Recommended β-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy

Lucie Seyler, Frédéric Cotton, Fabio Silvio Taccone, Daniel De Backer, Pascale Macours, Jean-Louis Vincent, Frédérique Jacobs, Lucie Seyler, Frédéric Cotton, Fabio Silvio Taccone, Daniel De Backer, Pascale Macours, Jean-Louis Vincent, Frédérique Jacobs

Abstract

Introduction: Sepsis is responsible for important alterations in the pharmacokinetics of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to pharmacokinetic changes. Current recommendations for antibiotic doses during CRRT combine data obtained from heterogeneous patient populations in which different CRRT devices and techniques have been used. We studied whether these recommendations met optimal pharmacokinetic criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT.

Methods: This open, prospective study enrolled consecutive patients treated with CRRT and receiving either meropenem (MEM), piperacillin-tazobactam (TZP), cefepime (FEP) or ceftazidime (CAZ). Serum concentrations of these antibiotics were determined by high-performance liquid chromatography from samples taken before (t = 0) and 1, 2, 5, and 6 or 12 hours (depending on the β-lactam regimen) after the administration of each antibiotic. Series of measurements were separated into those taken during the early phase (< 48 hours from the first dose) of therapy and those taken later (> 48 hours).

Results: A total of 69 series of serum samples were obtained in 53 patients (MEM, n = 17; TZP, n = 16; FEP, n = 8; CAZ, n = 12). Serum concentrations remained above four times the minimal inhibitory concentration for Pseudomonas spp. for the recommended time in 81% of patients treated with MEM, in 71% with TZP, in 53% with CAZ and in 0% with FEP. Accumulation after 48 hours of treatment was significant only for MEM.

Conclusions: In septic patients receiving CRRT, recommended doses of β-lactams for Pseudomonas aeruginosa are adequate for MEM but not for TZP, FEP and CAZ; for these latter drugs, higher doses and/or extended infusions should be used to optimise serum concentrations.

Figures

Figure 1
Figure 1
Pharmacokinetic profile of meropenem for patients receiving continuous renal replacement therapy. Data shown as mean serum concentrations (with standard deviation) measured in samples taken < 48 hours (circles) and > 48 hours (diamonds) from the start of the treatment. Dotted line, 2 μg/ml; dashed line, 8 μg/ml.
Figure 2
Figure 2
Pharmacokinetic profile of piperacillin for patients receiving continuous renal replacement therapy. Data shown as mean serum concentrations (with standard deviation) measured in samples taken < 48 hours (circles) and > 48 hours (diamonds) from the start of the treatment. Dotted line, 16 μg/ml; dashed line, 64 μg/ml.
Figure 3
Figure 3
Pharmacokinetic profile of cefepime for patients receiving continuous renal replacement therapy. Data shown as mean serum concentrations (with standard deviation) measured in samples taken < 48 hours (circles) and > 48 hours (diamonds) from the start of the treatment. Dotted line, 8 μg/ml; dashed line, 32 μg/ml.
Figure 4
Figure 4
Pharmacokinetic profile of ceftazidime for patients receiving continuous renal replacement therapy. Data shown as mean serum concentrations (with standard deviation) measured in samples taken < 48 hours (circles) and > 48 hours (diamonds) from the start of the treatment. Dotted line, 8 μg/ml; dashed line, 32 μg/ml.

