Dataset Information

175. Randomized Double-blind Controlled Trial of Short vs. Standard Course Outpatient Therapy of Community Acquired Pneumonia in Children (SCOUT-CAP)

ABSTRACT: Abstract

Background

Community-acquired pneumonia (CAP) in children is usually treated with 10 days of antibiotics. Shorter antibiotic courses may be beneficial if proven effective, with potentially fewer antibiotic adverse effects and decreased antibiotic exposure.

Methods

This randomized, double-blind, placebo-controlled superiority trial (NCT02891915) compared a strategy of short vs standard course ß-lactam therapy for outpatient CAP in children ages 6–71 months. Children demonstrating clinical improvement by day 3–5 of initial therapy were considered for enrollment. Enrolled children were randomized 1:1 to receive either 5 additional days of the originally prescribed antibiotic (standard) or matching placebo (short). The Desirability of Outcome Ranking (DOOR; PMID: 26113652) was the primary outcome, and was defined by classifying the global experience of children into an ordinal clinical response (OCR) that combined the response to CAP treatment and antibiotic adverse effects 11–15 days after the start of therapy. For those subjects with equivalent OCR, documented days of antibiotic administration was used to further rank the desirability of the outcome with the a priori assumption that shorter antibiotic exposure was more desirable. The OCR was a secondary outcome. The intention to treat population was used to estimate the probability of a more desirable outcome for the strategy of short vs. standard course therapy for both outcomes.

Results

385 children were enrolled; 380 had complete data for analysis. Baseline characteristics were similar between the two strategies. In both strategies, > 90% of children had an adequate response to CAP treatment and most antibiotic adverse effects were minor (Table). In the OCR analysis, short course therapy had a 48% probability (95% CI: 42%-53%) of a more desirable outcome. In the DOOR analysis, short course therapy was superior to standard therapy with a 69% probability (95% CI: 63%-72%; p< 0.001) of a more desirable outcome.

Conclusion

Among children with CAP demonstrating initial clinical improvement with outpatient therapy, both strategies had a similar response to CAP treatment and antibiotic adverse effects, but short course therapy was superior in our a priori defined outcome that incorporated decreased antibiotic exposure.

Disclosures

Emmanuel B. Walter, MD, MPH, Moderna (Grant/Research Support)Pfizer (Grant/Research Support) Jason Newland, MD, MEd, FPIDS, Merck (Grant/Research Support)Pfizer (Other Financial or Material Support, Industry funded clinical trial) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant) W. Charles Huskins, MD, MSc, ADMA Biologics (Consultant)Pfizer, Inc (Consultant)

