Malaria prophylaxis: A look at treatment options

Malaria is a serious febrile illness, transmitted by mosquitoes carrying the Plasmodium infection. Five species of Plasmodium can infect humans, with the majority of deaths caused by P. falciparum. The remaining four species all cause a milder form of malaria and are generally considered easier to cure. If left untreated or without prompt diagnosis, malaria can be fatal. Its associated symptoms are high fever, vomiting, muscle cramps, diarrhoea, sweats and chills.

Treatment protocols

Chemoprophylaxis forms a central component of the ABCD of malaria prevention:

• Awareness of Risk
• Bite Prevention
• Chemoprophylaxis
• Diagnose promptly and treat without delay

Antimalarial medication is considered to reduce the risk of contracting malaria by 90%. The type of medication prescribed is determined by a number of factors:

• Personal medical history
• Current medication (including any medical allergies and medications that may not be compatible with particular antimalarial medicines)
• The region of the world being visited (due to the different strains of Plasmodium parasites and associated drug resistance)
• Age
• Family medical history

Type of malaria prophylaxis

Causal prophylaxis is used to target the liver stage of the malaria parasite, which typically develops over a 7 day period. A successful drug intervention at this stage of parasite development prevents the progression of the parasite to infecting red blood cells. It is recommended that causal prophylaxis drugs are taken for a further 7 days after leaving a malarious area.

Suppressive prophylaxis is used where the liver stage of the parasite has evolved to the red blood cell stage, and subsequently they must be used for several weeks to prevent further infection.[1] Suppressive prophylactics must also be taken for up to 4 weeks after leaving a malarious area.

Medications used for malaria prophylaxis

Doxycycline

Doxycycline is a suppressive prophylactic and acts intracellularly, inhibiting protein synthesis. Doxycycline has a comparable efficacy to mefloquine.[2] As doxycycline has a low pH level, it may cause oesophagitis if is taken on an empty stomach or before lying flat. It has been known to cause mild photosensitivity, although much of the research in this area notes that it is a relatively short and transient side effect.[3] As it is also a broad spectrum antibiotic, there is a risk that in some individuals it will increase predisposition to vaginal candidiasis (thrush) or gastrointestinal disturbances. There is some evidence that doxycycline reduces the efficacy of the oral typhoid vaccine when given simultaneously. If travellers are receiving a booster dose of typhoid prior to their travel, antimalarial treatment should not be commenced until at least 72 hours afterwards.

Contraindications

• Tetracycline allergies
• Children under the age of 12
• Women who are breastfeeding
• Myasthenia Gravis

Groups required to exercise caution

• Pregnant women should not take doxycycline if possible. If no other antimalarial options are available, the full course of antimalarial medication should be completed before 15 weeks gestation.
• Groups with liver problems
• Groups with kidney problems

Doxycycline is taken in a 100mg daily dose, beginning 1-2 days before entering a high-risk area and lasting for the duration of the trip and a month after leaving.

Atovaquone/Proguanil

Proguanil acts as both a suppressive and causal prophylactic.[4] Due to the fact that very few regions of the world have strains of Plasmodium falciparum that are fully sensitive and responsive to proguanil in isolation, it is very rarely used as a single agent prophylaxis. It is often used with a parent drug such as atovaquone. Administered daily, this combination preparation must be taken for only an additional seven days after leaving a malarious region.[5]

Given growing levels of resistance to Proguanil in some regions of the world, it is not recommended as an effective prophylaxis across all parts of Africa.

It is widely used throughout the Indian subcontinent and other areas of the world where the risk of malaria infection remains relatively low.

Combination preparations involving proguanil are often advised to begin one week before travel departure and it has also been evidenced to have activity against the erythrocytic stages of parasites. Atovaquone with proguanil and is available in adult and junior strength, with adult doses recommended at 250mg atovaquone and 100mg proguanil daily. The medication is taken for the duration of the travel period, plus one week prior to travel and one week on return. Its main known side effects are diarrhoea, although mouth ulcers, stomatitis and headaches do occur occasionally.

