| 1. |
- Chen, Ricky Hao, et al.
(författare)
-
Is there a need to optimise pyrazinamide doses in patients with tuberculosis? A systematic review
- 2023
-
Ingår i: International Journal of Antimicrobial Agents. - : ELSEVIER. - 0924-8579 .- 1872-7913. ; 62:3
-
Forskningsöversikt (refereegranskat)abstract
- Pyrazinamide (PZA) is a first-line antituberculosis drug with potent sterilising activity. Variability in drug exposure may translate into suboptimal treatment responses. This systematic review, conducted according to PRISMA guidelines, aimed to evaluate the concentration-effect relationship. In vitro/in vivo studies had to contain information on the infection model, PZA dose and concentration, and microbiological outcome. Human studies had to present information on PZA dose, measures of drug exposure and maximum concentration, and microbiological response parameter or overall treatment outcome. A total of 34 studies were assessed, including in vitro (n = 2), in vivo (n = 3) and clinical studies (n = 29). Intracellular and extracellular models demonstrated a direct correlation between PZA dose of 15-50 mg/kg/day and reduction in bacterial count between 0.50-27.7 log(10) CFU/mL. Consistent with this, higher PZA doses (>150 mg/kg) were associated with a greater reduction in bacterial burden in BALB/c mice models. Human pharmacokinetic studies displayed a linear positive correlation between PZA dose (i.e. 21.4-35.7 mg/kg/day) and drug exposure (AUC range 220.6-514.5 mg center dot h/L). Additionally, human studies confirmed a dose-effect relationship, with an increased 2-month sputum culture conversion rate at AUC/MIC targets of 8.4-11.3 with higher exposure/susceptibility ratios leading to greater efficacy. A 5-fold variability in AUC was observed at PZA dose of 25 mg/kg. A direct concentration-effect relationship and increased treatment efficacy with higher PZA exposure to susceptibility ratios was observed. Taking into account variability in drug exposure and treatment response, further studies on dose optimisation are justified.
|
|
| 2. |
- Forsman, Lina Davies, et al.
(författare)
-
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
- 2018
-
Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 8:9
-
Tidskriftsartikel (refereegranskat)abstract
- 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 Mycobacterium tuberculosis 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.
|
|
| 3. |
- Kuhlin, Johanna, et al.
(författare)
-
Genotypic resistance of pyrazinamide but not MIC is associated with longer time to sputum culture conversion in patients with multidrug-resistant tuberculosis
- 2021
-
Ingår i: Clinical Infectious Diseases. - : Oxford University Press. - 1058-4838 .- 1537-6591. ; 73:9, s. E3511-E3517
-
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.
|
|
| 4. |
- Kuhlin, Johanna, et al.
(författare)
-
Sputuminduktion bör väljas före ventrikelsköljning vid tbc-prov [Is it time to use sputum induction as a complementary specimen collection procedure in adult patients with suspected pulmonary tuberculosis?]
- 2020
-
Ingår i: Läkartidningen. - Stockholm, Sweden : Läkartidningen Förlag AB. - 0023-7205 .- 1652-7518. ; 117
-
Tidskriftsartikel (refereegranskat)abstract
- Gastric aspiration (GA) and sputum induction (SI) are used for diagnosing pulmonary tuberculosis (TB) in patients who cannot spontaneously produce sputum. This meta-analysis compares the sensitivity of GA and SI as alternative strategies for TB specimen collection in adult patients and describes procedure preference across Swedish Departments for Infectious Diseases (DID). We searched PubMed for articles on SI, GA and TB in adults. The meta-analysis included six articles (418 patients) and resulted in a crude OR 3.5 (95% CI 1.6-7.8) for positive culture from SI compared with GA. We asked all DID which procedure they currently used for collecting TB specimens (Sep 2019). Answers were received from 27/29 DID of which 67% (18/27) used SI as the primary diagnostic strategy when a patient could not spontaneously submit sputum. In conclusion, SI seems more effective than GA in detecting culture positive pulmonary TB in adult patients.
