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BMJ 2006;333:1193 (9 December), doi:10.1136/bmj.38993.560984.BE (published 7 November 2006)
Jan Jelrik Oosterheert, research associate1, Marc J M Bonten, professor of infectious diseases1, Margriet M E Schneider, infectiologist1, Erik Buskens, associate professor of epidemiology2, Jan-Willem J Lammers, professor of pulmonology3, Willem M N Hustinx, infectiologist4, Mark H H Kramer, internist/haematologist5, Jan M Prins, infectiologist6, Peter H Th J Slee, internist7, Karin Kaasjager, internist8, Andy I M Hoepelman, professor of medicine1
1 Department of Internal Medicine and Infectious Diseases, University Medical Centre, PO Box 85500, 3508 GA Utrecht, Netherlands, 2 Julius Centre for Health Sciences and Primary Care, University Medical Centre, 3 Department of Pulmonology, University Medical Centre, 4 Department of Internal Medicine, Diakonessenhuis, Utrecht, 5 Department of Internal Medicine, Meander Medical Centre, Amersfoort, Netherlands, 6 Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and Aids, Academic Medical Centre, Amsterdam, Netherlands, 7 Department of Internal Medicine, St Antonius Hospital, Nieuwegein, Netherlands, 8 Department of Internal Medicine, Rijnstate Hospital, Arnhem, Netherlands
Correspondence to: A I M Hoepelman i.m.hoepelman{at}umcutrecht.nl
Design Multicentre randomised controlled trial.
Setting Five teaching hospitals and 2 university medical centres in the Netherlands.
Participants 302 patients in non-intensive care wards with severe community acquired pneumonia. 265 patients fulfilled the study requirements.
Intervention Three days of treatment with intravenous antibiotics followed, when clinically stable, by oral antibiotics or by 7 days of intravenous antibiotics.
Main outcome measures Clinical cure and length of hospital stay.
Results 302 patients were randomised (mean age 69.5 (standard deviation 14.0), mean pneumonia severity score 112.7 (26.0)). 37 patients were excluded from analysis because of early dropout before day 3, leaving 265 patients for intention to treat analysis. Mortality at day 28 was 4% in the intervention group and 6% in the control group (mean difference 2%, 95% confidence interval 3% to 8%). Clinical cure was 83% in the intervention group and 85% in the control group (2%, 7% to 10%). Duration of intravenous treatment and length of hospital stay were reduced in the intervention group, with mean differences of 3.4 days (3.6 (1.5) v 7.0 (2.0) days; 2.8 to 3.9) and 1.9 days (9.6 (5.0) v 11.5 (4.9) days; 0.6 to 3.2), respectively.
Conclusions Early switch from intravenous to oral antibiotics in patients with severe community acquired pneumonia is safe and decreases length of hospital stay by 2 days.
Trial registration Clinical Trials NCT00273676 [ClinicalTrials.gov] .
The concept of early transition from intravenous to oral antibiotics in the treatment of community acquired pneumonia has been evaluated before, but only in mild to moderately severe disease and rarely in randomised trials.4 5 6 7 8 9 10 11 12 13 14 For patients with more severe forms of the disease, effects on outcome and length of hospital stay have not been determined in randomised trials. Therefore, we conducted a multicentre randomised trial to evaluate the effectiveness of an early switch from intravenous to oral antibiotics compared with a seven day intravenous treatment regimen in patients with severe community acquired pneumonia.
An independent central randomisation centre used computer generated tables to allocate treatment. Patients were randomised to the intervention group, where clinically stable patients (defined as respiratory rate <25/min, oxygen saturation >90% or arterial oxygen pressure >55 mm Hg, haemodynamically stable, >1°C decrease in temperature in case of fever, absence of mental confusion, and the ability to take oral drugs10) were switched from intravenous to oral antibiotics on the third day in hospital to complete a total of 10 days of antibiotic treatment, or to the control group, where patients received a standard regimen of seven days of intravenous treatment. Additional antibiotic treatment thereafter was left to the discretion of the treating doctor. The attending consultant chose the antibiotics on the basis of Dutch treatment guidelines.15
Primary outcome measure was clinical cure. Secondary outcome measure was the length of hospital stay.
Patients
Adult patients (18 years) with severe community acquired pneumonia admitted to general hospital wards were eligible for inclusion in our study. We defined pneumonia as a new or progressive infiltrate on a chest radiograph plus at least two other criteria (cough, sputum production, rectal temperature >38°C or <36.1°C, auscultatory findings consistent with pneumonia, leucocytosis (>109 white blood cells/litre or >15% bands), C reactive protein more than three times the upper limit of normal, or positive culture of blood or pleural fluid).16 Severe pneumonia was defined as pneumonia severity index class IV or V or fulfilling the American Thoracic Society criteria for severe community acquired pneumonia.17 18 We excluded patients who needed mechanical ventilation in an intensive care unit and those with cystic fibrosis; a history of colonisation with Gram negative bacteria due to structural damage to the respiratory tract; malfunction of the digestive tract; life expectancy of less than one month because of underlying disease (assessed independently by the doctor caring for the patient); infections other than pneumonia that needed antibiotic treatment; and severe immunosuppression (neutropenia (<0.5x109 neutrophils/litre) or a CD4 count <200/mm3).
