The value of MALDI-TOF failure to provide an identification of Staphylococcal species direct from blood cultures and rule out Staphylococcus aureus bacteraemia:a post-hoc analysis of the RAPIDO trial

INTRODUCTION: Rapid differentiation between Staphylococcus aureus (SA) and coagulase-negative staphylococci (CoNS) is critical in clinical infection. Direct matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) identification from blood culture is highly accurate, but is associated with a significant failure rate, delaying identification. However, MALDI-TOF failure may itself be indicative of CoNS infection. AIM: We sought to examine whether failure of MALDI-TOF direct ID was indicative of CoNS infection and could be used as a diagnostic tool to promote antimicrobial stewardship. METHODOLOGY: Results of Gram stains, MALDI-TOF identification and formal identification were extracted from the large, multi-centre RAPIDO trial. All blood cultures with presumed staphylococci were included. MALDI-TOF performance (correct identification, incorrect identification, failed identification) was calculated for each sample and across sites. Risk of SA disease was calculated for each group (correct, incorrect, failed) and across sites. Logistic regression was used to identify if clinical features are associated with MALDI-TOF performance. RESULTS: In the RAPIDO trial, 4312 patients were allocated to the MALDI-TOF arm. After exclusions, 880 patients were eligible and had a blood culture with a Gram stain consistent with presumed staphylococci. In total, 204 of these (23.2 %) were ultimately identified as SA. MALDI-ID was successful 83.9 % of the time, and was 100 % accurate when successful. Failure was more common in CoNS isolates (124/641, 19.3 %) than in SA (13/191, 6.4 %). When MALDI-TOF failed, the risk of SA disease was 9.2 % across the whole cohort, although failure rates and risk of SA disease varied significantly between centres. MALDI-TOF failure was independent of clinical characteristics. CONCLUSION: Presumed staphylococci that fail direct MALDI-TOF identification from blood culture are significantly more likely to be CoNS isolates than SA. In low-risk or low-prevalence settings, SA therapy can be withheld if MALDI-TOF is unsuccessful

Patients with transplantation have reduced mortality in bacteraemia:Analysis of data from a randomised trial

Objectives Infection remains a major complication of organ transplantation. Paradoxically, epidemiological studies suggest better survival from serious infection. We analysed the relationship between organ transplantation and short -term mortality of patients with bloodstream infection. Methods Data on transplantation status was extracted from a large prospective, multi-centre clinical trial in bloodstream infection. Logistic regression for 28-day mortality was performed on the whole cohort and a propensity-matched cohort (3:1). Infective pathogen, focus of infection, and clinical variables were included in the model. Mediation analysis was performed on clinical variables to explore causation. Results 4,178 participants were included in the full cohort, with 868 in the matched cohort, of which 217 received an organ transplant. Haematopoietic stem cell transplants (HSCT) were the most common transplant (n = 99), followed by kidney (n = 70). The most common pathogens were staphylococci and Enterobacterales. Transplantation status was associated with a reduced mortality in both the whole (Odds Ratio, OR 0.53; 95% CI 0.28, 0.77) and matched (OR 0.55, 95% CI 0.34, 0.90) cohort, while steroid use was robustly associated with increased mortality OR 4.4 (95% CI 3.12, 6.20) in the whole cohort and OR 5.24 (95% CI 2.79, 9.84) in the matched cohort. There was no interaction between steroid use and transplant status, so transplant patients on steroids generally had increased mortality relative to those without either. Conclusions Organ transplantation is associated with a near halving of short term mortality in bloodstream infection, including a cohort matched for comorbidities, infective pathogen and focus. Steroid usage is associated with increased mortality regardless of transplant status. Understanding the mechanism and causation of this mortality benefit should be a focus of future research

Time-to-positivity in bloodstream infection is not a prognostic marker for mortality:analysis of a prospective multicentre randomized control trial

Objectives Time to positivity (TTP), calculated automatically in modern blood culture systems, is considered a proxy for microbial load and has been suggested as a potential prognostic marker in bloodstream infections. In this large, multicentre, prospectively collected cohort, our primary analysis aimed to quantify the relationship between the TTP of monomicrobial blood cultures and mortality. Methods Data from a multicentre randomized controlled trial (RAPIDO) in bloodstream infection were analysed. Bloodstream infections were classified into 13 groups/subgroups. The relationship between mortality and TTP was assessed by logistic regression, adjusted for site, organism, and clinical variables, and linear regression was applied to examine the association between clinical variables and TTP. Robustness was assessed by sensitivity analysis. Results In total 4468 participants were included in the RAPIDO. After exclusions, 3462 were analysed, with the most common organisms being coagulase-negative staphylococci (1072 patients) and Escherichia coli (861 patients); 785 patients (22.7%) died within 28 days. We found no relationship between TTP and mortality for any groups except for streptococci (odds ratio (OR) with each hour 0.98, 95%CI 0.96–1.00) and Candida (OR 1.03, 95%CI 1.00–1.05). There was large variability between organisms and sites in TTP. Fever (geometric mean ratio (GMR) 0.95, 95%CI 0.92–0.99), age (GMR per 10 years 1.01, 95%CI 1.00–1.02), and neutrophilia were associated with TTP (GMR 1.03, 95%CI 1.02–1.04). Conclusions Time to positivity is not associated with mortality, except in the case of Candida spp. (longer times associated with worse outcomes) and possibly streptococci (shorter times associated with worse outcomes). There was a large variation between median times across centres, limiting external validity

Is convalescent plasma futile in COVID-19?:A Bayesian re-analysis of the RECOVERY randomized controlled trial

Background: Randomized trials are generally performed from a frequentist perspective, which can conflate absence of evidence with evidence of absence. The RECOVERY trial evaluated convalescent plasma for patients hospitalized with coronavirus disease 2019 (COVID-19) and concluded that there was no evidence of an effect. Re-analysis from a Bayesian perspective is warranted. Methods: Outcome data were extracted from the RECOVERY trial by serostatus and time of presentation. A Bayesian re-analysis with a wide variety of priors (vague, optimistic, sceptical, and pessimistic) was performed, calculating the posterior probability for: any benefit, an absolute risk difference of 0.5% (small benefit, number needed to treat 200), and an absolute risk difference of one percentage point (modest benefit, number needed to treat 100). Results: Across all patients, when analysed with a vague prior, the likelihood of any benefit or a modest benefit with convalescent plasma was estimated to be 64% and 18%, respectively. The estimated chance of any benefit was 95% if presenting within 7 days of symptoms, or 17% if presenting after this. In patients without a detectable antibody response at presentation, the chance of any benefit was 85%. However, it was only 20% in patients with a detectable antibody response at presentation. Conclusions: Bayesian re-analysis suggests that convalescent plasma reduces mortality by at least one percentage point among the 39% of patients who present within 7 days of symptoms, and that there is a 67% chance of the same mortality reduction in the 38% who are seronegative at the time of presentation. This is in contrast to the results in people who already have antibodies when they present. This biologically plausible finding bears witness to the advantage of Bayesian analyses over misuse of hypothesis tests to inform decisions