Therapeutic drug monitoring and TB treatment outcomes in patients with diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) increases the risk of TB disease and poor treatment outcomes such as delayed sputum culture conversion due to inadequate drug exposure. Therapeutic drug monitoring (TDM) has improved these outcomes in some settings.METHODS: To compare treatment outcomes in programs with routine TDM vs. programs that did not use TDM, we conducted a retrospective study among people with DM and TB at health departments in four US states.RESULTS: A total of 170 patients were enrolled (73 patients in the non-TDM group and 97 patients in the TDM group). Days to sputum culture conversion and total treatment duration were significantly shorter in the TDM group vs. the non-TDM group. In adjusted analyses, patients who underwent TDM were significantly more likely to achieve sputum culture conversion at 2 months (P = 0.007).CONCLUSION: TDM hastened microbiological cure from TB among people with DM and a high risk for poor treatment outcomes in the programmatic setting.

A comparison of interview methods to ascertain fluoroquinolone exposure before tuberculosis diagnosis.

SUMMARY Fluoroquinolone use before tuberculosis (TB) diagnosis delays the time to diagnosis and treatment, and increases the risk of fluoroquinolone-resistant TB and death. Ascertainment of fluoroquinolone exposure could identify such high-risk patients. We compared four methods of ascertaining fluoroquinolone exposure in the 6 months prior to TB diagnosis in culture-confirmed TB patients in Tennessee from January 2007 to December 2009. The four methods included a simple questionnaire administered to all TB suspects by health department personnel (FQ-Form), an in-home interview conducted by research staff, outpatient and inpatient medical record review, and TennCare pharmacy database review. Of 177 TB patients included, 72 (41%) received fluoroquinolones during the 6 months before TB diagnosis. Fluoroquinolone exposure determined by review of inpatient and outpatient medical records was considered the gold standard for comparison. The FQ-Form had 61% [95% confidence interval (CI) 48-73] sensitivity and 93% (95% CI 85-98) specificity (agreement 79%, kappa = 0.56) while the in-home interview had 28% (95% CI 18-40) sensitivity and 99% (94-100%) specificity (agreement 68%, kappa = 0.29). A simple questionnaire administered by health department personnel identified fluoroquinolone exposure before TB diagnosis with moderate reliability.

Tuberculosis and the risk of infection with other intracellular bacteria: a population-based study.

SUMMARY Persons who develop tuberculosis (TB) may have subtle immune defects that could predispose to other intracellular bacterial infections (ICBIs). We obtained data on TB and five ICBIs (Chlamydia trachomatis, Salmonella spp., Shigella spp., Yersinia spp., Listeria monocytogenes) reported to the Tennessee Department of Health, USA, 2000-2011. Incidence rate ratios (IRRs) comparing ICBIs in persons who developed TB and ICBIs in the Tennessee population, adjusted for age, sex, race and ethnicity were estimated. IRRs were not significantly elevated for all ICBIs combined [IRR 0.87, 95% confidence interval (CI) 0.71-1.06]. C. trachomatis rate was lowest in the year post-TB diagnosis (IRR 0.17, 95% CI 0.04-0.70). More Salmonella infections occurred in extrapulmonary TB compared to pulmonary TB patients (IRR 14.3, 95% CI 1.67-122); however, this appeared to be related to HIV co-infection. TB was not associated with an increased risk of other ICBIs. In fact, fewer C. trachomatis infections occurred after recent TB diagnosis. Reasons for this association, including reduced exposure, protection conferred by anti-TB drugs or macrophage activation by Mycobacterium tuberculosis infection warrant further investigation.

Non-adherence and drug-related interruptions are risk factors for delays in completion of treatment for tuberculosis.

