Effect of Single vs Multiple Prophylactic Antibiotic Doses on PJI Following Primary THA in Patients With a Fracture

Study Overview
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Brief Summary
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Aim: To compare the effect of one single dose versus multiple doses of prophylactic antibiotics administered within 24 hours, on the development of PJI after surgery in patients undergoing primary THA due to an acute fracture or sequelae of proximal femoral or acetabular fractures. The study is designed as a cross-over, cluster randomized, non-inferiority trial. All Danish orthopedic surgery departments performing primary THA with the majority being within inclusion criteria will be involved: Based on national quality databases, two-year cohorts of approximately 2,000 primary THAs due to a fracture or sequelae to a fracture, conducted at all public and private orthopedic departments in Denmark, this includes 36 sites corresponding to a total of 39 departments.

Detailed Description
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The outcome measures will be extracted from the following national databases: The Civil Registration System (CRS), The Danish Hip Arthroplasty Register (DHR), The Danish National Patient Registry (DNRP), The Hospital Acquired Infections Database (HAIBA), The Danish National Prescription Database (NPR), Statistics Denmark and Danish Agency for Labour Market and Recruitment registry (STAR). Details regarding the Arms and Interventions: The preoperative dose of antibiotic must be administered prior to surgical incision and in cases of delay with regards to planned surgical incision: Dicloxacillin/Cloxacillin: If the preoperative antibiotic dose is administered >60 minutes prior to surgical incision, the initial dose must be repeated. Cefuroxime: If the preoperative antibiotic dose is administered >90 minutes prior to surgical incision, the initial dose must be repeated. Treatment A, Single-dose practice: For patients ≥ 120 kg: One preoperative single dose of either Dicloxacillin/Cloxacillin 3g OR Cefuroxime 3g administered intravenously prior to surgical incision. In cases of cephalosporin allergy or general beta lactam allergy one preoperative single dose of Clindamycin 900mg administered intravenously, prior to surgical incision, regardless of weight. Treatment B, Multiple-dose practice: For patients ≥ 120 kg: One preoperative single dose of either Dicloxacillin/Cloxacillin 3g OR Cefuroxime 3g administered intravenously prior to surgical incision, followed by 3 postoperative doses of Dicloxacillin/Cloxacillin 2g x 3 OR cefuroxime 1.5g x 3, administered within 24 hours after the preoperative dose, corresponding to 6, 12 and 18 hours postoperatively. After the first postoperative dose, the remaining doses may be administered perorally for pragmatic reasons. Dicloxacillin p.o. 1g, 12 and 18 hours postoperatively. OR Amoxicillin and clavulanic acid p.o. 875mg/125*mg, 12 and 18 hours postoperatively. *If the center or region does not have access to amoxicillin and clavulanic acid 875/125mg a dose of 1g / 125mg (this means amoxicillin 500mg + amoxicillin and clavulanic acid 500mg/125 mg) may be administered. In cases of cephalosporin allergy or general beta lactam allergy one preoperative single dose of Clindamycin 900mg administered intravenously, prior to surgical incision, regardless of weight, followed by 2 postoperative doses corresponding to: For patients <120kg: 300mg, 8 and 16 hours postoperatively. For patients ≥ 120kg: 600mg, 8 and 16 hours postoperatively. The same doses apply in cases of transmission to peroral antibiotics. Implementation: The senior biostatistician is responsible for the randomization process of the centers. Each center will be allocated a code by the senior biostatistician responsible and reported to a central database. The randomization and allocation procedure will be known for the given year conditioning the given center. Ethics and Dissemination: This trial has been approved by the Regional Ethical Committee (VEK) (21069108) and The Danish Medicines Agency (2021091723) without imposing an obligation to notify.

