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?
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%
Delay of effective antibiotic
equates
Increased mortality
Cole L, Bellomo R, Silvester W. Am J Respir Crit Care Med;2000:162:191–196
Kumar A, Roberts D, Wood KE, et al: Crit Care Med 2006; 34:1589–1596
Vincent JL, Bihari DJ, Suter PM, et al. JAMA 1995; 274: 639-44
Uchino S, Kellum JA, Bellomo R et al.mJAMA. 2005;294(7):813-818
Pk/Pd of antibiotics
8-10 X
Roberts JA, Lipman J. Clin Pharmacokinet 2006. 45:755-773
Pk/Pd of antibiotics
40-100%
1-5 X
Roberts JA, Lipman J. Clin Pharmacokinet 2006. 45:755-773
Pk/Pd of antibiotics
6-8 X
AUC 24 / MIC
100-125
Roberts JA, Lipman J. Clin Pharmacokinet 2006. 45:755-773
Pk/Pd of antibiotics
Initial Dose
- Volume of distribution (Vd)
- not relate to clearance
Vd from studies with
critical
illness
- agent
specific and renal failure
- but partly due to critical illness / renal failure
- ciprofloxacin / meropenem – same
- ceftriaxone ↑
- ceftazidime ↑- renal failure
Fluoroquinolones – EUCAST/BSAC clinical MIC breakpoints
MacGowana AP and Wiseb R
European Committee on Antimicrobial Susceptibility Testing (EUCAST)
British Society for Antimicrobial Chemotherapy (BSAC) 2005
Cephalosporin – EUCAST/BSAC clinical MIC breakpoints
Dose
protein binding
breakpoint (mg/L)
susceptible ≤
Ceftazidime
2 g iv
10%
Enterobacteriaceae
2/8
resistant ≥
4/16
Pseudomonas spp.
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 Techniques
CVVH - Continuous VenoVenous Hemofiltration
CVVHD - Continuous VenoVenous HemoDialysis
CVVHDF - Continuous VenoVenous HemoDiaFiltration
HVVF - High volume VenoVenous Hemofiltration
Solute clearance by CRRT
In 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; 37:633-637
Chow 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
Pore Size
HCO 1100 Polyflux Gambro
Size is important – but………
Urea (60)
Cr (113)
10 KDa
IL-1ra
Myoglobin
TNF-α monomeric
(17kDa)
20 KDa
Vancomycin (1448 Da)
Teicoplanin (1878 Da)
IL-6
(28kDa)
30 KDa
40 KDa
TNF-α
Trimeric
(51kDa)
50 KDa
Albumin
(68kDa)
60 KDa
IgG
(140kDa)
Importance of protein binding
Hemofiltration (CVVH)
(post-dilution)
Reproduced with permission from ICU web (www.aic.cuhk.edu.hk/web8).
Sieving / 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 ultrafiltrate
C-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
Equations for calculating CRRT clearance
from first principles
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
Li Am, Gomersall CD, Choi G et al. J Antimicrob Chemother. 2009;64(5):929-37.
SC ~ (1 – protein bound fraction)
? ? Can we estimate SC
by published protein binding ??
Levofloxacin
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.
Sieving coefficient
Cefpirome
1
0.8
0.6
0.4
0.2
0
PAN
Polyamide
Filter material
Phillips G: J Clin Pharm Ther 23(5) 353 – 359 2002
Ceftriaxone
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.
Protein binding in ICU
Free fraction (%)
Ceftriaxone
Joynt Gm, Lipman J, Gomersall CD et. Al. J Antimicrob Chemother;47,421;2001
Reduced Protein binding
Disease states besides uremia,
cirrhosis
nephrotic syndrome
epilepsy
hepatitis
pregnancy
severe burns
trauma
Differences in clearance
Levofloxacin
Authors
Clearance (ml/min)
Ultrafiltration rate (ml/h)
Guenter et al
15.7
1000
Malone et al
11.5
840-1320
Traunmüller et al
27.6
3240 ± 900
Hansen et al
21
1300
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
Loading dose=Desired
concentration x Vd
CRRT clearance
based on mode of
CRRT, formulae
in text
CalculateCalculate
CRRT
clearance
based
on
mode of CRRT
Total clearance Cl(tot)
= calculated CRRT clearance + non-CRRT clearance
Total clearance (Cl ) =calculated CRRT clearance+non-CRRT clearance
tot
Time above threshold
concentration
Pharmacokinetic
Pharmacokinteic
target?
