Introduction 1 2. Objectives 2 3. Parasite species 2 4. Risk groups 2 5. Clinical presentation and diagnosis 3 5.1 Symptoms and signs 3 5.2 Laboratory diagnosis 5 5.2 Referral criteria 6 6. Treatment 8 6.
Drugs used in the treatment of Plasmodium falciparum malaria 11 6.1.3.1 Artemisinin-based combination therapy 11 6.1.3.
Treatments not recommended for falciparum malaria 13 6.2 Treatment of non-Plasmodium falciparum infections 14 6.3 Treatment of mixed Plasmodium species infections 15 6.
Management of severe malaria in pregnancy 17 6.
Managing severe malaria in young children 19 6.
Severe malaria 22 7.1 Features indicating severe malaria 22 7.2 Treatment 24 7.3 Chemotherapy 24 7.4 Loading doses 25 7.5 Maintenance doses 25 7.6 Other chemotherapeutic options 26 7.7 General management pf severe malaria 26 7.
Splenic rupture 35 8. References 37 9. Dosage guidelines for the treatment of malaria 42 10. Summary of malaria treatment guidelines 45 11.
Considerable success has been achieved in the control andmanagement of malaria in South Africa in recent years. This is despite the ongoing development of parasite and vector resistance to drugs and insecticides, respectively.
It gives me great pleasure to introduce these guidelines on the treatment of malaria in South Africa.
The objectives of these publications are to provide all those involved in the management of malaria with clear and practical guidelines for the diagnosis and appropriate treatment of malaria.
The intended treatment outcomes are the prevention of malaria morbidity and mortality. In addition the recommendations are intended to contribute to a reduced malaria transmission and tolimit resistance to anti-malarial drugs.
These guidelines are based on the World Health Organization's guidelines for the treatment of malaria. Additional literature surveyshave been undertaken. Factors that were considered in the choice of therapeutic options included: effectiveness, safety, and impact on malaria transmission and on the emergence andspread of anti-malarial resistance.
The previous guidelines were compiled in August 2002. Advances in the availability of antimalarial drugs and changes in respect of transmission, intensity, drug resistance and health care delivery in South Africa have prompted revision of these guidelines.
It is hoped these guidelines will facilitate effective, appropriate and timeous treatment of malaria, thereby reducing the burden of this disease in our communities and in South Africa.
initiated these revised treatment guidelines. Without the contribution of the key persons mentioned below, these updated guidelines would not have become a reality.
Moonasar (CDC), Ms Tsakani Furumele (CDC), Dr. Eunice Misiani (CDC), Dr. Frew Benson
Furthermore, I would like to express my gratitude to those persons who reviewed the guidelines.
Department of Clinical Pharmacology, University of Cape Town.
Plasmodium falciparum accounts for the majority of malaria cases in Southern Africa and may be associated with severe and fatal disease. Almost all South Africans are nonimmune, including residents of seasonalmalaria transmission areas, and are therefore at risk for developing severe malaria.
The diagnosis and management of malaria is urgent. Delayed diagnosis and inappropriate treatment are associated with significantly increased morbidity and mortality. Classically, malaria presents with fever, rigors, headache and body pains, but the clinical features are non-specific and may be confused with many other diseases, especially influenza. A definitive diagnosis should be made promptly bydemonstrating the parasite on microscopy of a blood smear or by using a rapid malariaantigen test.
The choice of anti-malarial agents is dependent on the severity of illness and the pattern of drug resistance of the parasite in the geographical area where malaria wasacquired. In keeping with the WHO recommendations, using anti-malarial drugs in combination is essential, and artemisinin-based combinations are preferred. For uncomplicated malaria acquired in South Africa, artemether-lumefantrine (Coartem®) or alternatively quinine plus either doxycycline or clindamycin is recommended. High-level resistance precludes the use of chloroquine for falciparum malaria. Sulfadoxinepyrimethamine (SP) is no longer recommended.
For severe malaria, quinine (with the addition of doxycycline or clindamycin) is currently recommended. Patients with severe malaria will require hospital admission. All patients with malaria require careful clinical and parasitological follow-up. The major complications of malaria include: cerebral malaria, hypoglycaemia, anaemia, renal failure, acute respiratory distress syndrome (ARDS) and metabolic acidosis, and these carry high mortality rates especially in children, pregnant woman and in those living with HIV and AIDS. These complications require specificmanagement.
This material is intended for use by healthcare professionals. It has been compiled from information currently available, and although the greatest care has been taken the Department ofHealth and its Malaria Advisory Groupdo notaccept responsibilityfor errors or omissions. Readers are referred to the reference articles for further information and should exercise their own professional judgement in confirming and interpreting the findings presented in the publication. These guidelines were issued in 2008 by the National Department of Health, and replace all previousguidelines.
U ncomplicated P.
Add clindamycin ordoxycycline as soon as can be tolerated after quinine is started. C lindamycin is preferred in children <8 years and pregnantwomen.
* If unsure of species, treat as for P. falciparum. If mixed infection of P. falciparum plus P. vivax / ovale, treat as for P.
P. ovale or P.
P. falciparum, has necessitated ongoing updates of chemoprophylaxis and treatment policies globally.
In South Africa, chloroquine resistance was first demonstrated in KwaZulu-Natal (KZN), and later in Mpumalanga. This prompted a policy change from chloroquine to sulphadoxine-pyrimethamine (SP) as first line treatment for uncomplicated malaria in KZN in 1988 and in Mpumalanga and Limpopo provinces in 1997.
The development of significant SP resistance in KZN led to a further policy change in 2001, with artemether-lumefantrine replacing SP as first line treatment for uncomplicated P. falciparum infections. Subsequently, in December 2004, Limpopo Province also replaced SP with artemether-lumefantrine. Mpumalanga Province used SP-artesunate in the public sector from 2001 to end of 2005, but moved to an artemether-lumefantrine policy in January 2006.
In order to combat the pattern of continued drug resistance of sequential single drug therapy, combination chemotherapy, preferably using an artemisinin derivative, is the decided policy. Additional benefits include improved treatment outcomes and a decrease in malaria transmission, resulting in greater costeffectiveness.
These guidelines have been compiled using both international and local information. In South Africa there is ongoing monitoring of malaria prevalence and distribution, and the therapeutic efficacy of anti-malarial drugs. New information arising from suchmonitoring activities will inform future guidelines.
More than 90% of human malaria infections in sub-Saharan Africa are due to Plasmodium falciparum while the rest are due to Plasmodium ovale, Plasmodium vivax, or Plasmodium malariae. Occasionally mixed infections occur. Infections due to P. falciparum may be severe and complicated. These complications occur almost invariably as a result of delay in diagnosis and/or treatment of an uncomplicated infection, the use of ineffective therapy or under dosing with effective drugs.
South Africans are non-immune, including residents in areas where malaria transmission occurs. Partial immunity may be acquired after long-term, repeated exposure to P. falciparum infection, a situation that occurs in residents of high transmission areas, such as parts of Mozambique, Malawi, Tanzania and some other southern African countries.
Particular high-risk groups for the development of severe P. falciparum malaria in South Africa include: non-immune travellers to malaria areas and residents (of all age groups) in malaria areas. Pregnant women, young children, the elderly, splenectomised and immuno-compromised individuals are particularly vulnerable.
There is increasing data on the interaction between HIV and malaria, showing increased clinical attacks of malaria and higher parasite densities in semiimmune adults who are HIV infected. There is also evidence that non-immune patients co-infected with HIV have a higher risk of severe malaria and malariarelated mortality.
