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British Journal of Clinical Pharmacology Jan 2021Despite evidence of the efficacy of anti-tubercular drug regimens in clinical practice, the rationale underpinning the selection of doses and companion drugs for... (Meta-Analysis)
Meta-Analysis
AIMS
Despite evidence of the efficacy of anti-tubercular drug regimens in clinical practice, the rationale underpinning the selection of doses and companion drugs for combination therapy remains empirical. Novel methods are needed to optimise the antibacterial activity in combination therapies. A drug-disease modelling framework for rational selection of dose and drug combinations in tuberculosis is presented here.
METHODS
A model-based meta-analysis was performed to assess the antibacterial activity of different combinations in infected mice. Data retrieved from the published literature were analysed using a two-state bacterial growth dynamics model, including fast- and slow-growing bacterial populations. The contribution of each drug to the overall antibacterial activity of the combination was parameterised as relative change to the potency of the backbone drug (EC -F and/or EC -S). Rifampicin and bedaquiline were selected as paradigm drugs to evaluate the predictive performance of the modelling approach.
RESULTS
Pyrazinamide increased the potency (EC -F and EC -S) of rifampicin (RZ) and bedaquiline (BZ) by almost two-fold. By contrast, pretomanid and isoniazid were found to worsen the antibacterial activity of BZ and RZ, respectively. Following extrapolation of in vivo pharmacokinetic-pharmacodynamic relationships, the dose of rifampicin showing maximum bactericidal effect in tuberculosis patients was predicted to be 70 mg·kg when given in combination with pyrazinamide.
CONCLUSIONS
The use of a drug-disease modelling framework may provide a more robust rationale for extrapolation and selection of dose and companion drugs in humans. Our analysis demonstrates that RZ and BZ should be considered as a backbone therapy in prospective novel combination regimens against tuberculosis.
Topics: Animals; Antitubercular Agents; Drug Combinations; Drug Therapy, Combination; Humans; Isoniazid; Mice; Prospective Studies; Pyrazinamide; Tuberculosis
PubMed: 32415743
DOI: 10.1111/bcp.14371 -
Antimicrobial Agents and Chemotherapy Feb 2018Tuberculosis (TB) recently became the leading infectious cause of death in adults, while attempts to shorten therapy have largely failed. Dormancy, persistence, and drug...
Tuberculosis (TB) recently became the leading infectious cause of death in adults, while attempts to shorten therapy have largely failed. Dormancy, persistence, and drug tolerance are among the factors driving the long therapy duration. Assays to measure drug susceptibility of bacteria in pulmonary lesions are needed if we are to discover new fast-acting regimens and address the global TB threat. Here we take a first step toward this goal and describe an assay developed to measure the cidal activity of anti-TB drugs against bacilli present in cavity caseum obtained from rabbits with active TB. We show that caseum bacilli are largely nonreplicating, maintain viability over the course of the assay, and exhibit extreme tolerance to many first- and second-line TB drugs. Among the drugs tested, only the rifamycins fully sterilized caseum. A similar trend of phenotypic drug resistance was observed in the hypoxia- and starvation-induced nonreplicating models, but with notable qualitative and quantitative differences: (i) caseum exhibits higher drug tolerance than nonreplicating in the Wayne and Loebel models, and (ii) pyrazinamide is cidal in caseum but has no detectable activity in these classic nonreplicating assays. Thus, caseum constitutes a unique tool to evaluate drug potency against slowly replicating or nonreplicating bacilli in their native caseous environment. Intracaseum cidal concentrations can now be related to the concentrations achieved in the necrotic foci of granulomas and cavities to establish correlations between clinical outcome and lesion-centered pharmacokinetics-pharmacodynamics (PK-PD) parameters.
Topics: Animals; Antitubercular Agents; Drug Tolerance; Mycobacterium tuberculosis; Pyrazinamide; Rabbits; Rifamycins; Tuberculosis
PubMed: 29203492
DOI: 10.1128/AAC.02266-17 -
Antimicrobial Agents and Chemotherapy Apr 2016There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive... (Clinical Trial)
Clinical Trial
There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (Cmax) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 μg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 μg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC0-8) were 12.1, 24.7, 239.4, and 5.1 μg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed inCmax(geometric mean ratio [GMR],2.55; 95% confidence interval [CI], 1.47 to 4.41;P= 0.001) and AUC0-8(GMR, 2.52; 95% CI, 1.34 to 4.73;P= 0.005). HIV status was associated with lower pyrazinamideCmax(GMR, 0.85; 95% CI, 0.75 to 0.96;P= 0.013) and AUC0-8(GMR, 0.79; 95% CI, 0.69 to 0.90;P< 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.).
