Refined innate plasma signature after rVSVΔG-ZEBOV-GP immunization is shared among adult cohorts in Europe and North America

BackgroundDuring the last decade Ebola virus has caused several outbreaks in Africa. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSVΔG-ZEBOV-GP) vaccine has proved safe and immunogenic but is reactogenic. We previously identified the first innate plasma signature response after vaccination in Geneva as composed of five monocyte-related biomarkers peaking at day 1 post-immunization that correlates with adverse events, biological outcomes (haematological changes and viremia) and antibody titers. In this follow-up study, we sought to identify additional biomarkers in the same Geneva cohort and validate those identified markers in a US cohort.MethodsAdditional biomarkers were identified using multiplexed protein biomarker platform O-link and confirmed by Luminex. Principal component analysis (PCA) evaluated if these markers could explain a higher variability of the vaccine response (and thereby refined the initial signature). Multivariable and linear regression models evaluated the correlations of the main components with adverse events, biological outcomes, and antibody titers. External validation of the refined signature was conducted in a second cohort of US vaccinees (n=142).ResultsEleven additional biomarkers peaked at day 1 post-immunization: MCP2, MCP3, MCP4, CXCL10, OSM, CX3CL1, MCSF, CXCL11, TRAIL, RANKL and IL15. PCA analysis retained three principal components (PC) that accounted for 79% of the vaccine response variability. PC1 and PC2 were very robust and had different biomarkers that contributed to their variability. PC1 better discriminated different doses, better defined the risk of fever and myalgia, while PC2 better defined the risk of headache. We also found new biomarkers that correlated with reactogenicity, including transient arthritis (MCP-2, CXCL10, CXCL11, CX3CL1, MCSF, IL-15, OSM). Several innate biomarkers are associated with antibody levels one and six months after vaccination. Refined PC1 correlated strongly in both data sets (Geneva: r = 0.97, P < 0.001; US: r = 0.99, P< 0.001).ConclusionEleven additional biomarkers refined the previously found 5-biomarker Geneva signature. The refined signature better discriminated between different doses, was strongly associated with the risk of adverse events and with antibody responses and was validated in a separate cohort

Therapeutic drug monitoring of the β-lactam antibiotics: what is the evidence and which patients should we be using it for?

Traditional antibiotic dosing was not designed for today's escalating antibiotic resistance, lack of novel antibiotics and growing complexity in patient populations. Dosing that ensures optimal antibiotic exposures should be considered essential to increase the likelihood of effective patient treatment. Given the variability in these exposures across different patients, a ‘one-dose-fits-all' approach is increasingly problematic. Therapeutic drug monitoring (TDM) of the β-lactams, the most widely used antibiotic class, is underutilized in certain populations. Clinical experience with β-lactam TDM remains relatively scarce. Patients most likely to benefit from such an intervention include the critically ill, the obese, the elderly and those with cystic fibrosis. Most centres actively performing β-lactam TDM target a minimum 100% of the time during the dosing interval that the free (unbound) concentration of antibiotic exceeds the MIC of the pathogen (100% fT>MIC), which is higher than a traditional target supported by in vitro data. Ideally, isolated pathogens should undergo MIC testing along with TDM on a regular basis, allowing clinicians to address the triad of bug, drug and patient (‘mug') in equal measur

Infectious olecranon and patellar bursitis: short-course adjuvant antibiotic therapy is not a risk factor for recurrence in adult hospitalized patients

Objectives No evidence-based recommendations exist for the management of infectious bursitis. We examined epidemiology and risk factors for recurrence of septic bursitis. Specifically, we compared outcome in patients receiving bursectomy plus short-course adjuvant antibiotic therapy (≤7 days) with that of patients receiving bursectomy plus longer-course antibiotic therapy (>7 days). Patients and methods Retrospective study of adult patients with infectious olecranon and patellar bursitis requiring hospitalization at Geneva University Hospital from January 1996 to March 2009. Results We identified 343 episodes of infectious bursitis (237 olecranon and 106 patellar). Staphylococcus aureus predominated among the 256 cases with an identifiable pathogen (85%). Three hundred and twelve cases (91%) were treated surgically; 142 (41%) with one-stage bursectomy and closure and 146 with two-stage bursectomy. All received antibiotics for a median duration of 13 days with a median intravenous component of 3 days. Cure was achieved in 293 (85%) episodes. Total duration of antibiotic therapy [odds ratio (OR) 0.9; 95% confidence interval (95% CI) 0.8-1.1] showed no association with cure. In multivariate analysis, only immunosuppression was linked to recurrence (OR 5.6; 95% CI 1.9-18.4). Compared with ≤7 days, 8-14 days of antibiotic treatment (OR 0.6; 95% CI 0.1-2.9) or >14 days of antibiotic treatment (OR 0.9; 95% CI 0.1-10.7) was equivalent, as was the intravenous component (OR 1.1; 95% CI 1.0-1.3). Conclusions In severe infectious bursitis requiring hospitalization, adjuvant antibiotic therapy might be limited to 7 days in non-immunosuppressed patient

Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials

The available evidence supports first-line treatment of lower urinary tract infections with nitrofurantoin as clinical efficacy is similar to that seen for trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin, rates of microbiological cure are good, short- term toxicity is generally mild and acquired resistance is still relatively rar

Association between women's authorship and women's editorship in infectious diseases journals : a cross-sectional study

Funding: The European Society of Clinical Microbiology and Infectious Diseases.Background Gender inequity is still pervasive in academic medicine, including journal publishing. We aimed to ascertain the proportion of women among first and last authors and editors in infectious diseases journals and assess the association between women's editorship and women's authorship while controlling for a journal's impact factor. Methods In this cross-sectional study, we randomly selected 40 infectious diseases journals (ten from each 2020 impact factor quartile), 20 obstetrics and gynaecology journals (five from each 2020 impact factor quartile), and 20 cardiology journals (five from each 2020 impact factor quartile) that were indexed in Journal Citation Reports, had an impact factor, had retrievable first and last author names, and had the name of more than one editor listed. We retrieved the names of the first and last authors of all citable articles published by the journals in 2018 and 2019 that counted towards their 2020 impact factor and collected the names of all the journals' editors-in-chief, deputy editors, section editors, and associate editors for the years 2018 and 2019. We used genderize.io to predict the gender of each first author, last author, and editor. The outcomes of interest were the proportions of women first authors and women last authors. We assessed the association between women's editorship and women's authorship by fitting quasi-Poisson regression models comprising the variables: the proportion of women last authors or women first authors; the proportion of women editors; the presence of a woman editor-in-chief; and journal 2020 impact factor. Findings We found 11 027 citable infectious diseases articles, of which 167 (1·5%) had an indeterminable first author gender, 155 (1·4%) had an indeterminable last author gender, and seven (0·1%) had no authors indexed. 5350 (49·3%) of 10 853 first authors whose gender could be determined were predicted to be women and 5503 (50·7%) were predicted to be men. Women accounted for 3788 (34·9%) of 10 865 last authors whose gender could be determined and men accounted for 7077 (65·1%). Of 577 infectious diseases journal editors, 190 (32·9%) were predicted to be women and 387 (67·1%) were predicted to be men. Of the 40 infectious diseases journals, 13 (32·5%) had a woman as editor-in-chief. For infectious diseases journals, the proportion of women editors had a significant effect on women's first authorship (incidence rate ratio 1·32, 95% CI 1·06–1·63; p=0·012) and women's last authorship (1·92, 1·45–2·55; p<0·0001). The presence of a woman editor-in-chief, the proportion of women last or first authors, and the journal's impact factor exerted no effect in these analyses. Interpretation The proportion of women editors appears to influence the proportion of women last and first authors in the analysed infectious diseases journals. These findings might help to explain gender disparities observed in publishing in academic medicine and suggest a need for revised policies towards increasing women's representation among editors.PostprintPeer reviewe

Towards Precision Medicine: Therapeutic Drug Monitoring–Guided Dosing of Vancomycin and β-lactam Antibiotics to Maximize Effectiveness and Minimize Toxicity

Purpose The goal of this review is to explore the role of antimicrobial therapeutic drug monitoring (TDM), especially in critically ill, obese, and older adults, with a specific focus on β-lactams and vancomycin. Summary The continued rise of antimicrobial resistance prompts the need to optimize antimicrobial dosing. The aim of TDM is to individualize antimicrobial dosing to achieve antibiotic exposures associated with improved patient outcomes. Initially, TDM was developed to minimize adverse effects during use of narrow therapeutic index agents. Today, patient and organism complexity are expanding the need for precision dosing through TDM services. Alterations of pharmacokinetics and pharmacodynamics (PK/PD) in the critically ill, obese, and older adult populations, in conjunction with declining organism susceptibility, complicate attainment of therapeutic targets. Over the last decade, antimicrobial TDM has expanded with the emergence of literature supporting β-lactam TDM and a shift from monitoring vancomycin trough concentrations to monitoring of the ratio of area under the concentration (AUC) curve to minimum inhibitory concentration (MIC). PK/PD experts should be at the forefront of implementing precision dosing practices. Conclusion Precision dosing through TDM is expanding and is especially important in populations with altered PK/PD, including critically ill, obese, and older adults. Due to wide PK/PD variability in these populations, TDM is vital to maximize antimicrobial effectiveness and decrease adverse event rates. However, there is still a need for studies connecting TDM to patient outcomes. Providing patient-specific care through β-lactam TDM and transitioning to vancomycin AUC/MIC monitoring may be challenging, but with experts at the forefront of this initiative, PK-based optimization of antimicrobial therapy can be achieved

