Improved efficacy with amodiaquine instead of chloroquine in sulfadoxine/pyrimethamine combination treatment of falciparum malaria in Uganda: experience with fixed-dose formulation.

Amodiaquine (AQ) is an affordable compound, chemically related to chloroquine (CQ) but often effective against CQ resistant Plasmodium falciparum. In Uganda, a pre-packed fixed-dose combination of CQ plus sulfadoxine/pyrimethamine (CQ+SP) called Homapak is used in the home based management of fever program (HBM). We performed a single blind randomized trial to determine the efficacy of AQ+SP in comparison with the fixed-dose CQ+SP (Homapak) in the treatment of uncomplicated falciparum malaria in Ugandan children aged 6 months to 5 years. The study was done in 2004 at Walkuba Health Center, a sub-urban area in Jinja district, Uganda. Primary outcome was the day 14 per protocol clinical and parasitological response according to the WHO. A total of 183 children were included (mean age 28 months) and 90% completed 28 days of follow up. The day 14 adequate clinical and parasitological response was 70.9% for CQ+SP and 97.4% for AQ+SP (p<0.001). In those given CQ+SP, treatment failure rates for the 6 months to 2 years age group were much higher (48.2%) than in the older children (18.2%, p=0.004). The day 28 PCR adjusted parasitological failure rates were also higher in the CQ+SP (31.3%) than in the AQ+SP group (13.1%) (p=0.003), with a higher gametocyte carriage among the CQ+SP group. We conclude that the efficacy of AQ+SP was significantly superior to the fixed-dose CQ+SP (Homapak), particularly among the youngest children. Thus, AQ could be used instead of CQ in combination with SP to improve the effectiveness against falciparum malaria in Uganda.

Epidemiology and clinical features of imported dengue fever in Europe: sentinel surveillance data from TropNetEurop.

Travelers have the potential both to acquire and to spread dengue virus infection. The incidence of dengue fever (DF) among European travelers certainly is underestimated, because few centers use standardized diagnostic procedures for febrile patients. In addition, DF is currently not reported in most European public health systems. Surveillance has commenced within the framework of a European Network on Imported Infectious Disease Surveillance (TropNetEurop) to gain information on the quantity and severity of cases of dengue imported into Europe. Descriptions of 294 patients with DF were analyzed for epidemiological information and clinical features. By far the most infections were imported from Asia, which suggests a high risk of DF for travelers to that region. Dengue hemorrhagic fever occurred in 7 patients (2.4%) all of whom recovered. Data reported by member sites of the TropNetEurop can contribute to understanding the epidemiology and clinical characteristics of imported DF.

The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quinine in vivo.

OBJECTIVE: To investigate the roles of CYP3A4 and CYP1A2 in the 3-hydroxylation of quinine in vivo. METHODS: In a randomized, three-way crossover study, nine healthy Swedish volunteers received single oral doses of quinine hydrochloride (500 mg), quinine hydrochloride (500 mg) plus ketoconazole (100 mg twice daily for 3 days), and quinine hydrochloride (500 mg) plus fluvoxamine (25 mg twice daily for 2 days) on three different occasions. Blood and urine samples were collected before quinine intake and up to 96 hours thereafter. Plasma and urine samples were analyzed for both quinine and its main metabolite 3-hydroxyquinine with HPLC methods. RESULTS: Coadministration with ketoconazole (which inhibits CYP3A4) decreased the mean apparent oral clearance of quinine significantly (P < .001) by 31% (from 8.7 to 6.0 L/h), whereas coadministration with fluvoxamine (which inhibits CYP1A2 and to some extent CYP2C19) had no significant effect (P > .05) on the mean apparent oral clearance of quinine. Coadministration with ketoconazole also decreased the mean area under the plasma concentration versus time curve (AUC) of 3-hydroxyquinine (from 28.4 to 19.7 micromol x h x L(-1); P < .001), whereas coadministration with fluvoxamine increased 3-hydroxyquinine AUC significantly (from 28.4 to 30.2 micromol x h x L(-1); P < .05). CONCLUSION: Cytochrome P450 3A4 is important for the 3-hydroxylation of quinine in vivo. On the other hand, CYP1A2 had no significant effect on this metabolic pathway.

Standard and reduced doses of mefloquine for treatment of Plasmodium falciparum in Tanzania: whole blood concentrations in relation to adverse reactions, in vivo response, and in vitro susceptibility.

