Melarsoprol refractory T-b. gambiense from Omugo, north-western Uganda

Culture adapted T. b. gambiense isolated from Northwest Uganda were exposed to 0.001-0.14 mug/ml melarsoprol or 1.56-100 mug/ml DL-alpha -difluorometh ylornithine (DFMO). Minimum inhibitory concentrations (MICs) of each drug w ere scored for each isolate after a period of 10 days drug exposure. The re sults indicate that T. b. gambiense isolates from Northwest Uganda had elev ated MIC values for melarsoprol ranging from 0.009 to 0.072 mug/ml as compa red with T. b. gambiense isolates from Cote d'Ivoire with MIC values rangin g from 0.001 to 0.018 mug/ml or with T. b. rhodesiense from Southeast Ugand a with MIC values from 0.001 to 0.009 mug/ml. All MIC values obtained fell below expected peak melarsoprol concentrations in serum of treated patients . However, it may not be possible to maintain constant drug concentrations in serum of patients as was the case in our in vitro experiments. Important ly, the MIC of 0.072 mug/ml exhibited by one of the isolates from Northwest Uganda was above levels attainable in CSF indicating that this isolate wou ld probably not be eliminated from CSF of treated patients. PCR amplificati on of the gene encoding the P2-like adenosine transporter followed by restr iction digestion with Sfa NI enzyme revealed presence of fragments previous ly observed in a trypanosome clone with laboratory-induced arsenic resistan ce. From our findings it appears that reduced drug susceptibility may be on e factor for the frequent relapses of sleeping sickness after melarsoprol t reatment occuring in Northwest Uganda.