The importance of clinical pharmacokinetic–pharmacodynamic studies in unraveling the determinants of early and late tuberculosis outcomes

Tuberculosis remains a major infectious cause of morbidity and mortality worldwide. Current antibiotic regimens, constructed prior to the development of modern pharmacokinetic-pharmacodynamic (PK–PD) tools, are based on incomplete understanding of exposure–response relationships in drug susceptible and multidrug resistant tuberculosis. Preclinical and population PK data suggest that clinical PK–PD studies may enable therapeutic drug monitoring for some agents and revised dosingf or others. Future clinical PK–PD challenges include: incorporation of PK methods to assay free concentrations for all active metabolites; selection of appropriate early outcome measures which reflect therapeutic response; elucidation of genetic contributors to interindividual PK variability; conduct of targeted studies on special populations (including children); and measurement of PK–PD parameters at the site of disease.Publisher PDFPeer reviewe

The role of delamanid in the treatment of drug-resistant tuberculosis

Tuberculosis (TB) remains a significant cause of death worldwide, and emergence of drug-resistant TB requires lengthy treatments with toxic drugs that are less effective than their first-line equivalents. New treatments are urgently needed. Delamanid, previously OPC-67863, is a novel drug of the dihydro-nitroimidazole class with potent anti-TB activity and great promise to be effective in the treatment of drug-resistant TB. This review examines the preclinical and clinical development of delamanid, reviews current guidance on its use and evaluates the opportunities and challenges for its future role in TB management.Publisher PDFPeer reviewe

Management of multidrug-resistant TB : novel treatments and their expansion to low resource settings

This article received no specific funding. JL is supported by the Wellcome Trust as a clinical PhD fellow [grant number 109105/Z/15/Z].Despite overall progress in global TB control, the rising burden ofmultidrug-resistant TB (MDR-TB) threatens to undermine efforts to end theworldwide epidemic. Of the 27 countries classified as high burden for MDR-TB, 17 are in 'low' or 'low-middle' income countries. Shorter, all oral and less toxic multidrug combinations are required to improve treatment outcomes in these settings. Suitability for safe co-administration with HIV drugs is also desirable. A range of strategies and several new drugs (including bedaquiline, delamanid and linezolid) are currently undergoing advanced clinical evaluations to define their roles in achieving these aims. However, several clinical questions and logistical challenges need to be overcome before these new MDR-TB treatments fulfil their potential.Publisher PDFPeer reviewe

Automated methods for tuberculosis detection/diagnosis : a literature review

Funding: Welcome Trust Institutional Strategic Support fund of the University of St Andrews, grant code 204821/Z/16/Z.Tuberculosis (TB) is one of the leading infectious causes of death worldwide. The effective management and public health control of this disease depends on early detection and careful treatment monitoring. For many years, the microscopy-based analysis of sputum smears has been the most common method to detect and quantify Mycobacterium tuberculosis (Mtb) bacteria. Nonetheless, this form of analysis is a challenging procedure since sputum examination can only be reliably performed by trained personnel with rigorous quality control systems in place. Additionally, it is affected by subjective judgement. Furthermore, although fluorescence-based sample staining methods have made the procedure easier in recent years, the microscopic examination of sputum is a time-consuming operation. Over the past two decades, attempts have been made to automate this practice. Most approaches have focused on establishing an automated method of diagnosis, while others have centred on measuring the bacterial load or detecting and localising Mtb cells for further research on the phenotypic characteristics of their morphology. The literature has incorporated machine learning (ML) and computer vision approaches as part of the methodology to achieve these goals. In this review, we first gathered publicly available TB sputum smear microscopy image sets and analysed the disparities in these datasets. Thereafter, we analysed the most common evaluation metrics used to assess the efficacy of each method in its particular field. Finally, we generated comprehensive summaries of prior work on ML and deep learning (DL) methods for automated TB detection, including a review of their limitations.Publisher PDFPeer reviewe

Defining the roles of Data Manager and Epidemiologist in emergency medical teams

Funding: Hong Kong Jockey Club Charity Trust within the collaborative project “Training and Research Development for Emergency Medical Teams with reference to the WHO Global EMTs initiative, classification, and standards” between the Humanitarian and Conflict Response Institute (HCRI; Manchester, United Kingdom) and the Hong Kong Jockey Club Disaster Preparedness and Response Institute (HKJCDPRI; Aberdeen, Hong Kong).Medical and epidemiological documentation in disasters is pivotal: the former for recording patient care and the latter for providing real-time information to the host country. Furthermore, documentation informs post-hoc analysis to improve the effectiveness of future deployments. Although documentation is considered important and indeed integral to health care response, there are many barriers and challenges. Some of these challenges include: working without well-established standards for medical documentation; and working with international guidelines which provide minimal guidance as to how health data should be managed practically to ensure accuracy and completion. Furthermore, there is a shift in mindset in disaster contexts wherein most health care focus shifts to direct clinical care and diverts almost all attention from quality documentation. This report distinguishes between the tasks of the epidemiologist and the data manager (DM) in an emergency medical team (EMT) and discusses the importance of data collection in the specific case of an EMT deployment. While combining these roles is sometimes possible if resources are limited, it is better to separate them, as the two are quite distinct. Although there is overlap, to achieve the goals of either role, preferentially they should be carried out by two people working closely together with complementary skill sets. The main objective of this report is to provide guidance and task descriptions to EMTs and field hospitals when training, recruiting, and preparing DMs and epidemiologists to work within their teams. Clear delineation of tasks will lead to better quality data, as it commits DMs to being concerned with the provision of real-time documentation from patient arrival through to compiling daily reports. It also commits epidemiologists to providing enhanced disease surveillance; outbreak investigation; and a source of reliable and actionable information for decision makers and stakeholders in the disaster management cycle.PostprintPeer reviewe

