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INTRODUCTION: No previous systematic reviews have comprehensively investigated the features of Xpert MTB/XDR and other rapid tests to diagnose pre-XDR/XDR-TB. The aim of this systematic review is to assess existing rapid diagnostics for pre-XDR/XDR-TB from a point-of-care perspective and describe their technical characteristics (i.e., sensitivity, specificity, positive and negative predictive values). METHODS: Embase, PubMed, Scopus, and Web of Science were searched to detect the articles focused on the accuracy of commercially available rapid molecular diagnostic tests for XDR-TB according to PRISMA guidelines. The analysis compared the diagnostic techniques and approaches in terms of sensitivity, specificity, laboratory complexity, time to confirmed diagnosis. RESULTS: Of 1298 records identified, after valuating article titles and abstracts, 97 (7.5%) records underwent full-text evaluation and 38 records met the inclusion criteria. Two rapid World Health Organization (WHO)-endorsed tests are available: Xpert MTB/XDR and GenoType MTBDRsl (VER1.0 and VER 2.0). Both tests had similar performance, slightly favouring Xpert, although only 2 studies were available (sensitivity 91.4-94; specificity 98.5-99; accuracy 97.2-97.7; PPV 88.9-99.1; NPV 95.8-98.9). CONCLUSIONS: Xpert MTB/XDR could be suggested at near-point-of-care settings to be used primarily as a follow-on test for laboratory-confirmed TB, complementing existing rapid tests detecting at least rifampicin-resistance. Both Xpert MTB/XDR and GenoType MTBDRsl are presently diagnosing what WHO defined, in 2021, as pre-XDR-TB.

Background: Concerns have been raised on the impact of coronavirus disease (COVID-19) on lung transplant (LTx) patients. The aim of this study was to evaluate the transplant function pre- and post-COVID-19 in LTx patients. Methods: Data were retrospectively collected from LTx patients with confirmed COVID-19 from all 3 Dutch transplant centers, between February 2020 and September 2021. Spirometry results were collected pre-COVID-19, 3- and 6-months post infection. Results: Seventy-four LTx patients were included. Forty-two (57%) patients were admitted, 19 (26%) to the intensive care unit (ICU). The in-hospital mortality was 20%. Twelve out of 19 ICU patients died (63%), a further 3 died on general wards. Patients with available spirometry (78% at 3 months, 65% at 6 months) showed a significant decline in mean forced expiratory volume in 1 second (FEV1) (ΔFEV1 138 ± 39 ml, p = 0.001), and forced vital capacity (FVC) (ΔFVC 233 ±74 ml, p = 0.000) 3 months post infection. Lung function improved slightly from 3 to 6 months after COVID-19 (ΔFEV1 24 ± 38 ml; ΔFVC 100 ± 46 ml), but remained significantly lower than pre-COVID-19 values (ΔFEV1 86 ml ± 36 ml, p = 0.021; ΔFVC 117 ± 35 ml, p = 0.012). FEV1/FVC was > 0.70. Conclusions: In LTx patients COVID-19 results in high mortality in hospitalized patients. Lung function declined 3 months after infection and gradually improved at 6 months, but remained significantly lower compared to pre-COVID-19 values. The more significant decline in FVC than in FEV1 and FEV1/FVC > 70%, suggested a more restrictive pattern.

BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation. Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively. Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed. Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.

