| 1. |
- Keutzer, Lina, et al.
(författare)
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A modeling-based proposal for safe and efficacious reintroduction of bedaquiline after dose interruption : A population pharmacokinetics study
- 2022
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Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 11:5, s. 628-639
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Tidskriftsartikel (refereegranskat)abstract
- Bedaquiline (BDQ) is recommended for treatment of multidrug-resistant tuberculosis (MDR-TB) for the majority of patients. Given its long terminal half-life and safety concerns, such as QTc-prolongation, re-introducing BDQ after multiple dose interruption is not intuitive and there are currently no existing guidelines. In this simulation-based study, we investigated different loading dose strategies for BDQ re-introduction, taking safety and efficacy into account. Multiple scenarios of time and length of interruption as well as BDQ re-introduction, including no loading dose, 1- and 2-week loading doses (200 mg and 400 mg once daily), were simulated from a previously published population pharmacokinetic (PK) model describing BDQ and its main metabolite M2 PK in patients with MDR-TB. The efficacy target was defined as 95.0% of the average BDQ concentration without dose interruption during standard treatment. Because M2 is the main driver for QTc-prolongation, the safety limit was set to be below the maximal average M2 metabolite concentration in a standard treatment. Simulations suggest that dose interruptions between treatment weeks 3 and 72 (interruption length: 1 to 6 weeks) require a 2-week loading dose of 200 mg once daily in the typical patient. If treatment was interrupted for longer than 8 weeks, a 2-week loading dose (400 mg once daily) was needed to reach the proposed efficacy target, slightly exceeding the safety limit. In conclusion, we here propose a strategy for BDQ re-introduction providing guidance to clinicians for safe and efficacious BDQ dosing.
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| 2. |
- Davies Forsman, Lina, et al.
(författare)
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Fatal bupivacaine overdose through intrathecally positioned epidural catheter
- 2013
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Ingår i: Scandinavian Journal of Forensic Science. - : Walter de Gruyter. - 1503-9552. ; 19:1, s. 10-12
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Tidskriftsartikel (refereegranskat)abstract
- We describe a fatality due to an intrathecally positioned epidural catheter and an infusion rate of bupivacaine set 10 times higher than planned. The undetected misplacement, despite safety routines, is discussed along with the toxicological findings and new information on the intrathecal distribution of bupivacaine. From a clinical point of view, the human factor, in combination with an indistinct decimal point on the pump, was considered as the reason for the unfortunate overdose. In continuous epidural infusion of local anesthetics, the importance of guidelines and informed staff in managing complications of epidural lumbar infusion as well as careful monitoring of the vital functions is essential. Guidelines are also vital during the procedure of insertion of epidural catheters. When using combined spinal and epidural anaesthesia, we believe that an epidural catheter should be inserted, and its position tested, prior to spinal anesthesia. The case also illustrates the need of innovative investigation techniques to confirm the suspicion of unusual manifestations of inadvertent drug effects. Segmental analysis, together with analyses in a control case, enabled us to elucidate the high and varying tissue concentrations in the central nervous system.
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| 3. |
- Davies Forsman, Lina, et al.
(författare)
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Minimum Inhibitory Concentrations of Fluoroquinolones and Pyrazinamide Susceptibility Correlate to Clinical Improvement in Multidrug-resistant Tuberculosis Patients: A Nationwide Swedish Cohort Study Over 2 Decades
- 2019
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Ingår i: Clinical Infectious Diseases. - : OXFORD UNIV PRESS INC. - 1058-4838 .- 1537-6591. ; 69:8, s. 1394-1402
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Tidskriftsartikel (refereegranskat)abstract
- Background. Minimum inhibitory concentration (MIC) testing, unlike routine drug susceptibility testing (DST) at a single critical concentration, quantifies drug resistance. The association of MICs and treatment outcome in multidrug-resistant (MDR)-tuberculosis patients is unclear. Therefore, we correlated MICs of first- and second-line tuberculosis drugs with time to sputum culture conversion (tSCC) and treatment outcome in MDR-tuberculosis patients. Methods. Clinical and demographic data of MDR-tuberculosis patients in Sweden, including DST results, were retrieved from medical records from 1992 to 2014. MIC determinations were performed retrospectively for the stored individual Mycobacterium tuberculosis (Mtb) isolates using broth microdilution in Middlebrook 7H9. We fitted Cox proportional hazard models correlating MICs, DST results, and clinical variables to tSCC and treatment outcome. Results. Successful treatment outcome was observed in 83.5% (132/158) of MDR-tuberculosis patients. Increasing MICs of fluoroquinolones, diabetes, and age amp;gt;40 years were significantly associated with unsuccessful treatment outcome. Patients treated with pyrazinamide (PZA) had a significantly shorter tSCC compared to patients who were not (median difference, 27 days). Conclusions. Increasing MICs of fluoroquinolones were correlated with unsuccessful treatment outcome in MDR-tuberculosis patients. Further studies, including MIC testing and clinical outcome data to define clinical Mtb breakpoints, are warranted. PZA treatment was associated with shorter tSCC, highlighting the importance of PZA DST.
