Combination therapy
The problem of the development of malaria resistance must be weighed against
the essential goal of anti-malarial care; that is to reduce
orbidity
and mortality. Thus a balance must be reached that attempts to achieve both
goals whilst not compromising either too much by doing so. The most successful
attempts so far have been in the administration of combination therapy. This can
be defined as, �the simultaneous use of two or more blood schizonticidal drugs
with independent modes of action and different biochemical targets in the
parasite�. There is much evidence to support the use of combination therapies,
some of which has been discussed previously, however several problems prevent
the wide use in the areas where its use is most advisable. These include:
problems identifying the most suitable drug for different epidemiological
situations, the expense of combined therapy (it is over 10 times more expensive
than traditional mono-therapy), how soon the programmes should be introduced and
problems linked with policy implementation and issues of compliance.
The combinations of drugs currently prescribed can be divided into two
categories: Non-artemesinin and Quinine based combinations and, Artemesinin
based combinations.
Non-Artemesinin based combinations
- Sulfadoxine-Pyrimethamine (SP)�This combination has been used for many
years and has wide-spread resistance. It has serious adverse effects but is
cheap and is available in a single dose, thus decreasing problems associated
with adherence and compliance. The recommended dose is 25mg/kg of
sulfadoxine and 1.25mg/kg of pyrimethamine.
- Sulfadoxine-pyrimethamine plus Chloroquine�This is another
cost-effective combination, which benefits from the drugs having similar
pharmacokinetic profiles but different biochemical parasitic targets. There
is already some level of parasite resistance present and numerous
side-effects are associated with the use of SP. Chloroquine is recommended
at 25mg/kg over 3 days with a single dose of SP as described above.
- Sulfadoxine-pyrimethamine plus Amodiaquine�This combination has been
shown to produce a faster rate of clinical recovery than SP and Chloroquine,
however there are serious adverse reactions associated with use that have
limited its distribution. It is thought to have a longer therapeutic
lifetime than other combinations and may be a more cost-effective option to
introduce in areas where resistance is likely to develop. This is unlikely
to occur until more information regarding its safety has been obtained. The
recommended dose is 10mg/kg of Amodiaquine per day for 3 days with a single
standard dose of SP.
- Sulfadoxine-Pyrimethamine plus Mefloquine�This is produced as a single
dose pill and has obvious advantages over some of the more complex regimes.
This combination of drugs has very different pharmokinetic properties with
no
synergistic action. This characteristic is potentially thought to delay
the development of resistance, however it is counteracted by the very long
half life of Mefloquine which could exert a high selection pressure in areas
where intensive malaria transmission occurs. It is also an expensive
combination and has not been recommended for used since 1990 due to
Mefloquine resistance.
- Tetracycline or Doxycycline plus Quinine�Despite the increasing levels
of resistance to Quinine this combination has proven to be particularly
efficacious. The longer half-life of the Tetracycline component ensures a
high cure rate. Problems with this regime include the relatively complicated
drug regimen, where Quinine must be taken every 8 hours for 7 days.
Additionally, there are severe side effects to both drugs (Cinchonism in
Quinine) and Tetracyclines are contraindicated in children and pregnant
women. For these reasons this combination is not recommended as first-line
therapy but can be used for non-responders who remain able to take oral
medication. Quinine should be taken in 10mg/kg doses every 8 hours and
Tetracycline in 4mg/kg doses every 6 hours for 7 days.
Artemesinin-based combinations Artemesinin has a very different mode of action than conventional anti-malarials
(see information above), this makes is particularly useful in the treatment of
resistant infections, however in order to prevent the development of resistance
to this drug it is only recommended in combination with another non-artemesinin
based therapy. It produces a very rapid reduction in the parasite biomass with
an associated reduction in clinical symptoms and is known to cause a reduction
in the transmission of gametocytes thus decreasing the potential for the spread
of resistant alleles. At present there is no known resistance to Artemesinin and
very few reported side-effects to drug usage, however this data is limited.
- Artesunate and Chloroquine�This combination has been thoroughly tested
in randomised controlled trials and has demonstrated that it is well
tolerated with few side effects. However, in one study there was less than
85% cure in areas where Chloroquine resistance was known. It is not approved
for use in combination therapy and is unadvised in areas of high P.
falciparum resistance.
- Artesunate and Amodiaquine�This combination has also been tested and
proved to be more efficacious and similarly well tolerated to the
Chloroquine combination. The cure rate was greater than 90%, potentially
providing a viable alternative where levels of Chloroquine resistance are
high. The main disadvantage is a suggested link with
neutropenia. Dosage is recommended as 4mg/kg of Artesunate and 10mg/kg
of Amodiaquine per day for 3 days.
- Artesunate and Mefloquine�This has been used as an efficacious
first-line treatment regimen in areas of Thailand for many years. Mefloquine
is known to cause vomiting in children and induces some neuropsychiatric and
cardiotoxic effects, interestingly these adverse reactions seem to be
reduced when the drug is combined with Artesunate, it is suggested that this
is due to a delayed onset of action of Mefloquine. This is not considered a
viable option to be introduced in Africa due to the long half-life of
Mefloquine, which potentially could exert a high selection pressure on
parasites. The standard dose required is 4mg/kg per day of Artesunate plus
25mg/kg of Mefloquine as a split dose of 15 mg/kg on day 2 and 10 mg/kg on
day three.
- Artemether and
Lumefantrine�(Coartem, Riamet, and Lonart) This combination has been
extensively tested in 16 clinical trials, proving effective in children
under 5 and has been shown to be better tolerated than Artesunate plus
Mefloquine combinations. There are no serious side effects documented but
the drug is not recommended in pregnant or lactating women due to limited
safety testing in these groups. This is the most viable option for
widespread use and is available in fixed-dose formulas thus increasing
compliance and adherence.
- Artesunate and Sulfadoxine/Pyrimethamine�This is a well tolerated
combination but the overall level of efficacy still depends on the level of
resistance to Sulfadoxine and Pyrimethamine thus limiting is usage. It is
recommended in doses of 4mg/kg of Artesunate per day for 3 days and a single
dose of 25mg/kg of SP.
Other combinations There are several anti-malarial combinations currently being developed that
are hoped to be highly efficacious, cost-effective, safe and well tolerated.
These are to be newly developed compounds and not derivatives of currently used
drugs, thus decreasing the likelihood of resistance.
-
Piperaquine-ihydroartemisinin-rimethoprim
(rtecom)
and Artecom combined with Primaquine has been studied in resistant areas of
China and Vietnam. The drug has been shown to be highly efficacious (greater
than 90%) even to strains resistant to Primaquine. Prior to introduction
more information is required on safety and tolerability in pregnant women
and children and toxicology data.
-
Pyronaridine and
Artesunate has been tested and demonstrated a clinical response rate of
100% in one trial in
ainan (an
area with high levels of P. falciparum resistance to Pyronaridine).
-
Chlorproguanil-apsone
and Artesunate (Lapdap plus) is the most tested drug currently under
development and could be introduced in African countries imminently. It is
not recommended as a monotherapy due to concerns of resistance developing
thus threatening the future use of related compounds.
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