Baseline, follow-up, and outcome measurements
Patients were followed up for 28 days. On admission (day 0), we performed physical examination, chest radiography, and blood sampling for arterial blood gases, haematological analysis, and biochemical markers. We recorded demographic and clinical data and initial intravenous treatment. During follow-up, in-hospital clinical data were recorded. We evaluated clinical stability after three days of intravenous treatment in both groups and evaluated preset discharge criteria (temperature <37.8°C, oxygen saturation >92%, normal blood pressure, heart rate <100/min, respiratory rate <25/min, absence of mental confusion, and ability to take oral drugs) daily thereafter. Patients discharged within 28 days were asked to return to the outpatient clinic 28 days after inclusion, where history, physical examination, blood chemistry analysis, and chest radiograph were performed.
We used questionnaires to measure the effect of early discharge on adverse events, compliance, and how the route of administration affected freedom of movement.
Treatment failure was defined as death, still in hospital at day 28 of the study, or clinical deterioration (increase in temperature after initial improvement or the need for mechanical ventilation, switch back to intravenous antibiotics, or readmission for pulmonary reinfection after discharge). Clinical cure was defined as discharged in good health without signs and symptoms of pneumonia and no treatment failure during follow-up.16
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We used Binax NOW-tests to detect Legionella pneumophila and Streptococcus pneumoniae antigens in urine. 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. We considered the following results indicative of infection: for M pneumoniae, a fourfold or greater increase in titre in paired sera or a single titre of 1:40 or greater19 (immune fluorescence agglutination, Serodia-MycoII, Fujirebio); for L pneumophila, a fourfold increase in the antibody titre to 1:128 or greater, or single titres of 1:256 or more20; and for C pneumoniae, detection of IgM above established values, seroconversion of IgG between acute and convalescence samples, high amounts of IgG in single titres, or a combination of these (enzyme linked immunosorbent assay, Savyon Diagnostics).
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Differences in continuous variables are shown as absolute differences with corresponding 95% confidence intervals. We used 2 statistics to compare dichotomous data. Differences in percentage cure rate are shown with 95% confidence intervals. We performed intention to treat analysis and per protocol analysis of patients who had received antibiotics for at least the duration dictated by the study protocol and who were clinically stable at day 3 after admission to hospital and eligible for an early switch from intravenous to oral antibiotics.
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In the control group, five patients did not receive intravenous antibiotics for all seven days because of phlebitis associated with intravenous treatment; none of them needed treatment for line related sepsis. Overall duration of antibiotic treatment was 10.1 days in the intervention group and 9.3 days in the control group (mean difference 0.8 days, 95% confidence interval 0.6 to 2.0).
Clinical outcome
In intention to treat analysis, treatment failed in 22 (17%) and 20 (15%) patients in the intervention group and the control group (2%, 10% to 7%; table 3). In the control group, nine (7%) patients were still in hospital on day 28, eight (6%) had deteriorated clinically, and eight (6%) had died. In the intervention group, six (5%) patients were still in hospital, six (5%) had deteriorated clinically, and five (4%) had died.
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Strengths and limitations
Our study provides evidence that an early switch from intravenous to oral antibiotics is safe in patients with severe community acquired pneumonia. In most previous studies, a non-randomised design was used,4 5 9 specific patient populations in military hospitals or moderately ill patients were studied,6 sample sizes were small,8 or the patients were switched relatively latefor example, after two to three consecutive days without fever.8 14
Our study had several limitations. The number of patients included was lower than calculated before the start of the study. Because results show small and non-significant differences in rates of treatment failure, however, it is highly unlikely that an early switch is more than 10% less effective. Moreover, mortality rates were even lower in the intervention group.
The effects of switching treatment may have been overestimated for two reasons. Firstly, in patients who were clinically stable at day 3, protocol dictated an intravenous to oral switch, but it is uncertain how many patients would have been switched in daily practice. With growing confidence in the safety of an early switch strategy this effect might decrease. Secondly, the minimum duration of intravenous treatment for the control group of seven days was also dictated by protocol, and shorter durations would have decreased the benefits of an early switch as long as failure rates remained the same.
In contrast, the effects of switching treatment could have been underestimated for two reasons. Firstly, the protocol did not cover discharge, and doctors' views on continued stay in hospital strongly influenced delayed discharge of clinically stable patients. With growing confidence, this phenomenon may decrease. Although clinical instability at discharge is associated with adverse clinical outcomes, clinical deterioration after reaching clinical stability is rare.21 In our study, only three (2%) patients were restarted on intravenous drugs after being switched to oral treatment. Secondly, the protocol only allowed patients to be switched to oral drugs when they were clinically stable on day 3. Patients who were clinically stable before day 3 could possibly be switched earlier, which could enhance the benefits of this strategy.
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Contributors: JJO coordinated the study, helped supervise enrolment and follow-up, analysed and interpreted the data, and wrote the paper. MJMB, EB, MMES, J-WJL, and AIMH designed the study protocol, and helped supervise enrolment and follow-up, interpret the data, and prepare the paper. EB and MJMB supervised the statistical analysis. J-WJL, WMNH, MHHK, JMP, PHThJS, and KK helped in enrolment and follow-up and helped prepare the final version of the paper. AIMH is guarantor.
Competing interests: None declared.
Ethical approval: Ethics committees of participating institutions.
The study was presented in part at the Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract O-1607, Washington DC, USA, 2004.
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