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Advances in Medical Sciences Mar 2016The global control and management of tuberculosis (TB) is faced with the formidable challenge of worsening scenarios of drug-resistant disease. Pyrazinamide (PZA) is an... (Review)
Review
The global control and management of tuberculosis (TB) is faced with the formidable challenge of worsening scenarios of drug-resistant disease. Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of TB. It plays a key role in reducing TB relapse rates, shortening the course of the disease treatment from 9-12 months to 6 months, and the treatment of patients infected with bacillary strains that are resistant to at least isoniazid and rifampicin. Additionally, it is the only first-line anti-TB drug most likely to be maintained in all new regimens, which are aimed at reducing the treatment period of susceptible, multi-drug resistant and extensively drug-resistant TB. It has a preferential sterilizing activity against non-replicating persister bacilli with low metabolism at acid pH in vitro or in vivo during active inflammation where other drugs may not act so well. PZA seem to have a non-specific cellular target and instead, exerts its anti-mycobacterial effect by disrupting the membrane energetics, the trans-translation process, acidification of the cytoplasm and perhaps coenzyme A synthesis, which is required for survival of Mycobacterium tuberculosis (MTB) persisters. Indeed, the emergence of MTB strains resistant to PZA represents an important clinical and public health problem. The essential role of PZA in TB treatment underlines the need for accurate and rapid detection of its resistance. This article presents an updated review of the molecular mechanisms of drug action and resistance in MTB against PZA, commenting on the several research gaps and proposed drug targets for PZA.
Topics: Animals; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis
PubMed: 26521205
DOI: 10.1016/j.advms.2015.09.007 -
The Indian Journal of Tuberculosis Apr 2023Tuberculosis is a serious contagious disease mainly affecting the lungs and is common in the developing countries. The essential component of all antitubercular regimens...
Tuberculosis is a serious contagious disease mainly affecting the lungs and is common in the developing countries. The essential component of all antitubercular regimens include Isoniazid, pyrazinamide as first-line drugs. A serious cutaneous adverse drug reaction namely exfoliative dermatitis (erythroderma) is associated with isoniazid use though uncommon but is common among pyrazinamide users. Here we report 3 cases of tuberculosis patients on antitubercular therapy (ATT) for 8 weeks, came to hospital OP (outpatient) with severe generalized redness and scaling with itching distributed all over the body and trunk. Immediately ATT was discontinued and all the three patients were administered antihistaminic and corticosteroid. The patients recovered within 3 weeks. To confirm ATT induced erythroderma and narrow down the offending agents, sequential rechallenge with ATT was done and again these patients had similar lesions erupt all over the body only with isoniazid and pyrazinamide. Antihistamine, steroids were started and the symptoms resolved and completely recovered within 3 weeks. Prompt withdrawal of the culprit drug along with appropriate medications and supportive measures is necessary for good prognosis. Physicians must be judicious while prescribing ATT especially, isoniazid and pyrazinamide as these can precipitate fatal cutaneous adverse reactions. Strict vigilance may help in early detection of this type ADR and timely management.
Topics: Humans; Isoniazid; Pyrazinamide; Dermatitis, Exfoliative; Antitubercular Agents; Tuberculosis
PubMed: 37100585
DOI: 10.1016/j.ijtb.2022.08.001 -
International Journal of Infectious... Feb 2022The shorter treatment regimen (STR) for multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) has achieved successful outcomes in many countries. However, there... (Observational Study)
Observational Study
SETTING
The shorter treatment regimen (STR) for multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) has achieved successful outcomes in many countries. However, there are few studies on high-dose gatifloxacin-based STR with adverse drug reactions (ADRs) and management.
DESIGN
A prospective observational study was conducted with MDR/RR-TB patients who were treated with a standardized 9 or 12 - month regimen: including gatifloxacin (Gfx), clofazimine (Cfz), ethambutol (EMB), and pyrazinamide (PZA), and supplemented by amikacin (Am), isoniazid (INH), and prothionamide (Pto) during an intensive phase of 4 or 6 - month. Monitored ADRs monthly until treatment completion and then followed up every three months for one year.
