In rural tropical areas, patients frequently present with malaria and require urgent therapy. Facilities may not exist for parenteral drug administration, and oral dosing is precluded by obtundation or vomiting. In these circumstances, the rectal route of administration may allow initiation of antimalarial therapy while patients await transfer to hospital, a process that may take many hours.Artesunate (ARS) is a water-soluble hemisuccinate dihydroartemisinin (DHA) derivative being developed for the treatment of malaria and is particularly valuable against multidrugresistant infections (2, 13). ARS is currently formulated for administration by the oral and parenteral routes (3, 11). ARS suppositories (Rectocaps; 50 mg of artesunate; Mepha Pharmaceuticals Ltd.) Aesch-Basle, Switzerland) have recently undergone preliminary assessment in Gabonese children (8). However, formal bioavailability studies with this formulation are lacking. Circulating ARS is quickly converted to DHA by blood esterases and hepatic metabolism (14). As DHA is the principal antimalarial metabolite of ARS, the bioavailability of DHA was studied by comparing intrarectally (i.r.) and intravenously (i.v.) administered ARS in Ghanaian children with moderate malaria. High-performance liquid chromatography (HPLC) with electrochemical detection, currently the most precise and sensitive assay, was used to measure ARS and DHA levels. This crossover study was also designed to test the hypothesis that within the first 24 h there is no disease effect on the pharmacokinetics of ARS. These studies are critical to the design of larger (phase III-IV) studies seeking to use rectal ARS to reduce mortality from malaria. MATERIALS AND METHODS Study design description.This was an open, randomized, crossover comparison between i.v. ARS and ARS suppositories conducted on a pediatric research ward at Komfo-Anokye Teaching Hospital, Kumasi, Ghana, from August to October 1996. This study was approved by The Committee of Research, Publication and Ethics of the School of Medical Sciences, University of Science and Technology, Kumasi, Ghana, and the Review Board of the World Health Organization. A computer-generated randomization list allocating patients to one of three treatment categories was prepared (in permuted blocks of 12 patients). The treatment category for each patient was provided in an opaque sealed envelope opened only when a patient entered the study. Treatment categories were as follows: group I, i.r. ARS at 10 mg/kg of body weight, followed 12 h later by i.v. ARS at 2.4 mg/kg; group II, i.r. ARS at 20 mg/kg, followed 12 h later by i.v. ARS at 2.4 mg/kg; and group III, i.v. ARS at 2.4 mg/kg, followed 12 h later by i.r. ARS at 20 mg/kg. The doses of i.r. ARS were based on preliminary pharmacodynamic analysis of a similar study of i.r. ARS in Thai adults with moderate malaria (S. Looareesuwan, personal communication).Inclusion criteria. Patients aged 18 months to 7 years (inclusive) with a diagnosis of moderate Plasmodium falciparum malaria were eligible, pro...

BackgroundSubstantial decline in malaria transmission, morbidity and mortality has been reported in several countries where new malaria control strategies have been implemented. In Gabon, the national malaria policy changed in 2003, according to the WHO recommendations. The trend in malaria morbidity was evaluated among febrile children before and after their implementation in Libreville, the capital city of Gabon.MethodsFrom August 2000 to December 2008, febrile paediatric outpatients and inpatients, under 11 years of age, were screened for malaria by microscopic examination at the Malaria Clinical Research Unit (MCRU) located in the largest public hospital in Gabon. Climatic data were also collected.ResultsIn total, 28,092 febrile children were examined; those under five years always represented more than 70%. The proportion of malaria-positive slides was 45% in 2000, and declined to 15% in 2008. The median age of children with a positive blood smear increased from 24(15-48) to 41(21-72) months over the study period (p < 0.01). Rainfall patterns had no impact on the decline observed throughout the study period.ConclusionThe decrease of malaria prevalence among febrile children during the last nine years is observed following the introduction of new strategies of malaria cases management, and may announce epidemiological changes. Moreover, preventive measures must be extended to children older than five years.

BackgroundSepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking.ObjectivesTo determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS).MethodsData were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed.ResultsA one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome.ConclusionsSimulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.

The burden of malaria in regions of high endemicity frequently overwhelms hospitals' capacity to provide effective care. A rapid, simple method of identifying children who are at highest risk is vital to reduce mortality among hospitalized children. Multiple regression analysis identified prognostic variables predicting mortality in severely ill children admitted to a Ghanaian teaching hospital. These variables were compared in children with and without malaria. A total of 1492 (90.2%) of 1654 severely ill children referred for assessment had evaluable outcomes. Low Blantyre coma score (BCS), high blood lactate level, and high body mass index were independent predictors of mortality among children with malaria (area under the receiver operating characteristic curve [AUC/ROC], 0.84). In children without malaria, BCS and lactate level also predicted mortality, but the addition of respiratory distress and hematocrit improved the model (AUC/ROC, 0.77). Predictors of mortality in children with malaria differ from those for other severe illnesses and reflect differences in underlying pathophysiological processes.