Contraindications

• Allergy to proguanil

Groups required to exercise caution

• Individuals with renal impairment
• Pregnant women

Mefloquine

Mefloquine is a suppressive prophylactic[6], with a protective efficacy greater than 90%.[7] It is not an appropriate prophylactic for use in some parts of the Amazon Basin and South East Asia due to the resistance of P.falciparum to mefloquine.[8] Several studies have suggested that the use of mefloquine may increase the risk of anxiety reactions and psychosis, but have ruled out its role in the onset of first-time diagnosis depression[9] and hospitalisation as a result of adverse medical reaction.[10][11] Much of the known research on negative effects associated with mefloquine has focused on its association with neuropsychiatric adverse events when compared with other antimalarial medications. Research highlights that increased neuropsychiatric adverse events have been reported (especially in women) when compared with outcomes for those using doxycycline or a combination of atovaquone plus proguanil [12].

Contraindications

• Mental Health: current or previous history of depression, anxiety disorders, psychosis, suicide attempts and/or thoughts, schizophrenia and other psychiatric disorders.
• A history of Blackwater fever
• Impairment of liver function
• Epilepsy, or convulsions of any origin
• Quinine / quinidine hypersensitivity

Groups required to exercise caution

• Pregnant Mothers
• Mothers who are breastfeeding
• Individuals with cardiac conduction orders
• Infants under 5kg (not recommended)
• Individuals who have suffered a traumatic brain injury require a full risk assessment prior to determine if mefloquine is a suitable medication.

Mefloquine is taken orally and is available in 250mg tablets. A weekly dosage is administered 2-3 weeks before travel time to assess individual tolerability to the drug. If the medication is suitable, it should be taken for the duration of the trip and for an additional 4 weeks after leaving the malarious area.

References 

1. Franco-Paredes C, Santos-Preciado JI. Problem pathogens: prevention of malaria in travellers. Lancet Infectious Disease. 2006; 6:139-49.
2. Ohrt, C, Richie TL, Widjaja H et al. Mefloquine compared with doxycycline for the prophylaxis of malaria in Indonesian soldiers. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine. 1997;126:963-72.
3. Bryant SG, Fisher S, Kluge RM. Increased frequency of doxycycline side effects. Pharmacotherapy. 1987;7:125-9.
4. Limsomwong N, Pang LW, Singharaj P. Malaria prophylaxis with proguanil in children living in a malaria-endemic area. American Journal of Tropical Medicine & Hygiene. 1988;38:231-6.
5. Berman JD, Nielsen R, Chulay JD. Causal prophylactic efficacy of atovaquone-proguanil (Malarone) in a human challenge model. Transactions of the Royal Society of Tropical Medicine & Hygiene . 2001;95:429-32.
6. Moore DA, Grant AD, Armstrong M, Stumpfle R, Behrens RH. Risk factors for malaria in UK travellers. Transactions of the Royal Society of Tropical Medicine & Hygiene. 2004;98:55-63.
7. Schlagenhauf P, Tschopp A, Johnson R et al. Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study. British Medical Journal. 2003;327:1078.
8. Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. Epidemiology of drug-resistant malaria. Lancet Infectious Diseases. 2002;2:209-18.
9. Schlagenhauf P, Adamcova M, Regep L, Schaerer MT, Rhein H-G. The position of mefloquine as a 21st century malaria chemoprophylaxis. Malaria Journal. 2010. 9:357
10. Wells TS, Smith TC, Smith B et al. Mefloquine use and hospitalizations among US service members, 2002¬2004. American Journal of Tropical Medicine & Hygiene. 2006;74:744-9.
11. Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Safety. 2004;27, 25-61.
12. Tan KR, Magill AJ, Parise ME, Arguin PM. Doxycycline for malaria chemoprophylaxis and treatment: report from the CDC expert meeting on malaria chemoprophylaxis. Am J Trop Med Hyg. 2011 Apr;84(4):517-31.