SUBMITTER: Williams D

PROVIDER: S-EPMC7776421 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Project description:ImportanceChildhood community-acquired pneumonia (CAP) is usually treated with 10 days of antibiotics. Shorter courses may be effective with fewer adverse effects and decreased potential for antibiotic resistance.ObjectiveTo compare a short (5-day) vs standard (10-day) antibiotic treatment strategy for CAP in young children.Design, setting, and participantsRandomized double-blind placebo-controlled clinical trial in outpatient clinic, urgent care, or emergency settings in 8 US cities. A total of 380 healthy children aged 6 to 71 months with nonsevere CAP demonstrating early clinical improvement were enrolled from December 2, 2016, to December 16, 2019. Data were analyzed from January to September 2020.InterventionOn day 6 of their originally prescribed therapy, participants were randomized 1:1 to receive 5 days of matching placebo or 5 additional days of the same antibiotic.Main outcomes and measuresThe primary end point was the end-of-treatment response adjusted for duration of antibiotic risk (RADAR), a composite end point that ranks each child's clinical response, resolution of symptoms, and antibiotic-associated adverse effects in an ordinal desirability of outcome ranking (DOOR). Within each DOOR rank, participants were further ranked by the number of antibiotic days, assuming that shorter antibiotic durations were more desirable. Using RADAR, the probability of a more desirable outcome was estimated for the short- vs standard-course strategy. In a subset of children, throat swabs were collected between study days 19 and 25 to quantify antibiotic resistance genes in oropharyngeal flora.ResultsA total of 380 children (189 randomized to short course and 191 randomized to standard course) made up the study population. The mean (SD) age was 35.7 (17.2) months, and 194 participants (51%) were male. Of the included children, 8 were Asian, 99 were Black or African American, 234 were White, 32 were multiracial, and 7 were of unknown or unreported race; 33 were Hispanic or Latino, 344 were not Hispanic or Latino, and 3 were of unknown or unreported ethnicity. There were no differences between strategies in the DOOR or its individual components. Fewer than 10% of children in either strategy had an inadequate clinical response. The short-course strategy had a 69% (95% CI, 63-75) probability of a more desirable RADAR outcome compared with the standard-course strategy. A total of 171 children were included in the resistome analysis. The median (range) number of antibiotic resistance genes per prokaryotic cell (RGPC) was significantly lower in the short-course strategy compared with the standard-course strategy for total RGPC (1.17 [0.35-2.43] vs 1.33 [0.46-11.08]; P = .01) and β-lactamase RGPC (0.55 [0.18-1.24] vs 0.60 [0.21-2.45]; P = .03).Conclusions and relevanceIn this study, among children responding to initial treatment for outpatient CAP, a 5-day antibiotic strategy was superior to a 10-day strategy. The shortened approach resulted in similar clinical response and antibiotic-associated adverse effects, while reducing antibiotic exposure and resistance.Trial registrationClinicalTrials.gov Identifier: NCT02891915.

Project description:AimTo study the significance of cap-fitted colonoscopy in improving cecal intubation time and polyp detection rate.MethodsThis study was a prospective randomized controlled trial conducted from March 2008 to February 2009 in a tertiary referral hospital at Sydney. The primary end point was cecal intubation time and the secondary endpoint was polyp detection rate. Consecutive cases of total colonoscopy over a 1-year period were recruited. Randomization into either standard colonoscopy (SC) or cap-assisted colonoscopy (CAC) was performed after consent was obtained. For cases randomized to CAC, one of the three sizes of cap was used: D-201-15004 (with a diameter of 15.3 mm), D-201-14304 (14.6 mm) and D-201-12704 (13.0 mm). All of these caps were produced by Olympus Medical Systems, Japan. Independent predictors for faster cecal time and better polyp detection rate were also determined from this study.ResultsThere were 200 cases in each group. There was no significant difference in terms of demographic characteristics between the two groups. CAC, when compared to the SC group, had no significant difference in terms of cecal intubation rate (96.0% vs 97.0%, P = 0.40) and time (9.94 +/- 7.05 min vs 10.34 +/- 6.82 min, P = 0.21), or polyp detection rate (32.8% vs 31.3%, P = 0.75). On the subgroup analysis, there was no significant difference in terms of cecal intubation time by trainees (88.1% vs 84.8%, P = 0.40), ileal intubation rate (82.5% vs 79.0%, P = 0.38) or total colonoscopy time (23.24 +/- 13.95 min vs 22.56 +/- 9.94 min, P = 0.88). On multivariate analysis, the independent determinants of faster cecal time were consultant-performed procedures (P < 0.001), male patients (P < 0.001), non-usage of hyoscine (P < 0.001) and better bowel preparation (P = 0.01). The determinants of better polyp detection rate were older age (P < 0.001), no history of previous abdominal surgery (P = 0.04), patients not having esophagogastroduodenoscopy in the same setting (P = 0.003), trainee-performed procedures (P = 0.01), usage of hyoscine (P = 0.01) and procedures performed for polyp follow-up (P = 0.01). The limitations of the study were that it was a single-center experience, no blinding was possible, and there were a large number of endoscopists.ConclusionCAC did not significantly different from SC in term of cecal intubation time and polyp detection rate.

