Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Anesthesiology
Published in: BMC Anesthesiology 1/2011

Open Access 01-12-2011 | Study protocol

Antibiotic dosing in the 'at risk' critically ill patient: Linking pathophysiology with pharmacokinetics/pharmacodynamics in sepsis and trauma patients

Authors: Jason A Roberts, Michael S Roberts, Andrew Semark, Andrew A Udy, Carl MJ Kirkpatrick, David L Paterson, Matthew J Roberts, Peter Kruger, Jeffrey Lipman

Published in: BMC Anesthesiology | Issue 1/2011

Login to get access

Abstract

Background

Critical illness, mediated by trauma or sepsis, can lead to physiological changes that alter the pharmacokinetics of antibiotics and may result in sub-therapeutic concentrations at the sites of infection. The first aim of this project is to identify the clinical characteristics of critically ill patients with significant trauma that have been recently admitted to ICU that may predict the dosing requirements for the antibiotic, cefazolin. The second aim of this is to identify the clinical characteristics of critically ill patients with sepsis that may predict the dosing requirements for the combination antibiotic, piperacillin-tazobactam.

Methods/Design

This is an observational pharmacokinetic study of patients with trauma (cefazolin) or with sepsis (piperacillin-tazobactam). Participants will have samples from blood and urine, collected at different intervals. Patients will also have a microdialysis catheter inserted into subcutaneous tissue to measure interstitial fluid penetration of the antibiotic. Participants will be administered sinistrin, indocyanine green and sodium bromide as well as have cardiac output monitoring performed and tetrapolar bioimpedance to determine physiological changes resulting from pathology. Analysis of samples will be performed using validated liquid chromatography tandem mass-spectrometry. Pharmacokinetic analysis will be performed using non-linear mixed effects modeling to determine individual and population pharmacokinetic parameters of antibiotics.

