Antibiotic Dosing and

CRRT2011

Department of Anaesthesia and Intensive Care

Prince of Wales HospitalHong Kong

Gordon Choi

Important concepts to consider

• Pk/Pd of antibiotics

• Principles of CRRT

• Problems with published data

• Our philosophy on how it should be done?

Renal Failure KillsRenal failure is not uncommon:

-1 to 25% in single centre

-6% in multi-international study (BEST)

Mortality rate

- up to 79% in the 90’s

- ~60% in BEST

Douma CE, Redekop WK, Van der Meulen JHP et al. J Am Soc Nephrol;1997:8:111–117

Cosentino F, Chaff C ,Piedmonte M. Nephrol. Dial. Transplant. 1994; 9 (Suppl. 4):179–182.

Uchino S, Kellum JA, Bellomo R et al.mJAMA. 2005;294(7):813-818

Sepsis is common in acute renal failure ~ 50%

Vincent JL, Bihari DJ, Suter PM, et al. JAMA 1995; 274: 639-44Uchino S, Kellum JA, Bellomo R et al.mJAMA. 2005;294(7):813-818

Cole L, Bellomo R, Silvester W. Am J Respir Crit Care Med;2000:162:191–196

Delay of effective antibiotic equates

Increased mortality

Kumar A, Roberts D, Wood KE, et al: Crit Care Med 2006; 34:1589–1596

Pk/Pd of antibiotics

Roberts JA, Lipman J. Clin Pharmacokinet 2006. 45:755-773

8-10 X

Pk/Pd of antibiotics

Roberts JA, Lipman J. Clin Pharmacokinet 2006. 45:755-773

40-100%

1-5 X

Pk/Pd of antibiotics

Roberts JA, Lipman J. Clin Pharmacokinet 2006. 45:755-773

6-8 X

AUC 24 / MIC 100-125

Pk/Pd of antibiotics

Initial Dose

- Volume of distribution (Vd)

- not relate to clearance

- but partly due to critical illness / renal failure

- agent specific

- ciprofloxacin / meropenem – same

- ceftriaxone ↑

- ceftazidime ↑- renal failure

Vd from studies with critical illness and renal failure

MacGowana AP and Wiseb R European Committee on Antimicrobial Susceptibility Testing (EUCAST)British Society for Antimicrobial Chemotherapy (BSAC) 2005

Fluoroquinolones – EUCAST/BSAC clinical MIC breakpoints

Dose protein binding breakpoint (mg/L)

susceptible ≤ resistant ≥

Ceftazidime 2 g iv 10% 2/8 4/16

Enterobacteriaceae Pseudomonas spp.

Cephalosporin – EUCAST/BSAC clinical MIC breakpoints

MacGowana APand Wiseb R European Committee on Antimicrobial Susceptibility Testing (EUCAST)British Society for Antimicrobial Chemotherapy (BSAC) 2005

?? How does it work ??

洗腎 = washing kidney

Continuous TechniquesContinuous Techniques

CVVHCVVH - - CContinuousontinuous VVenoenoVVenousenous HHemofiltrationemofiltration

CVVHDCVVHD - - CContinuousontinuous VVenoenoVVenousenous HHemoDDialysis

CVVHDFCVVHDF - - CContinuousontinuous VVenoenoVVenousenous HemoemoDDiaiaFFiltrationiltration

HVVFHVVF - - HHighigh vvolumeolume VVenoenoVVenousenous HHemofiltrationemofiltration

Solute clearance by CRRTIn general:

- hydrophilic drug

- > than 30% of clearance by renal route

- Low volume of distribution (<1L/Kg)

but ? Ciprofloxaxin / levofloxacin

- Low protein binding

but ?? Ceftriaxone

- Non renal indications of CRRT (Burns, trauma)

Gonzalez MA, Moranchel AH, Duran S et al: Clin Pharmacol Ther 1985; 37:633-637Chow AT, Fowler C, Williams RR et al: Antimicrob Agents Chemother 2001; 45:2122-2125Guenter SG, Iven H, Boos C, Bruch HP et al:Pharmacotherapy 2002; 22:175-183

HCO 1100 Polyflux Gambro

Pore Size

20 KDa10 KDa 30 KDa

Urea (60)Cr (113)

IL-1raMyoglobinTNF-α monomeric

(17kDa)

IL-6(28kDa)

40 KDa 50 KDa 60 KDa

TNF-α Trimeric(51kDa)

Vancomycin (1448 Da)

Teicoplanin (1878 Da)

Albumin (68kDa)

IgG(140kDa)

Size is important – but………

Reproduced with permission from ICU web (www.aic.cuhk.edu.hk/web8).