Project description:BackgroundPneumonia is the most common hospital-acquired infection affecting patients in the intensive care unit (ICU). However, current national guidelines for the treatment of hospital-acquired pneumonia (HAP) are several years old and the diagnosis of pneumonia in mechanically ventilated patients (VAP) has been subject to considerable recent attention. The optimal duration of antibiotic therapy for HAP in the critically ill is uncertain.ObjectivesTo assess the effectiveness of short versus prolonged-course antibiotics for HAP in critically ill adults, including patients with VAP.Search methodsWe searched CENTRAL (2015, Issue 5), MEDLINE (1946 to June 2015), MEDLINE in-process and other non-indexed citations (5 June 2015), EMBASE (2010 to June 2015), LILACS (1982 to June 2015) and Web of Science (1955 to June 2015).Selection criteriaWe considered all randomised controlled trials (RCTs) comparing a fixed 'short' duration of antibiotic therapy with a 'prolonged' course for HAP (including patients with VAP) in critically ill adults.Data collection and analysisTwo review authors conducted data extraction and assessment of risk of bias. We contacted trial authors for additional information.Main resultsWe identified six relevant studies involving 1088 participants. This included two new studies published after the date of our previous review (2011). There was substantial variation in participants, in the diagnostic criteria used to define an episode of pneumonia, in the interventions and in the reported outcomes. We found no evidence relating to patients with a high probability of HAP who were not mechanically ventilated. For patients with VAP, overall a short seven- or eight-day course of antibiotics compared with a prolonged 10- to 15-day course increased 28-day antibiotic-free days (two studies; N = 431; mean difference (MD) 4.02 days; 95% confidence interval (CI) 2.26 to 5.78) and reduced recurrence of VAP due to multi-resistant organisms (one study; N = 110; odds ratio (OR) 0.44; 95% CI 0.21 to 0.95), without adversely affecting mortality and other recurrence outcomes. However, for cases of VAP specifically due to non-fermenting Gram-negative bacilli (NF-GNB), recurrence was greater after short-course therapy (two studies, N = 176; OR 2.18; 95% CI 1.14 to 4.16), though mortality outcomes were not significantly different. One study found that a three-day course of antibiotic therapy for patients with suspected HAP but a low Clinical Pulmonary Infection Score (CPIS) was associated with a significantly lower risk of superinfection or emergence of antimicrobial resistance, compared with standard (prolonged) course therapy.Authors' conclusionsOn the basis of a small number of studies and appreciating the lack of uniform definition of pneumonia, we conclude that for patients with VAP not due to NF-GNB a short, fixed course (seven or eight days) of antibiotic therapy appears not to increase the risk of adverse clinical outcomes, and may reduce the emergence of resistant organisms, compared with a prolonged course (10 to 15 days). However, for patients with VAP due to NF-GNB, there appears to be a higher risk of recurrence following short-course therapy. These findings do not differ from those of our previous review and are broadly consistent with current guidelines. There are few data from RCTs comparing durations of therapy in non-ventilated patients with HAP, but on the basis of a single study, short-course (three-day) therapy for HAP appears not to be associated with worse clinical outcome, and may reduce the risk of subsequent infection or the emergence of resistant organisms when there is low probability of pneumonia according to the CPIS.

