| 1. |
- Kuhlin, Johanna, et al.
(författare)
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Genotypic resistance of pyrazinamide but not MIC is associated with longer time to sputum culture conversion in patients with multidrug-resistant tuberculosis
- 2021
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press. - 1058-4838 .- 1537-6591. ; 73:9, s. E3511-E3517
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: PZA resistance in multidrug-resistant tuberculosis (MDR-TB) is common and it is not clear how it affects interim and treatment outcomes. Although rarely performed, phenotypic drug susceptibility testing (pDST) is used to define PZA resistance but genotypic DST (gDST) and minimum inhibitory concentration (MIC) could be beneficial. We aimed to assess the impact of PZA gDST and MIC on time to sputum culture conversion (SCC) and treatment outcome in patients with MDR-TB.METHODS: Clinical, microbiological and treatment data was collected in this cohort study for all patients diagnosed with MDR-TB in Sweden 1992-2014. MIC, pDST and whole genome sequencing of the pncA, rpsA and panD genes were used to define PZA resistance. A Cox regression model was used for statistical analyses.RESULTS: Of 157 patients with MDR-TB, 56.1% (n=88) had PZA resistant strains and 49.7% (n=78) were treated with PZA. In crude and adjusted analyses, PZA gDST resistance was associated with a 29-day longer time to SCC (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.36-0.89, p=0.013 and HR 0.49, 95% CI 0.29-0.82, p=0.007, respectively). A two-fold decrease in dilutions of PZA MIC for PZA susceptible strains showed no association with SCC in crude or adjusted analyses (HR 0.98, 95% CI 0.73-1.31, p=0.89). Genotypic DST and MIC for PZA were not associated with treatment outcome.CONCLUSION: In patients with MDR-TB, gDST PZA resistance was associated with a longer time to SCC. Rapid PZA gDST is important to identify patients who may benefit from PZA treatment.
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| 2. |
- Andersson, Blanka, et al.
(författare)
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A novel mycobacterial growth inhibition assay employing live-cell imaging of virulent M. tuberculosis and monitoring of host cell viability
- 2020
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Ingår i: Tuberculosis. - : CHURCHILL LIVINGSTONE. - 1472-9792 .- 1873-281X. ; 124
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Tidskriftsartikel (refereegranskat)abstract
- Our aim was to develop a Mycobacterium tuberculosis (Mtb) growth inhibition assay (MGIA) as a summary estimate of host immune control of virulent Mtb. Mycobacterial growth inhibition (MGI) using previously frozen human PBMCs infected with H37Rv was assessed by live-cell imaging (Incucyte (c)) complemented by imaging flow cytometry analysis of phagocytosis. MGI measured as relative fluorescence units (RFU) was calibrated to time to positive culture (TTP) in BACTEC 960 MGIT. At a MOI (multiplicity of infection) of 5, there was a wide range of MGI of blood donors (1.1*10(6)-2.7*10(6) RFU, n = 14). Intra- and inter-assay variability were at most 17.5 and 20.7 CV%. Cell viability at day 5 was 57 and 62% monitored by the LDH and Draq7 assays respectively. There was a strong correlation between a readout for Mtb growth using CFU counts or TTP compared to RFU (r2 >= 0.96). Our MGIA enabling live-cell imaging and monitoring of cell viability was able to detect a wide range of Mtb growth inhibition by PBMCs and was calibrated to several readout options for bacterial growth. This MGIA may be valuable as a surrogate marker of host immunity in a personalized medicine approach.
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| 3. |
- Ekqvist, David, et al.
(författare)
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Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin : a study protocol of a phase II clinical trial (HighShort-RP)
- 2022
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Increased dosing of rifampicin and pyrazinamide seems a viable strategy to shorten treatment and prevent relapse of drug-susceptible tuberculosis (TB), but safety and efficacy remains to be confirmed. This clinical trial aims to explore safety and pharmacokinetics-pharmacodynamics of a high-dose pyrazinamide-rifampicin regimen.Methods and analysis: Adult patients with pulmonary TB admitted to six hospitals in Sweden and subjected to receive first-line treatment are included. Patients are randomised (1:3) to either 6-month standardised TB treatment or a 4-month regimen based on high-dose pyrazinamide (40 mg/kg) and rifampicin (35 mg/kg) along with standard doses of isoniazid and ethambutol. Plasma samples for measurement of drug exposure determined by liquid chromatography tandem-mass spectrometry are obtained at 0, 1, 2, 4, 6, 8, 12 and 24 hours, at day 1 and 14. Maximal drug concentration (C-max) and area under the concentration-time curve (AUC(0-24h)) are estimated by non-compartmental analysis. Conditions for early model-informed precision dosing of high-dose pyrazinamide-rifampicin are pharmacometrically explored. Adverse drug effects are monitored throughout the study and graded according to Common Terminology Criteria for Adverse Events V.5.0. Early bactericidal activity is assessed by time to positivity in BACTEC MGIT 960 of induced sputum collected at day 0, 5, 8, 15 and week 8. Minimum inhibitory concentrations of first-line drugs are determined using broth microdilution. Disease severity is assessed with X-ray grading and a validated clinical scoring tool (TBscore II). Clinical outcome is registered according to WHO definitions (2020) in addition to occurrence of relapse after end of treatment. Primary endpoint is pyrazinamide AUC(0-24h) and main secondary endpoint is safety.Ethics and dissemination: The study is approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. Informed written consent is collected before study enrolment. The study results will be submitted to a peer-reviewed journal.
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| 4. |
- Niward, Katarina, et al.
(författare)
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Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting
- 2018
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Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 73:10, s. 2838-2845
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Tidskriftsartikel (refereegranskat)abstract
- Background: Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs. Objectives: To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs. Methods: Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (C-high) were determined, as well as estimates of C-high/MIC and area under the concentration-time curve (AUC(0-6))/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261). Results: After 2 weeks of treatment, the median C-high values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (amp;lt;8 mg/L), 19% for isoniazid (amp;lt;3 mg/L), 27% for pyrazinamide (amp;lt;35 mg/L) and 16% for ethambutol (amp;lt;2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC(0-6)/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid. Conclusions: We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.
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