scholarly journals Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis

2020 ◽  
Author(s):  
Wael A Alghamdi ◽  
Mohammad H Al-Shaer ◽  
Maia Kipiani ◽  
Ketevan Barbakadze ◽  
Lali Mikiashvili ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Strong Association ◽  
Compartmental Analysis ◽  
Multidrug Resistant ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Drug Resistant ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Liquid Chromatography Tandem Mass

Abstract Background Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use. Objectives To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis. Methods A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4–6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored. Results Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0–24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0–12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine. Conclusions We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.

scholarly journals Effect of tablet crushing on drug exposure in the treatment of multidrug-resistant tuberculosis

2019 ◽  
Vol 23 (10) ◽  
pp. 1068-1074 ◽  
Author(s):  
R. Court ◽  
M. T. Chirehwa ◽  
L. Wiesner ◽  
N. de Vries ◽  
J. Harding ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Geometric Mean ◽  
Area Under The Curve ◽  
Compartmental Analysis ◽  
Multidrug Resistant ◽  
Geometric Mean Ratio ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

SETTING: Treatment outcomes in multidrug-resistant tuberculosis (MDR-TB) are poor. Due to drug toxicity and a long treatment duration, approximately half of patients are treated successfully. Medication is often crushed for patients who have difficulty swallowing whole tablets. Whether crushing tablets affects drug exposure in MDR-TB treatment is not known.OBJECTIVE AND DESIGN: We performed a sequential pharmacokinetic study in patients aged >18 years on MDR-TB treatment at two hospitals in Cape Town, South Africa. We compared the bioavailability of pyrazinamide, moxifloxacin, isoniazid (INH), ethambutol and terizidone when the tablets were crushed and mixed with water before administration vs. swallowed whole. We sampled blood at six time points over 10 h under each condition separated by 2 weeks. Non-compartmental analysis was used to derive the key pharmacokinetic measurements.RESULTS: Twenty participants completed the study: 15 were men, and the median age was 31.5 years. There was a 42% reduction in the area under the curve AUC0–10 of INH when the tablets were crushed compared with whole tablets (geometric mean ratio 58%; 90%CI 47–73). Crushing tablets of pyrazinamide, moxifloxacin, ethambutol and terizidone did not affect the bioavailability significantly.CONCLUSION: We recommend that crushing of INH tablets in the MDR-TB treatment regimen be avoided. Paediatric INH formulations may be a viable alternative if the crushing of INH tablets is indicated.

scholarly journals Evaluation of Saliva as a Potential Alternative Sampling Matrix for Therapeutic Drug Monitoring of Levofloxacin in Patients with Multidrug-Resistant Tuberculosis

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Samiksha Ghimire ◽  
Bhagwan Maharjan ◽  
Erwin M. Jongedijk ◽  
Jos G. W. Kosterink ◽  
Gokarna R. Ghimire ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Multidrug Resistant ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Time Curve ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Liquid Chromatography Tandem Mass ◽  
Mdr Tb

ABSTRACT Saliva may be a useful alternative matrix for monitoring levofloxacin concentrations in multidrug-resistant tuberculosis (MDR-TB) patients. The objectives of this study were (i) to evaluate the correlation between plasma and salivary levofloxacin (Lfx) concentrations in MDR-TB patients and (ii) to gauge the possibility of using saliva as an alternative sampling matrix for therapeutic drug monitoring of Lfx in areas where TB is endemic. This was a prospective pharmacokinetic study that enrolled MDR-TB patients receiving levofloxacin (750- to 1,000-mg once-daily dosing) under standardized treatment regimen in Nepal. Paired blood and saliva samples were collected at steady state. Lfx concentrations were quantified using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental kinetics. Lfx drug exposures were evaluated in 23 MDR-TB patients. During the first month, the median (interquartile range [IQR]) areas under the concentration-time curve from 0 to 24 h (AUC0–24) were 67.09 (53.93 to 98.37) mg ⋅ h/liter in saliva and 99.91 (76.80 to 129.70) mg ⋅ h/liter in plasma, and the saliva plasma (S/P) ratio was 0.69 (0.53 to 0.99). Similarly, during the second month, the median (IQR) AUC0–24 were 75.63 (61.45 to 125.5) mg ⋅ h/liter in saliva and 102.7 (84.46 to 131.9) mg ⋅ h/liter in plasma, with an S/P ratio of 0.73 (0.66 to 1.18). Furthermore, large inter- and intraindividual variabilities in Lfx concentrations were observed. This study could not demonstrate a strong correlation between plasma and saliva Lfx levels. Despite a good Lfx penetration in saliva, the variability in individual saliva-to-plasma ratios limits the use of saliva as a valid substitute for plasma. Nevertheless, saliva could be useful in semiquantitatively predicting Lfx plasma levels. (This study has been registered at ClinicalTrials.gov under identifier NCT03000517.)

scholarly journals Levofloxacin Population Pharmacokinetics in South African Children Treated for Multidrug-Resistant Tuberculosis

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Paolo Denti ◽  
Anthony J. Garcia-Prats ◽  
Heather R. Draper ◽  
Lubbe Wiesner ◽  
Jana Winckler ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Older Children ◽  
Dose Selection ◽  
Mixed Effects Modeling ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Similar Dose ◽  
Mdr Tb

