Plasma Protein Binding and PK/PD of Total and Unbound Temocillin Non-ICU Patients

NCT03557840 | Unknown

• 1 other identifier: temocillin prot-bind non-ICU
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Multidrug resistance towards Gram-negative pathogens makes essential the re-examination of older compounds. Temocillin is a penicillin originally marketed in the 1980s but then largely abandoned. It, however, shows a marked ß-lactamase stability (including most classical and extended-spectrum TEM, SHV, CTX-M enzymes and AmpC ß-lactamase). Temocillin is approved for the treatment of bacterial infections of the chest, the lungs, the kidney, the bladder, as well as bacterial infections of the bloodstream and wound infections. Temocillin efficacy depends primarily from the time interval during which the unbound plasma concentration remains above the minimal inhibitory concentration (MIC) of the antibiotic against the target organism(s). Unfortunately, no comprehensive pharmacokinetic data are available in non-critically-ill patients. The primary objective of the study is characterize the pharmacokinetics of total and unbound temocillin in non-ICU patients, and, on this basis, to propose optimized dosage regimens in this population. The secondary objectives are (i) to look for possible correlations between the plasma protein profile and the unbound temocillin concentrations; (ii) to investigate the impact of the level and nature of circulating plasma proteins on the unbound temocillin concentration. The study will be non-randomized, uncontrolled, prospective, open label, interventional, and monocentric. It will include a population pharmacokinetic-pharmacodynamic analysis of the data obtained. The study will enroll patients ≥ 18 years in need of a treatment with temocillin for (i) complicated urinary tract infection and pyelonephritis (associated or not with bacteremia), or (ii) lower respiratory tract infection, or (iii) abdominal infection, and requiring ≥ 4 days of hospitalization. Blood samples will be obtained at day 0 (control) and after 2 and 4 days of drug treatment (full pharmacokinetic evaluation over 8 to 12 h post-administration). Total and unbound temocillin concentrations in plasma will be quantified by a validated analytical method. A population pharmacokinetic/pharmacodynamics model of plasma total and unbound concentrations of temocillin will be obtained by Bayesian algorithms using Pmetrics software, driven by the predicted plasma total and unbound concentration. The model will be used to assess the probability of target attainment of temocillin.

Conditions

Pharmacokinetics; Antibacterial Agents; Infections, Bacterial; Infection; Drug Monitoring; Temocillin

Keywords

temocillin; free concentration; total concentration; pharmacokinetics; pharmacodynamic; probability of target attainment; non-ICU

Outcome Measures

Primary Outcomes (2)

• pharmacokinetics of total plasma temocillin

  Measurement of total plasma temocillin concentrations (measurement by a validated HPLC-MS-MS after suitable extraction; no predefined value set \[exploratory\])

  12 days

• pharmacokinetics of unbound plasma temocillin

  Measurement of unbound plasma temocillin concentrations (measurement by a validated HPLC-MS-MS after separation from protein-bound temocillin; no predefined value set \[exploratory\])

  12 days

Secondary Outcomes (11)

• Pharmacokinetic analysis and population pharmacokinetics: Cmax (total and free)

  36 months

• Pharmacokinetic analysis and population pharmacokinetics: Cmin (total and free)

  36 months

• Pharmacokinetic analysis and population pharmacokinetics: time above a critical concentration value for total and free concentrations

  36 months

• Covariables analysis (biometric values): weight

  36 months

• Covariables analysis (biometric values): height

  36 months

Study Arms (1)

Temocillin treatment

EXPERIMENTAL

Patients treated with temocillin and sampled as per the protocol

Drug: temocillin

Interventions

temocillin DRUG

Drug dosing and blood sampling as per the protocol

Also known as: NEGABAN

Temocillin treatment

Eligibility Criteria

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

You may qualify if:

• ≥ 18 years old
• prescribed temocillin for a complicated urinary tract infection and pyelonephritis associated or not with bacteraemia; or a l ower respiratory tract infection; or an abdominal infection
• requiring ≥ 4 days hospitalization
• having signed and informed consent (or signed by the legal representative)

You may not qualify if:

• Patients \< 18 years old
• Patients allergic to β-lactams
• Patients Ig-E mediated allergy to penicillin
• Patients with acute or chronic renal failure (GFR \< 30ml/min)

Sponsors & Collaborators

• Paul M. Tulkens: lead

Study Sites (1)

