Population Pharmacokinetics and Pharmacodynamics of Beta-lactams of Interest in Adult Patients From Intensive Care Units

NCT03440216 | Unknown DMC

• 1 other identifier: Pop PK/PD betalactams ICU
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Antibiotics are still most often administered on an empiric fashion, as defined for the general population with dosages only adapted based on weight and renal and/or hepatic functions. As a result, serum concentrations show important interpatient variations with the risk of being subtherapeutic or toxic. Recent studies with temocillin, ceftriaxone, or meropenem confirm this for patients in intensive care units. The aim of the study will be to measure the total and free concentrations of temocillin, ceftriaxone, and meropenem in patients hospitalized in Intensive Care Units for pulmonary infections or another infection for which one of the above mentioned antibiotics is indicated. Patients will be stratified according to the level of their renal function. The antibiotics will be assayed in plasma as well as other accessible fluids in order to assess their pharmacokinetic properties.

Conditions

Pharmacokinetics; Anti-Bacterial Agents; Infection, Bacterial; Infections, Respiratory; Infection; Drug Monitoring

Keywords

temocillin; ceftriaxone; meropenem; pharmacokinetics; pharmacodynamics; Intensive Care; dosing; total concentration; free concentration

Outcome Measures

Primary Outcomes (1)

• Impact of renal function on total plasma concentrations

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

  36 months

Secondary Outcomes (14)

• Impact of the plasma protein concentration and of their nature on the free concentration of antibiotics

  36 months

• Tissular and fluid penetration of antibiotics (total)

  36 months

• Tissular and fluid penetration of antibiotics (free)

  36 months

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

  36 months

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

  36 months

Study Arms (2)

Sampling if GFR = or > 30 mL/min

EXPERIMENTAL

Note: GFR = Glomerular Filtration Rate Patients with a normal of moderately decreased renal function * Temocillin: 6 g in continuous infusion over 24 h; * Ceftriaxone: bolus 2 g (in 30 min) every 12h * Meropenem: prolonged infusion (3 h) of 2 g every 8h Blood sampling for antibiotic (temocillin, ceftriaxone or meropenem) pharmacokinetic analysis / Tissue sampling (lung) for determination of antibiotic content when possible / Collection of fluid samples (bronchoalveolar lavage, drainage fluid) for determination of antibiotic concentration when possible

Drug: blood sampling; Drug: Tissue sampling (lung); Drug: Collection of fluid samples

Sampling if GFR < 30 mL/min

EXPERIMENTAL

Patients with severe renal insufficiency or hemodialysis: * Temocillin: 6 g in continuous infusion over 24 h; * Ceftriaxone: bolus 2 g (in 30 min) every 12h * Meropenem: prolonged infusion (3 h) of 2 g every 8h Blood sampling for antibiotic (temocillin, ceftriaxone or meropenem) pharmacokinetic analysis / Tissue sampling (lung) for determination of antibiotic content if possible / Collection of fluid samples (bronchoalveolar lavage, drainage fluid) for determination of antibiotic concentration if possible

Drug: blood sampling; Drug: Tissue sampling (lung); Drug: Collection of fluid samples

Interventions

blood sampling DRUG

* temocillin: blood sampling every day for 7 days * ceftriaxone: blood sampling 12h after administration for 7 days * meropenem: blood sampling at 1h, 3h, 5h and 8h after initiation of the administration at days 1 and 2; one sampling at 8h on days 3 to 7

Also known as: temocillin, ceftriaxone, meropenem

Sampling if GFR < 30 mL/min; Sampling if GFR = or > 30 mL/min

Tissue sampling (lung) DRUG

Sampling of tissue (lung) when possible during treatment for measurement of the content in antibiotic (temocillin, ceftriaxone, or meropenem, depending on the drug received by the patient)

Also known as: temocillin, ceftriaxone, meropenem

Sampling if GFR < 30 mL/min; Sampling if GFR = or > 30 mL/min

Collection of fluid samples DRUG

Collection of fluid samples (bronchoalveolar lavage, drainage fluid) for determination of antibiotic ((temocillin, ceftriaxone, or meropenem, depending on the drug received by the patient) concentration when possible during treatment

Also known as: temocillin, ceftriaxone, meropenem

Sampling if GFR < 30 mL/min; Sampling if GFR = or > 30 mL/min

Eligibility Criteria

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

You may qualify if:

• Patients with suspicion or documentation of of an infection requiring intravenous antibiotic therapy (this includes any patient admitted to the Intensive Care Unit for an infection (or developing an infection) that calls for administration of temocillin, ceftriaxone or meropenem).

You may not qualify if:

• Patients allergic to β-lactams
• IgE-mediated hypersensibility to penicillins
• any biological abnormality that the attending physician considers as susceptible to delay or perturb in a significant manner the interpretation of the trial
• lack of accepted informed consent
• patient with therapeutic limitations

Sponsors & Collaborators

• Université Catholique de Louvain: lead

Study Sites (1)

Cliniques universitaires Saint-Luc

Brussels, 1200, Belgium

RECRUITING

Related Publications (32)

• Goncalves-Pereira J, Silva NE, Mateus A, Pinho C, Povoa P. Assessment of pharmacokinetic changes of meropenem during therapy in septic critically ill patients. BMC Pharmacol Toxicol. 2014 Apr 14;15:21. doi: 10.1186/2050-6511-15-21.

