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Background: Ribavirin is used in the treatment of respiratory paramyxovirus infection in lung transplant recipients; however, its pharmacokinetic profile in the transplant population is unknown despite the potential for alterations due to underlying pathology. Furthermore, the ability of current regimens to meet exposure targets has not been established.Objectives: This study examined the pharmacokinetics of ribavirin in a lung transplant population for which current and alternative dosing regimens were assessed.Methods: Population pharmacokinetic modelling was conducted in NONMEM using concentration-time data from 24 lung transplant recipients and 6 healthy volunteers. Monte Carlo simulation was used to assess the ability of dosing regimens to achieve pre-specified target concentrations.Results and conclusions: A three-compartment model with first-order elimination most adequately described ribavirin concentration-time data, with CLCR and patient type (i.e. lung transplant) identified as significant covariates in the model. Simulations indicate that current regimens achieve efficacious concentrations within 24 h of treatment initiation that increase to supra-therapeutic levels over the treatment period. A regimen of 8 mg/kg q6h orally for 48 h followed by 8 mg/kg q24h orally for the remainder of the treatment period was predicted to result in >90% of patients exhibiting concentrations within the defined target range throughout the entire treatment course. Additional work to formally establish target therapeutic concentrations is required; however, this study provides a valuable first step in determining optimal ribavirin treatment regimens for paramyxovirus infections in the lung transplant population.

Background In TB, therapeutic drug monitoring (TDM) is recommended for linezolid; however, implementation is challenging in endemic settings. Non-invasive saliva sampling using a mobile assay would increase the feasibility of TDM. Objectives To validate a linezolid saliva assay using a mobile UV spectrophotometer. Methods The saliva assay was developed using NanoPhotometer NP80® and linezolid concentrations were quantified using second-order derivative spectroscopy. Sample preparation involved liquid–liquid extraction of saliva, using saturated sodium chloride and ethyl acetate at 1:1:3 (v/v/v). The assay was validated for accuracy, precision, selectivity, specificity, carry-over, matrix effect, stability and filters. Acceptance criteria were bias and coefficient of variation (CV) Results Linezolid concentrations correlated with the amplitude between 250 and 270 nm on the second-order derivative spectra. The linezolid calibration curve was linear over the range of 3.0 to 25 mg/L (R2 = 0.99) and the LLOQ was 3.0 mg/L. Accuracy and precision were demonstrated with bias of −7.5% to 2.7% and CV ≤5.6%. The assay met the criteria for selectivity, matrix effect, carry-over, stability (tested up to 3 days) and use of filters (0.22 μM Millex®-GV and Millex®-GP). Specificity was tested with potential co-medications. Interferences from pyrazinamide, levofloxacin, moxifloxacin, rifampicin, abacavir, acetaminophen and trimethoprim were noted; however, with minimal clinical implications on linezolid dosing. Conclusions We validated a UV spectrophotometric assay using non-invasive saliva sampling for linezolid. The next step is to demonstrate clinical feasibility and value to facilitate programmatic implementation of TDM.

Background Previously treated tuberculosis (TB) patients are a widely reported risk factor for multidrug-resistant tuberculosis. Identifying patients’ problems during treatment is necessary to control TB, especially in a high-burden setting. We therefore explored barriers to successful TB treatment from the patients’ perspective, aiming to identify potential patient-centred care strategies to improve TB treatment outcome in Indonesia. Methods A qualitative study was conducted in a province of Indonesia with high TB prevalence. Participants from various backgrounds (i.e., TB patients, physicians, nurses, pharmacists, TB activist, TB programmers at the district and primary care levels) were subject to in-depth interviews and focus group discussions (FGDs). All interviews and FGDs were transcribed verbatim from audio and visual recordings and the respective transcriptions were used for data analysis. Barriers were constructed by interpreting the codes’ pattern and co-occurrence. The information’s trustworthiness and credibility were established using information saturation, participant validation and triangulation approaches. Data were inductively analysed using the Atlas.ti 8.4 software and reported following the COREQ 32-items. Results We interviewed 63 of the 66 pre-defined participants and identified 15 barriers. The barriers were classified into three themes, i.e., socio-demography and economy; knowledge and perception and TB treatment. Since the barriers can be interrelated, we determined five main barriers across all barrier themes, i.e., lack of TB knowledge, stigmatisation, long distance to the health facility, adverse drug reaction and loss of household income. Conclusion The main treatment barriers can be considered to strengthen patient-centred care for TB patients in Indonesia. A multi-component approach including TB patients, healthcare providers, broad community and policy makers is required to improve TB treatment success.

Glucocorticoids (GCs) are rapidly released in response to stress and play an important role in the physiological adjustments to re-establish homeostasis. The mode of action of GCs for stress coping is mediated largely by the steroid binding to the glucocorticoid receptor (GR), a ligand-bound transcription factor, and modulating the expression of target genes. However, GCs also exert rapid actions that are independent of transcriptional regulation by modulating second messenger signaling. However, a membrane-specific protein that transduces rapid GCs signal is yet to be characterized. Here, using freshly isolated hepatocytes from rainbow trout (Oncorhynchus mykiss) and fura2 fluorescence microscopy, we report that stressed levels of cortisol rapidly stimulate the rise in cytosolic free calcium ([Ca2+]i). Pharmacological manipulations using specific extra- and intra-cellular calcium chelators, plasma membrane and endoplasmic reticulum channel blockers and receptors, indicated extracellular Ca2+ entry is required for the cortisol-mediated rise in ([Ca2+]i). Particularly, the calcium release-activated calcium (CRAC) channel gating appears to be a key target for the rapid action of cortisol in the ([Ca2+]i) rise in trout hepatocytes. To test this further, we carried out in silico molecular docking studies using the Drosophila CRAC channel modulator 1 (ORAI1) protein, the pore forming subunit of CRAC channel that is highly conserved. The result predicts a putative binding site on CRAC for cortisol to modulate channel gating, suggesting a direct, as well as an indirect regulation (by other membrane receptors) of CRAC channel gating by cortisol. Altogether, CRAC channel may be a novel cortisol-gated Ca2+ channel transducing rapid nongenomic signalling in hepatocytes during acute stress.

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.

Contains fulltext : 225854.pdf (Publisher’s version ) (Open Access) Major epidemics, including some that qualify as pandemics, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV, influenza A (H1N1)pdm/09 and most recently COVID-19, affect the lung. Tuberculosis (TB) remains the top infectious disease killer, but apart from syndemic TB/HIV little is known regarding the interaction of viral epidemics and pandemics with TB. The aim of this consensus-based document is to describe the effects of viral infections resulting in epidemics and pandemics that affect the lung (MERS, SARS, HIV, influenza A (H1N1)pdm/09 and COVID-19) and their interactions with TB. A search of the scientific literature was performed. A writing committee of international experts including the European Centre for Disease Prevention and Control Public Health Emergency (ECDC PHE) team, the World Association for Infectious Diseases and Immunological Disorders (WAidid), the Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC) was established. Consensus was achieved after multiple rounds of revisions between the writing committee and a larger expert group. A Delphi process involving the core group of authors (excluding the ECDC PHE team) identified the areas requiring review/consensus, followed by a second round to refine the definitive consensus elements. The epidemiology and immunology of these viral infections and their interactions with TB are discussed with implications for diagnosis, treatment and prevention of airborne infections (infection control, viral containment and workplace safety). This consensus document represents a rapid and comprehensive summary on what is known on the topic.

The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter., The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata, C. albicans, and C. parapsilosis, respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant (Ke) was 0.09 (SD, 0.04) h−1, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h−1, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h−1. A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients.

Recently updated World Health Organisation (WHO) and American Thoracic Society (ATS) guidelines include recommendations for therapeutic drug monitoring (TDM) during treatment for Mycobacterium tuberculosis (TB) in patients at risk of altered drug exposure or poor prognosis [1, 2]. Sub-optimal drug exposure may be associated with acquired resistance and poor treatment outcomes [3] whereas supra-therapeutic concentrations may lead to toxicity. TDM is indicated in patients at risk of altered pharmacokinetics ( e.g. HIV, diabetes mellitus, gastrointestinal abnormalities, drug-drug interactions, renal impairment) and/or worsened treatment prognosis (inadequate treatment response despite adherence or on second line drugs, especially for fluoroquinolones, linezolid and aminoglycosides) [1, 2, 4]. 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. KIM has nothing to disclose. Conflict of interest: Mr. Ulbricht has nothing to disclose. Conflict of interest: Dr. Ahn has nothing to disclose. Conflict of interest: Dr. Cho has nothing to disclose. Conflict of interest: Lee has nothing to disclose. Conflict of interest: Dr. Lieu has nothing to disclose. Conflict of interest: Dr. Nguyen has nothing to disclose. Conflict of interest: Dr. Young has nothing to disclose. Conflict of interest: Dr. Cho has nothing to disclose. Conflict of interest: Dr. Alffenaar has nothing to disclose.

Delamanid, a-first-in-class bicyclic nitroimidazole, was recently approved for multidrug-resistant tuberculosis treatment. Pitted against the hope for improving treatment outcomes is the threat of the rapid resistance emergence. This review provides information on the mechanisms of action, resistance emergence, and drug susceptibility testing (DST) for delamanid. Delamanid resistance has already been reported in both in vitro experiments and clinical settings. Although mutations conferring delamanid resistance have been identified in fbiA, fbiB, fbiC, ddn, and fgd1 genes of Mycobacterium tuberculosis, knowledge about the molecular resistance mechanisms is limited, and there remains no standardized DST method. The rapid acquisition of delamanid resistance emphasizes the need for optimal use of new drugs, the need for drug resistance surveillance, and a comprehensive understanding of drug resistance mechanisms. Further studies are necessary to investigate genetic and phenotypic changes that determine clinically relevant delamanid resistance to help develop a rapid delamanid DST.

Background Prospective studies correlating pharmacokinetic/pharmacodynamic (PK/PD) indices to clinical responses are urgently needed. This study aimed to find clinically relevant PK/PD thresholds that can be used for treatment optimization. Methods Pharmacokinetic sampling and minimum inhibitory concentration (MIC) measurements were performed for patients with culture-confirmed tuberculosis (TB). Classification and regression tree (CART) analysis was applied to obtain PK and/or PD thresholds for first-line drugs predictive of 2-week/month culture conversion, treatment outcome determined at 6–8 months, acute kidney injury (AKI), and drug-induced liver injury (DILI). Least absolute shrinkage and selection operator (LASSO) logistic regression was used for model development and validation. Results Finally, 168 and 52 patients with TB were included in development and validation cohorts for analysis, respectively. Area under the concentration-time curve (AUC)/MIC below CART-derived thresholds for pyrazinamide of 8.42, pyrazinamide of 2.79, or rifampicin of 435.45 were the predominant predictors of 2-week culture conversion, 2-month culture conversion, or treatment success, respectively. Isoniazid AUC >21.78 mg · h/L or rifampicin AUC >82.01 mg · h/L were predictive of DILI or AKI during TB treatment. The predictive performance of trained LASSO models in the validation cohort was evaluated by receiver operating characteristic curves and ranged from 0.625 to 0.978. Conclusions PK/PD indices and drug exposure of TB drugs were associated with clinical outcome and adverse events. The effect of CART-derived thresholds for individualized dosing on treatment outcome should be studied in a randomized controlled trial.

The impact of the theology of Dirk Postma on Reformed Hermeneutics: At the 150th commemoration of the founding of the Theological Seminary of the Reformed Churches of South-Africa, this article explores the specific historical origins and characteristics of Reformed Hermeneutics. By determining the rules of exegesis, Reformed Hermeneutics indeed has a fundamental influence on the development of Reformed Theology. The research indicates that the theological views of Dirk Postma lay at the heart of Reformed Hermeneutics. His views can further be traced to those of Aegidius Francken, a product of the Nadere Reformatie . An analysis of two recent publications outlining Reformed Hermeneutics indicates that the same hermeneutical principles that Dirk Postma upheld, still hold sway in Reformed Theology today. These principles are outlined and are put forward as standard for the future development of Reformed Theology.

Treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging due to high treatment failure rate and adverse drug events. This study aimed to develop and validate a simple LC-MS/MS method for simultaneous measurement of five TB drugs in human plasma and to facilitate therapeutic drug monitoring (TDM) in MDR-TB treatment to increase efficacy and reduce toxicity. Moxifloxacin, levofloxacin, prothionamide, pyrazinamide and ethambutol were prepared in blank plasma from healthy volunteers and extracted using protein precipitation reagent containing trichloroacetic acid. Separation was achieved on an Atlantis T3 column with gradient of 0.1% formic acid in water and acetonitrile. Drug concentrations were determined by dynamic multiple reaction monitoring in positive ion mode on a LC-MS/MS system. The method was validated according to the United States' Food and Drug Administration (FDA) guideline for bioanalytical method validation. The calibration curves for moxifloxacin, levofloxacin, prothionamide, pyrazinamide and ethambutol were linear, with the correlation coefficient values above 0.993, over a range of 0.1-5, 0.4-40, 0.2-10, 2-100 and 0.2-10 mg/L, respectively. Validation showed the method to be accurate and precise with bias from 6.5% to 18.3% for lower limit of quantification and -5.8% to 14.6% for LOW, medium (MED) and HIGH drug levels, and with coefficient of variations within 11.4% for all levels. Regarding dilution integrity, the bias was within 7.2% and the coefficient of variation was within 14.9%. Matrix effect (95.7%-112.5%) and recovery (91.4%-109.7%) for all drugs could be well compensated by their isotope-labelled internal standards. A benchtop stability test showed that the degradation of prothionamide was over 15% after placement at room temperature for 72 h. Clinical samples (n = 224) from a cohort study were analyzed and all concentrations were within the analytical range. The signal of prothionamide was suppressed in samples with hemolysis which was solved by sample dilution. As the method is robust and sample preparation is simple, it can easily be implemented to facilitate TDM in programmatic MDR-TB treatment.

At the 150th commemoration of the founding of the Theological Seminary of the Reformed Churches of South-Africa, this article explores the specific historical origins and characteristics of Reformed Hermeneutics. By determining the rules of exegesis, Reformed Hermeneutics indeed has a fundamental influence on the development of Reformed Theology. The research indicates that the theological views of Dirk Postma lay at the heart of Reformed Hermeneutics. His views can further be traced to those of Aegidius Francken, a product of the Nadere Reformatie. An analysis of two recent publications outlining Reformed Hermeneutics indicates that the same hermeneutical principles that Dirk Postma upheld, still hold sway in Reformed Theology today. These principles are outlined and are put forward as standard for the future development of Reformed Theology.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has attracted interest because of its global rapid spread, clinical severity, high mortality rate, and capacity to overwhelm healthcare systems [1, 2]. SARS-CoV-2 transmission occurs mainly through droplets, although surface contamination contributes and debate continues on aerosol transmission [3–5].

Purpose This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients. Methods Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes. Results TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients. Conclusion Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide. Electronic supplementary material The online version of this article (10.1007/s00134-020-06050-1) contains supplementary material, which is available to authorized users.

Respiratory tract infection with Pneumoviruses (PV) and Paramyxoviruses (PMV) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTR). Ribavirin may be a treatment option but its effectiveness is unclear, especially with respect to infection severity. We retrospectively analyzed ten years of PV/PMV infections in LTR. Main endpoints were FEV1 at three and six months post‐infection, expressed as a percentage of pre‐infection FEV1 and incidence of new or progressed CLAD six months post‐infection. A total of 139 infections were included; 88 (63%) severe infections (defined as >10% FEV1 loss at infection), 51 (37%) mild infections (≤10% FEV1 loss). Overall post‐infection CLAD incidence was 20%. Associations were estimated on post‐infection FEV1 for ribavirin vs. no ribavirin (+13.2% [7.79;18.67]) and severe vs. mild infection (‐11.1% [‐14.76; ‐7.37). Factors associated with CLAD incidence at six months were ribavirin treatment (OR 0.24 [0.10–0.59]), severe infection (OR 4.63 [1.66;12.88]) and mycophenolate mofetil use (OR 0.38 [0.14;0.97]). This data provides valuable information about the outcomes of lung transplant recipients with these infections and suggests possible associations of ribavirin use and infection severity with long‐term outcomes. Well‐designed prospective trials are needed to confirm these findings.

Tuberculosis (TB) elimination requires innovative approaches. The new Global Tuberculosis Network (GTN) aims to conduct research on key unmet therapeutic and diagnostic needs in the field of TB elimination using multidisciplinary, multisectorial approaches. The TB Pharmacology section within the new GTN aims to detect and study the current knowledge gaps, test potential solutions using human pharmacokinetics informed through preclinical infection systems, and return those findings to the bedside. Moreover, this approach would allow prospective identification and validation of optimal shorter therapeutic durations with new regimens. Optimized treatment using available and repurposed drugs may have an increased impact when prioritizing a person-centered approach and acknowledge the importance of age, gender, comorbidities, and both social and programmatic environments. In this viewpoint article, we present an in-depth discussion on how TB pharmacology and the related strategies will contribute to TB elimination., An enhanced understanding of tuberculosis (TB) pharmacology aims to use pharmacokinetics and pharmacodynamics, operational research, and therapeutic drug monitoring to support TB elimination.

Background: d-cycloserine is used to treat multidrug-resistant tuberculosis. Its efficacy, contribution in combination therapy, and best clinical dose are unclear, also data on the d-cycloserine minimum inhibitory concentration (MIC) distributions is scant.Methods: We performed a systematic search to identify pharmacokinetic and pharmacodynamic studies performed with d-cycloserine. We then performed a combined exposure-effect and dose fractionation study of d-cycloserine in the hollow fiber system model of tuberculosis (HFS-TB). In parallel, we identified d-cycloserine MICs in 415 clinical Mycobacterium tuberculosis (Mtb) isolates from patients. We utilized these results, including intracavitary concentrations, to identify the clinical dose that would be able to achieve or exceed target exposures in 10000 patients using Monte Carlo experiments (MCEs).Results: There were no published d-cycloserine pharmacokinetics/pharmacodynamics studies identified. Therefore, we performed new HFS-TB experiments. Cyloserine killed 6.3 log10 colony-forming units (CFU)/mL extracellular bacilli over 28 days. Efficacy was driven by the percentage of time concentration persisted above MIC (%TMIC), with 1.0 log10 CFU/mL kill achieved by %TMIC = 30% (target exposure). The tentative epidemiological cutoff value with the Sensititre MYCOTB assay was 64 mg/L. In MCEs, 750 mg twice daily achieved target exposure in lung cavities of 92% of patients whereas 500 mg twice daily achieved target exposure in 85% of patients with meningitis. The proposed MCE-derived clinical susceptibility breakpoint at the proposed doses was 64 mg/L.Conclusions: Cycloserine is cidal against Mtb. The susceptibility breakpoint is 64 mg/L. However, the doses likely to achieve the cidality in patients are high, and could be neurotoxic.

A World Health Organization workshop systematically examined the evidence base for dosing second-line tuberculosis drugs, identifying knowledge gaps. To fill these in, pharmacokinetics/pharmacodynamics, Monte Carlo experiments, and artificial intelligence algorithms were used in hollow-fiber model studies and clinical data analyses.

AIMS: The aim of this study is to evaluate the potential association between N-acetyltransferase type 2 (NAT2) polymorphisms and drug-induced liver injury during anti-TB treatment (AT-DILI). METHODS: We conducted a systematic review and performed a meta-analysis to clarify the role of NAT2 polymorphism in AT-DILI. PubMed, Medline and EMBASE databases were searched for studies published in English to December 31, 2017, on the association between the NAT2 polymorphism and AT-DILI risk. Outcomes were pooled with random-effects meta-analysis. Details were registered in the PROSPERO register (number: CRD42016051722). RESULTS: Thirty-seven studies involving 1527 cases and 7184 controls were included in this meta-analysis. The overall odds ratio (OR) of AT-DILI associated with NAT2 slow acetylator phenotype was 3.15 (95% CI 2.58-3.84, I(2) = 51.3%, P = 0.000). The OR varied between different ethnic populations, ranging from 6.42 (95% CI 2.41-17.10, I(2) = 2.3%) for the West Asian population to 2.32 (95% CI 0.58-9.24, I(2) = 80.3%) for the European population. Within the slow NAT2 genotype, variation was also observed; NAT2*6/*7 was associated with the highest risk of AT-DILI (OR = 1.68, 95% CI 1.09-2.59) compared to the other slow NAT2 acetylators combined. CONCLUSIONS: NAT2 slow acetylation was observed to increase the risk of AT-DILI in tuberculosis patients. Our results support the hypothesis that the slow NAT2 genotype is a risk factor for AT-DILI.