Plasmodium species (Malaria) - General Principles of Antiparasitic Therapy

General Principles

            Antimalarial treatment should give a rapid reduction in parasite load, which is especially important in the treatment of severe malaria. Moreover, in an attempt to reduce the rapid spread of antimalarial drug resistance, and to prevent recrudescence of the infection, is the World Health Organisation now recommends that P. falciparum infections everywhere be treated with a combination of antimalarial drugs. The combinations of choice are artemisinin based combination treatments or ACTs. Combinations of drugs will mutually protect each other against selection of resistant clones, since the mutant strain will still be sensitive to the partner drug. The choice of antimalarial treatment is determined by the likely susceptibility of the infecting parasites, and the pharmacokinetic and pharmacodynamic properties of the drugs. The gametocytocidal properties of the drug, which will reduce transmission, can also be taken into consideration. Where diagnostic facilities exist, antimalarial treatment should be given only to symptomatic patients with positive blood smears. In non-immune or semi-immune subjects any parasitemia associated with fever indicates that malaria is the likely cause of that fever, but in areas of higher transmission asymptomatic parasitemia is common. In this context parasitemia may co-exist with fever caused by another infection. Different thresholds are therefore used to differentiate malaria from incidental parasitaemias, e.g. in areas of very high transmission a threshold of 10,000 parasites/µl is often used to distinguish fever caused by malaria and that caused by other infections.

 

Antimalarial Drug Pharmacokinetics and Pharmacodynamics

            The pharmacokinetic properties of many antimalarial drugs are altered during acute disease. This results from impaired absorption in acute illness, alterations in tissue and plasma protein binding which alter the volume of distribution, and reductions in hepatic biotransformation or elimination, which lowers systemic clearance.

            The pharmacokinetic properties of antimalarials that are relevant to the therapeutic effect are the stage specificity of activity, which is of relevance to severe malaria and the maximum effect on inhibition of multiplication, which determines parasite clearance in uncomplicated malaria. Drugs which act earlier in the asexual life cycle of P. falciparum, are preferable in severe malaria e.g., the artemisinins prevent ring form development and thus cytoadherence, but quinine does not. In uncomplicated malaria activity may be described by the fractional reduction in parasite numbers per asexual life cycle or parasite reduction ratio (PRR). This ranges from 10,000 fold (artemisinins) to 10 fold (tetracycline) per asexual life cycle. As there may be up to 1013 parasites in an infection it is evident that at least four asexual 48 hour life cycles must be covered by treatment to clear all parasites. Thus if rapidly eliminated drugs are used (artemisinins or quinine alone) then at least seven days treatment is required, and drugs with lower parasite reduction ratios need to "cover" (i.e. provide maximal parasite reduction ratio values) for longer periods to ensure cure.

Severe Malaria

            Falciparum malaria is defined as severe malaria when the disease presents with one ore more severity signs, including coma or severe prostration, severe anaemia (< 20 % with parasite count >100,000/ mm3), severe jaundice (bilirubin > 2.5 mg/dl), acute renal failure (> 3 mg/dl with urine <400 ml/24 hours), respiratory failure, hypoglycaemia (venous glucose < 40 mg/dl), shock (systolic blood pressure < 80 mm Hg with cool extremities), hyperparasitaemia (peripheral asexual stage parasitaemia > 10 %) or metabolic acidosis (peripheral venous lactate > 4 mmol/l, peripheral venous bicarbonate < 15 mmol/l).

            The objective of treatment in severe malaria is to save life. Prevention of recrudescence is of secondary concern. Patients with severe malaria require intensive care treatment (see below). The mortality of severe malaria is high; approximately 20% of adults and 16% of children with cerebral malaria will die despite optimum treatment. It is essential, therefore that therapeutic antimalarial drug concentrations are achieved as soon as possible once the diagnosis is made. As most deaths occur within the first 48 hours following the start of treatment, fears over significant antimalarial toxicity are secondary to the risks of inadequate treatment. Undertreatment is seldom recognized and may be fatal.

            Chloroquine-resistant P. falciparum has reached almost all areas of the tropics, and Chloroquine is therefore no longer recommended for the treatment of severe malaria. Two classes of drugs are currently available for the parenteral treatment of severe malaria: the cinchona alkaloids (quinine and quinidine) and the artemisinin derivatives (artesunate, artemether, and artemotil or arteether). In adult patients with severe malaria randomized trials comparing artesunate and quinine show clear evidence of benefit with artesunate. In the largest ever multicentre trial of severe malaria, which enrolled 1461 patients, mortality was reduced from 22% to 15%, a relative reduction of 34.7% (95% CI: 18.5 to 47.6%, p=0.002). Moreover quinine was more frequently associated with hypoglycaemia (RR=3.2, p=0.009). The artemisinin derivatives are thus more effective, safer, and also easier to use than quinine. The large randomized trials comparing the oil soluble artemisinin derivative artemether with quinine have not shown a significant reduction in mortality for artemether over quinine. This is likely to be explained by the less favourable pharmacokinetic profile of artemether compared to water-soluble artesunate. Erratic absorption of artemether (and the related compound artemotil) after i.m. injection has been documented, especially in severely ill patients. Artesunate should be the treatment of choice for adults with severe malaria. There are, however, still insufficient data for children, particularly from high transmission settings to make the same conclusions, but randomized trials are under way. Until more evidence emerges, children with severe malaria can be treated with either quinine, artesunate or artemether, but, of these three, the authors prefer water-soluble artesunate.