Pyrazinamide is one of the first-line antituberculosis drugs. The efficacy of pyrazinamide is associated with the ratio of 24-h area under the concentration–time curve (AUC(24)) to MIC. The objective of this study was to develop and validate a limited sampling strategy (LSS) based on a population pharmacokinetic (popPK) model to predict AUC(24). A popPK model was developed using an iterative two-stage Bayesian procedure and was externally validated. Using data from 20 treatment-naive adult tuberculosis (TB) patients, a one compartment model with transit absorption and first-order elimination best described pyrazinamide pharmacokinetics and fed state was the only significant covariate for absorption rate constant (k(a)). External validation, using data from 26 TB patients, showed that the popPK model predicted AUC(24) with a slight underestimation of 2.1%. LSS were calculated using Monte Carlo simulation (n = 10,000). External validation showed LSS with time points 0 h, 2 h, and 6 h performed best with RMSE of 9.90% and bias of 0.06%. Food slowed absorption of pyrazinamide, but did not affect bioavailability, which may be advantageous in case of nausea or vomiting in which food can be used to diminish these effects. In this study, we successfully developed and validated a popPK model and LSS, using 0 h, 2 h, and 6 h postdose samples, that could be used to perform therapeutic drug monitoring (TDM) of pyrazinamide in TB patients.

Introduction Dosing of antibiotics in people with cystic fibrosis (CF) is challenging, due to altered pharmacokinetics, difficulty of lung tissue penetration, and increasing presence of antimicrobial resistance. Areas covered The purpose of this work is to critically review original data as well as previous reviews and guidelines on pharmacokinetics of systemic and inhaled antibiotics in CF, with the aim to propose strategies for optimization of antibacterial therapy in both children and adults with CF. Expert opinion For systemic antibiotics, absorption is comparable in CF patients and non-CF controls. The volume of distribution (Vd) of most antibiotics is similar between people with CF with normal body composition and healthy individuals. However, there are a few exceptions, like cefotiam and tobramycin. Many antibiotic class-dependent changes in drug metabolism and excretion are reported, with an increased total body clearance for ss-lactam antibiotics, aminoglycosides, fluoroquinolones, and trimethoprim. We, therefore, recommend following class-specific guidelines for CF, mostly resulting in higher dosages per kg bodyweight in CF compared to non-CF controls. Higher local antibiotic concentrations in the airways can be obtained by inhalation therapy, with which eradication of bacteria may be achieved while minimizing systemic exposure and risk of toxicity.

Coronavirus disease has disrupted tuberculosis services globally. Data from 33 centers in 16 countries on 5 continents showed that attendance at tuberculosis centers was lower during the first 4 months of the pandemic in 2020 than for the same period in 2019. Resources are needed to ensure tuberculosis care continuity during the pandemic.

The continuous flow of new research articles on MDR-TB diagnosis, treatment, prevention and rehabilitation requires frequent update of existing guidelines. This review is aimed at providing clinicians and public health staff with an updated and easy-to-consult document arising from consensus of Global Tuberculosis Network (GTN) experts. The core published documents and guidelines have been reviewed including the recently published MDR-TB WHO rapid advice and ATS/CDC/ERS/IDSA guidelines. After a rapid review of epidemiology and risk factors, the clinical priorities on MDR-TB diagnosis (including whole genome sequencing and drug-susceptibility testing interpretations) and treatment (treatment design and management, TB in children) are discussed. Furthermore, the review comprehensively describes the latest information on contact tracing and LTBI management in MDR-TB contacts, while providing guidance on post-treatment functional evaluation and rehabilitation of TB sequelae, infection control and other public health priorities.

Therapeutic Drug Monitoring (TDM) is increasingly recommended to ensure the correct drug dose thereby minimizing adverse events and maximizing regimen efficacy. To facilitate implementation in TB programs, a framework for TDM is urgently needed. TDM is only useful for dose optimization if a patient is on an appropriate regimen guided by drug susceptibility testing. TDM using a targeted approach selecting patients with risk factors for suboptimal drug exposure (e.g. diabetes) or not responding to treatment for drugs with a clear concentration-response relationship may provide the best value for money. Semiquantitative point-of-care tests for detection of low or high drug concentration should be implemented at community level while quantitative assays can be performed at regional or central level. Expanding PK/PD research followed by clinical trials including both clinical outcome as well as cost-effectiveness will increase the level of evidence supporting TDM. Keywords: AR-JP, PINK1, Parkin, Parkinson’s disease, Mitophagy, Ubiquitin, Proteasome, Autophagy