Topics: Anti-Bacterial Agents; Area Under Curve; Coinfection; Drug Dosage Calculations; Ethambutol; Female; HIV; HIV Infections; Humans; Infant; Infant, Newborn; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary
PubMed: 26810651
DOI: 10.1128/AAC.02600-15 -
MBio Apr 2022Mycobacterium tuberculosis segregates within multiple subcellular niches with different biochemical and biophysical properties that, upon treatment, may impact...
Mycobacterium tuberculosis segregates within multiple subcellular niches with different biochemical and biophysical properties that, upon treatment, may impact antibiotic distribution, accumulation, and efficacy. However, it remains unclear whether fluctuating intracellular microenvironments alter mycobacterial homeostasis and contribute to antibiotic enrichment and efficacy. Here, we describe a live dual-imaging approach to monitor host subcellular acidification and M. tuberculosis intrabacterial pH. By combining this approach with pharmacological and genetic perturbations, we show that M. tuberculosis can maintain its intracellular pH independently of the surrounding pH in human macrophages. Importantly, unlike bedaquiline (BDQ), isoniazid (INH), or rifampicin (RIF), the drug pyrazinamide (PZA) displays antibacterial efficacy by disrupting M. tuberculosis intrabacterial pH homeostasis . By using M. tuberculosis mutants, we confirmed that intracellular acidification is a prerequisite for PZA efficacy . We anticipate this imaging approach will be useful to identify host cellular environments that affect antibiotic efficacy against intracellular pathogens. We still do not completely understand why tuberculosis (TB) treatment requires the combination of several antibiotics for up to 6 months. M. tuberculosis is a facultative intracellular pathogen, and it is still unknown whether heterogenous and dynamic intracellular populations of bacteria in different cellular environments affect antibiotic efficacy. By developing a dual live imaging approach to monitor mycobacterial pH homeostasis, host cell environment, and antibiotic action, we show here that intracellular localization of M. tuberculosis affects the efficacy of one first-line anti-TB drug. Our observations can be applicable to the treatment of other intracellular pathogens and help to inform the development of more effective combined therapies for tuberculosis that target heterogenous bacterial populations within the host.
Topics: Antitubercular Agents; Homeostasis; Humans; Hydrogen-Ion Concentration; Mycobacterium tuberculosis; Phagosomes; Pyrazinamide; Tuberculosis
PubMed: 35323041
DOI: 10.1128/mbio.00117-22 -
BMC Infectious Diseases Feb 2019Tuberculosis (TB) is the leading cause of death from an infectious disease and the roll-out of rapid molecular diagnostics for rifampin resistance has resulted in a...
Underestimated pyrazinamide resistance may compromise outcomes of pyrazinamide containing regimens for treatment of drug susceptible and multi-drug-resistant tuberculosis in Tanzania.
BACKGROUND
Tuberculosis (TB) is the leading cause of death from an infectious disease and the roll-out of rapid molecular diagnostics for rifampin resistance has resulted in a steady rise in the number of patients with multidrug-resistant (MDR)-TB referred for treatment. Pyrazinamide is used in susceptible TB treatment for 6 months when used in combination with rifampin, isoniazid and ethambutol and is an important companion drug in novel MDR-TB trials. This study was undertaken to determine the prevalence of pyrazinamide resistance by either phenotypic or pncA testing among patients admitted to a referral hospital in Tanzania for drug-susceptible and MDR-TB treatment.
METHODS
Surveillance sputa were sent among subjects beginning TB therapy at the national MDR-TB referral hospital during a 6 month period in 2013-2014. Mycobacterial cultures of pretreatment sputa were performed at the Kilimanjaro Clinical Research Institute (KCRI) in the BACTEC mycobacterial growth indicator tubes (MGIT) 960 system. Speciation of M. tuberculosis complex was confirmed by MTBc assay. Isolates were sub-cultured on to Lowenstein-Jensen (LJ) slants. Phenotypic resistance to pyrazinamide was performed in the MGIT system while a real-time PCR with High Resolution Melt (HRM) technique was used to determine mutation in the pncA gene from the same pure subculture. Sputa were then collected monthly to determine the time to culture negativity. Final treatment outcome was determined.
