Serum Ceftazidime Concentrations in Hemodialysis Patients

NCT03634904 | Unknown

• 1 other identifier: CHUCHARLEROIPKPD001
• Study Type: interventional
• Target: 20
• Locations: 0 countries
• Sites: N/A

Brief Summary

There is evidence that the current dosing recommendations of ceftazidime in hemodialysis patients may not reach the critical pharmacokinetic/pharmacodynamics thresholds associated with maximal efficacy. The primary objective is to assess whether the standard doses of ceftazidime (1 or 2 g) administered at the end of the dialysis session (intermittent dialysis) allow to obtain a trough level equal or superior to 8 mg/L if the causative organism is not identified or 1 x the MIC if it is identified and its in vitro susceptibility to ceftazidime established. The secondary objectives will be (i) to assess whether a trough level equal or superior to 32 mg/L (if the causative organism is not identified) and 4 x its MIC (if identified and its in vitro susceptibility established) can be obtained; (ii) whether the criteria mentioned above also apply to the free fractions of ceftazidime; (iii) to assess whether reaching the desired free and total trough concentrations impacts the clinical outcome of the patient; (iv) to assess whether the main hemodialysis parameters impact on ceftazidime total and free serum concentrations; (v) to assess the impact of patient's residual renal function on the ceftazidime serum free and total concentrations; (vi) to assess the impact of potential drug-drug interactions on ceftazidime serum free and total concentrations; (vii) to assess how the MIC of the causative organism (if known) affects the expected effectiveness of ceftazidime. The study will be prospective and monocentric. Drug assay will be made High Performance Liquid Chromatography (HPLC) and UV photometric detection (confirmed by tandem mass spectrometry detection\[HPLC-MS-MS\]). Free concentration will be measured after separation by membrane sieving. The expected number of enrolled patients will be 20 (arbitrarily chosen but compatible with previous studies and the possibilities of the Institution in which the study will be performed. The standard dose of ceftazidime will be (i) a loading dose of 2 g followed by a maintenance dose of 1 g (the dose may be modified by the clinician in charge if deemed necessary and recorded accordingly). The data obtained will be used for pharmacokinetic modelling and population pharmacokinetics, followed by Monte-Carlo simulations to obtain population-wide predictions and to draw conclusions that could be applicable to a larger population.

Conditions

Bacterial Infections; Ceftazidime; Renal Failure Chronic Requiring Hemodialysis

Keywords

antibiotic dosing; pharmacokinetics; pharmacodynamics; hemodialysis

Outcome Measures

Primary Outcomes (1)

• Trough level at 8 mg/L or 1 x the MIC

  total trough serum concentration of ceftazidime after its administration (loading dose and maintenance dose) and determining if it is higher or equal to 8 mg/L of 1 x the MIC

  7 days

Secondary Outcomes (18)

• Trough level at 32 mg/L or 4 x the MIC

  7 days

• Free trough level at 8 mg/L or 1 x the MIC

  7 days

• Free trough level at 32 mg/L or 4 x the MIC

  7 days

• Impact of trough levels at 8 mg/L ot 1 x the MIC on clinical outcome

  7 days

• Impact of trough levels at 32 mg/L ot 4 x the MIC on clinical outcome

  7 days

Study Arms (1)

Drug Blood sampling

EXPERIMENTAL

* Drug Blood sampling * Pharmacokinetic study measuring total and free ceftazidime concentrations

Drug: Drug bood sampling

Interventions

Drug bood sampling DRUG

Total: 6 per patient * after the first administration of ceftazidime (loading dose): sampling #1: at trough before 1st dialysis; sampling #2: after the end of the dialysis session; * after the second administration of ceftazidime (maintenance dose): sampling #3: at trough before 2d dialysis session; * after the third administration of ceftazidime (maintenance dose): sampling #4: at trough before 3d dialysis session; * after the fourth third administration of ceftazidime (maintenance dose): sampling #5: at trough before 4th dialysis session; sampling #6: after the end of the dialysis session

Drug Blood sampling

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• any patient with 18 years of age or older and chronically treated by hemodialysis in the hemodialysis ward of the Institution, and
• for whom ceftazidime is administered for treating a suspected or confirmed infection for which ceftazidime is indicated, and
• who has given her/his informed consent.

You may not qualify if:

• patient with suspected or confirmed allergy to beta-lactam antibiotics
• pregnant women (based on patient's declaration)
• nursing women

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Charleroi: lead
• Université Catholique de Louvain: collaborator

Related Publications (18)

• Kollef MH. Broad-spectrum antimicrobials and the treatment of serious bacterial infections: getting it right up front. Clin Infect Dis. 2008 Sep 15;47 Suppl 1:S3-13. doi: 10.1086/590061.

  PMID: 18713047 BACKGROUND

• Wurtz R, Itokazu G, Rodvold K. Antimicrobial dosing in obese patients. Clin Infect Dis. 1997 Jul;25(1):112-8. doi: 10.1086/514505.

  PMID: 9243045 BACKGROUND

• Falagas ME, Karageorgopoulos DE. Adjustment of dosing of antimicrobial agents for bodyweight in adults. Lancet. 2010 Jan 16;375(9710):248-51. doi: 10.1016/S0140-6736(09)60743-1. Epub 2009 Oct 28. No abstract available.

  PMID: 19875163 BACKGROUND

• Erstad BL. Dosing of medications in morbidly obese patients in the intensive care unit setting. Intensive Care Med. 2004 Jan;30(1):18-32. doi: 10.1007/s00134-003-2059-6. Epub 2003 Nov 19.

