Cryptococcal meningitis : epidemiology and therapeutic options

Cryptococcal meningitis causes morbidity and mortality worldwide. The burden of disease is greatest in middle- and low-income countries with a high incidence of human immunodeficiency virus (HIV infection. Patients taking immunosuppressive drugs and some immunocompetent hosts are also at risk. Treatment of cryptococcal meningitis consists of three phases: Induction, consolidation, and maintenance. Effective induction therapy requires potent fungicidal drugs (amphotericin B and flucytosine, which are often unavailable in low-resource, high-endemicity settings. As a consequence, mortality is unacceptably high. Wider access to effective treatment is urgently required to improve outcomes. For human immunodeficiency virus-infected patients, judicious management of asymptomatic cryptococcal antigenemia and appropriately timed introduction of antiretroviral therapy are important.Publisher PDFPeer reviewe

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

Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings

BACKGROUND: Despite the advent and increasingly wide availability of antiretroviral therapy, cryptococcal meningitis (CM) remains a significant cause of mortality and morbidity amongst individuals with HIV infection in resource-limited settings. The ideal management of CM remains unclear. The aim of this review is to assess the evidence for deciding on which antifungal regimen to use as well as other modalities of management to utilise especially resource poor settings in order to achieve the best possible outcome and enable an individual with CM to survive their acute illness and benefit from antiretroviral therapy. OBJECTIVES: To determine the most effective initial and consolidation treatment strategy for CM in HIV infected adults. SEARCH STRATEGY: The Cochrane HIV/AIDS group search strategy was used. Key words in the search included, meningitis, cryptococcus neoformans, treatment, trial, human immunodeficiency virus, acquired immunodeficiency syndrome, antifungal agents, amphotericin, flucytosine, fluconazole, azole, lumbar puncture, cerebrospinal fluid (CSF) pressure and acetazolamide. SELECTION CRITERIA: Randomised of HIV-infected adults with a first episode of CM diagnosed on CSF examination, by India ink staining, CSF culture or cryptococcal antigen testing. DATA COLLECTION AND ANALYSIS: Data were extracted using standardised forms and analysed using Rev Man 4.2.7 software. MAIN RESULTS: Six studies are included in the review. Five of the studies compared antifungal treatments and one study addressed lowering intracranial pressure. This study was stopped early due to excess adverse effects. The results of the other five studies as summarised as follows.Mayanja-Kizza 1998 compared fluconazole to fluconazole with 5 flucytosine. The dose of fluconazole used 200mg initially is lower than the recommended initial dose of 400mg. No survival advantage was found with the use of 5 flucytosine in addition to fluconazole.Two studies Brouwer 2004 and van der Horst 1997 compared Amphotericin (AmB) to AmB with 5 flucytosine. Both drugs were given at currently recommended doses for 2 weeks. No survival difference was found at 14 days or at 10 weeks (only recorded in Brouwer 2004). There were significantly more patients with sterile CSF cultures at 14 days in the group that received AmB with flucytosine.Brouwer 2004 compared AmB given alone to AmB given with flucytosine and fluconazole alone or in combination. This was a small study and no differences in mortality were noted between the groups.Bicanic 2008 compared high to standard dose AmB both with flucytosine. There was no difference in mortality between the two groups or adverse events.Leenders 1997 compared standard AmB to liposomal AmB. There was no difference in death rates between the two groups. But there were significantly fewer side effects in the group treated with liposomal AmB. AUTHORS' CONCLUSIONS: The main aim of this review was to determine the best treatment for cryptococcal meningitis in resource-limited settings. In these settings usually only AmB and fluconazole are available. No studies suitable for inclusion in the review were found that compared these two drugs. Therefore we are unable to recommend either treatment as superior to the other. The recommended treatment for CM is a combination of AmB and flucytosine. The optimal dosing of AmB remains unclear. Liposomal AmB is associated with less adverse events than AmB and may be useful in selected patients where resources allow.Future research into the management of cryptococcal meningitis in resource-limited settings should focus on the most effective use of medications that are available in these settings.Flucytosine in combination with AmB leads to faster and increased sterilisation of CSF compared to using AmB alone. As Flucytosine is often not available in developing countries, policy makers and national departments of heath should consider procuring this drug for HIV treatment programmes.Publisher PDFPeer reviewe

Investigation into mycobacterial persistence and early markers of outcome in the treatment of pulmonary tuberculosis

Background: Development of ultra-short chemotherapy for tuberculosis (TB) is thwarted by drug-tolerant bacillary persistence and a lack of surrogate endpoints to predict outcome from early clinical studies. Characterising bacillary elimination amongst TB patients may provide important new information. Bacilli harbouring intra-cytoplasmic lipid bodies (LBs) may represent a drug-tolerant phenotype, responsible for delayed bacterial clearance. Methods: Malawian adults with pulmonary TB were treated with standard 6 month therapy. Two quantitative sputum culture methods were used to model bacillary elimination during the first 2 months; serial sputum colony counting (SSCC) and time to positivity (TTP) in BACTEC MGIT broth. Fluorescence microscopy was used to assess the proportion of LB positive bacilli on sputum smears. Plasma concentrations of anti-TB drugs were assayed at day 14 or 21. Patients were followed until one year post-treatment. Outcomes were defined as favourable (stable cure) or unfavourable (failure/relapse). The effect of microbiological and pharmacological factors on outcome was assessed. Results: 169 patients (59% with HIV co-infection) were recruited. Of 133 final outcomes, 15 (11%) were unfavourable. Partial likelihood non-linear mixed effects (NLME) modelling of SSCC data from 86 (64%) patients showed biphasic bacillary elimination; slow late-phase eradication of persisters was associated with unfavourable outcome (p=0.001). Linear mixed effects (LME) modelling of TTP data from 124 (93%) patients showed that a slower MGIT Bacillary Elimination Rate (MBER) was associated with unfavourable outcome (p=0.007). 28% (range 0-79%) of acid-fast bacilli in baseline sputum samples were LB positive. During the first month there was a trend towards higher LB counts in patients who went on to have unfavourable vs. favourable outcomes (p=0.085). Low plasma rifampicin and isoniazid concentrations were reported in 87% and 50% patients respectively. A lower isoniazid AUC(0-6hr) exposure was associated with unfavourable outcome (p=0.035). Conclusions: The two main findings were: 1. Modelling of bacillary elimination during the first 2 months of TB therapy predicted long-term outcome. The MBER, in particular, could be calculated for 93% of patients and should be considered as a surrogate marker for early clinical trials. 2. The observation of a higher proportion of LB positive bacilli in later sputum samples from patients with unfavourable outcomes suggests that these may be drug-tolerant persister cells, with negative implications for treatment efficacy

Tuberculosis bacteria detection and counting in fluorescence microscopy images using a multi-stage deep learning pipeline

The manual observation of sputum smears by fluorescence microscopy for the diagnosis and treatment monitoring of patients with tuberculosis (TB) is a laborious and subjective task. In this work, we introduce an automatic pipeline which employs a novel deep learning-based approach to rapidly detect Mycobacterium tuberculosis (Mtb) organisms in sputum samples and thus quantify the burden of the disease. Fluorescence microscopy images are used as input in a series of networks, which ultimately produces a final count of present bacteria more quickly and consistently than manual analysis by healthcare workers. The pipeline consists of four stages: annotation by cycle-consistent generative adversarial networks (GANs), extraction of salient image patches, classification of the extracted patches, and finally, regression to yield the final bacteria count. We empirically evaluate the individual stages of the pipeline as well as perform a unified evaluation on previously unseen data that were given ground-truth labels by an experienced microscopist. We show that with no human intervention, the pipeline can provide the bacterial count for a sample of images with an error of less than 5%.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