The Ministry of Public Health of Guyana, National Malaria Program and Pan-American Health

Organization presents the “Malaria Treatment Guideline for health facilities in Guyana” updated,

MINISTRY OF PUBLIC HEALTH 2015, Georgetown.

All rights reserved. This document may be reviewed, summarized, cited, reproduced, or translated

freely, in part or in its entirety with credit given to the Ministry of Public Health in Guyana. It

cannot be sold or used for commercial purposes.

Requests for further information on this publication should contact: National Malaria Control

Program of Guyana, Ministry of Public Health in Guyana JUNE 2015.

Acknowledgments

This version of Malaria treatment Guideline manual was updated by the Ministry of Health in

Guyana with support from the Pan-American Health Organization/World Health Organization.

We would like to express our gratitude to the Participants in the National Treatment Guidelines

Review.

For the Technical and Secretarial support the ministry of Health would like to acknowledge

either those who reviewed, commented or supported the update and additions of the 2013

Malaria Treatment Guideline.

Dr Shamdeo Persaud

Chief Medical Officer

Ministry of Health

TABLE OF CONTENTS

Acknowledgments…………………………………………………………………..II

Table of context……………………………………………………………….… III-IV

Abbreviations…………………………………………………………………….. VI

Glossary………………………………………………………………………… VII-IX

Foreword…………………………………………………………………………….X

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ABBREVIATIONS

ACT Artemisinin-based combination therapy

AL Artemether-lumefantrine combination

AS Artesunate

AS+MQ Artesunate + mefloquine combination

ATM Arthemeter

ATM-LUM Arthemeter-Lumefantrine

CI Confidence interval

CQ Chloroquine

DIC Disseminated intravascular coagulation

EBT Exchange Blood Transfusion

EIR Entomological inoculation rate

GCS Glasgow coma scale

GPHC Georgetown Public Hospital Corporation

G6PD Glucose-6-Phosphate Dehydrogenase Deficiency

HIV/AIDS Human immunodeficiency virus/

Acquired immunodeficiency syndrome

IM Intramuscular

IV Intravenous

MOH Ministry of Health

MQ Mefloquine

NVCS National Vector Control Services

PAHO Pan American Health Organization

Pf Plasmodium falciparum

Pm Plasmodium malariae

Pq Primaquine

Pv Plasmodium vivax

RAVREDA Amazon Network for Surveillance of Antimalarial Drug Resistance

(Spanish acronym).

RBM Roll Back Malaria

RDT Rapid Diagnostic Test

SP Sulfadoxine–pyrimethamine

VBD Vector Borne Disease

WHO World Health Organization

GLOSSARY

Acute renal failure (ARF) : Also known as acute kidney failure, is a rapid loss of renal function

due to damage to the kidneys, resulting in retention of nitrogenous (urea and creatinine) and

non-nitrogenous waste products that are normally excreted by the kidney, patient remains

oliguric (<0.4 ml of Urine /kg, per hour).

Afebrile: Without fever.

Anaemia: A reduction in the quantity of the oxygen-carrying pigment haemoglobin in the

blood.

Anti-pyretic: A drug such as paracetamol that relieves fever without affecting the causative

agent (in this case the parasite).

Adequate clinical and parasitological response (ACPR): Absence of parasitaemia on day 28,

irrespective of axillary temperature, in patients who did not previously meet any of the criteria

of early treatment failure, late clinical failure or late parasitological failure.

Artemisinin-based combination therapy (ACT). A combination of artemisinin or one of its

derivatives with an antimalarial or antimalarials of a different class.

Asexual cycle. The life-cycle of the malaria parasite in host red blood cells (intraerythrocytic

development) from merozoite invasion to schizont rupture (merozoite ring stage, trophozoite,

schizont, merozoites). Duration approximately 48 hrs in P. falciparum, P. ovale and P. vivax;

72 hrs in P. malariae.

Asexual parasitaemia. The presence of asexual parasites in host red blood cells. The level of

asexual parasitaemia can be expressed in several different ways: the percentage of infected red

blood cells, the number of infected cells per unit volume of blood, the number of parasites seen

in one microscopic field in a high-power examination of a thick blood film, or the number of

parasites seen per 200–1000 white blood cells in a high-power examination of a thick blood

film.

Base: The main active part of a drug (see salt).

Cerebral malaria. Severe falciparum malaria with coma (Glasgow coma scale <11, Blantyre

coma scale <3). Malaria with coma persisting for >30 min after a seizure is considered to be

cerebral malaria.

Chemoprophylaxis: The protection from, or prevention of, disease by the use of drugs.

Cinchonism: Poisoning caused by an overdose of cinchona or the alkaloids quinine, quinidine,

or cinchonine derived from it.

Combination treatment (CT). A combination of two or more different classes of antimalarial

medicines with unrelated mechanisms of action.

Cure. Elimination of the symptoms and asexual blood stages of the malaria parasite that caused

the patient or carrier to seek treatment.

Drug resistance. Reduced susceptibility of the causal agent to a drug. WHO defines resistance

to antimalarials as the ability of a parasite strain to survive and/or multiply despite the

administration and absorption of a medicine given in doses equal to – or higher than – those

usually recommended but within the tolerance of the subject, with the caveat that the form of

the drug active against the parasite must be able to gain access to the parasite or the infected red

blood cell for the duration of the time necessary for its normal action. Resistance to antimalarials

arises because of the selection of parasites with genetic mutations or gene amplifications that

confer reduced susceptibility.

Early treatment failure: Danger signs or severe malaria on day 1, 2 or 3 in the presence of

parasitaemia; parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature;

parasitaemia on day 3 with axillary temperature ≥ 37.5 ºC; parasitaemia on day 3 ≥ 25% of

count on day 0.

Endemicity: Occurring frequently in a particular region or population

Febrile: With an increase in temperature compared with the normal.

Febrile convulsions: Convulsions occurring in children aged 6/12 - 6yrs due to fever caused

by infection outside the central nervous system

Fever: Arise in body temperature above the normal temperature i.e. above an oral temperature

of 37.5°C.

G6PD deficiency: G6PD is a critical housekeeping enzyme in red blood cells that intervenes,

with no alternative pathways, against oxidative challenge. G6PD deficiency is an inherited

genetic disorder, which is associated with some protection against severe P. falciparum malaria

infections, but also with increased susceptibility to oxidant haemolysis. In G6PD-deficient

patients, a 14-day regimen of primaquine may induce dose dependent haemolysis.

Gametocytes. Sexual stages of malaria parasites present in the host red blood cells, which are

infective to the anopheline mosquito.

Glasgow coma scale: Is a neurological scale that aims to give a reliable, objective way of

recording the conscious state of a person for initial as well as subsequent assessment

Immunity: All those natural processes which prevent infection, re-infection, or super infection,

or which assist in destroying parasites or limiting their multiplication, or which reduce the

clinical effects of infection.

Heamoglobinuria: Pass urine with blood (Haemoglobin).

Hyperlacticaemia: High lactic levels in the blood.

Hyperparasitemia: A high density of parasites in the blood, which increase the risk of

deterioration to sever malaria (although the risk varies in different endemic areas according to

the level of transmission) and of subsequent treatment failure. In this document, the term is used

to refer to a parasite density >4 %( ~200,000/µl). Patients with P falciparum parasites densities>

10% and patients with P knowlezi parasite density >100 00 do not have evidence of vital organ

dysfunction

Hyperpyrexia: Temperature over 39.5°C

Hypersensitivity: Prone to respond abnormally to the presence of a particular antigen, this may

cause a variety of tissue reactions ranging from serum sickness to an allergy.

Hypnozoites. Persistent liver stages of P. vivax and P. ovale malaria that remain dormant in

host hepatocytes for a fixed interval (3–45 weeks) before maturing to hepatic schizonts. These

then burst and release merozoites, which infect red blood cells. Hypnozoites are the source of

relapses.

Late clinical failure: Danger signs or severe malaria on any day between day 4 and day 28 in

the presence of parasitaemia in patients who did not previously meet any of the criteria of early

treatment failure; presence of parasitaemia on any day between day 4 and day 28 with axillary

temperature ≥ 37.5 ºC (or history of fever) in patients who did not previously meet any of the

criteria of early treatment failure.

Late parasitological failure: Presence of parasitaemia on any day between day 7 and day 28

with axillary temperature < 37.5 ºC in patients who did not previously meet any of the criteria

of early treatment failure or late clinical failure.

Lumbar puncture: The insertion of a needle into the fluid-filled space of the spinal cord in the

lumbar region and the removal of a sample of fluid for examination.

Malaria pigment (haemozoin). A dark brown granular pigment formed by malaria parasites

as a by-product of haemoglobin catabolism. The pigment is evident in mature trophozoites and

schizonts.

Merozoites. Parasites released into the host bloodstream when a hepatic or erythrocytic

schizont bursts. These then invade the red blood cells.

Metabolic acidosis: Is a state in which the blood pH is low (less than 7.35) due to increased

production of H+ by the body or the inability of the body to form bicarbonate (HCO3-) in the

kidney. Its causes are diverse, and its consequences can be serious, including diarrhoea, coma

and death. Together with respiratory acidosis, it is one of the two general types of acidosis.

Monotherapy. Antimalarial treatment with a single medicine (either a single active compound

or a synergistic combination of two compounds with related mechanism of action).

New case. Person with a positive diagnosis for malaria

Non-inmune: Having no immunity at all to a particular organism or disease.

Opistotonic: (opisthotonus): Neurology; A type of spasm in which the head and heels arch

backward in extreme hyperextension and the body forms a reverse bow.

Parenteral: The provision of medication into the body by any means other than through the

alimentary canal (oral route or rectal), such as by subcutaneous, intramuscular or intravenous

injection.

Plasmodium. A genus of protozoan invertebrate blood parasites that includes the causal agents

of malaria. Plasmodium falciparum, P. malariae, P. ovale and P. vivax cause malaria in humans.

Pre-erythrocytic development. The life-cycle, generally asymptomatic, of the malaria parasite

when it first enters the host. Following inoculation into a human by the female anopheline

mosquito, sporozoites invade parenchyma cells in the host liver and multiply within the

hepatocytes for 5–12 days, forming hepatic schizonts. These then burst liberating merozoites

into the bloodstream, which subsequently invade red blood cells.

Pruritus: Itching caused by local irritation of the skin or sometimes nervous disorders.

Radical cure. In P. vivax and P. ovale infections, this comprises cure as defined above plus

prevention of relapses.

Rapid diagnostic test (RDT). An antigen-based stick, cassette or card test for malaria in which

a coloured line indicates that plasmodial antigens have been detected.

Recheck. A smear done to follow up a patient that has received treatment for a new infection.

A recheck is positive when parasites are found on or before day 28. Patients follow up are

suggested to be done on days 7, 14, 21 and 28. If positive after day 28, it will be considered a

new case.

Recrudescence. The recurrence of asexual parasitaemia after treatment of the infection with

the same infection that caused the original illness (in endemic areas now defined by molecular

genotyping). This results from incomplete clearance of parasitaemia by treatment and is

therefore different to a relapse in P. vivax infections.

Renewed manifestation of infection believed due to the survival of malaria parasites in the

blood.

Recurrence. The recurrence of asexual parasitaemia following treatment. This can be caused

by a recrudescence, a relapse (in P. vivax and P. ovale infections only) or a new infection.

Relapse. The recurrence of asexual parasitaemia in P. vivax and P. ovale malaria deriving from

persisting liver stages. Relapse occurs when the blood stage infection has been eliminated but

hypnozoites persist in the liver and mature to form hepatic schizonts. After a variable interval

of weeks (tropical strains) or months (temperate strains) the hepatic schizonts burst and liberate

merozoites into the bloodstream.

Resistance: The ability of a parasite to multiply or survive in the presence of concentrations of

a drug that normally destroys parasites of the same species or prevents their multiplication.

Ring stage. Young usually ring-shaped intra-erythrocytic malaria parasites, before malaria

pigment is evident under microscopy.

Salt: Any compound of a base and an acid, e.g. Quinine dichloride or quinine sulphate.

Schizonts. Mature malaria parasites in host liver cells (hepatic schizonts) or red blood cells

(erythrocytic schizonts) that are undergoing nuclear division, process called schizogony.

Selection pressure. Resistance to antimalarials emerges and spreads because of the selective

survival advantage that resistant parasite have in the presence of antimalarials that they are

resistant to. Selection pressure describes the intensity and magnitude of the selection process;

the greater the proportion of parasites in a given parasite population exposed to concentrations

of an antimalarials that allow proliferation of resistant, but not sensitive parasites, the greater is

the selection pressure.

Sensitivity: Possessing the ability to respond to a stimulus.

Severe anaemia: Haemoglobin concentration of < 5 g/100 ml (haematocrit < 15%).

Severe falciparum malaria: Acute falciparum malaria with signs of severity and/or evidence

of vital organ dysfunction

Shock: Clinical syndrome characterized by inadequate oxygenation and perfusion to supply the

body's metabolic needs. There is simply a loss of sufficient blood pressure to generate an

adequate pressure gradient to maintain tissue perfusion. This leads to a loss of oxygen supply

and the deterioration of energy dependent processes at cellular level and lactic acidosis.

Spontaneous bleeding: Haemorrhagic from gums, nose, gastrointestinal tract, etc., and /or

substantial laboratory evidence of DIC (Disseminated intra-vascular coagulation) and

Coagulopathy.

Sporozoites. Motile malaria parasites that are infective to humans, inoculated by a feeding

female anopheline mosquito. The sporozoites invade hepatocytes.

Steven–Johnson Syndrome: An inflammatory condition characterized by fever, large blisters

on the skin, and ulceration of the mucous membranes. It may be a severe allergic reaction to

certain infections or drugs.

Transmission intensity. The intensity of malaria transmission measured by the frequency with

which people living in an area are bitten by anopheline mosquitoes carrying sporozoites. This

is often expressed as the annual entomological inoculation rate (EIR), which is the number of

inoculations of malaria parasites received by one person in one year.

Treatment failure: Defined as a failure to achieve the desired therapeutic response after the

initiation of therapy. Treatment failure is not synonymous with drug resistance.

Trophozoites. Stage of development of the malaria parasites within host red blood cells from

the ring stage and before nuclear division. Mature Trophozoites contain visible malaria pigment.

Uncomplicated malaria. Symptomatic infection with malaria parasitaemia without signs of

severity and/or evidence of vital organ dysfunction.

Foreword …. Malaria remains a serious public health problem worldwide. It has more than 500 million cases and costs

more than $ 1.5 million annually. Historically and today, malaria remains a scourge of the poor and

vulnerable. It is an obstacle to achieving the Millennium Development Goals (MDGs) and the initiative

to Roll Back Malaria.

Guyana has achieved significant progress in the fight against malaria and we believe that the medicines

to treat malaria must be well known, managed by health personnel and available to all patients who need

them. However, the main problem is often limited access, misuse of those and other medicines.

New medicines against malaria are rapidly becoming available and the ability of a country to quickly

access to them depends on several prerequisites, including the availability of funds, the ability of human

capital and the recognition that behavior, underdevelopment and poverty are the main determinants of

disease dynamics.

In preparing this guide for the treatment of malaria, we have embarked on the development of one

strategy for early diagnosis and treatment for the people of Guyana, in the fight against malaria. This is

a review of the first version developed in 2004 with all updated content, adding further complicated

treatment guidelines, malaria in pregnancy (complicated and uncomplicated) making it more a complete

guide.

Working to achieve profound changes in these factors are the essential ingredients for proper treatment,

to take control and if possible, elimination of this public health problem. Diagnosis by microscopy and

rapid tests are also very important for a successful fight against malaria. Therefore, our strategies must

be clearly aimed at making it accessible to a quick diagnosis and treatment, taking advantage of these

new tools to break the transmission of this disease.

