Efficacy and Safety of Antimicrobial Durations Treatment of Infections Associated With Osteosynthesis Material

Study Overview
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Brief Summary
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Infections associated with osteosynthesis material are among the most feared and challenging complications of trauma surgery and can lead to total function loss or limb amputation when complete recovery is to be expected without infection. This is a clinical trial with the purpose of evaluate the optimal duration of antibiotic therapy in Infections Associated With Osteosynthesis Material Implanted when implant is retained.

Detailed Description
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Orthopedic implants for fracture fixation or osteosynthesis material are used for internal fixation of fractures, allowing their stability and consolidation. Infection associated with osteosynthesis material is one of the most feared and challenging complications of trauma surgery and can lead to total loss of function or amputation of the limb, when complete recovery is to be expected without infection. Furthermore, they involve excessive consumption of antimicrobials, with inadequate prescriptions and prolonged durations that favour superinfections by multidrug-resistant microorganisms, in addition to the drug-related toxicities, especially diarrhea due to Clostridium difficile. Most studies and recommendations on the management of orthopedic implant-associated infections have focused on prosthetic joint infections, and while they share similarities with Infections Associated With Osteosynthesis Material Implanted, there are major differences in terms of risk factors, diagnosis, treatment, and prevention. While the extrapolation of knowledge from prosthetic joint infections to the field of Infections Associated With Osteosynthesis Material Implanted has helped orthopedic surgeons and internists/infectologists in their management, there are large gaps and unanswered questions that represent a new challenge for research in this field. One of these challenges, and focusing on the field of infection treatment, is the search for the best surgical procedure according to the age of the implant and fracture healing, to determine the duration of antibiotic treatment and whether it should be maintained until fracture healing, and which is the most appropriate treatment in each of the scenarios. The identification of conditions in which the duration of the antimicrobial treatment can be shortened, and in case of prolonged treatments, which antimicrobial has the best safety profile and less impact on the induction of bacterial resistances is of special interest, due to the frequent appearance of toxicities and the increase of bacterial resistances and superinfections by multidrug-resistant bacteria. If the hypothesis of non-inferiority of short vs. long antibiotic treatments is demonstrated, and the efficacy of antibiotics with less ecological impact in long treatments, the impact on reduction of bacterial resistance, toxicity and health costs will be observed. The project also aims to promote quality and multidisciplinary care, homogenising clinical practice in the management of Infections Associated With Osteosynthesis Material Implanted based on scientific knowledge. Early and personalised patient care with Infections Associated With Osteosynthesis Material Implanted allows for faster recovery, both clinically and functionally, enabling earlier mobility recovery.

Official Title
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Efficacy and Safety of Different Antimicrobial Durations for the Treatment of Infections Associated With Osteosynthesis Material Implanted After Long Bone Fractures (DURATIOM). Phase 3 Pragmatic Multicenter Open Labelled Randomized Trial.

Conditions
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Infections

Intervention / Treatment
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* Combination Product: Short course of antibiotherapy
* Combination Product: Long course of antibiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to 14 years. Stable fracture, even if unconsolidated. Controlled infection (absence of signs or symptoms of sepsis). Early or delayed infection. Availability of antibiotics active against the isolated microorganism. Absence of bone exposure. Patients who initially had bone exposure but during the debridement surgery bone coverage was performed by any method (skin approximation, grafting, vacuum therapy) can be included in the criteria. Signed written informed consent. If there is a possibility of pregnancy (in women of childbearing potential) or paternity, agree to use a highly effective method of birth control recommended by the Clinical Trial Facilitation Group (CTFG) during the treatment phase of the trial Exclusion Criteria: Late infections Infections of revision osteosynthesis material or occurring after previous surgeries. Patients who are not expected to be followed up for at least 1 year after completion of antibiotic treatment. Pregnant or lactating women. Patients in whom there may be drug interactions or contraindications described in the technical data sheets of the investigational drugs used in this trial.

