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Drug resistance in malaria

Peter B. Bloland

World Health Organization

Department of Communicable Disease Surveillance and
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Drug resistance
in malaria
Peter B. Bloland
Malaria Epidemiology Branch
Centers for Disease Control and Prevention
Chamblee, GA, United States of America

World Health Organization



The World Health Organization wishes to acknowledge the support of the United States Agency for Inter-
national Development (USAID) in the production of this document.

World Health Organization 2001

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1. Introduction 1
2. Disease incidence and trends 2
2.1 Geographical distribution and populations at risk 2
2.2 Causative agents 3
2.3 Diagnosis 3
2.3.1 Microscopy 3
2.3.2 Clinical (presumptive) diagnosis 3
2.3.3 Antigen detection tests 5
2.3.4 Molecular tests 5
2.3.5 Serology 5
2.4 Drugs available for treatment of malaria 5
2.4.1 Quinine and related compounds 5
2.4.2 Antifolate combination drugs 9
2.4.3 Antibiotics 9
2.4.4 Artemisinin compounds 9
2.4.5 Miscellaneous compounds 9
2.4.6 Combination therapy with antimalarials 10
2.5 Current status of drug-resistant malaria 10
3. Causes of resistance 12
3.1 Definition of antimalarial drug resistance 12
3.2 Malaria treatment failure 12
3.3 Mechanisms of antimalarial resistance 12
3.3.1 Chloroquine resistance 12
3.3.2 Antifolate combination drugs 13
3.3.3 Atovaquone 13
3.4 Factors contributing to the spread of resistance 13
3.4.1 Biological influences on resistance 13
3.4.2 Programmatic influences on resistance 15
4. Detection of resistance 16
4.1 In vivo tests 16
4.2 In vitro tests 17
4.3 Animal model studies 17
4.4 Molecular techniques 17
4.5 Case reports and passive detection of treatment failure 18
5. Treatment 19
6. The future: prevention of drug resistance 20
6.1 Preventing drug resistance 20
6.1.1 Reducing overall drug pressure 21
6.1.2 Improving the way drugs are used 21
6.1.3 Combination therapy 21


7. Conclusions and recommendations 23

7.1 Priorities 23
8. Bibliography 24

Figure and tables

Figure 1. Approximate distribution of malaria 2
Table 1. Comparative descriptions of available malaria diagnostic methods 4
Table 2. Antimalarial drugs for uncomplicated malaria 6
Table 3. Distribution of drug-resistant Plasmodium falciparum malaria 10


1. Introduction

Malaria remains an important public health of the greatest challenges facing malaria control
concern in countries where transmission occurs today. Drug resistance has been implicated in the
regularly, as well as in areas where transmission has spread of malaria to new areas and re-emergence of
been largely controlled or eliminated. Malaria is a malaria in areas where the disease had been eradi-
complex disease that varies widely in epidemiology cated. Drug resistance has also played a significant
and clinical manifestation in different parts of the role in the occurrence and severity of epidemics in
world. This variability is the result of factors such some parts of the world. Population movement has
as the species of malaria parasites that occur in a introduced resistant parasites to areas previously free
given area, their susceptibility to commonly used of drug resistance. The economics of developing
or available antimalarial drugs, the distribution and new pharmaceuticals for tropical diseases, includ-
efficiency of mosquito vectors, climate and other ing malaria, are such that there is a great disparity
environmental conditions and the behaviour and between the public health importance of the
level of acquired immunity of the exposed human disease and the amount of resources invested in
populations. In particular, young children, developing new cures (1, 2). This disparity comes
pregnant women, and non-immune visitors to at a time when malaria parasites have demonstrated
malarious areas are at greatest risk of severe or fatal some level of resistance to almost every anti-
illness. Many malaria control strategies exist, but malarial drug currently available, significantly
none are appropriate and affordable in all contexts. increasing the cost and complexity of achieving
Malaria control and prevention efforts need to be parasitological cure.
designed for the specific environment in which they The purpose of this review is to describe the state
will be used and need to take into account the of knowledge regarding drug- resistant malaria and
local epidemiology of malaria and the level of avail- to outline the current thinking regarding strategies
able resources and political will. to limit the advent, spread, and intensification of
Antimalarial drug resistance has emerged as one drug-resistant malaria.


2. Disease incidence and trends

2.1 Geographical distribution and (5) and the Medicines for Malaria Venture (6) a
populations at risk history of unpredictable support for malaria-related
Malaria occurs in over 90 countries worldwide. research and control activities in endemic countries
According to figures provided by the World Health have left many of these countries with little techni-
Organization (3), 36% of the global population live cal capacity for malaria control activities.
in areas where there is risk of malaria transmission, Each year an estimated 300 to 500 million clini-
7% reside in areas where malaria has never been cal cases of malaria occur, making it one of the most
under meaningful control, and 29% live in areas common infectious diseases worldwide. Malaria can
where malaria was once transmitted at low levels be, in certain epidemiological circumstances, a
or not at all, but where significant transmission has devastating disease with high morbidity and mor-
been re-established (3). The development and tality, demanding a rapid, comprehensive response.
spread of drug-resistant strains of malaria parasites In other settings, it can be a more pernicious pub-
has been identified as a key factor in this resur- lic health threat. In many malarious areas of the
gence and is one of the greatest challenges to world, especially sub-Saharan Africa, malaria is
malaria control today. Although there is currently ranked among the most frequent causes of mor-
an increase in attention and resources aimed at bidity and mortality among children and is often
malaria, including such initiatives as Roll Back the leading identifiable cause. WHO estimates that
Malaria (4), the Multilateral Initiative on Malaria more than 90% of the 1.5 to 2.0 million deaths



attributed to malaria each year occur in African 2.3.1 Microscopy

children (3). Other estimates based on a more Simple light microscopic examination of Giemsa-
rigorous attempt to calculate the burden of disease stained blood films is the most widely practised and
in Africa support this level of mortality (7). In useful method for definitive malaria diagnosis.
addition to its burden in terms of morbidity and Advantages include differentiation between species,
mortality, the economic effects of malaria infection quantification of the parasite density, and ability
can be tremendous. These include direct costs for to distinguish clinically important asexual parasite
treatment and prevention, as well as indirect costs stages from gametocytes which may persist with-
such as lost productivity from morbidity and mor- out causing symptoms. These advantages can be
tality, time spent seeking treatment, and diversion critical for proper case-management and evaluat-
of household resources. The annual economic bur- ing parasitological response to treatment. Specific
den of malaria infection in 1995 was estimated at disadvantages are that slide collection, staining, and
US$ .8 billion, for Africa alone (8). This heavy toll reading can be time-consuming and microscopists
can hinder economic and community development need to be trained and supervised to ensure con-
activities throughout the region. sistent reliability. While availability of microscopic
Malaria transmission occurs primarily in tropi- diagnosis has been shown to reduce drug use in
cal and subtropical regions in sub-Saharan Africa, some trial settings (10), in practice, results are
Central and South America, the Caribbean island often disregarded by clinicians (11). Any pro-
of Hispaniola, the Middle East, the Indian subcon- gramme aimed at improving the availability of
tinent, South-East Asia, and Oceania (figure1). In reliable microscopy should also retrain clinicians
areas where malaria occurs, however, there is con- in the use and interpretation of microscopic
siderable variation in the intensity of transmission diagnosis.
and risk of malaria infection. Highland (>1500 m) A second method is a modification of light
and arid areas (<1000 mm rainfall/year) typically microscopy called the quantitative buffy coat
have less malaria, although they are also prone to method (QBCTM, Becton-Dickinson). Originally
epidemic malaria when parasitaemic individuals developed to screen large numbers of specimens for
provide a source of infection and climate condi- complete blood cell counts, this method has been
tions are favourable to mosquito development (3). adapted for malaria diagnosis (12). The technique
Although urban areas have typically been at lower uses microhaematocrit tubes precoated with fluo-
risk, explosive, unplanned population growth has rescent acridine orange stain to highlight malaria
contributed to the growing problem of urban parasites. With centrifugation, parasites are con-
malaria transmission (9). centrated at a predictable location. Advantages to
QBC are that less training is required to operate
2.2 Causative agents the system than for reading Giemsa-stained blood
films, and the test is typically quicker to perform
In humans, malaria infection is caused by one or
than normal light microscopy. Field trials have
more of four species of intracellular protozoan para-
shown that the QBC system may be marginally
site. Plasmodium falciparum, P. vivax, P. ovale, and
more sensitive than conventional microscopy
P. malariae differ in geographical distribution,
under ideal conditions (13, 14). Disadvantages are
microscopic appearance, clinical features (periodic-
that electricity is always required, special equipment
ity of infection, potential for severe disease, and
and supplies are needed, the per-test cost is higher
ability to cause relapses), and potential for devel-
than simple light microscopy, and species-specific
opment of resistance to antimalarial drugs. To date,
diagnosis is not reliable.
drug resistance has only been documented in two
of the four species, P. falciparum and P. vivax.
2.3.2 Clinical (presumptive) diagnosis
2.3 Diagnosis (Table 1) Although reliable diagnosis cannot be made on the
basis of signs and symptoms alone because of the
Direct microscopic examination of intracellular
non-specific nature of clinical malaria, clinical
parasites on stained blood films is the current stand-
diagnosis of malaria is common in many malarious
ard for definitive diagnosis in nearly all settings.
areas. In much of the malaria-endemic world,
However, several other approaches exist or are in
resources and trained health personnel are so scarce
development and will be described here.
that presumptive clinical diagnosis is the only real-



Method Sensitivity/specificity Advantages Disadvantages Cost* References

Rapid diagnostic test sens: Differentiates P. falciparum from non- Cannot differentiate between non- 1.00
based on pLDH: spec: falciparum infections. falciparum species.
(OptiMal - Flow Inc) Speed and ease of use; minimal training Will not quantify parsitaemia
requirements to achieve reliable result. (+/- only).
Reportedly does not remain positive
after clearance of parasites.
No electricity, no special equipment
needed; could be used in community
outreach programmes.

