Non-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.
To 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.
A 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.
Prescription 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.
There 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.
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.
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.
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.
IntroductionLong-acting reversible contraceptives (LARCs) are effective birth control methods that do not depend on patient compliance. They include injections, intrauterine devices (IUDs) and ...sub-dermal implants. Kenya had over 1.5 million people living with HIV in 2015 with female sex workers (FSWs) known to be at a higher risk for both unintended pregnancies and HIV infection. HIV clinical trials test novel compounds whose effects in fetuses are unknown thus require female subjects to use LARCs to avoid pregnancies. Clinical trials also aim to recruit high-risk individuals to closely study infection dynamics in a representative natural infection cohort. Therefore, it is crucial to investigate the preference for contraception in a HIV-high risk population such as FSWs to inform the design and conduct of HIV vaccine clinical trials, especially in the resource-limited Sub-Saharan Africa. The on-going Simulated Vaccine Efficacy Trial (SiVET) Study at KAVI-ICR may provide answers to this.MethodsData on use of modern contraception methods (pills, injectables, implants, IUDs and surgicals) are collected from FSWs during screening, and confirmed by a contraceptive card or the presence of an implant or IUD strings. The proportion of women per method used is determined.ResultsSeventy nine women with an age range of 18–50 years have been screened since 2016. Most (89%, n=73) were already using contraception. Of these; 63% (n=46) were on injectables, 22% on implants (n=16), 8% IUCDs (n=6), 4% pills (n=3) and 3% (n=2) had undergone a surgical method. No pregnancy while two HIV infections were reported at screening.ConclusionThere is high contraceptive use among the FSWs with the majority preferring injectables. This practice is encouraging and thus, discontinuation of volunteers from the clinical trial due to pregnancy is unlikely. At the end of trial in 2018, data will be collected on changes in contraceptive, number of pregnancies, condom use, HIV infections and experience on use of the contraception.
Mycetoma is a neglected tropical disease (NTD) with devastating morbidity and stigma. Despite increased awareness and international collaboration, the burden of mycetoma is largely unknown and ...diagnosis and treatment are difficult. Addressing mycetoma globally aligns with several United Nation's Sustainable Development Goals (SDGs). Little progress has been made since the WHO's NTD roadmap publication in 2020. The Global Mycetoma Working Group proposes an enhanced mycetoma-control roadmap to meet the SDGs, stimulate progress and improve the lives of patients experiencing mycetoma. By aligning mycetoma management with the goals and targets of this enhanced roadmap, it becomes possible to leverage existing resources, infrastructure and partnerships to improve the lives of affected individuals and communities. This updated assessment is designed for the benefit of health workers and providers in mycetoma-endemic areas, NTD government officials, civil society and funding and implementing agencies.
Abstract
Background
Fosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data ...exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking.
Objectives
To generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data.
Methods
The NeoFosfo study (NCT03453177) was a randomized trial that examined the safety and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model was developed in NONMEM and simulations were performed.
Results
In total, 238 plasma and 15 CSF concentrations were collected. A two-compartment disposition model, with an additional CSF compartment and first-order absorption, best described the data. Bioavailability was estimated as 0.48 (95% CI = 0.347–0.775) and the CSF/plasma ratio as 0.32 (95% CI = 0.272–0.409). Allometric weight and postmenstrual age (PMA) scaling was applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on CSF/plasma ratio.
Conclusions
Through this analysis a population pharmacokinetic model has been developed that can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin dose based on an infant’s PMA, PNA and weight.
Abstract
S4.5 Mycetoma Clinical Trial on fosravuconazole treatment in eumycetoma– Top Line Results, September 22, 2022, 10:30 AM - 12:00 PM
Objectives
Eumycetoma is a neglected tropical disease ...characterized by large subcutaneous swellings and the formation of grains and most commonly caused by Madurella mycetomatis. The currently recommended therapy is a combination of antifungal therapy with an azole and surgery. Itraconazole is the current recommended drug and fosravuconazole, the pro-drug of ravuconzole, is currently clinically investigated. At the moment, there are no epidemiological cut-off values (ECV) for M. mycetomatis for either of these drugs or rapid diagnostic tests which can predict the therapeutic outcome of these treatments. Therefore, in this study, we determined the ECV for these drugs and determined whether there was a correlation between minimal inhibitory concentration (MIC) and the DNA sequence of the azole target gene CYP51A. We also assessed beta-glucan concentrations in the serum of mycetoma patients during treatment to establish whether any of these values were predictive for therapeutic outcomes.
Methods
In order to determine the ECV for M. mycetomatis, MIC distributions for itraconazole and ravuconazole were determined in genetically diverse clinical M. mycetomatis isolates using the ECOFFinder software. CYP51A sequences were sequenced and comparisons were made between the different CYP51A variants and the MIC distributions. Beta-glucan concentrations were measured in serum with the WAKO beta-glucan assay. Time points analyzed were 0, 22, 85, 176, 267, 358, and 455 days after the start of treatment.
Results
For M. mycetomatis 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. The MIC distributions for itraconazole and ravuconazole were similar between the two variants. No mutations linked to decreased susceptibility were found. Before the start of treatment, beta-glucan concentrations ranged from below the detection limit to 217.9 pg/ml. Of these patients, 61.2% had a beta-glucan concentration above 7 pg/ml, the recommended cut-off value for positivity by the manufacturer, 72.8% had a beta-glucan concentration above 5.5 pg/ml, the recommended cut-off value for M. mycetomatis. During the first months of azole treatment, the beta-glucan concentrations remained relatively stable. After surgery, a sharp decrease in beta-glucan concentration in serum was noted. At the end of the observation period, only 13 patients had a beta-glucan concentration above 7 pg/ml and 14 above 5.5 pg/ml. Of these patients, for only 3, there was clinical evidence of a recurrence. For the remaining 4 patients with clinical evidence of a recurrence, the beta-glucan concentration was below the cut-off value for positivity.
Conclusion
In conclusion, so far there was no link established with the initial in vitro susceptibility and failure or success of the treatment therapy. Beta-glucan levels, in general, remained high during azole treatment, and a sharp drop in beta-glucan concentration in serum was only noted after surgery. A positive beta-glucan concentration at the end of the treatment was not indicative of a recurrence.
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.
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.
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.
ClinicalTrials.gov, (NCT03721302).
Abstract
Objectives
This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis.
Methods
...Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens.
Results
A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.
Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index < 0.5 (synergy) and most in the range 0.5–1 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains.
Conclusions
PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis.
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