RESULTS
Among the 42 eligible patients, 35 (83.3%) completed treatment successfully, 1 (2.4%) lost to follow-up (LTFU), and 6 (14.3%) failed due to ADRs, with no death. The most important ADR was drug-induced liver damage, which occurred in 24 out of 42 (57.1%) patients and resulted in 4 (9.5%) failed treatments and 4 (9.5%) adjusted treatments. QT interval prolongation occurred in 17 out of 42 (40.5%) patients, 9 (21.4%) of them with the corrected QT interval according to Fridericia (QTcF) > 500 ms resulting in 7 (16.7%) adjusted treatments.
CONCLUSIONS
This study confirmed the effectiveness of the high-dose gatifloxacin-based STR but severe ADRs, especially hepatotoxicity and QT interval prolongation should never be ignored.
Topics: Antitubercular Agents; Gatifloxacin; Humans; Isoniazid; Pyrazinamide; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 34861398
DOI: 10.1016/j.ijid.2021.11.037 -
Clinical Infectious Diseases : An... Aug 2022In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis...
Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study.
BACKGROUND
In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands.
METHODS
Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg ∙ h/L).
RESULTS
In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6-13, 13-20. and 20-25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs.
CONCLUSIONS
Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands.
Topics: Adult; Antitubercular Agents; Child; Drug Combinations; Ethambutol; Female; Humans; Infant; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Tablets; Tuberculosis
PubMed: 34665866
DOI: 10.1093/cid/ciab908 -
Trends in Pharmacological Sciences Dec 2019Inclusion of pyrazinamide (PZA) in the tuberculosis (TB) drug regimen during the 1970s enabled a reduction in treatment duration from 12 to 6 months. PZA has this... (Review)
Review
Inclusion of pyrazinamide (PZA) in the tuberculosis (TB) drug regimen during the 1970s enabled a reduction in treatment duration from 12 to 6 months. PZA has this remarkable effect in patients despite displaying poor potency against Mycobacterium tuberculosis (Mtb) in vitro. The pharmacological basis for the in vivo sterilizing activity of the drug has remained obscure and its bacterial target controversial. Recently it was shown that PZA penetrates necrotic caseous TB lung lesions and kills nongrowing, drug-tolerant bacilli. Furthermore, it was uncovered that PZA inhibits bacterial Coenzyme A biosynthesis. It may block this pathway by triggering degradation of its target, aspartate decarboxylase. The elucidation of the pharmacological and molecular mechanisms of PZA provides the basis for the rational discovery of the next-generation PZA with improved in vitro potency while maintaining attractive pharmacological properties.
Topics: Animals; Antitubercular Agents; Humans; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis
PubMed: 31704175
DOI: 10.1016/j.tips.2019.10.005 -
Antimicrobial Agents and Chemotherapy Jul 2018The 4-drug regimen of rifampin, isoniazid, pyrazinamide, and ethambutol is an inexpensive, reliable option for treating patients with drug-susceptible tuberculosis (TB)....
The 4-drug regimen of rifampin, isoniazid, pyrazinamide, and ethambutol is an inexpensive, reliable option for treating patients with drug-susceptible tuberculosis (TB). Its efficacy could be further improved by determining the free drug concentrations in plasma, knowing that only the unbound drug can freely penetrate to the tissues. Using an ultrafiltration technique, we determined the protein binding (PB) extent and variability of the first-line anti-TB drugs when given simultaneously to TB patients, representing a real-life case scenario. We used clinical samples routinely received by our laboratory. Plasma proteins were also measured. A protein-free medium was used to determine the nonspecific binding. Plasma samples from 22 patients were included, of which plasma proteins were measured for 18 patients. The median PB was determined for rifampin (88%; range, 72 to 91%), isoniazid (14%; range, 0 to 34%), pyrazinamide (1%; range, 0 to 7%), and ethambutol (12%; range, 4 to 24%). Plasma proteins were not found to be significant predictors for the PB of first-line anti-TB drugs. Rifampin PB was positively correlated with its plasma concentration ( value = 0.0051). Conversely, isoniazid PB was negatively correlated with its plasma concentration ( value = 0.0417). Age was found to have a significant effect on isoniazid PB ( value = 0.0376). No correlations were observed in pyrazinamide or ethambutol. In conclusion, we have determined variable PB of rifampin, isoniazid, pyrazinamide, and ethambutol in patient plasma samples, with median values of 88, 14, 1, and 12%, respectively. In this small study, PB of rifampin and that of isoniazid are dependent on their plasma concentrations.
Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Protein Binding; Pyrazinamide; Rifampin; Tuberculosis
PubMed: 29735566
DOI: 10.1128/AAC.00641-18 -
Pyrazinamide and Pyrazinoic Acid Derivatives Directed to Mycobacterial Enzymes Against Tuberculosis.Current Protein & Peptide Science 2016Tuberculosis (TB) is an infectious diseases responsible for thousands of deaths worldwide. Due to the use of antimycobacterial drugs, TB prevalence seemed to be... (Review)
Review
Tuberculosis (TB) is an infectious diseases responsible for thousands of deaths worldwide. Due to the use of antimycobacterial drugs, TB prevalence seemed to be controlled, but with the appearance of resistant tuberculosis cases, the concern about the disease had become significant again, as well as the need for new alternatives to TB treatment. Since pyrazinamide (PZA) is part of the firstline agents in TB treatment, several derivatives of this drug were described, besides pyrazinoic acid (POA) derivatives, the active form of PZA. POA has been used mainly to design prodrugs to be activated by mycobacterial esterases, while PZA derivatives should be activated specifically by the nicotinamidase/ pyrazinamidase (PZAse), or other PZAse-independent pathways. The intention of this paper is to discuss the state of art of PZA and POA derivatives and their activity against Mycobacterium tuberculosis and other mycobacteria, besides the therapeutic potential. Focus was given in prodrugs and derivatives directed to mycobacterial enzymes involved in its activation or mechanism of action.
Topics: Animals; Anti-Bacterial Agents; Humans; Mycobacterium tuberculosis; Prodrugs; Pyrazinamide; Tuberculosis
PubMed: 26427385
DOI: 10.2174/1389203716666151002114839 -
Journal of Clinical Pharmacology Oct 2022Patients with tuberculosis (TB) coinfected with HIV are more likely to have low blood concentrations of the first-line anti-TB drugs (associated with poor outcomes)....
Patients with tuberculosis (TB) coinfected with HIV are more likely to have low blood concentrations of the first-line anti-TB drugs (associated with poor outcomes). Therapeutic drug monitoring (TDM) is recommended for certain patient populations with TB at increased risk for a poor outcome. Our objective was to estimate the diagnostic accuracy of a 2-hour TDM serum sample for the first-line anti-TB drugs among patients with HIV/TB and evaluate the information gained by an additional 6-hour sample. We created a virtual (n = 1000) HIV/TB patient population and performed pharmacokinetic simulations using published population models for isoniazid, rifampin, pyrazinamide, and ethambutol. We performed receiver operating characteristic analysis to compare the diagnostic performance of a single 2-hour serum sample with samples obtained at 2 and 6 hours after dosing. The sensitivity of a single 2-hour serum concentration to identify patients with HIV/TB with adequate serum exposures was lowest for rifampin (54.9%; 95%CI, 50.79%-59.41%) and highest for ethambutol (70.8%; 95%CI, 66.06%-72.61%) for maximum concentration (C ) targets. Diagnostic accuracy of a single 2-hour serum sample for the area under the concentration-time curve (AUC) from time 0 to 24 hours target was highest for isoniazid (93%; 95%CI, 90.9%-94.1%) and lowest for pyrazinamide (66.3%; 95%CI, 62.6%-70.0%). In summary, the diagnostic performance of TDM for C and AUC from time 0 to 24 hours targets demonstrated variability across the first-line anti-TB drugs. The addition of a 6-hour serum sample led to the highest statistically significant improvement (P < .001) and highest increase in diagnostic accuracy (area under the receiver operating characteristic curve) for rifampin for C and AUC. The other first-line drugs had modest/negligible increases in diagnostic accuracy.
