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.
Patient aged 18 years and above at the time of study inclusion
Patient consulting at a recruiting hospital center
Clinical and biological suspicion of leptospirosis, confirmed by serological rapid testing or PCR at most 72 hours after start of antibiotic treatment
Affiliated or beneficiary of a social security scheme (For French Guiana, patients benefiting from State Medical Aid (AME) will be considered, in accordance with the provisions of article L1121-8-1 of the Public Health Code
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 (73)
Hematologic failure with hemoglobin <7 g / dL requiring red blood cell transfusion (74) or platelets <20 G / L requiring platelet transfusion (75)
Ventilatory failure defined by PaO2 / Fi O2 ratio <300 mmHg (76) or resort to mechanical ventilation
Renal failure defined by serum creatinine > 301 μmol / L 76) or resort to renal dialysis
Parallel
3 days of antibiotherapy
DrugReduce at 3 days of antibiotherapy for the treatment of mild leptospirosis
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
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,
Treatment failure
death
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
Evolution functional signs according to 3-day versus 7-day treatment duration
Assessment of functional signs
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)
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
Click on the lead sponsor to view all of their trials.
University Hospital Center of Martinique
Lead sponsor
University Hospital of Guadeloupe
Collaborator
Centre Hospitalier de Cayenne
Collaborator
Centre Hospitalier Universitaire de la Réunion
Collaborator
Hôpital de Mayotte
Collaborator
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