Artesunate, Artemether and Arteether: Artesunate is formulated as artesunic acid powder and is prepared immediately before injection by dissolving this powder in 1 ml of 5% sodium bicarbonate solution (provided as an ampoule together with the powder). This is then diluted in 5 ml of 5% dextrose and injected over 1 - 2 minutes intravenously, or given by deep intramuscular injection to the anterior thigh. Artesunate is given in an initial dose of 2.4mg/kg followed by the same those after 12 hours, 24 hours and then daily. To prevent recrudescence of the infection, follow on medication should be given once the patient is able to take oral medication. Several regimens are possible, such as a full course of oral artemether-lumefantrine (Co-artemR), or a combination of oral artesunate (2 mg/kg per day, total course 7 days including the parenteral form) and doxycycline (4 mg/kg per day for 7 days, contraindicated in small children ≤ 8 y/o and pregnant women). Mefloquine is not recommended as maintenance antimalarial drug, because of its association with post-malaria neurological syndrome.

            Artemether is given by deep intramuscular injection to the anterior thigh in an initial dose of 3.2mg/kg followed by 1.6mg/kg daily. Artemotil (arteether) is very similar to artemether, differing only in the substitution of an ethyl for a methyl group, and that it is suspended in sesame seed oil whereas artemether is suspended usually in groundnut oil. Dose regimens provisionally are similar to those for artemether. Artesunate is absorbed very rapidly after intramuscular injection whereas the absorption of artemether or arteether is slow and erratic, particularly in shocked children. The parenteral artemisinin derivatives are safe and very easy to use; they have no evident local or systemic toxicity, and no dose modification is required in renal failure or with severe hepatic dysfunction.

            In Vietnam suppository formulations of artemisinin have proved as effective as parenteral artesunate or artemether in the treatment of severe malaria. These can be used in rural tropical areas where parenteral treatment is not possible, pending transfer to hospital. Formulations of artesunate for rectal administration are also satisfactorily absorbed after rectal administration. A randomised study in African children and adults with moderately severe malaria showed more rapid parasite clearance after rectal artesunate compared to parenteral quinine. Very large community based evaluations have just been completed.

Quinine: Quinine should be given by careful rate-controlled infusion and, as for chloroquine, should never be given by intravenous injection. In order that therapeutic concentrations are reached as soon as possible in the course of treatment an initial loading dose should be given, either of 20mg salt/kg infused over 4 hours or 7mg salt/kg infused over half an hour, followed immediately by 10mg salt/kg infused over 4 hours. The initial dose is the most important of all, and should only be reduced if there is good evidence of previous quinine treatment (>40mg/kgin 48 hours for an adult). The safety of this approach has been established in recent large randomised trials. A lower loading dose of 15mg salt/kg has been proposed for the treatment of African children, but this has been disputed. Most debate has centered on the risks of significant cardiovascular or nervous system toxicity resulting from quinine - but this is very rare. A treatment history is often unavailable, or there may be uncertainly whether the patient has received quinine treatment before admission to hospital. Quinine toxicity might result if a full loading dose were given in addition to the earlier treatment. If 40mg salt/kg or more has been given over the preceding 48 hours then a loading dose should not be given, but if less has been taken, or, most importantly, there is uncertainly, then the loading dose should be administered. As there is now extensive evidence in nearly one thousand carefully followed patients of safety with the 20mg/kg dose, and reducing the initial dose increases the risk of undertreatment in the critical initial phase of treatment of this life threatening infection, the initial 20mg/kg dose should only be reduced if there are compelling reasons. The maintenance dose of quinine is 10mg salt/kg given 8-hourly. Quinine doses are similar at all ages, and in pregnancy. The infusion should not be given faster than over a 2-hour period (nor greater than 5 mg/kg/hour). Although quinine is light sensitive, photodegradation is not significant over a 24-hour period and there is no need to protect solutions from light. Quinine may be given in either normal saline or 5% dextrose. In general quinine is well tolerated provided the administration rates are not too rapid (which, as for chloroquine, may produce potentially lethal hypotension). If intravenous infusions cannot be given, or supervised properly, then quinine should be given by intramuscular injection to the anterior thighs (Table 7). The principal adverse effect of quinine in severe malaria is hypoglycaemia. This results from quinine-induced insulin secretion. It usually occurs after quinine has been given for 24 hours and is more likely in patients with severe malaria and, in particular, in pregnant women. Fifty percent of pregnant women with severe malaria treated with quinine will become hypoglycaemic. Hypoglycaemia is usually recurrent and all patients receiving quinine should have their blood glucose monitored frequently. Even if an artemisinin derivative is substituted, the slow elimination of quinine means that the risk of hypoglycaemia will persist for up to two days.

