Having a representative population in randomized clinical trials (RCTs) improves external validity and generalizability of trial results. There are limited data examining differences between ...RCT-enrolled and real-world populations in bloodstream infections (BSI).
We conducted a scoping review aiming to review studies assessing generalizability of BSI RCT populations, to identify sub-groups that have been systematically under-represented and to explore approaches to improve external validity of future RCTs.
MEDLINE, Embase, and Cochrane Library databases were searched for terms related to external validity or generalizability, BSI, and clinical trials in papers published up to 1 August 2023. Studies comparing enrolled versus nonenrolled patients, or papers discussing external validity or generalizability in the context of BSI RCTs were included.
Sixteen papers were included in the final review. Five compared RCT-enrolled and nonenrolled participants from the same source population. There were significant differences between the two groups in all studies, with nonenrolled patients having a greater comorbidity burden and consistently worse outcomes including mortality. We identified several barriers to improving generalizability of RCT populations and outlined potential approaches to reduce these barriers, such as alternative/simplified consent processes, streamlining eligibility criteria and follow-up procedures, quota-based sampling techniques, and ensuring diversity in site and study team selection.
Study cohorts in BSI RCTs are not representative of the general BSI patient population. As we increasingly adopt large pragmatic trials in infectious diseases, it is important to recognize the importance of maximizing generalizability to ensure that our research findings are of direct relevance to our patients.
The use of positron emission tomography/computed tomography (PET/CT) in the evaluation of patients with Staphylococcus aureus bacteraemia can improve the diagnosis of infectious foci and guide ...clinical management. We aimed to evaluate the cost-utility of PET/CT among adults hospitalized with Staphylococcus aureus bacteraemia.
A cost-utility analysis was conducted from the healthcare payer perspective using a probabilistic Markov cohort model assessing three diagnostic strategies: (a) PET/CT in all patients, (b) PET/CT in high-risk patients only, and (c) routine diagnostic workup. Primary outcomes were quality-adjusted life years (QALYs), costs in Canadian dollars, and an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses were conducted to evaluate parameter uncertainty.
Routine workup resulted in an average of 16.64 QALYs from the time of diagnosis at a lifetime cost of $209 060/patient. This was dominated by PET/CT in high-risk patients (i.e. greater effectiveness at lower costs) with average 16.88 QALYs at a cost of $199 552. Compared with PET/CT in high-risk patients only, PET/CT for all patients cost on average $11 960 more but resulted in 0.14 more QALYs, giving an incremental cost-effectiveness ratio of $83 500 (cost per additional QALY gained); however, there was a high degree of uncertainty comparing these two strategies. At a willingness-to-pay threshold of $50 000/QALY, PET/CT in high-risk patients was the most cost-effective strategy in 58.6% of simulations vs. 37.9% for PET/CT in all patients.
Our findings suggest that a strategy of using PET/CT in high-risk patients is more cost-effective than no PET/CT. Randomized controlled trials should be conducted to evaluate the use of PET/CT in different patient groups.
Waning antibody levels post-vaccination and the emergence of variants of concern (VOCs) capable of evading protective immunity have raised the need for booster vaccinations. However, which ...combination of coronavirus disease 2019 (COVID-19) vaccines offers the strongest immune response against the Omicron variant is unknown.
This randomized, participant-blinded, controlled trial assessed the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. A total of 100 BNT162b2-vaccinated individuals were enrolled and randomized 1:1 to either homologous (BNT162b2 + BNT162b2 + BNT162b2; "BBB") or heterologous messenger RNA (mRNA) (BNT162b2 + BNT162b2 + mRNA-1273; "BBM") booster vaccine. The primary end point was the level of neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type and VOCs at day 28.
A total of 51 participants were allocated to BBB and 49 to BBM; 50 and 48, respectively, were analyzed for safety and immunogenicity outcomes. At day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22 382 IU/mL; 95% confidence interval CI, 18 210 to 27 517) vs BBM (29 751 IU/mL; 95% CI, 25 281 to 35 011; P = .034) as was the median level of neutralizing antibodies: BBB 99.0% (interquartile range IQR, 97.9% to 99.3%) vs BBM 99.3% (IQR, 98.8% to 99.5%; P = .021). On subgroup analysis, significant higher mean spike antibody titer, median surrogate neutralizing antibody level against all VOCs, and live Omicron neutralization titer were observed only in older adults receiving BBM. Both vaccines were well tolerated.
Heterologous mRNA-1273 booster vaccination compared with homologous BNT123b2 induced a stronger neutralizing response against the Omicron variant in older individuals.
NCT05142319.
COVID-19 imposes challenges in antibiotic decision-making due to similarities between bacterial pneumonia and moderate to severe COVID-19. We evaluated the effects of antibiotic therapy on the ...clinical outcomes of COVID-19 pneumonia patients and diagnostic accuracy of key inflammatory markers to inform antibiotic decision-making.