Moxifloxacin is an attractive drug for the treatment of isoniazid-resistant rifampicin-susceptible tuberculosis (TB) or drug-susceptible TB complicated by isoniazid intolerance. However, co-administration with rifampicin decreases moxifloxacin exposure. It remains unclear whether this drug-drug interaction has clinical implications. This retrospective study in a Dutch TB centre investigated how rifampicin affected moxifloxacin exposure in patients with isoniazid-resistant or -intolerant TB. Moxifloxacin exposures were measured between 2015 and 2020 in 31 patients with isoniazid-resistant or -intolerant TB receiving rifampicin, and 20 TB patients receiving moxifloxacin without rifampicin. Moxifloxacin exposure, i.e. area under the concentration-time curve (AUC0-24h), and attainment of AUC0-24h/minimal inhibitory concentration (MIC) > 100 were investigated for 400 mg moxifloxacin and 600 mg rifampicin, and increased doses of moxifloxacin (600 mg) or rifampicin (900 mg). Moxifloxacin AUC0-24h and peak concentration with a 400 mg dose were decreased when rifampicin was co-administered compared to moxifloxacin alone (ratio of geometric means 0.61 (90% CI (0.53, 0.70) and 0.81 (90% CI (0.70, 0.94), respectively). Among patients receiving rifampicin, 65% attained an AUC0-24h/MIC > 100 for moxifloxacin compared to 78% of patients receiving moxifloxacin alone; this difference was not significant. Seven out of eight patients receiving an increased dose of 600 mg moxifloxacin reached the target AUC0-24h/MIC > 100. This study showed a clinically significant 39% decrease in moxifloxacin exposure when rifampicin was co-administered. Moxifloxacin dose adjustment may compensate for this drug-drug interaction. Further exploring the impact of higher doses of these drugs in patients with isoniazid resistance or intolerance is paramount.

BackgroundChest X-ray (CXR) screening is a useful diagnostic tool to test individuals at high risk of tuberculosis (TB), yet image interpretation requires trained human readers who are in short supply in many high TB burden countries. Therefore, CXR interpretation by computer-aided detection software (CAD) may overcome some of these challenges, but evidence on its accuracy is still limited.We established a CXR library with images and metadata from individuals and risk groups that underwent TB screening in a variety of countries to assess the diagnostic accuracy of three commercial CAD solutions through an individual participant meta-analysis.Methods and findingsWe collected digital CXRs and demographic and clinical data from 6 source studies involving a total of 2756 participants, 1753 (64%) of whom also had microbiological test information. All CXR images were analyzed with CAD4TB v6 (Delft Imaging), Lunit Insight CXR TB algorithm v4.9.0 (Lunit Inc.), and qXR v2 (Qure.ai) and re-read by an expert radiologist who was blinded to the initial CXR reading, the CAD scores, and participant information. While the performance of CAD varied across source studies, the pooled, meta-analyzed summary receiver operating characteristic (ROC) curves of the three products against a microbiological reference standard were similar, with area under the curves (AUCs) of 76.4 (95% CI 72.1-80.3) for CAD4TB, 83.3 (95% CI 78.4-87.2) for Lunit, and 76.4 (95% CI 72.1-80.3) for qXR. None of the CAD products, or the radiologists, met the targets for a triage test of 90% sensitivity and 70% specificity. At the same sensitivity of the expert radiologist (94.0%), all CAD had slightly lower point estimates for specificity (22.4% (95% CI 16.9-29.0) for CAD4TB, 34.6% (95% CI 25.3-45.1) for qXR, and 41.0% (95% CI 30.1-53.0) for Lunit compared to 45.6% for the expert radiologist). At the same specificity of 45.6%, all CAD products had lower point estimates for sensitivity but overlapping CIs with the sensitivity estimate of the radiologist.ConclusionsWe showed that, overall, three commercially available CAD products had a reasonable diagnostic accuracy for microbiologically confirmed pulmonary TB and may achieve a sensitivity and specificity that approximates those of experienced radiologists. While threshold setting and cost-effectiveness modelling are needed to inform the optimal implementation of CAD products as part of screening programs, the availability of CAD will assist in scaling up active case finding for TB and hence contribute to TB elimination in these settings.

