Comparison Between Two Durations of Antibiotherapy for Non-surgically-treated Diabetic Foot Osteomyelitis (CHRONOS-2)

Study Overview
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Brief Summary
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The aim of this clinical study is to compare the efficacy and tolerance of 3 versus 6 weeks of antibiotherapy in patients with diabetic foot osteomyelitis treated medically.

Detailed Description
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The fight against multi-drug resistant bacteria is a global matter and a major health public issue. The excessive exposure of microorganisms to drugs increases their ability to develop survival mechanisms, causing an emerging threat and a health challenge. Several recent studies showed that 18-35% of patients with diabetic foot infections harbored multiply drug-resistance to organisms (MDRO), the most common is Staphylococcus aureus (MRSA). Hospitalization, surgical procedures and long antibiotic therapy induce the development of MDRO or MRSA In diabetic foot, Osteomyelitis (DFO) is a well recognize risk factor for major amputation and mortality rates that occurs in more than 20% of moderate infections and 50% to 60 % of severe infections. In this context, the aim of this study is to evaluated that reducing time of antibiotic administration (3 weeks) is not substantially worse than the current treatment guidelines (6 weeks) in DFO managed nonsurgically.

Official Title
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Three Weeks Versus Six Weeks Antibiotic Therapy for Nonsurgically Treated Diabetic Foot Osteomyelitis : a Multicenter, Randomized, Open-label and Controlled Study

Conditions
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Osteomyelitis - Foot

Intervention / Treatment
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* Drug: Reduction in the duration of antibiotic therapy 3 weeks or 6 weeks


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient aged ≥ 18 years Informed, written consent obtained from patient Patient having the rights to Frenc social insurrance For women of childbearing potential : any effective contraceptive is required Type 1 or 2 diabetic patients Diabetic patients treated non-surgically for an osteomyelitis of the forefoot affecting only one osteoarticular part/radial supported by adequate diagnostic imaging and bone biopsy performed through uninfected tissue. Two peripheral pulses or transcutaneous oxygen tension measurement (TcPO2 > 30mmHg) or ankle brachial index (ABI > 0.9) Patient without antibiotherapy during 2 weeks before D1. Glycated hemoglobin (HbA1C) < 12% ( measured maximum 2 months before D1) Use of offloading boot for diabetic foot is feasible Exclusion Criteria: Bone fragmentation, articular destruction requiring bone resection or amputation. Gangrene More than one osteoarticular part/radial affected Contraindication for the use of offloading boot Contraindication for bone biopsy Contraindication for the full course of antibiotics (allergy or based on RCP) Other drug-drug interaction that contraindicated the full course of antibiotics Charcot foot Patient undergoing radiotherapy of chimiotherapy for malignant neoplasms Hepatic insufficiency (ASAT and/or ALAT > 3 times the normal level) Any disease or behaviour making impossible to follow the protocol or difficult to interpret the results Any disease or context making difficult to allow regular monitoring of the patient Participation in other interventional research during the study Curator or guardianship of patient placed under judicial protection Pregnancy or lactating women

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3 weeks antibiotherapy<br>Patients are treated 3 weeks with appropriate antibiotics after antibiogram evaluation. | Drug: Reduction in the duration of antibiotic therapy 3 weeks or 6 weeks<br>* Drugs : Rifampin (IP an PO) : 10mg/Kg/12h Ofloxacin (PO) : 200Mg/8h Levofloxacin (PO) : 500mg ot 1g/ twice a day Ciprofloxacin : IV : 400mg/8h if Pseud spp ; 400mg/12h for others Gram-negative bacilli strains; PO : 1gr/12h if Pseud spp ; 750mg/12h for others Gram-negative bacilli strains Clindamycin : 600-900mg/8h Fusidic Acid : 500mg/8h Teicoplanin : 10mg/kg/12h for 5 dosis in combination, then in monotherapy. Ceftasidim : 2g/8h if Pseud spp ; 2g/12h for others Gram-negative bacilli strains Trimethoprim-sulfamethoxazole (800mg/160mg) : once per day if patient < 80Kg ; one and a half per day if patient > 80Kg. Doxycyclin : 200mg/day Minocyclin : 100mg/8h to 12h Ceftriaxon : 1g to 2g/day in IV, IM or SC Cefotaxim : 1g to 2g/day in IV Pristinamycin : 1g thrice a day<br>|
| Experimental: 6 weeks antibiotherapy<br>Patients are treated 6 weeks with appropriate antibiotics after antibiogram evaluation. | Drug: Reduction in the duration of antibiotic therapy 3 weeks or 6 weeks<br>* Drugs : Rifampin (IP an PO) : 10mg/Kg/12h Ofloxacin (PO) : 200Mg/8h Levofloxacin (PO) : 500mg ot 1g/ twice a day Ciprofloxacin : IV : 400mg/8h if Pseud spp ; 400mg/12h for others Gram-negative bacilli strains; PO : 1gr/12h if Pseud spp ; 750mg/12h for others Gram-negative bacilli strains Clindamycin : 600-900mg/8h Fusidic Acid : 500mg/8h Teicoplanin : 10mg/kg/12h for 5 dosis in combination, then in monotherapy. Ceftasidim : 2g/8h if Pseud spp ; 2g/12h for others Gram-negative bacilli strains Trimethoprim-sulfamethoxazole (800mg/160mg) : once per day if patient < 80Kg ; one and a half per day if patient > 80Kg. Doxycyclin : 200mg/day Minocyclin : 100mg/8h to 12h Ceftriaxon : 1g to 2g/day in IV, IM or SC Cefotaxim : 1g to 2g/day in IV Pristinamycin : 1g thrice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of treated patients achieving remission from the diabetic foot osteomyelitis at the end of follow-up | Remission is defined as one of following events : No relapse of infection at the initial or a contiguous site leading to make a new antibiogram. Absence of pathology exacerbation visible by radiological results (comparison with Day 0) Absence of orthopedic surgery or amputation of the foot infected initially. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison in each group of patients of the time needed for a complete wound healing. | A wound healing is complete with epithelial wound closure maintained 28 days minimum of the initial site of injury caused by osteomyelitis. | 12 months | 
| Rates of reinfection at the initial site in each group of patients. | Reinfection is defined by a relapse of infection of soft tissues and osteomyelitis. | 12 months | 
| Rates of occurrence of a new wound after healing, on the same site initially traited in each group of patients. | A new wound is defined by a skin injury under the malleolus evolving over three weeks. | 12 months | 
| Rates of occurrence of a new wound after healing on the same foot but not the same infection site in each group of patients. | A new wound is defined by a skin injury under the malleolus evolving over three weeks. | 12 months | 
| Rates of occurrence of a peripheral neuroathropathy (Charcot foot) in each group of patients. | Neurologic exam includes monofilament test and tuning fork test for assessing the loss of protective sensation. | 12 months | 
| Rates of amputation in each group of patients. | Minor amputation is defined as an amputation below the ankle (malleolus). Major amputation is defined as an amputation above the ankle (malleolus). | 12 months | 
| Rates of major amputation in each group of patients. | Major amputation is defined as an amputation above the ankle (malleolus). | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Antibiotic Treatment