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| 4. |
- Davies Forsman, Lina
(författare)
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Novel treatment strategies for multidrug-resistant tuberculosis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tuberculosis is the leading cause of death from a single infectious agent in the world, surpassing the annual death toll of both malaria and HIV combined. The rise in multidrug-resistant tuberculosis (MDR-TB) has further exacerbated the situation, as this form of TB is more difficult and time-consuming to treat, with dismal cure rates. There is an urgent need to improve treatment of MDR-TB and to avoid the development of resistance during TB treatment. This thesis will delve deeper into the intricate relationship of bacterial resistance, drug exposure and host response, with the aim of exploring the role of repurposed drugs, the importance of the level of drug resistance of TB-drugs as well as therapeutic drug monitoring in the fight against TB and MDR-TB. Repurposing already approved drugs may accelerate the availability of new drug alternatives and two such alternatives were explored in Study I & II. The minimum inhibitory concentration (MIC) in vitro was determined for trimethoprim-sulfamethoxazole and meropenem-clavulanic acid, showing good activity against highly drug-resistant Mycobacterium tuberculosis (M.tuberculosis) isolates. Explorative pharmacometric modelling showed a high probability of target attainment for clinically achievable doses of trimethoprim-sulfamethoxazole (800 mg sulfamethoxazole thrice daily). However, there are no clinical trials evaluating the effect of trimethoprim-sulfamethoxazole in MDR-TB treatment. Meropenem-clavulanic acid is recommended by World Health Organization as an add-on agent in difficult to treat cases. The importance of the level of bacterial resistance was explored in Study III, a national cohort study in Sweden including all MDR-TB cases from 1992-2014 (no= 158). Increments of MIC for fluoroquinolones, rather than binary resistance testing, were associated with increased risk of unsuccessful treatment outcome. A similar association was seen for increasing age and patients with diabetes. Furthermore, pyrazinamide treatment was associated with reduced time to sputum culture conversion for patients with pyrazinamide-susceptible M.tuberculosis isolates. Bacterial resistance, as well as individual drug exposure, were studied in Study IV, where drug concentrations were measured in a prospective cohort study of susceptible TB. The drug exposure of first-line drugs in TB-patients was often lower than recommended (16-42%), despite the use of recommended dosages. The number of patients with low drug concentrations of rifampicin was particularly pronounced (13/31, 42%), with great inter-individual variability. When taking individual MICs into account, the ratios of drug exposure and the MICs were still low, possibly contributing to the overall successful treatment outcome. Subtherapeutic drug exposure can be revealed by therapeutic drug monitoring. The result of this study has led to the development of a prospective cohort study in China, studying drug exposure in relation to bacterial MIC in MDR-TB patients. In conclusion, a more holistic approach, taking the level of bacterial susceptibility, individual drug exposure as well as comorbidities into account, is needed for an individualised, improved treatment of TB. For clinicians, therapeutic drug monitoring might be a useful tool for selected patients, with the aim of preventing acquired drug resistance and improving treatment outcome of TB and MDR-TB.
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| 5. |
- Forsman, Lina Davies, et al.
(författare)
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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
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 8:9
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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.
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| 6. |
- Hedin, Wilhelm, et al.
