Phase I, Single-Dose, Dose-Escalating Study of Inhaled Dry Powder Capreomycin: a New Approach to Therapy of Drug-Resistant Tuberculosis

ABSTRACT Multidrug-resistant tuberculosis (MDR-TB) threatens global TB control. The lengthy treatment includes one of the injectable drugs kanamycin, amikacin, and capreomycin, usually for the first 6 months. These drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. Advances in particulate drug delivery have led to the formulation of capreomycin as the first antituberculosis drug available as a microparticle dry powder for inhalation and clinical study. Delivery by aerosol may result in successful treatment with lower doses. Here we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability in healthy subjects and measuring pharmacokinetic (PK) parameters. Twenty healthy adults ( n = 5 per group) were recruited to self-administer a single dose of inhaled dry powder capreomycin (25-mg, 75-mg, 150-mg, or 300-mg nominal dose) using a simple, handheld delivery device. Inhalations were well tolerated by all subjects. The most common adverse event was mild to moderate transient cough, in five subjects. There were no changes in lung function, audiometry, or laboratory parameters. Capreomycin was rapidly absorbed after inhalation. Systemic concentrations were detected in each dose group within 20 min. Peak and mean plasma concentrations of capreomycin were dose proportional. Serum concentrations exceeded 2 μg/ml (MIC for Mycobacterium tuberculosis ) following the highest dose; the half-life ( t 1/2 ) was 4.8 ± 1.0 h. A novel inhaled microparticle dry powder formulation of capreomycin was well tolerated. A single 300-mg dose rapidly achieved serum drug concentrations above the MIC for Mycobacterium tuberculosis , suggesting the potential of inhaled therapy as part of an MDR-TB treatment regimen

Phase I, single-dose, dose-escalating study of inhaled dry powder capreomycin : a new approach to therapy of drug-resistant tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) threatens global TB control. The lengthy treatment includes one of the injectable drugs kanamycin, amikacin, and capreomycin, usually for the first 6 months. These drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. Advances in particulate drug delivery have led to the formulation of capreomycin as the first antituberculosis drug available as a microparticle dry powder for inhalation and clinical study. Delivery by aerosol may result in successful treatment with lower doses. Here we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability in healthy subjects and measuring pharmacokinetic (PK) parameters. Twenty healthy adults (n = 5 per group) were recruited to self-administer a single dose of inhaled dry powder capreomycin (25-mg, 75-mg, 150-mg, or 300-mg nominal dose) using a simple, handheld delivery device. Inhalations were well tolerated by all subjects. The most common adverse event was mild to moderate transient cough, in five subjects. There were no changes in lung function, audiometry, or laboratory parameters. Capreomycin was rapidly absorbed after inhalation. Systemic concentrations were detected in each dose group within 20 min. Peak and mean plasma concentrations of capreomycin were dose proportional. Serum concentrations exceeded 2 μg/ml (MIC for Mycobacterium tuberculosis) following the highest dose; the half-life (t1/2) was 4.8 ± 1.0 h. A novel inhaled microparticle dry powder formulation of capreomycin was well tolerated. A single 300-mg dose rapidly achieved serum drug concentrations above the MIC for Mycobacterium tuberculosis, suggesting the potential of inhaled therapy as part of an MDR-TB treatment regimen.Gates Foundation.http://aac.asm.orghb2013ay201

Rapid impact of effective treatment on transmission of multidrug-resistant tuberculosis

BACKGROUND: Effective treatment for drug-susceptible tuberculosis (TB) rapidly renders patients noninfectious, long before conversion of sputum acid-fast smear or culture to negative. Multidrug-resistant TB (MDR-TB) patients on treatment are currently assumed to remain infectious for months. While the resources required for prolonged hospitalization are a barrier to the scale-up of MDR-TB treatment, the safety of community treatment is clear. OBJECTIVES : To estimate the impact of treatment on infectiousness among MDR-TB patients. METHODS: A series of five human-to-guinea pig TB transmission studies was conducted to test various interventions for infection control. Guinea pigs in adjacent chambers were exposed to exhaust air from a hospital ward occupied by mostly sputum smear- and culture-positive MDR-TB patients. The guinea pigs then underwent tuberculin skin testing for infection. Only the control groups of guinea pigs from each study (no interventions used) provide the data for this analysis. The number of guinea pigs infected in each study is reported and correlated with Mycobacterium tuberculosis drug susceptibility relative to treatment. RESULTS : Despite exposure to presumably infectious MDR-TB patients, infection percentages among guinea pigs ranged from 1% to 77% in the five experiments conducted. In one experiment in which guinea pigs were exposed to 27 MDR-TB patients newly started on effective treatment for 3 months, there was minimal transmission. In four other experiments with greater transmission, guinea pigs had been exposed to patients with unsuspected extensively drug-resistant tuberculosis who were not on effective treatment. CONCLUSIONS : In this model, effective treatment appears to render MDR-TB patients rapidly noninfectious. Further prospective studies on this subject are needed.NIOSH R01OH009050http://www.ingentaconnect.com/content/iuatld/ijtldhb201

