Acta Tropica, 56(1994) 143-156

1994 Elsevier Science B.V. All rights reserved 0001-706X/94/$06.00

143

ACTROP 00348

Epidemiology of drug resistance in malaria

Walther H. Wernsdorfer*
Institute of Specific Prophylaxis and Tropical Medicine, Universityof Vienna, Kinderspitalgasse 15, A-1095
Vienna, Austria and Centrefor Drug Research, UniversitiSains Malaysia, 11800 U.S.M., Pulau Pinang,
Malaysia

In the late 1950's chloroquine resistance to Plasmodiumfalciparum occurred in South America and on the
Indochina Subcontinent. Since then it has conquered most of the areas where the parasite species is
endemic. This has necessitated the use of alternative drugs such as sulphonamide pyrimethamine combinations, quinine/tetracyclines, mefloquine, halofantrine, and recently also artemisinin-based compounds. In
wide areas of South-east Asia, western Oceania and South America sulphonamide-pyrimethamine combinations have lost adequate efficacy. The situation is most serious in the Thai/Cambodia and
Thai/Myanmar border areas where multiresistance necessitated the shift to the last line drug, i.e., the
artemisinin derivatives. Selection of resistant parasites due to drug pressure, and their subsequent propagation by local transmission and migration of reservoirs are key factors in the dynamics of drug resistance.
Selection is the result of the interplay of parasite, drug and human host, and is largely influenced by
immune factors and the pharmacokinetics and pharmacodynamics of the drug. Spread of resistance is
determined by eco-epidemiological factors among which migration and vectorial parameters play a major
role. Rational drug use, especially adequate, monitored, therapeutic administration according to strict
criteria, should curb the onset and spread of resistance, but this concept may not be readily accepted by
health services whose primary goal is clinical amelioration of the disease rather than the more stringent
target of epidemiologically desirable results.
Key words: Plasmodiumfalciparum; Drug resistance; Chloroquine; Antimalarial agent

Introduction
The use o f h e r b a l medicines a g a i n s t m a l a r i a l fevers has a l o n g history. T w o o f these
materials, isolated f r o m Cinchona trees a n d Artemisia annua, have s t o o d the test o f
time - the f o r m e r c o n t i n u o u s l y , the latter after t e m p o r a r y oblivion. O c c a s i o n a l
resistance to quinine, the m a i n a l k a l o i d o f Cinchona ledgeriana, was r e p o r t e d as
early as 1910 ( N e i v a , 1910; N o c h t a n d Werner, 1910), b u t it was the fear o f being
cut off f r o m quinine supplies, r a t h e r t h a n d r u g resistance, t h a t p r o m p t e d the search
for synthetic a n t i m a l a r i a l s . Toxicological c o n s i d e r a t i o n s m a y have h e l p e d in this
quest t h a t p r o d u c e d its first success in the d e v e l o p m e n t o f p a m a q u i n e a n d m e p a c r i n e .
F u r t h e r efforts were directed at better t o l e r a t e d a n d m o r e effective drugs, a n d yielded
the 4 - a m i n o q u i n o l i n e s a n d v a r i o u s antifolates some 50 years ago. It was only after
the onset o f c h l o r o q u i n e resistance in Plasmodiumfalciparum at the end o f the 1950s
t h a t d i m i n i s h i n g efficacy to this c o m p o u n d b e c a m e the m a j o r m o t i v a t o r o f further
d r u g d e v e l o p m e n t , resulting in a variety o f alternative m e d i c a m e n t s , e.g., s u l p h o n a *Corresponding author. Present address: Cranachstr. 8, A-1130 Vienna, Austria. Fax: +43 1 8040764.
SSDI 0001-7064(93)E0081-V