An observational cohort study was conducted in patients hospitalised with COVID-19 at the National Centre for Infectious Diseases and Tan Tock Seng Hospital, Singapore, from January to April 2020. Patients were defined as receiving empiric antibiotic treatment for COVID-19 if started within 3 days of diagnosis.
Of 717 patients included, 86 (12.0%) were treated with antibiotics and 26 (3.6%) had documented bacterial infections. Among 278 patients with COVID-19 pneumonia, those treated with antibiotics had more diarrhoea (26, 34.7% vs. 24, 11.8%,
< 0.01), while subsequent admissions to the intensive care unit were not lower (6, 8.0% vs. 10, 4.9%
= 0.384). Antibiotic treatment was not independently associated with lower 30-day (adjusted odds ratio, aOR 19.528, 95% confidence interval, CI 1.039-367.021) or in-hospital mortality (aOR 3.870, 95% CI 0.433-34.625) rates after adjusting for age, co-morbidities and severity of COVID-19 illness. Compared to white cell count and procalcitonin level, the C-reactive protein level had the best diagnostic accuracy for documented bacterial infections (area under the curve, AUC of 0.822). However, the sensitivity and specificity were less than 90%.
Empiric antibiotic use in those presenting with COVID-19 pneumonia did not prevent deterioration or mortality. More studies are needed to evaluate strategies to diagnose bacterial co-infections in these patients.
Over 2021, COVID-19 vaccination programs worldwide focused on raising population immunity through the primary COVID-19 vaccine series. In Singapore, two mRNA vaccines (BNT162b2 and mRNA-1273) and the ...inactivated vaccine CoronaVac are currently authorized under the National Vaccination Programme for use as the primary vaccination series. More than 90% of the Singapore population has received at least one dose of a COVID-19 vaccine as of December 2021. With the demonstration that vaccine effectiveness wanes in the months after vaccination, and the emergence of Omicron which evades host immunity from prior infection and/or vaccination, attention in many countries has shifted to how best to maintain immunity through booster vaccinations.
The objectives of this phase 3, randomized, subject-blinded, controlled clinical trial are to assess the safety and immunogenicity of heterologous boost COVID-19 vaccine regimens (intervention groups 1-4) compared with a homologous boost regimen (control arm) in up to 600 adult volunteers. As non-mRNA vaccine candidates may enter the study at different time points depending on vaccine availability and local regulatory approval, participants will be randomized at equal probability to the available intervention arms at the time of randomization. Eligible participants will have received two doses of a homologous mRNA vaccine series with BNT162b2 or mRNA-1273 at least 6 months prior to enrolment. Participants will be excluded if they have a history of confirmed SARS or SARS-CoV-2 infection, are immunocompromised, or are pregnant. Participants will be monitored for adverse events and serious adverse events by physical examinations, laboratory tests and self-reporting. Blood samples will be collected at serial time points pre-vaccination/screening (day - 14 to day 0), day 7, day 28, day 180, day 360 post-vaccination for assessment of antibody and cellular immune parameters. Primary endpoint is the level of anti-SARS-CoV-2 spike immunoglobulins at day 28 post-booster and will be measured against wildtype SARS-CoV-2 and variants of concern. Comprehensive immune profiling of the humoral and cellular immune response to vaccination will be performed.
This study will provide necessary data to understand the quantity, quality, and persistence of the immune response to a homologous and heterologous third booster dose of COVID-19 vaccines. This is an important step in developing COVID-19 vaccination programs beyond the primary series.
ClinicalTrials.gov NCT05142319 . Registered on 2 Dec 2021.
The utility of follow-up blood cultures (FUBCs) in patients with Gram-negative bloodstream infection (GN-BSI) is controversial. Observational studies have suggested significant mortality benefit but ...may be limited by single-centre designs, immortal time bias, and residual confounding. We examined the impact of FUBCs on mortality in patients with GN-BSI in a retrospective population-wide cohort study in Ontario, Canada.
Adult patients with GN-BSI hospitalized between April 2017 and December 2021 were included. Primary outcome was all-cause mortality within 30 days. FUBC was treated as a time-varying exposure. Secondary outcomes were 90-day mortality, length of stay, and number of days alive and out of hospital at 30 and 90 days.
Thirty-four thousand one hundred patients were included; 8807 (25.8%) patients received FUBC, of which 966 (11.0%) were positive. Median proportion of patients receiving FUBC was 18.8% (interquartile range, 10.0–29.7%; range, 0–66.1%) across 101 hospitals; this correlated with positivity and contamination rate. Eight hundred ninety (10.1%) patients in the FUBC group and 2263 (8.9%) patients in the no FUBC group died within 30 days. In the fully adjusted model, there was no association between FUBC and mortality (hazard ratio, 0.97; 95% CI, 0.90–1.04). Patients with FUBC had significantly longer length of stay (median, 11 vs. 7 days; adjusted risk ratio, 1.18; 95% CI, 1.16–1.21) and fewer number of days alive and out of hospital at 30 and 90 days.
