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Pharmaceutics
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Optimization of Tuberculosis Drugs and Treatment Strategies to End Tuberculosis...
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Optimization of Tuberculosis Drugs and Treatment Strategies to End Tuberculosis (TB)

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (20 March 2024) | Viewed by 5773

Special Issue Editors

Prof. Dr. Jan-Willem Alffenaar

E-Mail Website
Guest Editor
1. School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
2. Westhead Hospital, West Mead, NSW 2145, Australia
3. Sydney Institute of Infectious Diseases, The University of Sydney, Camperdown, NSW 2006, Australia
Interests: tuberculosis; pharmacokinetics; pharmacodynamics; therapeutic drug monitoring; clinical trials; personalized dosing
Dr. Lina Davies Forsman

E-Mail Website
Guest Editor
1. Department of Infectious Diseases, Karolinska University Hospital, 10176 Stockholm, Sweden
2. Department of Medicine, Division of Infectious Diseases, Karolinska Institutet, 10176 Solna, Sweden
Interests: tuberculosis; non-tuberculous mycobacteria; therapeutic drug monitoring and precision medicine; randomized controlled trials; minimum inhibitory concentrations; global health
Dr. Jin-Gun Cho

E-Mail Website
Guest Editor
1. Department of Respiratory and Sleep Medicine, Westmead Clinical School, University of Sydney, Faculty of Medicine and Health, Westmead, NSW 2145, Australia
2. Parramatta Chest Clinic, Western Sydney Local Health District, Sydney, NSW 2150, Australia
Interests: tuberculosis; respiratory diseases; evidence-based medicine; clinical trials; pulmonary rehabilitation
Dr. Andrew Burke

E-Mail Website
Guest Editor
1. The Prince Charles Hospital, Brisbane, QLD 4032, Australia
2. Faculty of Medicine, University of Queensland Centre for Clinical Research, Brisbane, QLD 4032, Australia
Interests: tuberculosis; pharmacokinetics; therapeutic drug monitoring; non-tuberculous mycobacteria; real world trials

Special Issue Information

Dear Colleagues,

Tuberculosis remains a global health tread. Significant progress has been made in the development of three new anti-TB drugs (bedaquiline, delamanid and pretomanid), and several other drugs are undergoing preclinical or clinical development. Strategies to develop shorter regimens using different dosing strategies of available TB drugs have been evaluated in large trials for preventative treatment, drug-susceptible TB as well as drug-resistant TB. In addition, in vitro and in vivo models as well as modeling and simulation have resulted in a better understanding of how treatment outcome can be improved. This Special Issue of Pharmaceutics is dedicated to presenting the latest evidence and information on new drugs and drug trials, drug dose optimization strategies and tools to support the management of TB treatment to ensure that it is safe and effective.

Prof. Dr. Jan-Willem Alffenaar
Dr. Lina Davies Forsman
Dr. Jin-Gun Cho
Dr. Andrew Burke
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tuberculosis
  • drug development
  • pharmacokinetics
  • pharmacogenetics
  • pharmacodynamics
  • drug formulation
  • clinical trials
  • treatment outcome

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Published Papers (4 papers)

