Tuberculosis impacts multiple aspects in quality of life in a Romanian cohort of drug-susceptible and drug resistant patients: A patient-reported outcome measures study.

BACKGROUND: Tuberculosis (TB), and especially its drug resistant forms, is responsible for not only significant mortality, but also considerable morbidity, still under-quantified. This study used four Patient-Reported Outcome Measures (PROMS) to assess the status of persons affected by drug-susceptible and drug-resistant TB during their TB treatment or after treatment completion, in Romania, the highest TB burden country in the EU. METHODS: People affected by TB in two different regions in Romania were included during and after treatment, following a cross-sectional design. PROMs used were SF-36, EQ-5D-5L, WPAI and the app-based audiometry screening tool 'uHear.' Descriptive statistics and relevant statistical tests were used to compare groups between themselves and with the general Romanian population. RESULTS: Both patients with drug-susceptible and drug-resistant TB experience, with drug-resistant patients experiencing statistically significantly more pain and hearing loss. PROMs show some improvement in the after-treatment group; however, compared with the general Romanian population for which data were available, all groups scored lower on all outcome measures. CONCLUSION: PROMs offer the possibility of obtaining a more comprehensive view of patients' status, by involving them directly in the medical process and could guide a rehabilitation strategy.

Traditional healers' perception on scabies causation and management in Ghana.

INTRODUCTION: Scabies is an underdiagnosed skin infestation caused by the Sarcoptes scabiei mite. The infection causes severe itching and a skin rash but can be effectively treated using topical or systemic drugs. Scabies outbreaks are commonly reported in resource-poor countries, including Ghana. Traditional healers play an important role in primary care in rural areas. The role of these traditional healers in the management of scabies has so far not been explored. The aim of this study was therefore to investigate the perceptions of traditional healers regarding the causation and management of scabies. METHODS: A phenomenological qualitative approach was employed. Traditional healers in the Asante Akim North and Central districts in Ghana were approached with an interview request. Using a semi-structured interview protocol, 15 traditional healers were interviewed. The results were coded and analysed, after which seven themes were extrapolated. RESULTS: Scabies infections were frequently reported by traditional healers. Itching and skin rash were unanimously regarded as the major symptoms of scabies. The majority acknowledged the infectious nature of scabies, but no participant reported the causative organism. A dichotomous disease classification was noted, consisting of 'natural' and 'spiritual' variants each with a unique disease profile and management requirements, as reported by the traditional healers. All but two traditional healers reported to treat scabies using almost exclusively herbs and spiritual rituals. CONCLUSION: The majority of traditional healers were open to collaboration with allopathic healthcare providers. Collaboration could broaden the primary care network in rural areas, but mistrust and lack of transparency form potential barriers to collaboration. We, therefore, emphasise the need for additional efforts to investigate strategies for future collaboration.

Prevalence and determinants of impetigo in Ghana: a cross-sectional study.

INTRODUCTION: Skin diseases such as impetigo pose a significant public health challenge in low resource settings. Despite this, there is a dearth of epidemiological data on the prevalence of this condition in Ghana. METHODS: We conducted a cross sectional study in three settings in Ghana: community members in East Mamprusi district in the North East region, a secondary school in Sekyere East district, and inmates of the Kumasi central prisons both in the Ashanti region. Following a period of training, we performed a standardised skin examination on each participant to assess for scabies and impetigo. We calculated the prevalence of each skin condition and investigated determinants of impetigo. RESULTS/ FINDINGS: Of the 1327 participants [males 64.1% and median age 22 (16-29) years], 746 (56.2%) had scabies and 186 (14%) had impetigo which was usually very mild or mild in severity. Most participants with impetigo also had scabies (161/186, 86.6%). Having an itch [RR 6.05 (95% CI 2.53-14.47)], presence of scabies burrows [RR 1.99 (95% CI 1.54-2.59)], clinical scabies [RR 3.15 (2.11-4.72)] or being in preschool [RR 4.56 (1.78-11.67)] increased the risk for impetigo. A combination of the presence of clinical scabies, age, sex and itch most accurately predicted the odds of having impetigo. CONCLUSIONS: There is substantial burden of impetigo and scabies in Ghana. There is a need to institute measures to improve detection and control of these common dermatoses as part of Universal Health Coverage package to reduce the scourge of the diseases in this setting.

