RESUMEN
Measurement of adherence to oral pre-exposure prophylaxis (PrEP) in real-time has been challenging. We developed DOT Diary, a smartphone application that combines automated directly observed therapy with a PrEP adherence visualization toolkit, and tested its ability to measure PrEP adherence and to increase adherence among a diverse cohort of young men who have sex with men (MSM). We enrolled 100 MSM in San Francisco and Atlanta and randomly assigned them 2:1 to DOT Diary versus standard of care. Concordance between DOT Diary measurement and drug levels in dried blood spots was substantial, with 91.0% and 85.3% concordance between DOT Diary and emtricitabine-triphosphate and tenofovir-diphosphate, respectively. There was no significant difference in the proportion of participants with detectable PrEP drug levels at 24 weeks between study arms. These results suggest DOT Diary is substantially better than self-reported measures of adherence, but additional interventions are needed to improve PrEP adherence over time.
RESUMEN: La medición de la adherencia a la profilaxis oral previa a la exposición (PrEP) en tiempo real ha constituido un desafío. Hemos desarrollado DOT Diary, una aplicación para teléfonos inteligentes que combina la terapia automatizada observada de forma directa con un kit de herramientas para visualizar la adherencia a la PrEP, y testeamos su capacidad para medir la adherencia a la PrEP, así como para aumentar la adherencia entre una cohorte variada de hombres jóvenes que tienen sexo con hombres (HSH). Reclutamos a 100 HSH en San Francisco y Atlanta y los asignamos aleatoriamente 2:1 a DOT Diary con respecto a la asistencia estándar. La concordancia entre la medición del DOT Diary y los niveles de fármacos en gotas de sangre seca fue sustancial, con un 91,0% y un 85,3% de concordancia entre el uso del DOT Diary y el de emtricitabina-trifosfato y tenofovir-difosfato, respectivamente. No hubo diferencias significativas en la proporción de participantes con niveles detectables del fármaco de la PrEP a las 24 semanas entre los brazos del estudio. Estos resultados sugieren que DOT Diary es sustancialmente superior a las medidas de adherencia que se notifican de forma personal, aunque hacen falta intervenciones adicionales para mejorar la adherencia a la PrEP a largo plazo.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Masculino , Humanos , Homosexualidad Masculina , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Tenofovir/uso terapéutico , Terapia por Observación Directa , Fármacos Anti-VIH/uso terapéutico , Cumplimiento de la Medicación , Profilaxis Pre-Exposición/métodosRESUMEN
Young men who have sex with men (YMSM) are highly vulnerable to HIV. While pre-exposure prophylaxis (PrEP) has demonstrated effectiveness, adherence has been low among YMSM and difficult to measure accurately. In collaboration with a healthcare company, we configured an automated directly-observed therapy (aDOT) platform for monitoring and supporting PrEP use. Based on interest expressed in focus groups among 54 YMSM, we combined aDOT with an electronic sexual diary to provide feedback on level of protection during sex and to motivate app use. In an 8-week optimization pilot with 20 YMSM in San Francisco and Atlanta, the app was found to be highly acceptable, with median System Usability Scale scores in the "excellent" range (80/100). App use was high, with median PrEP adherence of 91% based on aDOT-confirmed dosing. Most (84%) participants reported the app helped with taking PrEP. These promising findings support further evaluation of DOT Diary in future effectiveness studies.
Asunto(s)
Infecciones por VIH , Aplicaciones Móviles , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Inteligencia Artificial , Electrónica , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Humanos , Masculino , Cumplimiento de la Medicación , San FranciscoRESUMEN
Current strategies to prevent sexually transmitted infections (STIs) are not controlling the epidemic. The efficacy of doxycycline STI postexposure prophylaxis shows promise in pilot studies, but wider acceptability is unknown. A majority (84%) of diverse individuals using a gay social networking application were interested in doxycycline STI postexposure prophylaxis. Doxycycline STI postexposure prophylaxis should be examined in larger trials.
