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7 versus 14 days of antibiotic treatment for critically ill patients with bloodstream infection: a pilot randomized clinical trial.

ABSTRACT: BACKGROUND:Shorter-duration antibiotic treatment is sufficient for a range of bacterial infections, but has not been adequately studied for bloodstream infections. Our systematic review, survey, and observational study indicated equipoise for a trial of 7 versus 14 days of antibiotic treatment for bloodstream infections; a pilot randomized clinical trial (RCT) was a necessary next step to assess feasibility of a larger trial. METHODS:We conducted an open, pilot RCT of antibiotic treatment duration among critically ill patients with bloodstream infection across 11 intensive care units (ICUs). Antibiotic selection, dosing and route were at the discretion of the treating team; patients were randomized 1:1 to intervention arms consisting of two fixed durations of treatment - 7 versus 14 days. We recruited adults with a positive blood culture yielding pathogenic bacteria identified while in ICU. We excluded patients with severe immunosuppression, foci of infection with an established requirement for prolonged treatment, single cultures with potential contaminants, or cultures yielding Staphylococcus aureus or fungi. The primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. Secondary outcomes included 90-day, ICU and hospital mortality, relapse of bacteremia, lengths of stay, mechanical ventilation and vasopressor duration, antibiotic-free days, Clostridium difficile, antibiotic adverse events, and secondary infection with antimicrobial-resistant organisms. RESULTS:We successfully achieved our target sample size (n?=?115) and average recruitment rate of 1 (interquartile range (IQR) 0.3-1.5) patient/ICU/month. Adherence to treatment duration was achieved in 89/115 (77%) patients. Adherence differed by underlying source of infection: 26/31 (84%) lung; 18/29 (62%) intra-abdominal; 20/26 (77%) urinary tract; 8/9 (89%) vascular-catheter; 4/4 (100%) skin/soft tissue; 2/4 (50%) other; and 11/12 (92%) unknown sources. Patients experienced a median (IQR) 14 (8-17) antibiotic-free days (of the 28 days after blood culture collection). Antimicrobial-related adverse events included hepatitis in 1 (1%) patient, Clostridium difficile infection in 4 (4%), and secondary infection with highly resistant microorganisms in 10 (9%). Ascertainment was complete for all study outcomes in ICU, in hospital and at 90 days. CONCLUSION:It is feasible to conduct a RCT to determine whether 7 versus 14 days of antibiotic treatment is associated with comparable 90-day survival. TRIAL REGISTRATION:ClinicalTrials.gov , identifier: NCT02261506 . Registered on 26 September 2014.

SUBMITTER: Daneman N

PROVIDER: S-EPMC5816399 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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7 versus 14 days of antibiotic treatment for critically ill patients with bloodstream infection: a pilot randomized clinical trial.

Daneman Nick N Rishu Asgar H AH Pinto Ruxandra R Aslanian Pierre P Bagshaw Sean M SM Carignan Alex A Charbonney Emmanuel E Coburn Bryan B Cook Deborah J DJ Detsky Michael E ME Dodek Peter P Hall Richard R Kumar Anand A Lamontagne Francois F Lauzier Francois F Marshall John C JC Martin Claudio M CM McIntyre Lauralyn L Muscedere John J Reynolds Steven S Sligl Wendy W Stelfox Henry T HT Wilcox M Elizabeth ME Fowler Robert A RA

Trials 20180217 1

<h4>Background</h4>Shorter-duration antibiotic treatment is sufficient for a range of bacterial infections, but has not been adequately studied for bloodstream infections. Our systematic review, survey, and observational study indicated equipoise for a trial of 7 versus 14 days of antibiotic treatment for bloodstream infections; a pilot randomized clinical trial (RCT) was a necessary next step to assess feasibility of a larger trial.<h4>Methods</h4>We conducted an open, pilot RCT of antibiotic t ...[more]