  PMID: 14625670 BACKGROUND

• Trotman RL, Williamson JC, Shoemaker DM, Salzer WL. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin Infect Dis. 2005 Oct 15;41(8):1159-66. doi: 10.1086/444500. Epub 2005 Sep 12.

  PMID: 16163635 BACKGROUND

• Taccone FS, Laterre PF, Dugernier T, Spapen H, Delattre I, Wittebole X, De Backer D, Layeux B, Wallemacq P, Vincent JL, Jacobs F. Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010;14(4):R126. doi: 10.1186/cc9091. Epub 2010 Jul 1.

  PMID: 20594297 BACKGROUND

• Seyler L, Cotton F, Taccone FS, De Backer D, Macours P, Vincent JL, Jacobs F. Recommended beta-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy. Crit Care. 2011;15(3):R137. doi: 10.1186/cc10257. Epub 2011 Jun 6.

  PMID: 21649882 BACKGROUND

• Zeitlinger MA, Derendorf H, Mouton JW, Cars O, Craig WA, Andes D, Theuretzbacher U. Protein binding: do we ever learn? Antimicrob Agents Chemother. 2011 Jul;55(7):3067-74. doi: 10.1128/AAC.01433-10. Epub 2011 May 2.

  PMID: 21537013 BACKGROUND

• Lam YW, Duroux MH, Gambertoglio JG, Barriere SL, Guglielmo BJ. Effect of protein binding on serum bactericidal activities of ceftazidime and cefoperazone in healthy volunteers. Antimicrob Agents Chemother. 1988 Mar;32(3):298-302. doi: 10.1128/AAC.32.3.298.

  PMID: 3284457 BACKGROUND

• 10. Ngougni Pokem et al. Protein binding of temocillin is lower in plasma from patients in intensive care units compared to healthy subjects: in vitro and in vivo studies ; 28th ECCMID - Session: Clinical pharmacokinetics - poster #P2219.

  BACKGROUND

• Roberts JA, Ulldemolins M, Roberts MS, McWhinney B, Ungerer J, Paterson DL, Lipman J. Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents. 2010 Oct;36(4):332-9. doi: 10.1016/j.ijantimicag.2010.06.008. Epub 2010 Aug 3.

  PMID: 20685085 BACKGROUND

• Nikolaidis P, Tourkantonis A. Effect of hemodialysis on ceftazidime pharmacokinetics. Clin Nephrol. 1985 Sep;24(3):142-6.

  PMID: 3899438 BACKGROUND

• 13. GlaxoSmithKline August 2010. Fortaz (ceftazidime for injection) prescribing information. GlaxoSmithKline, Mississauga, Ontario, Canada

  BACKGROUND

• Matzke GR, Frye RF, Joy MS, Palevsky PM. Determinants of ceftazidime clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis. Antimicrob Agents Chemother. 2000 Jun;44(6):1639-44. doi: 10.1128/AAC.44.6.1639-1644.2000.

  PMID: 10817721 BACKGROUND

• Loo AS, Neely M, Anderson EJ, Ghossein C, McLaughlin MM, Scheetz MH. Pharmacodynamic target attainment for various ceftazidime dosing schemes in high-flux hemodialysis. Antimicrob Agents Chemother. 2013 Dec;57(12):5854-9. doi: 10.1128/AAC.00474-13. Epub 2013 Sep 9.

  PMID: 24018264 BACKGROUND

• De Waele JJ, Carrette S, Carlier M, Stove V, Boelens J, Claeys G, Leroux-Roels I, Hoste E, Depuydt P, Decruyenaere J, Verstraete AG. Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: a randomised controlled trial. Intensive Care Med. 2014 Mar;40(3):380-7. doi: 10.1007/s00134-013-3187-2. Epub 2013 Dec 20.

  PMID: 24356862 BACKGROUND

• Vandecasteele SJ, Miranda Bastos AC, Capron A, Spinewine A, Tulkens PM, Van Bambeke F. Thrice-weekly temocillin administered after each dialysis session is appropriate for the treatment of serious Gram-negative infections in haemodialysis patients. Int J Antimicrob Agents. 2015 Dec;46(6):660-5. doi: 10.1016/j.ijantimicag.2015.09.005. Epub 2015 Oct 9.

  PMID: 26603304 BACKGROUND

• Miranda Bastos AC, Vandecasteele SJ, Spinewine A, Tulkens PM, Van Bambeke F. Temocillin dosing in haemodialysis patients based on population pharmacokinetics of total and unbound concentrations and Monte Carlo simulations. J Antimicrob Chemother. 2018 Jun 1;73(6):1630-1638. doi: 10.1093/jac/dky078.

  PMID: 29579214 BACKGROUND

MeSH Terms

Conditions

Bacterial Infections

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Study Officials

• Remy Demeester, MD

  Centre Hospitalier Universitaire de Charleroi

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Remy Demeester, MD

CONTACT

00-32-486-666-444; remy.demeester@chu-charleroi.be

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Doctor, Department of Internal Medicine

Model Details: Single group assignment

Study Record Dates

• First Submitted: August 9, 2018
• First Posted: August 17, 2018
• Study Start: September 15, 2018
• Primary Completion: September 15, 2020
• Study Completion: September 15, 2021
• Last Updated: August 17, 2018

Record last verified: 2018-08