Official Title
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The Effect of Single vs Multiple Prophylactic Antibiotic Doses on PJI Following Primary THA in Patients With a Fracture: A Cross-over, Cluster Randomized Controlled, Non-inferiority Trial Based on National Quality Databases: ProHipQ-F

Conditions
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Fracture of Hip, Total Hip Arthroplasty, Prosthetic-joint Infection, Fracture Acetabular

Intervention / Treatment
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* Other: Antibiotic dosage practice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients receiving a primary Total Hip Arthroplasty (THA) due to an acute- or sequelae of proximal femoral or acetabular fractures Exclusion Criteria: Patients receiving a primary THA due to bone tumor or metastasis Patients receiving a primary THA due to osteoarthritis and all reasons according to the Danish Hip Arthroplasty Register (DHR) except conditions mentioned in the inclusion criteria

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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The Pro-Hip-Quality Trial is a Cluster Randomized Trial with an embedded Cross-Over Design where each clinical center (C: 1, 2, 3, …., 36 individual sites) will be running a specific intervention (i.e. single- or multiple-dose antibiotics) throughout 12 months, and the subsequent year the clinical department will automatically switch to the opposite intervention (i.e. multiple- or single-dose antibiotics).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A, Single-dose practice<br>One preoperative single dose of either Dicloxacillin/Cloxacillin 2g OR Cefuroxime 1.5g administered intravenously prior to surgical incision. As the study is a non-inferiority trial, we have chosen the Experimental design category. | Other: Antibiotic dosage practice<br>* Patient inclusion starts day one, cross-over of departments from treatment A (single-dose) to B (multiple-dose) or vice versa after one year and end of inclusion happens after 2 years. All centers in Denmark use either Cloxacillin/Dicloxacillin, Cefuroxime or both drugs as standard prophylactic antibiotic practice for THA. In cases of cephalosporin allergy or general beta lactam allergy, the antibiotic clindamycin may be administered. In this trial, patients will be administered the standard prophylactic antibiotic practice of either single-dose (A) or multiple-doses (B) of antibiotics administered at each respective cluster that respective year. Both practices of dose administration for antibiotic prophylaxis (i.e. single- or multiple-dose) follow current standards of treatment and are based on present clinical practice guidelines.<br>|
| Active Comparator: Treatment B, Multiple-dose practice<br>One preoperative dose of either Dicloxacillin/Cloxacillin 2g OR Cefuroxime 1.5g administered intravenously prior to surgical incision followed by 3 postoperative doses of Dicloxacillin/Cloxacillin 1g x 3 OR Cefuroxime 750mg x 3 within 24 hours after the preoperative dose. | Other: Antibiotic dosage practice<br>* Patient inclusion starts day one, cross-over of departments from treatment A (single-dose) to B (multiple-dose) or vice versa after one year and end of inclusion happens after 2 years. All centers in Denmark use either Cloxacillin/Dicloxacillin, Cefuroxime or both drugs as standard prophylactic antibiotic practice for THA. In cases of cephalosporin allergy or general beta lactam allergy, the antibiotic clindamycin may be administered. In this trial, patients will be administered the standard prophylactic antibiotic practice of either single-dose (A) or multiple-doses (B) of antibiotics administered at each respective cluster that respective year. Both practices of dose administration for antibiotic prophylaxis (i.e. single- or multiple-dose) follow current standards of treatment and are based on present clinical practice guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Prosthetic joint infections (PJI) | The definition of PJI is based on revision surgery. Revision surgery is defined as a new surgical intervention the first time after the primary intervention including debridement alone or in combination with complete or partial removal or exchange of the implant. The definition of PJI is based on revision surgery. Revision surgery is defined as a new surgical intervention the first time after the primary intervention including debridement alone or in combination with complete or partial removal or exchange of the implant. Two or more intraoperative deep-tissue samples of phenotypically indistinguishable bacteria isolated from at least 3 deep-tissue samples One or more positive intraoperative samples from a closed fluid aspirate AND a biopsy (fluid AND tissue) of phenotypically indistinguishable bacteria isolated A PJI when an indication of deep infection is reported to The Danish Hip Arthroplasty Registry (DHR) by the surgeon upon