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/m(3) total room volume, or an average whole-room UV irradiance (fluence rate) of 5-7 µW/cm(2), calculated by a lighting computer-assisted design program modified for UV use.

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.

Surgical face masks worn by patients with multidrug-resistant tuberculosis: impact on infectivity of air on a hospital ward.

RATIONALE: Drug-resistant tuberculosis transmission in hospitals threatens staff and patient health. Surgical face masks used by patients with tuberculosis (TB) are believed to reduce transmission but have not been rigorously tested. OBJECTIVES: We sought to quantify the efficacy of surgical face masks when worn by patients with multidrug-resistant TB (MDR-TB). METHODS: Over 3 months, 17 patients with pulmonary MDR-TB occupied an MDR-TB ward in South Africa and wore face masks on alternate days. Ward air was exhausted to two identical chambers, each housing 90 pathogen-free guinea pigs that breathed ward air either when patients wore surgical face masks (intervention group) or when patients did not wear masks (control group). Efficacy was based on differences in guinea pig infections in each chamber. MEASUREMENTS AND MAIN RESULTS: Sixty-nine of 90 control guinea pigs (76.6%; 95% confidence interval [CI], 68-85%) became infected, compared with 36 of 90 intervention guinea pigs (40%; 95% CI, 31-51%), representing a 56% (95% CI, 33-70.5%) decreased risk of TB transmission when patients used masks. CONCLUSIONS: Surgical face masks on patients with MDR-TB significantly reduced transmission and offer an adjunct measure for reducing TB transmission from infectious patients.

What animal models teach humans about tuberculosis.

Animal models have become standard tools for the study of a wide array of human infectious diseases. Although there are no true animal reservoirs for Mycobacterium tuberculosis, many different animal species are susceptible to infection with this organism and have served as valuable tools for the study of tuberculosis (TB). The most commonly used experimental animal models of TB are the mouse, rabbit, and guinea pig. Although substantial differences in TB susceptibility and disease manifestations exist between these species, they have contributed significantly to the understanding of TB immunopathogenesis, host genetic influence on infection, efficacy of antimicrobial therapy, and host/pathogen interactions that determine the outcome or severity of infection. Among the three species, mice are relatively resistant to TB infection, followed by rabbits and then guinea pigs, which are extremely vulnerable to infection. Mice are most often used in experiments on immune responses to TB infection and drug regimens against TB. Rabbits, unlike the other two animal models, develop cavitary TB and offer a means to study the factors leading to this form of the disease. Guinea pigs, due to their high susceptibility to infection, have been ideal for studies on airborne transmission and vaccine efficacy. In addition to these three species, TB research has occasionally involved nonhuman primates and cattle models. Current concepts in TB pathogenesis have also been derived from animal studies involving experimentally induced infections with related mycobacteria (e.g., Mycobacterium bovis) whose manifestations in select animal hosts mimic human TB.

Natural infection of guinea pigs exposed to patients with highly drug-resistant tuberculosis.

A natural TB infection model using guinea pigs may provide useful information for investigating differences in transmission efficiency and establishment of active disease by clinical TB strains in a highly susceptible host under controlled environmental conditions. We sought to examine the capacity of naturally transmitted multidrug-resistant Mycobacterium tuberculosis to establish infection and produce active disease in guinea pigs. Guinea pigs were continuously exposed for 4 months to the exhaust air of a 6-bed multidrug-resistant tuberculosis inpatient hospital ward in South Africa. Serial tuberculin skin test reactions were measured to determine infection. All animals were subsequently evaluated for histologic disease progression at necropsy. Although 75% of the 362 exposed guinea pigs had positive skin test reactions [≥6 mm], only 12% had histopathologic evidence of active disease. Reversions (≥6 mm change) in skin test reactivity were seen in 22% of animals, exclusively among those with reactions of 6-13 mm. Only two of 86 guinea pigs with reversion had histological evidence of disease compared to 47% (31/66) of guinea pigs with large, non-reverting reactions. Immunosuppression of half the guinea pigs across all skin test categories did not significantly accelerate disease progression. In guinea pigs that reverted a skin test, a second positive reaction in 27 (33%) of them strongly suggested re-infection due to ongoing exposure. These results show that a large majority of guinea pigs naturally exposed to human-source strains of multidrug-resistant tuberculosis became infected, but that many resolved their infection and a large majority failed to progress to detectable disease.

Tuberculosis and HIV: a global menace exacerbated via sex trafficking.

OBJECTIVE: Global 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. METHODS: We 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. RESULTS: There 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. CONCLUSIONS: Although 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.