Target
Cmax:MIC & AUC 24:MIC
C max:MIC ratio
Calculate
elimination raterate
Calculate
elimination
= concentration x Cl
= concentration x totCltot
Calculate
half-life
Calculate half-life
= 0.693X
x Vd
/ Cl/totCl
=0.693
Vd
tot
Calculate
target mean
Calculate target mean
concentration
concentration
= target AUC24/24
= target AUC24/24
Calculate
time
to reach Calculate
Calculate time
to reach
interval
Calculatedosing
dosing interval
targettrough
trough concentration
Cltot / f)/ f)
= Dose/(Cpxx C
Target
concentration
= Dose/(Cp
tot
Maintenance
infusion
rate=
Maintenance
infusion rate=
elimination rate
elimination rate
Repeat
dose
at Repeat
dose
Repeatloading
loading dose
at at
Repeat loading
loading dose
at
calculated timetime
calculated
calculateddosing
dosing interval
calculated
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
Loading dose=Desired
concentration x Vd(33 l)
Loading dose=Desired concentration x Vd (33 l)
concentration ==8 8
x MIC
= 32 mg/l
Desired Desired
concentration
x MIC
= 32 mg/l
Loading dose = 32 x 33  1000 mg
Loading dose = 32 x 33≈ 1000 mg
Calculate CRRT clearance based on mode of CRRT, formulae in text
Calculate CRRT clearance based on mode of CRRT, formulae in text
& &values
in table
5
values in table
5
Cl (post) = =
(Qf (Qf
+ Qd )+x Sd
Cl
Qd) x Sd
HF (post)
= 2450
x 0.62 = 1519 ml/h  25 ml/min
= 2450 x 0.62 = 1519 ml/h ≈ 25 ml/min
HF
Amikacin
Non-Enterob
70 Kg
35ml/kg/hr
Total clearance
CRRT clearance+non-CRRT
clearance
Total clearance
(Cl(Cltot)) =calculated
=calculated
CRRT clearance
+ non-CRRT
=25 + 23 = 48 ml/min
clearance=25 + 23 = 48 ml/min
tot
Pharmacokinetic
Cmax
/ MIC
target?
Time above
threshold
concentration
Cmax :MIC &
AUC24 :MIC
Cmax :MIC ratio
Calculate half-life
Calculate half-life
=0.693= 0.693
x Vdx Vd
/ Cl
= 0.693 X 33000 / 48
/ Cl = 0.693 x 33000/48
Not required
Not required
=
467
min
=
7.8
h
= 487 min = 7.8 h
tot
Calculate time to reach target trough concentration
Calculate time to reach target trough concentration
Assuming
target
trough
it will
Assuming
target
trough ?1?1
mg/lmg/l
it will take
5 halftake
lives 5 half lives
for concentration
drop from
32 mg/l
for concentration
totodrop
from
32to target
mg/ltrough
to target trough
40 h
≈40 h
Repeat
loading dose
at
Repeat
loading
dose
at
calculated time (after 40 h)
calculated time (after 40h)
Choi G, Gomersall CD, Tian Q Crit Care Med. 2009 Jul;37(7):2268-82
LoadingLoading
dose=Desired
x Vd
dose=Desiredconcentration
concentration x Vd (28
l) (28 l)
concentration=
= 55xX
MIC
= 20 =
mg/l
DesiredDesired
concentration
MIC
20 mg/l
Loading dose = 20 x 28  500 mg
Loading dose = 20 X 28 ≈ 500 mg
Calculate CRRT clearance based on mode of CRRT, formulae in text
& values
table
5 formulae in text
Calculate CRRT clearance
based in
on mode
of CRRT,
& values in table 5
ClCVVH
(post) = Qf x Sc
ClCVVH (post) = Qf x Sd
= 2450= x2450
0.95
= =2327
ml/h
=ml/min
39 ml/min
x 0.95
2327 ml/h
= 39
Meropenem
Non-Enterob/
Entero/Stahpy
70 Kg
35ml/kg/hr
Total clearance
(Cltot
calculated
CRRT
+ non-CRRT
clearance
Total clearance
(Cl)tot)==calculated
CRRT
clearance+non-CRRT
clearance

39 + ≈
60100
100ml/min
ml/min = 0.1
l/min l/min
= 39 +=60
= 0.1
Pharmacokinetic
Time
above
MIC
target?
Time above
threshold
concentration
Cmax:MIC &
AUC24:MIC
Cmax:MIC ratio
Calculate
elimination
rate
Calculate
elimination
rate
=
concentration
x
Cl
= concentration x Cltottot
= 20 x 0.1 = 2 mg/min
= 20 X 0.1 = 2mg/min
Not required
Not required
Maintenance infusion
rate rate
Maintenance
infusion
= elimination rate
= elimination
rate
= 2 mg/min
= 2 mg/min
Choi G, Gomersall CD, Tian Q Crit Care Med. 2009 Jul;37(7):2268-82
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
Importance of protein binding
Hemodialysis (CVVHD)
Reproduced with permission from ICU web (www.aic.cuhk.edu.hk/web8).
Point of dilution
Vancomycin
Sieving coefficient
1
0.5
6:0
5:1
4:2
2:4
1:5
0:6
Pre:post dilution ratio
Uchino.S: Intensine Care Medicine 28(11) 1664 – 67 2002