Hospital of the University of Pennsylvania Malaria Adult Treatment Guidelines

(Modified from 2011 CDC guidelines and based on drugs available on HUP Formulary - not for use for children)

 
The Infectious Diseases consultation service should be consulted for management advice on all patients with malaria - Please page via the page operator

 

Clinical Diagnosis/
Plasmodium species
Region Infection Acquired Recommended Drug and Adult Dose
Uncomplicated malaria/
P. falciparum or
Species not identified
If “species not identified” is subsequently diagnosed as P. vivax or P ovale: see P. vivax and P ovale (below) re. treatment with primaquine

Chloroquine-resistant or unknown resistance
(It should be assumed that all P. falciparum malaria is possibly chloroquine resistant unless it was acquired in regions specified as chloroquine-sensitive. The few regions and countries with chloroquine-sensitive Plasmodia are llisted in the box below titled "Chloroquine-sensitive").

Of special note: Middle Eastern countries with chloroquine-resistant P. falciparum include Iran, Oman, Saudi Arabia, and Yemen.

Infections acquired in the Newly Independent States of the former Soviet Union and Korea to date have been uniformly caused by P. vivax and should therefore be treated as chloroquine-sensitive infections.)

Artemether-lumefantrine (Coartem™)1
1 tablet = 20mg artemether and 120 mg lumefantrine
3-day treatment schedule with a total of 6 oral doses. The patient should receive the initial dose, followed by the second dose 8 hours later, then 1 dose po bid for the following 2 days. 4 tablets per dose

 

Contraindications Comments Preg Category
no absolute

-headache, dizziness common

-caution in patients with prolonged QT interval or taking drugs that might affect QT interval

-may decrease effectiveness of hormonal contraceptives

C
Uncomplicated malaria/
P. falciparum or Species not identified
Chloroquine-sensitive
(Central America west of Panama Canal; Haiti; the Dominican Republic; and most of the Middle East)

Chloroquine phosphate (Aralen™ and generics) 1,000 mg po immediately, followed by 500 mg po at 6, 24, and 48 hours
Total dose: 2,500 mg. Supplied as chloroquine phosphate, 250 or 500 mg tablets.

Contraindications Comments Preg Category
no absolute   C


Uncomplicated malaria/
P. malariae or P. knowlesi
All regions Chloroquine phosphate: Treatment as above
Uncomplicated malaria/
P. vivax or
P. ovale
All regions
Note: for suspected chloroquine-resistant P. vivax, see row below

Chloroquine phosphate plus Primaquine phosphate2
Chloroquine phosphate: Treatment as above
Primaquine phosphate: 52.6 mg po qd x 14 days. Supplied as primaquine phosphate 26.2 mg tablets.

Primaquine
Contraindications Comments Preg Category

G6PD deficiency - but see CDC guidelines on this

Pregnancy

see alternates for radical cure in pregnancy C

 

Uncomplicated malaria/
P. vivax
Chloroquine-resistant3
(Papua New Guinea and Indonesia)

A. Quinine sulfate4 plus (Doxycycline or Clindamycin) plus Primaquine phosphate2
Quinine sulfate: 648 mg po tid x 3 or 7 days5; supplied as 324 mg capsules
Doxycycline: 100 mg po bid x 7 days; supplied as 50 & 100 mg capsules
Clindamycin: 20 mg /kg/day po divided tid x 7 days; supplied as 75,150 & 300 mg capsules
Primaquine phosphate: Treatment as above

Quinine
Contraindications Comments Preg Category
prolonged QT interval

-can cause profound hypoglycemia

-reported cases severe thrombocytopenia

-GI side effects common, may affect compliance

-adjust dosage for renal failure

C
Doxycycline
pregnancy, children less than 8 yrs

take with large volume of liquid to avoid esophagitis

see advice on use in pregnancy

D
Clindamycin
    B

 

B. Atovaquone-proguanil (Malarone™) plus Primaquine phosphate2
Atovaquone-proguanil: Adult tab = 250 mg atovaquone/ 100 mg proguanil
4 adult tabs po qd x 3 days
Primaquine phosphate: Treatment as above