However, in addition to access to these tools, sustainability is critical to controlling and ultimately

eliminating this disease. Only if we work in coordination to succeed, we can win!

I recommend this guide for the treatment of malaria, urging all to work with commitment and dedication

in health posts and hospitals in Guyana, the knowledge contained in this guideline will assist us to

achieve our goals and objectives, even in the most remote or inaccessible villages.

I want to express gratitude and thanks to all who worked on this document. I urge commitment from all,

to provide universal access to prevention services, treatment and care to all people, in particular, those

living in the regions of Guyana where malaria is a problem and we must remember that the goal is the

elimination of malaria by 2020.

With regards,

Dr. George Aubrey Norton

Minister of Public Health, Guyana.

1. Introduction The impact of malaria on the health and economic development of human populations is

greatest in the tropics and sub-tropics. The World Health Organization (WHO) has estimated

that malaria caused an estimated 198 million cases (range, 124–283 million) and 584,000 deaths

in 2013; but malaria is preventable and a curable disease.

Most countries in the Americas have adopted the WHO Global Strategy for Malaria Control

and the “Roll Back Malaria Initiative” (RBM) which emphasizes prompt and effective anti-

malarial treatments as the major means of reducing malaria morbidity and mortality. The

ultimate success of this strategy rests on the ability of Ministries of Health to provide anti-

malarial medicines with proven therapeutic efficacy.

Malaria has, over the last 10 years, posed a serious challenge to the public health of people

living and working in the hinterlands areas of Guyana. In responding to this challenge, the

Government through the Ministry of Health strives to implement comprehensive programs

integrated within the primary health delivery system, to achieve the objective of regional and

global initiatives in reducing the impact of malaria. The regional initiative through the Amazon

Initiative cooperation and RAVREDA has recommended early diagnosis and prompt treatment,

continuous surveillance and monitoring of treatment efficacy. The RBM Initiative of the World

Health Organization emphasizes the need for better coordinated approaches to malaria

management, following approved clinical guidelines and the selective integrated vector control

as joint actions to fight malaria. Guyana agreed to adopt and follow the generic

recommendations contained in the new WHO “Malaria Treatment Guidelines” published in

2006 and in 2010, as the base document for the preparation of these national guidelines for

malaria management in Guyana.

The goal of the National Malaria Control Program is to reduce the social and economic impact

of malaria on individual and communities, mitigating the negative contribution of malaria to

poverty, thus contributing to national development. Optimizing and building upon the

achievements of the previous period and to usher the country towards achieving the RBM and

the United Nations Millennium Development Goal targets.

The national treatments guidelines, recommended in this new revised version for malaria, are

based on evidence compiled by in vivo studies undertaken in Guyana. These guidelines

recommend antimalarials which are known to be efficacious and safe and which are unlikely to

be affected by resistance in the near future once correctly applied at all levels of the health care

system in Guyana.

The Manual consist of the following sections: the epidemiological situation of malaria in

Guyana updated until 2014, the antimalarial treatment policy, the guidelines for timely

diagnosis and adequate doses of the treatment for complicated and uncomplicated malaria and,

in unstable and specific populations in special circumstances.

The Ministry of Public Health’s goal is to provide the best standardized treatment of malaria

for the public and private sector in Guyana.

2. Global Epidemiological situation

The World Malaria Report 2011 summarizes information received from 106 malaria-endemic

countries and a range of other sources. It analyses prevention and control measures according

to a comprehensive set of indicators, and highlights continued progress towards global malaria

targets. This year's report builds primarily on data received from countries for the year 2010.

The report shows clear progress in the fight against malaria and a decline in estimated malaria

cases and deaths. For the first time, the report contains individual profiles for 99 countries with

ongoing malaria transmission.

During the past decade, malaria incidence and mortality rates have been cut in all regions of the

world, according to the World Malaria Report 2011. In 2010, there were an estimated 216

million cases of malaria in 106 endemic countries and territories in the world. An estimated

81% percent of these cases and 91% of deaths occurred in the WHO African Region. Globally,

86% of the victims were children under 5 years of age.

There were an estimated 655 000 malaria deaths in 2010, which is 36 000 lower than the year

before. While this 5% year-on-year decline represents significant progress, the mortality figures

are still disconcertingly high for a disease that is entirely preventable and treatable. The impact

of malaria on the health and economic development of the human population is the greatest in

the tropics and sub-tropics.

According to the World Malaria Report 2010, malaria continues to be prevalent in these 106

countries of the tropical and semitropical world, with 35 countries in central Africa bearing the

highest burden of cases and deaths. Compared to a century earlier, the area of malaria risk has

reduced from 53% to 27% of the Earth’s land surface and the number of countries exposed to

some level of malaria risk has fallen from 140 to 106. In 2007, 2.37 billion people were

estimated as being at risk of P. falciparum malaria worldwide, with 26% located in the WHO

AFRO region compared to 62% in the combined SEARO-WPRO regions. Of this total

population at risk, about 42% or almost 1 billion people lived under extremely low malaria risk.

2.1 Malaria- a deadly disease Malaria is a potentially deadly tropical disease characterized by cyclical bouts of fever with

muscle stiffness, shaking (rigors) and sweating. It is caused by a tiny parasite, genus

Plasmodium, that is transmitted by the female anopheline mosquito, genus Anopheles, when

she feeds on blood as a meal, to develop her eggs.

Humans are generally host to four species of malaria parasites: Plasmodium falciparum, P.

vivax, P. ovale, and P. malariae. However, reports from the forested regions of South-East Asia

and particularly the Island of Borneo suggested increased human infections with the monkey

malaria parasite P. knowlesi. P. falciparum causes the most dangerous complications, such as

cerebral malaria. It is the species that is most virulent and potentially lethal to humans.

Human malaria parasites only develop in anopheline mosquitoes. The parasites move to the

salivary glands of the mosquito and are injected into a human host by the feeding insect. The

rush hour contact with mosquitoes and malaria infection is between 5 pm to 5 am. Malaria can

also be acquired from an infected blood transfusion.

Signs and symptoms

Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia caused

by hemolysis, hemoglobinuria (blood in urine), retinal damage, and convulsions.

The classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor

and then fever and sweating lasting four to six hours, occurring every two days in P. vivax and

P. ovale infections, and every three days for P. malariae. P. falciparum can have recurrent fever

every 36–48 hours or a less pronounced and almost continuous fever.

Malaria has been found to cause cognitive impairments, especially in children. For reasons that

are poorly understood, but that may be related to high intracranial pressure, children with

malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage.

Widespread anaemia, caused by malaria during a period of rapid brain development, also

produces direct brain damage. Cerebral malaria, to which children are more vulnerable, is

associated with retinal whitening.

2.2 Malaria control in Guyana

The Republic of Guyana is bordered by the Atlantic Ocean to the north, Suriname to the east,

Venezuela on the west and Brazil to the south-west. Most of Guyana’s interior is classified as

parts of the Amazon Basin. With a land area of approximately 214,000 square kilometers, it is

divided into ten administrative regions (Regions 1 to 10) and four geographical regions; the

interior savannahs, the highland region, the hilly sand and clay area and the low coastal plain.

Based on the 2012 National Census, Guyana has a total population of 747,884; most of it, 89%,

lives in the coastal areas in regions 2, 3, 4, 5, 6 &10. The hinterland regions (1, 7, 8 and 9) have

a total of 81,623 which represents 10.9% of the country’s population.

The National Malaria Eradication Programme began in the 1950’s and by 1974 the number of

cases of malaria had decreased from thirty-two thousand to seventy two cases in the entire

country. Malaria was eliminated from the highly populated coastal area. With the decrease in

morbidity and mortality associated with the disease and the oil crisis in the late 1970’s, malaria

expenditure was reduced, resulting in a resurgence of the disease reaching a peak of more than

84,000 cases in 1995, mostly in the hinterland Regions 7, 8 and 9.

The national program was restructured in the late 1980s to a control program with emphasis on

early detection and treatment in the hinterland regions; along with strengthen capacity for

central supervision and management. Following these changes, there was a subsequent decrease

in the number of cases until 1999 with a total of 27,283 cases and maintained until 2004 at an

average of 25,900 cases annually. Reported new cases were further reduced during the period

2006 to 2009 following a spike in 2005 with almost 40,000 cases reported with more people

ventured further into the high risk malaria endemic areas to seek gold.

During the period 2006 to 2009, with renewed efforts supported by the Global Fund for control

by prompt diagnosis and treatment of all cases and the promotion of LLINs, the number of

reported cases decreased to an average of 14,500 cases annually in the period mentioned above.

However, once again in 2010, the escalating demand for gold on the global market lead to

increases in mining activities in the hinterland region, causing the reported number of cases to

increase to more than 31,000 in 2012 and 2013 (Figure 1).

P. vivax is currently the most frequent malaria species in Guyana (53% of the cases in 2014).

Approximately 97% of the cases are among persons who, either, reside permanently, or are

itinerant workers in Regions 1, 7, 8, 9, where mining and logging form the predominant source

of income.

The large itinerant population consists mainly of male adults, among whom the majority of

cases occur. Persons of all age groups are at risk depending on their behavior pattern. There is

risk of transmission in remote areas; there is no evidence of sustained transmission occurring

along the coastal area, which includes the capital city of Georgetown (Regions 2, 3, 6 and 10).

2.3 Disease management at the different levels of the health care delivery system

Health services in Guyana are delivered by a five level system based on the primary health care

system outlined in the Alma Ata declaration of 1974 for health for all. The entry point in

hinterland communities is the health posts, but most parts of the coastal area is served by

primary health centres managed by medical doctors and Medex (Medical Extension Officer).

Those entry points are supported by a referral network of district hospitals offering in and out

patient care, and regional hospitals offering more specialized services. The fifth level of the

system consist of the national referral hospital (Georgetown Public Hospital Corporation) and

other specialized facilities.

Disease management varies in complexity and specificity according to the different levels of

the referral system of the health care network in Guyana. At the entry points of the system the

emphasis is on preventative services and basic malaria diagnosis and treatment. District and

regional hospitals serve as management sites for more critical and complicated cases. The

national referral hospital in Georgetown provides critical care and treatment for cerebral malaria

and complicated malaria.

The central malaria clinic serves as a diagnostic and treatment site, and a training hub. Many of

the mobile populations access essential diagnostic and treatment services for malaria at this

facility.

2.4 Interventions

Several strategies of intervention are used in the malaria control in Guyana, these include:

prompt and reliable case management, integrated vector control, comprehensive

epidemiological surveillance, decentralization and integration of the malaria program into the

PHC service, and information, education, communication (IEC) with community participation.

Early diagnosis, prompt and appropriate treatment allows for effective management of the

disease. The diagnosis of malaria is based on clinical suspicion confirmed by the detection of

parasites in the peripheral blood. Prompt and accurate diagnosis in endemic areas is important

for the most vulnerable groups in the targeted population (young children, pregnant mothers

and the immunological naïve population). These vulnerable groups are at increased risk for

complications unless diagnosed early and adequately treated.

Accurate diagnosis will reduce unnecessary treatment and improve the management of other

illnesses that are also characterized by febrile attacks. Thus accurate malaria diagnosis is

important for the prognosis of patients with febrile illness.

Parasitological diagnosis has the following advantages:

1. Improved patient care in parasite positive patients.

2. Identification of parasite negative patients in whom other diagnosis must be sought.

3. Prevention of unnecessary use of anti-malarial.

4. Confirmation of treatment failure.

In the mining areas, easy access to medicines which are not recommended by the Ministry

of Health is a problem for the malaria control in Guyana. The indiscriminate use of these

drugs which can suppress clinical symptoms (for a period of time) makes it difficult to detect

cases by diagnosis and could lend to widespread resistance.

3. Antimalarial treatment policy

3.1 Historical outline of anti-malarial treatment policies in Guyana

Since 1940 the treatment protocols have varied for the treatment of P. falciparum, as shown

below.

Table 1 Chronological review of malaria treatment regimen in Guyana

PERIOD

BLOOD SCHIZONTICIDALS

TISSUE/GAMETOCYTOCIDALS 1940 – 1975 Chloroquine 25 mg/kg over 3 days Primaquine 0.75 mg/kg as a

single dose

1975 – 1978 Sulfadoxine 25 mg/kg + Pyrimethamine 1.25

mg/kg

1975 – 1979 Quinine10 mg/kg over 3 days + Tetracycline 5

mg/kg over 7 days

1980 Quinine10 mg/kg over 7 days + Tetracycline 5

mg/kg over 7 days

1980 Quinine10 mg/kg over 3 days + Sulfadoxine 25

mg/kg + Pyrimethamine 1.25 mg/kg on day 4

single dose

Primaquine 0.75 mg/kg on day 4

single dose

1980 – 1983 Quinine 10 mg/kg for 7 days

1984 – 1998 Quinine 10 mg/kg for 5 days + on day 6

Sulfadoxine 25 mg/kg + Pyrimethamine 1.25

mg/kg

Primaquine 0.75 mg/kg on day 6

1999 – 2002 Quinine 10 mg/kg For 7 days Primaquine 0.75 mg/kg on day

one

2002 – 2004 Mefloquine 25 mg/kg over 2 days Primaquine 0.75 mg/kg on day

one

2004 Co-artem® twice daily for 3 days Primaquine 0.75 mg/kg with

presence of gametocytes on day

one

2006 Artesunate + Mefloquine

2007-

present

Co-artem® twice daily for 3 days Primaquine 0.75 mg/kg as a

single Source MOH (this is compiled base on historical data).

3.2 Therapeutic efficacy of antimalarials medicines

As in the rest of the Amazon region, P. falciparum malaria in Guyana is resistant to chloroquine

and sulfadoxine-pyrimethamine. In 2004, Guyana’s antimalarial treatment policy changed and

introduced the use of therapeutic combinations with artemisinin derivatives as first line treatment

for uncomplicated P. falciparum malaria.

In 2004, under the Amazon Network for Surveillance of Antimalarials Drug Resistance

(Spanish acronym “La Red Amazónica de Vigilancia de la Resistencia de los Antimaláricos”)

(RAVREDA), the Ministry of Health initiated in-vivo studies to provide the required evidence-

base information to revise the national antimalarials treatment policy.

Arthemether/lumefantrine (Coartem®) was evaluated and proposed as the first line treatment

for P. falciparum malaria. Mefloquine and Artesunate as a combination therapy was assessed

and suggested as the second-line treatment. The results of both studies revealed that both

therapies demonstrated significant antimalarial responses to falciparum malaria.

3.2.1 Assessment of Artemether /Lumefantrine (Coartem®) /in vivo study

The efficacy and safety of the six-dose regimen of arthemether + lumefantrine (Co-artem®,

Novartis) was assessed on 73 patients according to the standard in-vivo study for Guyana

adopted from WHO standard protocol for in-vivo study (2004). A total of 72 patients were

enrolled. All the patients completed treatment and 65 of them ended the 28-day follow-up

period, only one was lost to follow-up. Co-artem® induced rapid clearance of parasites with

88.9% on day 2 and 100% on day 3. The 28-day cure rate was 100% (Adequate Clinical and

Parasitological Responses).

In 2007/2008 another clinical study was conducted to evaluate the efficacy of arthemether-

lumefantrine treatment in Guyana. In this new study 90 patients were included. Blood smears

and blood filter papers were collected during a 28 day follow-up and external microscopic

quality control (QC) data showed that no therapeutic failure had occurred after arthemether-

lumefantrine treatment. This was confirmed after PCR correction and genotyping.

3.2.2 Mefloquine vs Mefloquine with Artesunate

The Efficacy and Safety of Monotherapy Mefloquine against Mefloquine with Artesunate as

the treatment of acute, uncomplicated Plasmodium falciparum malaria infections in Mahdia,

was assessed on 86 patients for each arm of the standard in-vivo study WHO protocol in 2005.