References

    1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. SCCM/ESICM/ACCP/ATS/SIS. International Sepsis Definitions Conference. Crit Care Med. 2003;31:1250–1256. doi: 10.1097/01.CCM.0000050454.01978.3B.
    1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. SCCM/ESICM/ACCP/ATS/SIS. International Sepsis Definitions Conference. Intensive Care Med. 2003;29:530–538.
    1. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, Gomersall C, Sakr Y, Reinhart K. EPIC II Group of Investigators. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323–2329. doi: 10.1001/jama.2009.1754.
    1. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115:462–474. doi: 10.1378/chest.115.2.462.
    1. Zaragoza R, Artero A, Camarena JJ, Sancho S, Gonzalez R, Nogueira JM. The influence of inadequate empirical antimicrobial treatment on patients with bloodstream infections in an intensive care unit. Clin Microbiol Infect. 2003;9:412–418. doi: 10.1046/j.1469-0691.2003.00656.x.
    1. Pinder M, Bellomo R, Lipman J. Pharmacological principles of antibiotic prescription in the critically ill. Anaesth Intensive Care. 2002;30:134–144.
    1. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118:146–155. doi: 10.1378/chest.118.1.146.
    1. Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J. 1996;15:255–259. doi: 10.1097/00006454-199603000-00015.
    1. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1–10. doi: 10.1086/516284.
    1. Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Piperacillin penetration into tissue of critically ill patients with sepsis - bolus versus continuous administrationż. Crit Care Med. 2009;37:926–933. doi: 10.1097/CCM.0b013e3181968e44.
    1. Lipman J, Gomersall CD, Gin T, Joynt GM, Young RJ. Continuous infusion ceftazidime in intensive care: a randomized controlled trial. J Antimicrob Chemother. 1999;43:309–311. doi: 10.1093/jac/43.2.309.
    1. Lipman J, Wallis SC, Rickard C. Low plasma cefepime levels in critically ill septic patients: pharmacokinetic modeling indicates improved troughs with revised dosing. Antimicrob Agents Chemother. 1999;43:2559–2561.
    1. Martin JH, Fay MF, Udy A, Roberts J, Kirkpatrick C, Ungerer J, Lipman J. Pitfalls of using estimations of glomerular filtration rate in an intensive care population. Intern Med J. 2010. in press .
    1. Taccone FS, Laterre PF, Dugernier T, Spapen H, Delattre I, Wittebole X, De Backer D, Layeux B, Wallemacq P, Vincent JL, Jacobs F. Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010;14:R126. doi: 10.1186/cc9091.
    1. Choi G, Gomersall CD, Tian Q, Joynt GM, Li AM, Lipman J. Principles of antibacterial dosing in continuous renal replacement therapy. Blood Purif. 2010;30:195–212. doi: 10.1159/000321488.
    1. Trotman RL, Williamson JC, Shoemaker DM, Salzer WL. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin Infect Dis. 2005;41:1159–1166. doi: 10.1086/444500.
    1. Malone RS, Fish DN, Abraham E, Teitelbaum I. Pharmacokinetics of cefepime during continuous renal replacement therapy in critically ill patients. Antimicrob Agents Chemother. 2001;45:3148–3155. doi: 10.1128/AAC.45.11.3148-3155.2001.
    1. Matzke GR, Frye RF, Joy MS, Palevsky PM. Determinants of ceftazidime clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis. Antimicrob Agents Chemother. 2000;44:1639–1644. doi: 10.1128/AAC.44.6.1639-1644.2000.
    1. Mueller SC, Majcher-Peszynska J, Hickstein H, Francke A, Pertschy A, Schulz M, Mundkowski R, Drewelow B. Pharmacokinetics of piperacillin-tazobactam in anuric intensive care patients during continuous venovenous hemodialysis. Antimicrob Agents Chemother. 2002;46:1557–1560. doi: 10.1128/AAC.46.5.1557-1560.2002.
    1. Valtonen M, Tiula E, Backman JT, Neuvonen PJ. Elimination of meropenem during continuous veno-venous haemofiltration and haemodiafiltration in patients with acute renal failure. J Antimicrob Chemother. 2000;45:701–704. doi: 10.1093/jac/45.5.701.
    1. Buck C, Bertram N, Ackermann T, Sauerbruch T, Derendorf H, Paar WD. Pharmacokinetics of piperacillin-tazobactam: intermittent dosing versus continuous infusion. Int J Antimicrob Agents. 2005;25:62–67. doi: 10.1016/j.ijantimicag.2004.08.012.
    1. ICH Harmonised Tripartite Guideline. Q2(R1): Validation of Analytical Procedures: Text and Methodology.
    1. Clinical Breakpoints - Bacteria.
    1. Shorr AF. Review of studies of the impact on Gram-negative bacterial resistance on outcomes in the intensive care unit. Crit Care Med. 2009;37:1463–1469. doi: 10.1097/CCM.0b013e31819ced02.
    1. Li C, Du X, Kuti JL, Nicolau DP. Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections. Antimicrob Agents Chemother. 2007;51:1725–1730. doi: 10.1128/AAC.00294-06.
    1. Tam VH, McKinnon PS, Akins RL, Drusano GL, Rybak MJ. Pharmacokinetics and pharmacodynamics of cefepime in patients with various degrees of renal function. Antimicrob Agents Chemother. 2003;47:1853–1861. doi: 10.1128/AAC.47.6.1853-1861.2003.
    1. Thalhammer F, Traunmüller F, El Menyawi I, Frass M, Hollenstein UM, Locker GJ, Stoiser B, Staudinger T, Thalhammer-Scherrer R, Burgmann H. Continuous infusion versus intermittent administration of meropenem in critically ill patients. J Antimicrob Chemother. 1999;43:523–527. doi: 10.1093/jac/43.4.523.
    1. McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T > MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31:345–351. doi: 10.1016/j.ijantimicag.2007.12.009.
