1. health and fitness
2. disease

THE REPUBLIC OF BOTSWANA
MINISTRY OF HEALTH
DEPARTMENT OF PUBLIC HEALTH
NATIONAL MALARIA CONTROLPROGRAMME
GUIDELINES FOR THE DIAGNOSIS AND TREATMENT
OF MALARIA IN BOTSWANA
SEPTEMBER 2007
THE REPUBLIC OF BOTSWANA
MINISTRY OF HEALTH
DEPARTMENT OF PUBLIC HEALTH
NATIONAL MALARIA CONTROL PROGRAMME
GUIDELINES FOR THE DIAGNOSIS AND TREATMENT
OF MALARIA IN BOTSWANA
SEPTEMBER 2007
2
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
CONTENTS
Preface ....................................................................................................... 5
Acknowledgment ........................................................................................ 6
List of Abbreviations and Acronyms ........................................................... 7
1. Introduction ........................................................................................... 8
1.1 Overview of national treatment policy
and drug resistance pattern.................................................................... 9
2. Malaria disease................................................................................... 12
2.1 Parasite distribution ...................................................................... 12
2.2 Disease presentation.................................................................... 12
3. Malaria diagnosis ............................................................................... 16
3.1 Guidelines for malaria diagnosis in Botswana.............................. 16
3.2 Parasitological diagnosis .............................................................. 17
3.3 Guidelines for Malaria Laboratory Diagnosis in Botswana ........... 17
3.4 Microscopy ................................................................................... 18
3.5 Malaria Rapid Diagnostic Tests (RDTs) ....................................... 19
3.6 RDT in malaria management........................................................ 20
4. Management of P. falciparum malaria ................................................ 21
4.1 Treatment of uncomplicated malaria ............................................ 21
4.2 Use of anti-pyretic in uncomplicated malaria................................ 23
4.3 Treatment of malaria in specific populations ................................ 24
4.4 Treatment failure .......................................................................... 25
4.5 Recurrence after 14 days ............................................................. 26
4.6 Pre-referral treatment ................................................................... 26
4.7 Management of severe malaria .................................................... 27
5. Treatment of Malaria caused by other species ................................... 32
6. Malaria prevention .............................................................................. 32
6.1 Malaria prevention in pregnancy .................................................. 32
6.2 Chemoprophylaxis in the general travelers .................................. 33
7. Pharmacovigilance ............................................................................. 34
8. Drug Resistance Surveillance............................................................. 34
9. Disease management at different level
of health care delivery system .................................................................. 36
References ............................................................................................... 37
Annex I: Pharmacology of drugs in the treatment of malaria
in Botswana .............................................................................................. 38
Annex II: Criteria for Selecting AL Among Other ACT’s ........................... 48
Annex III: Performing and interpreting Malaria RDTs including plates ..... 50
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
3
Annex IV: Decision chart for treatment of malaria .................................... 53
Annex V: Glasgow and Blantyre Coma Monitoring Scales....................... 54
Annex VI: List of Technical working group................................................ 56
4
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
5
Acknowledgements
This document was developed by a broad based partnership from
different institutions as follows: Nyangabgwe Referral Hospital, BEDAP,
BDF, WHO and UNICEF.
The Ministry of Health would like to acknowledge the Malaria Technical
Working Group, which developed the initial draft, and the Malaria
Reference Group that finalized the guidelines. In addition the Ministry of
Health extends its acknowledgments to the editorial team and those
individual contributors who made the revision of these guidelines a
success.
Finally, the Ministry of Health would like to take this opportunity to
express its gratitude to UNICEF and WHO at country, inter-country and
headquarter levels for their technical support.
6
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
List of Abbreviations and Acronyms
AS + AQ
Artesunate-Amodiaquine
ACT
Artemisinin based Combination Therapy
AL
Artemether-Lumefantrine
AQ
Amodiaquine
AS + SP
Artesunate-Sulphadoxine-Pyrimethamine
BEDAP
Botswana Essential Drug Action Programme
CHW
Community Health Worker
CQ
Chloroquine
DDT
Dichloro-Diphenyl-Trichloride
DRU
Drug Regulatory Unit
MOH
Ministry of Health
MIP
Malaria in Pregnancy
MRG
Malaria Reference Group
NMCP
National Malaria Control Programme
NRH
Nyangabgwe Referral Hospital
PHS
Public Health Specialist
PV
Pharmcovigilance
QA/QC
Quality Assurance/Quality Control
Qn
Quinine
RDT
Rapid Diagnostic Test
SP
Sulphadoxine-Pyrimethamine
TWG
Technical Working Group
UNICEF
United Nations Children Fund
WHO
World Health Organization
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
7
1. Introduction
Malaria remains the most important parasitic disease that kills young
children and adults and is a major public health problem in most parts of
the world.
Malaria is one of the major health problems in Botswana and is
classified as a notifiable disease. Transmission is seasonal and closely
related to the amount of rainfall. There is therefore significant variation
in the degree transmission from year to year and major epidemics may
occur in years of heavy rainfall. The country experienced epidemics in
1988, 1993, 1996, and 1997. Since then the malaria disease burden
has decreased progressively
The seasonality of malaria transmission leads to what is referred to as
unstable type of malaria. This type confers negligible acquired immunity
leaving all age groups at risk of developing severe form of Malaria. The
level of malaria transmission varies throughout the country giving rise to
three epidemiological belts. Malaria is endemic in the northern part of
the country with regular and high transmission, a central belt of
intermediate transmission, and a southern belt where little or no malaria
occurs.
Within the northern and central zones there is significant
difference in the levels of transmission in different localities. In years of
heavy rainfall when both the distribution and intensity of transmission
increases, the transmission belt may move southwards such that
outbreaks of malaria occur in the central zone of the country, and
sporadic malaria cases occur in traditionally in non malarious areas.
8
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
1.1. Overview of National Treatment Policies and Drug Resistant
Pattern
Chloroquine was the recommended drug for treatment of uncomplicated
malaria in the whole country until mid 1990’s. There were anecdotal
reports of apparent increase in chloroquine treatment failures,
especially after the 1993 malaria epidemic. Between 1994 and 1997
several chloroquine sensitivity and review studies established that
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
9
parasite resistance to chloroquine and chloroquine treatment failures
had reached unacceptable levels. Drug resistance is defined by WHO
as the ability of a parasite strain to survive, and/or multiply despite the
administration and absorption of drug in doses equal to or higher than
that recommended but within the limits of tolerance of the subject.
A decision was taken after wide consultations to replace Chloroquine
with Sulphadoxine-Pyrimethamine (SP) as first line treatment for
uncomplicated malaria. This was achieved successfully in 1996 in the
Chobe sub-district and in 1998 in the entire country. Quinine (Qn) has
remained the recommended drug for severe malaria or treatment
failures with first line drugs; and so far no documented significant Qn
resistance is known.
Over a period of years, previous reports from the districts indicated that
patients were still responding very well to SP as first line treatment for
uncomplicated malaria. However, the 2006 SP efficacy studies revealed
failure rates of 9%. The findings from the 2006 efficacy studies are in
conformity to sub-regional and global situation as regards SP
resistance. In view of this level of resistance, and the regional move
towards malaria elimination, a decision was taken in 2007 to change the
first line drug policy from SP to ACTs.
