Ashwin S. Dharmadhikari

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.

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 (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.

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

BACKGROUND Effective treatment for drug-susceptible tuberculosis (TB) rapidly renders patients non-infectious, 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 non-infectious. Further prospective studies on this subject are needed.

Turning off the tap: stopping tuberculosis transmission through active case-finding and prompt effective treatment

Summary To halt the global tuberculosis epidemic, transmission must be stopped to prevent new infections and new cases. Identification of individuals with tuberculosis and prompt initiation of effective treatment to rapidly render them non-infectious is crucial to this task. However, in settings of high tuberculosis burden, active case-finding is often not implemented, resulting in long delays in diagnosis and treatment. A range of strategies to find cases and ensure prompt and correct treatment have been shown to be effective in high tuberculosis-burden settings. The population-level effect of targeted active case-finding on reducing tuberculosis incidence has been shown by studies and projected by mathematical modelling. The inclusion of targeted active case-finding in a comprehensive epidemic-control strategy for tuberculosis should contribute substantially to a decrease in tuberculosis incidence.

Syphilis and Hepatitis B Co-infection among HIV-Infected, Sex-Trafficked Women and Girls, Nepal

Sex trafficking may play a major role in spread of HIV across South Asia. We investigated co-infection with HIV and other sexually transmitted diseases among 246 sex-trafficked women and girls from Nepal. Those who were HIV positive were more likely than those who were HIV negative to be infected with syphilis and/or hepatitis B.

Inhaled drug treatment for tuberculosis: Past progress and future prospects

Since the 1990s the rising incidence of multiple drug resistant TB, particularly in the context of human immunodeficiency virus co-infected patients, has threatened global TB control. At that time funding agencies began to support formal investigation of aerosol therapy which until then had been the subject of case reports of individual investigators. Over the last decade, proponents of aerosol therapy have increased in number within the TB research community as the incidence of multiple and extremely drug resistant TB has increased dramatically around the world. Aerosol therapy offers the potential to deliver drug at target concentrations directly into the lungs, use the alveolar-capillary interface to achieve systemic levels, while reducing the risk of systemic toxicity seen with parentally administered doses. In addition, there are insufficient new drugs in the pipeline to anticipate the appearance of a new regimen in time to assure future control of drug resistance. Consequently, alternative strategies are critical to achieving global TB control, and inhaled therapies should be considered as one such strategy.

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.

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.

Aspiring to zero tuberculosis deaths among southern Africa's miners: is there a way forward?

Tuberculosis notification rates among South African miners range from 4,000 to 7,000 per 100,000 people. These rates far exceed national tuberculosis notification rates for the general population. Tuberculosis mortality also surpasses deaths caused by mining accidents. These extraordinarily high rates of disease are unambiguously linked to a series of contributing factors, including exposure to silica dust, HIV infection, and poor working and living conditions. We argue that the only way to stop the transmission of this airborne disease is to treat the mine and its living quarters as one should any other congregate setting with individuals who have high rates of infection with drug-susceptible and drug-resistant strains of tuberculosis. This means implementing interventions that have been demonstrated to stop the spread of tuberculosis over the last 60 years: immediate treatment of active tuberculosis, concurrent treatment of latent tuberculosis disease to reduce the burden of active cases, and appropriate management of patients infected with HIV. Because tuberculosis is also a social disease, biomedical interventions must be coupled with improved living and working conditions. Achieving zero deaths from tuberculosis in the mines is possible if a clear commitment is made to a strategy that recognizes and ameliorates the biological and social antecedents to this epidemic.