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

Infection Clinical Trial

— Pop-PK/PD  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03440216
• Other study ID #: Pop PK/PD betalactams ICU
• Status: Recruiting
• Phase: N/A
• Start date: March 15, 2018
• Est. completion date: December 15, 2022

Study information

• Verified date: May 2022
• Source: Université Catholique de Louvain
• Contact: Pierre-François Laterre, MD
• Phone: +3227642733
• Email: pierre-francois.laterre[@]uclouvain.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

1. Background, Literature Survey and Justification of The Study

1.1. Introduction

β-lactams efficacy depends primarily from the time interval during which the plasma concentration remains above the minimal inhibitory concentration (MIC) of the antibiotic against the target organism(s) (Craig, 1998). It is generally accepted that the free concentration of the antibiotic must remain above the MIC for at least 40 to 70% of the interval between two successive administrations, and should even reach 100% for severe infections in patients hospitalized in Intensive Care Units (MacGowan, 2011). The free concentration must reach a value of 4 x the MIC for 40 to 70% (Mohd Hafiz et al., 2012) or even 100 % (Tam et al., 2005) of the dosing interval in order to prevent the emergence of resistance.

Due to the large inter- and intraindividual variations between patients, it is difficult to reach the desired concentrations if relying only on usual dosage recommendations and/or using standard dosing regimens. Moreover, Intensive Care patients are difficult patients in this context (Roberts et al., 2014) due to gross perturbations related to underlying diseases and abnormalities (arterial hypertension, cardiac rhythm alterations, renal and/or hepatic insufficiency) and the necessary interventions (artificial ventilation, surgery, artificial feeding, and so on…). They also show important variations in the level of plasma proteins and rapid and unpredictable fluctuations of their renal function (Beumier et al., 2015; Goncalves-Pereira and Povoa, 2011; Roberts and Lipman, 2009), all of which are known to modulate the pharmacokinetics of β-lactams (Goncalves-Pereira and Povoa, 2011; Hayashi et al., 2013; Sime et al., 2012; Udy et al., 2012; Wong et al., 2013). The concentration of the free fraction will be especially modified for those β-lactams with large protein binding such as temocillin or ceftriaxone (Schleibinger et al., 2015; Ulldemolins et al., 2011; Van Dalen et al., 1987; Wong et al., 2013), but may also be altered for β-lactams that are mainly excreted via the renal route (temocillin, ceftriaxone, meropenem) (Carlier et al., 2013; Simon et al., 2006; Vandecasteele et al., 2015).

1.2. Clinical Interest of temocillin, ceftriaxone and meropenem and State of the Art Concerning their dosing

Temocillin is a carboxypenicillin with useful activity against Gram-negative bacteria (excluding P. aeruginosa) and with a large stability towards most β-lactamases, including ESBL), AmpC cephalosporinases, and some carbapenemases (Livermore et al., 2006; Zykov et al., 2016). Temocillin may stand as an alternative to carbapenems (Balakrishnan et al., 2011; Livermore and Tulkens, 2009). About 85% of temocillin in plasma is protein-bound and about 80% of the administered dose is eliminated in 24 h under an intact form by glomerular filtration and tubular secretion (Temocillin Summary of Product Characteristics [SmPC], 2015)

Ceftriaxone shows a moderately enlarged spectrum of activity and is stable towards certain β-lactamases but not to ESBLs, AmpC cephalosporinases and certain carbapenemases (Suankratay et al., 2008). It is an alternative to carbapenems when dealing with an infection with susceptible organisms (Paradis et al., 1992). Its protein binding is about 95%, and its elimination is mainly via the renal route (50 to 60% under an unchanged form) with the remaining eliminated via the bile to form microbiologically inactive metabolites (Ceftriaxone SmPC, 2015).

Meropenem shows a very large spectrum and is used in empiric therapy when fearing the presence of ESBL-producing organisms to which other antibiotics are resistant (Zykov et al., 2016). Meropenem has an unpredictable pharmacokinetic profile in patients with renal insufficiency or under hemodialysis (Carlier et al., 2013; Goncalves-Pereira et al., 2014). Meropenem is mainly excreted via the renal route (50 - 75 % under an unchanged form; SmPC meropenem, 2014).

Antibiotic are often prescribed empirically with doses based on what has been found appropriate for the general population, with some adaptation for weight and renal and/or hepatic function. As for any drug, however, there is increasing evidence that the concentrations observed after administration of a standard dose are actually highly variable and often different from the expected ones, leading to risks of sub-therapeutic or toxic effects.

Recent studies have shown that an intravenous administration of 6 g of temocillin by continuous infusion (Laterre et al., 2015), of 4 g of ceftriaxone in two administrations at 12 h interval (Roberts et al., 2007; Salvador et al., 1983), or of 6 g of meropenem in 3 administrations by prolonged infusion (3 h) at 8 h interval (Dulhunty et al., 2013; Frippiat et al., 2015; Jamal et al., 2015), allow to reach free plasma concentrations of 4 x the MIC against susceptible organisms during 40-70%, or even 100% of the dosing interval, with, however, large inter-individual variations, especially for molecules with high protein biding (temocillin, ceftriaxone) due to variations in their renal elimination. Very little information is available about their tissue levels but it is suspected that large inter-individual variations are also frequent.

2. Study Objectives

The goal is to measure the total and free concentrations of the antibiotics in plasma, accessible body fluids and, if possible, tissues after intravenous administration of:

• temocillin: 6 g by continuous infusion over 24 h;

• ceftriaxone: bolus administration of 2 g in a 30 min infusion twice daily;

• meropenem: prolonged infusion (3 h) of 2 g three times daily.

These doses will be adjusted in patients based on their renal function.

Primary objective:

To calculate and assess the values of key pharmacokinetic parameters (total clearance, volume of distribution, constants of elimination, plasma and tissue total exposure, and maximal and minimal plasma and body fluid concentrations.

Secondary objectives:

• the correlation between the plasma protein profile and the actual free antibiotic concentrations;

• the impact of the alterations of the renal function on the free and total plasma concentrations of the antibiotics;

• the impact of the level and nature of circulating proteins on the free fraction of the antibiotics;

• the extent of the tissular penetration of the antibiotics (in accessible samples) and of their penetration in pertinent body fluids (bronchoalveolar lavage, drainage and ascites fluids.

• to model the population pharmacokinetics of the antibiotics in the whole set of patients included in the study;

• to investigate and assess the influence of co-variates (using biometric, biochemical and clinical data) on the variability of the individual pharmacokinetic profiles.

3. Outcome measures

• Primary Outcome Measure: Impact of renal function on total plasma concentrations (Measurement of total plasma antibiotic concentrations)

• Secondary Outcome Measures:

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

• Tissular and fluid penetration of antibiotics (lung tissue, bronchoalveolar lavage, drainage fluids)

• Pharmacokinetic modeling

• Co-variates analysis

4. Conduct of the Study

4.1. Eligible patients

Patients hospitalized in Intensive Care Units and treated for pulmonary or abdominal infection, septicemia, or any other infection calling for the prescription of one of the three antibiotics mentioned above.

4.2. Study groups

Patients will be divided in two groups: :

• Group 1: patients with a glomerular filtration rate (GFR) ≥ 30 mL/min

• Group 2: patients with renal insufficiency or under hemodialysis

4.3. Safety considerations

The three β-lactams have each a long record of safe use in patients hospitalized in Intensive Care Units but may cause an alteration of the commensal flora, allergic reactions, neurotoxicity (at high doses). Ceftriaxone may case hemolytic anemia.

4.4. Exclusion criteria

• Patients of <18 years

• Allergy to β-lactams

• Hypersensitivity to penicillin (IgE-mediated)

• Any biological abnormality considered by the attending physician as susceptible to interfere in a significant manner on the interpretation of the data

• Absence of consensus

• Therapeutic limitation

4.5. Treatment duration: 7 days except for deep, non-controlled foci (extended to 10-14 days).

4.6. Follow up: First visit (visit #1) to determine eligibility criteria. Additional visits: each day during the treatment period.

5. Calculation of the number of patients

As this is a descriptive pharmacokinetic study without formal predefined hypothesis, no calculation of the size of the population has been made. Based on literature data and the experience of the investigators, a total of 20 patients in each arm should be sufficient to draw meaningful conclusions.

6. Sampling and processing of samples

• Sampling of serum and body fluids: typically at equilibrium for all three antibiotics, and at fixed times after administration of the bolus (ceftriaxone) or the prolonged infusion (meropenem), and performed by a research nurse according to a predefined schedule.

• Sampling of tissues: by Medical personnel when justified for diagnostic or treatment reasons.

• All samples will transferred to the laboratory where they will be treated using predefined and validated protocols.

Antibiotic assay: validated liquid chromatography - mass spectrometry methods (protocols and performance of the assay methods available upon request). The free fraction of each antibiotic will be measured after separation of the bound fraction by molecular sieving (Ngougni Pokem et al., 2015).

7. Statistical analysis and data analysis

Pharmacokinetic analyses will be performed using either NONMEM (NONlinear Mixed Effect Modeling) (http://www.iconplc.com/innovation/nonmem/ ) or PMETRICS (http://www.lapk.org/pmetrics.php) software. Mono-, bi-, and tri-compartmental models will be tested using plasma, tissular and body fluids antibiotic free and total antibiotic concentrations. The First-Order Conditional Estimation with Interaction (FOCE-I) method will be used to assess the objective functions (Jaruratanasirikul et al., 2015) in order to select the most appropriate model for the calculation of the pharmacokinetic parameters (Roberts et al. 2009).

8. Confidentiality and Rights of patients.

The identity and the personal data of the patients will remain confidential according to the applicable Belgian Law

Before enrollment, each patient (or his/her guardian) will provide a written informed consent. Each enrolled patients (or his/her guardian) will be allowed to withdraw from the study at any time without impact on his/her treatment.

9. Contacts

All questions concerning the study can be addressed to

• the responsible investigator: Professor Pr Pierre-François Laterre (phone: 00-32-2-764- 2733 (Intensive Care Unit) or 764-2735 (direct) at the Cliniques universitaire St Luc, Brussels, Belgium

• the associated investigators: Professor Françoise Van Bambeke (phone: 00-32-2-764-7378) and Pharm. Perrin Ngougni Pokem (phone 00-32-2-764-7225) at the Université catholique de Louvain (Louvain Drug Research Institute), Brussels, Belgium.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: December 15, 2022
• Est. primary completion date: October 15, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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).

Exclusion Criteria:

• Patients allergic to ß-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

Related Conditions & MeSH terms

• Anti-Bacterial Agents
• Bacterial Infections
• Communicable Diseases
• Drug Monitoring
• Infection
• Infection, Bacterial
• Infections
• Infections, Respiratory
• Pharmacokinetics
• Respiratory Tract Infections

Intervention

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

Locations

Country	Name	City	State
Belgium	Cliniques universitaires Saint-Luc	Brussels

Sponsors (1)

Lead Sponsor	Collaborator
Université Catholique de Louvain

Country where clinical trial is conducted

Belgium, 

References & 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. — View Citation

Hayashi Y, Lipman J, Udy AA, Ng M, McWhinney B, Ungerer J, Lust K, Roberts JA. ß-Lactam therapeutic drug monitoring in the critically ill: optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia. Int J Antimicrob Agents. — View Citation

Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA. Therapeutic drug monitoring of the ß-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. Epu — View Citation

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 intermitte — View Citation

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 se — View Citation

Kiem S, Schentag JJ. Interpretation of antibiotic concentration ratios measured in epithelial lining fluid. Antimicrob Agents Chemother. 2008 Jan;52(1):24-36. Epub 2007 Sep 10. Review. — View Citation

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. — View Citation

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. Epub 2006 Mar 10. — View Citation

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

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. Review. — View Citation

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 — View Citation

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.j — View Citation

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. Review. — View Citation

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: 10.101 — View Citation

Paradis D, Vallée 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 — View Citation

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 Pharmacodynamic — View Citation

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. E — View Citation

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 subcu — View Citation

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. Review. — View Citation

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. — View Citation

Schleibinger M, Steinbach CL, Töpper 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 — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Udy AA, Varghese JM, Altukroni M, Briscoe S, McWhinney BC, Ungerer JP, Lipman J, Roberts JA. Subtherapeutic initial ß-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations — View Citation

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. Review. — View Citation

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. — View Citation

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 — View Citation

Verdier MC, Tribut O, Tattevin P, Le Tulzo Y, Michelet C, Bentué-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. An — View Citation

Wong G, Briscoe S, Adnan S, McWhinney B, Ungerer J, Lipman J, Roberts JA. Protein binding of ß-lactam antibiotics in critically ill patients: can we successfully predict unbound concentrations? Antimicrob Agents Chemother. 2013 Dec;57(12):6165-70. doi: 10 — View Citation

Zykov IN, Sundsfjord A, Småbrekke L, Samuelsen Ø. 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 2 — View Citation

* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Impact of the plasma protein concentration and of their nature on the free concentration of antibiotics	Measurement of antibiotic plasma free concentrations and analysis of plasma protein profiles (measurement by a validated HPLC-MS-MS after suitable extraction; no predefined value set [exploratory])	36 months
Secondary	Tissular and fluid penetration of antibiotics (total)	Measurement of total concentrations of antibiotics in tissue samples and fluids (bronchoalveolar lavage, drainage fluids) when obtained (measurement by a validated HPLC-MS-MS after suitable extraction; no predefined value set [exploratory])	36 months
Secondary	Tissular and fluid penetration of antibiotics (free)	Measurement of free concentrations of antibiotics in tissue samples and fluids (bronchoalveolar lavage, drainage fluids) when obtained (measurement by a validated HPLC-MS-MS after suitable extraction; no predefined value set [exploratory])	36 months
Secondary	Pharmacokinetic analysis and population pharmacokinetics: Cmax (total and free)	Analysis of the antibiotic pharmacokinetic profiles by means of appropriate software to calculate the actual mean and median values of the total and free plasma Cmax of temocillin (in mg/L) in the study population and to determine their value in a simulated population (Monte Carlo simulations; 1000 simulated patients)	36 months
Secondary	Pharmacokinetic analysis and population pharmacokinetics: Cmin (total and free)	Analysis of the antibiotic pharmacokinetic profiles by means of appropriate software to calculate the actual mean and median values of the total and free plasma Cmin of temocillin (in mg/L) in the study population and to determine their values in a simulated population (Monte Carlo simulations; 1000 simulated patients)	36 months
Secondary	Pharmacokinetic analysis and population pharmacokinetics: time above a critical concentration value for total and free concentrations	Analysis of the antibiotic pharmacokinetic profiles by means of appropriate software to calculate the actual mean and median values of the fraction of the time between two successive drug administrations during which the total and free plasma concentrations of temocillin remain above a critical value ( "S" breakpoint of the corresponding antibiotic [temocillin: British Society of Antimicrobial Chemotherapy [BSAC] or Belgian Summary of Product Characteristics [SmPC] value; ceftriaxone and meropenem: European Committee for Antimicrobials Susceptibility Testing [EUCAST] value]) in the study population, and to determine its value in a simulated population (Monte Carlo simulations; 1000 simulated patients)	36 months
Secondary	Covariables analysis: biometric values: weight	Assessment of the impact of patient's weight [in kg]	36 months
Secondary	Covariables analysis: biometric values: height	Assessment of the impact of patient's height [in cm]	36 months
Secondary	Covariables analysis: biometric values: age	Assessment of the impact of patient's age [in years]	36 months
Secondary	Covariables analysis: biochemical data: serum total protein and albumin	Assessment of the impact of total serum protein [in g/L] and total serum albumin [in g/L].	36 months
Secondary	Covariables analysis: biochemical data: elevation hepatic transaminases	Assessment of the impact the elevation of the hepatic transaminases [in international units/L, with reference fo the local normal values]	36 months
Secondary	Covariables analysis: biochemical data: blood urea and creatinine	Assessment of the impact of the urea [in mol/L] and creatinine [in mg/L]) blood levels	36 months
Secondary	Covariable analysis: clinical status with respect to infection	clinical status of the patient (in 3 categories: moderately severe infection; severe infection; life-threatening infection) as per the judgment of the attending physician	36 months
Secondary	Covariable analysis: renal function	renal function based on calculated glomerular filtration with a dichotomic cut-off at < 30 ml/min or above	36 months

External 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