A high index of suspicion is the most important element in the diagnosis of malaria. Malaria areas in South Africa include north-eastern KwaZulu-Natal, and low altitude areas of Mpumalanga and Limpopo provinces, particularly those bordering Zimbabwe, Mozambique and Swaziland (see map). Very rarely, malaria is contracted in the North-West and Northern Cape provinces adjacent to the Molopo and Orange rivers respectively.
Malaria transmission occurs in almost all countries in sub-Saharan Africa with the exception of Lesotho. Within each country, geographical distribution of malaria will vary, and year-round transmission with seasonal disease peaks is usual. In southern Africa these peaks are typically from September to May.
Symptoms and signs of malaria may present as early as 7 days after exposure, with an average of 10 - 21 days elapsing after being bitten by an infected mosquito. Longer incubation periods may occur in patients who have been on chemoprophylaxis or selected antibiotics e.g. cotrimoxazole, tetracycline, macrolides, chloramphenicol and quinolones.
P. falciparum of 6 -18 months have been recorded. Malaria due to infections with P. vivax, P. ovale or P. malariae can take up to 12 months to first manifest clinically.
As signs and symptoms of malaria are very non-specific, a high index of suspicion is critical.
Presentation of P. falciparum malaria is very variable and may mimic many other diseases (and vice versa) including influenza, viral hepatitis, meningitis, septicaemia, typhoid, tick bite fever, gastroenteritis, viral haemorrhagic fever, trypanosomiasis, HIV seroconversion illness, urinary tract infection and relapsing fever.
Non-immune patients with uncomplicated malaria are at increased risk ofdisease progression to severe P. falciparum malaria. Life-threatening complications can develop rapidly in these patients. Malaria should be suspected in any person presenting with any of the above symptoms who has a history of travel to, or residence in, a malaria transmission area (See malaria risk map).
In a febrile patient in South Africa where there is no other obvious cause of fever and a recent history of visiting or living in a malaria area is not forthcoming, malaria should still be considered as infected mosquitoes have been occasionally documented to travel long distances by road, rail and air transport.
A diagnosis of malaria cannot be confirmed or excluded clinically. Since the clinical presentation is non-specific and may mimic many other diseases, patient's blood should be examined immediately to confirm or exclude the diagnosis. A blood test for parasites should be done irrespective of the time of the year or whether the patient has or has not taken chemoprophylaxis.
In the majority of malaria cases, examination of correctly stained blood smears will reveal malaria parasites. However, a negative smear does not exclude the diagnosis; repeat specimens should be examined regularly and urgently without waiting for fever peaks, until the diagnosis is confirmed, the patient has recovered or another definitive diagnosis is made. Examination of the peripheral blood smear will give an indication of the species of parasite as well as the parasite density. High levels of parasitaemia (>4% or â¥3+)* should be treated as severe malaria in non-immune patients. Importantly, the converse may not be true, with severe disease also occurring with low parasitaemias in the peripheral blood.
7.1: Severe malaria.
A number of commercial rapid diagnostic tests (RDTs) are available for early diagnosis in health facilities where microscopy is not immediately available.
The parasite density refers to the parasite load in the peripheral blood expressed semi-quantitatively (1 to 5+) or as a percentage of infected red blood cells. Quantification is often inaccurate and does not necessarily reflect the total parasite load in the patient.
dehydrogenase or aldolase. The majority of the tests will only detect P. falciparum; while a few will detect the other malaria species but are lesssensitive for these. The rapid tests for P. falciparum are generally highly sensitive. Performance is, however, dependent on the correct storage, usage and interpretation of results and the quality of the particular test used. These tests should be used only for diagnosis of acute malaria infections, and not for followup, as they may remain positive for several weeks even after successful treatment. The test may be negative early in the disease, and false positives may be encountered rarely.
If the diagnosis of malaria cannot be confirmed (unavailability of laboratory tests, or negative tests), the decision to commence malaria therapyshould bemade on clinical grounds, based on whether exposure to malaria parasites was possible and the severity of the clinical features. In cases of severe malaria a blood smear or rapid malaria test is likely to be positive. However, some patients with severe malaria may rarely have a negative smear due to sequestration of parasitized red blood cells. In patients who are treated empirically for malaria, it is imperative to continue to look for alternative diagnoses and to follow-up patients very carefully.
Thrombocytopenia is a common finding in patients with malaria. A blood smear should be checked for malaria parasites or an RDT performed whenever this laboratory finding is made unexpectedly. A malaria smear is indicated in patients with recurrent symptoms and a negative RDT, to exclude non-falciparum malaria.
Ideally all patients with malaria should be treated in hospital.
o Respiratory distress o Shock o Suspected treatment failure (including reappearance of parasites within 6 weeks of treatment).
The notification of all malaria cases is mandatory.
Healthcare worker (not necessarily a medical doctor): Diagnose (preferably a definitive diagnosis) and notify the malaria case using GW17/5 or applicable notification form, immediately, as some of the important information required on the notification form may not be available after the patient has left the healthcare facility. If possible, the malaria species should be specified in the notification form.
Local authority/hospital/district (whoever is responsible for disease containment) submits the GW17/3 summary of cases and GW17/4 summary of deaths forms weekly.
Regional/district office health information unit will collate and use this information to plan and monitor the impact of malaria control and case management interventions.
Africa each year, it is critical that these cases also get notified to the local authority to facilitate adequate provision of malaria diagnosis and management resources to healthcare facilities in these areas.
Patients should receive prompt treatment with the most effective regimen available. Where patients present in non-malaria areas, treatment should ideally be initiated in hospital. In malaria areas the majority of patients with uncomplicated malaria can be treated at primary health care level.
The choice of chemotherapy formalaria is dependenton theseverity of disease, the known or suspected resistance pattern of the parasite in the area where the malaria infection was acquired, the species of parasite, patient characteristics (age, pregnancy, co-morbidity, allergies, concomitant medications) and the presence or absence of vomiting.
Drug choices may change over time with the development of parasite resistance or the availability of new anti-malarial treatments.
It is important to attempt to differentiate between uncomplicated and severe malaria. Patients with uncomplicated malaria include: those who have mild symptoms, are ambulant and have no evidence of organ dysfunction either clinically or on laboratory tests and in whom the parasite count is less than 5% (see section 7: Severe malaria, for details). However, uncomplicated malaria may rapidly progress to severemalaria if the patient is not treated appropriately.
For patients with uncomplicated malaria, the recommended chemotherapy is the fixed dose artemisinin-based combination, artemether-lumefantrine (Coartem®) in all patients over 1 year of age and non-pregnant patients. In children â¤ 1 year and all pregnant patients, the recommended chemotherapy is quinine plus clindamycin.
When artemether-lumefantrine (Coartem®) is not available, uncomplicated malaria can also be treated with quinine plus either doxycycline or clindamycin. It is advisable that quinine only be used as observed treatment of inpatients, due to the possibility of adverse drug reactions and the poor tolerability of this 7-day regimen.
All first doses of drugs must be given under supervision and patients must be observed for at least an hour as vomiting is common in patients with malaria and treatment must be repeated if the patient vomits within the first hour. Vomiting oral treatment is one of the commonest reasons for treatment failure.
It is easy to underestimate the severity of disease and complications may arise despite apparent appropriate chemotherapy. Patients with malaria should be carefully assessed and closely monitored. The clinical and parasitological response of patients to treatment should be monitored regularly; in particular, the mental state, respiratory rate and urine output. Adequate fluids should be given, and antipyretics (paracetamol) administered when needed. Ibuprofen has been used but there is less experience with this compound. Other non-steroidal anti-inflammatory drugs (NSAIDS) should be avoided as they may increase the risk of renal failure in patients with malaria.