144
mide-pyrimethamine combinations, mefloquine, halofantrine and artemisinin.
Resistance to some of these alternative drugs has already become a problem in
several geographic locations.
Drug resistance has so far not been reported in Plasmodium ovale and P. malariae.
Early observations indicate a relatively poor response of hypnozoites of P. vivax to
primaquine in South West Pacific strains (Bruce-Chwatt et al., 1986), but this is
probably the expression of initial low sensitivity rather than acquired resistance.
Relative resistance of the erythrocytic forms of P. vivax has been reported from
Papua New Guinea (Rieckmann et al., 1989), and from the Solomon Islands
(Whitby et al., 1989), but this phenomenon seems until now to be restricted to
western Oceania. Drug resistance in P. falciparum is of much greater importance,
not only in frequency, degree and geographical distribution, but also because of the
significant mortality associated with falciparum malaria.
The geographic distribution of chloroquine resistance has now become identical
with that of autochthonous P. falciparum except in America north of the Panama
Canal and some areas in southwestern Asia. Resistance to sulphonamide-pyrimethamine combinations is widespread in South-east Asia, western Oceania and South
America, and is increasing in West Africa. Resistance to quinine and mefloquine
has become a problem in the Thai/Cambodia and Thai/Myanmar border areas.
In the context of this paper, only the response of P. falciparum to blood schizontocidal drugs is considered, since this is the major constraint to effective therapy.

The mechanics of antimalarial therapy

In P. falciparum pre-erythrocytic development of the parasite is strictly time limited
and an exhaustive event without residual exo-erythrocytic forms (Garnham, 1988).
In the non-immune subject, clinical manifestations commence when the asexual
parasite density in the blood rises beyond a critical threshold that varies with the
individual but is commonly believed to be less than 1000 parasites per gl blood. In
the absence of superinfection there will be no co-existing exoerythrocytic forms.
Under such circumstances, effective treatment with a blood schizontocidal drug
should lead to the complete elimination of blood schizogony and asexual parasites
(radical cure). As the production of gametocytes depends on merozoites resulting
from schizogony, no new gametocytes will occur, and those already present will
spontaneously disappear at the end of their life span, which is approximately
5-6 weeks.
Effective treatment is the result of a complex interaction between parasite, man
and medicament (Fig. 1). The definition of drug resistance reflects this in part as it
denotes "the ability of a parasite strain to multiply or to survive in the presence of
concentrations of a drug that normally destroy parasites of the same species or
prevent their multiplication" (Bruce-Chwatt et al., 1986). This is usually understood
as complete resistance, i.e., the ability to withstand drug concentrations following
maximum doses tolerated by the host.
In order to be effective, the drug must reach the intraerythrocytic parasite in an
adequate concentration. Such a concentration needs to be maintained over a critical
time span (Fig. 2). This principle certainly applies to the 'classical' drugs with

145
PHARMACOKINETICS

%NsU z

Fig. 1. Interactions in the chemotherapyof malaria.

t~,.

c~.

t
Fig. 2. Dependenceof radical curative blood schizontocidaltherapy on Cminand train.
enzyme-inhibiting activity (oxidative compounds of the artemisinin group seem to
behave differently, more in line with disinfectants; Wernsdorfer et al., 1992).
Drug concentration is a function of a variety of pharmacokinetic parameters
among which absorption, distribution, metabolism, elimination, and permeation of
the infected erythrocyte's membrane are the most important. These parameters are
subject to considerable individual variation. Variability may also be increased by
the specific clinical-pathological features of malaria.
As will be shown later, the drug alone is usually not able to kill all parasites.
Therapeutic efficacy depends, therefore, on contributory immune responses. In a
subject without prior malaria experience, these immune contributions will be

146
predominantly non-specific in nature and quite limited in their capacity. Increasing
malaria experience will produce specific immune responses which may enhance drug
action to the point where satisfactory therapeutic results can be obtained even in
the presence of moderately resistant parasite populations. A recent demonstration
of this was the treatment of patients with sulphadoxine-pyrimethamine in Irian
Jaya, Indonesia (Baird et al., 1991).
The interaction between host, medicament and parasite may be efficient in producing radical cure. This would be expected in the presence of fully sensitive parasites.
Secondly, the interaction may be grossly inadequate due to pharmacokinetic factors
or parasite resistance. In this case the clinical response will be poor, necessitating
an effective alternative medication. The third possibility is partially effective treatment inasmuch as clinical relief is obtained without the complete elimination of the
infection. This is the situation for the selection of resistant parasites. Such situations
arise frequently with inadequate dose regimens, mass drug administration (MDA)
and 'presumptive' treatment. Most health services are primarily interested in clinical
improvement in the short term, rather than the epidemiologically desirable elimination of the parasites.
Current experience suggests that resistance may occur to any antimalarial compound. Drug pressure is the essential prerequisite for this resistance. However, the
speed and intensity with which resistance emerges and propagates depends upon a
variety of factors related to the parasite, drug and man.
There are many observations on the in vivo and in vitro response of P. falciparum
to drugs. These are of interest, but they hardly reflect the dynamics of drug resistance.
Longitudinal studies are relatively rare. Nevertheless, a reasonable amount of experimental and epidemiological information is available which will facilitate the understanding of drug resistance.

