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Keywords:

  • malaria;
  • Plasmodium falciparum;
  • vivax;
  • ovale and malariae;
  • artemisinin combination therapies;
  • amodiaquine;
  • mefloquine;
  • primaquine;
  • quinine;
  • sulfadoxine/pyrimethamine;
  • chloroquine
  • malaria;
  • Plasmodium falciparum;
  • vivax;
  • ovale et malariae;
  • thérapies de combinaison à l’artémisinine;
  • amodiaquine;
  • méfloquine;
  • primaquine;
  • quinine;
  • sulfadoxine/pyriméthamine;
  • chloroquine
  • malaria;
  • Plasmodium falciparum;
  • vivax;
  • ovale y malariae;
  • terapias de ombinación;
  • artemisinina;
  • amodiquina;
  • mefloquina;
  • quinina;
  • sulfadoxina-pirimetamina;
  • cloroquina

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Guiding principles for the treatment of uncomplicated malaria
  5. The essential anti-malarial drugs for children
  6. Treatment regimens against Plasmodium falciparum
  7. Conclusions
  8. References

Understanding the optimal treatment of uncomplicated malaria in children is challenging because of the availability of new drugs and the shift to combination therapies. This is a review of the guiding principles for the treatment of uncomplicated malaria, the essential anti-malarial drugs for children, and the treatment regimens currently recommended.

Comprendre le traitement optimal de la malaria non compliquée chez les enfants est un défil à cause de la disponibilité de nouveaux médicaments et du passage à des thérapies de combinaison.Il s’agit ici d’une revue des principes directeurs pour le traitement de la malaria non compliquée, des médicaments antimalariques essentiels chez les enfants et des régimes de traitement actuellement recommandés.

El entender cual es el tratamiento óptimo para la malaria no complicada en niños supone un reto debido a la disponibilidad de medicamentos esenciales y al cambio hacia terapias de combinación. En esta revisión se ofrece una guía de los principios para el tratamiento de la malaria no complicada, los antimaláricos esenciales para niños y los regimenes de tratamiento que actualmente se recomiendan.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Guiding principles for the treatment of uncomplicated malaria
  5. The essential anti-malarial drugs for children
  6. Treatment regimens against Plasmodium falciparum
  7. Conclusions
  8. References

These are good times for the treatment of malaria. Never have there been so many therapeutic regimens available or in the pipeline. In addition to the development of new drugs, there has been an important shift to combination therapies, containing, with few exceptions, an artemisinin derivative. These recent developments make understanding the range of existing anti-malarials and their combinations more complicated. A review of anti-malarial therapy, particularly of drugs for children in whom the burden of malaria is greatest, is necessary: many practitioners feel uncertain as to which anti-malarial drugs to prescribe. Similarly, policymakers receive little information on the rational choice for first- and second-line treatments of uncomplicated malaria, or on drugs that have become less useful because of changing resistance patterns.

Children with uncomplicated malaria are generally treated with oral medication, except those who are vomiting or otherwise unable to take oral drugs and are thus given parenteral treatment. Uncomplicated malaria is defined as malaria infection in the absence of any signs of severity or evidence of vital organ dysfunction. Signs of severity include coma or severe prostration, convulsions, severe anaemia, jaundice, acute renal failure, respiratory distress, hypoglycaemia, shock, hyperparasitaemia, metabolic acidosis, abnormal bleeding or haemoglobinuria. Children with malaria associated with any signs of severity or evidence of vital organ dysfunction should be treated parenterally.

In this review, we discuss the guiding principles for the treatment of uncomplicated malaria, the essential anti-malarial drugs for children, and the treatment regimens currently recommended. The treatment principles and regimens are based on the guidelines published by WHO in 2006. WHO is now developing a Model List of Essential Medicines for Children (http://mednet3.who.int/EMl/expcom/expcom16/watermark_mr_16_AUG_list.pdf), which provided us with a framework for the discussion of essential drugs. We reviewed the literature through PubMed using the keywords: malaria, Plasmodium falciparum, vivax, ovale and malariae, artemisinin combination therapies, amodiaquine, mefloquine, primaquine, quinine, sulfadoxine/pyrimethamine, and chloroquine. Emphasis was placed on recent therapeutic and pharmacokinetic studies and review articles, especially those which focused on children in developing countries. We encountered insufficient data on anti-malarial pharmacokinetics by age group and on safety and tolerability in young children. Because of the paucity of drug information in the paediatric age group, we included papers on adults when deemed relevant.

Dosages of the recommended first-line treatments are given below but a detailed paediatric dosage table is not included in this review. The reader is directed to standard references (WHO 2005) which present dosages by weight group, although we acknowledge that there are unresolved issues of age-based versus weight-based dosing. A detailed discussion on preferred drug dosage forms by age, administration volumes, size of unit dosage, taste and the acceptability and safety of excipients in relation to the age and development status of the child can be found in a WHO working document (WHO 2008) but is beyond the scope of this review.

Guiding principles for the treatment of uncomplicated malaria

  1. Top of page
  2. Summary
  3. Introduction
  4. Guiding principles for the treatment of uncomplicated malaria
  5. The essential anti-malarial drugs for children
  6. Treatment regimens against Plasmodium falciparum
  7. Conclusions
  8. References

Malaria caused by Plasmodium falciparum

In non-immune or semi-immune individuals, any P. falciparum parasitaemia associated with fever indicates that the parasite is the likely cause of that fever. In areas of high transmission, where individuals have developed immunity from previous episodes of malaria starting at a young age, asymptomatic parasitaemia is common. In this context, coincident parasitaemia may be detected during febrile episodes caused by another infection (Smith et al. 1994; Mwangi et al. 2005). Parasitaemia level thresholds or cut-offs are used to differentiate malaria from incidental parasitaemias (Schellenberg et al. 1994). Thresholds are useful in research (Bejon et al. 2007) but since they vary with age and levels of transmission, they are of limited use for clinicians. At any rate, coincident parasitaemia among patients with diagnoses other than malaria warrants treatment as this is associated with an increased risk of clinical malaria episodes, anaemia and increased gametocyte carriage.

Where diagnostic facilities exist, anti-malarial treatment should be given only to patients with positive rapid diagnostic tests or blood smears. This is to ensure that the drugs are given only to patients with malaria, which would limit the emergence of resistance, avoid unnecessary side effects and ensure that diagnoses other than malaria are not missed. Particularly in low transmission settings and when the more expensive combination therapies are used, confirmation using rapid diagnostic tests or blood smears may be more cost-effective than presumptive treatment. However, in actual practice, blood examination to confirm and quantify parasitaemia is often not available. The WHO/UNICEF strategy for Integrated Management of Childhood Illness (IMCI) has developed practical algorithms for management of the sick child presenting with fever where there are no facilities for laboratory diagnosis (WHO 1999). The IMCI strategy recommends empiric anti-malarial treatment for fever episodes in children under 5 years of age in malaria-endemic areas. The IMCI places no emphasis on making a biological diagnosis. With the increasing cost of effective anti-malarial drugs and the decrease in malaria incidence in sub-Saharan Africa (Okiro et al. 2007) biologic testing is rapidly gaining relevance.

For many years, national guidelines of most falciparum-endemic countries recommended chloroquine as the first-line treatment for uncomplicated malaria. As resistance to chloroquine emerged, sulfadoxine–pyrimethamine became the drug of choice. Today, 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 anti-malarial drug resistance, falciparum malaria should be treated with combinations of two or more blood schizontocidal drugs with independent modes of action. Combinations of drugs will mutually protect each drug against selection of resistant clones, since the mutant strain will still be sensitive to the partner drug. The principles of combination therapy for malaria are comprehensively discussed elsewhere (White 1999).

In this review, we distinguish combinations of anti-malarials which include artemisinin derivatives (artemisinin combination therapies or ACT) and those that do not. The use of an artemisinin derivative as one of the combination partners has become the standard recommendation for treatment of uncomplicated malaria, since its potent anti-malarial capacity quickly reduces the total body parasite number, which will not only relieve symptoms rapidly, but will also reduce the chance of emergence of clones resistant against the partner drug (White 1996). ACTs have been recommended by the WHO as the first-line treatment of uncomplicated falciparum malaria (WHO 2006).

