Drug regimens
The following regimens are recommended by the
WHO,
UK HPA and
CDC for adults and children aged 12 and over:
-
chloroquine 300 to 310 mg once weekly, and
roguanil
200 mg once daily (started one week before travel, and continued for four
weeks after returning);
-
doxycycline 100 mg once daily (started one day before travel, and
continued for four weeks after returning);
-
mefloquine 228 to 250 mg once weekly (started two-and-a-half weeks
before travel, and continued for four weeks after returning);
-
Malarone 1 tablet daily (started one day before travel, and continued
for 1 week after returning).
Other chemoprophylactic regimens that are available:
- apsone
100 mg and
pyrimethamine 12.5 mg once weekly (available as a combination tablet
called Maloprim or Deltaprim): this combination is not routinely recommended
because of the risk of
agranulocytosis;
-
Primaquine 30 mg once daily (started the day before travel, and
continuing for seven days after returning): this regimen is not routinely
recommended because of the need for
G-6-PD testing prior to starting primaquine (see the article on
primaquine for more information).
- uinine
sulphate 300 to 325 mg once daily: this regimen is effective but not
routinely used because of the unpleasant side effects of quinine.
Resistance to antimalarials
Anti-malarial
drug resistance has been defined as: "the ability of a parasite to survive
and/or multiply despite the administration and absorption of a drug given in
doses equal to or higher than those usually recommended but within tolerance of
the subject. The drug in question must gain access to the parasite or the
infected red blood cell for the duration of the time necessary for its normal
action." In most instances this refers to parasites that remaining following on
from an observed treatment. Thus excluding all cases where anti-malarial
prophylaxis has failed. In order for a case to be defined as resistant, the
patient under question must have received a known and observed anti-malarial
therapy whilst the blood drug and metabolite concentrations are monitored
concurrently. The techniques used to demonstrate this are: in vivo, in
vitro,
nimal
model testing and the most recently developed molecular techniques.
Drug resistant parasites are often used to explain malaria treatment failure.
However, they are two potentially very different clinical scenarios. The failure
to clear
parasitemia and recover from an acute clinical episode when a suitable
treatment has been given and anti-malarial resistance in its true form. Drug
resistance may lead to treatment failure, but treatment failure is not
necessarily caused by drug resistance despite assisting with its development. A
multitude of factors can be involved in the processes including problems with
non-compliance and adherence, poor drug quality, interactions with other
pharmaceuticals, poor absorption, misdiagnosis and incorrect doses being given.
The majority of these factors also contribute to the development of drug
resistance.
The generation of resistance can be complicated and varies between plasmodium
species. It is generally accepted to be initiated primarily through a
spontaneous mutation that provides some
volutionary
benefit, thus giving an anti-malarial used a reduced level of sensitivity. This
can be caused by a single
point mutation or multiple mutations. In most instances a mutation will be
fatal for the parasite or the drug pressure will remove parasites that remain
susceptible, however some resistant parasites will survive. Resistance can
become firmly established within a parasite population, existing for long
periods of time.
The first type of resistance to be acknowledged was to Chloroquine in
Thailand in 1957. The biological mechanism behind this resistance was
subsequently discovered to be related to the development of an efflux mechanism
that expels Chloroquine from the parasite before the level required to
effectively inhibit the process of haem polymerization (that is necessary to
prevent build up of the toxic by products formed by haemoglobin digestion). This
theory has been supported by evidence showing that resistance can be effectively
reversed on the addition of substances which halt the efflux. The resistance of
other quinolone anti-malarials such as amiodiaquine, mefloquine, halofantrine
and quinine are thought to have occurred by similar mechanisms.
Plasmodium have developed resistance against
antifolate combination drugs, the most commonly used being sulfadoxine and
pyrimethamine. Two gene mutations are thought to be responsible, allowing
synergistic blockages of two enzymes involved in
folate synthesis. Regional variations of specific mutations give differing
levels of resistance.
Atovaquone is recommended to be used only in combination with another
anti-malarial compound as the selection of resistant parasites occurs very
quickly when used in mono-therapy. Resistance is thought to originate from a
single-point mutation in the gene coding for cytochrome-b.
Spread of resistance There is no single factor that confers the greatest degree of influence on
the spread of drug resistance, but a number of plausible causes associated with
an increase have been acknowledged. These include aspects of economics, human
behaviour, pharmokinetics, and the biology of
vectors and parasites.
