SummaryBackgroundArtemether–lumefantrine and artesunate–amodiaquine are used as first-line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine–artesunate and dihydroartemisinin–piperaquine are potentially useful for diversification of ACTs in this region, but further safety and efficacy data are required on malaria retreatment.MethodsWe did a randomised, multicentre, open-label, longitudinal, controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso, Guinea, and Mali. Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria (>0 to <200 000 parasites per μL of blood) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria, an alanine aminotransferase concentration of more than twice the upper limit of normal, or a QTc greater than 450 ms were excluded. Using a randomisation list for each site, masked using sealed envelopes, participants were assigned to either pyronaridine–artesunate or dihydroartemisinin–piperaquine versus either artesunate–amodiaquine or artemether–lumefantrine. Block sizes were two or four if two treatments were allocated, and three or six if three treatments were allocated. Microscopists doing the parasitological assessments were masked to treatment allocation. All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre. Patients were followed up as outpatients up to day 42, receiving clinical assessments on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Two primary outcomes were compared for non-inferiority: the 2-year incidence rate of all microscopically confirmed, complicated and uncomplicated malaria episodes in patients in the intention-to-treat population (ITT; non-inferiority margin 20%); and adequate clinical and parasitological response (ACPR) in uncomplicated malaria across all episodes (unadjusted and PCR-adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp) in the per-protocol population on days 28 and 42 (non-inferiority margin 5%). Safety was assessed in all participants who received one dose of study drug. This study is registered at the Pan African Clinical Trials Registry (PACTR201105000286876).FindingsBetween Oct 24, 2011, and Feb 1, 2016, we assigned 4710 eligible participants to the different treatment strategies: 1342 to pyronaridine–artesunate, 967 to artemether–lumefantrine, 1061 to artesunate–amodiaquine, and 1340 to dihydroartemisinin–piperaquine. The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine–artesunate versus artemether–lumefantrine (1·77, 95% CI 1·63–1·93 vs 1·87, 1·72–2·03; rate ratio [RR] 1·05, 95% CI 0·94–1·17); and versus artesunate–amodiaquine (1·39, 95% CI 1·22–1·59 vs 1·35, 1·18–1·54; RR 0·97, 0·87–1·07). Similarly, this endpoint was non-inferior for dihydroartemisinin–piperaquine versus artemether–lumefantrine (1·16...

SummaryBackgroundSparse data on the safety of pyronaridine-artesunate after repeated treatment of malaria episodes restrict its clinical use. We therefore compared the safety of pyronaridine-artesunate after treatment of the first episode of malaria versus re-treatment in a substudy analysis.MethodsThis planned substudy analysis of the randomised, open-label West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) phase 3b/4 trial was done at six health facilities in Mali, Burkina Faso, and Guinea in patients (aged ≥6 months and bodyweight ≥5 kg) with uncomplicated microscopically confirmed Plasmodium spp malaria (parasite density <200 000 per μL blood) and fever or history of fever. The primary safety endpoint was incidence of hepatotoxicity: alanine aminotransferase of greater than five times the upper limit of normal (ULN) or Hy's criteria (alanine aminotransferase or aspartate aminotransferase greater than three times the ULN and total bilirubin more than twice the ULN) after treatment of the first episode of malaria and re-treatment (≥28 days after first treatment) with pyronaridine-artesunate. Pyronaridine-artesunate efficacy was compared with artemether-lumefantrine with the adequate clinical and parasitological response (ACPR) in an intention-to-treat analysis. WANECAM is registered with PACTR.org, number PACTR201105000286876.FindingsFollowing first treatment, 13 (1%) of 996 patients had hepatotoxicity (including one [<1%] possible Hy's law case) versus two (1%) of 311 patients on re-treatment (neither a Hy's law case). No evidence was found that pyronaridine-artesunate re-treatment increased safety risk based on laboratory values, reported adverse event frequencies, or electrocardiograph findings. For all first treatment or re-treatment episodes, pyronaridine-artesunate (n=673) day 28 crude ACPR was 92·7% (95% CI 91·0–94·3) versus 80·4% (77·8–83·0) for artemether-lumefantrine (n=671). After exclusion of patients with PCR-confirmed new infections, ACPR was similar on treatment and re-treatment and greater than 95% at day 28 and greater than 91% at day 42 in both treatment groups.InterpretationThe findings that pyronaridine-artesunate safety and efficacy were similar on first malaria treatment versus re-treatment of subsequent episodes lend support for the wider access to pyronaridine-artesunate as an alternative artemisinin-based combination treatment for malaria in sub-Saharan Africa.FundingEuropean and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), UK Medical Research Council, Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), Malaria Research and Training Centre (Bamako, Mali), Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea).

