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Background: Current guidelines recommend adjunctive gentamicin for the treatment of Enterococcus faecalis infective endocarditis (EFIE) despite a risk of toxicity. We sought to revisit the evidence for adjunctive therapy in EFIE and to synthesize the comparative safety and effectiveness of adjunctive use of the aminoglycosides versus ceftriaxone by systematic review and meta-analysis., Methods: For historical context, we reviewed the seminal case series and in vitro studies informing the evolution from penicillin monotherapy to modern-day regimens for EFIE. Next, we searched MEDLINE and Embase from inception to January 16, 2024 for studies of EFIE comparing 1) adjunctive aminoglycosides versus ceftriaxone or 2) adjunctive therapy versus monotherapy. Where possible, clinical outcomes were compared between regimens by random-effects meta-analysis. Otherwise, data were narratively summarized., Results: Results for the systematic review and meta-analysis were limited to 10 observational studies totaling 911 patients. All studies were at high risk of bias. Relative to adjunctive ceftriaxone, gentamicin had similar all-cause mortality (Risk Difference [RD]=-0.8%, 95% Confidence interval [95%CI]=-5.0, 3.5), relapse (RD=-0.1%, 95%CI=-2.4, 2.3), and treatment failure (RD=1.1%, 95%CI=-1.6, 3.7), but higher discontinuation due to toxicity (RD=26.3%, 95%CI=19.8, 32.7). The 3 studies comparing adjunctive therapy to monotherapy included only 30 monotherapy patients and heterogeneity precluded meta-analysis., Conclusion: Adjunctive therapy with ceftriaxone appeared to be equally effective and less toxic than gentamicin for the treatment of EFIE. The existing evidence does not clearly establish the superiority of either adjunctive therapy or monotherapy. Pending randomized evidence, if adjunctive therapy is to be used, ceftriaxone appears to be a reasonable option., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In Staphylococcus aureus bacteremia, mortality rates in randomized controlled trials (RCTs) are consistently lower than observational studies. Stringent eligibility criteria and omission of early deaths in RCTs contribute to this mortality gap. Clinicians should acknowledge the possibility of a lower treatment effect when applying RCT results to bedside care., Competing Interests: Potential conflicts of interest. M. P. C. reports grants from McGill Interdisciplinary Initiative in Infection and Immunity and grants from Canadian Institutes of Health Research during the conduct of the study; personal fees from GEn1E Lifesciences (as a member of the scientific advisory board) and personal fees from nplex biosciences (as a member of the scientific advisory board) and consulting fees from Astra Zaneca outside the submitted work. He is the co-founder of Kanvas Biosciences and owns equity in the company. In addition, M. P. C. has a patent Methods for detecting tissue damage, graft versus host disease, and infections using cell-free DNA profiling pending (Cornell Reference number 9401-01-US), and a patent Methods for assessing the severity and progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections using cell-free DNA pending (Cornell Reference number 9561-01-US) and rapid identification of antimicrobial resistance and other microbial phenotypes using highly multiplexed fluorescence in situ hybridization (Cooley Reference: BEEB-001/00US 342794-2002). T. C. L. and E. G. M. receive research salary support from the Fonds de recherche du Québec – Santé. M. L. reports having served on advisory boards for Sanofi, Pfizer, Medicago, Merck, Seqirus, Paladin Labs; Pan Data Safety, and Monitoring Committees for Medicago, CanSino biologics, National Institutes of Health (NIH), the World Health Organization (WHO) EML Antibiotic Working Group. E. G. M. reports being co-investigator on the SNAP staph aureus platform trial CIHR outside of the submitted work. T. C. L. reports operating funds for other studies from Canadian Institutes of Health Research and McGill Interdisciplinary Institute Infection and Immunity. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Staphylococcus aureus bacteremia (SAB) is a common infection worldwide. We compared SAB mortality in low- and middle-income countries (LMIC) versus high-income countries (HIC) in a meta-analysis., Methods: We searched MEDLINE, Embase, and Cochrane Database of Systematic Reviews from 1991-2021 and included observational, single-country studies on patients with positive blood cultures for S. aureus. The main outcome was the proportion of patients with SAB who died in the hospital. A generalized linear mixed random-effects model was used to pool estimates, and a meta-regression was used to adjust for study-level characteristics., Results: A total of 332 studies involving 517,671 patients in 39 countries were included. No study was conducted in a low-income country. Only 33 (10%) studies were performed in middle-income countries (MIC), which described 6,216 patients. The pooled in-hospital mortality was 32.4% (95% confidence interval [CI] 27.2%-38.2%, T 2  = 0.3063) in MIC and 22.3% (95% CI 20.1%-24.6%, T 2  = 0.3257) in HIC. In a meta-regression model, MIC had higher in-hospital mortality (adjusted odds ratio 1.37, 95% CI 1.11-1.71; P = 0.0042) than HIC., Conclusion: In SAB studies, LMIC are poorly represented. In-hospital mortality was significantly higher in MIC than in HIC. Research should be conducted in LMIC to characterize differences in care processes driving the mortality gap., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Precise estimates of mortality in Staphylococcus aureus bacteraemia (SAB) are important to convey prognosis and guide the design of interventional studies., Objectives: We performed a systematic review and meta-analysis to estimate all-cause mortality in SAB and explore mortality change over time., Data Sources: The MEDLINE and Embase databases, as well as the Cochrane Database of Systematic Reviews, were searched from January 1, 1991 to May 7, 2021., Study Eligibility Criteria: Human observational studies on patients with S. aureus bloodstream infection were included., Participants: The study analyzed data of patients with a positive blood culture for S. aureus., Methods: Two independent reviewers extracted study data and assessed risk of bias using the Newcastle-Ottawa Scale. A generalized, linear, mixed random effects model was used to pool estimates., Results: A total of 341 studies were included, describing a total of 536,791 patients. From 2011 onward, the estimated mortality was 10.4% (95% CI, 9.0%-12.1%) at 7 days, 13.3% (95% CI, 11.1%-15.8%) at 2 weeks, 18.1% (95% CI, 16.3%-20.0%) at 1 month, 27.0% (95% CI, 21.5%-33.3%) at 3 months, and 30.2% (95% CI, 22.4%-39.3%) at 1 year. In a meta-regression model of 1-month mortality, methicillin-resistant S. aureus had a higher mortality rate (adjusted OR (aOR): 1.04; 95% CI, 1.02-1.06 per 10% increase in methicillin-resistant S. aureus proportion). Compared with prior to 2001, more recent time periods had a lower mortality rate (aOR: 0.88; 95% CI, 0.75-1.03 for 2001-2010; aOR: 0.82; 95% CI, 0.69-0.97 for 2011 onward)., Conclusions: SAB mortality has decreased over the last 3 decades. However, more than one in four patients will die within 3 months, and continuous improvement in care remains necessary., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

To evaluate whether health facility-based HIV interventions align with UNAIDS 90-90-90 targets, we performed a systematic review through the lens of UNAIDS targets. We searched 11 databases, retrieving 5201 citations with 26 eligible studies classified by country income and UNAIDS target. We analyzed whether reporting of study outcome metrics was in line with UNAIDS targets using a standardized extraction form and results were summarized in a narrative synthesis given data heterogeneity. We also assessed the quality of randomized trials with the Cochrane Risk of Bias Tool and observational studies with the Newcastle-Ottawa Scale. Stratification of interventions by country income level revealed themes in successful interventions that provide insight for scale-up in similar resource contexts. Few studies reported outcomes using metrics according to UNAIDS targets. Standardization of reporting according to the UNAIDS framework could facilitate comparability of interventions and inform country-level progress on an international scale., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Deaths following Staphylococcus aureus bacteremia (SAB) may be related or unrelated to the infection. In SAB therapeutics research, the length of follow-up should be optimized to capture most attributable deaths and minimize nonattributable deaths. We performed