Moxidectin and Ivermectin Inhibit SARS-CoV-2 Replication in Vero E6 Cells but Not in Human Primary Bronchial Epithelial Cells.

Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 µM. These limited in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. However, in April 2021, the World Health Organization stated the following: "The current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive." It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to-head comparison of the antiviral activity of ivermectin and the structurally related, but metabolically more stable moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that these compounds predominantly act on the steps following virus cell entry. Surprisingly, however, in human-airway-derived cell models, both moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at concentrations of 10 µM. These disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on their activity in Vero cells. Altogether, these findings suggest that even using a high-dose regimen of ivermectin, or switching to another drug in the same class, is unlikely to be useful for treatment of SARS-CoV-2 in humans.

Country-specific approaches to latent tuberculosis screening targeting migrants in EU/EEA* countries: A survey of national experts, September 2019 to February 2020.

BackgroundMigrants in low tuberculosis (TB) incidence countries in the European Union (EU)/European Economic Area (EEA) are an at-risk group for latent tuberculosis infection (LTBI) and are increasingly included in LTBI screening programmes.AimTo investigate current approaches and implement LTBI screening in recently arrived migrants in the EU/EEA and Switzerland.MethodsAt least one TB expert working at a national level from the EU/EEA and one TB expert from Switzerland completed an electronic questionnaire. We used descriptive analyses to calculate percentages, and framework analysis to synthesise free-text responses.ResultsExperts from 32 countries were invited to participate (30 countries responded): 15 experts reported an LTBI screening programme targeting migrants in their country; five reported plans to implement one in the near future; and 10 reported having no programme. LTBI screening was predominantly for asylum seekers (n = 12) and refugees (n = 11). Twelve countries use 'country of origin' as the main eligibility criteria. The countries took similar approaches to diagnosis and treatment but different approaches to follow-up. Six experts reported that drop-out rates in migrants were higher compared with non-migrant groups. Most of the experts (n = 22) called for a renewed focus on expanding efforts to screen for LTBI in migrants arriving in low-incidence countries.ConclusionWe found a range of approaches to LTBI screening of migrants in the EU/EEA and Switzerland. Findings suggest a renewed focus is needed to expand and strengthen efforts to meaningfully include migrants in these programmes, in order to meet regional and global elimination targets for TB.

Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial.

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions. METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437. FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts. INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

Predominance of CTX-M-15-producing ST131 strains among ESBL-producing Escherichia coli isolated from asylum seekers in the Netherlands.

OBJECTIVES: Numerous studies show increased prevalence of MDR bacteria amongst asylum seekers, but data on the molecular profiles of such strains are limited. We aimed to evaluate the molecular profiles of ESBL-producing Escherichia coli (ESBL-E. coli) strains isolated from asylum seekers and investigate their phylogenetic relatedness. METHODS: WGS data of ESBL-E. coli isolates from asylum seekers, retrieved from 1 January to 31 December 2016, were analysed to assess MLST STs, fim types, phylogroups and resistance genes. Fifty-two ESBL-E. coli isolates from the Dutch-German border region were used for genome comparison purposes as a control group. RESULTS: Among 112 ESBL-E. coli isolates from asylum seekers, originating mostly from Syria (n = 40) and Iraq (n = 15), the majority belonged to ST131 (21.4%) and ST10 (17.0%). The predominant gene for ß-lactam resistance was blaCTX-M-15 (67.9%), followed by the often co-detected blaTEM-1B (39.3%). No mcr or carbapenemase genes were detected. The majority of the strains belonged to phylogroups B2 (38.4%) and A (32.1%), carrying fimH27 (25%) and fimH30 (19.6%). A core genome MLST minimum spanning tree did not reveal clusters containing strains from the asylum seekers and the control group. Five clusters were formed within the asylum seeker group, by strains isolated from people originating from different countries. CONCLUSIONS: The most frequently isolated clones in this study were isolated on a regular basis within the Dutch population before the increase in the asylum seeker population. No mcr- or carbapenemase-producing clones were detected among the asylum seeker population. Minor clustering was observed amongst the asylum seeker strains.

