Costs and Effects of Early Switch of Intravenous to Oral Antibiotics in Severe Community-Acquired Pneumonia: a Multicenter Randomized Trial

Study design A multi-center, randomized open label clinical trial was performed in 2 university medical centers and 5 teaching hospitals in the Netherlands. The study was approved by the medical ethics committees of all participating hospitals and all patients provided written informed consent prior to enrollment.

After inclusion in the trial, treatment allocation was established through an independent central randomization center. Stratified randomization per center was based on computer generated tables. Patients were either randomized to the intervention group, where clinically stable patients were switched from IV to oral antibiotics on the 3rd day of hospitalization to complete a total of 10 days antibiotic treatment, or to the control group, who received a standard regimen of 7 days of intravenous therapy. Clinical stability was defined as respiratory rate < 25/min, O2 saturation > 90% or arterial pO2>55mmHg, hemodynamically stable, > 1oC decrease in temperature in case of fever, absent mental confusion and the ability to take oral medication 10. Antibiotic choices were left to the discretion of the attending consultant and were based on Dutch treatment guidelines 20.

Patients Adult patients (age 18 or above) with severe CAP admitted to general hospital wards were eligible for inclusion in the study. Pneumonia was defined as a new or progressive infiltrate on a chest X-ray plus at least two of the following criteria: cough, sputum production, rectal temperature > 38oC or < 36.1oC, auscultatory findings consistent with pneumonia, leucocytosis (>10.000/mm3, or >15% bands), C-reactive protein > 3 times the upper limit of normal, positive blood culture or positive culture of pleural fluid. 21 Severe pneumonia was defined as Fine class IV or V or fulfilling the ATS-criteria for severe community-acquired pneumonia. 16;22 Patients with cystic fibrosis, a history of colonization with Gram negative bacteria due to structural damage to the respiratory tract, malfunction of the digestive tract, life expectancy of less than 1 month due to underlying diseases, infections other than pneumonia needing antibiotic treatment, severe immunosuppression (neutropenia (<0,5 x 109 / l) or a CD4 count < 200 / mm3) and needing mechanical ventilation in an intensive care unit were excluded.

Baseline, follow up and outcome measurements Patients were followed for a maximum of 28 days. On admission, a complete physical examination, chest radiography and blood sampling for arterial blood gas analysis and for hematological and biochemical analysis were performed. Demographic data, initial intravenous therapy and clinical data were recorded. During the follow-up period, in-hospital clinical data were recorded. Clinical stability was evaluated after 3 days of intravenous therapy in both study groups and discharge criteria (temperature < 37.8 oC, saturation >92%, normal blood pressure, heart rate < 100/min, respiratory rate < 25/min, absence of mental confusion and ability to take oral medication ) were evaluated daily thereafter. If patients were discharged within 28 days after admission they were asked to return to the out-patient clinic 28 days after inclusion, where history, physical examination, blood chemistry analysis and a chest X-ray were taken and health-care consumption after discharge was recorded.

Questionnaires were used to evaluate the effects on health care resource use outside the hospital (recorded daily after discharge). Quality of life was determined with the short form health survey questionnaire (www.sf-36.org) recorded at days 3, 10 and 28 of the study. Additional questionnaires were used to measure the effects of an early discharge on the workload for family members (questionnaire at day 28 of study) and effects of administration route on freedom of movement, adverse events and compliance (questionnaire at day 7 of study). Treatment failures were defined as death, clinical deterioration (clinical worsening such that the patient needed mechanical ventilation, re-administration of intravenous antibiotics after a switch to oral therapy, readmission for pulmonary reinfection after discharge, increase in temperature after initial improvement) or hospitalization at day 28 of the study. Clinical cure was defined as discharged in good health without signs and symptoms of pneumonia and no treatment failures during the follow-up period. 21