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398 DRUG RESISTANCE
of some of the most successful drugs ever synthesized,
such as chloroquine in the treatment
of malaria, and ivermectin in the treatment of
onchocerciasis. In stark contrast to this, many
of the drugs directed against parasites have
far from optimal pharmacological properties,
with narrow therapeutic indices and limiting
host toxicity. The arsenal of anti-protozoal drugs
is thus limited, and this is exacerbated by the
emergence of drug resistance. With the development
of new drugs proceeding slowly, the
emergence of drug resistance in parasitic
protozoa and helminths is becoming a major
public health problem, and several parasitic
diseases were recently included in the World
Health Organisation’s list of diseases where
antimicrobial resistance is a major issue
(Chapter 17) (www.who.int/infectious-dieasereport/2000/ch4.htm).
In this chapter we
will attempt to give an overview of the drug
resistance mechanisms found to operate in
parasites and helminths. We will attempt to
focus on human parasites and emphasize
resistance mechanisms as characterized in field
isolates.
GENERAL MECHANISMS OF
RESISTANCE
Parasites, like other living cells, can evade drug
action by a number of diverse and elegant biochemical
mechanisms. The general biochemical
frameworks of resistance are often similar.
Cells may evade drug action by hiding in sanctuary
sites, by modifying drug uptake systems
or alterating membrane composition, thereby
thwarting drug uptake. Once inside the parasite,
drugs may be inactivated, excreted, chemically
modified to facilitate excretion, or routed into
compartments away from the target site. Drug
activation mechanisms may be suppressed
or lost. The interaction of the drug with the
target may be made less effective by increasing
the level of competing substrates or by
altering the target to make it less sensitive
to the drug. Finally, the cell may learn to live
with a blocked target by bypassing the block
(Figure 16.1).
Resistance mechanisms have been studied
mostly in parasites selected for resistance in
the laboratory, or in a few cases, were deduced
from work carried out in clinical isolates. Work
on in vitro selected cell lines is justified. One
can work with genetically defined cloned populations.
Furthermore, by a detailed comparison
of resistant mutants and the parental strain
one can usually determine, or at least get important
insights into, the resistance mechanisms.
Resistance in clinical samples is less easily
defined: parasite populations are often heterogeneous
and the parent strain is not available
for comparison. A further complication is that
in the process of growing adequate amounts
of material for analysis, the parasite resistance
phenotype can change or a parasite subpopulation,
which is not representative of the
resistant population, expands to become the
major genotype. It should nonetheless be possible
to verify whether resistance mechanisms
defined in the laboratory play a role in the field.
This can be done by using sensitive tools, such
as the polymerase chain reaction and monoclonal
antibodies, to analyse potential resistance
mechanisms in the few parasites that can
be obtained from infected individuals.
In the following sections we will concentrate
on the mechanisms of resistance against the
main anti-parasitic drugs used against some
of the most prevalent parasites. In particular, we
will review the biochemical and molecular characterization
of drug resistance in protozoa and
helminths. We will also describe the possible
implications of our increased understanding
of drug resistance for the improved management
and treatment of parasitic diseases.
MEDICAL APPLICATIONS