Leptospirosis is a globally distributed neglected tropical disease affecting subtropical and tropical areas, such as the Caribbean and the Indian Ocean, with favorable climatic conditions for disease transmission. It shows a strong seasonality, with epidemic potential especially after heavy rainfall. A recent systematic review by Costa et al. (2015) places leptospirosis among the leading zoonotic causes of morbidity and mortality worldwide, with 1.03 million cases and 58,900 deaths each year. Leptospirosis is an important public health problem, particularly within economically vulnerable populations. It is also emerging as a health threat in new settings due to globalization and climate change. Disasters and extreme weather events are recognized to precipitate epidemics. Clinical manifestations are highly polymorphic, ranging from an anicteric, influenza-like form to severe forms with hepato-renal or pulmonary failures which are associated with high mortality. Antibiotic therapy should be prescribed early, as soon as leptospirosis is suspected and preferably within the first 5 days, before leptospira spread to the tissues. In the treatment of mild forms, usual antibiotics are oral amoxicillin or doxycycline for a standard treatment duration of 7 days. In hospitalized cases of leptospirosis, parenteral antibiotic therapy with ceftriaxone is often favored as first-line therapy. The most widely used antibiotics in the French Caribbean and Indian Ocean regions are amoxicillin, doxycyclin and third generation cephalosporins such as ceftriaxone. Research hypothesis: The effects of shorter antibiotic therapy periods for other infectious diseases have been explored by several authors. The efficacy of short ceftriaxone treatment has been highlighted for typhoid fever or meningococcal meningitis. In a retrospective series of 21 cases, the interest of short treatment periods (3-6 days) for mild and severe leptospirosis has also been described. A minimal 3-day therapy period would seem necessary in order to biologically confirm leptospirosis diagnosis and to rule out other community-acquired infections. Our study proposal is the conduct of a non-inferiority trial comparing a shortened antibiotic therapy period of 3 days with the standard treatment period of 7 days in patients with mild leptospirosis and seen at the hospital in 5 French overseas departments (Martinique, Guadeloupe, French Guiana, Reunion, Mayotte). Originality and innovative aspects: To our knowledge, the efficacy of a 3-day antibiotic therapy for mild leptospirosis, as compared to the standard 7 day period, has not yet been explored. In addition, the LEPTO3 study will be among the first clinical trials to focus on the endemic public health problem, which is leptospirosis, at a large geographical level (Caribbean and Indian Ocean regions) and to involve a high level of collaboration between medical and scientific teams of these territories.
Leptospirosis is a globally distributed neglected tropical disease affecting subtropical and tropical areas, such as the Caribbean and the Indian Ocean, with favorable climatic conditions for disease transmission. It shows a strong seasonality, with epidemic potential especially after heavy rainfall. A recent systematic review by Costa et al. (2015) places leptospirosis among the leading zoonotic causes of morbidity and mortality worldwide, with 1.03 million cases and 58,900 deaths each year. Leptospirosis is an important public health problem, particularly within economically vulnerable populations. It is also emerging as a health threat in new settings due to globalization and climate change. Disasters and extreme weather events are recognized to precipitate epidemics. Clinical manifestations are highly polymorphic, ranging from an anicteric, influenza-like form to severe forms with hepato-renal or pulmonary failures which are associated with high mortality. Antibiotic therapy should be prescribed early, as soon as leptospirosis is suspected and preferably within the first 5 days, before leptospira spread to the tissues. In the treatment of mild forms, usual antibiotics are oral amoxicillin or doxycycline for a standard treatment duration of 7 days. In hospitalized cases of leptospirosis, parenteral antibiotic therapy with ceftriaxone is often favored as first-line therapy. The most widely used antibiotics in the French Caribbean and Indian Ocean regions are amoxicillin, doxycyclin and third generation cephalosporins such as ceftriaxone. Research hypothesis: The effects of shorter antibiotic therapy periods for other infectious diseases have been explored by several authors. The efficacy of short ceftriaxone treatment has been highlighted for typhoid fever or meningococcal meningitis. In a retrospective series of 21 cases, the interest of short treatment periods (3-6 days) for mild and severe leptospirosis has also been described. A minimal 3-day therapy period would seem necessary in order to biologically confirm leptospirosis diagnosis and to rule out other community-acquired infections. Our study proposal is the conduct of a non-inferiority trial comparing a shortened antibiotic therapy period of 3 days with the standard treatment period of 7 days in patients with mild leptospirosis and seen at the hospital in 5 French overseas departments (Martinique, Guadeloupe, French Guiana, Reunion, Mayotte). Originality and innovative aspects: To our knowledge, the efficacy of a 3-day antibiotic therapy for mild leptospirosis, as compared to the standard 7 day period, has not yet been explored. In addition, the LEPTO3 study will be among the first clinical trials to focus on the endemic