In the Mefloquine arm (25mg/kg), 86 patients were enrolled, 3 (3.4 %) were lost to follow up

and 1 (1.2 %) was a withdrawal. From the 82 patients remaining, 79 (96.3%) had an adequate

clinical/parasitological response, 2 (2.4%) presented as early treatment failure and 1 (1.2%) as

late treatment failure.

In the Mefloquine with Artesunate arm (25mg/kg in 2 days dose /12mg/kg in 3 days), 86

patients were enrolled and 4 (4.6%) were lost to follow up. From 82 patients remaining in the

study, 81 (98.8%) presented adequate clinical and parasitological responses and 1 (1.2%) as a

late parasitological failure.

These results confirmed the excellent efficacy and safety of the 6-dose regimen of artemether-

lumefantrine for the treatment of P. falciparum malaria in Guyana and the mefloquine and

mefloquine with artesunate as a second line. Further, to demonstrate adherence problems with

this 3-day treatment of Co-artem®, health awareness and education is a necessary component

(3) in Guyana.

4. Diagnosis Prompt and accurate diagnosis of malaria is part of effective disease management and will, if

implemented effectively, help to reduce unnecessary use of antimalarials. High sensitivity and

specificity of malaria diagnosis is important in all settings, to allow for prompt treatment, while

reducing unnecessary treatment with antimalarials and improving differential diagnosis of

febrile illness.

The diagnosis of malaria is based on clinical criteria (clinical diagnosis) confirmed by the

detection of parasites in the blood (parasitological or confirmatory diagnosis). There is the need

to always weigh the risk of withholding antimalarials treatment from a patient with malaria

against the risk associated with antimalarial treatment when given to a patient who does not

have malaria.

The first symptoms of malaria are nonspecific and similar to the symptoms of a minor systemic

viral illness. They comprise: headache, fatigue, abdominal discomfort and muscle and joint

aches, followed by fever, chills, perspiration, anorexia, vomiting and worsening malaise.

Infection with P. vivax, more than with other species, can be associated with well-defined

malarial paroxysms, in which fever spikes, chills and rigors occur at regular intervals.

4.1 Parasitological diagnosis The introduction of ACTs has increased the urgency of improving the specificity of malaria

diagnosis. The relatively high cost of these medicines makes waste through unnecessary

treatment of patients without parasitaemia unsustainable. In addition to cost savings,

parasitological diagnosis has the following advantages:

1. Improved patient care in parasite-positive patients owing to greater certainty that the patient

has malaria;

2. Identification of parasite-negative patients in whom another diagnosis must be sought;

3. Prevention of unnecessary exposure to antimalarials, thereby reducing side-effects, drug

interactions and selection pressure;

4. Improved health information;

5. Confirmation of treatment failures;

6. Avoid inappropriate use of medicines.

The two methods in use for parasitological diagnosis are light microscopy and rapid diagnostic

tests (RDTs). The diagnostic gold standard is the use of quality assured light microscopic

examination of the peripheral blood smears (thick and thin) to identify the parasite and

characterize the species by well-trained staff. RDTs for detection of parasite antigen are

generally more expensive, but the prices of some of these products have recently decreased to

an extent that makes their deployment cost-effective in some settings.

Their sensitivity and specificity are variable, and their vulnerability to high temperatures and

humidity is an important constraint. These concerns make it important for the Ministry of Public

Health to follow a thorough process to select the correct RDT to be used in the country. RDTs

make it possible to expand the use of confirmatory diagnosis, mainly in difficult to reach areas,

where microscopy is not available. Deployment of the RDTs, as well as of microscopy, must

be accompanied by quality assurance.

4.1.1 Selective use of RDTs

Microscopy is the gold standard method for malaria diagnosis according to WHO. Microscopy

has further advantages in that it can be used for speciation and quantification of parasites, and

identification of other causes of fever. The choice for a Rapid Diagnostic Test will depend on

the following circumstances (Figure Z):

Unavailability of skills: in few health facilities, the skills for microscopy are not

available, either the microscopes or a skilled microscopist. In these places, RDT will be

the only method used for malaria diagnostic. The routine quality of positive RDTs will

be done by collecting samples on slides from the patients that will be evaluated by a

Quality Control Officer.

Case management at the community level: this is a new strategic line (Malaria National

Strategic Plan 2015-2020) adopted by the country in which rapid malaria diagnostic

tests will be performed by volunteers (in mining and logging settings).

Case-load of suspected cases at the facility level: when the case load is high (more than

XXX slides per microscopist in a day), the surplus number of patients will be tested for

malaria using RDTs

Patients seen in extra-hours at the facility level: the normal working day starts at 8:00

AM to 4:00 PM. All patients seen out of this interval will be tested with RDTs. During

holidays, RDTs will also be the main method to test patients for malaria.

Figure Z

5. Treatment Policy

5.1 Policy recommendation in Guyana Parasitological confirmation of the diagnosis of malaria is recommended before administration

of antimalarial medicine. This is vital also to differentiate between the different species of

Plasmodium so as to allow for the correct treatment..

5.2 Treatment objectives

The objective of treating uncomplicated malaria is to cure the infection. This is important as it

will help prevent progression to severe. Cure means eradication from the body of the infection

that caused the illness; it is necessary to follow patients long enough to document cure.

The public health goal of treatment is to reduce transmission by reducing the infectious

reservoir. An 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.

5.3 Treatment recommendation for Guyana

5.3.1 Uncomplicated falciparum infection: first-line treatment.

5.3.2 Uncomplicated falciparum infection: second line treatment.

a. First line: Artemether -lumefantrine (Coartem) – AL (3 days) + Primaquine

(as a single dose)

b. Second line: Artesunate + Mefloquine – AS (3 days) + MQ (2 days) + Primaquine

(as a single dose)

b. (i) Alternate second line (choice 1): Quinine + clindamycin or doxycycline or

tetracycline+ Primaquine (as a single dose)

b. (ii) Alternate second line (choice 2) : Artesunate + clindamycin + Primaquine

(as a single dose)

5.3.3 Treatment of uncomplicated vivax malaria

a. First line: Chloroquine (3 days) + Primaquine (14 days)

b. Second Line: Coartem (3 days) + Primaquine (14 days)

5.3.4 Treatment of uncomplicated malariae malaria

a. Chloroquine (3 days) + Primaquine ( 7 days)

5.3.5 Treatment of mixed infections

First Line

a. Falciparum + vivax: artemether - lumefantrine (Coartem) + Primaquine (14 days)

b. Falciparum + malariae: artemether - lumefantrine (Coartem) + Primaquine (7

days)

c. Vivax + malariae: chloroquine (3 days) + Primaquine (14 days)

d. Falciparum + vivax + malariae: artemether - lumefantrine (Coartem) + Primaquine

(14 days)

Second Line

a. Falciparum + vivax: artemether - lumefantrine (Coartem) + chloroquine (3

days) + Primaquine (14 days)

5. 4 Doses of treatment of uncomplicated malaria in Guyana

5.4.1 Falciparum infection- First-line treatment: Arthemether + lumefantrine (Coartem®)

with a single dose of Primaquine.

This is currently available as co-formulated tablets containing 20 mg of artemether and 120 mg

of lumefantrine marketed as Coartem®. The total recommended treatment is a 6-dose regimen

of arthemether+lumefantrine twice a day for 3 days (see table 2).

Lumefantrine absorption is enhanced by co-administration with fat. Low blood levels, with

resultant treatment failure, could potentially result from inadequate fat intake, and so it is

essential that patients or careers are informed of the need to take this ACT with milk or fat-

containing food, particularly on the second and third days of treatment.

Day 1 Day 2 Day 3

ACT ACT ACT

Primaquine (PQ)

Table 2 Artemether-lumefantrine (Coartem®) dosage

Table 2.1 Primaquine Treatment for P. falciparum cases

Age Dose Weight

<6 mths 0 6-10 kg

6-11 mths ½ tab (7.5 mg) 11-14 kg

1-2 yrs ½ tab (7.5 mg) 15-24 kg

3-6 yrs 1 tab (15 mg) 25-34 kg

7-11 yrs 2 tabs (30 mg) 35-49 kg

12-14 yrs 3 tabs (45 mg) 35-49 kg

>15 yrs 3tabs (45 mg) 50> kg

= 0.75mg/kg body weight as a single dose on day one.

5.4.2. Falciparum infection: second-line treatment

a. Indications for second line treatment:

Treatment failure or recrudescence with the first line treatment - this is defined as re-

appearance of symptoms and /or parasites on rechecks within 28 days of the onset of

treatment (Note: reappearance of symptoms and /or parasites after 28 days of onset of

initial treatment should be considered a new infection and re-treated with the first line

medicine - Coartem).

Allergy to first line medicine.

Non- tolerability of the first line medicine.

Unavailability of the first line treatment.

b. The recommended second line treatment for uncomplicated falciparum malaria is:

Artesunate + mefloquine + single dose of Primaquine.

b. (i) Alternate second line treatment (choice 1): Quinine + tetracycline or

doxyclycline or clindamycin + a single dose of Primaquine.

b. (ii) Alternate second line treatment (choice 2): Artesunate + Clindamycin + a

single dose of Primaquine.

Mefloquine with Artesunate

This is currently available as separate scored tablets containing 50 mg of artesunate and 250

mg base of mefloquine, respectively. Co-formulated tablets are under development but are not

available at present. The total recommended treatment is 4 mg/kg of artesunate given once a

day for 3 days and 25 mg base/kg of mefloquine usually split over 2 or 3 days.

Age (in years) No. of tablets at approximate timing of dosing Body weight(kg)

0 h 8 h 24 h 36 h 48 h 60 h

< 3 1 1 1 1 1 1 5-14

≥3-8 2 2 2 2 2 2 15-24

≥9-14 3 3 3 3 3 3 25-34

>14 4 4 4 4 4 4 >34

To reduce acute vomiting and optimize absorption, the 25 mg/kg dose is usually split and given

either as 15 mg/kg (usually on the second day) followed by 10 mg/kg one day later. Mefloquine

is associated with an increased incidence of nausea, vomiting, dizziness, dysphoria and sleep

disturbance in clinical trials, but these are seldom debilitating and in general, where this ACT

has been deployed, it has been well tolerated.

Table 3 Mefloquine and Artesunate dosage Age Dose in mg (Number of tablets)

Artesunate (50mg ) Mefloquine (250mg)

Day 1 Day 2 Day 3 Day 1 Day 2 Day 3

≥ 5-11 months 25 (½) 25 (½) 25 (½) - 125 (½) -

≥ 1-6 50 (1) 50 (1) 50 (1) - 250 (1) -

≥ 7-13 100 (2) 100 (2) 100 (2) - 500 (2) 250 (1)

>13 years 200 (4) 200 (4) 200 (4) - 1000 (4) 500 (2)

Table 3.1 Primaquine Treatment for P. falciparum cases Age Dose Weight

< 6 months 0 6-10 kg

6-11 months ½ tab (7.5 mg) 11-14 kg

1-2 years ½ tab (7.5 mg) 15-24 kg

3-6 years 1 tab (15 mg) 25-34 kg

7-11 years 2 tabs (30 mg) 35-49 kg

12-14 years 3 tabs (45 mg) 35-49 kg

>15 years 3 tabs (45 mg) 50 > kg

= 0.75/kg body weight as a single dose on day one

Alternate second Line treatment for uncomplicated falciparum malaria (Choice 1)

Quinine Sulphate 300mg tab

Age

Morning

Midday

Afternoon

< 1 year ¼ (75 mg) ¼ (75 mg) ¼ (75 mg)

1-2 years ½ (150 mg) ½ (150 mg) ½ (150 mg)

3-6 years ½ (150 mg) 1 (300 mg) ½ (150 mg)

7-11 years 1 (300 mg) 1 (300 mg) 1 (300 mg)

10-14 years 1 (300 mg) 2 (600 mg) 1 (300 mg)

>15 years 2 (600 mg) 2 (600 mg) 2 (600 mg)

PLUS Tetracycline 4mg/kg four times a day

Or

Doxycycline 3.5mg/kg once a day

Or

Clindamycin 10mg/kg twice a day

N.B. Any of these combinations should be given for seven days.

PLUS single dose of Primaquine

Age

Dose

Weight

< 6 months 0 6-10 kg

6-11 months ½ tab (7.5mg) 11-14 kg

1-2 years ½ tab (7.5mg) 15-24 kg

3-6 years 1 tab (15mg) 25-34 kg

7-11 years 2 tabs (30mg) 35-49 kg

12-14 years 3 tabs (45mg) 35-49 kg

>15 years 3tabs (45mg) 50 > kg

= 0.75/kg body weight as a single dose on day one

Alternate Second Line treatment for uncomplicated falciparum malaria (Choice2)

Artesunate (50mg tab)

Age Dose in mg (Number of tablets)

Day 1 Day 2 Day 3

≥ 5-11 months 25 (½) 25 (½) 25 (½)

≥ 1-6 50 (1) 50 (1) 50 (1)

≥ 7-13 100 (2) 100 (2) 100 (2)

>13 years 200 (4) 200 (4) 200 (4)

PLUS Clindamycin 10mg/kg twice a day

PLUS Single dose of Primaquine (as follows)

Age

Dose

Weight

< 6 months 0 6-10 kg

6-11 months ½ tab (7.5 mg) 11-14 kg

1-2 years ½ tab (7.5 mg) 15-24 kg

3-6 years 1 tab (15 mg) 25-34 kg

7-11 years 2 tabs (30 mg) 35-49 kg

12-14 years 3 tabs (45 mg) 35-49 kg

>15 years 3 tabs (45 mg) 50 > kg

= 0.75/kg body weight as a single dose on day one

5.4.3 Treatment of P. vivax malaria

The recommended first line drug for the treatment of vivax in Guyana remains chloroquine and

Primaquine, to achieve radical cure.

Chloroquine is given at a dose of 25mg/kg (base) over 3 days. A detail of the dosing schedule

is given in table 4 below:

D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14

CQ CQ CQ

PQ PQ PQ PQ PQ PQ PQ PQ PQ PQ PQ PQ PQ PQ

Table 4 Chloroquine dosage (150mg base / tablet) Age in

years

Weight

in Kg

Duration in Days of chloroquine treatment

Day 1 Day 2 Day3

< 6 months <6 ¼ ¼ ¼

6-11 months 6-10 ½ ½ ½

1-2 11-14 1 ½ ½

3-6 15-24 1 1 1

7-11 25-34 2 1 ½ 1 ½

12-14 35-49 3 2 2

≥15 50 4 3 3

Primaquine is given at a dose of 0.25mg/kg daily for 14 days. Table 4.1 below gives the

dosing schedule. Primaquine for 14 days should be given as per prescribed guidelines only.

Table 4.1 daily dosing for Primaquine for 14 days

Age Daily dose

(15mg tablets)

Daily dose

(7.5mg tablets)

< 6months Nil Nil

6-11 months ¼ ⅓

1-2 years ¼ ½

3-6 years ½ 1

7-11 years 1 1½

12-14 years 1 1⅔

≥15 years 1 2

Second Line P. vivax treatment Artemether-lumefantrine (Coartem®) dosage

PLUS Daily dosing for Primaquine (as follows) for 14 days

Age in

years

Daily dose

(15mg tablets)

Daily dose

(7.5mg tablets)

< 6 months Nil Nil

6-11 months ¼ ⅓

1-2 ¼ ½

3-6 ½ 1

7-11 1 1½

12-14 1 1⅔

≥15 1 2

5.4.4 Treatment of P. malariae malaria

Infections caused by this species are considered to be generally sensitive to chloroquine.

Experience indicates that P. malariae is also susceptible to amodiaquine, mefloquine and the

artemisinin derivatives. Their susceptibility to antifolate antimalarials such as sulfadoxine-

pyrimethamine is less certain.

The recommended treatment for P. malariae is the standard regimen of chloroquine and

primaquine. Chloroquine dosis is of 25mg/kg (base) divided over three days; primaquine is

given at 0.25mg/kg daily for seven days.

