Oral Switch During Treatment of Left-sided Endocarditis Due to Multi-susceptible Streptococcus
Oral Switch During Treatment of Left-sided Endocarditis Due to Multi-susceptible Streptococcus
Infective endocarditis (IE) is a serious infection with a significant burden for patients and
 hospitals (in France, median length of hospital stay = 43 days), partly due to the long
 duration of intravenous (IV) antibacterial treatment recommended by international guidelines,
 between 4 and 6 weeks in most situations.

 A recent survey of practices regarding the management of IE in France showed that a switch
 from IV to oral antibiotics is feasible, when patients with left-sided
 Streptococcus-Enterococcus IE are stable after an initial course of IV antibiotic treatment,
 with or without valvular surgery.

 These practices have not been associated with unfavourable outcome, while significantly
 reducing the duration and cost of hospitalization, the risk of nosocomial infection, and
 patients' discomfort.

 There has been no randomized controlled trial (RCT) in the field of IE over the last 20
 years; current guidelines are mostly based on expert advice, in vitro studies, animal
 experiments, or clinical studies performed before the 90's.

 The RODEO 2 project is an unprecedented opportunity to bring back evidence-based medicine in
 the field of IE.

 Most experts acknowledge that the pharmacological PK/PD characteristics of antibiotics such
 as amoxicillin allow a high level of efficacy in the treatment of IE when orally
 administrated after an IV period of induction.

 It's needed to conduct RCTs that clearly demonstrate the clinical non-inferiority of this
 strategy for streptococci, and enterococci IE with a benefit regarding costs.

 The RODEO 2 project corresponds to one pragmatic trial assessing the impact of a switch
 strategy, making it a comparative effectiveness trial that should be able to feed the next
 revision of IE international guidelines and to change practices in IE management.
The RODEO 2 study is designed to determine the safety and efficacy of partial oral treatment
 of IE compared with traditional full-length parenteral treatment. Our primary objective is to
 demonstrate that in patients with left-sided multi-susceptible Streptococcus-Enterococcus IE
 who have received at least 10 days of IV antibiotic treatment with or without valvular
 surgery, a switch to an oral combination of amoxicillin between Day 10 and Day 28 after
 initiation of the IV antibiotic treatment, is not inferior to the continuation of the
 conventional IV antibiotic treatment regarding to treatment failure within 3 months after the
 end of antibiotic treatment.

 Nationwide, noninferiority, multicenter, randomized, controlled, open-label trials.

 Randomisation will only be offered to patients who have received at least 10 days of IV
 conventional antibiotic treatment of IE, and fulfil the inclusion criteria.

 Randomisation will take place between Day 10 and Day 28 after initiation of parenteral
 antibiotic therapy or valvular surgery, thus ensuring to have at least 14 days of oral
 therapy in the experimental group.

 Patients will be eligible whether they have undergone valvular surgery or not. This will
 imply that surgery procedure prior to randomisation will be heterogeneous, but randomisation
 will be stratified on the requirement of valvular surgery as part of the treatment of the
 current episode of IE or not.
Inclusion Criteria:

 -  Left-sided IE (Defined according to Duke criteria) on native or prosthetic valve

 -  due to one isolate of Streptococcus/Enterococcus sp. susceptible to amoxicillin (MCI ≤
 0.5 mg/l)

 -  in an adult ≥18 year old

 -  appropriate parenteral antibiotics treatment received for at least 10 days

 -  in case of valvular surgery, appropriate parenteral antibiotics treatment received for
 at least 10 days after valvular surgery

 -  planned duration of antibiotics will extend for at least 14 days at the time of
 randomisation i.e. a potential switch to oral treatment between Day 10 and Day 28 thus
 ensuring to have at least 14 days of oral therapy remaining in the experimental group

 -  apyrexia (temperature < 38°C) at each time point during the last 48 hours (at least
 two measures/day) at the time of randomisation

 -  blood cultures have been sterile for at least 5 days at the time of randomisation

 -  informed, written consent obtained from patient

 -  subject covered by or having the rights to French social security

 Exclusion Criteria:

 -  body mass index <15 kg/m² or > 40 kg/m²

 -  glomerular filtration rate < 30 ml/min/1,73m²

 -  patient unable or unwilling to take oral treatment (digestive intolerance, significant
 malabsorption) at the time of randomisation

 -  expected difficulties regarding compliance with oral antibiotic treatment or follow-up
 (e.g. severe cognitive impairment, severe psychiatric disease...)

 -  patient without entourage to support and watch him at discharge

 -  valvular surgery planned within the next 6 months

 -  for patients with cardiac devices (pace-maker, implantable cardiac defibrillator) and
 suspected device-related IE (vegetation on the leads) if removal of the device was not
 performed

 -  breast feeding or pregnant women, or women on childbearing age without effective
 contraception

 -  expected duration of follow-up < 7 months at the time of randomisation (e.g. expected
 life expectancy < 7 months, patient living abroad...)

 -  past medical history of IE in the last 3 months

 -  other infection requiring parenteral antibiotic therapy

 -  taking of an estrogen-progesterone treatment interacting with rifampicin

 -  patient with contra-indication to oral antibiotics administered in the experimental
 arm (i.e. amoxicillin) - including anticipated non-manageable drug interactions, and
 allergy.