Importance of protein binding

Hemofiltration (CVVH) (post-dilution)

Sieving / Saturating coefficientSieving / Saturating coefficientThe capacity of a drug to pass through the hemofilter membrane

Sc = C-uf / (C-pa + C-pv) ÷ 2

Sd = C-dialystae / (C-pa + C-pv) ÷ 2

C-uf = drug concentration in the ultrafiltrateC-dialysate = drug concentration in the dialysate

C-pa = drug concentration in the plasma (arterial)

C-pv = drug concentration in the plasma (venous)AUC = Area Under Curve

0 to 1

CL (post) = S Χ Qf Blood flow rate

CL (pre) = S Χ Qf Χ -------------------------------------------------------- Blood flow rate + substitution rate

Bohler: Kidney Int Suppl, Volume 56 Supplement No. 72.November 1999.S-24-S-28

Mode of CRRT Calculation of CRRT clearance

CVVH (post-dilution) ClCVVH (post) = Qf x Sc

CVVH (pre-dilution) ClCVVH (pre) = Qf x Sc x Qb / (Qb + Qrep)

CVVHD ClCVVHD = Qd x Sd

CVVHDF ClCVVHDF = (Qf + Qd) X Sd

Equations for calculating CRRT clearance from first principles

Li Am, Gomersall CD, Choi G et al. J Antimicrob Chemother. 2009;64(5):929-37.

?? ? ? Can we estimate SCCan we estimate SC by published by published protein binding protein binding ????

SC ~ (1 – protein bound fraction)SC ~ (1 – protein bound fraction)

Authors Sieving coefficient

Guenter et al 0.77 ± 0.16

Malone et al 0.67

Traunmüller et al 0.47 ± 0.27

Hansen et al 0.97 ± 0.14

Guenter S. G., et al. Pharmacotherapy 22 (2):175-183, 2002.Malone R. S., et al. Antimicrob.Agents Chemother 45 (10):2949-2954, 2001.Traunmüller F., et al. J.Antimicrob.Chemother 47 (2):229-231, 2001.Hansen E., et al. Intensive Care Med 27:371-375, 2001.

Levofloxacin

0

0.2

0.4

0.6

0.8

1

PAN Polyamide

Filter material

Sie

ving

coe

ffici

ent

Cefpirome

Phillips G: J Clin Pharm Ther 23(5) 353 – 359 2002

Authors Sieving coefficient

Kroh et al 0.69

Matzka et al 0.48 – AN69

0.82 -PS

0.86 - PMMA

Kroh et al. J Clin Pharmacol. 36(12):1114-9, 1996

Matzka et al. Pharmacotherapy 20(6):635-643, 2000.

Ceftriaxone

Protein binding in ICUProtein binding in ICU CeftriaxoneCeftriaxone

Free

frac

tion

(%)

Joynt Gm, Lipman J, Gomersall CD et. Al. J Antimicrob Chemother;47,421;2001

Reduced Protein bindingReduced Protein binding

Disease states besides uremia,

cirrhosis

nephrotic syndrome

epilepsy

hepatitis

pregnancy

severe burns

trauma

Authors Clearance (ml/min)

Guenter et al 15.7

Malone et al 11.5

Traunmüller et al 27.6

Hansen et al 21

Ultrafiltration rate (ml/h)

1000

840-1320

3240 ± 900

1300

Differences in clearance Levofloxacin

Guenter S. G., et al. Pharmacotherapy 22 (2):175-183, 2002.Malone R. S., et al. Antimicrob.Agents Chemother 45 (10):2949-2954, 2001.Traunmüller F., et al. J.Antimicrob.Chemother 47 (2):229-231, 2001.Hansen E., et al. Intensive Care Med 27:371-375, 2001.

Li Am, Gomersall CD, Choi G et al. J Antimicrob Chemother. 2009;64(5):929-37.

Loading dose=Desired concentration xVd

Calculate CRRT clearance based on mode of CRRT, formulae in text

Pharmacokinetictarget?

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 reachtarget trough concentration

Repeat loading dose atcalculated time

Calculate target meanconcentration

= target AUC24/24

Calculate dosing interval= Dose/(Cp x Cltot / f)

Time above thresholdconcentration

Cmax:MIC & AUC24:MIC

Cmax:MIC ratio

Repeat loading dose atcalculated dosing interval

Loading dose=Desired concentration x Vd

Calculate CRRT clearance based on mode of CRRTTotal clearance Cl(tot) = calculated CRRT clearance + non-CRRT clearance

Pharmacokinteic Target

Calculate elimination rate= concentration x Cltot

Maintenance infusion rate=elimination rate

Calculate half-life=0.693 X Vd / Cltot

Calculate time to reachTarget trough concentration

Repeat loading dose atcalculated time

Calculate target meanconcentration

= target AUC24/24

Calculate dosing interval= Dose/(Cp x Ctot / f)

