pneumonia: a multi center

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1 9 Costs and effects of early switch from IV to oral treatment in severe community-acquired pneumonia: a multi center randomized trial Submitted JJ Oosterheert, MJM Bonten, MME Schneider, E Buskens, JWJ Lammers, WMN Hustinx, MHH Kramer, J Prins, PTJ Slee, K Kaasjager, IM Hoepelman

2 Chapter 91 Abstract Background: Early conversion of intravenous (IV) to oral antibiotic therapy in the treatment of mild and moderate community-acquired pneumonia (CAP) is assumed to reduce costs of antibiotics and length of hospital stay (LOS). However, efficacy and economic data from randomized trials are lacking and this strategy has not been evaluated for patients hospitalized with severe CAP (SCAP) Methods: Patients hospitalized in non-icu wards with SCAP (Fine IV, V, or ATS-criteria for severe CAP) in 5 hospitals in the Netherlands were randomized to either 3 days IV therapy followed by 7 days oral antibiotics (intervention group) when clinically stable at day 3 (respiratory rate <25 /min, hemodynamically stable, resolution of fever, no mental confusion and able to take oral medication) or to 7 days IV antibiotics (control group). Choices of antibiotics reflected local treatment policies. Clinical cure and treatment costs both inside and outside the hospital were evaluated. Analyses were performed according to the intention-to-treat principle. Results: 302 patients were randomized (mean age 69.5 ± 14.0, mean Fine score ± 26.0), 150 in the intervention group and 152 in the control group. In the intervention group, 106 (71%) were eligible for the IV to oral antibiotic switch at day 3. Mortality at day 28 was 4 % in the intervention group and 6% in the control group (mean difference: -2%, 95% CI -8-3%). Clinical cure at day 28 was 83% in the intervention group and 85% in the control group (mean difference -1.7, 95% CI 7 10%). Duration of IV therapy and length of hospital stay were reduced in the intervention group, with mean differences of 3.4 days (95% CI days) and 1.9 days (95% CI days), respectively. Calculated cost-reductions with early switch therapy were 680 (95% CI: ) per patient (including 118 for antibiotics and 542 for hospital stay) Conclusions: Early conversion from IV to PO antibiotic in patients hospitalized with severe CAP is safe, decreased length of hospital stay by 2 days and reduced treatment costs by 680 (17%). 152

3 Chapter 9 Introduction Community-acquired pneumonia (CAP) is a common and potentially fatal infection with high healthcare costs. (1-3) Initial antibiotic treatment for patients needing hospitalization usually is administered intravenously to warrant optimal tissue levels. The duration of intravenous therapy is an important determinant of length of hospital stay (LOS) for these patients. (4) In conventional treatment approaches, intravenous therapy is continued until definite clinical cure has been achieved. A switch to treatment with oral antibiotics may allow early discharge, reduce drug costs and decrease risk of complications associated with the use of intravenous catheters. Possible disadvantages of this strategy are treatment failures due to low compliance or inadequate absorption of oral medication, resulting in relapses or reinfections, readmissions or deaths. Furthermore, early discharge may lead to increased burden for family-members or health-care professionals outside the hospital. The concept of early transition from intravenous to oral antibiotics in the treatment of CAP has been evaluated before, though only in patients with mild to moderately severe CAP, rarely in a randomised design and always without cost-effectiveness analyses. (4-14) For patients with severe CAP, effects of early switch approach on outcome, LOS, treatment costs and healthcare resource use have not been determined in randomized trials. In recent European and North- American treatment guidelines there are no rigid recommendations of the timing of switch to oral treatment in severe CAP, mainly because the only available evidence is coming from non-randomized studies among patients with mild episodes of CAP and low risks of complications. (15-19) Therefore, a multi-center randomized trial was conducted to evaluate the cost-effectiveness of an early intravenous to oral switch strategy compared to a 7 day intravenous treatment regimen in patients with severe CAP. Patients and Methods Study design A multi-center, randomized open label clinical trial was performed in 2 153