In response to increasing resistance to SP, other countries in the region
have changed their treatment policies to Artemisinin-based Combination
Therapy (ACTs) following WHO recommendations. To date almost all
the countries in the sub region have adapted ACT policy. Artemisininbased Combination therapy is defined as the simultaneous use of two
or more blood schizonticidal drugs with different biochemical targets
in the parasites and independent modes of action. Artemisinin-based
combination therapy is an antimalarial combination therapy with an
artemisinin derivative as one component of the combination.
Guidelines for the Diagnosis and Treatment
10
of Malaria in Botswana
Artemisinin-based Combination Antimalarial Therapy is preferred over
other combinations not containing artemisisnins
for the following
reasons:
•
Rapid and sustained reduction of the parasite biomass
•
Reduction of gametocyte carriage thus breaks the malaria
parasite’s life cycle.
•
Rapid resolution of clinical symptoms.
•
Safety profile is high.
•
Excellent
tolerability,
well
tolerated
compared
to
other
antimalarials.
•
AL
is
a
fixed
dose
combination
treatment
enhancing
Guidelines for the Diagnosis and Treatment
11
compliance.
•
High cure rates (more than 95 %).
•
Minimizes emergence of resistance.
of Malaria in Botswana
2. Malaria Disease Malaria disease is caused by infection with any of
the four species of genus plasmodia known to infect man namely;
Plasmodium falciparum, P. ovale, P. vivax and P. malariae.
Malaria
infection in humans is transmitted mainly through the bite of an infected
female anopheles mosquito. In Southern Africa, the most common type
is the Anopheles gambiae complex. The most prevalent closely related
species of anopheles vector found in Botswana is Anopheles arabiensis.
2.1 Parasite Distribution
The major malaria parasite species in Botswana is P. falciparum, which
constitutes up to 98% of all malaria cases. P. malariae and P. ovale
share the remaining 2%. P. vivax malaria has not been reported in
Botswana.
2.2. Disease Presentation
Malaria may present clinically as either uncomplicated malaria, severe
malaria or remain as asymptomatic infection especially in people living
in malaria endemic areas. In Botswana, due to the highly seasonal and
epidemic nature of malaria transmission, infection with malaria
invariably leads to clinical manifestation of disease.
Uncomplicated Malaria:
Uncomplicated malaria is defined as symptomatic malaria without signs
of severity or evidence of vital organ dysfunction. In acute P. falciparum
malaria there is a continuum of presentation ranging from mild to severe
forms of malaria.
Uncomplicated malaria characteristically presents with fever, but fever
may be absent. Other symptoms may include:-:
12
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
•
Headache,
•
Joint or muscle aches,
•
Chills and rigors.
•
Fatigue,
•
Abdominal discomfort, anorexia, nausea, vomiting.
In children malaria may present subtly as refusal to eat, lethargy and
irritability.
Assessment of Uncomplicated Malaria:
The primary goal of assessment of a case of uncomplicated malaria is
to be able to:
•
Promptly and effectively treat malaria to prevent progression to
severe disease.
•
Limit duration of disease and minimize the risk of the spread of
drug resistant parasites.
•
Exclude other common causes of febrile illness.
History:
In addition to the symptoms, age, place of residence, recent history
of travel and drugs taken prior to or during current illness are important.
History should focus on asking for;
•
Nature, frequency, duration and pattern of fever and associated
chills and rigors, if any
•
In children cough, difficulty of breathing, diarrhea, ear pain,
history of measles in last 3 months.
Signs:
Look for:
Prostration, (extreme weakness), irritability,
Feel for:
•
Increased body temperature (> 38.5º c)
•
Pallor, especially in children and pregnant women
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
13
•
Enlarged liver, spleen or both, especially in children
Presentation of malaria may mimic other acute febrile diseases or
illness. Therefore, it is important to consider malaria in any febrile illness
and in travelers coming from malaria endemic regions. The diagnosis of
uncomplicated malaria is based on history of fever with high index of
suspicion for malaria in the absence of signs of severe malaria and
having excluded other possible cause of acute febrile illness. Key is
early detection, correct diagnosis and prompts treatment
Severe Malaria
The definition of severe malaria disease varies in children and adults.
The definition of severe disease is described as in a patient with a P.
falciparum asexual parasitaemia and no other confirmed cause for
symptoms, the presence of one or more of the clinical or laboratory
features associated with severe malaria.
Clinical features associated with severe malaria
•
Prostration
•
Impaired consciousness
•
Respiratory distress
•
convulsions
•
Circulatory collapse
•
Pulmonary oedema
•
Abnormal bleeding
•
Jaundice
•
Haemoglobinuria
Laboratory Features
14
•
Severe anaemia
•
Hypoglycaemia
•
Acidosis
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
•
Hyperparasitaemia
•
Renal impairment
Diagnosis of severe malaria disease has to always be confirmed by
parasitological evidence of the presence of malaria parasites either by
blood slide or RDT. However, rapid initiation of treatment is critical for
improved outcome for the treatment of malaria.
Hence the non-
availability of laboratory results should not delay initiation of treatment of
suspected severe malaria as a blood slide or blood sample for RDTs
and blood sugar where possible would have been taken.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
15
3. Malaria Diagnosis
Prompt and accurate diagnosis of malaria is part of effective disease
management. High sensitivity of malaria diagnosis is important to
identify those positive cases in all settings, in particular for the most
vulnerable population groups, such as young children, in which the
disease can be rapidly fatal. High specificity is also vital to pick negative
cases, which can reduce unnecessary treatment with antimalarials and
improve differential diagnosis of febrile illness.
The diagnosis of malaria is based on clinical criteria (clinical diagnosis)
supplemented by the detection of parasites in the blood (parasitological
or confirmatory diagnosis).
3.1. Clinical diagnosis
Clinical diagnosis alone has very low specificity, as the signs and
symptoms of malaria are non-specific. Malaria is clinically diagnosed
mostly on the basis of fever or a history of fever. The following WHO
recommendations are still considered valid for clinical diagnosis:
a) In settings where the risk of malaria is low, clinical diagnosis of
uncomplicated malaria should be based on the degree of
exposure to malaria and a history of fever in the previous 3
days with no features of other severe diseases.
b) Where the risk of malaria is high, clinical diagnosis should be
based on a history of fever in the previous 48h and/or the
presence of anaemia, for which pallor of the palms appears to
be the most reliable sign in young children.
16
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
3.2. Parasitological Diagnosis
Parasitological diagnosis has the following advantages:
•
Improved patient care in parasite-positive patients owing to
greater certainty that the patient has malaria
•
Parasite species identification
•
Identification of parasite-negative patients in whom another
diagnosis must be sought
•
Prevention of unnecessary exposure to antimalarials, thereby
reducing side-effects, drug interactions and selection pressure
for drug resistance
•
Cost savings considering the high cost of ACTs
•
Improved health information
•
Confirmation of treatment failures.
The two methods in use for parasitological diagnosis are light
microscopy and rapid diagnostic tests (RDTs) for detecting parasite
antigens.
Note: The results of parasitological diagnosis should be available within
a short time (less than 2 hours) of the patient presenting. If this is not
possible, the patient must be treated on the basis of a clinical diagnosis.
