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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?.

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Antibiotic Dosing and CRRT 2011


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    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 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

    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 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

    5. Pk/Pd of antibiotics 8-10 X Roberts JA, Lipman J. Clin Pharmacokinet 2006. 45:755-773

    6. Pk/Pd of antibiotics 40-100% 1-5 X Roberts JA, Lipman J. Clin Pharmacokinet 2006. 45:755-773

    7. Pk/Pd of antibiotics 6-8 X AUC 24 / MIC 100-125 Roberts JA, Lipman J. Clin Pharmacokinet 2006. 45:755-773

    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. 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

    10. Cephalosporin – EUCAST/BSAC clinical MIC breakpoints Dose protein bindingbreakpoint (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

    11. ?? How does it work ?? 洗腎 = washing kidney

    12. Continuous Techniques CVVH - ContinuousVenoVenousHemofiltration CVVHD - ContinuousVenoVenousHemoDialysis CVVHDF - ContinuousVenoVenousHemoDiaFiltration HVVF - HighvolumeVenoVenousHemofiltration

    13. 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

    14. Pore Size HCO 1100 Polyflux Gambro

    15. Size is important – but……… Albumin (68kDa) IL-1ra Myoglobin TNF-α monomeric (17kDa) TNF-α Trimeric (51kDa) IL-6 (28kDa) Urea (60) Cr (113) 10 KDa 20 KDa 30 KDa 40 KDa 50 KDa 60 KDa IgG (140kDa) Vancomycin (1448 Da) Teicoplanin (1878 Da)

    16. Importance of protein binding Hemofiltration (CVVH) (post-dilution) Reproduced with permission from ICU web (www.aic.cuhk.edu.hk/web8).

    17. 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

    18. Blood flow rate CL (pre) = S Χ Qf Χ -------------------------------------------------------- Blood flow rate + substitution rate CL (post) = S Χ Qf Bohler: Kidney Int Suppl, Volume 56 Supplement No. 72.November 1999.S-24-S-28

    19. Equations for calculating CRRT clearance from first principles Li Am, Gomersall CD, Choi G et al. J Antimicrob Chemother. 2009;64(5):929-37.

    20. ?? Can we estimate SC by published protein binding ?? SC ~ (1 – protein bound fraction)

    21. 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.

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

    23. Ceftriaxone • Kroh et al. J Clin Pharmacol. 36(12):1114-9, 1996 • Matzka et al. Pharmacotherapy 20(6):635-643, 2000.

    24. Protein binding in ICUCeftriaxone Free fraction (%) Joynt Gm, Lipman J, Gomersall CD et. Al. J Antimicrob Chemother;47,421;2001

    25. Reduced Protein binding Disease states besides uremia, cirrhosis nephrotic syndrome epilepsy hepatitis pregnancy severe burns trauma

    26. 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.

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

    28. Loading dose=Desired concentration x Vd Loading dose=Desired 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 clearance+non - 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 dosing interval calculated time Choi G, Gomersall CD, Tian Q Crit Care Med. 2009 Jul;37(7):2268-82

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

    30. Acknowledgement Tian Qi Charles Gomersall Jeff Lipman Gavin Joynt Patricia Leung Alex Li Dr. So & Prof. Gin

    31. Loading dose=Desired concentration x Vd(33 l) Desired concentration = 8 x MIC = 32 mg/l Loading dose = 32 x 33≈ 1000 mg 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 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 clearance=25 + 23 = 48 ml/min Total clearance ( Cl ) =calculated CRRT clearance+non - 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 Jul;37(7):2268-82

    32. Loading dose=Desired concentration x Vd (28 l) Desired concentration = 5 X MIC = 20 mg/l Loading dose = 20 X 28 ≈ 500 mg 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 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 clearance+non - 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 Cmax:MIC & 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 Jul;37(7):2268-82

    33. 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

    34. Importance of protein binding Hemodialysis (CVVHD) Reproduced with permission from ICU web (www.aic.cuhk.edu.hk/web8).

    35. Point of dilution Vancomycin 1 Sieving coefficient 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