The various artemisinin derivatives available in oral formulations (dihydroartemisinin, artesunate, artemether and the mother compound artemisinin itself) are all suitable for use in ACT, although they slightly differ in their stability, oral absorption, bioavailability and metabolism. To ensure treatment courses that do not exceed 3 days, the partner drug to the artemisinin derivative should have a longer half-life in order to kill the remaining parasites (about 103 to 105 of the initial 108 to 1013). Possible partner drugs in ACT regimens include amodiaquine, atovaquone–proguanil, clindamycin, doxycycline, lumefantrine, mefloquine, piperaquine, pyronaridine, chlorproguanil–dapsone, proguanil–dapsone, sulfadoxine–pyrimethamine and tetracyclines. Of these partner drugs, lumefantrine, mefloquine and piperaquine have proven efficacy even in areas of multidrug resistant P. falciparum. The combinations of an artemisinin derivative with amodiaquine or sulfadoxine–pyrimethamine are effective only in areas where amodiaquine and sulfadoxine–pyrimethamine monotherapy failure rates do not exceed 20%. Chloroquine cannot be recommended as a partner drug because of widespread high-level resistance. Other partner drugs such as pyronaridine are currently being evaluated in phase III trials. The clinical development of chlorproguanil–dapsone was stopped in 2008 due to safety concerns (http://www.reuters.com/article/healthNews/idUSL2933087820080229). Another potential partner drug, atovaquone–proguanil, is simply too expensive for widespread deployment in malaria endemic regions. Wider deployment of atovaquone–proguanil is also likely to be followed by the rapid emergence of resistance (Srivastava et al. 1999; Durand et al. 2008; Rose et al. 2008; Savini et al. 2008). Of these combinations, artemether–lumefantrine, dihydroartemisinin–piperaquine, artesunate–mefloquine and artesunate–amodiaquine are now available as fixed combinations. Wide spread availability of fixed combinations will preclude the use of artemisinin monotherapy, which is an important strategy to reduce the spread of drug resistance.

Malaria due to Plasmodium vivax, ovale, malariae and knowlesi

Plasmodium vivax is responsible for over 50% of malaria outside Africa, notably in Central and South America and in Southeast Asia and the Indian subcontinent. It also accounts for around 10% of cases in Eastern and Southern Africa but has only limited prevalence in West Africa. In most vivax-endemic areas, malaria transmission rates are low, resulting in low immunity against this parasite in affected populations. Consequently, people of all ages are at risk. The other two human malaria parasite species, P. malariae and P. ovale, are generally less prevalent.

Among the five species of Plasmodia that affect humans, only P. vivax and P. ovale are known to form hypnozoites, parasite stages in the liver that can result in multiple relapses of infection, weeks to months after the primary infection. The goal of treating malaria caused by P. vivax and P. ovale is to cure both the blood stage and the liver stage infections, preventing both relapse and recrudescence. This is called radical cure. Currently there is limited experience in the treatment of human infections with P. knowlesi (Singh et al. 2004; Cox-Singh et al. 2008).

In general P. vivax, ovale and malariae are sensitive to chloroquine, which remains the treatment of choice and radical cure can be achieved by the addition of primaquine. However, important chloroquine-resistant vivax malaria has been reported, especially from Papua New Guinea and parts of Indonesia. In these settings, dihydroartemisinin–piperaquine and artemether–lumefantrine are an effective treatment for vivax malaria (Ratcliff et al. 2007).

The essential anti-malarial drugs for children

  1. Top of page
  2. Summary
  3. Introduction
  4. Guiding principles for the treatment of uncomplicated malaria
  5. The essential anti-malarial drugs for children
  6. Treatment regimens against Plasmodium falciparum
  7. Conclusions
  8. References

The recent guidelines (WHO 2006) state that anti-malarial treatment should be 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, are also taken into consideration. The therapeutic anti-malarials in the WHO Model List of Essential Medicines for Children are shown in Table 1. In this provisional list, it is emphasized that medicines for the treatment of P. falciparum malaria cases should be used in combination. Combinations according to the WHO treatment guidelines are recommended whilst recognizing that not all of these fixed-drug combinations are currently licensed. The development and rigorous testing of fixed-drug combinations, as well as formulations and dosage forms appropriate for children is encouraged.

Table 1.   The provisional WHO Model List of Essential Medicines for Children for treatment of malaria (http://mednet3.who.int/EMl/expcom/expcom16/watermark_mr_16_AUG_list.pdf)
AmodiaquineTablet: 153 mg or 200 mg (as hydrochloride) To be used (a) in combination with artesunate 50 mg   OR (b) may be used alone for the treatment of P. vivax,   P. ovale and P. malariae infections
ArtemetherOily injection: 80 mg/ml in 1-ml ampoule For use in the management of severe malaria
Artemether + lumefantrineTablet: 20 mg + 120 mg Not recommended in the first trimester of pregnancy or in children below 5 kg
ArtesunateInjection: ampoules, containing 60 mg anhydrous artesunic acid with a separate ampoule of 5% sodium bicarbonate solution For use in the management of severe malaria Rectal dosage form: 50 mg; 200 mg (for pre-referral treatment of severe malaria only) Tablet: 50 mg To be used in combination with either amodiaquine,   mefloquine or sulfadoxine + pyrimethamine
ChloroquineOral liquid: 50 mg (as phosphate or sulphate)/5 ml Tablet: 100 mg; 150 mg (as phosphate or sulphate) For use only in central American regions, for use for P. vivax
DoxycyclineCapsule: 100 mg (as hydrochloride) Tablet (dispersible): 100 mg (as monohydrate) For use only in combination with quinine
MefloquineTablet: 250 mg (as hydrochloride) To be used in combination with artesunate 50 mg
PrimaquineTablet: 7.5 mg; 15 mg (as diphosphate) Only for use to achieve radical cure of P. vivax and P. ovale infections, given for 14 days
QuinineInjection: 300 mg quinine hydrochloride/ml in 2-ml ampoule Tablet: 300 mg (quinine sulphate) or 300 mg (quinine bisulphate) For use only in the management of severe malaria, and  should be used in combination with doxycycline
Sulfadoxine + pyrimethamineTablet: 500 mg + 25 mg Only in combination with artesunate 50 mg

Amodiaquine

  • Tablet containing 200 mg of amodiaquine base as hydrochloride or 153.1 mg of base as chlorohydrate.

Amodiaquine is a Mannich base 4-aminoquinoline with a mode of action similar to that of chloroquine. Although there is cross-resistance, amodiaquine is more active than chloroquine against low-level chloroquine resistant parasites (Olliaro et al. 1996) but in areas with high-level chloroquine resistance, amodiaquine is also not effective (Lemnge et al. 2006; Mandi et al. 2008; Nsimba et al. 2008). Amodiaquine hydrochloride is readily absorbed from the gastrointestinal tract. It is rapidly converted in the liver to the active metabolite desethylamodiaquine, which contributes nearly all of its anti-malarial effect. There are insufficient data on the terminal plasma elimination half-life of desethylamodiaquine. Both amodiaquine and desethylamodiaquine have been detected in the urine several months after administration.

Amodiaquine has been associated with agranulocytosis (Kennedy 1955; Bell et al. 2008). The adverse effects of amodiaquine, thought to be similar to those of chloroquine, have played a major part in the low uptake of this drug. Amodiaquine is associated with less pruritus and is more palatable than chloroquine, but is associated with a much higher risk of agranulocytosis and, to a lesser degree, of hepatitis when used for prophylaxis (Hatton et al. 1986). The risk of a serious adverse reaction with prophylactic use (which is no longer recommended) appears to be between 1 in 1000 and 1 in 5000. It is not clear whether the risks would be lower when amodiaquine is used widely to treat malaria. But several studies have shown the efficacy and good tolerability of amodiaquine (Massaga et al. 2003) and artesunate plus amodiaquine (Adjuik et al. 2002; Brasseur et al. 2007).

After overdosage, cardiotoxicity appears to be less frequent than with chloroquine. Large doses of amodiaquine have been reported to cause syncope, spasticity, convulsions and involuntary movements. There are insufficient data to comment on drug interactions. The mechanism of resistance against amodiaquine is similar to chloroquine resistance and is described below in the chloroquine section.