Repeat loading dose atcalculated dosing interval

Choi G, Gomersall CD, Tian Q Crit Care Med. 2009 Jul;37(7):2268-82

Conclusion

-Knowledge of antibiotics

-Knowledge of CRRT

-Understanding of published data

-Ideas of underlying disease process / organ failure

-Application of basic principles

Acknowledgement

Tian QiCharles GomersallJeff Lipman Gavin JoyntPatricia LeungAlex LiDr. So & Prof. Gin

AmikacinNon-Enterob70 Kg35ml/kg/hr

Choi G, Gomersall CD, Tian Q Crit Care Med. 2009 Jul;37(7):2268-82

Loading dose=Desired concentration x Vd (33 l)Desired concentration = 8 x MIC = 32 mg/l

Loading dose = 32 x 33 1000 mg

Calculate CRRT clearance based on mode of CRRT, formulae in text& values in table 5

ClHF (post) = (Qf + Qd ) x Sd= 2450 x 0.62 = 1519 ml/h 25 ml/min

Pharmacokinetictarget?

Total clearance (Cltot) =calculated CRRT clearance+non-CRRT clearance=25 + 23 = 48 ml/min

Calculate half-life= 0.693 x Vd / Cltot = 0.693 x 33000/48

= 467 min = 7.8 h

Calculate time to reach target trough concentrationAssuming target trough ?1 mg/l it will take 5 half lives for concentration to drop from 32 mg/l to target trough

40 h

Repeat loading dose atcalculated time (after 40 h)

Cmax:MIC ratio

Repeat loading dose atcalculated time (after 40 h)

Time abovethreshold

concentration

Cmax :MIC &AUC24:MIC

Not required Not required

Loading dose=Desired concentration x Vd(33 l)Desired concentration = 8 x MIC = 32 mg/l

Loading dose = 32 x 33≈ 1000 mg

Calculate CRRT clearance based on mode of CRRT, formulae in text& values in table 5

Cl HF (post) = (Qf + Qd) x Sd= 2450 x 0.62 = 1519 ml/h ≈ 25 ml/min

Total clearance (Cltot) =calculated CRRT clearance + non-CRRT clearance=25 + 23 = 48 ml/min

Calculate half-life=0.693 x Vd / Cl = 0.693 X 33000 / 48

= 487 min = 7.8 h

Calculate time to reach target trough concentrationAssuming target trough ?1 mg/l it will take 5 half lives for concentration to drop from 32 mg/l to target trough

≈40 h

Repeat loading dose atcalculated time (after 40h)

Cmax / MIC

MeropenemNon-Enterob/Entero/Stahpy70 Kg35ml/kg/hr

Choi G, Gomersall CD, Tian Q Crit Care Med. 2009 Jul;37(7):2268-82

Loading dose=Desired concentration x Vd (28 l)Desired concentration = 5 x MIC = 20 mg/l

Loading dose = 20 x 28 500 mg

Calculate CRRT clearance based on mode of CRRT, formulae in text& values in table 5

ClCVVH (post) = Qf x Sd= 2450 x 0.95 = 2327 ml/h = 39 ml/min

Pharmacokinetictarget?

Total clearance (Cltot) =calculated CRRT clearance+non-CRRT clearance= 39 + 60 100 ml/min = 0.1 l/min

Calculate elimination rate= concentration x Cltot= 20 x 0.1 = 2 mg/min

Maintenance infusion rate= elimination rate

= 2 mg/min

Time abovethreshold

concentrationCmax:MIC ratio

Cmax:MIC&AUC24:MIC

Not required Not required

Loading dose=Desired concentration x Vd (28 l)Desired concentration = 5 X MIC = 20 mg/l

Loading dose = 20 X 28 ≈ 500 mg

Calculate CRRT clearance based on mode of CRRT, formulae in text& values in table 5ClCVVH (post) = Qf x Sc

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

Total clearance (Cltot) = calculated CRRT + non-CRRT clearance= 39 + 60 ≈ 100 ml/min = 0.1 l/min

Time above MIC

Calculate elimination rate= concentration x Cltot

= 20 X 0.1 = 2mg/min

Maintenance infusion rate= elimination rate

= 2 mg/min

Sepsis Kills

Severe sepsis is common

-51% EPIC-II (European Prevalence of Infection in Intensive Care)

-71% of patients on antibiotics

- 25% vs 11% ICU mortality (p<0.01)

- 33% vs 15% Hospital mortality (p<0.01)

odds ratio- 1.36-1.68 (p<0.01)

Vincent JL, Rello J, Marshall JC, et al. JAMA 2009; 21:2123-9

Hemodialysis (CVVHD)

Reproduced with permission from ICU web (www.aic.cuhk.edu.hk/web8).

Importance of protein binding

Sie

ving

coe

ffici

ent

1

0.5

6:0 5:1 4:2 2:4 1:5 0:6

Point of dilutionVancomycin

Pre:post dilution ratio

Uchino.S: Intensine Care Medicine 28(11) 1664 – 67 2002