Barbara Seaworth

Delamanid for Multidrug-Resistant Pulmonary Tuberculosis

BACKGROUND Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis. METHODS In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months. RESULTS Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid. CONCLUSIONS Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.).

CURRENT ROLE OF SURGERY IN MYCOBACTERIUM TUBERCULOSIS

From January 1986 through December 1993, we operated on 59 patients with documented Mycobacterium tuberculosis infection. Indications for operation were as follows: multidrug-resistant tuberculosis (MDRTB) in 19 patients; bronchopleural fistula secondary to Mycobacterium tuberculosis infection in 12; massive hemoptysis in 5; destroyed lung in 7; solitary nodule in 7; trapped lung in 3; complicated cavity in 4; and empyema in 2. Sixty-five operative procedures were performed: pneumonectomy with latissimus muscle flap in 15 patients; pneumonectomy in 3; lobectomy in 16; segmental or wedge resection in 11; decortication in 5; window thoracostomy in 3; thoracoplasty with myoplasty in 4; tube thoracostomy in 4; return to operating room for bleeding in 2; Clagett procedure in 1; and drainage of a cold abscess in 1. There were no operative deaths. Major postoperative complications occurred in 5 patients. The two late deaths were in patients with MDRTB: 1 with progressive disease and massive hemoptysis and the other with a relapse of MDRTB. Of the patients operated on as part of their therapeutic regimen for MDRTB, 17 (89%) of 19 have remained culture negative. We conclude that (1) surgery still plays an important role in the management of patients with Mycobacterium tuberculosis infection; (2) surgical intervention can be performed with acceptable mortality and morbidity; (3) a variety of procedures are needed to effect cure; and (4) encouraging results in patients with MDRTB support surgical therapy in this difficult group of patients.

Transmission of Drug-Resistant Tuberculosis in Texas and Mexico

ABSTRACT To examine the transmission of drug-resistant (DR) tuberculosis between Texas and Mexico, Mycobacterium tuberculosis isolates resistant to one or more of the first-line antimycobacterial drugs were obtained from 606 patients who resided in Texas and 313 patients who resided in Mexico, primarily within the state of Tamaulipas. The isolates were genotyped by IS6110-based restriction fragment length polymorphism (RFLP) analysis and spoligotyping. Of the 919 isolates genotyped, 413 (45%) grouped into 105 clusters containing 2 or more isolates with identical genotypes. In addition to having identical genotypes, identical drug resistance patterns were identified in 250 isolates in 78 clusters (DR clusters). Twenty DR clusters, containing isolates from 32% of the total number of patients infected with DR strains, were geographically distributed across Mexico and Texas. Within this population of 919 patients infected with DR isolates, the probability of being in a DR cluster was the same for residents of Mexico and Texas. In Texas, the significant independent predictors of clustering within DR clusters as opposed to genotype clusters were found to be race, age, country of birth, human immunodeficiency virus (HIV) infection status, and resistance to more than one drug. Specifically, isolates from African Americans, individuals under age 65, individuals born in the United States, and HIV-positive individuals were each more likely to be associated with a DR cluster. By contrast, no significant independent predictors of clustering in a DR cluster were identified in Mexico. Although some DR M. tuberculosis strains are geographically restricted, this study suggests that a number of strains are transmitted between Mexico and the United States.

Access to new medications for the treatment of drug-resistant tuberculosis: Patient, provider and community perspectives

Multidrug-resistant tuberculosis (MDR-TB) is on the rise, and is difficult to treat. The approval of two new drugs, bedaquiline and delamanid, and growing evidence for the use of linezolid, offer renewed hope for addressing MDR-TB. However, access to these medicines remains a significant challenge. These drugs have not been registered for TB in most settings; barriers to preapproval access persist; and high pricing and intellectual property restrictions limit access. Many unanswered research questions about optimal use of these drugs also limit access, particularly for vulnerable populations. This review outlines challenges in accessing drugs encountered from the perspective of clinicians, patients and affected communities, and offers potential solutions.

Drug-resistant tuberculosis: controversies and challenges in pediatrics.

Tuberculosis remains one of the top two causes of death caused by a single infectious disease worldwide, despite curative therapy. Children with tuberculosis are especially difficult to detect, since acid fast bacilli smears and cultures are usually negative and clinical signs are nonspecific or lacking. Multidrug-resistant tuberculosis, or tuberculosis resistant to at least isoniazid and rifampin, has emerged in most areas of the world over the past 20 years. Treatment of multidrug-resistant tuberculosis is more expensive and difficult. The second-line tuberculosis medications required for treatment are more toxic and less efficacious than standard treatment. These medications are not readily available in many areas of the world where drug resistance is most common. Fluoroquinolones are one of the most promising classes of second-line medications, but are not generally recommended for use in children. Ethambutol is recommended in the initial treatment of tuberculosis in children treated in areas where there is a risk of drug-resistant disease and the susceptibility of the source case is not known. Some experts have been hesitant to use ethambutol due to the risk of visual impairment associated with the drug and the difficulties in monitoring vision in young children. Pediatric drug formulations are not available for most antituberculosis medications, even the first-line tuberculosis drugs. Treatment of children exposed, infected or ill with multidrug-resistant tuberculosis is reviewed with special emphasis on second-line drugs, including recommended dosage, available formulations and necessary monitoring. While new cases of multidrug-resistant tuberculosis have decreased in most developed countries over the past 10 years, cases continue to increase in many developing countries and among immigrants from high-risk areas. Tuberculosis and multidrug-resistant tuberculosis are serious threats requiring worldwide strategies to control and treat. Better diagnostic tests, medications, public health strategies and vaccines will all be needed to eliminate tuberculosis.