In all cases if there is a strong clinical suspicion, the patient should be
treated as malaria and the reason for treatment clearly indicated. In the
instances were a treatment has been made on clinical diagnosis, a
blood slide should have been taken before the initiation of treatment for
future classification.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
17
3.3. Guidelines for Malaria Laboratory Diagnosis in Botswana:
•
All patients suspected of having malaria should have a malaria
parasite slide collected and malaria rapid diagnostic test done
before commencing on anti-malarial treatment.;
•
Repeat MP slide and RDT after six hours t in all patients in
whom there are strong grounds to suspect malaria but the initial
slide/RDT was negative
•
All febrile patients living in the endemic areas or with history of
travel to malarious areas will have a MP slide/Malaria collected
and Rapid Diagnostic Test done
•
Clinicians must adhere to the MP slide/RDT result for the
management of uncomplicated malaria. Treatment of non
confirmed uncomplicated malaria should be on strong clinical
reasons or the patient having one or more characteristics of
severe malaria as stipulated above, in which case the
classification of the disease becomes severe disease. These
should be indicated in the patients file as a standard of good
clinical the management practice.
MP slide results in line with the treatment outcome of the patient should
be an indispensable tool for quality assurance in management of
malaria. And, there should be a continuous flow of information between
laboratory and clinical staff
Analysis of MP slide results is an indispensable tool for diagnostic
quality assurance in the management of malaria.
3.4. Microscopy
Microscopy remains the operational gold standard and will be
performed in all health facilities with microscope services. In all other
facilities without microscopy, Rapid Diagnostic Test (RDTs) will be
18
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
performed.
However, for all cases being suspected for malaria, a
peripheral blood smear will be taken and sent to the nearest laboratory,
alongside performing RDT. RDT and Microscopy have to be performed
concurrently at all health facility levels. As NMCP moves from malaria
control to malaria elimination, the two malaria investigation tools are
mandatory to improve the quality of diagnosis and surveillance of
malaria in Botswana.
3.5. Malaria Rapid Diagnostic Tests (RDTs)
Brief Overview
Malaria Rapid Diagnostic Test is a device, which detects specific
antigens (proteins) produced by malaria parasites. These antigens are
present in the blood of infected or recently infected people with malaria.
The three main groups of antigens detected by commercially available
RDTs are:
• Histidine-rich protein 2 (HRP2), specific to P. falciparum
• Plasmodium lactate dehydrogenase (pLDH), currently used in
products that include P. falciparum-specific, pan-specific, and
P. vivax-specific pLDH antibodies
• Aldolase (pan-specific).
Presently the RDT used in Botswana is specific for Plasmodium
falciparum (Pf) only due to the fact that 98% of the malaria parasites are
P.falciparum. The Iatter employs the detection of the Pf Histidine Rich
Protein 2 (HRP 2) antigens released from infected red blood cells to the
blood. Most RDTs have a sensitivity of 95% at parasite densities of
100/µl of blood.
The sensitivity of malaria RDTs is determined by the:
•
Species of parasite
•
Number of parasites present in the blood
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
19
•
Condition of the RDT
•
Correctness of technique used to perform the test.
•
Correctness of interpretation by the reader.
•
Parasite viability and variation in production of antigen by the
parasite.
3.6. Malaria Rapid Diagnostic Tests (RDTs) in Malaria Management
Malaria Rapid Diagnostic Tests (RDTs) do provide a useful guide to the
presence of clinically significant malaria infection. They complement
microscopy based diagnosis where such services are not available.
However, RDTs should not replace microscopy as the sole means of
malaria diagnosis.
The general management of a malaria patient
should base treatment decisions not only on results but also other
clinical parameters. In case of uncomplicated malaria, the rationale of
treatment for a MP slide/RDT negative should be clearly defined by the
managing clinician.
Like all laboratory procedures the accuracy of an MP slide /RDT is
dependent on the care and expertise with which it is prepared and
interpreted.
20
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
4. Management of P. falciparum Malaria
4.1. Treatment of Uncomplicated Malaria
Treatment Objectives
The primary objective of treating uncomplicated malaria is to cure the
infection. This is important, as it will prevent progression to severe
disease and prevent additional morbidity associated with treatment
failure. Cure of the infection means eradication from the body of the
parasites that caused the illness.
The public health goal of treatment is to reduce transmission of the
infection to others, i.e. to reduce the infectious reservoir.
A secondary but equally important objective of treatment is to prevent
the emergence and spread of resistance to antimalarials. Tolerability,
the adverse effect profile and the speed of therapeutic response are
also important considerations in choosing the type of treatment to give.
4.1 Treatment of Uncomplicated Malaria
The first line medicine/drug for the treatment of uncomplicated
malaria in Botswana is Artemether-Lumefantrine (AL).
Treatment of acute uncomplicated malaria with AL is effective against
malaria caused by P. falciparum even in areas of multidrug
resistance. It is also effective against all other malaria species.
An advantage of this combination is that Lumefantrine is not available
as a monotherapy and has never been used as a monotherapy
treatment for malaria. Lumefantrine absorption is enhanced by coadministration with fatty foods. So it is essential that patients or
Guidelines for the Diagnosis and Treatment
21
of Malaria in Botswana
caregivers be informed of the need to take these tablets with milk or fatcontaining food or any type of food if such fatty containing food is
not available.
Dosage;
AL is currently available as co-formulated tablets containing 20 mg
Artemether and 120 mg Lumefantrine.
Weight of patient has to be taken for dosage schedule. ArtemetherLumefantrine is recommended for patients with weight equal to or
greater than 5 kg. In areas were there is no weighing scale age could
be used as a proxy to the dosing schedule as shown in the table below.
The total recommended treatment dosing using AL is a 6 dose regimen
for 3 days for optimum effect and reduce chances of recrudescence.
The dosing schedule of AL in all age groups is as follows:
st
•
1 dose at clinic under Direct Observed Treatment
•
2
•
Subsequently the 3
nd
dose given after 8 hours.
rd
to the 6
th
dose is given twice daily
(morning and evening) for two more days.
Table 1: Dosing schedule for Artemether-Lumefantrine
Body
Weight
KG
5-14
1 tablet
1 tablet
15-24
6 months–
2 yrs
3-8
Day 2
Give twice
a day
1 tablet
2 tablets
2 tablets
2 tablets
2 tablets
25-34
9-14
3 tablets
3 tablets
3 tablets
3 tablets
>34
>14
4 tablets
4 tablets
4 tablets
4 tablets
22
in
Age
Years
in
st
1 dose
Day1
After 8hrs
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
Day 3
Give twice
a day
1 tablet
Notes: It is important to note that AL is not recommended for infants
less than 5 kg body weight. Infants that fall under this weight category
will be treated with quinine.
Partial treatment should not be given even when the diagnosis is
uncertain. A full course of effective treatment should be given once a
decision to give antimalarial treatment has been reached.
Health Workers are strongly urged to perform and rely on blood slide
(BS)/RDTs results for the treatment with AL. However, in instances
where BS/ RDTs are not available or the test is negative but the
clinician has high index of suspicion, treatment should be initiated on
the basis of clinical grounds and justification for treatment provided in
the patient record form.