Contraindications Comments Preg Category
caution in renal failure (Ccr<30) P. falciparum malaria acquired in SE Asia may be resistant. Use alternate therapy C

 

Uncomplicated malaria: alternatives for pregnant women6 Chloroquine-sensitive
(see uncomplicated malaria sections above for chloroquine-sensitive species by region)
Chloroquine phosphate: Treatment as above
Chloroquine resistant P. falciparum
(see sections above for regions with chloroquine resistant P. falciparum)
Quinine sulfate plus Clindamycin
Quinine sulfate: Treatment as above
Clindamycin: Treatment as above
Chloroquine-resistant P. vivax
(see uncomplicated malaria sections above for regions with chloroquine-resistant P. vivax)
Quinine sulfate
Quinine sulfate: 648 mg po tid x 7 days; supplied as 324 mg tablets
Severe malaria7, 8 All regions

Quinidine gluconate8 plus one of the following: Doxycycline or Clindamycin
Quinidine gluconate: 10 mg /kg loading dose IV over 1-2 hrs, then 0.02 mg /kg/min continuous infusion for at least 24 hours. An alternative regimen is 24 mg /kg loading dose IV infused over 4 hours, followed by 12 mg /kg) infused over 4 hours every 8 hours, starting 8 hours after the loading dose (see package insert). Once parasite density <1% and patient can take oral medication, complete treatment with oral quinine, dose as above. Quinidine/quinine course = 7 days in Southeast Asia; = 3 days in Africa or South America. Quinidine gluconate for IV injection is supplied at 80 mg/ml concentration.

Quinidine
Contraindications Comments Preg Category

2nd or 3rd degree heart block without pacemaker

drugs prolonging QT interval

Must be given in monitored setting C


Doxycycline: Treatment as above. If patient not able to take oral medication, give 100 mg IV every 12 hours and then switch to oral doxycycline (as above) as soon as patient can take oral medication. For IV use, avoid rapid administration. Treatment course = 7 days.


Clindamycin: Treatment as above. If patient not able to take oral medication, give 10 mg /kg loading dose IV followed by 5 mg /kg IV every 8 hours. Switch to oral clindamycin (oral dose as above) as soon as patient can take oral medication. For IV use, avoid rapid administration. Treatment course = 7 days.


Artesunate9 (contact CDC for information (770) 488-7788 Monday-Friday 8 am to 4:30 pm EST, (770) 488-7100 after hours, weekends and holidays):
Artesunate followed by one of the following: Atovaquone-proguanil (Malarone™), or Doxycycline (Clindamycin in pregnant women)

1 Take artemether/lumefantrine with with food or whole milk. If patient vomits within 30 minutes of taking a dose, then they should repeat the dose.

2Primaquine is used to eradicate any hypnozoites that may remain dormant in the liver, and thus prevent relapses, in P. vivax and P. ovale infections. Because primaquine can cause hemolytic anemia in G6PD-deficient persons, G6PD screening must occur prior to starting treatment with primaquine. For persons with borderline G6PD deficiency or as an alternate to the above regimen, primaquine may be given 45 mg orally one time per week for 8 weeks; consultation with an expert in infectious disease and/or tropical medicine is advised if this alternative regimen is considered in G6PD-deficient persons. Primaquine must not be used during pregnancy.

3There are two options (A or B) available for treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax. High treatment failure rates due to chloroquine-resistant P. vivax have been well documented in Papua New Guinea and Indonesia. Rare case reports of chloroquine-resistant P. vivax have also been documented in Burma (Myanmar), India, and Central and South America. Persons acquiring P. vivax infections outside of Papua New Guinea or Indonesia should be started on chloroquine. If the patient does not respond, the treatment should be changed to a chloroquine-resistant P. vivax regimen and CDC should be notified (Malaria Hotline number (770) 488-7788 Monday-Friday 8 am to 4:30 pm EST  (770) 488-7100 after hours, weekends and holidays). For treatment of chloroquine-resistant P. vivax infections, options A or B are equally recommended.

4US manufactured quinine sulfate capsule is in a 324mg dosage; therefore 2 capsules should be sufficient for each adult dose.

5For infections acquired in Southeast Asia, quinine treatment should continue for 7 days. For infections acquired elsewhere, quinine treatment should continue for 3 days.