Table 7. Antimalarial Treatment of Severe Malaria

     Artesunate1

2.4 mg/kg i.v. or i.m. on admission, at 12, 24 hours, then daily. Artesunic acid (60mg) is dissolved in 1ml of 5% sodium bicarbonate and further diluted into 5ml with 5% dextrose or normal saline for intravenous injection (given as a bolus over 2 min). 1 ampoule=60mg

 

     Artemether

3.2 mg/kg i.m. on admission followed by 1.6 mg/kg daily. NOT for i.v. administration. 1 ampoule = 80mg. Injections to the anterior thigh.

 

     Quinine

20mg /kg of dihydrochloride salt by intravenous infusion over 4 hrs followed by 10 mg/kg infused over 2 - 8 hrs every 8 hours.

If intravenous route not possible then give by intramuscular injection to the anterior thigh. The first dose should be divided; 10mg salt/kg to each thigh. Quinine should be diluted, inject no more than 180mg/ml.

 

     Quinidine

10 mg base/kg infused at constant rate over 1-2 hr followed by 0.02 mg/kg/min as constant infusion, with electrocardiographic monitoring.

 

 

1 Parenteral artesunate is the drug of choice for the treatment of severe malaria in adults. For children in high transmission areas there is as yet insufficient evidence to recommend any of the above antimalarial medicines over another.

 

            As soon as the patient can take solids by mouth oral treatment should be substituted to complete a 7-day course of treatment. A 7-day course of tetracycline, doxycycline (for children >8 years and for non-pregnant adults) or clindamycin should be started as soon as renal function has returned to normal. If there is no improvement in the overall condition by 48 hours after starting intravenous quinine treatment the total daily dose should be reduced by 30 - 50% to avoid accumulation to toxic levels. The same applies if the patient requires dialysis because of acute renal failure. Doses should not be reduced before 48 hours unless there is clear evidence of toxicity. If plasma concentration monitoring is available the total plasma concentration should be kept between 8 - 15mg/L (this corresponds approximately to free quinine concentrations between 0.8 and 1.5 mg/L). Although quinine produces an average of 10% prolongation of the electrocardiogram QT interval (mainly as a result of QRS lengthening) electrocardiographic monitoring is not mandatory during quinine treatment. However monitoring is advisable in the very young and very old, and in the management of acute renal failure where electrolyte disturbances are also likely. Where intravenous infusions cannot be given quinine may be given by deep intramuscular injection. Parenteral quinine is usually formulated as the dihydrochloride salt. This is acidic (pH 2) and painful if injected undiluted. In tropical areas intramuscular quinine administration has been associated with subsequently lethal tetanus (213). Intramuscular quinine should be given to the anterior thigh (never the buttock or arm) with scrupulous aseptic technique. The quinine should be diluted 1:1 to 1:5 in normal saline before injection. Subsequent doses should be given into alternate thighs. Untreated severe malaria is usually fatal, and antimalarial drugs save life by killing and arresting the development of malaria parasites. Although both quinine and chloroquine have "anti-inflammatory" or "anti-cytokine" activities there is no evidence that these contribute to the therapeutic effect of these drugs in vivo.
 

Quinidine: In situations where quinine is not available but quinidine is, the latter drug may be used although there is some controversy over the correct dosage regimens. In comparison with the quinine treatment of severe falciparum malaria for which there is extensive information, there are few data on which to base treatment recommendations for quinidine. Both drugs share each other's properties, although there are significant pharmacokinetic differences between them and quinidine has greater cardiac and antimalarial effects. It is therefore more potent and more toxic. The therapeutic range for the antiarrhythmic activity of quinidine at steady state has been estimated at between 3 and 8 mg/L when measured by the extraction-fluorescence method (which also measures the bioactive metabolites) and approximately 2 to 5 mg/L when measured by specific HPLC. The therapeutic range for antimalarial treatment with quinidine is not known precisely, but considering the experience in cardiovascular disease, and the 2-3 fold greater activity against P. falciparum in-vitro compared with quinine, it has been suggested that total plasma concentrations between 4 and 8 mg/L should represent a reasonable compromise between efficacy and toxicity (compared to 8-20 mg/L for quinine, which corresponds to a free concentration of 0.8-2 mg/L).