Utility of broad-spectrum antibiotics for diagnosing pulmonary tuberculosis in adults : a systematic review and meta-analysis

Funding: Helse Nord RHF, Wellcome Trust, and the UK Commonwealth Scholarship Commission.Suboptimal diagnostics for pulmonary tuberculosis drive the use of the so-called trial of antibiotics, a course of broad-spectrum antibiotics without activity against Mycobacterium tuberculosis that is given to patients who are mycobacteriology negative but symptomatic, with the aim of distinguishing pulmonary tuberculosis from bacterial lower respiratory tract infection. The underlying assumption—that patients with lower respiratory tract infection will improve, whereas those with pulmonary tuberculosis will not—has an unclear evidence base for such a widely used intervention (at least 26·5 million courses are prescribed per year). We aimed to collate available evidence on the diagnostic performance of the trial of antibiotics.Publisher PDFPeer reviewe

Vitamin D deficiency in Malawian adults with pulmonary tuberculosis : risk factors and treatment outcomes

The study was supported by a Wellcome Trust (London, UK) Clinical PhD Fellowship awarded to DS (086757/Z/08/A) and the Malawi Liverpool Wellcome Trust (MLW) Core grant from the Wellcome Trust.SETTING: Vitamin D deficiency is common in African adults with tuberculosis (TB), and may be exacerbated by the metabolic effects of anti-tuberculosis drugs and antiretroviral therapy (ART). It is unclear whether vitamin D deficiency influences response to antituberculosis treatment. OBJECTIVES : To describe risk factors for baseline vitamin D deficiency in Malawian adults with pulmonary TB, assess the relationship between serum 25-hydroxy vitamin D (25[OH]D) concentration and treatment response, and evaluate whether the administration of anti-tuberculosis drugs and ART is deleterious to vitamin D status during treatment. DESIGN: A prospective longitudinal cohort study. RESULTS : The median baseline 25(OH)D concentration of the 169 patients (58% human immunodeficiency virus [HIV] infected) recruited was 57 nmol/l; 47 (28%) had vitamin D deficiency (<50 nmol/l). Baseline 25(OH)D concentrations were lower during the cold season (P < 0.001), with food insecurity (P = 0.034) or in patients who consumed alcohol (P = 0.019). No relationship between vitamin D status and anti-tuberculosis treatment response was found. 25(OH)D concentrations increased during anti-tuberculosis treatment, irrespective of HIV status or use of ART. CONCLUSIONS : Vitamin D deficiency is common among TB patients in Malawi, but this does not influence treatment response. Adverse metabolic effects of drug treatment may be compensated by the positive impact of clinical recovery preventing exacerbation of vitamin D deficiency during anti-tuberculosis treatment.Publisher PDFPeer reviewe

Linezolid pharmacokinetics in MDR-TB : a systematic review, meta-analysis and Monte Carlo simulation

This work was supported by the Wellcome Trust (grant numbers 109129/Z/15/Z to JM and 105620/Z/14/Z to DS and MC).Objectives The oxazolidinone linezolid is an effective component of drug - resistant TB treatment, but use is limited by toxicity and the optimum dose is uncertain . Current strategies are not informed by clinical pharmacokinetic/pharmacodynamic (PK/PD) data, we aimed to aimed to address this gap. Methods We defined linezolid PK/PD targets for efficacy; free area under the time - concentration curve: minimum inhibitory concentration ratio (ƒAUC0-24:M IC) >119m g/L/hr and safety; free minimum concentration (Cmin) <1.38mg/L . We extracted individual - level linezolid PK data from existing studies on TB patients and performed meta - analysis; producing summary estimates of ƒAUC0-24 and ƒCmin for published doses . Combining these with a published MIC distribution, we performed Monte Carlo simulations of target attainment. Results The efficacy target was attained in all simulated individuals at 300mg q12h and 600mg q12h , but only 20.7% missed the safety target at 300mg q12h versus 98.5% at 600mg q12h . Although suggesting 300mg q12h should be used preferentially, these data were reliant on a single centre . Efficacy and safety targets were missed by 41.0% and 24.2% respectively at 300mg q24h , and 44.5% and 27.5% at 600mg q24h . However, the confounding effect of between study heterogeneity on target attainment for q24h regimens was considerable. Conclusions 300mg q12h linezolid dosing may retain the efficacy of the 600mg q12h licensed dosing with improved safety. Data to evaluate commonly used 300mg q24h and 600mg q24h doses is limited. Comprehensive, prospectively obtained PK/PD data for linezolid doses in drug - resistant TB treatment are required.Publisher PDFPeer reviewe