Co-infection of HIV in patients with Buruli ulcer disease in Central Ghana.

BACKGROUND: Previous studies have reported that presence and severity of Buruli ulcer (BU) may reflect the underlying immunosuppression in HIV infected individuals by causing increased incidence of multiple, larger and ulcerated lesions. We report cases of BU-HIV coinfection and the accompanying programmatic challenges encountered in central Ghana. METHODS: Patients with PCR confirmed BU in central Ghana who were HIV positive were identified and their BU01 forms were retrieved and reviewed in further detail. A combined 16S rRNA reverse transcriptase / IS2404 qPCR assay was used to assess the Mycobacterium ulcerans load. The characteristics of coinfected patients (BU+HIV+) were compared with a group of matched controls. RESULTS: The prevalence of HIV in this BU cohort was 2.4% (compared to national HIV prevalence of 1.7%). Eight of 9 BU+HIV+ patients had a single lesion and ulcers were the most common lesion type. The lesions presented were predominantly category II (5/9) followed by category I lesions. The median (IQR) time to healing was 14 (8-28) weeks in the BU+HIV+ compared to 28 (12-33) weeks in the control BU+HIV- group (p = 0.360). Only one BU+HIV+ developed a paradoxical reaction at week 16 but the lesion healed completely at week 20. The median bacterial load (16SrRNA) of BU+HIV+ patients was 750 copies /ml (95% CI 0-398,000) versus 500 copies/ml (95% CI 0-126,855,500) in BU+HIV- group. Similarly, the median count using the IS2404 assay was 500 copies/ml (95% CI 0-500) for BU+HIV+ patients versus 500 copies/ml (95% CI 500-31,000) for BU+HIV- patients. BU+HIV- patients mounted a significantly higher interferon-γ response compared to the BU+HIV+ co-infected patients with respective median (range) responses of [1687(81.11-4399) pg/ml] versus [137.5(4.436-1406) pg/ml, p = 0.03]. There were challenges with the integration of HIV and BU care in this cohort. CONCLUSION: The prevalence of HIV in the BU+ infected population was not significantly increased when compared to the prevalence of HIV in the general population. There was no clear relationship between BU lesion severity and HIV viral load or CD4 counts. Efforts should be made to encourage the integration of care of patients with BU-HIV coinfection.

High-Dose Rifamycins Enable Shorter Oral Treatment in a Murine Model of Mycobacterium ulcerans Disease.

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an 8-week course of rifampin (RIF) at 10 mg/kg of body weight and 150 mg/kg streptomycin (STR). Recently, the injectable STR has been shown to be replaceable with oral clarithromycin (CLR) for smaller lesions for the last 4 weeks of treatment. A shorter, all-oral, highly efficient regimen for BU is needed, as the long treatment duration and indirect costs currently burden patients and health systems. Increasing the dose of RIF or replacing it with the more potent rifamycin drug rifapentine (RPT) could provide such a regimen. Here, we performed a dose-ranging experiment of RIF and RPT in combination with CLR over 4 weeks of treatment in a mouse model of M. ulcerans disease. A clear dose-dependent effect of RIF on both clinical and microbiological outcomes was found, with no ceiling effect observed with tested doses up to 40 mg/kg. RPT-containing regimens were more effective on M. ulcerans All RPT-containing regimens achieved culture negativity after only 4 weeks, while only the regimen with the highest RIF dose (40 mg/kg) did so. We conclude that there is dose-dependent efficacy of both RIF and RPT and that a ceiling effect is not reached with the current standard regimen used in the clinic. A regimen based on higher rifamycin doses than are currently being evaluated against tuberculosis in clinical trials could shorten and improve therapy of Buruli ulcer.

Darunavir Population Pharmacokinetic Model Based on HIV Outpatient Data.

BACKGROUND: Darunavir is a second-generation protease inhibitor and is registered for the treatment of HIV-1 infection. The aim of this study was to develop and validate a darunavir population pharmacokinetic model based on data from daily practice. METHODS: Data sets were obtained from 2 hospitals: ASST Fatebenefratelli Sacco University Hospital, Italy (hospital A), and University Medical Center Groningen, the Netherlands (hospital B). A pharmacokinetic model was developed using data from the largest data set using the iterative two-stage Bayesian procedure within the MWPharm software package. External validation was conducted using data from the smaller data set with Passing-Bablok regression and Bland-Altman analyses. RESULTS: In total, data from 198 patients from hospital A and 170 patients from hospital B were eligible for inclusion. A 1-compartment model with first-order absorption and elimination resulted in the best model. The Passing-Bablok analysis demonstrated a linear correlation between measured concentration and predicted concentration with r = 0.97 (P < 0.05). The predicted values correlated well with the measured values as determined by a Bland-Altman analysis and were overestimated by a mean value of 0.12 mg/L (range 0.23-0.94 mg/L). A total of 98.2% of the predicted values were within the limits of agreement. CONCLUSIONS: A robust population pharmacokinetic model was developed, which can support therapeutic drug monitoring of darunavir in daily outpatient settings.

Sensitivity and specificity of routine diagnostic work-up for tuberculosis in lung clinics in Yogyakarta, Indonesia: a cohort study.

BACKGROUND: Establishing a correct diagnosis is challenging. We aimed to investigate the sensitivity and specificity of routine tuberculosis (TB) diagnostic work-up in lung clinics in Indonesia, a country with the third highest TB burden and the second highest gap between notifications of TB cases and the best estimate of incident cases in the world. METHODS: In the lung clinics of the Province of Yogyakarta, Indonesia, we recruited all consecutive patients with symptoms suggesting TB, aged ≥18 years. Routine TB examination consisted of clinical evaluation, sputum smear microscopy, and chest radiography. For research purposes, we added sputum culture, Human Immunodeficiency Virus (HIV) testing, and follow-up for 1.5 years or 2.5 years if culture results disagreed with the initial clinical diagnosis. The initial diagnosis was considered incorrect if patients did not respond to treatment. We calculated sensitivity and specificity of the TB routine examination using culture and a composite reference standard (CRS - a combination of routine examination, culture, and follow-up) as the reference standards. All analyses were conducted with IBM SPSS Statistics 25 (IBM Corp., Armonk, NY, USA). RESULTS: Between 2013 and 2015, we included 360 participants, and 21 were excluded due to incomplete data. Among those analyzed, 115 were initially diagnosed with smear-positive TB, 12 with smear-negative TB, and 212 non-TB. In 15 study participants, the diagnosis was changed after median 45 (range: 14-870) days; 14 participants initially not diagnosed with TB were later diagnosed with TB, while one subject initially diagnosed with TB actually did not have TB. Compared with culture and CRS, TB routine examination had sensitivity of 85% (95%CI: 77-91) and 90% (95%CI: 84-94), and specificity of 86.3% (95%CI: 81-91) and 99.5% (95%CI: 97-100), respectively. CONCLUSIONS: A combination of clinical evaluation with sputum microscopy and chest radiography provided high sensitivity and specificity in diagnosing TB in lung clinics; in only 4.4% the diagnosis was incorrect. There is a need to improve routine TB diagnostic work by using clinical evaluation, sputum smear microscopy, and chest radiography all together in other settings, such as in primary health centers. TRIAL REGISTRATION: NCT02219945 , clinicaltrials.gov . Registered 19 August 2014 (retrospectively registered).

Risk factors contributing to a low darunavir plasma concentration.

