Michael D. Iseman

Treatment of Multidrug-Resistant Tuberculosis

The frequency of infections with M. tuberculosis resistant to antituberculous drugs is increasing in the United States and globally. This increase is a major threat to tuberculosis treatment and control programs. To prevent this situation from worsening, initial treatment programs that entail directly observed therapy supported by effective inducements or enforcements must be used. Retreatment of patients who have multidrug-resistant tuberculosis should be carried out in programs with comprehensive microbiologic, pharmacokinetic, psychosocial, and nutritional support systems. Regimens of multiple drugs, which generally are poorly tolerated and more toxic than traditional regimens, must be administered for 18 to 36 months. Resectional surgery may be required for substantial numbers of patients. For patients with AIDS who acquire tuberculosis caused by multiply-resistant strains, the disease may prove lethal before effective therapy can be implemented. Ultraviolet irradiation systems should be used to protect health care personnel and other patients in high-risk environments. Enhanced federal, state, and local programs for prevention and control are urgently needed, and research to identify new medications and systems for their delivery is essential.

Directly Observed Treatment of Tuberculosis -- We Can't Afford Not to Try It

In many areas of the United States the battle against tuberculosis is being lost. Two major markers of this failure are the increasing incidence of tuberculosis and the rising prevalence of drug-re...

Aminoglycoside Toxicity: Daily versus Thrice-Weekly Dosing for Treatment of Mycobacterial Diseases

Aminoglycoside use is limited by ototoxicity and nephrotoxicity. This study compared the incidences of toxicities associated with 2 recommended dosing regimens. Eighty-seven patients with tuberculosis or nontuberculous mycobacterial infections were prospectively randomized by drug to receive 15 mg/kg per day or 25 mg/kg 3 times per week of intravenous streptomycin, kanamycin, or amikacin. Doses were adjusted to achieve target serum concentrations. The size of the dosage and the frequency of administration were not associated with the incidences of ototoxicity (hearing loss determined by audiogram), vestibular toxicity (determined by the findings of a physical examination), or nephrotoxicity (determined by elevated serum creatinine levels). Risk of ototoxicity (found in 32 [37%] of the patients) was associated with older age and with a larger cumulative dose received. Vestibular toxicity (found in 8 [9%] of the patients) usually resolved, and nephrotoxicity (found in 13 [15%] of the patients) was mild and reversible in all cases. Subjective changes in hearing or balance did not correlate with objective findings. Streptomycin, kanamycin, and amikacin can be administered either daily or 3 times weekly without affecting the likelihood of toxicity.

Multidrug-resistant and extensively drug-resistant tuberculosis: a review.

Purpose of review The spread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) is a major medical and public health concern for the world. These two forms of highly drug-resistant TB threaten to make TB into an untreatable and highly fatal disease, particularly in resource-poor countries with a high prevalence of AIDS. The focus of this review is to highlight the current extent of the problem. Recent findings There is a great variability in clinical outcomes for MDR-TB, in part due to differences in the definitions of outcome measures and retrospective nature of the studies. Outcomes for XDR-TB are uniformly worse than those for MDR-TB. Summary A multifaceted approach is needed to prevent a more widespread epidemic of MDR-TB and XDR-TB. Rapid diagnostic assays to detect highly drug-resistant TB are essential in preventing delays in treatment of MDR-TB and XDR-TB and curbing their spread. Development of new drugs to effectively treat all forms of TB in a shorter period of time is urgently needed.

Mycobacterium avium complex and the normal host: the other side of the coin.

IN an era that has seen the recognition of important new infectious diseases and syndromes such as the acquired immunodeficiency syndrome (AIDS), legionellosis, and toxic shock, and the subsidence ...

Effects of Gender and Age at Diagnosis on Disease Progression in Long-term Survivors of Cystic Fibrosis

RATIONALE Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts. OBJECTIVES Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF. METHODS Retrospective analysis of the Colorado CF Database (1992-2008), CF Foundation Registry (1992-2007), and Multiple Cause of Death Index (1992-2005). MEASUREMENTS AND MAIN RESULTS Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV(1) decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV(1) declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV(1) decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV(1) improvement in response to CF center care. CONCLUSIONS For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.