6For pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. falciparum or chloroquine-resistant P. vivax infection, treatment with doxycycline or tetracycline is generally not indicated. However, doxycycline or tetracycline may be used in combination with quinine (as recommended for non-pregnant adults) if other treatment options are not available or are not being tolerated, and the benefit is judged to outweigh the risks.
Atovaquone-proguanil and artemether-lumefantrine are generally not recommended for use in pregnant women, particularly in the first trimester due to lack of sufficient safety data. For pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. falciparum infection, atovaquone-proguanil or artemether-lumefantrine may be used if other treatment options are not available or are not being tolerated, and if the potential benefit is judged to outweigh the potential risks.
For P. vivax and P. ovale infections, primaquine phosphate for radical treatment of hypnozoites should not be given during pregnancy. Pregnant patients with P. vivax and P. ovale infections should be maintained on chloroquine prophylaxis for the duration of their pregnancy. The chemoprophylactic dose of chloroquine phosphate is 300 mg base (=500 mg salt) orally once per week. After delivery, pregnant patients who do not have G6PD deficiency should be treated with primaquine.

7Persons with a positive blood smear OR history of recent possible exposure and no other recognized pathology who have one or more of the following clinical criteria (impaired consciousness/coma, severe normocytic anemia, renal failure, pulmonary edema, acute respiratory distress syndrome, circulatory shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, repeated generalized convulsions, and/or parasitemia of > 5%) are considered to have manifestations of more severe disease. Severe malaria is most often caused by P. falciparum. The WHO definition differs slightly and is shown below.
Consider exchange transfusion if the parasite density (i.e. parasitemia) is > 10% OR if the patient has altered mental status, non-volume overload pulmonary edema, or renal complications. The parasite density should be monitored every 12 hours. Exchange transfusion should be continued until the parasite density is <1% (usually requires 8-10 units). IV quinidine administration should not be delayed for an exchange transfusion and can be given concurrently throughout the exchange transfusion.
Pregnant women diagnosed with severe malaria should be treated aggressively with parenteral antimalarial therapy.

8 Patients diagnosed with severe malaria should be treated aggressively with parenteral antimalarial therapy. Treatment with IV quinidine should be initiated as soon as possible after the diagnosis has been made. Patients with severe malaria should be given an intravenous loading dose of quinidine unless they have received more than 40 mg/kg of quinine in the preceding 48 hours or if they have received mefloquine within the preceding 12 hours. Consultation with a cardiologist and a physician with experience treating malaria is advised when treating malaria patients with quinidine. During administration of quinidine, blood pressure monitoring (for hypotension) and cardiac monitoring (for widening of the QRS complex and/or lengthening of the QTc interval) should be monitored continuously and blood glucose (for hypoglycemia) should be monitored periodically. Cardiac complications, if severe, may warrant temporary discontinuation of the drug or slowing of the intravenous infusion.

9Intravenous artesunate has been shown to be superior to quinine treatment for severe P. falciparum malaria. This is available only from CDC. Request artesunate for every severe case of P. falciparum malaria ASAP. Do not delay quinidine therapy while waiting for arrival of the artesunate.

WHO Definitions of Uncomplicated and Severe Malaria
Uncomplicated malaria
Uncomplicated malaria is defined as symptomatic malaria without signs of severity or
evidence (clinical or laboratory) of vital organ dysfunction. The signs and symptoms of
uncomplicated malaria are nonspecific. Malaria is, therefore, suspected clinically mostly
on the basis of fever or a history of fever.

