Lina Davies Forsman

Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: A multicentre study

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents. 428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92–280) days and exposed to bedaquiline for 168 (86–180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively). Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30–60) days and 60 (33–90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related. Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions. Bedaquiline is safe and effective in treating MDR- and XDR-TB patients http://ow.ly/6MWK30adHkw

Determination of MIC Breakpoints for Second-Line Drugs Associated with Clinical Outcomes in Multidrug-Resistant Tuberculosis Treatment in China

ABSTRACT Our study aims to identify the clinical breakpoints (CBPs) of second-line drugs (SLDs) above which standard therapy fails in order to improve multidrug-resistant tuberculosis (MDR-TB) treatment. MICs of SLDs were determined for M. tuberculosis isolates cultured from 207 MDR-TB patients in a prospective cohort study in China between January 2010 and December 2012. Classification and regression tree (CART) analysis was used to identify the CBPs predictive of treatment outcome. Of the 207 MDR-TB isolates included in the present study, the proportion of isolates above the critical concentration recommended by WHO ranged from 5.3% in pyrazinamide to 62.8% in amikacin. By selecting pyrazinamide as the primary node (CBP, 18.75 mg/liter), 72.1% of sputum culture conversions at month four could be predicted. As for treatment outcome, pyrazinamide (CBP, 37.5 mg/liter) was selected as the primary node to predict 89% of the treatment success, followed by ofloxacin (CBP, 3 mg/liter), improving the predictive capacity of the primary node by 10.6%. Adjusted by identified confounders, the CART-derived pyrazinamide CBP remained the strongest predictor in the model of treatment outcome. Our findings indicate that the critical breakpoints of some second-line drugs and PZA need to be reconsidered in order to better indicate MDR-TB treatment outcome.

Safety and tolerability of clarithromycin in the treatment of multidrug-resistant tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are an emerging global threat. An estimated 3.3% of newly diagnosed TB patients and 20% of previously treated patients worldwide have MDR-TB [1]. Moreover, 9.7% of MDR-TB cases are suffering from XDR-TB. Treatment of TB is becoming more difficult since the resistance pattern of Mycobacterium tuberculosis is expanding and treatment success rate is decreasing, with newly emerging drug-resistant strains [2]. Therefore, evaluation of antimicrobial drugs active against M. tuberculosis is necessary. Clarithromycin (CLR) is a macrolide antibiotic previously listed as a World Health Organization (WHO) group 5 drug, but not included in the new WHO classification because it has only modest bacteriostatic effects against M. tuberculosis [3]. However, the in vitro synergy of CLR in combination with linezolid, ethambutol and spectinomycin, and its immunomodulatory effects, hold promise [4–6]. Despite the introduction of newer drugs such as bedaquiline and delamanid, clarithromycin may have added value for the treatment of TB patients in cases of extensive resistance but proven susceptibility to clarithromycin. Unfortunately, real-life data on the use of clarithromycin to guide physicians in the treatment of MDR-TB is scarce. Clarithromycin had a good tolerability and safety profile as assessed in MDR-TB patients receiving prolonged treatment http://ow.ly/r8Jh306Ac0u

Fixed-dose combination and therapeutic drug monitoring in tuberculosis : friend or foe?

Tuberculosis (TB) remains one of the worlds deadliest infectious diseases. The World Health Organization (WHO) estimated that, in 2014 alone, 9.6 million people fell ill with TB and 1.5 million died due to the disease [1]. South-East Asia and Western Pacific Regions accounted for 58% of these [1]. As most deaths from TB can now be prevented, efforts must be accelerated to ensure the targets of the Sustainable Development Goals are reached [1]. Fixed-dose combination and therapeutic drug monitoring can be combined in programmatic treatment of tuberculosis http://ow.ly/sCtd302h0Ka

Therapeutic drug monitoring to prevent acquired drug resistance of fluoroquinolones in the treatment of tuberculosis