Rapid diagnostic stick sens: 84% 97% Speed and ease of use; minimal training Will not diagnose non-falciparum 0.80 to (23)
test based on PfHRP-II: spec: 81%100% requirements to achieve reliable results. malaria although subsequent 1.00
(ParaSight-F No electricity, no special equipment generation tests will be able to do this.
Becton Dickinson; lower values probably needed; could be used at health post/ Will not quantify parasitaemia (22)
Malaria PfTest due to low parasite community outreach. (+/- only).
ICT Diagnostics) densities Card format easier to use for individual Can remain positive after clearance of
tests; dipstick test easier to use for parasites.
batched testing.

Light microscopy Optimal conditions: Species-specific diagnosis. Requires relatively high degree of 0.03 to (22)
sens: >90% Quantification of parasitaemia aids training and supervision for reliable 0.08** (11)
spec: 100% treatment follow-up. results.
Sensitivity and specificity dependent
Typical field conditions: on training and supervision.
sens: 25%100% Special equipment and supplies needed.
spec: 56%100% Electricity desirable.

Fluorescent microscopy: AO: 42%93% sens/ Results attainable more quickly than Special equipment and supplies needed. 0.03 (AO) (24)
Acridine orange [AO] 5293% spec normal microscopy. Sensitivity of AO poor with low parasite to 1.70 (22)
stained thick blood densities. (QBC)
smears); Electricity required.
Quantitative Buffy QBC: 89% sens/ >95% Unreliable species diagnosis; non-specific
Coat (QBCTM) spec staining of debris and non-parasitic cells.
(Becton-Dickinson) QBC will not quantify parasitaemia.
Acridine orange is a hazardous material.

Clinical, especially Variable depending on Speed and ease of use. Can result in high degree of misdiagnosis Variable (111)
based on formal level of clinical No electricity, no special equipment and over-treatment for malaria. depending
algorithm such as competency, training, needed beyond normal clinical Requires close supervision and on (112)
Integrated Manage- and malaria risk equipment (thermometer, stethoscope, retraining to maximize reliability. situation.
ment of Childhood (endemicity): otoscope, timer).
Illnesses (IMCI) or with IMCI:
similar algorithm low risk: sens: 87%
spec: 8%
high risk: sens: 100%
spec: 0%

Table modified from Stennies, 1999, CDC unpublished document.

* Approximate or projected cost given in US dollars per test performed and reflects only cost of expendable materials unless otherwise noted.
** Cost includes salaries of microscopists and expendable supplies; does not include cost of training, supervision, or equipment.

istic option. Clinical diagnosis offers the advantages symptoms of malaria and other frequent diseases,
of ease, speed, and low cost. In areas where malaria especially acute lower respiratory tract infection
is prevalent, clinical diagnosis usually results in all (ALRI), and can greatly increase the frequency of
patients with fever and no apparent other cause misdiagnosis and mistreatment (16).
being treated for malaria. This approach can iden- Attempts to improve the specificity of clinical
tify most patients who truly need antimalarial treat- diagnosis for malaria by including signs and symp-
ment, but it is also likely to misclassify many who toms other than fever or history of fever have met
do not (15). Over-diagnosis can be considerable with only minimal success (17). The Integrated
and contributes to misuse of antimalarial drugs. Management of Childhood Illnesses (IMCI) pro-
Considerable overlap exists between the signs and gramme defined an algorithm that has been devel-


oped in order to improve diagnosis and treatment 2.3.4 Molecular tests

of the most common childhood illnesses in areas Detection of parasite genetic material through
relying upon relatively unskilled health care work- polymerase-chain reaction (PCR) techniques is
ers working without access to laboratories or becoming a more frequently used tool in the diag-
special equipment. With this algorithm, every nosis of malaria, as well as the diagnosis and sur-
febrile child living in a high-risk area for malaria veillance of drug resistance in malaria. Specific
should be considered to have, and be treated for, primers have been developed for each of the four
malaria. High risk has been defined in IMCI species of human malaria. One important use of
Adaptation Guides as being any situation where as this new technology is in detecting mixed infec-
little as 5% of febrile children between the ages of tions or differentiating between infecting species
2 and 59 months are parasitaemic (18), a defini- when microscopic examination is inconclusive (27).
tion that will likely lead to significant over-diagno- In addition, improved PCR techniques could prove
sis of malaria in areas with low to moderate malaria useful for conducting molecular epidemiological
transmission. investigations of malaria clusters or epidemics (28).
Primary disadvantages to these methods are overall
2.3.3 Antigen detection tests (also known as rapid high cost, high degree of training required, need
or dipstick tests) for special equipment, absolute requirement for
A third diagnostic approach involves the rapid electricity, and potential for cross-contamination
detection of parasite antigens using rapid immuno- between samples.
chromatographic techniques. Multiple experimen-
tal tests have been developed targeting a variety of 2.3.5 Serology
parasite antigens (19 20 21). A number of com-
Techniques also exist for detecting anti-malaria
mercially available kits (e.g. ParaSight-F, Becton-
antibodies in serum specimens. Specific serologi-
Dickinson; Malaquick, ICT, Sydney, New South
cal markers have been identified for each of the four
Wales, Australia) are based on the detection of the
species of human malaria. A positive test generally
histidine-rich protein 2 (HRP-II) of P. falciparum.
indicates a past infection. Serology is not useful for
Compared with light microscopy and QBC, this
diagnosing acute infections because detectable
test yielded rapid and highly sensitive diagnosis of
levels of anti-malaria antibodies do not appear
P. falciparum infection (22, 23). Advantages to this
until weeks into infection and persist long after
technology are that no special equipment is re-
parasitaemia has resolved. Moreover, the test is rela-
quired, minimal training is needed, the test and
tively expensive, and not widely available.
reagents are stable at ambient temperatures, and
no electricity is needed. The principal disadvan-
tages are a currently high per-test cost and an 2.4 Drugs available for treatment
inability to quantify the density of infection. of malaria
Furthermore, for tests based on HRP-II, detect- There are only a limited number of drugs which
able antigen can persist for days after adequate treat- can be used to treat or prevent malaria (Table 2).
ment and cure; therefore, the test cannot adequately The most widely used are quinine and its deriva-
distinguish a resolving infection from treatment tives and antifolate combination drugs.
failure due to drug resistance, especially early after
treatment (23). Additionally, a test based on detec-
2.4.1 Quinine and related compounds
tion of a specific parasite enzyme (lactate dehydro-
genase or pLDH) has been developed (OptiMAL, Quinine, along with its dextroisomer quinidine, has
Flow Inc. Portland, OR, USA) and reportedly only been the drug of last resort for the treatment of
detects viable parasites, which if true, eliminates malaria, especially severe disease. Chloroquine is a
prolonged periods of false positivity post-treatment 4-aminoquinoline derivative of quinine first syn-
(24, 25, 26). Newer generation antigen detection thesized in 1934 and has since been the most widely
tests are able to distinguish between falciparum and used antimalarial drug. Historically, it has been the
non-falciparum infections, greatly expanding their drug of choice for the treatment of non-severe or
usefulness in areas where non-falciparum malaria uncomplicated malaria and for chemoprophylaxis,
is transmitted frequently. although drug resistance has dramatically reduced
its usefulness. Amodiaquine is a relatively widely



Drug name Use Half- Dosing (all per os) Contra- Cost Comments
life indications (US$)*
(hours) Adult Paediatric
Mefloquine Treatment of non- M: (14 15 mg (base)/kg to 15 mg (base)/kg See under 3.90 Safety of artemisinins & MQ
+ severe falciparum 18 days) maximum of 1000 mg mefloquine on 2nd mefloquine during first trimester of
Artesunate infections thought mefloquine base on day of treatment monotherapy. pregnancy not established.
to be chloroquine Art: 0.5 second day of treat- followed by 10 mg/kg Vomiting after mefloquine
and SP resistant. 1.4 ment, followed by mefloquine on 3rd can be reduced by
10 mg (base)/kg to day. administering mefloquine
maximum of 500 mg on the second and third day
mefloquine base on after an initial dose of
3rd day. artesunate.
Artemisinin (10 mg/kg po
4 mg/kg artesunate 4 mg/kg artesunate daily for 3 days) can be
daily for 3 days. daily for 3 days. substituted for artesunate.

Sulfadoxine/ Treatment of non- S: 100 25 mg/kg sulfa/1.25 By weight: Known SP 1.12 This combination has not
Pyrimethamine severe falicparum 200 mg/kg pyrimethamine 25 mg/kg sulfa/1.25 allergy. been evaluated as
+ infections thought per kg as single dose. mg/kg pyrimethamine extensively as MQ +
Artesunate to be chloroquine P: 80 per kg as single dose. artesunate.
resistant. 100 Average adult dose: Safety of artemisinin during
3 tablets as a single By age: first trimester of pregnancy
Art: 0.5 dose (equivalent to < 1 year: 2 tablet not established.
1.4 1500 mg sulfa /75 mg 13 years: 3/4 tablet Artemisinin (10 mg/kg po
pyrimethamine). 48 years: 1 tablet daily for 3 days) can be
914 years: 2 tablets substituted for artesunate.
>14 years: 3 tablets

4 mg/kg artesunate 4 mg/kg artesunate

daily for 3 days. daily for 3 days.

Lumefantrine Treatment of non- L: 36 Semi-immune patients: Tablets per dose by 7.30 Fixed-dose combination
+ severe falciparum days 4 tablets per dose at 0, body weight: (Cameroon with each tablet containing
Artemether infections thought 8, 24, and 48 hours street 20 mg artemether and
to be chloroquine Art: 411 (total 16 tablet). 1014 kg: 1 tablet price); 120 mg lumefantrine.
Trade name: and SP resistant. 1524 kg: 2 tablets Safety during pregnancy
Co-artem; Riamet Non-immune patients: 2534 kg: 3 tablets 57 not established.
4 tablets per dose at 0 >34 kg: 4 tablets (Europe)
and 8 hrs, then twice
daily for 2 more days given in same schedule
(total 24 tablets) as for adults, depend-
ing on immune status.

Chloroquine (CQ) Treatment of non- (4114 Treatment: 25 mg Treatment: 25 mg 0.08 Widespread resistance in
Trade names: falciparum infections. days) base/kg divided over base/kg divided P. falciparum in most
Nivaquine, Treatment of P. falci- 3 days. over 3 days. regions.
Malaraquine, parum infections in Resistance in P. vivax occurs.
Aralen, areas where chloro- Average adult: 1 g Prophylaxis: 5 mg Can cause pruritus in dark-
many others quine remains chloroquine (salt), base/kg once per skinned patients, reducing
effective. followed by 500 mg week. compliance.
Chemoprophylaxis (salt) in 6-8 hours and
in areas where 500 mg (salt) daily for
chloroquine remains 2 more days.
Prophylaxis: 500 mg
salt once per week.


TABLE 2 (continued)

Drug name Use Half- Dosing (all per os) Contra- Cost Comments
life indications (US$)*
(hours) Adult Paediatric
Amodiaquine (AQ) Treatment of non- Treatment: 25 mg Treatment: 25 mg 0.14 Cross-resistance with
Trade names: severe falciparum base/kg divided base/kg divided over chloroquine limits useful-
Camoquine, infections thought to over 3 days. 3 days. ness in areas with high rates
others be chloroquine of chloroquine resistance.
resistant. Has been associated with
toxic hepatitis and
agranulocytosis when used
as prophylaxisrisk when
used for treatment
unknown but likely to be

Sulfadoxine/ Treatment of non- SD: 100 25 mg/kg sulfa/1.25 By weight: Known sulfa 0.12 Efficacy for vivax infections
pyrimethamine severe falciparum 200 mg/kg pyrimethamine 25 mg/kg sulfa/1.25 allergy may be poor.
(SP); infections thought per kg as single dose. mg/kg pyrimethamine Widespread resistance in
to be chloroquine SL: 65 per kg as single dose: P. falciparum in some
Sulfalene/ resistant. Average adult: regions.
pyrimethamine P: 80100 1500 mg sulfa/75 mg By age: Can cause severe skin
(Metakelfin) pyrimethamine as < 1 year: 1/2 tablet disease when used prophy-
single dose. 13 years: 3/4 tablet lactically; risk when used as
48 years: 1 tablet treatment unknown but
(Equivalent to 3 tablets 914 years: 2 tablets likely to be very low.
as a single dose.) >14 years: 3 tablets

Mefloquine (MQ) Treatment of non- (1418 Treatment: 750 mg Treatment: 15 mg Known 1.92 Vomiting can be a common
Trade names: severe falciparum days) base to 1500 mg (base)/kg to 25 mg or suspected problem among young
Lariam, infections thought to base depending on (base)/kg depending history of children.
Mephaquine be chloroquine and local resistance pat- on local resistance neuro- In some populations (e.g.
SP resistant. terns. Larger doses patterns. Larger doses psychiatric very young African
Chemoprophylaxis (>15 mg/ kg) best (>15 mg/kg) best disorder. children), unpredictable
in areas with chloro- given in split doses given in split doses history of blood levels, even after
quine resistance. over 2 days. over 2 days. seizures appropriate dosing, can
concomitant produce frequent
Prophylaxis: 250 mg Prophylaxis: 5 mg use of treatment failure.
once per week. base/kg once per halofantrine. Use of lower dose may
week. facilitate development of

Halofantrine Treatment of 1090 8 mg base/kg 8 mg base/kg every Preexisting 5.31 Cross-resistance with
suspected multidrug- every 6 hours for 6 hours for 3 doses. cardiac mefloquine has been
resistant falciparum. 3 doses. disease. reported.
Congenital Reported to have highly
Average adult: prolongation variable bioavailability.
1500 mg base of QTc interval. Risk of fatal cardiotoxicity.
divided into 3 doses Treatment
as above. with meflo-
quine within
prior 3 weeks.

Quinine Treatment of severe 1012 Non-severe malaria: Non-severe malaria: 1.51 Side-effects can greatly
malaria. 8 mg (base)/kg 3 8 mg (base)/kg 3 reduce compliance.
Treatment of multi- times daily for 7 days. times daily for 7 days. Used in combination with
drug-resistant Average adult: Severe: see section tetracycline, doxycycline,
P. falciparum. 650 mg 3 times per on treatment of clindamycin, or SP (where
Treatment of malaria day for 7 days. severe malaria. effective) and in areas
during 1st trimester Severe: see section on where quinine resistance
of pregnancy. treatment of severe not prevalent; duration of
malaria. quinine dosage can be
reduced to 3 days when
used in combination.


TABLE 2 (continued)

Drug name Use Half- Dosing (all per os) Contra- Cost Comments
life indications (US$)*
(hours) Adult Paediatric
Tetracycline In combination with Tetra: 10 Tetra: 250 mg/kg Tetra: 5 mg/kg Age less than Used only in combination
(tetra)/ Doxy- quinine, can increase 4 times per day for 4 times per day for 8 years. with a rapidly acting
cycline (doxy) efficacy of treatment Doxy: 16 7 days. 7 days. Pregnancy. schizonticide such as
in areas with quinine quinine.
resistance and/or Doxy: 100 mg/kg Doxy: 2 mg/kg
reduce likelihood of 2 times per day for twice per day
quinine-associated 7 days. for 7 days.
side-effects by
reducing duration of Prophylaxis: 100 mg Prophylaxis: 2 mg/kg
quinine treatment. doxy per day. doxy per day up to
Prophylaxis. 100 mg.

Clindamycin For patients unable 3 300 mg 4 times per 20 to 40 mg/kg/day Severe hepatic Is not as effective as
to take tetracycline. day for 5 days. divided in 3 daily or renal tetracycline, especially
In combination with doses for 5 days. impairment. among non-immune
quinine, can increase History of patients.
efficacy of treatment gastrointestinal Used only in combination
in areas with quinine disease, with a rapidly acting
resistance and/or especially schizonticide such as
reduce likelihood of colitis. quinine.
side effects by
reducing duration of
quinine treatment.

Atovaquone/ Treatment of Atv: 59 1000 mg atovaquone No pediatric formula- 35.00 Fixed dose combination.
proguanil multidrug resistant + 400 mg proguanil tion currently available, Reportedly safe in
P. falciparum Prog: 24 daily for 3 days. but for patients pregnancy and young
Trade name: infections. between 11 and 40 kg children.
Malarone body weight: Drug donation program
1120 kg: 1/4 adult dose Pediatric formulation in
2130 kg: 1/2 adult dose development.
3140 kg: 3/4 adult dose

Artesunate Treatment of multi- 0.51.4 4 mg/kg on the first 4 mg/kg on the first 1.503.40 Safety for use in pregnancy
drug resistant day followed by day followed by not fully established,
P. falciparum 2 mg/kg daily for 2 mg/kg daily for especially for use in first
infections. total of 5 to 7 days. total of 5 to 7 days. trimester (available data
Artemisinin compounds

suggest relative safety for

Artemisinin 27 20 mg/kg on the first 20 mg/kg on the first 1.503.40 second or third trimester).
day followed by 10 day followed by Other artemisinin
mg/kg daily for 10 mg/kg daily for derivatives include
total of 5 to 7 days. total of 5 to 7 days. arteether, dihydro-
artemisinin, artelinate.
Artemether 411 4 mg/kg on the first 4 mg/kg on the first 3.604.80
day followed by day followed by
2 mg/kg daily for 2 mg/kg daily for
total of 5 to 7 days. total of 5 to 7 days.

Primaquine Treatment of P. vivax 6 14 mg base per day 0.3 mg (base)/kg G6PD Primaquine has also been
infections (reduce for 14 days. daily for 14 days. deficiency. investigated for prophy-
likelihood of relapse). 45 mg once per Pregnancy. laxis use.
Gametocytocidal week for 8 weeks. Shorter courses have been
agent. used for falciparum
infections for gameto-
cytocidal action.