revision surgery | Within 90 days from index surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with one or more Serious Adverse Events (SAEs) | SAEs are defined according to the ICH-GCP guidelines. SAE refers to an event involving a significant risk of death or disability of the patient (or their offspring), including, but not limited to, an event that: results in death is life-threatening - in the investigator's opinion the patient was in immediate risk of death from the adverse event when it appeared requires hospitalization or prolongs existing hospitalization results in permanent or significant disability is a congenital anomaly SAEs are recorded from The Danish National Patient Registry (DNPR). | Within 90 days from index surgery | 
| Incidence of Potential PJI referred to as PJI-likely | PJI-likely is defined as at least one of the two criteria: One single intraoperatively obtained positive culture (aspiration fluid OR tissue biopsy) regardless of microorganism One single positive culture obtained from aspiration of synovial fluid regardless of microorganism AND any antibiotic prescriptions (ATC category J01) redeemed | Within 90 days from index surgery | 
| Length of hospital stay (LOS) | LOS defined as number of postoperative overnight stays, including transferals to other departments and hospitals. Data on LOS is acquired from DNPR. | Within 90 days from index surgery | 
| Incidence of Thromboembolic complications incl VTE, MI, AF, stroke | VTE is defined a priori as both deep venous thromboembolisms confirmed by compression ultrasound and pulmonary embolism confirmed by spiral computed tomography (CT), ventilation-perfusion scintigraphy or pathological removal of an embolus and based on the following diagnostic ICD10 codes: I26, I80.1-I80.9, I82.1-I82.9, or T81.7B-D. Data will be extracted from DNPR. | Within 90 days from index surgery | 
| Hospital-treated infections (excluding Surgical Site infections) | Any Hospital-treated infection is defined as any first-time hospital admission with a primary or secondary infection diagnosis after discharge from index THA surgery. Hospital-treated infections are identified from DNPR. The list of infections includes chronic and more rare infections, to detect possible flare-up in any possible ongoing infections. The list will exclude urinary tract infections (UTI) due to a high risk of different registration praxis registration for UTI among hospitals in Denmark. | Within 90 days from index surgery | 
| Proportion of patients with at least one dispensing for antibiotic | Community-based antibiotic use (any community-treated infection or antibiotic use after discharge) is defined as at least one dispensing after discharge from index THA surgery within 90 days for narrow- and broad-spectrum antibiotics based on the Anatomical Therapeutic Chemical classification (ATC) codes. All antibiotics in Denmark require prescriptions from a physician. The Danish National Health Service Prescription Database has registered all reimbursed prescriptions from all community pharmacies since 2004. Medications are coded according to the following ATC codes: J01CE, J01CF, J01DB, J01DC, J01DD, J01DE, J01DH, J01DI, J01CR, J01CA, J01F. J01E, J01MA ,J01AA | Within 90 days from index surgery | 
| Proportion of patients with a least one dispensing for opioids | Prescriptions redeemed is defined as at least 1 prescription dispensing of any opioid. Prescriptions of analgesics will be identified through The Danish National Prescription Registry. The registry contains information on all prescriptions redeemed by Danish residents in community pharmacies since 1995 (excluding hospital dispensaries). Information on Anatomical Classification System (ATC) codes and dispensation date will be applied to identify opioids. Following ATC codes (including all sub codes) are included: N01AH (opioid anesthetics), N02A (opioids), N07BC02 (methadone), and R05DA04 (codeine). Duration of treatment will be calculated based on no. of packages and volume. | Within 90 days from index surgery | 
| Proportion of patients with dispensing for acetaminophen or non-steroid anti-inflammatory drug | Prescription redeemed is defined as at least 1 prescription dispensing of any acetaminophen or NSAID within 90 days after index THA surgery. Prescriptions of analgesics are identified using the Danish National Prescription Registry. Information on Anatomical Classification System (ATC) codes and dispensation date will be applied to identify acetaminophen and NSAID. Following ATC codes (including all sub codes) are included M01A (NSAIDs). Duration of treatment will be calculated based on no. of packages and volume. | Within 90 days from index surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PJI, Antibiotic Prophylaxis, Hip Fracture, Acetabular Fracture, Total Hip Replacement, Total Hip Arthroplasty, Prosthetic Joint Infection, Cluster Randomized Controlled Trial, Randomized Controlled Trial, RCT, THA