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BMJ Open Oct 2018Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective...
Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study.
INTRODUCTION
Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in multidrug-resistant TB (MDR-TB) are scarce. This translational study aims to characterise the area under the concentration-time curve of individual MDR-TB drugs, divided by the MIC for isolates, to explore associations with markers of treatment progress and to develop useful strategies for clinical implementation of TDM in MDR-TB.
METHODS AND ANALYSIS
Adult patients with pulmonary MDR-TB treated in Xiamen, China, are included. Plasma samples for measure of drug exposure are obtained at 0, 1, 2, 4, 6, 8 and 10 hours after drug intake at week 2 and at 0, 4 and 6 hours during weeks 4 and 8. Sputum samples for evaluating time to culture positivity and MIC determination are collected at days 0, 2 and 7 and at weeks 2, 4, 8 and 12 after treatment initiation. Disease severity are assessed with a clinical scoring tool (TBscore II) and quality of life evaluated using EQ-5D-5L. Drug concentrations of pyrazinamide, ethambutol, levofloxacin, moxifloxacin, cycloserine, prothionamide and para-aminosalicylate are measured by liquid chromatography tandem-mass spectrometry and the levels of amikacin measured by immunoassay. Dried blood spot on filter paper, to facilitate blood sampling for analysis of drug concentrations, is also evaluated. The MICs of the drugs listed above are determined using custom-made broth microdilution plates and MYCOTB plates with Middlebrook 7H9 media. MIC determination of pyrazinamide is performed in BACTEC MGIT 960.
ETHICS AND DISSEMINATION
This study has been approved by the ethical review boards of Karolinska Institutet, Sweden and Fudan University, China. Informed written consent is given by participants. The study results will be submitted to a peer-reviewed journal.
TRIAL REGISTRATION NUMBER
NCT02816931; Pre-results.
Topics: Adult; Female; Humans; Male; Antitubercular Agents; China; Cohort Studies; Drug Monitoring; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prospective Studies; Serum Bactericidal Test; Tuberculosis, Multidrug-Resistant; Observational Studies as Topic
PubMed: 30287613
DOI: 10.1136/bmjopen-2018-023899 -
Antimicrobial Agents and Chemotherapy Dec 2018Short-course regimens for multidrug-resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug bedaquiline (BDQ) may have the potential...
Short-course regimens for multidrug-resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug bedaquiline (BDQ) may have the potential to shorten MDR-TB treatment to less than 6 months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modeling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modeling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (4 months) while still maintaining a very high treatment success rate (100% for daily BDQ for 2 weeks, or 95% for daily BDQ for 1 week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes, then we anticipate clear cost savings and a subsequent improvement in the efficiency of national TB programs.
Topics: Antitubercular Agents; Clofazimine; Colony Count, Microbial; Computer Simulation; Diarylquinolines; Dose-Response Relationship, Drug; Drug Dosage Calculations; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Host-Pathogen Interactions; Humans; Immunity, Innate; Isoniazid; Kanamycin; Macrophages; Microbial Sensitivity Tests; Models, Statistical; Moxifloxacin; Mycobacterium tuberculosis; Ofloxacin; Prothionamide; Pyrazinamide; Time Factors; Tuberculosis, Multidrug-Resistant
PubMed: 30249697
DOI: 10.1128/AAC.01487-18 -
Antimicrobial Agents and Chemotherapy Sep 2018The substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of...
The substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for SLC family transporter-mediated uptake, using oocytes and stably transfected HEK-293 cells The result suggested that ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. A cellular uptake study was performed, and the values of ethambutol were found to be 526.1 ± 15.6, 212.0 ± 20.1, 336.8 ± 20.1, and 455.0 ± 28 μM for organic cation transporter 1 (OCT1), OCT2, OCTN1, and OCTN2, respectively. Similarly, the of prothionamide was 805.8 ± 23.4 μM for OCT1, while the values of isoniazid and amoxicillin for organic anion transporter 3 (OAT3) were 233.7 ± 14.1 and 161.4 ± 10.6 μM, respectively. The estimated drug-drug interaction indexes from transporter inhibition kinetics for verapamil, probenecid, and ibuprofen against ethambutol, prothionamide, isoniazid, and amoxicillin were found to show potential for clinical drug interactions. In conclusion, this is the first study that demonstrated 22 antituberculosis drug interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions, and pharmacokinetics of these antituberculosis drugs.