            The dose recommendations for quinidine in severe malaria are based on two studies. In the first, conducted in 14 adults Thai patients with severe falciparum malaria, intravenous quinidine gluconate was given in a dose of 15 mg base/kg over 4 hours followed by 7.5 mg base/kg eight hourly until oral treatment could be substituted (i.e. 52.5 mg/kg in 48 hours). Mean (SD) total plasma quinidine concentrations, measured by the extraction fluorescence method, were 9.2 (2.7) mg/L with a range of 4.4 to 14.3 mg/L at the end of the initial loading dose infusion. Post infusion plasma concentrations generally declined thereafter reflecting increased clearance and expansion of the apparent volume of distribution with recovery. A similar pattern over a nearly two-fold higher plasma concentration range was observed for quinine treatment. In the second study conducted in the United States intravenous quinidine was given in a dose of 6.2 mg base/kg infused over 1-2 hours followed by 0.75 mg base/kg/hour by constant infusion (i.e. a dose 22.5% lower than in the Thai study). Five patients with acute falciparum malaria (4 adults 1 child) and >5% parasitemia received this infusion alone, and ten (7 adults 2 children) received this together with exchange transfusion. Compared with the first study plasma concentrations of quinidine, measured by specific HPLC, were lower (although precise details are not given) and only two had concentrations exceeding 7 mg/L whereas in the Thai study all patients' plasma concentrations exceeded 5.8 mg/L after the initial infusion, a concentration considered to correspond with the maximum MIC value for Thai P. falciparum isolates at the time. Also exchange transfusion would be expected to result in an increased free fraction of quinidine because of the normal alpha 1-acid glycoprotein (AAGP) concentrations in the exchanged blood - and this would change the relationship between total plasma quinidine levels and toxicity. These two studies were sufficient to justify use of quinidine as an alternative to quinine in North America, as quinidine was widely available whereas quinine was not, but they were both relatively small and certainly cannot be considered definitive. Plasma quinidine levels vary considerably between individuals (three-fold in the Thai study), and the individual concentration-effect relationships are not predictable. In order to avoid cardiotoxicity patients with severe falciparum malaria receiving quinidine require careful monitoring. Reversible hypotension and significant QT prolongation are relatively common (whereas they are rare with quinine treatment). Frequent monitoring of blood pressure and continuous EKG monitoring is necessary to avoid cardiotoxicity. The higher dosage recommendation is an initial loading dose of 10mg base/kg given over 2 hours followed by constant infusion of 0.02 mg base/kg/min until the patient is able to take oral medication. As with quinine, quinidine blood concentrations may continue to rise in patients who do not respond rapidly to treatment, so that if there is no improvement in the overall condition by 48 hours the total daily dose should be reduced by 30 - 50% to avoid toxic levels. Some authorities recommend the lower initial dose regimen of 6.25mg base/kg followed by 0.0125mg base/kg/min. The debate has centered on the relative risks of toxicity with the higher dose regimen versus the risks of under treatment with the lower dosage. As argued earlier, undertreatment is difficult to recognize and may be fatal whereas overtreatment is easily detected and easily reversed. If the QRS interval widens by >50%, the QT interval exceeds 0.60 sec, or the QTc interval is prolonged by more than 25% of the baseline value, the infusion should be stopped until the QRS or QT interval prolongations falls below these values. Quinidine is usually formulated as the gluconate salt. There are no data on intramuscular quinidine in severe malaria.

 

Uncomplicated Malaria

            Uncomplicated malaria is defined as malaria infection in the absence of any signs of severity or evidence of vital organ dysfunction, including coma or severe prostration, convulsions, severe anaemia (< 20 % with parasite count > 100,000/ mm3), severe jaundice (bilirubin > 2.5 mg/dl), acute renal failure (> 3 mg/dl with urine < 400 ml/24 hours), respiratory failure, hypoglycaemia (venous glucose < 40 mg/dl), shock (systolic blood pressure < 80 mm Hg with cool extremities), hyperparasitaemia (peripheral asexual stage parasitaemia > 10 %) or metabolic acidosis (peripheral venous lactate > 4 mmol/l, peripheral venous bicarbonate < 15 mmol/l)

 

Treatment of P. vivax or P. ovale Malaria (table 8)

            For most P. vivax and all P. ovale infections, the drugs of choice are a combination of chloroquine plus primaquine. Chloroquine resistance is increasingly reported from Papua New Guinea and Indonesia where high-level resistance is prevalent, and South America. There are also reports from India and Burma.

            Chloroquine (total dose 25mg base/kg) should be given in standard doses and combined with primaquine given in an adult dose of 15mg base (0.25 mg base/kg) daily for 14 days. In South East Asia and Oceania higher doses of primaquine are recommended (0.375 to 0.5mg base/kg/day). Primaquine should be taken after a meal not on an empty stomach. Chloroquine is available in tablet and liquid (pediatric) suspensions. It is cheap, well absorbed, well tolerated, and effective in a treatment course of 2 - 3 days. Chloroquine may be used in very young children and in pregnant women. The traditional treatment regimen has been an initial dose of 10mg base/kg followed at 6, 24, and 48 hours by further doses of 5mg/kg. This may be compressed into a 36-hour administration of 10mg/kg initially, followed at 12-hour intervals by 5mg base/kg. Oral chloroquine is generally well tolerated although it has a bitter taste, which children may not like. Nausea and dysphoria may occur, and in dark-skinned subjects pruritus is common and may be sufficiently severe to prevent usage of the drug. Chloroquine is dangerous in overdose, producing cardiovascular and neurological toxicity, although these are both very rare with therapeutic doses. Diazepam is a specific antidote. Occasional neuropsychiatric reactions follow antimalarial treatment. Cerebellar dysfunction has been reported particularly from the Indian sub-continent. These reactions resolve spontaneously without treatment. Long-term prophylactic use for 5 years or more has been associated with retinopathy, but this is not relevant to acute treatment use. Chloroquine is still amongst most widely used drugs in the world and still in some parts of Africa the majority of the population has detectable levels of chloroquine in their urine.

