Comparing Two Antibiotic Therapy Periods (3 Versus 7 Days) in Patients With Mild Leptospirosis and Seen at the Hospital in 5 French Overseas Departments (Martinique, Guadeloupe, French Guiana, Reunion, Mayotte)
Comparing Two Antibiotic Therapy Periods (3 Versus 7 Days) in Patients With Mild Leptospirosis and Seen at the Hospital in 5 French Overseas Departments (Martinique, Guadeloupe, French Guiana, Reunion, Mayotte)
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
Inclusion Criteria:

 1. Patient aged 18 years and above at the time of study inclusion

 2. Patient consulting at a recruiting hospital center

 3. Clinical and biological suspicion of leptospirosis, confirmed by PCR at most 72 hours
 after start of antibiotic treatment

 4. Affiliate or beneficiary of a social security scheme.

 5. Acceptance of participation in the clinical trial and in the follow-up process at 7
 and 21 days (from start of antibiotic therapy), as well as signed consent form

 Exclusion Criteria:

 -  1. Presence of severity criteria appearing between the time of first patient care at
 the hospital and study inclusion:

 1. 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

 2. Hematologic failure with hemoglobin <7 g / L requiring red blood cell transfusion
 or platelets <20 G / L requiring platelet transfusion

 3. Ventilatory failure defined by PaO2 / Fi O2 ratio <300 mmHg or resort to
 mechanical ventilation

 4. Renal failure defined by serum creatinine > 301 μmol / L or resort to renal
 dialysis

 5. Hepatic failure defined by total bilirubinemia> 101 μmol / L 2. Diagnosis of
 another bacterial infection documented during initial patient assessment (e.g.
 Gram-negative bacteremia, digestive tract infection, bacterial pneumonia) 3.
 Intake of antibiotics, active on leptospirosis, the week before clinical and
 biological suspicion of leptospirosis 4. Leptospirosis diagnosis by PCR after the
 7th day from symptom onset or after the 3rd day from beginning of treatment 5.
 Pregnant or lactating woman 6. Absence of contraception 7. Allergy or
 contraindication to amoxicillin and doxycycline