Complicated or severe malaria

Presence of one or more of the following features qualifies as severe malaria

Clinical features
– impaired consciousness or unrousable coma
– prostration, i.e. generalized weakness so that the patient is unable walk
or sit up without assistance
– failure to feed
– multiple convulsions – more than two episodes in 24 h
– deep breathing, respiratory distress (acidotic breathing)
– circulatory collapse or shock, systolic blood pressure < 70 mm Hg in adults
and < 50 mm Hg in children
– clinical jaundice plus evidence of other vital organ dysfunction
– haemoglobinuria
– abnormal spontaneous bleeding
– pulmonary oedema (radiological)
Laboratory features
– hypoglycaemia (blood glucose < 2.2 mmol/l or < 40 mg/dl)
– metabolic acidosis (plasma bicarbonate < 15 mmol/l)
– severe normocytic anaemia (Hb < 5 g/dl, packed cell volume < 15%)
– haemoglobinuria
– hyperparasitaemia (> 2%/100 000/μl in low intensity transmission areas or > 5%
or 250 000/μl in areas of high stable malaria transmission intensity)
– hyperlactataemia (lactate > 5 mmol/l)
– renal impairment (serum creatinine > 265 μmol/l)
Drug Summaries from the WHO Malaria Treatment Guide

Artemether
Molecular weight: 298.4

Artemether is the methyl ether of dihydroartemisinin. It is more lipid soluble than artemisinin or artesunate. It can be given as an oil-based intramuscular injection or orally. It is also coformulated with lumefantrine (previously referred to as benflumetol) for combination therapy.

Formulations
intramuscular injection containing 80 mg of artemether in 1 ml for adults or 40 mg of artemether in 1 ml for paediatric use. In a coformulation with lumefantrine:artemether and 120 mg of lumefantrine.

Pharmacokinetics
Peak plasma concentrations occur around 2–3 h after oral administration. Following 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. Artemether is metabolized to dihydroartemisinin, the active metabolite. After intramuscular administration, artemether predominates, whereas after oral administration dihydroartemisinin predominates. Biotransformation is mediated via the cytochrome P450 enzyme CYP3A4. Autoinduction of metabolism is less than with artemisinin. Artemether is 95% bound to plasma proteins. The elimination half-life is approximately 1 h, but following intramuscular administration the elimination phase is prolonged because of continued absorption. No dose modifications are necessary in renal or hepatic impairment.

Toxicity
In all species of animals tested, intramuscular artemether and artemotil cause an unusual selective pattern of neuronal damage to certain brain stem nuclei. Neurotoxicity in experimental animals is related to the sustained blood concentrations that follow intramuscular administration, since it is much less frequent when the same doses are given orally, or with similar doses of water-soluble drugs such as artesunate. Clinical, neurophysiological and pathological studies in humans have not shown similar findings with therapeutic use of these compounds. Toxicity is otherwise similar to that of artemisinin (see below).

Artemisin Toxicity
Artemisinin and its derivatives are safe and remarkably well tolerated. There have been reports of mild gastrointestinal disturbances, dizziness, tinnitus, reticulocytopenia, neutropenia, elevated liver enzyme values, and electrocardiographic abnormalities, including bradycardia and prolongation of the QT interval, although most studies have not found any electrocardiographic abnormalities. The only potentially serious adverse effect been reported with this class of drugs is type 1 hypersensitivity reactions in approximately 1 in 3000 patients. Neurotoxicity has been reported in animal studies, particularly with very high doses of intramuscular artemotil and artemether, but has not been substantiated in humans. Similarly, evidence of death of embryos and morphological abnormalities in early pregnancy have been demonstrated in animal studies. Artemisinin has not been evaluated in the first trimester of pregnancy so should be avoided in first trimester patients with uncomplicated malaria until more information is available.


Drug interactions
None known.

Artesunate
Molecular weight: 384.4

Artesunate is the sodium salt of the hemisuccinate 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. There are no coformulations currently available.


Formulations
intramuscular or intravenous injection containing 60 mg of anhydrous artesunaic acid with a separate ampoule of 5% sodium bicarbonate solution.artesunate.

Pharmacokinetics
Artesunate is rapidly absorbed, with peak plasma levels occurring 1.5 h, 2 h and 0.5 h after oral, rectal and intramuscular administration, respectively. It is almost entirely converted to dihydroartemisinin, the active metabolite. Elimination of artesunate is very rapid, and antimalarial activity is determined by dihydroartemisinin elimination (half-life approximately 45 min). The extent of protein binding is unknown. No dose modifications are necessary in renal or hepatic impairment.


Toxicity
As for artemisinin.


Drug interactions
None known.

