Antibiotic Dosing

1
Antibiotic Dosing and CRRT 2011
Gordon Choi
Department of Anaesthesia and Intensive Care
Prince of Wales Hospital Hong Kong
2
Important concepts to consider

• Pk/Pd of antibiotics
• Principles of CRRT
• Problems with published data
• Our philosophy on how it should be done?

3
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 90s -
60 in BEST
Douma CE, Redekop WK, Van der Meulen JHP et al. J
Am Soc Nephrol19978111117
Cosentino F, Chaff C ,Piedmonte M. Nephrol. Dial.
Transplant. 1994 9 (Suppl. 4)179182.
Uchino S, Kellum JA, Bellomo R et al.mJAMA.
2005294(7)813-818
4
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 Med2000162191196
Kumar A, Roberts D, Wood KE, et al Crit Care Med
2006 3415891596
Vincent JL, Bihari DJ, Suter PM, et al. JAMA
1995 274 639-44
Uchino S, Kellum JA, Bellomo R et al.mJAMA.
2005294(7)813-818
5
Pk/Pd of antibiotics
8-10 X
Roberts JA, Lipman J. Clin Pharmacokinet 2006.
45755-773
6
Pk/Pd of antibiotics

40-100
1-5 X
Roberts JA, Lipman J. Clin Pharmacokinet 2006.
45755-773
7
Pk/Pd of antibiotics
6-8 X
AUC 24 / MIC 100-125
Roberts JA, Lipman J. Clin Pharmacokinet 2006.
45755-773
8
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
9
(No Transcript)
10
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
11
Cephalosporin 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.
MacGowana APand Wiseb R European Committee on
Antimicrobial Susceptibility Testing
(EUCAST) British Society for Antimicrobial
Chemotherapy (BSAC) 2005
12
?? How does it work ??
?? washing kidney
13
Continuous Techniques

• CVVH - Continuous VenoVenous Hemofiltration
• CVVHD - Continuous VenoVenous HemoDialysis
• CVVHDF - Continuous VenoVenous HemoDiaFiltration
• HVVF - High volume VenoVenous Hemofiltration

14
Solute clearance by CRRT
In general - hydrophilic drug - gt than 30 of
clearance by renal route - Low volume of
distribution (lt1L/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 37633-637 Chow AT, Fowler
C, Williams RR et al Antimicrob Agents Chemother
2001 452122-2125 Guenter SG, Iven H, Boos C,
Bruch HP et alPharmacotherapy 2002 22175-183
15
Pore Size
HCO 1100 Polyflux Gambro
16
Size is important but
Albumin (68kDa)
IL-1ra Myoglobin TNF-a monomeric (17kDa)
TNF-a Trimeric (51kDa)
IL-6 (28kDa)
Urea (60) Cr (113)
20 KDa
10 KDa
30 KDa
40 KDa
50 KDa
60 KDa
IgG (140kDa)
Vancomycin (1448 Da) Teicoplanin (1878 Da)
17
Importance of protein binding
Hemofiltration (CVVH) (post-dilution)
Reproduced with permission from ICU web
(www.aic.cuhk.edu.hk/web8).
18
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
19
Blood flow rate CL (pre) S ? Qf ?
--------------------------------------------------
------ Blood flow rate substitution
rate
CL (post) S ? Qf
Bohler Kidney Int Suppl, Volume 56 Supplement
No. 72.November 1999.S-24-S-28
20
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. 200964(5)929-37.
21
? ? Can we estimate SC by published protein
binding ??
SC (1 protein bound fraction)
22
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.Chemothe
r 47 (2)229-231, 2001.Hansen E., et al.
Intensive Care Med 27371-375, 2001.
23
Cefpirome
Phillips G J Clin Pharm Ther 23(5) 353 359 2002
24
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.
25
Protein binding in ICU Ceftriaxone
Free fraction ()
Joynt Gm, Lipman J, Gomersall CD et. Al. J
Antimicrob Chemother47,4212001
26
Reduced Protein binding
Disease states besides uremia, cirrhosis
nephrotic syndrome epilepsy hepatitis
pregnancy severe burns trauma
27
Differences in clearance Levofloxacin
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
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.Chemothe
r 47 (2)229-231, 2001.Hansen E., et al.
Intensive Care Med 27371-375, 2001.
28
Li Am, Gomersall CD, Choi G et al. J Antimicrob
Chemother. 200964(5)929-37.
29
Loading doseDesired concentration x Vd
Loading doseDesired concentration xVd
Calculate CRRT clearance based on mode of CRRT
Calculate CRRT clearance based on mode of CRRT,
formulae in text
Total clearance Cl(tot) calculated CRRT
clearance non-CRRT clearance
Total clearance (
Cl
) calculated CRRT
clearancenon
-
CRRT clearance
tot
Pharmacokinteic Target
Pharmacokinetic
target?
Time above threshold
C
MIC
AUC
MIC
max
24
concentration
C
MIC
ratio
max
Calculate target mean concentration target
AUC24/24
Calculate elimination rate concentration x Cltot
Calculate half-life 0.693 X Vd / Cltot
Calculate half
-
life
Calculate target mean
Calculate elimination rate
concentration
0.693 x
Vd
/
Cl
concentration x
Cl
tot
tot
target AUC
/24
24
Calculate time to reach Target trough
concentration
Calculate dosing interval Dose/(Cp x Ctot / f)
Calculate time to reach
Calculate dosing interval
target trough concentration