ObjectivesMalnutrition is associated with a twofold higher risk of dying in patients with tuberculosis (TB) and considered an important potentially reversible risk factor for failure of TB treatment. The construct of malnutrition has three domains: intake or uptake of nutrition; body composition and physical and cognitive function. The objectives of this systematic review are to identify malnutrition assessment methods, and to quantify how malnutrition assessment methods capture the international consensus definition for malnutrition, in patients with TB.DesignDifferent assessment methods were identified. We determined the extent of capturing of the three domains of malnutrition, that is, intake or uptake of nutrition, body composition and physical and cognitive function.ResultsSeventeen malnutrition assessment methods were identified in 69 included studies. In 53/69 (77%) of studies, body mass index was used as the only malnutrition assessment method. Three out of 69 studies (4%) used a method that captured all three domains of malnutrition.ConclusionsOur study focused on published articles. Implementation of new criteria takes time, which may take longer than the period covered by this review. Most patients with TB are assessed for only one aspect of the conceptual definition of malnutrition. The use of international consensus criteria is recommended to establish uniform diagnostics and treatment of malnutrition.PROSPERO registration numberCRD42019122832.

Whole-genome sequencing (WGS) of Mycobacterium tuberculosis (MTB) isolates can be used to get an accurate diagnosis, to guide clinical decision making, to control tuberculosis (TB) and for outbreak investigations. We evaluated the performance of long-read (LR) and/or short-read (SR) sequencing for anti-TB drug-resistance prediction using the TBProfiler and Mykrobe tools, the fraction of genome recovery, assembly accuracies and the robustness of two typing approaches based on core-genome SNP (cgSNP) typing and core-genome multi-locus sequence typing (cgMLST). Most of the discrepancies between phenotypic drug-susceptibility testing (DST) and drug-resistance prediction were observed for the first-line drugs rifampicin, isoniazid, pyrazinamide and ethambutol, mainly with LR sequence data. Resistance prediction to second-line drugs made by both TBProfiler and Mykrobe tools with SR- and LR-sequence data were in complete agreement with phenotypic DST except for one isolate. The SR assemblies were more accurate than the LR assemblies, having significantly (P

Tuberculosis (TB) is the world-leading cause of infectious disease related mortality, apart from COVID-19 presently [1]. Standard TB treatment for drug-susceptible (DS) TB takes 6–9 months and requires daily intake of multiple medications [1]. Notably, proper treatment adherence is essential for successful treatment outcome [1, 2]. To improve adherence, counseling and education are important. For specific patient groups, such as those with drug-resistant TB, HIV co-infection and those on intermittent treatment regiments, the World Health Organization (WHO) advises to use the Directly Observed Treatment (DOT) strategy. However, even with DOT, treatment completion is still challenging and cure rates and outcomes remain suboptimal [3].