RESULTS
Ninety-one M. tuberculosis isolates from individual patients were available for analysis of which 30 (32.9%) had MDR-TB, the mean (±SD) age was 33 ± 10 years, and the majority 23 (76.7%) were males. Of the 30 MDR-TB patients, 15(50%) had isolates with pyrazinamide resistance by conventional MGIT testing. This proportion expectedly exceeded the number with pyrazinamide resistance in the 61 patients without MDR-TB, 13 (21.3%) (p = 0.008). Six (20%) of MDR-TB patients had a poor outcome including treatment failure. Among patients with treatment failure, 5 (83%) had pyrazinamide resistance compared to only 10 (41.6%) with treatment success (p = 0.08). Two patients died, and both had isolates with pyrazinamide resistance. No other pretreatment characteristic was associated with treatment outcome.
CONCLUSION
Pyrazinamide susceptibility appears to be important in clinical outcomes for MDR-TB patients, and susceptibility testing appears to be a critical adjunct to TB care. The high proportion of PZA resistance in non-MDR TB cases calls for further local investigation.
Topics: Adult; Amidohydrolases; Antitubercular Agents; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Prevalence; Pyrazinamide; Tanzania; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult
PubMed: 30732572
DOI: 10.1186/s12879-019-3757-1 -
Antimicrobial Agents and Chemotherapy Nov 2012The role of pyrazinamide in the current treatment of multidrug-resistant (MDR) tuberculosis (TB) is uncertain. From a territory-wide registry of MDR-TB cases diagnosed...
The role of pyrazinamide in the current treatment of multidrug-resistant (MDR) tuberculosis (TB) is uncertain. From a territory-wide registry of MDR-TB cases diagnosed between 1995 and 2009, we assembled a cohort of 194 patients with MDR pulmonary TB given fluoroquinolone-containing regimens. Stratified by pyrazinamide use and susceptibility, there were 83 users with pyrazinamide-susceptible MDR-TB (subgroup A), 24 users with pyrazinamide-resistant MDR-TB (subgroup B), 40 nonusers with pyrazinamide-susceptible MDR-TB (subgroup C), and 47 nonusers with pyrazinamide-resistant MDR-TB (subgroup D). We estimated the adjusted risk ratio (ARR) of early sputum culture conversion (ARR-culture) that occurred within 90 days posttreatment and that of cure or treatment completion (ARR-success) that occurred by 2 years posttreatment due to pyrazinamide use with susceptibility. In comparison with subgroup B, ARR-culture and ARR-success were 1.38 (95% confidence interval [CI], 0.89 to 2.12) and 1.38 (95% confidence interval [CI], 0.88 to 2.17), respectively. Corresponding findings were 0.99 (95% CI, 0.81 to 1.22) and 0.99 (95% CI, 0.78 to 1.26) in comparison with subgroup C and 1.09 (95% CI, 0.84 to 1.42) and 0.94 (95% CI, 0.74 to 1.20) in comparison with subgroup D. Early culture conversion significantly increased the incidence proportion of cure or treatment completion by 71% (95% CI, 26% to 133%). Selection bias among pyrazinamide nonusers might have underestimated the role of pyrazinamide. Comparison of pyrazinamide users showed that pyrazinamide increased the incidence proportion of early culture conversion and that of cure or treatment completion by a best estimate of 38% for both. This magnitude of change exceeded the 15 to 20% increase in the 2-month culture conversion rate of drug-susceptible TB that results from adding pyrazinamide to isoniazid and rifampin. Pyrazinamide is likely important in fluoroquinolone-based treatment of MDR-TB.
Topics: Adult; Aged; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Isoniazid; Longitudinal Studies; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Risk; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary
PubMed: 22869570
DOI: 10.1128/AAC.01300-12 -
American Journal of Respiratory and... Nov 2008Recent studies have demonstrated that combined substitutions of rifapentine for rifampin and moxifloxacin for isoniazid in the standard, daily, short-course regimen of...
RATIONALE
Recent studies have demonstrated that combined substitutions of rifapentine for rifampin and moxifloxacin for isoniazid in the standard, daily, short-course regimen of rifampin, isoniazid, and pyrazinamide produces stable cure in 12 weeks or less. This study was designed to more precisely evaluate the contribution of moxifloxacin and isoniazid to rifapentine-based regimens.
OBJECTIVES
We compared bactericidal activity and treatment-shortening potential between regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide administered either thrice-weekly or daily.
METHODS
Using a mouse model of tuberculosis, we assessed bactericidal activity by performing quantitative cultures of lung homogenates over the first 12 weeks of treatment. Relapse rates were assessed after completing 8, 10, and 12 weeks of treatment to determine the duration of treatment necessary for stable cure.
MEASUREMENTS AND MAIN RESULTS
After 4 weeks of treatment, daily and thrice-weekly therapy with rifapentine, moxifloxacin, and pyrazinamide was significantly more active than treatment with rifapentine, isoniazid, and pyrazinamide. By 8 weeks of treatment, all mice receiving the moxifloxacin-containing regimens were lung culture negative, whereas those mice receiving the isoniazid-containing regimens continued to be lung culture positive. However, the duration of treatment necessary to achieve stable cure was 10 weeks for daily regimens and 12 weeks for thrice-weekly regimens, regardless of whether isoniazid or moxifloxacin was used. All mice receiving standard daily therapy with rifampin, isoniazid, and pyrazinamide relapsed after 12 weeks of treatment.
CONCLUSIONS
These results suggest that regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide may dramatically shorten the duration of treatment needed to cure human tuberculosis.
Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluoroquinolones; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Moxifloxacin; Pyrazinamide; Quinolines; Recurrence; Rifampin; Time Factors; Treatment Outcome; Tuberculosis
PubMed: 18723432
DOI: 10.1164/rccm.200807-1029OC -
Chest Apr 2023The role of sex differences in clinical presentation, TB drug pharmacokinetic variables, and treatment outcomes is unclear.
BACKGROUND
The role of sex differences in clinical presentation, TB drug pharmacokinetic variables, and treatment outcomes is unclear.
RESEARCH QUESTION
What is the effect of sex on TB disease severity, drug exposure, and treatment outcome?
STUDY DESIGN AND METHODS
This study was a prospective cohort study conducted in India. It assessed TB disease severity; risk of unfavorable treatment outcomes (failure, recurrence, and death) according to sex; and risk factors for unfavorable outcomes stratified according to sex. Effects of sex on the pharmacokinetic variables (maximum concentration and area under the curve) of rifampicin, isoniazid, and pyrazinamide were estimated by using noncompartmental analyses.
RESULTS
Of 1,541 people with microbiologically confirmed TB, 567 (37%) were women. Women had a lower risk of high mycobacterial burden (smear grade ≥ 2 and/or time to detection < 7 days) with an adjusted OR of 0.70 (95% CI, 0.56-0.87). Among the 744 participants who were followed up prospectively, 261 (35%) were women. Women had a lower risk of unfavorable treatment outcomes (adjusted incidence risk ratio, 0.60; 95% CI, 0.43-0.85), mostly because recurrence was lower (adjusted incidence risk ratio, 0.45; 95% CI, 0.23-0.86). Isoniazid (but not rifampicin and pyrazinamide) maximum concentration and area under the curve were significantly higher among women (P < .01) than men. Among women, unfavorable outcomes were more likely among those with cavitary disease, but among men, increased risk of unfavorable outcomes was associated with alcohol use, higher BMI, and lower glycated hemoglobin level.
INTERPRETATION
Women present with lower mycobacterial burden, achieve higher TB drug exposure, and are less likely to have unfavorable treatment outcomes than men. Strategies to improve TB treatment success should take into account sex differences in risk factors for unfavorable outcomes.
Topics: Humans; Female; Male; Antitubercular Agents; Isoniazid; Pyrazinamide; Prospective Studies; Sex Characteristics; Rifampin; Treatment Outcome; India
PubMed: 36174745
DOI: 10.1016/j.chest.2022.09.024 -
European Spine Journal : Official... Nov 2008This is an experimental study on the distribution of antituberculosis drugs such as rifampin, isoniazid, and pyrazinamide in pathologic vertebrae of spinal tuberculosis...
This is an experimental study on the distribution of antituberculosis drugs such as rifampin, isoniazid, and pyrazinamide in pathologic vertebrae of spinal tuberculosis in order to provide the regimen of chemotherapy and surgical treatment of spinal tuberculosis. The distribution of antituberculosis drugs in pathologic vertebral tissues matters greatly to the clinical effect of spinal tuberculosis' treatment. However, few pharmacokinetic studies and clinical reports about the concentrations of antituberculosis drugs in vertebral foci have been published so far. Twenty-four patients with spinal tuberculosis were divided into sclerotic group (n = 15) or non-sclerotic group (n = 9) according to radiographic features of lesion. All patients received chemotherapy with 2HRZ/2.5H(2)R(2)Z(2) for a duration of 4.5 months. Four weeks after chemotherapy all patients underwent surgery and the specimen of serum, ilium, and pathologic vertebral tissues, including sclerotic wall, subnormal osseous tissue, and foci were obtained during operation in 120-130 and 180-190 min after oral intake in the morning, respectively. The levels of three drugs in the specimen were measured using HPLC method. The concentration levels of isoniazid, rifampin and pyrazinamide varied greatly in different tissues of spinal tuberculosis, of which the bactericidal concentration values of isoniazid and rifampin and fivefold minimal inhibitory concentration (MICs) of pyrazinamide were found in subnormal vertebral bone and self-contrast ilium, the MICs of all drugs were found in sclerotic wall outside foci, and undetected level was found in foci inside the sclerotic wall. To patients without vertebral sclerotic wall around the foci, the isoniazid in foci was of bactericidal level and rifampin and pyrazinamide in foci corresponded to the MICs respectively. The sclerotic bone of affected vertebra plays an important role in blocking the antituberculosis drug's penetration into tuberculosis focus.
Topics: Adult; Antitubercular Agents; Biopsy; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Sclerosis; Spine; Tomography, X-Ray Computed; Tuberculosis, Spinal; Young Adult
PubMed: 18795341
DOI: 10.1007/s00586-008-0778-7 -
The Lancet. Microbe Jun 2022Enteropathy is prevalent in tuberculosis-endemic areas, and it has been shown to impair intestinal absorptive function; therefore, enteropathogen burden might negatively...
BACKGROUND
Enteropathy is prevalent in tuberculosis-endemic areas, and it has been shown to impair intestinal absorptive function; therefore, enteropathogen burden might negatively affect antimycobacterial pharmacokinetics, particularly among malnourished children. We sought to quantify enteropathogen burden among children initiating tuberculosis treatment in rural Tanzania and determine the effect of enteropathogen burden on serum antimycobacterial pharmacokinetics.
METHODS
We performed a prospective cohort study at one site in rural Tanzania as an exploratory substudy of a large multicountry cohort study. We included children younger than 15 years of age with confirmed or probable tuberculosis undergoing treatment with first-line tuberculosis therapy; children were excluded from the study if they were unable to undergo sample collection. Participants were consecutively recruited from the inpatient paediatric wards or the outpatient tuberculosis clinic at Haydom Lutheran Hospital, Tanzania. The main outcome was to quantify symptomatic enteropathogen burden and the effect on serum antimycobacterial pharmacokinetics. We quantified enteropathogen burden (defined as the sum of distinct enteropathogens detected in stool) using a multipathogen PCR capable of simultaneous detection of 37 bacterial, viral, and parasitic species or species groups from stool collected within 72 h of treatment initiation. Comprehensive clinical assessment, including presence of gastrointestinal symptoms, was performed at baseline, and serum was collected approximately 2 weeks after treatment initiation at steady state and throughout the dosing interval with concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol measured by liquid chromatography with a tandem mass spectrometry assay to quantify peak (C) and total area under the concentration curve (AUC), as determined by non-compartmental analysis. Enteropathogen burden was compared with pharmacokinetic measurements using bivariable and multivariable linear regression.
FINDINGS
58 children were assessed for eligibilty and enrolled between June 25, 2016, and Feb 6, 2018; 44 had complete stool testing and serum pharmacokinetic data, and they were included in the analyses. 20 (45%) were female, and 24 (55%) were male. 37 (84%) had moderate or severe malnutrition. A mean of 2·1 (SD 1·3) enteropathogens were detected per participant. Target peak concentrations of rifampicin were reached in eight (18%) of 44 participants, isoniazid in 24 (54%) of 44 participants, pyrazinamide in 28 (74%) of 38 participants, and ethambutol in six (15%) of 39 participants. Compared with controlled comparisons, each summative additional bacterial enteropathogen detected was associated with a 40% lower rifampicin C (95% CI -62 to -5) and a 36% lower ethambutol C (-52 to -14), while viral pathogens were associated with a 51% lower isoniazid C (-75 to -7). The combination of gastrointestinal symptoms and detection of an additional enteropathogen was associated with a 27% reduction in rifampicin AUC (95% CI -47 to -1).
INTERPRETATION
Tanzanian children undergoing tuberculosis treatment rarely attained pharmacokinetic targets; enteropathogen carriage was common and enteropathogen burden was associated with significant reductions in the concentrations of some antimycobacterial drugs. Further research should explore mechanistic relationships of individual pathogens and antimycobacterial pharmacokinetics in larger cohorts, or determine if screening for and treating enteropathogens at tuberculosis treatment initiation improves pharmacokinetic target attainment.
FUNDING
National Institute of Allergy and Infectious Diseases, National Institutes of Health.
TRANSLATION
For the Swahili translation of the abstract see Supplementary Materials section.
Topics: Antitubercular Agents; Child; Cohort Studies; Ethambutol; Female; Humans; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Tanzania; Tuberculosis; United States
PubMed: 35659902
DOI: 10.1016/S2666-5247(21)00308-6