Asunto(s)
Antibacterianos/administración & dosificación , Doxiciclina/administración & dosificación , Aplicaciones Móviles , Profilaxis Posexposición , Enfermedades de Transmisión Sexual/prevención & control , Red Social , Adulto , Ciudades , Homosexualidad Masculina , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
We describe school-based screening events in four Detroit, Michigan public high schools. To examine trends, we analyzed Chlamydia trachomatis data from 2010 to 2015. Prevalence of C. trachomatis decreased significantly (P < .01): from 10.24% to 6.27%. Future school-based screening events may bring about similar results if the program is instituted in a high-prevalence area and can achieve high student participation.
Asunto(s)
Infecciones por Chlamydia/epidemiología , Tamizaje Masivo , Servicios de Salud Escolar , Estudiantes/estadística & datos numéricos , Adolescente , Antibacterianos/administración & dosificación , Infecciones por Chlamydia/tratamiento farmacológico , Infecciones por Chlamydia/prevención & control , Chlamydia trachomatis/aislamiento & purificación , Humanos , MichiganRESUMEN
Avibactam is a novel non-ß-lactam ß-lactamase inhibitor that has been shown in vitro to inhibit class A, class C, and some class D ß-lactamases. It is currently in phase 3 of clinical development in combination with ceftazidime. In this study, the efficacy of ceftazidime-avibactam was evaluated in a murine septicemia model against five ceftazidime-susceptible (MICs of 0.06 to 0.25 µg/ml) and 15 ceftazidime-resistant (MICs of 64 to >128 µg/ml) species of Enterobacteriaceae, bearing either TEM, SHV, CTX-M extended-spectrum, or AmpC ß-lactamases. In the first part of the study, ceftazidime-avibactam was administered at ratios of 4:1 and 8:1 (wt/wt) to evaluate the optimal ratio for efficacy. Against ceftazidime-susceptible isolates of Klebsiella pneumoniae and Escherichia coli, ceftazidime and ceftazidime-avibactam demonstrated similar efficacies (50% effective doses [ED50] of <1.5 to 9 mg/kg of body weight), whereas against ceftazidime-resistant ß-lactamase-producing strains (ceftazidime ED50 of >90 mg/kg), the addition of avibactam restored efficacy to ceftazidime (ED50 dropped to <5 to 65 mg/kg). In a subsequent study, eight isolates (two AmpC and six CTX-M producers) were studied in the septicemia model. Ceftazidime-avibactam was administered at a 4:1 (wt/wt) ratio, and the efficacy was compared to that of the 4:1 (wt/wt) ratio of either piperacillin-tazobactam or cefotaxime-avibactam. Against the eight isolates, ceftazidime-avibactam was the more effective combination, with ED50 values ranging from 2 to 27 mg/kg compared to >90 mg/kg and 14 to >90 mg/kg for piperacillin-tazobactam and cefotaxime-avibactam, respectively. This study demonstrates that the potent in vitro activity observed with the ceftazidime-avibactam combination against ceftazidime-resistant Enterobacteriaceae species bearing class A and class C ß-lactamases translated into good efficacy in the mouse septicemia model.
Asunto(s)
Compuestos de Azabiciclo/uso terapéutico , Proteínas Bacterianas/metabolismo , Ceftazidima/uso terapéutico , Escherichia coli/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Ácido Penicilánico/análogos & derivados , beta-Lactamasas/metabolismo , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/farmacología , Proteínas Bacterianas/genética , Ceftazidima/farmacología , Combinación de Medicamentos , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/microbiología , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Masculino , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Ácido Penicilánico/farmacología , Ácido Penicilánico/uso terapéutico , Piperacilina/farmacología , Piperacilina/uso terapéutico , Combinación Piperacilina y Tazobactam , Sepsis/tratamiento farmacológico , Sepsis/microbiología , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , beta-Lactamasas/genéticaRESUMEN
The ß-lactamase inhibitor avibactam (NXL104) displays potent inhibition of both class A and C enzymes. The in vitro antibacterial activity of the combination ceftazidime-avibactam was evaluated against a clinical panel of Pseudomonas aeruginosa isolates. Avibactam offered efficient protection from hydrolysis since 94% of isolates were susceptible to ceftazidime when combined with 4 µg/ml avibactam, compared with 65% susceptible to ceftazidime alone. Ceftazidime-avibactam also demonstrated better antipseudomonal activity than imipenem (82% susceptibility), a common reference treatment.
