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Short-course antimicrobial therapy for paediatric respiratory infections (SAFER): study protocol for a randomized controlled trial.

ABSTRACT: BACKGROUND:Community-acquired pneumonia (CAP) is commonly diagnosed in children. The Infectious Disease Society of America guidelines recommend 10 days of high-dose amoxicillin for the treatment of non-severe CAP but 5-day "short course" therapy may be just as effective. Randomized trials in adults have already demonstrated non-inferiority of 5-day short-course treatment for adults hospitalized with severe CAP and for adults with mild CAP treated as outpatients. Minimizing exposure to antimicrobials is desirable to avoid harms including diarrhoea, rashes, severe allergic reactions, increased circulating antimicrobial resistance, and microbiome disruption. METHODS:The objective of this multicentre, randomized, non-inferiority, controlled trial is to investigate whether 5 days of high-dose amoxicillin is associated with lower rates of clinical cure 14-21 days later as compared to 10 days of high-dose amoxicillin, the reference standard. Recruitment and enrolment will occur in the emergency departments of McMaster Children's Hospital and the Children's Hospital of Eastern Ontario. All children in the study will receive 5 days of amoxicillin after which point they will receive either 5 days of a different formulation of amoxicillin or a placebo. Assuming a clinical failure rate of 5% in the reference arm, a non-inferiority margin of 7.5%, one-sided alpha set at 0.025 and power of 0.80, 270 participants will be required. Participants from a previous feasibility study (n?=?60) will be rolled over into the current study. We will be performing multiplex respiratory virus molecular testing, quantification of nasopharyngeal pneumococcal genomic loads, salivary inflammatory marker testing, and faecal microbiome profiling on participants. DISCUSSION:This is a pragmatic study seeking to provide high-quality evidence for front-line physicians evaluating children presenting with mild CAP in North American emergency departments in the post-13-valent pneumococcal, conjugate vaccine era. High-quality evidence supporting the non-inferiority of short-course therapy for non-severe paediatric CAP should be generated prior to making changes to established guidelines. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02380352 . Registered on 2 March 2015.

SUBMITTER: Pernica J

PROVIDER: S-EPMC5796490 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Short-course antimicrobial therapy for paediatric respiratory infections (SAFER): study protocol for a randomized controlled trial.

Pernica Jeffrey J Harman Stuart S Kam April A Bailey Jacob J Carciumaru Redjana R Khan Sarah S Fulford Martha M Thabane Lehana L Slinger Robert R Main Cheryl C Smieja Marek M Loeb Mark M

Trials 20180201 1

<h4>Background</h4>Community-acquired pneumonia (CAP) is commonly diagnosed in children. The Infectious Disease Society of America guidelines recommend 10 days of high-dose amoxicillin for the treatment of non-severe CAP but 5-day "short course" therapy may be just as effective. Randomized trials in adults have already demonstrated non-inferiority of 5-day short-course treatment for adults hospitalized with severe CAP and for adults with mild CAP treated as outpatients. Minimizing exposure to an ...[more]

PMID: 29391051

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Project description:BackgroundThe successful treatment of intraabdominal infection requires a combination of anatomical source control and antibiotics. The appropriate duration of antimicrobial therapy remains unclear.MethodsWe randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days. The primary outcome was a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days after the index source-control procedure, according to treatment group. Secondary outcomes included the duration of therapy and rates of subsequent infections.ResultsSurgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, -0.5 percentage point; 95% confidence interval [CI], -7.0 to 8.0; P=0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, -4.0 days; 95% CI, -4.7 to -3.3; P<0.001). No significant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes.ConclusionsIn patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials.gov number, NCT00657566.).

Project description:BACKGROUND:Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a 4- to 8-week course of high-dose oral prednisolone, which may be associated with significant adverse effects. There is a clear association between upper respiratory tract infection (URTI) and relapse development. Previous studies in developing nations have suggested that introducing a 5- to 7-day course of daily prednisolone during an URTI may prevent a relapse developing and the need for a treatment course of high-dose prednisolone. The aim of PREDNOS 2 is to evaluate the effectiveness of a 6-day course of daily prednisolone therapy during an URTI in reducing the development of a subsequent relapse in a developed nation. METHODS/DESIGN:The subjects will be 300 children with relapsing SSNS (?2 relapses in preceding year), who will be randomised to receive either a 6-day course of daily prednisolone or no change to their current therapy (with the use of placebo to double blind) each time they develop an URTI over 12 months. A strict definition for URTI will be used. Subjects will be reviewed at 3, 6, 9 and 12 months to capture data regarding relapse history, ongoing therapy and adverse effect profile, including behavioural problems and quality of life. A formal health economic analysis will also be performed. The primary end point of the study will be the incidence of URTI-related relapse (3 days of Albustix +++) following the first infection during the 12-month follow-up period. DNA and RNA samples will be collected to identify a potential genetic cause for the disease. Subjects will be recruited from over 100 UK centres with the assistance of the Medicines for Children Research Network.PREDNOS 2 is funded by the National Institute for Health Research Health Technology Assessment Programme (11/129/261). DISCUSSION:We propose that PREDNOS 2 will be a pivotal study that will inform the future standard of care for children with SSNS. If it is possible to reduce the disease relapse rate effectively and safely, this will reduce the morbidity and cost associated with drug treatment, notwithstanding hospital admission and parental absence from employment. TRIAL REGISTRATION:Current Controlled Trials (ISRCTN10900733).