(författare)
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A Rough Colony Morphology of Mycobacterium abscessus Is Associated With Cavitary Pulmonary Disease and Poor Clinical Outcome
- 2023
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 227:6, s. 820-827
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Mycobacterium abscessus complex (MABC) is a difficult to treat mycobacterium with two distinct morphologies: smooth and rough. As the clinical implications are unclear, we explored the morphology of MABC in relation to disease and outcome.Methods: We performed a retrospective multicenter cohort study including patients with confirmed MABC in Sweden, 2009-2020, with treatment outcome as the primary outcome. MABC colony morphology was determined by light microscopy on Middlebrook 7H10 agar plates.Results: Of the 71 MABC isolates, a defined morphology could be determined for 63 isolates, of which 40 were smooth (56%) and 23 were rough (32%). Immunosuppression, pulmonary disease, and cavitary lesion on chest radiographs were significantly associated with a rough isolate morphology. Participants with smooth isolates had more favorable treatment outcomes (12/14, 86%) compared to those with rough isolates (3/10, 30%). In an age-adjusted logistic regression, rough morphology of MABC was associated to lower odds of clinical cure compared to smooth morphology (adjusted odds ratio, 0.12; P = .049).Conclusions: Study participants with rough MABC colony morphology of isolates had a worse clinical outcome compared to those with smooth isolates. The biological mechanisms should be further characterized and colony morphology of MABC taken into account during clinical management.
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| 7. |
- 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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| 8. |
- 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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| 9. |
- Niward, Katarina, 1971-, et al.
(författare)
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Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay
- 2018
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Ingår i: Antimicrobial Agents and Chemotherapy. - : AMER SOC MICROBIOLOGY. - 0066-4804 .- 1098-6596. ; 62:5
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Tidskriftsartikel (refereegranskat)abstract
- The plasma tuberculosis drug activity (TDA) assay may be an alternative tool for therapeutic drug monitoring in resource-limited settings. In tuberculosis (TB) patients (n = 30), TDA and plasma levels of first-line drugs were analyzed 2 h post-dose, 2 weeks after treatment initiation. Patients with plasma levels of rifampin lower than 8 mg/liter had a significantly lower median TDA (1.40 versus 1.68, P = 0.0013). TDA may be used to identify TB patients with suboptimal rifampin levels during TB treatment.
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| 10. |
- Shao, Ge, et al.
(författare)
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Population pharmacokinetics and model-based dosing evaluation of bedaquiline in multidrug-resistant tuberculosis patients
- 2023
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Ingår i: Frontiers in Pharmacology. - : FRONTIERS MEDIA SA. - 1663-9812. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Bedaquiline is now recommended to all patients in the treatment of multidrug-resistant tuberculosis (MDR-TB) using standard dosing regimens. As the ability to measure blood drug concentrations is very limited, little is known about drug exposure and treatment outcome. Thus, this study aimed to model the population pharmacokinetics as well as to evaluate the currently recommended dosage.Methodology: A bedaquiline population pharmacokinetic (PK) model was developed based on samples collected from the development cohort before and 1, 2, 3, 4, 5, 6, 8, 12, 18, and 24 h after drug intake on week 2 and week 4 of treatment. In a prospective validation cohort of patients with MDR-TB, treated with bedaquiline-containing standardized regimen, drug exposure was assessed using the developed population PK model and thresholds were identified by relating to 2-month and 6-month sputum culture conversion and final treatment outcome using classification and regression tree analysis. In an exploratory analysis by the probability of target attainment (PTA) analysis, we evaluated the recommended dosage at different MIC levels by Middlebrook 7H11 agar dilution (7H11).Results: Bedaquiline pharmacokinetic data from 55 patients with MDR-TB were best described by a three-compartment model with dual zero-order input. Body weight was a covariate of the clearance and the central volume of distribution, albumin was a covariate of the clearance. In the validation cohort, we enrolled 159 patients with MDR-TB. The 7H11 MIC mode (range) of bedaquiline was 0.06 mg (0.008-0.25 mg/L). The study participants with AUC(0-24h)/MIC above 175.5 had a higher probability of culture conversion after 2-month treatment (adjusted relative risk, aRR:16.4; 95%CI: 5.3-50.4). Similarly, those with AUC(0-24h)/MIC above 118.2 had a higher probability of culture conversion after 6-month treatment (aRR:20.1; 95%CI: 2.9-139.4), and those with AUC(0-24h)/MIC above 74.6 had a higher probability of successful treatment outcome (aRR:9.7; 95%CI: 1.5-64.8). Based on the identified thresholds, simulations showed that the WHO recommended dosage (400 mg once daily for 14 days followed by 200 mg thrice weekly) resulted in PTA >90% for the majority of isolates (94%; MICs =0.125 mg/L).Conclusion: We established a population PK model for bedaquiline in patients with MDR-TB in China. Based on the thresholds and MIC distribution derived in a clinical study, the recommended dosage of bedaquiline is sufficient for the treatment of MDR-TB.
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