Topics: Antitubercular Agents; Drug Monitoring; Ethambutol; HIV Infections; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis
PubMed: 35588142
DOI: 10.1002/jcph.2068 -
International Journal of Antimicrobial... Dec 2023Data on protein binding are incomplete for first-line antituberculosis drugs, and lacking for second-line antituberculosis drugs that are used extensively for...
Data on protein binding are incomplete for first-line antituberculosis drugs, and lacking for second-line antituberculosis drugs that are used extensively for multi-drug-resistant tuberculosis (levofloxacin, linezolid and moxifloxacin). Thus, the main purposes of this study were to investigate: (i) the relationship between carrier protein concentration and drug binding; and (ii) the feasibility of predicting free drug concentration using in-vitro and in-vivo results. In-vitro experiments were performed on spiked plasma mimicking real-case samples (drug combinations from clinical practice). Median in-vivo protein binding was 1.5% for ethambutol, 9.7% for isoniazid, 0.7% for pyrazinamide and 88.2% for rifampicin; and median in-vitro protein binding was 26.2% for levofloxacin, 12.8% for linezolid and 46.3% for moxifloxacin. Albumin concentration (<30 g/L) had a moderate impact on moxifloxacin binding and a strong impact on levofloxacin, linezolid and rifampicin binding. Determination of the free drug concentration seems to be of little value for ethambutol, isoniazid, moxifloxacin and pyrazinamide; limited value for linezolid because of its low binding; and major value for rifampicin in hypoalbuminaemic patients with tuberculosis, and levofloxacin because total concentration was an inaccurate reflection of free concentration. The free concentration predicted by the mathematical model was suitable for levofloxacin and linezolid, whereas the real free concentration should be measured for rifampicin. Further investigations should be carried out to investigate the benefit of using free concentration for levofloxacin, linezolid and rifampicin, particularly in the critical period of active tuberculosis associated with hypoalbuminaemia.
Topics: Humans; Antitubercular Agents; Isoniazid; Linezolid; Rifampin; Ethambutol; Pyrazinamide; Levofloxacin; Moxifloxacin; Protein Binding; Tuberculosis
PubMed: 37838149
DOI: 10.1016/j.ijantimicag.2023.106999 -
International Journal of... 2020Because pyrazinamide (PZA) is only effective for Mycobacterium tuberculosis at an acidic pH, susceptibility tests are more difficult to perform than those for other...
BACKGROUND
Because pyrazinamide (PZA) is only effective for Mycobacterium tuberculosis at an acidic pH, susceptibility tests are more difficult to perform than those for other anti-tuberculosis (TB) drugs. The purpose of our work was to investigate the effectiveness of colorimetric methods to detect PZA susceptibility and to detect pncA gene mutations in resistant isolates by sequence analysis.
METHODS
In this study, 30 clinical isolates and 2 reference isolates were used, 15 of which were resistant to PZA. The PZA susceptibility of all the isolates was determined by the BACTEC MGIT 960 reference method. As colorimetric methods, Resazurin Microtiter Assay (REMA), Nitrate Reductase Assay (NRA), Malachite Green Decolorization Assay (MGDA), and Crystal Violet Decolorization Assay (CVDA) methods were included in the study. In addition, mutations in the pncA gene were investigated using sequence analysis in PZA-resistant isolates.
RESULTS
As a result of the comparison of the colorimetric methods with the reference method, agreement was determined as 93.3% in REMA and NRA, 90% in MGDA, and 93.3% in CVDA. In 13 of 15 resistant isolates, the pncA gene mutation was detected by sequence analysis.
CONCLUSIONS
As a result of the work, the results from the colorimetric methods were found to be at a high level of concordance with the reference method. They are also inexpensive and easily applicable methods.
Topics: Amidohydrolases; Colorimetry; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Oxazines; Pyrazinamide; Sequence Analysis, DNA; Tuberculosis, Multidrug-Resistant; Xanthenes
PubMed: 32862160
DOI: 10.4103/ijmy.ijmy_42_20