Age (in

years)

No. of tablets at approximate timing of dosing Body

weight(kg) 0 h 8 h 24 h 36 h 48 h 60 h

< 3 1 1 1 1 1 1 5-14

≥ 3-8 2 2 2 2 2 2 15-24

≥ 9-14 3 3 3 3 3 3 25-34

> 14 4 4 4 4 4 4 > 34

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

CQ CQ CQ

PQ PQ PQ PQ PQ PQ PQ

Table 5 Chloroquine dosage (150mg base/tablet) Age in years

Weight in Kg Duration in Days of chloroquine treatment

Day 1 Day 2 Day3

<6 months < 6 ¼ ¼ ¼

6-11 months 6-10 ½ ½ ½

1-2 11-14 1 ½ ½

3-6 15-24 1 1 1

7-11 25-34 2 1 ½ 1 ½

12-14 35-49 3 2 2

≥ 15 50 4 3 3

PLUS Primaquine for 7 days. Dosing as follows in table 5.1 below

Table 5.1 Daily dosing for Primaquine

Age in years Daily dose

(15mg tablets)

Daily dose

(7.5mg tablets)

< 6 months Nil Nil

6-11 months ¼ ⅓

1-2 ¼ ½

3-6 ½ 1

7-11 1 1½

12-14 1 1⅔

≥15 1 2

5.4.5 Treatment for mixed infections

Mixed malaria infections are common and usually underestimated by routine microscopy.

ACTs are effective against all malaria species and are the treatment of choice. Radical treatment

with Primaquine should be given along with ACT’s.

Table 6 treatment of mixed infections

To review the doses of each medicine used for the treatment of mixed

infections; see tables above ….

table #

Falciparum + malariae: artemether - lumefantrine (Coartem) +

Primaquine (7 days)

2 & 5.1

Vivax + malariae: chloroquine (3 days) + Primaquine ( 14 days) 4 & 4.1

Falciparum + vivax + malariae: artemether - lumefantrine (Coartem) +

Primaquine (14 days)

2 & 4.1

Falciparum + vivax: artemether - lumefantrine (Coartem) +

Primaquine (14 days)

2 & 4.1

6. Treatment of severe P. falciparum malaria

6.1 Definition “Severe P. falciparum malaria”

In a patient with P. falciparum asexual parasitaemia and no other obvious cause of detected

symptoms, with the presence of one or more of the following (Table 6.1 below) clinical

and/or laboratory features, the patient is diagnosed as suffering from severe falciparum

malaria. Severe falciparum malaria is defined as an acute falciparum infection with signs of

severity and/or evidence of vital organ dysfunction.

Table 6.1 Clinical and laboratory findings for Severe Falciparum malaria

Clinical findings:

- Impaired consciousness or coma,(hallucinations, disorientation in time place or person)

–Prostration, i.e. generalized weakness so that the patient is unable walk or sit up without

Assistance

–Failure to feed (unable to swallow)

–Multiple convulsions – more than two episodes in 24 hrs

–Deep slow breathing, respiratory distress (acidotic breathing)

–Circulatory collapse or shock, systolic blood pressure < 70 mm Hg in adults and < 50 mm

Hg in children

–Clinical jaundice plus evidence of other vital organ dysfunction

–Haemoglobinuria (as distinct to haematuria)

–Abnormal spontaneous bleeding (blood-shots in conjunctiva or about body)

–Pulmonary oedema (radiological or clinical observation).

Laboratory findings:

Test values in severe malaria Normal test values – Hypoglycaemia (blood glucose < 40

mg/dL or < 2.2 mmol/L)

80 to 120 mg/dl

– Metabolic acidosis (plasma bicarbonate <

15 mmol/L)

19 to 25 mEq/liter

– Severe normocytic anaemia (Hb < 7 g/dL;

Packed Cell Volume (PCV) < 15%)

Male (M) Hb = 13.5-17.5 g/dl; PCV = 40-52

%

Female (F) Hb = 11.5-15.5 g/dl; PCV 36-48

%

– Haemoglobinuria, Normally, hemoglobin does not appear in

the urine.

– Hyperparasitaemia (> 2%/100 000/μl in

low intensity transmission areas or > 5 %.

In local settings a qualitative parasite

count of +++ (“3 plus”) or greater with or

without gametocytaemia.

Parasite does not appear in the smear.

– Hyperlactataemia (lactate > 5 mmol/L) 0.5–2.1 mmol/L

Renal impairment (serum creatinine > 265

μmol/L or > 3mg/dL).

F= 0.5 to 1.0 mg/dl (about 45-90 μmol/L)

M= 0.7 to 1.2 mg/dl (60-110 μmol/L)

To Note:

Severe malaria is caused by Plasmodium falciparum infection and usually occurs as a result

of delay in treating an uncomplicated attack of falciparum malaria. Sometimes, however,

especially in children, severe malaria may develop very rapidly.i Recognizing and promptly

treating uncomplicated P. falciparum malaria is therefore of vital importance.

In non-transmission, and low-transmission areas, the risk is greatest among travelers returning

with undiagnosed malaria infection from any area where P. falciparum transmission occurs.

6.2 Treatment objectives The most important objective is to prevent the patient from dying. Secondary objectives

include prevention of disabilities and prevention of recrudescence.

In the treatment of severe malaria in pregnancy, saving the life of the mother should be the

primary objective.

The mortality of untreated severe malaria (particularly cerebral malaria) is thought to approach

100%. With prompt, effective antimalarial treatment and supportive care, the mortality falls to

15–20% overall; although within the broad definition there are syndromes associated with lower

mortality rates (e.g. severe anaemia) and others with higher (e.g. metabolic acidosis).

Death from severe malaria often occurs within hours of admission to hospital or clinic, so it is

essential that therapeutic concentrations of highly effective antimalarials are achieved as soon

as possible.

The management of severe malaria comprises four main areas:

1. Clinical assessment of the patient.

2. Specific antimalarial treatment.

3. Adjunctive therapy.

4. Supportive care.

6.2.1 Clinical assessment of the patient Severe malaria is a medical emergency; it is thus important to have an extensive and prompt

medical history to determine the patient’s condition and set the diagnosis or suspicion of

severe falciparum malaria.

An open airway should be secured in unconscious patients and breathing and circulation

(blood pressure) assessed. The patient should be weighed or body weight estimated, so that

medicines, including antimalarials and fluids, can be given accordingly.

An intravenous cannula should be inserted (for fluid therapy) and immediate measurements of

blood glucose (stick test), haematocrite/haemoglobin, parasitaemia and, mainly in adults, renal

function should be taken.

A detailed clinical examination should be conducted, including a record of the coma score.

Several coma scores have been advocated. The Glasgow coma scale is suitable for adults, and

the simple Blantyre modification or children’s Glasgow coma scale are easily performed in

children.

Unconscious patients should have a lumbar puncture for cerebrospinal fluid analysis to exclude

bacterial meningitis. If facilities are available, arterial or capillary blood pH and gases (the

plasma bicarbonate or venous lactate level) should be measured in patients who are

i Management of severe malaria: a practical handbook. – 2nd edition. WHO

unconscious, hyperventilating or in shock as the degree of acidosis is an important determinant

of outcome.

Blood should be taken for cross-match, full blood count, platelet count, clotting studies, blood

culture and full biochemistry (wherever possible). The assessment of fluid balance is critical in

severe malaria. Respiratory distress, in particular with acidotic breathing in severely anaemic

children, often indicates hypovolaemia and requires prompt re-hydration and, where indicated,

blood transfusion.

6.2.1.1 Differential diagnosis The differential diagnosis of fever in a severely ill patient is broad. Coma and fever may result

from meningo-encephalitis or malaria. To note are the following:

Cerebral malaria is not associated with signs of meningeal irritation (neck stiffness,

photophobia or Kerning’s sign), but the patient may be opistotonic.

As untreated bacterial meningitis is almost invariably fatal, a diagnostic lumbar

puncture should be performed to exclude this condition.

There is also considerable clinical overlap between septicaemia, pneumonia and severe

malaria – and these conditions may coexist. In malaria endemic areas, particularly where

parasitaemia is common in the young age group, it is often impossible to rule out

septicaemia in a shocked or severely ill, obtund child.

Where possible, blood should always be taken on admission for culture and, if there is

any doubt about the diagnosis, empirical antibiotic treatment should be started

immediately along with antimalarial treatment.

Other differential diagnoses that should also be considered include enteric fever, salmonella

sepsis/septicaemia, dengue fever, leptospirosis, acute hepatitis, acute pyelonephritis,

pneumonia or bronchopneumonia, pyogenic processes (abscesses), etc.

6.2.2 Specific antimalarial treatment It is essential that effective, parenteral (or rectal) antimalarial treatment in full doses be given

promptly in severe malaria. Two classes of medicines are available for the parenteral treatment

of severe malaria:

The cinchona alkaloids (quinine and quinidine) or

The artemisinin derivatives (artesunate, artemether and artemotil).

Parenteral chloroquine is no longer recommended for the treatment of severe malaria, because

of widespread resistance. Intramuscularly, sulfadoxine-pyrimethamine is also not

recommended.

6.2.2.1 Pre-referral treatment options

The risk of death from severe malaria is greatest in the first 24 hrs, yet, in most malaria endemic

countries, the transit time between referral and arrival at health facilities able to administer

intravenous treatment is usually prolonged; this delays the commencement of appropriate

antimalarial treatment. As during this time the patient may deteriorate or die, it is recommended

that patients be treated with the first dose of one of the recommended treatments before referral

(unless the referral time is less than 6 hrs.).

The following are options for pre-referral treatment:

Artesunate IM (single dose) and refer ASAP

Artemether IM (if artesunate is not available)

Quinine IM (if artesunate and artemether are not available)

Rectal artesunate (where IM artesunate is not available for young children of less than

6 years of age, the use of rectal Artesunate (10 mg/kg bw) has been shown to reduce

the risk of death and permanent disability).ii

6.2.2.2 (Specific treatment) Artemisinin derivatives

Various artemisinin derivatives have been used in the treatment of severe malaria, including

artemether, artemisinin (rectal), artemotil and artesunate.

Artesunate offers several programmatic advantages over quinine in terms of not requiring rate

controlled infusion or cardiac monitoring.

Intravenous Artesunate should be used in preference to quinine for the treatment of severe P.

falciparum malaria in adults.iii

6.2.2.2.1 Artesunate

Artesunate is dispensed as a powder of artesunic acid. This is dissolved in sodium bicarbonate

(5%) to form sodium artesunate. The solution is then diluted in approximately 5 ml of 5%

dextrose and given by intravenous injection or by intramuscular injection to the anterior thigh.

The solution should be prepared freshly for each administration and should not be stored.

Artesunate has preferable Pharmacokinetic properties to artemether or artemotil, as it is water-

soluble and can be given either by intravenous or intramuscular injection. There are rectal

formulations of artesunate, artemether, artemisinin and dihydro-artemisinin.

Artesunate (2.4 mg/kg bw IV or IM) is given on admission (time = 0), then at 12 and 24 hours.

From the second day, once dose a day is the recommended treatment. Children weighing less

than 20kg should receive a higher parenteral dose of Artesunate (3mg/kg bw IV or IM on

admission, at 12 and 24 hours, then once a day) to ensure equivalent drug exposure (v).

The artesunate suppository should be administered rectally with a dosis of 10 mg/kg body

weight, single dose, as soon as the presumptive diagnosis of severe malaria is made. If an

artesunate suppository is expelled from the rectum within 30 min of insertion, a second

suppository should be inserted and, especially in young children, the buttocks should be held

together for 10 min to ensure retention of the rectal dose of artesunate.

6.2.2.2.2 Artemether

Artemether and quinine are acceptable alternatives if parenteral artesunate is not available.

Artemether and artemotil are formulated in oil and are only to be administered by intramuscular

-IM- injection (not suitable for intravenous- IV- administration). They are both absorbed

erratically, particularly in very severely ill patients. Artemether dosis used is 3.2 mg/kg bw IM

given on admission then 1.6 mg/kg BW per day. Presentations are available in 2 ml vials 40

mg/ml, in coconut or peanut oil.

6.2.2.3 Quinine

Quinine treatment for severe malaria was established before modern clinical trial methods were

developed. Several salts of quinine have been formulated for parenteral use, but the

dihydrochloride is the most widely used. The maintenance dose of quinine (10 mg salt/kg Body

weight) is administered at 8 hour intervals; starting 8 hours after the first dose. Pharmacokinetic

modeling studies suggest that a loading dose of quinine (i.e. 20 mg salt/kg body weight – twice

the maintenance dose) reduces the time needed to reach therapeutic plasma concentrations. If

ii Guidelines for the treatment of malaria – 2nd edition WHO iii Guidelines for the treatment of malaria – 2nd edition WHO

there is no improvement in the patient’s condition within 48 hrs, the dose should be reduced by

one third, i.e. to 10mg salt/kg bw every 12 hrs.

6.2.2.3.1 Intravenous (IV) route In Guyana, parenteral (IV) quinine is usually available as Quinine Dihydrochloride 300 mg/ml

in 2 ml vials (600 mgs base salt). Rapid administration of quinine is unsafe. Each dose of

parenteral quinine must be administered as a slow, rate controlled infusion (usually diluted in

5% dextrose and infused over 4 hours). The infusion rate should not exceed 5 mg salt/kg body

weight per hour.

Dosage for a 60kg patient is usually 1(one) vial 8 hourly by slow IV infusion diluted in 5%

Dextrose over 4 hours, to avoid quinine induced hypoglycaemia. Quinine must never be given

by intravenous bolus injection, as lethal hypotension may result.

6.2.2.3.2 Intramuscular (IM) route (in exceptional circumstances) Undiluted quinine dihydrochloride at a concentration of 300 mg/ml is acidic (pH 2) and painful

when given by intramuscular injection, so it is best either formulated or diluted to

concentrations of 60–100 mg/ml for intramuscular injection.

6.2.2.4 Quinidine

Quinidine commonly causes hypotension and concentration-dependent prolongation of

ventricular depolarization (QT prolongation). Quinidine is thus considered more toxic than

quinine and should only be used if no other effective parenteral drugs are available.

Electrocardiography monitoring and frequent assessment of vital signs are required if Quinidine

is used.iv

6.2.2.5 Follow-up treatment

Following initial parenteral treatment, once the patient can tolerate oral therapy, it is essential

to continue and complete treatment with an effective oral antimalarial using a full course of an

effective ACT. This may be artemether plus lumefantrine or dihydroartemisinin plus

piperaquine, or artesunate plus clindamycin or doxycycline. Doxycycline is preferred to other

tetracyclines because it can be given once daily, and does not accumulate in renal failure.

Other follow-up treatment options include quinine plus clindamycin or doxycycline. As

treatment with doxycycline only starts when the patient has recovered sufficiently, the 7-day

doxycycline course finishes after the quinine, artemether or artesunate course.

To note that clindamycin is a better option compared with doxycycline in children and pregnant

women, as doxycycline cannot be given to these groups.

Regimens containing mefloquine should be avoided if the patient presented initially with

impaired consciousness. This is because of an increased incidence of neuropsychiatry

complications associated with mefloquine following cerebral malaria.

Any combination used as follow up treatment, the one dose primaquine should always be used

as per the guidelines of P falciparum malaria.

The current recommendation from experts’ opinion is that, before starting the oral follow-up

treatment of severe malaria, parenteral antimalarials should have been given for a minimum of

24 hours once started (irrespective of the patient’s ability to tolerate oral medication earlier) or

until the patient is about to tolerate oral medication.

iv, v Guidelines for the treatment of malaria – 2nd & 3rd edition WHO

6.2.3 Additional aspects of therapy and management

6.2.3.1 Adjustment of dosing in renal failure or hepatic dysfunction

The dosage of artemisinin derivatives does not need adjustment in vital organ dysfunction.