Features underlying drug resistance

Natural populations of P. fah'iparum, as represented by fresh isolates from untreated
patients, are composed of different populations of parasites with different degrees
of drug sensitivity (Thaithong et al., 1984). In this 'undisturbed' population the
distribution of individuals, based on drug sensitivity, is log-concentration normal
(Fig. 3). Sensitive isolates include a large majority of organisms which succumb to
the minimum effective concentration (Cmin, derived from in vivo observations).
However, there is usually a small proportion of parasites that is able to survive
concentrations > Cmin under in vitro conditions. These parasites are certainly damaged and inhibited in their growth, but after the removal of the drug they show
slow recovery and eventually will divide normally. Under in vivo conditions the
damaged parasites and their host cells will be recognized and removed by nonspecific and specific immune mechanisms, leading to radical cure. Cm~nwill vary,
dependent upon the degree of acquired immunity, with an inverse relation between
Cmin and degree of immunity.
If a parasite population is exposed to drug concentrations Cx < Cmin the drug will
eliminate the sensitive part of the population, but leave individuals able to withstand
Cx+. This results in the selection of a new population that is less sensitive compared
to the population prior to drug exposure (Fig. 3B). As drug response is genetically
determined, the new population will maintain its response pattern in the absence of

147

AB

I
I
I
I
|

11

0.01

0.1

c o n e . --*

lO

Fig. 3. Log-concentrationnormal distribution of individual asexual intraerythrocyticP. falciparum parasites according to their sensitivityto chloroquine. A = sensitive, B= slightly resistant. C = markedly resistant population. Concentrations in ~tmol/1blood.
further drug pressure, unless resistance is linked with biological advantage or disadvantage. However, upon renewed drug pressure, further selection will take place,
resulting in enhanced resistance (Fig. 3C).
The drug response pattern of asexual parasites will also be reflected in the gametocyte's and, in consequence, the gamete's, genome. Mating will result in recombination
which may conceivably reduce or enhance the expression of resistance in the
offspring, especially where resistance is multifactorial.
In the past, spontaneous or induced mutation to a status of lesser drug sensitivity,
followed by selection of the mutants under drug pressure, was considered to be the
major causative mechanism of resistance. However, with a frequency of natural
mutations in the order of 10 -8 to 10 9 (Beale, 1980) and in the absence ofmutagenic
activity of the current antimalarials, this mechanism is not likely to contribute
significantly to the emergence of resistance.
Biological advantage of chloroquine-resistant P. faleiparum has been demonstrated
by more productive sporogony in Anopheles stephensi (Wilkinson, 1976) and in An.
balabacensis balabaeensis, now An. dirus (Sucharit et al., 1977). These observations
may explain the efficiency with which chloroquine resistance has been propagated
in southeastern Asia and western Oceania in the 1960s.
There is also evidence of biological advantage of chloroquine-resistant asexual
intraerythrocytic P. falciparum in vitro, which show a significant inverse correlation
between productivity of schizont maturation in the absence of the drug and chloroquine sensitivity (Warsame et al., 1991a). Based on the observations of Landgraf
(1993) it was shown that such biological advantage is also reflected in a significantly
increased geometric mean parasite density in oligosymptomatic carriers of P. faleiparum in a hyperendemic area of tropical West Africa. Appropriate investigations
failed to show a similar biological advantage in relation to quinine, mefloquine or
sulphadoxine-pyrimethamine sensitivity (Landgraf. 1993).
The rapid propagation of chloroquine-resistant P. faleiparum in South America
has been ascribed to a particularly efficient compatibility between the resistant
parasite and An. nuneztovari, similar to that observed with An. dirus in southeastern

148

Asia (Wernsdorfer and Payne. 1991). The reverse seems to be the case with An.
maculatus and An. annularis as shown by the long absence of autochthonous transmission of chloroquine-resistant P. falciparum in southern central areas of Asia
where these species are the main vectors. There is no evidence of a particularly
efficient or inefficient relationship between the major tropical African malaria vectors
and chloroquine-resistant P. falciparum.
Correlations between the response to different drugs are usually related to the
chemical structure of the compounds. Thus, resistance to chloroquine also results
in reduced sensitivity to amodiaquine, which belongs to the same chemical class
(4-aminoquinolines). Similarly, the activity of the stereo-isomers quinidine and
quinine is closely correlated (Wernsdorfer, 1990). Positive correlations were documented for mefloquine and quinine (Suebsaeng et al., 1986; Warsame et al., 1991a;
Brasseur et al., 1992), chloroquine and pyronaridine (Schildbach et al., 1990;
Warsame et al., 1991b) as well as mefloquine and halofantrine (Wongsrichanalai
et al., 1992a). These positive correlations do not mean that resistance to one drug
is automatically manifested in resistance to the other, but it will probably hasten
such an event as demonstrated by the observations of Childs et al. (1991) and
Ketrangsee et al. (1992).
An inverse relationship between chloroquine and mefloquine resistance has been
suggested by van der Kaay et al. (1985) and confirmed by Landgraf (1993). The
observations of Sowunmi et al. (1992) point in the same direction. This may explain
reports of reduced chloroquine resistance in areas where mefloquine sensitivity is
decreasing (Thaithong et al., 1988; Wongsrichanalai et al., 1992b).

Impact of drug use

In the absence of a new infection, effective treatment will result in radical cure.
There will be no residual parasites with reduced drug sensitivity. For the classical
antimalarials, acting through specific enzyme inhibition or blocking, the principle
of maintaining drug concentrations > Cmi, over tmincan be realized through appropriate drug regimens.
Concentrations < Cmin during 0-train, o r maintenance of concentrations at > Cmin
for time spans < t~n will result in drug failure and selection of parasites for resistance.
Such situations may result from inadequate doses, inappropriate dose regimens,
haphazard drug intake, poor drug compliance, or abnormal individual pharmacokinetic parameters in the presence of primarily sensitive parasites. With resistant
parasites Cmin can usually not be reached with the maximum tolerated doses. A
special case is post-therapeutic selection of resistance in newly arriving parasites.
This is associated with the use of drugs with a long elimination half-life in areas
with intensive malaria transmission. These are real-life scenarios, often seen in
combination.
It is probable that mass drug administration (MDA) exerts the highest selection
pressure, especially if sub-therapeutic doses are used. The most far-reaching, almost
universal form of MDA, was the use of medicated salt (Pinotti, 1954). While
pyrimethaminized salt produced almost instantaneous resistance in P. falciparum
and was quickly discontinued, chloroquinized salt was used over longer periods of
time before this form of MDA was withdrawn for logistic reasons. Due to widely

149
varying intake of medicated salt, leakage of drug, and clandestine supplies of nonmedicated salt, this form of M D A produced the most widely varying drug levels in
the population. The first cases of chloroquine-resistant P. falciparum infections
originated in fact from or near areas where chloroquinized salt was used operationally (Payne, 1988).
Single rounds of M D A with regular tablet formulations were occasionally used
in the context of malaria eradication operations to complement residual spraying
with insecticides, in order to accelerate the disappearance of the parasite reservoir.
In the absence of appropriate investigations there is no evidence that this practice
has promoted the occurrence of resistance. On the other hand, effective residual
spraying would have reduced or interrupted malaria transmission and given little
chance to propagate a residual parasite population.
The scenario is different where M D A is given in the presence of uncontrolled,
intensive malaria transmission. There are several examples, including the investigations of Draper et al. (1985) in North Mara, Tanzania. Here, regular M D A with
chloroquine in children under 10 years produced resistance within 3 years (Fig. 4).
After a decrease of efficacy the chloroquine dose was increased, and finally the dose
interval was shortened. These factors and absenteeism of 20-30% per round have
combined to bring about the rapid selection of resistant parasites.
Similar conditions exist where a sizeable proportion of the population practices
self-medication in areas with intensive malaria transmission. This occurred in forestfringe areas of South-east Asia where exophilic An. dirus was not accessible to vector
control measures. Similar conditions prevail in parts of the Amazon Basin where
Kremsner et al. (1989) observed significant differences in chloroquine response of
P. falciparum within the same geographic area according to the ease with which
chloroquine was available to the inhabitants (Fig. 5).
Ineffectual treatment of an individual may also hasten the propagation of resistant
parasite populations, especially when the large majority of malaria cases are detected
p,mol/I Blood
2.5