Darunavir is an efficacious drug; however, pharmacokinetic variability has been reported. The objective of this study was to find predisposing factors for low darunavir plasma concentrations in patients starting the once- or twice-daily dosage. Darunavir plasma concentrations from January 2010 till December 2014 of human immunodeficiency virus-infected individuals treated in the outpatient clinic of the University Medical Center Groningen were retrospectively reviewed. The first darunavir plasma concentration of patients within 8 weeks after initiation of darunavir therapy was selected. A dichotomous logistic regression analysis was conducted to select the set of variables best predicting a darunavir concentration below median population pharmacokinetic curve. In total 113 patients were included. The variables best predicting a darunavir concentration besides food intake included age together with estimated glomerular filtration rate (Hosmer-Lemeshow test P = 0.945, Nagelkerke R2  = 0.284). Systematic evaluation of therapeutic drug monitoring results may help to identify patients at risk for low drug exposure.

Screening for infectious diseases of asylum seekers upon arrival: the necessity of the moral principle of reciprocity.

BACKGROUND: With a large number of forcibly displaced people seeking safety, the EU is facing a challenge in maintaining solidarity. Europe has seen millions of asylum seekers crossing European borders, the largest number of asylum seekers since the second world war. Endemic diseases and often failing health systems in their countries of origin, and arduous conditions during transit, raise questions around how to meet the health needs of this vulnerable population on arrival in terms of screening, vaccination, and access to timely and appropriate statutory health services. This paper explores the potential role of the principle of reciprocity, defined as the disposition 'to return good in proportion to the good we receive, and to make reparations for the harm we have done', as a mid-level principle in infectious disease screening policies. MAIN TEXT: More than half of the European countries implemented screening programmes for newly arrived asylum seekers. Screening may serve to avoid potential infectious disease risks in the receiving countries as well as help identify health needs of asylum seekers. But screening may infringe upon basic rights of those screened, thus creating an ethical dilemma. The use of the principle of reciprocity can contribute to the identification of potential improvements for current screening programmes and emphasizes the importance of certain rights into guidelines for screening. It may create a two way moral obligation, upon asylum seekers to actively participate in the programme, and upon authorities to reciprocate the asylum seekers' participation and the benefits for the control of public health. CONCLUSION: The authors argue that the reciprocity principle leads to a stronger ethical justification of screening programmes and help achieve a balance between justifiable rights claims of the host population and the asylum seekers. The principle deserves a further and more thorough exploration of its potential use in the field of screening, migration and infectious diseases.

Divergent approaches in the vaccination of recently arrived migrants to Europe: a survey of national experts from 32 countries, 2017.

BackgroundMigrants within the European Union and European Economic Area (EU/EEA) may be underimmunised and lack documentation on previous vaccinations. We investigated approaches to vaccination in recently arrived adult and child migrants, and guideline availability and implementation. Methods: Between March and May 2017, a national vaccination expert from every EU/EEA country and Switzerland completed an electronic questionnaire. We used descriptive analyses to calculate percentages, and framework analysis to synthesise free-text responses. Results: We approached 32 countries (response rate 100%). Although 28 experts reported vaccination guidance at national level, specific guidelines for recently arrived migrants were only available in six countries and not consistently implemented. Twenty-three countries administered vaccinations during on-arrival health checks. Most experts recommended multiple vaccination opportunities be made available: at point of entry (n = 13) or at holding level (reception centres, migrant camps, detention centres) (n = 21). In 30 countries, child migrants without evidence of previous vaccination were re-vaccinated according to the national schedule. Diphtheria-pertussis-tetanus and polio vaccinations were given to migrant children in all countries, measles-mumps-rubella (MMR) in 31 countries, hepatitis B vaccination in 25. Low levels of catch-up vaccination were reported in adult migrants, with only 13 countries offering MMR and 10 countries charging fees. Conclusion: Existing guidance is often not migrant-specific and may not be applied in practice; clarification is needed on which vaccines should be given. Strategies are needed specifically for catch-up vaccination in adult migrants. Vaccinations should be offered in multiple settings, free of charge, with sufficient guidance and training provided to front-line healthcare professionals.

Virulence potential of Staphylococcus aureus isolates from Buruli ulcer patients.