Artemether

  • Ampoule for injection containing 80 mg/ml.
  • In a fixed-drug combination with lumefantrine: tablets containing 20 mg of artemether and 120 mg of lumefantrine (Coartem®).

Artemether is the methyl ether of dihydroartemisinin. This lipid soluble artemisinin derivative can be given as an oil-based intramuscular injection for the treatment of severe malaria or in a fixed-drug combination with lumefantrine for oral treatment. Peak plasma concentrations of artemether occur around 2–3 h after oral administration (Ezzet et al. 1998). After intramuscular injection, absorption is very variable, especially in children with poor peripheral perfusion: peak plasma concentrations generally occur after around 6 h but absorption is slow and erratic and times to peak can be 18 h or longer in some cases (Murphy et al. 1997; Hien et al. 2004; Mithwani et al. 2004). Artemether is metabolized to dihydroartemisinin, the active metabolite. Biotransformation is mediated via the cytochrome P450 enzyme CYP3A4. Artemether is 95% bound to plasma proteins. The elimination half-life is approximately 1 h.

In all species of animals tested, intramuscular artemether causes an unusual selective pattern of neuronal damage to certain brain stem nuclei. Neurotoxicity in experimental animals is associated with sustained blood concentrations that follow intramuscular administration (Brewer et al. 1994) but is much less frequent when the same doses are given orally, or with similar doses of water-soluble drugs such as artesunate (Nontprasert et al. 2002). Clinical, neurophysiological and pathological studies in humans have not shown such findings with therapeutic use of these compounds (Kissinger et al. 2000; Van Vugt et al. 2000; Hien et al. 2003). Toxicity is otherwise similar to that of artemisinin. The only potentially serious adverse effect reported with this class of drugs is type 1 hypersensitivity reactions in approximately 1 in 3000 patients (Leonardi et al. 2001). Drug interactions have not been reported.

Amplification of Pfmdr1 is associated with relatively small but significant reductions in susceptibility to artemisinins but most isolates of P. falciparum are extremely sensitive to artemisinin and its derivatives (White 2008). The report that P. falciparum parasites from French Guiana with point mutations in the gene encoding PfATPase6 were relatively resistant to artemether seemed to have fulfilled the molecular Koch’s postulates for this target but these findings have not been reproduced elsewhere (Jambou et al. 2005). Yang et al. reported reduction by a factor of 3.3 in the susceptibility of P. falciparum to artesunate between 1988 and 1999 in Yunnan, Southwest China (Yang et al. 2003). This is a region where artemisinins have been used extensively for more than 20 years. It was believed that resistance would spare the artemisinins for an extended period. However, there have been recent reports of P. falciparum with reduced susceptibility detected in Pailin, along the Thai/Cambodian border (Denis et al. 2006; Alker et al. 2007; Wongsrichanalai & Meshnick 2008). This is an area notorious as the epicenter from which chloroquine-resistant and later multidrug-resistant P. falciparum spread 50 years ago (Verdrager 1986, 1995). Intensive studies are underway to assess the geographic extent of the problem, to characterize the in vivo and in vitro responses further and, if possible, to identify the molecular basis of the artemisinin tolerant phenotype (White 2008).

Lumefantrine

  • Available only as a fixed-drug combination with artemether: tablet containing 20 mg of artemether and 120 mg of lumefantrine (Coartem®).

Lumefantrine (formerly benflumetol) belongs to the aryl aminoalcohol group of anti-malarials, which also includes quinine, mefloquine and halofantrine. It has a similar mechanism of action as these drugs. It was discovered in the Peoples’ Republic of China and has been extensively used there for several years. Lumefantrine is active against all the human malaria parasites including multidrug resistant P. falciparum (although there is some cross resistance with halofantrine and mefloquine). It is available only as an oral fixed-drug combination with artemether. This coformulation is highly effective against multidrug-resistant P. falciparum and is increasingly becoming the first-line therapy against uncomplicated malaria in sub-Saharan Africa. The oral bioavailability is variable and is highly dependent on administration with fatty foods (Ezzet et al. 1998; White et al. 1999). Absorption increases by 108% after a meal and is lower in patients with acute malaria than in convalescing patients. Peak plasma levels occur approximately 10 h after administration. The terminal elimination half life is around 3 days. Despite similarities with the structure and pharmacokinetic properties of halofantrine, lumefantrine does not significantly prolong the electrocardiographic QT interval, and it has no other significant toxicity (van Vugt et al. 1999). In fact the drug seems to be remarkably well tolerated. Reported side effects are generally mild – nausea, abdominal discomfort, headache and dizziness – and cannot be distinguished from symptoms of acute malaria.

Artemether-lumefantrine

  • A fixed-drug combination tablet containing 20 mg of artemether and 120 mg of lumefantrine (Coartem®).

This is the first fixed-drug combination of an artemisinin derivative and a second unrelated anti-malarial compound. Packaging of the drug is by weight group. Artemether-lumefantrine was previously mainly used at an adult oral dose of 80/480 mg given at 0, 8, 24 and 48 h. This has given satisfactory cure rates in semi-immune subjects, but in non-immunes, the drug combination 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 500 ng/ml are associated with >90% cure rates (Ezzet et al. 2000). 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 80/480 mg at 0, 8, 24, 36, 48, 60 h) 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 (van Vugt et al. 1998). A more recent study found that failure rates at day 42 were 13% [95% confidence interval (CI), 9.6-17%] for the four-dose regimen and 3.2% (95% CI, 1.8-4.6%) for the six-dose regimen. The lumefantrine plasma concentration profile was found to be the main determinant of efficacy of artemether-lumefantrine; the six-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients (Price et al. 2006). A meta-analysis showed that the six-dose regimen of artemether-lumefantrine is more effective than the four-dose regimen in adolescents and adults without compromising safety. (Omari et al. 2004, 2005, 2006; Mueller et al. 2006).

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 anti-malarial treatments.

Artesunate

  • Ampoule containing 60 mg anhydrous artesunic acid with a separate ampoule of 5% sodium bicarbonate solution.
  • Rectal capsule containing 100 mg or 400 mg of sodium artesunate.
  • Tablet containing 50 mg or 200 mg of sodium artesunate.
  • Co-formulated with artesunate: paediatric artesunate 25 mg and mefloquine 55 mg of adult dose artesunate 100 mg and mefloquine 220 mg (ASMQ®).

Artesunate is the sodium salt of the haemisuccinate ester of artemisinin. It is soluble in water but has poor stability in aqueous solutions at neutral or acid pH. In the injectable form, artesunic acid is drawn up in sodium bicarbonate to form sodium artesunate immediately before injection. Artesunate can be given orally, rectally or by the intramuscular or intravenous routes. ASMQ, a new fixed-dose combination of artesunate (AS) and mefloquine (MQ), is now registered and available in Brazil (http://www.actwithasmq.org/index2.php?inter=0&&hight=0). Artesunate is rapidly absorbed, with peak plasma levels occurring 1.5 h and 2 h and 0.5 h after oral, rectal and intramuscular administration, respectively(Bethell et al. 1997; Batty et al. 1998; Newton et al. 2000; Krishna et al. 2001; Ilett et al. 2002). In 2 to 3 hours time artesunate is almost entirely converted to dihydroartemisinin (DHA), which is threefold to fivefold more active than the parent compound (Navaratnam et al. 2000). DHA is then eliminated rapidly by glucuronidation with a terminal half-life of approximately 1 h, both in healthy volunteers and patients with malaria. The extent of protein binding is around 73–81% (Li et al. 2006). No dose modifications are necessary in renal or hepatic impairment.

Artemisinin and its derivatives including artemether and artesunate are safe and remarkably well tolerated (Ribeiro & Olliaro 1998; Price et al. 1999b). As mentioned above, artemisinin-related type 1 hypersensitivity reactions, although rare, are the only clinically important side effect. There have been reports of mild gastrointestinal disturbances, dizziness, tinnitus, reticulocytopenia, neutropenia, elevated liver enzyme values, and electrocardiographic abnormalities, including bradycardia and a slight prolongation of the QTc interval on the ECG. It should be noted, however, that the QTc interval prolongs during recovery from malaria, irrespective of the drug used (White 2007). A recent study looking at QTc times after high dose intravenous artesunate during the acute phase of falciparum malaria could not detect any significant QTc prolongation. Neurotoxicity from studies could not be confirmed in humans (see section on artemether). Drug interactions have not been reported.

