Antimicrobials in continuous renal replacement therapy ...

Antimicrobials incontinuous renal replacement therapy (CRRT)

Dr Catherine McKenzie PhD FFRPS FRPHARMSConsultant PharmacistGuys‘and St. Thomas’ NHS Foundation TrustSenior Clinical Lecturer School of Medicine and PharmacyKings College London

ESCMID 2015 Ferney-Voltaire

ESCMID Online Lecture Library

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Challenges

z PK alteration in critical illness superimposedz Different modes have different PK parametersz Much of older literature is out of datez Drug dosing probably requires individualised

approach


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Original literature values

Filter UFR (L/hr)

DFR (L/hr)

Dose

Ceftazidime AN69 0.43m2

0.5 1, 2 1g 24hrly Davies 1991

Ciprofloxacin AN69 0.43m2

0.4 1, 2 200mg 12-8hrly

Davies 1992

Fluconazole AN69 0.43m2

- 1 200mg 24hrly

Nicolau 1994


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Original literature…..what’s wrong with it

Assumed that RRT was equivalent to severe renal failure

• Rates were never higher than 20ml/minute

• Majority 10ml per minutes

• Does anyone ever run RRT at 10ml per minute

Took no account of critical illness

Little appreciation of resistant bacteria and variable MIC

Recommend once a day. What happens if one miss that dose

• E.g Once daily ceftriaxone in pneumococcal meningitis


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Drug Factors

z Protein bindingz Volume of distributionz Method of total body clearance (Cl)z Metabolismz PharmacodynamicsESCMID Online Lectu

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z Most medicines < 500 Dy MDZ 325 Da, LZP 320Da, Vecuronium 700Da,

Membrane cut - off: 20 -40,000 D

Does medicine size matter


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Drug factors protein binding

z The higher the binding the more likely that the antimicrobial is NOT removed by CRRT

z Albumin, 1-acid glycoprotein, lipoproteinz Drug-protein = 50,000 D

z Changes in ICU patients• pH• Albumin (), AAG ()• bilirubin• other drugs


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Protein bindingHigh (~90%)

y Ceftriaxone y Teicoplaniny Clindamycin y Amphotericin y Rifampicin

Low (<15%)

y Meropenemy Gentamicin y Fluconazoley Metronidazole y Acicloviry Fluconazolw


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Drug factores Volume of distribution (Vd)

Any medicine has to be in the central compartment to be removed by CRRT

Thus small Vd, more likely to be effectively removed by CRRT

In theory !<1L/kg removed>2L/kg unlikely


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Vd of antimicrobials commonly prescribed in critical care

z Aciclovir 0.6L/kgz Cefotaxime 0.3L/kgz Colistin 0.34L/kgz Piperacillin 0.18L/kgz Vancomycin 0.7L/kgz Linezolid 0.6L/kgz Gentamicin 0.25 l/kg

z Itraconazole 10L/kgz Moxifloxacin 2L/kgz Voriconazole 4.6L/kgz Tedizolid 1.0-1.1 L/kg


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Clearance (Cl)

z Drugs that are largelyExcreted unchanged byGFRz Likely removed by

CRTTz There are exceptions-DigoxinESCMID Online Lectu

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Total Clearance (ml/min)

= Cl renal + Cl non renal (+ Cl filter)

Cl renal > 25-30%

Pk of Clearance


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Renal clearance

High

y Benzylpenicillin (85%)

y Cefuroxime (96%)

y Ceftazidime (84%)

y Gentamicin (95%)

Low (<25%)

y Erythromyciny Clindamyciny Amphotericiny Anidulafunginy Caspofunginy Posaconazole


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Is CRRT clearance important?Vd (L/kg) % renal

Meropenem 0.25 70%Gentamicin 0.25 100%Fluconazole 0.7 75%Metronidazole 0.7 10%

Aciclovir 0.7 75%Ganciclovir 0.6 90%

Dose related neutropenia


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Is CRRT clearance important?

Protein VdBinding (L/kg)

Benzylpenicillin 60% 0.3

Cefuroxime 33% 0.19

Ceftazidime 21% 0.23

Digoxin 25% 5-8


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z Antimicrobials metabolised in liver y Tend to be, lipophilic- high protein biding, larger Vd,

reduced renal Clz Don’t forget ..pro drugs

y Pro drugs………oseltamivir to oseltamivir carbxylate. Active compound is renally excreted.

z Or active metabolites toxicityy Methylflucloxacillin, hepatotoxicity in renal failure

EMC, Kucers and Bennett

Drug Factors…. hepatic metabolism


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S = Chf / Cpre-filter

x Haemofiltrationx Protein binding

(Golper 1991)

Absolute Value -Sieving coefficient


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Important consideration in drug therapy (especially, antimicrobials)

Early therapy essential, amount often forgotten,

Vd= volume of distribution

Cp= plasma concentration

Loading dose is independent of renal function

A high initial dose may be preferred when treating infection in the intensive care

Vale et al Antibiotic therapy in severe sepsis: does the dose matter? Critical Care 2010)


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Classification of antibiotic according to their solubility and pharmacokinetic /pharmacodynamic properties


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Aminoglycosides, fluoroquinolones, colistin High initial dose required for maximum effect gentamicin, larger peak

greater reduction in mortaility(CID 2000) Ciprofloxacin, Inhibitory ratio , pkarea/MIC

Larger, less frequent dosing can be associated with less adverse events

Aminoglycoside nephrotoxicity, uptake into renal cortex saturable, less dosing less uptake

Begg et al what is the evidence for once daily aminoglycoside

Clinical Pharmacokinetics 2001


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Time dependence Beta lactams vancomycin

Achieve the target concentration quickly and maintain it Loading dose or large initial dose still important Optimal effect when time > MIC ?