PMID: 29452598

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Project description:BACKGROUND:The optimal treatment duration for patients with bloodstream infection is understudied. The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) pilot randomized clinical trial (RCT) determined that it was feasible to enroll and randomize intensive care unit (ICU) patients with bloodstream infection to 7 versus 14 days of treatment, and served as the vanguard for the ongoing BALANCE main RCT. We performed this BALANCE-Ward pilot RCT to examine the feasibility and impact of potentially extending the BALANCE main RCT to include patients hospitalized on non-ICU wards. METHODS:We conducted an open pilot RCT among a subset of six sites participating in the ongoing BALANCE RCT, randomizing patients with positive non-Staphylococcus aureus blood cultures on non-ICU wards to 7 versus 14 days of antibiotic treatment. The co-primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. We compared feasibility outcomes, patient/pathogen characteristics, and overall outcomes among those enrolled in this BALANCE-Ward and prior BALANCE-ICU pilot RCTs. We estimated the sample size and non-inferiority margin impacts of expanding the BALANCE main RCT to include non-ICU patients. RESULTS:A total of 134 patients were recruited over 47 site-months (mean 2.9 patients/site-month, median 1.0, range 0.1-4.4 patients/site-month). The overall recruitment rate exceeded the BALANCE-ICU pilot RCT (mean 1.10 patients/site-month, p < 0.0001). Overall protocol adherence also exceeded the adherence in the BALANCE-ICU pilot RCT (125/134, 93% vs 89/115, 77%, p = 0.0003). BALANCE-Ward patients were older, with lower Sequential Organ Failure Assessment scores, and higher proportions of infections caused by Escherichia coli and genito-urinary sources of bloodstream infection. The BALANCE-Ward pilot RCT patients had an overall 90-day mortality rate of 17/133 (12.8%), which was comparable to the 90-day mortality rate in the ICU pilot RCT (17/115, 14.8%) (p = 0.65). Simulation models indicated there would be minimal sample size and non-inferiority margin implications of expanding enrolment to increasing proportions of non-ICU versus ICU patients. CONCLUSION:It is feasible to enroll non-ICU patients in a trial of 7 versus 14 days of antibiotics for bloodstream infection, and expanding the BALANCE RCT hospital-wide has the potential to improve the timeliness and generalizability of trial results. TRIAL REGISTRATION:Clinicaltrials.gov, NCT02917551. Registered on September 28, 2016.

Project description:BackgroundThe gut microbiome is believed to contribute to bloodstream infection (BSI) via translocation of dominant gut bacteria in vulnerable patient populations. However, conclusively linking gut and blood organisms requires stringent approaches to establish strain-level identity.MethodsWe enrolled a convenience cohort of critically ill patients and investigated 86 bloodstream infection episodes that occurred in 57 patients. Shotgun metagenomic sequencing was used to define constituents of their gut microbiomes, and whole genome sequencing and assembly was done on 23 unique bloodstream isolates that were available from 21 patients. Whole genome sequences were downloaded from public databases and used to establish sequence-identity distribution and define thresholds for unrelated genomes of BSI species. Gut microbiome reads were then aligned to whole genome sequences of the cognate bloodstream isolate and unrelated database isolates to assess identity.ResultsGut microbiome constituents matching the bloodstream infection species were present in half of BSI episodes, and represented >30% relative abundance of gut sequences in 10% of episodes. Among the 23 unique bloodstream organisms that were available for whole genome sequencing, 14 were present in gut at the species level. Sequence alignment applying defined thresholds for identity revealed that 6 met criteria for identical strains in blood and gut, but 8 did not. Sequence identity between BSI isolates and gut microbiome reads was more likely when the species was present at higher relative abundance in gut.ConclusionIn assessing potential gut source for BSI, stringent sequence-based approaches are essential to determine if organisms responsible for BSI are identical to those in gut: of 14 evaluable patients in which the same species was present in both sites, they were identical in 6/14, but were non-identical in 8/14 and thus inconsistent with gut source. This report demonstrates application of sequencing as a key tool to investigate infection tracking within patients.