Artesunate should be the treatment of choice for adults with severe malaria (Dondorp et al. 2005). 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. The artemisinin derivatives are 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 intramuscular injection has been documented, especially in severely ill patients.

Chloroquine

  • Oral liquid: 50 mg as phosphate or sulphate/5 ml.
  • Tablets: 100 mg or 150 mg of chloroquine base as hydrochloride, phosphate or sulphate.

Chloroquine is a 4-aminoquinoline that has been used extensively for the treatment and prevention of malaria. Widespread resistance has now rendered it virtually useless against P. falciparum infections in most parts of the world, although it still remains the standard treatment for P. vivax, P. ovale and P. malariae infections. As with other 4-aminoquinolines, it does not produce radical cure in P. vivax and P. ovale malaria. Chloroquine interferes with parasite haem detoxification (Krugliak & Ginsburg 1991; Bray et al. 1998). Resistance is related to genetic changes in transporters (PfCRT, PfMDR), which reduce the concentrations of chloroquine at its site of action, the parasite food vacuole.

Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract when taken orally, although peak plasma concentrations can vary considerably. Chloroquine is extensively distributed into body tissues, including the placenta and breast milk, and has an enormous total apparent volume of distribution. Some 60% of chloroquine is bound to plasma proteins, and the drug is eliminated slowly from the body via the kidneys, with an estimated terminal elimination half-life of 1–2 months. Chloroquine is metabolized in the liver, mainly to monodesethylchloroquine, which has similar activity against P. falciparum. Chloroquine has a low safety margin and is very dangerous in overdosage. Larger doses of chloroquine are used for the treatment of rheumatoid arthritis than for malaria, so adverse effects are seen more frequently in patients with arthritis.

The drug is generally well tolerated. Chloroquine may be used even in very young children. The principle limiting adverse effects in practice are the unpleasant taste, which may upset children, and pruritus, which may be severe in dark-skinned patients (Mnyika & Kihamia 1991). Other less common side effects include headache, various skin eruptions and gastrointestinal disturbances, such as nausea, vomiting and diarrhoea. More rarely central nervous system toxicity including, convulsions and mental changes may occur. Chronic use (>5 years continuous use as prophylaxis) may lead to eye disorders, including keratopathy and retinopathy. Other uncommon effects include myopathy, reduced hearing, photosensitivity and loss of hair. Blood disorders, such as aplastic anaemia, are extremely uncommon (Taylor & White 2004).

Acute overdosage is extremely dangerous and death can occur within a few hours. The patient may progress from feeling dizzy and drowsy with headache and gastrointestinal upset, to developing sudden visual disturbance, convulsions, hypokalaemia, severe hypotension related to its negative inotropic and vasodilatory effects and cardiac arrhythmias. Both tachycardias or bradycardia with atrioventricular block may occur, and there is consistent intraventricular conduction delay (widening of the QRS interval). There is no specific treatment, although diazepam and epinephrine (adrenaline) administered together are beneficial (Riou et al. 1988; Clemessy et al. 1996a,b). The role of diazepam as a specific antidote has been recently disputed.

Major interactions are very unusual. There is a theoretical increased risk of arrhythmias when chloroquine is given with halofantrine or other drugs that prolong the electrocardiograph QT interval; a possible increased risk of convulsions with mefloquine; reduced absorption with antacids; reduced metabolism and clearance with cimetidine; an increased risk of acute dystonic reactions with metronidazole; reduced bioavailability of ampicillin and praziquantel; reduced therapeutic effect of thyroxine; a possible antagonistic effect on the antiepileptic effects of carbamazepine and sodium valproate; and increased plasma concentrations of cyclosporine.

Resistance of P. falciparum to chloroquine now occurs throughout most of the tropical world. Chloroquine sensitivity may still be retained in pockets of Central America north of the Panama Canal, Haiti, North Africa and parts of the Middle East, and some parts of Asia such as peninsular Malaysia, and remaining malaria endemic parts of the Philippines. In many areas resistance is low-grade and partial clinical responses to chloroquine treatment are observed. In many areas of the tropics chloroquine is still used as a first-line treatment despite resistance and even though clinical responses are unsatisfactory or the drug is ineffective. This is partly because of its low cost (approximately five US cents for a treatment course), familiarity and access. High-level chloroquine resistance is now prevalent in many areas of South America and sub-Saharan Africa and in these areas there is usually no therapeutic response at all to chloroquine. In fact the continued use of chloroquine in the face of resistance leads to increased mortality which has been demonstrated by Trape et al. (1998). It is of academic interest that chloroquine was found efficacious in the treatment for malaria, 12 years after it was withdrawn from use in Malawi (Laufer et al. 2006). However until chloroquine resistant strains of P. falciparum have been eliminated from the surrounding region the re-introduction of chloroquine can not be considered.

Although it is no longer recommended for P. falciparum malaria, chloroquine in combination of with primaquine is the treatment of choice for most P. vivax and all P. ovale infections. It should be noted that chloroquine resistance has been increasingly reported from Papua New Guinea, Indonesia and South America. The traditional treatment regimen is an initial dose of 10mg base/kg followed at 6, 24 and 48 h by further doses of 5 mg/kg. This may be compressed into a 36-h administration of 10mg/kg initially, followed at 12-h intervals by 5 mg base/kg (Pussard et al. 1991). For radical cure, chloroquine (total dose 25 mg base/kg) should be given in combination with primaquine, which is further discussed below.

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) (Pukrittayakamee et al. 2000a). 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 treatment occurs around 6 weeks after treatment. Relapses should be treated in the same way as the primary infection, with both chloroquine and primaquine. Relapse intervals over 6 months are unusual in tropical vivax infections.

For P. malariae infections, the drug of choice is chloroquine at standard doses. Radical treatment with primaquine is not necessary as there is no persistent exoerythrocytic stage in this infection. Chloroquine resistance has to date only been reported in one study from Indonesia (Maguire et al. 2002).

Doxycycline

  • Capsule containing 100 mg as hydrochloride and dispersible tablet containing 100 mg as monohydrate.

Doxycycline is a tetracycline derivative with uses similar to those of tetracycline. It is recommended for use in malaria only in combination with quinine or an artemisinin, although the authors note that only its combination with quinine is recommended in the essential drugs list. It may be preferred to tetracycline because of its longer half-life, more reliable absorption and better safety profile in patients with renal insufficiency, where it may be used with caution. It is relatively water insoluble but very lipid soluble. It may be given orally or intravenously. It is available as the hydrochloride salt or phosphate complex, or as a complex prepared from the hydrochloride and calcium chloride. Doxycycline is readily and almost completely absorbed from the gastrointestinal tract and absorption is not affected significantly by the presence of food. Peak plasma concentrations occur 2 h after administration. Some 80-95% is protein-bound and half-life is 10-24 h (Newton et al. 2005). It is widely distributed in body tissues and fluids. In patients with normal renal function, 40% of doxycycline is excreted in the urine, more if the urine is alkalinized. It may accumulate during renal failure. However, the majority of the dose is excreted in the faeces.

All tetracyclines have similar adverse effect profiles. Gastrointestinal effects, such as nausea, vomiting and diarrhoea, are common, especially with higher doses, and are due to mucosal irritation. Dry mouth, glossitis, stomatitis, dysphagia and oesophageal ulceration have also been reported. Overgrowth of Candida and other bacteria occurs, presumably due to disturbances in gastrointestinal flora as a result of incomplete absorption of the drug. This effect is seen less frequently with doxycycline, which is better absorbed. Pseudomembranous colitis, hepatotoxicity and pancreatitis have also been reported. The use of out-of-date tetracycline can result in the development of a reversible Fanconi-type syndrome characterized by polyuria and polydipsia with nausea, glycosuria, aminoaciduria, hypophosphataemia, hypokalaemia and hyperuricaemia with acidosis and proteinuria. These effects have been attributed to the presence of degradation products, in particular anhydroepitetracycline.