Asunto(s)
Antibacterianos/farmacología , Compuestos de Azabiciclo/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Ceftazidima/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Inhibidores de beta-Lactamasas , Proteínas Bacterianas/metabolismo , Combinación de Medicamentos , Humanos , Imipenem/farmacología , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/aislamiento & purificación , beta-Lactamasas/metabolismoRESUMEN
PURPOSE: The Michigan Department of Health and Human Services, in collaboration with St. John Providence Health System, initiated voluntary school-wide sexually transmitted disease (STD) screenings in four Detroit public high schools. We sought to assess the cost-effectiveness of the STD screening program from 2010 to 2015, with a focus on chlamydia. METHODS: The costs and effectiveness of the school-based screening were compared with those of a "no school screening" scenario using a healthcare system perspective. A decision tree model was constructed to project cases of chlamydia, epididymitis, and pelvic inflammatory disease (PID) in each of the two scenarios among students tested positive and their partners. Health effects were measured as cases of PID prevented, and quality-adjusted life-years (QALYs) gained. Cost estimates included program costs, chlamydia testing/treatment costs in the absence of school screening, and treatment costs for epididymitis, PID, and PID sequelae. The incremental cost-effectiveness ratio (ICER) was measured as cost/QALY gained. Multivariate sensitivity analyses were conducted on key parameter estimates and assumptions used. RESULTS: Under base-case assumptions, at a total program cost of $333,848 over 5 years, the program prevented an estimated 1.9 cases of epididymitis and 17.3 cases of PID, resulting in an ICER of $38,235/QALY gained (yearly ICER ranging from $27,417 to $50,945/QALY). Of 10,000 Monte Carlo simulation runs, the yearly ICER remained ≤$50,000/QALY in 64%-98% of the simulation runs. CONCLUSIONS: We found favorable cost-effectiveness ratios for Michigan's school-wide STD screening program in Detroit. School-based STD screening programs of this type warrant careful considerations by policy makers and program planners.
Asunto(s)
Infecciones por Chlamydia , Tamizaje Masivo , Infecciones por Chlamydia/diagnóstico , Análisis Costo-Beneficio , Humanos , Masculino , Michigan , Años de Vida Ajustados por Calidad de Vida , Instituciones AcadémicasRESUMEN
BACKGROUND: Young men who have sex with men (YMSM) are disproportionately impacted by HIV and other sexually transmitted infections (STIs) in the United States (US) and have low rates of HIV/STI testing. Provision of HIV self-testing and STI self-collection can increase testing rates, and access to these kits through mobile applications (apps) could help facilitate YMSM using HIV self-testing and STI self-collection. METHODS: Data for this study comes from two pilot randomized controlled trials (RCTs) of mobile apps within the Adolescent Trials Network-LYNX and MyChoices-aimed to increase HIV/STI testing among YMSM (age 15-24) who had not recently tested for HIV and were at high risk for HIV acquisition across five US cities. Both apps include the ability to order a HIV self-test with rapid results and a kit for STI self-collection and mailing of samples for syphilis, gonorrhea and chlamydia to a lab for testing. Using assessments of app users (n=80) at pre-randomization and at 3- and 6-months post-randomization and online interview data from a purposive sample of app users (n=37), we report on experiences and lessons learned with HIV self-testing and STI self-collection kits ordered via the apps. RESULTS: Participants were on average 20.7 years of age (SD =2.4), and 49% were non-White or multiple race/ethnicity. Sixty-three percent had a prior HIV test. Over half (58%) had a prior STI test, but only 3% had tested within the past 3 months. Nearly two-thirds ordered an HIV self-testing kit; of whom, 75% reported using at least one self-test kit over the study period. STI self-collection kit ordering rates were also high (54%); however, STI self-collection kit return rates were