Pharmacokinetics and Safety of Antimicrobial Agents Administered by Subcutaneous Route in Patients AGEd Over 65 Years

Study Overview
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Brief Summary
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Elderly people are more prone to develop infection with a poorer prognosis compared to young people. Physicians may encounter difficulties regarding antimicrobial agents administration route. In fact, poor venous access and behavioral disturbance are frequent issues. The subcutaneous (SC) route may be a safe alternative, but sparse data are available in the literature. The present study aims to describe Pharmacokinetics (PK) / Pharmacodynamics (PD) characteristics of antibiotics (amoxicillin/clavulanate, ceftriaxone and piperacillin/tazobactam) subcutaneous administration in patients aged over 65.

Detailed Description
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Antibiotic administration through subcutaneous (SC) injection is common practice in France, especially in Geriatrics as an alternative to intravenous (IV) route in case of poor venous access or delirium (Forestier et al. CMI 2015). Whereas tolerance of such a practice seems to be reasonable (Roubaud-Baudron et al. Age and Ageing 2017), sparse PK/PD data are available. Most PK/PD studies include young and healthy subjects, yet elderly patients often have multimorbidity , poly medication, renal insufficiency and cachexia which may disturb antibiotics PK/PD. Compared to intravenous (IV) route, SC route is less painful and less frequently associated with infectious or thrombotic complication. A recent study carried out in Bordeaux University Hospital comparing PK/PD data on ertapenem SC or IV administrations in patients aged over 75 showed that area under the curve (AUC) and probability to maintain free ertapenem concentration above the Minimum inhibitory concentration (MIC) during at least 40% of time (fT>MIC>40%) were not significantly different (manuscript in progress). The investigator's hypothesis is that SC administration of amoxicillin-clavulanate, ceftriaxone and piperacillin-tazobactam has favorable pharmacokinetics and acceptable tolerance compared with IV infusion in elderly patients. Patients receiving one of the three antibiotics by IV or SC route will be included at steady state (depending on antibiotic treatment) for several blood tests (3 or 4 depending of routes choice) and followed until 15 days after completion of antibiotic treatment in order to evaluate tolerance and efficacy of antibiotic treatment. Physicians in charge of patients will decide antibiotic prescription including administration route. The study will not influence these choices because patients will be included after antibiotic initiation.

Official Title
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Pharmacokinetics and Safety of Antimicrobial Agents Administered by Subcutaneous Route in Patients AGEd Over 65 Years

Conditions
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Antimicrobials, Subcutaneous Injection, Antibiotic, Older People

Intervention / Treatment
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* Drug: Subcutaneous (SC) route for antibiotic treatment
* Drug: Intravenous (IV) route for antibiotic treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged over 65 To receive ceftriaxone (1g daily) or amoxicillin-clavulanate (1g/0.2g every 8h) or piperacillin-tazobactam (4g/0.5g every 8h) by SC or IV infusion (30-60minutes) at steady state (48h, 24h and 24h respectively) Free, written and informed consent signed by the participant or by a proxy in case of delirium Exclusion Criteria: criteria for legislation (justice protection, subject participating to another research including a period of exclusion) previous inclusion in this study

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| amoxicillin-clavulanate<br>followed of SC and IV cohort without any randomization because the route will be chosen before inclusion by the physician in charge. | Drug: Subcutaneous (SC) route for antibiotic treatment<br>* Patients receiving one of the three antibiotics by SC route without any randomization because the route will be chosen before inclusion by the physician in charge.<br>Drug: Intravenous (IV) route for antibiotic treatment<br>* Patients receiving one of the three antibiotics by IV route without any randomization because the route will be chosen before inclusion by the physician in charge.<br>|
| ceftriaxone<br>followed of SC and IV cohort without any randomization because the route will be chosen before inclusion by the physician in charge. | Drug: Subcutaneous (SC) route for antibiotic treatment<br>* Patients receiving one of the three antibiotics by SC route without any randomization because the route will be chosen before inclusion by the physician in charge.<br>Drug: Intravenous (IV) route for antibiotic treatment<br>* Patients receiving one of the three antibiotics by IV route without any randomization because the route will be chosen before inclusion by the physician in charge.<br>|
| piperacillin-tazobactam<br>followed of SC and IV cohort without any randomization because the route will be chosen before inclusion by the physician in charge. | Drug: Subcutaneous (SC) route for antibiotic treatment<br>* Patients receiving one of the three antibiotics by SC route without any randomization because the route will be chosen before inclusion by the physician in charge.<br>Drug: Intravenous (IV) route for antibiotic treatment<br>* Patients receiving one of the three antibiotics by IV route without any randomization because the route will be chosen before inclusion by the physician in charge.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma antibiotic concentrations | Describe and compare pharmacokinetics of amoxicillin-clavulanate, ceftriaxone and piperacillin-tazobactam administered by SC and IV routes | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events | Occurrence of adverse events (AEs) up to 15 days after the end of local antibiotherapy (edema, pain, erythema, necrosis) and systemic (AEs described in the Summary of Product Characteristics for antibiotics) | Day 21 | 
| Number of infection cure | rate of infection cure at the end of antibiotic treatment up to 15 days after the end of antibiotic therapy | Day 21 | 
| Number of hospitalisation days | Describe the times of hospitalisation | Day 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antimicrobial agents, subcutaneous administration, safety, pharmacokinetics, elderly