Imipenem pharmacokinetics/pharmacodynamics in preclinical hollow fiber model, dose-finding in virtual patients, and clinical evidence of efficacy for Mycobacterium abscessus lung disease.

Background: Guideline-based therapy (GBT) for Mycobacterium abscessus (Mab) lung disease achieves sputum culture conversion rates (SCC) of 35%. This poor GBT efficacy is mirrored in the hollow fiber system model of Mab (HFS-Mab). While imipenem is part of GBT, biological effect with or without β-lactamase inhibitors, is unproven.

Nutritionally acquired immunodeficiency must be addressed with the same urgency as HIV to end tuberculosis.

Tuberculosis (TB) is the leading infectious killer worldwide, with 10.6 million cases and 1.6 million deaths in 2021 alone.

Intestinal Parasitic Infections May Be Overlooked Drivers of the Tuberculosis Pandemic.

The burden of tuberculosis (TB) is disproportionate in tropical and subtropical regions, where parasitic coinfections are common. Given the significant geographical overlap between TB and intestinal parasitic infections, it is important to consider the implications of intestinal parasitic infections for the TB pandemic. Intestinal parasitic infections have been theorized to increase vulnerability to TB by altering the inflammatory milieu, inducing undernutrition that blunts the immune response, and affecting drug pharmacokinetics.

Geographic Variation and Environmental Predictors of Nontuberculous Mycobacteria in Laboratory Surveillance, Virginia, USA, 2021-2023.

Because epidemiologic and environmental risk factors for nontuberculous mycobacteria (NTM) have been reported only infrequently, little information exists about those factors. The state of Virginia, USA, requires certain ecologic features to be included in reports to the Virginia Department of Health, presenting a unique opportunity to study those variables. We analyzed laboratory reports of Mycobacterium avium complex (MAC) and M.

Development and Validation of a UPLC-MS/MS Method for Therapeutic Drug Monitoring, Pharmacokinetic and Stability Studies of First-Line Antituberculosis Drugs in Urine.

Tuberculosis (TB) remains one of the leading global causes of mortality. Several methods have been established to detect anti-TB agents in human plasma and serum. However, there is a notable absence of studies analyzing TB drugs in urine.

Point-of-care glycated hemoglobin a1c testing for the identification of hyperglycemia severity among individuals with dual tuberculosis and diabetes mellitus in Tanzania.

Background: Poor glycemic control during tuberculosis (TB) treatment is challenging, as the optimum treatment strategy remains unclear. We assessed hyperglycemia severity using glycated hemoglobin (HbA1c) test and predictors of severe hyperglycemia at the time of TB diagnosis in three resources-diverse regions in Tanzania.

Methods: This was a substudy from a large cohort study implemented in three regions of Tanzania.

Etiology of Fever and Associated Outcomes Among Adults Receiving Chemotherapy for the Treatment of Solid Tumors in Uganda.

Background: Little is known about the microbiology and outcomes of chemotherapy-associated febrile illness among patients in sub-Saharan Africa. Understanding the microbiology of febrile illness could improve antibiotic selection and infection-related outcomes.

Methods: From September 2019 through June 2022, we prospectively enrolled adult inpatients at the Uganda Cancer Institute who had solid tumors and developed fever within 30 days of receiving chemotherapy.

Simplified urine-based method to detect rifampin underexposure in adults with tuberculosis: a prospective diagnostic accuracy study.

Variable pharmacokinetics of rifampin in tuberculosis (TB) treatment can lead to poor outcomes. Urine spectrophotometry is simpler and more accessible than recommended serum-based drug monitoring, but its optimal efficacy in predicting serum rifampin underexposure in adults with TB remains uncertain. Adult TB patients in New Jersey and Virginia receiving rifampin-containing regimens were enrolled.

Implementing Innovative Approaches to Improve Health Care Delivery Systems for Integrating Communicable and Non-Communicable Diseases Using Tuberculosis and Diabetes as a Model in Tanzania.

Many evidence-based health interventions, particularly in low-income settings, have failed to deliver the expected impact. We designed an Adaptive Diseases Control Expert Programme in Tanzania (ADEPT) to address systemic challenges in health care delivery and examined the feasibility, acceptability and effectiveness of the model using tuberculosis (TB) and diabetes mellitus (DM) as a prototype. : This was an effectiveness-implementation hybrid type-3 design that was implemented in Dar es Salaam, Iringa and Kilimanjaro regions.

New approach to rifampicin stability and first-line anti-tubercular drug pharmacokinetics by UPLC-MS/MS.

Successful tuberculosis (TB) therapy requires achieving sufficient exposure to multiple drugs. Limited stability of several first-line anti-TB drugs might compromise reliable therapeutic drug monitoring (TDM). We developed and validated a sensitive and selective UPLC-MS/MS method for simultaneous quantification of isoniazid (INH), pyrazinamide (PZA), rifampicin (RIF), its metabolite 25-desacetylrifampicin and degradation products: rifampicin quinone and 3-formyl-rifampicin.

Omadacycline pharmacokinetics/pharmacodynamics in the hollow fiber model and clinical validation of efficacy to treat pulmonary Mycobacterium abscessus disease.

Background: Guideline-based therapy (GBT) for pulmonary Mycobacterium abscessus (Mab) disease achieves sustained sputum culture conversion (SSCC) rates of 30%; this is reflected by poor efficacy of GBT in the hollow fiber system model of Mab (HFS-Mab), which killed ∼1.22 log CFU/mL. This study was performed to determine which clinical dose of omadacycline, a tetracycline antibiotic, should be used in combination therapy to treat pulmonary Mab disease for relapse-free cure.

Rifampin urinary excretion to predict serum targets in children with tuberculosis: a prospective diagnostic accuracy study.

Objective: Pharmacokinetic variability drives tuberculosis (TB) treatment outcomes but measurement of serum drug concentrations for personalised dosing is inaccessible for children in TB-endemic settings. We compared rifampin urine excretion for prediction of a serum target associated with treatment outcome.

Design: Prospective diagnostic accuracy study.

Roadblocks and resilience: A qualitative study of the impact of pediatric tuberculosis on Tanzanian households and solutions from caregivers.

Distinct from quantifying the economic sequelae of tuberculosis (TB) in adults, data are scarce regarding lived experiences of youth and their caregivers seeking and sustaining TB treatment in low income communities. Children ages 4-17 diagnosed with TB and their caregivers were recruited from rural and semi-urban northern Tanzania. Using a grounded theory approach, a qualitative interview guide was developed, informed by exploratory research.

Protocol for a feasibility randomized controlled trial to evaluate the efficacy, safety and tolerability of N-acetylcysteine in reducing adverse drug reactions among adults treated for multidrug-resistant tuberculosis in Tanzania.

Background: Adverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients.

Decision Analytic Modeling for Global Clinical Trial Planning: A Case for HIV-Positive Patients at High Risk for Sepsis in Uganda.

Sepsis is a significant cause of mortality among people living with human immunodeficiency virus (HIV) in sub-Saharan Africa. In the planning period prior to the start of a large multi-country clinical trial studying the efficacy of the immediate empiric addition of anti-tuberculosis therapy to standard-of-care antibiotics for sepsis in people living with HIV, we used decision analysis to assess the costs and potential health outcome impacts of the clinical trial design based on preliminary data and epidemiological parameter estimates. The purpose of this analysis was to highlight this approach as a case example where decision analysis can estimate the cost effectiveness of a proposed clinical trial design.

Alternative Methods for Therapeutic Drug Monitoring and Dose Adjustment of Tuberculosis Treatment in Clinical Settings: A Systematic Review.

Background And Objective: Quantifying exposure to drugs for personalized dose adjustment is of critical importance in patients with tuberculosis who may be at risk of treatment failure or toxicity due to individual variability in pharmacokinetics. Traditionally, serum or plasma samples have been used for drug monitoring, which only poses collection and logistical challenges in high-tuberculosis burden/low-resourced areas. Less invasive and lower cost tests using alternative biomatrices other than serum or plasma may improve the feasibility of therapeutic drug monitoring.

Whole-genome sequencing of SARS-CoV-2 isolates from symptomatic and asymptomatic individuals in Tanzania.

Background: Coronavirus Disease-2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) accounts for considerable morbidity and mortality globally. Paucity of SARS-CoV-2 genetic data from Tanzania challenges in-country tracking of the pandemic. We sequenced SARS-CoV-2 isolated in the country to determine circulating strains, mutations and phylogenies and finally enrich international genetic databases especially with sequences from Africa.

Clinical Audit for Integration of Communicable and Non-Communicable Diseases at the Primary Health Care Level in Tanzania.

Introduction: Poor quality of health care services remains an important challenge in health care delivery systems. Here, we validate clinical audit tools and describe audit results of selected clinical standards related to communicable disease (CD) and non-communicable disease (NCD) integration at the primary health care level.

Methodology: A multi-methods approach, including a retrospective cohort and cross-sectional design, was deployed concurrently at Health Centres.

Isoniazid pharmacokinetics/pharmacodynamics as monotherapy and in combination regimen in the hollow fiber system model of Mycobacterium kansasii.

Background: There is limited high quality evidence to guide the optimal doses of drugs for the treatment of Mycobacterium kansasii pulmonary disease (Mkn-PD).

Methods: We performed (1) minimum inhibitory concentration experiment, (2) isoniazid dose-response study using the hollow fiber system model (HFS-Mkn) to determine PK/PD optimized exposure, and (3) another HFS-Mkn study to determine the efficacy of high dose isoniazid (15 mg/kg/day) with standard dose rifampin (10 mg/kg/day) and ethambutol (15 mg/kg/day). Inhibitory sigmoid maximal effect model and linear regression was used for data analysis.

Pharmacogenetic variability and the probability of site of action target attainment during tuberculosis meningitis treatment: A physiologically based pharmacokinetic modeling and simulations study.

Objective And Methods: Our objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M.

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

Background: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.

Methods: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents.