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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.

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

Amikacin and kanamycin are considered important and effective drugs in the treatment of multidrug-resistant tuberculosis (MDR-TB). Unfortunately, the incidence of toxicity is high and is related to elevated drug exposure. In order to achieve a balance between efficacy and toxicity, a population pharmacokinetic (PPK) model may help to optimise drug exposure. Patients with MDR-TB who had received amikacin or kanamycin as part of their treatment and who had routinely received therapeutic drug monitoring were evaluated. A PPK model was developed and subsequently validated. Using this model, a limited sampling model was developed. Eleven patients receiving amikacin and nine patients receiving kanamycin were included in this study. The median observed 24-h area under the concentration-time curve (AUC(0-24h)) was 77.2 mg h/L [interquartile range (IQR) 64.7-96.2 mg h/L] for amikacin and 64.1 mg h/L (IQR 55.6-92.1 mg h/L) for kanamycin. The PPK model was developed and validated using n-1 cross-validation. A robust population model was developed that is suitable for predicting the AUC(0-24h) of amikacin and kanamycin. This model, in combination with the limited sampling strategy developed, can be used in daily routine to guide dosing but also to assess AUC0_24h in phase 3 studies. (C) 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

ObjectivesWe evaluated treatment outcomes and predictors for poor treatment outcomes for tuberculosis (TB) among native- and foreign-born patients with drug-susceptible TB (DSTB) in the Netherlands.MethodsThis retrospective cohort study included adult patients with DSTB treated from 2005 to 2015 from a nationwide exhaustive registry. Predictors for unsuccessful treatment outcomes (default and failure) and TB-associated mortality were analysed using multivariate logistic regression.ResultsAmong 5,674 identified cases, the cumulative incidence of unsuccessful treatment and mortality were 2.6% (n/N = 146/5,674) and 2.0% (112/5,674), respectively. Although most patients were foreign-born (71%; 4,042/5,674), no significant differences in these outcomes were observed between native- and foreign-born patients (p > 0.05). Significant predictors for unsuccessful treatment were age of 18–24 years [odds ratio (OR), 2.04; 95% confidence interval (CI): 1.34–3.10], homelessness (OR, 2.56; 95% CI: 1.16–5.63), prisoner status (OR, 5.39; 95% CI: 2.90–10.05) and diabetes (OR, 2.02; 95% CI: 1.03-3.97). Furthermore, predictors for mortality were age of 74–84 (OR, 5.58; 95% CI: 3.10–10.03) or ≥85 years (OR, 9.35, 95% CI: 4.31–20.30), combined pulmonary and extra-pulmonary TB (OR, 4.97; 95% CI: 1.42–17.41), central nervous system (OR, 120, 95% CI: 34.43–418.54) or miliary TB (OR, 10.73, 95% CI: 2.50–46.02), drug addiction (OR, 3.56; 95% CI: 1.34–9.47) and renal insufficiency/dialysis (OR, 3.23; 95% CI: 1.17–8.96).ConclusionsNative- and foreign-born patients exhibited similar TB treatment outcomes. To further reduce disease transmission and inhibit drug resistance, special attention should be given to high-risk patients.