Exposure to orally administered antibiotics during the initial phase of infection in non-critically ill, febrile patients

Rationale: Patients hospitalized with serious infectious diseases are in general initially treated with parental antimicrobial therapy. In case of a favourable response after 48-72h, intravenous (IV) antibiotic therapy is followed by an oral course of antibiotic therapy. This switch to oral therapy has been shown to lower the length of hospital stay, the risk of new infections and healthcare costs, without compromising the clinical outcome. The initial treatment when patients are acutely ill is started intravenously, because of the high likelihood that adequate antibiotic plasma levels are achieved. It is possible that adequate plasma concentrations are also achieved with oral antibiotics. If this is the case, we might be able to obtain the evident benefits of oral therapy earlier than the currently set time frame.

Objective: The primary objective is to determine whether the exposure to orally administered ciprofloxacin and amoxicillin is altered in hospitalized non-critically ill patients when they are acutely ill and febrile, i.e. first 24 hours of antibiotic therapy, compared to when they are afebrile, i.e. >48 hours after start of therapy. The secondary objective is to determine whether target attainment can be achieved with oral treatment regimens.

Study design: Longitudinal cohort study with repeated measurements

Study population: Hospitalized non-critically ill, febrile patients, aged 18 years or above, with an indication for IV antibiotic therapy.
Intervention (if applicable): The exposure to ciprofloxacin and amoxicillin will be investigated separately in two studies, using the same study design and procedures. Patients will receive a single oral tablet of the study antibiotic when they are febrile and again when they are afebrile, in addition to the antibiotic treatment prescribed by the treating physician. To measure the antibiotic plasma concentrations, blood samples will be obtained at 4 time points on both study days.

Main study parameters/endpoints: Endpoints are AUC, Cmax and Tmax, calculated after oral administration of ciprofloxacin and amoxicillin, which will be compared between the febrile and afebrile phase. In addition, the amount of patients that achieve target attainment, expressed as percentage of the total number of subjects will be assessed in both phases.

To determine whether the exposure to orally administered ciprofloxacin and amoxicillin is altered in hospitalized non-critically ill patients when they are acutely ill and febrile compared to when they are afebrile. With this knowledge the possibility of an earlier IV-to-oral switch therapy can be assessed.

two study day visits for each patient.

Subjects will receive a single oral dose of ciprofloxacin or amoxicillin in addition to the IV antibiotic treatment prescribed for their febrile illness during their initial phase of disease when they are febrile, and again when they are afebrile. During both study visits, a maximum of 4 blood samples will be collected after ingestion of the antibiotic to measure the antibiotic plasma concentrations.