Geographic Variation and Environmental Predictors of Nontuberculous Mycobacteria in Laboratory Surveillance, Virginia, USA, 2021-20231.

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. abscessus infections in Virginia during 2021-2023. MAC/M. abscessus was isolated from 6.19/100,000 persons, and 2.37/100,000 persons had MAC/M. abscessus lung disease. M. abscessus accounted for 17.4% and MAC for 82.6% of cases. Saturated vapor pressure was associated with MAC/M. abscessus prevalence (prevalence ratio 1.414, 95% CI 1.011-1.980; p = 0.043). Self-supplied water use was a protective factor (incidence rate ratio 0.304, 95% CI 0.098-0.950; p = 0.041). Our findings suggest that a better understanding of geographic clustering and environmental water exposures could help develop future targeted prevention and control efforts.

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. Thus, our objective was to validate a method for quantifying first-line anti-TB agents: isoniazid (INH), pyrazinamide (PZA), ethambutol (ETH), and rifampicin (RIF), along with its metabolite 25-desacetylrifampicin, and degradation products: rifampicin quinone and 3-formyl-rifampicin in 10 µL of urine. Chromatographic separation was achieved using a Kinetex Polar C18 analytical column with gradient elution (5 mM ammonium acetate and acetonitrile with 0.1% formic acid). Mass spectrometry detection was carried out using a triple-quadrupole tandem mass spectrometer operating in positive ion mode. The lower limit of quantification (LLOQ) was 0.5 µg/mL for INH, PZA, ETH, and RIF, and 0.1 µg/mL for RIF's metabolites and degradation products. The method was validated following FDA guidance criteria and successfully applied to the analysis of the studied compounds in urine of TB patients. Additionally, we conducted a stability study of the anti-TB agents under various pH and temperature conditions to mimic the urine collection process in different settings (peripheral clinics or central laboratories).

Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.

BACKGROUND: Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. METHODS: Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug's area under the concentration-time curve over 24 hours (AUC0-24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0-24/MIC exposures. RESULTS: Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21-11.56; P = .022); levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. CONCLUSIONS: Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs-fluoroquinolones, pyrazinamide, clofazimine-were predictive and should be optimized to improve clinical outcome. CLINICAL TRIALS REGISTRATION: NCT03559582.

Nouveau short-course therapy and morphism mapping for clinical pulmonary Mycobacterium kansasii.

Standard therapy [isoniazid, rifampin, ethambutol], with or without a macrolide, for pulmonary Mycobacterium kansasii lasts more than a year. Therefore, shorter treatment duration regimens are required. We used data from 32 Taiwanese patients treated with standard therapy who were followed using repetitive sampling-based sputum Mkn time-to-positivity in liquid cultures to calculate kill slopes [γ] based on ordinary differential equations and time-to-extinction of each patient's bacterial burden. The γ was 0.18 [95% Confidence Interval (CI): 0.16-0.20] log10 CFU/mL/day on standard therapy. Next, we identified Mkn time-to-extinction in the hollow fiber system model of pulmonary M. kansasii disease [HFS-Mkn] treated with standard therapy, which was a γ of 0.60 [95% CI: 0.45-0.69) log10 CFU/mL/day. The γs and time-to-extinctions between the two datasets formed structure-preserving maps based on category theory: thus, we could map them from one to the other using morphisms. This mapping identified a multistep non-linear transformation-factor for time-to-extinction from HFS-Mkn to patients. Next, a head-to-head study in the HFS-Mkn identified median time-to-extinction for standard therapy of 38.7 [95% CI: 29.1-53.2) days, isoniazid-rifampin-ethambutol-moxifloxacin of 21.7 [95% CI: 19.1-25) days, isoniazid-rifampin-moxifloxacin of 22 [96% CI: 20.1-24.5) days, and rifampin-moxifloxacin-tedizolid of 20.7 [95% CI:18.5-29) days. Our transformation-factor based translation predicted the proportion of patients of 90.7 [88.74-92.35)% achieving cure with standard therapy at 12 months, and 6-months cure rates of 99.8 [95% CI: 99.27-99.95)% for isoniazid-rifampin-ethambutol-moxifloxacin, 92.2 [90.37-93.71)% for isoniazid-rifampin-moxifloxacin, and 99.9 [99.44-99.99)% for rifampin-moxifloxacin-tedizolid. Thus, rifampin-moxifloxacin-tedizolid and isoniazid-rifampin-ethambutol-moxifloxacin are predicted to be short-course chemotherapy regimens for pulmonary M. kansasii disease.