* Cost is given for a full adult (60kg) treatment course. Prices have been derived from a variety of sources including Management Sciences for Health, World Health
Organization, drug companies, published reports, and personal communication and are presented for relative comparison purposes onlyactual local prices may
differ greatly.


available compound closely related to chloroquine. 2.4.4 Artemisinin compounds

Other quinine-related compounds in common use A number of sesquiterpine lactone compounds have
include primaquine (specifically used for eliminat- been synthesized from the plant Artemisia annua
ing the exoerythrocytic forms of P. vivax and P. ovale (artesunate, artemether, arteether). These com-
that cause relapses), and mefloquine (a quinoline- pounds are used for treatment of severe malaria and
methanol derivative of quinine). have shown very rapid parasite clearance times and
faster fever resolution than occurs with quinine. In
2.4.2 Antifolate combination drugs some areas of South-East Asia, combinations of
artemisinins and mefloquine offer the only reliable
These drugs are various combinations of dihydro-
treatment for even uncomplicated malaria, due to
folate-reductase inhibitors (proguanil, chlorpro-
the development and prevalence of multidrug-
guanil, pyrimethamine, and trimethoprim) and
resistant falciparum malaria (32). Combination
sulfa drugs (dapsone, sulfalene, sulfamethoxazole,
therapy (an artemisinin compound given in com-
sulfadoxine, and others). Although these drugs have
bination with another antimalarial, typically a
antimalarial activity when used alone, parasitologi-
long half-life drug like mefloquine) has reportedly
cal resistance can develop rapidly. When used in
been responsible for inhibiting intensification of
combination, they produce a synergistic effect on
drug resistance and for decreased malaria transmis-
the parasite and can be effective even in the pres-
sion levels in South-East Asia (32, 33) (see section
ence of resistance to the individual components.
Typical combinations include sulfadoxine/
pyrimethamine (SP or Fansidar 1 ), sulfalene-
pyrimethamine (metakelfin), and sulfametho- 2.4.5 Miscellaneous compounds (not exhaustive)
xazole-trimethoprim (co-trimoxazole). Halofantrine is a phenanthrene-methanol com-
A new antifolate combination drug is currently pound with activity against the erythrocytic stages
being tested in Africa. This drug, a combination of of the malaria parasite. Its use has been especially
chlorproguanil and dapsone, also known as Lap- recommended in areas with multiple drug-resist-
Dap, has a much more potent synergistic effect on ant falciparum. Recent studies have indicated, how-
malaria than existing drugs such as SP. Benefits of ever, that the drug can produce potentially fatal
this combination include 1) a greater cure rate, even cardiac conduction abnormalities (specifically,
in areas currently experiencing some level of SP prolongation of the PR and QT interval), limiting
resistance, 2) a lower likelihood of resistance devel- its usefulness (34). Atovaquone is a hydroxynaptho-
oping because of a more advantageous pharmaco- quinone that is currently being used most widely
kinetic and pharmacodynamic profile, and 3) for the treatment of opportunistic infections in
probable low cost (currently estimated at less than immunosuppressed patients. It is effective against
US$ 1 per adult treatment course) (29). chloroquine-resistant P. falciparum, but because,
when used alone, resistance develops rapidly,
2.4.3 Antibiotics atovaquone is usually given in combination with
proguanil (35, 36). A new fixed dose antimalarial
Tetracycline and derivatives such as doxycycline are
combination of 250 mg atovaquone and 100 mg
very potent antimalarials and are used for both treat-
proguanil (Malarone TM ) is being brought to
ment and prophylaxis. In areas where response to
market worldwide and is additionally being distrib-
quinine has deteriorated, tetracyclines are often used
uted through a donation programme (37, 38). Two
in combination with quinine to improve cure rates.
drugs originally synthesized in China are currently
Clindamycin has been used but offers only limited
undergoing field trials. Pyronaridine was report-
advantage when compared to other available anti-
edly 100% effective in one trial in Cameroon (39);
malarial drugs. Parasitological response is slow to
however, it was only between 63% and 88% effec-
clindamycin and recrudescence rates are high (30,
tive in Thailand (40). Lumefantrinel, a fluoro-
31). Its efficacy among non-immune individuals
methanol compound, is being produced as a fixed
has not been fully established.
combination tablet with artemether (41, 42).

Note: Use of trade names is for identification only and does
not imply endorsement by the Public Health Service or by
the US Department of Health and Human Services.


2.4.6 Combination therapy with antimalarials translate into prolonged useful life span for either
The use of two antimalarials simultaneously, drug.
especially when the antimalarials have different Another combination therapy approach, com-
mechanisms of action, has the potential for inhib- bining an artemisinin derivative with other, longer
iting the development of resistance to either of the half-life antimalarials, is discussed in section
components. The efficacy of a combination of a 6.1.3.
4-aminoquinoline drug (either chloroquine or amo-
diaquine) with sulfadoxine/pyrimethamine has 2.5 Current status of drug-resistant
been reviewed (43). The results of this review sug- malaria
gested that the addition of either chloroquine or Resistance to antimalarial drugs has been described
amodiaquine to SP marginally improved for two of the four species of malaria parasite that
parasitological clearance (compared with SP alone). naturally infect humans, P. falciparum and P. vivax.
The studies reviewed were mostly done in areas and P. falciparum has developed resistance to nearly all
at times when both SP and chloroquine/amodi- antimalarials in current use, although the geo-
aquine retained a fair amount of efficacy, and it is graphical distribution of resistance to any single
not clear from these studies how well such a antimalarial drug varies greatly (Table 3). P. vivax
combination would act in areas where one of the infection acquired in some areas has been shown
components was significantly compromised. to be resistant to chloroquine and/or primaquine
Additionally, to date, there are no data to suggest (44, 45).
whether this slightly improved clearance would Chloroquine-resistant P. falciparum malaria has


Region Resistance reported1 Comments

CQ SP MQ Others
Central America (Mexico, N N N North-west of Panama Canal only
Belize, Guatemala, Honduras,
El Salvador, Nicaragua,
Costa Rica, NW Panama)

Caribbean (Haiti and N N N

Dominican Republic only)

South America (SE Panama, Y Y Y QN Resistance to MQ and QN, although reported, is considered to occur infrequently
Columbia, Venezuela,
Ecuador, Peru, Brazil, Bolivia, )

Western Africa Y Y Y Incidence of resistance to CQ variable, but very common in most areas

Eastern Africa Y Y N Incidence o f resistance to SP highly variable, with some reports of focally high incidence,
but generally uncommon

Southern Africa Y Y N Resistance to SP, although reported, is considered to be generally uncommon

Indian Subcontinent Y N N

South-East Asia and Oceania Y Y Y HAL, Border areas of Thailand, Cambodia, and Myanmar highest risk for multiple-drug-resistant
QN infections; in other areas, incidence of resistance to SP and MQ highly variable and absent
in many areas

East Asia (China) Y Y ? Resistance greatest problem in southern China

Reports of resistance to a given agent occurring in an area does not necessarily mean that occurrence is frequent enough to pose a significant public health risk.
Bold Y indicates agents to which significant resistance occurs in a given area (although actual risk may be highly focal, e.g. South-East Asia, where MQ resistance,
while very frequent in some limited areas, is infrequent or absent in most others). Regular Y indicates that, while resistance to agent has been reported, it is not
believed to occur frequently enough to pose a significant public health risk.

CQ = chloroquine QN = quinine SP = sulfadoxine-pyrimethamine HAL = halofantrine MQ = mefloquine


been described everywhere that P. falciparum is increasingly being relied upon as a replacement
malaria is transmitted except for malarious areas of for chloroquine. Mefloquine resistance is frequent
Central America (north-west of the Panama in some areas of South-East Asia and has been
Canal), the island of Hispaniola, and limited areas reported in the Amazon region of South America
of the Middle East and Central Asia. Sulfadoxine- and sporadically in Africa (46). Cross-resistance
pyrimethamine (SP) resistance occurs frequently in between halofantrine and mefloquine is suggested
South-East Asia and South America. SP resistance by reduced response to halofantrine when used to
is becoming more prevalent in Africa as that drug treat mefloquine failures (47).


