Exploring prospects of novel drugs for tuberculosis

Tuberculosis remains a disease with an enormous impact on public health worldwide. With the continuously increasing epidemic of drug-resistant tuberculosis, new drugs are desperately needed. However, even for the treatment of drug-sensitive tuberculosis, new drugs are required to shorten the treatment duration and thereby prevent development of drug resistance. Within the past ten years, major advances in tuberculosis drug research have been made, leading to a considerable number of antimycobacterial compounds which are now in the pipeline. Here we discuss a number of these novel promising tuberculosis drugs, as well as the discovery of two new potential drug targets for the development of novel effective drugs to curb the tuberculosis pandemic, ie, the coronin 1 and protein kinase G pathways. Protein kinase G is secreted by mycobacteria and is responsible for blocking lysosomal delivery within the macrophage. Coronin 1 is responsible for activating the phosphatase, calcineurin, and thereby preventing phagosome-lysosome fusion within the macrophage. Blocking these two pathways may lead to rapid killing of mycobacteri

Simple flow cytometric detection of haemozoin containing leukocytes and erythrocytes for research on diagnosis, immunology and drug sensitivity testing

<p>Abstract</p> <p>Background</p> <p>Malaria pigment (haemozoin, Hz) has been the focus of diverse research efforts. However, identification of Hz-containing leukocytes or parasitized erythrocytes is usually based on microscopy, with inherent limitations. Flow cytometric detection of depolarized Side-Scatter is more accurate and its adaptation to common bench top flow cytometers might allow several applications. These can range from the <it>ex-vivo </it>and <it>in-vitro </it>detection and functional analysis of Hz-containing leukocytes to the detection of parasitized Red-Blood-Cells (pRBCs) to assess antimalarial activity.</p> <p>Methods</p> <p>A standard benchtop flow cytometer was adapted to detect depolarized Side-Scatter. Synthetic and <it>Plasmodium falciparum </it>Hz were incubated with whole blood and PBMCs to detect Hz-containing leukocytes and CD16 expression on monocytes. C5BL/6 mice were infected with <it>Plasmodium berghei </it>ANKA or <it>P. berghei </it>NK65 and Hz-containing leukocytes were analysed using CD11b and Gr1 expression. Parasitized RBC from infected mice were identified using anti-Ter119 and SYBR green I and were analysed for depolarized Side Scatter. A highly depolarizing RBC population was monitored in an <it>in-vitro </it>culture incubated with chloroquine or quinine.</p> <p>Results</p> <p>A flow cytometer can be easily adapted to detect depolarized Side-Scatter and thus, intracellular Hz. The detection and counting of Hz containing leukocytes in fresh human or mouse blood, as well as in leukocytes from <it>in-vitro </it>experiments was rapid and easy. Analysis of CD14/CD16 and CD11b/Gr1 monocyte expression in human or mouse blood, in a mixed populations of Hz-containing and non-containing monocytes, appears to show distinct patterns in both types of cells. Hz-containing pRBC and different maturation stages could be detected in blood from infected mice. The analysis of a highly depolarizing population that contained mature pRBC allowed to assess the effect of chloroquine and quinine after only 2 and 4 hours, respectively.</p> <p>Conclusions</p> <p>A simple modification of a flow cytometer allows for rapid and reliable detection and quantification of Hz-containing leukocytes and the analysis of differential surface marker expression in the same sample of Hz-containing <it>versus </it>non-Hz-containing leukocytes. Importantly, it distinguishes different maturation stages of parasitized RBC and may be the basis of a rapid no-added-reagent drug sensitivity assay.</p

Long-lasting insecticidal net source, ownership and use in the context of universal coverage: a household survey in eastern Rwanda

Contains fulltext : 162707.pdf (publisher's version ) (Open Access)BACKGROUND: Universal long-lasting insecticidal net (LLIN) coverage (ULC) has reduced malaria morbidity and mortality across Africa. Although information is available on bed net use in specific groups, such as pregnant women and children under 5 years, there is paucity of data on their use among the general population. Bed net source, ownership and determinants of use among individuals from households in an eastern Rwanda community 8 months after a ULC were characterized. METHODS: Using household-based, interviewer-administered questionnaires and interviewer-direct observations, data on bed net source, ownership and key determinants of net use, including demographics, socio-economic status indicators, house structure characteristics, as well as of bed net quantity, type and integrity, were collected from 1400 randomly selected households. Univariate and mixed effects logistic regression modelling was done to assess for determinants of bed net use. RESULTS: A total of 1410 households and 6598 individuals were included in the study. Overall, the proportion of households with at least one net was 92 % while bed net usage was reported among 72 % of household members. Of the households surveyed, a total ownership of 2768 nets was reported, of which about 96 % were reportedly LLINs received from the ULC. By interviewer-physical observation, 88 % of the nets owned were of the LLIN type with the remaining 12 % did not carry any mark to enable type recognition. The odds of bed net use were significantly lower among males and individuals: from households of low socio-economic status, from households with /=two sleeping spaces, and those reporting to have not slept on a bed. CONCLUSION: In this study, despite high a bed net coverage, over 25 % of members reported not to have slept under a bed net the night before the survey. Males were particularly less likely to use bed nets even where nets were available. Household socio-economic status, number of bed nets and type and number of sleeping spaces were key determinants of bed net use. To maximize impact of ULC, strategies that target males as well as those that ensure ITN coverage for all, address barriers to feasible and convenient bed net use including covering over all sleeping space types, and provide net hanging supports, are needed.10 p