Ages Eligible for Study
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Minimum Age: 14 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: Parallel Assignment
Interventional Model Description: Pragmatic, multicenter, non-inferiority, open labelled, randomized trial comparing different durations of antibiotherapy in osteosynthesis material infections after long bone fractures treated with debridement and material retention (see design algorithm and inclusion criteria). The CONSORT extension for pragmatic designs will be used.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Short course of antibiotherapy<br>Patients enrolled in this arm, will receive 8 weeks of antibiotherapy in case of early infection (< 2 week), and 12 weeks of antibiotherapy in case of delayed infection (2-10 weeks) | Combination Product: Short course of antibiotherapy<br>* Short duration of authorized antibiotic therapy according to its data sheet in infections associated with osteosynthesis material<br>|
| Active Comparator: Long course of antibiotherapy<br>Patients enrolled in this arm, will receive 12 weeks of antibiotherapy in case of early infection (< 2 week), and until fracture healing of antibiotherapy in case of delayed infection | Combination Product: Long course of antibiotherapy<br>* Long duration of authorized antibiotic therapy according to its data sheet in infections associated with osteosynthesis material<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with clinical cure in the test of cure | A success at the test of cure is the resolution of infection symptoms, the absence of clinical signs and symptoms of infection (persistence of symptoms of infection, relapse of infection after a period without symptoms, or superinfection by a different microorganism) without antibiotic therapy and with C-reactive protein <10 mg/L (unless another cause justifies a higher C-reactive protein value); If the patient dies, when the death was not related to the infection; and no need for chronic suppressive antibiotic therapy to control of the infection. | 12 months after completion of antimicrobial treatment | 
| Radiological healing in the test of cure | Radiological healing is defined as the presence of radiological signs of fracture consolidation (plain radiographic or CT) of the infected bone. Non-union or absence of consolidation of a fractured bone is defined when it has not completely healed within 9 months after osteosynthesis surgery or when it has not shown progression towards fracture callus formation in 3 consecutive months on serial radiographs | 12 months after completion of antimicrobial treatment | 
| Definitive soft tissue coverage at test of cure | Number of patients who present definitive soft tissue coverage at test of cure | 12 months after completion of antimicrobial treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presentation of adverse events (frequency and severity). | To evaluate the presentation of adverse events (frequency and severity) during the study. | Through study completion (12 months) | 
| Performance of an antibiogram to assess the development of antimicrobial resistance | Standard microbiological techniques will be used to identify microorganisms recovered and to determine antimicrobial susceptibility according to EUCAST recommendation (EUCAST guidelines for detection of resistance mechanisms and specific resistances of clinical and/or epidemiological importance, Version 2.0, 2017) https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Resistance_mechanisms/EUCAST_detection_of_resistance_mechanisms_170711.pdf | 8 months and 12 months | 
| Surgical wound culture to assess the development of secondary infections | To evaluate the appearance of secondary infections during antibiotic treatment that standard microbiological techniques will be used to identify microorganisms recovered and to determine antimicrobial susceptibility according to EUCAST recommendation (EUCAST guidelines for detection of resistance mechanisms and specific resistances of clinical and/or epidemiological importance, Version 2.0, 2017) https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Resistance_mechanisms/EUCAST_detection_of_resistance_mechanisms_170711.pdf | 8 months and 12 months | 
| Recurrence rate | To evaluate the recurrence rate during antibiotic treatment. | 8 months and 12 months | 
| Evaluate the need for new surgeries, such as debridement, removal of material, coverage or amputation, through radiological evaluation of fracture union. | To evaluate the need for new surgeries through radiological evaluation | Day 28, week 8, week 12, month 6 and month 12. | 
| Evaluation of the functional status, defined as the recovery of the functionality of the limb prior to the fracture, by completing the Quick Disabilities of Arm, Shoulder and Hand questionnaire. | The functional state, normal or reduced, will be evaluated with respect to the situation prior to the fracture. Lower extremity mobility is classified as: walks unassisted; with 1 cane; with 2 canes; with walker; wander home alone; not wandering.. | 6 months and 12 months (visit 6 and 7) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infections associated with osteosynthesis material, Fracture-related infection, Long bone fractures, Antibiotics duration, Antimicrobial therapy, Multidrug-resistant bacteria, Biofilm fracture healing, Antibiotic toxicity, Investigator-driven clinical trial