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. Serum and urine samples were collected over 24 h. Rifampin serum concentrations were measured using validated liquid chromatography-tandem mass spectrometry, and total exposure (area under the concentration-time curve) over 24 h (AUC0-24) was determined through noncompartmental analysis. The Sunahara method was used to extract total rifamycins, and rifampin urine excretion was measured by spectrophotometry. An analysis of 58 eligible participants, including 15 (26%) with type 2 diabetes mellitus, demonstrated that urine spectrophotometry accurately identified subtarget rifampin AUC0-24 at 0-4, 0-8, and 0-24 h. The area under the receiver operator characteristic curve (AUC ROC) values were 0.80 (95% CI 0.67-0.90), 0.84 (95% CI 0.72-0.94), and 0.83 (95% CI 0.72-0.93), respectively. These values were comparable to the AUC ROC of 2 h serum concentrations commonly used for therapeutic monitoring (0.82 [95% CI 0.71-0.92], P = 0.6). Diabetes status did not significantly affect the AUC ROCs for urine in predicting subtarget rifampin serum exposure (P = 0.67-0.92). Spectrophotometric measurement of urine rifampin excretion within the first 4 or 8 h after dosing is a simple and cost-effective test that accurately predicts rifampin underexposure. This test provides critical information for optimizing tuberculosis treatment outcomes by facilitating appropriate dose adjustments.

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. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Omadacycline Pharmacokinetics/Pharmacodynamics in the Hollow Fiber System Model and Potential Combination Regimen for Short Course Treatment of Mycobacterium kansasii Pulmonary Disease.

The 12-month therapy duration for the treatment of Mycobacterium kansasii pulmonary disease calls for more efficacious drugs for better treatment outcomes and to shorten the therapy duration. We performed (i) omadacycline MIC with M. kansasii ATCC 12478 strain and 21 clinical isolates, (ii) dose-response study in the hollow fiber system model of M. kansasii (HFS-Mkn) with six human equivalent omadacycline daily doses to determine the optimal drug exposure for the maximal kill, and (iii) a second HFS-Mkn study to determine the efficacy of omadacycline (300 mg/day) plus moxifloxacin (600 mg/day) plus tedizolid (200 mg/day) combination regimen with standard regimen as comparator. GraphPad Prism was used for data analysis and graphing. MIC of the reference strain was 4 mg/L but ranged from 8 to 32 mg/L among the 21 clinical isolates. In the HFS-Mkn, the exposure required for 50% of the maximal effect (EC50) was an omadacycline area under the concentration-time curve to MIC (AUC0-24/MIC) ratio of 1.95. The optimal exposure was an AUC0-24/MIC of 3.05, which could be achieved with 300 mg/day clinical dose. The omadacycline-moxifloxacin-tedizolid combination sterilized the HFS-Mkn in 14 days with a linear-regression based kill rate of -0.309 ± 0.044 log10 CFU/mL/day compared to the kill rate of -0.084 ± 0.036log10 CFU/mL/day with the standard regimen or 3.7-times faster. Omadacycline has efficacy against M. kansasii and could be used at 300 mg/day in combination with moxifloxacin and tedizolid for the treatment of M. kansasii pulmonary diseases with the potential to shorten the currently recommended 12-month therapy duration.

Rifampin Pharmacokinetics/Pharmacodynamics in the Hollow-Fiber Model of Mycobacterium kansasii Infection.