Epidemiological and clinical characteristics of international travelers with enteric fever and antibiotic resistance profiles of their isolates: A GeoSentinel analysis

Copyright © 2020 American Society for Microbiology. All Rights Reserved. Enteric fever, caused by Salmonella enterica serovar Typhi (S. Typhi) and S. enterica serovar Paratyphi (S. Paratyphi), is a common travel-related illness. Limited data are available on the antimicrobial resistance (AMR) patterns of these serovars among travelers. Records of travelers with a culture-confirmed diagnosis seen during or after travel from January 2007 to December 2018 were obtained from GeoSentinel. Traveler demographics and antimicrobial susceptibility data were analyzed. Isolates were classified as nonsusceptible if intermediate or resistant or as susceptible in accordance with the participating site’s national guidelines. A total of 889 travelers (S. Typhi infections, n = 474; S. Paratyphi infections, n = 414; coinfection, n = 1) were included; 114 (13%) were children of (41%) traveled to visit friends and relatives (VFRs) and acquired the infection in South Asia (71%). Child travelers with S. Typhi infection were most frequently VFRs (77%). The median trip duration was 31 days (interquartile range, 18 to 61 days), and 448 of 691 travelers (65%) had no pretravel consultation. Of 143 S. Typhi and 75 S. Paratyphi isolates for which there were susceptibility data, nonsusceptibility to antibiotics varied (fluoroquinolones, 65% and 56%, respectively; co-trimoxazole, 13% and 0%; macrolides, 8% and 16%). Two S. Typhi isolates (1.5%) from India were nonsusceptible to third-generation cephalosporins. S. Typhi fluoroquinolone nonsusceptibility was highest when infection was acquired in South Asia (70 of 90 isolates; 78%) and sub-Saharan Africa (6 of 10 isolates; 60%). Enteric fever is an important travel-associated illness complicated by AMR. Our data contribute to a better understanding of region-specific AMR, helping to inform empirical treatment options. Prevention measures need to focus on high-risk travelers including VFRs and children

Multidrug-resistant TB in Zambia: review of national data from 2000 to 2011

Multidrug-resistant tuberculosis (MDR-TB) is posing a great threat to global TB control. The burden in Zambia is not well defined because routine surveillance data are scarce. We reviewed national MDR-TB data for the last decade to inform future public health policy with respect to MDR-TB in Zambia

Individualizing management of extensively drug-resistant tuberculosis:diagnostics, treatment, and biomarkers

Contains fulltext : 170267.pdf (Publisher’s version ) (Open Access)INTRODUCTION: Success rates for treatment of extensively drug resistant tuberculosis (XDR-TB) are low due to limited treatment options, delayed diagnosis and inadequate health care infrastructure. Areas covered: This review analyses existing programmes of prevention, diagnosis and treatment of XDR-TB. Improved diagnostic procedures and rapid molecular tests help to select appropriate drugs and dosages. Drugs dosages can be further tailored to the specific conditions of the patient based on quantitative susceptibility testing of the M. tuberculosis isolate and use of therapeutic drug monitoring. Pharmacovigilance is important for preserving activity of the novel drugs bedaquiline and delamanid. Furthermore, biomarkers of treatment response must be developed and validated to guide therapeutic decisions. Expert commentary: Given the currently poor treatment outcomes and the association of XDR-TB with HIV in endemic regions, a more patient oriented approach regarding diagnostics, drug selection and tailoring and treatment evaluation will improve treatment outcome. The different areas of expertise should be covered by a multidisciplinary team and may involve the transition of patients from hospitalized to home or community-based treatment

On the potential for discontinuing atovaquone-proguanil (AP) ad-hoc post-exposure and other abbreviated AP-regimens: Pharmacology, pharmacokinetics and perspectives

According to current guidelines, atovaquone-proguanil (AP) malaria chemoprophylaxis should be taken once daily starting one day before travel and continued for seven days post-exposure. However, drug-sparing regimens, including discontinuing AP after leaving malaria-endemic areas are cost-saving and probably more attractive to travelers, and may thus enhance adherence. AP has causal prophylactic effects, killing malaria parasites during the hepatic stage. If early hepatic stages were already targeted by AP, AP could possibly be discontinued upon return. Pharmacokinetic data and studies on drug-sparing AP regimens suggest this to be the case. Nevertheless, the evidence is weak and considered insufficient to modify current recommendations. Field trials require large numbers of travelers and inherently suffer from the lack of a control group. Safely-designed controlled human malaria infection trials could significantly reduce study participant numbers and safely establish an effective AP abbreviated regimen which we propose as the optimal trial design to test this concept

Dried blood spots can help decrease the burden on patients dually infected with multidrug-resistant tuberculosis and HIV

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