Using (1,3)-β-D-glucan concentrations in serum to monitor the response of azole therapy in patients with eumycetoma caused by Madurella mycetomatis

Introduction: (1,3)-β-D-glucan is a panfungal biomarker secreted by many fungi, including Madurella mycetomatis, the main causative agent of eumycetoma. Previously we demonstrated that (1,3)-β-D-glucan was present in serum of patients with eumycetoma. However, the use of (1,3)-β-D-glucan to monitor treatment responses in patients with eumycetoma has not been evaluated. Materials and Methods: In this study, we measured (1,3)-β-D-glucan concentrations in serum with the WAKO (1,3)-β-D-glucan assay in 104 patients with eumycetoma treated with either 400 mg itraconazole daily, or 200 mg or 300 mg fosravuconazole weekly. Serial serum (1,3)-β-D-glucan concentrations were measured at seven different timepoints. Any correlation between initial and final (1,3)-β-D-glucan concentrations and clinical outcome was evaluated. Results: The concentration of (1,3)-β-D-glucan was obtained in a total of 654 serum samples. Before treatment, the average (1,3)-β-D-glucan concentration was 22.86 pg/mL. During the first 6 months of treatment, this concentration remained stable. (1,3)-β-D-glucan concentrations significantly dropped after surgery to 8.56 pg/mL. After treatment was stopped, there was clinical evidence of recurrence in 18 patients. Seven of these 18 patients had a (1,3)-β-D-glucan concentration above the 5.5 pg/mL cut-off value for positivity, while in the remaining 11 patients, (1,3)-β-D-glucan concentrations were below the cut-off value. This resulted in a sensitivity of 38.9% and specificity of 75.0%. A correlation between lesion size and (1,3)-β-D-glucan concentration was noted. Conclusion: Although in general (1,3)-β-D-glucan concentrations can be measured in the serum of patients with eumycetoma during treatment, a sharp decrease in β-glucan concentration was only noted after surgery and not during or after antimicrobial treatment. (1,3)-β-D-glucan concentrations were not predictive for recurrence and seem to have no value in determining treatment response to azoles in patients with eumycetoma.</p

Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS)

BACKGROUND: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. METHODS AND FINDINGS: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. CONCLUSION: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302)

Factors associated with treatment type of non-malarial febrile illnesses in under-fives at Kenyatta National Hospital in Nairobi, Kenya.

BackgroundNon-malarial febrile illnesses comprise of almost half of all fever presenting morbidities, among under-five children in sub-Saharan Africa. Studies have reported cases of prescription of antimalarial medications to these febrile under-fives who were negative for malaria. The treatment of these children with antimalarial medications increases incidences of antimalarial drug resistance as well as further morbidities and mortalities, due to failure to treat the actual underlying causes of fever.AimTo identify clinical and demographic factors associated with treatment type (malarial/non-malarial) of non-malarial febrile illnesses (NMFI) in children aged ≤5 at the Kenyatta National Hospital in Nairobi, Kenya.MethodsA positivist epistemological approach, cross sectional descriptive study design was used. A structured questionnaire was used on a sample of 341 medical records of children aged ≤5 years to extract data on clinical examinations (recorded as yes or no), diagnostic test results, and demographic data on the child's sex and age. Descriptive and inferential analysis was applied to the data.ResultsPrescription of antimalarial drugs despite negative microscopy results was found in 44 (12.9%) of the children, with mortality reported in 48 (14.1%). Assessment of respiratory distress was 0.13 (0.03,0.58) times associated with less likelihood of prescribing an antimalarial in those with a negative microscopy. A male patient was 0.21 (0.05,0.89) times less likely to receive an intravenous antimalarial after a negative microscopy. Patients aged ˂1 with a negative microscopy result were more likely to receive an antimalarial than older children.ConclusionThere is a need to eliminate incorrect treatment of NMFI with antimalarial medication, while ensuring correct diagnosis and treatment of the specific illness occurs. This requires strengthening and adherence to diagnostic and treatment guidelines of febrile illnesses in under-fives, consequently reducing morbidities and mortalities associated with inadequate management of NMFIs

Data from: Volunteer motivators for participating in HIV vaccine clinical trials in Nairobi, Kenya