Tetracyclines are deposited in deciduous and permanent teeth during their formation and cause discoloration and enamel hypoplasia. They are also deposited in calcifying areas in teeth, bone and nails and interfere with bone growth. Thus tetracyclines, including doxycycline, should not be given to children less than 8 years of age.

Raised intracranial pressure in adults and infants has also been documented. Hypersensitivity reactions occur, although they are less common than for β-lactam antibiotics. Rashes, fixed-drug reactions, drug fever, angioedema, urticaria, pericarditis and asthma have all been reported. Photosensitivity may develop and, rarely, haemolytic anaemia, eosinophilia, neutropenia and thrombocytopenia. Pre-existing systemic lupus erythematosus may be worsened and tetracyclines are contraindicated in patients with the established disease. Gastrointestinal effects are fewer with doxycycline than with tetracycline, although oesophageal ulceration can still be a problem if insufficient water is taken with tablets or capsules.

Doxycycline has a lower affinity for binding with calcium than other tetracyclines, so may be taken with food or milk. However, antacids and iron may still affect absorption. Metabolism may be accelerated by drugs that induce hepatic enzymes, such as carbamazepine, phenytoin, phenobarbital and rifampicin and by chronic alcohol use.

Mefloquine

  • Tablets containing either 250 mg salt (United States of America) or 250 mg base (elsewhere).
  • In fixed dose with artesunate; paediatric formulation containing 50 mg artesunate and 125 mg mefloquine (Artequine® Paediatric Stickpack).
  • Co-formulated with artesunate: (i) paediatric artesunate 25 mg and mefloquine 55 mg, or (ii) adult dose artesunate 100 mg and mefloquine 220 mg (ASMQ®).

Mefloquine is a 4-methanolquinoline and is related to quinine. It is administered by mouth as a hydrochloride salt (250 mg base equivalent to 274 mg hydrochloride salt). It is soluble in alcohol but only very slightly soluble in water. It should be protected from light. The drug is effective against all forms of malaria.

Mefloquine is reasonably well absorbed from the gastrointestinal tract but there is marked interindividual variation in the time required to achieve peak plasma concentrations. Splitting the 25 mg/kg dose into two parts given at an interval of 6–24 h augments absorption and improves tolerability (Price et al. 1999a). Mefloquine undergoes enterohepatic recycling. It is approximately 98% bound to plasma proteins and is widely distributed throughout the body. The pharmacokinetics of mefloquine may be altered by malaria infection with reduced absorption and accelerated clearance (Krishna & White 1996; Simpson et al. 1999). When administered with artesunate, blood concentrations are increased, probably as an indirect effect of increased absorption resulting from more rapid resolution of symptoms (Price et al. 1999a). It has a long elimination half-life of around 21 days, which is shortened in malaria to about 14 days, possibly because of interrupted enterohepatic cycling (Slutsker et al. 1990; Karbwang et al. 1991; Nosten et al. 1991b). Mefloquine is metabolized in the liver and excreted mainly in the bile and faeces.

Minor adverse effects are common following mefloquine treatment, most frequently nausea, vomiting, abdominal pain, anorexia, diarrhoea, headache, dizziness, loss of balance, dysphoria, somnolence and sleep disorders, notably insomnia and abnormal dreams. Neuropsychiatric disturbances (seizures, encephalopathy, psychosis) occur in approximately 1 in 10 000 travellers receiving mefloquine prophylaxis, 1 in 1000 patients treated in Asia, 1 in 200 patients treated in Africa, and 1 in 20 patients after severe malaria (Bem et al. 1992; ter Kuile et al. 1995; Phillips-Howard & ter Kuile 1995; Nguyen et al. 1996). Other side effects reported rarely include skin rashes, pruritus and urticaria, hair loss, muscle weakness, liver function disturbances and very rarely thrombocytopenia and leukopenia. Cardiovascular effects have included postural hypotension, bradycardia and, rarely, hypertension, tachycardia or palpitations and minor changes in the electrocardiogram. Fatalities have not been reported following overdosage, although cardiac, hepatic and neurological symptoms may be seen.

Mefloquine should not be given with halofantrine because it exacerbates QT prolongation. There is no evidence of an adverse interaction with quinine (Eckstein-Ludwig et al. 2003). There is a possible increase in the risk of arrhythmias if mefloquine is given together with other drugs such as digoxin or antidepressants; there is also a possible increase in the risk of convulsions with chloroquine and quinine. Mefloquine concentrations are increased when given with ampicillin, tetracycline and metoclopramide.

Mefloquine resistance appears to be associated with amplification and increased expression of the PfMDR1 gene (Wilson et al. 1993; Cowman et al. 1994; Price et al. 1999c). Moreover, point mutations in this gene have been correlated with mefloquine resistance. This gene codes for a P-glycoprotein pump which is thought to remove mefloquine from the parasite’s food vacuole, where the drug should exert its action by inhibiting haem-polymerization.

In Thailand (where mefloquine was first deployed alone) resistance developed over a 6-year period between 1984 and 1990 despite control of drug deployment (Nosten et al. 1991a). By mid-1994 on the Western border 50% of malaria patients treated with high dose mefloquine recrudesced and 10% did not clear parasites at all. Resistance is also present on the Thai-Cambodian border, and is increasing in Southern Vietnam. Mefloquine resistance is still relatively unusual outside South East Asia. Parasites from West Africa appear to be intrinsically mefloquine-resistant (Oduola et al. 1992).

Primaquine

  • Tablets containing 5.0, 7.5 or 15.0 mg of primaquine base as diphosphate.

Primaquine is an 8-aminoquinoline and is effective against intrahepatic forms of all types of malaria parasite. It is used to provide radical cure of P. vivax and P. ovale malaria, in combination with a blood schizontocide for the erythrocytic parasites. Primaquine is also gametocytocidal against P. falciparum and has significant blood stage activity against P. vivax (and some against asexual stages of P. falciparum). Its mechanism of action is unknown.

Primaquine is readily absorbed from the gastrointestinal tract. Peak plasma concentrations occur around 1–2 h after administration and then decline, with a reported elimination half-life of 3-6 h (Mihaly et al. 1984, 1985; Ward et al. 1985). Primaquine is widely distributed into body tissues. It is rapidly metabolized in the liver. The major metabolite is carboxyprimaquine, which may accumulate in the plasma with repeated administration. The most important adverse effects are haemolytic anaemia in patients with G6PD deficiency, other defects of the erythrocytic pentose phosphate pathway of glucose metabolism, or some other types of haemoglobinopathy (Chan et al. 1976). In patients with the African variant of G6PD deficiency, the standard course of primaquine generally produces a benign self-limiting anaemia. In the Mediterranean and Asian variants, haemolysis may be much more severe. Therapeutic doses may also cause abdominal pain if administered on an empty stomach. Larger doses can cause nausea and vomiting. Methaemoglobinaemia may occur. Other uncommon effects include mild anaemia and leukocytosis. Overdosage may result in leukopenia, agranulocytosis, gastrointestinal symptoms, haemolytic anaemia and methaemoglobinaemia with cyanosis. Drugs liable to increase the risk of haemolysis or bone marrow suppression should be avoided.

The dose of primaquine used for radical treatment of vivax and ovale malaria is 0.25 mg base/kg bw daily or the adult dose of 15 mg base for 14 days. Primaquine should be taken after a meal and not on an empty stomach. This treatment course of 2–3 days is cheap, well absorbed and well tolerated. The efficacy of primaquine in preventing relapse of P. vivax varies. In South East Asia and Oceania higher doses of primaquine (0.5 mg base/kg bw) are required than elsewhere to prevent relapse of P. vivax (Collins & Jeffery 1996). The mechanism for this variable susceptibility is not known. If a patient is known to be severely G6PD deficient then primaquine should not be given. For the majority of patients with mild variants of the deficiency, primaquine should be given in a dose of 0.75 mg base/kg once a week for 8 weeks. If significant haemolysis occurs on treatment then primaquine should be stopped.

Quinine

  • Tablets of quinine hydrochloride, quinine dihydrochloride, quinine sulphate and quinine bisulphate containing 82%, 82.6% and 59.2% quinine base, respectively.
  • Ampoule for injection containing 150 mg or 300 mg quinine hydrochloride/ml.