3. Causes of resistance

3.1 Definition of antimalarial drug incorrect dosing, non-compliance with duration of

resistance dosing regimen, poor drug quality, drug interac-
Antimalarial drug resistance has been defined as the tions, poor or erratic absorption, and misdiagnosis.
ability of a parasite strain to survive and/or multi- Probably all of these factors, while causing treat-
ply despite the administration and absorption of a ment failure (or apparent treatment failure) in the
drug given in doses equal to or higher than those individual, may also contribute to the development
usually recommended but within tolerance of the and intensification of true drug resistance through
subject. This definition was later modified to increasing the likelihood of exposure of parasites
specify that the drug in question must gain access to suboptimal drug levels.
to the parasite or the infected red blood cell for the
duration of the time necessary for its normal action 3.3 Mechanisms of antimalarial resistance
(48). Most researchers interpret this as referring only
In general, resistance appears to occur through
to persistence of parasites after treatment doses of
spontaneous mutations that confer reduced sensi-
an antimalarial rather than prophylaxis failure, al-
tivity to a given drug or class of drugs. For some
though the latter is a useful tool for early warning
drugs, only a single point mutation is required to
of the presence of drug resistance (49).
confer resistance, while for other drugs, multiple
This definition of resistance requires demonstra-
mutations appear to be required. Provided the
tion of malaria parasitaemia in a patient who has
mutations are not deleterious to the survival or
received an observed treatment dose of an antima- reproduction of the parasite, drug pressure will
larial drug and simultaneous demonstration of remove susceptible parasites while resistant para-
adequate blood drug and metabolite concentrations sites survive. Single malaria isolates have been found
using established laboratory methods (such as high to be made up of heterogeneous populations of
performance liquid chromatography) or in vitro parasites that can have widely varying drug response
tests (see section 4.2). In practice, this is rarely done characteristics, from highly resistant to completely
with in vivo studies. In vivo studies of drugs for sensitive (51). Similarly, within a geographical area,
which true resistance is well known (such as chlo- malaria infections demonstrate a range of drug sus-
roquine) infrequently include confirmation of drug ceptibility. Over time, resistance becomes estab-
absorption and metabolism; demonstration of per- lished in the population and can be very stable,
sistence of parasites in a patient receiving directly persisting long after specific drug pressure is re-
observed therapy is usually considered sufficient. moved.
Some drugs, such as mefloquine, are known to pro- The biochemical mechanism of resistance has
duce widely varying blood levels after appropriate been well described for chloroquine, the antifolate
dosing and apparent resistance can often be ex- combination drugs, and atovaquone.
plained by inadequate blood levels (50).
3.3.1 Chloroquine resistance
3.2 Malaria treatment failure As the malaria parasite digests haemoglobin, large
A distinction must be made between a failure to amounts of a toxic by-product are formed. The
clear malarial parasitaemia or resolve clinical dis- parasite polymerizes this by-product in its food
ease following a treatment with an antimalarial drug vacuole, producing non-toxic haemozoin (malaria
and true antimalarial drug resistance. While drug pigment). It is believed that resistance of
resistance can cause treatment failure, not all treat- P. falciparum to chloroquine is related to an in-
ment failure is due to drug resistance. Many fac- creased capacity for the parasite to expel chloro-
tors can contribute to treatment failure including quine at a rate that does not allow chloroquine to


reach levels required for inhibition of haem polym- 3.4.1 Biological influences on resistance
erization (52). This chloroquine efflux occurs at a Based on data on the response of sensitive parasites
rate of 40 to 50 times faster among resistant para- to antimalarial drugs in vitro and the pharma-
sites than sensitive ones (53). Further evidence sup- cokinetic profiles of common antimalarial drugs,
porting this mechanism is provided by the fact that there is thought to always be a residuum of para-
chloroquine resistance can be reversed by drugs sites that are able to survive treatment (57). Under
which interfere with this efflux system (54). It is normal circumstances, these parasites are removed
unclear whether parasite resistance to other quino- by the immune system (non-specifically in the case
line antimalarials (amodiaquine, mefloquine, of non-immune individuals). Factors that decrease
halofantrine, and quinine) occurs via similar mecha- the effectiveness of the immune system in clearing
nisms (52). parasite residuum after treatment also appear to
increase survivorship of parasites and facilitate de-
3.3.2 Antifolate combination drugs velopment and intensification of resistance. This
mechanism has been suggested as a significant con-
Antifolate combination drugs, such as sulfadoxine
tributor to resistance in South-East Asia, where
+ pyrimethamine, act through sequential and
parasites are repeatedly cycled through populations
synergistic blockade of 2 key enzymes involved with
of non-immune individuals (58, 59); the non-
folate synthesis. Pyrimethamine and related com-
specific immune response of non-immune individu-
pounds inhibit the step mediated by dihydrofolate
als is less effective at clearing parasite residuum than
reductase (DHFR) while sulfones and sulfonamides
the specific immune response of semi-immune
inhibit the step mediated by dihydropteroate
individuals (60). The same mechanism may also
synthase (DHPS) (48). Specific gene mutations
explain poorer treatment response among young
encoding for resistance to both DHPS and DHFR
children and pregnant women (60).
have been identified. Specific combinations of these
The contribution to development and intensi-
mutations have been associated with varying de-
fication of resistance of other prevalent immuno-
grees of resistance to antifolate combination drugs
suppressive states has not been evaluated. Among
refugee children in the former Zaire, those who were
malnourished (low weight for height) had signifi-
3.3.3 Atovaquone cantly poorer parasitological response to both
Atovaquone acts through inhibition of electron chloroquine and SP treatment (61). Similarly, evi-
transport at the cytochrome bc1 complex (56). dence from prevention of malaria during pregnancy
Although resistance to atovaquone develops very suggests that parasitological response to treatment
rapidly when used alone, when combined with a among individuals infected with the human
second drug, such as proguanil (the combination immunodeficiency virus (HIV) may also be poor.
used in MalaroneTM) or tetracycline, resistance de- HIV-seropositive women require more frequent
velops more slowly (35). Resistance is conferred by treatment with SP during pregnancy in order to
single-point mutations in the cytochrome-b gene. have the same risk of placental malaria as is seen
among HIV-seronegative women (62). Para-
sitological response to treatment of acute malaria
3.4 Factors contributing to the spread among HIV-seropositive individuals has not been
of resistance evaluated. The current prevalence of malnutrition
Numerous factors contributing to the advent, among African children under 5 years has been es-
spread, and intensification of drug resistance exist, timated to be 30% and an estimated 4 to 5 million
although their relative contribution to resistance is children are expected to be infected with HIV at
unknown. Factors that have been associated with the beginning of this new century (63). If it is
antimalarial drug resistance include such disparate proven that malnutrition or HIV infection plays a
issues as human behaviour (dealt with in detail else- significant role in facilitating the development or
where), vector and parasite biology, pharmacoki- intensification of antimalarial drug resistance, the
netics, and economics. As mentioned previously, prevalence of these illnesses could pose a tremen-
conditions leading to malaria treatment failure may dous threat to existing and future antimalarial
also contribute to the development of resistance. drugs.
Some characteristics of recrudescent or drug-
resistant infections appear to provide a survival


advantage or to facilitate the spread of resistance drug is not chemically related to drugs previously
conferring genes in a population (32). In one study, experienced (72). The underlying mechanism of
patients experiencing chloroquine treatment fail- this plasticity is currently unknown, but this
ure had recrudescent infections that tended to be capacity may help explain the rapidity with which
less severe or even asymptomatic (64). Schizont South-East Asian strains of falciparum develop
maturation may also be more efficient among re- resistance to new antimalarial drugs.
sistant parasites (65, 66). The choice of using a long half-life drug (SP,
There is some evidence that certain combina- MQ) in preference to one with a short half-life (CQ,
tions of drug-resistant parasites and vector species LapDap, QN) has the benefit of simpler, single-
enhance transmission of drug resistance, while other dose regimens which can greatly improve compli-
combinations inhibit transmission of resistant para- ance or make directly observed therapy feasible.
sites. In South-East Asia, two important vectors, Unfortunately, that same property may increase the
Anopheles stephensi and A. dirus, appear to be more likelihood of resistance developing due to prolonged
susceptible to drug-resistant malaria than to drug- elimination periods. The relative contribution of
sensitive malaria (67, 68). In Sri Lanka, research- low compliance versus use of long half-life drugs
ers found that patients with chloroquine-resistant to development of resistance is not known.
malaria infections were more likely to have Parasites from new infections or recrudescent
gametocytaemia than those with sensitive infections parasites from infections that did not fully clear will
and that the gametocytes from resistant infections be exposed to drug blood levels that are high enough
were more infective to mosquitos (64). The reverse to exert selective pressure but are insufficient to
is also truesome malaria vectors may be some- provide prophylactic or suppressive protection (57).
what refractory to drug-resistant malaria, which When blood levels drop below the minimum in-
may partially explain the pockets of chloroquine hibitory concentration (the level of drug that fully
sensitivity that remain in the world in spite of very inhibits parasite growth), but remain above the EC5
similar human populations and drug pressure (e.g. (the concentration of drug that produces 5% inhi-
Haiti). bition of parasite growth), selection of resistant
Many antimalarial drugs in current usage are parasites occurs. This selection was illustrated in
closely related chemically and development of one study in Kenya that monitored drug sensitiv-
resistance to one can facilitate development of re- ity of parasites reappearing after SP treatment. Para-
sistance to others. Chloroquine and amodiaquine sites reappearing during a period when blood levels
are both 4-aminoquinolines and cross-resistance were below the point required to clear pyrimeth-
between these two drugs is well known (69, 70). amine-resistant parasites, but still above that level
Development of resistance to mefloquine may also required to clear pyrimethamine-sensitive parasites,
lead to resistance to halofantrine and quinine. were more likely to be pyrimethmaine-resistant than
Antifolate combination drugs have similar action those reappearing after levels had dropped below
and widespread use of sulfadoxine/ pyrimethamine the level required to clear pyrimethamine-sensitive
for the treatment of malaria may lead to increased parasites (73). This period of selective pressure lasts
parasitological resistance to other antifolate com- for approximately one month for mefloquine,
bination drugs (29). Development of high levels of whereas it is only 48 hours for quinine (57).
SP resistance through continued accumulation of In areas of high malaria transmission, the prob-
DHFR mutations may compromise the useful life ability of exposure of parasites to drug during this
span of newer antifolate combination drugs such period of selective pressure is high. In Africa, for
as chlorproguanil/dapsone (LapDap) even before instance, people can be exposed to as many as 300
they are brought into use. This increased risk of infective bites per year (in rare cases, even as much
resistance due to SP use may even affect non- as 1000 infective bites per year), and during peak
malarial pathogens; use of SP for treatment of transmission, as many as five infective bites per
malaria increased resistance to trimethoprim/sufa- night (74, 75).
methoxazole among respiratory pathogens (71). Mismatched pharmacokinetics can also play a
There is an interesting theory that development role in facilitating the development of resistance.
of resistance to a number of antimalarial drugs The elimination half-life of pyrimethamine is be-
among some falciparum parasites produces a level tween 80 and 100 hours, and is between 100 and
of genetic plasticity that allows the parasite to 200 hours for sulfadoxine, leaving an extended
rapidly adapt to a new drug, even when the new period when sulfadoxine is unprotected by