public health problem, which is leptospirosis, at a large geographical level (Caribbean and Indian Ocean regions) and to involve a high level of collaboration between medical and scientific teams of these territories. Main objective : Compare the efficacy of a 3-day antibiotic therapy period with the standard period of 7 days in mild leptospirosis patients seen at the hospital in 5 French overseas departments (Martinique, Guadeloupe, French Guiana, Reunion, Mayotte) Secondary objectives : * Compare the evolution of clinical and biological characteristics in the 2 groups of patients (antibiotic therapy duration 3 days versus 7 days) * Compare lengths of hospital stay in the 2 groups of patients (antibiotic therapy duration 3 days versus 7 days) * Examine factors linked to a potential treatment failure in patients * Assess patient tolerance to treatment
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
220
Reduce at 3 days of antibiotherapy for the treatment of mild leptospirosis
Centre Hospitalier Andrée Rosemond (CH de Cayenne)
Cayenne, French Guiana
University Hospital of Guadeloupe
Pointe-à-Pitre, Guadeloupe
Centre Hospitalier Universitaire de Martinique
Fort-de-France, Martinique
Centre Hospitalier de Mayotte
Mamoudzou, Mayotte
Centre Hospitalier Universitaire Sud Réunion
Saint-Pierre, Reunion
Treatment failure
\- occurrence of a complication: * Hemodynamic failure with onset of septic shock defined by persisting hypotension requiring vasopressor amines to maintain mean arterial pressure ≥65 mm Hg and blood lactates \>2 mmol/L despite adequate volume resuscitation * hematologic failure with hemoglobin \<7 g / L requiring red blood cell transfusion or platelets \< 20 G / L requiring platelet transfusion * Ventilatory failure defined by PaO2 / Fi O2 ratio \<300 mmHg or resort to mechanical ventilation * Renal failure defined by serum creatinine \> 301 μmol / L or resort to renal dialysis * Hepatic failure defined by total bilirubinemia\> 101 μmol / L * Heart failure (eg: ECG anomalies, myocarditis, cardiogenic shock) * Neurologic affection such as meningitis, encephalitis, intracerebral hemorragia, stroke * Ocular symptoms such as uveitis. * Hemoptysis, lesional pulmonary oedema for pulmonary affection * Hemorrhagic syndrome , or
Time frame: 7 days from the beginning of antibiotic therapy
Treatment failure
continued fever (body temperature \>38°C) 5 days after the start of antibiotic therapy, or fever reappearance (body temperature \>38°C) observed 24 hours after initial apyrexia (body temperature \<38°C). Both cases exclude fever due to a cause not attributable to leptospirosis infection. Or,
Time frame: 7 days from the beginning of antibiotic therapy
Treatment failure
death
Time frame: 7 days from the beginning of antibiotic therapy
Evolution of clinical characteristics according to 3-day versus 7-day treatment duration
measure of body temperature * assessment of functional signs * no evolution of infection at 21 days from start of antibiotic therapy) * Absence of clinical symptoms (jaundice, nausea, abdominal pain, myalgia, and arthlagia) * Normalization of biological parameters (creatinine, bilirubin, platelets, hemoglobin) * Quality of life criteria evaluated by the EQ5D questionnaire
Time frame: 21 days
Evolution functional signs according to 3-day versus 7-day treatment duration
Assessment of functional signs
Time frame: 21 days
No evolution of infection at 21 days from start of antibiotic therapy according to 3-day versus 7-day treatment duration
Absence of clinical symptoms such as jaundice, nausea, abdominal pain, myalgia, and arthlagia Normalization of biological parameters (creatinine, bilirubin, platelets, hemoglobin)
Time frame: 21 days
Evolution of Quality of life according to 3-day versus 7-day treatment duration
Quality of life criteria evaluated by the EQ5D questionnaire (scale from 0 to 100 with 0 means worst imaginable health state; 100 means best imaginable health state
Time frame: 21 days
Evolution of bilirubinemia values according to 3-day versus 7-day treatment duration
μmol / L
Time frame: 21 days
Evolution of serum creatinine values according to 3-day versus 7-day treatment duration
μmol / L
Time frame: 21 days
Evolution of hemoglobin values according to 3-day versus 7-day treatment duration
G / L
Time frame: 21 days
Length of hospital stay according to 3-day versus 7-day treatment duration
Time frame: 21 days
Factors associated with treatment failure : Serogroup of leptospira
Time frame: 7 days
Factors associated with treatment failure : Genovar of leptospira
Time frame: 7 days
Factors associated with treatment failure : quantitative leptospiremia (blood) before antibiotic treatment
quantitative leptospiremia (blood) at start of antibiotic therapy
Time frame: 7 days
Factors associated with treatment failure : quantitative leptospiremia (blood) Day+3 of antibiotic treatment
quantitative leptospiremia (blood) at 3 days from start of antibiotic therapy
Time frame: 3 days
Factors associated with treatment failure : Delay between symptom onset and beginning of treatment
day (unit)
Time frame: From day of frist symptoms until enrollment (with a maximum of 7 days between first symptom and date of enrollement)
Factors associated with treatment failure : Presence of co-morbidities
day (unit)
Time frame: From the enrollment, until followup visit 1 (Day 0+7days)
Tolerance to treatment
Tolerance to treatment assessed by the occurrence of Jarisch-Herxheimer reactions, as well as adverse event reporting based on a standardized and internationally recognized toxicity table for adults
Time frame: 21 days
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