Once-daily combination therapy for uncomplicated malaria: is this the way forward?

Article published in Clinical Infectious DiseasesThere are several problems associated with treatment of malaria, especially in sub-Saharan Africa: effectiveness, access (financial and physical), safety and tolerability, and adherence. Even in an ideal situation in which the first 3 factors are not a problem, adherence would still be problematic, especially when dealing with rural populations in developing countries, where relief of symptoms of malaria is often interpreted as “cure” and where there is, therefore, great reluctance to continue taking the rest of the medication as prescribed. Adherence has been defined as “the extent to which a patient fulfills the intention of the prescriber in taking medication” [1, p. 7]. Several drug-associated factors may affect adherence [1], including appropriateness of the prescription, side effects, dose regimen, drug presentation and formulation, number of drugs prescribed concurrently, and duration of treatment

The Distribution and economic importance of the Mangrove forests of Kenya

Volume: 7

Some basic facts on combination therapy

What are the problems with malaria? • The disease • The drugs • The policies • The finance COMBINATION THERAPY: DEFINITION • CT is the simultaneous use of two or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasites • • CTs can be either fixed ratio combinations or multiple-drug therapy, in which components are co-administered in separate tablets or capsules

Evaluation of Malaria Infection In Relation to Age and Residential Area in Nandi County, Kenya

Objective: To investigate malaria infection in relation to age and residential area.Design: A cross sectional study.Setting: Kipsamoite Dispensary of Nandi County in Kenya.Subjects: The demographic details and medical history for all consenting patients was taken by the clinical officer/nurse.Intervention: Clinical examination was done followed by presumptive diagnosis for clinical malaria.Main outcomes: A total of 349 patients were examined and tested for malaria during the period under study.Results: Whereas infection distribution was significantly associated with age groups P<0.05 (χ2 = 4.190); no significant difference in mean parasite density  distribution over the seven residential area categories (P = 0.261) (F = 1.305) was found.Conclusion: Patients aged > 5 years were found to be infected more than those aged <5 years. On overall, there is a need to start targeting patients above five years of age and encourage them to access malaria control interventions especially the use of insecticide treated bed nets to minimise their infection rate

Chloramphenicol Pharmacokinetics in African children with severe malaria

Article published in Journal of tropical pediatricsThe objective of this study was to determine if the current dosage regimen for chloramphenicol (CAP) administered to children with severe malaria (SM) for presumptive treatment of concomitant bacterial meningitis achieves steady state plasma CAP concentrations within the reported therapeutic range of 10–25 mg/l. Fifteen children (11 male, 4 female) with a median age of 45 months (range: 10–108 months) and having SM, were administered multiple intravenous doses (25 mg/kg, 6 hourly for 72 h) of chloramphenicol sodium succinate (CAPS) for presumptive treatment of concomitant bacterial meningitis. Blood samples were collected over 72 h, and plasma CAPS, CAP and CSF CAP concentrations determined by high performance liquid chromatography. Average steady state CAP concentrations were approximately 17 mg/l, while mean fraction unbound (0.49) and CSF/plasma concentration ratio (0.65) were comparable to previously reported values in Caucasian children. Clearance was variable (mean^4.3 l/h), and trough plasma concentrations during the first dosing interval were approximately 6 mg/l. Simulations indicated that an initial of loading dose of 40 mg/kg CAPS, followed by a maintenance dose of 25 mg/kg every 6 h would result in trough CAP concentrations of approximately 10 mg/l and peak concentrations _25 mg/l throughout the treatment period. The current dosage regimen for CAP needs to include a loading dose of 40 mg/kg CAPS to rapidly achieve plasma CAP concentrations within the reported therapeutic range.The objective of this study was to determine if the current dosage regimen for chloramphenicol (CAP) administered to children with severe malaria (SM) for presumptive treatment of concomitant bacterial meningitis achieves steady state plasma CAP concentrations within the reported therapeutic range of 10–25 mg/l. Fifteen children (11 male, 4 female) with a median age of 45 months (range: 10–108 months) and having SM, were administered multiple intravenous doses (25 mg/kg, 6 hourly for 72 h) of chloramphenicol sodium succinate (CAPS) for presumptive treatment of concomitant bacterial meningitis. Blood samples were collected over 72 h, and plasma CAPS, CAP and CSF CAP concentrations determined by high performance liquid chromatography. Average steady state CAP concentrations were approximately 17 mg/l, while mean fraction unbound (0.49) and CSF/plasma concentration ratio (0.65) were comparable to previously reported values in Caucasian children. Clearance was variable (mean=4.3 l/h), and trough plasma concentrations during the first dosing interval were approximately 6 mg/l. Simulations indicated that an initial of loading dose of 40 mg/kg CAPS, followed by a maintenance dose of 25 mg/kg every 6 h would result in trough CAP concentrations of approximately 10 mg/l and peak concentrations <25 mg/l throughout the treatment period. The current dosage regimen for CAP needs to include a loading dose of 40 mg/kg CAPS to rapidly achieve plasma CAP concentrations within the reported therapeutic range