Fifty-three asymptomatic Tanzanian school children with 400-31,000 asexual Plasmodium falciparum parasites/microliter of blood were given standard, one-half, one-quarter, or one-eighth of the recommended mefloquine treatment dose of 25 mg base/kg body weight. Mefloquine and main metabolite concentrations were determined in 100 microliters of capillary blood using a high performance liquid chromatographic method. In the standard, one-half, and one-quarter dose groups, all children cleared the parasites within three days after treatment. Reappearance was noted in one of the children in the one-quarter dose group during 49-56 days of followup. Among the children given one-eighth of a dose, two had an RII response and four had an RI response with early recrudescence. All 24-hour in vitro micro-tests (n = 30) showed full susceptibility for mefloquine. Adverse gastrointestinal reactions were reported by eight children on the first day after treatment, four of whom had been given a standard dose. These children had higher mefloquine concentrations one day after treatment than the other children in this group (P less than 0.05). In the standard dose group (n = 13), the area under the curve of capillary whole blood concentrations of mefloquine versus time was 52.4-112.1 mumol/liter x days. The highest concentration on day 1 was 2.75-7.20 mumol/liter and the median terminal half-life was 17.4 days. The highest concentrations of the main metabolite were observed 1-2 weeks after treatment and the median half-life was 18.9 days. The concentrations in the other groups were approximately proportional to those in the standard dose group both for mefloquine and the metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidemiology and clinical features of vivax malaria imported to Europe: sentinel surveillance data from TropNetEurop.

BACKGROUND: Plasmodium vivax is the second most common species among malaria patients diagnosed in Europe, but epidemiological and clinical data on imported P. vivax malaria are limited. The TropNetEurop surveillance network has monitored the importation of vivax malaria into Europe since 1999. OBJECTIVES: To present epidemiological and clinical data on imported P. vivax malaria collected at European level. MATERIAL AND METHODS: Data of primary cases of P. vivax malaria reported between January 1999 and September 2003 were analysed, focusing on disease frequency, patient characteristics, place of infection, course of disease, treatment and differences between network-member countries. RESULTS: Within the surveillance period 4,801 cases of imported malaria were reported. 618 (12.9%) were attributed to P. vivax. European travellers and immigrants were the largest patient groups, but their proportion varied among the reporting countries. The main regions of infection in descending order were the Indian subcontinent, Indonesia, South America and Western and Eastern Africa, as a group accounting for more than 60% of the cases. Regular use of malaria chemoprophylaxis was reported by 118 patients. With 86 (inter-quartile range 41-158) versus 31 days (inter-quartile range 4-133) the median symptom onset was significantly delayed in patients with chemoprophylaxis (p < 0.0001). Common complaints were fever, headache, fatigue, and musculo-skeletal symptoms. All patients survived and severe clinical complications were rare. Hospitalization was provided for 60% and primaquine treatment administered to 83.8% of the patients, but frequencies varied strongly among reporting countries. CONCLUSIONS: TropNetEurop data can contribute to the harmonization of European treatment policies.

Audiometry as a possible indicator of quinine plasma concentration during treatment of malaria.

The spread of chloroquine-resistant malaria has led to a resurgence of quinine in clinical use. One of the well-known side effects of quinine, reversible hearing loss, is closely related to the plasma concentration. We suggest that this hearing effect could be used as an aid in therapy control when quinine drug assay is not available.

Susceptibility of Plasmodium falciparum to quinine in vitro: effects of drug concentrations and time of exposure.

We have studied the relationship between quinine concentrations ranging from 0.16 to 332 mumol/L in a blood-medium mixture and the time of exposure (12-168 h) needed for inhibition of Plasmodium falciparum (F32 strain) in continuous culture. When we exposed the parasites for 12 h, only brief inhibition was observed. After 24 h of exposure, parasites were inhibited for 2-3 d at quinine concentrations > or = 10.4 mumol/L. With 48 and 72 h of exposure, the inhibition lasted for 6-8 d at concentrations > or = 1.3 mumol/L and for 8-11 d at concentrations between 2.6 and 166 mumol/L. After 96 h of exposure, parasites were inhibited for 11-17 d at concentrations > or = 0.65 mumol/L. With 168 h of exposure, parasites were inhibited at all quinine concentrations > or = 0.65 mumol/L during 28 d of post-exposure cultivation. After reappearance, parasites multiplied on average 7.6 fold during each parasite schizogony cycle. The calculated parasite elimination rate in the presence of effective concentrations of quinine was 99.7-99.9% per cycle. We conclude that the elimination rate of the parasites is concentration-dependent at low concentrations of quinine in vitro. As soon as a threshold concentration of 0.65-2.6 mumol/L is attained, only the exposure time determines parasite elimination. These experiments suggest that it might be preferable to reduce each dose rather than the duration of treatment in areas where P. falciparum is susceptible to quinine.

Standard and reduced doses of sulfadoxine-pyrimethamine for treatment of Plasmodium falciparum in Tanzania, with determination of drug concentrations and susceptibility in vitro.

