Stefaan J. Vandecasteele, MD, PhD Department Nephrology and Infectious diseases

AZ Sint-Jan, Brugge, Belgium

Antibiotic dosing in patients with altered renal function:

An evidence-based approach.

Kollef, 1999, Chest, 462-474

Seyler, 2011,Crit Care, R137

Ambrose, 2007, CID, 79-86

Craig, 1998, CID, 1-12

1. Importance of adequate AB

1. Inadequate AB → mortality ↑ 2,37 x in ICU population

.

Prospective data

All ICU admission

2000 patients

655 infections

42,0 %

17,7 %

No AB

Resistance to AB

Inadequate dose

2. Treatment failure = continuum

Microbiological success

Clinical success

Prevention resistance

Marilyn, 2012, AAC, 2795-2805

Ambrose, 2007, CID, 79-86

Craig, 1998, CID, 1-12

.

ANTIBIOTIC CONCENTRATION

MIC

RO

BIO

LO

GIC

AL

CU

RE

CLIN

IC

AL

CU

RE

PE

RS

IST

AN

T

SU

BP

OP

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NS

DE

VE

LO

PM

EN

T

OF R

ES

IST

AN

CE

SLO

W T

RE

AT

ME

NT

R

ES

PO

NS

E

FU

LL T

RE

AT

ME

NT

FA

ILU

RE

2. How to determine AB dose ?

.

Paradigm = PK/PD targets Marilyn, 2012, AAC, 2795-2805

Ambrose, 2007, CID, 79-86

Craig, 1998, CID, 1-12

Marilyn, 2012, AAC, 2795-2805

DOSING

+ EFFECT/

TOXICITY

NORMAL

KIDNEY

FUNCTION

DOSING

(+ EFFECT/

TOXICITY) ?

DECREASED

KIDNEY

FUNCTION

Patel et al, JAC, 2010, 2285-2290 Verbeeck et al, Eur J Clin Pharmacol, 2009, 757-773

Pea et al, Clin Pharmacokinet, 2007, 997-1038 Scoville, 2013, AJKD, 490-500

CLplasma

Vd

Plasma T1/2

EXTRAPOLATION

How are drug dosed in CKD ?

Accumulation of extrapolations = REASON FOR INAPPROPRIATE DOSING

1. Non-renal effects of CKD on PK/PD

ABSORPTION (F, bioavailibility) 1. Tmax may ↑ 2. phosphate binders (fluoroquinolones)

DISTRIBUTION 1. ↓ protein binding acid drugs unbound

fraction↑ : impact on plasma clearance

: total plasma concentration may ↓

: free concentration = 2. Volume of distribution (Vd): generally ↑, sometimes

↓ (ethambutol)

ELIMINATION: SUM of Non-renal clearance + Renal clearance

Pharmacokinetics = the way the body manipulates the drug

Non- Renal ELIMINATION: → Alteration of drug-metabolism (in ESRD):

1. CYP450 enzymes (CYP3A, erythromycine – 30 %; CYP2C9, warfarin – 50 %)

and acetyltranferases 2. Accumulation of phase I and II metabolites, which may be

active, e.g. glucuronide conjugates, opioids 3. Renal phase I metabolism, e.g. Imipenem

: Usually not measured

: Usually not measured, e.g. ↑ effect enoxaparin

Pharmaco-dynamics = effects of a drug and mechanism of action

PK/PD indices = quantitative relation between PK, PD and microbiological effects

: Usually not measured

Patel et al, JAC, 2010, 2285-2290 Verbeeck et al, Eur J Clin Pharmacol, 2009, 757-773

