Antibiotic Plasma Concentrations During Continuous Renal Replacement Therapy With a High Adsorption Membrane (oXiris®)

Sepsis Clinical Trial

Official title:

Antibiotic Plasma Concentrations During Continuous Renal Replacement Therapy With a High Adsorption Membrane (oXiris®)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04033029
• Other study ID #: HCC-PIP-2018-01
• Status: Completed
• Start date: January 1, 2021
• Est. completion date: June 30, 2023

Study information

• Verified date: October 2023
• Source: Hospital Universitari de Bellvitge
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

• Study: Open label, non-randomized, observational, descriptive and prospective pharmacokinetic.

• Patients: sepsis patients undergoing continuous renal replacement therapy (CRRT) and admitted at the Intensive care unit of Bellvitge University Hospitals. No power calculations needed.

• Antibiotic treatment: piperacillin, ceftazidime, cefepime, ceftolozane and daptomycin as their standard of care and doses will be at the discretion of the treating physician.

• CRRT treatment: continuous venovenous hemodiafiltration (CVVHDF) will be performed by using the PrismafleX eXeed™ system with a high adsorbent membrane (oXiris®).

• Antibiotic concentrations: blood pre and post filter, urine and ultrafiltrate samples will be collected at steady state conditions. Samplig time will depend on dosage regimens of each antibiotic.

Description:

The study is an open label, non-randomized, observational, descriptive and prospective pharmacokinetic study.

Setting: this study will be conducted at the Intensive Care Unit at the Bellvitge University Hospital.

Study aims: the primary objective is to determine the PK/PD target attainment of piperacillin, ceftazidime, cefepime, ceftolozane and daptomycin in septic critically ill patients treated with CVVHDF using oXiris® membrane. Secondary aims are: i) to characterize the PK of piperacillin, ceftazidime, cefepime, ceftolozane and daptomycin in critically ill patients under CVVHDF therapy using oXiris® membrane by developing a population PK model; ii) to identify the clinical and demographic sources of PK variability observed in these patient and iii) to develop individualized dosing recommendations based on the PK/PD index associated with therapy success.

Recruitment process: patients who meet the inclusion criteria will be enrolled for at least 72 hours (maximum 96 hours).

Sample size: no power calculations are required for this study as it aims to investigate the PK of these antibiotics and does not intend to measure the effect of an intervention between two groups.

Antibiotic treatment: patients will receive piperacillin, ceftazidime, cefepime, ceftolozane/tazobactam or daptomycin as their standard of care. Doses will be at the discretion of the treating physician. At the same time, patients will be treated under continuous renal replacement techniques (CRRT) with continuous venovenous hemodiafiltration mode (CVVHDF) using PrismafleX eXeed™ system and high adsorbent polyethyleneimide membrane (oXiris®). Filtration parameters will be determined following the local protocol (dose of 25-30 ml/kg/h) CRRT initiation will be determined by the treating physician on charge, according with the current recommendations of clinical practice and prescriptions of CRRT and local management protocols. The decision to stop the treatment will be determined by:

• Adequate renal recovery status: adequate capacity to effectively maintain fluid and electrolyte homeostasis and urinary output (>450 ml in 24 h) without the use of diuretics.

• Hemodynamic stability without renal function recovery. Therapy will be continued as intermittent hemodialysis.

Antibiotic concentrations: blood, either pre and post filtration through oXiris® membrane, urine and ultrafiltrate samples will be obtained. Samples will be collected at 1) steady state conditions and 2) after minimum 24h from the concomitant administration of CRRT and antibiotic for piperacillin, ceftazidime, cefepime, ceftolozane and 48h for daptomycin. Sampling times will depend on the dosage regimen of each antibiotic therapy. Drug concentrations will be determined using a previously developed and validated measurement procedure based on ultra-high performance liquid chromatography-tandem mass spectrometry.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: June 30, 2023
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients in the setting of sepsis and requirements of CRRT with high adsorption membranes for at least 48 h

• Age >18 years

• Treatment with piperacillin, ceftazidime, cefepime, ceftolozane and daptomycin prescribed at the discretion of the treating intensive care physician.

• Written informed consent will be required before the inclusion of a patient whenever possible and will be requested from the nearest relatives in the other cases.

Exclusion Criteria: none.

Related Conditions & MeSH terms

• Acute Kidney Injury
• Hemodiafiltration
• Sepsis

Intervention

Device:
• Continuous venovenous hemodiafiltration with high adsorption membrane (oXiris®)
CRRT initiation will be determined by the treating physician on charge, according with the current recommendations of clinical practice and prescriptions of CRRT and local management protocols. The CVVHDF mode will be performed by using PrismafleX eXeed™ system and high adsorbent polyethyleneimide membrane (oXiris®). Filtration parameters will be determined following the local protocol (dose of 25-30 ml/kg/h).

Drug:
• Antibiotics
Antibiotic concentration-time data will be collected and analyzed.

