Individualised, short-course antibiotic treatment versus usual long-course treatment for ventilator-associated pneumonia (REGARD-VAP): a multicentre, individually randomised, open-label, non-inferiority trial.

BACKGROUND: Ventilator-associated pneumonia (VAP) is associated with increased mortality, prolonged hospitalisation, excessive antibiotic use and, consequently, increased antimicrobial resistance. In this phase 4, randomised trial, we aimed to establish whether a pragmatic, individualised, short-course antibiotic treatment strategy for VAP was non-inferior to usual care. METHODS: We did an individually randomised, open-label, hierarchical non-inferiority-superiority trial in 39 intensive care units in six hospitals in Nepal, Singapore, and Thailand. We enrolled adults (age ≥18 years) who met the US Centers for Disease Control and Prevention National Healthcare Safety Network criteria for VAP, had been mechanically ventilated for 48 h or longer, and were administered culture-directed antibiotics. In culture-negative cases, empirical antibiotic choices were made depending on local hospital antibiograms reported by the respective microbiology laboratories or prevailing local guidelines. Participants were assessed until fever resolution for 48 h and haemodynamic stability, then randomly assigned (1:1) to individualised short-course treatment (≤7 days and as short as 3-5 days) or usual care (≥8 days, with precise durations determined by the primary clinicians) via permuted blocks of variable sizes (8, 10, and 12), stratified by study site. Independent assessors for recurrent pneumonia and participants were masked to treatment allocation, but clinicians were not. The primary outcome was a 60-day composite endpoint of death or pneumonia recurrence. The non-inferiority margin was prespecified at 12% and had to be met by analyses based on both intention-to-treat (all study participants who were randomised) and per-protocol populations (all randomised study participants who fulfilled the eligibility criteria, met fitness criteria for antibiotic discontinuation, and who received antibiotics for the duration specified by their allocation group). This study is registered with ClinicalTrials.gov, number NCT03382548. FINDINGS: Between May 25, 2018, and Dec 16, 2022, 461 patients were enrolled and randomly assigned to the short-course treatment group (n=232) or the usual care group (n=229). Median age was 64 years (IQR 51-74) and 181 (39%) participants were female. 460 were included in the intention-to-treat analysis after excluding one withdrawal (231 in the short-course group and 229 in the usual care group); 435 participants received the allocated treatment and fulfilled eligibility criteria, and were included in the per-protocol population. Median antibiotic treatment duration for the index episodes of VAP was 6 days (IQR 5-7) in the short-course group and 14 days (10-21) in the usual care group. 95 (41%) of 231 participants in the short-course group met the primary outcome, compared with 100 (44%) of 229 in the usual care group (risk difference -3% [one-sided 95% CI -∞ to 5%]). Results were similar in the per-protocol population. Non-inferiority of short-course antibiotic treatment was met in the analyses, although superiority compared with usual care was not established. In the per-protocol population, antibiotic side-effects occurred in 86 (38%) of 224 in the usual care group and 17 (8%) of 211 in the short-course group (risk difference -31% [95% CI -37 to -25%; p<0·0001]). INTERPRETATION: In this study of adults with VAP, individualised shortened antibiotic duration guided by clinical response was non-inferior to longer treatment durations in terms of 60-day mortality and pneumonia recurrence, and associated with substantially reduced antibiotic use and side-effects. Individualised, short-course antibiotic treatment for VAP could help to reduce the burden of side-effects and the risk of antibiotic resistance in high-resource and resource-limited settings. FUNDING: UK Medical Research Council; Singapore National Medical Research Council. TRANSLATIONS: For the Thai and Nepali translations of the abstract see Supplementary Materials section.

Reducing antibiotic treatment duration for ventilator-associated pneumonia (REGARD-VAP): a trial protocol for a randomised clinical trial.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in intensive care units (ICUs). Using short-course antibiotics to treat VAP caused by Gram-negative non-fermenting bacteria has been reported to be associated with excess pneumonia recurrences. The "REducinG Antibiotic tReatment Duration for Ventilator-Associated Pneumonia" (REGARD-VAP) trial aims to provide evidence for using a set of reproducible clinical criteria to shorten antibiotic duration for individualised treatment duration of VAP. METHODS AND ANALYSIS: This is a randomised controlled hierarchical non-inferiority-superiority trial being conducted in ICUs across Nepal, Thailand and Singapore. The primary outcome is a composite endpoint of death and pneumonia recurrence at day 60. Secondary outcomes include ventilator-associated events, multidrug-resistant organism infection or colonisation, total duration of antibiotic exposure, mechanical ventilation and hospitalisation. Adult patients who satisfy the US Centers for Disease Control and Prevention National Healthcare Safety Network VAP diagnostic criteria are enrolled. Participants are assessed daily until fever subsides for >48 hours and have stable blood pressure, then randomised to a short duration treatment strategy or a standard-of-care duration arm. Antibiotics may be stopped as early as day 3 if respiratory cultures are negative, and day 5 if respiratory cultures are positive in the short-course arm. Participants receiving standard-of-care will receive antibiotics for at least 8 days. Study participants are followed for 60 days after enrolment. An estimated 460 patients will be required to achieve 80% power to determine non-inferiority with a margin of 12%. All outcomes are compared by absolute risk differences. The conclusion of non-inferiority, and subsequently superiority, will be based on unadjusted and adjusted analyses in both the intention-to-treat and per-protocol populations. ETHICS AND DISSEMINATION: The study has received approvals from the Oxford Tropical Research Ethics Committee and the respective study sites. Results will be disseminated to patients, their caregivers, physicians, the funders, the critical care societies and other researchers. TRIAL REGISTRATION NUMBER: NCT03382548.