However, quinine and quinidine levels may accumulate in severe vital organ dysfunction. If the

patient remains in acute renal failure or has hepatic dysfunction, then the dose of these drugs

should be reduced by one third (to 10mg salt/kg bw every 12 hours) after 48 hrs. Dosage

adjustments are not necessary if patients are receiving either hemodialysis or hemofiltration.

6.2.3.2 Immediate clinical management of severe manifestations and complications of

P. falciparum malaria a

Coma (cerebral

malaria)

Maintain airway; place patient on his or her side; exclude other treatable

causes of coma (e.g. hypoglycemia, bacterial meningitis); avoid harmful

ancillary treatment, such as corticosteroids, heparin and adrenaline;

intubate if necessary.

Hyperpyrexia Administer tepid sponging, fanning, a cooling blanket and antipyretic

drugs. Paracetamol is preferred over more nephrotoxic drugs (e.g.

NSAIDs b)

Hypoglycemia Correct hypoglycemia with glucose containing infusion and maintain on

check blood glucose.

Convulsions Maintain airways; treat promptly with intravenous or rectal diazepam or

intramuscular paraldehyde. Check blood glucose.

Severe anemia Transfuse with screened fresh whole blood.

Acute

pulmonary

edema c

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 hypoxemia.

Acute renal

failure

Exclude pre-renal causes, check fluid balance and urinary sodium; if in

established renal failure add hemofiltration or hemodialysis or if

unavailable, peritoneal dialysis.

Spontaneous

bleeding and

Coagulopathy

Transfuse with screened fresh whole blood and cryoprecipitate, fresh

frozen plasma or platelets, if available; give vitamin K injection.

Metabolic

acidosis

Exclude or treat hypoglycemia, hypovolemia and septicemia. If severe,

add hemofiltration or hemodialysis.

Shock Suspect septicemia, take blood for cultures; give parenteral broad-

spectrum antimicrobials, correct hemodynamic disturbances. a It is assumed that appropriate antimalarial treatment would have been started in all cases. b Non-steroidal anti-inflammatory drugs. c Prevent by avoiding excess hydration.

6.2.4 Supportive management Patients with severe malaria require intensive nursing care, preferably in an intensive care unit

where possible. Clinical observations and adjustments in therapy should be made as frequently

as possible.

The supportive management should include:

Monitoring of vital signs, coma score, and urine output, as well as blood glucose every

four hours, if possible, particularly in unconscious patients.

Fluid requirements should be assessed individually. Adults with severe malaria are very

vulnerable to fluid overload. Children, on the other hand, are more likely to be

dehydrated. The fluid regimen must also be tailored around infusion of the antimalarial

drugs.

Central venous pressure should be maintained at 0–5 cm. If available, hemofiltration

(dialysis) should be started early for acute renal failure and severe metabolic acidosis,

which are unresponsive to re-hydration.

If blood glucose is < 2.2 mmol/l (40 mg/dl), then hypoglycemia should be treated

immediately (0.3–0.5 g/kg body weight of glucose IV (50% Dextrose diluted in 5%

Dextrose or Dextro-Saline)). Hypoglycemia should be suspected in any patient who

deteriorates suddenly.

Patients with severe malaria with clinically significant disseminated intra-vascular

coagulation should be given fresh whole blood transfusions and vitamin K.

Patients with secondary pneumonia or with clear evidence of aspiration should be given

empirical treatment with a third-generation cephalosporin, or the appropriate antibiotic

of known sensitivity in that locality.

In children with persistent fever despite parasite clearance, other possible causes of

fever should be excluded. These include a systemic Salmonella infection and urinary

tract infections, especially in catheterized patients. However, in most cases of persistent

fever, no other pathogen is identified after parasite clearance. Antibiotic treatments

should then be based on culture and sensitivity results, or, if not available, consider local

antibiotic sensitivity patterns.

6.2.4.1 Fluid therapy

The degree of fluid depletion varies considerably in patients with severe malaria. Thus, it is not

possible to give general recommendations on fluid replacement. Each patient must be

individually assessed and fluid resuscitation based on estimated deficit.

In high-transmission settings, children commonly present with severe anemia and

hyperventilation (sometimes termed “respiratory distress”) resulting from severe metabolic

acidosis and anemia; they should be treated by blood transfusion. In general, children tolerate

rapid fluid resuscitation better than adults; they are less likely to develop pulmonary edema. In

adults, there is a very thin dividing line between over-hydration, which may produce pulmonary

edema, and under-hydration contributing to shock, worsening acidosis and renal impairment.

Careful and frequent evaluations of the jugular venous pressure, peripheral perfusion, venous

filling, skin turgor and urine output should be made. Where the nursing facilities permit, a

central venous catheter should be inserted and the central venous pressure measured directly

(target 0–5 cm H2O).

6.2.4.2 Treatments not recommended

Several other supportive strategies and interventions have been used in severe malaria patients

to further reduce the mortality, but very few are supported by evidence of benefit and many

have proved harmful. The following products are not recommended for the treatment of severe

malaria:

Heparin, prostacyclin, desferoxamine, pentoxifylline, low molecular weight dextran, urea,

high-dose corticosteroids, acetylsalicylic acid, deferoxamine, anti-tumor necrosis factor

antibody, cyclosporin, dichloroacetate, adrenaline and hyper immune serum. In addition, the

use of corticosteroids increases the risk of gastrointestinal bleeding and seizures, and has been

associated with prolonged coma resolution times when compared with placebos.

6.2.4.3 Blood transfusion

Severe malaria is associated with rapid development of anemia as infected and uninfected

erythrocytes are hemolyzed and/or removed from the circulation by the spleen. Ideally fresh

cross-matched blood should be transfused. However, in most settings cross-matched, virus-free

blood is in short supply. As with fluid resuscitation, there have not been enough studies to

provide strong evidence-based recommendations on the indications for transfusion, so the

recommendations given here are based on expert opinion.

In high-transmission settings, blood transfusion is generally recommended for children with a

hemoglobin level of < 5 g/100ml (hematocrit < 15%). In low-transmission settings, a threshold

of 20% (hemoglobin 7 g/100 ml) is recommended. However, these general recommendations

still need to be tailored to the individual, as the pathological consequences of rapid development

of anemia are worse than those of chronic or acute anemia where there has been adaptation and

a compensatory right shift in the oxygen dissociation curve.

6.2.4.4 Exchange blood transfusion

There have been many anecdotal reports and several series claiming benefit for exchange blood

transfusion (EBT) in severe malaria but no comparative trials, and there is no consensus on

whether it reduces mortality or how it might work.

Exchange blood transfusion requires intensive nursing care and a relatively large volume of

blood, and it carries significant risks. There is no consensus on the indications, benefits and

dangers involved, or on practical details such as the volume of blood that should be exchanged.

It is, therefore, not possible to make any recommendation regarding the use of EBT.

6.2.4.5 Use of anticonvulsants

The treatment of convulsions in cerebral malaria with intravenous (or, if this is not possible,

rectal) benzodiazepines or intramuscular paraldehyde is similar to that for repeated seizures

from any cause. A 20 mg/kg dose of Phenobarbital should not be given without respiratory

support, but whether a lower dose would be effective and safer, or whether if ventilation is

given, mortality would not be increased is not known. In the absence of further information,

prophylactic anticonvulsants are not recommended.

6.2.4.6 Concomitant use of antibiotics

The threshold for administering antibiotic treatment should be low in severe malaria.

Septicemia and severe malaria are associated and there is a diagnostic overlap, particularly in

children. Unexplained deterioration may result from a supervening bacterial infection.

Although enteric bacteria (notably Salmonella) have predominated in most trial series, a variety

of bacteria have been cultured from the blood of patients diagnosed as having severe malaria;

so broad- spectrum antibiotic treatment should be given initially until a bacterial infection is

excluded.

7. Additional aspects of clinical management 7.1 Can the patient take oral medications?

Some patients cannot tolerate oral treatment, and will require parenteral or rectal administration

for 1–2 days until they can swallow and retain oral medication reliably. Although such patients

may not show signs of severity, they should receive the same antimalarial dose regimens as for

severe malaria.

7.2 Does the patient have very high parasitaemia (hyperparasitaemia) a?

Some patients may have no signs of severity but on examination of the blood film are found to

have very high parasitaemia. The risks associated with high parasitaemia vary depending on

the age of the patient and on transmission intensity. Thus cut-off values and definitions of

hyperparasitaemia also vary. Patients with high parasitaemia are at an increased risk of

treatment failure and of developing severe malaria, and therefore have an increased risk of

dying. These patients can be treated with the oral ACTs recommended for uncomplicated

malaria. However, they require close monitoring to ensure that the drugs are retained and that

signs of severity do not develop, and they may require a longer course of treatment to ensure

cure. a In Guyana hyperparasitemia means +++ (3 plus) and above.

7.3 Use of antipyretics (management of fever)

Fever is a cardinal feature of malaria, and is associated with constitutional symptoms of

lassitude, weakness, headache, anorexia and often nausea. In young children, high fevers are

associated with vomiting, inclusive of medication, and seizures.

Fever treatment is with antipyretics and, if necessary, tepid sponging. Care should be taken to

ensure that the water is not too cool as, paradoxically, this may raise the core temperature by

inducing cutaneous vasoconstriction. Paracetamol (acetaminophen) 15 mg/kg every 4 hours is

widely used; it is safe and well tolerated given orally or as a suppository.

Ibuprofen (5 mg/kg) has been used successfully as an alternative in malaria and other childhood

fevers, although there is less experience with this compound; however, acetylsalicylic acid

(aspirin) should not be used in children because of the risks of Reye’s syndrome.

There has been some concern that antipyretics might attenuate the host defense against malaria,

as their use is associated with delayed parasite clearance. However, this appears to result from

delaying cyto-adherence, which is likely to be beneficial. There is no reason to withhold

antipyretics in malaria.

7.4 Use of antiemetic

Vomiting is common in acute malaria and may be severe. Antiemetic are widely used, although

there have been no studies of their efficacy in malaria, and no comparisons between different

antiemetic compounds.

7.5 Management of seizures

Generalized seizures are more common in children with falciparum malaria than in those with

the other malarias. This suggests an overlap between the cerebral pathology resulting from

malaria and febrile convulsions. Sometimes these seizures are the prodrome (a symptom

indicating the onset of a disease) of cerebral malaria. If the seizure is ongoing, the airway should

be maintained and anticonvulsants given. If it has stopped and the core temperature is above

38.5 ºC the child should be treated as indicated in section 6.2.4.5. There is no evidence that

prophylactic anticonvulsants are beneficial in otherwise uncomplicated malaria.

7.6 Incorrect approaches to treatment

A potentially dangerous practice is to give only the first dose of the treatment course for patients

with suspected but unconfirmed malaria, with the intention of giving full treatment if the

diagnosis is eventually confirmed. This practice is not recommended; if malaria is suspected

and the decision to treat is made, then a full effective treatment is required whether the diagnosis

is confirmed by a test.

Except for artemether + lumefantrine, the partner medicines of all other ACTs have been

previously used as monotherapies, and continue to be available as such in many countries. Their

continued use as monotherapies can potentially compromise the value of ACTs by selecting for

drug resistance. The withdrawal of artemisinin and other monotherapies is recommended.

8. Treatment of malaria in specific populations and special situations

8.1 Treatment of malaria in pregnancy

Pregnant women with acute malaria are a high-risk group, and must receive prompt and

effective treatment with antimalarials. Malaria in pregnancy is associated with low birth weight,

fetal death, premature labor, anemia and, increased risk of severe malaria. Women in the second

and third trimesters of pregnancy are more likely to develop severe malaria than other adults

and this is often complicated by pulmonary edema and hypoglycemia. Maternal mortality from

severe malaria is approximately 50%, which is higher than in non-pregnant adults.

Therefore, all pregnant women living in malaria endemic areas in Guyana should have a malaria

smear, at each antenatal check-up, and if positive, start treatment with antimalarials promptly.

Also, all pregnant women who present with a fever, who are from or have visited a malaria

endemic area, require a malaria smear and treatment if the smear is positive. As malaria in

pregnancy can rapidly progress from uncomplicated to severe, with devastating consequences,

all women with malaria in pregnancy should be reviewed by a MEDEX or a doctor. If the

woman first presents to a health post, the Community Health Worker (CHW) should commence

oral therapy immediately and refer her to the health centre where she can be seen by a MEDEX

or a doctor. After assessment, and recommended observation, the MEDEX or the doctor can

seek expert obstetric advice. If severe malaria is suspected all pregnant women should start

treatment with parenteral antimalarials and be transferred to Georgetown Public Hospital

immediately.

Parenteral artesunate is preferred over quinine in the second and third trimesters, because

quinine is associated with recurrent hypoglycemia. In the first trimester, the risk of

hypoglycemia is lower and the uncertainties over the safety of the Artemisinin derivatives are

greater. However, weighing these risks against the evidence that artesunate reduces the risk of

death from severe malaria, treatment must not be delayed. If any one of the drugs artesunate,

artemether or quinine is available, then it should be started immediately. Obstetric advice

should be sought at an early stage, the pediatricians alerted, and blood glucose checked

frequently. Hypoglycemia should be expected, and it is often recurrent if the patient is receiving

quinine. Severe malaria may also present immediately following delivery. Postpartum bacterial

infection is a common complication in these cases.

There is insufficient information on the safety and efficacy of most antimalarials in pregnancy,

particularly for exposure in the first trimester, and so treatment recommendations are different

to those for non-pregnant adults. Organogenesis occurs mainly in the first trimester and this is

therefore the time of greatest concern for potential teratogenicity; the antimalarials available in

Guyana that are considered safe in the first trimester of pregnancy are quinine, chloroquine, and

clindamycin. Of these, quinine remains the most effective and can be used in all trimesters of

pregnancy including the first trimester.

While there is insufficient evidence to ensure the safety of artemisinin derivatives during

1sttrimester, registers of pregnancies inadvertently receiving ACT during the 1st trimester have

not demonstrated increased risk thus far. Therefore, inadvertent exposure to antimalarials is not

an indication for termination of the pregnancy. Moreover, artemisinin derivatives are

recommended in the 1st trimester, after treatment failure with quinine. Increasing experience

with artemisinin derivatives during the 2ndand 3rd trimesters have not demonstrated adverse

effects on the mother or the fetus and they are now routinely used. Given the disadvantages of

quinine, i.e. the long course of treatment, and the increased risk of hypoglycemia in the second

and third trimesters, ACTs are now recommended as 1st line treatment for these trimesters.

There is insufficient evidence to base the choice of a combination partner for the ACTs in

pregnancy. Clindamycin is considered safe, but both drugs (clindamycin and the artemisinin

partner) must be given for 7 days.

Primaquine and the tetracyclines SHOULD NOT be used in pregnancy.

8.1.1 Treatment of uncomplicated & severe P. falciparum malaria in pregnancy

The severity of a patient’s condition and their prognosis is dependent on several clinical

parameters. Assessing these parameters determines their status as uncomplicated malaria or

complicated/severe malaria, which in turn determines the appropriate treatment algorithm.

The table below summarizes the clinical and laboratory features of complicated or severe

malaria.

Clinical findings:

- Impaired consciousness or coma,(hallucinations, disorientation in time place or person)

–Prostration, i.e. generalized weakness so that the patient is unable walk or sit up without

Assistance

–Failure to feed ( unable to swallow )

–Multiple convulsions – more than two episodes in 24 hrs

–Deep slow breathing, respiratory distress (acidotic breathing)

–Circulatory collapse or shock, systolic blood pressure < 70 mm Hg in adults and < 50 mm

Hg in children

–Clinical jaundice plus evidence of other vital organ dysfunction

–Haemoglobinuria (as distinct to haematuria)

–Abnormal spontaneous bleeding (blood-shots in conjunctiva or about body)

–Pulmonary oedema (radiological or clinical observation).

