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The European Respiratory Journal Sep 2020The World Health Organization recommends supervising the treatment of tuberculosis. Intermittent regimens have the potential to simplify the supervision and improve...
BACKGROUND
The World Health Organization recommends supervising the treatment of tuberculosis. Intermittent regimens have the potential to simplify the supervision and improve compliance. Our objective was to analyse the sterilising activity of once-weekly regimens based on drugs with a long half-life, bedaquiline and rifapentine, in a murine model of tuberculosis.
METHODS
300 Swiss mice were infected intravenously infected with ×10 CFU H37Rv. Mice were treated once weekly with regimens containing: 1) bedaquiline, rifapentine and pyrazinamide (BPZ); 2) BPZ plus moxifloxacin (BPZM); 3) BPZM plus clofazimine (BPZMC); 4) the standard daily regimen of tuberculosis. All regimens were given for 4 or 6 months. Bactericidal and sterilising activity were assessed.
RESULTS
After 2 months of treatment, the mean count in lungs was 0.76±0.60 log CFU in mice treated with the daily control regimen and negative in all mice treated with once-weekly regimens (p<0.05 compared to the daily control). All mice had negative lung cultures on completion of either 4 or 6 months of treatment, whereas 3 months after 4 and 6 months of treatment, respectively, the relapse rate was 64% and 13% in the standard daily regimen, 5% and 0% in BPZ, 0% and 0% in BPMZ and 0% and 5% in BPMZC (p<0.05 for all once-weekly regimens 4-month daily control; p>0.05 for all once-weekly regimens 6-month daily control).
CONCLUSIONS
BPZ-based once-weekly regimens have higher sterilising activity than the standard daily regimen and could greatly simplify treatment administration and possibly shorten the duration of tuberculosis treatment.
Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis
PubMed: 32430417
DOI: 10.1183/13993003.02502-2019 -
Antimicrobial Agents and Chemotherapy Feb 2017We investigated the prevalence, trends, and risk factors for pyrazinamide (PZA) and moxifloxacin (MOX) resistance among tuberculosis (TB) cases in China and also...
We investigated the prevalence, trends, and risk factors for pyrazinamide (PZA) and moxifloxacin (MOX) resistance among tuberculosis (TB) cases in China and also analyzed the population structure of Mycobacterium tuberculosis strains. All the M. tuberculosis strains enrolled in this study were collected from the national TB prevalence surveys. Each strain was genotyped by analyzing the regions of RD105 and IS6110 in the NTF region. The Bactec MGIT 960 system was used to detect the drug susceptibility of M. tuberculosis isolates to PZA and MOX. Based on the genotyping results, 241 (66.4%) strains were classified as Beijing genotype in 2000, which was significantly lower than in 2010 (76.2%, P < 0.01). The proportion of the modern Beijing genotype increased significantly from 49.6% in 2000 to 68.1% in 2010 (P < 0.01), while no significant difference was observed in the rate of ancient Beijing genotype between 2000 and 2010 (P = 0.676). In addition, we found that the proportion of PZA resistance in 2010 (15.0%) was significantly higher than that in 2000 (9.6%, P = 0.04). For MOX, there were more MOX-resistant isolates detected in 2010 (7.7%) than in 2000 (3.0%). In conclusion, our data demonstrate that the Beijing genotype was the predominant M. tuberculosis lineage during the past decade. The proportion of Beijing genotype isolates significantly increased from 2000 to 2010, largely due to an increase in the modern Beijing sublineage. In addition, resistance to PZA and MOX increased significantly in China between 2000 and 2010.
Topics: Antitubercular Agents; China; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Genotype; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Prevalence; Pyrazinamide; Tuberculosis, Multidrug-Resistant
PubMed: 27919887
DOI: 10.1128/AAC.02170-16 -
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 -
Acta Medica Indonesiana 2005
Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Radiography; Rifampin; Tuberculosis, Osteoarticular
PubMed: 16317221
DOI: No ID Found -
Clinical Infectious Diseases : An... May 2017There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD)...
BACKGROUND
There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.