NOTE: Some patients cannot tolerate oral treatment (AL) and may
require parenteral quinine for 1-2 days until they can swallow and retain
oral medication reliably. When they are able to take orally, a full course
of AL should be administered.
4.2. Use of Antipyretics In Uncomplicated Falciparum Malaria
Fever is a cardinal feature of malaria and is associated with
constitutional
symptoms
of
lassitude,
weakness,
headache,
anorexia and nausea.
•
Use of Paracetamol 10 mg/kg in children or 500 – 1000 mg in
adults (1-2 tablets) every 4 hours is safe. It is tolerated well
when given orally or as a suppository and is recommended for
treating fever (more than > 38.5º C.)
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
23
4.3. Treatment of Uncomplicated Malaria In Specific Populations
Management of uncomplicated malaria in specific populations and
situations
Children Under 5kg
Malaria in children under 5 kg is uncommon but potentially fatal.
Fevers in such age groups are most likely to be associated with
septicemia.
As they constitute an acute emergency where possible
they should be managed under expert pediatric care. Quinine is the
drug of choice for managing malaria in this age group.
Pregnant Women
AL is not recommended for malaria treatment in first trimester. For
second and third trimester AL is the recommended drug of choice for
uncomplicated malaria. Oral quinine is the recommended drug of choice
for
pregnant
women
in
the
first
trimester
who
present
with
uncomplicated malaria.
Lactating Women
Lactating women who present with uncomplicated malaria will be
treated with AL.
Patients Co-infected with HIV and AIDS
Patient with HIV infection who develops uncomplicated malaria should
be treated with AL. The high incidence of HIV related fevers in this
category of people requires that confirmatory diagnosis is practiced but
treatment should be given when there is high suspicion of malaria.
24
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
Malnourished Patients
Although there are many reasons why drug kinetics may be different in
malnourished patients, there is insufficient evidence to suggest
changing current dosage recommendation of anti-malarial drugs. AL
remains the drug of choice for treatment of uncomplicated malaria in
malnourished patients.
Supportive Treatment
•
Ensure temperature stabilization. Give Paracetamol oral or
rectal, if temperature >38.5 degree Celsius. Expose child by
uncovering and do tepid sponging as a supportive measure.
•
Avoid aspirin in children.
•
Maintain adequate nutrition by offering small, frequent, high
energy density foods
4.4. Treatment Failures
Patients with uncomplicated malaria who deteriorate by developing
features of severe disease or do not improve whilst on ArtemetherLumefantrine treatment taken correctly for at least 48 hours showing
persistent parasitemia should be considered Artemether-Lumefantrine
treatment failures. For any treatment failure, the recommended 2
nd
line
drug is Quinine. This should be given for seven days, preferably
supervised. The table below is based on a dose of 10 mg salt/kg of
body weight 8 hourly for 7 days using tablets of 300 mg salt.
Treatment failure also refers to at least 2 episodes of confirmed Malaria
within a period of 14 days. Treat with Quinine. The entire 7 days
course may be given orally if the patient does not present with severe
malaria. The treatment should preferably be supervised.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
25
Table 2: Dosage schedule for quinine in case of treatment failure
Age (years)
NUMBER OF TABLETS
<1
1–3
4–6
7–11
12–15
15+
As adapted from guidelines
0.25
0.5
0.5
1
1.5
2
for treatment and diagnosis in the
African Region
The following condition should be considered in treatment failure.
•
•
•
Persistence or arising parasitaemia
Progression from uncomplicated to severe malaria
At least two episodes of malaria within 14 days
4.5. Recurrence after 14 days
Recurrence of fever and parasitaemia more than two weeks after
treatment, which could result either from new infection or recrudescence,
should be treated with first line treatment- AL. Parasitological
confirmation is desirable but not a pre-condition.
In both cases, the treatment is with AL and should be supervised
4.6. Pre-Referral Treatment
Intramuscular (IM) Quinine
IM Quinine is the recommended pre-referral treatment of choice in
Botswana. This is an alternative to IV Quinine in the treatment of all
Guidelines for the Diagnosis and Treatment
26
of Malaria in Botswana
cases of severe malaria, especially cerebral malaria, in facilities that are
not capable of starting an IV line and/or constituting and adequately
monitoring a Quinine IV infusion.
This refers particularly to remote clinics and health posts. A stat dose of
20mg/kg body weight if no prior ingestion of Chloquine, mefloquine,
quinidine or quinine in the last one week. Otherwise- 10mg/kg body
weight should be used.
It is understood that a patient with severe malaria started on IM Quinine
shall be transferred to a higher-level facility as soon as possible. The IM
Quinine is meant to ensure that appropriate antimalarial treatment is not
delayed.
Once the patient reaches the hospital, the Quinine should be continued
by the intravenous (IV) route until the patient is ready to take oral
medication.
In the event that referral is not possible, IM quinine should be continued
8 hourly until the patient is able to take orally. After two days of IM
injection, the dose should be reduced to 5-7mg/kg body weight, if there
is still justifiable need.
4.7. Management of Severe Malaria
Management Objectives
The main objective is to prevent the patient from dying; secondary
objectives are prevention of recrudescence, transmission or emergence
of resistance and prevention of disabilities.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
27
Death from severe malaria often occurs within hours of admission to
hospital or clinic, and so it is essential that therapeutic concentrations of
antimalarials are achieved as soon as possible
Treatment Recommendations for Severe Malaria
Parenteral quinine is the recommended drug for the treatment for
severe malaria. The importance of supportive or ancillary measures is
emphasized.
Patients with severe malaria will be treated with parenteral Quinine for
at least 48 hours. Thereafter if they are able to take oral medication the
patient will be discharged home on a full course of AL. Patients in
whom AL is contraindicated must complete a seven days course of oral
Quinine, preferably supervised.
Initial Treatment Considerations for Severe Malaria
•
Clear and maintain the airway.
•
Position semi-prone or on side.
•
Weigh the patient (if possible) and calculate dosage.
•
Make rapid clinical assessment.
•
Exclude hypoglycaemia/meningitis.
•
Start antimalarial chemotherapy.
•
Start treatment for hypoglycaemia/meningitis where indicated.
•
Measure and monitor urine output. If necessary insert urethral
catheter.
•
Take blood for diagnostic smear, haematocrit and other
laboratory tests. Monitor blood glucose.
•
Plan first 8 hours intravenous fluids, including diluents for
antimalarial drug, glucose therapy and blood transfusion.
28
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
•
o
If l temperature exceeds 37.5 C, remove patient’s clothes, tepid
sponge, and fan, use cooling blanket and give antipyretic.
•
Give anticonvulsant therapy if there is convulsion .
•
Consider need for additional drugs (vitamin K, antibiotic etc.).
Treatment Schedule for Severe Malaria Disease
A loading dose of intravenous (IV) quinine 20mg/kg (to a maximum of
1.2g quinine) diluted in IV solution containing 5% dextrose (1-2ml/kg) is
infused over four hours; Then four hours after completing the loading
dose (i.e. 8hrs after commencing quinine) give 10mg per kg infused
over 4 hours and continue the same dose 8hrly. If the patient requires
IV quinine for more than 48hrs reduce the dose to 5-7 mgs per kg
per dose 8hrly
Note:
•
The loading dose is not given if quinine, Chloroquine, or
Mefloquine have been given in any form during the previous
one week. In this case commence with a dose of 10 mg/kg of
body weight.