Buruli ulcer (BU) is a necrotizing infection of the skin and subcutaneous tissue caused by Mycobacterium ulcerans. BU wounds may also be colonized with other microorganisms including Staphylococcus aureus. This study aimed to characterize the virulence factors of S. aureus isolated from BU patients. Previously sequenced genomes of 21 S. aureus isolates from BU patients were screened for the presence of virulence genes. The results show that all S. aureus isolates harbored on their core genomes genes for known virulence factors like α-hemolysin, and the α- and ß-phenol soluble modulins. Besides the core genome virulence genes, mobile genetic elements (MGEs), i.e. prophages, genomic islands, pathogenicity islands and a Staphylococcal cassette chromosome (SCC) were found to carry different combinations of virulence factors, among them genes that are known to encode factors that promote immune evasion, superantigens and Panton-Valentine Leucocidin. The present observations imply that the S. aureus isolates from BU patients harbor a diverse repertoire of virulence genes that may enhance bacterial survival and persistence in the wound environment and potentially contribute to delayed wound healing.

Food intake and darunavir plasma concentrations in people living with HIV in an outpatient setting.

AIMS: Patients receiving darunavir are advised to take it concomitantly with food. The objectives of the present cross-sectional study were to evaluate the actual concomitant food intake of patients visiting an HIV outpatient clinic. METHODS: Sixty participants treated with darunavir/ritonavir once daily were subjected to a food recall questionnaire concerning their last concomitant food intake with darunavir. Darunavir trough concentrations were calculated. RESULTS: The median food intake was 507 (0-2707) kcal; protein intake, 20 (0-221)g; carbohydrate intake, 62 (0-267)g; fat intake: 14 (0-143)g; and dietary fibre: 4 (0-30)g. Twenty-five patients (42%) ingested their drug with between-meal snacks. No relationship was found between food intake and trough concentrations. CONCLUSIONS: Clear advice on the optimal caloric intake is needed, to avoid high caloric intake in patients who already have an increased risk of cardiovascular disease due to their HIV infection.

Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment-naive TB patients: a randomized cross-over trial.

OBJECTIVES: Concomitant food intake influences pharmacokinetics of first-line anti-TB drugs in healthy volunteers. However, in treatment-naive TB patients who are starting with drug treatment, data on the influence of food intake on the pharmacokinetics are absent. This study aimed to quantify the influence of food on the pharmacokinetics of isoniazid, rifampicin, ethambutol and pyrazinamide in TB patients starting anti-TB treatment. METHODS: A prospective randomized cross-over pharmacokinetic study was conducted in treatment-naive adults with drug-susceptible TB. They received isoniazid, rifampicin and ethambutol intravenously and oral pyrazinamide on day 1, followed by oral administration of these drugs under fasted and fed conditions on two consecutive days. Primary outcome was the bioavailability while fasting and with concomitant food intake. This study was registered with clinicaltrials.gov identifier NCT02121314. RESULTS: Twenty subjects completed the study protocol. Absolute bioavailability in the fasted state and the fed state was 93% and 78% for isoniazid, 87% and 71% for rifampicin and 87% and 82% for ethambutol. Food decreased absolute bioavailability of isoniazid and rifampicin by 15% and 16%, respectively. Pyrazinamide AUC0-24 was comparable for the fasted state (481 mg·h/L) and the fed state (468 mg·h/L). Food lowered the maximum concentrations of isoniazid, rifampicin and pyrazinamide by 42%, 22% and 10%, respectively. Time to maximum concentration was delayed for isoniazid, rifampicin and pyrazinamide. The pharmacokinetics of ethambutol were unaffected by food. CONCLUSIONS: Food decreased absolute bioavailability and maximum concentration of isoniazid and rifampicin, but not of ethambutol or pyrazinamide, in treatment-naive TB patients. In patients prone to low drug exposure, this may further compromise treatment efficacy and increase the risk of acquired drug resistance.

Correspondence: The African snakebite Alliance.

The goal to reduce the burden of snakebite envenoming is challenged by the gaps in evidence for clinical care and public health. These evidence gaps and the absence of a strong network are illustrated by bibliometrics. The African Snakebite Alliance is a multidisciplinary group focusing on research themes which will generate evidence needed to shape policy and practice.