FUBC collection in patients with GN-BSI varies widely across hospitals and may be associated with prolonged hospitalization without clear survival benefit. Residual confounding may be present given the observational design. Clear benefit should be demonstrated in a randomized trial before widespread adoption of routine FUBC.
Display omitted
IntroductionInformed consent forms (ICFs) for randomised clinical trials (RCTs) can be onerous and lengthy. The process has the potential to overwhelm patients with information, leading them to miss ...elements of the study that are critical for an informed decision. Specifically, overly long and complicated ICFs have the potential to increase barriers to trial participation for patients with mild cognitive impairment, those who do not speak English as a first language or among those with lower medical literacy. In turn, this can influence trial recruitment, completion and external validity.Methods and analysisSIMPLY-SNAP is a pragmatic, multicentre, open-label, two-arm parallel-group superiority RCT, nested within a larger trial, the Staphylococcus aureus Network Adaptive Platform (SNAP) trial. We will randomise potentially eligible participants of the SNAP trial 1:1 to a full-length ICF or a SIMPlified LaYered (SIMPLY) consent process where basic information is summarised with embedded hyperlinks to supplemental information and videos. The primary outcome is recruitment into the SNAP trial. Secondary outcomes include patient understanding of the clinical trial, patient and research staff satisfaction with the consent process, and time taken for consent. As an exploratory outcome, we will also compare measures of diversity (eg, gender, ethnicity), according to the consent process randomised to. The planned sample size will be 346 participants.Ethics and disseminationThe study has been approved by the ethics review board (Sunnybrook Health Sciences Research Ethics Board) at sites in Ontario. We will disseminate study results via the SNAP trial group and other collaborating clinical trial networks.Trial registration numberClinicalTrials.gov Registry (NCT06168474; www.clinicaltrials.gov).
Early treatment of high‐risk COVID‐19 patients may prevent disease progression. However, there are limited data to support treatment of hospitalized or fully vaccinated patients with mild‐to‐moderate ...disease. In this retrospective cohort study, we studied the effect of early use of sotrovimab and remdesivir in high‐risk hospitalized COVID‐19 patients. We included PCR‐confirmed COVID‐19 patients admitted to the National Centre for Infectious Diseases who presented within the first 5 days of illness, and who were not requiring oxygen or ICU care at presentation. Sotrovimab‐ and remdesivir‐treated groups were compared with control (no early treatment). A multiple propensity‐score adjusted multivariable regression analysis was conducted with a composite primary endpoint of in‐hospital deterioration (oxygen requirement, ICU admission, or mortality). Of 1118 patients, 841 were in the control group, 106 in the sotrovimab group and 169 in the remdesivir group. The median age was 63 years (IQR 46–74 years) and 505 (45.2%) were female. In unvaccinated patients, both remdesivir and sotrovimab treatment were protective (adjusted odds ratio aOR 0.19, 95% CI 0.064–0.60 and 0.18 95% CI 0.066–0.47), respectively. Contrarily, among the vaccinated patients there was no significant treatment effect with early remdesivir treatment (aOR 2.51, 95% CI 0.83–7.57, p = 0.10). Remdesivir and sotrovimab treatment, given early in the disease course to unvaccinated high‐risk patients, was effective in reducing the risk of in‐hospital deterioration and severe disease. This effect was not seen in fully vaccinated patients, which may be due to a small sample size or residual confounding.
Data on use of monoclonal antibodies (mAbs) in hospitalized patients are limited. In this cross-sectional study, we evaluated the use of mAbs for early treatment of unvaccinated hospitalized patients ...with mild-to-moderate COVID-19. All inpatients at our center were screened on 27 October 2021. Primary outcome was in-hospital deterioration as defined by a composite of oxygen requirement, intensive care unit (ICU) admission, or mortality within 28 days of admission. Ninety-four out of 410 COVID-19 inpatients were included in the final analysis, of whom 19 (20.2%) received early treatment with sotrovimab. The median age was 73 years (IQR 61-83), and 35 (37.2%) were female. Although the treatment group was significantly older and had more comorbidities, there was a lower proportion of progression to oxygen requirement (31.6% vs. 54.7%), ICU admission (10.5% vs. 24.0%), or mortality (5.3% vs. 13.3%). Kaplan-Meier curves showed a significant difference in time to in-hospital deterioration (log-rank test,
= 0.043). Cox proportional hazards model for in-hospital deterioration showed that sotrovimab treatment was protective (hazard ratio, 0.41; 95% CI, 0.17-0.99;
= 0.047) after adjustment for baseline ISARIC deterioration score. Our findings support the use of sotrovimab for early treatment in hospitalized patients with mild-to-moderate COVID-19 at a high risk of disease progression.
PDF