synergy with pyrimethamine (73). This sort of mis- gramme recommended 2 tablets (adult dose) of SP
matched pharmacokinetics is even more apparent for treating malaria based on studies suggesting that
in the mefloquine-sulfadoxine-pyrimethamine this was effective. Within a few years, this was no
(MSP) combination used in Thailand (mefloquine longer effective and the programme increased the
has an elimination half-life of approximately 336 regimen to 3 tablets. Although unproven, this may
to 432 hours (48, 76). have contributed to the rapid loss of SP efficacy
It is not clear what the relationship between there. Similar confusion over the proper SP dosing
transmission intensity and development of resist- regimen exists in Africa. To simplify treatment,
ance is, although most researchers agree that there many programmes dose children based on age
seems to be such an association. It is apparent that rather than weight and, depending on the regimen
there are more genetically distinct clones per per- being recommended, this has been shown to pro-
son in areas of more intense transmission than in duce systematic underdosing among children of
areas of lower transmission (77). However, the in- certain weight and age groups (ter Kuile, unpub-
terpretation of this and its implications for devel- lished data, 1997).
opment of resistance has variously been described The use of presumptive treatment for malaria
as resistance being more likely in low-transmission has the potential for facilitating resistance by greatly
environments (78, 79), high-transmission environ- increasing the number of people who are treated
ments (80, 77, 81), or either low- or high- but not unnecessarily but will still be exerting selective pres-
intermediate-transmission environments (82, 83). sure on the circulating parasite population. In some
This relationship between transmission intensity areas and at some times of the year, the number of
and parasite genetic structure is obviously complex patients being treated unnecessarily for malaria can
and subject to other confounding/contributing be very large (15).
factors (84, 83). What is clear is that the rate at Concurrent treatment with other drugs can in-
which resistance develops in a given area is sensi- crease the likelihood of treatment failure and may
tive to a number of factors beyond mere intensity contribute to development of drug resistance. Folate
of transmission (such as initial prevalence of muta- administration for treatment of anaemia and pos-
tions, intensity of drug pressure, population sibly when used as a routine supplement during
movement between areas, the nature of acquired pregnancy (CDC, unpublished data,1998), can
immunity to the parasite or its strains, etc.), but increase treatment failure rates (89). Similarly,
that reducing the intensity of transmission will concurrent illness may have an influence, as was
likely facilitate prolonging the useful life span of mentioned previously with regard to malnourish-
drugs (81, 85). ment.
Drug quality has also been implicated in in-
effective treatment and possibly drug resistance.
3.4.2 Programmatic influences on resistance Either through poor manufacturing practices, in-
Programmatic influences on development of anti- tentional counterfeiting, or deterioration due to
malarial drug resistance include overall drug pres- inadequate handling and storage, drugs may not
sure, inadequate drug intake (poor compliance or contain sufficient quantities of the active ingredi-
inappropriate dosing regimens), pharmacokinetic ents. In an analysis of chloroquine and antibiotics
and pharmacodynamic properties of the drug or available in Nigeria and Thailand, between 37%
drug combination, and drug interactions (86). and 40% of samples assayed had substandard
Additionally, reliance on presumptive treatment can content of active ingredients, mostly from poor
facilitate the development of antimalarial drug manufacturing practices (90). Another study in
resistance. Africa found chloroquine stored under realistic
Overall drug pressure, especially that exerted by tropical conditions lost at least 10% of its activity
programmes utilizing mass drug administration, in a little over a year (91).
probably has the greatest impact on development
of resistance (86, 87). Studies have suggested that
resistance rates are higher in urban and periurban
areas than rural communities, where access to and
use of drug is greater (88).
Confusion over proper dosing regimen has been
described. In Thailand, the malaria control pro-


4. Detection of resistance

In general, four basic methods have been routinely Of the available tests, in vivo tests most closely
used to study or measure antimalarial drug resist- reflect actual clinical or epidemiological situations
ance: in vivo, in vitro, animal model studies, and (i.e. the therapeutic response of currently circulat-
molecular characterization. Additionally, less rig- ing parasites infecting the actual population in
orous methods have been used, such as case reports, which the drug will be used). Because of the influ-
case series, or passive surveillance. Much discus- ence of external factors (host immunity, variations
sion has occurred regarding the relative merits of of drug absorption and metabolism, and potential
one test over another, with the implication always misclassification of reinfections as recrudescences),
being that one type of test should be used prefer- the results of in vivo tests do not necessarily reflect
entially. Careful consideration of the types of the true level of pure antimalarial drug resistance.
information each yields should indicate, however, However, this test offers the best information on
that these are complementary, rather than compet- the efficacy of antimalarial treatment under close
ing, sources of information about resistance. to actual operational conditionswhat can be ex-
Recognition of drug resistance (or, more appro- pected to occur among clinic patients if provider
priately, treatment failure) in individual patients is and patient compliance is high.
made difficult in many settings by operational The original methods for in vivo tests required
issues, such as availability and quality of microscopy. prolonged periods of follow-up (minimum of 28
Especially in Africa, where presumptive diagnosis days) and seclusion of patients in screened rooms
and treatment for malaria is the rule, detection of to prevent the possibility of reinfection. These
treatment failures also tends to be presumptive (per- methods have since been modified extensively and
sistence or reappearance of clinical symptoms in a the most widely used methods now involve shorter
patient recently receiving malaria treatment). periods of follow-up (7 to 14 days) without seclu-
Because of the non-specific nature of clinical signs sion, under the assumption that reappearance of
and symptoms of malaria and the many other causes parasites within 14 days of treatment is more likely
of febrile disease, this can lead to a false sense that due to recrudescence than reinfection (92). Addi-
a particular drug is not working when it is, or,
tional modifications reflect the increased emphasis
potentially, that an ineffective drug is working when
on clinical response in addition to parasitological
it is not. In cases where microscopy is used, pres-
response. Traditionally, response to treatment was
ence of parasitaemia in a supposedly fully treated
categorized purely on parasitological grounds as
patient may indicate treatment failure, but is not
Sensitive, RI, RII, and RIII (48). Later modifica-
necessarily evidence of drug resistance, as explained
tions have combined, to varying extent, para-
in section 3.1.
sitological and clinical indicators (93).
Because anaemia can be a major component of
4.1 In vivo tests malaria illness, in vivo methodologies allow inves-
An in vivo test consists of the treatment of a group tigation of haematological recovery after malaria
of symptomatic and parasitaemic individuals with therapy (94). This is obviously not possible with in
known doses of drug and the subsequent monitor- vitro or molecular techniques. Failure of complete
ing of the parasitological and/or clinical response parasitological clearance, even in situations where
over time. One of the key characteristics of in vivo recurrence of fever is rare, can be associated with
tests is the interplay between host and parasite. lack of optimal haematological recovery among
Diminished therapeutic efficacy of a drug can be anaemic patients.
masked by immune clearance of parasites among Unfortunately, these methodologies, while
patients with a high degree of acquired immunity termed standardized are, in practice, not stand-
(60). ardized. Major differences in sample size, enrolment


