Edward A. Nardell

Exogenous reinfection with tuberculosis in a shelter for the homeless.

We investigated an outbreak of tuberculosis in a large shelter for the homeless to assess the role of exogenous reinfection as opposed to reactivation of endogenous infection as the cause of secondary tuberculosis in this population. Exogenous reinfection is considered relatively unimportant in the United States and other developed countries. Of 49 shelter-related cases, 22 had cultures resistant to both isoniazid and streptomycin and of the same phage type, indicating recent transmission originating with a single index patient. The probable index patient had a 10-year history of isoniazid and streptomycin resistance--an uncommon pattern at the shelter during the three years preceding the outbreak. In 4 of the 22 cases, the patient had previously had documented tuberculosis infection or disease. These reinfected patients had extensive lung cavitation and numerous acid-fast bacilli on sputum smears--features associated with contagiousness. In contrast, patients with tuberculosis for the first time (primary tuberculosis) are usually less contagious. We conclude that exogenous reinfection may have been an important factor leading to highly contagious secondary cases and an acceleration of the usual pattern of tuberculosis transmission in this highly susceptible population.

Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study

BACKGROUND Mycobacterium tuberculosis strains that cause untreatable drug-resistant disease are a threat worldwide. We describe the treatment, management, and outcomes of patients with extensively drug-resistant tuberculosis in Tomsk, Russia. METHODS We undertook a retrospective cohort study of 608 patients with multidrug resistant tuberculosis who had treatment in civilian or prison services, between Sept 10, 2000, and Nov 1, 2004, according to the treatment strategy recommended by WHO. Clinical characteristics, management practices, and treatment outcomes of patients with extensively drug-resistant (XDR) tuberculosis and non-extensively drug-resistant (non-XDR) tuberculosis are described. The main outcome was the frequency of poor and favourable outcomes at the end of treatment. FINDINGS Of 608 patients with multidrug resistant tuberculosis, 29 (4.8%) patients had baseline XDR tuberculosis. Treatment failure was more common in patients with XDR tuberculosis than in those with non-XDR tuberculosis (31%vs 8.5%, p=0.0008). 48.3% of patients with XDR tuberculosis and 66.7% of patients with non-XDR tuberculosis had treatment cure or completion (p=0.04). The frequency and management of adverse events did not differ between patients with XDR and non-XDR tuberculosis. INTERPRETATION The chronic features of tuberculosis in these patients suggest that extensively drug-resistant tuberculosis may be acquired through previous treatments that include second-line drugs. Aggressive management of this infectious disease is feasible and can prevent high mortality rates and further transmission of drug-resistant strains of Mycobacterium tuberculosis.

Tuberculosis Infection Control in Resource-Limited Settings in the Era of Expanding HIV Care and Treatment

The opportunities for human immunodeficiency virus (HIV) care and treatment created by new treatment initiatives promoting universal access are also creating unprecedented opportunities for persons with HIV-associated immunosuppression to be exposed to patients with infectious tuberculosis (TB) within health care facilities, with the attendant risks of acquiring TB infection and developing TB disease. Infection control measures can reduce the risk of Mycobacterium tuberculosis transmission even in settings with limited resources, on the basis of a 3-level hierarchy of controls, including administrative or work practice, environmental controls, and respiratory protection. Further research is needed to define the most efficient interventions. The importance of preventing transmission of M. tuberculosis in the era of expanding HIV care and treatment in resource-limited settings must be recognized and addressed.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

The application of ultraviolet germicidal irradiation to control transmission of airborne disease: bioterrorism countermeasure

Bioterrorism is an area of increasing public health concern. The intent of this article is to review the air cleansing technologies available to protect building occupants from the intentional release of bioterror agents into congregate spaces (such as offices, schools, auditoriums, and transportation centers), as well as through outside air intakes and by way of recirculation air ducts. Current available technologies include increased ventilation, filtration, and ultraviolet germicidal irradiation (UVGI) UVGI is a common tool in laboratories and health care facilities, but is not familiar to the public, or to some heating, ventilation, and air conditioning engineers. Interest in UVGI is increasing as concern about a possible malicious release of bioterror agents mounts. Recent applications of UVGI have focused on control of tuberculosis transmission, but a wide range of airborne respiratory pathogens are susceptible to deactivation by UVGI. In this article, the authors provide an overview of air disinfection technologies, and an in-depth analysis of UVGI-its history, applications, and effectiveness.

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.

Molecular epidemiology of tuberculosis: achievements and challenges to current knowledge

Over the past 10 years, molecular methods have become available with which to strain-type Mycobacterium tuberculosis. They have allowed researchers to study certain important but previously unresolved issues in the epidemiology of tuberculosis (TB). For example, some unsuspected microepidemics have been revealed and it has been shown that the relative contribution of recently acquired disease to the TB burden in many settings is far greater than had been thought. These findings have led to the strengthening of TB control. Other research has demonstrated the existence and described the frequency of exogenous reinfection in areas of high incidence. Much recent work has focused on the phenotypic variation among strains and has evaluated the relative transmissibility, virulence, and immunogenicity of different lineages of the organism. We summarize the recent achievements in TB epidemiology associated with the introduction of DNA fingerprinting techniques, and consider the implications of this technology for the design and analysis of epidemiological studies.

Occupational Hazards to Hospital Personnel

Hospital personnel are subject to various occupational hazards. Awareness of these risks, compliance with basic preventive measures, and adequate resources for interventions are essential components of an occupational health program. Physical, chemical, and radiation hazards; important infectious risks; and psychosocial problems prevalent in hospital workers are reviewed. A rational approach to managing and preventing these problems is offered.