Oral Antimicrobial Treatment vs. Outpatient Parenteral for Infective Endocarditis

Study Overview
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Brief Summary
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Non-inferiority trial to determine whether partial oral treatment is non-inferior to OPAT(Outpatient parenteral therapy) in patients diagnosed with infective endocarditis

Detailed Description
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The trial will include patients diagnosed with left-side Infective Endocarditis according to the modified Duke criteria, with ≥10 days of appropriate parenteral antibiotic treatment overall and at least one week of appropriate parenteral treatment after valve surgery The patients will be randomized in two arms, one with oral antibiotic therapy and the other one with outpatient parenteral therapy This trial aims to demonstrate the non-inferiority of outpatient oral antibiotic therapy in comparison with outpatient parenteral antibiotic treatment (OPAT), to improve the quality of life of infective endocarditis (IE) patients, and to reduce the cost of the intervention without increasing morbidity and mortality rates

Official Title
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Oral Antimicrobial Treatment vs. Outpatient Parenteral for Infective Endocarditis

Conditions
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Endocarditis Infective

Intervention / Treatment
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* Drug: Cefaclor
* Drug: Ciprofloxacin Tablets
* Drug: Ciprofloxacin Injection
* Drug: Clindamycin Oral Capsule
* Drug: Clindamycin Injection
* Drug: Dicloxacillin Oral Capsule
* Drug: Dicloxacillin
* Drug: Fusidic Acid Only Product in Oral Dose Form
* Drug: Fusidic Acid Only Product in Parenteral Dose Form
* Drug: Levofloxacin Oral Tablet
* Drug: Levofloxacin Injection
* Drug: Linezolid Oral Tablet
* Drug: Linezolid Injectable Product
* Drug: Moxifloxacin tablet
* Drug: Moxifloxacin Injectable Product
* Drug: Rifampicin Only Product in Oral Dose Form
* Drug: Rifampicin Only Product in Parenteral Dose Form
* Drug: Sulfamethoxazole / Trimethoprim Oral Tablet [Bactrim]
* Drug: Sulfamethoxazole / Trimethoprim Injectable Product
* Drug: Tedizolid Oral Tablet
* Drug: Tedizolid Injection
* Drug: Amoxicillin Capsules
* Drug: Amoxicillin
* Drug: Cefaclor Capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Left-sided native or prosthetic infective endocarditis based on the modified Duke criteria infected with one of the following nonresistant microorganisms: Non-resistant streptococci and other gram positive cocci,e.g., Granulicatella and Abiotrophia; Enterococcus faecalis; Staphylococcus aureus;coagulase-negative staphylococci and HACEK group. Male or female 18 years old or older. 10 days or more of appropriate parenteral antibiotic treatment overall and at least one week of appropriate parenteral treatment after value surgery. Temperature inferior to 38ºC for more than two days. 5. C-reactive protein dropped to <25% of peak value or <20 mg/l, and white blood cell count <15x10^9/l during antibiotic treatment Transthoracic / transesophageal echocardiography performed within 48 hours of randomization Exclusion Criteria: Body mass index >40 Concomitant infection requiring intravenous antibiotic therapy Inability to give informed consent to participation Suspicion of reduced absorption of oral treatment due to abdominal disorder Microorganisms with no oral combinations for treatment (two active antibiotics of different families) Any immunosuppressive disease or any medical condition at the discretion of the investigator that may preclude oral or OPAT therapy No family or appropriate home support Reduced compliance Women of childbearing potential with a positive pregnancy test, or participants (male or female) who wish to plan a pregnancy during the trial period Women in lactancy period