If patients with uncomplicated malaria cannot be admitted to hospital for treatment, they (or their caregivers)should be warned of the symptoms and signs of severe malaria and advised of the urgency of then returning for hospitalisation and appropriate treatment.
Patients should experience a clinical response to therapy within 24 -48 hours. A repeat peripheral blood smear should be performed where possible after 72 hours of treatment: a decrease of at least 75% of the initial parasite count is expected with effective treatment.
Relapse due to P. ovale or P. vivax due to failure to treat hypnozoites NOTE: On a malaria peripheral blood smear, the presence of gametocytes, the stage of malaria parasite's lifecycle responsible for malaria transmission, does not indicate treatment failure, as these may be present for several weeks after successful treatment.
Treatment failures after completing a full course current first-line therapy of either 7-days of quinine (plus doxycycline or clindamycin) or a 3-day artemetherlumefantrine regimen are rare, as both these treatments have very high cure rates. Patients who have failed first-line treatment with artemether-lumefantrine should then be given a course of quinine with either doxycycline or clindamycin. Treatment failures following quinine treatment of uncomplicated malaria could be treated with artemether-lumefantrine, provided malaria complications are carefully excluded.
Artemisinin-based combination therapies (ACTs) are now generally considered as the best current treatment for uncomplicated falciparum malaria (WHO 2006). ACTs have the advantages of rapid clinical and parasitological response, improved cure rate, decreased malaria transmission and the potential to delay anti-malarial resistance. A number of artemisinin derivatives have been used successfully in the treatment of P. falciparum malaria including multi-drug resistant malaria and for the blood stages of P. vivax infections. The most evidence of efficacy and safety is currently available for the derivatives artemether and artesunate. This class of anti-malarial has a favourable safety profile. When used as single-drug therapy (monotherapy) for less than 7 days recrudescence is common. Therefore the artemisinin derivatives should always be used in combination with an effective, longer-acting antimalarial. Combination therapy is essential for delaying development of resistance to this crucial class of drugs. The choice of the second drug will depend on resistance, cost, side effect profile and efficacy. The only artemisinin derivative currently registered in South Africa is the combination of artemether with lumefantrine (Coartem). In patients with severe malaria, parenteral artemisinins are effective and intravenous artesunate reduced malaria related deaths by 32%.
This fixed dose combination containing 20mg artemether plus lumefantrine 120mg is the recommended first line treatment for uncomplicated malaria in all malaria transmission areas in South Africa. It has the advantages of a shorter treatment course (6 doses over 3 days) and far better tolerability than the only effective alternative, quinine. However, its indication is limited to the treatment of uncomplicated malaria as there is no evidence of its efficacy in more severe disease. Artemether-lumefantrine is contra-indicated in pregnancy and in those patients who have a history of allergy to artemether or lumefantrine. Data in children less than 1 year of age is limited. Adequate absorption of the lumefantrine component is critically dependent on co-administration with food or drink containing 1.3 g of fat (e.g. 100 ml milk). This drug has been best studied in patients weighing less than 65 kg and thus is not yet registered for use in patients weighing greater than 65 kg, although initial results in this group are encouraging. As this is a relatively new drug, no drug interactions or contra-indications other than pregnancy and allergy have been identified. Adverse effects identified include: sleep disturbances, headaches, dizziness, palpitations, abdominal pain, anorexia, cough, arthralgia, myalgia, asthma and fatigue. Rarely, hypersensitivity reactions have been reported. Adverse events or potential drug interactions should be reported to the National Adverse Drug Event Monitoring Centre [021- 4486181 (fax) or 021- 4066234 (tel)].
Parenteral artemisinin derivatives, notably artemether and artesunate, have been successfully used for treating severe malaria. In a randomized controlled trial of severe malaria in adults living in areas of low malaria transmission in Asia, the death rate was one-third lower among the adults who received intravenous artesunate compared to those who received quinine. Patients treated with IV artesunate have a 1/20 to 1/11 better survival rate than those getting IV quinine. This is the first published study on severe malaria, which showed a clear difference in mortality between the two treatments. Artesunate is also easier to use and is not associated with hypoglycemia, which can be caused or exacerbated by quinine. Similar studies are now being conducted in children in Africa. Until these results are available, and an intravenous parenteral artesunate is registered in South Africa, quinine remains the recommended treatment for severe malaria in South Africa.
Quinine is a rapidly acting, effective anti-malarial drug used for both uncomplicated and severe malaria acquired in sub-Saharan Africa. Quinine resistance is rare in this area, although increasing slowly in Southeast Asia. Oral quinine therapy is an alternative option recommended in uncomplicated malaria but the initial doses of quinineshould be administered intravenously if the patient is vomiting repeatedly. Quinine therapy should be continued for 7-10 days. The addition of asecond, effective, anti-malarial drug, i.e. doxycycline or clindamycin, is indicated to ensure complete parasite clearance and improve cure rates. One of these agents should be added as soon as can be tolerated (usually 2 - 3 days after commencement of the quinine), to ensure that possible adverse effects from the quinine are not confused with those of the second agent. In patients less than 8 years old or during pregnancy, clindamycin should be used rather than doxycycline or other tetracyclines. Shortened courses of quinine (3 days) cannot be recommended for treatment. Patients initially treated for severe malaria with quinine should complete the course of treatment with the same drug, as completion of therapy initiated with quinine with a course of artemetherlumefantrine has not been adequately evaluated.
It is most important that patients (or caregivers) understand that it is essential to complete the course of 7-10 days of quinine (with doxycycline or clindamycin) as adherence with this poorly tolerated treatment is generally low. Minor adverse effects, causing a syndrome known as cinchonism, are frequent during the treatment of malaria with quinine. Mild hearing impairment (notably high tone deafness), tinnitus, headache, nausea and slight visual disturbances occur in up to 70% of patients during quinine therapy and are not an indication to discontinue therapy. Major side effects include arrhythmias, hypersensitivity and hypoglycaemia. Hypoglycaemia is the most frequent serious adverse reaction.
Quinine toxicity presents with central nervous system (CNS) disturbances (primarily visual and auditory) and cardiovascular abnormalities (hypo tension, heart block, ventricular arrhythmias), and can be confused with severe malaria. Cardio toxicity is particularly related to rapid infusion of quinine.
Treatments not recommended for falciparum malaria Monotherapies (anti-malarial agents used on their own) are no longer recommended for the treatment of falciparum malaria. Artemisinin derivatives should never be used as monotherapy as this could select for resistance and compromise the value of artemisinin-based combination treatments (ACTs); taking artemisinin monotherapies for less than 7 days is strongly associated with treatment failure (recrudescence of infection). Chloroquine is not recommended following the emergence of high-level resistance in most parts of the world including South Africa. Sulphadoxine-pyrimethamine is no longer recommended in South Africa, due to the availability of more effective combination therapy, coupled with high-level resistance in some parts of the country.
Mefloquine is registered only for prophylaxis but not treatment, given the higher incidence of severe psychiatric adverse effects associated with treatment doses. Halofantrine treatment is not advisable given the associated cardio toxicity, variable bioavailability and drug interactions in patients who have taken mefloquine prophylaxis. Clindamycin and doxycycline are slow acting antimalarials and should never be used as monotherapy, but are added to quinine treatment regimens to improve cure rates.
In sub-Saharan Africa, a minority of the malaria infections are due to one of the other Plasmodium species, namely P. vivax, P. ovale or P. malariae. Infections contracted in the Caribbean and some countries in Central America and the Middle East are mostly due to P. vivax. Generally, disease due to infection with the non-falciparum malarias is uncomplicated, although P. vivax has rarely caused severe malaria and P malariae may be associated with the nephrotic syndrome in children. The parasite species should be reliably confirmed microscopically.
