Eric Leibert

Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis.

OBJECTIVE To determine whether linezolid is safe and well tolerated in the treatment of extensively drug-resistant tuberculosis (XDR-TB). MATERIALS AND METHODS The was conducted in a specialized tuberculosis ward for multidrug-resistant tuberculosis (MDR-TB) on the Chest Service of Bellevue Hospital Center, which is a 768-bed public hospital in New York City. Seven patients with confirmed MDR-TB or XDR-TB who were still culture positive despite appropriate directly observed therapy were treated with a regimen containing linezolid and at least one other active agent. RESULTS The linezolid-containing regimen led to sustained negative conversion of sputum cultures and radiographic improvement in all patients. Long-term therapy (longest duration of therapy, 28 months) was well tolerated in most patients. Neutropenia developed in three patients, but was reversible, and peripheral neuropathy developed in two patients. CONCLUSIONS Linezolid remains a promising possible addition to our therapeutic armamentarium against XDR-TB. Linezolid is associated with side effects that can be adequately managed. Further studies to define the mechanism of action and optimum dose should be performed.

Antibodies against immunodominant antigens of Mycobacterium tuberculosis in subjects with suspected tuberculosis in the United States compared by HIV status.

ABSTRACT The immunodominance of Mycobacterium tuberculosis proteins malate synthase (MS) and MPT51 has been demonstrated in case-control studies with patients from countries in which tuberculosis (TB) is endemic. The value of these antigens for the serodiagnosis of TB now is evaluated in a cross-sectional study of pulmonary TB suspects in the United States diagnosed to have TB, HIV-associated TB, or other respiratory diseases (ORD). Serum antibody reactivity to recombinant purified MS and MPT51 was determined by enzyme-linked immunosorbent assays (ELISAs) of samples from TB suspects and well-characterized control groups. TB suspects were diagnosed with TB (n = 87; 49% sputum microscopy negative, 20% HIV+) or ORD (n = 63; 58% HIV+). Antibody reactivity to MS and MPT51 was significantly higher in U.S. HIV+/TB samples than in HIV−/TB samples (P < 0.001), and it was significantly higher in both TB groups than in control groups with latent TB infection (P < 0.001). Antibody reactivity to both antigens was higher in U.S. HIV+/TB samples than in HIV+/ORD samples (P = 0.052 for MS, P = 0.001 for MPT51) but not significantly different between HIV−/TB and HIV−/ORD. Among U.S. HIV+ TB suspects, a positive anti-MPT51 antibody response was strongly and significantly associated with TB (odds ratio, 11.0; 95% confidence interval, 2.3 to 51.2; P = 0.002). These findings have implications for the adjunctive use of TB serodiagnosis with these antigens in HIV+ subjects.

New drugs to treat multidrug-resistant tuberculosis: the case for bedaquiline

Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually every drug in use. Courses of therapy select for these mutants and drug-resistant organisms emerge. The development of drug-resistant organisms has reached the point that drug resistance now threatens to undermine global success against tuberculosis (TB). New drugs are needed. The last new class of drugs specifically developed for treatment of TB was the rifamycins over 40 years ago. New funding sources and the development of product development partnerships have energized the TB drug development effort. There are now more TB drugs in development than at any time in the past. The first of these drugs to be developed and marketed was bedaquiline. Bedaquiline has an entirely novel mechanism of action and so should be active against otherwise highly resistant organisms. It acts on the transmembrane component of adenosine triphosphate synthase and acts by preventing electron transport. This raises the exciting possibility that bedaquiline may be active against less metabolically active organisms. Drug–drug interactions between rifamycins and the cytochrome P450-3A system will limit bedaquiline’s utility and create complexity in treatment regimens. In clinical trials, treatment with bedaquiline added to a background multidrug-resistant TB regimen was associated with earlier culture conversion and higher cure rates, but there were unexplained excess deaths in the bedaquiline arms of these trials. Food and Drug Administration approved bedaquiline for the treatment of multidrug-resistant TB when an effective treatment regimen cannot otherwise be provided. They required a black box warning about excess deaths and require that a phase III trial be completed. A planned Phase III trial is being reorganized. While bedaquiline is an exciting drug and marks a dramatic moment in the history of TB treatment, its ultimate place in the anti-TB drug armamentarium is unclear pending the Phase III trial and the development of other new drugs that are in the pipeline.

New drugs and regimens for treatment of TB.

Tools for effective TB control have been available for years. Case finding, active medications, case management and directly observed therapy are the foundations for the management of TB. The current TB epidemic, centered in resource-limited settings is fueled by the HIV-1 epidemic. Lack of ability to diagnose and treat drug-resistant TB has led to development of more extensive patterns of resistance. Among the currently available drugs, there is reason to hope that rifamycins paired with fluoroquinolones will lead to shorter treatment regimens for drug-susceptible TB. As the result of novel public–private collaborations and investments of resources, new drugs are being developed. These include TMC207, already shown to have activity early in the treatment of multidrug-resistant TB and others that are likely to be active against persistor organisms, and have the prospect to dramatically shorten treatment courses for active and latent TB. Given that these drugs have novel mechanisms of action, combinations have the prospect to be highly active even against multidrug-resistant organisms.

