TOC summary: Diabetes was associated with increased risk for slow response and low rifampin levels.

Background. Levofloxacin is used for the treatment of multidrug-resistant tuberculosis; however the optimal dose is unknown. Methods. We used the hollow fiber system model of tuberculosis (HFS-TB) to identify 0-24 hour area under the concentration-time curve (AUC 0-24) to minimum inhibitory concentration (MIC) ratios associated with maximal microbial kill and suppression of acquired drug resistance (ADR) of Mycobacterium tuberculosis (Mtb). Levofloxacin-resistant isolates underwent whole-genome sequencing. Ten thousands patient Monte Carlo experiments (MCEs) were used to identify doses best able to achieve the HFS-TBderived target exposures in cavitary tuberculosis and tuberculous meningitis. Next, we used an ensemble of artificial intelligence (AI) algorithms to identify the most important predictors of sputum conversion, ADR, and death in Tanzanian patients with pulmonary multidrug-resistant tuberculosis treated with a levofloxacin-containing regimen. We also performed probit regression to identify optimal levofloxacin doses in Vietnamese tuberculous meningitis patients. Results. In the HFS-TB, the AUC 0-24 /MIC associated with maximal Mtb kill was 146, while that associated with suppression of resistance was 360. The most common gyrA mutations in resistant Mtb were Asp94Gly, Asp94Asn, and Asp94Tyr. The minimum dose to achieve target exposures in MCEs was 1500 mg/day. AI algorithms identified an AUC 0-24 /MIC of 160 as predictive of microbiologic cure, followed by levofloxacin 2-hour peak concentration and body weight. Probit regression identified an optimal dose of 25 mg/kg as associated with >90% favorable response in adults with pulmonary tuberculosis. Conclusions. The levofloxacin dose of 25 mg/kg or 1500 mg/day was adequate for replacement of high-dose moxifloxacin in treatment of multidrug-resistant tuberculosis.

SettingKibong’oto National Tuberculosis Hospital (KNTH), Kilimanjaro, Tanzania.ObjectiveCharacterize the diagnostic process and interim treatment outcomes from patients treated for multidrug-resistant tuberculosis (MDR-TB) in Tanzania.DesignA retrospective cohort study was performed among all patients treated at KNTH for pulmonary MDR-TB between November 2009 and September 2011.ResultsSixty-one culture-positive MDR-TB patients initiated therapy, 60 (98%) with a prior history of TB treatment. Forty-one (67%) were male and 9 (14%) were HIV infected with a mean CD4 count of 424 (±106) cells/µl. The median time from specimen collection to MDR-TB diagnosis and from diagnosis to initiation of MDR-TB treatment was 138 days (IQR 101–159) and 131 days (IQR 32–233), respectively. Following treatment initiation four (7%) patients died (all HIV negative), 3 (5%) defaulted, and the remaining 54 (89%) completed the intensive phase. Most adverse drug reactions were mild to moderate and did not require discontinuation of treatment. Median time to culture conversion was 2 months (IQR 1–3) and did not vary by HIV status. In 28 isolates available for additional second-line drug susceptibility testing, fluoroquinolone, aminoglycoside and para-aminosalicylic acid resistance was rare yet ethionamide resistance was present in 9 (32%).ConclusionThe majority of MDR-TB patients from this cohort had survived a prolonged referral process, had multiple episodes of prior TB treatment, but did not have advanced AIDS and converted to culture negative early while completing an intensive inpatient regimen without serious adverse event. Further study is required to determine the clinical impact of second-line drug susceptibility testing and the feasibility of alternatives to prolonged hospitalization.

Tuberculosis (TB) elimination requires innovative approaches. The new Global Tuberculosis Network (GTN) aims to conduct research on key unmet therapeutic and diagnostic needs in the field of TB elimination using multidisciplinary, multisectorial approaches. The TB Pharmacology section within the new GTN aims to detect and study the current knowledge gaps, test potential solutions using human pharmacokinetics informed through preclinical infection systems, and return those findings to the bedside. Moreover, this approach would allow prospective identification and validation of optimal shorter therapeutic durations with new regimens. Optimized treatment using available and repurposed drugs may have an increased impact when prioritizing a person-centered approach and acknowledge the importance of age, gender, comorbidities, and both social and programmatic environments. In this viewpoint article, we present an in-depth discussion on how TB pharmacology and the related strategies will contribute to TB elimination.

Introduction Tuberculosis (TB) remains the leading cause of death from a curable infectious disease; drug-resistant TB threatens to dismantle all prior gains in global control. Suboptimal circulating anti-TB drug concentrations can lead to lack of cure and acquired drug resistance. Areas covered This review will introduce pharmacokinetic parameters for key anti-TB drugs, as well as the indications and limitations of measuring these parameters in clinical practice. Current and novel methodologies for delivering anti-TB pharmacokinetic-pharmacodynamic data are highlighted and gaps in operational research described. Expert opinion Individual pharmacokinetic variability is commonplace, underappreciated and difficult to predict without therapeutic drug monitoring (TDM). Pharmacokinetic thresholds associated with poor TB treatment outcome in drug-susceptible TB have recently been described and may now guide the application of TDM, but require validation in a variety of settings and comorbidities. Dried blood spots for TDM and prepackaged multidrug plates for minimum inhibitory concentration testing will overcome barriers of accessibility and represent areas for innovation. Operationalizing pharmacokinetics has the potential to improve TB outcomes in the most difficult-to-treat forms of the disease such as multidrug resistance. Clinical studies in these areas are eagerly anticipated and we expect will better define the rational introduction of novel therapeutics.