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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 -
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 -
Respiratory Research 2001Multidrug-resistant (MDR) strains of Mycobacterium tuberculosis have emerged worldwide. In many countries and regions, these resistant strains constitute a serious... (Review)
Review
Multidrug-resistant (MDR) strains of Mycobacterium tuberculosis have emerged worldwide. In many countries and regions, these resistant strains constitute a serious threat to the efficacy of tuberculosis control programs. An important element in gaining control of this epidemic is developing an understanding of the molecular basis of resistance to the most important antituberculosis drugs: isoniazid, rifampin, and pyrazinamide. On the basis of this information, more exacting laboratory testing, and ultimately more appropriate and timely treatment regimens, can be developed.
Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Resistance, Microbial; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin
PubMed: 11686881
DOI: 10.1186/rr54 -
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 -
Mikrobiyoloji Bulteni Apr 2022Pyrazinamide (PZA) is one of the first-line anti-tuberculous drugs used in the treatment of tuberculosis (TB). Considering the ability of PZA to shorten the treatment...
Pyrazinamide (PZA) is one of the first-line anti-tuberculous drugs used in the treatment of tuberculosis (TB). Considering the ability of PZA to shorten the treatment period from 9-12 months to six months by eliminating persistent bacilli, it appears to be an important cornerstone of TB therapy. While the main mechanism causing the PZA resistance is pncA mutations at a rate of 70-97%, it has been determined that rpsA and panD mutations can also cause resistance. In this study, we aimed to investigate the pncA, rpsA and panD gene mutations, the efficiency of the pyrazinamidase (PZAse) enzyme test in determining PZA resistance, the drug susceptibility and their families in PZA-resistant Mycobacterium tuberculosis isolates. Totally 46 PZA resistant M.tuberculosis isolates were included in the study. The pncA, rpsA and panD mutations caused by PZA resistance were investigated by in-house PCR followed by DNA sequencing method. Drug susceptibility was determined with Bactec MGIT 960 (Becton Dickinson, USA) system, the presence of PZAse was evaluated by colorimetric PZAse enzyme assay and the families were determined by the spoligotyping method. Of the 46 PZA-resistant isolates, 24 (52.2%) were identified as PZA monoresistant, 11 (23.9%) multidrug resistant (MDR)-TB and 11 (23.9%) poly drug resistant (PDR)-TB. Gene mutations associated with resistance were detected in 73.9% (34) of PZA-resistant M.tuberculosis isolates. The pncA, rpsA and panD mutations were found in 71.7% (33), 28.2% (12) and 4.3% (2) of the isolates, respectively. The coexistence of pncA/rpsA and pncA/panD gene mutations were determined in 12 and two isolates, respectively. The pncA gene mutations were observed in 3 (33.3%) of 9 (19.6%) isolates whose enzyme presence was detected by the colorimetric PZAse test. In the pncA gene, eight different point mutations in the form of missense mutation;A226C (27.3%), A152C (24.2%), C169G (21.2%) A422C (9.1%), G145A (6.1%), A29G (6.1%), A424G (3%) and T464G (3%) were detected. In the rpsA gene, A636C (42.9%) silent and G1318A (42.9%) missense mutations and in the panD gene, C66G (50%) nonsense and A145G (50%) missense mutations were the most common mutations detected. As a result of genotyping of PZA resistant isolates, the most common genotypes were found in T1 cluster with 17 (36.9%) isolates; followed by the families of Beijing with 7 (15.2%) isolates, H3 with 6 (13%) isolates, TUR with 5 (10.9%) isolates, and LAM 9 with 4 (8.7%) isolates, respectively. In addition, 2 (4.3%) isolates belonging to the ORPHAN family and one isolate belonging to each of LAM TUR, LAM 2, LAM 7, T2, T5-RUS1 families were identified. Our study is the first to investigate all pncA, rpsA and panD gene mutations that have been found to cause PZA resistance in Turkey. Epidemiological studies on PZA resistance will make important contributions to the determination of resistance mechanism and the development of methods that will provide rapid diagnosis for the detection of resistance.
Topics: Antitubercular Agents; Humans; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 35477224
DOI: 10.5578/mb.20229801 -
The American Journal of Tropical... Sep 2021
Topics: Adolescent; Antitubercular Agents; Ethambutol; Humans; Isoniazid; Knee; Lupus Vulgaris; Male; Pyrazinamide; Rifampin
PubMed: 34516400
DOI: 10.4269/ajtmh.21-0736 -
Journal of the American Medical... Mar 2021Tuberculosis is the leading cause of death from a single infectious agent. The emergence of antimicrobial resistant Mycobacterium tuberculosis strains makes the problem...
OBJECTIVE
Tuberculosis is the leading cause of death from a single infectious agent. The emergence of antimicrobial resistant Mycobacterium tuberculosis strains makes the problem more severe. Pyrazinamide (PZA) is an important component for short-course treatment regimens and first- and second-line treatment regimens. This research aims for fast diagnosis of M. tuberculosis resistance to PZA and identification of genetic features causing resistance.
MATERIALS AND METHODS
We use clinically collected genomic data of M. tuberculosis that are resistant or susceptible to PZA. A machine learning platform is built to diagnose PZA resistance using the whole genome sequence data, and to identify resistance genes and mutations. The platform consists of a deep convolutional neural network (DCNN) model for resistance diagnosis and a support vector machine (SVM) model as a surrogate to identify resistance genes and mutations.