Project description:BackgroundFever improves pathogen control at a significant metabolic cost. No randomized clinical trials (RCT) have compared fever treatment thresholds in critically ill children. We performed a pilot RCT to determine whether a definitive trial of a permissive approach to fever in comparison to current restrictive practice is feasible in critically ill children with suspected infection.MethodsAn open, parallel-group pilot RCT with embedded mixed methods perspectives study in four UK paediatric intensive care units (PICUs) and associated retrieval services. Participants were emergency PICU admissions aged > 28 days to < 16 years receiving respiratory support and supplemental oxygen. Subjects were randomly assigned to permissive (antipyretic interventions only at ≥ 39.5 °C) or restrictive groups (antipyretic interventions at ≥ 37.5 °C) whilst on respiratory support. Parents were invited to complete a questionnaire or take part in an interview. Focus groups were conducted with staff at each unit. Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between group separation of temperature and safety.ResultsOne hundred thirty-eight children met eligibility criteria of whom 100 (72%) were randomized (11.1 patients per month per site) without prior consent (RWPC). Consent to continue in the trial was obtained in 87 cases (87%). The mean maximum temperature (95% confidence interval) over the first 48 h was 38.4 °C (38.2-38.6) in the restrictive group and 38.8 °C (38.6-39.1) in the permissive group, a mean difference of 0.5 °C (0.2-0.8). Protocol deviations were observed in 6.8% (99/1438) of 6-h time periods and largely related to patient comfort in the recovery phase. Length of stay, duration of organ support and mortality were similar between groups. No pre-specified serious adverse events occurred. Staff (n = 48) and parents (n = 60) were supportive of the trial, including RWPC. Suggestions were made to only include invasively ventilated children for the duration of intubation.ConclusionUncertainty around the optimal fever threshold for antipyretic intervention is relevant to many emergency PICU admissions. A more permissive approach was associated with a modest increase in mean maximum temperature. A definitive trial should focus on the most seriously ill cases in whom antipyretics are rarely used for their analgesic effects alone.Trial registrationISRCTN16022198 . Registered on 14 August 2017.

Project description:BACKGROUND:In the critically ill, energy delivery from enteral nutrition (EN) is often less than the estimated energy requirement. Parenteral nutrition (PN) as a supplement to EN may increase energy delivery. We aimed to determine if an individually titrated supplemental PN strategy commenced 48-72 hours following ICU admission and continued for up to 7 days would increase energy delivery to critically ill adults compared to usual care EN delivery. METHODS:This study was a prospective, parallel group, phase II pilot trial conducted in six intensive care units in Australia and New Zealand. Mechanically ventilated adults with at least one organ failure and EN delivery below 80% of estimated energy requirement in the previous 24 hours received either a supplemental PN strategy (intervention group) or usual care EN delivery. EN in the usual care group could be supplemented with PN if EN remained insufficient after usual methods to optimise delivery were attempted. RESULTS:There were 100 patients included in the study and 99 analysed. Overall, 71% of the study population were male, with a mean (SD) age of 59 (17) years, Acute Physiology and Chronic Health Evaluation II score of 18.2 (6.7) and body mass index of 29.6 (5.8) kg/m2. Significantly greater energy (mean (SD) 1712 (511) calories vs. 1130 (601) calories, p?<?0.0001) and proportion of estimated energy requirement (mean (SD) 83 (25) % vs. 53 (29) %, p?<?0.0001) from EN and/or PN was delivered to the intervention group compared to usual care. Delivery of protein and proportion of estimated protein requirements were also greater in the intervention group (mean (SD) 86 (25) g, 86 (23) %) compared to usual care (mean (SD) 53 (29) g, 51 (25) %, p?<?0.0001). Antibiotic use, ICU and hospital length of stay, mortality and functional outcomes were similar between the two groups. CONCLUSIONS:This individually titrated supplemental PN strategy applied over 7 days significantly increased energy delivery when compared to usual care delivery. Clinical and functional outcomes were similar between the two patient groups. TRIAL REGISTRATION:Clinical Trial registry details: NCT01847534 (First registered 22 April 2013, last updated 31 July 2016).

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7 versus 14 days of antibiotic treatment for critically ill patients with bloodstream infection: a pilot randomized clinical trial.

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7 versus 14 days of antibiotic treatment for critically ill patients with bloodstream infection: a pilot randomized clinical trial.

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