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Background: The APEKS-cUTI study demonstrated the non-inferiority of cefiderocol to imipenem−cilastatin in the primary endpoint of the composite of clinical and microbiological outcome in patients with complicated urinary tract infections (cUTIs). We piloted a structured patient interview (SPI) to evaluate clinical outcomes based on patient-reported symptoms while conducting this pivotal randomized, double-blind, phase-2 study. The objectives were to assess the value of the SPI, using its performance relative to physician assessment, and also to strengthen the value of patient-reported measures in conducting clinical trials for cUTI treatment. Methods: In addition to the protocol-defined clinical and microbiological outcomes, patients randomized in the APEKS-cUTI study were interviewed by the investigator or qualified study personnel at screening/baseline, early assessment (EA), end of treatment (EOT), test of cure (TOC), and follow-up (FUP). The 14-element questionnaire graded cUTI symptoms as absent or present, and if present, as mild, moderate, or severe. Changes in post-baseline symptoms based on patients’ responses were rated by the interviewer. The overall clinical outcome was evaluated based on the responses provided by patients at each time point. Results: Among the 371 patients in the modified intention-to-treat population, the rate of SPI completion in each treatment arm exceeded 90% at each time point. SPI-assessed clinical cure rates were 89.7% in the cefiderocol arm and 84.9% in the imipenem–cilastatin arm. There was substantial agreement between SPI evaluation and investigator global assessment of clinical outcome at TOC and FUP, with lower agreement at EA and EOT. Conclusion: This analysis suggests that patient-reported symptoms can be effectively captured in hospitalized patients with cUTI in a clinical trial setting. Development of a validated patient-reported outcome for use in such a setting is warranted. Registration: NCT02321800 (registered on 22 December 2014).

BackgroundSingle-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.MethodsWe evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.ResultsViruses containing PA/I38X substitutions were identified 3–9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.ConclusionsThe emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.Clinical Trial RegistrationNCT02954354.

Background For new antibiotics developed to treat antibiotic-resistant Gram-negative infections, the US Food and Drug Administration (FDA) regulatory pathway includes complicated urinary tract infection (cUTI) clinical trials in which the clinical isolates are susceptible to the active control. This allows for inferential testing in a noninferiority study design. Although complying with regulatory guidelines, individual clinical trials may differ substantially in design and patient population. To determine variables that impacted patient selection and outcome parameters, 6 recent cUTI trials that were pivotal to an new drug application (NDA) submission were reviewed. Methods This selective descriptive analysis utilized cUTI trial data, obtained from publicly disclosed information including FDA documents and peer-reviewed publications, from 6 new antibiotics developed to treat multidrug-resistant Gram-negative infections: ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol, plazomicin, and fosfomycin. Eravacycline was not approved for cUTI and is not included. Results Microbiologic modified intent-to-treat sample size, age, proportions of female patients, acute pyelonephritis (AP), Escherichia coli and other pathogens at baseline, protocol-specified switch to oral antibiotic, and the noninferiority margin were compared. Outcome data included clinical response, microbiologic eradication, and composite outcomes, including a subset of patients with AP. Conclusions A study design can follow regulatory guidelines but still have variable populations. The proportion of AP within a study varied greatly and influenced population demographics (age, gender) and baseline microbiology. A smaller proportion of AP resulted in an older patient population, fewer females, less E coli, and lower proportions of patients achieving success. Fluoroquinolones and piperacillin/tazobactam should be reconsidered as active comparators given the high rates of resistance to these antibiotics., In cUTI trial data from 6 new antibiotics targeting MDR Gram-negative infections, proportion of acute pyelonephritis (AP) varied; influencing population demographics and baseline microbiology. Smaller proportion of AP resulted in older patient population, fewer females, less E coli, and lower treatment success.

Background Cefiderocol (CFDC), a novel siderophore cephalosporin, has potent in vitro activity against Gram-negative bacteria causing nosocomial pneumonia (NP). The non-inferiority of CFDC to meropenem in Day 14 all-cause mortality in NP was previously demonstrated. In this study, we assessed the intrapulmonary pharmacokinetics of CFDC in hospitalized and ventilated patients with bacterial pneumonia receiving standard of care (SOC) antibiotics. Methods A multicenter, single-arm, open-label study was conducted to assess epithelial lining fluid (ELF) and plasma concentrations of CFDC at steady state in mechanically ventilated patients with bacterial pneumonia receiving SOC antibiotics (NCT03862040). Seven patients received 2 g doses of CFDC (or renally adjusted doses), infused over 3 hours, q8h, or q6h for patients with augmented renal function (creatinine clearance estimated by Cockcroft-Gault equation >120 mL/min). One bronchoalveolar lavage (BAL) sample per patient was collected to determine ELF concentration at 3 or 5 hours after at least 3 CFDC doses (or ≥6 doses in patients with severe renal impairment). Four blood samples were collected per patient for plasma concentrations at 1, 3, 5, and 7 hours after the start of the infusion used for BAL sampling. Urea concentrations in blood and BAL were measured to calculate CFDC concentrations in ELF. Results Geometric mean (minimum, maximum) ELF concentration of CFDC was 7.63 (3.10, 20.7) µg/mL at the end of infusion (3 h after the start of infusion) (N=4) and 10.4 (7.19, 15.9) µg/mL at 2 hours after the end of infusion (5 h after the start of infusion) (N=3). ELF/free plasma concentration ratios were estimated to be 0.212 at the end of infusion and 0.547 at 2 hours after the end of infusion based on the in vitro unbound fraction of 0.422. Conclusion The individual ELF concentrations of CFDC were close to, or higher than, 4 µg/mL in pneumonia patients. Compared with the ELF/free plasma area under the curve ratio in healthy subjects (0.239), the ELF/free plasma concentration ratio at the end of infusion (0.212) was comparable, and at 2 hours after the end of infusion (0.422) was higher in pneumonia patients. These findings suggest delayed distribution and sustained exposure of CFDC in the ELF of pneumonia patients. Disclosures Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Simon Portsmouth, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Keith Rodvold, PharmD, FCCP, FIDSA, Shionogi Inc. (Consultant) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

