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Genotyping Analyses of Tuberculosis Cases in U.S.- and Foreign-Born Massachusetts Residents
We used molecular genotyping to further understand the epidemiology and transmission patterns of tuberculosis (TB) in Massachusetts. The study population included 983 TB patients whose cases were verified by the Massachusetts Department of Public Health between July 1, 1996, and December 31, 2000, and for whom genotyping results and information on country of origin were available. Two hundred seventy-two (28%) of TB patients were in genetic clusters, and isolates from U.S-born were twice as likely to cluster as those of foreign-born (odds ratio [OR] 2.29, 95% confidence interval [CI] 1.69, 3.12). Our results suggest that restriction fragment length polymorphism analysis has limited capacity to differentiate TB strains when the isolate contains six or fewer copies of IS6110, even with spoligotyping. Clusters of TB patients with more than six copies of IS6110 were more likely to have epidemiologic connections than were clusters of TB patients with isolates with few copies of IS6110 (OR 8.01, 95%; CI 3.45,18.93)
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
The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro
Polymyxins have previously been described to have activity against M. tuberculosis
(MTB), but further research was abandoned due to systemic toxicity concerns to
achieve the required MIC. Colistin methanesulfonate (CMS), a polymyxin, is well
tolerated when inhaled directly into the lungs, resulting in high local concentrations.
We report here for the first time, MIC and MBC data for CMS determined by the
microtiter Alamar Blue assay (MABA). We also determined how the MIC would be
affected by the presence of pulmonary surfactant (PS) and if any synergy with isoniazid (INH) and rifampicin (RIF) exists. The effect of CMS on the ultrastructure
of MTB was also determined. The MIC for CMS was 16 mg/L, while the MBC was
256 mg/L. MIC for CMS in PS was antagonised by eight fold. For synergy,
indifference was determined while time-kill assays revealed a greater killing effect
when CMS was used together with INH. Ultrastructure analysis suggests that the
disruption of the outer polysaccharide layer of MTB by CMS may lead to enhanced
uptake of INH. Our findings may provide insight for further investigations of CMS
against MTB.http://intl.elsevierhealth.com/journals/tube2016-07-30hb201
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
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