Pea et al, Clin Pharmacokinet, 2007, 997-1038

Cockcroft-Gault CKD-EPI MDRD

(140-age) x weight x (0.85 if F) (Scr) x 72

186 x Scr(mg/dl)-1.154 x age (age) – 0.203

x (1.212 if black) x (0.742 if female) 141 X min(Scr/κ,1)α X max(Scr/κ,1)-

1.209 X 0.993Age X 1.018 [if female] X 1.159 [if black]

Cockcroft DW and Gault, Nephron 1976; 16:31-41 Levey et al, JASN 2000; 11: 155A [Abstract]

Levey, Ann Int Med, 2009, 604-612

2. Methods to estimate GFR

0 20 40 60 80 100

FDA/EMEA

KDOQI100 15 30 45 60 80

CKD-1/2 CKD-3B CKD-3A CKD-4 CKD-5

Normal Moderate ↓ Mild ↓ Severe ↓ ESRD

50

Verbeeck et al, Eur J Clin Pharmacol, 2009, 757-773 NDT, 2010, 25, 2832-2836

Matsushita, JAMA, 2012, 1941-1951

CONTINUOUS VARIABLE

DICHOTOMOUS VARIABLE

Bacterial Population

• Infection = infectious population 10-1010

(e.g. 100.000.000 bacteria/ml pus)

Bacteria

3. Methods to estimate susceptibility

• MIC = minimal inhibitory concentration in

90 % of the population = MIC90

Variability in

susceptibility

between

bacterial

populations

http://www.eucast.org/

Within one bacterial population (e.g.109 bacteria)

Variable subpopulations (phenotypes/genotypes)

Ryall, Microbiol Molec Review, 2012, 597-625

4. Mutation selection kinetics

In vitro model

MIC < dose < MBC

Susceptible and resistant

Drusano, JID, 2009, 199, 219-226

Matinez, AAC, 2012, 56, 2795-2805

In vitro model

Growth of resistant mutants

Hydrophilic AB

• Beta-lactam •Penicillins •Cephalosporins •Carbapenems •Monobactams

• Glycopeptides • Aminoglycosides

No passive diffusion through cell membrane 1. Limited Vd

2. Mainly renal elimination as unchanged drug

3. Inactive against intracellular pathogens

4. Adaptation for dialysis Exp: ceftriaxone, oxacillin

Lipophilic AB

• Macrolides • Fluoroquinolones • Tetracyclines • Rifampicin • Linezolid • Chloramphenicol

Passive diffusion through cell membrane 1. Large Vd

2. Mostly eliminated after hepatic metabolism

3. Active against intracellular pathogens

4. No adaptation for dialysis Exp: Levofloxacin, ciprofloxacin

3. AB in CKD: rules of thumb

1. ALWAYS GIVE A LOADING DOSE: • Dose only depends on extracellular volume • Independent of CLPL

2. DOSE ADAPTATIONS: • For antibiotics with renal clearance • Usually only for advanced renal failure • 2 possible strategies:

1. Maintaining the dose, prolonging dosing interval 2. Maintaining the dose interval, decreasing the dose

3. EVIDENCE BASED DOSING IN CKD: • Chaotic, very incomplete ...

4. AB DOSING IN ESRD: • IV treatment on dialysis days only ??

Day 1 Day 7 Day 6 Day 5 Day 4 Day 3 Day2

Hydrophylic →Low Vd ↑ in ESRD : 0,2 – 0,4 L/kg

Variable, but generally low protein binding ↓ in ESRD (exception ceftriaxone, flucloxacillin)

Short T1/2 < 1 – 4 hours ↑ in ESRD

Drusano, 2004, Nat Rev Microbiol, 289-300 Gilbert, Infect Dis Clin North Am, 2009, 899-924

T > MIC: +/- 40 % carbapenems +/- 50 % cephalosporins 60-70 % penicillins

4. β-lactam antibiotics

Mainly renal elimination (unchanged): • High GFR • Tubular secretion (OAT, MDR) ~ 4 gr penicillin • Tubular reabsorption (PEP)

Wide therapeutic index : • Hypersensitivity reactions • hypokalemia (non-reabsorbable anion)

In case of accumulation: • Neurotoxicity • Bleeding disorders (cefazollin,

ticarcillin, ...