Project description:IntroductionAcute hypoxaemic respiratory failure (AHRF) in children is the most frequent reason for non-elective hospital admission. During the initial phase, AHRF is a clinical syndrome defined for the purpose of this study by an oxygen requirement and caused by pneumonia, lower respiratory tract infections, asthma or bronchiolitis. Up to 20% of these children with AHRF can rapidly deteriorate requiring non-invasive or invasive ventilation. Nasal high-flow (NHF) therapy has been used by clinicians for oxygen therapy outside intensive care settings to prevent escalation of care. A recent randomised trial in infants with bronchiolitis has shown that NHF therapy reduces the need to escalate therapy. No similar data is available in the older children presenting with AHRF. In this study we aim to investigate in children aged 1 to 4 years presenting with AHRF if early NHF therapy compared with standard-oxygen therapy reduces hospital length of stay and if this is cost-effective compared with standard treatment.Methods and analysisThe study design is an open-labelled randomised multicentre trial comparing early NHF and standard-oxygen therapy and will be stratified by sites and into obstructive and non-obstructive groups. Children aged 1 to 4 years (n=1512) presenting with AHRF to one of the participating emergency departments will be randomly allocated to NHF or standard-oxygen therapy once the eligibility criteria have been met (oxygen requirement with transcutaneous saturation <92%/90% (dependant on hospital standard threshold), diagnosis of AHRF, admission to hospital and tachypnoea ?35 breaths/min). Children in the standard-oxygen group can receive rescue NHF therapy if escalation is required. The primary outcome is hospital length of stay. Secondary outcomes will include length of oxygen therapy, proportion of intensive care admissions, healthcare resource utilisation and associated costs. Analyses will be conducted on an intention-to-treat basis.Ethics and disseminationEthics approval has been obtained in Australia (HREC/15/QRCH/159) and New Zealand (HDEC 17/NTA/135). The trial commenced recruitment in December 2017. The study findings will be submitted for publication in a peer-reviewed journal and presented at relevant conferences. Authorship of all publications will be decided by mutual consensus of the research team.Trial registration numberACTRN12618000210279.

Project description:Debate and scientific inquiries regarding airborne transmission of respiratory infections such as COVID-19 and influenza continue. Health authorities including the WHO and the US CDC have recognized the airborne transmission of COVID-19 in specific settings, although the ventilation requirements remain to be determined. In this work we consider the long-range airborne transmission as an extended short-range airborne route, which reconciles the link between short- and long-range airborne routes. The effective short-range distance is defined as the distance in short range at which long-range route has the same volumetric exposure value as that due to short-range route. Our data show that a decrease in ventilation rate or room volume per person, or an increase in the ratio of the number of infected to susceptible people reduces the effective short-range distance. In a normal breathing scenario with one out of five people infected and a room volume of 12 m3 per person to ensure an effective short-range distance of 1.5 m, a ventilation rate of 10 L/s per person is needed for a duration of 2 h. Our results suggest that effective environmental prevention strategies for respiratory infections require appropriate increases in the ventilation rate while maintaining a sufficiently low occupancy. PRACTICAL IMPLICATIONS: Demonstration of the long-range airborne route as an extended short-range airborne route suggests the significant role played by building ventilation in respiratory infection exposure. The reconciliation of short- and long-range airborne transmission suggests that the commonly observed dominance of close-contact transmission is a probable evidence of short-range airborne transmission, following a separate earlier study that revealed the relative insignificance of large droplet transmission in comparison with the short-range airborne-route. Existing ventilation standards do not account for respiratory infection control, and this study presents a possible approach to account for infection under new ventilation standards.

Project description:BackgroundShort-course antiretroviral therapy (ART) in primary human immunodeficiency virus (HIV) infection may delay disease progression but has not been adequately evaluated.MethodsWe randomly assigned adults with primary HIV infection to ART for 48 weeks, ART for 12 weeks, or no ART (standard of care), with treatment initiated within 6 months after seroconversion. The primary end point was a CD4+ count of less than 350 cells per cubic millimeter or long-term ART initiation.ResultsA total of 366 participants (60% men) underwent randomization to 48-week ART (123 participants), 12-week ART (120), or standard care (123), with an average follow-up of 4.2 years. The primary end point was reached in 50% of the 48-week ART group, as compared with 61% in each of the 12-week ART and standard-care groups. The average hazard ratio was 0.63 (95% confidence interval [CI], 0.45 to 0.90; P=0.01) for 48-week ART as compared with standard care and was 0.93 (95% CI, 0.67 to 1.29; P=0.67) for 12-week ART as compared with standard care. The proportion of participants who had a CD4+ count of less than 350 cells per cubic millimeter was 28% in the 48-week ART group, 40% in the 12-week group, and 40% in the standard-care group. Corresponding values for long-term ART initiation were 22%, 21%, and 22%. The median time to the primary end point was 65 weeks (95% CI, 17 to 114) longer with 48-week ART than with standard care. Post hoc analysis identified a trend toward a greater interval between ART initiation and the primary end point the closer that ART was initiated to estimated seroconversion (P=0.09), and 48-week ART conferred a reduction in the HIV RNA level of 0.44 log(10) copies per milliliter (95% CI, 0.25 to 0.64) 36 weeks after the completion of short-course therapy. There were no significant between-group differences in the incidence of the acquired immunodeficiency syndrome, death, or serious adverse events.ConclusionsA 48-week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment. There was no evidence of adverse effects of ART interruption on the clinical outcome. (Funded by the Wellcome Trust; SPARTAC Controlled-Trials.com number, ISRCTN76742797, and EudraCT number, 2004-000446-20.).

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Short-course antimicrobial therapy for paediatric respiratory infections (SAFER): study protocol for a randomized controlled trial.

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Short-course antimicrobial therapy for paediatric respiratory infections (SAFER): study protocol for a randomized controlled trial.

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