Project description:There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Project description:Vaccine effectiveness is usually determined in randomized controlled trials (RCT) and if effective, additional information, e.g. on cost-effectiveness, is required to allow evidence-based decision making. A prerequisite for proper health economic modelling is the availability of good quality data on health care resources use, health outcomes and quality-of-life (QoL) data. The "Collecting health outcomes and economic data on hospitalized Community Acquired Pneumonia (CHO-CAP)--a prospective cohort study" is executed alongside the Community Acquired Pneumonia Immunization Trial with Adults (CAPiTA trial) to capture health outcomes and economic data of elderly hospitalized with CAP and matched controls without CAP.CAPiTA is a placebo-controlled double-blind RCT evaluating the effectiveness of a 13-valent conjugated pneumococcal vaccine in preventing vaccine-type pneumococcal CAP in 84,496 elderly in the Netherlands. Participants of CAPiTA, who consented and provided information on health status (EQ-5D) and socio-demographic background at the time of vaccination, constitute the source population of CHO-CAP and are eligible for the nested matched cohort study. CHO-CAP patients hospitalized with CAP form the "diseased" cohort and the "non-diseased" cohort consists of unaffected persons (i.e. no CAP). Observations in the diseased cohort and in matched controls from the non-diseased cohort are used to determine excess costs and QoL changes attributable to CAP.Based on an estimated 2,000 CAPiTA participants being hospitalized with CAP and an assumed CHO-CAP participation rate of 30% of all CAPiTA participants (±25,000), 600 CAP episodes are expected among CHO-CAP participants (the "diseased" cohort). For each patient with CAP, two non-diseased CHO-CAP subjects will be selected from the CHO-CAP cohort, with matching for age, gender and EQ-5D baseline-score. Data on healthcare and non-healthcare resources use, quality-of-life (using EQ-5D and SF-36 questionnaires) and selected health outcomes will be collected at 0, 1, 6 and 12 months after hospitalization for CAP.The CHO-CAP study was approved by the Central Committee on Research involving Human Subjects in the Netherlands.With an expected 600 CAP episodes this study will be one of the biggest prospectively studied cohorts of hospitalized elderly with CAP with regard to resources use and Qol data. Strengths of this study further include collection of out-of-pocket costs of patients and productivity losses of both patients and their caregivers and the follow-up period of up to one year post-discharge. This study is therefore expected to add more in-depth knowledge on the short and longer term outcomes of pneumonia in elderly.ClinicalTrials.gov, NCT00812084.

Project description:BackgroundThis retrospective cohort study is the first in North America to examine population-level appropriate antibiotic use for community-acquired pneumonia (CAP) in older adults, by agent, dose and duration. With the highest rates of CAP reported in the elderly populations, appropriate antibiotic use is essential to improve clinical outcomes. Given the ongoing crisis of antimicrobial resistance, understanding inappropriate antibiotic prescribing is integral to direct community stewardship efforts.MethodsAll outpatient primary care visits for CAP (aged ≥65 years) were identified using physician billing codes between January 1 2014 to December 31 2018 in British Columbia (BC) and Ontario (ON). Categories of prescribing were derived from existing literature, and constructed for clinical relevance using Canadian and international guidelines available during the study period. Categories were mutually exclusive and included: guideline adherent (first-line agent, adherent dose/duration), clinically appropriate (non-first line agent, presence of comorbidities), effective but unnecessary (first-line agent, excess dose/duration), undertreatment (first-line agent, subtherapeutic dose/duration), and not recommended (non-first line agent, absence of comorbidities). Proportions of prescribing were examined by category. Temporal trends in prescribing were examined using Poisson regression.ResultsA total of 436,441 episodes of CAP were identified, with 46% prescribed an antibiotic in BC, and 52% in Ontario. Guideline adherent prescribing was minimal for both provinces (BC: 2%; ON: 1%) however the largest magnitude of increase was reported in this category by the final study year (BC-Rate Ratio [RR]: 3.4, 95% Confidence Interval [CI]: 2.7-4.3; ON-RR: 4.62, 95% CI: 3.4-6.5). Clinically appropriate prescribing accounted for the most antibiotics issued, across all study years (BC: 61%; ON: 74%) (BC-RR: 0.8, 95% CI: 0.8-0.8; ON-RR: 0.9, 95% CI: 0.8-0.9). Excess duration of therapy was the hallmark characteristic for effective but unnecessary prescribing (BC: 92%; ON: 99%). The most common duration prescribed was 7 days, followed by 10. Not recommended prescribing was minimal in both provinces (BC: 4%; ON: 7%) and remained stable by the final study year (BC-RR: 1.1, 95% CI: 0.9-1.2; ON-RR: 0.9, 95% CI: 0.9-1.1).ConclusionThree quarters of antibiotic prescribing for CAP was appropriate in Ontario, but only two thirds in BC. Shortening durations-in line with evidence for 3 to 5-day treatment presents a focused target for stewardship efforts.