P. falciparum should be administered. P. ovale and P. malariae are currently chloroquine-sensitive, but rare cases of chloroquine-resistant P. vivax have been documented in Oceania, Brazil, and Indonesia.
In South Africa P. ovale is the most common of the non-falciparum malarias. Anaemia may complicate chronic P. ovale infection.
P. malariae can be treated with chloroquine monotherapy, while the extra-hepatic phases of infections with P. vivax or P. ovale can be treated with chloroquine (or quinine or artemether-lumefantrine). For P. vivax or P. ovale a follow-up course of primaquine is essential to eradicate the residual hepatic phase to prevent relapse.
Primaquine must be given for 14 days at the recommended dosages. Primaquine is contra-indicated in children less than 1 year of age and during pregnancy. In pregnant women eradication of the hepatic stage must be delayed until after delivery. Patients with severe glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (<10% residual enzyme activity) should not receive primaquine due to the risk of severe haemolytic anaemia. There is no proven alternative for these patients, although continuing weekly prophylactic chloroquine (usually for 3 years) may be effective. Primaquine may be taken by patients with mild deficiency of G-6-PD (10 - 60% residual enzyme activity) at a reduced dose of 0.5 - 0.7 mg/kg body weight once every 7 days for 8 weeks. Such patients should be evaluated for anaemia and haemoglobinuria at 3, 7, and 10 days after the start of primaquine.
In patients with confirmed or suspected mixed infections i.e. P. falciparum with either P. vivax or P.
P. falciparum malaria (either quinine or artemether-lumefantrine) plus a follow-up course of primaquine is recommended. A mixed infection of P.
P. malariae should bemanaged as for P. falciparum malaria.
P. falciparum infection should dictate choice of initial therapy. Doubt frequently exists about the presence of P. falciparum in addition to other Plasmodium species. The patient should then be treated for P. falciparum, as this is the speciesmost frequently associated with severe infections and complications.
Pregnant women, particularly in the second and third trimesters of pregnancy, are more likely to develop severe malaria than other adults and have a higher malaria-related mortality rate. Malaria in pregnancy is particularly associated with complications such as cerebral malaria, hypoglycaemia, and pulmonary oedema/ARDS. In addition, maternal malaria increases the risk of spontaneous abortion, stillbirth, premature delivery, low birth weight (a leading cause of child mortality) and rarely, congenital malaria. Foetal distress may occur peripartum. The risk of severe malaria extends into the early postpartum period. It is important to carefully follow up pregnant women treated for malaria, and their infants, to promptly diagnose and adequately manage the known complications of malaria in pregnancy.
A high index of suspicion is the most important element in the diagnosis of malaria. Malaria is frequently missed or misdiagnosed in pregnancy and needs to be differentiated from complications of pregnancy e.g. intrauterine sepsis, eclampsia, or pyelonephritis, assigns and symptomsmay be similar.
Suspect malaria if the patient is resident in or has travelled to a malaria transmission area. A history of visiting a malaria transmission area should be explored in all pregnant women with fever. A malaria smear (repeated if initially negative) ormalaria antigen test is mandatory for any pregnantpatient with fever and a history of malaria exposure.
Fever is common, but may be absent in some cases.
It is important to attempt to differentiate between uncomplicated and severe malaria. However, uncomplicated malaria may progress rapidly to severe malaria in pregnancy if the patient is not treated urgently and appropriately.
Management of uncomplicated malaria in pregnancy The treatment of choice for uncomplicated malaria is quinine followed by a course of clindamycin. Doxycycline is contraindicated. Quinine has proved to be safe when used in normal therapeutic doses, and since the risks of malaria are great, there is no debate about using a less effective therapy. Quinine's main adverse effect in pregnancy is hypoglycaemia and patients should be closely monitored for this. Quinine may be oxytocic, but this effect may also be due to the malaria itself. The incidence of teratogenesis is unknown, although congenital abnormalities, notably CNS anomalies and limb defects have been occasionally reported with quinine use in the first trimester. With the doses used to treat malaria, the benefits of quinine therapy outweigh the risks.
Currently, the artemisinins are only recommended when no effective alternative anti-malarial is available. There is increasing experience with artemesinin derivatives in the 2nd and 3rd trimesters of pregnancy, and no adverse effects on the mother or human foetus have been documented to date. However, some animal studies have shown teratogenicity, particularly with high doses. Suboptimal absorption of lumefantrine (as in artemether-lumefantrine) in pregnancy has been suggested in one study. In lactating women, uncomplicated malaria should be treated with artemether-lumefantrine, and quinine and clindamycin used for severe malaria.
Hypoglycemia should be expected and is often recurrent if the patient is receiving quinine, and may be refractory to glucose administration.
It may be difficult to differentiate cerebral malaria from eclampsia.
It is critical therefore to monitor fluid balance very carefully. Fluid overload may potentiate the development of ARDS. Hypovolaemia however, may potentiate renal failure, metabolic acidosis and circulatory collapse. Accurate recording of fluid input and output is essential (CVP < 5 cm H2O).
The risk of severe malaria extends into the early post partum period.
Infants and young children (especially those <5 years) are particularly at risk for severe malaria and complications can develop very rapidly without warning. The symptoms of malaria in children may differ from those in adults, and therefore malaria should be suspected if a child who has been in a malaria transmission area develops a febrile illness. Poor feeding, lethargy, irritability, coughing and convulsions (frequently subtle), are important presenting features. Hypoglycaemia, cerebral malaria, anaemia, and metabolic acidosis are important complications. Agitation and respiratory distress (as a result of metabolic acidosis) are ominous signs. Secondary bacterial infections, including septicaemia, are common and broad-spectrum antibiotics should be given to children with severe malaria. Renal failure and acute respiratory distress syndrome are rare in young children. Meningitis is important in the differential diagnosis ofmalaria.
In children over 1 year of age with uncomplicated malaria, recommended treatment is artemether-lumefantrine or quinine plus clindamycin. However, children have a higher risk of developing complicated malaria so should ideally be admitted for treatment under close supervision.
For children â¤ 1 year of age with uncomplicated malaria the treatment of choice is quinine plus clindamycin. This is because of the risk of rapid development of complications. As there is no quinine syrup available, it can be difficult to administer to children. Crushed tablets mixed in mashed bananas, chocolate syrup or jam can be used tomake the quininemore palatable. Pharmacistsmay be able to specially prepare quinine syrup.
Children who are vomiting but who have no other indications of severe malaria should be given parenteral quinine in the recommended doses (see Section 9, Dosage Guidelines) until the child can take medication orally. Particular care must be taken to ensure that the correct dosage is administered. Once oral intake is confirmed then switch to any of the 2 regimens above (depending on the child's age).
Children with severe malaria need to be managed differently to children with uncomplicated/non-severe malaria. Section 6.5.2 explains the management of severemalaria in children.
Intravenous (parenteral) quinine is indicated for severe malaria in children and the usual loading dose of 20mg/kg is used. Particular care must be taken to ensure that the correct dosage is administered. Where intravenous quinine is not promptly available, or cannot be given safely, initial administration of quinine by deep intra-muscular injection using scrupulous aseptic technique, should be considered prior to referral. When given intramuscularly, quinine dihydrochloride should be diluted to reduce pain and prevent sterile abscess formation. Dilutions to between 60 and 100 mg/ml should be made.
Check airway, breathing, circulation (ABC) Agitation and respiratory distress (as a result of metabolic acidosis) are ominous signs Children who present with shock and acidosis should be given a bolus (20 mg/kg) of fluid, either colloid (plasma) OR crystalloid (Ringers lactate, or normal saline if this is unavailable) Secondary bacterial infections, including septicaemia, are common and broad-spectrum antibiotics e.g.
Artemisinin derivatives have been shown to be safe and highly effective in children, including cases of severe malaria and multi-drug resistant malaria. Rectal artesunate is being developed to provide anti-malarial cover while a patient is being transferred to a hospital from a primary healthcare facility where parenteral treatment is not safely available. Intra-muscular artemether and intravenous artesunate have been shown to be safe and effective in the treatment of severe malaria in children. None of rectal artesunate, intra-muscular artemether or intravenous artesunate is registered for use in South Africa, although when these products become available they are expected to provide a safer and possibly more effective alternative to quinine.
A large number of HIV-infected patients either live in areas where malaria transmission occurs, or travel to these areas. Overlap of symptoms of the two diseases, especially fever, may result in HIV-positive patients with malaria presenting late to health facilities and the diagnosis of malaria being missed. Although acute malaria causes a temporary increase in replication of HIV and hence in plasma viral load, there is no evidence that malaria has a substantial effect on the clinical progression of HIV infection, HIV transmission or response to antiretroviral treatment. HIV-infected individuals who live in areas of stable malaria transmission and are thus expected to be malaria semi-immune, are at increased risk of symptomatic parasitaemia and/or may exhibit higher levels of peripheral parasitaemia than semi-immune adults who are HIV-negative. HIVinfected patients who are malaria non-immune are at higher risk of severe malaria and of dying from malaria. As HIV progresses and immuno-suppression worsens, the risks of severe malaria increase. Renal failure has been identified as a particular complication in this group of patients. Secondary bacterial infection is common and empiric antibiotic treatment should be given, e.g. a third generation cephalosporin. Electrolyte disturbances are common and close monitoring is essential. Thus, patients co-infected with HIV/AIDS and malaria should be admitted for treatment and close monitoring at the highest level of care available, preferably a level 2 or level 3 hospitals.
It is unclear how HIV infection modifies the therapeutic response to antimalarials. Increased parasite burdens and reduced host immunity, both of which occur with HIV infection, may be associated with delayed parasite clearance and increased failure rates. Patients with HIV infection who develop malaria should receive the recommended anti-malarial regimens, although more closely monitored, to ensure an adequate response. There are limited data regarding interaction of anti-malarials with antiretroviral drugs. Pharmacological interactions between certain anti-retrovirals (ARVs) and anti-malarial drugs are theoretically possible and might lead to toxicity or sub-therapeutic drug levels. However there are no documented interactions. WHO suggests that patients receiving protease inhibitors and the NNRTI delavirdine should avoid halofantrine (Note: this drug is not recommended for malaria treatment in South Africa). Since lumefantrine is related to halofantrine, the combination artemetherlumefantrine may therefore have the potential to interact with ARVs.
Unless P. falciparum malaria is promptly diagnosed and treated, the clinical picture may deteriorate rapidly. Severe malaria carries a significant morbidity and mortality.
Young children, pregnant women, immuno-suppressed patients and any nonimmune persons are at risk for the development of complications. One can assume that all South Africans living in the malaria areas in this country and all South African travellers are non-immune.
Biochemical Features Renal impairment - serum creatinine >265 µmol/litre or rapidly rising creatinine (>2.5 µmol/kg/day) or urine output <400 ml/day (adult) Acidosis (plasma bicarbonate <15 mmol/litre) (serum lactate > 5 mmol/liter) Hepatic impairment (transaminases > 3 times normal) Hypoglycaemia (blood glucose <2.
Haematological Features Parasitaemia â¥ 5% or â¥ 3+ Anaemia: haemoglobin < 6 g/dL or haematocrit <20% â¥5% neutrophils contain malaria pigment Presence of schizonts of P.
An overall scale is made by adding the score in the three areas assessed, e.g.
The patient should be treated in the highest level of care available. Management of severe malaria comprises 4 main areas: clinical assessment of the patient, specific anti-malarial treatment, adjunctive therapy and supportive care.
o The airway should be secured in unconscious patients and breathing and circulation assessed o The patient should be weighed or body weight estimated so that drugs, including anti-malarials, and fluids can be given on a body weight basis o An intravenous cannula should be inserted and an immediate measurement of blood glucose (rapid test) done o A detailed clinical examination should be conducted, with particular note of the level of consciousness and record of the comascore o A lumbar puncture for cerebrospinal fluid analysis to exclude bacterial meningitis should be considered in unconscious patients o The degree of acidosis is an important determinant of outcome; the plasma bicarbonate or venous lactate level should therefore be measured if possible. If facilities are available, arterial or capillary blood pH and gases should bemeasured in patients who are unconscious, hyperventilating orin shock o Submit blood urgently for full blood count, platelet count, and measurement of urea, creatinine and electrolytes and obtain results urgently o The assessment of fluid balance is critical in severe malaria. Respiratory distress, with acidotic breathing, in severely anaemic children, often indicates hypovolaemia and requires prompt rehydration and, where indicated, blood transfusion.
Quinine is the drug of choice for the treatment of severe malaria in South Africa. Intravenous quinine is the preferred route of administration, especially where the patient is comatose, vomiting or severely ill. Quinine administration is always by slow, rate-controlled intravenous administration, never by bolus injection.
Where intravenous quinine administration is not feasible, not available or considered unsafe, the intra-muscular route may be used initially.
In severe malaria an initial loading dose must be given, by slow intravenous infusion over 4 hours. The rationale for the loading dose is to rapidly reach a therapeutic level.
The loading dose is quinine dihydrochloride salt, 20 mg/kg body weight diluted in 5-10 ml/kg body weight of 5% dextrose water over 4 hours. The loading dose is given strictly according to body weight. The disposition of quinine in very obese patients is not known. It has been suggested that there is a ceiling dose above which quinine should not be given, but there is no evidence to support this.
The loading dose should be omitted if the patient has received quinine, or mefloquine prophylaxis, in the preceding 24 hours. In these cases, ECG monitoring is necessary.
Six to eight hours after starting the loading dose, a maintenance dose of quinine dihydrochloride salt, 10 mg/kg diluted in 5-10 ml/kg body weight of a dextrosecontaining solution should be commenced and infused over 4-6 hours. Intravenous quinine should be administered every 8 hours until the patient can take oralmedication (usually by 48 hours). For obese patients, themaintenance dose should be calculated according to ideal body weight.
Males: IBW (Kg) = 0.9 x height in cm - 88 Females: IBW (Kg) = 0.
The total duration of therapy is 7-10 days.
The use of additional doxycycline or clindamycin does not add initial therapeutic benefit for severe malaria and may contribute to drug side effects. They should be added once the patient is improving.
Once the patient is improving, oral treatment should be continued as per the recommendations for uncomplicated malaria. The dose of quinine should be reduced in renal failure (See 7.8.4).
Quinine has a narrow therapeutic window, although serious side effects (cardiovascular or nervous system) during anti-malarial treatment are unusual. The most frequent side effect during intravenous therapy is hypoglycaemia, especially in pregnant women and children. Hypotension, heart block, ventricular arrhythmias, tinnitus and neurological problems, including convulsions and visual disturbances, occur rarely.
In cases of suspected quinine resistance, where there has been a poor parasitological response to quinine, an artemisinin derivative (not yet registered in SA) may be considered, when available. Parenteral artemisinin derivatives, notably artemether and artesunate, have been successfully used for treating severemalaria. See Section 6.1.3.1.
Patient should be admitted to the highest level of care, ideally an intensive care unit.
Appropriate anti-malarial chemotherapy must be commenced urgently.
Dosesmust be calculated on a mg/kg of body weight basis. A loading dose of drug should be administered immediately on diagnosis. It is therefore important, whenever possible, to weigh the patient (see 7.5 on ideal IBW). This is particularly important for children. Do not confuse the doses of salt and base. Quinine doses are usually prescribed assalt (10 mg ofsalt = 8.
Other treatable causes of coma (e.g.
A rapid initial check of the blood glucose level and frequent monitoring for hypoglycaemia are important. Where this is not possible and the patient has a depressed level of consciousness and/or convulsions, glucose should be given as 50% dextrose solution intravenously. See section 7.8.
Monitor fluid balance carefully. Avoid over- and under-hydration. Fluid overload is extremely dangerous as it may precipitate potentially fatal respiratory failure. Hypovolaemia however, may potentiate renal failure, metabolic acidosis and circulatory collapse. Accurate recording of fluid input and output is essential as fluid balance should be according to urine output and normal and excess fluid loss. Frequent central venous pressure (CVP) monitoring is recommended; maintain the CVP at between 0-5 cm of water.
Reduce high body temperatures (> 39oC) by vigorous tepid sponging and fanning. Antipyretics may also be given.
Look for and manage any complicating or associated infections. A broad-spectrum antibiotic is recommended e.g.
A haemoglobin level â¤ 6 g/dL or a haematocrit â¤ 20%. Anaemia is a common complication of malaria, especially in young children and pregnant women. It occurs as a result of haemolysis and/or bone marrow dysfunction. Severe anaemia may manifest as cardiac failure, shock, hypoxia or confusion. There may be other causes contributing to anaemia in some patients.
Blood transfusion should be considered in patients in whom the Hb is 6 g/dL or less, or the haematocrit is less than 20%, especially those with cardiovascular decompensation and shock. Caution should be exercised and fluid overload should be avoided. If no fresh blood is available packed red cell concentrate may be used.
A blood glucose level <2.2 mmol/l.
Hypoglycaemia is common in severe malaria, particularly in pregnancy, in children, and in patients on intravenous quinine. Blood glucose should be monitored 4-6 hourly. Hypoglycaemia may not always present with classical symptoms of sweating, anxiety, dilatation of pupils or tachycardia. It must always be excluded in patients with malaria who present with depressed levels of consciousness, including coma and convulsions.
Management Adults: 50 ml of 50% dextrose water given intravenously as a bolus. Children: 1 ml of 50% dextrose water/kg body weight. This should be followed by continuous intravenous infusion of 5 or 10% dextrose solution. Avoid fluid overload.
Any patient with a depressed level of consciousness, ranging from agitation or confusion, to coma.
Cerebral malaria can resemble bacterial or viral infections of the central nervous system, or any cause of raised intra-cranial pressure. The clinical features are not specific; the patient may be flaccid, spastic, exhibit meningism, photophobia or symmetrical upper motor neurone signs. Papilloedema or cerebral oedema is not usually found. It is very important to exclude hypoglycaemia. If meningitis is suspected, a lumbar puncture should be performed. Cerebral malaria may occur as an isolated complication, or as part of multi-organ failure.
Convulsions may occur as a result of cerebral malaria, accompanying fever or in association with hypoglycaemia.
Prophylactic anticonvulsants are currently not recommended. Treatment of convulsions is with standard anticonvulsant drugs and supportive measures.
Supportive treatment should include: treatment of convulsions, monitoring of level of consciousness and effective protection of the airway when the GCS <9. Dexamethasone and mannitol are not recommended.
A serum creatinine greater than 265 µmol/l, or a rapidly rising creatinine of more than 2.5 µmol/kg/day, and/ora urine outputof less than 0.5ml/kg/hr or less than 400 ml/day in an adult should be regarded as renal failure. When patients present in a polyuric phase it is critical to replace fluid losses adequately.
Renal failure is generally an early complication of malaria in adults, and occurs rarely in children. Hypovolaemia, sequestration of parasitized red cells in the renal vasculature, intravascular haemolysis and haemoglobinuria are incriminated in the development of renal dysfunction in malaria. This may lead to acute tubular necrosis and renal failure. Acute renal failure is usually reversible with appropriate management.
Dehydration, if present, must be corrected carefully. Excessive administration of fluids should be avoided to minimise the risk of pulmonary oedema. A central venous catheter should be inserted where possible and maintained between 0-5 cm of water. Meticulous attention to fluid intake and output is essential to avoid fluid overload.
Early dialysis is recommended, where available, as renal failure in malaria occurs against a background of a hypercatabolic state. Early referral for dialysis is recommended if the serum creatinine is rising by more than 2.5 µmol/kg/day. Veno-venous hemofiltration is the most effective mode of dialysis in malaria.
Patients with impaired renal function require a reduction in maintenance quinine dihydrochloride salt to 5-7 mg/kg every 8 hours, after 48 hours of treatment with the full dose. Quinine is not removed by dialysis.
Systolic blood pressure less than 80 mmHg in adults and children >13 years. In younger children (<13 years) clinical assessment can be a more reliable indication of circulatory collapse than blood pressure measurement because, firstly, the correct cuff size is often unavailable and secondly, children are able to maintain normal blood pressure in the face of severe circulatory collapse more efficiently than adults.
Cool/cold and clammy extremities e.g.
Mottled/pale skin indicating poor perfusion An exact cut-off point for systolic blood pressure in children is difficult as blood systolic blood pressure increases with age from approximately 75 mmHg (at birth) to 124 mmHg at 13 years. However a systolic blood pressure <50 mmHg at any age indicatessevere circulatory collapse.
Circulatory collapse may be seen in patients with metabolic acidosis, severe anaemia, dehydration, ARDS, a ruptured spleen or septicaemia.
Ideally, a central venous catheter should be inserted and hypovolaemia corrected with an appropriate volume expander (blood or plasma) or isotonic saline. Start inotropes if the CVP is >5 cm of water and the patient is still shocked, and start broad-spectrum antibiotics e.g.3rd generation cephalosporin.
Measurement of acid-base status is a very useful tool in assessing a patient with malaria. Metabolic acidosis, especially lactic acidosis, is an important indicator of severe malaria, even if no other complications are present, and is a poor prognostic sign. Metabolic acidosis may present as shock and/or respiratory distress; in children severe anaemia may present with metabolic acidosis.
Correct any reversible cause of acidosis, in particular dehydration, convulsions and severe anaemia. Take care not to give excessive fluid. The routine use of bicarbonate is not recommended.
Packed cells 10-20 ml/kg over 4-6 hours ivi.
Crystalloid (0,9% saline) or Ringers lactate 10-20 ml/kg ivi over 4 hours. (rate of infusion based on clinical judgment) Exclude metabolic acidosis with a blood gas. Other causes for increased respiratory rate may be excluded with a chest X-ray.
Acute respiratory distress syndrome (ARDS) is an uncommon, but often-fatal complication of severe malaria, and is a particularly severe problem in pregnancy. ARDS may appear several days after chemotherapy has been started, and the general condition of the patient appears to have improved.
An increase in the respiratory rate, bilateral crepitations, clinical and laboratory evidence of cyanosis, confusion, agitation, or an arterial oxygen saturation of less than 90%, should alert the clinician to the possibility of ARDS. Pulmonary oedema as a result of iatrogenic fluid overload, or pneumonia, should also be considered.
Treatment depends on the severity of the respiratory complications. Fluids must be restricted. Diuretics should be given where indicated. Oxygen should be administered, and in some patients ventilatory support may be required.
Although a raised indirect bilirubin due to haemolysis is a frequent finding in malaria, the clinical presence of jaundice or the finding of raised hepatic transaminases (â¥ 3 x normal)should alert the clinician of the probability of severe malaria. The presence of jaundice combined with renal failure and acidosis is cause for great concern.
DIC is rare in patients with severe malaria. Moderate degrees of thrombocytopenia are noted in the majority of cases of uncomplicated malaria, but bleeding is not common. However severe degrees of thrombocytopeniamay be an indication of severe malaria and may be associated with bleeding. With effective malaria treatment, platelet counts return to normal within a few days. DIC ismostly associated with multi-organ failure, orhyperparasitaemia, andmay in some cases be due tosecondary bacterial infection or septicaemia.
Fresh whole blood if indicated, and available; and platelet transfusions if the platelet count is very low or there is evidence of bleeding; alternatively red cell concentrate plus fresh dried plasma and vitamin K.
Secondary bacterial infections may complicate malaria: aspiration pneumonia, urinary tract infections in catheterised patients, and nosocomial infections in hospitalised patients. Secondary bacterial infections are a particular problem in HIV co-infected patients. In asignificant number ofpatients with severemalaria, especially in children, bacteraemia and septicaemia have been noted, and Gramnegative and Gram-positive bacteria have been cultured. This syndrome is associated with high mortality, and is a particular problem in children.
Antibiotics (3rd generation cephalosporin) should be administered to all children with severe malaria, HIV-positive patients and to any patient in whom septicaemia is suspected. Although this is a bigger problem in children, most guidelines recommend antibiotics for adults too as the features of bacterial and malarial sepsis overlap. A broad-spectrum antibiotic should be administered to cover both Gram-positive and Gram-negative bacteria e.g. a 3rd generation cephalosporin.
In general, peripheral parasite counts above 5% should be regarded as severe malaria as this is associated with increased morbidity. Low parasite counts do not exclude severe malaria or complications, and a parasite count must always be interpreted together with the clinical picture and other laboratory findings. Parasite counts are not always accurate, and counts can vary cyclically, depending on when the smear is taken.
The peripheral parasite count does not accurately reflect the parasite load. In highly endemic malarious areas, semi-immune persons may tolerate high parasite densities, without clinical symptoms and complications. The presence of schizonts of P. falciparum in a peripheral blood smear is an important indicator of severe malaria.
The patient should be managed with a rapidly acting effective anti-malarial drug. The use of artemether-lumefantrine in hyperparasitaemia has not yet been studied and it is possible that the course of artemisinsin-derivative would be too short to see the same benefits of 7 days of artesunate. As hyperparasitaemia increases the risk ofmalaria complications (which are often underdiagnosed) and of malaria mortality, initial intravenous quinine therapy should be considered. The patient should be especially closely monitored for complications, even if these are not present initially. Exchange transfusion possibly has a role to play in patients with hyperparasitaemia whose parasite counts increase or fail to decrease significantly despite appropriate therapy.
The pathogenesis is unknown. The condition is seen in patients with G-6-PD deficiencies, which are treated with anti-malarial drugs, notably oxidant drugs like primaquine. The condition occasionally occurs in patients with severe malaria and in those with malaria treated with quinine. Intravascular haemolysis leads to anaemia, passage of haemoglobin in the urine, and varying degrees of renal failure.
Continue appropriate malaria chemotherapy: quinine may be continued (primaquine must be avoided in patients with G-6-PD deficiency). Supportive therapy should include blood transfusions for severe anaemia, adequate fluids and renal dialysis where indicated.
The role of exchange transfusion in severe malaria is controversial and there are no controlled studies to support its use.
Exchange transfusion may be considered for use in selected patients e.g. patients with hyperparasitaemia in whom the parasite count increases despite appropriate chemotherapy, and patients who develop multi-organ dysfunction despite appropriate chemotherapy.
The requirements for exchange transfusion include a safe bloodsupply, a skilled operator and a haemodynamically stable patient. The exchange volume should be 4-10 litres of blood for an adult.
Splenic rupture is a rare complication of malaria, and is more common in P. vivax infections.
Baird JK, Hoffman SL. Primaquine therapy for malaria.
Barnes KI et al. Efficacy of rectal artesunate compared to parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study.
Beg MA et al. Cerebral involvement in benign tertian malaria.
Boland ME, Roper SM, Henry JA. Complications of quinine poisoning.
Boland PB et al. Maternal HIV infection and infant mortality in Malawi: evidence for increased mortality due to placental malaria infection.
Cohen C, Karstaedt A, Frean J, et al. Increased prevalence of severe malaria in HIV-infected adults in South Africa.
English M and Marsh K.
Falade C, Makanga M, Premij Z, et.al. Efficacy and safety of artemetherlumefantrine (Coartem®) tablets (six-dose regime) in African infants and children with acute, uncomplicated falciparum malaria.
Gaye O et al. Diagnosis of Plasmodium falciparum malaria using ParaSight F, ICT malaria PF and malaria IgG CELISA assays.
Grimwade K et al. HIV infection as a cofactor for severe falciparum malaria in adults living in a region of unstable malaria transmission in South Africa.
Grimwade K et al. Childhood malaria in a region of unstable transmission and high humans' immunodeficiency virus prevalence.
Hien TT et al. Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria.
Igbal J, Khalid N, Hira PR. Comparison of two commercial assays with expert microscopy for confirmation of symptomatically diagnosed malaria.
Krishna S, White N J. Pharmokinetics of quinine, chloroquine and amodiaquine. Clinical implications.
Marsh K et al. Clinical Algorithm for malaria in Africa.
McGready R, Cho T, Keo N K et al. Artemisinin anti-malarials in pregnancy: a prospective treatment study of 539 episodes of multi-drug resistant Plasmodium falciparum.
Newton PN et al. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria.
Pasvol G et al. Quinine treatment of severe falciparum malaria in African children: a randomized comparison of three regimens.
Phan GT et al. Artemesinin or chloroquine for blood stage Plasmodium vivax malaria in Vietnam.
Riddle MS, Jackson JL et al. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis.
Ringwald P. Monitoring anti-malarial drug efficacy.
Ter Kuile F et al. The burden of co-infection with human immunodeficiency virus type 1 and malaria in pregnant women in sub-Saharan Africa.
Taylor WR. Anti-malarial drug toxicity: a review.
Toovey S, Jamieson A. Co-artemether has been used in ambulatory treatment of falciparum malaria.
van Hensbroek M B et al. Quinine pharmacokinetics in young children with severe malaria American Journal of Tropical Medicine and Hygiene 1996; 54: 237 - 242 van Hensbroek M B, Onyiorah E, Jaffar S. et al. A trial of artemether versus quinine in children with cerebral malaria. New England Journal of Medicine 1996; 335: 69-75 von Seidlein L et al. A randomized controlled trial of artemether/benflumetol, a new anti-malarial, and pyrimethamine/sulphadoxine in the treatment of uncomplicated falciparum malaria in African children; American Journal of Tropical Medicine and Hygiene 1998; 58: 638 - 644 van Vugt M, Wilairatana P, Gemperli B, et al. Efficiency of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria. American Journal of Tropical Medicine and Hygiene 1999; 60(6): 936-942 van Vugt M, Looareesuwan S, Wilairatana P, et al. Artemether-lumefantrine for the treatment of multidrug-resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 2000; 94: 545-548 van Vugt M et al. A case-control auditory evaluation of patients treated with artemisinin derivatives for multi-drug resistant Plasmodium falciparum malaria. American Journal of Tropical Medicine and Hygiene 2000; 62: 65-69 van VugtMV et al. Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria.
White NJ. Optimal regimes for parenteral quinine.
White NJ. The treatment of malaria.
White NJ. The assessment of anti-malarial drug efficacy.
White NJ, Olliaro PL. Strategies for the prevention of anti-malarial drug resistance: rationale for combination chemotherapy for malaria.
White NJ, Looareesuwan S, Warrell DA, et al. Quinine loading dose in cerebral malaria. American Journal of Tropical Medicine and Hygiene 1983; 32: 1-5.
Malaria treatment guidelines Final Draft 23 June 2009 WHO Expert Committee on Malaria. Twentieth Report. Geneva, World Health Organization 2000; (WHO Technical Report, Series No.
QUININE (parenteral) 1 ampoule (1 ml) usually contains 300 mg quinine dihydrochloride Loading dose: Quinine dihydrochloride salt 20 mg/kg by IV infusion over 4 hours in 5% dextrose saline: [Important Note: No loading dose to be given if the patient has definitely received treatment doses of mefloquine, quinine (morethan 40 mg/kg in the previous 2 days), or quinidine or halofantrine (in the last 24 hours). If in doubt the loading dose should be given.] Maintenance dose: Eight hours after the start of the loading dose, give 10 mg/kg quinine dihydrochloride salt infused over 4-6hours, repeated every 8 hours until the patient can take oral quinine. Important Note: If a treatment dose of mefloquine has been taken in the 12 hours before severe malaria treatment starts, ECG monitoring would be advisable.]The required dose, diluted preferably in 5% dextrose to counteract hypoglycaemia, is given in a total volume of 5-10 ml/kg (depending on patient's fluid balance) by infusion into a large vein. Where facilities for IV infusion do not exist, quinine can begiven IM in the same dosage. The required dose, diluted to between 60 mg and 100 mg/ml, should be given as half the dose in each anterior thigh. Total quinine (parenteral and/or oral) duration at least 7-10days, or until smears are negative. Paediatric dose: Same as adult dose. All patients should ideally have cardiac monitoring. The dose of IV quinine should be reduced by 1/3-1/2 (to 5-7 mg/kg) on the third day of treatment if parenteral therapy is required for more than 48 hours because there has been nosignificant improvement in the clinical condition of the patient, or acute renal failure has developed.
QUININE (oral) 600 mg (i.e.
1 tablet usually every 8 hours for 7 days or 10 8 hours for 7 days. The tablets contains 300 mg mg salt/kg (maximum usually may be crushed with banana, quinine sulphate 600 mg) 8 hourly for 7 days jam or chocolate syrup.
Use in combination tolerated after starting quinine. years old.
with quinine 200 mg stat; followed by 100200 mg daily for 7 days. Avoid in pregnancy. 4 mg/kg stat, then 2 mg/kg daily for at least 7 days or until negative smears.
Use in combination tolerated after starting quinine mg/kg tds for 7 days.
with quinine in 10 mg/kg bd for 7 days or 5 pregnancy and mg/kg tds for 7 days.
artemether 20 mg plus lumefantrine 120 mg. 15-<25 kg: Two tablets stat, followed by two after 8 hours and then two twice daily on each of the following two days (total course = 12 tablets) 25-<35 kg: Three tablets stat, followed by three after 8 hours andthen three twice daily on each of the following two days (total course = 18 tablets) 35-<65 kg: Four tablets stat, followed by four after 8 hours and then four twice daily on each of the following two days (totalcourse = 24 tablets). >65 kg: Dose as for > 35 kg above, although inadequate experience in this weight group justifies closer monitoring of treatment response. Administer with food/milk containing at least 1.3g fat to ensure adequate absorption.
CHLOROQUINE Orally: 1.
1 tablet contains 150 later, and 300 mg once daily on regimen.
mg chloroquine base second and third days.
PRIMAQUINE 1 tablet usually contains 26.3 mg primaquine phosphate = 15 mg primaquine base. Orally: 15 mg base daily for 14 days following standard treatment or 0.25 mg base/kg daily for 14 days. In mild G-6-PD Deficiency (1060% residual G-6-PD activity): 45 mg base weekly/0.5-0.8 mg base/kg body weight once a week for six to eight weeks. Contra-indicated in children under 1 year old. 0.25-0.3 mg base/kg daily for 14 days following standard treatment. In mild G-6-PD Deficiency: 0.50.8 mg base/kg weekly for 8 weeks.
MEFLOQUINE (not registered for treatment of malaria in South Africa) 1 tablet contains 250 mg base Oral, 25 mg/kg base (maximum total dose 1.5 g) in 2-3 divided doses 6-8 hours apart as follows: loading dose, 750 mg; then 500 mg after 6-8 hours and 250 mg after a further 6-8 hours. Oral, 25 mg/kg base as a single dose or 2 divided doses.
Adapted with permission from the Malaria Update, edited by A. Swart of the Medicines Information Centre, UCT.
Patients, who vomit less than 30 minutes after receiving the drug orally, should be given a second full dose. If they vomit 30-60 minutes after the dose, an additional half-dose should be given.
When treating severe malaria, oral treatment should be substituted as soon as the patient can take tablets by mouth and at least 3 doses of parenteral quinine have been given.
For P. vivax malaria acquired in Oceania and southeast Asia the dose of primaquine should be increased to 0.33-0.5 mg base/kg daily for 14 days.
Malaria is a progressive and unpredictable disease.
Complications may develop despite treatment.
Severity of disease is frequently underestimated, so careful monitoring of all patients is mandatory.
Only patients with malaria who are ambulant, with normalmental state, adequate urine output, able to take oral medication, and not vomiting excessively can be considered as uncomplicated. Note: All pregnant women and children < 1 year should be regarded as high-risk patients and treated with quinine at the highest level of care available.
Severe vomiting, diarrhoea or dehydration, decreased urine output (<0.
Monitor fluid balance carefully. Avoid over-OR under-hydration. Fluid overload is extremely dangerous as it may precipitate potentially fatal respiratory failure. Hypovolaemia is also dangerous and may potentiate renal failure, metabolic acidosis and circulatory collapse. Accurate recording of fluid input and output is essential. Frequent central venous pressuremonitoring is recommended; maintain between 0 and 5 cm H2O.
A rapid initial measurement of blood glucose level and 4-6 hourly monitoring for hypoglycaemia are essential.
Regular monitoring of temperature, respiratory rate, blood pressure, and level of consciousness is mandatory.
Look for and manage any associated infections. Where indicated, bacterial meningitis should be excluded by lumbar puncture, or covered by appropriate empiric antibiotic treatment.
Reduce fever > 39 ºC by tepid sponging, and paracetamol.
Transfuse if haemoglobin â¤ 6 g/dl (haematocrit < 20%) or anaemia associated with haemodynamic compromise.
Laboratory tests: Regular monitoring of haemoglobin, urea and electrolytes, acid-base status, and an initial assessment of liver function.
Level of parasitaemia should be assessed daily; at 72 hours, level of parasitaemia should be less than 25% of baseline.
Early dialysis (haemo- or peritoneal dialysis) is recommended and may be life-saving. Indications for dialysis include metabolic acidosis, hyperkalaemia, fluid overload, rapidly rising creatinine or patients who remain anuric after adequate re-hydration.
Treat seizures promptly with intravenous benzodiazepines (check for hypoxia and hypoglycaemia).
Respiratory failure (ARDS/pulmonary oedema): Administer oxygen, furosemide, assisted ventilation (PEEP) if required.
As malaria complications develop rapidly, regular monitoring and urgent interventionsmay be lifesaving.