AZ Delta ziekenhuis

Roeselare, West-Vlaanderen, 8800, Belgium

RECRUITING

Related Publications (22)

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  PMID: 23153962 RESULT

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  PMID: 16531428 RESULT

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  PMID: 19095679 RESULT

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  PMID: 2186240 RESULT

• Ngougni Pokem P, Miranda Bastos AC, Tulkens PM, Wallemacq P, Van Bambeke F, Capron A. Validation of a HPLC-MS/MS assay for the determination of total and unbound concentration of temocillin in human serum. Clin Biochem. 2015 May;48(7-8):542-5. doi: 10.1016/j.clinbiochem.2015.02.006. Epub 2015 Feb 21.

  PMID: 25712752 RESULT

• RCP Temocillin. Temocillin Summary of Product Characteristics. Centre Belge d'Information Pharmacothérapeutique (C.B.I.P.asbl) . 2014. 4-1-2016 http://bijsluiters.fagg-afmps.be/registrationSearchServlet?key=BE467724&leafletType=rcp

  RESULT

• Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009 Mar;37(3):840-51; quiz 859. doi: 10.1097/CCM.0b013e3181961bff.

  PMID: 19237886 RESULT

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  PMID: 25808018 RESULT

• Sime FB, Roberts MS, Peake SL, Lipman J, Roberts JA. Does Beta-lactam Pharmacokinetic Variability in Critically Ill Patients Justify Therapeutic Drug Monitoring? A Systematic Review. Ann Intensive Care. 2012 Jul 28;2(1):35. doi: 10.1186/2110-5820-2-35.

  PMID: 22839761 RESULT

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  PMID: 16640454 RESULT

• Udy AA, Varghese JM, Altukroni M, Briscoe S, McWhinney BC, Ungerer JP, Lipman J, Roberts JA. Subtherapeutic initial beta-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest. 2012 Jul;142(1):30-39. doi: 10.1378/chest.11-1671.

  PMID: 22194591 RESULT

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  PMID: 3588249 RESULT

• 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 RESULT

• Wong G, Briscoe S, Adnan S, McWhinney B, Ungerer J, Lipman J, Roberts JA. Protein binding of beta-lactam antibiotics in critically ill patients: can we successfully predict unbound concentrations? Antimicrob Agents Chemother. 2013 Dec;57(12):6165-70. doi: 10.1128/AAC.00951-13. Epub 2013 Sep 30.

  PMID: 24080664 RESULT

• Zykov IN, Sundsfjord A, Smabrekke L, Samuelsen O. The antimicrobial activity of mecillinam, nitrofurantoin, temocillin and fosfomycin and comparative analysis of resistance patterns in a nationwide collection of ESBL-producing Escherichia coli in Norway 2010-2011. Infect Dis (Lond). 2016 Feb;48(2):99-107. doi: 10.3109/23744235.2015.1087648. Epub 2015 Sep 28.

  PMID: 26414659 RESULT

• Wijnant GJ, Ngougni Pokem P, Coessens M, Cottone E, Ermtraud J, Goeman L, Vervaeke S, Wicha SG, Van Bambeke F. Pharmacokinetics and pharmacological target attainment of standard temocillin dosing in non-critically ill patients with complicated urinary tract infections. J Antimicrob Chemother. 2024 Sep 3;79(9):2204-2212. doi: 10.1093/jac/dkae215.

  PMID: 38985543 DERIVED

MeSH Terms

Conditions

Bacterial Infections; Infections

Interventions

temocillin

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses

Study Officials

• Françoise Van Bambeke, PharmD, PhD

  Université cathollique de Louvain, Louvain Drug Research Institute

  STUDY DIRECTOR

• Paul M. Tulkens, MD, PhD

  Université catholique de Louvain, Louvain Drug Research Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Steven Vervaeke, MD

CONTACT

0013251237196; Steven.Vervaeke@azdelta.be

Perrin Ngougni Pokem, Pharm

CONTACT

003227647225; perrin.ngougni@uclouvain.be

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: All patients will be simultaneously studied (disregarding the nature of their infection or the dose/schedule of temocillin)

Study Record Dates

• First Submitted: June 4, 2018
• First Posted: June 15, 2018
• Study Start: April 1, 2019
• Primary Completion: April 1, 2023
• Study Completion: April 1, 2023
• Last Updated: May 31, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)