johnston-Wright ProfessorStroke In ECMO Multi-institutional study of ECMO

indications for ECMO indications for ECMO support · Avalon DLC ECMO cannula January 2009: First aeromedical ECMO retrieval in NSW 17 year-old female, community-acquired pneumonia,

ECMO Pediatrico

EuroELSO 2017 · results in ECMO patients ECCO2R Auditorium 2 Pathophysiology issues in VV-ECMO Controversies in VA-ECMO Designing a better ECMO-system: clues for the future Complications

Animal model to study feasibility of VV ECMO using RRT platform – Pilot study

MODALITIES OF RRT in · 2016. 5. 23. · dyselectrolytemias catabolism drugs nutrition recovery function survival hemodynamic stability timing delivered dose nursing techs education

ECMO monitoring & nursing

ECMO circuit & oxygenator

MATERIAL DE APOIO PARA TREINAMENTO ECMO · 2019. 4. 2. · 4 1. Aspectos gerais da ECMO/ECLS 1.1. CONCEITO DE ECMO/ECLS - ELSO ECMO: Extracorporeal Membrane Oxygenation ECLS: Extracorporeal

Desired Orientation RRT (DO-RRT) for Autonomous Vehicle in …dyros.cafe24.com/paper/iros2016_sh.pdf · Desired Orientation RRT (DO-RRT) for Autonomous Vehicle in Narrow Cluttered

Ecmo presentation final

What is ECMO? - Welcome to Point of Care.net · What is ECMO? Chris Beaty, BSN, RN, ... Neonatal ECMO –Late 1970s-early 1980s . ECMO History ... Patient Management

Ecmo Garrahan

complicanze ECMO

ECOS-TCS › wp-content › uploads › 2020 › 0… · Life after ECMO Interactive session around VV ECMO Workshop: ECMO and CRTT List Workshop: ECMO cannulation Workshop: ECMO

ECMO Basics

ECMO: circuito

ANTIBIOTIC DOSE AND DOSE INTERVALS IN RRT and … 3/0… · · 2016-04-13ANTIBIOTIC DOSE AND DOSE INTERVALS IN RRT and ECMO Department of Intensive Care Medicine Royal Brisbane