a secondary analysis of a systematic review to describe attributable mortality in SAB over time., Methods: We systematically searched Medline, Embase, and Cochrane Database of Systematic Reviews from 1 January 1991 to 7 May 2021 for human observational studies of SAB. To be included in this secondary analysis, the study must have reported attributable mortality. Two reviewers extracted study data and assessed risk of bias independently. Pooling of study estimates was not performed due to heterogeneity in the definition of attributable deaths., Results: Twenty-four observational cohort studies were included. The median proportion of all-cause deaths that were attributable to SAB was 77% (interquartile range [IQR], 72%-89%) at 1 month and 62% (IQR, 58%-75%) at 3 months. At 1 year, this proportion was 57% in 1 study. In 2 studies that described the rate of increase in mortality over time, 2-week follow-up captured 68 of 79 (86%) and 48 of 57 (84%) attributable deaths that occurred by 3 months. By comparison, 1-month follow-up captured 54 of 57 (95%) and 56 of 60 (93%) attributable deaths that occurred by 3 months in 2 studies., Conclusions: The proportion of deaths that are attributable to SAB decreases as follow-up lengthens. Follow-up duration between 1 and 3 months seems optimal if evaluating processes of care that impact SAB mortality., Clinical Trials Registration: PROSPERO CRD42021253891., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Reaching the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets to end the HIV epidemic relies on effective interventions that engage untested HIV+ individuals and retain them in care. Evidence on community-based interventions through the lens of the targets has not yet been synthesized, reflecting a knowledge gap. We conducted a systematic review and meta-analysis to shed light on successful community-based interventions that have been effective in contributing, directly or indirectly, towards the UNAIDS 90-90-90 targets: knowledge of HIV status, linkage to care/on treatment, and viral suppression. Linkage to care was also included in this review due to the limitations of studies., Methods: We conducted a systematic review and meta-analysis of the period 2007-2018. Eleven databases were searched to identify community-based interventions designed to improve knowledge of HIV status (in particular HIV testing), linkage to care/on treatment, and/or viral suppression. Eligible studies were classified by intervention, population, country income level, outcomes and success. Success was defined as interventions demonstrating statistical significance between intervention and control group or that reached any target by proportion; 90% testing, 81% linked to care/on treatment and 73% viral suppression., Results: Of 82 eligible studies, 51.2% (42/82) reported on HIV testing (first 90), 20.7% (17/82) on linkage to care/ on treatment (second 90), and 45.1% (37/82) on viral suppression (third 90). In all, 67.1% (55/82) of studies reported success; 21 studies on the first 90, 9 towards linkage to care/on treatment, and 25 towards the third. By strategies, 36.6% deployed community workers/peers, 22% used combined test and treat strategies, 12.2% used educational methods, 8.5% used mobile testing, 7.3% used campaigns and 13.4% used technology. For HIV testing/linkage, combined test/treat interventions were often used, for viral suppression, educational interventions and technologies were commonly deployed. Our pooled analysis suggested that deployment of community health care workers/peer workers significantly improved viral suppression (pooled OR: 1.40 95% CI 1.06-1.86). Of the studies published after 2014, 50.0% reported metrics aligned with UNAIDS targets., Conclusions: Data on linkage to care/on treatment (second target) remained weak, because many studies reported successes on the first and third targets. Stratification by targets and country income levels is informative and guides adaptation of successful interventions in comparable settings. Consistent reporting of clear metrics aligned with UNAIDS targets will aid in synergy of study data with programmatic data that will help reportage. Exploration of innovative interventions, for engagement and linkage and deployment of community/ peer workers is strongly encouraged., Competing Interests: The authors have declared that no competing interests exist.