Laboratory findings:

Test values in severe malaria Normal test values

– Hypoglycaemia (blood glucose < 40 mg/dl) 80 to 120 mg/dl

– Metabolic acidosis (plasma bicarbonate <

15 mmol/L)

19 to 25 mEq/liter

– Severe normocytic anaemia (Hb < 7 g/dl;

Packed Cell Volume (PCV) < 15%) Male (M) Hb = 13.5-17.5 g/dl; PCV = 40-52 %

Female (F) Hb = 11.5-15.5 g/dl; PCV 36-48 %

– Haemoglobinuria, Normally, hemoglobin does not appear in the

urine.

– Hyperparasitaemia (> 2%/100 000/μl in low

intensity transmission areas or > 5 %.

Parasite does not appear in the smear.

In local settings a qualitative parasite count

of +++ (“3 plus”) or greater with or without

gametocytaemia.

– Hyperlactataemia (lactate > 5 mmol/L) 0.5–2.1 mmol/L

Renal impairment (serum-creatinine > 265

μmol/L).

F= 0.5 to 1.0 mg/dl (about 45-90 μmol/L)

M= 0.7 to 1.2 mg/dl (60-110 μmol/L)

For quick reference, an easier distinction might be the following table:

Uncomplicated malaria in

pregnancy

Severe malaria

Fever

Shivers/ chills/ rigors

Headaches

Muscle& joint pains

Nausea or vomiting

False labour pains

Signs of uncomplicated malaria

+ one or more of the following:

dizziness

breathlessness or difficulty

breathing

sleepy, drowsy or coma

confusion

fits (seizures)

jaundice (yellow skin & eyes)

severe dehydration

8.1.1.1 Treatment of uncomplicated P. falciparum malaria in Pregnancy

Uncomplicated falciparum malaria can be treated with oral medication. The choice of drug is

dependent on the gestational age of the pregnancy to reduce the risk of teratogenicity.

Table 7 Treatment for pregnant women with falciparum infection by trimester

TREATMENT OF UNCOMPLICATED MALARIA:

1ST TRIMESTER:

QUININE 600mg orally, three times daily (or 450mg if <50kg) for 7 days

PLUS

CLINDAMYCIN 450mg orally, three times daily (or 300mg if <50kg) for 7 days

2ND & 3RD TRIMESTER:

Age (in years) No. of tablets at approximate timing of dosing Body weight(kg)

0 h 8 h 24 h 36 h 48 h 60 h

≥9-14 3 3 3 3 3 3 25-34

>14 4 4 4 4 4 4 >34

*Coartem®tab: 20mg artemether + 120mg lumefantrine.

**Adult dose (>35kg) = 4 tabs

8.1.1.2 Treatment of severe or complicated falciparum malaria in pregnancy

Complicated falciparum malaria is an emergency. Treatment should be given according to the

severity and associated complications, best resolved by the treating physicians and meticulous

nursing care.

Table 7.1 Treatment of complicated malaria in pregnancy

1ST TRIMESTER

TREATMENT OF SEVERE/COMPLICATED MALARIA :

QUININE 600mg IV in 5% Dextrose over 4hrs, every 8 hrs (10mg/kg, max 700mg)

Should not exceed 5mg salt/kg over 4hr body weight per hr

PLUS

CLINDAMYCIN 600mg IV, every 12 hours (10mg/kg)

Should not exceed 1.2g in a single dose

PARENTERAL ANTIMALARIALS for a minimum of 24 hours & until well enough

to tolerate oral medication, then switch to oral quinine & clindamycin for a total of 7

days.

2ND & 3RD TRIMESTER

ARTEMETHER 160mg IM loading dose ; followed by 80mg IM daily

(3.2mg/kg BW/day IM) (1.6mg/kg BW/day IM)

OR

QUININE 600mg IV in 5% Dextrose, over 4hrs, every 8 hrs(10mg/kg, max 700mg)

PLUS

CLINDAMYCIN 600mg IV, every 12 hours (10mg/kg)

PARENTERAL ANTIMALARIALS for a minimum of 24hours & until well enough

to tolerate oral medication, then switch to Coartem® for minimum of 3 days.

NB: Quinine, should never be given undiluted IV. It is usually diluted in 5% dextrose to prevent

hypoglycaemia. A loading dose of Quinine is no longer given, as evidence suggests no

improvement in outcome. Doses are calculated at 10 mg/ kg given 8 hourly and the infusion rate

should not exceed 5 mg/kg per hour. The parenteral treatment should be given for a minimum of

24 hours and once the patient tolerates oral therapy, oral Quinine and Clindamycin, should be

given to complete 7 days of treatment. Intravenous quinine should be administered at the

recommended dosage for the first 48 hours even if acute renal failure (ARF) or severe jaundice is

present. If there is no clinical improvement after 48 hours of parenteral therapy, the maintenance

dose of parenteral quinine should be reduced by one third.

All patients receiving IV quinine should be monitored for hypoglycaemia. As the risk of

hypoglycaemia also increases in the 2nd & 3rd trimesters of pregnancy, women receiving IV

quinine at this time should be monitored particularly carefully with RBS checked every 3-4 hours.

8.1.2 Treatment options for P. vivax & P. malariae

Chloroquine 25mg/kg divided over 3 days is the recommended treatment in pregnancy.

Primaquine is contraindicated in pregnancy and should be withheld until after delivery. All

women with malaria in pregnancy should be scheduled for a follow up visit for malaria review,

postpartum.

Treatment of the blood stage:

Table 8 Number of tablets of Chloroquine 150 mg base to be given daily

Age in years Duration in Days

Day 1 Day 2 Day3

12-14 3 2 2

≥15 4 3 3

Only clinically vivax infections that have been confirmed microscopically should be treated.

Radical Cure: In women who are pregnant or breastfeeding, consider weekly

chemoprophylaxis with chloroquine until delivery and breastfeeding are completed, then on the

basis of G6PD status, treat with primaquine to prevent future relapse.

8.2 Lactating women The amounts of antimalarials that enter breast milk and are therefore likely to be consumed by

the breast-feeding infant are relatively small. Tetracycline is contraindicated because of their

effect on the infant’s bone s and teeth. Primaquine should not be given to lactating women due

to the risk of hemolysis in breast-feeding infants with G6PD deficiency. The treatment of

lactating women is the same as that of non-pregnant women (see Table 4.1) once their breast

fed infants have been checked for G6PD deficiency.

In patients known to be G6PD deficient, primaquine may be considered at a dose of 0.75mg

base/kg bw once a week for 8 wks. The decision to give or withhold primaquine should depend

on the possibility of giving the treatment under close medical supervision, with ready access to

health facilities with blood transfusion services.(vi)

If G6PD testing is not available, a decision to prescribe or withhold primaquine should be based

on the balance of the probability and benefits of preventing relapse against the risks of

primaquine-induced haemolytic anaemia. This depends on the population prevalence of G6PD

deficiency, the severity of the prevalent genotypes and on the capacity of health services to

identify and manage primaquine-induced haemolytic reactions.(vii)

8.3 Treatment of malaria in under 5kg (6 months)

It is essential to refer all such infants to health facilities where comprehensive investigations

can be undertaken to adequately rule out possible differentials of fever, as malaria is not a

common cause of fever in this age group. Even where malaria is the cause of the fever, this can

co-exist with other potentially serious bacterial infections, which should be adequately

diagnosed and treated. Treat infants weighing < 5kg with uncomplicated P. falciparum malaria

with an ACT at the same mg/kg bw target dose as for children weighing 5kg. However, Quinine

(10mg base/kg three times daily for 7 days) with Clindamycin (7 mg per oral (PO), or 10 mg /

kg IV, every 12 hours) can also be used. If PO isn’t possible and the referral center is at least 6

hours away, give 1 dose of artemeter per rectum (10 mg/ kg).

vi, vii

Guideline for the treatment of malaria- 3rd edition WHO (2015)

8.4 People living with HIV or other high risk groups for Malaria Worsening HIV-related immunosuppression may lead to more severe manifestations of

malaria. In HIV-infected pregnant women, the adverse effects of placental malaria on birth

weight are increased. In stable endemic areas, HIV-infected patients with partial immunity to

malaria may suffer more frequent and higher density infections; while in areas of unstable

transmission, HIV infection is associated with an increased risk of severe malaria and malaria-

related deaths. There is limited information at present on how HIV infection modifies the

therapeutic responses to ACTs or on interactions between antimalarial medicines and

antiretroviral. The most significant interactions seem to be the additional risk of hepatotoxicity

with Efavirenz and anaemia with Zidovudine. Early studies with less effective regimens

suggested that increasing HIV-related immunosuppression was associated with decreased

treatment response, increased parasite burdens and reduced host immunity. Both of them are

now known to occur with HIV infection. Therefore as with all high risk groups early detection

and prompt treatment with effective antimalarials is required to prevent progression to severe

malaria.

8.5 Other conditions Other groups at high risk of acquiring malaria and developing severe malaria include the

elderly, people with severe malnutrition and immunocompromised people for whatever reason,

e.g., uncontrolled diabetes. For all these groups prompt diagnosis and treatment is

recommended to prevent progression to severe disease.

(Guidelines for the treatment of malaria – 2nd & 3rd edition WHO).

Fig. 1

COMPLICATED OR SEVERE MALARIA

REQUIRES PARENTERAL THERAPY & ADMISSION TO HDU/ICU

DOES SHE HAVE ANY OF THE FOLLOWING SIGNS OR RESULTS….

impaired consciousness

generalised weakness -unable to walk or sit without assistance

failure to feed

multiple convulsions (>2 in 24hs)

respiratory distress

shock sBP<70mmHg

jaundice

coke coloured urine “black water fever”

abnormal spontaneous bleeding

pulmonary oedema (on xray)

hypoglycaemia (RBS <40mg/dL)

metabolic acidosis (bicarb<15mmol/L, lactate>5mmol/L)

severe anaemia (Hb<5g/dL)

renal impairment (Cr>265umol/L)

haemoglobinuria

hyperparasitaemia (>2% or +++).

FLOWCHART FOR TREATMENT OF MALARIA IN PREGNANCY

UNCOMPLICATED MALARIA

FOR ORAL THERAPY ON THE WARD

IS SHE < 12 WEEKS GESTATION

1ST

TRIMESTER

QUININE 600mg IV in 5% Dextrose over 2hrs tid PLUS CLINDAMYCIN 600mg IV tid for minimum 24 hours & tolerating orals, then change to oral quinine & clindamycin for a total of 7 days

2ND

& 3RD

TRIMESTER

ARTEMETHER 160mg IMI stat followed by 80mg daily OR QUININE 600mg IV in 5% Dextrose over 2hrs, tid PLUS CLINDAMYCIN 600mg IV, tid

1ST

TRIMESTER

QUININE po 600mg po tid (or 450mg if <50kg)

PLUS CLINDAMYCIN po 450mg po tid (or 300mg if <50kg) For a total of 7 days

2ND

& 3RD

TRIMESTER

COARTEM tabs (20/120) Day 1- 4 tabs po stat & in 8 hrs Day 2 & 3- 4 tabs mane & nocte

after minimum 24hrs & able to tolerate oral medication

NO YES

YES NO YES NO

Simplified Flow Chart of Treatment for Malaria in Pregnancy

Uncomplicated malaria in

pregnancy

Severe malaria

Fever

Shivers/ chills/ rigors

Headaches

Muscle& joint pains

Nausea or vomiting

False labour pains

Signs of uncomplicated malaria

+ one or more of the following:

dizziness

breathlessness or difficulty breathing

sleepy, drowsy or coma

confusion

fits (seizures)

jaundice (yellow skin & eyes)

severe dehydration

Uncomplicated Symptoms Complicated Symptoms

Patient <14 weeks Gestation

1st Trimester

Quinine 600mg PO TID x 7/7

+

Clindamycin 450mg PO BD x

7/7

Second Line

Artesunate 2mg/kg PO OD x

7/7

+

Clindamycin 10mg/kg PO BD

7/7

YES NO

1st Trimester

Quinine 600mg incorporated in 5%

Dextrose Saline over 4 hours TID x

7/7

+

Clindamycin 600mg IV BD x 7/7

2nd and 3rd Trimester

Artemeter 160mg IM stat then 80mg OD

x 3/7

Or

Quinine + Clindamycin for seven days is

safe in all trimesters

2ND and 3rd Trimester

Coartem 4 tabs PO BD x 3/7

9. References

1. World Health Organization (2006). Guidelines for the treatment of Malaria.

WHO/HTM/MAL/2006.1108, Geneva.

2. World Health Organization (2001). The use of antimalarials drugs. Report for a WHO

informal consultation. 13-17 of November, 2002. Geneva.

3. World Health Organization, 2010. Guidelines for the treatment of malaria (ii, iii, iv).

4. Pr Stéphane PICOT Malaria Research Unit ICBMS : Institut de Chimie et Biochimie

Moléculaire et Supramoléculaire (UMR 5246 CNRS– UCBL1-INSA).

5. World Health Organization, 2015. Guidelines for the treatment of malaria- 3rd edition (v,

vi, vii).

6. Management of severe malaria: a practical handbook. – 2nd edition. WHO (i)

10. Annexes Antimalarial Medicines

CHLOROQUINE

10. Annexes: Antimalarial Medicines

CHLOROQUINE

Formulations:

Tablets containing 100 mg or150 mg of chloroquine base as phosphate or sulfate.

Syrup containing 50 mg of base as chloroquine phosphate or sulfate in 5 ml.

Efficacy: Chloroquine is a 4-aminoquinoline that has marked and rapid schizonticidal activity

against all infections of P. malariae and P. ovale and against chloroquinesensitive infections of

P. falciparum and P. vivax. It is also gametocytocidal against P. vivax, P. malariae and P. ovale

as well as immature gametocytes (stages 1-3) of P. falciparum. It is not active against

intrahepatic forms, and should therefore be used with Primaquine to effect radical cure of P.

vivax. and P. ovale.

Drug disposition: Chloroquine is absorbed efficiently when administered orally, peak plasma

concentrations being achieved within 3 h (range 2-12 h). The concentration reached in the

plasma within 30 min after administration of a single dose of 10 mg/kg is usually substantially

greater than the therapeutic level for chloroquine-sensitive P. falciparum parasites. The drug

has a high capacity for binding to tissues, particularly the melanin-containing tissues of the skin

and eye.

Binding to plasma proteins, about 50% is much less than expected from its extensive tissue

binding. It is preferentially concentrated in erythrocytes and this concentration is enhanced in

parasitized erythrocytes.

Chloroquine is metabolized slowly by de-ethylating of the side chain leading successively to

monodesethyl- and bisdesethylchloroquine, followed by dealkylation.

The antimalarial activity and pharmacokinetic profile of desethylchloroquine are similar to

those of the parent drug. Chloroquine is eliminated slowly, the parent drug and its metabolites

being detected in the blood for up to 56 days with an elimination half-life of around 10 days,

depending on the sensitivity of the assay methods used. Chloroquine is predominantly excreted

as the parent drug, desethylchloroquine accounting for only about 25% of the total drug

excreted (11, 110).

Adverse effects: Serious adverse reactions to chloroquine are rare at the usual antimalarial

dosages, but pruritus, which may be intolerable, is common among dark-skinned people. It can

sometimes be alleviated by calamine lotion. As pruritus may compromise compliance, it is

advisable to use an alternative effective and rapidly acting blood schizonticide in the event of

reinfection.

Transient headaches, nausea, vomiting, gastrointestinal symptoms and “blurred vision” may

also be experienced following chloroquine administration. This may be avoided by

administering the dose after a meal. Attacks of acute porphyria and psoriasis may be

precipitated in susceptible individuals. Very rarely adverse events include leukopenia,

bleaching of the hair and, extremely rarely, aplastic blood and neurological disorders, such as

polyneuritis, ototoxicity, seizures and neuromyopathy.