Atovaquone
Molecular weight: 366.8

Atovaquone is a hydroxynaphthoquinone antiparasitic drug active against all Plasmodium species. It also inhibits pre-erythrocytic development in the liver, and oocyst development in the mosquito. It is combined with proguanil for the treatment of malaria – with which it is synergistic. Atovaquone interferes with cytochrome electron transport.


Formulations
Atovaquone is available for the treatment of malaria in a coformulation with proguanil.atovaquone and 100 mg of proguanil hydrochloride for adults.atovaquone and 25 mg of proguanil hydrochloride for paediatric use.

Pharmacokinetics
Atovaquone is poorly absorbed from the gastrointestinal tract but bioavailability following oral administration can be improved by taking the drug with fatty foods. Bioavailabillity is reduced in patients with AIDS. Atovaquone is 99% bound to plasma proteins and has a plasma half-life of around 66–70 h due to enterohepatic recycling. It is excreted almost exclusively in the faeces as unchanged drug. Plasma concentrations are significantly reduced in late pregnancy.


Toxicity
Atovaquone is generally very well tolerated. Skin rashes, headache, fever, insomnia, nausea, diarrhoea, vomiting, raised liver enzymes, hyponatraemia and, very rarely, haematological disturbances, such as anaemia and neutropenia, have all been reported.


Drug interactions
Reduced plasma concentrations may occur with concomitant administration of metoclopramide, tetracycline and possibly also acyclovir, antidiarrhoeal drugs, benzodiazepines, cephalosporins, laxatives, opioids and paracetamol. Atovaquone decreases the metabolism of zidovudine and cotrimoxazole. Theoretically, it may displace other highly protein-bound drugs from plasma-protein binding sites.

Chloroquine
Molecular weight: 436.0

Chloroquine is a 4-aminoquinoline which 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 maintains considerable efficacy for the treatment of P. vivax, P. ovale and P. malariae infections. As with other 4-aminoquinolines, it does not produce radical cure.


Chloroquine interferes with parasite haem detoxification (1, 2). 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.


Formulations
chloroquine base as phosphate or sulfate.


Pharmacokinetics
Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract when taken orally, although peak plasma concentrations can vary considerably. Absorption is also very rapid following intramuscular and subcutaneous administration. Chloroquine is extensively distributed into body tissues, including the placenta and breast milk, and has an enormous total apparent volume of distribution. The relatively small volume of distribution of the central compartment means that transiently cardiotoxic levels may occur following intravenous administration unless the rate of parenteral delivery is strictly controlled. 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.


Toxicity
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 the former. The drug is generally well tolerated. 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. 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. 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 loss, convulsions, hypokalaemia, hypotension and cardiac arrhythmias. There is no specific treatment, although diazepam and epinephrine (adrenaline) administered together are beneficial.


Drug interactions
Major interactions are very usual. 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.

Clindamycin
Molecular weight: 425.0

Clindamycin is a lincosamide antibiotic, i.e. a chlorinated derivative of lincomycin. It is very soluble in water. It inhibits the early stages of protein synthesis by a mechanism similar to that of the macrolides. It may be administered by mouth as capsules containing the hydrochloride or as oral liquid preparations containing the palmitate hydrochloride. Clindamycin is given parenterally as the phosphate either by the intramuscular or the intravenous route. It is used for the treatment of anaerobic and Gram-positive bacterial infections, babesiosis, toxoplasmosis and Pneumocystis carinii pneumonia.


Formulations
clindamycin base as hydrochloride.


Pharmacokinetics
About 90% of a dose is absorbed following oral administration. Food does not impede absorption but may delay it. Clindamycin phosphate and palmitate hydrochloride are rapidly hydrolysed to form the free drug. Peak concentrations may be reached within 1 h in children and 3 h in adults. It is widely distributed, although not into the cerebrospinal fluid. It crosses the placenta and appears in breast milk. It is 90% bound to plasma proteins and accumulates in leukocytes, macrophages and bile. The half-life is 2–3 h but this may be prolonged in neonates and patients with renal impairment. Clindamycin undergoes metabolism to the active N-demethyl and sulfoxide metabolites, and also some inactive metabolites. About 10% of a dose is excreted in the urine as active drug or metabolites and about 4% in the faeces. The remainder is excreted as inactive metabolites. Excretion is slow and takes place over many days. Clindamycin is not effectively removed from the body by dialysis.


