Beta-lactam Intermittent Versus Continuous Infusion and Combination Antibiotic Therapy in Sepsis

Inclusion Criteria:

• Adults (≥ 18 years)

• Hospital-acquired sepsis or septic shock diagnosed in the past 24 hours (accordingto sepsis 3.0 definitions)

• One of the following risk factors for gram negative multidrug resistant pathogens:

• Prior intravenous antibiotic use within 7 days prior to sepsis onset with theexception of antibiotic effective only against Gram-positive bacteria,penicillin A and macrolides

• Prolonged hospital stay (≥ 15 days of hospitalization) within 90 days prior tothe occurrence of sepsis

• Prolonged mechanical ventilation (≥ 5 days on mechanical ventilation) within 90days prior to sepsis onset

• Patients with indwelling devices (dialysis access lines, intravascular lines,urinary catheter, endotracheal or tracheostomy tube, gastrostomy or jejunostomyfeeding tube)

• Patients known to be infected, colonized or carriers of MDR gram negativebacteria in the past 3 months

• Exposure to an antibiotic (amoxicillin-clavulanic acid, C2G, C3G,fluoroquinolones) in the previous 3 months

• A trip abroad within 3 months to known geographical areas at risk (inparticular the Indian subcontinent, South-East Asia, the Middle East and NorthAfrica, the Mediterranean Basin)

• A functional or organic abnormality of the urinary tract in case of urinarytract infection.

• Appropriate bacteriological sampling performed before starting antimicrobial therapy

• Expected stay in ICU of more than 3 days

Exclusion Criteria:

• A priori known resistance to all the proposed beta-lactams or to amikacin Need forextrarenal treatment at inclusion according to the criteria of Gaudry et al.

• Known hypersensitivity to ceftazidim, piperacillin-tazobactam, cefepim, meropenem,ceftazidim-avibactam, ceftazolane-avibactam or to any of the excipients included inthe corresponding pharmaceutical drugs,

• Known hypersensitivity to any cephalosporin antibacterial agent,

• Know hypersentitivity to any penem antibacterial agent,

• Severe known hypersensitivity (eg, anaphylactic reaction, severe skin reaction) toany other beta-lactam antibiotic (eg, penicillins or monobactam ) or to any of itsexcipients.

• Known contraindication to the aminoglycoside family including

• Hypersensitivity to the active substance, to any aminoglycoside antibacterial agentor to any of the excipients included in the corresponding pharmaceutical drugs,

• Cirrhosis of grades B and C according to the Child-Pugh classification.

• Myasthenia gravis.

• Simultaneous administration of another aminoglycoside

• Association with ataluren

• Non-complicated urinary tract infection (with the exception of acute prostatitis)

• Bone marrow transplant or chemotherapy-induced neutropenia

• Infections for which long-term antibiotic treatment > 8 days is strongly recommended (i.e., infective endocarditis, osteoarticular infections, anterior mediastinitisafter cardiac surgery, hepatic or cerebral abscesses, chronic prostatitis forinstance

• Presence of antibiotic therapy for the new sepsis (if sepsis acquired in thehospital outside the resuscitation> 2 doses of antibiotics)

• Hospitalization in a short stay hospital of more than 48 hours

• Limitation of life support (comfort care applied only) at the time of screening

• Enrolment to another interventional study

• Pregnancy or breastfeeding

• Subject deprived of freedom, subject under a legal protective measure

• Non affiliation to any health insurance system

• Refusal to participate to the study (patient or legal representative or familymember or close relative if present)