antibiotic dosing and crrt 2011 department of anaesthesia and intensive care prince of wales...
TRANSCRIPT
Antibiotic Dosing
and
CRRT
2011
Department of Anaesthesia and Intensive Care
Prince of Wales Hospital
Hong 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 Kills
Renal 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; 45:2122-2125
Guenter 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-1ra
Myoglobin
TNF-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 coefficient
The 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
Siev
ing
coef
ficie
nt
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
Fre
e fr
acti
on
(%
)
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 Qi
Charles Gomersall
Jeff Lipman
Gavin Joynt
Patricia Leung
Alex Li
Dr. 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
ffic
ient
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