Dose/(Cp x Cl
/ f)
Maintenance infusion rate elimination rate
tot
Maintenance infusion rate
elimination rate
Repeat loading dose at calculated time
Repeat loading dose at calculated dosing interval
Repeat loading dose at
Repeat loading dose at
calculated time
calculated dosing interval
Choi G, Gomersall CD, Tian Q Crit Care Med. 2009
Jul37(7)2268-82
30
Conclusion

• Knowledge of antibiotics
• Knowledge of CRRT
• Understanding of published data
• Ideas of underlying disease process / organ
  failure
• Application of basic principles

31
Acknowledgement
Tian Qi Charles Gomersall Jeff Lipman Gavin
Joynt Patricia Leung Alex Li Dr. So Prof. Gin
32
Loading doseDesired concentration x Vd(33
l) Desired concentration 8 x MIC 32
mg/l Loading dose 32 x 33 1000 mg
Loading doseDesired 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
Calculate CRRT clearance based on mode of CRRT,
formulae in text
values in table 5
Cl
(post) (
Qf

Qd
) x
Sd
HF

2450 x 0.62 1519 ml/h
25 ml/min
Amikacin Non-Enterob 70 Kg 35ml/kg/hr
Total clearance (Cltot) calculated CRRT
clearance non-CRRT clearance25 23 48
ml/min
Total clearance (
Cl
) calculated CRRT
clearancenon
-
CRRT clearance
tot
25 23 48 ml/min
Cmax / MIC
Pharmacokinetic
target?
Time above
C
MIC

max
threshold
AUC
MIC
24
concentration
Calculate half-life 0.693 x Vd / Cl 0.693 X
33000 / 48 487 min 7.8 h
C
MIC
ratio
max
Calculate half
-
life
0.693 x
Vd
/
Cl
0.693 x 33000/48
Not required
Not required
tot
467 min 7.8 h
Calculate time to reach target trough
concentration Assuming target trough ?1 mg/l it
will take 5 half lives for concentration to drop
from 32 mg/l to target trough 40 h
Calculate time to reach target trough
concentration
Assuming 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 at calculated time (after 40h)
Repeat loading dose at
Repeat loading dose at
calculated time (after 40 h)
calculated time (after 40 h)
Choi G, Gomersall CD, Tian Q Crit Care Med. 2009
Jul37(7)2268-82
33
Loading doseDesired concentration x Vd (28
l) Desired concentration 5 X MIC 20
mg/l Loading dose 20 X 28 500 mg
Loading doseDesired 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 Sc 2450 x 0.95 2327 ml/h 39
ml/min
Calculate CRRT clearance based on mode of CRRT,
formulae in text
values in table 5
Cl
(post)
Qf
x
Sd
CVVH
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
Total clearance (
Cl
) calculated CRRT
clearancenon
-
CRRT clearance
tot

39 60
100 ml/min 0.1 l/min
Meropenem Non-Enterob/ Entero/Stahpy 70
Kg 35ml/kg/hr
Time above MIC
Pharmacokinetic
target?
Time above
CmaxMIC

threshold
AUC
MIC
24
concentration
C
MIC
ratio
max
Calculate elimination rate concentration x
Cltot 20 X 0.1 2mg/min
Calculate elimination rate
concentration x
Cl
Not required
Not required
tot
20 x 0.1 2 mg/min
Maintenance infusion rate elimination rate 2
mg/min
Maintenance infusion rate
elimination rate
2 mg/min
Choi G, Gomersall CD, Tian Q Crit Care Med. 2009
Jul37(7)2268-82
34
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 (plt0.01) - 33 vs
15 Hospital mortality (plt0.01) odds ratio-
1.36-1.68 (plt0.01)
Vincent JL, Rello J, Marshall JC, et al. JAMA
2009 212123-9
35
Importance of protein binding
Hemodialysis (CVVHD)
Reproduced with permission from ICU web
(www.aic.cuhk.edu.hk/web8).
36
Point of dilution Vancomycin
1
Sieving coefficient
0.5
60
51
42
24
15
06
Prepost dilution ratio
Uchino.S Intensine Care Medicine 28(11) 1664
67 2002