            Primaquine is an oxidant drug and may cause haemolysis, particularly in subjects who are G6PD deficient. In patients who have mild variants of G6PD deficiency, primaquine 45mg base (0.75mg/kg) should be given once weekly for six weeks. In parts of SE Asia and Oceania, the exoerythrocytic (liver) stages of P. vivax are more resistant to primaquine and higher doses are required; 22.5-30mg base/day (0.375-0.5mg/kg) for 14 days. Primaquine also has weak asexual stage activity against P. vivax. Relapses with most tropical "strains" of P. vivax occur at intervals of 3-6 weeks. If a short acting drug is used (quinine, artemisinin derivative) then relapses tend to occur within one month. Except in those few areas with significant resistance, chloroquine levels in blood following treatment are sufficient to suppress this first relapse. Therefore, in most cases the first relapse after chloroquine (or mefloquine) treatment occurs around 6 weeks following treatment. Relapses should be treated in the same way as the primary infection, with both chloroquine and primaquine. Relapse intervals over six months are unusual in tropical vivax infections. The newly introduced 8-aminoquinoline, tafenoquine, is at least ten times more active compared with primaquine, and preliminary clinical trials with courses as short as a single dose of this compound have shown encouraging results. Its long half-life can however be a disadvantage in case of G6PD deficiency since it will cause prolonged exposure of the sensitive erythrocytes to the oxidative properties of tafenoquine.

            For chloroquine-resistant vivax malaria relatively few data are available. Amodiaquine is efficacious, and there is some evidence that mefloquine and quinine can also be used. Artemisinin combination therapies, like artemether-lumefantrine, are a good alternative. High-level pyrimethamine-sulphadoxine resistance is common in P. vivax and should therefore not be used.

Table 8. Treatment of Uncomplicated Vivax and Ovale Malaria.

·     Chloroquine 25 mg base/kg bw divided over 3 days, combined with primaquine 0.25 mg base/kg bw, taken with food once daily for 14 days is the treatment of choice for chloroquine-sensitive infections. In Oceania and South-East Asia the dose of primaquine should be 0.5 mg/kg bw.  

·    Amodiaquine (30 mg base/kg bw divided over 3 days as 10mg/kg bw single daily doses) combined with primaquine should be given for chloroquine-resistant vivax malaria.

                                                                                                    

·     In moderate G6PD deficiency, primaquine 0.75 mg base/kg bw should be given once a week for 8 weeks. In severe G6PD deficiency, primaquine should not be given.

 

·     Where ACT has been adopted as the first-line treatment for P. falciparum malaria, it may also be used for P. vivax malaria in combination with primaquine for radical cure. Artesunate plus sulfadoxine-pyrimethamine is the exception as it will not be effective against P. vivax in many places.

P. malariae (Quartan) Malaria

            For P. malariae, the drug of choice is chloroquine at standard doses. Radical treatment with primaquine is not necessary as there are no persistent exoerythrocytic stages in this infection. Chloroquine resistance has to date only been reported in one study from Indonesia.

 

Uncomplicated Falciparum Malaria

            Resistance of P. falciparum against chloroquine has reached most parts of the tropics and resistance against the usual next alternative, sulfadoxine pyrimethamine, is rapidly spreading. To ensure efficacy and to limit the chances of de-novo appearance and spread of antimalarial drug resistance, P. falciparum infections should be treated with combinations of two or more blood schizontocidal drugs with independent modes of action, as in the treatment of AIDS and tuberculosis. The use of an artemisinin derivative as one of the combination partners has become the standard recommendation, since its potent antimalarial capacity quickly reduces the total body parasite number, which will not only relief symptoms rapidly, but also reduces the chance of emergence of clones resistant against the partner drug . Artemisinin combination therapies (ACT) are now recommended by the WHO as the first line treatment of uncomplicated falciparum malaria. The different artemisinin derivatives available in oral formulations (dihydroartemisinin, artesunate, and artemether) are all suitable for use in ACT, although they do differ slightly in oral absorption rates bioavailability and disposition. The partner drugs have longer elimination half-lives in order to kill the parasites that remain after three days of artemisinin (about 103 to 105 of the initial 1011 to 1013). Possible partner drugs in ACT regimens include amodiaquine, atovaquone-proguanil, chloroquine, clindamycin, doxycycline, lumefantrine, mefloquine, piperaquine, pyronaridine, proguanil-dapsone, sulfadoxine-pyrimethamine, and tetracyclines. Of these partner drugs, lumefantrine and mefloquine have proven efficacy in areas of multidrug resistant P. falciparum, whereas the combinations with amodiaquine or sulfadoxine-pyrimethamine have shown to be effective in areas where monotherapy failure rates following of amodiaquine and sulfadoxine-pyrimethamine did not exceed 20%.

