Remdesivir is a nucleoside monophosphoramidate prodrug that has been FDA-approved for COVID-19. However, the clinical efficacy of remdesivir for COVID-19 remains contentious, as several trials have not found statistically significant differences in either time to clinical improvement or mortality between remdesivir-treated and control groups. Similarly, the inability for remdesivir to provide a clinically significant benefit above other investigational agents in patients with Ebola contrasts with strong, curative preclinical data generated in rhesus macaque models. For both COVID-19 and Ebola, significant discordance between the robust preclinical data and remdesivir's lackluster clinical performance have left many puzzled. Here, we critically evaluate the assumptions of the models underlying remdesivir's promising preclinical data and show that such assumptions over-predict efficacy and minimize toxicity of remdesivir in humans. Had the limitations of in vitro drug efficacy testing and species differences in drug metabolism been considered, the underwhelming clinical performance of remdesivir for both COVID-19 and Ebola would have been fully anticipated.Amikacin and kanamycin are second line injectables used in the treatment of multidrug resistant tuberculosis (MDR-TB), based on the clinical utility of streptomycin, another aminoglycoside and first line anti-TB drug. While streptomycin was tested as a single agent in the first controlled TB clinical trial, introduction of amikacin and kanamycin into MDR-TB regimens was not preceded by randomized controlled trials. A recent large retrospective meta-analysis revealed that compared with regimens without any injectable drug, amikacin provided modest benefits, and kanamycin was associated with worse outcomes. Although their long-term use can cause irreversible ototoxicity, they remain part of MDR-TB regimens because they have a role in preventing emergence of resistance to other drugs. To quantify the contribution of amikacin and kanamycin to second-line regimens, we applied 2-dimensional MALDI mass spectrometry imaging in large lung lesions, quantified drug exposure in lung and lesions of rabbits with active TB, and measured the concentrations required to kill or inhibit growth of the resident bacterial populations. Using these metrics, we applied site-of-action pharmacokinetic and pharmacodynamic (PK-PD) concepts and simulated drug coverage in patients' lung lesions. The results provide a pharmacological explanation for the limited clinical utility of both agents and reveal better PK-PD lesion coverage for amikacin than kanamycin, consistent with retrospective data of contribution to treatment success. Together with recent mechanistic studies dissecting antibacterial activity from aminoglycoside ototoxicity, the limited but rapid penetration of streptomycin, amikacin and kanamycin to the sites of TB disease supports the development of analogs with improved efficacy and tolerability.Objectives Objectives of this study were to evaluate the pattern of antibiotic prescription for endodontic infections (EIs) among Italian dental practitioners (DPs), and to explore the role of potential predictors of antibiotic over-prescription. Methods A nationwide cross-sectional survey was conducted between 1st April to 30th October 2019 using a structured questionnaire. Information was gathered on demographics and professional characteristics, and practices regarding antibiotic prescription both for therapeutic and prophylactic purposes. Results Of the 1250 invited DPs, 563 answered the general questionnaire (response rate 52.6%). The proportions of DPs who prescribed an antibiotic without indication for therapeutic and prophylactic purposes is 33.3% and 30.2%, respectively. The acute alveolar abscess without systemic involvement represents the clinical scenario at high risk of over-prescription for therapeutic purposes. Possible predictors of over-prescribing included demographics and professional characteristics, and it was found to be higher in EIs without indication than in the cases in which the prescription is indicated for therapeutic purposes. The odds of over-prescription for prophylactic purposes were higher in the cases of acute apical periodontitis and lower in the cases of symptomatic irreversible pulpitis compared with acute and chronic alveolar abscess, in which the prescription is indicated. Conclusions The main findings of the present study provide an up-to-date insight about the pattern of antibiotic prescriptions for EIs and evidence useful to identify opportunities to reduce over-prescription among DPs through tailored interventions. The development of practical antibiotic prescribing guidelines with a clear description of indications and regimens ease of use is strongly needed.Infections with rapid-growing-mycobacteria (RGM) are often difficult to treat.….Abiotrophia and Granulicatella species are fastidious organisms, representing around 1%-3% of infective endocarditis (IE). Little is known about the optimal antibiotic treatment of these species, and daptomycin has been suggested as a therapeutic option. Bulevirtide mouse We describe the antimicrobial profile in Abiotrophia and Granulicatella IE isolates, investigate high-level daptomycin resistance (HLDR) development and evaluate daptomycin activity in combination therapy. In vitro studies with 16 IE strains (6 A. defectiva, 9 G. adiacens and 1 G. elegans) were performed using microdilution to determine minimal inhibitory concentration (MIC) and time-kill methodology to evaluate combination therapy. Daptomycin non-susceptibility (DNS; MIC≥ 2 mg/L) and HLDR (MIC≥256 mg/L) were based on existing Clinical and Laboratory Standards (CLSI) breakpoints for viridans streptococci. All isolates were susceptible to vancomycin G. adiacens was more susceptible to penicillin and ampicillin than A. defectiva (22% vs. 0%, and 67% vs. 33%) but less susceptible to ceftriaxone and daptomycin (56% vs. 83%, and 11% vs. 50%). HLDR developed in both A. defectiva (33%) and G. adiacens (78%) after 24h exposure to daptomycin. Combination therapy did not prevent the development of daptomycin resistance with ampicillin (2/3 strains), gentamicin (2/3 strains), ceftriaxone (2/3 strains) or ceftaroline (2/3 strains). Once developed, HLDR was stable for a prolonged time (>3 weeks) in G. adiacens, whereas in A. defectiva the HLDR it reversed to baseline MIC at day 10. This study is first to demonstrate rapid HLDR development in Abiotrophia and Granulicatella species in vitro. Resistance was stable, and most combination therapies did not prevent it.