Brenda E. Jones

Evaluation of an Intensive Intermittent-Induction Regimen and Duration of Short-Course Treatment for Human Immunodeficiency Virus-Related Pulmonary Tuberculosis

This study examined whether adding levofloxacin to a standard four-drug regimen improved the 8-week culture response and compared effectiveness of 9 versus 6 months of intermittent therapy for human immunodeficiency virus-related pansusceptible pulmonary tuberculosis. Patients were randomized to receive either four or five drugs, the fifth being levofloxacin. Patients who completed induction therapy were randomized to complete 9 versus 6 months of intermittent therapy with isoniazid and rifampin. In the randomized induction phase, 97.3% of patients in the four-drug group and 95.8% in the five-drug group had sputum culture conversion at 8 weeks (P = 1.00). In the continuation phase, one patient (2%) assigned to 9 months and two patients (3.9%) assigned to 6 months of therapy had treatment failure/relapse (P = 1.00). In conclusion, this study showed that levofloxacin added no benefit to a highly effective, largely intermittent, four-drug induction regimen. Both 9 and 6 months of intermittent therapy were associated with low treatment failure/relapse rates.

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing

ABSTRACT The current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P = 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with trough-only data allowed 97% (93 to 102%; P = 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of ≥400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter.

Treatment for Preventing Tuberculosis in Children and Adolescents: A Randomized Clinical Trial of a 3-Month, 12-Dose Regimen of a Combination of Rifapentine and Isoniazid

IMPORTANCE Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited. OBJECTIVES To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children. DESIGN, SETTING, AND PARTICIPANTS A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection. INTERVENTIONS Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months. MAIN OUTCOMES AND MEASURES We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%. RESULTS Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion. CONCLUSIONS AND RELEVANCE Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00023452.

Clinical and radiographic features of HIV-related tuberculosis.

Human immunodeficiency virus (HIV)-related tuberculosis can be life-threatening for the individual, transmissible to others, and difficult to diagnose. We review the clinical, radiographic, and histopathologic features of HIV-related tuberculosis, and the ways in which these features are affected by the degree of immunodeficiency. At CD4 cell counts greater than 350 cells/microL, HIV-related tuberculosis has a similar presentation to tuberculosis in HIV-uninfected adults, predominantly pulmonary involvement with fibronodular and/or cavitary infiltrates. With progressive immunodeficiency, extrapulmonary involvement becomes increasingly common. Pulmonary involvement remains common at all stages of HIV disease, but the radiographic pattern is very different among persons with advanced immunodeficiency, in whom the most common abnormalities are intrathoracic adenopathy, focal lower or middle lobe infiltrates, and diffuse miliary or nodular infiltrates. The keys to the diagnosis of HIV-related tuberculosis are knowledge of the epidemiology of tuberculosis, recognition of the ways that immunodeficiency changes the clinical presentation, and an assiduous effort to obtain specimens for mycobacterial smear and culture.

Brainstem tuberculoma in the immunocompetent: Case report and literature review

Brainstem tuberculoma is an uncommon entity especially in the immunocompetent adult. The authors describe the case of a 32-year-old immunocompetent woman with no systemic signs or symptoms of tuberculosis, presenting with sudden-onset hemiparesis and diplopia. MRI of brain revealed an enhancing lesion in the midbrain and thalamus. Cerebrospinal fluid examination was normal. Chest imaging was consistent with miliary tuberculosis; however initial expectorated sputum was culture negative. Bronchosopy sputum culture was positive for Mycobacterium tuberculosis. Her PPD was negative. Patient became asymptomatic with treatment for tuberculosis and follow-up MRI showed complete resolution of the lesion a year later. We conclude that a high index of suspicion is essential to make an early diagnosis of intracranial tuberculoma, since often, traditional TB tests like PPD and sputum examinations can be negative.

Pulmonary manifestations of HIV/AIDS in the tropics.

The most significant pulmonary opportunistic infections in the tropics are TB and pneumococcal pneumonia. Guidelines for the diagnosis and management of these and other pulmonary manifestations of HIV are discussed. Ultimately, unless concerted efforts are made to treat underlying HIV infection in regions most devastated by AIDS, the impact of these diseases will continue to grow.

Clinical Evaluation of the Nelfinavir‐Rifabutin Interaction in Patients with Tuberculosis and Human Immunodeficiency Virus Infection

Study Objective. To characterize the bidirectional interaction between twice‐daily nelfinavir and twice‐weekly rifabutin and isoniazid in patients with tuberculosis and human immunodeficiency virus (HIV) infection.