Irreversible visual impairment resulting from accumulation of Chloroquine in the retina is a

rare but recognized complication of long-term, high-dosage therapy. Cumulative total doses of

1 g of base per kg body weight or 50-100 g of base have been associated with retinal damage.

Retinopathy has rarely, if ever, resulted from doses recommended for malaria

chemoprophylaxis.

Twice-yearly screening for the detection of early retinal changes should be undertaken in

anyone who has taken 300 mg of Chloroquine weekly for over 5 years and requires further

chemoprophylaxis. In travellers who have taken 100 mg daily, screening should be carried out

after 3 years. If changes are observed, an alternative drug should be prescribed.

Contraindications: Chloroquine administration is contraindicated in persons with known

hypersensitivity, a history of epilepsy or suffering from psoriasis.

Overdose: Chloroquine has a low safety margin. Acute Chloroquine poisoning is extremely

dangerous and death may occur within a few hours. Poisoning may result after oral ingestion

by adults of a single amount of 1.5-2.0 g, i.e. 2-3 times the daily treatment dose. Symptoms

include headache, nausea, diarrhoea, dizziness, muscular weakness and blurred vision, which

may be dramatic with loss of vision. However, the main effect of over dosage is cardiovascular

toxicity with hypotension and cardiac arrhythmias progressing to cardiovascular collapse,

convulsions, cardiac and respiratory arrest, and death.

If the patient is seen within a few hours of the event, emesis must be induced or gastric lavage

undertaken as rapidly as possible. If not, treatment is symptomatic and directed particularly to

sustaining cardiovascular and respiratory function.

MEFLOQUINE

Formulations: Tablets containing 274 mg of mefloquine hydrochloride, equivalent to 250 mg

of mefloquine base. The formulation available in the USA contains 250 mg of mefloquine

hydrochloride equivalent to 228 mg of mefloquine base. The three commercial preparations

currently available show differences in bio-equivalence of both mefloquine and its carboxylic

acid metabolite as indicated by differences in maximum plasma concentration (Cmax) and area

under the curve (AUC, time-concentration).

Efficacy: Mefloquine is a 4-quinoline methanol chemically related to quinine. It is a potent

long-acting blood schizonticidal active against P. falciparum resistant to 4- aminoquinolines

and Sulphur drug–pyrimethamine combinations. It is also highly active against P. vivax and, P.

malariae and most probably P. ovale. It is not gametocytocidal and is not active against the

hepatic stages of malaria parasites.

Owing to its long elimination half-life and consequent long-lived sub-therapeutic

concentrations in the blood, the development of resistance is to be expected especially in areas

of high transmission. Since the late 1980s, resistance of P. falciparum to mefloquine has

developed in areas near the borders between Cambodia and Thailand and between Myanmar

and Thailand, and > 50% of patients have recrudescences of parasitaemia within 28 days after

a dose of 15 mg/kg. The sensitivity of P. falciparum populations recrudescing after treatment

with mefloquine is substantially reduced compared with the original population. P. falciparum

resistance to mefloquine is accompanied by cross-resistance to halofantrine and reduced

sensitivity to quinine. In contrast, laboratory studies have shown some increase in the sensitivity

of mefloquine-resistant isolates to chloroquine in Thailand. High levels of resistance have not

been documented outside South-East Asia, although sporadic reports of drug failure and in vitro

evidence of reduced sensitivity have been reported from Brazil and several countries in Asia,

Africa and the Middle East.

Drug disposition: Mefloquine is highly protein bound (98% in plasma) and has a long

elimination half-life, varying between 10 and 40 days in adults but tending to be shorter in

children and pregnant women. The elimination half-life was found to be longer in Caucasians

than Africans or Thais, the variations being attributed to differences in lipid stores. The

Pharmacokinetic parameters of mefloquine are changed in acute falciparum malaria; the drug

reaches a higher Cmax, probably due to a contraction of the apparent volume of distribution.

The drug shows stereo-specific elimination with a significantly longer half-life of 531 h for (-

)-mefloquine compared to 206 h for (+)-mefloquine. Mefloquine is extensively metabolized in

the liver and mainly eliminated in the faeces.

The main metabolite, carboxymefloquine, appears 2–4 h after drug intake with concentrations

surpassing that of the parent drug by the end of the first week. It is eliminated more slowly than

the parent drug. The metabolite lacks antimalarial activity but has a similar toxicity profile to

the parent compound. Urinary excretion of mefloquine and its metabolites accounts for 13% of

the total dose.

Adverse effects: Between 1984, when it was first registered, and the end of 1995, nearly 11

million people were exposed to mefloquine and another 5 million received it in combination

with sulfadoxine and pyrimethamine. The use of mefloquine is, however, subject to diverse

opinions, particularly related to its safety. The main problem relates to the drug’s potential for

inducing neuropsychiatry adverse reactions. There have also been concerns that other adverse

effects, such as dizziness, may impair the ability of patients performing activities that require a

high level of precision; that vomiting may affect treatment efficacy; and that use of the drug

during pregnancy and in persons taking cardio-active drugs for other indications may lead to an

increased risk of adverse events (see below).

Frequent adverse effects: These include dizziness, mild to moderate nausea, vomiting,

diarrhoea and abdominal pain (self-limiting but may be severe in some users). Vomiting was

nearly three times higher in young children receiving treatment with single doses of 25 mg/kg

mefloquine than in those given 15 mg/kg.

Splitting the higher dose over 2 days (15 mg/kg followed 24 h later with 10 mg/kg) halved the

incidence of vomiting. Transient post-treatment dizziness was significantly more frequent in

patients given 25 mg/kg and took twice as long to resolve. Adverse events have been observed

in 18.7% of travellers using mefloquine prophylaxis, a similar incidence to those reported

following the use of chloroquine or chloroquine plus proguanil.

Neuropsychiatry adverse reactions: Between 1985 and mid-1995, Hoffmann-La Roche

received reports of a total of 1574 neuropsychiatry adverse events associated with mefloquine

use, irrespective of causal relationship. These included affective disorders, anxiety disorders,

hallucinations, sleep disturbances including nightmares and, in a few people, overt psychosis,

toxic encephalopathy, convulsions and acute brain syndrome. The border between the very

unpleasant and “serious events” is difficult to delineate. Risks appear to vary with ethnic groups,

rates reported in Caucasians and Africans being higher than those in Asians for unknown

reasons. Risk is highest in people with a neurological or psychiatric history, a third of patients

reporting to the manufacturer with convulsions having had a personal or family history of such

events. More adverse events were reported in females than in males following prophylactic use,

which may reflect higher mg/kg dosing. On the basis of anecdotal reports, alcohol is postulated

to exacerbate the risk, but no adverse events occurred in 20 volunteers in a mefloquine-ethanol

interaction study.

The frequency of neuropsychiatry adverse reactions is reported to be more common following

mefloquine treatment than prophylactic use, occurring in 1 in 200 to 1 in 1200 patients,

depending on their ethnic origins. The severe events also appear to be dose-related and were

found to be seven-fold higher in those persons retreated with mefloquine within one month.

Symptoms occurred within 3 days in 73% of patients, with only 9% reporting onset 10 days or

more after treatment. The majority (78%) reported resolution of symptoms within 3 weeks.

Concomitant administration of quinine may increase the risk of serious neuropsychiatry

reactions and convulsions.

Following prophylactic use, the prevalence of “serious” neuropsychiatry reactions defined

according to the definitions of the Council for International Organizations of Medical Sciences

(CIOMS), has been reported to be relatively low, being in the order of 1 in 10,000 and usually

occurring early in the use of the drug. Retrospective assessment of these events reported to the

manufacturer indicates that 41% of cases experienced symptoms in the first week of chemo

prophylaxis, 59% by week two and 78% by the third week. Over 90% of effects occurred during

the first five weeks of chemo prophylaxis. In one study of Peace Corps Volunteers, in which

long-term weekly chemo prophylaxis was continued despite adverse events in several

participants, the rate of adverse reactions decreased with time.

The use of a loading dose during chemo prophylaxis may increase the risk of adverse reactions.

Strange dreams occurred more frequently after three daily loading doses of 250 mg of

mefloquine followed by 250 mg weekly, than after weekly chemo prophylaxis when steady

state was achieved in 7 weeks. Depressive feelings, which were more frequent with mefloquine

than with chloroquine, resolved as chemo prophylaxis continued.

A more recent study of British travellers taking mefloquine for chemo prophylaxis suggests that

the relative frequencies of adverse reactions vary with the criteria used. The frequency of

“serious” adverse events as defined by the CIOMS criteria was two cases for mefloquine and

one for chloroquine plus proguanil, each in a population of around 2300. However, more

pronounced differences were observed between the two regimens in self-reported adverse

reactions. Neuropsychiatry adverse events categorized by the traveller as “bad enough to

interfere with daily activities” (9.2% of users) or “bad enough to seek medical advice” (2.2%)

were each about twice as common with mefloquine than with chloroquine plus proguanil,

whereas the percentage of patients reporting any adverse reactions was similar in the two groups

(approximately 41%).

Cardiovascular effects: Bradycardia and sinus arrhythmia have been consistently reported in

up to 68% of patients treated with mefloquine in hospital-based studies, but comparative studies

show the incidence to be similar to that observed following treatment with chloroquine,

halofantrine or artesunate. No ECG or blood pressure changes were observed in 45 healthy

Australian volunteers who received 250 mg of mefloquine weekly for 4 weeks compared to 50

controls. Concomitant administration of mefloquine with other related compounds such as

quinine, quinidine and chloroquine may, however, produce ECG abnormalities and increase the

risk of convulsions. The use of halofantrine after mefloquine causes significant lengthening of

the QTc interval and has been linked with three cardiac arrests in patients treated with both

drugs.

Halofantrine should, therefore, not be used in persons who have recently received mefloquine.

Since the first use of mefloquine, there have been concerns that its co-administration with drugs

used to treat cardiovascular disease such as anti-arrhythmic drugs, beta-adrenergic blocking

agents and calcium channel blockers as well as antihistamines, tricyclic antidepressants and

phenothiazines might lead to severe adverse reactions. Theoretically, concomitant use of

mefloquine and such drugs might also contribute to the prolongation of the QTc interval.

However, no evidence of such drug interaction has been reported to date and co-medication

with such drugs is no longer contraindicated.

Rare events: Haematological events have been reported with mefloquine therapy, < 3% of

adverse events reported to the manufacturers being blood dyscrasias. Mefloquine causes

transient elevation of transaminases but is rarely associated with hepatitis. Three cases of

blackwater fever during mefloquine therapy have been reported. Rare dermatological events,

including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis,

have been temporally related to mefloquine exposure in a few individuals with no prior history

of a similar event.

Effects on performance: Dizziness is recognized as a frequent but transient adverse effect of

mefloquine use. Four of seven healthy Caucasian volunteers were severely incapacitated for 3-

4 days following administration of 25 mg/kg and all experienced light-headedness. This led to

the concern that chemo-prophylaxis with the drug may impair precision movements. There are,

however, indications that, if tolerated, mefloquine does not impede performance. No functional

compromise was identified in 203 United States Marines exposed to mefloquine prophylaxis or

in 23 trainee pilots who received mefloquine at 250 mg/day for 3 days, then weekly for a total

6 weeks.

However, sleep disturbances and loss of concentration were reported in volunteers given

mefloquine, although the incidence of the latter symptom was not statistically significant.

Balance and hearing were unaffected by weekly chemo-prophylaxis for 16 weeks in 10 healthy

Swedish volunteers and no effect was seen on subtle cerebral function, audiometry and

supine/erect blood pressure measurement in a placebo-controlled study of 45 healthy volunteers

taking weekly mefloquine.

Driving, i.e. road-tracking and car-following tests, has also been reported to be unaffected by

mefloquine prophylaxis. However, in view of the limited data WHO does not recommend the

use of mefloquine in persons, such as air pilots and machine operators, involved in tasks

requiring fine coordination and spatial discrimination. Any such persons who experience

adverse reactions after mefloquine intake should abstain from work (for at least 3 weeks after

treatment) until symptoms have fully resolved.

Drug interactions: Concurrent use of quinine can potentiate dose-related adverse reactions to

mefloquine. This may be related to the fact that higher quinine and mefloquine blood

concentrations than expected are observed when both drugs are given concurrently. In general,

mefloquine should not be administered within 12 h of the last dose of quinine. Co-

administration of mefloquine with tetracycline’s or ampicillin also produces higher mefloquine

blood concentrations.

Contraindications: The use of mefloquine is contraindicated in persons with a history of

allergy to mefloquine, with a history of severe neuropsychiatry disease, receiving halofantrine

treatment, who have received treatment with mefloquine in the previous 4 weeks and

performing activities requiring fine coordination and spatial discrimination e.g. air pilots and

machine operators.

Overdose: Induction of emesis and gastric lavage are of value if undertaken within a few hours

of ingestion. Cardiac function and neuropsychiatry status should be monitored for at least 1-3

days and symptomatic and intensive supportive treatment provided as required, particularly for

cardiovascular disturbances.

QUININE

Formulations:

•Tablets of quinine hydrochloride, quinine dihydrochloride or quinine sulphate containing 82%,

82% and 82.6% quinine base respectively. Quinine bisulphate formulations, containing 59.2%

base are less widely available.

•Injectable solutions of quinine hydrochloride, quinine dihydrochloride or quinine sulphate

containing 82%, 82% and 82.6% quinine base respectively.

Efficacy: Quinine is normally effective against falciparum infections that are resistant to

chloroquine and sulpha drug-pyrimethamine combinations. Decreasing sensitivity to quinine

has been detected in areas of South-East Asia where it has been extensively used for malaria

therapy. This has occurred particularly when therapy was given in an unsupervised and

ambulatory setting with regimens longer than 3 days. In these settings, patient adherence to

therapy is low, leading to incomplete treatment; this may have led to the selection of resistant

parasites.

There is some cross-resistance between quinine and mefloquine, suggesting that the wide use

of quinine in Thailand might have influenced the development of resistance to mefloquine in

that country. Strains of P. falciparum from Africa are generally highly sensitive to quinine.

Use in pregnancy: Quinine is safe in pregnancy. Studies have shown that therapeutic doses of

quinine do not induce labour and that the stimulation of contractions and evidence of Fetal

distress associated with the use of quinine may be attributable to fever and other effects of

malarial disease. The risk of quinine-induced hypoglycaemia is, however, greater than in non-

pregnant women, particularly in severe disease. Special vigilance is therefore required.

Drug disposition: Quinine is rapidly absorbed when taken orally, and peak plasma

concentrations are reached within 1-3 h. The drug is distributed throughout body fluids being

highly protein bound. It readily crosses the placental barrier and is found in cerebrospinal fluid.

Quinine is extensively metabolized in the liver, has an elimination half-life of 10-12 h in healthy

individuals and is subsequently excreted in the urine, mainly as hydroxylated metabolites.

Several Pharmacokinetic characteristics differ according to the age of the subject, and are also

affected by malaria. The volume of distribution is less in young children than in adults, and the

rate of elimination is slower in the elderly than in young adults. In patients with acute malaria,

the volume of distribution is reduced and systemic clearance is slower than in healthy subjects,

these changes being proportional to the severity of the disease. Protein binding of quinine is,

however, increased in patients with malaria, as a result of the increased circulating

concentration of the binding-protein (alpha-1 acid glycoprotein).

Adverse effects: Cinchonism, a symptom complex characterized by tinnitus, hearing

impairment, and sometimes vertigo or dizziness, occurs in a high proportion of treated patients.

Symptoms appear when the total plasma concentration of quinine is about 5mg/l, i.e. at the

lower limit of the therapeutic range of the drug, which is 5-15 mg/l. The symptoms that are

usually reversible generally develop on the second or third day of treatment and alone rarely

constitute a reason for withdrawing the drug.