Quinine is an alkaloid derived from the bark of the Cinchona tree. Four anti-malarial alkaloids can be derived from the bark: quinine (the main alkaloid), quinidine, cinchonine and cinchonidine. Quinine is the l-stereoisomer of quinidine. Quinine acts principally on the mature trophozoite stage of parasite development and does not prevent sequestration or further development of circulating ring stages of P. falciparum. Like other structurally similar anti-malarials, quinine also kills the sexual stages of P. vivax, P. malariae and P. ovale, but not mature gametocytes of P. falciparum. It does not kill the pre-erythrocytic stages of malaria parasites. The mechanisms of its anti-malarial actions are thought to involve inhibition of parasite haem detoxification in the food vacuole, but are not well understood. The pharmacokinetic properties of quinine are altered significantly by malaria infection, with reductions in apparent volume of distribution and clearance in proportion to disease severity (White et al. 1982).

In children under 2 years of age with severe malaria, concentrations are slightly higher than in older children and adults (van Hensbroek et al. 1996). There is no evidence for dose-dependent kinetics. Quinine is rapidly and almost completely absorbed from the gastrointestinal tract and peak plasma concentrations occur 1-3 h after oral administration of the sulphate or bisulphate. Plasma-protein binding, mainly to alpha 1-acid glycoprotein, is 80% in healthy subjects but rises to around 90% in patients with malaria (Silamut et al. 1985, 1991; Mansor et al. 1991). Quinine is widely distributed throughout the body including the cerebrospinal fluid (2-7% of plasma values), breast milk (approximate 30% of maternal plasma concentrations) and the placenta (Phillips et al. 1986). Extensive metabolism via the cytochrome P450 enzyme CYP3A4 occurs in the liver and elimination of more polar metabolites is mainly renal (Hall et al. 1973; Pukrittayakamee et al. 1997). The initial metabolite 3-hydroxyquinine contributes approximately 10% of the anti-malarial activity of the parent compound, but may accumulate in renal failure (Newton et al. 1999). Excretion is increased in acid urine. The mean elimination half-life is around 11 h in healthy subjects, 16 h in uncomplicated malaria and 18 h in severe malaria (White et al. 1982). Small amounts appear in the bile and saliva.

Administration of quinine or its salts regularly causes a complex of symptoms known as cinchonism, which is characterized in its mild form by tinnitus, impaired high tone hearing, headache, nausea, dizziness and dysphoria, and sometimes disturbed vision (Taylor & White 2004). More severe manifestations include vomiting, abdominal pain, diarrhoea and severe vertigo. Hypersensitivity reactions to quinine range from urticaria, bronchospasm, flushing of the skin and fever, through antibody-mediated thrombocytopenia and haemolytic anaemia, to life-threatening haemolytic-uraemic syndrome. Massive haemolysis with renal failure (‘black water fever’) has been linked epidemiologically and historically to quinine, but its etiology remains uncertain (Bruce-Chwatt 1987). The most important adverse effect in the treatment of severe malaria is hyperinsulinaemic hypoglycaemia (White et al. 1983). Intramuscular injections of quinine dihydrochloride are acidic (pH 2) and cause pain, focal necrosis and in some cases abscess formation, and in endemic areas are a common cause of sciatic nerve palsy. Hypotension and cardiac arrest may result from rapid intravenous injection. Intravenous quinine should be given only by infusion, never injection. Quinine causes an approximately 10% prolongation of the electrocardiograph QT interval mainly as a result of slight QRS widening (White et al. 1983). The effect on ventricular repolarization is much less than that with quinidine.

Quinine has been used as an abortifacient, but there is no evidence that it causes abortion, premature labour or fetal abnormalities in therapeutic use. Overdosage of quinine may cause oculotoxicity, including blindness from direct retinal toxicity, and cardiotoxicity, and can be fatal (Boland et al. 1985). Cardiotoxic effects are less frequent than those of quinidine and include conduction disturbances, arrhythmias, angina, hypotension leading to cardiac arrest and circulatory failure. Treatment is largely supportive, with attention being given to maintenance of blood pressure, glucose and renal function, and to treating arrhythmias.

There is a theoretical concern that drugs that may prolong the QT interval should not be given with quinine, although whether or not quinine increases the risk of iatrogenic ventricular tachyarrhythmia has not been established. Antiarrhythmics, such as flecainide and amiodarone, should probably be avoided. There might be an increased risk of ventricular arrhythmias with antihistamines such as terfenadine, and with antipsychotic drugs such as pimozide and thioridazine. Halofantrine, which causes potentially life threatening QT prolongation, should be avoided but combination with other anti-malarials, such as lumefantrine and mefloquine is safe. Quinine increases the plasma concentration of digoxin. Cimetidine inhibits quinine metabolism, causing increased quinine levels and rifampicin increases metabolic clearance leading to low plasma concentrations and an increased therapeutic failure rate (Pukrittayakamee et al. 2003).

Although quinine resistance was first documented in 1910, P. falciparum sensitivity to quinine is still retained throughout most of the world. Quinine may still be relied upon to treat severe falciparum malaria everywhere. Although there is evidence of a decline in the efficacy of quinine both in some areas of South East Asia and South America (Wernsdorfer 1994), there is still no well-documented case of high-level resistance with adequate blood levels of quinine (Pukrittayakamee et al. 1994). In Thailand, where the world’s most drug-resistant parasites are to be found, the efficacy of quinine alone in the treatment of uncomplicated falciparum malaria has declined in recent years, but the combinations of quinine with a tetracycline or clindamycin still retains over 85% efficacy (White 1992; Pukrittayakamee et al. 2000b; Looareesuwan et al. 1992a; b; Watt et al. 1992). In Thailand, there is evidence of declining efficacy in recent years in clinical and parasitological responses in severe malaria, but mortality rates have not changed significantly (Pukrittayakamee et al. 1994). Quinine resistance is usually correlated with mefloquine resistance, but there are well-documented exceptions to this rule.

If parenteral quinine is used for the treatment of severe malaria, it is important that a loading dose of twice the maintenance dose is administered (20 mg/kg bw over 4 h), in order to achieve therapeutical concentration more rapidly (WHO 2005). This should be reduced only if there is clear evidence of adequate pre-treatment before presentation, since omission can result in inadequate blood concentrations during the first 12 h of treatment. Quinine (and quinidine) levels may accumulate in severe vital organ dysfunction. If there is no clinical improvement or the patient remains in acute renal failure the dose should be reduced by one-third after 48 h. Dosage adjustments are not necessary if patients are receiving either haemodialysis or haemofiltration. Dosage reduction by one-third is necessary in patients with hepatic dysfunction.

Sulfadoxine-pyrimethamine

  • • 
    A fixed-drug combination of 20 parts sulfadoxine with 1 part pyrimethamine and may be administered orally or by the intramuscular route: Tablet containing 500 mg of sulfadoxine and 25 mg of pyrimethamine.

Sulfadoxine-pyrimethamine is used widely and is the usual next choice when continued use of chloroquine is precluded by resistance. Unfortunately resistance has also developed rapidly to sulfadoxine–pyrimethamine and similar combinations in many areas rendering them as obsolete as chloroquine. High-level sulfadoxine-pyrimethamine resistance is common in P. vivax, thus the combination is often not recommended as treatment. But in areas where P. vivax remains susceptible, then sulfadoxine–pyrimethamine may continue to be used for treatment (Hawkins et al. 2007) In the steadily decreasing number of areas where P. falciparum and vivax coexist, where both organisms are susceptible to sulfadoxine-pyrimethamine, and where species-specific diagnosis is unavailable, then sulfadoxine–pyrimethamine may be appropriate for unified treatment, most likely in combination with other drugs (Leslie et al. 2007).

Sulfadoxine

Sulfadoxine is a slowly eliminated sulfonamide. They are competitive inhibitors of dihydropteroate synthase, the bacterial enzyme responsible for the incorporation of paminobenzoic acid in the synthesis of folic acid. Sulfadoxine is readily absorbed from the gastrointestinal tract. Peak blood concentrations occur about 4 h after an oral dose. The terminal elimination half-life is 4–9 days. Around 90-95% is bound to plasma proteins. It is widely distributed to body tissues and fluids, passes into the fetal circulation and is detectable in breast milk. The drug is excreted in urine, primarily unchanged (Barnes et al. 2006).

