High Resistance of Plasmodium falciparum to Sulphadoxine/Pyrimethamine in Northern Tanzania and the Emergence of dhps Resistance Mutation at Codon 581

BACKGROUND: Sulphadoxine-pyrimethamine (SP) a widely used treatment for uncomplicated malaria and recommended for intermittent preventive treatment of malaria in pregnancy, is being investigated for intermittent preventive treatment of malaria in infants (IPTi). High levels of drug resistance to SP have been reported from north-eastern Tanzania associated with mutations in parasite genes. This study compared the in vivo efficacy of SP in symptomatic 6-59 month children with uncomplicated malaria and in asymptomatic 2-10 month old infants. METHODOLOGY AND PRINCIPAL FINDINGS: An open label single arm (SP) standard 28 day in vivo WHO antimalarial efficacy protocol was used in 6 to 59 months old symptomatic children and a modified protocol used in 2 to 10 months old asymptomatic infants. Enrolment was stopped early (87 in the symptomatic and 25 in the asymptomatic studies) due to the high failure rate. Molecular markers were examined for recrudescence, re-infection and markers of drug resistance and a review of literature of studies looking for the 581G dhps mutation was carried out. In symptomatic children PCR-corrected early treatment failure was 38.8% (95% CI 26.8-50.8) and total failures by day 28 were 82.2% (95% CI 72.5-92.0). There was no significant difference in treatment failures between asymptomatic and symptomatic children. 96% of samples carried parasites with mutations at codons 51, 59 and 108 in the dhfr gene and 63% carried a double mutation at codons 437 and 540. 55% carried a third mutation with the addition of a mutation at codon 581 in the dhps gene. This triple: triple haplotype maybe associated with earlier treatment failure. CONCLUSION: In northern Tanzania SP is a failed drug for treatment and its utility for prophylaxis is doubtful. The study found a new combination of parasite mutations that maybe associated with increased and earlier failure. TRIAL REGISTRATION: ClinicalTrials.gov NCT00361114

Azithromycin plus artesunate versus artemether-lumefantrine for treatment of uncomplicated malaria in Tanzanian children: a randomized, controlled trial.

BACKGROUND: Acute febrile illness is the most common cause of outpatient attendance and mortality for children in Africa. Malaria and bacterial disease are difficult to differentiate with limited diagnostic facilities. Combinations of antibiotics and antimalarials are potentially attractive for treatment of the syndrome. Azithromycin plus artesunate (AT+AS) is an effective antimalarial combination for adults in Asia. METHODS: We performed an individually randomized, open-label trial of AZ+AS versus artemether-lumefantrine (AL) involving children (age, 6-59 months) with uncomplicated malaria in Muheza, Tanzania. The primary outcome was parasitological failure by day 28. Parasitological failure by day 42 and failure corrected for reinfection were major secondary outcomes. RESULTS: Of 2497 children screened, 261 were eligible; 129 were randomized to the AZ+AS arm, and 132 were randomized to the AL arm; 92% and 91%, respectively, underwent follow-up to 28 days. Planned interim analysis was performed after 200 patients reached day 28 follow-up and led the Data and Safety Monitoring Board to halt further recruitment. All children had a complete initial response to treatment, but 69 (58%) of 119 children in the AZ+AS arm and 24 (20%) of 120 in the AL arm had asexual parasites at or by day 28 (adjusted odds ratio for failure with AZ+AS treatment, 6.1; 95% confidence interval, 3.3-11.4; P < .001). When analysis was restricted to children with recrudescence, the parasitological failure rate was 32% in the AZ+AS arm and 9% in the AL arm. This difference was maintained at day 42. CONCLUSIONS: This trial does not support the use of AZ+AS as treatment for malaria or acute febrile illness in children in areas of Africa with high levels of existing antimalarial drug resistance. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT00694694

Treatment guided by rapid diagnostic tests for malaria in Tanzanian children: safety and alternative bacterial diagnoses

<p>Abstract</p> <p>Background</p> <p>WHO guidelines for the treatment of young children with suspected malaria have recently changed from presumptive treatment to anti-malarial treatment guided by a blood slide or malaria rapid diagnostic test (RDT). However, there is limited evidence of the safety of this policy in routine outpatient settings in Africa.</p> <p>Methods</p> <p>Children 3-59 months of age with a non-severe febrile illness and no obvious cause were enrolled over a period of one year in a malaria endemic area of Tanzania. Treatment was determined by the results of a clinical examination and RDT result, and blood culture and serum lactate were also collected. RDT-negative children were followed up over 14 days.</p> <p>Results</p> <p>Over the course of one year, 965 children were enrolled; 158 (16.4%) were RDT-positive and treated with artemether-lumefantrine and 807 (83.4%) were RDT-negative and treated with non-anti-malarial medicines. Compared with RDT-positives, RDT-negative children were on average younger with a lower axillary temperature and more likely to have a history of cough or difficulty in breathing. Six (0.6%) children became RDT-positive after enrolment, all of whom were PCR-negative for <it>Plasmodium falciparum </it>DNA at enrolment. In addition, 12 (1.2%) children were admitted to hospital, one with possible malaria, none of whom died. A bacterial pathogen was identified in 9/965 (0.9%) children, eight of whom were RDT-negative and one was RDT-positive, but slide-negative. Excluding three children with <it>Salmonella typhi</it>, all of the children with bacteraemia were ≤12 months of age. Compared to double-read research slide results RDTs had a sensitivity of 97.8% (95%CI 96.9-98.7) and specificity of 96.3% (95%CI 96.3-98.4).</p> <p>Conclusions</p> <p>Use of RDTs to direct the use of anti-malarial drugs in young children did not result in any missed diagnoses of malaria although new infections soon after a consultation with a negative RDT result may undermine confidence in results. Invasive bacterial disease is uncommon in children with non-severe illness and most cases occurred in infants with a current fever.</p