4 Chapter 91 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 3 rd 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, O 2 saturation > 90% or arterial po 2 >55mmHg, hemodynamically stable, > 1 o C decrease in temperature in case of fever, absent mental confusion and the ability to take medication orally (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 > 38 o C or < 36.1 o C, auscultatory findings consistent with pneumonia, leucocytosis (>10.000/mm 3, 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 10 9 / l) or a CD 4 count < 200 / mm 3 ) and needing mechanical ventilation in an intensive care unit were excluded. 154

5 Chapter 9 Severe CAP N=302 Excluded from analysis: 37 9 other diagnosis (m. wegener, urosepsis, tuberculosis, cholangitis, pulmonary embolism, sinusitis, nefritis, urinary tract infection, pneumocystis carinii pneumonia) 4 protocol violation 7 deaths before d3 6 admitted to intensive care before day 3 11 withdrawn consent 265 randomized 132 switch therapy protocol (3 days IV therapy) 133 standard care (7 days IV therapy) Figure 1 Flow of patients throughout the trial 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 hematologic 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 o C, saturation >92%, normal blood pressure, heart rate < 100/min, respiratory rate < 25/min, absence of mental confusion and ability to take medication orally) 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 healthcare 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 ( recorded at days 3, 10 and 28 of the 155

6 Chapter 91 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) 156

7 Chapter 9 Intervention Group n=150 Control Group n=152 Patient characteristics Men 102 (68%) 97 (64%) Age (y) 69.9 ± ± 14.2 Nursing home patients 7 (5%) 5 (3%) Fine score ± ± 25.8 Fine class II III IV V 11 (7%) 14 (9%) 93 (62%) 32 (21%) 7 (5%) 7 (11%) 111 (73%) 23 (15%) Leukocytes (109 / l ) 17.2 ± ± 8.5 C-Reactive protein (mg/l) ± ± Heart Rate (/min) ± ± 23.0 Respiratory Rate (/min) 26.5 ± ± 8.5 Temperature ( o C) 38.5 ± ±1.2 Oxygen saturation (%) 93.3 ± ± 8.3 Po2 (mm Hg) 68.4 ± ± 23.1 Presenting symptoms Myalgia 43 (30%) 44 (29%) Nausea 34 (23% 40 (27%) Diarhoea 14 (10%) 25 (17%) Headache 30 (21%) 39 (26%) Dyspnea 129 (87%) 131 (87%) Chest pain 54 (36%) 47 (31%) Sore throat 12 (8%) 16 (11%) Productive Cough 94 (63%) 90 (60%) Hemoptoe 16 (11%) 18 (12%) Confusion 34 (23%) 43 (29%) Fever 100 (67%) 93 (61%) Comorbidities Neoplasm Liver disease Heart failure Cerebrovascular disease Renal disease Initial therapy Amoxicillin ± clavulanic acid Cephalosporin (2 nd and 3 rd gen) Fluoroquinolone Amoxi ± ca + macrolide Ceph + macrolide Other Table 1 Patient baseline characteristics 32 (21%) 0 (0%) 20 (13%) 11 (7%) 16 (10%) 90 (60%) 28 (20 %) 0 (0%) 15 (10%) 4 (3%) 13 (9%) 35 (23%) 3 (2%) 17 (11%) 16 (11%) 46 (30%) 84 (55%) 31 (20%) 1 (1%) 11 (7%) 8 (5%) 17 (11%) 157

8 Chapter 91 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 was measured for diagnostic and therapeutic interventions, consultations of medical or paramedic specialists and antibiotic use. 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 hospitalisations. Costs of antibiotics prescribed were estimated using Dutch 2002 formulary cost-prices (26) Intervention group N=150 Control group N=152 S. pneumoniae 29 (19%) 47 (31%) S. aureus 7 (5%) 5 (3%) H. influenzae 3 (2%) 3 (2%) M. catharalis 5 (3%) 0 (0%) C. pneumoniae 8 (5%) 7 (5%) M. pneumoniae 2 (1%) 6 (4%) L. pneumophila 3 (2%) 6 (4%) Other 17 (11%) 24 (16%) Unknown cause 84 (56%) 71 (47%) Multiple pathogens 10 (7%) 13 (9%) Table 2 Identified micro-organisms 158

