Resistance-Guided Treatment of Gonorrhea: A Prospective Clinical Study.

BACKGROUND: Novel treatment strategies to slow the continued emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae are urgently needed. A molecular assay that predicts in vitro ciprofloxacin susceptibility is now available but has not been systematically studied in human infections. METHODS: Using a genotypic polymerase chain reaction assay to determine the status of the N. gonorrhoeae gyrase subunit A serine 91 codon, we conducted a multisite prospective clinical study of the efficacy of a single oral dose of ciprofloxacin 500 mg in patients with culture-positive gonorrhea. Follow-up specimens for culture were collected to determine microbiological cure 5-10 days post-treatment. RESULTS: Of the 106 subjects possessing culture-positive infections with wild-type gyrA serine N. gonorrhoeae genotype, the efficacy of single-dose oral ciprofloxacin treatment in the per-protocol population was 100% (95% 1-sided confidence interval, 97.5-100%). CONCLUSIONS: Resistance-guided treatment of N. gonorrhoeae infections with single-dose oral ciprofloxacin was highly efficacious. The widespread introduction and scale-up of gyrA serine 91 genotyping in N. gonorrhoeae infections could have substantial medical and public health benefits in settings where the majority of gonococcal infections are ciprofloxacin susceptible. CLINICAL TRIALS REGISTRATION: NCT02961751.

Safety and Efficacy of a Novel Vaginal Anti-infective, TOL-463, in the Treatment of Bacterial Vaginosis and Vulvovaginal Candidiasis: A Randomized, Single-blind, Phase 2, Controlled Trial.

BACKGROUND: Bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) present serious reproductive health risks and management challenges, with poor control attributed to survival of treatment-resistant biofilm communities. Boric acid is used in various regimens for non-albicans VVC and recurrent BV. We investigated safety and efficacy of a novel boric acid-based vaginal anti-infective with enhanced antibiofilm activity (TOL-463) in treating BV and VVC. METHODS: In this phase 2 randomized, investigator-blinded trial conducted at 2 sexual health clinics, women with BV or VVC were randomly assigned (1:1) to 7 nights of TOL-463 vaginal gel or insert. The primary test of cure (TOC) was clinical cure at day 9-12; safety was assessed at TOC and day 21-30. RESULTS: One hundred six participants (53 with BV, 36 VVC, 17 both) were enrolled; most were African American (69%). Clinical cure rate of BV at TOC was 59% (95% confidence interval [CI], 41%-75%) for TOL-463 insert and 50% (95% CI, 31%-69%) for TOL-463 gel, and for VVC, 92% (95% CI, 67%-99%) for TOL-463 insert and 81% (95% CI, 57%-93%) for TOL-463 gel. Both products were safe and well tolerated with no secondary cases of VVC; vulvovaginal burning was the most common adverse event (9.6%). CONCLUSIONS: TOL-463, especially in vaginal insert form, is effective and safe in treating BV and VVC. Future studies should assess the potential role of TOL-463 as a biofilm disrupter in enhancing likelihood of cure relative to approved therapies, reducing recurrence rates, and combined with traditional antimicrobials. CLINICAL TRIALS REGISTRATION: NCT02866227.

Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea.

BACKGROUND: Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea. METHODS: We randomly assigned eligible men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had had sexual contact in the preceding 14 days with a person who had gonorrhea to receive a single oral dose of zoliflodacin (2 g or 3 g) or a single 500-mg intramuscular dose of ceftriaxone in a ratio of approximately 70:70:40. A test of cure occurred within 6±2 days after treatment, followed by a safety visit 31±2 days after treatment. The primary efficacy outcome measure was the proportion of urogenital microbiologic cure in the microbiologic intention-to-treat (micro-ITT) population. RESULTS: From November 2014 through December 2015, a total of 179 participants (167 men and 12 women) were enrolled. Among the 141 participants in the micro-ITT population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone. All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively. A total of 84 adverse events were reported: 24 in the group that received 2 g of zoliflodacin, 37 in the group that received 3 g of zoliflodacin, and 23 in the group that received ceftriaxone. According to investigators, a total of 21 adverse events were thought to be related to zoliflodacin, and most such events were gastrointestinal. CONCLUSIONS: The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin, but this agent was less efficacious in the treatment of pharyngeal infections. (Funded by the National Institutes of Health and Entasis Therapeutics; ClinicalTrials.gov number, NCT02257918 .).

Baseline EEG abnormalities in mild traumatic brain injury from the BIMA study.

The Brain Injury and Mechanisms of Action of HBO2 for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (BIMA), sponsored by the Department of Defense, is a randomized, double-blind, sham-controlled trial of hyperbaric oxygen (HBO2) in service members with persistent post-concussive symptoms following mild TBI, undergoing comprehensive assessments. The clinical EEG was assessed by neurologists for slow wave activity, ictal/interictal epileptiform abnormalities, and background periodic discharges. There is scant literature about EEG findings in this population, so we report baseline clinical EEG results and explore associations with other evaluations, including demographics, medication, neurological assessments, and clinical MRI outcomes. Seventy-one participants were enrolled: median age 32 years, 99% male, 49% comorbid PTSD, 28% with mTBI in the previous year, 32% blast injuries only, and 73% multiple injuries. All participants reported medication use (mean medications = 8, SD = 5). Slowing was present in 39%: generalized 37%, localized 8%, both 6%. No other abnormalities were identified. Slowing was not significantly associated with demographics, medication or neurological evaluation. Participants without EEG abnormalities paradoxically had significantly higher number of white matter hyperintensities as identified on MRI (p = 0.003). EEG slowing is present in more than one-third of participants in this study without evidence of associations with demographics, medications or neurological findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Sparse Semiparametric Nonlinear Model with Application to Chromatographic Fingerprints.

Traditional Chinese herbal medications (TCHMs) are comprised of a multitude of compounds and the identification of their active composition is an important area of research. Chromatography provides a visual representation of a TCHM sample's composition by outputting a curve characterized by spikes corresponding to compounds in the sample. Across different experimental conditions, the location of the spikes can be shifted, preventing direct comparison of curves and forcing compound identification to be possible only within each experiment. In this article we propose a sparse semiparametric nonlinear modeling framework for the establishment of a standardized chromatographic fingerprint. Data-driven basis expansion is used to model the common shape of the curves while a parametric time warping function registers across individual curves. Penalized weighted least squares with the adaptive lasso penalty provides a unified criterion for registration, model selection, and estimation. Furthermore, the adaptive lasso estimators possess attractive sampling properties. A back-fitting algorithm is proposed for estimation. Performance is assessed through simulation and we apply the model to chromatographic data of rhubarb collected from different experimental conditions and establish a standardized fingerprint as a first step in TCHM research.