Background Since in low incidence TB countries population migration and complex treatment of drug-resistant tuberculosis (DR-TB) patients are major issues, we aimed to analyse patient risk factors associated with the incidence of poor outcome of TB treatment among DR-TB patients in the Netherlands. Methods This retrospective cohort study included adult patients with confirmed DR-TB treated from 2005 to 2015. We obtained data from a nationwide exhaustive registry of tuberculosis patients in the Netherlands. Predictors for unsuccessful TB treatment (defaulted and failed treatment) and TB-associated mortality were analysed using multivariate logistic regression. Results Among 10,303 registered TB patients, 545 patients with DR-TB were analysed. Six types of DR-TB were identified from the included patients, i.e. isoniazid mono- or poly-resistance (68%); rifampicin mono- or poly-resistance (3.1%); pyrazinamide mono-resistance (8.3%); ethambutol mono-resistance (0.1%); multidrug-resistance (18.9%); and extensively drug-resistance (0.7%). The majority of patients were foreign-born (86%) and newly diagnosed TB (89%) patients. The cumulative incidence of unsuccessful treatment and mortality were 5 and 1%, respectively. Among all DR-TB cases, patients with Multi Drug-Resistant Tuberculosis (MDR-TB) (OR 4.43; 95%CI 1.70–11.60) were more likely to have unsuccessful treatment, while miliary and central nervous system TB (OR 15.60; 95%CI 2.18–111.52) may also be predictors for TB mortality. Additionally, patients with substance abuse and homelessness tend to have unsuccessful treatment. Conclusions In recent years, we identified a low incidence of DR-TB as well as the poor outcome of DR-TB treatment. The majority of cases were primary drug-resistant and foreign-born. To further improve treatment outcome, special attention should be given to the high-risk DR-TB patients. Electronic supplementary material The online version of this article (10.1186/s13756-019-0561-z) contains supplementary material, which is available to authorized users.

Anti-tuberculosis (TB) drugs can cause adverse drug reactions, particularly the older second-line drugs. Early intervention and adequate management of adverse drug reactions are important to prevent complications. Laboratory testing at baseline and during treatment, in addition to clinical monitoring, is protocolized to improve patient and treatment management. This chapter provides an overview of the most frequent and severe adverse effects caused by the first- and second-line drugs used for the treatment of tuberculosis. An approach on how to manage the adverse drugs effects is briefly described.

Increasing complexity of tuberculosis (TB) is one of the causes that TB is still the leading cause of death by an infectious disease. Among the complicating factors are increasing drug resistance and comorbidities. Patient-centred care, and even more individualised treatment, would be the way forward. The different aspects of patient-centred care model, including medical, social and supportive care are discussed.

RationaleInhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing for higher and therefore more effective pulmonary concentrations without dose limiting toxic effects.ObjectivesTo assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler.Methods12healthy volunteers were trained in inhaling HCQ correctly. Local tolerability and safety were assessed by pulmonary function tests, ECG and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation.Results and discussionDry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1post inhalation. The serum HCQ concentration remained below 10 µg/L in all samples.ConclusionInhaled dry powder HCQ is safe and well tolerated. Our data support further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy is warranted.

The persisting worldwide burden of tuberculosis (TB) is worrisome. In 2018, an estimated 10 million individuals developed TB and 1.45 million deceased [1]. The increase in drug resistance is an important point of concern. Resistance can be acquired by inappropriate drug management, non-compliance, and insufficient drug exposure [2, 3]. The last is frequently described for the first-line TB drugs rifampicin and isoniazid due to large inter-individual pharmacokinetic variability [3]. Therapeutic drug monitoring (TDM) can be used to verify drug exposure and adjust individual drug dosages if needed [4]. The efficacy of rifampicin and isoniazid is associated with the ratio of the steady-state area under the concentration-time curve from 0 to 24 h to minimal inhibitory concentration (AUC0–24/MIC) with a target value of >271 for rifampicin and >567 for isoniazid [5, 6]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. van den Elsen has nothing to disclose. Conflict of interest: Dr. Akkerman has nothing to disclose. Conflict of interest: Dr. Wessels has nothing to disclose. Conflict of interest: Dr. Jongedijk has nothing to disclose. Conflict of interest: Dr. Ghimire has nothing to disclose. Conflict of interest: Dr. van der Werf has nothing to disclose. Conflict of interest: Dr. Bolhuis has nothing to disclose. Conflict of interest: Dr. Touw has nothing to disclose. Conflict of interest: Dr. Alffenaar has nothing to disclose.

BACKGROUND: Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting.METHODS: This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer.RESULTS: Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63).CONCLUSION: Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates.

