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CPT: Pharmacometrics & Systems... Sep 2023Tuberculosis (TB) is a leading cause of mortality attributed to an infectious agent. TB primarily targets the lungs, but in about 16% cases can affect other organs as...
Tuberculosis (TB) is a leading cause of mortality attributed to an infectious agent. TB primarily targets the lungs, but in about 16% cases can affect other organs as well, giving rise to extrapulmonary TB (EPTB). However, an optimal regimen for EPTB treatment is not defined. Although the recommended treatment for most forms of EPTB is the same as pulmonary TB, the pharmacokinetics of EPTB therapy are not as well studied. To address this gap, we formulate a whole-body physiologically-based pharmacokinetic (PBPK) model for EPTB that for the first time includes the ability to simulate drug concentrations in the pleura and lymph node, the most commonly affected sites of EPTB. Using this model, we estimate the time-dependent concentrations, at potential EPTB infection sites, of the following four first-line anti-TB drugs: rifampicin, ethambutol, isoniazid, and pyrazinamide. We use reported plasma concentration kinetics data to estimate model parameters for each drug and validate our model using reported concentration data not used for model formulation or parameter estimation. Model predictions match the validation data, and reported pharmacokinetic parameters (maximum plasma concentration, time to reach maximum concentration) for the drugs. The model also predicts ethambutol, isoniazid, and pyrazinamide concentrations in the pleura that match reported experimental values from an independent study. For each drug, the predicted drug concentrations at EPTB sites are compared with their critical concentration. Simulations suggest that although rifampicin and isoniazid concentrations are greater than critical concentration values at most EPTB sites, the concentrations of ethambutol and pyrazinamide are lower than their critical concentrations at most EPTB sites.
Topics: Humans; Isoniazid; Pyrazinamide; Ethambutol; Rifampin; Tuberculosis; Antitubercular Agents
PubMed: 37431175
DOI: 10.1002/psp4.13008 -
Frontiers in Molecular Biosciences 2022As the first-line clinical drugs for tuberculosis (TB), isoniazid (INH), pyrazinamide (PZA), and rifampicin (RMP) are playing important roles for preventing the rapid...
A Simple and Sensitive UPLC-UV Method for Simultaneous Determination of Isoniazid, Pyrazinamide, and Rifampicin in Human Plasma and Its Application in Therapeutic Drug Monitoring.
As the first-line clinical drugs for tuberculosis (TB), isoniazid (INH), pyrazinamide (PZA), and rifampicin (RMP) are playing important roles for preventing the rapid spread of TB. Precise quantification of these drugs in biological samples is crucial to evaluate or improve the efficacy of advanced TB drug delivery systems, which are designed for reducing drug resistance, minimizing side effects, etc. Herein, a simple and sensitive method based on UPLC-UV was established and investigated for simultaneous quantification of PZA, INH, and RMP in human plasma and was applied to anti-TB drug therapeutic drug monitoring. The analytes were implemented on an HSS T3 C18 column at 40°C. The separation was performed with a gradient elution with methanol-acetonitrile-water (3:3:94) at 0.1 ml/min. The analysis only involved plasma with a small volume of 100 µL and a rapid one-step protein precipitation with methanol-acetonitrile (1:1). The results showed that the calibration curves for INH, PZA, and RMP were linear in a range of 0.5-20 μg/ml, 5-60 μg/ml, and 5-60 μg/ml, respectively. The intra- and inter-day precisions were both smaller than 15%, and the lower limit of quantitation (LLOQ) was identifiable and reproducible at 0.5 μg/ml for INH and 5 μg/ml for both PZA and RMP, respectively. The target drugs in plasma were stable after 21 days of storage at -80°C. The results indicated that our developed method is suitable for the simultaneous monitoring of INH, PZA, and RMP in human plasma.
PubMed: 35573738
DOI: 10.3389/fmolb.2022.873311 -
MBio Apr 2023Antituberculosis therapy (ATT) causes a rapid and distinct alteration in the composition of the intestinal microbiota that is long lasting in both mice and humans. This...
Antituberculosis therapy (ATT) causes a rapid and distinct alteration in the composition of the intestinal microbiota that is long lasting in both mice and humans. This observation raised the question of whether such antibiotic-induced changes in the microbiome might affect the absorption or gut metabolism of the tuberculosis (TB) drugs themselves. To address this issue, we utilized a murine model of antibiotic-induced dysbiosis to assay the bioavailability of rifampicin, moxifloxacin, pyrazinamide, and isoniazid in mouse plasma over a period of 12 h following individual oral administration. We found that 4-week pretreatment with a regimen of isoniazid, rifampicin, and pyrazinamide (HRZ), a drug combination used clinically for ATT, failed to reduce the exposure of any of the four antibiotics assayed. Nevertheless, mice that received a pretreatment cocktail of the broad-spectrum antibiotics vancomycin, ampicllin, neomycin, and metronidazole (VANM), which are known to deplete the intestinal microbiota, displayed a significant decrease in the plasma concentration of rifampicin and moxifloxacin during the assay period, an observation that was validated in germfree animals. In contrast, no major effects were observed when similarly pretreated mice were exposed to pyrazinamide or isoniazid. Thus, the data from this animal model study indicate that the dysbiosis induced by HRZ does not reduce the bioavailability of the drugs themselves. Nevertheless, our observations suggest that more extreme alterations of the microbiota, such as those occurring in patients on broad-spectrum antibiotics, could directly or indirectly affect the exposure of important TB drugs and thereby potentially influencing treatment outcome. Previous studies have shown that treatment of Mycobacterium tuberculosis infection with first-line antibiotics results in a long-lasting disruption of the host microbiota. Since the microbiome has been shown to influence the host availability of other drugs, we employed a mouse model to ask whether the dysbiosis resulting from either tuberculosis (TB) chemotherapy or a more aggressive course of broad-spectrum antibiotics might influence the pharmacokinetics of the TB antibiotics themselves. While drug exposure was not reduced in animals previously described as exhibiting the dysbiosis triggered by conventional TB chemotherapy, we found that mice with other alterations in the microbiome, such as those triggered by more intensive antibiotic treatment, displayed decreased availability of rifampicin and moxifloxacin, which in turn could impact their efficacy. The above findings are relevant not only to TB but also to other bacterial infections treated with these two broader spectrum antibiotics.
Topics: Humans; Animals; Mice; Antitubercular Agents; Rifampin; Isoniazid; Pyrazinamide; Biological Availability; Moxifloxacin; Dysbiosis; Tuberculosis
PubMed: 36877010
DOI: 10.1128/mbio.00353-23 -
Medicine Oct 2019Therapeutic drug monitoring has been employed in anti-tuberculosis (TB) drugs to assess optimal dose for maximum therapeutic effects and minimal toxicity. But the... (Observational Study)
Observational Study
Therapeutic drug monitoring has been employed in anti-tuberculosis (TB) drugs to assess optimal dose for maximum therapeutic effects and minimal toxicity. But the determinants of serum concentration need further evidences.In a retrospective case-control study, clinical and laboratory data were collected from 717 in-patients with TB at Xi'an Chest Hospital, China. Two hours serum concentrations of isoniazid, rifampicin, pyrazinamide as well as ethambutol were obtained and analyzed by liquid chromatography-tandem mass spectrometry.The month 2 culture conversion group had lower concentration of isoniazid, pyrazinamide, and ethambutol than month 1 group. Statistical analysis showed that serum concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol revealed a positive relationship with dose (mg/kg) (P < .001, P < .001, P < .001, and P = .003, respectively). Furthermore, isoniazid concentration was related to smoking (P = .009) and prior TB (P = .011), while rifampicin and pyrazinamide concentrations were correlated to sex (P = .004 and 0.025, respectively). Ethambutol concentration was associated with creatinine clearance (Ccr, P = .002).It is necessary to optimize drug doses using therapeutic drug monitoring while considering the following determinants: weight, smoking status, prior TB, sex, and Ccr. Furthermore, low 2 hours serum concentrations can be associated with longer culture conversion.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Case-Control Studies; China; Chromatography, Liquid; Creatinine; Dose-Response Relationship, Drug; Drug Monitoring; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Sex Factors; Smoking; Tuberculosis; Young Adult
PubMed: 31593125
DOI: 10.1097/MD.0000000000017523 -
The Journal of Antimicrobial... May 2022Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase...
BACKGROUND
Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB.
OBJECTIVES
To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB.
METHODS
We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions.
RESULTS
Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions.
CONCLUSIONS
Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.
Topics: Adult; Antitubercular Agents; Child; Ethambutol; Humans; Infant; Isoniazid; Pyrazinamide; South Africa; Tuberculosis, Pulmonary
PubMed: 35468189
DOI: 10.1093/jac/dkac103 -
PloS One 2018Resistance to isoniazid is the most common form of drug-resistance in tuberculosis. However only a tiny proportion of TB patients in the world have access to isoniazid... (Clinical Trial)
Clinical Trial
BACKGROUND
Resistance to isoniazid is the most common form of drug-resistance in tuberculosis. However only a tiny proportion of TB patients in the world have access to isoniazid drug susceptibility testing-the widely implemented Xpert MTB/RIF technology only tests for resistance to rifampicin. Patients with isoniazid mono resistance that is not identified at baseline are treated with a standard regimen that effectively results in rifampicin mono-therapy during the latter four months of the six month treatment course, exposing remaining viable organisms to a single agent and greatly increasing the risk of development of multi drug-resistant TB. Unusually, Peru has pioneered universal pre-treatment drug susceptibility testing with methods that identify isoniazid resistance and has thus identified a large number of individuals requiring tailored therapy. Since 2010, treatment in Peru for isoniazid-resistant tuberculosis without multidrug-resistant tuberculosis (Hr-TB) has been with a standardized nine-month regimen of levofloxacin, rifampicin, ethambutol and pyrazinamide. The objectives of this study were to evaluate the outcomes of treatment for patients with Hr-TB initiating treatment with this regimen between January 2012 and December 2014 and to determine factors affecting these outcomes.
METHODS
Retrospective cross-sectional study; case data were obtained from the national registry of drug-resistant tuberculosis. Patients diagnosed with isoniazid resistant TB without resistance to rifampicin, pyrazinamide, ethambutol and quinolones as determined by either a rapid drug susceptibility testing (DST) (nitrate reductase test, MODS, Genotype MTBDRplus) or by the proportion method were included.
FINDINGS
A total of 947 cases were evaluated (a further 403 without treatment end date were excluded), with treatment success in 77.2% (731 cases), loss to follow-up in 19.7% (186 cases), treatment failure in 1.2% (12 cases), and death in 1.9% (18 cases). Unfavorable outcomes were associated in multivariate analysis with male gender (OR 0.50, 95% CI 0.34-0.72, p<0.05), lack of rapid DST (OR 0.67, 95% CI 0.50-0.91, p = 0.01), additional use of an injectable second-line anti-tuberculous drug (OR 0.46, 95% CI 0.31-0.70, p<0.05), and treatment initiation in 2014 (OR 0.77, 95% CI 0.62-0.94, p = 0.01).
INTERPRETATION
The treatment regimen implemented in Peru for isoniazid resistant TB is effective for TB cure and is not improved by addition of an injectable second-line agent. Access to rapid DST and treatment adherence need to be strengthened to increase favorable results.
Topics: Adolescent; Adult; Child; Child, Preschool; Cross-Sectional Studies; Drug Therapy, Combination; Ethambutol; Female; Humans; Infant; Infant, Newborn; Isoniazid; Levofloxacin; Male; Middle Aged; Peru; Pyrazinamide; Retrospective Studies; Rifampin; Sex Factors; Time Factors; Tuberculosis, Multidrug-Resistant
PubMed: 30513085
DOI: 10.1371/journal.pone.0206658 -
BMC Infectious Diseases Jan 2020Macrophages play a key role in the infection process, and alternatively activated macrophages (M2 polarization) play important roles in persistent infection via the...
BACKGROUND
Macrophages play a key role in the infection process, and alternatively activated macrophages (M2 polarization) play important roles in persistent infection via the immune escape of pathogens. This suggests that immune escape of pathogens from host immunity is an important factor to consider in treatment failure and multidrug-resistant tuberculosis (MDR-TB)/extensively drug-resistant tuberculosis (XDR-TB). In this study, we investigated the association between macrophage polarization and MDR-TB/XDR-TB and the association between macrophage polarization and the anti-TB drugs used.
METHODS
iNOS and arginase-1, a surface marker of polarized macrophages, were quantified by immunohistochemical staining and imaging analysis of lung tissues of patients who underwent surgical treatment for pulmonary TB. Drug susceptibility/resistance and the type and timing of anti-tuberculosis drugs used were investigated.
RESULTS
The M2-like polarization rate and the ratio of the M2-like polarization rate to the M1-like polarization rate were significantly higher in the MDR-TB/XDR-TB group than in the DS-TB group. The association between a high M2-like polarization rate and MDR-TB/XDR-TB was more pronounced in patients with a low M1-like polarization rate. Younger age and a higher M2-like polarization rate were independent associated factors for MDR-TB/XDR-TB. The M2-like polarization rate was significantly higher in patients who received anti-TB drugs containing pyrazinamide continuously for 4 or 6 weeks than in those who received anti-TB drugs not containing pyrazinamide.
CONCLUSIONS
The M2-like polarization of macrophages is associated with MDR-TB/XDR-TB and anti-TB drug regimens including pyrazinamide or a combination of pyrazinamide, prothionamide and cycloserine.
Topics: Adult; Antitubercular Agents; Cycloserine; Extensively Drug-Resistant Tuberculosis; Female; Humans; Lung; Macrophage Activation; Macrophages; Male; Middle Aged; Mycobacterium tuberculosis; Prothionamide; Pyrazinamide; Treatment Failure; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary
PubMed: 31996142
DOI: 10.1186/s12879-020-4802-9 -
Bioorganic & Medicinal Chemistry Nov 2022Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB...
Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the coenzyme A biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative molecules were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10-fold more potent than POA. Further development and mechanistic analysis of these analogs may lead to a next generation POA analog for treating TB.
Topics: Humans; Pyrazinamide; Antitubercular Agents; Mycobacterium tuberculosis; Amidohydrolases; Tuberculosis; Mutation; Structure-Activity Relationship; Carboxylic Acids; Microbial Sensitivity Tests; Drug Resistance, Bacterial
PubMed: 36228522
DOI: 10.1016/j.bmc.2022.117046 -
Marine Drugs Sep 2019Pyrazinamide (PZA) is the only drug for the elimination of latent (MTB) isolates. However, due to the increased number of PZA-resistance, the chances of the success of... (Review)
Review
Pyrazinamide (PZA) is the only drug for the elimination of latent (MTB) isolates. However, due to the increased number of PZA-resistance, the chances of the success of global TB elimination seems to be more prolonged. Recently, marine natural products (MNPs) as an anti-TB agent have received much attention, where some compounds extracted from marine sponge, Haliclona sp. exhibited strong activity under aerobic and hypoxic conditions. In this study, we screened articles from 1994 to 2019 related to marine natural products (MNPs) active against latent MTB isolates. The literature was also mined for the major regulators to map them in the form of a pathway under the dormant stage. Five compounds were found to be more suitable that may be applied as an alternative to PZA for the better management of resistance under latent stage. However, the mechanism of actions behind these compounds is largely unknown. Here, we also applied synthetic biology to analyze the major regulatory pathway under latent TB that might be used for the screening of selective inhibitors among marine natural products (MNPs). We identified key regulators of MTB under latent TB through extensive literature mining and mapped them in the form of regulatory pathway, where SigH is negatively regulated by RshA. PknB, RshA, SigH, and RNA polymerase (RNA-pol) are the major regulators involved in MTB survival under latent stage. Further studies are needed to screen MNPs active against the main regulators of dormant MTB isolates. To reduce the PZA resistance burden, understanding the regulatory pathways may help in selective targets of MNPs from marine natural sources.
Topics: Antitubercular Agents; Biological Products; Drug Resistance; Humans; Latent Tuberculosis; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Pyrazinamide
PubMed: 31561525
DOI: 10.3390/md17100549 -
Hong Kong Medical Journal = Xianggang... Dec 2021In 2018, the World Health Organization recommended a 6-month treatment regimen that included levofloxacin and pyrazinamide for isoniazid-resistant without rifampicin...
INTRODUCTION
In 2018, the World Health Organization recommended a 6-month treatment regimen that included levofloxacin and pyrazinamide for isoniazid-resistant without rifampicin resistance (Hr-TB). Susceptibility testing for both drugs is not routinely performed for Hr-TB in Hong Kong. This study examined the prevalences of levofloxacin and pyrazinamide resistances in Hr-TB and explored associated risk factors.
METHODS
All Hr-TB isolates archived during 2018 were retrieved. Isolates were de-duplicated to identify unique cases. Levofloxacin susceptibility testing was performed using the MGIT 960 System; pncA gene sequencing was used as a surrogate indicator of pyrazinamide susceptibility. Previous laboratory records for each case were analysed.
RESULTS
In total, 160 phenotypic Hr-TB cases were identified from among 3411 patients with tuberculosis (4.7%). Among these, 157 were analysed, revealing 0.6% (n=1) levofloxacin resistance and 4.5% (n=7) pyrazinamide resistance, respectively. Independent risk factors associated with mutations included history of tuberculosis in the affected patient and isoniazid poly-resistance (ie, double and triple resistances), but not mono-resistance.
CONCLUSION
For Hr-TB in Hong Kong, levofloxacin resistance is rare and pyrazinamide resistance-associated mutations are uncommon. Routine susceptibility testing for these drugs is not indicated unless related risk factors are identified.
Topics: Amidohydrolases; Antitubercular Agents; Hong Kong; Humans; Isoniazid; Levofloxacin; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Prevalence; Tuberculosis, Multidrug-Resistant
PubMed: 34949730
DOI: 10.12809/hkmj208553