Discussion

The study will describe cefazolin and piperacillin-tazobactam concentrations in plasma and the interstitial fluid of tissues in trauma and sepsis patients respectively. The results of this study will guide clinicians to effectively dose these antibiotics in order to maximize the concentration of antibiotics in the interstitial fluid of tissues.
Literature
1.
Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J: Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med. 2004, 30 (4): 589-96. 10.1007/s00134-004-2157-0.CrossRefPubMed
2.
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 (2): 462-74. 10.1378/chest.115.2.462.CrossRefPubMed
3.
Roberts JA, Lipman J: Antibiotic dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet. 2006, 45 (8): 755-773. 10.2165/00003088-200645080-00001.CrossRefPubMed
4.
van Lent-Evers NA, Mathot RA, Geus WP, van Hout BA, Vinks A: Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis. Ther Drug Monit. 1999, 21 (1): 63-73. 10.1097/00007691-199902000-00010.CrossRefPubMed
5.
Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ: Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother. 1993, 37 (5): 1073-81.CrossRefPubMedPubMedCentral
6.
Scaglione F, Esposito S, Leone S, Lucini V, Pannacci M, Ma L, Drusano GL: Feedback dose alteration significantly affects probability of pathogen eradication in nosocomial pneumonia. Eur Respir J. 2009, 34 (2): 394-400. 10.1183/09031936.00149508.CrossRefPubMed
7.
Roberts JA, Ulldemolins M, Roberts MS, McWhinney BC, Ungerer JPJ, Paterson DL, Lipman J: Therapeutic Drug Monitoring of Beta-lactams in Critically Ill Patients: Proof of concept. Int J Antimicrob Agents. 2010, 36 (4): 332-9. 10.1016/j.ijantimicag.2010.06.008.CrossRefPubMed
8.
Joukhadar C, Frossard M, Mayer BX, Brunner M, Klein N, Siostrzonek P, Eichler HG, Müller M: Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med. 2001, 29: 385-391. 10.1097/00003246-200102000-00030.CrossRefPubMed
9.
Khol BA, Deutschman CS: The inflammatory response to surgery and trauma. Curr Opin Crit Care. 2006, 12 (4): 325-32. 10.1097/01.ccx.0000235210.85073.fc.CrossRef
10.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee, American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992, 101 (6): 1644-55. 10.1378/chest.101.6.1644.CrossRefPubMed
11.
Parillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP: Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Int Med. 1990, 113 (3): 227-42.CrossRef
12.
Brown R, Babcock R, Talbert J, Greunenberg J, Czurak C, Cambell M: Renal function in the critically ill pot-operative patients: sequential assessment of creatinine osmolar and free water clearance. Crit Care Med. 1980, 8 (2): 68-72. 10.1097/00003246-198002000-00004.CrossRefPubMed
13.
Loirat P, Rohan J, Baillet A, Beaufils F, David R, Chapman A: Increased glomerular filtration rate in patients with major burns and its effect on the pharmacokinetics of tobramycin. N Engl J Med. 299 (17): 915-9. 10.1056/NEJM197810262991703.
14.
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
15.
Hoste EA, Damen J, Vanholder RC, Norbert H, Lameire JR, Van den Hauwe KD, Colardyn FA: Assessment of renal function in recently admitted critically ill patients with normal serum creatinine. Nephrol Dial Transplant. 2005, 20 (4): 747-53. 10.1093/ndt/gfh707.CrossRefPubMed
16.
Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J: Augmented Renal Clearance: Implications for Antibacterial Dosing in the Critically III. Clin Pharmacokinet. 2010, 49 (1): 1-16. 10.2165/11318140-000000000-00000.CrossRefPubMed
17.
Lipman J, Wallis SC, Rickard CM, Fraenkel D: Low cefpirome levels during twice daily dosing in critically ill septic patients: pharmacokinetic modelling calls for more frequent dosing. Intensive Care Med. 2001, 27 (2): 363-70. 10.1007/s001340000741.CrossRefPubMed
18.
Young RJ, Lipman J, Gin T, C D Gomersall CD, Joynt GM, Oh TE: Intermittent bolus dosing of ceftazidime in critically ill patients. J Antimicro Chemother. 1997, 40 (2): 269-73. 10.1093/jac/40.2.269.CrossRef
19.
