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- 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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- Moberg, Anna, 1976-
(författare)
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Diagnosing pneumonia in primary care : Aspects of the value of clinical and laboratory findings and the use of chest X-ray
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is important to identify patients with pneumonia because it is potentially a serious disease, often of bacterial origin, that should be treated with antibiotics. It is equally important to identify those with acute bronchitis, a self-limiting disease, that should not be treated with antibiotics. Because bacterial resistance is increasing, over-prescribing of antibiotics should be avoided. However, it is sometimes difficult to differentiate between the two diagnoses, and guidelines concerning the assessment do not conform. The general aim of this thesis was to investigate if diagnostics of pneumonia in primary care can be improved and whether this could contribute to reduced prescription of antibiotics. As a first step, different anamnestic, clinical and laboratory findings and the doctor’s degree of suspicion of pneumonia in primary care were compared with chest X-ray (CXR) findings. The doctor’s degree of suspicion of pneumonia was shown to be a good predictor. When the physician was sure of the diagnosis, the likelihood for radiographic pneumonia was high and when quite sure, CXR was positive in less than half of the cases. To further improve the diagnostics of pneumonia, and thus reduce antibiotic prescriptions, patients were referred for CXR when the physician was unsure or quite sure of a pneumonia diagnosis. The intervention did not result in any decrease in antibiotic prescriptions compared with a control group. However, it emerged that the physicians did not fully trust the CXR outcome, but prescribed antibiotics even when the results were negative. To gain insight into the contribution of C-reactive protein (CRP) levels to the degree of suspicion, physicians were asked to estimate their degree of suspicion of pneumonia before and after CRP testing. CRP affected the degree of suspicion to a great extent, and most often resulted in a lowered degree of suspicion and thereby in the clinical decision of dismissing the diagnosis of pneumonia. The use of different diagnostic tests and prescription of antibiotics in the assessment of acute bronchitis and pneumonia over time was evaluated in a register-based study. The study showed that the use of diagnostic tests for both diagnoses has increased, and that there has been a reduction in antibiotic prescriptions for acute bronchitis. In conclusion, the doctor’s degree of suspicion of pneumonia seems to be a good predictor of the condition. When the physician is sure of the diagnosis, no further investigation is needed, and antibiotics can be prescribed on reliable grounds. CRP testing affects the degree of suspicion and is most valuable when unsure of the diagnosis where it can be helpful to exclude pneumonia. In contrast, more extensive use of CXR does not contribute to a decrease in antibiotic prescriptions in the diagnostics of pneumonia.
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- Moberg, Anna, et al.
(författare)
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Use of chest X-ray in the assessment of community acquired pneumonia in primary care - an intervention study
- 2020
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Ingår i: Scandinavian Journal of Primary Health Care. - : Taylor & Francis. - 0281-3432 .- 1502-7724. ; 38:3, s. 323-329
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The aim of this study was to explore if consequent use of chest X-ray (CXR), when the physician is not sure of the diagnosis of pneumonia after clinical examination and CRP-testing, favors a more restrictive prescribing of antibiotics. Design This was an intervention study conducted between September 2015 and December 2017. Setting Two intervention primary health care centers (PHCCs) and three control PHCCs in the southeast of Sweden. Intervention All patients were referred for CXR when the physician s suspicion of pneumonia was unsure, or quite sure after CRP-testing. Control units managed patients according to their usual routine after clinical examination and CRP-testing. Subjects A total of 104 patients were included in the intervention group and 81 patients in the control group. The inclusion criteria of the study were clinically suspected pneumonia in patients >= 18 years, with respiratory symptoms for more than 24 h. Main outcome measure:Antibiotic prescribing rate. Results In the intervention group, 85% were referred for CXR and 69% were prescribed antibiotics, as compared to 26% and 77% in the control group. The difference in antibiotic prescribing rate was not statistically significant, unadjusted OR 0.68 [0.35-1.3] and adjusted OR 1.1 [CI 0.43-3.0]. A total of 24% of patients with negative CXR were prescribed antibiotics. Conclusion This study could not prove that use of CXR when the physician was not sure of the diagnosis of pneumonia results in lowered antibiotic prescribing rate in primary care. In cases of negative findings on CXR the physicians do not seem to rely on the outcome when it comes to antibiotic prescribing.
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- 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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| 7. |
- 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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| 8. |
- Niward, Katarina, 1971-
(författare)
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Towards individualised treatment of tuberculosis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Each year, around 10 million of individuals develop active tuberculosis (TB). Worldwide, TB is the leading cause of death from an infectious agent surpassing both malaria and HIV. Current treatment regimens are long and therefore encompass a risk of nonadherence and development of acquired drug-resistance, reflected in the increase of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Indeed, this calls for prudent use of existing TB drugs and improvement of TB treatment strategies. The aim of this thesis was to investigate the current drug susceptibility testing (DST) breakpoints for Mycobacterium tuberculosis (M. tuberculosis), the pharmacokinetics and pharmacodynamics (PK/PD) of TB treatment and to explore the role of therapeutic drug monitoring (TDM) for optimising TB treatment.Drug resistance in M. tuberculosis is expressed over a continuous scale and for some drugs it may be identified as low- and high-level resistance. This has been poorly reflected in currently used binary susceptibility breakpoints for TB drugs. Results from genome sequencing and phenotypic DST of ofloxacin and levofloxacin were compared in study I and current breakpoints were found to misclassify up to 25% of M. tuberculosis isolates with resistance mutations in gyrA as susceptible to fluoroquinolones. This finding may have implications for the classification of XDR-TB, treatment of MDR-TB and the evaluation of fluoroquinolones in clinical studies.Study II was a prospective cohort study of susceptible TB in Sweden, where drug concentrations of first-line TB drugs were measured along with the susceptibility level of the bacteria defined by the minimum inhibitory concentration (MIC) of M. tuberculosis. First-line drug concentrations below the reference range (16-42%) were common and most pronounced for rifampicin (13/31, 42%). An exploratory investigation of PK/PD parameters displayed a wide distribution of ratios between drug exposures and MICs. Rifampicin exhibited higher level of individual fluctuations over time during TB treatment compared with isoniazid. In study III the plasma drug concentrations of rifampicin were compared to the tuberculosis drug activity assay (TDA) and results showed that rifampicin drug levels, but not drug levels of the other first-line drugs, correlated with TDA. Patients with rifampicin drug levels below 8 mg/L had significantly lower median TDA. This finding supports the use of TDA as a potential indicator for low rifampicin exposure in resource-constrained settings without access to drug concentration analysis. The study design in study II has been further developed in study IV, which is a prospective cohort study of MDR-TB in China, where drug exposure will be explored in relation to individual bacterial MIC and measurements of treatment outcome.In summary, the work in this thesis emphasises the importance of reliable DST of M. tuberculosis and the need to re-evaluate the currently used breakpoints. Therapeutic drug monitoring (TDM) based on drug concentrations and MICs is a useful tool to avoid suboptimal drug exposure and to individualise TB treatments. Such strategies may improve treatment regimens and avoid further development of resistance.
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