            The artemisinins and the recommended ACTs are discussed below.

Artemisinin and Its Derivatives: Although highly active against all Plasmodium species, the short half-life of these drugs have always limited their use as a single agent, since a minimal treatment course of seven days is needed in order to cover at least 3 erythrocytic cycles of the parasite. However, their potent action and short half-lives reduces the risk of resistance development, and makes the drugs an ideal candidate for the use in combination therapies. Artemisinin and its derivatives are remarkably well tolerated, with very rare serious adverse effects. The only evidence of toxicity documented in large clinical trials to date has been a temporary depression in reticulocyte counts, which does not translate into anemia, acute (type 1) hypersensitivity reactions, and in common with quinine, an association with blackwater fever. The artemisinin derivatives are the most rapidly acting of all antimalarial drugs and produce the fastest clinical responses to treatment. They have a broad spectrum of antimalarial activity acting against the young ring form parasites and preventing their development to the more mature pathogenic stages. Oral artemether and oral artesunate have equivalent antimalarial activity and dose regimens of the two drugs are similar. In combination with mefloquine, the addition of artemether or artesunate (4mg/kg/day) consistently improves cure rates and has the advantage of producing a more rapid clinical response to treatment, prevention of malaria transmission, and, where deployed extensively in low transmission areas, a reduction in malaria incidence. A three-day course of the artemisinin derivative in combination with a partner drug is required for optimum cure rates. Two and one day courses are insufficient.

Artesunate plus sulfadoxine-pyrimethamine (table 3): Sulfadoxine-pyrimethamine is a fixed combination of a long-acting sulfonamide (25 mg sulfadoxine) and the antifolate pyrimethamine (500 mg). Minor adverse effects are unusual. Serious sulphonamide toxicity is also unusual with a single-dose treatment of malaria. The anti-folate properties of pyrimethamine rarely produce toxicity. The combination with artesunate is available as separate scored tablets containing 50 mg of artesunate and tablets containing 500 mg of sulfadoxine and 25 mg of pyrimethamine. The total recommended treatment is 4 mg/kg bw of artesunate, given once a day for 3 days and a single administration of sulfadoxine-pyrimethamine 1.25/25 mg base/ kg bw on admission. The combination has been evaluated in children with uncomplicated malaria in Sub-saharan Africa and is sufficiently efficacious in areas where 28-days cure rates with sulfadoxine-pyrimethamine alone exceed 80%. Since sulfadoxine-pyrimethamine, sulfalene-pyrimethamine and trimethoprim-sulfamethoxazole (co-trimoxazole) are still widely used, resistance is likely to worsen.

Table 3. Dosing Schedule for Artesunate plus Sulfadoxine-Pyrimethamine

 

Age

Dose in mg (no. of tablets)

Artesunate

Sulfadoxine-pyrimethamine

Day 1

Day 2

Day 3

Day 1

Day 2

Day 3

5–11 months

25 (½)

25

25

250/12.5 (½)

1–6 years

50 (1)

50

50

500/25 (1)

7–13 years

100 (2)

100

100

1000/50 (2)

>13 years

200 (4)

200

200

1500/75 (3)

 

Artesunate plus amodiaquine (table 2): Amodiaquine, like chloroquine, is a 4-aminoquinoline, but it is effective against chloroquine resistant strains of P. falciparum, although there is some cross-resistance. It is generally well tolerated and more palatable than chloroquine. The serious adverse effects that have been associated with its prophylactic use (agranulocytosis and severe liver toxicity) are rare when amodiaquine is used in malaria treatment. The combination of amodiaquine with artesunate is currently available as separate scored tablets containing 50 mg of artesunate and 153 mg base of amodiaquine, but co-formulated tablets are under development. The total recommended treatment is 4 mg/kg bw of artesunate and 10 mg base/kg bw of amodiaquine once a day for 3 days. It has proven to be an efficacious combination in areas where 28-day cure rates with amodiaquine monotherapy exceed 80%.

            In those areas where resistance to sulphonamide-pyrimethamine, chloroquine and amodiaquine is prevalent, then artemisinin combinations with either lumefantrine or mefloquine are the alternatives.