The Importance of Nontuberculous Mycobacterial Lung Disease

In this issue of the Journal (pp. 1066–1074), investigators from the National Institutes of Health (NIH) report a distinctive morphotype among a selected cohort of 63 patients with nontuberculous mycobacterial (NTM) lung disease (1). Consistent with other recently published series, the great majority were middle-aged white females (2, 3). Prominent features included being tall and slender, and having scoliosis, pectus excavatum, and mitral valve prolapse. A higher than anticipated number of these patients had mutations of the CFTR genes. Extensive assessment of cell-mediated immunity did not identify deficits. Previously alluded to as ‘‘Lady Windermere’s syndrome’’ by Reich and Johnson (too ‘‘fastidious’’ to cough effectively), this current cohort did not appear unwilling to cough (4). Case series of NTM lung disease from North America, Europe, and Japan were published sporadically in the latter half of the 20th century. Males with underlying chronic obstructive pulmonary disease or pneumoconiosis constituted the bulk of the patients in these reports (5). However, in 1989, a group from Philadelphia reported 21 cases, 17 females, of Mycobacterium avium complex (MAC) lung disease occurring in patients without obvious predispositions (6). Since then, there has been increasing awareness among clinicians of NTM lung infections, with an apparent but unexplained predilection for slender women (7). Nontuberculous mycobacteria, especially MAC, are found widely distributed in the environment, with recovery of strains consistent with human pathogenic isolates (8, 9). Assuming that exposure to such organisms must be nearly universal, the question of mechanisms of vulnerability is compelling, particularly among women presenting with this infection, most of whom have led medically ‘‘blameless’’ lives. The clear identification of phenotypic features in this NIH study provides several hypothesisgenerating leads. Although broad, systematic data have not been compiled, there is a perception among many clinicians and public health tuberculosis (TB) workers that new cases of NTM lung disease may significantly exceed case rates for TB in their communities or regions. The best data for North America come from Ontario where a single laboratory identifies more than 90% of the NTM isolates in the province. This system has provided an opportunity to study the epidemiology of NTM infection at a truly population-based level. Although adequate clinical information regarding the presence of disease, or advanced infection, is lacking in the Ontario laboratory database, it was observed that nontuberculous mycobacteria were far more frequently isolated from pulmonary specimens than was M. tuberculosis (10). Conservatively assuming that 20–40% of pulmonary NTM isolates are associated with disease (11), the incidence of new cases of pulmonary NTM disease in Ontario presumably approximates the incidence of TB. Rather than comparing ‘‘incidence’’ ratios for NTMs and TB, determining the number of patients who experience clinical illness and undergo therapy in any given timeframe (i.e., prevalence) may be a more accurate way to assess the burdens on the community and the health system. In 2004, there were roughly 14,500 new cases of TB reported in the United States (12). Centers for Disease Control and Prevention data indicated that roughly 82% of patients completed therapy within 12 months, and relapse rates have been consistently less than 5% with modern regimens. By contrast, patients with pulmonary MAC usually suffer through long periods of clinical illness before a diagnosis is made; they are then recommended to take 18 months of three-drug therapy and have a nearly 50% likelihood of recurrence that entails retreatment. While treatment duration ranges from 6 to 9 months for most cases of TB in the United States and Canada, most patients become asymptomatic within weeks of commencing therapy. By contrast, we believe that symptomatic disease duration for pulmonary NTM is likely an order of magnitude greater. In 2003, there were 657 cases of TB reported in the province of Ontario, corresponding to an incidence rate of 5.4 per 100,000. In contrast, we estimate that there were likely 420 new cases of pulmonary NTM disease in Ontario in the same year, corresponding to an incidence rate of 3.5 per 100,000. Preliminary prevalence estimates have been made, assuming that the disease duration for TB is 8 months and for pulmonary NTM is within the range of 4 to 10 years. Using these estimates, the prevalence of TB in Ontario was 3.6 per 100,000 in 2003, whereas the contemporary prevalence of pulmonary NTM disease was in the range of 14 to 35 per 100,000. Using this model, the burden of TB may be expected to steadily decline in industrialized nations with mature TB programs. Data from the United States, Canada, and several West European nations describe steadily declining numbers of indigenous TB cases, with the preponderance of new cases occurring among foreign-born individuals. By contrast, the prevalence of NTM disease may be expected to steadily increase. The Ontario experience has reflected a slow but steady decrease in cases of TB, an annual decrement of 4%, whereas rates of NTM isolation increases at an annual rate of 8% (12). This comparison between TB and NTM disease is not intended to be adversarial but to call attention to a burgeoning medical challenge. The medications for NTM infections are expensive, typically difficult to tolerate, and often entail intravenous administration. Many of these patients require physically demanding and time-consuming bronchial hygiene. Limited experience suggests that some of these patients might benefit from resectional lung surgery (13). These observations make it imperative that more extensive research be done on the epidemiology, sources of infection, risk factors, treatment, and prevention of NTM lung disease. Cases of NTM lung disease are no longer just ‘‘curiosities’’ but may well be the leading edge of a major public health problem. The time for action is now.