ABSTRACT Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

scholarly journals Use of fluorescein diacetate (FDA) staining to detect viable Mycobacterium tuberculosis

2012 ◽  
Vol 11 (4) ◽  
pp. 322-330 ◽  
Author(s):  
Shamima Islam ◽  
Farjana Rahman ◽  
Saurab Kisore Munshi ◽  
Jewel Ahmed ◽  
S M Mostafa Kamal ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Treatment Failure ◽  
Medical Science ◽  
Multidrug Resistant ◽  
Fluorescein Diacetate ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Auramine O

Objective: Drug resistant tuberculosis has long been a common problem prevailing in developing countries including Bangladesh. Present study focused on the rapid identification of live Mycobacterium tuberculosis among treatment failure cases.Materials and Methods: Sputum samples from a total of 100 category-I and category-II treatment failure cases, assumed as multidrug resistant tuberculosis, were studied through fluorescein diacetate (FDA) staining under light emitting diode (LED) fluorescence microscope. Considering culture method as gold standard, we also compared the results of FDA staining with that of auramine O staining.Results: A total of 85% acid-fast bacilli were detected by FDA staining, 82% by auramine O staining and a total of 85% isolates were detected in Lowenstein-Jensen (LJ) culture. The sensitivity of FDA staining (96.47%) was estimated to be slightly higher than that of auramine O staining (91.76%). Moreover,76.47% cases were detected as multidrug resistant tuberculosis (MDR-TB). Conclusion: Taken together, FDA staining method has been proposed to be appropriate for the rapid diagnosis of drug resistant tuberculosis. DOI: http://dx.doi.org/10.3329/bjms.v11i4.12605 Bangladesh Journal of Medical Science Vol. 11 No. 04 Oct’12

scholarly journals Multidrug-Resistant Tuberculosis in Alberta and British Columbia, 1989 to 1998

1999 ◽  
Vol 6 (2) ◽  
pp. 155-160 ◽  
Author(s):  
Ahmed Hersi ◽  
Kevin Elwood ◽  
Robert Cowie ◽  
Dennis Kunimoto ◽  
Richard Long
Keyword(s):  
British Columbia ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Foreign Born ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Culture Positive

OBJECTIVE: To describe the extent of the problem of multidrug-resistant tuberculosis (MDR-TB) in Alberta and British Columbia from 1989 to 1998.DESIGN: A retrospective, population-based descriptive study of all notified MDR-TB cases in the context of all notified TB cases, all notified culture-positive TB cases and all notified drug-resistant TB cases.SETTING: Provinces of Alberta and British Columbia, and their TB registries.PATIENTS: All people with TB reported to the TB registries of Alberta and British Columbia between January 1, 1989 and June 30, 1998.MAIN OUTCOME MEASURES: Drug susceptibility testing was performed in all cases of culture-positive TB. Demographic, clinical and laboratory data on all cases of MDR-TB were recorded.RESULTS: Of 4606 notified cases of TB, 3553 (77.1%) were culture positive. Of these, 365 (10.3%) were drug resistant; of the drug-resistant cases, 24 (6.6%) were MDR. Most MDR-TB patients were foreign-born; of the four Canadian-born patients, two were infected while travelling abroad. Although foreign-born patients were significantly more likely to harbour drug-resistant strains, 14.3% versus 4.8%, respectively (P<0.001), among those who were harbouring a drug-resistant strain, the proportion of Canadian-born versus foreign-born patients with an MDR strain was the same (6.7% versus 6.6%, respectively). From 1994 to 1998 versus 1989 to 1993, the proportion of all drug-resistant strains that were MDR was greater (9.0% versus 4.3%, respectively), but the difference was not statistically significant. Isolates from 16 of the 24 MDR-TB cases had been archived. Each of these was fingerprinted and found to be unique. Most MDR-TB cases (88%) were respiratory. Of those tested for human immunodeficiency virus (n=17), only one was seropositive. MDR-TB was ‘acquired’ in 67% and ‘primary’ in 33% of cases. Eight (33%) of the MDR-TB cases received curative courses of treatment, six (25%) are still being treated, and the remainder have either died (five, 21%), transferred out (four, 17%) or become ‘chronic’ (one, 4%). No secondary case of MDR-TB has been identified in Alberta and British Columbia.CONCLUSIONS: Most MDR-TB in Alberta and British Columbia is imported. The proportion of all drug-resistant cases that are MDR appears to be increasing, but not because of disease acquired from recent contact with MDR-TB in Canada.

scholarly journals Novel drugs against tuberculosis: a clinician's perspective

2014 ◽  
Vol 45 (4) ◽  
pp. 1119-1131 ◽  
Author(s):  
Ioana Diana Olaru ◽  
Florian von Groote-Bidlingmaier ◽  
Jan Heyckendorf ◽  
Wing Wai Yew ◽  
Christoph Lange ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Phase Ii Clinical Trials ◽  
Multidrug Resistant Tuberculosis ◽  
Novel Drugs ◽  
Phase Ii And Iii

The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens.

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