PubMed: 30012768
DOI: 10.1128/AAC.00512-18 -
Infection and Drug Resistance 2018Ethionamide (ETA) and prothionamide (PRO) are interchangeably used in tuberculosis (TB) chemotherapy regimens. Subtle discrepancies between biochemical and genetic...
Ethionamide (ETA) and prothionamide (PRO) are interchangeably used in tuberculosis (TB) chemotherapy regimens. Subtle discrepancies between biochemical and genetic information on the modes of sensitivity and resistance of isoniazid (INH) and ETA warrants further studies. We report a new mutation - EthA - in Bacillus Calmette-Guérin that corresponds with co-resistance to both PRO and ETA, which to the best of our knowledge has not been reported before. Our findings suggest that mutation EthA could be used as a marker site for testing PRO and ETA cross-resistance.
PubMed: 29942141
DOI: 10.2147/IDR.S163965 -
PloS One 2018Prothionamide (PTH), a second line antitubercular drug is used to administer in conventional oral route. However, its unpredictable absorption and frequent...
Prothionamide (PTH), a second line antitubercular drug is used to administer in conventional oral route. However, its unpredictable absorption and frequent administration limit its use. An alternate approach was thought of administering PTH through pulmonary route in a form of nanoparticles, which can sustain the release for several hours in lungs. Chitosan, a bio-degradable polymer was used to coat PTH and further freeze dried to prepare dry powder inhaler (DPI) with aerodynamic particle size of 1.76μm. In vitro release study showed initial burst release followed by sustained release up to 96.91% in 24h. In vitro release further correlated with in vivo study. Prepared DPI maintained the PTH concentration above MIC for more than 12h after single dose administration and increased the PTH residency in the lungs tissue more than 24h. Animal study also revealed the reduction of dose in pulmonary administration, which will improve the management of tuberculosis.
Topics: Animals; Chitosan; Nanoparticles; Particle Size; Powders; Prothionamide
PubMed: 29370192
DOI: 10.1371/journal.pone.0190976 -
The European Respiratory Journal Dec 2017A clear understanding of the genetic basis of antibiotic resistance in is required to accelerate the development of rapid drug susceptibility testing methods based on...
A clear understanding of the genetic basis of antibiotic resistance in is required to accelerate the development of rapid drug susceptibility testing methods based on genetic sequence.Raw genotype-phenotype correlation data were extracted as part of a comprehensive systematic review to develop a standardised analytical approach for interpreting resistance associated mutations for rifampicin, isoniazid, ofloxacin/levofloxacin, moxifloxacin, amikacin, kanamycin, capreomycin, streptomycin, ethionamide/prothionamide and pyrazinamide. Mutation frequencies in resistant and susceptible isolates were calculated, together with novel statistical measures to classify mutations as high, moderate, minimal or indeterminate confidence for predicting resistance.We identified 286 confidence-graded mutations associated with resistance. Compared to phenotypic methods, sensitivity (95% CI) for rifampicin was 90.3% (89.6-90.9%), while for isoniazid it was 78.2% (77.4-79.0%) and their specificities were 96.3% (95.7-96.8%) and 94.4% (93.1-95.5%), respectively. For second-line drugs, sensitivity varied from 67.4% (64.1-70.6%) for capreomycin to 88.2% (85.1-90.9%) for moxifloxacin, with specificity ranging from 90.0% (87.1-92.5%) for moxifloxacin to 99.5% (99.0-99.8%) for amikacin.This study provides a standardised and comprehensive approach for the interpretation of mutations as predictors of drug-resistant phenotypes. These data have implications for the clinical interpretation of molecular diagnostics and next-generation sequencing as well as efficient individualised therapy for patients with drug-resistant tuberculosis.