2.49
==1979 []1982

1.5 _L

0.82
0.5
0 ~

1
2.0

ECso

0.25

0.8

ECgo

EC~

Fig. 4. ECs0, EC90 and EC99 valuesfor chloroquinein P. falciparum from North Mara, Tanzania, 1979
and 1982 (based on in vitro data from Draper et al., 1985).

150

i.Lmol/I Blood
3

2.8095

2.5
i
2

1.5
1.2849
1

0.5

0.8484

II

0.4638

EC~

ECho

Fig. 5. ECs0 and EC9o values for chloroquine of P. falciparum in Acre, Brazil, 1987. R = i s o l a t e s from
riverine dwellers with easy access to chloroquine. I = isolates from persons residing in the interior at some
distance from rivers, without ready access to the drug (based on data from Kremsner et al., 1989).

and treated, leaving only the selected parasites for transmission. This has obviously
happened with sulphadoxine-pyrimethamine in Thailand when subtherapeutic doses
ware employed for 'presumptive' treatment. A similar effect, resulting from poor
compliance with a cumbersome and poorly tolerated multidose regimen, was
observed in the same country with a combination of quinine and tetracycline, for
radical treatment of microscopically confirmed falciparum malaria (Suebsaeng et al.,
1986). In the absence of R-II and R-III responses and post-treatment follow-up,
residual infections remained undetected and became ready reservoirs for the transmission of parasites with reduced quinine sensitivity. Representative investigations
showed a recrudescence rate of 32%, explaining the relative rapidity with which
quinine sensitivity had decreased. Incidentally, mefloquine sensitivity showed a significant, albeit proportionally smaller, reduction over the same time span, although
this drug was not used in Thailand before 1985, except in very limited hospitalbased clinical trials (Fig. 6).
Pharmacokinetic factors may favour the selection of resistant parasites.
Observations of Karbwang et al. (1991) with mefloqulne suggest this, since patients
showing recrudescences had a lower Cmaxand lower day-1 and day-2 plasma concentrations of mefloquine compared with successfully treated patients. Such a phenomenon can be expected to be particularly pronounced with drugs which are poorly or
irregularly absorbed from the gastrointestinal tract. Correlating therapeutic results
and halofantrine plasma concentrations, Karbwang (1992) found treatment failure
to be associated with low drug levels.
Another important pharmacokinetic parameter is the elimination half-life of drugs.
In areas with intensive malaria transmission it is common that parasites originating
from new infections enter the blood in the presence of significant post-therapeutic
drug concentrations. When these concentrations are < Cmin, drug-induced selection
for lower sensitivity will take place. It is quite likely that active selection will extend

151
p.molll
1.0

0.8249

E] 1982 [] 1984 ,

0.5

0.0

EC~

ECgo
QUININE

ECso

ECgo
MEFLOQUINE

Fig. 6. ECso and EC9ovalues for quinine and mefloquinein Thailand 1982 and 1984when quinine was
routinely used for the treatment of confirmed P. falciparum infections (based on data from Suebsaeng
et al., 1986).
to relatively low effective concentration (EC) levels (Fig. 7). Watkins and Mosoba
(1993) showed that this mechanism was responsible for the relatively fast acquisition
of resistance to sulphadoxine-pyrimethamine of P. falciparum in Kenya. The recent,
almost explosive occurrence of mefloquine resistance in the Thai/Cambodia border
area (Wongsrichanalai et al., 1992a) and also on the Thai/Myanmar border is also
ascribed to the same phenomenon. Most infections treated by the Thai health
services in these areas were contracted outside Thai territory. Soon after treatment
most patients return to their places of residence in Cambodia or Myanmar where
malaria transmission is intensive and unabated. Residual, selective mefloquine levels
are maintained for at least 2 months, ample time for new infections to come under
selection pressure. Under these circumstances the occurrence of resistance is rapid.
Similar events are likely to occur if mefloquine is used in hyper-and holoendemic
areas of tropical Africa.

Epidemiological considerations

Details of the early events in the occurrence of chloroquine resistance are unfortunately unknown, since the methods for precise assessment of drug response in vivo
and in vitro were either in their infancy or non-existent in the late 1950s. The first
reports of clinical-parasitological refractoriness came almost simultaneously from
Venezuela, Colombia and areas on the Thai/Cambodia border (Maberti, 1960;
Moore and Lanier, 1961; Harinasuta et al., 1962). The American and Asian foci
were apparently unconnected and occurred in the vicinity of medicated salt projects.
The Pailin focus, which produced the first Asian cases, was incidentally also the first

152

t,,,

!
..... EQ

SPAN OF SELECTION

Fig. 7. Selection pressure of post-therapeutic residual drug on new infections with blood invasion after
concentrations have dropped below Cmin-

from which resistance to sulphadoxine-pyrimethamine was reported (Verdrager,

1986).
While there may have been multiple tbci of primary selection especially in the
case of South America, the general picture of the propagation of chloroquine
resistance in South-east Asia rather suggests progressive expansion through migrants
introducing resistant parasites to new areas. In South America the expansion of
chloroquine resistance was relatively rapid. Within about 10 years the distribution
of chloroquine resistance became identical with that of P. falciparum, probably
facilitated by the homogeneity of the vector fauna in the Amazon Basin. Chloroquine
resistance reached southern Panama in 1965 and has not yet crossed the Panama
Canal, possibly on account of poor compatibility of chloroquine-resistant P. falciparum with the vectors of Central America.
In southern Asia and western Oceania, propagation of chloroquine-resistant P.
falciparum was initially rapid within the area of distribution of An. dirus and An.
farauti, but the westward spread beyond the An. dirus area was relatively slow and
incomplete. This may be due to the need for resistant parasites to adapt to new
vector species, e.g., An. culicifacies and An. stephensi.
In tropical Africa the advent of chloroquine resistance was masked by communal
immunity. The first cases of chloroquine-resistant falciparum malaria from this
region were detected in non-immune visitors after their return to Europe or the
USA. Infections had been contracted in Kenya and Tanzania in 1977 and 1978
(Fogh et al., 1979; Campbell et al., 1979). Since then this phenomenon has reoccurred
quite often and there are numerous reports of such sentinel cases from Central and
West Africa; these observations usually heralded the confirmation of resistance in
the place of the infections' origins.

153

It is not known whether chloroquine resistance in Africa originated from imported

infections or from local selection. Considering the high drug pressure exerted by
MDA in many African countries and the earlier demonstrated ability of African P.
falciparum to develop resistance to chloroquine (Nguyen-Dinh and Trager, 1978)
an autochthonous origin is more likely. The propagation of chloroquine resistance
throughout tropical Africa was completed within a decade. Considering the size of
the area involved, the spread of drug- resistant malaria was even more rapid than
in South America and in the An. dirus areas of South-east Asia. This may be ascribed
to the almost uniform vector fauna with An. gambiae, An. funestus and An. arabiensis
as the main species, the virtual absence of contiguous natural boundaries to malaria
transmission between the main river system of Africa, high population mobility often enhanced by civil strife - and considerable drug pressure in the presence of
intensive, uncontrolled malaria transmission.
The origin and propagation of resistance are inseparable. They need a set of
conditions namely drug pressure for the selection of resistant parasite populations
and their transmission to new hosts. Different eco-epidemiological situations will
determine the dynamics of propagation.
In areas where malaria transmission is naturally low or is low due to vector
control measures, there will be little reason for MDA or widespread self-medication.
In such situations herd immunity is also low, malaria infections will be symptomatic
and the patients will seek treatment. The health services in such areas are usually
of a good standard and able to administer effective medication. Here the risk of
selection comes from unrecognized drug failure of the R-I type. The patient may
obtain clinical relief from the therapy and in the absence of post-treatment followup a recrudescing parasitaemia is not recognized. Such infections are likely to stay
clinically unrecognised for some time as the patient develops increasing immunity
to the parasite. These infections serve as the source for subsequent transmission.
Since fully sensitive infections will respond with radical cure, only resistant parasite
populations will remain. An appropriate example of such a gradual process is the
reduction of quinine sensitivity in Thailand between 1982 and 1984 (Suebsaeng
et al., 1986) where poor compliance with the quinine-tetracycline regimen produced
only a 68% cure. Drug failures were practically all of the R-I type and remained
unnoticed for the lack of follow-up. An epidemic was avoided by the availability of
an early warning system which directed focal vector control measures to all areas
with increased malaria incidence.
A similar situation existed in the area of Balcad, Somalia, where malaria was
originally in the higher range of mesoendemicity, but under effective control with a
variety of antivectorial measures (Warsame et al., 1990). A low-level incidence of
malaria occurred throughout the year, with little seasonal variation. Most of the P.
falciparum infections were symptomatic. Cases were treated with, and responded
well to, chloroquine. As subsequent events proved, this continuous source of sanitation by treatment was instrumental in preventing an upsurge of malaria as the vector
parameters of local An. arabiensis remained essentially unchanged. After the importation of resistant P. falciparum with migrant labourers, chloroquine sensitivity
dropped by 1988 and unrecognized recrudescences increased the reservoir level,
upsetting the precarious transmission balance. The result was an epidemic which
very rapidly re-established malaria endemicity at the pre-control level.
Warsame et al. (1991c) compared the Balcad situation with that in the area of