lower (13%), but with a high positivity rate (5.3%). Both HIV self-testing and STI self-collection kits were highly acceptable, and 87% reported that it was extremely/very helpful to be able to order these kits through the apps. The most common reason for not ordering the HIV/STI kits was preferring to test at a clinic. In interviews, participants expressed feeling empowered by being able to test at home; however, they also raised concerns around STI sample collection. CONCLUSIONS: HIV self-testing and STI self-collection kit ordering via mobile apps is feasible, acceptable and may show promise in increasing testing rates among YMSM. The LYNX and MyChoices apps are currently being tested in a full-scale efficacy trial, and if successful, these innovative mobile apps could be scaled up to efficiently increase HIV/STI testing among youth across the US.
RESUMEN
NXL104 is a potent inhibitor of class A and C serine ß-lactamases, including KPC carbapenemases. Native and NXL104-inhibited TEM-1 and P99 ß-lactamases analyzed by liquid chromatography-electrospray ionization-time of flight mass spectrometry revealed that the inactivated enzymes formed a covalent adduct with NXL104. The principal inhibitory characteristics of NXL104 against TEM-1 and P99 ß-lactamases were determined, including partition ratios, dissociation constants (K), rate constants for deactivation (k(2)), and reactivation rates. NXL104 is a potent inhibitor of TEM-1 and P99, characterized by high carbamylation efficiencies (k(2)/K of 3.7 × 10(5) M(-1) s(-1) for TEM-1 and 1 × 10(4) M(-1) s(-1) for P99) and slow decarbamylation. Complete loss of ß-lactamase activity was obtained at a 1/1 enzyme/NXL104 ratio, with a k(3) value (rate constant for formation of product and free enzyme) close to zero for TEM-1 and P99. Fifty percent inhibitory concentrations (IC(50)s) were evaluated on selected ß-lactamases, and NXL104 was shown to be a very potent inhibitor of class A and C ß-lactamases. IC(50)s obtained with NXL104 (from 3 nM to 170 nM) were globally comparable on the ß-lactamases CTX-M-15 and SHV-4 with those obtained with the comparators (clavulanate, tazobactam, and sulbactam) but were far lower on TEM-1, KPC-2, P99, and AmpC than those of the comparators. In-depth studies on TEM-1 and P99 demonstrated that NXL104 had a comparable or better affinity and inactivation rate than clavulanate and tazobactam and in all cases an improved stability of the covalent enzyme/inhibitor complex.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Inhibidores de beta-Lactamasas , Compuestos de Azabiciclo/química , Concentración 50 Inhibidora , Estructura Molecular , Espectrometría de Masa por Ionización de Electrospray , beta-LactamasasRESUMEN
BACKGROUND: Young men who have sex with men (YMSM) in the United States have among the highest incidence of HIV and sexually transmitted infection (STI) and the lowest uptake of HIV and STI testing and pre-exposure prophylaxis (PrEP). Nearly universal mobile phone ownership among youth provides an opportunity to leverage mobile health apps to increase HIV/STI testing and PrEP uptake among YMSM. OBJECTIVE: The goals of this project are to develop and refine LYNX, a novel mobile app to support linkage to HIV/STIs testing and PrEP services among YMSM in the United States, and to evaluate the acceptability and feasibility of LYNX in a pilot randomized controlled trial (RCT). METHODS: This research protocol will be conducted in 3 phases: an iterative development phase with a series of 3 focus groups among 20 YMSM to refine the LYNX app; an open technical pilot among 15 YMSM to optimize usability of the app; and then a 6-month pilot RCT among 60 HIV-uninfected YMSM at risk for HIV acquisition. Developed using the Information, Motivation, and Behavioral skills theoretical model, the LYNX app includes an electronic diary to track sexual behaviors (information), a personalized risk score to promote accurate risk perception (information/motivation), testing reminders (motivation/behavioral skills), and access to home-based HIV/STI testing options and geospatial-based HIV/STI testing care sites (behavioral skills). Feasibility