The most influential causes are examined below:
- The biological influences are based on the parasites ability to survive
the presence of an anti-malarial thus enabling the persistence of resistance
and the potential for further transmission despite treatment. In normal
circumstances any parasites that persist after treatment are destroyed by
the host�s immune system, therefore any factors that act to reduce the
elimination of parasites could facilitate the development of resistance.
This attempts to explain the poorer response associated with
immunocompromised individuals, pregnant women and young children.
- There has been evidence to suggest that certain parasite-vector
combinations can alternatively enhance or inhibit the transmission of
resistant parasites, causing �pocket-like� areas of resistance.
- The use of anti-malarials developed from similar basic chemical
compounds can increase the rate of resistance development, for example
cross-resistance to chloroquine and amiodiaquine, two 4-aminoquinolones and
mefloquine conferring resistance to quinine and halofantrine. This
phenomenon may reduce the usefulness of newly developed therapies prior to
large-scale usage.
- The resistance to anti-malarials may be increased by a process found in
some species of plasmodium, where a degree of
phenotypic plasticity was exhibited, allowing the rapid development of
resistance to a new drug, even if the drug has not been previously
experienced.
- The pharmokinetics of the chosen anti-malarial are key; the decision of
choosing a long-half life over a drug that is metabolised quickly is complex
and still remains unclear. Drugs with shorter half-life�s require more
frequent administration to maintain the correct plasma concentrations,
therefore potentially presenting more problems if levels of adherence and
compliance are unreliable, but longer-lasting drugs can increase the
development of resistance due to prolonged periods of low drug
concentration.
- The pharmokinetics of anti-malarials is important when using combination
therapy. Mismatched drug combinations, for example having an �unprotected�
period where one drug dominates can seriously increase the likelihood of
selection for resistant parasites.
- Ecologically there is a linkage between the level of transmission and
the development of resistance, however at present this still remains
unclear.
- The treatment regime prescribed can have a substantial influence on the
development of resistance. This can involve the drug intake, combination and
interactions as well as the drug�s pharmokinetic and dynamic properties.
Prevention of resistance The prevention of anti-malarial drug resistance is of enormous
public health importance. It can be assumed that no therapy currently under
development or to be developed in the foreseeable future will be totally
protective against malaria. In accordance with this, there is the possibility of
resistance developing to any given therapy that is developed. This is a serious
concern, as the rate at which new drugs are produced by no means matches the
rate of the development of resistance. In addition, the most newly developed
therapeutics tend to be the most expensive and are required in the largest
quantities by some of the poorest areas of the world. Therefore it is apparent
that the degree to which malaria can be controlled depends on the careful use of
the current drugs to limit, insofar as it is possible, any further development
of resistance.
Provisions essential to this process include the delivery of fast primary
care where staff are well trained and supported with the necessary supplies for
efficient treatment. This in itself is inadequate in large areas where malaria
is endemic thus presenting an initial problem. One method proposed that aims to
avoid the fundamental lack in certain countries health care
infrastructure is the privatisation of some areas, thus enabling drugs to be
purchased on the open market from sources that are not officially related to the
health care industry. Although this is now gaining some support there are many
problems related to limited access and improper drug use, which could
potentially increase the rate of resistance development to an even greater
extent.
There are two general approaches to preventing the spread of resistance:
preventing malaria infections and, preventing the transmission of resistant
parasites.
Preventing malaria infections developing has a substantial effect on the
potential rate of development of resistance, by directly reducing the number of
cases of malaria thus decreasing the requirement for anti-malarial therapy.
Preventing the transmission of resistant parasites limits the risk of resistant
malarial infections becoming endemic and can be controlled by a variety of
non-medical methods including
insecticide-treated
bed nets,
indoor residual spraying, environmental controls (such as swamp draining)
and personal protective methods such as using
mosquito repellent. Chemoprophylaxis is also important in the transmission
of malaria infection and resistance in defined populations (for example
travellers).
A hope for future of anti-malarial therapy is the development of an effective
malaria vaccine. This could have enormous public health benefits, providing
a cost-effective and easily applicable approach to preventing not only the onset
of malaria but the transmission of gametocytes, thus reducing the risk of
resistance developing. Anti-malarial therapy could be also be diversified by
combining a potentially effective vaccine with current chemotherapy, thereby
reducing the chance of vaccine resistance developing.
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