The measures already mentioned are important in the delay of the development of resistance. Once resistance is present, however, other interventions become necessary.
When resistance to diminazene, ISMM or homidium is present, the use of the other drug of the sanative pair is still possible. The second drug should be used with caution in order to avoid resistance development here again. Integrated control measures, such as reducing vector numbers to reduce the number of drug treatments, will be of great importance. The same is true in cases of multiple resistance associated with mixed infections. Administration of various drugs to which the different subpopulations are sensitive, will eliminate the whole trypanosome population (Mulugeta et al., 1997).
Once resistance is present, it is unwise to increase the dose of the drug. Although some temporary benefits might be obtained, such an action would inevitably increase the selection pressure and, thus, the level of resistance. The use of a double dose of diminazene (two normal doses with an interval of eight or 24 hours between them) only slightly improved the therapeutic efficacy for resistant T. congolense (Silayo et al., 1992). Similarly, although the intravenous administration of ISMM enhanced the therapeutic activity of the compound as compared with the intramuscular injection, it was not effective in eliminating resistant parasites (Sutherland et al., 1992).
If multiple resistance is expressed at the level of the individual trypanosome, chemotherapy can become increasingly ineffectual. To counteract multiple resistance in such a case, intervention at the level of the vector is required. Peregrine et al. (1994) showed that in the Ghibe valley, Ethiopia, multiple drug-resistant trypanosome infections (at the clonal level) could be controlled effectively using an integrated approach involving tsetse fly control (targets) and chemotherapy of clinically sick animals (using diminazene). The relative density of the main vector, Glossina pallidipes, fell from an average of 1.9 flies per trap per day before the introduction of tsetse control to 0.4 flies per trapper day during the first year of the control. Simultaneously, the apparent prevalence of T. congolense infections fell from approximately 30 percent before the tsetse control programme to ± 5 percent one year after the start of the control programme. The apparent prevalence of diminazene-resistant infections decreased by about 75 percent during the same period. Although this experiment had to be interrupted as a result of political instability in the region, it showed that such an approach can be successful. A similar level of success was also reported by Fox et al. (1993) at the Mkwaja Ranch in the United Republic of Tanzania using a deltamethrin dipping programme to overcome the problem of drug resistance. Interestingly, cattle productivity increased significantly and the cost of the dip was more than offset by savings on trypanocidal drugs and oxytetracycline, and thereby overall treatment costs were reduced by 50 percent.