SETTING: A key program performance objective established by the Centers for Disease Control and Prevention (CDC) is that ≥93% of tuberculosis (TB) cases complete treatment within 12 months. OBJECTIVE: To determine the rate of and risk factors for delay in anti-tuberculosis treatment completion. DESIGN: Nested case-control study among TB cases reported to the Tennessee Department of Health between 1 January 2000 and 31 December 2010. Time to complete treatment was calculated using treatment start and stop dates documented in the Tuberculosis Information Management System (TIMS). RESULTS: Of 2627 cases, 261 (9.9%) required >12 months to complete treatment. In adjusted conditional logistic regression analyses, cavitary disease and positive cultures after 2 months of therapy (OR 5.85, 95%CI 1.98-17.32, P = 0.001), non-adherence (OR 4.13, 95%CI 1.76-9.72, P < 0.001), and interruptions in treatment due to drug-related issues (OR 6.91, 95%CI 3.76-12.70, P < 0.001) were independently associated with delay in completion of TB treatment. CONCLUSION: From 2000 to 2010, the proportion of TB cases completing treatment within 12 months increased from 84.6% to 94.9%, and remained above the CDC target during 2009-2010. Efforts to improve patient adherence and reduce interruptions in treatment due to anti-tuberculosis drug-related issues could improve the proportion of TB cases completing treatment within 12 months.

Fluoroquinolone exposure prior to tuberculosis diagnosis is associated with an increased risk of death.

SETTING: Fluoroquinolone (FQ) exposure before tuberculosis (TB) diagnosis is common, but its effect on outcomes, including mortality, is unclear. DESIGN: Among TB patients reported to the Tennessee Department of Health from 2007 to 2009, we assessed FQ exposure within 6 months before TB diagnosis. The primary outcome was the combined endpoint of death at the time of TB diagnosis and during anti-tuberculosis treatment. RESULTS: Among 609 TB cases, 214 (35%) received FQs within 6 months before TB diagnosis. A total of 71 (12%) persons died; 10 (2%) were dead at TB diagnosis and 61 (10%) died during anti-tuberculosis treatment. In multivariable logistic regression analysis, factors independently associated with death were older age (OR 1.05 per year, 95%CI 1.04-1.07), human immunodeficiency virus infection (OR 8.08, 95%CI 3.83-17.06), US birth (OR 3.03, 95%CI 1.03-9.09), and any FQ exposure before TB diagnosis (OR 1.82, 95%CI 1.05-3.15). Persons with FQ exposure before TB diagnosis were more likely to have culture- and smear-positive disease than unexposed persons. CONCLUSIONS: Among this patient population, FQ exposure before TB diagnosis was associated with an increased risk of death. These findings underscore the need for cautious use of FQs in persons with possible TB.

Chronic lung disease and HIV infection are risk factors for recurrent tuberculosis in a low-incidence setting.

SETTING: Programmatic data from the United States on tuberculosis (TB) recurrence are limited. OBJECTIVES: To determine the TB recurrence rate and to determine if chronic lung disease (CLD) and human immunodeficiency virus (HIV) infection are risk factors for recurrence in this population. DESIGN: Nested case-control study among TB cases reported to the Tennessee Department of Health between 1 January 2000 and 31 December 2006. Time at risk for recurrence was through 31 December 2007. Multiple imputation accounted for missing data. RESULTS: Of 1431 TB cases, 20 cases recurred (1.4%, 95%CI 0.9-2.1). Median time at risk for recurrence was 4.5 years (interquartile range 2.7-6.1). Initial and recurrent Mycobacterium tuberculosis isolates were available for genotyping for 15 patients; 12 were consistent with relapse (0.8%, 95%CI 0.4-1.5) and three with re-infection (0.2%, 95%CI 0.04-0.6). HIV infection (OR 5.01, P = 0.04) and CLD (OR 5.28, P = 0.03) were independently associated with recurrent TB, after adjusting for a disease risk score. HIV infection was a risk factor for TB re-infection (P < 0.001). CONCLUSIONS: In this low-incidence US population, the TB recurrence rate was low, but CLD and HIV were independent risk factors for recurrence. HIV infection was also a risk factor for TB re-infection.

Normal chest radiography in pulmonary tuberculosis: implications for obtaining respiratory specimen cultures.