Background: The Joint United Nations Programme on HIV/AIDS (UNAIDS) Fast-Track initiative seeks to eliminate AIDS as a health threat by 2030, with its focus on UNAIDS 90-90-90 targets. Effective policies and programs, if scaled nationally, have the potential to generate a greater impact on HIV control, yet a synthesis of successful HIV policies/programs aligned to the targets is currently unavailable. To fill this gap, we conducted a systematic review to evaluate successful HIV policies and programs to direct future interventions., Methods: For the period 2007-2018, we searched 8 databases and classified eligible studies by country income level, UNAIDS targets, intervention type, and reported outcomes. Study outcomes were classified as per UNAIDS targets; proportionally: 90% target 1, 81% target 2, and 73% target 3., Results: We retrieved 5201 citations and a final set of eight studies on policies. Break up by income: three (38%) from high income, one (12%) from middle income and four (50%) from low income. Break up by outcomes reported: 36% (4/11) focused on HIV testing, 46% (5/11) on antiretroviral therapy initiation, and 18% (2/11) on viral suppression. Across studies, UNAIDS targets were met in high-income countries, where policies and guidelines were adhered to, whereas in low and middle-income countries, non-adherence led to failure to reach the targets. Targets were also met when country infrastructure supported a targeted program and stakeholders were actively engaged., Conclusions: From the studies identified, we deduced a clear, positive correlation between implementation of policies and programs that resulted in an increase in patient awareness and an increase in partner notification with services that encouraged them, and together these resulted in increasing testing rates, and deployment of linkage/retention programs that improved retention in care. An analysis of these studies also suggests that policies, combined with the scale-up incentives, are needed to change the status quo. Incentives to improve the targets must exist; performance incentives at the health care worker level and country level incentives that could transform the nature of care. Given the complexity in reporting of targets, a one size fits all model is not a feasible option. However, the policies created a strong framework to shape future interventions., Competing Interests: The authors have declared that no competing interests exist.

We evaluated Sofosbuvir (SOF), the anti-hepatitis C virus prodrug of β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine-5'-monophosphate, for potential inhibitory activity against DENV replication. Both cell-based and biochemical assays, based on use of purified DENV full-length NS5 enzyme, were studied. Cytopathic effect protection and virus yield reduction assays confirmed that SOF possessed anti-DENV activity in cell culture with a 50% effective concentration (EC 50 ) of 4.9 µM and 1.4 µM respectively. Real-time RT-PCR verified that SOF inhibits generation of viral RNA with an EC 50 of 9.9 µM. Purified DENV NS5 incorporated the active triphosphate form (SOF-TP) into nascent RNA, causing chain-termination. Relative to the natural UTP, the incorporation efficiency of SOF-TP was low (discrimination value = 327.5). In a primer extension assay, SOF-TP was active against DENV NS5 wild-type polymerase activity with an IC 50 of 14.7 ± 2.5 µM. The S600T substitution in the B Motif of DENV polymerase conferred 4.3-fold resistance to SOF-TP; this was due to decreased incorporation efficiency rather than enhanced excision of the incorporated SOF nucleotide. SOF has antiviral activity against DENV replication. The high discrimination value in favor of UTP in enzyme assays may not necessarily preclude antiviral activity in cells. SOF may be worthy of evaluation against severe DENV infections in humans.

Background: The viral RNA-dependent RNA polymerase (RdRp) enzymes of the Flaviviridae family are essential for viral replication and are logically important targets for development of antiviral therapeutic agents. Zika virus (ZIKV) is a rapidly re-emerging human pathogen for which no vaccine or antiviral agent is currently available., Methods: To facilitate development of ZIKV RdRp inhibitors, we have established an RdRp assay using purified recombinant ZIKV NS5 polymerase., Results: We have shown that both the hepatitis C virus (HCV) nucleoside inhibitor sofosbuvir triphosphate and a pyridoxine-derived non-nucleoside small-molecule inhibitor, DMB213, can act against ZIKV RdRp activity at IC 50 s of 7.3 and 5.2 μM, respectively, in RNA synthesis reactions catalysed by recombinant ZIKV NS5 polymerase. Cell-based assays confirmed the anti-ZIKV activity of sofosbuvir and DMB213 with 50% effective concentrations (EC 50 s) of 8.3 and 4.6 μM, respectively. Control studies showed that DMB213 did not inhibit recombinant HIV-1 reverse transcriptase and showed only very weak inhibition of HIV-1 integrase strand-transfer activity. The S604T substitution in motif B of the ZIKV RdRp, which corresponds to the S282T substitution in motif B of HCV RdRp, which confers resistance to nucleotide inhibitors, also conferred resistance to sofosbuvir triphosphate, but not to DMB213. Enzyme assays showed that DMB213 appears to be competitive with natural nucleoside triphosphate (NTP) substrates., Conclusions: Recombinant ZIKV RdRp assays can be useful tools for the screening of both nucleos(t)ide compounds and non-nucleotide metal ion-chelating agents that interfere with ZIKV replication., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)