Eligible subjects will be those age 18 years or more with mono-microbial blood stream infection caused by E. coli, Klebsiella species, Enterobacter species, Serratia species, Citrobacter species, or Proteus species, who have achieved adequate source control, are afebrile and hemodynamically stable for 48 hours or more and have received microbiologically active intravenous therapy for 3-5 days. The bloodstream isolate must be susceptible to amoxicillin, amoxicillin-clavulanate, fluoroquinolones, oral cephalosporins and/or trimethoprim-sulfamethoxazole and the subject must be able to take oral medication directly or through a feeding tube. Exclusions criteria include allergy to all in-vitro active antimicrobials which are available in oral formulations, pregnancy, infective endocarditis, central nervous system infection, terminal illness with expected survival less than 14 days, absolute neutrophil count less than 1,000/ml and hematopoietic or solid organ transplantation within the preceding 90 days. Randomization will be stratified by urinary versus non-urinary source of bacteremia. The primary outcome is treatment failure at 90-days with 10% margin for non-inferiority in the 95% confidence interval around the difference in outcome between the two study groups.

Oral antimicrobial therapy mitigates vascular line associated complications such as infection, thrombosis and pain, facilitating early mobilization and discharge and reducing healthcare costs. Efficacy and safety of step-down to oral antimicrobial therapy in patients with Enterobacteriaceae bacteremia has never been confirmed in a randomized clinical trial. The aim of this clinical trial is to evaluate the safety and efficacy of oral step down strategy in patients with Gram-negative blood stream infections.

Eligible subjects will be those age 18 years or more with mono-microbial blood stream infection caused by E. coli, Klebsiella species, Enterobacter species, Serratia species, Citrobacter species, or Proteus species, who have achieved adequate source control, are afebrile and hemodynamically stable for 48 hours or more and have received microbiologically active intravenous therapy for 3-5 days. The bloodstream isolate must be susceptible to amoxicillin, amoxicillin-clavulanate, fluoroquinolones, oral cephalosporins and/or trimethoprim-sulfamethoxazole and the subject must be able to take oral medication directly or through a feeding tube. Exclusions criteria include allergy to all in-vitro active antimicrobials which are available in oral formulations, pregnancy, infective endocarditis, central nervous system infection, terminal illness with expected survival less than 14 days, absolute neutrophil count less than 1.0x109/L and hematopoietic or solid organ transplantation within the preceding 90 days.

The primary endpoint is treatment failure at 90-days, defined as a composite of the death from any cause, need for additional antimicrobial therapy with one or more microbiologically active agents before complete resolution of signs and symptoms of infection, microbiological relapse (same species from any clinical site) and infection-related re-admission.

Eligible subjects will be randomized using permuted blocks of variable sizes to full intravenous antimicrobial therapy course (IV Group) or intravenous followed by step-down to oral therapy (PO Group). Randomization will be stratified by urinary versus non-urinary source of bacteremia. The primary analysis will include all patients who were randomized and received at least one dose of the assigned treatment. The difference in primary outcome rate between the intervention and control groups will be presented alongside a 95% confidence interval (CI), adjusted by source of bacteremia. If the upper limit of the 95% CI for the difference in overall response is below 10%, non-inferiority will be concluded.

A Data and Safety Monitoring Board will oversee the trial. An interim analysis will be performed after the first 50% of the target sample have completed the 90-day study period. The Data and Safety Monitoring Board can make a binding recommendation to terminate the study if the results of the interim analysis indicate very high likelihood for positive effect or futility.

Inclusion Criteria:

• Age ≥18 years.
• Mono-microbial blood stream infection.
• Isolation of E. coli, Klebsiella species, Enterobacter species, Serratia species, Citrobacter species, or Proteus species from ≥1 blood culture(s).
• Adequate source control within ≤5 days of staring in-vitro active intravenous antimicrobial therapy.
• Afebrile (Tmax <38 degrees Celsius) for ≥48 hours.
• Hemodynamically stable for ≥48 hours (SBP ≥100 mmHg, no vasopressors).
• Microbiologically active intravenous therapy for 3-5 days.
• Bloodstreams isolate in-vitro susceptibility to amoxicillin, amoxicillin-clavulanate, fluoroquinolones, oral cephalosporins and/or trimethoprim-sulfamethoxazole.
• Ability to take oral medication directly or through a feeding tube.

Exclusion Criteria:

• Allergy to all in-vitro active antibiotics which are available in oral formulations.
• Pregnancy.
• Infective endocarditis.
• Central nervous system infection.
• Terminal illness with expected survival <14 days.
• Neutropenia (absolute neutrophil count <1.0x10^9/L).
• Hematopoietic or solid organ transplantation within the preceding 90 days.