Institutional tuberculosis transmission : controlled trial of upper room ultraviolet air disinfection : a basis for new dosing guidelines

RATIONALE : Transmission is driving the global tuberculosis epidemic, especially in congregate settings. Worldwide, natural ventilation is the most common means of air disinfection, but it is inherently unreliable and of limited use in cold climates. Upper room germicidal ultraviolet (UV) air disinfection with air mixing has been shown to be highly effective, but improved evidence-based dosing guidelines are needed. OBJECTIVES : To test the efficacy of upper room germicidal air disinfection with air mixing to reduce tuberculosis transmission under real hospital conditions, and to define the application parameters responsible as a basis for proposed new dosing guidelines. METHODS : Over an exposure period of 7 months, 90 guinea pigs breathed only untreated exhaust ward air, and another 90 guinea pigs breathed only air from the same six-bed tuberculosis ward on alternate days when upper room germicidal air disinfection was turned on throughout the ward. MEASUREMENTS AND MAIN RESULTS : The tuberculin skin test conversion rates (.6 mm) of the two chambers were compared. The hazard ratio for guinea pigs in the control chamber converting their skin test to positive was 4.9 (95% confidence interval, 2.8–8.6), with an efficacy of approximately 80%. CONCLUSIONS : Upper room germicidal UV air disinfection with air mixing was highly effective in reducing tuberculosis transmission under hospital conditions. These data support using either a total fixture output (rather than electrical or UV lamp wattage) of 15–20 mW/m3 total room volume, or an average whole-room UV irradiance (fluence rate) of 5–7 mW/cm2, calculated by a lighting computer-assisted design program modified for UV use.http://www.atsjournals.org/journal/ajrccm2016-08-31hb201

Leveraging transit-based investment to retrofit urban corridors in Houston, Texas

Public transportation and infrastructure development continue to be a part of the evolving agenda in growing cities. Despite projects in the past and ongoing efforts, public transportation has been only limited success in its assimilation in the lifestyle of Americans. I take the example of Houston, where there are already existing rail lines through downtown and the existing bus service has just been revamped. In addition, planning efforts towards a bus-oriented Transitway through the Post Oak boulevard project seem to be incorporating transit oriented infrastructure. In this report, I investigate the relationship between transit and development along Houston’s Westheimer Road corridor through analysis of the existing conditions and framework. I assimilate the necessary components to create the structure of a successful project. I do so by researching the existing literature and the best practices to understand the framework and nature of Bus Rapid Transit and its financial implications. Building on those lines, I strategize to create a structure of stakeholder involvement through collaboration to achieve a successful corridor project. In this study, I add on to the ongoing transit oriented development movement in Houston by proposing a Bus Rapid Transit corridor along Westheimer Road. In addition, I propose street infrastructure development to support and enhance the quality of the public realm in the corridor. Through this approach I explore the intersection of urban design and transportation planning, and their significance to a holistic approach. Further, I analyze this proposal for financial feasibility through proforma research and corroborating strategies for implementation. Finally, I make the case that to be successful, transit projects need to involve a critical component of design and finance.Community and Regional PlanningUrban Desig

Tuberculosis and HIV: a global menace exacerbated via sex trafficking

SummaryObjectiveGlobal tuberculosis (TB) elimination requires recognition and management of TB/HIV co-infected individuals, including those in marginalized and/or understudied populations. We sought to examine the prevalence of TB among repatriated sex trafficked Nepalese girls and women in whom a high HIV prevalence was previously reported.MethodsWe reviewed case records for cases of TB among 287 sex trafficked girls and women repatriated to a single, rehabilitation non-governmental organization in Kathmandu, Nepal between 1997 and 2005. TB case detection was based on sputum smear results for acid-fast bacilli, radiographs, or histories, as reported in medical tests and/or case records.ResultsThere were 17 cases of TB that developed after rescue within the sample of girls and women who were aged 7–32 years when they were trafficked. The majority of cases (70%) were likely pulmonary TB. Nearly 9 in 10 individuals who developed TB were HIV co-infected.ConclusionsAlthough preliminary in nature, our findings highlight the need for more comprehensive exploration of TB prevalence within sex trafficked populations, particularly in light of the large numbers of individuals who are sex trafficked in South Asia, the high prevalence of HIV documented in this group, and the risk of transmission of TB from and to others