|
|
| 5. |
- Kuhlin, Johanna
(författare)
-
Treatment optimisation of multidrug-resistant tuberculosis
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A successful treatment outcome is seen in only 60% of persons treated for multidrugresistant tuberculosis (MDR-TB) worldwide, defined as resistance to both rifampicin and isoniazid. To improve these disturbingly low numbers, treatment optimisation is highly needed. Therefore, this thesis will evaluate how to optimise a treatment regimen using both older and repurposed drugs in studies on regimen composition, resistance detection, target attainment for efficacy, and reduction of adverse drug reactions. In the first retrospective observational study (study I), we evaluated the effect of pyrazinamide treatment on end-of-treatment outcomes in a cohort (n=508) of persons affected by MDR-TB in Karakalpakstan, Uzbekistan. We found no evidence (aOR 0.86, 95% CI 0.51-1.44, p=0.6) that pyrazinamide treatment was associated with end-oftreatment outcomes. In study II, pyrazinamide treatment was evaluated using time to sputum culture conversion in a historical Swedish MDR-TB cohort (n=157). We found strong evidence that no pyrazinamide treatment compared to receiving pyrazinamide treatment was associated with a longer time to sputum culture conversion (aHR 0.49, 95% CI 0.29-0.82, p=0.007), when accounting for genotypic drug susceptibility testing (DST). In study III, we assessed the total exposure of moxifloxacin and levofloxacin over the minimum inhibitory concentration of the infecting Mycobacterium tuberculosis strain in persons with MDR-TB in Xiamen (n=32), China. In this prospective observational study, we showed that no participants treated with levofloxacin, and 60-73% receiving moxifloxacin, reached the proposed efficacy targets when dosed according to the Chinese national guidelines. In the last retrospective observational study (study IV), we evaluated risk factors for adverse drug reactions associated with linezolid treatment (n=132) for MDR-TB in Sweden. We found strong evidence that a daily linezolid dose of ≥12 mg/kg was associated with a higher risk of peripheral neuropathy (aHR 2.92, 95% CI 1.09-7.84, p=0.033), anaemia, or leukopenia. Moreover, in an exploratory analysis, a linezolid trough concentration of ≥2 mg/L was associated with a higher risk of anaemia and thrombocytopenia. In conclusion, treatment with pyrazinamide seems to have a role in MDR-TB, at least in terms of improving interim outcomes. The use of genotypic DST is highly promising and may simplify and shorten the time to resistance testing. Adequate dosing of fluoroquinolones is important as underdosing could reduce treatment effects. Linezolid dose adjustment based on weight, or a high trough level might avoid adverse drug reactions. Importantly, dose adjustment needs to consider both efficacy and risk of adverse drug reactions, therefore, therapeutic drug monitoring can be a useful tool in the quest to personalise treatment.
|
|
| 6. |
- Zheng, Xubin, et al.
(författare)
-
Development and validation of a simple LC-MS/MS method for simultaneous determination of moxifloxacin, levofloxacin, prothionamide, pyrazinamide and ethambutol in human plasma
- 2020
-
Ingår i: Journal of chromatography. B. - : ELSEVIER. - 1570-0232 .- 1873-376X. ; 1158
-
Tidskriftsartikel (refereegranskat)abstract
- Treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging due to high treatment failure rate and adverse drug events. This study aimed to develop and validate a simple LC-MS/MS method for simultaneous measurement of five TB drugs in human plasma and to facilitate therapeutic drug monitoring (TDM) in MDR-TB treatment to increase efficacy and reduce toxicity. Moxifloxacin, levofloxacin, prothionamide, pyrazinamide and ethambutol were prepared in blank plasma from healthy volunteers and extracted using protein precipitation reagent containing trichloroacetic acid. Separation was achieved on an Atlantis T3 column with gradient of 0.1% formic acid in water and acetonitrile. Drug concentrations were determined by dynamic multiple reaction monitoring in positive ion mode on a LC-MS/MS system. The method was validated according to the United States Food and Drug Administration (FDA) guideline for bioanalytical method validation. The calibration curves for moxifloxacin, levofloxacin, prothionamide, pyrazinamide and ethambutol were linear, with the correlation coefficient values above 0.993, over a range of 0.1-5, 0.4-40, 0.2-10, 2-100 and 0.2-10 mg/L, respectively. Validation showed the method to be accurate and precise with bias from 6.5% to 18.3% for lower limit of quantification and -5.8% to 14.6% for LOW, medium (MED) and HIGH drug levels, and with coefficient of variations within 11.4% for all levels. Regarding dilution integrity, the bias was within 7.2% and the coefficient of variation was within 14.9%. Matrix effect (95.7%-112.5%) and recovery (91.4%-109.7%) for all drugs could be well compensated by their isotope-labelled internal standards. A benchtop stability test showed that the degradation of prothionamide was over 15% after placement at room temperature for 72 h. Clinical samples (n = 224) from a cohort study were analyzed and all concentrations were within the analytical range. The signal of prothionamide was suppressed in samples with hemolysis which was solved by sample dilution. As the method is robust and sample preparation is simple, it can easily be implemented to facilitate TDM in programmatic MDR-TB treatment.
|
|