88 asymptomatic Tanzanian schoolchildren with Plasmodium falciparum parasitaemia were given all, half or quarter of the recommended standard therapeutic dose of sulfadoxine-pyrimethamine (Fansidar). All children cleared the parasites by day 3 and all remained negative during 28-42 days of follow-up. All 32 successful in vitro micro-tests showed full sensitivity. High performance liquid chromatographic methods were applied for drug determinations. Using 100 microliter capillary blood dried on filter paper for sulfadoxine determination the inter-individual variation during follow-up of the standard dose group was 2-4 fold and the median half life was 8.9 d. Sulfadoxine concentrations in the half and quarter dose groups were roughly proportional to those in the standard dose group. The median whole blood to plasma concentration ratio for sulfadoxine was 0.72 and the correlation coefficient 0.95. There was only a weak correlation (r=0.46) between plasma concentrations of sulfadoxine and pyrimethamine. The uniform efficacy of sulfadoxine-pyrimethamine in vivo, even when reduced doses were used, makes this combination a good alternative for treatment of P. falciparum in Tanzania.

Plasma concentrations of sulfadoxine-pyrimethamine and of mefloquine during regular long term malaria prophylaxis.

The plasma concentrations of sulfadoxine, pyrimethamine, mefloquine and its major metabolite were determined in 18 healthy male volunteers who had regularly taken either 500 mg of sulfadoxine and 25 mg of pyrimethamine (Fansidar) weekly or 250 mg mefloquine regularly every 14 d during 6 months for malaria prophylaxis. The mean trough concentrations of sulfadoxine, pyrimethamine and mefloquine were 194, 0.28 and 1.48 mumol/litre and the mean half lives were 7.7, 4.2 and 25 d respectively. The variation in area under the curve for the 3 drugs was only 2-3 fold. The findings do not indicate that drug accumulation or induction of metabolism occurred during long-term usage.

Imported schistosomiasis in Europe: sentinel surveillance data from TropNetEurop.

BACKGROUND: Schistosomiasis is a major parasitic disease, increasingly imported into temperate climates by immigrants from and travelers to endemic areas. METHOD: To generate valid data on imported infectious diseases to Europe and to recognize trends over time, the European Network on Imported Infectious Diseases Surveillance (TropNetEurop) was founded in 1999. Three hundred and thirty-three reports of schistosomiasis were analyzed for epidemiologic and clinical features. RESULTS: Male patients accounted for 64% of all cases. The average age of all patients was 29.5 years. The majority of patients were of European origin (53%). Europeans traveled predominantly for tourism (52%). Main reasons for travel for people from endemic areas were immigration and refuge (51%) and visits to relatives and friends (28%). The majority of infections were acquired in Africa; 92 infections were clearly attributable to Schistosoma haematobium, 130 to Schistosoma mansoni, and 4 to Schistosoma intercalatum. Praziquantel was the only treatment used. No deaths were recorded. CONCLUSION: TropNetEurop sentinel provides valuable epidemiologic and clinical data on imported schistosomiasis to Europe.

[Mefloquine and sulfadoxine/pyrimethamine overdose in malaria tropica]. / Mefloquin- und Sulfadoxin/Pyrimethamin-Uberdosierung bei Malaria tropica.

A 39 year-old man with malaria due to Plasmodium falciparum received 3500 mg mefloquine over 3 days, in addition to 3250 mg chloroquine and 175/3500 mg sulfadoxine/pyrimethamine. He developed severe neuropsychiatric symptoms and had to be hospitalized. Treatment with diazepam, haloperidol and thioridazine achieved relief of the severe symptoms after 4 days. The patient was still suffering from discrete neuropsychiatric symptoms 8 months after treatment.

[Clostridium difficile-associated diarrhea--a growing problem in geriatric care]. / Clostridium difficile-associerad diarré--ett växande problem inom geriatriken.

From 1994 to 1998 the incidence of Clostridium difficile-associated diarrhoea (CDAD) in the Department of Geriatric Medicine, Huddinge University Hospital increased from 0.5% to 2.2% of all admissions. Corresponding figures for the whole hospital were 0.3% and 0.6%, respectively. The increase in CDAD at the Department of Geriatric Medicine was parallel with a more than doubled consumption of antibiotics. All geriatric patients with CDAD had been treated with antibiotics before onset of diarrhoea. Out of the antibiotic prescriptions 48% were a cephalosporin (mainly cefuroxim). In a matched reference group of geriatric patients 51% had been treated with antibiotics during the hospital stay. The patients with CDAD spent 27 +/- 14 days in hospital as compared to 13 +/- 9 days (P < 0.05) in the reference population.