Search

Background 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 aminoglycosides versus ceftriaxone by systematic review and meta-analysis. Methods For historical context, we reviewed seminal case series and in vitro studies on the evolution from penicillin monotherapy to modern-day regimens for EFIE. Next, we searched MEDLINE and Embase from inception to 16 January 2024 for studies of EFIE that compared adjunctive aminoglycosides versus ceftriaxone or adjunctive versus monotherapy. Where possible, clinical outcomes were compared between regimens using random effects meta-analysis. Otherwise, data were narratively summarized. Results The meta-analysis was limited to 10 observational studies at high risk of bias (911 patients). Relative to adjunctive ceftriaxone, gentamicin had similar all-cause mortality (risk difference [RD], –0.8%; 95% confidence interval [CI], −5.0 to 3.5), relapse (RD, −0.1%; 95% CI, −2.4 to 2.3), and treatment failure (RD, 1.1%; 95% CI, −1.6 to 3.7) but higher discontinuation due to toxicity (RD, 26.3%; 95% CI, 19.8 to 32.7). The 3 studies that compared adjunctive therapy to monotherapy included only 30 monotherapy patients, and heterogeneity precluded meta-analysis. Conclusions Adjunctive 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. [ABSTRACT FROM AUTHOR]

Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP, including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone. To compare the efficacy and safety of PCP prophylaxis regimens in PWH by network meta-analysis. Embase, MEDLINE, and CENTRAL from inception to June 21, 2023. Comparative randomized controlled trials (RCTs). PWH. Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo. Cochrane risk-of-bias tool for RCTs 2. Title or abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked by network meta-analysis. Subgroup analyses of primary versus secondary prophylaxis, by year, and by dosage were performed. A total of 26 RCTs, comprising 55 treatment arms involving 7516 PWH were included. For the prevention of PCP, TMP-SMX was ranked the most favourable agent and was superior to DBRs (risk ratio [RR] = 0.54; 95% CI, 0.36–0.83) and AP (RR = 0.53; 95% CI, 0.36–0.77). TMP-SMX was also the only agent with a mortality benefit compared with no treatment/placebo (RR = 0.79; 95% CI, 0.64–0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR = 1.25; 95% CI, 1.01–1.54) and AP (7.20; 95% CI, 5.37–9.66). No significant differences in PCP prevention or mortality were detected among the other regimens. The findings remained consistent within subgroups. TMP-SMX is the most effective agent for PCP prophylaxis in PWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Standalone nucleic acid amplification tests (NAATs) are frequently used to diagnose Clostridioides difficile infections (CDI), although they may be unable to distinguish colonization from disease. A 2-stage algorithm pairing NAATs with toxin immunoassays (Toxin) may improve specificity. We evaluated clinical outcomes of patients who were NAAT+/Toxin+ versus NAAT+/Toxin− and treated versus untreated NAAT+/Toxin− cases through systematic review and meta-analysis. Methods We searched EMBASE and MEDLINE from inception to April 1, 2023 for articles comparing CDI outcomes among symptomatic patients tested by NAAT and Toxin tests. The risk differences (RD) of all-cause mortality and CDI recurrence were computed by random effects meta-analysis between patients who were NAAT+/Toxin+ and NAAT+/Toxin−, as well as between patients who were NAAT+/Toxin− and treated or untreated. Results Twenty-six observational studies comprising 12 737 patients were included. The 30-day all-cause mortality was not significantly different between those who were NAAT+/Toxin+ (8.4%) and NAAT+/Toxin− (6.7%) (RD = 0.41%, 95% confidence interval [CI] = −.67, 1.49). Recurrence at 60 days was significantly higher among patients who were NAAT+/Toxin+ (19.8%) versus NAAT+/Toxin− (11.0%) (RD = 7.65%, 95% CI = 4.60, 10.71). Among treated compared to untreated NAAT+/Toxin- cases, the all-cause 30-day mortalities were 5.0% and 12.7%, respectively (RD = −7.45%, 95% CI = −12.29, −2.60), but 60-day recurrence was not significantly different (11.6% vs 7.0%, respectively; RD = 5.25%, 95% CI −1.71, 12.22). Conclusions Treatment of patients who were NAAT+/Toxin− was associated with reduced all-cause mortality but not recurrence. Although subject to the inherent limitations of observational studies, these results suggest that some patients who are NAAT+/Toxin− may benefit from treatment. [ABSTRACT FROM AUTHOR]

Composed of an elaborate ecosystem of bacteria, fungi, viruses and protozoa residing in the human digestive tract, the gut microbiome influences metabolism, immune modulation, bile acid homeostasis and host defence. Through observational and preclinical data, the gut microbiome has been implicated in the pathogenesis of a spectrum of chronic diseases ranging from psychiatric to gastrointestinal in nature. Until recently, the lack of unequivocal evidence supporting a causal link between gut microbiome and human health outcomes incited controversy regarding its significance. However, recent randomised controlled trial (RCT) evidence in conditions, such as Clostridioides difficile infection , cancer immunotherapy and ulcerative colitis, has supported a causal relationship and has underscored the potential of the microbiome as a therapeutic target. This review delineates the RCT evidence substantiating the potential for a causal relationship between the gut microbiome and human health outcomes, the seminal observational evidence that preceded these RCTs and the remaining knowledge gaps., Competing Interests: JP reports grants from MedImmune, grants and personal fees from Merck and personal fees from AstraZeneca, all outside the submitted work. TCL has operating grants from the CIHR and receives salary support from the Fonds de Recherche du Québec—Santé outside of this work. HS is the cofounder and chief technical officer of Kanvas Biosciences and owns equity in the company. PB is the chief scientific officer of Kanvas Biosciences. LS is the chief development officer of Kanvas Biosciences. BR has received grant funding from Davolterra and Kanvas and honoraria from Merck, BMS and AstraZeneca and is the cofounder of Curebiota. CPY reports being on an independent data monitoring committee for Medicago. MPC reports operating grants from the Canadian Institutes of Health Research during the conduct of the study and salary support from the Fonds de Recherche du Québec—Santé, both unrelated to this work; personal fees from GEn1E Lifesciences and Nomic Bio as a member of the scientific advisory board; personal fees from AstraZeneca as a scientific consultant; research support from Cidara Therapeutics, Scynexis and Amplyx Pharmaceutics during the conduct of the study but outside the submitted work; is the cofounder of Kanvas Biosciences and owns equity in the company; and has pending patents, including: (1) methods for detecting tissue damage, graft-versus-host disease and infections using cell-free DNA profiling, (2) methods for assessing the severity and progression of SARS-CoV-2 infections using cell-free DNA pending and (3) rapid identification of antimicrobial resistance and other microbial phenotypes using highly multiplexed fluorescence in situ hybridisation. The other authors declare no conflicts of interest., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)