Short Versus Long Antibiotic Course for Pleural Infection Management (SLIM Trial): a Randomized Controlled Open Label Trial
Phase: NA
Conditions: Pleural Infection
Sponsor: Alexandria University

 
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SLIM trial_V1.3_13.10.2020 
Title: Short versus Long antibiotic course for pleural Infection Management (SLIM trial): 
protocol of a randomized controlled open label trial  
Version and date: Version 1.3 – 13th Oct 2020 
Sponsor:  
Alexandria University Faculty of Medicine and Alexandria University Hospitals 
Champlion Street, Azarita, Alexandria, Egypt 
Study personnel: 
Principal investigator 
Dr Maged Hassan 
Lecturer of Chest Diseases 
Alexandria University Faculty of Medicine 
Study co-investigator 
Dr Ahmed S Sadaka 
Lecturer of Chest Diseases 
Alexandria University Faculty of Medicine 
 
Ethics approval: the protocol of the study was approved by the Alexandria University 
Faculty of Medicine Ethics Committee (ref 0304785) 
 
Registration: pending (protocol to be submitted to an open-access registry) 
 
 
 

 
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SLIM trial_V1.3_13.10.2020 
Introduction 
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. 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[9]. 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 (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[10]. 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.  
 
 

 
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SLIM trial_V1.3_13.10.2020 
Table 1: Components of the RAPID score[4] 
 
Parameter 
Value 
Score 
Renal function 
(blood urea nitrogen) 
<14 mg/dL 
14-23 mg/dL 
>23 mg/dL 
0 
1 
2 
Age 
< 50 years 
50 – 70 years 
> 70 years 
0 
1 
2 
Purulence of pleural fluid 
Purulent 
Non-purulent 
0 
1 
Infection Source 
Community-acquired 
Hospital-acquired 
0 
1 
Dietary factors 
(serum albumin) 
>2.7 g/dL 
<2.7 g/dL 
0 
1 
 
 
 

 
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SLIM trial_V1.3_13.10.2020 
Methods 
This protocol is written in accordance with the guidance of the Standard Protocol Items: 
Recommendations for Interventional Trials (SPIRIT)[11].  
Trial design and study setting 
SLIM is an open label randomized controlled clinical trial that will recruit patients admitted 
with pleural infection to a University Hospital. Consecutive patients admitted with pleural 
infection will be invited to take part in an observational study (the Pleural Infection Cohort 
Study) and consenting to SLIM will occur at the same time of consenting to the cohort study. 
This design is termed trials within cohorts.[12] 
Inclusion of other hospitals as recruiting sites is not planned but will be considered if 
recruitment is deemed slow. 
Eligibility criteria 
Inclusion 
- 
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:  
a) the presence of pus in the pleural space;  
b) positive pleural fluid gram stain or culture; or  
c) 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: 
- 
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). 
Patients will only be randomised to one of the study arms of SLIM if found eligible, and for 
ineligible patients, their data collection will follow the protocol of the cohort study with no 
change in their care. 
Interventions 

 
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SLIM trial_V1.3_13.10.2020 
The study intervention is the modification of the length of the antibiotic course at the point 
of discharge from hospital. All other aspects of care will be carried out according to 
recognised clinical standards. The choice of the antibiotics will rely on results of 
microbiological studies, and if non-informative will follow international guidelines for 
treating pleural infection and local patterns of microbiology[1,6]. A separate document will be 
prepared to provide guidance for outpatient antibiotics in the absence of culture results. 
In the active arm, patients who are ready for discharge will be prescribed an oral antibiotic 
course for a minimum period of 7 days and a maximum period that makes the overall length 
of antibiotic administration 21 days (total number of antibiotic days 14-21 days). In the 
control arm, at the point of discharge, patients will be prescribed an oral antibiotic course 
for a minimum of 14 days and a maximum period that makes the overall length of antibiotic 
administration 42 days (total number of antibiotic days 28-42 days). Treatment duration 
allocation will be open label. 
Baseline data 
Besides patient demographics and infection source, the following data will be collected at 
the points of admission and discharge as appropriate: 
- Date of admission 
- Vital signs 
-Blood investigations (minimum: urea and electrolytes, full blood count, C-reactive protein, 
and serum albumin) 
- Pleural fluid parameters (macroscopic appearance, biochemistry, cultures (blood and 
pleural fluid), pH) 
- Chest X-ray at baseline and at discharge 
- Thoracic ultrasound (TUS) images at baseline (effusion size and extent of septations) 
- Chest computed tomography images at baseline (presence of pleural split sign, lung 
consolidation or microbubbles) 
- Treatments received as inpatient (chest tube size and time till removal, volume of effusion 
drained, intravenous and oral antibiotics given) 
- Total length of hospital admission 
 
Participant timeline: 
Participants admitted to hospital for treatment of pleural infection will be approached to 
take part in both the observational and interventional studies. For patients who sign an 
informed consent to both, and upon confirmation of their eligibility to the trial, they will be 
randomised to a study arm once a decision is made about fitness for discharge from hospital 
which is within 14 days from admission.  