There is limited high-quality evidence to guide the optimal treatment of Mycobacterium kansasii pulmonary disease. We retrospectively collected clinical data from 33 patients with M. kansasii pulmonary disease to determine the time-to-sputum culture conversion (SCC) upon treatment with a standard combination regimen consist of isoniazid-rifampin-ethambutol. Next, MIC experiments with 20 clinical isolates were performed, followed by a dose-response study with the standard laboratory strain using the hollow-fiber system model of M. kansasii infection (HFS-Mkn). The inhibitory sigmoid maximum effect (Emax) model was used to describe the relationship between the bacterial burden and rifampin concentrations. Finally, in silico clinical trial simulations were performed to determine the clinical dose to achieve the optimal rifampin exposure in patients. The SCC rate in patients treated with combination regimen containing rifampin at 10 mg/kg of body weight/day was 73%, the mean time to SSC was 108 days, and the mean duration of therapy was 382 days. The MIC of the M. kansasii laboratory strain was 0.125 mg/L, whereas the MICs of the clinical isolates ranged between 0.5 and 4 mg/L. In the HFS-Mkn model, a maximum kill (Emax) of 7.82 log10 CFU/mL was recorded on study day 21. The effective concentration mediating 80% of the Emax (EC80) was calculated as the ratio of the maximum concentration of drug in serum for the free, unbound fraction (fCmax) to MIC of 34.22. The target attainment probability of the standard 10-mg/kg/day dose fell below 90% even at the MIC of 0.0625 mg/L. Despite the initial kill, there was M. kansasii regrowth with the standard rifampin dose in the HFS-Mkn model. Doses higher than 10 mg/kg/day, in combination with other drugs, need to be evaluated for better treatment outcome.

Impact of early diagnosis of impaired glucose regulation in tuberculosis: Comparison of clinical outcomes in people with tuberculosis in Tanzania.

OBJECTIVE: Diabetes mellitus (DM) has been known to compromise tuberculosis (TB) treatment outcomes. Association data are limited for early hyperglycaemia detection and TB treatment outcomes. Thus, we assessed treatment outcomes including time to sputum conversion and death in TB participants with or without hyperglycaemia. METHODS: A prospective cohort study recruited TB participants receiving anti-TB treatment at health facilities in Tanzania between October 2019 and September 2020. Hyperglycaemia was defined as having pre-existing DM or pre-treatment random blood glucose of ≥7.8 mmol/L, in combination categorised as impaired glucose regulation (IGR). Those with IGR were further screened for hyperglycaemia severity using glycated haemoglobin. In case of unknown status, participants were tested for HIV. Time to death was determined at 6 months of TB treatment. RESULTS: Of 1344 participants, 187 (13.9%) had IGR, of whom 44 (23.5%) were HIV co-infected. Overall treatment success was 1206 (89.7%), and was similar among participants with or without IGR (p > 0.05). Time to death for participants with and without IGR was 18 versus 28 days (p = 0.870), respectively. Age ≥ 40 years (p = 0.038), bacteriological positive (p = 0.039), HIV (p = 0.009), or recurrent TB (p = 0.017) predicted death or treatment success during TB treatment in adjusted multivariable models. CONCLUSION: IGR did not influence clinical outcomes in TB patients with or without IGR in a programme of early IGR diagnosis and integration TB, HIV and DM care. Early detection and co-management of multi-morbidities among people diagnosed with TB may reduce likelihood of poor treatment outcomes in a programmatic setting.

Therapeutic Drug Monitoring of Anti-infective Drugs: Implementation Strategies for 3 Different Scenarios.

