Pharmacological Comparison of Continuous and Intermittent Infusions of Cloxacillin

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

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.

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.

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