The new short-course World Health Organization (WHO)-endorsed regimen for multidrug-resistant (MDR) tuberculosis (TB) resistant to rifampicin and isoniazid gives hope for patients and care-givers. However, there is still an unacceptable proportion of treatment failure and evidence of man-made acquired drug resistance of fluoroquinolones during programmatic treatment of MDR-TB [1]. The appropriate use of fluoroquinolones is crucial in MDR-TB treatment, perhaps even more so in the new WHO-endorsed short-course MDR-TB regimen. Current shortcomings with inappropriate use of fluoroquinolones, such as underdosing, need to be avoided in order to prevent failure of the new short-course regimen. Therapeutic drug monitoring of fluoroquinolones might prevent acquired XDR-TB http://ow.ly/jj6b309QXyZ

Risk factors of multidrug-resistant tuberculosis: A global systematic review and meta-analysis

OBJECTIVES Since the risk of multidrug-resistant tuberculosis (MDR-TB) may depend on the setting, we aimed to determine the associations of risk factors of MDR-TB across different regions. METHODS A systematic review and meta-analysis was performed with Pubmed and Embase databases. Information was retrieved on 37 pre-defined risk factors of MDR-TB. We estimated overall Mantel-Haenszel odds ratio as a measure of the association. RESULTS Factors of previous TB disease and treatment are the most important risk factors associated with MDR-TB. There was also a trend towards increased risk of MDR-TB for patients 40 years and older, unemployed, lacking health insurance, smear positive, with non-completion and failure of TB treatment, showing adverse drug reaction, non-adherent, HIV positive, with COPD and with M. Tuberculosis Beijing infection. Effect modification by geographical area was identified for several risk factors such as male gender, married patients, urban domicile, homelessness and history of imprisonment. CONCLUSIONS Assessment of risk factors of MDR-TB should be conducted regionally to develop the most effective strategy for MDR-TB control. Across all regions, factors associated with previous TB disease and treatment are essential risk factors, indicating the appropriateness of diagnosis, treatment and monitoring are an important requirements.

Outcomes of patients with drug-resistant-tuberculosis treated with bedaquiline-containing regimens and undergoing adjunctive surgery

OBJECTIVES No study evaluated the contribution of adjunctive surgery in bedaquiline-treated patients. This study describes treatment outcomes and complications in a cohort of drug-resistant pulmonary tuberculosis (TB) cases treated with bedaquiline-containing regimens undergoing surgery. METHODS This retrospective observational study recruited patients treated for TB in 12 centres in 9 countries between January 2007 and March 2015. Patients who had surgical indications in a bedaquiline-treated programme-based cohort were selected and surgery-related information was collected. Patient characteristics and surgical indications were described together with type of operation, surgical complications, bacteriological conversion rates, and treatment outcomes. Treatment outcomes were evaluated according to the time of surgery. RESULTS 57 bedaquiline-exposed cases resistant to a median of 7 drugs had indication for surgery (52 retreatments; 50 extensively drug-resistant (XDR) or pre XDR-TB). Sixty percent of cases initiated bedaquiline treatment following surgery, while 36.4% underwent the bedaquiline regimen before surgery and completed it after the operation. At treatment completion 90% culture-converted with 69.1% achieving treatment success; 21.8% had unfavourable outcomes (20.0% treatment failure, 1.8% lost to follow-up), and 9.1% were still undergoing treatment. CONCLUSIONS The study results suggest that bedaquiline and surgery can be safely and effectively combined in selected cases with a specific indication.

Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting

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 (Chigh) were determined, as well as estimates of Chigh/MIC and area under the concentration-time curve (AUC0-6)/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 Chigh 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 (<8 mg/L), 19% for isoniazid (<3 mg/L), 27% for pyrazinamide (<35 mg/L) and 16% for ethambutol (<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 AUC0-6/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.

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

Introduction 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.