Drusano, 2004, Nat Rev Microbiol, 289-300 Gilbert, Infect Dis Clin North Am, 2009, 899-924

1. Piperacillin-tazobactam

• 105 ptn (pooled data 5 studies)

• Presumptions:

1. Model only for piperacillin

2. Clpip = (Clslope x eClcreat) + IC

3. PK/PD target = 50 %fT>MIC

4. Toxicity level ≤ 4x AUCratio

5. 2 compartment model

6. Monte-Carlo analysis for two eGFR

7. Limited N°of MIC in 0,25 – 32 µg/ml range

Patel, JAC, 2010, 65, 2285-2290 Patel, AAC, 2010, 460-465

21 ptn

AUC24S 3,375 gr EI/8 hr for Clcreat 40

AUC24S 3,375 gr EI/8 hr for Clcreat 100

AUC24S 3,375 gr EI/8 hr for Clcreat 20

AUC24S 3,375 gr EI/8 hr for Clcreat 100

1,54 2,00

Patel, JAC, 2010, 65, 2285-2290 Patel, AAC, 2010, 460-465

2. Cefazolin (HD) • T1/2-CKD0 →T1/2-CKD5 : 1,8 → 32 hours

Lavillaureix, 1975, Infection,105-114

• Use: 123 HD ptn, Pros Randomized Trial • vancomycin versus cefazolin, MSSA sepsis

• Dose cefazolin: 1 gr/24h elapse

• Treatment failure: 31% vanco-13% cefazolin (p .02)

Stryjjewsky, CID, 2007, 190-796

• HD dose cefazolin: 15 mg/kg/24 hour elapse ?? − 15 HD ptn, 20 mg/kg, pre-dialysis 42-46 µg/ml

Marx, AJKD, 1998, 410-414

− 15 HD ptn, 2 gr fixed dose, 84, 97 & 61 µg/ml pre-dialysis at 2, 4

and 7 days Kuypers, NDT, 1999, 2050-2051

− 25 HD ptn, 15 mg/kg, reduction rate 52-60 % Sowinski, AJKD, 2001, 766-776

− 34 HD ptn, 20 mg/kg, 72h pre conc 43 [9-98] µg/ml Ahern, Am J Health Syst Pharmacol, 2003, 178-181

3. Ceftazidime

• 6 ptn; ESRD + dialysis

Loo, AAC, 2013, 5854-5859

3. Ceftazidime

• 6 ptn; ESRD + dialysis

Loo, AAC, 2013, 5854-5859

→ Daily administration in case of ESRD

4. Temocillin (HD)

Number of subjects 16

Number of occasions 18

Gender (male/female) 14/2

Age (Y) 70.50 (IQR 66.50-76.25)

Dry body weight (kg) 75 (IQR 65-82)

1000mg dose – 24h cycle 7/63

2000mg dose – 48h cycle 39/63

3000mg dose – 72h cycle 17/63

Cycles per subject median 3.5 (min: 2, max: 8)

PK/PD study

HD patients

1 gram/24 h elapse

Agent Protein

Bind-ing

T1/2 Extraction

Rate/h

clearance

IV Dosage Dosing in

haemo-

dialysis

Normal

CrCl > 90

ESRD

CrCl < 15

Normal

ClCr > 90

CKD III

30 < < 60

CKD V

ClCr < 15

Penicillinase resistant-penicillins:

Fluxloxa-cillin

95 0.8 2.9 6 ml/min 2g/4h 2g/8h$

6-12g CI*

NA 2g/4-6h ClCr<15 DGAD

Aminopenicillins:

Ampicillin 17 1.2 17.4 61 ml/min 9 %

1-2g/4-6h 1-2g/4-6h 1-2g/8-12h ClCr<15 DGAD

Carboxypenicillins

Ticarcillin 50 1.2 13 50 % 2g/4h NA 2g/12h ClCr<15 DGAD

Temocillin 80 3.5 17.5 10 ml/min 8 %

2g/8h 4g CI*

NA 1-2g/24h 1g/24h 2g/48h 3g/72h

Ureidopenicillins

Piperacillin 30 1.4 2-3.6 8-90 ml/min

3.4g/4-6h 3.4g/6h$

3.4g/6-8h 3.4g/6h$

3.4g/8-12h 3.4g/12h$

ClCr<15 DGAD

First-generation cephalosporins

Cephazolin 80 1.8 32.0 31 ml/minA 62 %A

18 ml/minB 52 %B

1-2 g/6h 0.5-2g/12h 0.5-2g/24h 15 mg/kg/24

hour elapse

Trough ~ AUC Renal elimination

Wide overlap dose/response & dose/toxicity Nephrotoxicity and Ototoxicity

Vandecasteele, JAC, 2013, 68, 743-748 Vandecasteele, Kidney International, 2011, 77, 760-764

CID, 2006, 42, S35-S39

MIC

5. Vancomycin

Fundaments vancomycin dosing guidelines 1 study 1984, 56 ptn, among them 30 with CLCR < 10 ml/min (C & G)

Matzke, AAC, 1984, 25, 433-437

Vandecasteele, JAC, 2013, 68, 743-748.

Data Matzke 1984 (20 ptn) + extrapolation to target Trough 15-20 µg/ml

Trough 15-20 µg/ml

Plateau 20-25 µg/ml

3-fasic PK profile Trough 16,6 - 20,9 µg/mL 24h AUC/MIC 455 – 541 For a MIC=1µg/mL r2=0.97, p= 0.016

5 haemodialysis patients SA bloodstream infection Vancomycin IV

1st: AUC can be substituted by pre-dialysis trough levels

Vandecasteele, CID, 2011;53:124-9

Before intervention With VDC calculator

2nd: population PK/PD of vancomycin in dialysis patients

Vandecasteele, CID, 2011;53:124-9

211 122

VDC - Vancomycine Dose Calculator (release 1.2)

© 2011 Dr. Vandecasteele SJ & Dr. De Vriese AS, Department of Nefrology, AZ St-Jan Brugge-Oostende AV, Brugge, Belgium

Trough level before (µg/ml) 12 Recommended Loading Dose (mg) = 2225

Weight (kg) 89

Days to next dialysis 2 Recommended Maintenance Dose (mg) = 1300DOSE Expected TL

0 9,5 1335 15 20

50 9,8 2225 15 20

100 10,1 3115 15 20

150 10,4 2225 15 20

200 10,8 1300 15 20

250 11,1 15 20

300 11,4 15 20

350 11,7 15 20

400 12,0 15 20

450 12,3 15 20

500 12,6 15 20

550 12,9 15 20

600 13,2 15 20

650 13,5 15 20

700 13,8 15 20

750 14,1 15 20

800 14,5 15 20

850 14,8 15 20

900 15,1 15 20

950 15,4 15 20

1000 15,7 15 20

1050 16,0 15 20

1100 16,3 15 20

1150 16,6 15 20

1200 16,9 15 20

1250 17,2 15 20

1300 17,5 15 20

1350 17,9 15 20

1400 18,2 15 20

1450 18,5 15 20

1500 18,8 15 20

0

5

10

15

20

25

0 125 250 375 500 625 750 875 1000 1125 1250 1375 1500

EX

PE

CT

ED

TR

OU

GH

LE

VE

L (µg

/ml)

VANCOMYCINE DOSE (mg)

Multiple effector model 3 parameters → 94,7 % variability

3rd: validation Vancomycin Dose Calculator in dialysis patients

http://www.azbrugge.be/vancomycindosecalculator

Questions ?

Ahern, Am J Health Syst Pharmacol, 2003, 178-181