Topics: Antitubercular Agents; Bacterial Proteins; DNA, Bacterial; Data Interpretation, Statistical; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Phenotype; Sequence Analysis, DNA; Systematic Reviews as Topic; Tuberculosis, Multidrug-Resistant
PubMed: 29284687
DOI: 10.1183/13993003.01354-2017 -
The American Journal of Tropical... Feb 2018A Syrian asylum seeker with multidrug-resistant tuberculosis (TB) developed a bronchopleural fistula after pneumonectomy. Although screening tests were negative on...
A Syrian asylum seeker with multidrug-resistant tuberculosis (TB) developed a bronchopleural fistula after pneumonectomy. Although screening tests were negative on admission, carbapenemase-producing Enterobacteriaceae were cultured after a few months of TB treatment. Prevalence of multidrug-resistant organisms is reported to be increased in asylum seekers compared with the general Dutch population. Arduous conditions during transit and interrupted health care delivery in our patient led to multiple-resistant microorganisms that complicated treatment.
Topics: Adult; Amikacin; Carbapenem-Resistant Enterobacteriaceae; Clofazimine; Drug Monitoring; Humans; Linezolid; Male; Moxifloxacin; Netherlands; Prevalence; Prothionamide; Refugees; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant
PubMed: 29280429
DOI: 10.4269/ajtmh.17-0544 -
Frontiers in Microbiology 2017Prothionamide (PTH) has been widely used in the treatment of tuberculosis (TB), especially multidrug resistant tuberculosis (MDR-TB), while data regarding prevalence of...
Prothionamide (PTH) has been widely used in the treatment of tuberculosis (TB), especially multidrug resistant tuberculosis (MDR-TB), while data regarding prevalence of resistance-causing mutation is limited. In this study, we aimed to investigate the molecular characteristics of PTH-resistant MTB isolates, and also analyzed the risk factors for PTH resistance among (MTB) isolates in southern China. A total of 282 MTB isolates were enrolled in from Guangzhou Chest Hospital. Among these isolates, 46 (16.3%) were resistant to PTH. Statistical analysis revealed that PTH resistance was more likely to be associated with resistance to levofloxacin (LFX; OR: 2.18, 95% CI: 1.02-4.63; = 0.04). Of the 46 PTH-resistant MTB isolates, 37 (80.4%) isolates harbored 19 different mutation types, including 10 (21.7%) isolates with double nucleotide substitutions and 27 (58.7%) with single nucleotide substitution. The mutations in ethA (51.4%, 19/37) were most frequently observed among PTH-resistant isolates, followed by 16 (43.2%) in the promoter of inhA and 6 (16.2%) in inhA. In addition, no significant difference was found in the distribution of isolates with different mutation types between Beijing and non-Beijing genotypes ( > 0.05). In conclusion, our data demonstrate that high diversity of genetic mutations conferring PTH resistance is identified among MTB isolates from southern China. Mutations in inhA, ethA, mshA, and ndh genes confer increased resistance of MTB to PTH. Ancient Beijing genotype strains have higher proportion of drug resistance compared with modern Beijing strains. In addition, PTH resistance is more likely to be observed in the LFX-resistant MTB isolates.
PubMed: 29250048
DOI: 10.3389/fmicb.2017.02358 -
Antimicrobial Agents and Chemotherapy Feb 2018Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant...
Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant tuberculosis (MDR-TB) that is resistant to ofloxacin but susceptible to moxifloxacin. The purpose of the present study was to evaluate whether later-generation fluoroquinolones can improve treatment outcomes in patients with ofloxacin-resistant, moxifloxacin-susceptible MDR-TB. A retrospective cohort study was performed on 208 patients with moxifloxacin-susceptible MDR-TB who were treated between 2006 and 2011. Later-generation fluoroquinolones were used for all patients. Overall, 171 patients (82%) had ofloxacin-susceptible, moxifloxacin-susceptible MDR-TB (ofloxacin-susceptible group), and 37 (18%) had ofloxacin-resistant, moxifloxacin-susceptible MDR-TB (ofloxacin-resistant group). Compared to the ofloxacin-susceptible group, the ofloxacin-resistant group was more likely to have a history of MDR-TB treatment ( < 0.001) and cavitary lesions on chest radiography ( < 0.001). In addition, the ofloxacin-resistant group was more likely than the ofloxacin-susceptible group to have resistance to the drugs pyrazinamide ( = 0.003), streptomycin ( = 0.015), prothionamide ( < 0.001), and para-aminosalicylic acid ( < 0.001). Favorable outcomes were more frequently achieved for the ofloxacin-susceptible group than for the ofloxacin-resistant group (91% [156/171] versus 57% [21/37], respectively [ < 0.001]). In multivariable regression logistic analysis, the ofloxacin-susceptible group was about 5.36 (95% confidence interval, 1.55 to 18.53) times more likely than the ofloxacin-resistant group ( < 0.001) to have favorable outcomes. Despite moxifloxacin susceptibility, the frequency of favorable treatment outcomes for ofloxacin-resistant MDR-TB was significantly lower than that for ofloxacin-susceptible MDR-TB, even when later-generation fluoroquinolones were used, indicating that more-aggressive therapies may be needed for ofloxacin-resistant MDR-TB.
Topics: Adult; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Female; Fluoroquinolones; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Moxifloxacin; Mycobacterium tuberculosis; Ofloxacin; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 29203478
DOI: 10.1128/AAC.01784-17 -
Respiratory Medicine Oct 2017Rifampin (RIF) mono-resistant tuberculosis (RMR-TB) is a rare disease. Current guidelines recommend that RMR-TB be treated as multidrug-resistant TB (MDR-TB) but the...
Treatment outcomes of rifampin-sparing treatment in patients with pulmonary tuberculosis with rifampin-mono-resistance or rifampin adverse events: A retrospective cohort analysis.
BACKGROUND
Rifampin (RIF) mono-resistant tuberculosis (RMR-TB) is a rare disease. Current guidelines recommend that RMR-TB be treated as multidrug-resistant TB (MDR-TB) but the evidence is scarce.
METHODS
We conducted a retrospective cohort study on pulmonary TB patients to investigate the characteristics and outcomes of RMR-TB. The characteristics of RMR-TB were compared with those with adverse events to rifampin (RAE-TB).
RESULTS
Forty-four RMR-TB and 29 RAE-TB patients were enrolled. RMR-TB patients showed more alcohol use, prior history of TB, and radiologically severe disease, while RAE-TB patients were older and had more comorbidities and combined extrapulmonary TB. A fluoroquinolone (FQ) was the drug most commonly added (70.5%, RMR-TB; 82.8%, RAE-TB). Median treatment duration was 453 days in RMR-TB and 371 days in RAE-TB (p = 0.001) and treatment success rates were 87.2% (34/39) and 80.0% (20/25), respectively (p = 0.586). Subanalysis of the RMR-TB group by treatment regimen (standard regimen [n = 11], standard regimen + FQ [n = 12], MDR-TB regimen [n = 21]) revealed a higher rate of radiologically severe disease in the MDR-TB subgroup, with similar treatment success rates for the subgroups (85.7% [6/7]), 91.7% [11/12], and 85.0% [17/20], respectively) despite different durations of treatment (345, 405, and 528 days, respectively). Two recurrences (33.3% [2/6]) developed only in standard regimen subgroup, suggesting that standard regimen is not enough to treat RMR-TB patients.
CONCLUSIONS
The treatment outcome of RMR-TB with 1-line drugs + FQ was comparable to that of MDR-TB regimen. Shorter treatment duration may be considered for RMR-TB patients compared with MDR-TB patients.
Topics: Adult; Age Distribution; Aged; Alcohol Drinking; Aminosalicylic Acid; Antitubercular Agents; Cohort Studies; Comorbidity; Cycloserine; Ethambutol; Female; Fluoroquinolones; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Prothionamide; Pyrazinamide; Republic of Korea; Retrospective Studies; Rifampin; Severity of Illness Index; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary
PubMed: 28947041
DOI: 10.1016/j.rmed.2017.08.002