Increased probability of success with T>MIC at 90 to 100 % of the dosing interval.

In ICU –possibility of lower initial Cp and higher desired MIC

• Roberts J et al Lancet 2015,

• McKenzie CA Antibiotic Dosing in Critical Illness

JAC 2011ESCMID Online Lecture Library

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Aminoglycosides, fluoroquinolones, colistin High initial dose required for maximum effect

gentamicin, larger peak greater reduction

in mortaility(CID 2000) Ciprofloxacin, Inhibitory ratio , pkarea/MIC

Larger, less frequent dosing can also be associated with less adverse events

Aminoglycoside nephrotoxicity, uptake into renal cortex saturable, less dosing less uptake

Begg et al what is the evidence for once daily aminoglycoside Clinical Pharmacokinetics 2001McKenzie CA Antibiotics dosing in critical careJAC 2011


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System factors

z Filter typez Haemofiltration ratez Dialysate ratez Membrane Interactions


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Renal Replacement Therapy

• RRT = Life support treatment for renal failure• Includes dialysis, filtration and transplantation

• Terms:• PD – peritoneal dialysis (rarely used in ICU)• IHD – intermittent hemodialysis (rarely used in ICU outside USA)• SCUF – slow continuous ultrafiltration• CVVHD – continuous veno-venous hemodialysis• CVVHF – continuous veno-venous hemofiltration• CVVHDF – continuous veno-venous hemodiafiltration

• EDD(-f) – extended daily dialysis (diafiltration)• SLED

• IHD and PD standardised, everything else….


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System factorsHaemofiltration rate

z 1 to 4litre per hour , often expressed in ml/kgz Convective transport

z Transmembrane pressurey Blood pump speedy Hydrostatic pressurey Oncotic pressureESCMID Online Lectu

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System Factors CVVHD rate

z 1 - 4 L/hrz Dosed per ideal body weight (lean IBW)z Diffusive transport

z Blood : Dialysate = 150 : 17-34 ml/min z Maximise concentration gradient

y dialysate rateESCMID Online Lecture Library

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Only UNBOUND drug is filtered

Ultrafiltrate

FLOW

FLOW

Semi-permeable Membrane

RRT: Protein Binding

+/- Dialysate

Bound

Drug

Unbound

Drug

Protein


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Extended Dialysis

z In AKI or CKD if patient anuric, NO RENAL CLEARANCE

z Much considerations same as CKDz Give renally cleared drugsz E.g Vancomycin

y Aminoglycosidez Beginning of dialysisz Check serum level at completionObserved from clinical practice


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Patient Factors Pragmatic

z CRRT stops, filter clotsz Patients escapes for procedurez Consider omitting dose if lasts greater than 4 hours z Daily review essential by Clinical Pharmacist

Barret NB et al IJPP 20111Shulman RS et al Journal of Critical Care 2015


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Patient Factors Volume of distribution (Vd)

z Changes in critically ill patientsInfection !

Severe sepsisVd of many agents can increase as extracellular fluid

increasesx Increase in Vd in severe sepsis

z .y Serum albumin can dropy What happens to drug-albumin binding

Roberts et al Lancet Infect Dis. 2014 Jun; 14(6): 498–509


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Patient factors

z Altered PK-Pd of drugs in critical illnessy Effects of heart failurey Effects of liver failure- presence of ascites

z Deep tissue infectionsz Immune system/presence of immunosuppresantsz Co-morbidities, COPD, CVA, tissue burnsAllen JA et al JAC 2014McKenzie CA et al Critical Care 2005ESCMID Online Lectu

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Patient FactorSepsis changes PK and PD

Extracorporeal circuits (e.g. RRT)

Altered CL andIncreased Vd

? Plasma concentrations

If dosing does not account for these changes – sub-optimal levels!

Sub-optimal patient outcomes


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SO Which dose for your patient

z Literature valuez Calculatez Best guessz Conduct study ?z Refer to guidelines (that are up to date)


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Literature Values

z Ceftazidime 1 to 2g iv 12 hourly CVVH/HD/HDFz Ciprofloxacin 200 to 400mg iv 12 hourly

y @GSTT 800mg iv 8 hourly in obese patientsz Fluconazole 400mg to 800mg iv/po 24 hourly

y Drug interactions (antipsychotics)

Some now out of date ? For higher MIC

Trotman and colleagues CID 2005;41:1159-66


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Aciclovir –for HSV pneumonitis in CRRT

z Vd = 0.7l/kgz Renal eliminationz T half-lifez Neurotoxicity at high dosesz Dose in normal renal function is 10mg/kg 8hourlyz 10mg per kg (weight 50kg)

y Chest penetrationy ImmunocompromisedESCMID Online Lectu

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Aciclovir…….

z Depends on rate of CRRTz 30ml per kg per hour= 30ml per minutez Mild renal impairmentz I would recommend 10ml per kg 8 hourlyz Serum levelsz Review dose daily


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Looking forward………..

Don’t forget the pathogen !

• Rapid diagnosis will help

Point of Care Testing for

antimicrobials

Citrate –longer life circuits

• PKPD studies needed

Ostermannand colleagues Nephron 2015


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Antimicrobials in continuous renal replacement therapy ...

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