Plasma and cerebrospinal proteomes from childre with cerebral malaria differ from those of children with other encephalopathies

Journal article published in The Journal of Infectious DiseasesClinical signs and symptoms of cerebral malaria in children are nonspecific and are seen in other common encephalopathies in malaria-endemic areas. This makes accurate diagnosis difficult in resource-poor settings. Novel malaria-specific diagnostic and prognostic methods are needed. We have used 2 proteomic strategies to identify differentially expressed proteins in plasma and cerebrospinal fluid from children with a diagnosis of cerebral malaria, compared with those with a diagnosis of malaria-slide-negative acute bacterial meningitis and other nonspecific encephalopathies. Here we report the presence of differentially expressed proteins in cerebral malaria in both plasma and cerebrospinal fluid that could be used to better understand pathogenesis and help develop more-specific diagnostic methods. In particular, we report the expression of 2 spectrin proteins that have known Plasmodium falciparum–binding partners involved in the stability of the infected red blood cell, suppressing further invasion and possibly enhancing the red blood cell’s ability to sequester in microvasculature.Clinical signs and symptoms of cerebral malaria in children are nonspecific and are seen in other common encephalopathies in malaria-endemic areas. This makes accurate diagnosis difficult in resource-poor settings. Novel malaria-specific diagnostic and prognostic methods are needed. We have used 2 proteomic strategies to identify differentially expressed proteins in plasma and cerebrospinal fluid from children with a diagnosis of cerebral malaria, compared with those with a diagnosis of malaria-slide-negative acute bacterial meningitis and other nonspecific encephalopathies. Here we report the presence of differentially expressed proteins in cerebral malaria in both plasma and cerebrospinal fluid that could be used to better understand pathogenesis and help develop more-specific diagnostic methods. In particular, we report the expression of 2 spectrin proteins that have known Plasmodium falciparum–binding partners involved in the stability of the infected red blood cell, suppressing further invasion and possibly enhancing the red blood cell’s ability to sequester in microvasculature

Population pharmacokinetics of a single daily intramuscular dose of gentamicin in children with severe malnutrition

Article published in Journal of Antimicrobial ChemotherapyObjectives: The World Health Organization recommends that all children admitted with severe malnutrition should routinely receive parenteral ampicillin and gentamicin; despite this, mortality remains high. Since this population group is at risk of altered volume of distribution, we aimed to study the population pharmacokinetics of once daily gentamicin (7.5 mg/kg) in children with severe malnutrition and to evaluate clinical factors affecting pharmacokinetic parameters. Methods: Thirty-four children aged 0.5–10 years were studied. One hundred and thirty-two gentamicin concentrations (median of four per patient), drawn 0.4–24.6 h after administration of the intramuscular dose, were analysed. The data were fitted by a two-compartment model using the population package NONMEMw. Results: Gentamicin was rapidly absorbed and all concentrations measured within the first 2 h after administration were >8 mg/L (indicating that satisfactory peak concentrations were achieved). Ninetyeight percent of samples measured more than 20 h after the dose were <1 mg/L. The best model included weight, and it was found that high base deficit, high creatinine concentration and low temperature (all markers of hypovolaemic shock) reduced clearance (CL/F). Weight influenced volume of the central (V1/F) and peripheral (V2/F) compartments, and high base deficit reduced V2/F and intercompartmental CL (Q/F). Interindividual variability in CL was 26%, in V1/F 33% and in V2/F and Q/F was 52%. Individual estimates of CL/F ranged from 0.02 to 0.16 (median 0.10) L/h/kg and those of Vss/F from 0.26 to 1.31 (median 0.67) L/kg. Initial half-lives had a median of 1.4 h and elimination half-lives and a median of 14.9 h. Excessive concentrations were observed in one patient who had signs of renal impairment and shock. Conclusions: Although a daily dose of 7.5 mg/kg achieves satisfactory gentamicin concentrations in the majority of patients, patients with renal impairment and shock may be at risk of accumulation with 24 hourly dosing. Further studies of gentamicin pharmacokinetics in this group are now needed to inform future international guideline recommendations