MacArthur RD, Miller M, Albertson T, Panacek E, Johnson D, Teoh L, Barchuk W: Adequacy of early empiric antibiotic treatment and survival in severe sepsis: experience from the MONARCS Trial. Clin Infect Dis. 2004, 15 (2): 284-8. 10.1086/379825.CrossRef
20.
Roberts JA, Kruger P, Paterson DL, Lipman J: Antibiotic Resistance - What's dosing got to do with it?. Crit Care Med. 2008, 36 (8): 2433-40. 10.1097/CCM.0b013e318180fe62.CrossRefPubMed
21.
Poggio ED, Nef PC, Wang X, Greene T, Van Lente F, Dennis VW, Ha PM: Performance of the Cockcrof-Gault and modification of diet in renal disease equations in estimating GFR in ill hospitalized patients. Am J Kidney Dis. 2005, 46 (2): 242-52. 10.1053/j.ajkd.2005.04.023.CrossRefPubMed
22.
Snider RD, Kruse JA, Bander JJ, Dunn GH: Accuracy of estimated creatinine clearance in obese patients with stable renal function in the intensive care unit. Pharmacotherapy. 1995, 15 (6): 747-53.PubMed
23.
Buclin T, Pechere-Bertschi A, Sechaud R, Decosterd LA, Munafo A, Burnier M, Biollaz J: Sinistrin clearance for determination of glomerular filtration rate: a reappraisal of various approaches using a new analytical method. J Clin Pharmacol. 1997, 37 (8): 679-92.CrossRefPubMed
24.
Triginer C, Izquierdo I, Fernandez R, Rello J, Torrent J, Benito S, Net A: Gentamicin volume of distribution in critically ill septic patients. Intensive Care Med. 1990, 16 (5): 303-6. 10.1007/BF01706354.CrossRefPubMed
25.
Gosling P, Sanghera K, Dickson G: Generalized vascular permeability and pulmonary function in patients following serious trauma. J Trauma. 1994, 36: 477-81. 10.1097/00005373-199404000-00002.CrossRefPubMed
26.
Marik PE, Havlik I, Monteagudo FSE, Lipman J: The pharmacokinetics of amikacin in critically ill adult and paediatric patients: comparison of once- versus twice-daily dosing regimens. J Antimicrob Chemother. 1991, 27 (suppl C): 81-89.CrossRefPubMed
27.
Plank LD, Monk DN, Woollard GA, Hill GL: Evaluation of multifrequency bioimpedance spectroscopy for measurement of the extracellular water space in critically ill patients. Appl Radiat Isot. 1998, 49 (5-6): 481-3. 10.1016/S0969-8043(97)00060-2.CrossRefPubMed
28.
Cheng AT, Plank LD, Hill GL: Prolonged overexpansion of extracellular water in elderly patients with sepsis. Arch Surg. 1998, 133 (7): 745-51. 10.1001/archsurg.133.7.745.CrossRefPubMed
29.
Plank LD, Hill GL: Similarity of changes in body composition in intensive care patients following severe sepsis or major blunt injury. Ann NY Acad Sci. 2000, 904: 592-602. 10.1111/j.1749-6632.2000.tb06521.x.CrossRefPubMed
30.
Jaehde U, Sorgel F: Clinical pharmacokinetics in patients with burns. Clin Pharmacokinet. 1995, 29 (1): 15-28. 10.2165/00003088-199529010-00003.CrossRefPubMed
31.
Finfer S, Bellomo R, Boyce N, French J, Myburg J, Norton R, SAFE study investigators: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004, 350 (22): 2247-2256. 10.1056/NEJMoa040232.CrossRefPubMed
32.
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 (10): 2559-61.PubMedPubMedCentral
33.
Roberts JA, Paratz JD, Paratz E, Krueger WA, Lipman J: Continuous infusion of beta-lactam antibiotics in severe infections - a review of its role. Int J Antimicrob Agents. 2007, 30 (1): 11-8. 10.1016/j.ijantimicag.2007.02.002.CrossRefPubMed
34.
Ryan DM: Pharmacokinetics of antibiotics in natural and experimental superficial compartments in animals and humans. J Antimicrob Chemother. 1993, 31 (Suppl D): 1-16.CrossRefPubMed
35.
Busse MW, Zisowshy S, Henschen S, Panning B, Piepenbrock B: Plasma volume estimation using indocyanine green. A single intravenous injection method. Anaesthesia. 1993, 48 (1): 41-3. 10.1111/j.1365-2044.1993.tb06789.x.CrossRefPubMed
36.
Wong WW, Sheng HP, Morkeberg JC, Kosanovich JL, Clarke LL, Klein PD: Measurement of extracellular water volume by bromide ion chromatography. Am J Clin Nutr. 1989, 50: 1290-1294.PubMed
37.
Monk DN, Plank LD, Franch-Arcas G, Finn PJ, Streat SJ, Hill GL: Sequential changes in the metabolic response in critically injured patients during the first 25 days after blunt trauma. Ann Surg. 1996, 223: 395-405. 10.1097/00000658-199604000-00008.CrossRefPubMedPubMedCentral
38.