 
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SLIM trial_V1.3_13.10.2020 
Upon discharge, two face-to-face follow up visits will be planned to coincide with clinical 
practice of following up patients post admission for pleural infection. 
a- Two weeks post discharge (+/- 7 days) 
A clinical review to ascertain adherence to treatment and ensure no symptoms of 
recurrence are present (fever, night sweats, haemoptysis or purulent expectoration, 
chest pain). Any adverse events related to antibiotic treatment will be recorded. During 
this visit thoracic US (TUS) +/- chest X-ray will be performed. If a participant is not willing 
or able to attend in person, a remote review will be performed (via telephone). 
b- Six weeks from initial admission (+/- 7 days) 
During this visit the following will be performed: 
Clinical review of symptoms (relating to infection recurrence or adverse events due to 
antibiotic treatment) 
Check adherence to study treatment. Participants will be asked to bring back the used 
empty antibiotic packs.  
Blood to be sent for white cell count and C-reactive protein 
Chest X-ray 
c- Unscheduled Visits - Besides the two planned visits, participants will be allowed to 
contact the study team between the time points if they develop any of the 
symptoms of recurrence mentioned above. A study clinician will determine whether 
a clinical review is required and will arrange accordingly 
 
Outcomes 
Primary outcome: 
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). 
Secondary outcomes: 
- 
Total length of antibiotic treatment (in days) in the study arms 
- 
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) 
- 
Time (in days) to return to normal daily activities in participants of the study arms 

 
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SLIM trial_V1.3_13.10.2020 
- 
Readmission within 30 days from discharge 
Sample Size: 
This is a feasibility study and therefore no formal power calculation has been made. A 
sample size of 50 participants (25 per arm) was chosen by the study team simulating sizes 
chosen by trials examining outcomes in pleural infection in adult[8] and paediatric[13] 
populations.  
 
Randomisation and treatment allocation 
Patients will be randomised 1:1 to the active or the control arm. The permuted block 
randomisation method will be used and the sequence will be generated using the online 
platform Sealedenvelop.com.  At the point of randomisation, a member of the study team 
will log into the website and obtain the treatment allocation after confirmation of eligibility 
criteria. Being an open label study, allocation will be known to the patient and the study 
team performing assessments of study visits.  
Data management 
Data will be collected directly into paper case report forms that will bear the study number 
of the participants but no other identifiable information. No data sources (e.g. lab results, 
etc.) will be stored within the trial files to maintain confidentiality of patients’ medical data. 
A screening log will be kept electronically on a spreadsheet that is password protected on a 
secure computer. This log will have the name and demographics of patients approached for 
the study as well as study number and treatment allocation for randomised patients. 
At completion of study assessments for the last recruited patients, data will be transferred 
from paper CRFs to electronic form (spreadsheets) to allow statistical analysis. These 
spreadsheets will be stored securely after trial conclusion with the principal investigator and 
will be accessible to other members of the study team. Request to access study data by 
other teams will be expected via email and access will be granted by the principal 
investigator if the request is deemed reasonable. 
Statistics 
A per protocol analysis will be carried out for all outcomes. Given that this is a feasibility 
study, no replacement for participants lost to follow up will be attempted. Continuous 
variables will be compared between the study arms using t-test or Mann Whitney test 
according to the normality of the study data. Categorical variables (including primary 
outcome measure) will be compared using the Chi squared test or Fisher exact test as 
appropriate. 
Safety monitoring reporting 
The study intervention (shorter antibiotic course) is envisaged to cause less adverse events 
due to less exposure to antibiotics. All treatment-related adverse events will be collected 

 
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SLIM trial_V1.3_13.10.2020 
routinely as part of the study. As a safety measure, an interim analysis will be planned when 
half the recruitment target is reached to ensure that the study intervention does not impose 
unacceptable risks to subjects randomised to this arm. 
Ethics and dissemination 
Approval will be sought from the Ethics Committee of Alexandria Faculty of Medicine and 
the protocol will be registered in an open-access trials database before the recruitment of 
the first patient. All participants will be required to sign an informed consent form prior to 
enrolment in the study. A scientific report with the results of the study will be prepared 
once the recruitment finishes.   
 

 
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SLIM trial_V1.3_13.10.2020 
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