Cigarette Smoke Increases Susceptibility to Tuberculosis—Evidence From In Vivo and In Vitro Models

BACKGROUND Cigarette smoke (CS) exposure is an epidemiological risk factor for tuberculosis, although the biological basis has not been elucidated. METHODS We exposed C57BL/6 mice to CS for 14 weeks and examined their ability to control an aerosol infection of Mycobacterium tuberculosis Erdman. RESULTS CS-exposed mice had more M. tuberculosis isolated from the lungs and spleens after 14 and 30 d, compared with control mice. The CS-exposed mice had worse lung lesions and less lung and splenic macrophages and dendritic cells (DCs) producing interleukin12 and tumor necrosis factor α (TNF-α). There were significantly more interleukin 10-producing macrophages and DCs in the spleens of infected CS-exposed mice than in non-CS-exposed controls. CS-exposed mice also showed a diminished influx of interferon γ-producing and TNF-α-producing CD4(+) and CD8(+) effector and memory T cells into the lungs and spleens. There was a trend toward an increased number of viable intracellular M. tuberculosis in macrophages isolated from humans who smoke compared with nonsmokers. THP-1 human macrophages and primary human alveolar macrophages exposed to CS extract, nicotine, or acrolein showed an increased burden of intracellular M. tuberculosis. CONCLUSION CS suppresses the protective immune response to M. tuberculosis in mice, human THP-1 cells, and primary human alveolar macrophages.

Treatment Outcomes in Extensively Resistant Tuberculosis

The authors retrospectively analyzed 205 cases of multidrug-resistant tuberculosis to determine what percentage met the definition of extensively drug-resistant tuberculosis and compared the treatment outcomes. Odds ratios for treatment success in the group of patients who had multidrug-resistant tuberculosis, as compared with those who had extensively drug-resistant tuberculosis, were 23.4 for the initial outcome and 21.1 for the long-term outcome.

Bedfellows: mycobacteria and rheumatoid arthritis in the era of biologic therapy

In modern times a relationship between tuberculosis (TB) and rheumatoid arthritis (RA) has been firmly recognized, and is primarily attributable to the immunosuppressive therapies used to treat RA. Whereas TB can complicate the successful management of RA, nontuberculous mycobacteria have now perhaps become as important as (if not more so than) TB in the setting of RA, and can represent an even greater challenge to the rheumatologist wishing to use immunosuppressive therapies. This article reviews our most recent understanding of the epidemiological and clinical aspects of mycobacterial disease as it relates to RA, and the existing and emerging immunosuppressive therapies used to treat this disease.