METHODS
One hundred patients with pulmonary tuberculosis (65% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5-6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC (%TMIC).
RESULTS
Twenty-six percent of patients had Cmax of rifampicin <8 mg/L, pyrazinamide <35 mg/L, and isoniazid <3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was <4.6 mg/L and rifampicin Cmax/MIC <28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax >4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.
CONCLUSIONS
PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.
Topics: Adult; Antitubercular Agents; Coinfection; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary
PubMed: 28205671
DOI: 10.1093/cid/cix158 -
Clinical Infectious Diseases : An... Mar 2020The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood.
BACKGROUND
The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood.
METHODS
We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models.
RESULTS
Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-μg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01-1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05-1.28]). A 1-μg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01-1.11]).
CONCLUSIONS
Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.
Topics: Antitubercular Agents; Humans; India; Isoniazid; Prospective Studies; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis
PubMed: 31075166
DOI: 10.1093/cid/ciz380 -
CPT: Pharmacometrics & Systems... Nov 2021Tuberculosis (TB) remains a global health problem and there is an ongoing effort to develop more effective therapies and new combination regimes that can reduce duration... (Review)
Review
Tuberculosis (TB) remains a global health problem and there is an ongoing effort to develop more effective therapies and new combination regimes that can reduce duration of treatment. The purpose of this study was to demonstrate utility of a physiologically-based pharmacokinetic modeling approach to predict plasma and lung concentrations of 11 compounds used or under development as TB therapies (bedaquiline [and N-desmethyl bedaquiline], clofazimine, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, pyrazinamide, rifampicin, and rifapentine). Model accuracy was assessed by comparison of simulated plasma pharmacokinetic parameters with healthy volunteer data for compounds administered alone or in combination. Eighty-four percent (area under the curve [AUC]) and 91% (maximum concentration [C ]) of simulated mean values were within 1.5-fold of the observed data and the simulated drug-drug interaction ratios were within 1.5-fold (AUC) and twofold (C ) of the observed data for nine (AUC) and eight (C ) of the 10 cases. Following satisfactory recovery of plasma concentrations in healthy volunteers, model accuracy was assessed further (where patients' with TB data were available) by comparing clinical data with simulated lung concentrations (9 compounds) and simulated lung: plasma concentration ratios (7 compounds). The 5th-95th percentiles for the simulated lung concentration data recovered between 13% (isoniazid and pyrazinamide) and 88% (pyrazinamide) of the observed data points (Am J Respir Crit Care Med, 198, 2018, 1208; Nat Med, 21, 2015, 1223; PLoS Med, 16, 2019, e1002773). The impact of uncertain model parameters, such as the fraction of drug unbound in lung tissue mass (fu ), is discussed. Additionally, the variability associated with the patient lung concentration data, which was sparse and included extensive within-subject, interlaboratory, and experimental variability (as well interindividual variability) is reviewed. All presented models are transparently documented and are available as open-source to aid further research.
Topics: Antitubercular Agents; Humans; Isoniazid; Pyrazinamide; Standard of Care; Tuberculosis
PubMed: 34623770
DOI: 10.1002/psp4.12707 -
Emerging Microbes & Infections Dec 2023In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate... (Randomized Controlled Trial)
Randomized Controlled Trial
In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity (> 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.
Topics: Humans; Clofazimine; Prothionamide; Drug Therapy, Combination; Antitubercular Agents; Tuberculosis; Pyrazinamide; Treatment Outcome; Isoniazid
PubMed: 36872899
DOI: 10.1080/22221751.2023.2187247 -
Journal of Bacteriology Jan 2020nicotinamidase-pyrazinamidase (PZAse) is a metalloenzyme that catalyzes conversion of nicotinamide-pyrazinamide to nicotinic acid-pyrazinoic acid. This study...