9 Chapter 9 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. (α=0.05, 2 sided; 1-β=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 α=0.05 and 1-β=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. Results Characteristics of the patients and treatment assignment Between July 2000 and March 2004, 302 consecutive patients were randomized: 150 were assigned to receive a standard course of 7 days intravenous treatment and 152 were randomized to the early switch group. (Figure 1) Slower than expected enrollment lead to the inclusion of less than the precalculated 500 patients. Characteristics of clinical symptoms, co-morbidities and severity of infection were comparable in both study groups. More than 80% of patients in the study population were in Fine class IV or V. Most patients received empirical monotherapy with either amoxicillin or amoxicillin with 159

10 Chapter 91 clavulanic acid (57.6 %) or a cephalosporin (20%). (table 1) Most frequently identified micro-organism was S. pneumoniae (25%, table 2). Atypical pathogens were detected in 11 % of patients. (table 2) Before day 3, 37 (12%) patients were excluded from analysis, leaving 132 patients for analysis in the intervention group and 133 in the control group. Reasons for exclusion before day 3 were rejection of the initial diagnosis of CAP with another diagnosis established (n=9), withdrawn consent (n=11), protocol violation (n=4), need of ICU admission for mechanical ventilation (n=6) or death (n=7). After 3 days of intravenous therapy, 108/132 (81%) patients in the intervention group were switched to oral therapy of whom 102 (94.4%) received amxocillin + clavulanic acid 625 mg q8h. In the control group, 5 patients did not receive intravenous antibiotics for the full length of 7 days due to phlebitis associated with intravenous treatment but these patients were included in the intention to treat analysis. Clincal outome Intervention N=150 Control N=152 Difference 95% CI Mortality after day 3 5 (4%) 8 (6%) 2% -3% - 8% Clinical cure 110 (83.3%) 113 (85.0) -1.7% -10% - 7% Clinical failure 22 (16.7%) 20 (15.0%) -1.7% -10% - 7% Clinical cure but still hospitalized 7 (5%) 6 (5%) 0% -4% - 6% Clinical deterioration 9 (6%) 8 (6%) 0,1% -5% - 6% Death 5 (3%) 8 (5%) 2% -3% - 8% Clinical deterioration+death 14 (9%) 16 (11%) 1% -1% - 6% LOS 9.6 ± ± days Duration of IV therapy 3.6 ± ± days Table 3 Clinical outcome Clinical outcome Twenty two (16.7%) and 20 (15.0%) patients had treatment failures in the control group and the intervention group respectively (mean 160

11 Chapter 9 difference -1.7%, 95% CI -10% to 7%) (Table 3). In the intervention group, 7 (5%) patients were still hospitalized at day 28, 9 (7%) had clinical deterioration and 5 (4%) died. In the control group, 6 (5%) patients were still hospitalized, 8 (6%) had clinical deterioration and 8 (6%) had died. Based on the number of patients included, a 15% lower effectiveness of early switch, compared to standard intravenous therapy could be excluded (α=0.05 and 1-β=90). Incremental costs IV vs SAT ( ) % 0-0,25-0,15-0, ,05 0,15 0, % Therapy failure at day 28 IV vs SAT Figure 2 Incremental costs vs. effects of sequential antibiotic therapy vs. intravenous therapy Note: 90% of data points below x-axis, i.e. 90% certainty with regard to cost savings 68% of data points to the right of the y-axis, i.e. 68% certainty with regard to marginal difference in efficacy Duration of intravenous therapy was significantly shorter in the intervention group (3.6 ± 1.5 vs. d 7.0 ± 2.0 d, mean difference 3.4 days 95% CI days) (Figure 3). Average time to meet the discharge criteria was 5.2 ± 2.9 days in the early switch group vs. 5.7 ± 3.1 days in the intravenous group. (mean difference: 0.47 days (95% CI: ) (table 3) Total lengths of hospital stay (LOS) were 9.6 ± 4.9 and 11.5 ± 5.0 days days for patients randomized to the early switch group and standard group, respectively (mean difference 1.9 days (95% CI: days). (table 3) In the subset 161