Sulfadoxine shares the adverse effect profile of other sulfonamides, although allergic reactions can be severe because of its slow elimination. Nausea, vomiting, anorexia and diarrhoea may occur. Crystalluria causing lumbar pain, haematuria and oliguria is rare compared with more rapidly eliminated sulphonamides. Hypersensitivity reactions may affect different organ system. Cutaneous manifestations can be severe and include pruritus, photosensitivity reactions, exfoliative dermatitis, erythema nodosum, toxic epidermal necrolysis and Stevens-Johnson syndrome (Miller et al. 1986). Treatment with sulfadoxine should be stopped in any patient developing a rash because of the risk of severe allergic reactions (Bjorkman & Phillips-Howard 1991). Hypersensitivity to sulfadoxine may also cause interstitial nephritis, lumbar pain, haematuria and oliguria. This is due to crystal formation in the urine (crystalluria) and may be avoided by keeping the patient well hydrated to maintain a high urine output. Alkalinization of the urine will also make the crystals more soluble. Blood disorders that have been reported include agranulocytosis, aplastic anaemia, thrombocytopenia, leukopenia and hypoprothrombinaemia. Acute haemolytic anaemia is a rare complication, which may be antibody mediated or associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Other adverse effects, which may be manifestations of a generalized hypersensitivity reaction, include fever, interstitial nephritis, a syndrome resembling serum sickness, hepatitis, myocarditis, pulmonary eosinophilia, fibrosing alveolitis, peripheral neuropathy and systemic vasculitis, including polyarteritis nodosa. Anaphylaxis has been reported only rarely. Other adverse reactions that have been reported include hypoglycaemia, jaundice in neonates, aseptic meningitis, drowsiness, fatigue, headache, ataxia, dizziness, drowsiness, convulsions, neuropathies, psychosis and pseudomembranous colitis.

The marked synergy with sulfonamides and sulfones is very important for the anti-malarial activity of sulfa-pyrimethamine or sulfone-biguanide combinations. In P. falciparum, sulfonamide and sulfone resistance also develops by progressive acquisition of mutations in the gene encoding the target enzyme PfDHPS (which is a bifunctional protein with the enzyme PPPK). Specifically altered amino acid residues have been found at positions 436, 437, 540, 581 and 613 in the PfDHPS domain. The mutations at positions 581 and 631 do not occur in isolation, but always following an initial mutation (usually at position 437, alanine to glycine). Mutations in P. vivax DHPS (at positions 383 and 553) also appear to contribute to resistance.

Pyrimethamine

Pyrimethamine is a diaminopyrimidine used in combination with a sulfonamide, usually sulfadoxine or dapsone. It exerts its anti-malarial activity by inhibiting plasmodial dihydrofolate reductase thus indirectly blocking the synthesis of nucleic acids in the malaria parasite. It is a slow-acting blood schizontocide and is also possibly active against pre-erythrocytic forms of the malaria parasite and inhibits sporozoite development in the mosquito vector. It is effective against all four human malarials, although resistance has emerged rapidly. Pyrimethamine is no longer used alone as an anti-malarial, only in synergistic combination with slowly eliminated sulfonamides for treatment (sulfadoxine, sulfalene).

Pyrimethamine is almost completely absorbed from the gastrointestinal tract and peak plasma concentrations occur 2–6 h after an oral dose. It is mainly concentrated in the kidneys, lungs, liver and spleen, and about 80–90% is bound to plasma proteins. It is metabolized in the liver and slowly excreted via the kidneys. The plasma half-life is around 4 days. Pyrimethamine crosses the blood-brain barrier and the placenta and is detectable in breast milk. Absorption of the intramuscular preparation is incomplete and insufficiently reliable for this formulation to be recommended (Winstanley et al. 1992). Pyrimethamine is generally very well tolerated. Administration for prolonged periods may cause depression of haematopoiesis due to interference with folic acid metabolism. Skin rashes and hypersensitivity reactions also occur. Larger doses may cause gastrointestinal symptoms such as atrophic glossitis, abdominal pain and vomiting, haematological effects including megaloblastic anaemia, leukopenia, thrombocytopenia and pancytopenia and central nervous system effects such as headache and dizziness. Acute overdosage of pyrimethamine can cause gastrointestinal effects and stimulation of the central nervous system with vomiting, excitability and convulsions. Tachycardia, respiratory depression, circulatory collapse and death may follow. Treatment of overdosage is supportive. Administration of pyrimethamine with other folate antagonists such as cotrimoxazole, trimethoprim, methotrexate or with phenytoin may exacerbate bone marrow depression. Given with some benzodiazepines, there is a risk of hepatotoxicity.

Pyrimethamine and the active cyclic triazine metabolites of proguanil and chlorproguanil (cycloguanil and chlorcycloguanil respectively) all selectively inhibit plasmodial DHFR. Serial point mutations in DHFR and DHPS confer a stepwise reduction in the affinity for this group of anti-malarials (Reyes et al. 1982; Foote & Cowman 1994; Sirawaraporn et al. 1997). For pyrimethamine resistance the initial mutation is usually at position 108 (SER to ASN). This confers pyrimethamine resistance but only slightly reduced sensitivity to cycloguanil. Interestingly, the SER to THR mutation at position 108, when combined with ALA to VAL at position 16 confers cycloguanil resistance but not pyrimethamine resistance (Peterson et al. 1990). Additional mutations at positions 46, 51, 59 and 164 confer increasing resistance to both classes of drugs(Reeder et al. 1996). ‘Triple mutants’ (mutations at positions 108, 51, 59) now prevalent in many areas retain some susceptibility to sulfadoxine-pyrimethamine (SP) and are treated effectively by chlorproguanil-dapsone. The 164 mutation confers complete resistance to currently available antifols as has occurred in much of South East Asia and South America. In sub Saharan Africa, resistance is rapidly spreading, and the quadriple mutation, including the 164 mutation, has been reported from Malawi (Alker et al. 2005). Similar mutations are found in antifol resistant P. vivax. Resistance in both P. falciparum and P. vivax to proguanil and later to pyrimethamine both developed rapidly after the drugs were introduced as monotherapy in malaria endemic areas (Field & Edeson 1949; Field et al. 1954; Peters 1987). Proguanil and pyrimethamine are now prescribed in combination and no longer used alone for treatment.

A recent large intensive sampling pharmacokinetic study of sulfadoxine-pyrimethamine in 307 Mozambican and South-African patients of different age groups with uncomplicated falciparum malaria showed that with the usual dose of 25 mg/kg/1.25 mg/kg, the area under the concentration-time curves (AUCs) in children 2 to 5 years old were half of those in adults, which was caused by higher clearance (Barnes et al. 2006). This might have caused not only anti-malarial treatment failure in young children, but might well have contributed to the spread of resistance. This information has only come decades after introduction of sulfadoxine-pyrimethamine. Information on its pharmacokinetics in infants is still largely lacking.

Treatment regimens against Plasmodium falciparum

  1. Top of page
  2. Summary
  3. Introduction
  4. Guiding principles for the treatment of uncomplicated malaria
  5. The essential anti-malarial drugs for children
  6. Treatment regimens against Plasmodium falciparum
  7. Conclusions
  8. References

1. The following ACTs are currently recommended for treatment of uncomplicated falciparum malaria (WHO 2006):

  • Artemether-lumefantrine,
  • Artesunate + amodiaquine,
  • Artesunate + mefloquine,
  • Artesunate + sulfadoxine – pyrimethamine.

The specific choice of ACT in a country or region should ideally be based on the level of resistance of the partner medicine in the combination. For example, in areas of multidrug resistance of P. falciparum such as in parts of South-East Asia, artesunate + mefloquine or artemether – lumefantrine may be used. In Africa, artemether – lumefantrine, artesunate + amodiaquine, or artesunate + sulfadoxine – pyrimethamine may be considered for treatment of uncomplicated malaria.