154

Malable, situated about 170 km to the south. This is a hyperendemic area where
practically no vector control has been practised or even considered. Here the advent
of chloroquine resistance was surreptitious and would have remained almost unnoticed, had it not been for poor clinical response to treatment in infants and young
children. This is the pattern prevailing in the hyper- and holoendemic areas of
tropical Africa.
Outlook
While chloroquine has been lost as a first-line drug for the treatment of falciparum
malaria in most hypo- and mesoendemic areas of the world, this is not yet the case
in the hyper- and holoendemic areas of tropical Africa where partially immune
persons continue to derive clinical benefit from this drug (Ezedinachi et al., 1991;
Mutabingwa et al., 1991). The same situation is currently developing with
sulphonamide-pyrimethamine combinations.
The major impact of drug resistance is felt in areas with low herd immunity as
well as in infants and young children in areas with high malaria endemicity. In these
situations there is a need to use alternative drugs, but higher costs, reduced tolerability and limitations of compliance are substantial constraints. Schapira et al. (1993)
have realistically pointed out that we will have to live with drug-resistant malaria
in the future. However, even the realization of the most elementary objective of
malaria control, the elimination of mortality from the disease, may become impossible for economic reasons alone.
Thus the rational use of antimalarial drugs is imperative. Such rational use implies
the restriction of MDA, and the controlled use of alternative drugs in areas of
proven need, with post-treatment follow-up. Wherever antimalarial drugs have been
deployed for the control of transmission instead of using antivectorial measures,
rapid occurrence of drug resistance has resulted. This is sufficient reason to eliminate
this type of drug use from the operational repertoire.
Rational drug use alone will not be enough to overcome the problem of drug
resistance. The continued search for new drugs and the improvement of existing
medicaments through better formulations, better dose regimens, or synergistic combination with suitable partner compounds, deserve increased attention.
In parts of South-east Asia, i.e., in the Thai/Cambodia and Thai/Myanmar border
areas, a near desperate situation of multiresistance has recently arisen, necessitating
the use of the current last line of alternative drugs (the artemisinin class). Even the
most recent reports suggest that safe and effective drug schedules are not yet
available. The increased use of these last line drugs in areas where it is not yet
warranted on clinical grounds carries the risk of losing yet another useful and
promising group of compounds. We shall thus reach the point where there is no
alternative drug and we shall have to live with resistance. But how can this be done?
Such a challenge merits attention well in advance of the event, in order to avoid
gross mortality from malaria. The armamentarium of non-drug related individual
protection measures has not been exhausted. Together with the development of
specific immune responses, whether natural or induced, and some vestige of clinical
attenuation afforded by drugs, it may be possible to produce a state of bearable
coexistence - but a state that cannot be expected to be peaceful. This scenario may
hopefully result in innovative thoughts about novel vector control measures.

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