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Antibiotic Dosing and CRRT 2011. Gordon Choi. Department of Anaesthesia and Intensive Care Prince of Wales Hospital Hong Kong. Important concepts to consider. Pk/Pd of antibiotics Principles of CRRT Problems with published data Our philosophy on how it should be done?. - PowerPoint PPT Presentation
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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