12 Chapter 91 of patients without co-morbidities those randomized to the early switch group had an average reduction of total LOS of 3.3 days (95% CI: ), while no reduction in total length of stay was observed among patients with co-morbidities. Patients meeting discharge criteria were not always discharged immediately for several reasons. Incomplete resolution of all clinical criteria of pneumonia or co-morbid illness, the lack of continued care after discharge and the physician s considerations were the main reasons for continued hospitalization. Overall, patients treated with oral or intravenous antibiotics experienced the same problems with regard to problems in mobility and other side effects. Quality of life of patients treated in both study groups showed no differences in the domains covered by SF-36. (Table 5) Patients on IV therapy Treatment group Iv therapy Switch group 14 Day of switch to oral therapy Figure 3 Fraction of patients on IV therapy in both treatment groups Economic evaluation Clinical efficacy in both treatment groups was considered equal. 162

13 Chapter 9 Accordingly, initially a cost-minimization analysis was performed. Volume Unit costs ( ) Resource use IVgroup Costs (use * unit cost) Resource use Switch group Costs (use * unit cost) Hospital days Diagnostic procedures Pleural punction Bronchoscopies CT-thorax Broncho Alveolar Lavage Chest X-ray in follow up Medication IV antibiotics PO antibiotics Extra antibiotics Consults Fysiotherapists Pulmonary physician Other specialist General Practicioner Other care givers Home nursing Fysiotherapist at home Homecare Family care Treatment failure associated costs Reinfection Readmission Switch back to IV Temperature raise Mechanical ventilation Total direct medical costs ± ± 2070 Table 4 Resource use and costs Average total costs were ± 2070 in the intervention group and ± 1991 in the control group. (mean difference: 681 (95% CI , 17% reduction). Hospitalization costs accounted for 85% of total costs and were 2736 vs in 163

14 Chapter 91 the intervention and control group, respectively (mean difference: 542, 17% reduction). Costs for antibiotic treatment were reduced from in the control group to in the intervention group. (mean difference: , 47% reduction) However, outof-hospital costs for treatment and patient care were higher in the intervention group. ( vs , mean difference: 26.20, 42%) (table 4). Intervention group Control group Avg SD SD difference 95% CI Day 3 physical functioning 22,7 24,5 19,4 23,1 3,4-3,4 10,2 social functioning 43,3 30,0 43,8 29,0-0,5-9,1 8,2 role emotional 39,3 44,1 41,6 47,2-2,3-15,6 11,0 mental health 63,8 24,5 62,6 19,7 1,2-5,1 7,5 vitality 33,9 19,0 32,7 20,6 1,2-4,4 6,9 pain 48,0 36,7 51,2 33,0-3,2-13,0 6,7 general health 43,9 24,6 40,8 22,8 3,1-3,7 9,8 health change 68,0 25,4 63,8 24,4 4,2-2,8 11,2 Day 10 physical functioning 29,4 25,3 25,3 23,8 4,2-3,5 11,8 social functioning 57,9 27,3 50,8 29,9 7,0-2,1 16,2 role emotional 48,5 46,0 48,7 47,0-0,1-15,1 14,8 mental health 70,6 20,6 69,0 19,8 1,6-4,6 7,7 vitality 41,2 22,0 40,1 21,9 1,1-5,6 7,8 pain 72,9 28,6 65,8 30,9 7,1-2,0 16,3 general health 44,0 23,4 42,8 22,8 1,2-5,9 8,2 health change 70,7 22,2 67,5 23,3 3,3-3,6 10,1 Day 28 physical functioning 40,8 31,1 34,8 29,8 5,9-3,7 15,6 social functioning 61,1 27,5 58,2 29,1 3,0-6,4 12,4 role emotional 53,5 46,7 56,0 47,6-2,5-17,6 12,5 mental health 71,9 21,3 70,8 21,0 1,1-5,6 7,9 vitality 48,3 22,3 49,2 21,4-1,0-8,0 6,0 pain 78,4 26,5 70,1 26,9 8,4 0,0 16,7 general health 44,2 25,8 40,9 22,2 3,4-4,4 11,1 health change 65,4 19,1 61,8 23,6 3,5-3,2 10,2 Table 5 Quality of life scores (SF 36) 164