Molecular Characterization of the Peripheral Airway Field of Cancerization in Lung Adenocarcinoma

Field of cancerization in the airway epithelium has been increasingly examined to understand early pathogenesis of non-small cell lung cancer. However, the extent of field of cancerization throughout the lung airways is unclear. Here we sought to determine the differential gene and microRNA expressions associated with field of cancerization in the peripheral airway epithelial cells of patients with lung adenocarcinoma. We obtained peripheral airway brushings from smoker controls (n=13) and from the lung contralateral to the tumor in cancer patients (n=17). We performed gene and microRNA expression profiling on these peripheral airway epithelial cells using Affymetrix GeneChip and TaqMan Array. Integrated gene and microRNA analysis was performed to identify significant molecular pathways. We identified 26 mRNAs and 5 miRNAs that were significantly (FDR <0.1) up-regulated and 38 mRNAs and 12 miRNAs that were significantly down-regulated in the cancer patients when compared to smoker controls. Functional analysis identified differential transcriptomic expressions related to tumorigenesis. Integration of miRNA-mRNA data into interaction network analysis showed modulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway in the contralateral lung field of cancerization. In conclusion, patients with lung adenocarcinoma have tumor related molecules and pathways in histologically normal appearing peripheral airway epithelial cells, a substantial distance from the tumor itself. This finding can potentially provide new biomarkers for early detection of lung cancer and novel therapeutic targets.

Clinical and Radiographic Manifestations of Sputum Culture-Negative Pulmonary Tuberculosis.

Intervention at the earliest possible stage of pulmonary tuberculosis (PTB) reduces morbidity for the individual and transmission for the community. We characterize the clinical and radiographic manifestations of sputum culture-negative (Cx-) PTB in order to facilitate awareness of this under recognized and likely early disease state. In this cross-sectional sub-study, we reviewed the medical records of HIV-uninfected PTB patients enrolled from 2006–2014 within the context of a TB biomarker study in New York City. Cx- PTB was defined as clinical and/or radiographic presentation consistent with PTB, three initial mycobacterial sputum cultures negative, and no evidence of other respiratory disease. Diagnosis was confirmed by clinical and radiographic improvement on antituberculous treatment and/or culture, nucleic acid, or histological confirmation from a specimen other than the initial three sputa. Cx+ PTB was defined as above but with M. tuberculosis growth in at least one of the first three sputum cultures. Demographics, symptoms, and radiographic findings on initial presentation were compared between the two groups. Of 99 subjects diagnosed with PTB, 21 met the criteria of Cx- PTB. Cx- compared to Cx+ subjects presented with a significantly lower frequency of cough (70% vs. 91%, P = 0.02), sputum production (30% vs. 64%, P < 0.01), weight loss (25% vs. 54%, P = 0.02), and frequency of cavitation on chest CT (12% vs. 68%, P < 0.01). Our findings should raise awareness that neither a positive culture nor the hallmark symptoms are invariably associated with early TB disease.

Original ResearchChest InfectionsRisk Factors for and Outcomes of Detention of Patients With TB in New York City: An Update: 2002-2009

BACKGROUND One of the most controversial aspects of New York Citys highly effective TB control program is the use of public health law and court-ordered detention to treat persistently recalcitrant patients with active TB. We now report on characteristics and outcomes of patients undergoing detention for completion of TB treatment due to nonadherence in New York City from 2002 through 2009. METHODS A retrospective cohort study was designed to compare patients undergoing court-ordered detention (n = 79) and time-matched control subjects undergoing TB treatment in outpatient directly observed therapy (DOT) at Bellevue Hospital in New York City. RESULTS From January 1, 2002, through December 31, 2009, 79 patients underwent court-ordered detention for TB treatment. Compared with patients completing treatment in DOT, univariate analysis found that detainees were younger; more likely to be of minority race/ethnicity; to have a history of substance abuse, tobacco use, homelessness, incarceration, HIV infection; and to be born in the United States. Multivariate analysis adjusting for other variables found smear positivity (OR = 3.93; 95% CI, 1.05-14.75; P = .04), mental illness (OR = 5.80; 95% CI, 1.18-28.51; P = .03), and substance abuse (OR = 9.25; 95% CI, 2.81-30.39; P < .01) to be the strongest independent predictors of likelihood of detention. Of those initially detained, 46 (58%) completed treatment during inpatient detention, 29(37%) completed treatment under outpatient court-ordered DOT, and four died during their hospitalization. CONCLUSIONS The majority of patients undergoing court-ordered detention for TB treatment (95%) successfully completed therapy. Likelihood of detention was most strongly associated with factors expected to be associated with poor adherence, including mental illness and substance abuse.

Risk Factors for and Outcomes of Detention of Patients With TB in New York City: An Update: 2002-2009

BACKGROUND One of the most controversial aspects of New York Citys highly effective TB control program is the use of public health law and court-ordered detention to treat persistently recalcitrant patients with active TB. We now report on characteristics and outcomes of patients undergoing detention for completion of TB treatment due to nonadherence in New York City from 2002 through 2009. METHODS A retrospective cohort study was designed to compare patients undergoing court-ordered detention (n = 79) and time-matched control subjects undergoing TB treatment in outpatient directly observed therapy (DOT) at Bellevue Hospital in New York City. RESULTS From January 1, 2002, through December 31, 2009, 79 patients underwent court-ordered detention for TB treatment. Compared with patients completing treatment in DOT, univariate analysis found that detainees were younger; more likely to be of minority race/ethnicity; to have a history of substance abuse, tobacco use, homelessness, incarceration, HIV infection; and to be born in the United States. Multivariate analysis adjusting for other variables found smear positivity (OR = 3.93; 95% CI, 1.05-14.75; P = .04), mental illness (OR = 5.80; 95% CI, 1.18-28.51; P = .03), and substance abuse (OR = 9.25; 95% CI, 2.81-30.39; P < .01) to be the strongest independent predictors of likelihood of detention. Of those initially detained, 46 (58%) completed treatment during inpatient detention, 29(37%) completed treatment under outpatient court-ordered DOT, and four died during their hospitalization. CONCLUSIONS The majority of patients undergoing court-ordered detention for TB treatment (95%) successfully completed therapy. Likelihood of detention was most strongly associated with factors expected to be associated with poor adherence, including mental illness and substance abuse.