nicotinamidase-pyrazinamidase (PZAse) is a metalloenzyme that catalyzes conversion of nicotinamide-pyrazinamide to nicotinic acid-pyrazinoic acid. This study investigated whether a metallochaperone is required for optimal PZAse activity. and PZAses (PZAse-MT and PZAse-EC, respectively) were inactivated by metal depletion (giving PZAse-MT-Apo and PZAse-EC-Apo). Reactivation with the metallochaperone ZnuA or Rv2059 (the analog) was measured. This was repeated following proteolytic and thermal treatment of ZnuA and Rv2059. The CDC1551 reference strain had the Rv2059 coding gene knocked out, and PZA susceptibility and the pyrazinoic acid (POA) efflux rate were measured. ZnuA (200 μM) achieved 65% PZAse-EC-Apo reactivation. Rv2059 (1 μM) and ZnuA (1 μM) achieved 69% and 34.3% PZAse-MT-Apo reactivation, respectively. Proteolytic treatment of ZnuA and Rv2059 and application of three (but not one) thermal shocks to ZnuA significantly reduced the capacity to reactivate PZAse-MT-Apo. An Rv2059 knockout strain was Wayne positive and susceptible to PZA and did not have a significantly different POA efflux rate than the reference strain, although a trend toward a lower efflux rate was observed after knockout. The metallochaperone Rv2059 restored the activity of metal-depleted PZAse Although Rv2059 is important , it seems to have a smaller effect on PZA susceptibility It may be important to mechanisms of action and resistance to pyrazinamide in Further studies are needed for confirmation. Tuberculosis is an infectious disease caused by the bacterium and remains one of the major causes of disease and death worldwide. Pyrazinamide is a key drug used in the treatment of tuberculosis, yet its mechanism of action is not fully understood, and testing strains of for pyrazinamide resistance is not easy with the tools that are presently available. The significance of the present research is that a metallochaperone-like protein may be crucial to pyrazinamide's mechanisms of action and of resistance. This may support the development of improved tools to detect pyrazinamide resistance, which would have significant implications for the clinical management of patients with tuberculosis: drug regimens that are appropriately tailored to the resistance profile of a patient's individual strain lead to better clinical outcomes, reduced onward transmission of infection, and reduction of the development of resistant strains that are more challenging and expensive to treat.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Escherichia coli; Metallochaperones; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nicotinamidase; Pyrazinamide
PubMed: 31636108
DOI: 10.1128/JB.00331-19 -
Antimicrobial Agents and Chemotherapy Sep 2022TBI-166, derived from riminophenazine analogues, shows more potent anti-TB activity than clofazimine and is being assessed against tuberculosis (TB) in a phase IIa...
TBI-166, derived from riminophenazine analogues, shows more potent anti-TB activity than clofazimine and is being assessed against tuberculosis (TB) in a phase IIa clinical trial in China. Preclinical regimen studies containing TBI-166 will support the phase IIb clinical trials of TBI-166. In the present study, we compared the efficacy in three murine TB models of an all-oral drug-resistant TB drug regimen of TBI-166 with bedaquiline (BDQ) and pyrazinamide (PZA) with the first-line regimen of isoniazid (INH) with rifampin (RFP) and PZA (HRZ regimen), the most effective reported TBI-166-containing regimen of TBI-166 with BDQ and linezolid (LZD), and the Nix-TB clinical trial regimen of BDQ with pretomanid and LZD (BPaL regimen). In the C3HeB/FeJ murine TB model, for the TBI-166+BDQ+PZA regimen, the lungs of mice were culture negative at 4 weeks, and there were no relapses at 8 weeks of treatment. The reduction in bacterial burden and relapse rate were greater than those of the HRZ regimen and the TBI-166+BDQ+LZD regimen. Compared with the BPaL regimen, the TBI-166+BDQ+PZA regimen had similar or stronger early bactericidal activity, bactericidal activity, and sterilizing activity in the BALB/c murine TB model. The bacterial burden in the TBI-166+BDQ+PZA regimen group decreased significantly more than that in the BPaL regimen group and was almost or totally relapse free (<13.33% after 8 weeks). In conclusion, oral short-course three-drug regimens, including TBI-166 with high efficacy, were identified. The TBI-166+BDQ+PZA regimen is recommended for further study in a TBI-166 phase IIb clinical trial.
Topics: Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Isoniazid; Linezolid; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 35924925
DOI: 10.1128/aac.00658-22