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

• ClinicalTrials.gov Identifier: NCT04615286
• Recruitment Status: Completed
• First Posted: November 4, 2020
• Last Update Posted: December 21, 2021
• Sponsor: Alexandria University
• Information provided by (Responsible Party): Alexandria University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Pleural Infection	Other: Short course (2-3 weeks) of antibiotics; Other: Standard (long course) of antibiotics	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Short Versus Long Antibiotic Course for Pleural Infection Management (SLIM Trial): a Randomized Controlled Open Label Trial
• Actual Study Start Date: September 28, 2020
• Actual Primary Completion Date: November 10, 2021
• Actual Study Completion Date: December 6, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Short course; Antibiotic course of 2-3 weeks overall duration for treating pleural infection	Other: Short course (2-3 weeks) of antibiotics; Shorter course of antibiotic than standard care of 4-6 weeks
Active Comparator: Long course; Antibiotic course of 4-6 weeks overall duration for treating pleural infection	Other: Standard (long course) of antibiotics; 4-6 weeks of antibiotics

Outcome Measures

Primary Outcome Measures :

1. Number of participants with failure of medical treatment [ Time Frame: Outcome assessed at six weeks post diagnosis ]
   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 Outcome Measures :

1. Length of antibiotic treatment in days [ Time Frame: Outcome assessed at six weeks post diagnosis ]
   Total length of antibiotic treatment (in days) in the study arms
2. Number of participants with chest X ray worsening at 6 weeks [ Time Frame: Outcome assessed at six weeks post diagnosis ]
   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)
3. Time to return to normal daily activities in days [ Time Frame: Outcome assessed at six weeks post diagnosis ]
   Time (in days) to return to normal daily activities in participants of the study arms
4. Number of participants requiring readmission within 30 days from discharge [ Time Frame: 30 days from discharge ]
   Readmission within 30 days from discharge

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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:

  1. the presence of pus in the pleural space;
  2. positive pleural fluid gram stain or culture; or
  3. 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).

Contacts and Locations

Locations

Egypt

Alexandria University Faculty of Medicine

Alexandria, Egypt

Sponsors and Collaborators

Alexandria University

Investigators

• Principal Investigator: Maged Hassan, PhD; Alexandria University Faculty of Medicine

  Study Documents (Full-Text)

Documents provided by Alexandria University:

Study Protocol  [PDF] October 13, 2020

More Information

Publications:

Davies HE, Davies RJ, Davies CW; BTS Pleural Disease Guideline Group. Management of pleural infection in adults: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010 Aug;65 Suppl 2:ii41-53. doi: 10.1136/thx.2010.137000. Review.

Cargill TN, Hassan M, Corcoran JP, Harriss E, Asciak R, Mercer RM, McCracken DJ, Bedawi EO, Rahman NM. A systematic review of comorbidities and outcomes of adult patients with pleural infection. Eur Respir J. 2019 Oct 1;54(3). pii: 1900541. doi: 10.1183/13993003.00541-2019. Print 2019 Sep.

Maskell NA, Lee YC, Gleeson FV, Hedley EL, Pengelly G, Davies RJ. Randomized trials describing lung inflammation after pleurodesis with talc of varying particle size. Am J Respir Crit Care Med. 2004 Aug 15;170(4):377-82. Epub 2004 May 13.

Corcoran JP, Psallidas I, Gerry S, Piccolo F, Koegelenberg CF, Saba T, Daneshvar C, Fairbairn I, Heinink R, West A, Stanton AE, Holme J, Kastelik JA, Steer H, Downer NJ, Haris M, Baker EH, Everett CF, Pepperell J, Bewick T, Yarmus L, Maldonado F, Khan B, Hart-Thomas A, Hands G, Warwick G, De Fonseka D, Hassan M, Munavvar M, Guhan A, Shahidi M, Pogson Z, Dowson L, Popowicz ND, Saba J, Ward NR, Hallifax RJ, Dobson M, Shaw R, Hedley EL, Sabia A, Robinson B, Collins GS, Davies HE, Yu LM, Miller RF, Maskell NA, Rahman NM. Prospective validation of the RAPID clinical risk prediction score in adult patients with pleural infection: the PILOT study. Eur Respir J. 2020 Nov 26;56(5). pii: 2000130. doi: 10.1183/13993003.00130-2020. Print 2020 Nov. Erratum in: Eur Respir J. 2020 Dec 17;56(6):.

Bedawi EO, Hassan M, Rahman NM. Recent developments in the management of pleural infection: A comprehensive review. Clin Respir J. 2018 Aug;12(8):2309-2320. doi: 10.1111/crj.12941. Review.

Hassan M, Cargill T, Harriss E, Asciak R, Mercer RM, Bedawi EO, McCracken DJ, Psallidas I, Corcoran JP, Rahman NM. The microbiology of pleural infection in adults: a systematic review. Eur Respir J. 2019 Oct 1;54(3). pii: 1900542. doi: 10.1183/13993003.00542-2019. Print 2019 Sep.

Bhatnagar R, Maskell N. The modern diagnosis and management of pleural effusions. BMJ. 2015 Sep 8;351:h4520. doi: 10.1136/bmj.h4520. Review.

Hooper CE, Edey AJ, Wallis A, Clive AO, Morley A, White P, Medford AR, Harvey JE, Darby M, Zahan-Evans N, Maskell NA. Pleural irrigation trial (PIT): a randomised controlled trial of pleural irrigation with normal saline versus standard care in patients with pleural infection. Eur Respir J. 2015 Aug;46(2):456-63. doi: 10.1183/09031936.00147214. Epub 2015 May 28.

Rahman NM, Kahan BC, Miller RF, Gleeson FV, Nunn AJ, Maskell NA. A clinical score (RAPID) to identify those at risk for poor outcome at presentation in patients with pleural infection. Chest. 2014 Apr;145(4):848-855. doi: 10.1378/chest.13-1558.

• Responsible Party: Alexandria University
• ClinicalTrials.gov Identifier: NCT04615286
• Other Study ID Numbers: 3/24/11/10/2020
• First Posted: November 4, 2020
• Last Update Posted: December 21, 2021
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The spreadsheets with de-identified patient information 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 persons outside the study teams will be expected via email and access will be granted by the principal investigator if the request is deemed reasonable.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: 5 years after study completion
• Access Criteria: The data that support the findings of this study will be available on request from the corresponding author upon publishing the manuscript with the main results.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Infections; Communicable Diseases; Disease Attributes; Pathologic Processes; Anti-Bacterial Agents; Antibiotics, Antitubercular; Anti-Infective Agents; Antitubercular Agents