Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs plac...

Antimicrobial stewardship programs (ASPs) have made immense strides in optimizing antibiotic, antifungal, and antiviral use in clinical settings. However, although ASPs are required institutionally by regulatory agencies in the United States and Canada, they are not mandated for transplant centers or programs specifically. Despite the fact that solid organ transplant recipients in particular are at increased risk of infections from multidrug-resistant organisms, due to host and donor factors and immunosuppressive therapy, there currently are little rigorous data regarding stewardship practices in solid organ transplant populations, and thus, no transplant-specific requirements currently exist. Further complicating matters, transplant patients have a wide range of variability regarding their susceptibility to infection, as factors such as surgery of transplant, intensity of immunosuppression, and presence of drains or catheters in situ may modify the risk of infection. As such, it is not feasible to have a "one-size-fitsall" style of stewardship for this patient population. The objective of this white paper is to identify opportunities, risk factors, and ASP strategies that should be assessed with solid organ transplant recipients to optimize antimicrobial use, while producing an overall improvement in patient outcomes. We hope it may serve as a springboard for development of future guidance and identification of research opportunities. K E Y W O R D S antibiotic prophylaxis, ethics and public policy, health services and outcomes research, infection and infectious agents, organ transplantation in general How to cite this article: So M, Hand J, Forrest G, et al. White paper on antimicrobial stewardship in solid organ transplant recipients.

for the DMID 13-0032 H7N9 Vaccine Study Group IMPORTANCE Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China.OBJECTIVE To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014.INTERVENTIONS The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 μg of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700). MAIN OUTCOMES AND MEASURESProportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer Ն40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7.RESULTS Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 μg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95% CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95% CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95% CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 μg of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95% CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95% CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 μg doses (n = 34 [35%; 95% CI, 25%-45%] vs n = 47 [47%; 95% CI, 37%-58%], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant.CONCLUSIONS AND RELEVANCE Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59% of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes.

We determined the target enzyme interactions of garenoxacin (BMS-284756, T-3811ME), a novel desfluoroquinolone, in Staphylococcus aureus by genetic and biochemical studies. We found garenoxacin to be four-to eightfold more active than ciprofloxacin against wild-type S. aureus. A single topoisomerase IV or gyrase mutation caused only a 2-to 4-fold increase in the MIC of garenoxacin, whereas a combination of mutations in both loci caused a substantial increase (128-fold). Overexpression of the NorA efflux pump had minimal effect on resistance to garenoxacin. With garenoxacin at twice the MIC, selection of resistant mutants (<7.4 ؋ 10 ؊12 to 4.0 ؋ 10 ؊11 ) was 5 to 6 log units less than that with ciprofloxacin. Mutations inside or outside the quinolone resistance-determining regions (QRDR) of either topoisomerase IV, or gyrase, or both were selected in single-step mutants, suggesting dual targeting of topoisomerase IV and gyrase. Three of the novel mutations were shown by genetic experiments to be responsible for resistance. Studies with purified topoisomerase IV and gyrase from S. aureus also showed that garenoxacin had similar activity against topoisomerase IV and gyrase (50% inhibitory concentration, 1.25 to 2.5 and 1.25 g/ml, respectively), and although its activity against topoisomerase IV was 2-fold greater than that of ciprofloxacin, its activity against gyrase was 10-fold greater. This study provides the first genetic and biochemical data supporting the dual targeting of topoisomerase IV and gyrase in S. aureus by a quinolone as well as providing genetic proof for the expansion of the QRDRs to include the 5 terminus of grlB and the 3 terminus of gyrA.

Premafloxacin is a novel 8-methoxy fluoroquinolone with enhanced activity against Staphylococcus aureus. We found premafloxacin to be 32-fold more active than ciprofloxacin against wild-type S. aureus. Single mutations in either subunit of topoisomerase IV caused a four-to eightfold increase in the MICs of both quinolones. A double mutation (gyrA and either grlA or grlB) caused a 32-fold increase in the MIC of premafloxacin, while the MIC of ciprofloxacin increased 128-fold. Premafloxacin appeared to be a poor substrate for NorA, with NorA overexpression causing an increase of twofold or less in the MIC of premafloxacin in comparison to a fourfold increase in the MIC of ciprofloxacin. The frequency of selection of resistant mutants was 6.4 ؋ 10 ؊10 to 4.0 ؋ 10 ؊7 at twofold the MIC of premafloxacin, 2 to 4 log 10 less than that with ciprofloxacin. Single-step mutants could not be selected at higher concentrations of premafloxacin. In five single-step mutants, only one previously described uncommon mutation (Ala116Glu), and four novel mutations (Arg43Cys, Asp69Tyr, Ala176Thr, and Pro157Leu), three of which were outside the quinolone resistance-determining region (QRDR) were found. Genetic linkage studies, in which incross of grlA ؉ and outcross of mutations were performed, showed a high correlation between the mutations and the resistance phenotypes, and allelic exchange experiments confirmed the role of the novel mutations in grlA in resistance. Our results suggest that although topoisomerase IV is the primary target of premafloxacin, premafloxacin appears to interact with topoisomerase IV in a manner different from that of other quinolones and that the range of the QRDR of grlA should be expanded.

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Nontuberculous mycobacteria (NTM) are a diverse group of organisms that are ubiquitous in the environment, and the incidence of cutaneous infections due to NTM has been steadily increasing. Cutaneous infections due to NTM can be difficult to diagnose, due to their wide spectrum of clinical presentations and histopathological findings that are often nonspecific. A variety of modalities including tissue culture and polymerase chain reaction (PCR) assays may be necessary to identify the organism. Treatment can also be challenging, as it can depend on multiple factors, including the causative organism, the patient's immunological status, and the extent of disease involvement. In this review, we discuss the common presentations of cutaneous NTM infections, diagnostic tools, and treatment recommendations. A multi-disciplinary approach that involves good communication between the clinician, the histopathologist, the microbiologist, and infectious disease specialists can help lead to successful diagnosis and management.

Gatifloxacin, an 8-methoxyfluoroquinolone, was found to be two-to fourfold more active against wild-type Staphylococcus aureus ISP794 than its desmethoxy derivative, AM-1121, and ciprofloxacin, another desmethoxy fluoroquinolone. Single grlBA mutations caused two-to fourfold increases in the MIC of gatifloxacin, and a single gyrase mutation was silent. Double mutations in gyrA and grlA or grlB caused a 32-fold increase in the MIC of gatifloxacin, in contrast to a 128-fold increase for ciprofloxacin and AM-1121. Overexpression of the NorA efflux pump had minimal effect on the MIC of gatifloxacin. The bactericidal activity of the three quinolones at four times the MIC differed only for a double mutant, with gatifloxacin exhibiting a killing pattern similar to that for ISP794, whereas ciprofloxacin and AM-1121 failed to show any killing. With gatifloxacin, selection of resistant mutants at twice the MIC was 100-to 1,000-fold less frequent than with the comparison quinolones, and mutants could rarely be selected at four times the MIC. The limit resistance in ISP74 was 512 times the MIC of gatifloxacin and 1,024 times the MICs of ciprofloxacin and AM-1121. Novel mutations in topoisomerase IV were selected in five of the six single-step mutants, three of which were shown to cause quinolone resistance by genetic studies. In conclusion, topoisomerase IV is the primary target of gatifloxacin. In contrast to comparison quinolones, mutations in both topoisomerase IV and gyrase are required for resistance to gatifloxacin by clinical breakpoints and do not abolish bactericidal effect, further supporting the benefit of the 8-methoxy substituent in gatifloxacin.