Health Care Workers and Researchers Traveling to Developing-World Clinical Settings: Disease Transmission Risk and Mitigation

Abstract With the recent emphasis on funding and training opportunities for global health and humanitarian aid and the increased interest in the field, many health care workers and medical researchers are traveling from resource-replete to resource-limited settings. This type of travel brings unique disease risks not routinely considered for the business or vacationing traveler. This review provides practical advice for this special population of travelers, targeted to specific health care-related risks (needlestick, hemorrhagic fever viruses, severe viral respiratory disease, and tuberculosis), with suggestions for risk mitigation.

The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosis-affected communities.

WHO has issued normative guidance on bedaquiline, 2 which is available on the market in the USA and through compassionate use in other countries. As the fi rst new drug from a novel class approved to treat tuberculosis in more than 40 years, bedaquiline’s implications for improving treatment of drug-resistant tuberculosis and possible application to create shorter fi rst-line regimens for treatment of drugsusceptible tuberculosis is still unclear. Existing drugs must be taken for months (drug-susceptible tuberculosis) or years (drug-resistant tuberculosis), burdening patients and health systems; even then, cure rates for drugresistant disease range from 11% to 79% dependent on the extent of resistance. 3,4 However, community voices on bedaquiline’s use to treat drug-resistant tuberculosis and future development as a potential treatment for drugsusceptible disease have been largely unheard. We provide a community perspective on this issue and list seven questions concerning bedaquiline’s safety that researchers should answer before the launch of clinical trials of bedaquiline for drug-susceptible tuberculosis. Developed by Janssen, bedaquiline (Sirturo) received accelerated approval from the FDA based on two phase 2b studies of 440 people with multidrug-resistant tuberculosis. 5,6 More patients who received bedaquiline, rather than placebo, in combination with other drugs for drug-resistant tuberculosis converted their sputum cultures from positive to negative after 8 and 24 weeks of treatment. The proportion of culture conversion at week 8 was 47·6% in the bedaquiline group and 8·7% in the placebo group, whereas the proportion at week 24 was 81% for the bedaquiline group versus 65·2% for the placebo group. 5,6 Culture conversion at 2 months is a

Therapy of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

The global epidemic of multidrug-resistant tuberculosis (MDR-TB) caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampin was recently reported as larger than previously estimated, with at least 580,000 new cases reported in 2015. Extensively drug-resistant tuberculosis (XDR-TB), MDR-TB with additional resistance to a second-line fluoroquinolone and injectable, continues to account for nearly 10% of MDR cases globally. Cases in India, China, and the Russian Federation account for >45% of the cases of MDR-TB. Molecular testing helps identify MDR more quickly, and treatment options have expanded across the globe. Despite this, only 20% are in treatment, and treatment is challenging due to the toxicity of medications and the long duration. In 2016 the World Health Organization updated guidelines for the treatment of MDR-TB. A new short-course regimen is an option for those who qualify. Five effective drugs, including pyrazinamide (PZA) when possible, are recommended during the initial treatment phase and four drugs thereafter. Revised drug classifications include the use of linezolid and clofazimine as key second-line drugs and the option to use bedaquiline and delamanid to complete a five-drug regimen when needed due to poor medication tolerance or extensive resistance. Despite multiple drugs and long-duration treatment regimens, the outcomes for MDR and especially XDR-TB are much worse than for drug-susceptible disease. Better management of toxicity, prevention of transmission, and identification and appropriate management of infected contacts are important challenges for the future.

Characteristics and costs of multidrug-resistant tuberculosis in-patient care in the United States, 2005-2007.

OBJECTIVE A population-based study of 135 multidrug-resistant tuberculosis (MDR-TB) patients reported to the Centers for Disease Control and Prevention (CDC) during 2005-2007 found 73% were hospitalized. We analyzed factors associated with hospitalization. METHODS We assessed statistically significant multivariable associations with US in-patient TB diagnosis, frequency of hospitalization, length of hospital stay, and in-patient direct costs to the health care system. RESULTS Of 98 hospitalized patients, 83 (85%) were foreign-born. Blacks, diabetics, or smokers were more likely, and patients with disseminated disease less likely, to receive their TB diagnosis while hospitalized. Patients aged ⩾65 years, those with the acquired immune-deficiency syndrome (AIDS), or with private insurance, were hospitalized more frequently. Excluding deaths, length of stay was greater for patients aged ⩾65 years, those with extensively drug-resistant TB (XDR-TB), those residing in Texas, those with AIDS, those who were unemployed, or those who had TB resistant to all first-line medications vs. others. Average hospitalization cost per XDR-TB patient (US

Multidrug-Resistant Tuberculosis. Recommendations for Reducing Risk during Travel for Healthcare and Humanitarian Work

285 000) was 3.5 times that per MDR-TB patient (US