BACKGROUND Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents. METHODS We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population. RESULTS In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P

Background Baloxavir marboxil (BXM), a selective cap-dependent endonuclease inhibitor, has demonstrated efficacy + safety for influenza in otherwise healthy patients. We present subgroup analyses for (i) United States vs. Japan (J), (ii) time (t) of treatment (early: ≥0 to ≤24 hours, vs. late: >24 to ≤48 hours), and (iii) influenza type B infections from the global Ph 3 trial (16/17 season). Methods A multicenter, randomized, double-blind, placebo (PLC)- and oseltamivir (OV)-controlled study recruited patients in Japan (n = 846) and United States (n = 590). Inclusion criteria: age 12–64 years, fever + flu symptoms, and ≤48 hours from symptom onset. Patients (20–64 years) randomized (2:2:1) to a single oral dose of BXM, PLC, or 75 mg OV BID for 5 days; patients 12–19 years were randomized (2:1) to receive BXM or PLC. BXM dose: 40/80 mg for BW Results BXM reduced the median TTAS by 30.6 hours versus PLC (87.3 versus 117.9 hours, P = 0.1373) in the US pop and t to cessation of viral shedding: 24 versus 72 hours for PLC (P < .0001). Median TTAS in the United States versus J pop was longer, due to imbalances between groups. In both early/late treatments from symptom onset, BXM reduced TTAS versus PLC (Table 1). Regardless of the t to treatment from symptom onset, BXM reduced virus titer significantly from BL versus PLC and OV (Table 2). No significant reduction in TTAS was seen, while BXM reduced virus titer versus PLC and OV in type B virus infection. Conclusion Outcomes for United States were aligned with the Ph 3 Results. Early treatment with BXM leads to a significantly faster TTAS vs. PLC. BXM caused significant viral titer reduction regardless of treatment time versus OV. BXM reduced virus titer vs. PLC and OV in type B virus infection. Disclosures K. Kawaguchi, Shionogi & Co., Ltd.: Employee, Salary. S. Portsmouth, Shionogi Inc: Employee, Salary. T. Shishido, Shionogi & Co., Ltd.: Employee, Salary.T. Uehara, Shionogi & Co., Ltd.: Employee, Salary. F. Hayden, Shionogi & Co., Ltd.: Scientific Advisor, Consulting fee (donated) and travel support for attending 6th ESWI meeting, 10–13 September 2017, Latvia, to present phase 3 OWH results.

BACKGROUND: The Study of Aldesleukin with and without antiretroviral therapy (STALWART) evaluated whether intermittent interleukin-2 (IL-2) alone or with antiretroviral therapy (ART) around IL-2 cycles increased CD4(+) counts compared to no therapy. METHODOLOGY: Participants not on continuous ART with > or = 300 CD4(+) cells/mm(3) were randomized to: no treatment; IL-2 for 5 consecutive days every 8 weeks for 3 cycles; or the same IL-2 regimen with 10 days of ART administered around each IL-2 cycle. CD4(+) counts, HIV RNA, and HIV progression events were collected monthly. PRINCIPAL FINDINGS: A total of 267 participants were randomized. At week 32, the mean CD4(+) count was 134 cells greater in the IL-2 alone group (p

Background Research is an increasingly important aspect of higher medical training for many doctors. Studies investigating sources of stress, isolation, and workplace bullying have not previously sought information in this setting. Methods An internet based questionnaire survey of doctors undertaking research (n = 259) was conducted to examine stressors and levels of job satisfaction in this potentially vulnerable group. In order to assess overall levels of satisfaction, we asked whether doctors would recommend their research post to a colleague. Results There was a statistically significant association between those who would not recommend their post to a colleague and those who had difficulties in arranging funding and in writing up (p Conclusions Stress and bullying are common in doctors undertaking research. These findings have important implications for medical training and for doctors choosing research projects. Setting up systems of support may have important benefits.

Background: A4001078 is a study in therapy naive patients of Maraviroc (MVC) plus boosted atazanavir. The Trofile ES (ESTA) was used to determine tropism at Screening. Few re-analyses of genotypic tropism have examined all screened and non-reportable (NR) populations. We aimed to define correlations between methods at screening and evaluate the quantity of X4 using virus in discordant results using ultra-deep sequencing (UDS). Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV Infection http://www.biomedcentral.com/content/pdf/1758-2652-13-S4-info.pdf Conference: Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UK (Published: 8 November 2010) doi:10.1186/1758-2652-13-S4-P128 Cite this article as: Portsmouth et al.: Population and ultra-deep sequencing for tropism determination are correlated with Trofile ES: genotypic re-analysis of the A4001078 maraviroc study. Journal of the International AIDS Society 2010 13(Suppl 4):P128. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3112903/