Short Versus Long Antibiotic Course for Pleural Infection Management (SLIM Trial)

Study Overview
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Brief Summary
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Infection of the pleural space is serious condition that requires hospitalization, invasive interventions and long courses of antibiotics[1]. Treatment of pleural infection requires long hospital admission with a median of 19 days[2] and medical treatments fails requiring surgical intervention in up to 30% of cases[3]. The mortality from pleural infection is around 10% at 3 months[4]. Besides drainage of the infected fluid, antibiotics are a core component of management of pleural infection[5] and are typically given intravenously in the first few days of treatment until the condition is stabilized at which stage patients are shifted to oral antibiotics of equivalent spectrum. In almost half of the cases of pleural infection, the choice of antibiotics is entirely empirical due to low yield of microbiological tests on pleural fluid in these cases[6]. International guidelines cite a minimum length of antibiotic course of pleural infection of four weeks[5,7] with antibiotic courses typically lasting six weeks[8]. However, these recommendations are based on expert opinion with no robust evidence to support such durations. The RAPID (renal function, age, purulence, infection source and dietary factors) score has recently been validated as a robust tool to predict 3-month mortality of patients with pleural infection based on demographic and laboratory data (table 1)[4]. A low score (0-2) is associated with 2-3% mortality, medium score (3-4) 9% mortality and high score (5-7) 30% mortality at three months[9]. The utility for this score in clinical management is yet to be determined and this study will attempt using this score to stratify lengths of antibiotic treatment based on proposed risk of adverse outcomes as stipulated by the RAPID score. The aim of this study is to investigate the feasibility and safety of prescribing shorter courses of antibiotics (2-3 weeks) versus the standard longer courses (4-6 weeks) in medically-treated patients with pleural infection at lower risk of mortality (RAPID score 0-4) who can be safely discharged home within 14 days of hospitalization and how this impacts success of medical treatment.

Detailed Description
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Infection of the pleural space is serious condition that requires hospitalization, invasive interventions and long courses of antibiotics. Treatment of pleural infection requires long hospital admission with a median of 19 days and medical treatments fails requiring surgical intervention in up to 30% of cases. The mortality from pleural infection is around 10% at 3 months. Besides drainage of the infected fluid, antibiotics are a core component of management of pleural infection and are typically given intravenously in the first few days of treatment until the condition is stabilized at which stage patients are shifted to oral antibiotics of equivalent spectrum. In almost half of the cases of pleural infection, the choice of antibiotics is entirely empirical due to low yield of microbiological tests on pleural fluid in these cases. International guidelines cite a minimum length of antibiotic course of pleural infection of four weeks with antibiotic courses typically lasting six weeks[8]. However, these recommendations are based on expert opinion with no robust evidence to support such durations. A recent trial compared a two-week versus a three-week antibiotic course for parapneumonic pleural infections. The trial that concluded prematurely due to inability to recruit to target sample size and found that the two regimens were equivalent in terms of risk of failure of medical treatment. Besides being an underpowered study, the results are only applicable to parapneumonic effusions but not primary pleural infections. The RAPID score has recently been validated as a robust tool to predict 3-month mortality of patients with pleural infection based on demographic and laboratory data. A low score (0-2) is associated with 2-3% mortality, medium score (3-4) 9% mortality and high score (5-7) 30% mortality at three months. The utility for this score in clinical management is yet to be determined and this study will attempt using this score to stratify lengths of antibiotic treatment based on proposed risk of adverse outcomes as stipulated by the RAPID score. A shorter antibiotic course that is as effective as the standard long course is desirable given the common occurrence of side effects with antibiotic treatment. The presence of a robust predictive score of outcome seems as an attractive tool to help stratify patients who can be safely treated with shorter antibiotic courses. The aim of this study is to investigate the feasibility and safety of prescribing shorter courses of antibiotics (2-3 weeks) versus the standard longer courses (4-6 weeks) in medically-treated patients with pleural infection at lower risk of mortality (RAPID score 0-4) who can be safely discharged home within 14 days of hospitalization and how this impacts success of medical treatment.

Official Title
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Short Versus Long Antibiotic Course for Pleural Infection Management (SLIM Trial): a Randomized Controlled Open Label Trial

Conditions
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Pleural Infection

Intervention / Treatment
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* Other: Short course (2-3 weeks) of antibiotics
* Other: Standard (long course) of antibiotics


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (>18 years old) Willing to provide informed consent Admitted to hospital for treatment of pleural infection (both parapneumonic and primary pleural infections included). Pleural infection will be defined by the presence of one of the following: the presence of pus in the pleural space; positive pleural fluid gram stain or culture; or pleural fluid pH < 7.2 or pleural fluid glucose < 40 mg/dL in the setting of acute respiratory infection. RAPID low or intermediate score (0-4) Fit for discharge within 14th day of admission Exclusion Criteria: Failure of medical treatment within 14 days of admission and need for surgical referral Need for hospital admission beyond 14 days due to medical reasons Admission to recurrent ipsilateral pleural infection within the last three months RAPID high score (5 or more) Pleural infection not amenable to drainage at time of diagnosis and therefore upfront decision to treat with prolonged antibiotics Residual pleural collection (despite attempted drainage) that the managing clinician indicated is for prolonged oral suppressive therapy (i.e. six weeks of oral antibiotics).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Short course<br>Antibiotic course of 2-3 weeks overall duration for treating pleural infection | Other: Short course (2-3 weeks) of antibiotics<br>* Shorter course of antibiotic than standard care of 4-6 weeks<br>|
| Active Comparator: Long course<br>Antibiotic course of 4-6 weeks overall duration for treating pleural infection | Other: Standard (long course) of antibiotics<br>* 4-6 weeks of antibiotics<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with failure of medical treatment | Incidence of failure of treatment as judged by trial clinician requiring further antibiotics and/or tube drainage and/or surgical intervention by six weeks post initial admission. Failure will be determined based on the one or more of the following parameter: clinical (recurrence of symptoms), biochemical (worsening of WCC [by 2000/mm3] or CRP [by > 20%] from discharge values) and radiological (chest X-ray +/- TUS evidence of increasing or new pleural collection). | Outcome assessed at six weeks post diagnosis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of antibiotic treatment in days | Total length of antibiotic treatment (in days) in the study arms | Outcome assessed at six weeks post diagnosis | 
| Number of participants with chest X ray worsening at 6 weeks | Number of participants with worsening in the 6-week chest X-ray as compared to discharge chest X-ray in the study arms. Chest X-ray pairs (discharge vs 6-week) will be read by a respiratory physician blinded to treatment allocation who will judge whether there is worsening (versus stability or improvement) | Outcome assessed at six weeks post diagnosis | 
| Time to return to normal daily activities in days | Time (in days) to return to normal daily activities in participants of the study arms | Outcome assessed at six weeks post diagnosis | 
| Number of participants requiring readmission within 30 days from discharge | Readmission within 30 days from discharge | 30 days from discharge |