Toxicity
Diarrhoea occurs in 2–20% of patients. In some, pseudomembranous colitis may develop during or after treatment, which can be fatal. Other reported gastrointestinal effects include nausea, vomiting, abdominal pain and an unpleasant taste in the mouth. Around 10% of patients develop a hypersensitivity reaction. This may take the form of skin rash, urticaria or anaphylaxis. Other adverse effects include leukopenia, agranulocytosis, eosinophilia, thrombocytopenia, erythema multiforme, polyarthritis, jaundice and hepatic damage. Some parenteral formulations contain benzyl alcohol, which may cause fatal “gasping syndrome” in neonates.


Drug interactions
Clindamycin may enhance the effects of drugs with neuromuscular blocking activity and there is a potential danger of respiratory depression. Additive respiratory depressant effects may also occur with opioids. Clindamycin may antagonize the activity of parasympathomimetics.

Doxycycline
Molecular weight: 444.4

Doxycycline is a tetracycline derivative with uses similar to those of tetracycline. It may be preferred to tetracycline because of its longer halflife, 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.


Formulations
doxycycline salt as hydrochloride.


Pharmacokinetics
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 halflife is 10–24 h. It is widely distributed in body tissues and fluids. In patients with normal renal function, 40% of doxycycline is excreted in the urine, although more if the urine is alkalinized. It may accumulate in renal failure. However, the majority of the dose is excreted in the faeces.


Toxicity
As for tetracycline. Gastrointestinal effects are fewer than with tetracycline, although oesophageal ulceration can still be a problem if insufficient water is taken with tablets or capsules. There is less accumulation in patients with renal impairment. Doxycycline should not be given to pregnant or lactating women, or children aged up to 8 years.

Tetracycline toxicityAll the 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. Tetracyclines accumulate in patients with renal impairment and this may renal failure. In contrast doxycycline accumulates less and is preferred in patient with renal impairment. The use of out-of-date tetracycline can result in the development of a reversible Fanconitype 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 bone and the nails and interfere with bone growth in young infants or pregnant women. Raised intracranial pressure in adults and infants has also been documented. Tetracyclines use in pregnancy has also been associated with acute fatty liver. Tetracyclines should therefore not be given to pregnant or lactating women, or children aged up to 8 years. 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.


Drug interactions
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.

Lumefantrine (benflumetol)
Molecular weight: 528.9

Lumefantrine belongs to the aryl aminoalcohol group of antimalarials, which also includes quinine, mefloquine and halofantrine. It has a similar mechanism of action. Lumefantrine is a racemic fluorine derivative developed in China. It is only available in an oral preparation coformulated with artemether. This ACT is highly effective against multidrug resistant P. falciparum.


Formulations
Available only in an oral preparation coformulated with artemether. artemether and 120 mg of lumefantrine.


Pharmacokinetics
Oral bioavailability is variable and is highly dependant on administration with fatty foods. 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.


Toxicity
Despite similarities with the structure and pharmacokinetic properties of halofantrine, lumefantrine does not significantly prolong the electrocardiographic QT interval, and has no other significant toxicity (50). 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.


Drug interactions
The manufacturer of artemether-lumefantrine recommends avoiding the following: grapefruit juice; antiarrhythmics, such as amiodarone, disopyramide, flecainide, procainamide and quinidine; antibacterials, such as macrolides and quinolones; all antidepressants; antifungals such as imidazoles and triazoles; terfenadine; other antimalarials; all antipsychotic drugs; and beta blockers, such as metoprolol and sotalol. However, there is no evidence that coadministration with these drugs would be harmful.

Primaquine
Molecular weight: 259.4


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 stages activity against P. vivax (and some against asexual stages of P. falciparum). The mechanism of action is unknown.


Formulations
primaquine base as diphosphate.


Pharmacokinetics
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. 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.

Toxicity
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. 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.


Drug interactions
Drugs liable to increase the risk of haemolysis or bone marrow suppression should be avoided.

