Periarticular Penetration of Cefazolin and Clindamycin in Second Stage Revision Arthroplasty of the Hip (CONCENTRATE)

To prevent periprosthetic joint infection (PJI), optimal penetration of antibiotics into the joint-space is needed. In revision arthroplasty, the incidence of PJI is increased compared to primary arthroplasty. In this study, the penetration of antibiotic agents into the synovial fluid and bone will be analyzed. The concentration of antibiotics will be related tot the to the susceptibility (minimal inhibitory concentration; MIC-90) of microorganisms that frequently cause PJI.

Study Overview

• Status: Not yet recruiting
• Conditions: Pharmacokinetics; Bone and Joint Infection; PJI
• Intervention / Treatment: Drug: sampling blood; Drug: Sampling synovial fluid; Drug: Sampling bone tissue

Detailed Description

Periprosthetic joint infection (PJI) is a feared complication of joint replacement, with an incidence of 0.5-1% after primary joint replacement and 3-5% after revision arthroplasty. For orthopaedic surgery involving a prosthesis, the administration of systemic antibiotic prophylaxis is strongly recommended to prevent PJI. Cefazolin is widely used as agent of choice in surgical antibiotic prophylaxis. Previous studies, all performed in patients undergoing primary joint replacement, demonstrated that the concentration of cefazolin in bone and synovial fluid was dose-dependent and exceeds the MIC90 for methicillin susceptible Staphylococcus aureus (MSSA), when given as 1 to 4 gram single dose shortly before incision. When a PJI is already present, clindamycin is used as treatment option in PJI caused by staphylococci (when combined with rifampicin) or cutibacteria. A limited number of studies have been performed to analyse the penetration of clindamycin into bone. These studies showed that clindamycin penetrates well into the bone and concentrations exceeded the MIC90 for MSSA. No studies have been performed to analyse the penetration of antibiotic agents into the periarticular tissue in patients who will undergo revision arthroplasty. In revision arthroplasty a foreign body (prosthesis) is in situ and periarticular tissue condition can be compromised due to previous surgical procedures and the presence of bone reaction to the prosthesis. It is not known whether the difference in PJI incidence after primary and revision arthroplasty may be explained by different penetration of the surgical antibiotic prophylaxis. The aim of this explorative study is to analyse the penetration of cefazolin and clindamycin into synovial fluid and bone and whether the concentration of the agents exceeds the MIC90 for micro-organisms frequently causing PJI.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Karin Veerman, MD; Phone Number: +31683845606; Email: karin.veerman@radboudumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 16 years or older.
2. Scheduled second stage revision arthroplasty (reimplantation) of the hip prosthesis during clindamycin 600mg three times a day orally for PJI, started at least 3 days before reimplantation (steady state).

Exclusion Criteria:

1. Antibiotic prophylaxis other than cefazolin 2000mg i.v.
2. Cefazolin use within 4 days previous to the reimplantation, other than the single dose administration of surgical prophylaxis just before incision.
3. Clindamycin loaded bone cement in situ.
4. BMI more than 35 kg/m2.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: cefazolin; The cefazolin antimicrobial prophylaxis (2000mg single dose intravenously 15-60 minutes before incision) is part of standard of care.	Drug: sampling blood; During the reimplantation, 3 serum samples will be taken at different timepoint during the procedure.; Drug: Sampling synovial fluid; During the reimplantation 1 synovial fluid sample will be taken prior to incision.; Drug: Sampling bone tissue; During the reimplantation 2 cortical bone samples will be taken at different timepoints during the procedure.
OTHER: Clindamycin; The clindamycin (600mg three times daily orally) PJI therapy is part of standard care.	Drug: sampling blood; During the reimplantation, 3 serum samples will be taken at different timepoint during the procedure.; Drug: Sampling synovial fluid; During the reimplantation 1 synovial fluid sample will be taken prior to incision.; Drug: Sampling bone tissue; During the reimplantation 2 cortical bone samples will be taken at different timepoints during the procedure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
penetration cefazolin into synovial fluid	The ratio (%) of the concentration of cefazolin in synovial fluid to serum.	during surgical procedure prior to incision the synovial fluid sample will be taken
penetration cefazolin into bone tissue	The ratio (%) of the concentration of cefazolin in synovial fluid to serum.	during surgical procedure prior to incision the synovial fluid sample will be taken
penetration clindamycin into bone tissue	The ratio (%) of the concentration of cefazolin in bone tissue to serum.	during surgical procedure, directly after opening the joint and before reimplantation of the prosthesis the bone samples will be taken

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC/MIC90 of cefazolin	The ratio of area under the curve of cefazolin to the minimal inhibitory concentration-90 of microorganisms	sampling during procedure
AUC/MIC90 of clindamycin	The ratio of area under the curve of cefazolin to the minimal inhibitory concentration-90 of microorganisms	sampling during procedure
factors associated with reduced cefazolin concentration	univariable and multivariable (if possible) analysis for factors that are associated with reduced concentration of cefazolin (i.e., BMI, age, ..)	sampling during procedure
factors associated with reduced clindamycin concentration	univariable and multivariable (if possible) analysis for factors that are associated with reduced concentration of cefazolin (i.e., BMI, age, ..)	sampling during procedure

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Sint Maartenskliniek
• Investigators: Principal Investigator: Nynke Jager, PhD, Radboud University Medical Center; Principal Investigator: Jon Goosen, MD, PhD, Sint Maartenskliniek

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): September 1, 2022
• Primary Completion (ANTICIPATED): September 1, 2023
• Study Completion (ANTICIPATED): December 1, 2023

Study Registration Dates

• First Submitted: June 7, 2022
• First Submitted That Met QC Criteria: June 13, 2022
• First Posted (ACTUAL): June 16, 2022

Study Record Updates

• Last Update Posted (ACTUAL): June 16, 2022
• Last Update Submitted That Met QC Criteria: June 13, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: 2022-13583

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No