Pharmacological Comparison of Continuous and Intermittent Infusions of Cloxacillin

Study Overview
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Brief Summary
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Our objective is to establish pharmacological equivalence of intermittent and continuous infusion of cloxacillin during methicillin-susceptible Staphylococcus aureus (MSSA) bone and joint infections (BJI). Twelve patients suffering MSSA BJI will receive both administration modalities and serum concentrations of cloxacillin will be determined after 3 days of II and 3 days of continuous infusion in a prospective, randomized, open-label, monocentric crossover study design.

Detailed Description
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Introduction Staphylococcus aureus is the main causative agent of bone and joint infections (BJI). More than 80% of the strains isolated in France are methicillin-susceptible (MSSA). During the early phase of MSSA BJI management national and international guidelines recommend the use of intra-venous type M penicillin with a dosage ranging from 100 to 200 mg/kg/day. Pharmacological properties of this class of penicillin require 4 to 6 infusions by day. Continuous infusion of beta-lactams is increasingly used especially in intensive care units. It allows an improvement of pharmacokinetic/pharmacodynamics (PK/PD) parameters and a reduction in time dedicated to infusion preparations by the nurses. However pharmacological data regarding such administration is required for type M penicillin. Design A 6-day, prospective, randomized, open-label, monocentric crossover study Participants Twelve adult patients with MSSA BJI Intervention Patients will be randomized in two groups: the first group will receive 3 days of cloxacillin (150 mg/kg/day) through 4 intermittent infusions/day followed by 3 days of cloxacillin (150 mg/kg/day) through continuous infusion (2 infusions during 12 hours). In the second group the infusion modalities will be inverted and continuous infusion will be preceded by a loading dose. Serum concentrations of cloxacillin will be determined at Day 3 and Days 6 The area under the curve / minimal inhibitory concentration ratio will be use to establish the equivalence between both administration modalities.

Official Title
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Pharmacological Comparison of Continuous and Intermittent Infusions of Cloxacillin During Bone and Joint Infections: a Prospective, Randomized, Open-label, Monocentric Crossover Study.

Conditions
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Infection, Methicillin Susceptible Staphylococcus Aureus Infection, Cloxacillin Treatment

Intervention / Treatment
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* Drug: Modification for administration mode of cloxacillin antibiotic


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Staphylococcus aureus sensitive to methicillin and to be treated with cloxacillin by injectable antibiotic monotherapy For patients with Osteo-articular infection on material Presence of a fistula in contact with the prosthesis or implant. Pus in the joint or in contact with the prosthesis or implant Presence of at least 1 positive sample (1 sampling by articular puncture or 1 peroperative sampling or by blood culture) A histological analysis of the peri-prosthetic osteo-articular tissue which is the object of acute inflammation is a strong argument in favor of an Osteo-articular infection on material For spondylodiscitis Culture of a disco-vertebral biopsy puncture to isolate a methicillin sensitive S. aureus Positive haemocultures for S. aureus sensitive to methicillin with imaging examination (CT or MRI of the spine) showing images of spondylodiscitis For primitive arthritis : Culture of a positive methicillin-sensitive S. aureus articular fluid puncture Cultivation of a methicillin-sensitive S. aureus-positive surgical joint lavage fluid For osteitis the diagnosis is based on the following criterion: *Culture of surgical specimens from a focal zone of methicillin-sensitive S. aureus-positive osteitis Exclusion Criteria: Allergy to betalactamines Taking penicillin M within 36 hours before inclusion Renal function impaired with a glomerular filtration rate measured by MDRD formula of less than 30 ml / min Patient with renal function expected to change within 6 days of inclusion Hepatocellular insufficiency, whatever the degree -*Methotrexate intake Polytransfused (more than 2 CGR) in the previous week Patients requiring resuscitation

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intermittent administration of cloxacillin<br> | Drug: Modification for administration mode of cloxacillin antibiotic<br>* For intermittent administration, patients will benefit from cloxacillin treatment in conventional hospitalization, in accordance with national guidelines, at a dose of 150 mg / kg per day in 4 infusions, not exceeding the maximum daily dose of 12 g / day according to. For continuous administration the same quantity of cloxacillin 150 mg / kg per day, without exceeding the maximum daily dose of 12 g / day, will be delivered by a self-propelled syringe in twice 12 hours. Patients randomly assigned to receive continuous administration will receive a dose of cloxacillin equivalent to the dose administered 4 times daily during iterative administration using a self-pulsating syringe. For the first day of the study, this loading dose will be subtracted from the 150 mg / kg dose to be administered continuously over the remaining 23 hours of the first day of the study and never exceed 12g / day. Pharmacological dosages will be performed on the third and sixth day in both arms<br>|
| Experimental: continuous administration of cloxacillin<br> | Drug: Modification for administration mode of cloxacillin antibiotic<br>* For intermittent administration, patients will benefit from cloxacillin treatment in conventional hospitalization, in accordance with national guidelines, at a dose of 150 mg / kg per day in 4 infusions, not exceeding the maximum daily dose of 12 g / day according to. For continuous administration the same quantity of cloxacillin 150 mg / kg per day, without exceeding the maximum daily dose of 12 g / day, will be delivered by a self-propelled syringe in twice 12 hours. Patients randomly assigned to receive continuous administration will receive a dose of cloxacillin equivalent to the dose administered 4 times daily during iterative administration using a self-pulsating syringe. For the first day of the study, this loading dose will be subtracted from the 150 mg / kg dose to be administered continuously over the remaining 23 hours of the first day of the study and never exceed 12g / day. Pharmacological dosages will be performed on the third and sixth day in both arms<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The equivalence of the Pharmacokinetic-Pharmacodynamic indicators commonly used for the study of betalactamines: T> minimal inhibitory concentration |  | Six days | 
| The equivalence of the Pharmacokinetic-Pharmacodynamic indicators commonly used for the study of betalactamines: the area under the curve (AUC) / minimal inhibitory concentration |  | Six days |