trans

430 DRUG RESISTANCE
efforts for global surveillance programs. It is
hoped that these programs will contribute to
reduce the dissemination of resistant isolates.
We are far from this ideal for parasitic diseases.
Indeed, in addition to our incomplete understanding
of the genetic basis of resistance, networks
of surveillance for resistant parasites are
not yet organized and in place to affect national
policies and treatment guidelines in defined
geographical regions.
The understanding of resistance mechanisms
and mechanism of action of drugs may also
point the way to more rational use of drugs and
drug combinations to minimize development
of resistance and to achieve more effective
chemotherapy. Indeed, there is now considerable
evidence demonstrating that drug combinations,
with different mechanisms of action
and resistance, will on the one hand increase
the efficiency of treatment and on the other
hand reduce the probability of selecting for
resistant parasites. Thus the understanding of
the mode of action of drugs, of their pharmacology,
and of resistance mechanisms should
facilitate the choice of drugs to be used in
combination in clinical trials. The concept of
combination chemotherapy is already well
established for treating HIV, cancer, tuberculosis
and leprosy, and it is expected to grow in
popularity in the coming years for other
microorganisms. Few drugs are available in the
treatment of parasitic diseases, and there is
increasing agreement that the use of simultaneous
or sequential combinations of agents
must be implemented in order to protect the
limited precious resource of therapeutically
effective drugs. Several studies using drug combinations
against malaria have highlighted their
potential, and combination chemotherapy is
rapidly being seen as the norm; this is at least
in the planning stage for all the parasites causing
disease in man and animals. Drug combinations
have already been used empirically
to treat (successfully) refractory isolates. Obviously,
controlled clinical trials will be required
to assess the efficacy and safety of such drug
combinations.
Finally, studies of drug resistance will permit
the identification of key intracellular targets and
parasite defense mechanisms, which can be
exploited for the rational development of drug
analogs not affected by the most common
defenses. There is a large body of evidence
demonstrating efflux-mediated resistance in a
number of parasites. Strategies and inhibitors
to modulate the activity of efflux pumps are
being developed, and analogs of these, in
combination with our currently available drugs,
could be useful in the treatment of parasitic
diseases when a transport-related mechanism
is the main resistance mechanism. In vitro work
on antimony resistance in Leishmania has
demonstrated that an increase in trypanothione
and in transport systems are implicated in
resistance. The use of trypanothione biosynthesis
inhibitors such as buthionine sulfoxime
(BSO) and DFMO (Figure 16.2) (two drugs
already approved for use in humans) in combination
with antimony was shown to reverse
antimony resistance in vitro, and if warranted
this combination could be used in vivo.
Similarly, since arsenicals and trypanothione
metabolism appear to be linked in T. brucei,
MelB may turn out to be more effective when
used in combination with BSO or DFMO. Our
understanding of pyrimethamine resistance
in Plasmodium and of its associated mutations
in DHFR has led to the synthesis and testing of
new antifolates such as WR99210 that have
less potential for the selection of resistance.
Using pyrimethamine and WR99210 in combination
may serve to slow down the emergence
of resistance, as was demonstrated for the combination
AZT–3TC against HIV.
The structure of protein targets at the atomic
level will permit a detailed structure–function
MEDICAL APPLICATIONS