  PMID: 24731745 RESULT

• Hayashi Y, Lipman J, Udy AA, Ng M, McWhinney B, Ungerer J, Lust K, Roberts JA. beta-Lactam therapeutic drug monitoring in the critically ill: optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia. Int J Antimicrob Agents. 2013 Feb;41(2):162-6. doi: 10.1016/j.ijantimicag.2012.10.002. Epub 2012 Nov 13.

  PMID: 23153962 RESULT

• Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA. Therapeutic drug monitoring of the beta-lactam antibiotics: what is the evidence and which patients should we be using it for? J Antimicrob Chemother. 2015 Dec;70(12):3178-83. doi: 10.1093/jac/dkv201. Epub 2015 Jul 17.

  PMID: 26188037 RESULT

• Jamal JA, Mat-Nor MB, Mohamad-Nor FS, Udy AA, Wallis SC, Lipman J, Roberts JA. Pharmacokinetics of meropenem in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration. Int J Antimicrob Agents. 2015 Jan;45(1):41-5. doi: 10.1016/j.ijantimicag.2014.09.009. Epub 2014 Oct 18.

  PMID: 25455853 RESULT

• Jaruratanasirikul S, Thengyai S, Wongpoowarak W, Wattanavijitkul T, Tangkitwanitjaroen K, Sukarnjanaset W, Jullangkoon M, Samaeng M. Population pharmacokinetics and Monte Carlo dosing simulations of meropenem during the early phase of severe sepsis and septic shock in critically ill patients in intensive care units. Antimicrob Agents Chemother. 2015;59(6):2995-3001. doi: 10.1128/AAC.04166-14. Epub 2015 Mar 9.

  PMID: 25753628 RESULT

• Kiem S, Schentag JJ. Interpretation of antibiotic concentration ratios measured in epithelial lining fluid. Antimicrob Agents Chemother. 2008 Jan;52(1):24-36. doi: 10.1128/AAC.00133-06. Epub 2007 Sep 10. No abstract available.

  PMID: 17846133 RESULT

• Laterre PF, Wittebole X, Van de Velde S, Muller AE, Mouton JW, Carryn S, Tulkens PM, Dugernier T. Temocillin (6 g daily) in critically ill patients: continuous infusion versus three times daily administration. J Antimicrob Chemother. 2015 Mar;70(3):891-8. doi: 10.1093/jac/dku465. Epub 2014 Nov 27.

  PMID: 25433006 RESULT

• Livermore DM, Hope R, Fagan EJ, Warner M, Woodford N, Potz N. Activity of temocillin against prevalent ESBL- and AmpC-producing Enterobacteriaceae from south-east England. J Antimicrob Chemother. 2006 May;57(5):1012-4. doi: 10.1093/jac/dkl043. Epub 2006 Mar 10. No abstract available.

  PMID: 16531428 RESULT

• Livermore DM, Tulkens PM. Temocillin revived. J Antimicrob Chemother. 2009 Feb;63(2):243-5. doi: 10.1093/jac/dkn511. Epub 2008 Dec 18.

  PMID: 19095679 RESULT

• MacGowan A. Revisiting Beta-lactams - PK/PD improves dosing of old antibiotics. Curr Opin Pharmacol. 2011 Oct;11(5):470-6. doi: 10.1016/j.coph.2011.07.006. Epub 2011 Aug 19.

  PMID: 21862409 RESULT

• Martin C, Ragni J, Lokiec F, Guillen JC, Auge A, Pecking M, Gouin F. Pharmacokinetics and tissue penetration of a single dose of ceftriaxone (1,000 milligrams intravenously) for antibiotic prophylaxis in thoracic surgery. Antimicrob Agents Chemother. 1992 Dec;36(12):2804-7. doi: 10.1128/AAC.36.12.2804.

  PMID: 1482149 RESULT

• McWhinney BC, Wallis SC, Hillister T, Roberts JA, Lipman J, Ungerer JP. Analysis of 12 beta-lactam antibiotics in human plasma by HPLC with ultraviolet detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Jul 15;878(22):2039-43. doi: 10.1016/j.jchromb.2010.05.027. Epub 2010 May 24.

  PMID: 20561826 RESULT

• Mohd Hafiz AA, Staatz CE, Kirkpatrick CM, Lipman J, Roberts JA. Continuous infusion vs. bolus dosing: implications for beta-lactam antibiotics. Minerva Anestesiol. 2012 Jan;78(1):94-104. Epub 2011 Jul 6.

  PMID: 21730935 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

• Paradis D, Vallee F, Allard S, Bisson C, Daviau N, Drapeau C, Auger F, LeBel M. Comparative study of pharmacokinetics and serum bactericidal activities of cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin. Antimicrob Agents Chemother. 1992 Oct;36(10):2085-92. doi: 10.1128/AAC.36.10.2085.