SETTING: Urban tuberculosis (TB) clinic, Nashville, Tennessee, USA. OBJECTIVE: Chest radiographs (CXRs) help in the diagnosis of pulmonary TB, but may be normal. Mycobacterium tuberculosis in culture is diagnostic of TB, but cultures are not routinely obtained in resource-poor settings. We examined rates and risk factors for pulmonary TB associated with normal CXR. DESIGN: An observational cohort study was performed among all respiratory culture-positive TB cases referred to the Nashville Health Department from October 1992 to July 2003. Clinical factors, demographics and underlying medical conditions were assessed. RESULTS: Of 601 study patients, 53 (9%) had normal CXRs: 31/138 (22%) were human immunodeficiency virus (HIV) infected and 22/463 (5%) were non-HIV-infected/unknown (P<0.001). Among HIV-infected patients, normal CXR was more likely in persons with renal failure (13% vs. 3%, P=0.048). Among non-HIV-infected/unknown patients, normal CXR was more likely in those who were asymptomatic at presentation (32% vs. 13%, P=0.022). In multivariable logistic regression analysis, HIV infection was associated with an increased risk of normal CXR (odds ratio [OR] 6.61, P<0.0001); factors associated with reduced risk were dyspnea (OR 0.24, P=0.026), positive sputum smear (OR 0.45, P=0.028) and cough (OR 0.48, P=0.038). CONCLUSIONS: The rate of normal CXR among persons with culture-confirmed pulmonary TB was high. Respiratory specimen cultures should be obtained in TB suspects with a normal CXR, particularly HIV-infected persons.

A comparison of skyshine computational methods.

A variety of methods employing radiation transport and point-kernel codes have been used to model two skyshine problems. The first problem is a 1 MeV point source of photons on the surface of the earth inside a 2 m tall and 1 m radius silo having black walls. The skyshine radiation downfield from the point source was estimated with and without a 30-cm-thick concrete lid on the silo. The second benchmark problem is to estimate the skyshine radiation downfield from 12 cylindrical canisters emplaced in a low-level radioactive waste trench. The canisters are filled with ion-exchange resin with a representative radionuclide loading, largely 60Co, 134Cs and 137Cs. The solution methods include use of the MCNP code to solve the problem by directly employing variance reduction techniques, the single-scatter point kernel code GGG-GP, the QADMOD-GP point kernel code, the COHORT Monte Carlo code, the NAC International version of the SKYSHINE-III code, the KSU hybrid method and the associated KSU skyshine codes.

Mechanism of migration of the trimethylsilyl group during reactions of methoxy[(trimethylsilyl)ethoxy]carbene with N-phenylmaleimide and C(60).

A novel migration of the trimethylsilyl group during reaction of methoxy[(trimethylsilyl)ethoxy]carbene with N-phenylmaleimide (NPM) and with C(60), reported earlier, was examined by means of deuterium labeling of the carbene. For the NPM case it was found that the CD(2)CH(2)SiMe(3) group, initially bound to oxygen, became the CH(2)CD(2)SiMe(3) group bound to carbon in the end product. Not only had the trimethylsilylethyl group moved from oxygen to carbon, but the TMS group had also migrated 1,2 along the ethyl chain. For the C(60) case, complete scrambling of the CD(2) group was observed, strongly implying the involvement of a silacyclopropane carbocation responsible for product formation. The labeling study supports the mechanism that was tentatively advanced earlier for addition to NPM and one of the possibilities suggested for addition to C(60).

The first 2,2-dialkoxythiirane.

[reaction: see text] Thermolysis of 1 at 110 degrees C in benzene containing adamantanethione leads to thiirane 2 in 92% yield, as an isolable, stable solid. Compound 2 is the first example of the hitherto unknown 2,2-dialkoxythiiranes. It shows some reactions characteristic of thiiranes.

Novel products from thermolysis of 5,5-dimethyl-2, 2-diphenoxy-Delta(3)-1,3,4- oxadiazoline in the presence of DMAD

Thermolysis of 1 at 110 degrees C in benzene containing DMAD (dimethyl acetylenedicarboxylate) leads to triester 2 and bicyclo[1. 1.0]butanes, 3 and 4.

Silicon migration from oxygen to carbon and decarbonylation in methoxytriphenylsiloxycarbene.

[reaction: see text] Thermolysis of 2-methoxy-2-triphenylsiloxy-5,5-dimethyl-Delta(3)-1,3, 4-oxadiazoline affords methyl triphenylsilylformate and methyl triphenylsilyl ether via methoxytriphenylsiloxycarbene. Kinetics show that the carbene undergoes reversible 1,2-triphenylsilyl migration (Brook rearrangement) as well as irreversible decarbonylation. Computed transition states and activation energies (B3LYP/6-31+G) suggest that the migration of the silyl group from oxygen to carbon occurs through an "in plane" transition state with the carbene lone pair forming a new bond to silicon. Decarbonylation involves a four-membered ring, achieved by nucleophilic attack of the oxygen atom of the methoxy group at silicon.