Pan-resistome characterization of uropathogenic Escherichia coli and Klebsiella pneumoniae strains circulating in Uganda and Kenya, isolated from 2017-2018

Funding: The Holistic Approach to Unravel Antibacterial Resistance in East Africa is a 3-year Global Context Consortia Award (MR/S004785/1) funded by the National Institute for Health Research, Medical Research Council and the Department of Health and Social Care. The award is also part of the EDCTP2 program supported by the European Union.Urinary tract infection (UTI) develops after a pathogen adheres to the inner lining of the urinary tract. Cases of UTIs are predominantly caused by several Gram-negative bacteria and account for high morbidity in the clinical and community settings. Of greater concern are the strains carrying antimicrobial resistance (AMR)-conferring genes. The gravity of a UTI is also determined by a spectrum of other virulence factors. This study represents a pilot project to investigate the burden of AMR among uropathogens in East Africa. We examined bacterial samples isolated in 2017–2018 from in- and out-patients in Kenya (KY) and Uganda (UG) that presented with clinical symptoms of UTI. We reconstructed the evolutionary history of the strains, investigated their population structure, and performed comparative analysis their pangenome contents. We found 55 Escherichia coli and 19 Klebsiella pneumoniae strains confirmed uropathogenic following screening for the prevalence of UTI virulence genes including fimH, iutA, feoA/B/C, mrkD, and foc. We identified 18 different sequence types in E. coli population while all K. pneumoniae strains belong to ST11. The most prevalent E. coli sequence types were ST131 (26%), ST335/1193 (10%), and ST10 (6%). Diverse plasmid types were observed in both collections such as Incompatibility (IncF/IncH/IncQ1/IncX4) and Col groups. Pangenome analysis of each set revealed a total of 2862 and 3464 genes comprised the core genome of E. coli and K. pneumoniae population, respectively. Among these are acquired AMR determinants including fluoroquinolone resistance-conferring genes aac(3)-Ib-cr and other significant genes: aad, tet, sul1, sul2, and cat, which are associated with aminoglycoside, tetracycline, sulfonamide, and chloramphenicol resistance, respectively. Accessory genomes of both species collections were detected several β-lactamase genes, blaCTX-M, blaTEM and blaOXA, or blaNDM. Overall, 93% are multi-drug resistant in the E. coli collection while 100% of the K. pneumoniae strains contained genes that are associated with resistance to three or more antibiotic classes. Our findings illustrate the abundant acquired resistome and virulome repertoire in uropathogenic E. coli and K. pneumoniae, which are mainly disseminated via clonal and horizontal transfer, circulating in the East African region. We further demonstrate here that routine genomic surveillance is necessary for high-resolution bacterial epidemiology of these important AMR pathogens.Publisher PDFPeer reviewe

Health professionals' experiences of tuberculosis cohort audit in the North West of England : a qualitative study

This research was supported by Public Health England and the Centre for Applied Health Research and Delivery, Liverpool School of Tropical Medicine (LSTM).Objectives. Tuberculosis cohort audit (TBCA) was introduced across the North West (NW) of England in 2012 as an ongoing, multidisciplinary, systematic case review process, designed to improve clinical and public health practice. TBCA has not previously been introduced across such a large and socioeconomically diverse area in England, nor has it undergone formal, qualitative evaluation. This study explored health professionals' experiences of the process after 1515 cases had been reviewed. Design. Qualitative study using semistructured interviews. Respondents were purposively sampled from 3 groups involved in the NW TBCA: (1) TB nurse specialists, (2) consultant physicians and (3) public health practitioners. Data from the 26 respondents were triangulated with further interviews with key informants from the TBCA Steering Group and through observation of TBCA meetings. Analysis. Interview transcripts were analysed thematically using the framework approach. Results. Participants described the evolution of a valuable 'community of practice' where interprofessional exchange of experience and ideas has led to enhanced mutual respect between different roles and a shared sense of purpose. This multidisciplinary, regional approach to TB cohort audit has promoted local and regional team working, exchange of good practices and local initiatives to improve care. There is strong ownership of the process from public health professionals, nurses and clinicians; all groups want it to continue. TBCA is regarded as a tool for quality improvement that improves patient safety. Conclusions. TBCA provides peer support and learning for management of a relatively rare, but important infectious disease through discussion in a no-blame atmosphere. It is seen as an effective quality improvement strategy which enhances TB care, control and patient safety. Continuing success will require increased engagement of consultant physicians and public health practitioners, a secure and ongoing funding stream and establishment of clear reporting mechanisms within the public health system.Publisher PDFPeer reviewe