Locations

Country	Name	City	State
Spain	Helena Colom Codina	Barcelona

Sponsors (2)

Lead Sponsor	Collaborator
Hospital Universitari de Bellvitge	Baxter Healthcare Corporation

Country where clinical trial is conducted

Spain, 

References & Publications (17)

Bauer SR, Salem C, Connor MJ Jr, Groszek J, Taylor ME, Wei P, Tolwani AJ, Fissell WH. Pharmacokinetics and pharmacodynamics of piperacillin-tazobactam in 42 patients treated with concomitant CRRT. Clin J Am Soc Nephrol. 2012 Mar;7(3):452-7. doi: 10.2215/CJN.10741011. Epub 2012 Jan 26. — View Citation

Brun-Buisson C. The epidemiology of the systemic inflammatory response. Intensive Care Med. 2000;26 Suppl 1(Suppl 1):S64-74. doi: 10.1007/s001340051121. — View Citation

Carcelero San Martin E, Soy Muner D. [Dosage of antipseudomonal antibiotics in patients with acute kidney injury subjected to continuous renal replacement therapies]. Med Intensiva. 2013 Apr;37(3):185-200. doi: 10.1016/j.medin.2012.02.012. Epub 2012 Apr 3. Spanish. — View Citation

Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998 Jan;26(1):1-10; quiz 11-2. doi: 10.1086/516284. — View Citation

Heinemeyer G, Link J, Weber W, Meschede V, Roots I. Clearance of ceftriaxone in critical care patients with acute renal failure. Intensive Care Med. 1990;16(7):448-53. doi: 10.1007/BF01711224. — View Citation

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 Jul;118(1):146-55. doi: 10.1378/chest.118.1.146. — View Citation

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 Feb;115(2):462-74. doi: 10.1378/chest.115.2.462. — View Citation

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. — View Citation

Pinder M, Bellomo R, Lipman J. Pharmacological principles of antibiotic prescription in the critically ill. Anaesth Intensive Care. 2002 Apr;30(2):134-44. doi: 10.1177/0310057X0203000203. — View Citation

Rigo-Bonnin R, Ribera A, Arbiol-Roca A, Cobo-Sacristan S, Padulles A, Murillo O, Shaw E, Granada R, Perez-Fernandez XL, Tubau F, Alia P. Development and validation of a measurement procedure based on ultra-high performance liquid chromatography-tandem mas — View Citation

Roberts DM, Roberts JA, Roberts MS, Liu X, Nair P, Cole L, Lipman J, Bellomo R; RENAL Replacement Therapy Study Investigators. Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: a multicentre pharmacokinetic study. Crit Care Med. 2012 May;40(5):1523-8. doi: 10.1097/CCM.0b013e318241e553. — View Citation

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 Mar;37(3):926-33. doi: 10.1097/CCM.0b013e3181968e44. — View Citation

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 — View Citation

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. — View Citation

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 May;45(5):701-4. doi: 10.1093/jac/45.5.701. — View Citation

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 Dec 2;302(21):2323-9. doi: 10.1001/jama.2009.1754. — View Citation

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 May;9(5):412-8. doi: 10.1046/j.1469-0691.2003.00656.x. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of individuals attaining a defined pharmacokinetic-pharmacodynamic target for antimicrobial therapy	Time above minimum inhibitory concentration (%fT > k× MIC) for betalactams, and total-drug AUC24/MIC = 666 for daptomycin	01/08/2019 - 31/12/2021
Secondary	Antibiotic concentration-time data.	Antibiotic concentration-time data will be collected and analysed to characterize the PK profile of piperacillin, ceftazidime, cefepime, ceftolozane and daptomycin in critically ill patients under CRRT therapy using oXiris® membrane and a population PK model will be developed.	01/08/2019 - 31/12/2021
Secondary	Blood flow (mL/min). CRRT covariate that can affect drug exposure and PK parameters.	Effect of CRRT settings, physiopathological and demographic data on drug exposure and PK parameters.	01/08/2019 - 31/12/2021
Secondary	Dialysate flow rate (L/h).	CRRT covariate that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed.	01/08/2019 - 31/12/2021
Secondary	Ultrafiltrate flow rate (L/h).	CRRT covariate that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed.	01/08/2019 - 31/12/2021
Secondary	Replacement fluid (mL/h).	CRRT covariate that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed.	01/08/2019 - 31/12/2021
Secondary	Extraction rate (L/h).	CRRT covariate that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed.	01/08/2019 - 31/12/2021
Secondary	Urine output (mL/day).	Physiopathological variables that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed.	01/08/2019 - 31/12/2021
Secondary	Albumin (g/L).	Physiopathological variables that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed.	01/08/2019 - 31/12/2021
Secondary	Weight (Kg).	Physiopathological variables that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed.	01/08/2019 - 31/12/2021
Secondary	Admission diagnosis: surgical, medical, trauma.	Physiopathological variables that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed.	01/08/2019 - 31/12/2021
Secondary	Dosage (mg, frequency of administration and mode of administration) needed to achieve the PK/PD target.	Monte-Carlo Simulations using the population PK parameters of the final models in order to generate concentration-time profiles of n hypothetical subjects per dosing regimen will be performed. With this data, we will calculate the probability of target attainment of the PK/PD indices associated to antibiotic therapy success, which will translate in the development of individualized dosing recommendations for our patient population.	01/08/2019 - 31/12/2021