A systematic review and meta-analysis of individual patient data from 16 randomized trials (total of 5948 people) studied the effects of the addition of artesunate to monotherapy for falciparum malaria (Adjuik et al. 2004). The analysis compared odds ratios (ORs) of parasitological failure at days 14 and 28 (artesunate combination compared to monotherapy) and calculated combined summary ORs across trials using standard methods. For many countries, artemether – lumefantrine and artesunate + mefloquine may give the highest cure rates, but there may be problems of affordability and availability of these products. There is currently insufficient safety and tolerability data on artesunate + mefloquine at the recommended dose of 25 mg/kg in African children to support its recommendation there. Trials with mefloquine monotherapy (25 mg/kg) have also raised concerns of tolerability in African children. Countries may therefore opt to use artesunate + amodiaquine and artesunate + sulfadoxine –pyrimethamine, which may have lower cure rates because of resistance.

The combination of amodiaquine + sulfadoxine – pyrimethamine may be considered as an interim option where ACT cannot be made available, provided that efficacy of both amodiaquine and sulfadoxine – pyrimethamine is high (Yeka et al. 2005). 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. Although still effective in some areas, amodiaquine and sulfadoxine – pyrimethamine are widely available as monotherapy, providing continued selection pressure, and it is likely that resistance will continue to worsen despite deployment of the corresponding ACTs. This may be a particular problem in settings where sulfadoxine –pyrimethamine is being used for intermittent preventive treatment in pregnancy; artesunate + sulfadoxine – pyrimethamine should probably not be used in such settings.

Parenteral artesunate, artemether, or quinine are generally reserved for treatment of severe falciparum malaria. However, in clinical settings, children who are vomiting everything but otherwise do not fulfil criteria for severe malaria are given parenteral quinine. In these circumstances, parenteral quinine should be discontinued as soon as oral medications can be given. Treatment should be completed by giving a full course of ACT or oral quinine + doxycycline. In children less than 8 years old, clindamycin should be used instead of doxycycline, although the authors note that clindamycin is not currently in the provisional WHO essential drugs list. Even in areas with multi-drug resistant falciparum malaria cure rates with the quinine-tetracycline or quinine-clindamycin combination exceed 85% (Meek et al. 1986; Looareesuwan et al. 1992a; b; Watkins et al. 1993; Pukrittayakamee et al. 2000b).

Recommended ACT preparations and dosage

Artemether–lumefantrine has until recently been the only co-formulated artemisinin-containing combination and is widely deployed in malaria-endemic countries where it is becoming increasingly the first line treatment. It is not recommended for use in children below 5 kg. The dose is 1.5 mg/kg artemether and 12 mg/kg lumefantrine at 0 and 8 h on day 1 and every 12 h on days 2 and 3. The recommended weight-based regimen has four weight categories: 5 ≤ 15 kg (one tablet), 16-25 kg (two tablets), 26-35 (three tablets) and > 35 kg (four tablets) (Omari et al. 2004, 2005, 2006).

The combination of amodiaquine with artesunate is currently available as separate scored tablets containing 50 mg of artesunate and 153 mg base of amodiaquine 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. Taylor and coworkers evaluated age-based dosing of the fixed-dose combination of artesunate and amodiaquine. They found that the optimal paediatric (p) and adult (a) strength tablets contain 25/67.5 and 100/270 mg artesunate/amodiaquine, respectively. A regimen with five age categories: 0-1 months (1/2 p), 2-11 months (1 p), 1-5 years (2 p), 6-13 years (1 a) and > 14 years (2 a) had an overall dosing accuracy of 83.4% and 99.9% for amodiaquine and artesunate, respectively (Taylor et al. 2006). It has proven to be an efficacious combination in areas where 28-day cure rates with amodiaquine monotherapy exceed 80%. But pharmacokinetic and safety studies in health volunteers have raised dosing and safety questions regarding this combination (Orrell et al. 2008). Safety concerns have been reported when HIV-infected children are treated with the combination amodiaquine plus artesunate (Gasasira et al. 2008). While highly efficacious the combination therapy was associated with neutropenia which based on earlier experience, is likely to be caused by the amodiaquine component. In areas where resistance to sulphonamide-pyrimethamine, chloroquine and amodiaquine is prevalent, then artemisinin combinations with either lumefantrine or mefloquine are the alternatives (Ndayiragije et al. 2004).

Combining artesunate or artemether (4 mg/kg/day for 3 days) with mefloquine has many advantages. The cure rate is increased, resistance is prevented, and if mefloquine is not given until the second day of treatment then absorption is increased but adverse effects are lessened (Omari et al. 2004). In 2008, Farmanguinhos/Fiocruz in collaboration with Drugs for Neglected Diseases initiative (DNDi) have introduced a coformulation of mefloquine with artesunate in two doses (i) paediatric artesunate 25 mg and mefloquine 55 mg and (ii) adult dose artesunate 100 mg and mefloquine 220 mg (ASMQ).

The combination of artesunate with sulfadoxine – pyrimethamine 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 presentation. The combination has been evaluated in children with uncomplicated malaria in sub-Saharan Africa and is sufficiently efficacious in areas where 28-day cure rates with sulfadoxine-pyrimethamine alone exceed 80% (Dorsey et al. 2002; Adjuik et al. 2004; Bell et al. 2008) Since sulfadoxine-pyrimethamine, sulfalene-pyrimethamine and trimethroprim-sulfamethoxazole are widely used, increased resistance is likely to worsen.

Other drugs for treatment of falciparum malaria

Non-artemisinin based combinations (non-ACTs) include sulfadoxine–pyrimethamine with chloroquine (SP+CQ) or amodiaquine (SP+AQ). However, the prevailing high levels of resistance have compromised the efficacy of these combinations. There is no convincing evidence that SP+CQ provides any additional benefit over SP. It adds costs and risks of adverse events. So this combination is not recommended; SP+AQ can be more effective than either drug alone, but needs to be considered in comparison with ACTs (Bell et al. 2008; Fanello et al. 2008).

The fixed-drug combination of atovaquone–proguanil has been shown to be safe and effective as a combination partner but is not recommended for deployment in endemic areas because of its very high cost (Osei-Akoto et al. 2005; Nakato et al. 2007). This fixed-drug combination is currently not on the essential drugs list for children. Halofantrine has not yet been evaluated as an ACT partner medicine and is not included in these recommendations because of safety concerns including the risk of sudden death (White 2007). Dihydroartemisinin (artenimol)- piperaquine has been shown to be safe and effective in large trials, but is not recommended as it is not yet available as a formulation manufactured under good manufacturing practices, and has not yet been evaluated sufficiently in Africa (Tran et al. 2004; Grande et al. 2007). Pyronaridine-artesunate is currently undergoing clinical evaluation. Several other new anti-malarial compounds are in development but do not yet have sufficient clinical evidence to support recommendation here.

Treatment regimens against Plasmodium vivax, ovale and malariae

The following are currently recommended for treatment of uncomplicated vivax malaria:

  • chloroquine + primaquine,
  • amodiaquine+ primaquine (for chloroquine–resistant), or
  • artemisinin-based combination therapy (except artesunate + sulfadoxine–pyrimethamine)

Treatment of severe vivax malaria is the same as for severe falciparum malaria.

The recommended treatment for malaria caused by P. ovale is the same as that given to achieve radical cure in vivax malaria, i.e. with chloroquine and primaquine. P. malariae should be treated with the standard regimen of chloroquine as for vivax malaria, but it does not require radical cure with primaquine (WHO 2006).

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Guiding principles for the treatment of uncomplicated malaria
  5. The essential anti-malarial drugs for children
  6. Treatment regimens against Plasmodium falciparum
  7. Conclusions
  8. References

There are now several new drugs and drug combinations available for the therapy of uncomplicated malaria in children. ACTs are now recommended for treatment of uncomplicated falciparum and several of these have become available in the past recent years. The introduction of the more expensive ACTs as first line therapy may require a reassessment of the IMCI strategy to administer anti-malarials empirically to febrile children presenting for care in malaria-endemic settings. More emphasis on diagnostic confirmation may be needed.

This review reveals large gaps in knowledge about anti-malarial pharmacokinetics by age-group, the lack of formulations and dosage forms appropriate for children, the unresolved issue of age-based versus weight-based dosing, and the difficulties of assessing safety and tolerability in young children. These should be considered as urgent areas for research and development.

References

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  3. Introduction
  4. Guiding principles for the treatment of uncomplicated malaria
  5. The essential anti-malarial drugs for children
  6. Treatment regimens against Plasmodium falciparum
  7. Conclusions
  8. References
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