Study on Costs and Safety of Early Conversion From Intravenous to Oral Antibiotic Treatment in Patients With Severe Community-Acquired Pneumonia
Study on Costs and Safety of Early Conversion From Intravenous to Oral Antibiotic Treatment in Patients With Severe Community-Acquired Pneumonia
Patients with severe community-acquired pneumonia are included Half of the patients are
 treated with a 3 day course of intravenous antibiotics, followed, when clinical stable, by a
 course of oral antibiotics. Efficacy of this treatment is compared to a standard course of 7
 days of intravenous antibiotics, which treatment is assigned to the other half of patients.
 Outcomes measured are clinical cure and costs.
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

 Microbiological analyses Sputum samples and blood samples were collected, cultured and
 evaluated following standard procedures. Micro-organisms cultured in blood or sputum were
 recorded. In addition, Binax NOW-tests were used to detect urinary antigen for Legionella
 pneumophila and S. pneumoniae. Acute and convalescent serology samples were collected and
 evaluated for Mycoplasma pneumoniae, L. pneumophila and Chlamydia pneumonia. Any
 non-contaminating micro-organism cultured from a blood or sputum sample or detected by
 urinary antigen testing was considered a cause for the episode of pneumonia. For Mycoplasma
 pneumoniae, a fourfold or greater increase in titer in paired sera or a single titer of
 greater than or equal to 1:40 was considered indicative of infection. 23 (Immune fluorescence
 agglutination, Serodia-MycoII ®, Fujirebio, inc.) For Legionella pneumophila, a fourfold
 increase in the antibody titer to 1:128 or greater, or single titers of 1:256 or more were
 considered suggestive of Legionella pneumonia.24 For Chlamydia pneumoniae, detection of IgM
 above established values, seroconversion of IgG between acute and convalescence samples, high
 amounts of IgG in single titers or a combination of these factors were considered serological
 evidence of infection, according to the manufacturers instructions. (ELISA, Savyon
 Diagnostics Ltd)

 Economic evaluation The societal perspective was used to calculate direct medical costs
 associated with the treatment in both study groups. Costs were assessed in 2002 euros. Costs
 per patient were calculated by multiplying resource use by the unit costs. Resource use
 during hospital stay for diagnostic and therapeutic interventions, consultations of medical
 or paramedic specialists and antibiotic use was measured. Resource use outside the hospital
 was evaluated using questionnaires which recorded contacts with general practitioners,
 specialists, extra diagnostic procedures, use of medication, readmissions, home care and
 other disease-related costs. Additional costs associated with specific diagnostic tests were
 based on tariffs. Costs of hospital stay, diagnostic procedures and specialist consultations,
 were calculated using unit costs as determined within the realm of the Dutch guidelines for
 pharmaco-economic analyses 25. Costs for readmissions and reinfections were assessed
 specifically for the study cohort and included costs for extra diagnostic procedures,
 treatment and hospitalizations. Costs of antibiotics prescribed were estimated using Dutch
 2002 formulary cost-prices 26

 Sample size and statistical analysis To demonstrate equivalence in efficacy of the two
 treatment groups, initially, the sample size was set at 250 patients in each study group
 based on an expected cure rate of 85% in the IV group and acceptance of a 75% cure rate in
 the switch group. (=0.05, 2 sided; 1-=0.80). The absolute difference in cure rate including
 95% CI was calculated. Equivalence was rejected if the lower limit of the CI exceeded -10%.
 Eventually, with less than anticipated enrolment, a 15% lower effectiveness in the
 intervention group could be excluded with =0.05 and 1-=0.80.

 Analyses were performed on an intention-to-treat basis. Differences in continuous variables
 were presented as absolute differences with their corresponding 95% CI´s. Dichotomous data
 were compared with chi-square statistics. Alike cure rate differences in proportions were
 presented including 95% CI´s. For cost-calculations, arithmetic means of both study groups
 were compared. The uncertainty surrounding the cost-calculations was evaluated by means of
 standard bootstrap techniques. 27 Ultimately, the balance between costs and effects was
 compared for both strategies and incremental costs per therapy failure averted at 28 days
 were calculated. The uncertainty surrounding the incremental cost-effectiveness ratio was
 again evaluated by means of bootstrapping.
Inclusion Criteria:

 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

 Exclusion Criteria:

 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.

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