Artemether – Lumefantrine (table 4): This is the first fixed combination of an artemisinin derivative and a second unrelated antimalarial compound. Lumefantrine (formerly benflumetol) is an aryl amino-alcohol in the same general group as mefloquine and halofantrine. It was discovered in the Peoples' Republic of China. Lumefantrine is active against all the human malaria parasites including multidrug resistant P. falciparum (although there is some cross resistance with halofantrine and mefloquine). Artemether-lumefantrine has been used mainly at an adult oral dose of 80/480mg given at 0, 8, 24 and 48 hours. This has given satisfactory cure rates in semi-immune subjects, but in non-immunes has proved inferior to artesunate-mefloquine. Pharmacokinetic-pharmacodynamic (PK-PD) studies indicated that the principal PK determinant of cure was the area under the plasma lumefantrine concentration time curve (AUC), or its surrogate, the day 7 lumefantrine level. Day 7 levels over 500ng/mL were associated with >90% cure rates. Lumefantrine absorption (like that of atovaquone and halofantrine) is critically dependent on co-administration with fats and thus plasma concentrations vary markedly between patients. To increase the AUC and thus cure rate, a six-dose regimen (adult dose 80/480mg at 0, 8, 24, 36, 48, 60 hours) was evaluated. This has proved highly effective and remarkably well tolerated. Against multidrug resistant falciparum malaria the six dose regimen of artemether-lumefantrine was as effective and better tolerated than artesunate-mefloquine. Artemether-lumefantrine is becoming increasingly available in tropical countries. The rapid and reliable therapeutic response, the high level of efficacy, and the mutual protection provided by each of the drugs against resistance selection makes combinations such as this ideal antimalarial treatments.

Table 2. Dosing Schedule for Artesunate plus Amodiaquine

 

 

Age

Dose in mg (no. of tablets)

Artesunate

Amodiaquine (base)

Day 1

Day 2

Day 3

Day 1

Day 2

Day 3

5–11 months

25 (½)

25

25

76 (½)

76

76

1–6 years

50 (1)

50

50

153 (1)

153

153

7–13 years

100 (2)

100

100

306 (2)

306

306

>13 years

200 (4)

200

200

612 (4)

612

612

 

Artesunate plus mefloquine (table 5): Mefloquine is a quinoline methanol compound related to quinine. Several different mefloquine formulations are now available with different oral bioavailability. Employment of mefloquine as monotherapy for the treatment of malaria has lead to rapid spread of resistance, mediated at least in part, by an increase in copy number and expression of the P. falciparum multi-drug resistance (MDR) gene. There is theoretical evidence to suggest that initial use of the lower dose of mefloquine encourages resistance, and that high doses, preferably in combination with an artemisinin derivative deployed de-novo are less likely to fall to resistance. The dose should be split at 15mg/kg initially followed 8 - 24 hours later by a second 10mg/kg or as 8.3mg/kg daily for 3 days to improve bioavailability and reduce vomiting. There is no liquid formulation of mefloquine for children. Despite earlier restrictions there is no reason to withhold mefloquine from young children. Limited information suggested that mefloquine was probably safe in pregnancy, although the observation in Thailand of an increased stillbirth risk when mefloquine was used in treatment at any stage of pregnancy has cast uncertainty over its use in pregnant women. Mefloquine commonly induces nausea, dysphoria, and dizziness, and in approximately 1:1,000 Asian patients, and up to 1:200 Caucasians or African subjects, mefloquine treatment induces a self-limiting acute neuropsychiatric syndrome manifest by coma, convulsions, or psychosis. Suidcide has been reported. The risks of this acute neuropsychiatric syndrome are increased if the patient has a previous history of psychiatric illness or epilepsy, and may be increased if mefloquine follows quinine administration. There is a considerable increase in the risk if mefloquine is used following severe malaria. Approximately 1:20 patients with severe malaria given mefloquine following recovery will have an acute reaction and therefore mefloquine should not be used in this group. Neuropsychiatric reactions are also more common if mefloquine has been used in the previous month, and therefore mefloquine should not be used to treat recrudescent infections occurring within one month of treatment. However in practice the principle adverse effect of mefloquine is vomiting. This is more likely in young children, and even if the drug is administered again, low blood levels and an increased risk of treatment failure result. Combining artesunate or artemether (4mg/kg/day for 3 days) with mefloquine has many advantages. The cure rate is increased, resistance is prevented, and if mefloquine is split as 8.3mg/kg/day for 3 days or not given until the second day of treatment then absorption is increased and adverse effects are lessened.

Table 5. Dosing Schedule for Artesunate plus Mefloquine*

 

Age

Dose in mg (no. of tablets)

Artesunate

Mefloquine (base)

Day 1

Day 2

Day 3

Day 1

Day 2

Day 3

5–11 months

25 (½)

25

25

125 (½)

1–6 years

50 (1)

50

50

250 (1)

7–13 years

100 (2)

100

100

500 (2)

250 (1)

>13 years

200 (4)

200

200

1000 (4)

500 (2)

*alternatively the total dose of mefloquine may be split into three, with one third of the dose being taken on days 1, 2 and 3.

Non-artemisinin based combination therapies

Atovaquone plus proguanil (MalaroneR): Malarone is a fixed combination of two blood schizonticides (Atovaquone and Proguanil, 15/6 mg/kg, usual adult dose is 4 tablets once a day for 3 days) that demonstrate synergistic activity against multi-drug-resistant Plasmodium falciparum. Either used alone or in combination with artesunate in areas of drug resistance it is a highly effective treatment.