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12 pages, 271 KiB  
Article
Determination of NAT2 Genotypes in a Cohort of Patients with Suspected TB in the State of Rio de Janeiro
by Cecília Alvim Dutra, Raquel Lima de Figueiredo Teixeira, Márcia Quinhones Pires Lopes, Victória de Moraes Silva, Philip Noel Suffys, Ricardo de Souza Carvalho, Adriana Rezende Moreira, Adalberto Rezende Santos and Afrânio Lineu Kritski
Pharmaceutics 2024, 16(7), 917; https://doi.org/10.3390/pharmaceutics16070917 - 10 Jul 2024
Viewed by 432
Abstract
The human N-acetyltransferase 2 enzyme, encoded by the NAT2 gene, plays an important role in the metabolism of isoniazid, the main drug used to treat tuberculosis. The interindividual variation in the response of patients to drug treatment for tuberculosis may be responsible for [...] Read more.
The human N-acetyltransferase 2 enzyme, encoded by the NAT2 gene, plays an important role in the metabolism of isoniazid, the main drug used to treat tuberculosis. The interindividual variation in the response of patients to drug treatment for tuberculosis may be responsible for the occurrence of unfavorable outcomes. The presence of polymorphisms in genes associated with the metabolism and transport of drugs, receptors, and therapeutic targets has been identified as a major determinant of this variability. The objective of this study was to identify the genetic profile of NAT2 in the study population. Using the obtained genomic DNA followed by PCR amplification and sequencing, the frequency of nine SNPs as well as alleles associated with slow (47.9%), intermediate (38.7%), and fast acetylation phenotypes (11.3%), in addition to those whose phenotype has not yet been characterized (2.1%), was estimated. The NAT2*5B allele was identified more frequently (31.3%). The description of SNPs in pharmacogenes and the establishment of their relationship with the pharmacokinetics of an individual offer an individualized approach that allows us to reduce the unfavorable outcomes of a therapy, ensure better adherence to treatment, prevent the emergence of MDR strains, reduce the cost of treatment, and improve the quality of patients’ lives. Full article
(This article belongs to the Special Issue Optimization of Tuberculosis Drugs and Treatment Strategies to End Tuberculosis (TB))
15 pages, 4711 KiB  
Article
Drug Exposure and Susceptibility of Pyrazinamide Correlate with Treatment Response in Pyrazinamide-Susceptible Patients with Multidrug-Resistant Tuberculosis
by Shulan Dong, Ge Shao, Lina Davies Forsman, Sainan Wang, Shanshan Wang, Jiayi Cao, Ziwei Bao, Judith Bruchfeld, Jan-Willem C. Alffenaar, Jia Liu, Yi Hu and Meiying Wu
Pharmaceutics 2024, 16(1), 144; https://doi.org/10.3390/pharmaceutics16010144 - 21 Jan 2024
Cited by 1 | Viewed by 1137
Abstract
Exploring the influence of pyrazinamide exposure and susceptibility on treatment response is crucial for optimizing the management of multidrug-resistant tuberculosis (MDR-TB). This study aimed to investigate the association between pyrazinamide exposure, susceptibility, and response to MDR-TB treatment, as well as find clinical thresholds [...] Read more.
Exploring the influence of pyrazinamide exposure and susceptibility on treatment response is crucial for optimizing the management of multidrug-resistant tuberculosis (MDR-TB). This study aimed to investigate the association between pyrazinamide exposure, susceptibility, and response to MDR-TB treatment, as well as find clinical thresholds for pyrazinamide. A prospective multi-center cohort study of participants with MDR-TB using pyrazinamide was conducted in three TB-designated hospitals in China. Univariate and multivariate analyses were applied to investigate the associations. Classification and Regression Tree (CART) analysis was used to identify clinical thresholds, which were further evaluated by multivariate analysis and receiver operating characteristic (ROC) curves. The study included 143 patients with MDR-TB. The exposure/susceptibility ratio of pyrazinamide was associated with two-month culture conversion (adjusted risk ratio (aRR), 1.1; 95% confidence interval (CI), 1.07–1.20), six-month culture conversion (aRR, 1.1; 95% CI, 1.06–1.16), treatment success (aRR, 1.07; 95% CI, 1.03–1.10), as well as culture conversion time (adjusted hazard ratio (aHR) 1.18; 95% CI,1.14–1.23). The threshold for optimal improvement in sputum culture results at the sixth month of treatment was determined to be a pyrazinamide AUC0–24h/MIC ratio of 7.8. In conclusion, the exposure/susceptibility ratio of pyrazinamide is associated with the treatment response of MDR-TB, which may change in different Group A drug-based regimens. Full article
(This article belongs to the Special Issue Optimization of Tuberculosis Drugs and Treatment Strategies to End Tuberculosis (TB))
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23 pages, 2367 KiB  
Article
A Single-Run HPLC–MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis
by Niklas Köhler, Hande Karaköse, Hans-Peter Grobbel, Doris Hillemann, Sönke Andres, Christina König, Barbara Kalsdorf, Thomas Theo Brehm, Laura Böttcher, Inna Friesen, Harald Hoffmann, Dražen Strelec, Dagmar Schaub, Charles A. Peloquin, Stefan Schmiedel, Laurent A. Decosterd, Eva Choong, Sebastian G. Wicha, Rob E. Aarnoutse, Christoph Lange and Patricia M. Sánchez Carballoadd Show full author list remove Hide full author list
Pharmaceutics 2023, 15(11), 2543; https://doi.org/10.3390/pharmaceutics15112543 - 27 Oct 2023
Cited by 1 | Viewed by 1807
Abstract
The treatment of drug-resistant Mycobacterium tuberculosis relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we [...] Read more.
The treatment of drug-resistant Mycobacterium tuberculosis relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we aimed to develop a single-run multiplex assay using high-performance liquid chromatography–mass spectrometry (HPLC–MS) for TDM of patients with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis. A target profile for sufficient performance, based on the intended clinical application, was established and the assay was developed accordingly. Antibiotics were analyzed on a zwitterionic hydrophilic interaction liquid chromatography column and a triple quadrupole mass spectrometer using stable isotope-labeled internal standards. The assay was sufficiently sensitive to monitor drug concentrations over five half-lives for rifampicin, rifabutin, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, terizidone/cycloserine, ethambutol, delamanid, pyrazinamide, meropenem, prothionamide, and para-amino salicylic acid (PAS). Accuracy and precision were sufficient to support clinical decision making (≤±15% in clinical samples and ±20–25% in spiked samples, with 80% of future measured concentrations predicted to fall within ±40% of nominal concentrations). The method was applied in the TDM of two patients with complex drug-resistant tuberculosis. All relevant antibiotics from their regimens could be quantified and high-dose therapy was initiated, followed by microbiological conversion. In conclusion, we developed a multiplex assay that enables TDM of the relevant first- and second-line anti-tuberculosis medicines in a single run and was able to show its applicability in TDM of two drug-resistant tuberculosis patients. Full article
(This article belongs to the Special Issue Optimization of Tuberculosis Drugs and Treatment Strategies to End Tuberculosis (TB))
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13 pages, 770 KiB  
Systematic Review
Impact of Whole-Genome Sequencing of Mycobacterium tuberculosis on Treatment Outcomes for MDR-TB/XDR-TB: A Systematic Review
by Druti Hazra, Connie Lam, Kiran Chawla, Vitali Sintchenko, Vijay Shree Dhyani and Bhumika T. Venkatesh
Pharmaceutics 2023, 15(12), 2782; https://doi.org/10.3390/pharmaceutics15122782 - 15 Dec 2023
Cited by 1 | Viewed by 1616
Abstract
The emergence and persistence of drug-resistant tuberculosis is a major threat to global public health. Our objective was to assess the applicability of whole-genome sequencing (WGS) to detect genomic markers of drug resistance and explore their association with treatment outcomes for multidrug-resistant/extensively drug-resistant [...] Read more.
The emergence and persistence of drug-resistant tuberculosis is a major threat to global public health. Our objective was to assess the applicability of whole-genome sequencing (WGS) to detect genomic markers of drug resistance and explore their association with treatment outcomes for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB). Methods: Five electronic databases were searched for studies published in English from the year 2000 onward. Two reviewers independently conducted the article screening, relevant data extraction, and quality assessment. The data of the included studies were synthesized with a narrative method and are presented in a tabular format. Results: The database search identified 949 published articles and 8 studies were included. An unfavorable treatment outcome was reported for 26.6% (488/1834) of TB cases, which ranged from 9.7 to 51.3%. Death was reported in 10.5% (194/1834) of total cases. High-level fluoroquinolone resistance (due to gyrA 94AAC and 94GGC mutations) was correlated as the cause of unfavorable treatment outcomes and reported in three studies. Other drug resistance mutations, like kanamycin high-level resistance mutations (rrs 1401G), rpoB Ile491Phe, and ethA mutations, conferring prothionamide resistance were also reported. The secondary findings from this systematic review involved laboratory aspects of WGS, including correlations with phenotypic DST, cost, and turnaround time, or the impact of WGS results on public health actions, such as determining transmission events within outbreaks. Conclusions: WGS has a significant capacity to provide accurate and comprehensive drug resistance data for MDR/XDR-TB, which can inform personalized drug therapy to optimize treatment outcomes. Full article
(This article belongs to the Special Issue Optimization of Tuberculosis Drugs and Treatment Strategies to End Tuberculosis (TB))
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