criteria, exclusion criteria, length and intensity of ferential die-off of parasites can occur. If, for in-
follow-up, loss-to-follow-up rates, and interpreta- stance, resistant strains are less likely to adapt, the
tion and reporting of results are apparent in pub- results would be biased towards sensitive responses.
lished papers on in vivo trials. These differences are Because venous blood is typically needed, resist-
at times so dramatic, that it is difficult, if not im- ance in the more vulnerable younger age groups is
possible, to compare results from one study to often not studied. Finally, these tests are techno-
another with any level of confidence (CDC, un- logically more demanding and relatively expensive,
published data, 1999). which makes them potentially more difficult to
The methodology currently being used and adapt successfully to routine work in the field.
promoted, especially in sub-Saharan Africa, is a
system that emphasizes clinical response over 4.3 Animal model studies
parasitological response (95). Close adherence to
this protocol does provide comparable data; how- This type of test is, in essence, an in vivo test con-
ever, these data are not readily comparable to data ducted in a non-human animal model and, there-
collected using other in vivo methods. Although fore, is influenced by many of the same extrinsic
not called for in the protocol, categorization of the factors as in vivo tests. The influence of host im-
parasitological response using the standard WHO munity is minimized by using lab-reared animals
definitions (95) would allow some ability to com- or animal-parasite combinations unlikely to occur
in nature, although other host factors would still
pare to historical levels and provide useful para-
be present. These tests allow for the testing of para-
sitological results that would aid in interpreting the
sites which cannot be adapted to in vitro environ-
clinical results.
ments (provided a suitable animal host is available)
and the testing of experimental drugs not yet
4.2 In vitro tests approved for use in humans. A significant disad-
From the point of view of a researcher interested in vantage is that only parasites that can grow in, or
pure drug resistance, in vitro tests avoid many of are adaptable to, non-human primates can be
the confounding factors which influence in vivo investigated.
tests by removing parasites from the host and
placing them into a controlled experimental envi- 4.4 Molecular techniques
ronment. In the most frequently used procedure,
These tests are in the process of being developed
the micro-technique, parasites obtained from a
and validated, but offer promising advantages to
finger-prick blood sample are exposed in microtitre the methods described above. Molecular tests use
plates to precisely known quantities of drug and polymerase chain reaction (PCR) to indicate the
observed for inhibition of maturation into schizonts presence of mutations encoding biological resist-
(96). ance to antimalarial drugs (98). Theoretically, the
This test more accurately reflects pure anti- frequency of occurrence of specific gene mutations
malarial drug resistance. Multiple tests can be per- within a sample of parasites obtained from patients
formed on isolates, several drugs can be assessed from a given area could provide an indication of
simultaneously, and experimental drugs can be the frequency of drug resistance in that area analo-
tested. However, the test has certain significant dis- gous to information derived from in vitro meth-
advantages. The correlation of in vitro response with ods. Advantages include the need for only small
clinical response in patients is neither clear nor con- amounts of genetic material as opposed to live para-
sistent, and the correlation appears to depend on sites, independence from host and environmental
the level of acquired immunity within the popula- factors, and the ability to conduct large numbers
tion being tested. Prodrugs, such as proguanil, of tests in a relatively short period of time. Disad-
which require host conversion into active meta- vantages include the obvious need for sophisticated
bolites cannot be tested. Neither can drugs that equipment and training, and the fact that gene
require some level of synergism with the hosts im- mutations that confer antimalarial drug resistance
mune system. Although adaptation of erythrocytic are currently known or debated for only a limited
forms of P. vivax to continuous culture has been number of drugs (primarily for dihydrofolate
achieved, non-falciparum erythrocytic parasites reductase inhibitors [pyrimethamine], dihydro-
generally cannot be evaluated in vitro (97). In pteroate synthase inhibitors [sulfadoxine], and
addition, because parasites must be cultured, dif- chloroquine) (98, 99). Confirmation of the asso-


ciation between given mutations and actual drug help formulate recommendations for chemo-
resistance is difficult, especially when resistance prophylaxis of non-immune travellers to endemic
involves more than one gene locus and multiple areas (100).
mutations. If these complexities can be resolved, Another method that has been used is passive
molecular techniques may become an extremely detection of treatment failure. In this system,
valuable surveillance tool for monitoring the patients are treated following usual treatment guide-
occurrence, spread, or intensification of drug re- lines and told to come back to the clinic or hospi-
sistance. tal if symptoms persist or return. Those cases which
do return are considered to represent the popula-
tion of treatment failures. Because this system does
4.5 Case reports and passive detection
of treatment failure not ensure compliance with treatment regimens
through directly observed therapy and does not
Additional methods for identifying or monitoring attempt to locate and determine the outcome of
antimalarial drug resistance include the use of case patients who do not return on their own, data are
reports or case series of spontaneously reported seriously biased. In one study conducted in Ethio-
treatment failure. In general, these methods require pia and Eritrea using this method, only 1706/39
far less investment in time, money, and personnel 824 (4.6%) patients returned to clinic (101). The
and can be done on an ongoing basis by individual assumption was that those patients who did not
health care centres. They suffer, however, from pre- return did not have resistant parasites, yielding a
senting a potentially biased view of drug resistance very low prevalence of resistance (1.8% to 4.8%,
primarily because denominators are typically un- depending on region). These results contrast
known and rates of resistance cannot be calculated. dramatically with results from standard 7-day in
Nonetheless, case reports can be useful and may vivo trials conducted at two sites in Eritrea in 1994
indicate a problem that should be confirmed using (CDC, unpublished data,1994) and one site in
one of the other methods. In the United States, for Ethiopia in 19931994 which found between 58%
instance, case reports, especially when occurring in and 86% RII/RIII level resistance (102).
clusters, of prophylaxis failure have been used to


5. Treatment

In theory, recommended treatment regimens should Multidrug resistance (typically referring to re-
be tailored specifically to a given region based on sistance to both chloroquine and SP, but may also
resistance patterns found in that area. Other con- include resistance to other compounds as well)
siderations include cost, cost-effectiveness, availabil- occurs frequently in Amazonia and South-East Asia.
ity, ease of administration, capabilities of the health In these areas, a wide range of treatment options
care infrastructure (i.e. do health care workers have are used. Quinine, either alone or in combination
the equipment and training to safely use parenteral with tetracyclines, or mefloquine tend to be the
routes of administration?), perceived efficacy, and drugs of choice for multidrug-resistant malaria,
real and perceived safety of the drug (acceptability although declining quinine efficacy and high rates
of the drug by the population). In practice, cur- of mefloquine resistance have been reported in some
rently recommended treatment regimens often do areas of South-East Asia. In limited areas of Thai-
not reflect the current state of antimalarial drug land, where falciparum is resistant to many of the
resistance. available drugs, a combination of high-dose
Chloroquine remains the drug of choice for mefloquine (25 mg/kg in a divided dose) and
treatment of non-falciparum infections and non- artesunate (4 mg/kg daily for 3 days) or 7 days of
severe falciparum infections acquired in areas of artesunate alone is required to achieve reliable clear-
known chloroquine sensitivity. Because drug resist- ance of parasites.
ance is not an all-or-nothing phenomenon, chlo- Table 2 summarizes various treatment options,
roquine still retains adequate efficacy even in areas not all of which would be available or necessarily
of known resistance for continued use to be justifi- appropriate in all contexts. One of the primary lim-
able for the time being (for instance, some areas of iting factors to the use of a highly effective antima-
West Africa continue to use chloroquine success- larial and a willingness to change policy to facilitate
fully, although efficacy rates are declining). Much its use, is the cost of the drug itself. Although a
of Africa, however, is currently investigating alter- number of evaluations have been able to show the
natives to chloroquine. Malawi, Kenya, South cost-effectiveness of changing between certain
Africa, and Botswana have moved away from chlo- drugs, in many cases, the total cost associated with
roquine and are using sulfadoxine/ pyrimethamine use of a given drug may be prohibitively high (103).
(SP) extensively or exclusively for treatment of non- Additional costs of interventions to improve use of
severe falciparum infections. The United Republic drugs or patients adherence to treatment regimens
of Tanzania recently indicated that it is moving (such a provider and user training, innovative pack-
towards SP as first-line treatment of malaria, and aging) would further add to the total cost of using
Ethiopia, Eritrea, Uganda, and others are in the some drugs or drug combinations.
process of considering similar policy changes.


6. The future: prevention of drug resistance

The future of antimalarial drug resistance and household level (104). This approach is gaining
efforts to combat it is defined by a number of support internationally. This approach is also in
assumptions. First, antimalarial drugs will continue direct conflict with the primary methods for in-
to be needed long into the future. No strategy in hibiting development of drug resistance, limited
existence or in development, short of an unfore- access to and judicious use of chemotherapeutic
seen scientific breakthrough or complete eradica- agents. Clearly, some middle ground will need to
tion, is likely to be 100% effective in preventing be identified that will improve access to antimalar-
malaria infection. Second, as long as drugs are used, ial drugs for those who need to be treated while at
the chance of resistance developing to those drugs the same time reducing the inappropriate use of
is present. P. falciparum has developed resistance to those same drugs.
nearly all available antimalarial drugs and it is highly Prevention strategies can be divided into those
likely that the parasite will eventually develop aimed specifically at preventing malaria infection
resistance to any drug that is used widely. The and those aimed at reducing the likelihood of de-
advent of P. vivax resistant to chloroquine and pri- velopment of drug resistance. Reduction of overall
maquine may, in time, result in a resurgence of vivax malaria infection rates or transmission rates have
malaria as has been seen with P. falciparum. Third, an indirect impact on development of drug resist-
development of new drugs appears to be taking ance by reducing the number of infections need-
longer than development of parasitological resist- ing to be treated (and therefore, overall drug
ance. The development of resistance to antimalar- pressure) and by reducing the likelihood that re-
ial drugs in South-East Asia has been far quicker sistant parasites are successfully transmitted to new
than the estimated 12 to 17 years it takes to de- hosts. Full discussion of these strategies is beyond
velop and market a new antimalarial compound the scope of this review but they include the use of
(2). Fourth, affordability is an essential considera- insecticide-treated bednets, indoor residual insec-
tion for any strategy to control drug-resistant ticide spraying, environmental control (mosquito
malaria, especially in Africa. breeding site or source reduction), other personal
The future, especially in Africa, will also be de- protection measures (e.g. use of repellent soap or
fined by how well the central tenets of malaria con- screening windows) and chemoprophylaxis in
trol can be reconciled with the central tenets of defined populations (use of mass prophylaxis is typi-
control of drug resistance. One of the cornerstones cally not recommended). An effective and deliver-
of the current approach to malaria control is the able vaccine would also be greatly beneficial.
provision of prompt, effective malaria treatment.
In much of Africa, easy access to public sector health 6.1 Preventing drug resistance
care is limited and when it is accessible, health care
staff are often inadequately trained, insufficiently Interventions aimed at preventing drug resistance,
supplied and supported, ineffectively supervised per se, generally focus on reducing overall drug
and/or poorly motivated. One response to this situ- pressure through more selective use of drugs; im-
ation has been the intentional liberalization of proving the way drugs are used through improving
access to drugs; instead of relying so heavily on the prescribing, follow-up practices, and patient com-
formal public sector to distribute antimalarial drugs, pliance; or using drugs or drug combinations which
some people are suggesting that the best way to are inherently less likely to foster resistance or have
reduce the time between onset of illness and first properties that do not facilitate development or
treatment with an antimalarial drug is by making spread of resistant parasites.
these drugs widely available on the open market,
from unofficial sources of health care, and at the