Effectiveness of a sepsis programme in a resource-limited setting: a retrospective analysis of data of a prospective observational study (Ubon-sepsis).

OBJECTIVE: To evaluate the effectiveness of a Sepsis Fast Track (SFT) programme initiated at a regional referral hospital in Thailand in January 2015. DESIGN: A retrospective analysis using the data of a prospective observational study (Ubon-sepsis) from March 2013 to January 2017. SETTING: General medical wards and medical intensive care units (ICUs) of a study hospital. PARTICIPANTS: Patients with community-acquired sepsis observed under the Ubon-sepsis cohort. Sepsis was defined as modified Sequential Organ Failure Assessment (SOFA) Score ≥2. MAIN EXPOSURE: The SFT programme was a protocol to identify and initiate sepsis care on hospital admission, implemented at the study hospital in 2015. Patients in the SFT programme were admitted directly to the ICUs when available. The non-exposed group comprised of patients who received standard of care. MAIN OUTCOME: The primary outcome was 28-day mortality. The secondary outcomes were measured sepsis management interventions. RESULTS: Of 3806 sepsis patients, 903 (24%) were detected and enrolled in the SFT programme of the study hospital (SFT group) and 2903 received standard of care (non-exposed group). Patients in the SFT group had more organ dysfunction, were more likely to receive measured sepsis management and to be admitted directly to the ICU (19% vs 4%). Patients in the SFT group were more likely to survive (adjusted HR 0.72, 95% CI 0.58 to 0.88, p=0.001) adjusted for admission year, gender, age, comorbidities, modified SOFA Score and direct admission to the ICUs. CONCLUSIONS: The SFT programme is associated with improved sepsis care and lower risk of death in sepsis patients in rural Thailand, where some critical care resources are limited. The survival benefit is observed even when all patients enrolled in the programme could not be admitted directly into the ICUs. TRIAL REGISTRATION NUMBER: NCT02217592.

Early management of sepsis in medical patients in rural Thailand: a single-center prospective observational study.

BACKGROUND: The burden of sepsis is highest in low- and middle-income countries, though the management of sepsis in these settings is poorly characterized. Therefore, the objective of this study was to assess the early management of sepsis in Thailand. METHODS: Pre-planned analysis of the Ubon-sepsis study, a single-center prospective cohort study of Thai adults admitted to the general medical wards and medical intensive care units (ICUs) of a regional referral hospital with community-acquired sepsis. RESULTS: Between March 2013 and January 2017, 3,716 patients with sepsis were enrolled. The median age was 59 years (IQR 44-72, range 18-101), 58% were male, and 88% were transferred from other hospitals. Eighty-six percent of patients (N = 3,206) were evaluated in the Emergency Department (ED), where median length of stay was less than 1 hour. Within the first day of admission, most patients (83%, N = 3,089) were admitted to the general medical wards, while 17% were admitted to the ICUs. Patients admitted to the ICUs had similar age, gender, and comorbidities, but had more organ dysfunction and were more likely to receive measured sepsis management interventions. Overall, 84% (N = 3,136) had blood cultures ordered and 89% (N = 3,308) received antibiotics within the first day of hospital admission. Among the 3,089 patients admitted to the general medical wards, 38% (N = 1,165) received an adrenergic agent, and 21% (N = 650) received invasive mechanical ventilation. Overall mortality at 28 days was 21% (765/3,716), and 28-day mortality in patients admitted to the ICUs was higher than that in patients admitted to the general medical wards within the first day (42% [263/627] vs. 16% [502/3,089], p < 0.001). CONCLUSIONS: Sepsis in a regional referral hospital in rural Thailand, where some critical care resources are limited, is commonly managed on general medical wards despite high rates of respiratory failure and shock. Enhancing sepsis care in the ED and general wards, as well as improving access to ICUs, may be beneficial in reducing mortality. TRIAL REGISTRATION: The Ubon-sepsis study was registered on clinicaltrials.gov (NCT02217592).

Adenosine deaminase activity level as a tool for diagnosing tuberculous pleural effusion.

The yield for using a pleural fluid culture to diagnose tuberculous pleural effusion (TPE) is low. Adenosine deaminase activity (ADA) has been shown to have good diagnostic value for TPE. The ADA cutoff point for the diagnosis of TPE is unclear. We attempted to determine the ADA level cutoff point for diagnosing of TPE in Thailand, where tuberculosis is endemic. We reviewed the medical records of patients with newly diagnosed pleural effusion aged >15 years who had a pleural fluid ADAlevel and who underwent a pleural biopsy. The study period was from March 1, 2010 to January 31, 2011. The diagnoses of TPE and malignant pleural effusion (MPE) were based on pathological findings. The diagnostic cutoff level for using ADA to diagnose TPE was determined. Forty-eight patients met study criteria. Of those, 18 patients (37.5%) were diagnosed with TPE. The mean ADA level was significantly higher among patients in the TPE group than in the MPE group (38.2 vs 14.8 U/l, p < 0.001). The cutoff level of 17.5 U/l gave sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 88.9%, 73.3%, 3.33, and 0.15, respectively. An ADA level >17.5 U/l had good diagnostic values among TPE patients in our study.