Antibiotic use by clinical presentation across all healthcare providers in rural Burkina Faso: a healthcare visit exit survey.

BACKGROUND: To guide antibiotic stewardship interventions, understanding for what indications antibiotics are used is essential. METHODS: In rural Burkina Faso, we measured antibiotic dispensing across all healthcare providers. From October 2021 to February 2022, we surveyed patients in Nanoro district, Burkina Faso, following visits to health centres (3), pharmacies (2), informal medicine vendors (5) and inpatients in health centres. We estimated prevalence of antibiotic use and the proportion of Watch group antibiotics by provider type and by clinical presentation, assessing compliance with WHO's AWaRe Antibiotic Book. We estimated per capita antibiotic use by multiplying prevalence of antibiotic use, mean DDD per adult treatment course, and the rate of healthcare visits per 1000 inhabitants per day, estimated from a prior household survey. RESULTS: Outpatient antibiotic use was more frequent after health centre visits (54.8%, of which 16.5% Watch, n = 1249) than after visits to pharmacies (26.2%, 16.3% Watch, n = 328) and informal medicine vendors (26.9%, 50.0% Watch, n = 349). The frequency of antibiotic use was highest for bronchitis (79.9% antibiotic use, of which 12.6% Watch), malaria (31.9%, 23.1% Watch), gastroenteritis (76.0%, 31.7% Watch), rhinopharyngitis (40.4%, 8.3% Watch) and undifferentiated fever (77.0%, 44.8% Watch). Compliance with WHO AWaRe guidance could have averted at least 68.4% of all Watch antibiotic use in outpatients at health centres. Community-wide, 2.9 DDD (95% CI 1.9-3.9) were used per 1000 adult inhabitants per day. CONCLUSIONS: Most Watch antibiotic use at community level or primary care deviated from WHO guidance. Antibiotic stewardship should focus on key clinical presentations and include primary care and self-medication.

Evolution of Pfdhps and Pfdhfr mutations before and after adopting seasonal malaria chemoprevention in Nanoro, Burkina Faso.

Seasonal Malaria Chemoprevention consisting of monthly administration of amodiaquine/sulfadoxine-pyrimethamine to children aged 3-59 months during the transmission season could promote SP-resistance. Mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes were assessed before and after SMC adoption in Burkina Faso. A total of 769 dried blood spots were selected from studies conducted in Nanoro, Burkina Faso, between 2010 and 2020. Of those, 299 were pre-SMC (2010-2012) and 470 were post-SMC-samples. Pfdhps and Pfdhfr genes were PCR-amplified and sequenced. A systematic review/meta-analysis of published studies conducted in Burkina Faso (2009-2023) was additionally performed. In Nanoro, the prevalence of Pfdhfr triple mutations (CIRNI) rose from 43.6% pre-SMC to 89.4% post-SMC (p < 0.0001). There was no mutation in Pfdhfr 164 and Pfdhps 540; Pfdhps A437G mutation increased from 63.9% (2010-2012) to 84.7% (2020) (p < 0.0001). The VAGKGS haplotype was 2.8% (2020). Pfdhfr/Pfdhps quintuple mutant IRN-436A437G rose from 18.6% (2010-2012) to 58.3% (2020) (p < 0.0001). Meta-analysis results from Burkina Faso showed an increase in mutations at Pfdhfr N51I, C59R, S108N, and Pfdhps A437G after SMC adoption. Post-SMC, the pyrimethamine-resistance marker prevalence increased, while the sulfadoxine-resistance marker prevalence remained stable. Detection of emerging PfdhpsVAGKGS haplotypes in 2020 underscores the importance of continuous SP-resistance monitoring.

Pharmacokinetics of Ganaplacide and Lumefantrine in Adults, Adolescents, and Children with Plasmodium falciparum Malaria Treated with Ganaplacide Plus Lumefantrine Solid Dispersion Formulation: Analysis of Data from a Multinational Phase 2 Study.

The novel antimalarial ganaplacide combined with lumefantrine solid dispersion formulation (LUM-SDF) was effective and well tolerated in the treatment of uncomplicated falciparum malaria in adults, adolescents, and children in a multinational, prospective, randomized, active-controlled Phase II study conducted between August 2017 and June 2021 (EudraCT 2020-003284-25, Clinicaltrials.gov NCT03167242). Pharmacokinetic data from that study are reported here. The trial comprised three parts: a run-in part in 12 adult/adolescent patients treated with a single dose of ganaplacide 200 mg plus LUM-SDF 960 mg assessed potential pharmacokinetic (PK) interactions between ganaplacide and lumefantrine; in Part A, adult/adolescent patients received one of the six ganaplacide-LUM-SDF regimens or artemether-lumefantrine; and in Part B, three dose regimens identified in Part A, and artemether-lumefantrine, were assessed in children aged 2 to <12 years, with body weight ≥10 kg. A rich blood sampling schedule was used for all 12 patients in the PK run-in part and a subset of patients (N = 32) in Part A, with sparse sampling for remaining patients in Parts A (N = 275) and B (N = 159). Drug concentrations were determined by a validated protein precipitation and reverse phase liquid chromatography with tandem mass spectrometry detection method. Parameters including AUCinf, AUClast, AUC0-t, Cmax, and tmax were reported where possible, using non-compartmental analysis. In the PK run-in part, there was no notable increase in ganaplacide or lumefantrine exposure when co-administered. In Parts A and B, ganaplacide exposures increased with dose, but lumefantrine exposure was numerically under dose-proportional. Lumefantrine exposure was higher with ganaplacide-LUM-SDF than with artemether-lumefantrine, although high variability was observed. Ganaplacide and lumefantrine exposures (Cmax and AUC0-24 h) were comparable across age and body weight groups. Drug exposures needed for efficacy were achieved using the dose regimen 400 mg ganaplacide plus lumefantrine 960 mg once daily for 3 days under fasted conditions.

Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial.

BACKGROUND: Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria. METHODS: This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (>1000 and <150 000 parasites per µL). Part A identified the optimal dose regimens in adults and adolescents (aged ≥12 years) and in part B, the selected doses were assessed in children (≥2 years and <12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to <6 years and 6 to <12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020-003284-25) and ClinicalTrials.gov (NCT03167242). FINDINGS: Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81-98] with 1 day, 47 of 48 [98%, 89-100] with 2 days, and 42 of 43 [98%, 88-100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83-99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93-100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92-100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86-100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83-99] vs 21 of 22 [96%, 77-100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study. INTERPRETATION: Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633). FUNDING: Novartis and Medicines for Malaria Venture.