Buclin T, Sechaud R, Bertschi AP, Decosterd LA, Belaz N, Appenzeller M, Burnier M, Biollaz J: Estimation of glomerular filtration rate by sinistrin clearance using various approaches. Ren Fail. 1998, 20 (2): 267-76. 10.3109/08860229809045111.CrossRefPubMed
39.
Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J: Piperacillin penetration into tissue of critically ill patients with sepsis-Bolus versus continuous administration. Crit Care Med. 2009, 37 (3): 926-933. 10.1097/CCM.0b013e3181968e44.CrossRefPubMed
40.
Roberts JA, Kirkpatrick CMJ, Roberts MS, Robertson TA, Dalley AJ, Lipman J: Meropenem dosing in critically ill patients with sepsis and without renal dysfunction - intermittent bolus vs continuous administration? Monte-Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother. 2009, 64: 142-50. 10.1093/jac/dkp139.CrossRefPubMed
41.
Cherry RA, Eachempati SR, Hydo L, Barie PS: Accuracy of short-duration creatinine clearance determinations in predicting 24-hour creatinine clearance in critically ill and injured patients. J Trauma. 2002, 53 (2): 267-71. 10.1097/00005373-200208000-00013.CrossRefPubMed
42.
Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B: Quantification of Lean Bodyweight. Clinical Pharmacokinetics. 2005, 44 (10): 1051-1065. 10.2165/00003088-200544100-00004.CrossRefPubMed
43.
Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron. 1976, 16: 31-41. 10.1159/000180580.CrossRef
44.
Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med. 1985, 13: 818-829. 10.1097/00003246-198510000-00009.CrossRefPubMed
45.
Antonelli M, Moreno R, Vincent JL: Application of SOFA score to trauma patients. Sequential Organ Failure Assessment. Intensive Care Med. 1999, 25: 389-394. 10.1007/s001340050863.CrossRefPubMed
46.
Champion HR, Sacco WJ, Copes WS, Gann DS, Gennarelli TA, Flanagan ME: A revision of the Trauma Score. J Trauma. 1989, 29 (5): 623-629. 10.1097/00005373-198905000-00017.CrossRefPubMed
47.
Zeitlinger BS, Zeitlinger M, Leitner I, Müller M, Joukhadar C: Clinical Scoring System for the Prediction of Target Site Penetration of Antimicrobials in Patients with Sepsis. Clinical Pharmacokinetics. 2007, 46 (1): 75-83. 10.2165/00003088-200746010-00004.CrossRefPubMed
48.
Faul F, Erdfelder E, Lang A, Buchner A: G*power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007, 39: 175-19. 10.3758/BF03193146.CrossRefPubMed
49.
Roos JF, Lipman J, Kirkpatrick CM: Population pharmacokinetics and pharmacodynamics of cefpirome in critically ill patients against Gram-negative bacteria. Intensive Care Med. 2007, 33 (5): 781-8. 10.1007/s00134-007-0573-7.CrossRefPubMed
50.
Roos JF, Bulitta J, Lipman J, Kirkpatrick CM: Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units. J Antimicrob Chemother. 2006, 58 (5): 987-93. 10.1093/jac/dkl349.CrossRefPubMed
Metadata
Title
Antibiotic dosing in the 'at risk' critically ill patient: Linking pathophysiology with pharmacokinetics/pharmacodynamics in sepsis and trauma patients
Authors
Jason A Roberts
Michael S Roberts
Andrew Semark
Andrew A Udy
Carl MJ Kirkpatrick
David L Paterson
Matthew J Roberts
Peter Kruger
Jeffrey Lipman
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Anesthesiology / Issue 1/2011
Electronic ISSN: 1471-2253
DOI
https://doi.org/10.1186/1471-2253-11-3

Other articles of this Issue 1/2011

BMC Anesthesiology 1/2011 Go to the issue

Research article

Single-center experience with levosimendan in children undergoing cardiac surgery and in children with decompensated heart failure

Research article

Short term non-invasive ventilation post-surgery improves arterial blood-gases in obese subjects compared to supplemental oxygen delivery - a randomized controlled trial

Research article

Metabolic acidosis may be as protective as hypercapnic acidosis in an ex-vivo model of severe ventilator-induced lung injury: a pilot study

Correspondence

A bibliometric search of citation classics in anesthesiology

Technical advance

Subcutaneous dissociative conscious sedation (sDCS) an alternative method for airway regional blocks: a new approach

Research article

Assessment of a continuous blood gas monitoring system in animals during circulatory stress