RESULTS
The DCNN model achieves a PZA resistance diagnosis accuracy of 93%. Each prediction takes less than a second. The SVM has revealed 2 novel genes, embB and gyrA, besides the well-known pncA gene, and 9 mutations that harbor PZA resistance.
DISCUSSION
The DCNN and SVM machine learning platform, if used together with the real-time genome sequencing machines, could allow for rapid PZA diagnosis, allowing for critical time to ensure good patient outcomes, and preventing outbreaks of deadly infections. Furthermore, identifying pertinent resistance genes and mutations will help researchers better understand the biological mechanisms behind resistance.
CONCLUSIONS
Machine learning can be used to achieve high-accuracy resistance prediction, and identify genes and mutations causing the resistance.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Humans; Machine Learning; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Neural Networks, Computer; Pyrazinamide; Support Vector Machine; Tuberculosis
PubMed: 33215194
DOI: 10.1093/jamia/ocaa233 -
Rapid Communications in Mass... Jan 2023Tuberculosis (TB) remains a challenging global infectious disease, mainly affecting the lungs. First-line anti-TB drugs play a crucial role in slowing down the rapid...
RATIONALE
Tuberculosis (TB) remains a challenging global infectious disease, mainly affecting the lungs. First-line anti-TB drugs play a crucial role in slowing down the rapid spread of TB. In addition, the patient might benefit from therapeutic drug monitoring since it has become an accepted clinical tool for optimizing TB treatment.
METHODS
A simple and sensitive liquid chromatography/tandem mass spectrometry method was developed to monitor the plasma level of isoniazid, ethambutol and pyrazinamide in plasma samples. A one-step extraction procedure using an Ostro™ plate was applied, and extracts were analyzed by gradient elution followed by detection on a mass spectrometer by multiple reaction monitoring mode.
RESULTS
The analytes were separated within 4.2 min and over the concentration range of 0.2-10 μg/ml for isoniazid and ethambutol and 1-65 μg/ml for pyrazinamide. The method was successfully validated according to the European Medicine Agency guideline for the selectivity, linearity and lower limit of detection, precision and accuracy, matrix effect, extraction recovery, carryover, dilution integrity and stability, and applied for quantification of analytes in clinical samples from TB patients.
CONCLUSIONS
The presented method allows sensitive and reproducible determination of selected anti-TB drugs with advantages such as low sample volume requirement, short run time of analysis, one-step sample preparation procedure with capabilities for phospholipids removal, and a low quantification limit as well as a high degree of selectivity.
Topics: Humans; Ethambutol; Pyrazinamide; Isoniazid; Chromatography, Liquid; Tandem Mass Spectrometry; Antitubercular Agents; Tuberculosis; Chromatography, High Pressure Liquid
PubMed: 36329637
DOI: 10.1002/rcm.9425 -
Antimicrobial Agents and Chemotherapy Jun 2017The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the...
The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration () of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) was 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC) was 307 (83) μg · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution (/) than men, and both clearance (CL/) and / increased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a of >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.
Topics: Adult; Aged; Antitubercular Agents; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis; Young Adult
PubMed: 28289033
DOI: 10.1128/AAC.02625-16 -
The Indian Journal of Medical Research Apr 2017Concomitant feeding and anti-tuberculosis (TB) drug administration are likely to reduce nausea and enhance compliance to treatment. However, food could lower plasma drug...
BACKGROUND & OBJECTIVES
Concomitant feeding and anti-tuberculosis (TB) drug administration are likely to reduce nausea and enhance compliance to treatment. However, food could lower plasma drug concentrations. This study was undertaken to examine the effect of food on two-hour plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA), and pharmacokinetics of these drugs in adult TB patients.
METHODS
Newly diagnosed adult TB patients were recruited from the Revised National Tuberculosis Control Programme (RNTCP) treatment centres in Chennai Corporation, Chennai, India. Two-hour post-dosing plasma concentrations were determined in 25 patients, and a semi-intensive pharmacokinetic study was undertaken in six patients. RMP, INH and PZA concentrations were determined by high-performance liquid chromatography.
RESULTS
The geometric mean two-hour concentrations with food and under fasting conditions were 2.2 and 5.5 μg/ml for RMP (P<0.001), 3.9 and 11.3 μg/ml for INH (P<0.001), and 18.0 and 28.2 μg/ml for PZA (P<0.001), respectively. Drug administration with food caused the plasma concentration to decrease by 50, 45 and 34 per cent for RMP, INH and PZA, respectively. Significant decreases in peak concentrations and exposures of drugs and delay in time to attain peak concentrations of drugs when taken with food were also observed.
INTERPRETATION & CONCLUSIONS
Our findings showed that food lowered anti-TB drug concentrations significantly and delayed absorption. Patients may be explained the beneficial effects of taking anti-TB drugs in a fasting state and advised to do so. There is a need for more research on optimization of dosing to maximize efficacy and safety of currently used drugs.
Topics: Adult; Antitubercular Agents; Fasting; Female; Food; Humans; India; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis
PubMed: 28862186
DOI: 10.4103/ijmr.IJMR_552_15