  PMID: 1444289 RESULT

• Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, Hope WW, Farkas A, Neely MN, Schentag JJ, Drusano G, Frey OR, Theuretzbacher U, Kuti JL; International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014 Jun;14(6):498-509. doi: 10.1016/S1473-3099(14)70036-2. Epub 2014 Apr 24.

  PMID: 24768475 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

• Roberts JA, Boots R, Rickard CM, Thomas P, Quinn J, Roberts DM, Richards B, Lipman J. Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study. J Antimicrob Chemother. 2007 Feb;59(2):285-91. doi: 10.1093/jac/dkl478. Epub 2006 Nov 28.

  PMID: 17135183 RESULT

• 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 administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother. 2009 Jul;64(1):142-50. doi: 10.1093/jac/dkp139. Epub 2009 Apr 27.

  PMID: 19398460 RESULT

• Salvador P, Smith RG, Weinfeld RE, Ellis DH, Bodey GP. Clinical pharmacology of ceftriaxone in patients with neoplastic disease. Antimicrob Agents Chemother. 1983 Apr;23(4):583-8. doi: 10.1128/AAC.23.4.583.

  PMID: 6305263 RESULT

• Schleibinger M, Steinbach CL, Topper C, Kratzer A, Liebchen U, Kees F, Salzberger B, Kees MG. Protein binding characteristics and pharmacokinetics of ceftriaxone in intensive care unit patients. Br J Clin Pharmacol. 2015 Sep;80(3):525-33. doi: 10.1111/bcp.12636. Epub 2015 Jun 11.

  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

• Simon N, Dussol B, Sampol E, Purgus R, Brunet P, Lacarelle B, Berland Y, Bruguerolle B, Urien S. Population pharmacokinetics of ceftriaxone and pharmacodynamic considerations in haemodialysed patients. Clin Pharmacokinet. 2006;45(5):493-501. doi: 10.2165/00003088-200645050-00004.

  PMID: 16640454 RESULT

• Suankratay C, Jutivorakool K, Jirajariyavej S. A prospective study of ceftriaxone treatment in acute pyelonephritis caused by extended-spectrum beta-lactamase-producing bacteria. J Med Assoc Thai. 2008 Aug;91(8):1172-81.

  PMID: 18788687 RESULT

• Tam VH, Schilling AN, Neshat S, Poole K, Melnick DA, Coyle EA. Optimization of meropenem minimum concentration/MIC ratio to suppress in vitro resistance of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2005 Dec;49(12):4920-7. doi: 10.1128/AAC.49.12.4920-4927.2005.

  PMID: 16304153 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

• Ulldemolins M, Roberts JA, Rello J, Paterson DL, Lipman J. The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients. Clin Pharmacokinet. 2011 Feb;50(2):99-110. doi: 10.2165/11539220-000000000-00000.

  PMID: 21142293 RESULT

• Van Dalen R, Vree TB, Baars IM. Influence of protein binding and severity of illness on renal elimination of four cephalosporin drugs in intensive-care patients. Pharm Weekbl Sci. 1987 Apr 24;9(2):98-103. doi: 10.1007/BF01960743.

  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

• Verdier MC, Tribut O, Tattevin P, Le Tulzo Y, Michelet C, Bentue-Ferrer D. Simultaneous determination of 12 beta-lactam antibiotics in human plasma by high-performance liquid chromatography with UV detection: application to therapeutic drug monitoring. Antimicrob Agents Chemother. 2011 Oct;55(10):4873-9. doi: 10.1128/AAC.00533-11. Epub 2011 Jul 25.

  PMID: 21788467 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

Related Links

• Ceftriaxone. Ceftriaxone Summary of Product Characteristics. Centre Belge d'Information Pharmacothérapeutique (C.B.I.P.asbl). Available from: http://www.cbip.be Last updated: 2015
• Méropénème. Meropenem Summary of Product Characteristics. Centre Belge d'Information Pharmacothérapeutique (C.B.I.P.asbl). Available from: http://www.cbip.be Last updated: 9-1-2014
• Temocilline. Temocillin Summary of Product Characteristics. Centre Belge d'Information Pharmacothérapeutique (C.B.I.P.asbl). Available from: http://cbip.be/ Last updated: 2014

MeSH Terms

Conditions

Bacterial Infections; Respiratory Tract Infections; Infections

Interventions

Blood Specimen Collection; temocillin; Ceftriaxone; Meropenem

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Cefotaxime; Cephacetrile; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Thienamycins; Carbapenems

Study Officials

• Pierre-François Laterre, MD

  Université Catholique de Louvain

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Pierre-François Laterre, MD

CONTACT

+3227642733; pierre-francois.laterre@uclouvain.be

Françoise Van Bambeke, PharmD

CONTACT

+3227647378; francoise.vanbambeke@uclouvain.be

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 2 groups of patients studied in parallel

Study Record Dates

• First Submitted: January 18, 2018
• First Posted: February 22, 2018
• Study Start: March 15, 2018
• Primary Completion: October 15, 2022
• Study Completion: December 15, 2022
• Last Updated: May 25, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)