            Generally, atovaquone/proguanil (AQ/PG) is very well tolerated. Treatment limiting adverse events occur in <1% of patients, whereas and no serious adverse effects have been reported. Its high costs limit widespread use in tropical countries, but it can be recommended for travelers returning to non-endemic countries (table 6).

Table 6. Recommendations on the Treatment of Falciparum Malaria in Non-immune Travellers

For travelers returning to non-endemic countries:1

  1. Artemether-lumefantrine (1.5 mg/12 mg/kg twice daily for 3 days)
  2. Atovaquone-proguanil (1 g/400 mg once daily for 3 days)
  3. Quinine (10 mg salt/kg 8-hourly) plus Doxycycline2 (3.5 mg/kg once daily) or
    Clindamycin (10 mg/kg 12-hourly); all drugs to be given for 7 days.

 

For severe malaria:

    Antimalarial treatment of severe malaria in travelers is the same as the general recommendation
         (table 7)

    Travellers with severe malaria should be managed in an intensive care unit

    Haemofiltration or haemodialysis should be started early in acute renal failure or severe
         metabolic acidosis

    Positive pressure ventilation should be started in case of respiratory distress and coma with breathing
abnormalities

1 Halofantrine is not recommended as first-line treatment for uncomplicated malaria because of cardiotoxicity.

2 Doxycycline should not be used in children under 8 years of age and in pregnancy.

Amodiaquine plus pyrimethamine: Amodiaquine plus sulfadoxine-pyrimethamine combinations has shown to be effective if there is not significant resistance to either drug. The combination is generally well tolerated, although some studies report a higher incidence of sinus bradycardia and vomiting compared to amodiaquine or sulfadoxine-pyrimethamine alone.

Quinine plus tetracycline, doxycycline or clindamycin: Although short courses of quinine (3-5 days) are sometimes considered effective in areas of high transmission in semi-immune subjects, as explained previously, quinine should be given for at least seven days for optimum cure rates. As quinine is extremely bitter and reliably induces the symptom complex of cinchonism (tinnitus, dysphoria, high-tone deafness nausea, dizziness) compliance with 7-day regimens is notoriously poor and treatment failure rates in practice are usually higher than those reported in carefully observed clinical trials. Quinine should be combined with tetracycline or doxycycline (in non-pregnant adults and children over 8 years old) or clindamycin, also given for 7 days. Even in areas with multi-drug resistant falciparum malaria cure rates with the quinine-tetracycline or quinine-clindamycin combination exceed 85%. Although minor toxicity is common with quinine, more serious toxicity is unusual. Occasional idiosyncratic or allergic reactions such as urticaria, immune thrombocytopenia and, rarely, haemolytic uraemic syndrome have been reported. Quinine reliably augments pancreatic insulin secretion and in pregnancy may cause hypoglycemia even in uncomplicated falciparum malaria. The tetracyclines may be associated with diarrhea, candida infection, and photosensitivity rashes. With the exception of doxycycline they should not be given to patients with renal impairment. Clindamycin combined with quinine has the advantage that it can be used in young children and pregnant women although it is relatively expensive. There is no advantage to the use of quinidine in uncomplicated malaria, and this should not be used.

Combinations with halofantrine: Halofantrine is intrinsically better tolerated and slightly more effective than mefloquine. Conventionally three doses (total 24 mg base/kg) are given in 24 hours. The manufacturer recommends that non-immune patients should receive a second dose after 7 days. However, in areas of mefloquine resistance the single day treatment with halofantrine usually recommended is insufficient and a longer initial course was found to be required for optimum therapeutic responses. Nausea, vomiting or diarrhea is unusual and there are usually no subjective adverse effects. Unfortunately halofantrine and its desbutyl metabolite predictably induce concentration-dependent prolongation of the electrocardiograph QT interval, reflecting delayed ventricular repolarisation Delayed atrioventricular conduction also occurred. Halofantrine use is associated with an increased risk of ventricular tachyarrhythmia and sudden death. This precludes the use of increased doses of halofantrine and has even led the manufacturer to recommend that standard doses of the drug should not be given with fats (which augment absorption). Halofantrine should only be used in patients, with a normal electrocardiograph QT interval before drug treatment, which is not taking other drugs known to prolong the QT interval. Because of these safety concerns, halofantrine is not recommended either as an ACT partner drug or alone. There is no evidence that the combination of chloroquine with sulfadoxine-pyrimethamine provides any additional benefit over pyrimethamine-pyrimethamine alone, and because of the increasing resistance to chloroquine in all settings this combination is not recommended.

 

Immunocompromised Patients

            There is no reason to treat malaria in immunocompromised patients any differently to immunocompetent patients. Patients with previous splenectomies are more vulnerable to severe malaria, and will have longer parasite clearance times - but treatment regimens should not be altered. The pharmacological interactions between antimalarials and antiretrovirals are largely unexplored. Patients receiving rifampicin for tuberculosis eliminate quinine more rapidly and have a higher treatment failure rate.