•
IV fluids given with quinine should be based on hydration status,
urine output, etc. Once the IV fluid rate has been decided then
quinine is added to the amount of IV fluid to be infused over 4
hour period or as a separate IV infusion or piggy bag in 5%
Dextrose.
•
Monitor blood sugar with dextrostix every 4 hours and
whenever symptom of hypoglycemia occurs, e.g. convulsions or
changing level of consciousness.
•
Patient with severe malaria will be treated with quinine as long
as they remain in hospital and the treatment is supervised. If
the patient is well enough to be discharged home before
completing 7 (seven) day treatment, a full course of AL should
be given.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
29
How to Give IM Quinine
•
Weigh the patient or (in children) estimate the weight using the
formula:
2 x age (years) + 8 = weight in kg (gives a good estimate up to
age 10 Years)
•
Draw up 5 ml sterile normal saline.
•
Draw up 300 mg (1 ml) Quinine from an ampoule into the same
syringe.
•
The syringe now has 50 mg Quinine per ml of solution
•
Give 10 mg (0.2 ml) per kg body weight by IM injection into the
upper thigh. If the volume to be injected is more than 3 ml, give
half into each thigh.
Note:
• The adult dose for IM Quinine is the same as for children, i.e. 10
mg/kg.
• In the case of heavy adults who might require up to 16 ml of the
diluted Quinine preparation the total will need to be divided into 3
or 4 parts of 3 or 4 ml, each which can be injected into different
sites.
•
The Quinine that is used for IM injection is the same preparation,
which is given IV. In other words there is no difference in the
ampoules, which can therefore be used for either IM or IV
administration.
However when given IM it must be diluted as
described above.
30
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
Treatment of Complications of Severe Malaria Disease.
Table 3: Treatment of Other Severe Malaria Complications.
Manifestation/
complication
Immediate management
Coma (cerebral malaria)
Maintain airway, place patient on his or her side, exclude
other treatable causes of coma (e.g. hypoglycaemia, bacterial
meningitis); avoid harmful ancillary treatment such as
corticosteroids, heparin and adrenaline; intubate if necessary.
Hyperpyrexia
Administer tepid sponging, fanning, cooling blanket and
antipyretic drugs.
Convulsions
Maintain airways; treat promptly with intravenous or rectal
diazepam or intramuscular paraldehyde.
Hypoglycaemia
(blood
glucose concentration of
<2.2 mmol/l;
<40 mg/100ml)
Check blood glucose, correct hypoglycaemia and maintain
with glucose-containing infusion.
Severe
anaemia
(haemoglobin
<5 g/100ml or packed
cell volume <15%)
Transfuse with screened fresh whole blood
Acute
oedema
Prop patient up at an angle of 45 , give oxygen, give a
diuretic, stop intravenous fluids, intubate and add positive
end-expiratory pressure/continuous positive airway pressure
in life-threatening hypoxaemia.
pulmonary
o
Acute renal failure
Exclude pre-renal causes, check fluid balance and urinary
sodium; if in established renal failure add haemofiltration or
haemodialysis, or if unavailable, peritoneal dialysis. The
benefits of diuretics/dopamine in acute renal failure are not
proven.
Spontaneous
bleeding
and coagulopathy
Transfuse with screened fresh whole blood (cryoprecipitate,
fresh frozen plasma and platelets if available); give vitamin K
injection.
Metabolic acidosis
Exclude or treat hypoglycaemia, hypovolaemia and
septicemia. If severe add haemofiltration or haemodialysis.
Shock
Suspect septicemia, take blood for cultures; give potential
antimicrobials, correct haemodynamic disturbances. Monitor
frequently
As adapted from the Guideline for the treatment and Diagnosis of
malaria in the Africa region.
NB: IV Quinine shall continue to be the initial treatment of choice
for severe malaria in hospitals until the patient is ready to take
oral medication.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
31
5. Treatment of Malaria Caused By Other Species
AL is the recommended 1
st
line treatment of choice for all types of
uncomplicated malaria species including P. vivax, malariae and ovale.
6. Malaria Prevention
6.1. Malaria Prevention in Pregnancy
Effective chemoprophylaxis during the second and third trimester of
pregnancy greatly reduces the impact of malaria on low birth weight and
episodes of clinical malaria. This led to the recommendation of
systematic regular chemoprophylaxis for pregnant women exposed to
malaria (WHO, 1990). The implementation of this policy has been
limited by a number of factors: increased drug resistance, particularly to
chloroquine;
poor
compliance
associated
with
routine
chemoprophylaxis; patient beliefs about side effects; acceptability and
access to antenatal services; cost of efficacious antimalarial drugs.
Presently, use of chloroquine alone as a prophylactic in pregnancy is
not recommended in areas where P. falciparum resistance to
chloroquine is high. In areas of low to moderate levels of chloroquine
resistance,
WHO
recommends
three
interventions
for
malaria
prevention and control during pregnancy. These are effective case
management, prevention by use of ITNs and Intermittent Preventive
Treatment (IPT) in areas of high transmission.
In Botswana where malaria transmission is low, intermittent treatment
with SP (IPT) is not recommended. A combined regimen of chloroquine
and proquanil continues to be recommended in Botswana. The
recommended dose for Proquanil 200 mg daily and for chloroquine is 5
32
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
mg/kg of body weight weekly, i.e. 300 mg base given weekly throughout
pregnancy. This combination provides substantial protection.
Botswana,
there
is
need
to
evaluate
the
impact
of
In
routine
chemoprophylaxis in pregnancy against the overall malaria burden in
pregnant women.
6.2. Chemoprophylaxis in the General Travelers
There is no safe, effective and affordable anti-malarial drug that can be
used for chemoprophylaxis on a large scale. Secondly, it should be well
understood that no drug can guarantee absolute and complete
protection against malaria. Therefore, the use of personal protective
measures such as the use of ITNs, insect repellents and protective
clothing is recommended. Chloroquine and proguanil is a recommended
drug of choice for chemoprophylaxis for local travelers in Botswana
against all species of plasmodium.
For prophylaxis, chloroquine 5
mg/kg base preferably weekly beginning two weeks before arrival with
daily proguanil 200mg/day, throughout the period of stay and continued
4 weeks after the last possible exposure. Mefloquine prophylaxis is
recommended for travelers to foreign countries. Consultations are
underway to review prophylaxis for local travelers in Botswana.
Table 4: showing Mefloquine dosage
Weight (Kg)
Age(Years)
Number of Tablets per
week
<5
<3 month
Not recommende4d
5-12
3-23 month
1/4
13-=24
2-7
1/2
25-35
8-10
3/4
36-50+
11-14
1
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
33
7. Pharmacovigilance
The use of a new drug or combination of dugs in the population requires
careful monitoring of adverse drug reactions that maybe associated with
the use of such drugs in the broader population. WHO defines
pharmacovigilance (PV) as the science and activities relating to the
detection, assessment, understanding and prevention of adverse effects
or any other medicine-related problem. Pharmacovigilance therefore is
a critical component for the implementation of the new drug policy.