BACKGROUND: Therapeutic drug monitoring (TDM) supports personalized treatment. For successful implementation, TDM must have a turnaround time suited to the clinical needs of patients and their health care settings. Here, the authors share their views of how a TDM strategy can be tailored to specific settings and patient groups. METHODS: The authors selected distinct scenarios for TDM: high-risk, complex, and/or critically ill patient population; outpatients; and settings with limited laboratory resources. In addition to the TDM scenario approach, they explored potential issues with the legal framework governing dose escalation. RESULTS: The most important issues identified in the different scenarios are that critically ill patients require rapid turnaround time, outpatients require an easy sampling procedure for the sample matrix and sample collection times, settings with limited laboratory resources necessitate setting-specific analytic techniques, and all scenarios warrant a legal framework to capture the use of escalated dosages, ideally with the use of trackable dosing software. CONCLUSIONS: To benefit patients, TDM strategies need to be tailored to the intended population. Strategies can be adapted for rapid turnaround time for critically ill patients, convenient sampling for outpatients, and feasibility for those in settings with limited laboratory resources.

Mycobactericidal Effects of Different Regimens Measured by Molecular Bacterial Load Assay among People Treated for Multidrug-Resistant Tuberculosis in Tanzania.

Rifampin or multidrug-resistant tuberculosis (RR/MDR-TB) treatment has largely transitioned to regimens free of the injectable aminoglycoside component, despite the drug class' purported bactericidal activity early in treatment. We tested whether Mycobacterium tuberculosis killing rates measured by tuberculosis molecular bacterial load assay (TB-MBLA) in sputa correlate with composition of the RR/MDR-TB regimen. Serial sputa were collected from patients with RR/MDR- and drug-sensitive TB at days 0, 3, 7, and 14, and then monthly for 4 months of anti-TB treatment. TB-MBLA was used to quantify viable M. tuberculosis 16S rRNA in sputum for estimation of colony forming units per ml (eCFU/ml). M. tuberculosis killing rates were compared among regimens using nonlinear-mixed-effects modeling of repeated measures. Thirty-seven patients produced 296 serial sputa and received treatment as follows: 13 patients received an injectable bedaquiline-free reference regimen, 9 received an injectable bedaquiline-containing regimen, 8 received an all-oral bedaquiline-based regimen, and 7 patients were treated for drug-sensitive TB with conventional rifampin/isoniazid/pyrazinamide/ethambutol (RHZE). Compared to the adjusted M. tuberculosis killing of -0.17 (95% confidence interval [CI] -0.23 to -0.12) for the injectable bedaquiline-free reference regimen, the killing rates were -0.62 (95% CI -1.05 to -0.20) log10 eCFU/ml for the injectable bedaquiline-containing regimen (P = 0.019), -0.35 (95% CI -0.65 to -0.13) log10 eCFU/ml for the all-oral bedaquiline-based regimen (P = 0.054), and -0.29 (95% CI -0.78 to +0.22) log10 eCFU/ml for the RHZE regimen (P = 0.332). Thus, M. tuberculosis killing rates from sputa were higher among patients who received bedaquiline but were further improved with the addition of an injectable aminoglycoside.

A mobile microvolume UV/visible light spectrophotometer for the measurement of levofloxacin in saliva.

INTRODUCTION: Therapeutic drug monitoring (TDM) for personalized dosing of fluoroquinolones has been recommended to optimize efficacy and reduce acquired drug resistance in the treatment of MDR TB. Therefore, the aim of this study was to develop a simple, low-cost, robust assay for TDM using mobile UV/visible light (UV/VIS) spectrophotometry to quantify levofloxacin in human saliva at the point of care for TB endemic settings. METHODS: All experiments were performed on a mobile UV/VIS spectrophotometer. The levofloxacin concentration was quantified by using the amplitude of the second-order spectrum between 300 and 400 nm of seven calibrators. The concentration of spiked samples was calculated from the spectrum amplitude using linear regression. The method was validated for selectivity, specificity, linearity, accuracy and precision. Drugs frequently co-administered were tested for interference. RESULTS: The calibration curve was linear over a range of 2.5-50.0 mg/L for levofloxacin, with a correlation coefficient of 0.997. Calculated accuracy ranged from -5.2% to 2.4%. Overall precision ranged from 2.1% to 16.1%. Application of the Savitsky-Golay method reduced the effect of interferents on the quantitation of levofloxacin. Although rifampicin and pyrazinamide showed analytical interference at the lower limit of quantitation of levofloxacin concentrations, this interference had no implication on decisions regarding the levofloxacin dose. CONCLUSIONS: A simple UV/VIS spectrophotometric method to quantify levofloxacin in saliva using a mobile nanophotometer has been validated. This method can be evaluated in programmatic settings to identify patients with low levofloxacin drug exposure to trigger personalized dose adjustment.

