trans

426 DRUG RESISTANCE
some 50 million people each year, of whom 70
to 100 000 die. As with Giardia and Trichomonas
the drug of choice for the treatment of amebiasis
is metronidazole.
Metronidazole
The development of high-level metronidazole
resistance in E. histolytica is much more
difficult than has been the experience with
Trichomonas and Giardia. Also in contrast to
Trichomonas and Giardia, E. histolytica selected
for metronidazole resistance in the laboratory
is found to have levels of PFOR equivalent or
slightly greater than those in the susceptible
parent isolate. Furthermore there is no evidence
for the involvement of an active drug
efflux transporter in metronidazole-resistant
E. histolytica. Resistance in these parasites is
related to the overexpression of iron superoxide
dismutase and peroxiredoxin, and a decrease
in the expression of ferredoxin and flavin
reductase. The critical involvement of iron
superoxide dismutase and peroxiredoxin was
confirmed by episomal transfection of these
antioxidant enzymes into metronidazolesusceptible
isolates, which was associated
with reduced drug susceptibility.
Emetine resistance
Laboratory-induced resistance to emetine in
E. histolytica displays a classic MDR phenotype
associated with reduced drug accumulation
which can be reversed by agents such as
verapamil. Molecular analysis has revealed
the involvement of two MDR-type drug efflux
pumps: Ehpg1, which is upregulated in resistant
parasites by a C/EBP-like factor and a
multiprotein complex; and Ehpgp5, which is
upregulated by the drug through AP-1 and
HOX factors. Transfection studies suggest that
Ehpgp1 is responsible for low-level or basal
emetine resistance, with Ehpgp5 contributing
to high-level resistance.
HELMINTHS AND
CHEMOTHERAPY
Helminth infections, which are responsible for
debilitating diseases such as schistosomiasis,
filariasis, intestinal helminth infection and
onchocerciasis affect more than half a billion
people, contributing significantly to the world
disease burden. Helminths are also important
parasites of man’s livestock and cause serious
economic losses. In the absence of effective
vaccines, worm infections in man and animals
are controlled most efficiently by treatment
with anthelmintics. The availability of broadspectrum
anthelmintics as single dose therapy
and their use in mass treatment control programs
has helped in the control of worm
infections. Bona fide drug resistance in common
worm infections is not yet widespread in
human medicine. However, drug resistance is
widespread in veterinary medicine, and thus
the potential for resistance is important in
worms infecting humans.
Resistance to praziquantel and other
anti-schistosome drugs
Schistosomes are multicellular parasites, whose
life cycle includes both human and snail hosts.
It is estimated that 200 million people are
infected, of whom more than 50% are symptomatic.
Chemotherapy is presently the only
efficient way to control schistosome infections.
Praziquantel (Figure 16.8) is the drug of choice
for treatment since it is active against all
the Schistosoma species, particularly against
S. mansoni, S. haematobium and S. japonicum.
Praziquantel also has good activity against
cestode infections. The mechanism of action
MEDICAL APPLICATIONS