Dose-related cardiovascular, gastrointestinal and central nervous system effects may arise

following excessive infusion or from accumulation following oral administration. Severe

hypotension may develop if the drug is injected too rapidly. Quinine may enhance the effects

of cardio suppressant drugs and should be prescribed with caution in individuals taking drugs

such as beta-adrenergic blocking agents, digoxin and calcium channel blocking agents,

especially in those with cardiac disease. Enhanced cardiac toxicity may occur if quinine therapy

is administered to individuals who have taken mefloquine for malaria chemo prophylaxis.

Hypoglycaemia may be caused by quinine since the drug stimulates secretion of insulin from

pancreatic beta-cells. Hypoglycaemia is particularly likely to develop after intravenous infusion

of quinine in pregnancy, since beta-cells are more susceptible to a variety of stimuli at that time.

Overdose: A single dose of quinine of > 3 g is capable of causing serious and potentially fatal

intoxication in adults, preceded by depression of the central nervous system and seizures. Much

smaller doses can be lethal in children. Dysrhythmias, hypotension and cardiac arrest can result

from the cardiotoxic action and visual disorders may be severe, leading to blindness in rare

cases. Emesis should be induced and gastric lavage undertaken as rapidly as possible.

ARTEMISININ AND ITS DERIVATIVES

Artemisinin (qinghaosu) is the antimalarial principle isolated by Chinese scientists from

Artemisia annua L. It is a sesquiterpene lactone with a peroxide bridge linkage. Artemisinin is

poorly soluble in oils or water but the parent compound has yielded dihydro-artemisinin, the

oil-soluble derivatives artemether and arteether, and the more water-soluble derivatives sodium

artesunate and artelinic acid. These derivatives have more potent blood schizonticidal activity

than the parent compound and are the most rapidly effective antimalarial drugs known. They

are used for the treatment of severe and uncomplicated malaria. They are not hypnozoiticidal

but gametocytocidal activity has been observed.

Formulations: A wide variety of formulations for oral or parenteral use or as suppositories are

available (see below). China and Vietnam continue to be the main producers of artemisinin and

its derivatives.

Efficacy: The antimalarial activity of artemisinin and its derivatives is extremely rapid and

most patients show clinical improvement within 1-3 days after treatment. However, the

recrudescence rate is high when the drugs are used in monotherapy, depending on the drug dose

administered, the duration of treatment and the severity of disease, but not at present on parasite

resistance.

Treatment for < 7 days gave unacceptably high recrudescence rates. So far there is no confirmed

in vivo evidence of resistance of P. falciparum to artemisinin and its derivatives. The

susceptibility of P. falciparum strains from the China-Lao People’s Democratic Republic and

China-Myanmar border areas to various antimalarial drugs have been tested in vitro. The results

have indicated declining susceptibility of P. falciparum to artemisinin derivatives.

Under exceptional circumstances, such as when there is a history of an adverse reaction to the

combination agent, artemisinin monotherapy may be indicated, but a 7-day course of therapy

is recommended and efforts should be made to improve adherence to the treatment. Preliminary

results from Africa indicate that combinations of artesunate plus amodiaquine or sulfadoxine–

pyrimethamine are highly efficacious, although efficacy may be compromised in areas with

moderate to high levels of resistance to sulfadoxine-pyrimethamine.

These compounds are not recommended as first line treatment of malaria due to P. vivax, P.

malariae or P. ovale since other effective antimalarial drugs are available for this purpose.

However, they may be used in the absence of microscopic diagnosis or the recommended first

line treatment and for mixed infections with P. falciparum.

Drug disposition: High-performance liquid chromatography-electron capture detection

(HPLCECD) and bioassay methods for studying the Pharmacokinetic of artemisinin and its

derivatives have now been validated. HPLC-ECD detects separately the parent compound and

the major metabolite, dihydro-artemisinin, whereas bioassays measure total activity, i.e. parent

compound plus metabolite(s). Both methods are cumbersome and only a limited number of

laboratories have the capability of conducting assays, especially using HPLC-ECD, which

requires a reductive-mode electrochemical analysis and must be performed under oxygen free

conditions.

An alternative HPLC method that uses ultraviolet detection is somewhat easier and quicker to

use. So far, all methods are for plasma only; no method is available to measure levels in whole

blood. With few exceptions, the lower limit of detection of HPLC-based methods is ≤ 5mg/ml.

Oral bio availability varies with the derivative and is influenced by disease status. All

derivatives, but not artemisinin itself are metabolized to a common bioactive metabolite,

dihydro-artemisinin, at variable rates.

Adverse effects: Extensive clinical trials in China, Myanmar, Thailand and Vietnam

demonstrated no acute cardiovascular or other vital organ toxicity. However, animal studies

have demonstrated severe neurotoxicity following parenteral administration of very high doses

of artemether or arteether. Both drugs produced a unique pattern of selective neuropathy with

chromatolysis and necrosis of scattered neurons in vestibular, motor and auditory brain stem

nuclei in rats, dogs and rhesus monkeys.

Such effects have not been observed with oral administration of any artemisinin derivative or

with intravenous artesunate. This has led to the suggestion that the effect is related to specific

molecules and their route of administration. The cause, however, appears to be due to

sustainable high levels of the drugs and their metabolites, which may occur following

intramuscular injection, rather than to the route of administration itself (T.G. Brewer, personal

communication, 1996).

There is no clinical evidence to date of serious neurotoxicity resulting from the use of any

artemisinin drug in humans in prospective studies of more than 10 000 patients or in the more

than 2 million persons who have received these drugs. In Thailand, full neurological

examinations in more than 1 100 patients who had received an artemisinin drug showed no

specific pattern of neurological abnormalities. Studies in Thailand and Vietnam provided no

evidence of any brain stem toxicity attributable to artemisinin and artesunate. There is some

concern about cerebellar dysfunction, and prolonged or repetitive treatment with artemisinin

and its derivatives, which may occur in areas of high transmission, must be viewed with caution.

Additional studies to monitor subtle neurological changes and hearing loss are required,

especially in patients undergoing repetitive treatment. Post-marketing surveillance in countries

where these drugs are marketed and used is recommended.

ARTEMETHER

Formulations:

• Capsules containing 40 mg of artemether (China).

• Composite tablets containing 50 mg of artemether (China).

• Ampoules of injectable solution for intramuscular injection containing 80 mg in 1 ml (China

and France), or 40 mg in 1 ml for paediatric use (France).

Efficacy: Artemether is an oil-soluble methyl ether derivative of dihydroartemisinin. As with

artemisinin, it is effective against P. falciparum resistant to all other operationally used

antimalarial drugs. It is not hypnozoiticidal but it reduces gametocyte carriage.

Drug disposition: The pharmacokinetics of artemether following oral administration appear to

be similar to those for artemisinin with mean peak plasma concentrations and mean plasma

half-lives of 1-2 h and 2-3 h, respectively. The plasma concentrations of artemether are similar

in healthy subjects and those with acute uncomplicated malaria. Plasma antimalarial activity is

significantly greater with intramuscular administration than with oral use because the first-pass

bio-transformation is bypassed. Bio-availability of artemether following intramuscular

administration was increased and clearance reduced in patients with acute renal failure.

Adverse effects: Toxicity studies in dogs and rats indicate that dose-dependent and potentially

fatal neurotoxic effects may occur after intramuscular injection of artemether at doses higher

than those used for malaria treatment. These changes can be widespread but mainly affect areas

associated with vestibular, motor and auditory functions. No similar findings have been

reported in humans treated with normal therapeutic doses of artemether.

Contraindications: Similar to artemisinin.

Overdose: Similar to artemisinin.

ARTESUNATE

Formulations:

• Tablets containing 50 mg of sodium artesunate (China, France and Vietnam) or 200 mg of

sodium artesunate (Switzerland).

• Ampoules for intramuscular or intravenous injection containing 60 mg of sodium artesunate

in 1 ml of injectable solution (China and Vietnam).

• Suppositories of sodium artesunate (China).

• Rectal capsules containing 100 mg or 400 mg of sodium artesunate (Switzerland).

Efficacy: Artesunate, a water-soluble hemisuccinate derivative of dihydro-artemisinin, is the

most widely used member of this family of drugs. It is unstable in neutral solutions and is

therefore only available for injections as artesunic acid. It is effective against P. falciparum

resistant to all other operationally used antimalarial drugs. It does not have hypnozoiticidal

activity. It reduces gametocyte carriage rate.

Drug disposition: The pharmacokinetics of artesunate following oral administration appear to

be similar to those for artemisinin, with mean peak plasma concentrations and mean plasma

half-lives of 1-2 h and 2-3 h, respectively. The plasma concentrations of artesunate are more

erratic following administration by suppository compared to the intravenous route, but

inadequate absorption is unusual.

Adverse effects: Prospective clinical studies of more than 10 000 patients, and post-marketing

surveillance of over 4 600 patients in Thailand has not shown any serious drug related adverse

reactions.

PRIMAQUINE

Formulations: Tablets containing 5.0 mg, 7.5 mg or 15.0 mg of primaquine base as

diphosphate.

Efficacy: Primaquine is an 8-aminoquinoline highly active against the gametocytes of all

malaria species found in humans and against hypnozoites of the relapsing malarial parasites, P.

vivax and P. ovale. It is the only drug currently used for the treatment of relapsing malaria,

although another 8-aminoquinoline, CDRI 80/53 (bulaquine) has recently completed phase III

clinical trials and another, tafenoquine, is still undergoing clinical trials. There are geographical

variations in the sensitivity of hypnozoites of P. vivax to primaquine. P. vivax from India seems

to be the most sensitive, while parasites from the southern regions of South-East Asia and

Oceania are the least susceptible. Infections in the Americas, the Mediterranean region, and

Europe generally appear to have an intermediate sensitivity. The anti-relapse effect of

primaquine is a function of the total dose rather than the duration of treatment. As a

gametocytocidal for P. falciparum, it is effective given in a single dose of 30-45 mg of base

(0.5-0.75 mg of base per kg).

In Central America, treatment with amodiaquine followed by 5-day (15 mg of base per day) or

1-day (45 mg of base) regimens of primaquine has been shown to reduce significantly the

frequency of recurrent P. vivax parasitaemia when compared to amodiaquine alone over a 9-

month follow up period. Primaquine has causal chemo-prophylactic activity but, until recently

this property had not been evaluated under conditions of natural exposure, partially due to the

prevailing view that primaquine was too toxic for routine chemo-prophylaxis.

Studies in Irian Jaya and Kenya have now shown that daily doses of 0.5 mg/kg (30 mg daily in

an adult) can be effective in protecting both adults and children against falciparum and vivax

infections. The drug was well tolerated for one year in adult males who had normal glucose-6-

phosphate dehydrogenase (G6PD) levels and in children aged 9–14 years for the study period

of 11 weeks. Studies are currently under way to investigate the prophylactic use of primaquine

in combination with other antimalarial drugs such as doxyclycline.

Primaquine has also been shown to be active against asexual blood stages of P. vivax at doses

of 15-30 mg daily for 14 days in studies in Thailand. It also has some activity against the asexual

blood stages of P. falciparum, but only at doses that would be expected to be toxic.

Drug disposition: Primaquine is readily absorbed when taken orally but there is a considerable

inter-individual variation in pharmacokinetics profile in humans. Peak plasma concentrations

occur within 1-3 h, with a plasma half-life of about 5 h. Primaquine is rapidly metabolized in

the liver and only a small amount is excreted unchanged in the urine, which suggests extensive

intra-hepatic recycling. Two major metabolic pathways have been described. One leads to the

formation of 5-hydroxyprimaquine and 5-hydroxy-demethylprimaquine, both of which have

antimalarial activity and cause methaemoglobin formation. The other pathway results in the

formation of N-acetylprimaquine and a desaminocarboxylic acid. The carboxyclic acid

metabolite is the major metabolite in humans and does not appear to be active.

Adverse effects: Primaquine may cause anorexia. Other adverse effects include nausea,

vomiting, abdominal pain and cramps. These symptoms are dose related and are relatively rare

at daily doses of up to 0.25 mg of base per kg (15 mg of base daily in an adult). Gastric

intolerance can be avoided by administering the drug with food. Primaquine has also been

known to cause weakness, uneasiness in the chest, anaemia, methemoglobinaemia, leucopoenia

and suppression of myeloid activity. In chemo-prophylaxis trials, a daily dose of 30 mg of base

in persons with normal G6PD status showed good safety and tolerance when compared with

placebo and other antimalarial drugs.

The more severe adverse reactions at higher doses are related to the effect of primaquine on the

formed elements of the blood and bone marrow. Primaquine does not normally cause

granulocytopenia at the doses recommended for malaria therapy. The haemolytic action of

primaquine is increased in subjects with G6PD deficiency. It is usually self-limiting but blood

transfusions may be necessary in severe cases.

Contraindications: Primaquine is contraindicated in pregnancy, breast-feeding women and in

children less than 6 months of age because of the risk of haemolysis if the baby has G6PD

deficiency. The drug is also contraindicated in conditions predisposing to granulocytopenia,

including active rheumatoid arthritis and lupus erythematosus.

Drug interactions: Primaquine should not be administered with any other drug that may induce

haematological disorders.

Overdose: Gastrointestinal symptoms, weakness, methemoglobinaemia, cyanosis, haemolytic

anaemia, jaundice and bone marrow depression may occur with over-dosage. There is no

specific antidote and treatment is symptomatic.

CLINDAMYCIN

Formulations: Capsules containing 75 mg, 150 mg or 300 mg of clindamycin base as

hydrochloride.

Efficacy and use: Clindamycin is a semi-synthetic antibiotic derived from lincomycin. Like

tetracycline, it is an efficient blood schizonticidal with a relatively slow action and a similar

spectrum of activity. Along with tetracycline and doxyclycline, it is an option for use in

combination with quinine for treatment of falciparum malaria when decreased susceptibility to

quinine has been reported. However, it is more toxic and costly than tetracycline and

doxyclycline and should therefore, only be used when these drugs are contraindicated or

unavailable. It should not be used alone for the treatment of malaria because of its slow action.

It is not suitable for chemo-prophylaxis. Recent studies have demonstrated high efficacy in 3-

day courses of clindamycin in combination with quinine in Africa and in a 7-day course of the

same combination in Thailand.

Use in pregnancy: Unlike tetracycline and doxyclycline, clindamycin use has not been

reported to cause adverse events in pregnancy, although it does cross the placenta and may be

accumulated in the fetal liver. It is also excreted in breast milk but without any apparent effect.

Therefore, clindamycin is not contraindicated for malaria therapy in pregnancy although

experience in this regard is limited.

Drug disposition: About 90% of clindamycin is absorbed from the gastrointestinal tract, peak

plasma concentrations after oral administration being reached in about 1 h. The drug is rapidly

hydrolyzed to the free base and widely distributed in body tissues and fluids. Over 90% of

circulating clindamycin is bound to plasma proteins. The plasma half-life is 2-3 h although this

may be extended in neonates and persons with renal impairment.

Clindamycin is partly metabolized, probably in the liver, to active and inactive metabolites, but

most of the drug is eliminated unchanged in the faeces. Elimination of metabolites is slow over

several days.

Adverse effects: Nausea, vomiting, abdominal pain or cramps have been reported and some

patients (2-20%) may experience diarrhoea. Pseudo-membranous colitis, a potentially fatal

condition caused by Clostridium difficile toxin, may develop in some cases. Hypersensitivity

reactions, including skin rashes and urticaria, and neutropenia and thrombocytopenia occur

rarely.

Clindamycin should be withdrawn if diarrhoea or colitis occurs. Vancomycin in doses of 125-

500 mg every 6 h has been used successfully to treat pseudo-membranous colitis.

Contraindications: Clindamycin is contraindicated in persons with hypersensitivity to

clindamycin or lincomycin, a history of gastrointestinal disease, particularly colitis and severe

hepatic or renal impairment.