Proguanil
Molecular weight: 253.7

Proguanil is a biguanide compound that is metabolized in the body via the polymorphic cytochrome P450 enzyme CYP2C19 to the active metabolite, cycloguanil. Approximately 3% of Caucasian and African populations and 20% of Oriental people are “poor metabolizers” and have considerably reduced biotransformation of proguanil to cycloguanil (55,56). Cycloguanil inhibits plasmodial dihydrofolate reductase. The parent compound has weak intrinsic antimalarial activity through an unknown mechanism. It is possibly active against pre-erythrocytic forms of the parasite and is a slow blood schizontocide. Proguanil also has sporontocidal activity, rendering the gametocytes non-infective to the mosquito vector. Proguanil is given as the hydrochloride salt in combination with atovaquone. It is not used alone for treatment as resistance to proguanil develops very quickly. Cycloguanil was formerly administered as an oily suspension of the embonate by intramuscular injection.


Formulations
proguanil hydrochloride containing 87 mg of proguanil base. In coformulation with atovaquone: atovaquone and 100 mg of proguanil hydrochloride for adults.atovaquone and 25 mg of proguanil hydrochloride for paediatric use.


Pharmacokinetics
Proguanil is readily absorbed from the gastrointestinal tract following oral administration. Peak plasma levels occur at about 4 h, and are reduced in the third trimester of pregnancy. Around 75% is bound to plasma proteins. Proguanil is metabolized in the liver to the active antifolate metabolite, cycloguanil, and peak plasma levels of cycloguanil occur an hour after those of the parent drug. The elimination half-lives of both proguanil and cycloguanil is approximately 20 h. Elimination is about 50% in the urine, of which 60% is unchanged drug and 30% cycloguanil, and a further amount is excreted in the faeces. Small amounts are present in breast milk. The elimination of cycloguanil is determined by that of the parent compound. The biotransformation of proguanil to cycloguanil via CYP2C19 is reduced in pregnancy and women taking the oral contraceptive pill.


Toxicity
Apart from mild gastric intolerance, diarrhoea and occasional aphthous ulceration and hair loss there are few adverse effects associated with usual doses of proguanil hydrochloride. Haematological changes (megaloblastic anaemia and pancytopenia) have been reported in patients with severe renal impairment. Overdosage may produce epigastric discomfort, vomiting and haematuria. Proguanil should be used cautiously in patients with renal impairment and the dose reduced according to the degree of impairment.


Drug interactions
Interactions may occur with concomitant administration of warfarin. Absorption of proguanil is reduced with concomitant administration of magnesium trisilicate.

Quinine
Molecular weight: 324.4

Quinine is an alkaloid derived from the bark of the Cinchona tree. Four antimalarial 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 antimalarials, 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 antimalarial actions are thought to involve inhibition of parasite haem detoxification in the food vacuole, but are not well understood.


Formulations
quinine hydrochloride, quinine dihydrochloride, quinine sulfate and quinine bisulfate containing 82%, 82%, 82.6% and 59.2% quinine base respectively.quinine hydrochloride, quinine dihydrochloride and quinine sulfate containing 82%, 82% and 82.6% quinine base respectively.


Pharmacokinetics
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. In children under 2 years of age with severe malaria, concentrations are slightly higher than in older children and adults (63). 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 sulfate or bisulfate (64). It is well absorbed after intramuscular injection in severe malaria. Plasma-protein binding, mainly to alpha 1-acid glycoprotein, is 70% in healthy subjects but rises to around 90% in patients with malaria. 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. Extensive metabolism via the cytochrome P450 enzyme CYP3A4 occurs in the liver and elimination of more polar metabolites is mainly renal . The initial metabolite 3-hydroxyquinine contributes approximately 10% of the antimalarial activity of the parent compound, but may accumulate in renal failure. 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. Small amounts appear in the bile and saliva.


Toxicity
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. 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 . The most important adverse effect in the treatment of severe malaria is hyperinsulinaemic hypoglycaemia. This is particularly common in pregnancy (50% of quinine-treated women with severe malaria in late pregnancy). 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. 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. 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.


Drug interactions
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 marked QT prolongation, should be avoided but combination with other antimalarials, 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 (77).

 

10/19/2010 (ver 5) P. Edelstein and S. Gluckman; updated 6/22/12 PE