Article Authors Metrics Comments Related Content Abstract Introduction Materials and methods Results Discussion Limitations Conclusion Supporting information Acknowledgments References Reader Comments (0) Media Coverage (0) Figures Abstract Background: 1.5 million Kenyans are living with HIV/AIDS as per 2015 estimates. Though there is a notable decline in new HIV infections, continued effort is still needed to develop an efficacious, accessible and affordable HIV vaccine. HIV vaccine clinical trials bear risks, hence a need to understand volunteer motivators for enrolment, retention and follow-up. Understanding the factors that motivate volunteers to participate in a clinical trial can help to strategize, refine targeting and thus increase enrolment of volunteers in future HIV vaccine clinical trials. The health belief model classifies motivators into social benefits such as ‘advancing research’ and collaboration with science, and personal benefits such as health benefits and financial interests. Method: A thematic analysis was carried out on data obtained from four HIV clinical trials conducted at KAVI-Institute of Clinical Research in Nairobi Kenya from 2009 to 2015. Responses were obtained from a Questionnaire administered to the volunteers during their screening visit at the research site. Results: Of the 281 healthy, HIV-uninfected volunteers participating in this study; 38% were motivated by personal benefits including, 31% motivated by health benefits and 7% motivated by possible financial gains. In addition, 62% of the volunteers were motivated by social benefits with 20% of who were seeking to help their family/society/world while 42% were interested in advancing research. Conclusion: The majority of volunteers in the HIV vaccine trials at our site were motivated by social benefits, suggesting that altruism can be a major contributor to participation in HIV vaccine studies. Personal benefits were a secondary motivator for the volunteers. The motivators to volunteer in HIV clinical trials were similar across ages, education level and gender. Education on what is needed (including volunteer participation) to develop an efficacious vaccine could be the key to greater volunteer motivation to participate in HIV vaccine clinical trials

Volunteer motivators for participating in HIV vaccine clinical trials in Nairobi, Kenya.

1.5 million Kenyans are living with HIV/AIDS as per 2015 estimates. Though there is a notable decline in new HIV infections, continued effort is still needed to develop an efficacious, accessible and affordable HIV vaccine. HIV vaccine clinical trials bear risks, hence a need to understand volunteer motivators for enrolment, retention and follow-up. Understanding the factors that motivate volunteers to participate in a clinical trial can help to strategize, refine targeting and thus increase enrolment of volunteers in future HIV vaccine clinical trials. The health belief model classifies motivators into social benefits such as 'advancing research' and collaboration with science, and personal benefits such as health benefits and financial interests.A thematic analysis was carried out on data obtained from four HIV clinical trials conducted at KAVI-Institute of Clinical Research in Nairobi Kenya from 2009 to 2015. Responses were obtained from a Questionnaire administered to the volunteers during their screening visit at the research site.Of the 281 healthy, HIV-uninfected volunteers participating in this study; 38% were motivated by personal benefits including, 31% motivated by health benefits and 7% motivated by possible financial gains. In addition, 62% of the volunteers were motivated by social benefits with 20% of who were seeking to help their family/society/world while 42% were interested in advancing research.The majority of volunteers in the HIV vaccine trials at our site were motivated by social benefits, suggesting that altruism can be a major contributor to participation in HIV vaccine studies. Personal benefits were a secondary motivator for the volunteers. The motivators to volunteer in HIV clinical trials were similar across ages, education level and gender. Education on what is needed (including volunteer participation) to develop an efficacious vaccine could be the key to greater volunteer motivation to participate in HIV vaccine clinical trials

Volunteer Motivators Dataset

The data file contains the socio-demographic variables of the respondents and their motivators which were labelled into recurring themes (codes)

Health belief model components.

<p>Health belief model components.</p

Volunteer motivators by gender.

<p>Volunteer motivators by gender.</p

Motivation codes.

<p>Motivation codes.</p

Epidemiological cut-off values for itraconazole and ravuconazole for Madurella mycetomatis, the most common causative agent of mycetoma

Background Eumycetoma is a neglected tropical disease. It is a chronic inflammatory subcutaneous infection characterised by painless swellings which produce grains. It is currently treated with a combination of itraconazole and surgery. In an ongoing clinical study, the efficacy of fosravuconazole, the prodrug of ravuconazole, is being investigated. For both itraconazole and ravuconazole, no clinical breakpoints or epidemiological cut-off values (ECV) to guide treatment are currently available. Objective To determine tentative ECVs for itraconazole and ravuconazole in Madurella mycetomatis, the main causative agent of eumycetoma. Materials and Methods Minimal inhibitory concentrations (MICs) for itraconazole and ravuconazole were determined in 131 genetically diverse clinical M. mycetomatis isolates with the modified CLSI M38 broth microdilution method. The MIC distributions were established and used to determine ECVs with the ECOFFinder software. CYP51A sequences were sequenced to determine whether mutations occurred in this azole target gene, and comparisons were made between the different CYP51A variants and the MIC distributions. Results The MICs ranged from 0.008 to 1 mg/L for itraconazole and from 0.002 to 0.125 mg/L for ravuconazole. The M. mycetomatis ECV for itraconazole was 1 mg/L and for ravuconazole 0.064 mg/L. In the wild-type population, two CYP51A variants were found for M. mycetomatis, which differed in one amino acid at position 499 (S499G). The MIC distributions for itraconazole and ravuconazole were similar between the two variants. No mutations linked to decreased susceptibility were found. Conclusion The proposed M. mycetomatis ECV for itraconazole is 1 mg/L and for ravuconazole 0.064 mg/L