and acceptability will be assessed through app analytics of usage patterns and acceptability scales administered via computer-assisted self-interview at 3 and 6 months. We will also evaluate preliminary efficacy by comparing the proportion of YMSM who test at least once during the 6-month pilot and the proportion who successfully link to a PrEP provider in the intervention versus control groups. RESULTS: Formative work is currently underway. The LYNX pilot RCT will begin enrollment in October 2018, with study results available in 2019. CONCLUSIONS: The LYNX app is one of the first mobile apps designed to increase HIV/STI testing and PrEP uptake among YMSM. As low-perceived risk is a barrier to HIV/STI testing and PrEP use among youth, the personalized risk assessment and interactive sexual diary in LYNX could assist YMSM in better understanding their HIV risk and providing motivation to test for HIV/STIs and initiate PrEP. Coupled with community-based recruitment, this novel mobile app has great potential to reach and engage YMSM not currently involved in care and increase rates of HIV/STI testing and PrEP uptake in this vulnerable population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03177512; https://clinicaltrials.gov/ct2/show/NCT03177512 (Archived by WebCite at http://www.webcitation.org/73c917wAw). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/10659.
RESUMEN
Inhibitors of the GyrA and ParC subunits of the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, respectively, belong to classes of antibiotics that are among the most successful of the past 50 years, both in a therapeutic and a commercial sense. The initial promise of progressive modification of an antibiotic scaffold to extend the antibacterial spectrum and to modulate pharmacokinetic/pharmacodynamic parameters of existing antibiotics in an advantageous manner has been tempered by the frequent concomitant appearance of serious toxicity. The merits of the most prominent novel antibiotics that have reached, or are expected to reach the clinical phase of drug development are summarized in this review.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Topoisomerasa de ADN IV/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Topoisomerasa II , Animales , Proteínas Bacterianas/metabolismo , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/metabolismo , Farmacorresistencia Bacteriana , Humanos , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/metabolismo , Quinolonas/farmacologíaRESUMEN
BACKGROUND: Patients considered for electrophysiologic study (EPS) are often first referred for stress myocardial perfusion scintigraphy (MPS) to assess for inducible ischemia before testing. The purpose of this investigation was to determine the utility of this approach by examining the relationship between MPS and any interim cardiac catheterization and revascularization, as well as the results and safety of EPS. METHODS AND RESULTS: All patients undergoing EPS within 30 days after MPS at our institution between January 1997 and June 2000 were studied. Two hundred fifty-one patients met the inclusion criteria. The incidence of inducible sustained monomorphic ventricular tachycardia at EPS (IND) was 16%. One hundred twenty-nine patients had MPS ischemia (83 with high-risk features), but only twelve patients in all underwent revascularization between MPS and EPS. There were no ischemic complications during EPS. The presence of isolated ischemia on MPS was associated with a low rate of IND, not different from normal MPS findings (2%-3%). The combination of infarct and ischemia on MPS was associated with a high rate of IND that was similar to infarct alone (34% and 50%, respectively; P =.28). CONCLUSIONS: Patients with high-risk MPS results are more likely to undergo revascularization before EPS than patients with low-risk or normal MPS results. However, most patients with high-risk MPS results undergo EPS without interim revascularization, and no patient had an ischemia-related complication at EPS. Larger studies will be required to confirm this observation. MPS infarct, not ischemia, is associated with IND at EPS.