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
Interventional Model Description: National multi-center study, open, controlled, and randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: OPAT<br>Patients with infective endocarditis diagnostic, who have completed at least 10 days of intravenous therapy, and/ or seven days in the case of cardiac valvular surgery, and shown good clinical evolution and no clinical or echocardiographic signs of potential bad prognosis will be randomized. If assigned to this arm the patient will recieve parenteral antibiotics until the end of treatment. | Drug: Cefaclor<br>* cefaclor intravenous 2 gr/day<br>Drug: Ciprofloxacin Injection<br>* 1200 mg/day maximum dose IV<br>Drug: Clindamycin Injection<br>* 600 mg/8 hours (maximum 1.800 mg x day) IV<br>Drug: Dicloxacillin<br>* 1g/8 hours (maximum 4 g x day) IV<br>Drug: Fusidic Acid Only Product in Parenteral Dose Form<br>* 0,75 g/12 hours (maximum 1,5 g x day)<br>Drug: Levofloxacin Injection<br>* 0.5g/12-24hours (maximum 1 g x day)<br>Drug: Linezolid Injectable Product<br>* 0,6 g/12 hours (maximum 1200 mg x day)<br>Drug: Moxifloxacin Injectable Product<br>* 0,4 g/day (maximum 400 mg x day)<br>Drug: Rifampicin Only Product in Parenteral Dose Form<br>* 0,3-0,6 g/12 hours (maximum 1200 mg x day)<br>Drug: Sulfamethoxazole / Trimethoprim Injectable Product<br>* sulfamethoxazole 1600 mg/trimethoprin 320 mg (maximum x day)<br>Drug: Tedizolid Injection<br>* 200 mg (maximum x day)<br>Drug: Amoxicillin<br>* 1 gr/6 hours (4 g x day) Intravenous<br>|
| Experimental: Oral Therapy<br>Patients with infective endocarditis diagnostic, who have completed at least 10 days of intravenous therapy, and/ or seven days in the case of cardiac valvular surgery, and shown good clinical evolution and no clinical or echocardiographic signs of potential bad prognosis will be randomized. If assigned to this arm the patient will recieve oral antibiotics until the end of treatment. | Drug: Ciprofloxacin Tablets<br>* 500-750 mg/12 hrs (maximum 3g x day)<br>Drug: Clindamycin Oral Capsule<br>* 600 mg/8 hours (maximum 1.800 mg x day)<br>Drug: Dicloxacillin Oral Capsule<br>* 1g/8 hours (maximum 4 gr day)<br>Drug: Fusidic Acid Only Product in Oral Dose Form<br>* 0,750g/12 hours (maximum 1,5 g x day)<br>Drug: Levofloxacin Oral Tablet<br>* 0.5g/12-24hours (maximum 1 g x day)<br>Drug: Linezolid Oral Tablet<br>* 0,6 g/12 hours (maximum 1200 mg x day)<br>Drug: Moxifloxacin tablet<br>* 0,4 g/day (maximum 400 mg x day)<br>Drug: Rifampicin Only Product in Oral Dose Form<br>* 0,3-0,5 g/12 hours (maximum 1200 mg x day)<br>Drug: Sulfamethoxazole / Trimethoprim Oral Tablet [Bactrim]<br>* sulfamethoxazole 1600 mg/trimethoprin 320 mg (maximum x day)<br>Drug: Tedizolid Oral Tablet<br>* 200 mg tedizolid (maximum x day)<br>Drug: Amoxicillin Capsules<br>* 1 gr/6 hours (4 g x day)<br>Drug: Cefaclor Capsules<br>* 2 gr/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-inferiority of outpatient oral vs parenteral antibiotic therapy measured by the number of unplanned hospitalizations |  | At any time during the study duration (up to 24 months) | 
| Non-inferiority of outpatient oral vs parenteral antibiotic therapy measured by the number of all-cause mortality |  | At any time during the study duration (up to 24 months) | 
| Non-inferiority of outpatient oral vs parenteral antibiotic therapy measured by the number of relapses of Infective Endocarditis |  | within 6 months from diagnosis of Infective Endocarditis | 
| Non-inferiority of outpatient oral vs parenteral antibiotic therapy measured by the number of patients requiring cardiac surgery |  | At any time during the study duration (up to 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life and patient satisfaction of infective endocarditis patients. It will be measured through the standardized Saillen questionnaire of antibiotic treatment satisfaction |  | At any time during the study duration (up to 24 months) | 
| Costs of both interventions, measured through a pharmaco-economic sub-study including direct and indirect costs, following the methodology described by Lacroix A et al Med Mal Infect. 2014 | through a pharmacoeconomic analysis | At any time during the study duration (up to 24 months) | 
| The complications related to parenteral and oral administration of antibiotics will be measured through the number of antibiotic adverse reactions, catheter-related adverse events, and number of superinfections | such as antibiotic or catheter-related adverse events e.g.,phlebitis and line-related bloodstream infections, and superinfections | At any time during the study duration (up to 24 months) |