15 Chapter 9 As can be observed in figure 2, bootstrap analysis showed that sequential antibiotic therapy reduced costs with a certainty level of 90%, i.e. 90% of the bootstrap replicates indicate cost savings for sequential antibiotic therapy. Similarly, figure 2 reveals that early switch might be associated with a marginal difference in effectiveness. (68% certain) The estimated incremental cost-effectiveness ratio of sequential antibiotic therapy as compared to standard care was per prevented therapy failure. This ratio indicates that is saved at the expense of one additional therapy failure. One could also think of this ratio as investments needed to prevent one therapy failure in case standard therapy would be maintained. Discussion Patients hospitalized with severe CAP can be managed safely and more efficiently by an early switch from IV to oral medication. Based on predefined criteria, 81% of patients could be switched to oral antibiotics on day 3. Early conversion to oral therapy reduced overall treatment costs by 17% ( 681), antibiotic costs by 47% ( ) and length of hospital stay by 1.91 days. Bootstrap analysis showed that needs to be invested to prevent one therapy failure. Patients without co-morbidity benefited most from an early conversion to oral antibiotics. This is the first randomized study evaluating costs and effects, both inside and outside the hospital of early switch to oral therapy in patients admitted because of severe community-acquired pneumonia. Our findings appear, at least to some extent, to be generalizable, as the average length of stay in the control group, etiology and mortality rate of 7% are very similar to other cohorts of patients with severe CAP. (8;14) With an estimated annual number of hospitalisations for CAP of in the Netherlands with about 40% of them being severe, nationwide implementation of an early IV-oral switch strategy would lead to a cost-reduction of ,- in our country. The results from this study are in line with other reports that suggested the cost-benefit of early IV-oral switch programs in patients with nonsevere CAP. In comparison to these studies, however, the current study does provide sound evidence. Most of the previous studies had a non-randomized design (4;5;9), were restricted to specific patient 165

16 Chapter 91 populations of veterans or moderately ill patients (6;28), had small sample sizes, (8) or patients were switched late in the course of the disease, e.g. after 2-3 consecutive days without fever. (8;14) Moreover, effects on costs made outside the hospital have not been evaluated in any of the previous studies. Our study also has limitations. The number of patients included was lower than calculated prior to study start. Nevertheless, we feel that because the results show only minimal and non-significant differences in therapy failure rates, a more than 10% lower effectiveness of early switch is highly unlikely. Moreover, mortality-rates were even lower in the intervention group. Thus, unfeasibly high patient numbers would be needed to demonstrate a possible mortality disadvantage for patients treated with early switch. Furthermore, the delicate balance between mimicking real-life situations and strict protocol adherence can easily be disturbed in randomized trials in which treatment processes are evaluated. The effects of switch therapy may, therefore, have been overestimated for two reasons. First, in case of clinical stability at day 3, protocol dictated a switch to oral antibiotic therapy. It remains uncertain how many patients would have been switched if the decision had been left to the discretion of the treating physician. With growing confidence in the safety of an early switch strategy this effect might well decrease, but initially, some reluctance of physicians may be anticipated. Secondly, the minimal length of IV treatment for the control group of 7 days was also dictated by protocol. Obviously, shorter lengths of intravenous treatment in the control group would have decreased the benefits of early switch, provided that failure rates would have remained the same. However, controlled trials that specifically have addressed the question how long pulmonary infections should be treated are lacking and the optimal duration of treatment of SCAP remains unknown. On the other hand, the effects of switch therapy could also have been underestimated for two reasons. First, discharge was not protocolized and the physician s considerations for continued hospitalization were important reasons for delayed discharge of clinically stable patients. Again, with growing confidence in the concept of early switch therapy, this phenomenon may decrease over time, leading to further costssavings. Although clinical instability on discharge is associated 166

17 Chapter 9 with adverse clinical outcomes, clinical deterioration after reaching clinical stability is rare. (29) In our study, only 3 (2%) patients were restarted on IV therapy after being switched to oral therapy. Yet, optimal standards for discharge remain to be established. Second, by protocol, a switch to oral therapy was only allowed when patients were clinically stable on day 3. Possibly, patients that are clinically stable before day 3 can be switched earlier, which could further enhance the benefits of this strategy. Based on the results of this trial and the evidence mounting from previous non-randomized studies, early conversion to oral antibiotics should be implemented in clinical practice not only for patients with mild or moderately severe episodes of CAP, but also for those with severe CAP that do not need treatment in the intensive care unit. 167

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