Levofloxacin pharmacokinetics in saliva as measured by a mobile microvolume UV spectrophotometer among people treated for rifampicin-resistant TB in Tanzania.

BACKGROUND: Early detection and correction of low fluoroquinolone exposure may improve treatment of MDR-TB. OBJECTIVES: To explore a recently developed portable, battery-powered, UV spectrophotometer for measuring levofloxacin in saliva of people treated for MDR-TB. METHODS: Patients treated with levofloxacin as part of a regimen for MDR-TB in Northern Tanzania had serum and saliva collected concurrently at 1 and 4 h after 2 weeks of observed levofloxacin administration. Saliva levofloxacin concentrations were quantified in the field via spectrophotometry, while serum was analysed at a regional laboratory using HPLC. A Bayesian population pharmacokinetics model was used to estimate the area under the concentration-time curve (AUC0-24). Subtarget exposures of levofloxacin were defined by serum AUC0-24 <80 mg·h/L. The study was registered at Clinicaltrials.gov with clinical trial identifier NCT04124055. RESULTS: Among 45 patients, 11 (25.6%) were women and 16 (37.2%) were living with HIV. Median AUC0-24 in serum was 140 (IQR = 102.4-179.09) mg·h/L and median AUC0-24 in saliva was 97.10 (IQR = 74.80-121.10) mg·h/L. A positive linear correlation was observed with serum and saliva AUC0-24, and a receiver operating characteristic curve constructed to detect serum AUC0-24 below 80 mg·h/L demonstrated excellent prediction [AUC 0.80 (95% CI = 0.62-0.94)]. Utilizing a saliva AUC0-24 cut-off of 91.6 mg·h/L, the assay was 88.9% sensitive and 69.4% specific in detecting subtarget serum AUC0-24 values, including identifying eight of nine patients below target. CONCLUSIONS: Portable UV spectrophotometry as a point-of-care screen for subtarget levofloxacin exposure was feasible. Use for triage to other investigation or personalized dosing strategy should be tested in a randomized study.

TB or not TB? Definitive determination of species within the Mycobacterium tuberculosis complex in unprocessed sputum from adults with presumed multidrug-resistant tuberculosis.

OBJECTIVES: Differences among Mycobacterium tuberculosis complex (MTC) species may predict drug resistance or treatment success. Thus, we optimised and deployed the genotype MTBC assay (gMTBC) to identify MTC to the species level, and then performed comparative genotypic drug-susceptibility testing to anti-tuberculosis drugs from direct sputum of patients with presumed multidrug-resistant tuberculosis (MDR-TB) by the MTBDRplus/sl reference method. METHODS: Patients with positive Xpert® MTB/RIF (Xpert) results were consented to provide early-morning-sputum for testing by the gMTBC and the reference MTBDRplus/sl. Chi-square or Fisher's exact test compared proportions. Modified Poisson regression modelled detection of MTC by gMTBC. RESULTS: Among 73 patients, 53 (73%) were male and had a mean age of 43 (95% CI; 40-45) years. In total, 34 (47%), 36 (49%) and 38 (55%) had positive gMTBC, culture and MTBDR respectively. Forty patients (55%) had low quantity MTC by Xpert, including 31 (78%) with a negative culture. gMTBC was more likely to be positive in patients with chest cavity 4.18 (1.31-13.32, P = 0.016), high-quantity MTC by Xpert 3.03 (1.35-6.82, P = 0.007) and sputum smear positivity 1.93 (1.19-3.14, P = 0.008). The accuracy of gMTBC in detecting MTC was 95% (95% CI; 86-98; κ = 0.89) compared to MTBDRplus/sl. All M. tuberculosis/canettii identified by gMTB were susceptible to fluoroquinolone and aminoglycosides/capreomycin. CONCLUSIONS: The concordance between the gMTBC assay and MTBDRplus/sl in detecting MTC was high but lagged behind the yield of Xpert MTB/RIF. All M. tuberculosis/canettii were susceptible to fluoroquinolones, a core drug in MDR-TB treatment regimens.