Worldwide, a child dies every two minutes due to malaria with Africa bearing about 90% of all malaria deaths particularly among children. This study aimed to describe malaria prevalence and its associated factors among children aged 6 months to 9 years in Guinea. We conducted a cross-sectional household survey between 02 and 29 August 2014 in children aged 6 months to 9 years in the four natural regions of the country. A five-level cluster sampling using the national database from the national institute of statistics was used to select study participants. A total of 1984 children aged 6 months to 9 years were enrolled. The mean age was 50 months (SD, 27). The rapid diagnostic test showed a high malaria prevalence (44%) countrywide along with regional variation ranging from 38% to 61%. A multivariate analysis showed that living in Forest Guinea (AOR: 2.48; 95% CI: 1.78–3.46), in rural areas (AOR: 1.91; 95% IC: 1.45–2.5) and having a splenomegaly (AOR: 2.66; 95% CI: 1.75–4.04) were highly associated with malaria. This study shows that malaria is still prevalent in Guinea among children aged 6 months to 9 years of age.

Leclercia adecarboxylata (LAD) is a member of Enterobacteriaceae family that is usually reported as an opportunistic human pathogen. A few reports have described resistant strains in the literature. The aim of this paper was to describe the antimicrobial resistance pattern of a LAD strain isolated from a urinary tract infection in a 39-year-old immunocompetent man. The bacterial identification and antibiotic sensitivity tests were performed on Vitek 2 Compact 15. The results revealed the presence of LAD with a particular multidrug resistance pattern. It was sensitive only to imipenem (=1 µg/ml), and totally resistant to association of trimethoprim/sulfamethoxazole (≥320 µg/ml), ticarcillin (≥128 µg/ml), nitrofurantoin (=128 µg/ml), cefalothin (≥64 µg/ml), cefoxitin (≥64 µg/ml), cefotaxime (≥64 µg/ml), ceftazidime (≥64 µg/ml), amikacin (≥64 µg/ml), ampicillin (≥32 µg/ml), nalidxic acid (≥32 µg/ml), and a combination of amoxicillin/clavulanic acid (≥32 µg/ml), gentamicin (≥16 µg/ml), tobramycin (≥16 µg/ml), ofloxacin (≥8 µg/ml), and ciprofloxacin (≥4 µg/ml). It showed the intermediate sensitivity to the association of piperacillin/tazobactam (=64 µg/ml), and ertapenem (=4 µg/ml). The findings showed that this isolate of LAD had a multidrug resistance pattern to almost all the antibiotics tested (except imipenem). This suggests that LAD could be considered as an emergent bacterial pathogen capable of causing infections in human and carrying multidrug resistance pattern to numerous antibiotic families in Guinea.

Guinea’s reference ranges for biological parameters rely on those of Caucasian values. Variability in reference ranges according to the context is well-documented. We conducted this study for the purpose of future malaria clinical trials that assess the efficacy and safety of malaria drugs. A repeated cross-sectional study was carried out, in an apparently healthy cohort population. Surveys took place in Maferinyah rural community, which is located at 75 km from the capital. The 2.5th and 97.5th percentiles were determined nonparametrically and stood for reference intervals. Reference values were determined separately for males and females according to ranges of age (6-10 years of age; 11-15 years of age; 16-45 years of age). Differences between genders were tested using the Mann-Whitney test, while the Friedman test was performed to test differences within each gender group according to the seasons. A total of 450 volunteers were enrolled. The median age was 13. Males 16-45 years of age had significantly higher hematologic and biochemical values compared to a female of the same age (for hematological parameters: Mean Cell Hemoglobin Concentration MCHC p≤0.001, Platelets p≤0.001, monocytes p=0.0305, eosinophils p=0.0225; for biochemical parameters: Aspartate aminotransferase AST p≤0.001, Alanine Aminotransferase ALT p≤0.001, creatinine p≤0.001). We noticed significant seasonal variations for all the biochemical parameters and some hematologic parameters (Mean Corpuscular Hemoglobin MCH, MCHC, Mean Cell volume). This is the first study establishing hematologic and biochemical parameters in Guinea. These findings provide a useful guide for the clinical researchers and care providers. Studies on large scale and in different settings would be also desirable.