BACKGROUND: Despite considerable efforts to globally eradicate TB, and the availability of effective antibiotics, TB elimination goals are falling behind. While non-adherence to TB drug regimens may compromise effective treatment, its full impact is still unknown.OBJECTIVE: To determine the clinical and economic impact of non-adherence to TB medication on treatment outcomes in drug-susceptible TB patients (DS-TB).METHODS: A systematic review was performed using PubMed and Embase for studies published between 2009 and 2019 reporting associations between adherence and WHO-defined TB treatment outcomes and economic outcomes in DS-TB patients.RESULTS: A total of 14 studies were included. Eight focused on the association between non-adherence and death, 2 on treatment failure, 1 study on successful treatment outcome, 1 study on both successful and unsuccessful treatment outcomes and 2 on cost outcomes. Most studies (71.4%) were retrospective cohort or case-control studies. The results showed that non-adherence to TB drug regimens was associated with death, treatment failure and lower cure rates.CONCLUSION: Non-adherence to TB drugs has a profound impact on both clinical and economic TB outcomes. To reach WHO TB elimination goals, preventing non-adherence and the implementation of cost-effective intervention programmes should receive the highest priority.

Background: Pseudomonas aeruginosa (Pa) is the predominant pulmonary pathogen in patients with cystic fibrosis (CF). Tobramycin nebulization is used for the eradication of Pa infection. Nowadays, tobramycin dry powder inhalation (DPI) is available as well. This study reports the results of eradicating Pa with tobramycin DPI versus nebulization. Methods: Adult CF patients with a Pa isolation between September 2010 and September 2017 from the University Medical Centre Groningen (UMCG), the Netherlands, were included in this retrospective study. Results: In total 27 Pa isolations were recorded. In 13 of these, eradication was attempted with tobramycin, 7 with DPI and 6 with nebulization. DPI eradicated Pa successfully in six isolations (85.7%). Of these, one patient received additional oral ciprofloxacin and one received intravenous ceftazidime. Nebulization eradicated three Pa isolations (50.0%), in two of these, additional oral ciprofloxacin was given. Conclusion: Eradication rates of DPI tobramycin are comparable with those for nebulized tobramycin reported in the literature. This study suggests that DPI tobramycin is an alternative to nebulized tobramycin for eradication of Pa. Trial registration: The Medical Ethics Committee of the UMCG granted a waiver (METC2017-349), as they concluded that this study was not subject to the Medical Research Involving Human Subjects Act. The reviews of this paper are available via the supplemental material section.

SUMMARY BACKGROUND: There are no data comparing the 6–9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD). METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ~18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy. RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B–L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations. CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.

We report the experiences of 5 patients taking bedaquiline with delamanid in combination: 1 patient was cured; 3 culture converted, with 2 continuing and 1 changing therapy; and 1 died from respiratory insufficiency. For 2 patients, QT-interval prolongation but no arrhythmias occurred. Use of this therapy is justified for patients with limited options.

Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed to develop a population pharmacokinetic model to predict the area under the concentration curve (AUC) for linezolid using a limited number of blood samples.Data from patients with MDR-/XDR-TB who received linezolid and therapeutic drug monitoring as part of their TB treatment were used. Mw\Pharm 3.82 (Mediware, Zuidhorn, The Netherlands) was used to develop a population pharmacokinetic model and limited sampling strategy (LSS) for linezolid. LSS was evaluated over a time span of 6 h. Blood sampling directly before linezolid administration and 2 h after linezolid administration were considered to be the most clinically relevant sampling points.The model and LSS were evaluated by analysing the correlation between AUC(12h,observed) and AUC(12h,estimated). In addition, LSS was validated with an external group of patients with MDR-/XDR-TB from Sondalo, Italy.Fifty-two pharmacokinetic profiles were used to develop the model. Thirty-three profiles with a 300 mg dosing regimen and 19 profiles with a 600 mg dosing regimen were obtained. Model validation showed prediction bias of 0.1% and r(2) of 0.99. Evaluation of the most clinically relevant LSS showed prediction bias of 4.8% and r(2) of 0.97. The root mean square error corresponding to the most relevant LSS was 6.07%.The developed LSS could be used to enable concentration-guided dosing of linezolid. (C) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