6.1.1 Reducing overall drug pressure. ture to locate patients in the community or a com-
Because overall drug pressure is thought to be the munity willing to return on a given date, regardless
single most important factor in development of re- of whether they feel ill or not. With this system,
sistance, following more restrictive drug use and patients who fail initial treatment, for whatever
prescribing practices would be helpful, if not reason, are identified quickly and re-treated until
essential, for limiting the advent, spread, and in- parasitologically cured, decreasing the potential for
tensification of drug resistance. This approach has spread of resistant parasites (107).
gained support in North America and Europe for
fighting antibacterial drug resistance (105, 106). 6.1.3 Combination therapy
The greatest decrease in antimalarial drug use
A strategy that has received much attention recently
could be achieved through improving the diagno-
is the combination of antimalarial drugs, such as
sis of malaria. Although programs such as IMCI
mefloquine, SP, or amodiaquine, with an
aim to improve clinical diagnosis through well-
artemisinin derivative (108). Artemisinin drugs are
designed clinical algorithms, a large number of
highly efficacious, rapidly active, and have action
patients will continue to receive unnecessary anti-
against a broader range of parasite developmental
malarial therapy, especially in areas of relatively low
stages. This action apparently yields two notable
malaria risk (18). Basing treatment on the results
results. First, artemisinin compounds, used in com-
of a diagnostic test, such as microscopy or a rapid
bination with a longer acting antimalarial, can rap-
antigen test, however, would result in the greatest
idly reduce parasite densities to very low levels at a
reduction of unnecessary malaria treatments and
time when drug levels of the longer acting antima-
decrease the probability that parasites are exposed
larial drug are still maximal. This greatly reduces
to subtherapeutic blood levels of drug.
both the likelihood of parasites surviving initial
There are notable exceptions to this, however.
treatment and the likelihood that parasites will be
Presumptive therapy with SP during pregnancy has
exposed to suboptimal levels of the longer acting
been shown to be an operationally sustainable in-
drug (32). Second, the use of artemisinins has been
tervention that offers significant protection from
shown to reduce gametocytogenesis by 8- to
low birth weight associated with placental malaria
18-fold (33). This reduces the likelihood that
(62). There may be a role for presumptive treat-
gametocytes carrying resistance genes are passed
ment or even mass drug administration in response
onwards and potentially may reduce malaria trans-
to an epidemic, although its cost-effectiveness has
mission rates. Use of combination therapy has been
not been proven. Prophylaxis programmes, how-
linked to slowing of the development of mefloquine
ever, should be used only among populations where
resistance and reductions in overall malaria trans-
compliance is likely to be high and where a highly
mission rates in some parts of Thailand and has
effective prophylactic drug can be used.
been recommended for widespread use in sub-
Saharan Africa (108). This interpretation and the
6.1.2 Improving the way drugs are used recommendation for rapid adoption of combina-
Other disease control programmes, such as for TB, tion therapy in Africa, however, has been questioned
STDs, and HIV, have begun to rely heavily on (109, 110).
directly observed therapy (DOT) as a way to en- It should be noted that this argument contra-
sure a high degree of compliance. While this has dicts a previously mentioned argument in that it
not yet received serious consideration for malaria, promotes the use of a drug combination with
the use of drugs with single-dose regimens (SP, grossly mismatched half-lives. Theoretically, in
mefloquine) could potentially make DOT possi- areas where malaria transmission rates are quite low,
ble. The benefits of using single-dose DOT need such as where this strategy has been most inten-
to be weighed against the costs of using drugs with sively studied in Thailand, this is of minimal con-
long half-lives. cern (i.e. the likelihood of being bitten by an
Another approach that has not been widely infective mosquito during the period when drug
adopted is the close follow-up and re-treatment, if levels are suboptimal is very low). In areas where
necessary, of patients. The success of this approach transmission rates are very high (for example,
is dependant on availability of reliable microscopy Africa where inoculation rates can be as high as five
(to diagnose the illness initially as well as to con- infective bites per night), this likelihood is very high.
firm treatment failure), and either an infrastruc- The relative contribution to development of resist-


ance of parasites surviving initial malaria treatment In the future, antimalarial therapy may be ex-
compared with new parasites being exposed to sub- panded by combining chemotherapy with vaccines
optimal drug levels is unknown. (or other drugs) specifically designed to inhibit
As second concern about combination therapy transmission of malaria. These transmission-block-
is the extent to which the components might be ing vaccines or drugs could reduce the potential
used for monotherapy outside official health serv- for onward transmission of gametocytes carrying
ices. Already, artemisinin compounds are available resistance genes, even if a relatively large number
in the pharmacies and markets of Africa. As supply of parasites survive initial treatment. This could
increases and the price drops, these drugs will be work through using drugs or vaccines with a high
used increasingly for the treatment of fever and, degree of specific antigametocytocidal activity (such
because of the rapidity of action, they may in fact as primaquine and related drugs), drugs that non-
become the communitys drug of choice. It is un- specifically reduce the likelihood of gametocytes
likely, in this scenario, that they would be used in developing (such as appears to be the case with the
combination with another drug, whether SP or artemisinins), or drugs or vaccines that interfere
mefloquine. Similarly, in Africa, SP is both widely with sexual reproduction and infection of the para-
available and inexpensive and may continue to be site within the mosquitos when taken up with a
used alone. Any benefits of combination therapy blood meal (although short acting, the combina-
in preventing development or intensification of tion of atovaquone and proguanil has this type of
resistance may be lost due to unofficial and incor- activity).
rect use of the component drugs outside of official
health services.


7. Conclusions and recommendations

Because of the realities of health care infrastructure face of high levels of self-treatment and un-
and the influence of the private sector, approaches official use of component drugs (or related
to malaria therapy, especially in sub-Saharan compounds) as monotherapy and in various
Africa, will probably favour increased access to epidemiological contexts (especially high-
drugs (and, therefore, loss of control over how they transmission areas).
are used) over restricted access (and, therefore, more
3. Investigate how a combination therapy strat-
control over how they are used). If this proves to
egy could be financed. This strategy, if proven
be true, while only minor advances against anti-
cost-effective, will nonetheless be more ex-
malarial drug resistance can be expected, short-term
pensive than current strategies. What mecha-
reductions in malaria morbidity and mortality may
nisms might be developed to assist countries
be achieved.
in adopting this strategy?
Long-term success of this strategy, however, will
depend on a continuous supply of new and afford- B. Invest significantly in identifying strategies to
able drugs and on the development of effective and improve acceptance of and compliance with
implementable control measures to reduce overall drug regimens, especially a combination therapy
burden of disease. A more cautious approach would strategy, at all levels of official and unofficial
be to avoid placing too much faith in future scien- health care systems, private sector, and com-
tific advances and technology and to invest in meth- munity. Similarly, investigate to teach concepts
ods to improve the way people and antimalarial of judicious use of antimicrobials (including
drugs interact in an environment of essentially antimalarial drugs) to health care providers.
uncontrolled use. The objective of this investment C. Investigate ways to improve effectiveness of drug
would be to prolong the useful life span of drugs regulatory systems and ability to control intro-
enough to increase the likelihood that new drugs duction of new antimalarials within endemic
or other methods of malaria control will indeed be countries. This is required to avoid uncontrolled
developed and implemented. use of new antimalarials resulting in develop-
Significant advances against antimalarial drug ment of resistance before they are needed which
resistance is probably unlikely without major could significantly compromise their efficacy
change in health infrastructure leading to higher- when they are needed.
quality services that are more readily available.
D. Support new drug development. Investigate
new approaches to drug delivery, such as time-
7.1 Priorities released formulations or novel delivery systems
A. Investigate combination therapy: that would allow use of short half-life drugs
while optimizing compliance. Investigate drugs
1. Fast-track a chlorproguanil/dapsone/
(or vaccines?) that have transmission-blocking
artesunate fixed dose formulation. From a
effect that could be used in combination with
theoretical basis, this would offer the best
drugs active against blood-stage parasites.
combination of overall efficacy, synergy be-
tween the antifolate-sulfa components, short E. Improve access to and use of definitive diagno-
half-life, reasonably well-matched pharma- sis-based treatment.
cokinetics, and probable cost. Because of
F. Support more widespread use of insecticide-
growing use of and resistance to SP, an
treated materials or other appropriate vector
urgency exists to field this promising agent.
control strategies to reduce frequency of clini-
2. Investigate effectiveness of combination cal illness (and therefore, treatment) as well as
therapy in terms of robustness of strategy in overall malaria transmission.


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