Drug-Resistant Malaria - libdoc.who.int - World Health Organization

72 / CONTROL
In relation to the prevention of drug resistance, the
complementary use of primaquine together with blood schizontocides
is probably the most valuable measure that can be taken since this
compound is equally effective against the gametocytes of
drug-sensitive or multiple drug-resistant P.falciparum, a single
30 mg base (adult) dose being sufficient for this purpose.
The large-scale deployment of an additive mixture of chloroquine
with pyrimethamine which was selected purely empirically,
with no substantiating experimental background proved, in the
event, not to prevent the emergence of pyrimethamine-resistant
and, in some areas, multiple drug-resistant strains of
P .falciparum. There is good experimental evidence, however, to
suggest that other additive drug mixtures may be effective ~n
delaying the selection of resistant mutants.
Potentiating mixtures of DHFR inhibitors with sulfonamides or
sulfones may delay significantly, but do not entirely prevent the
development of parasites that are resistant even to these
mixtures, and the example of Fansidar resistance in Brazil and
Thailand bears this out. It should be noted that the development
of a serious problem of resistance to Fansidar required at least a
decade of large-scale drug use even in a situation where resistance
to pyrimethamine alone was already present. However, once
established, resistance to Fansidar appears to spread quite
rapidly.
Drug Monitoring
In order to be forewarned of any possible change in the drug
response pattern in a given area, to interpret its significance
and to plan and implement any essential, appropriate operational
answers, it is necessary to establish baseline data and an
effective monitoring system. Such a system should monitor the
sensitivity status related to all operational and advanced
candidate blood schizontocidal drugs and be based on the use of in
vivo and in vitro methods, and, if so indicated, be complemented
~pharmacokinetic studies. The development of standardized
methods of ~n vivo and ~n vitro tests for drugs other than
4-aminoquinolines, the provision of standardized test material,
and the establishment of threshold levels of in vitro data as
related to in vivo response require urgent attention.
Management of Established Drug Resistance
Drug-resistant micro-organisms as a general rule suffer from
a number of bilogical disadvantages over the drug-sensitive parent
stocks. In the absence of drug selection pressure there is
generally a reversion towards a normal response to the drug due to
the overgrowth of resistant organisms by sensitive ones. For
antimalarial DHFR inhibitors there appears to be evidence that
after the withdrawal of pyrimethamine from a pilot area in