A systematic review assessing the under-representation of elderly adults in COVID-19 trials

Coronavirus disease (COVID-19) has caused a pandemic threatening millions of people worldwide. Yet studies specifically assessing the geriatric population are scarce. We aimed to examine the participation of elderly patients in therapeutic or prophylactic trials on COVID-19

Duration of antibiotic treatment for Gram-negative bacteremia - Systematic review and individual participant data (IPD) meta-analysis

Background: We aim to compare the effect of short versus long treatment duration in Gram-negative bacteremia on all-cause mortality in pre-specified sub-groups. Methods: Individual participant data meta-analysis of randomized controlled trials (RCTs) comparing short (≤7) versus longer (&gt;7 days) antibiotic treatment for Gram-negative bacteremia. Participants were adults (≥18 years), with Gram-negative bacteremia during hospital stay. We searched PubMed, Cochrane Central Register of Controlled Trials, and Web of Science to identify trials conducted up to May 2022. Primary outcome was 90-day all-cause mortality. Secondary outcomes were 30-day mortality, relapse of bacteremia, length of hospital stay, readmission, local or distant infection complications, adverse events, and resistance emergence.Outcomes were assessed in pre-specified subgroups: women vs men; non-urinary vs urinary source; presence vs absence of hypotension on initial presentation; immunocompromised patients versus non-immunocompromised patients, and age (above/below 65). Fixed-effect meta-analysis model was used to estimate pooled odds ratio (OR) and 95% confidence interval (CI). All three trials had low risk of bias for allocation generation and concealment. Findings: Three RCTs (1186 patients) were included; 1121 with enterobacterales bacteremia. No significant difference in mortality was demonstrated between 7- and 14-days treatment (90-day mortality: OR 1.08, 95% CI 0.73-1.58; 30-day mortality: 1.08, 0.62-1.91). Relapse (1.00, 0.50-1.97); length of hospital stay (P&nbsp;=&nbsp;0.78); readmission (0.96, 0.80-1.22); and infection complications (local: 1.62 0.76-3.47; distant: 2.00, 0.18-22.08), were without significant difference, and so were adverse events or resistance emergence.No significant difference in clinical outcomes between 7 and 14 days of antibiotics was demonstrated in the subgroups of gender, age, hemodynamic status, immune status, and source of infection. Interpretation: For patients hemodynamically stable and afebrile at 48&nbsp;h prior to discontinuation, seven days of antibiotic therapy for enterobacterales bacteremia result in similar outcomes as 14 days, in terms of mortality, relapse, length of hospital stay, complications of infection, resistance emergence, and adverse events. These results apply for any adult age group, gender, source of infection, immune status, and hemodynamic status on presentation. Funding: There was no funding source for this study

guide to clinicians

Funding This work received an unrestricted grant from GSK Portugal and was supported by Sociedade Portuguesa de Ginecologia (SPG).Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In this context, biomarkers could be considered as indicators of either infection or dysregulated host response or response to treatment and/or aid clinicians to prognosticate patient risk. More than 250 biomarkers have been identified and evaluated over the last few decades, but no biomarker accurately differentiates between sepsis and sepsis-like syndrome. Published data support the use of biomarkers for pathogen identification, clinical diagnosis, and optimization of antibiotic treatment. In this narrative review, we highlight how clinicians could improve the use of pathogen-specific and of the most used host-response biomarkers, procalcitonin and C-reactive protein, to improve the clinical care of patients with sepsis. Biomarker kinetics are more useful than single values in predicting sepsis, when making the diagnosis and assessing the response to antibiotic therapy. Finally, integrated biomarker-guided algorithms may hold promise to improve both the diagnosis and prognosis of sepsis. Herein, we provide current data on the clinical utility of pathogen-specific and host-response biomarkers, offer guidance on how to optimize their use, and propose the needs for future research.publishersversionepub_ahead_of_prin