Hence, the monitoring, documentation and reporting of adverse drug
reaction by health workers cannot be over emphasized.
All health care providers and patients are therefore advised to identify
report and document all new and already noted adverse effects and
report to Ministry of Health National Malaria Control Programme. The
programme will have a policy and programme for PV and a set of
reporting forms to allow ease of reporting and transmission at all levels.
Pharmacovigilance of AL is important as it will go a long way in
providing information thereby providing a tool for decision making to
preventing harm to our patients.
8. Drug Resistance Surveillance
Antimalarial drug resistance has emerged as a leading threat to ongoing
malaria control efforts. As resistance to one or more antimalarial drugs
occurs more frequently, malaria control programmes and other
concerned institutions need to be able to evaluate antimalarial drug
efficacy in a way that provides timely, relevant, reliable, and
understandable information. Data derived from these evaluations are
essential not only for maintaining confidence that current treatment
recommendations are adequate in relation to malaria patients' needs,
34
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
but also, should that not be the case, for generating convincing
evidence that current treatment recommendations are in need of
change. When such evaluations are conducted consistently over time
and in a reasonable and representative selection of sites, programmes
should be able to monitor drug efficacy in a way that will allow changes
in treatment recommendations or policies to be made early enough to
minimize the impact of a failing treatment regimen. WHO has
standardized protocols for Monitoring Drug Efficacy.
Botswana will
adopt these guidelines to suit country situation.
AL drug sensitivity and resistance survey of Plasmodium parasite has to
be done periodically. The frequency of the study has to be every 2
years after the start of using AL for the treatment of uncomplicated
malaria. Currently the treatment efficacy sentinel sites are in Chobe,
Ngami, Okavango, Boteti and Tutume.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
35
9. Disease Management at Different Levels of the Health Care
Delivery System
The goals of malaria case management are stated against each level. It
is hoped that this will serve as a useful guide in focusing the use of this
training manual to the desired target group.
HEALTH CARE
FACILITY
Tertiary
CADRE OF STAFF
Consultant,
EXPECTED HEALTH
CARE LEVEL
Intensive care for
Referral Hospitals
Specialists, Medical
severe disease as
officers, Nurses,
well as all the
Pharmacy and
services listed under
Medical Laboratory
primary and
Personnel
secondary care levels
Secondary
Medical officers,
In-patient care
District, Primary,
Nurses Pharmacy
Basic laboratory
Mission, Mines and
and Medical
support for confirming
Private Hospitals
Laboratory
diagnosis and
Personnel.
monitoring. Assessing
complications
Primary
Syndromic approach
Clinics with/without
Medical officers and
focusing on disease
maternity, Health
Nurses
identification, initiation
Posts and Mobile
of appropriate
Stops
treatment and urgent
referral of severe
malaria, Rapid test
36
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
REFERENCES:
1. Guidelines for the Treatment of Malaria, World Health
Organization, 2006.
2. Malaria Manual for Health workers In Botswana, Second
Edition, 1999.
3. The Diagnosis and Management of Uncomplicated and
Severe Malaria, facilitators Guide, Republic of Botswana,
June 2004.
4. The Diagnosis and Management of Uncomplicated and
Severe Malaria, Learners guide, Republic of Botswana, June
2004.
5. Malaria case management operational manual draft. World
Health Organization. 2006
6. Use of Antimalarial Drugs. Report of an Informal Consultation.
World Health Organization. 2000.
7. The Use of Rapid Diagnostic Test, World Health Organization,
2004.
8. Novartis; Coartem Monograph 2001.
9. WHO: Report of World Health Organization Technical
Consultation, 25 – 26 October 2004. (Pre- Publication Copy).
10. Malaria Diagnosis and Treatment Guidelines for Health
Workers in Ethiopia, July 2004.
11. World Health Organization. Management of Severe Malaria- a
nd
Practical Handbook, 2 edition. 1991.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
37
Annex I: Pharmacology of the Drugs used for the treatment of
malaria in Botswana
1. Pharmacology of Artemether - Lumefantrine
Mode of Actions of AL: The precise anti-malarial action of Artemether
and Lumefantrine is unknown, although both appear to act on the
parasite’s cell structures. Artemether contains an endoperoxide bridge,
which interacts with iron in the hemoglobin to generate reactive oxygen
radicals which damage the parasite leading to its death. Lumefantrine is
thought to interfere with haem polymerizations, a critical detoxifying
pathway for the malaria parasite. Artemether rapidly reduces parasite
biomass and quickly resolves clinical symptoms while long acting
Lumefantrine prevents recrudescence. This dual effect also appears to
reduce the selective pressure on the parasite to develop resistance.
Adverse/Side
Effects
and
Their
Management:
Artemether-
Lumefantrine is relatively safer compared to other antimalarial drugs.
The side effects are minimal and these may include:
•
Common side effects: Gastrointestinal disturbances such as
abdominal pain, anorexia, nausea, vomiting, diarrhea, central
nervous system such as headache, dizziness which cannot be
distinguished from symptoms of acute malaria.
•
Less common side effects: Pruritus and rash (<2% of
patients) others include neutropenia, liver enzymes elevation.
Cardiovascular
effects-
bradycardia,
palpitation
and
prolongation of QT interval. Sleep disturbances, cough,
asthenia, arthralgia, and myalgia.
•
Most of these side effects will resolve without discontinuing
treatment. However, in severe cases, treatment with AL must
be discontinued and the recommended second line anti-
38
malarial prescribed.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
Some of the side effects may be managed as follows;
•
Anorexia:-Encourage the patients to eat any food that he/she
enjoys or is palatable to him/her.
•
Nausea and vomiting: - Patients should be advised to take the
medication with food.
•
Diarrhoea: - Patients should be advised to drink water often or
use ORS.
•
Rash and Pruritus (mild):– Reassure the patient that it will stop
after a short time, if severe, discontinue.
Precautions; Caution should be applied in patients known to have,
electrolyte disturbances, hepatic and renal impairment.
Concomitant
use AL with drugs known to cause QT-interval prolongation (e.g.
quinine and mefloquine) should be discouraged. Monitor patients who
are unable to take food while on AL therapy, as they are at greater risk
of recrudescence.
Contra indications: AL is contraindicated in patients with history of
arrhythmias, clinically relevant bradycardia, heart failure, family history
of sudden death or of congenital, QT interval prolongation and persons
with known hypersensitivity to either of the components in AL.
•
It is contraindicated in children weighing less than 5 Kg.
•
It is also contraindicated in severe malaria and first trimester of
pregnancy.
•
However if AL is the only available antimalarial, it may be used
even in the first trimester to save the life of the pregnant woman.
Drug Interaction: Patients should avoid grapefruit juice, antiarrhythmic
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
Guidelines for the Diagnosis and Treatment
39
of Malaria in Botswana
blockers, such as metoprolol and sotalol. However, there is no evidence
that co-administration with these drugs would be harmful especially in
short
term
treatment.
But
where
possible,
avoid
concomitant
administration of AL with any of the drugs above or administer giving a
sufficient time in-between the drugs.
2. Pharmacology of Quinine
Quinine is an alkaloid derived from the bark of the Cinchona tree.
Quinine is the L-stereoisomer of quinidine. It acts principally on the
mature trophozoite stage of parasite development and does not prevent
sequestration or further development stage of circulating ring stages of
P. falciparum. It also kills the sexual stages of P. vivax, P.malariea and
p. ovale but not mature gametocytes of P. falciparum. It does not kill the
pre-erythrocytic stages of malaria parasites.
The mode of action is
thought to involve inhibition of parasite haem detoxification in the food
vacuole, but are not well understood. It is also believed to depress
oxygen uptake and carbohydrate metabolism; intercalates into DNA,
disrupting the parasites replication and transcription.
Pharmacokinetics: The pharmacokinetic properties of quinine are
altered significantly by malaria infection, with reduction in apparent
volume of distribution and clearance in proportion to disease severity.
The concentration is slightly higher in older children and adult with
severe malaria than in children under 2 years of age. Quinine is rapidly
and completely absorbed from Gastro Intestinal Tract (GIT) and peak
plasma concentration is reached in 1-3 hours after oral administration of
the sulphate. Also it is well absorbed in after I.M administration in
severe malaria. Quinine is widely distributed through out the body
including the cerebrospinal fluid, breast milk and placenta. Extensively
metabolized in liver and the elimination of more polar metabolites is
mainly renal. Excretion is increased in acid urine. The mean elimination
40
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
half-life is around 11 h in healthy subjects, 16 h in uncomplicated
malaria and 18 in severe malaria. Small amount appear in the bile and
saliva.
Adverse effects/ Toxicity: Quinine causes complex of symptoms known
as cinchonism which could be mild or severe. Mild symptoms include
tinnitus, impaired hearing, headache, dizziness and dysphoria and
disturbed vision.
Severe manifestations include vomiting, abdominal pain, diarrhea and
severe vertigo. Others include hypersensitivity reactions such as
urticaria, bronchospasm, flushing, and fever, thrombocytopenia and
haemolytic anaemia. The
most
important
adverse
effect
is
hyperinsulinaemic hypoglycemia and this is particularly common
in pregnancy. I.M injection of quinine HCL causes pain, focal necrosis
and in some cases abscess formation. Hypotension and cardiac arrest
may result from rapid intravenous injection. I.V quinine should be given
by
infusion
never
injection.
It
causes
prolongation
of
the
electrocardiograph QT interval. Quinine has been used as an
abortificient, but there is no evidence that it causes abortion, premature
labour or fetal abnormalities in therapeutic use.
Stability: Protect from light.
Precautions: Use with caution in patients with cardiac arrhythmias and
patients with myasthenia gravis.
Contraindication: Quinine is should not be used in patients with tinnitus,
optic neuritis, G-6-Phosphat Dehydrognase deficiency, hypersensitivity
to quinine or any component, history of black water fever (massive
haemolysis with renal failure)
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
41
Drug interactions: Quinine may not be given concurrently with drugs
that cause prolongation of QT interval Flecainide and amidiarone,
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 thioridiazine. 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. Cimetidiine inhibits quinine metabolism, causing increased
quinine levels and rifampicin metabolic clearance leading to low plasma
concentrations and an increased therapeutic failure rate.
3. Pharmacology of Chloroquine
Chloroquine is a 4-aminoquinoline that has been used extensively for
the treatment and prevention of malaria. Widespread resistance has
now rendered it virtually useless against P. falciparum infections in most
parts of the world, although it still 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: Tablets containing 100 mg or 150 mg of chloroquine base
as hydrochloride, 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 (3–
Guidelines for the Diagnosis and Treatment
42
of Malaria in Botswana
5). 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
onodesethylchloroquine,
which
in
has
the
similar
liver,
mainly
to
activity
against
P.
falciparum.
Toxicity: Chloroquine has a low safety margin and is very dangerous in
over dosage. Larger doses of chloroquine are used for the treatment of
rheumatoid arthritis than for malaria, so adverse effects are seen more
frequently in patients with arthritis. The drug is generally well tolerated.
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 over dosage is extremely dangerous and death can occur within
a few hours. The patient may progress from feeling dizzy and drowsy
with headache and gastrointestinal upset, to developing sudden visual
disturbance, convulsions, hypocalcaemia, hypotension and cardiac
Guidelines for the Diagnosis and Treatment
43
of Malaria in Botswana
arrhythmias. There is no specific treatment, although diazepam and
epinephrine (adrenaline) administered together are beneficial.
Drug interactions: Major interactions are very unusual. There is a
theoretical increased risk of arrhythmias when chloroquine is given with
halofantrine or other drugs that prolong the ectrocardiograph 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.
4. Pharmacology of Mefloquine
Mefloquine is a 4-methanolquinoline and is related to quinine. It is
soluble in alcohol but only very slightly soluble in water. It should be
protected from light. The drug is effective against all forms of malaria.
Formulations: Mefloquine is administered by mouth as the hydrochloride
salt (250 mg base equivalent to 274 mg hydrochloride salt). Tablets
containing either 250 mg salt (United States of America) or 250 mg
base (elsewhere)
Pharmacokinetics: Mefloquine is reasonably well absorbed from the
gastrointestinal tract but there is marked inter individual variation in the
time required to achieve peak plasma concentrations. Splitting the 25
mg/kg dose into two parts given at an interval of 6–24 h augments
absorption and improves tolerability). Mefloquine undergoes enter
hepatic recycling. It is approximately 98% bound to plasma proteins and
is widely distributed throughout the body. The
Guidelines for the Diagnosis and Treatment
44
of Malaria in Botswana
Pharmacokinetics: Mefloquine may be altered by malaria infection with
reduced absorption and accelerated clearance. . When administered
with artesunate, blood concentrations are increased, probably as an
indirect effect of increased absorption resulting from more rapid
resolution of symptoms. Mefloquine is excreted in small amounts in
breast milk. It has a long elimination half-life of around 21 days, which is
shortened in malaria to about 14 days, possibly because of interrupted
enterohepatic cycling. Mefloquine is metabolized in the liver and
excreted mainly in the bile and faeces. Its pharmacokinetics show
enantioselectivity after administration of the racemic mixture, with higher
peak plasma concentrations and area under the curve values, and
lower volume of distribution and total clearance of the SR enantiomer
than its RS antipode.
Toxicity: Minor adverse effects are common following mefloquine
treatment, most frequently nausea, vomiting, abdominal pain, anorexia,
diarrhoea, headache, dizziness, loss of balance, dysphoria, somnolence
and sleep disorders, notably insomnia and abnormal dreams.
Neuropsychiatric
disturbances
(seizures,
encephalopathy,
and
psychosis occur in approximately 1 in 10 000 travellers receiving
mefloquine prophylaxis, 1 in 1000 patients treated in Asia, 1 in 200
patients treated in Africa, and 1 in 20 patients following severe malaria
(24–27). Other side effects reported rarely include skin rashes, pruritus
and urticaria, hair loss, muscle weakness, liver function disturbances
and very rarely thrombocytopenia and leukopenia. Cardiovascular
effects have included postural hypotension, bradycardia and, rarely,
hypertension, tachycardia or palpitations and minor changes in the
electrocardiogram. Fatalities have not been reported following over
dosage, although cardiac, hepatic and neurological symptoms may be
seen. Mefloquine should not be given with halofantrine because it
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
45
exacerbates QT prolongation. There is no evidence of an adverse
interaction with quinine.
Drug interactions: There is a possible increase in the risk of arrhythmias
if mefloquine is given Together with beta-blockers, calcium channel
blockers, amiodarone, and pimozide. Digoxin or antidepressants; there
is also a possible increase in the risk of convulsions with chloroquine
and quinine. Mefloquine concentrations are increased when given with
ampicillin,
tetracycline
and
metoclopramide.
Caution
should
be
observed with alcohol.
5. Pharmacology of Proguanil
Proguanil is a biguanide compound that is metabolized in the body via
the polymorphic lytochrome 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 noninfective 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: Tablets of 100 mg of Proguanil hydrochloride containing
87 mg of Proguanil base. In co-formulation with atovaquone.
• Film-coated tablets containing 250 mg of atovaquone and 100 mg of
Guidelines for the Diagnosis and Treatment
46
of Malaria in Botswana
proguanil hydrochloride for adults.
• Tablet containing 62.5 mg of 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 1 h 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 its 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, 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. Over dosage 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.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
47
Annex II: Criteria for Selecting Artemether – Lumefantrine (AL)
over other artemisinin combinations (ACT’s).
WHO recommends the following combinations for use in African
region:1. Artemether/Lumefantrine (AL)
2. Artesunate/Amodiaquine (AA)
3. Artesunate/SP (A/SP)
The following criteria were used to select AL among other ACT:
Artesunate/Amodiaquine (AA) was not selected because Amodiaquine
is very similar to Chloroquine. Both are 4-aminoquinolines with similar
mode of anti-malarial activity, and cross resistance does exist. This
would make the useful life amodiaquine very limited given the high
levels parasite resistance to chloroquine
Artesunate Sulphadoxine-Pyrimethamine (A/SP) was not selected
because SP is a failing anti-malarial medicine in Botswana with
resistance levels up to 23% as from DES 2006. An important principle in
the choice of a combination therapy is that individual drugs used in the
combination must have efficacy of above 95% or better..
For the above reasons AL was the only combination that Botswana
could adopt. In addition the following were extra advantages in favor of
AL.
•
It is already registered for use in Botswana by the Drug
Regulatory Unit (DRU).
•
Lumefantrine is not available as a monotherapy, and has
never been used for malaria in Botswana
•
AL is available as co-formulated tablets containing 20mg of
Artemether and 120mg of Lumefantrine, unlike other
combinations that are available as separate tablets. Coformulation of medications has the advantage of increased
compliance over non-formulated preparations.
48
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
•
AL is widely used in most counties in the SADC region as
first line treatment against malaria. (Namibia, South Africa,
Zambia, Zimbabwe). This is a very important consideration
when one is considering the “cross-border” anti-malarial
initiatives in the region. It will be much easier to share
experiences
with
our
neighbors
if
we
use
similar
medications.
•
The price of AL (Coartem) has recently been reduced by
the manufacturer, Novartis, to half for younger children, and
a quarter for adults. This has made AL more affordable than
before.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
49
Annex III: Performing and Interpreting malaria Rapid Diagnostic
Test including Plates for performing and interpreting RDTs.
Performing and Interpreting the Test
If the preparation is delayed after opening the envelope, the humidity
can damage the RDT. Test lines may become positive several hours
after preparation; and should be read only within the time limit specified
by the manufacturers. The result of malaria RDT should always be
interpreted in the light of the patient’s clinical state, taking into account
the fallibility of the test. A control line must be present for the result to
be valid. Repetition of the test after 1 or 2 days may therefore be
indicated if illness persists or if the patient’s condition deteriorates and
the initial RDT result was negative.
Acting on the Test Result
•
Treatment algorithms and health workers training allow for the
commencement of anti-malarial treatment of cases in which
RDT result is negative, whenever there is a strong suspicion of
malaria.
•
Appropriate further investigation of all case of fever with
negative RDT results is essential.
•
The possibility of concomitant non-malarial illness in which
parasites have been demonstrated should also be considered.
Sometimes RDT results may mislead:
•
A negative test result does not always exclude malaria with
certainty as :
-
There may be insufficient parasites to register a
positive result.
-
The RDT may have been damaged thereby reducing
its sensitivity.
-
50
Illness may be caused by another species of malaria
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
51
52
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
Annex IV: DECISION CHART FOR TREATMENT OF MALARIA
Patient with fever, other signs and symptoms
(Suspected Case of Malaria )
Reports to health care facility
Health Care Worker to do
Rapid Diagnostic Test
and take
Peripheral Blood Smear for Malarial Parasite
RDT or Slide Positive
RDT or Slide Negative
Confirmed Malaria
Malaria unconfirmed
Severe
Disease
Commence treatment
with quinine and refer
to higher health care
facility. Take blood
slide before treatment
Uncomplicated
Disease
Treat with AL
Search for other illnesses. Provide
supportive treatment and manage
accordingly. Repeat slide/RDT after 6
hours. If slide positive, treat as
malaria, if still negative, review after
24 hours for another RDT/blood slide.
Advise to return to health centre
anytime if symptoms become severe
before the 24hrs review
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
53
ANNEX V: COMA MONITORING SCALES
Table 1:. The Glasgow Coma Score (for Adults and Children over 12yrs)
Eyes open
- Spontaneously
- To speech
- To pain
- Never
4
3
2
1
Best verbal
- oriented
- response- confused
- in appropriate words
- incomprehensible sounds
- none
5
4
3
2
1
Best motor response
- obeys commands
- localizes pain
flexion to pain:
withdrawal
abnormal
6
5
- extension to pain
- none
2
1
Total
4
3
3-15
To obtain the Glasgow coma score obtain the score for each section add the
three figures to obtain a total.
54
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
Table 2: The Malaria Coma scale (The Blantyre Coma Scale) (for children
< 12 years)
Eyes movement
-Directed
(eg follows mothers face)
- Not directed
1
Verbal response
- Appropriate cry
- Moan or inappropriate cry
- None
2
1
0
Best motor response
- Localizes painful stimulus (a or c)
- Withdraws limb from pain (b)
- Non-specific or absent response
2
1
0
Total
0-5
0
Press knuckles firmly on the patients sternum
Press firmly on the thumbnail bed with side of a horizontal pencil
Press firmly on the supra-orbital groove with the thumb
The scales can be used repeatedly to assess improvement or deterioration.
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana
55
Annex VI: List of Technical Working Group
Dr. L. Grezl
Consultant Physician,
Nyangabgwe Referral Hospital
Dr Abebe Gobeze
Public Health Specialist UNICEF,
Botswana
Dr. P. G. Chikuta
Chief Medical Officer,
Tutume Primary Hospital
Dr. S. K. Madan
Pediatrician,
Nyangabwe Referral Hospital (NRH)
Mr. A. Okoye
Pharmacist, BEDAP, Ministry of Health
Dr. Nesredin J. Oumer
Public Health Specialist,
Malaria Control Programme
Dr. N. T. Gokhale
Consultant Microbiologist, (NRH)
Mr. B. Khupe
Chief Medical Laboratory Technician,
NRH
Ms. T. Mosweunyane
Manager,
National Malaria Control Programme
56
Guidelines for the Diagnosis and Treatment
of Malaria in Botswana