BACKGROUND: Spinal tuberculosis (TB) accounts for approximately 1% to 3% of all TB cases and it can cause a wide range of neurological symptoms, from none to a complete spinal cord injury (SCI), resulting in complete paraplegia or tetraplegia.OBJECTIVES: To describe the functional and neurological outcome of SCI caused by TB.METHODS: Retrospective data on the admission period was combined with prospectively collected data on long-term follow-up. Primary outcome was neurological outcome in terms of motor function. Secondary outcome measures were functional outcome in terms of level of independence and community participation. Results were compared to the outcome in patients with SCI due to trauma.RESULTS: Six TB patients with complete motor SCI (American Spinal Injury Association Impairment Scale (AIS) A or B) were compared to eighteen patients with traumatic SCI. Most TB patients regained almost full neurological function (median motor score improved from 50 to 100), and reached high levels of independence, whereas trauma patients did not improve neurologically (median motor score remained 50) and reached a plateau in level of independence.CONCLUSIONS: SCI due to tuberculosis in the Netherlands shows remarkable improvement in both neurological and functional outcome, especially compared with traumatic SCI.

BACKGROUND: Bedaquiline has not been extensively studied among HIV drug-resistant tuberculosis (DR-TB) co-infected patients. We compared treatment outcomes in DR-TB patients treated with bedaquiline- and linezolid-containing regimens to historic controls treated with second-line injectable-containing regimens. METHODS: Retrospective cohort study of consecutive DR-TB patients initiated on bedaquiline- and linezolid-containing regimens at a TB referral hospital in KwaZulu-Natal, South Africa. Participants were prospectively followed through 24 months for treatment outcome, and adverse events. Outcomes were compared to a historic control cohort of DR-TB HIV patients enrolled at the same facility prior to bedaquiline introduction. RESULTS: Adult DR-TB patients initiating bedaquiline between January 2014 and November 2015 were enrolled (N=151). The majority of patients were female (52%), HIV co-infected (77%) and on antiretroviral therapy (100%). End of treatment outcomes included cure (63%), TB culture conversion (83%), completion (0.7%), loss-to-follow-up (15%), treatment failure (5%), and death (17%). Compared to historic controls (N=105), patients treated with bedaquiline experienced significantly higher TB culture conversion and cure, with significantly lower mortality. Adverse effects were common (92%) and most frequently attributed to linezolid (24.1%). QT segment prolongation was common but without clinical sequelae. CONCLUSION: Treatment with bedaquiline- and linezolid-containing regimens was associated with improved treatment outcomes and survival in DR-TB HIV patients.

BACKGROUND Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

BackgroundAs a vulnerable population, children and adolescents with tuberculosis (TB) are faced with many challenges, even those who live in low TB incidence countries. We aimed to evaluate factors associated with TB treatment outcomes allowing more focused interventions to support this population once diagnosed.MethodsA retrospective cohort study using a nationwide surveillance database was performed in children and adolescents (aged 0–18 years) treated for TB in the Netherlands from 1993 to 2018. Logistic regression analyses were used to estimate adjusted odds ratios (aOR) for associated factors of mortality and loss to follow-up (LTFU).ResultsAmong 3253 eligible patients with known outcomes, 94.4% (95.9% children and 92.8% adolescents) were cured or completed treatment, 0.7% died during treatment and 4.9% were LTFU. There were no reported treatment failures. Risk factors of death included children aged 2–4 years (aOR 10.42), central nervous system TB (aOR 5.14), miliary TB (aOR 10.25), HIV co-infection (aOR 8.60), re-treated TB cases (aOR 10.12) and drug-induced liver injury (aOR 6.50). Active case-finding was a protective factor of death (aOR 0.13). Risk factors of LTFU were adolescents aged 15–18 years (aOR 1.91), illegal immigrants (aOR 4.28), urban domicile (aOR 1.59), unknown history of TB contact (aOR 1.99), drug-resistant TB (aOR 2.31), single adverse drug reaction (aOR 2.12), multiple adverse drug reactions (aOR 7.84) and treatment interruption >14 days (aOR 6.93). Treatment in recent years (aOR 0.94) and supervision by public health nurses (aOR 0.14) were protective factors of LTFU.ConclusionHighly successful treatment outcomes were demonstrated in children and adolescents routinely treated for TB. Special attention should be given to specific risk groups to improve treatment outcomes.

Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has emerged as a core drug in MDR-TB treatment regimens [2, 3], despite its toxicity, e.g. anemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4, 5]. Currently, linezolid is used off-label, as part of Group A “Medicines to be prioritised” of the World Health Organization MDR-TB treatment guideline [2] and in several large trials [6], such as the NIX- TB and END-TB trials. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Bolhuis has nothing to disclose. Conflict of interest: Dr. van der Werf has nothing to disclose. Conflict of interest: Dr. Kerstjens has nothing to disclose. Conflict of interest: Dr. de Lange has nothing to disclose. Conflict of interest: Dr. Alffenaar has nothing to disclose. Conflict of interest: Dr. Akkerman has nothing to disclose.

Introduction: Treatment of MDRTB is complex: regimens require microbiological data; adverse events are frequent; availability of drugs and authorization for new drugs varies. The aim of this study was to scope the available national resources. Method: A survey to determine whether practising physicians could access MDRTB advice was sent to TBnet members by email. The ERS Office also contacted national respiratory societies. Questions included the name and contact details for their national advisory service, whether it was national policy to use the service for each patient with MDRTB and whether advice was required to access bedaquiline and delaminid. Results: 65 replies were received (14 were uninformative). 26/31 EU/EEA and 10/19 other countries in the WHO European Region were represented. 7 countries referred all MDRTB to a tertiary centre; 12 countries had tertiary referral centres that also gave advice to physicians treating MDRTB. 11 countries had an electronic system for advice, 6 with multidisciplinary team meetings to review patients’ progress. Lead clinicians were identified for a further 8 countries, one of which had no national advisory service and the other 7 had not responded by the time of abstract submission. For 18 (58%) countries, discussion of MDRTB by a national /regional committee was national policy and most (15/18) required consultation to use bedaquiline or delamanid. Electronic platforms had a wide range of functionality but few retained anonymised data and audited patient outcomes. Conclusion: MDRTB management is often concentrated in tertiary centres. Clinical governance, regarding audit and outcome, are at an early stage in managing MDRTB.

Background: Malnutrition is common in patients with tuberculosis (TB) and leads to negative changes in body composition, i.e. loss of muscle mass and a decrease in physical function.1,2 Aims and Objectives: Since it is unclear how body composition and strength change in malnourished patients with drug-susceptible TB, we aimed to assess changes during initial treatment. Methods: Between September 2016 and October 2017 14 patients with drug-susceptible TB admitted to our hospital were diagnosed with malnutrition by the Scored Patient-Generated Subjective Global Assessment. Patients were assessed within 10 days of the primary start of drug-treatment (T0), after 1 month (T1) and after 2 months (T2) with regard to body weight, BMI, Fat Free Mass (FFM), Phase Angle (PA), and Hand Grip Strength (HGS). Variables were normally distributed and tested for significance by paired sample t-test at P Results: N=14 unless stated otherwise Conclusions: Malnourished patients with drug-susceptible TB improve in all parameters of body composition and physical function during initial treatment, especially in the first month after start of treatment except for PA. References: 1. Cederholm, T. et al, Clin Nutr. 2017;36:49–64 2. Frediani, JK et al, Clin Nutr 2016;35(1):205-212.