Clofazimine for treatment of multidrug-resistant non-tuberculous mycobacteria.

BACKGROUND: /QUESTION: Nontuberculous mycobacteria (NTM) infections are increasingly detected but difficult to cure given complex drug-resistance patterns. Select U.S. centers have incorporated clofazimine in the treatment of NTM but experience is limited as procurement restrictions hamper widespread use. METHODS: A prospective cohort study was performed in patients diagnosed with pulmonary or extrapulmonary NTM infection and treated with clofazimine between February 2015 and April 2019 at a tertiary referral hospital. Treatment success was defined by a combined outcome of clinical stabilization, microbiologic cure and radiologic improvement. Secondary outcomes included all-cause mortality and time to sputum culture conversion. Uni/multi-variate regression were used to define associations between pre-determined predictor variables and overall treatment outcome. RESULTS: Of 44 patients enrolled, 39 (89 %) received clofazimine along with a median of 3 concomitant antibiotics. Thirty-one (80 %) of patients had pulmonary NTM infection, with Mycobacterium abscessus group and Mycobacterium avium complex being the most common species groups identified. Of 36 people with evaluable outcomes, 35 (97 %) survived and 22 (58 %) had treatment success, including 12 of 19 (63 %) with Mycobacterium abscessus group. In multivariate analysis, patients with Mycobacterium abscessus group were more likely to experience treatment success (OR 18.22, 95%CI 0.972-341.43, p = 0.052), while macrolide resistance predicted a lack of treatment success (OR 0.053, 95%CI 0.003-0.841, p = 0.037). Clofazimine was well-tolerated. CONCLUSION: Adding clofazimine to multi-class antibiotic regimens for drug-resistant NTM infection led to treatment success in the majority treated. Randomized controlled studies are needed to determine the individual impact of clofazimine within an otherwise optimized drug regimen.

Integrating Pharmacokinetics and Pharmacodynamics in Operational Research to End Tuberculosis.

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.

Comparison of a Novel Regimen of Rifapentine, Tedizolid, and Minocycline with Standard Regimens for Treatment of Pulmonary Mycobacterium kansasii.

The combination of isoniazid, rifampin, and ethambutol is recommended by the American Thoracic Society (ATS) for treatment of pulmonary Mycobacterium kansasii, while the British Thoracic Society (BTS) recommends clarithromycin, rifampin and ethambutol. Unfortunately, therapy duration for both regimens lasts for years. In this study, we administered tedizolid, minocycline, clarithromycin, and rifapentine as monotherapy as well as novel combinations in the intracellular hollow-fiber model system of M. kansasii (HFS-Mkn) in a 28-day study. The ATS and BTS regimens were used as comparators. Repetitive sampling was used to validate the intended intrapulmonary pharmacokinetics of each drug and to monitor changes in M. kansasii burden. As monotherapy, tedizolid at an observed area under the concentration-time curve from 0 to 24 h (AUC0-24)/MIC of 5.85 and minocycline at an AUC0-24/MIC of 5.77 failed to kill the bacteria below day 0 (stasis), clarithromycin at an AUC0-24/MIC of 2.4 held the bacterial burden at stasis, but rifapentine at an AUC0-24/MIC of 140 killed 2 log10 CFU/ml below stasis. The BTS regimen kill slope was -0.083 ± 0.035 CFU/ml/day, which was significantly superior to the ATS regimen slope of -0.038 ± 0.038 CFU/ml/day. The rifapentine-tedizolid-minocycline combination kill slope was -0.119 ± 0.031 CFU/ml/day, superior to that of the ATS regimen and comparable to that of the BTS regimen. In conclusion, the BTS regimen and the novel rifapentine-tedizolid-minocycline regimen showed better kill of intracellular bacteria in the HFS-Mkn However, the efficacy of the new combination regimen remains to be tested in clinical settings.

Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis.

Ethionamide (ETA), an isonicotinic acid derivative, is part of the multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines have deprioritized ETA because it is potentially less effective than other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens in order to assess target attainment. This study included subjects from four different sites, including healthy volunteers and patients with MDR-TB. The TB centers included were two in the United States and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, regimens with a total of 1,000 to 2,250 mg daily were simulated, and target attainment using published MICs and targets of 1.0-log kill and resistance suppression was assessed with the Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag time. The mean (standard deviation [SD]) final population parameter estimates were as follows: absorption rate constant, 1.02 (1.11) h-1; elimination rate constant, 0.69 (0.46) h-1; volume of distribution, 104.16 (59.87) liters; lag time, 0.43 (0.32) h. A total daily dose of 1,500 mg or more was needed for ≥90% attainment of the 1.0-log kill target at a MIC of 1 mg/liter, and 2,250 mg/day led to 80% attainment of the resistance suppression target at a MIC of 0.5 mg/liter. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the predefined targets supporting the current recommendations for ETA deprioritization.

Gridlock from diagnosis to treatment of multidrug resistant tuberculosis (MDR-TB) in Tanzania: patients' perspectives from a focus group discussion.

BACKGROUND: Molecular diagnostics have revolutionized the diagnosis of multidrug resistant tuberculosis (MDR-TB). Yet in Tanzania we found delay in diagnosis with more than 70% of MDR-TB patients having a history of several previous treatment courses for TB signaling prior opportunities for diagnosis. We aimed to explore patients' viewpoints and experiences with personal and socio-behavioral obstacles from MDR-TB diagnosis to treatment in an attempt to understand these prior findings. METHODS: The study was conducted in December 2016 with MDR-TB patients admitted at Kibong'oto Infectious Diseases Hospital. A qualitative approach deploying focus group discussions (FGDs) was used to gather information. Groups were sex aggregated to allow free interaction and to gauge gender specific issues in the social and behavioral contexts. The FGDs explored pathways and factors in the service delivery that may have contributed in the delay in accessing MDR-TB diagnostics and/or treatment. Collected data were coded, categorized and thematically interpreted. RESULTS: Forty MDR-TB patients participated in six FGDs. Challenges and barriers contributing to the delay in accessing MDR-TB diagnosis to treatment were as follows: 1) Participants had a different understanding of MDR-TB that led to seeking services outside the conventional health system; 2) Socio-economic adversity made health-seeking behavior difficult and often unproductive; 3) In the health system, challenges included inadequacy of MDR-TB diagnostic centers, lack of knowledge on behalf of health care providers to consider MDR-TB and order appropriate diagnostics; 4) The specimen referral system for early diagnosis of MDR-TB was inefficient. Non-adherence of TB patients to first-line anti-TB drugs prior to MDR-TB diagnosis, given the multitude of barriers discussed, was coupled with both intentional and unintentional non-adherence of health care providers to international standards of TB care. CONCLUSION: Patient-centered strategies bridging communities and the health system are urgently required for optimum MDR-TB control in Tanzania.

Drug-Susceptible and Multidrug-Resistant Mycobacterium tuberculosis in a Single Patient.

A patient who had initial infection with mixed strains of drug-susceptible and multidrug-resistant tuberculosis was presumed to have acquired drug resistance before confirmation that sequential strains were genotypically distinct. Transmitted infection with mixed strains is likely underappreciated; identifying these infections requires spoligotyping and whole-genome sequencing.