A rho GDP dissociation inhibitor produced by apoptotic T-cells inhibits growth of Mycobacterium tuberculosis.

In this study, we found that a subpopulation of CD4+CD25+ (85% Foxp3+) cells from persons with latent tuberculosis infection (LTBI) inhibits growth of M. tuberculosis (M. tb) in human monocyte-derived macrophages (MDMs). A soluble factor, Rho GDP dissociation inhibitor (D4GDI), produced by apoptotic CD4+CD25+ (85% Foxp3+) cells is responsible for this inhibition of M. tb growth in human macrophages and in mice. M. tb-expanded CD4+CD25+Foxp3+D4GDI+ cells do not produce IL-10, TGF-β and IFN-γ. D4GDI inhibited growth of M. tb in MDMs by enhancing production of IL-1β, TNF-α and ROS, and by increasing apoptosis of M. tb-infected MDMs. D4GDI was concentrated at the site of disease in tuberculosis patients, with higher levels detected in pleural fluid than in serum. However, in response to M. tb, PBMC from tuberculosis patients produced less D4GDI than PBMC from persons with LTBI. M. tb-expanded CD4+CD25+ (85% Foxp3+) cells and D4GDI induced intracellular M. tb to express the dormancy survival regulator DosR and DosR-dependent genes, suggesting that D4GDI induces a non-replicating state in the pathogen. Our study provides the first evidence that a subpopulation of CD4+CD25+ (85% Foxp3+) cells enhances immunity to M. tb, and that production of D4GDI by this subpopulation inhibits M. tb growth.

Relationship of Acute Phase Reactants and Fat Accumulation during Treatment for Tuberculosis

Background. Tuberculosis causes inflammation and muscle wasting. We investigated how attenuation of inflammation relates to repletion of body composition during treatment in an underserved population. Design. Twenty-four patients (23 to 79 years old) with pulmonary tuberculosis and inflammation (pretreatment albumin = 2.96 ± 0.13 g/dL, C-reactive protein [CRP] = 6.71 ± 1.34 μg/dL, and beta-2-microglobulin = 1.68 ± 0.10 μg/L) were evaluated and had BIA over 24 weeks. Results. Weight increased by 3.02 ± 0.81 kg (5.5%; P = 0.007) at week 4 and by 8.59 ± 0.97 kg (15.6%; P < 0.0001) at week 24. Repletion of body mass was primarily fat, which increased by 2.09 ± 0.52 kg at week 4 and 5.05 ± 0.56 kg at week 24 (P = 0.004 and P < 0.0001 versus baseline). Fat-free mass (FFM), body cell mass (BCM), and phase angle did not increase until study week 8. Albumin rose to 3.65 ± 0.14 g/dL by week 4 (P < 0.001) and slowly increased thereafter. CRP levels declined by ∼50% at each interval visit. Conclusions. During the initial treatment, acute phase reactants returned towards normal. The predominant accrual of fat mass probably reflects ongoing, low levels of inflammation.

Can mycobacterial katG genetic changes in isoniazid-resistant tuberculosis influence human disease features?

BACKGROUND Isoniazid-resistant (INHr) Mycobacterium tuberculosis isolates often have katG mutations, and katG is a virulence factor in animal models. It is unclear if katG mutations or other mutations influence the characteristics of human disease. OBJECTIVE To determine if the presence of INHr-conferring mutations were associated with distinct clinical features of tuberculosis (TB). METHODS In a retrospective case-control study, INHr-conferring mutations were determined by DNA sequencing. We examined associations between clinical characteristics in patients with INHr M. tuberculosis (stratified by groups of relevant INHr-conferring mutations, including katG-S315T and inhA-C(-)15T mutations) and pan-susceptible (PS) isolates. RESULTS Twenty-nine INHr TB cases and 50 PS controls were evaluated. Disease characteristics were not statistically different between INHr and PS cases. However, patients infected with non-katG mutants were associated with a higher rate of sputum culture conversion at 1 month after adjustment for relevant covariates (adjusted OR [aOR] 4.4, 95%CI 1.1-23.6, P = 0.04). Patients infected with katG mutants were associated with a higher rate of unilateral disease (aOR 4.7, 95%CI 1.0-34.3, P = 0.05). CONCLUSIONS Most INHr TB cases with non-katG mutations have disease associated with faster response to treatment, and most cases with katG mutants have localized lung involvement.