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Eshetu, Teferi (2011): Efficacy and Tolerability of Antimalarials and Molecular Resistance Markers of Falciparum Malaria in Jimma Region, Ethiopia. Dissertation, LMU München: Faculty of Medicine
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Abstract

Due to increasing drug resistance, artemisinin-based combination chemotherapy (ACT) has become the first-line treatment of falciparum malaria in many endemic countries. Ethiopia has also adopted artemether/lumefantrine (AL) as first-line treatment in 2004 and its broad introduction was achieved in 2006. However, irreversible ototoxicity associated with AL has been reported and suggested to be a serious limitation in the use of ACT. The aim of this study was to compare ototoxicity, tolerability, and efficacy of ACT with that of quinine and atovaquone/proguanil in the treatment of uncomplicated falciparum malaria. 97 patients in Jimma area, Ethiopia with slide-confirmed malaria were randomly assigned to receive either artemether/lumefantrine or quinine or atovaquone/proguanil and followed-up on days 7, 28, and 90. Comprehensive audio-vestibular testing by pure tone audiometry (PTA), transitory evoked (TE) and distortion product (DP) otoacoustic emissions (OAE) and brain stem evoked response audiometry (BERA) was done before enrolment and on follow-up days. PTA and DP-OAE levels revealed transient significant cochlear hearing loss in patients treated with quinine but not in those treated with artemether/lumefantrine or atovaquone/proguanil. There was no evidence of drug-induced brain stem lesions by BERA measurements. Hence, there was no detrimental effect of a standard oral regimen of artemether/lumefantrine on peripheral hearing or brainstem auditory pathways in patients with uncomplicated falciparum malaria. In contrast, transient hearing loss was evidenced with quinine therapy due to temporary outer hair cell dysfunction. Reinfection and recrudescence were determined by RFLP of msp-1 and msp-2 genes. Mutations associated with drug resistance were characterized in Pfmdr1, Pfdhfr, Pfcytb, and Pfserca genes. Single nucleotide polymorphisms (SNPs) previously reported to be associated with resistance to the study drugs were identified in both recrudescent and treatment sensitive isolates. A total of seven recrudescences were obtained. The Pfmdr1 N86Y mutation was found in 84.5% of isolates. The triple mutation 51I, 59R, 108N of the Pfdhfr gene occurred in high frequency (83.3%) but no Pfcytb mutation was detected. Sequencing showed a variety of previously described and new mutations in the Pfserca gene. The prevalence of high degree of mutations in Pfmdr1 and Pfdhfr is a reminiscent of the impact of previously used drugs in the area, chloroquine and sulfadoxine/pyrimethamine as first-line treatments. The broad introduction of AL and the cessation of the former drug regimens might probably change the current distribution of polymorphisms, possibly leading to decreased sensitivity to AL in the future. Continuous surveillance of molecular patterns in this region is, therefore, recommended.