    1. Drusano GL. Antimicrobial pharmacodynamics: critical interactions of 'bug and drug'. Nat Rev Microbiol. 2004;2:289–300. doi: 10.1038/nrmicro862.
    1. Nicolau DP, Onyeji CO, Zhong M, Tessier PR, Banevicius MA, Nightingale CH. Pharmacodynamic assessment of cefprozil against Streptococcus pneumoniae: implications for breakpoint determinations. Antimicrob Agents Chemother. 2000;44:1291–1295. doi: 10.1128/AAC.44.5.1291-1295.2000.
    1. Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet. 2005;44:1009–1034. doi: 10.2165/00003088-200544100-00002.
    1. Reed RL, Ericsson CD, Wu A, Miller-Crotchett P, Fischer RP. The pharmacokinetics of prophylactic antibiotics in trauma. J Trauma. 1992;32:21–27. doi: 10.1097/00005373-199201000-00005.
    1. Triginer C, Izquierdo I, Fernández R, Torrent J, Benito S, Net A, Jane F. Changes in gentamicin pharmacokinetic profiles induced by mechanical ventilation. Eur J Clin Pharmacol. 1991;40:297–302. doi: 10.1007/BF00315213.
    1. Uchino S, Cole L, Morimatsu H, Goldsmith D, Bellomo R. Clearance of vancomycin during high-volume haemofiltration: impact of pre-dilution. Intensive Care Med. 2002;28:1664–1667. doi: 10.1007/s00134-002-1495-z.
    1. Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Microbiol Infect Dis. 1995;22:89–96. doi: 10.1016/0732-8893(95)00053-D.
    1. Mouton JW, Punt N. Use of the t > MIC to choose between different dosing regimens of β-lactam antibiotics. J Antimicrob Chemother. 2001;47:500–501. doi: 10.1093/jac/47.4.500.
    1. Mouton JW, den Hollander JG. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrob Agents Chemother. 1994;38:931–936.
    1. Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988;158:831–847. doi: 10.1093/infdis/158.4.831.
    1. Tam VH, McKinnon PS, Akins RL, Rybak MJ, Drusano GL. Pharmacodynamics of cefepime in patients with Gram-negative infections. J Antimicrob Chemother. 2002;50:425–428. doi: 10.1093/jac/dkf130.
    1. Turnidge JD. The pharmacodynamics of β-lactams. Clin Infect Dis. 1998;27:10–22. doi: 10.1086/514622.
    1. Tam VH, Gamez EA, Weston JS, Gerard LN, Larocco MT, Caeiro JP, Gentry LO, Garey KW. Outcomes of bacteremia due to Pseudomonas aeruginosa with reduced susceptibility to piperacillin-tazobactam: implications on the appropriateness of the resistance breakpoint. Clin Infect Dis. 2008;46:862–867. doi: 10.1086/528712.
    1. Thalhammer F, Schenk P, Burgmann H, El Menyawi I, Hollenstein UM, Rosenkranz AR, Sunder-Plassmann G, Breyer S, Ratheiser K. Single-dose pharmacokinetics of meropenem during continuous venovenous hemofiltration. Antimicrob Agents Chemother. 1998;42:2417–2420.
    1. Ververs TF, van Dijk A, Vinks SA, Blankestijn PJ, Savelkoul JF, Meulenbelt J, Boereboom FT. Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration. Crit Care Med. 2000;28:3412–3416. doi: 10.1097/00003246-200010000-00006.
    1. Krueger WA, Schroeder TH, Hutchison M, Hoffmann E, Dieterich HJ, Heininger A, Erley C, Wehrle A, Unertl K. Pharmacokinetics of meropenem in critically ill patients with acute renal failure treated by continuous hemodiafiltration. Antimicrob Agents Chemother. 1998;42:2421–2424.
    1. Valtonen M, Tiula E, Takkunen O, Backman JT, Neuvonen PJ. Elimination of the piperacillin/tazobactam combination during continuous venovenous haemofiltration and haemodiafiltration in patients with acute renal failure. J Antimicrob Chemother. 2001;48:881–885. doi: 10.1093/jac/48.6.881.
    1. van der Werf TS, Mulder PO, Zijlstra JG, Uges DR, Stegeman CA. Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal failure, treated with continuous veno-venous hemofiltration (CVVH) Intensive Care Med. 1997;23:873–877. doi: 10.1007/s001340050424.
    1. Allaouchiche B, Breilh D, Jaumain H, Gaillard B, Renard S, Saux MC. Pharmacokinetics of cefepime during continuous venovenous hemodiafiltration. Antimicrob Agents Chemother. 1997;41:2424–2427.
    1. Traunmuller F, Schenk P, Mittermeyer C, Thalhammer-Scherrer R, Ratheiser K, Thalhammer F. Clearance of ceftazidime during continuous venovenous haemofiltration in critically ill patients. J Antimicrob Chemother. 2002;49:129–134. doi: 10.1093/jac/49.1.129.
    1. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis. 2007;44:357–363. doi: 10.1086/510590.
    1. Benko AS, Cappelletty DM, Kruse JA, Rybak MJ. Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected Gram-negative infections. Antimicrob Agents Chemother. 1996;40:691–695.
    1. Roberts JA, Kirkpatrick CM, Roberts MS, Dalley AJ, Lipman J. First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents. 2010;35:156–163. doi: 10.1016/j.ijantimicag.2009.10.008.
    1. Langgartner J, Vasold A, Gluck T, Reng M, Kees F. Pharmacokinetics of meropenem during intermittent and continuous intravenous application in patients treated by continuous renal replacement therapy. Intensive Care Med. 2008;34:1091–1096. doi: 10.1007/s00134-008-1034-7.
    1. Roberts JA, Kirkpatrick CM, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administrationż Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother. 2009;64:142–150. doi: 10.1093/jac/dkp139.
    1. Roberts JA, Ulldemolins M, Roberts MS, McWhinney B, Ungerer J, Paterson DL, Lipman J. Therapeutic drug monitoring of β-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents. 2010;36:332–339. doi: 10.1016/j.ijantimicag.2010.06.008.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit