The species traditionally collectively termed "protozoa" are not closely related to each other,

and have only superficial similarities (eukaryotic, unicellular, motile, though with
exceptions.) Examples include Entamoeba histolytica, Plasmodium (some of which cause
malaria), and Giardia lamblia. Trypanosoma brucei, transmitted by the tsetse fly and the
cause of African sleeping sickness, is another example.

Chemotherapy of Malaria

The term 'Malaria' is coined from the Italian phrase 'mal aria', meaning 'bad air'. The disease
was very active in Rome for centuries, and at least four Popes are believed to have lost their
lives due to malaria.

Malaria is caused by parasitic protozoa of the genus Plasmodium and is characterised by

fever with rigor, anemia and splenomegaly. The morbidity due to malaria in Asia and Africa
has been greatly underestimated. Currently, it is estimated that nearly half a billion people in
the world suffer from malaria, and more than a million die from malaria every year, most of
them from the developing countries. Nearly 50% of the cases the world over are caused by P.
falciparum.

Life cycle of plasmodium:

There are four major types of plasmodia which infect man:

P. vivax
P. falciparum
P. ovale; and
P. malariae

P. vivax causes benign tertian malaria which, though mild, has a tendency to relapse. P.
falciparum infection results in malignant tertian malaria, a fulminating infection, which, if
not treated, may result in death; but the disease, once cured, has no tendency to relapse. In
both infections, the infected individual develops pyrexia with rigors every 3rd day, and hence
the term 'tertian'. P. ovale and P. malariae infections are usually mild; the individual
develops pyrexia every 4th day and hence, it is described as 'benign quartan'. Recently, P.
knowlesi has been shown to infect human beings. In order to understand the actions of
antimalarials, it is necessary to know parasite life cycle.
An individual is infected by malarial parasites through the bite of a female Anopheles
mosquito. The disease can also be transmitted by transfusion of infected blood and from
mother to the foetus across the placenta. The salivary glands of the infected mosquito contain
a large number of sporozoites, which are introduced into of the host during mosquito bite (Fig
56.1). After the entry, the sporozoites develop further through various stages:

(1) Pre-erythrocytic Stage

(2) Erythrocytic Stage;

(3) Development of sexual forms.

In the pre-erythrocytic stage, sporozoites disappear rapidly from the circulation and invade
the hepatic cells (Hepatic cycle - Site I). The duration of the pre-erythrocytic stage varies
with the species of plasmodium. It is 5 to 7 days for P. falciparum and 8 days to several
months for P. vivax. The host does not develop any symptoms during this phase. At the
completion of this phase, the infected reticuloendothelial cell, is termed tissue schizont
(primary exoerythrocyte).

Fig. 56.1: Life cycle of malarial parasite (P. falciparum form) releases several thousand
merozoites into the blood stream.
In the erythrocytic stage (Site II), merozoites invade the erythrocytes and undergo further
development and multiplication, giving rise to erythrocytic schizonts (asexual erythrocyte
forms). The infected RBCs eventually rupture, and release thousands of merozoites into the
blood. This periodic release of merozoites is associated with paroxysms of fever with rigor.
The merozoites thus released invade fresh erythrocytes, and the cycle of erythrocytic
schizogony repeats.

Development of sexual forms starts with the differentiation of some of the released
merozoites into male (macro) and female (micro) gametocytes (Site III). During a mosquito
bite, these forms are sucked in from the blood and mature into gametes in the mosquito gut.
The female gamete is fertilised by the motile male gamete to form a zygote. The zygote
invades the gut wall of the mosquito to form an oocyst. The mature oocyst contains thousands
of sporozoites.

After about 1 to 4 weeks, depending upon the species of plasmodium, the oocyst ruptures
releasing free sporozoites which reach the salivary glands of the mosquito and are ready to be
injected in the host.

The above cycle in case of P. falciparum, terminates at this point. However P. vivax and P.
ovale have persistent hepatic cycle due to presence of hypnozoites, also known as latent
tissue phase or exo-erythrocytic phase. The delayed formation of tissue schizonts from such
latent hypnozoites explains the relapses of P. vivax and P. ovale malaria. In case of P.
malariae, the relapse may originate from erythrocytic forms remaining in the body for upto
30 years, due to no exoerythrocytic schizogony.

The larger number of merozoites released by P. falciparum and the short incubation period
explain the high levels of parasitaemia and severity of this infection. If left untreated, the P.
falciparum infection lasts for less than one year and the P. vivax and P. ovale infections
usually take 3-4 years to die out. Infection due to P. malariae may, however, persist for many
years.

Clinical classification of antimalarial drugs:

I. True causal prophylactics:

These are the drugs that would destroy the sporozoites before their invasion of the host
reticuloendothelial cells. No drug of this type, however, is available.
II. Causal prophylactics:

These drugs prevent the maturation of or destroy the sporozoites within the infected hepatic
cells (Site I) and thus prevent erythrocytic invasion. They are also known as primary tissue
schizonticides. Primaquine, pyrimethamine and proguanil act as causal prophylactics against
P. falciparum but their efficacy against P. vivax is doubtful.

III. Suppressives:

These drugs (schizonticides) inhibit erythrocytic schizogony (Site II) and prevent the rupture
of the infected erythrocytes. This leads to freedom from rigors and pyrexia (clinical cure).
However, they do not eradicate the infection.

Suppressives can cure P. falciparum infection as the parasite does not undergo secondary
exoerythrocytic schizogony but they do not affect the persistent tissue phase of P. vivax
(hypnozoites) and hence relapses can occur with the stoppage of suppressive therapy. The
suppressive agents include:

(a) Rapidly acting quinine, 4-aminoquinolines, mefloquine, artemisinin, atovaquone and

(b) Slowly acting proguanil, pyrimethamine, sulfadoxine and tetracycline.

IV. Radical curatives:

These drugs eradicate both, erythrocytic and secondary exoerythrocytic schizogony so that
relapse does not occur. For radical cure of vivax infection, primaquine and proguanil are
effective (See later). Radical cure of falciparum malaria can be achieved with suppressives
alone.

V. Gametocytocidal drugs:

The suppresives such as chloroquine, quinine and artesunate are effective against
gametocytes of all species, except P. falciparum. Primaquine is, however, highly effective
against gametocytes of all species, including P. falciparum.

Proguanil and pyrimethamine do not destroy gametocytes but prevent their development in
the mosquito. They are also known as sporonticidal drugs.
Chemical classification:

I. Cinchona alkaloids: Quinine, Quinidine

II. Quinoline derivatives:

(a) 4-Aminoquinolines: Chloroquine, Amodiaquine, Pyronaridine.

(b) 8-Aminoquinolines: Primaquine, Tafenoquine, Bulaquine.

(c) Quinoline methanol: Mefloquine,

III. Phenanthrene methanol: Halofantrine, Lumefantrine.

IV. Antifolates:

(a) Biguanides: Proguanil.

(b) Diaminopyrirnidines: Pyrimethamine.

(c) Sulfonamides: Sulfadoxine.

V. Artemisinin compounds: Artesunate, Artether, Artemether.

VI. Antimicrobials: Doxycycline, Clindamycin, Atovaquone.

Table 56.1: Actions of commonly used drugs on the life cycle of the malarial parasites

Development
Erythrocytic phase Latent tissue
of gametocytes
Hepatic phase
Drug in the mosquito
phase Asexual Sexual forms (responsible
(sporonticidal
parasites (gametocytes) for relapse)
action)
Active against
P. vivax and P.
Quinine No action Fast action malariae. No No action No action
direct action on
P. falciparum
Chloroquine
and No action Fast action As quinine No action No action
Amodiaquine
Direct and fast
Active and
action on all
can be used
Primaquine Weakly active species but Highly active Highly active
for
particularly P.
prophylaxis
falciparum
Active
particularly Active but
Proguanil No direct action No action Highly active
on P. relatively slow
falciparum
 Development
Erythrocytic phase Latent tissue
of gametocytes
Hepatic phase
Drug in the mosquito
phase Asexual Sexual forms (responsible
(sporonticidal
parasites (gametocytes) for relapse)
action)
No evidence of Some action on
Pyrimethamine As proguanil As proguanil Little evidence
direct action P. vivax
Sulfones and Possible As
Action slow Little evidence --
Sulfonamides action pyrimethamine
Marked but
Mefloquine No action As quinine No action No action
slow
Active against
Artesunate No action Fastest acting No action No action
P. vivax
More active
Atovaquone No than No No No
Chloroquine

Cinchona Alkaloids

QUININE is an alkaloid isolated from the bark of the cinchona tree, originally a native of
Peru, South America, and known for many years as 'Jesuit's bark'. Quinine, the oldest of all
the therapeutic agents used to treat malaria is still useful in the treatment of cerebral malaria
and chloroquine-resistant P. falciparum infection.

Pharmacological actions:

Antimalarial action: Quinine is schizonticidal and is useful only as a suppressive. It is

also gametocidal against all species except P. falciparum. It has no effect on the
sporozoites, the pre-erythrocytic stage and the persistent tissue forms. Mechanism of
action of quinine is like that of chloroquine (see later) but as the drug is not extensively
concentrated in the parasites, other mechanisms may also be involved.
Quinine has been termed as a 'general protoplasmic poison'. It depresses various
enzymatic processes, reduces ciliary activity, and inhibits phagocytosis and the growth of
fibroblasts.
Local irritant action: Quinine causes pain, edema, and reactive fibrosis. Sterile injection
abscesses and venous thrombosis may occur.
GI tract: Quinine has an intensely bitter taste and can cause nausea, vomiting and
epigastric pain.
Cardiovascular actions: Like quinidine, another cinchona alkaloid, quinine is also a direct
depressant of the myocardium. It reduces excitability, conductivity and lengthens the
refractory period. Quinine IV can produce profound hypotension due to cardiac
depression and dilatation of the arterioles.
Miscellaneous actions: It has a mild analgesic and antipyretic activity. It stimulates the
uterine smooth muscle. However, in the doses in which it is used in malaria, it has hardly
 any adverse effect on the pregnant uterus. It has a curarimimetic action on the skeletal
muscles.

Absorption, fate and excretion: Administered orally, it is almost completely and rapidly
absorbed from the small intestine; and the peak plasma levels are reached within 1 to 3 hours.
It readily crosses the placental barrier.

Quinine is mainly metabolised in the liver. Its plasma t1/2 is about 10 hours but it is usually
prolonged in the acute stage of falciparum infection because of hepatic impairment.
Approximately 5% of the total dose appears in urine unchanged.

Adverse reactions: The major reason for the decline in popularity of quinine is its toxicity.
The salient toxic manifestations are:

Cinchonism: This syndrome which occurs when quinine is administered for a long time,
resembles salicylism. Mild symptoms consist of ringing in the ears, nausea, headache and
visual impairment. With large doses, tinnitus deafness, vertigo, blurred vision,
disturbance of colour vision and photophobia appear. Toxic amblyopia occasionally
leading to total blindness has been rarely reported.
Severe intoxication causes, skin rashes, headache, fever, vomiting, diarrhoea, confusion
and delirium. The respiration is depressed, BP falls, and eventually death may occur due
to respiratory arrest. Even if the patient recovers, visual and auditory impairment may not
be entirely corrected. The treatment is essentially symptomatic.
Idiosyncrasy: The commonest manifestation is intense flushing accompanied by
generalised pruritus and urticaria. Quinine may precipitate angioneurotic edema or
asthmatic attacks in .sensitive individuals. Rarely, it causes thrombocytopenic purpura,
hemolytic anemia and agranulocytosis.
Cardiovascular toxicity: Quinine is a myocardial depressant and can cause cardiac arrest
when given IV.
Black water fever: It is characterised by acute intravascular hemolysis, hemoglobinuria,
fever and acute renal failure. It is encountered with chronic P. falciparum malaria. Focal
hepatic necrosis may develop in severe cases. Blackwater fever may occur during the
natural course of malaria, and is often triggered by quinine treatment.
It is probable that the reaction has immunological basis and is caused by a state of
hypersensitivity attributable to the presence of incompletely suppressed falciparum
infection. It is important to continue appropriate antimalarial therapy in such a patient.
Fresh blood transfusion to maintain hematocrit above 20% may be necessary. The fluid
and electrolyte imbalance should be corrected along with treatment of hypotension.
Alkalinisation of urine and use of glucocorticoids are controversial. Later, the patient
should be evaluated for his G6PD status.
 Hypoglycemia: Quinine can cause hypoglycemia by releasing insulin from the pancreatic
beta cells.
Miscellaneous: Quinine IV may cause convulsions.

Preparations and dosage:

(i) Quinine sulfate tablet 300 mg. Dose: 300 to 600 mg.

(ii) Quinine hydrochloride tablet 300 mg. Dose: 300 to 600 mg.

(iii) Quinine sulfate injection contains 300 mg of the salt per ml. It can be administered by IV
infusion or by deep IM route. Dose: 300 to 600 mg.

Therapeutic uses:

Malaria: It is an important drug for treating severe falciparum infection (see later).
Myotonia congenita: This hereditary myopathy, characterised by tonic spasm of skeletal
muscles, is often benefitted by 300 to 600 mg of quinine hydrochloride given orally twice
or thrice daily.
Cramps: The drug has been used in the dose of 200 to 300 mg before retiring to prevent
nocturnal muscle cramps.

4-Aminoquinolines

The 4-aminoquinolines constitute the mainstay of suppressive therapy of malaria. In addition,

they are useful in a variety of other conditions. The therapeutically useful compounds of this
class are chloroquine, hydroxychloroquine and amodiaquine.

CHLOROQUINE: This is the most frequently used compound (Fig 56.2) and is used as the
diphosphate salt.

Fig. 56.2: Chloroquine

Mechanism of action: Malarial parasites digest haemoglobin in their lysosomes to utilise
amino acids. The released heme is highly toxic but is converted by the parasitic polymerase
to nontoxic hemozoin. Chloroquine, being a basic drug, concentrates in the acidic lysosomes
and binds to released heme, thus preventing its polymerisation. This results in oxidative
damage to organelles of parasites, causing death.

Pharmacological actions:

Antimalarial activity: As a suppressive, chloroquine is superior to quinine.

(i) It kills the erythrocytic forms of P. vivax and P. falciparum.

(ii) It is also effective against the gametocytes of P. vivax, P. ovale and P. malariae.

However, it has no effect on the sporozoites, the pre-erythrocytic stage and the persistent
tissue forms. Resistance to chloroquine by P. falciparum develops due to an efflux
mechanism by which the parasite pumps the drug out of the cell. Such organisms exhibit
cross-resistance to other 4-aminoquinolines.

Other antiparasitic actions: The drug is also effective in giardiasis, taeniasis and
extraintestinal amoebiasis.
CVS: Like quinine, chloroquine is a direct cardiac depressant and may exert a direct
relaxant effect on vascular smooth muscles causing hypotension.
Miscellaneous actions: It has some anti-inflammatory, antihistaminic and local
anaesthetic activities.

Absorption, fate and excretion: Chloroquine is rapidly and almost completely absorbed from
the gut. Effective plasma concentration is attained within 2-3 hours of oral dose and within 15
minutes of IM administration. About 55% of the drug in plasma is protein bound. It is highly
concentrated in the liver, spleen, kidney, lung and leucocytes. The brain and the spinal cord
levels, however, are only 10 to 30 times the plasma levels. Because of its high volume of
distribution, a loading dose is necessary to initiate therapy. Due to its affinity for the tissue
proteins, the drug persists in the body for a long time after discontinuation. It is metabolised
in the liver to the active metabolite 4-hydroxychloroquine. Acidification of urine hastens its
renal excretion.

Adverse reactions: Chloroquine used as an antimalarial is a relatively safe drug. Commonly

it causes nausea and vomiting. The drug, however, may produce serious toxicity when used
in large doses for prolonged periods as in RA. The important toxic manifestations are:
 Intolerance: Skin rashes with or without pruritus, angioneurotic edema, photosensitivity,
pigmentation and even exfoliative dermatitis have been reported. Long term treatment
may lead to bleaching of the scalp hair, eyebrows and eyelashes. Rarely,
thrombocytopenia, and pancytopenia may occur.
Eye: Ocular complications can occur with the high dosage, prolonged chloroquine
therapy of RA, discoid lupus and lupus erythematosus. They are very rare during the
treatment of malaria. Temporary loss of accommodation with blurring of vision or
diplopia may develop. Difficulties in focussing eyes have been reported in pilots taking
chloroquine prophylactically. It is reversible on discontinuation. Lenticular opacities and
posterior subcapsular cataracts have been reported. The retinal changes (retinopathy),
consist of constriction of the retinal arteries, edema and abnormal blue-black
pigmentation of the retina and depigmentation of the macula accompanied by macular
degeneration. The field of vision is constricted. These changes are not reversible and
need immediate discontinuation of the drug. Because of its prolonged sojourn in the body,
the ocular changes may appear even a few years after discontinuation of chloroquine.
Hence, patients on long term chloroquine therapy (as in RA) should undergo periodic
ophthalmoscopic examination.
Central Nervous System: Insomnia and transient depression are common. Acute
psychotic episodes, seizures and, neuromyopathy may occur. Ototoxicity has also been
reported.
Cardiovascular System: Abnormalities of ST segment and T waves are reported.
Chloroquine IV can cause abrupt hypotension and cardiac arrest especially in children.

Preparations and dosage:

(i) Chloroquine phosphate tablet 250 mg (150 mg of the base). Dose: as a suppressive in
acute attack: initial dose: 1 g followed by 0.5 g after 6 hours and 0.5 g daily thereafter for 2
days followed by 0.5g once a week for 3 months. For prophylaxis in an individual who is
going into an endemic area, 0.5 g weekly.

(ii) Chloroquine sulfate tablet contains 150 mg of chloroquine base. Dosage: same as above.

(iii) Chloroquine injection contains chloroquine phosphate or sulfate equivalent to 40 mg of

the base per ml. Dose: 200 to 300 mg of the base IM, divided between two injection sites, or
IV, slowly, diluted with 100 ml of glucose saline. The total parenteral dose within 24 hours
should not exceed 900 mg of the base.

Therapeutic uses:

Malaria: It is still the first line of treatment for P. vivax malaria and uncomplicated
falciparum malaria due to sensitive strains (See later). Chloroquine and amodiaquine are
considered safe antimalarials during pregnancy.
Hepatic amoebiasis: Chapter 57.
 Giardiasis: Although chloroquine phosphate, mepacrine and amodiaquine are effective in
this condition, metronidazole is preferred (Chapter 58).
Clonorchis sinensis (Chinese liver fluke) infestation: Chloroquine phosphate, 250 mg
daily, is given for 6 weeks.
Rheumatoid arthritis: Chapter 75.
Discoid lupus and disseminated lupus erythematosus: Chloroquine is useful only in the
milder forms of this disease and as a supplementary therapy to glucocorticoids in severely
ill patients. The arthritic and the cutaneous lesions improve markedly with chloroquine.
Chloroquine phosphate is given in the dose of 250 to 500 mg daily for 1 to 4 weeks or
until a clear response is obtained. The dose is then reduced to a maximum of 250 mg and
maintained subsequently.

HYDROXY CHLOROQUINE: This drug is less toxic than chloroquine, and has similar
properties and uses as chloroquine.

AMODIAQUINE: This drug is as effective as chloroquine, in a single oral dose. Its

pharmacological actions are similar to those of chloroquine. It is rapidly absorbed and is
concentrated in the liver and the spleen. It is largely metabolised in the body. The adverse
effects include GI disturbances, headache, photosensitivity reactions and rarely,
agranulocytosis.

Amodiaquine tablet contains 250 mg of the salt.

Dose : as a suppressive in an acute attack of malaria: 0.5 to 0.75 g (0.4 to 0.6 g of the base)
on the first day and then 2 tablets daily for two days.

P. falciparum strains resistant to chloroquine may still be sensitive to amodiaquine. However,

it is not recommended for prophylactic (chronic suppressive) therapy because of possible
hepatitis and agranulocytosis.

Amopyroquine has similar properties as amodiaquine but can also be given parenterally.

Pyronaridine, structurally related to amodiaquine, developed in China, is given orally as

well as parenterally. It has schizontocidal activity against P. falciparum and P. vivax and is
effective against chloroquine-resistant parasites. The drug needs further evaluation.
8-Aminoquinolines

PRIMAQUINE: This drug (Fig 56.3) is effective against:

The persistent tissue forms of P. vivax; and

The pre-erythrocytic (hepatic) and sexual forms (gametocytes) of all species of human
malarial parasites.

Fig. 56.3: Primaquine

Its precise mechanism of action is not known. It probably acts by generating toxic, reactive
species and/or by interfering with electron transport in the parasite.

Following the administration of primaquine, only a proportion of gametocytes in the blood

are destroyed, while the rest are rendered incapable of undergoing further maturation in the
mosquito. The drug has a weak schizonticidal activity against P. vivax but exerts no effect on
the schizonts of P. falciparum. It is, therefore, not effective as a suppressive but it is given
along with a 4-aminoquinoline, to achieve radical cure in P. vivax infection.

Absorption, fate and excretion: Given orally, it is rapidly and completely absorbed. It is
concentrated in the liver; large amounts are also present in the lung, brain, heart and the
skeletal muscle. It is rapidly metabolised in the liver, and the products excreted in the urine;
only 1 % of the drug is excreted unchanged.

Adverse reactions: At the recommended dosage, toxicity is uncommon. The ADRs are:

Gastrointestinal: Epigastric distress and abdominal cramps can be minimised by taking

the drug with or after food and by antacids.
Hemopoietic: Moderate doses cause mild anemia and leucopenia. Large doses may cause
methemoglobinemia, cyanosis and agranulocytosis.
In patients with G6PD deficiency, it can cause intravascular hemolysis (Chapter 36).
The drug should not be used in patients who have a tendency to granulocytopenia e.g. those
suffering from RA or lupus erythematosus and in patients receiving other potentially
hemolytic drugs. Proguanil potentiates its toxicity.

Although it has not been established that primaquine is teratogenic in humans, its use should
be postponed till after delivery. It can cause hemolysis in G6PD-deficient fetuses.

Preparations and dosage: Primaquine tablet contains 7.5 mg of primaquine base. The dose for
radical cure of vivax malaria is 15 mg daily for 14 days given along with chloroquine 1 g on
the first day and 500 mg daily for 2 days.

Bulaquine, an analogue of primaquine, is claimed to be as effective as primaquine.

Tafenoquine is a new, long acting, potent, primaquine-like drug which achieves radical cure
in 3 days. It is under evaluation.

Quinoline Methanol

MEFLOQUINE: is a quinoline methanol derivative. It probably acts like chloroquine. It:

Acts on the erythrocytic stage.

Is highly effective in a single dose against P. falciparum including chloroquine resistant
and MDR strains.
Can be given 12 hours after the last dose of quinine. However, because of long half life of
mefloquine, quinine should not be administered after it as both are cardiotoxic.
Has no action on the persistent tissue forms.

Given orally, mefloquine is rapidly and completely absorbed, is highly protein bound and is
extensively distributed in the tissues. It has a very long plasma t1/2 of about 20 days. It is
eliminated slowly in feces. The parasites can develop resistance to it.

Adverse reactions:
 GI tract: Mefloquine commonly causes dizziness, nausea, vomiting, diarrhoea or
abdominal pain; these generally resolve without specific treatment.
Neuropsychiatric disturbances: The most common of these are affective disorders,
anxiety disorders, hallucinations and sleep disturbances. A single dose may cause light
headedness and loss of concentration. Transient depressive feeling occurs more
commonly with mefloquine than with chloroquine. Rarely, psychosis, toxic
encephalopathy and convulsions have been reported. Patients treated a second time within
a month after the first dose are at seven fold risk of adverse effects.
CVS: Like chloroquine and halofantrine mefloquine causes bradycardia and sin~
arrhythmia. Patients who have recently received mefloquine should not receive
halofantrine which hastens QT prolongation.
Teratogenicity: Mefloquine is teratogenic and should be avoided in the first trimester of
pregnancy. However, it may be used in the second and third trimesters. The non-pregnant
women of childbearing age, should be advised to avoid pregnancy for three months after
the treatment. Women treated with mefloquine may continue breast-feeding.
Miscellaneous: Allergic skin reactions, hepatitis and blood dyscrasias can occur.

Preparations and dosage: Mefloquine is available as 250 mg tablets. A single dose of 750 mg
(15 mg/kg) orally is sufficient in most areas to treat uncomplicated malaria. However, in
certain areas, the same dose may have to be repeated in 6 hours to ensure a cure. In the single
dose of 1.5 gm, mefloquine is uniformly effective in curing multidrug resistant (MDR)
malaria in almost 100% of patients. However, such a dose invariably causes severe nausea
and vomiting. A second dose of 1 gm may have to be given to patients living in areas of
mefloquine resistance. Due to fear of the development of drug resistance, mefloquine is not
recommended as a single drug for prophylaxis in endemic areas.

Phenanthrene Methanol

HALOFANTRINE: This drug was discovered in the forties, was restudied nearly 40 years
later. It is:

An erythrocytic schizonticide and is as effective as chloroquine against chloroquine

sensitive strains of P. falciparum.
Also effective against strains resistant to chloroquine, pyrimethamine and quinine.

The mechanism of action is like that of other quinolines.

Given orally, it is slowly and .variably absorbed, peak concentration being reached 4-6 hours
after ingestion. The drug should not be taken along with fatty foods. Its plasma t1/2 is about 1-
2 days, although its active N-desbutyl metabolite has a longer half-life of 3-5 days. Unlike
most anti-malarials, the drug is palatable. It is given in three doses of 500 mg 6 hours apart,
repeated after 1 week, if necessary. It is available for parenteral use.

Adverse reactions: These include nausea, vomiting, abdominal pain, diarrhoea and rise in
liver enzymes. Its major disadvantage is that it causes prolongation of QT interval and even
fatal ventricular arrhythmias; it should not be used in patients receiving quinine, chloroquine
or quinidine, antidepressants and antipsychotics. It is not suitable for prophylaxis.

Lumefantrine is structurally similar to quinine. Used in combination with artemether, it is

well tolerated and efficacious in uncomplicated falciparum malaria, and is used where
resistance to monotherapies is being experienced. It can also be combined with mefloquine.

Biguanides

PROGUANIL (Chloroguanide): It is a prodrug. Its antimalarial action is attributed to its

conversion into a cyclic ring triazine metabolite, cycloguanil, in the human body. This
compound binds to an enzyme dihydrofolate reductase , which converts folic acid to folinic
acid, more strongly in the malarial parasite than in the human tissues. Deficiency of folinic
acid prevents the completion of schizogony. As the sulfonamides prevent the conversion of
PABA into folic acid, they synergise with the antimalarial effect of proguanil. It:

Is an effective schizonticide against both P. vivax and P. falciparum; but its action is
slower than that of 4-aminoquinolines.
Is effective against the primary preerythrocytic forms of P. falciparum, and for causal
prophylaxis of falciparum malaria.
Prevents the development of gametes encysted in the gut wall of the mosquito. It is, thus,
valuable in sporonticidal prophylaxis.

West African strains of P. falciparum are usually genetically resistant to proguanil while all
the varieties of plasmodia have developed an acquired resistance to this agent due to
mutation in the parasite.
Absorption, fate and excretion: Given orally, it is rapidly and adequately absorbed, mostly
from the small intestine. Approximately 75% is bound to proteins. The drug achieves a higher
concentration within erythrocytes than in plasma. Its elimination is slow, mainly in the urine,
with plasma t1/2 of 12-21 hours.

Adverse reactions: Proguanil is free from significant toxic effects when used in therapeutic
doses. GI disturbances, stomatitis, and mouth ulcers may develop occasionally. A reduction
in the leucocyte count and megaloblastic anemia may occur rarely.

Preparations and dosage: Proguanil hydrochloride tablets 100 mg. The base content of the salt
is approximately 87%.

Therapeutic uses: Given alone, it is not so useful for controlling an acute attack. For causal
prophylaxis, a dose of 100 to 200 mg daily is used depending upon the sensitivity of the
strain prevalent in the particular area.

Malarone is a combination of proguanil 100 mg with atovaquone 250 mg. It is used to treat
MDR falciparum malaria. The combination is generally well tolerated. (For doses, see later)
The drug appears to be safe during pregnancy but data is inadequate. It can be combined
with folinic acid 5 mg daily, to prevent megaloblastic anaemia. This does not affect its
efficacy.

Diamino pyrimidines

PYRIMETHAMINE: Like proguanil, it is selectively toxic to the malarial parasite by

binding to its dihydrofolate reductase (Fig. 56.4). It is more potent than proguanil. Its
antimalarial activity is enhanced by combination with sulfonamides. Unlike other
antimalarials, it is tasteless and, therefore, suitable for children.

Fig. 56.4: Pyrimethamine

Development of resistance to the drug in vivo has been reported and some degree of cross-
resistance between pyrimethamine and proguanil can also occur. Chloroquine resistant strains
of P. falciparum are frequently resistant to proguanil and pyrimethamine.

Absorption, fate and excretion: Pyrimethamine is completely but relatively slowly absorbed
from the small intestine. It is extensively metabolised and slowly excreted by the kidney.
Following a single dose of 25 mg, it persists in the plasma and gets excreted in the urine for
more than 14 days.

Adverse reactions: The drug is relatively safe. It can cause GI disturbances, ataxia and
megaloblastic anemia, which responds to oral folic acid. Folic acid does not block its
antimalarial activity. The drug appears to be safe in antimalarial doses during pregnancy.

Preparations and dosage: Pyrimethamine tablet 25 mg. For relief of an acute attack of P.
vivax 50 mg on the first day followed by 25 mg daily for 2 days. However, it is not the drug
of choice for acute attacks.

Therapeutic uses:

Malaria: It is generally used in combination with 500 mg sulfadoxine or with

sulfadimethopyrazine; dose: 2-3 tabs once weekly. Combination of pyrimethamine 12.5
mg with dapsone 100 mg is used for prophylaxis of P. falciparum. (See later).
Toxoplasmosis: It is used in the dose of 25 mg twice a day, followed by 25 mg on daily
for one month, along with sulfadiazine 4 gm daily. A loading dose of 50-100 mg of
pyrimethamine may be used in the event of ocular complications (Chapter 58).
Polycythemia vera.

Trimethoprim has similar anti-malarial actions (anti-folate) as pyrimethamine but is much

less potent (Chapter 45).

SULFONAMIDES: Sulfonamides and sulfones have antimalarial activity similar to

pyrimethamine, but their mechanism of action is different (Chapter 45). Although they are
effective against the asexual blood forms, their action is too slow. However, they potentiate
the action of pyrimethamine or proguanil (DHF reductase inhibitors). A long acting
sulfonamide such as sulfadoxine (t1/2 200 hours) with pyrimethamine is usually preferred.
These combinations have been used against P. falciparum infection resistant to chloroquine.

Sulfonamide-containing combinations are not recommended for prophylaxis because of

Stevens-Johnson syndrome.

The sulfone, DDS, has been used in the dose of 25 mg daily for 4 weeks from the 7th day of
illness onwards, in combination with quinine/chloroquine/pyrimethamine, to prevent
recrudescence in chloroquine-resistant falciparum malaria.

Artemisinin compounds

ARTEMISININ: This is obtained from the Chinese plant Artemisia annuta (Qinghaosu,
sweet worm wood) which has been used in China for the treatment of fever for almost 2000
years. Chemically, it is a sesquiterpene lactone endoperoxide. The drug is lipophilic and
poorly soluble in water. Derivatives of artemisinin include artesunate (water soluble), artether
and artemether (both lipid soluble).

Mechanism of action: Artemisinin and related compounds covalently bind to parasitic

proteins. Intraparasitic heme iron catalyses cleavage of endoperoxide bridge in artemisinin.
The resultant free radicals damage parasitic proteins.

Artemisinin compounds act mainly as schizonticides against all malarial parasites, including
those resistant to chloroquine and quinine. They reduce parasitemia rapidly and dramatically.
They have no effect on the hepatic stage. Recrudescence may occur. They are also useful in
cerebral malaria. So far, there is no evidence of high level resistance to this drug.

Absorption, fate and excretion: Orally, they are well absorbed and are metabolised to the
active form, dihydro-artemisinin. The t1/2 of artesunate is short, about 23 minutes, while that
of artemether is about 45 minutes. This is a major disadvantage.

Adverse reactions: No serious adverse reactions have been reported. ADRs include nausea,
vomiting, abdominal pain, anorexia and leucopenia. Higher doses may produce bradycardia,
prolongation of PR and QT and transient increase in SGOT/SGPT. They are contraindicated
during the first trimester of pregnancy, lactation, and in immuno-compromised patients.

Preparations and dosage:

(i) Artesunate 50 mg tablets.

Artesunate injection for IV/IM use contains 60 mg. It is administered in a dose of 120 mg on
day one, followed by 60 mg 12 hours later; and 60 mg once daily for the next 4 days.

(ii) Artether is a synthetic ethyl derivative of artemisinin. Dose is 150 mg IM once daily for 3
consecutive days. Children are given 3mg/kg for 3 days.

(iii) Artemether injection containing 80 mg/ml in arachis oil. Dose is 80 mg IM on first day
followed by 80 mg daily for the next 5 days.

(iv) They are available as suppository.

Therapeutic uses:

Artemisinin and its derivatives are safe and effective alternative to quinine in the treatment of
falciparum malaria. However, its use should be restricted to the treatment of MDR malaria. It
is recommended that artemisinin derivatives should be used only in combination with other
drugs to prevent or slow down the development of drug resistance. For use of artemether in
schistosomiasis, see Chapter 60.

Antimicrobials

DOXYCYCLINE: This drug exerts a slow but potent action against the blood schizonts and
the primary exo-erythrocytic forms of P. falciparum, including those resistant to chloroquine
and proguanil. It is used in combination in resistant cases as resistance to tetracyclines is rare
(See later).

CLINDAMYCIN has also been found useful in combination with other drugs (see later).

ATOVAQUONE: This is a highly lipophilic, hydroxynaphthoquinone compound which has

potent activity (in animal models) against P. jiroveci, Plasmodia and T. gondii. It acts by
selectively interfering with mitochondrial electron transport in susceptible parasites.
Proguanil potentiates the antimalarial activity of atovaquone.

Its oral absorption is slow and incomplete but is increased threefold by fatty foods. Its plasma
t1/2 is 2-3 days and it is excreted, mostly unchanged, in feces. When used alone, the parasites
develop resistance to it rapidly, by mutation.

Adverse reactions: These include fever, vomiting, anorexia, headache, diarrhoea, dose related
maculopapular rash, anemia and neutropenia.

Therapeutic uses:

(1) Atovaquone + proguanil is useful as a prophylactic against P. falciparum and in treating

MDR malaria. The combination is active against the circulating parasites but not the hepatic
stage of plasmodium. It is claimed to be more effective than mefloquine.

The combination contains atovaquone 250 mg + Proguanil 100 mg for adult use and
atovaquone 62.5 mg + Proguanil 25 mg for pediatric use. For prophylaxis, the dose is one
tablet daily taken with food. For treatment of MDR malaria, it is 4 tablets as a single dose for
3 consecutive days. Tetracycline, rifampicin and metoclopramide decrease the efficacy of
atovaquone.

(2) In the dose of 750 mg t.i.d. three times a day for 21 days, it is helpful in treating mild to
moderate P. jiroveci pneumoma in AIDS patients.

(3) It is also used in toxoplasmosis (Chapter 58).

Table 56.2: Half-life of the commonly used antimalarial drugs

Drug Half-life
Chloroquine and amodiaquine 3 weeks
Quinine 10-12 hours
Mefloquine 15-33 days
Primaquine 8.5 hours
Pyrimethamine 80-100 hours
Proguanil 12-21 hours
Sulfadoxine 100-200 days
Atovaquone 2-3 days
Doxycycline 18-22 hours

Table 56.2 shows the plasma t1/2 of the commonly used antimalarial drugs.

Management Of Malaria

Prophylaxis: When residents of a nonendemic area wish to travel to an endemic area, anti-
malarial drug(s) are recommended to prevent or suppress symptoms caused by malarial
parasites. The choice depends on the likely strain of malarial parasites in the region and its
known sensitivity pattern (Table 56.3). The therapy should be started before the start of the
travel, continued during the travel in endemic area and even after departure from the area.
Presumptive anti-relapse terminal prophylaxis to eliminate hepatic forms of P. vivax / P.
ovale is indicated for persons who have had prolonged exposure in malaria-endemic areas.

All infants and children travelling to endemic areas need antimalarial prophylaxis.
Chloroquine is the drug of choice. For areas with resistant strains, mefloquine is an option.
To use doxycycline, the age of the child should be above 8 years and for atovaquone /
proguanil weight should be at least 5 kg.

Ideally, pregnant women should be advised to avoid travel to endemic area. If it is not
possible, chemoprophylaxis is given, which reduces the incidence of severe maternal anaemia
and other adverse outcomes like abortion still birth, prematurity, and low birth weight.
Chloroquine remains the drug of choice for sensitive organisms, while mefloquine is
currently the only medication recommended for chloroquine resistant organisms.
Doxycycline is contraindicated and atovaquone/proguanil is not used because of insufficient
safety data.

Very small amounts of chloroquine and mefloquine are excreted in the breast milk and hence
can be given for prophylaxis in lactating women. Atovaquone/proguanil is not recommended.
Limited data are available for doxycycline. Primaquine is given only after testing the infant
for G6PD deficiency.

The traveller should also be urged to avoid contact with the night biting anopheles in the
endemic area by covering exposed parts, netting over the bed, fitting window-screens, using
insecticides and mosquito repellents.
Such chemoprophylaxis is not 100% effective; hence the diagnosis of malaria should be
considered in a patient who has visited an endemic area and gets fever after returning home
though he has received chemoprophylaxis.

Treatment of an acute attack: The diagnosis of malaria is confirmed by microscopy of stained

thick and thin blood films. The intracytoplasmic parasites should be identified (if the species
is uncertain, it should be considered to be P. falciparum) and counted. In severe malaria, the
developmental stage of the parasite should be noted. The prognosis worsens with P.
falciparum infection, higher parasitic counts and more mature parasites. In serious cases
smear examination should be repeated every 12 hours for monitoring the efficacy of therapy.

The initial treatment of acute malaria is the same irrespective of the species of parasite, unless
the infection is severe and due to P falciparum, particularly in children and in non-immune
subjects. It is the follow up therapy of relapsing malaria that differs. The drug regimens used
in an acute clinical attack of malaria with P. vivax, P. ovale, P. malariae and chloroquine
susceptible P. falciparum, in adults, are shown in Table 56.4.

Quinine still remains a potent and reliable antimalarial drug. Further, children tolerate it well.
It can be given orally as well as parenterally. However, it takes longer to exert the full effects
and hence, chloroquine is generally preferred. In case of severe P. falciparum infection,
particularly in a non-immune individual, treatment must be immediate and IV quinine may be
life-saving. Artemisinin suppositories can be used immediately at home before transferring
the patient to the hospital.

Postural hypotension uncomplicated malaria and is common in is exacerbated by quinine and

chloroquine. Febrile patients, both adults and children, should therefore be kept in the
horizontal position. Mothers should be advised that febrile babies should not be carried
vertically, especially after any of the above drugs is given parenterally. In non-endemic
areas, freedom from recrudescences of falciparum infection can be ensured by follow up
treatment with 300 mg (one tablet) of chloroquine, taken once a week for three months.

Most of these anti-malarial drugs are very bitter and hence, they may be given along with
milk or fruit juice. Care must be taken to ensure that the patient swallows the tablets and does
not vomit later. This can be helped by prior administration of prochlorperazine (Stemetil) or a
similar antiemetic drug, if necessary. If vomiting occurs within 1 hour of drug ingestion,
 repeat the full dose of the drug; in the case of mefloquine, repeat half the initial dose. If
vomiting occurs after one hour, it is not necessary to repeat the drug.

Since latent exoerythrocytic forms persist in the liver in infections with P. vivax and P. ovale
delayed true relapses occur in the majority of patients. In such cases, radical cure can be
obtained by primaquine in the dose of 7.5-15 mg daily for 14 days, started after treating the
acute attack. In this dosage, the drug is generally well tolerated and hemolysis, if it occurs, is
mild and self-limiting. In some cases, higher doses of primaquine (30 mg daily for 14 days)
may be needed; such regimen, however, needs supervision for possible adverse effects, In P.
falciparum malaria, primaquine is used in a single dose of 45 mg to destroy falciparum
gametocytes which are not affected by chloroquine or quinine. In pregnant women and
infants, chloroquine is given weekly as suppressive chemoprophylaxis for 3 months to prevent
relapse of P. vivax or P. ovale infection.

Table 56.3: Drug regimens for malarial prophylaxis

When to start before

Drug, dose, How long to continue
entering endemic Remarks
frequency after leaving the area
area
Chloroquine sensitive P. falciparum* and P. vivax / P. ovale
Choice for infants /
Chloroquine (base)
1 week 4 weeks children / pregnant &
300 mg OW
lactating mothers
Proguanil 200 mg OD 2 days 4 weeks -
Chloroquine-resistant P. falciparum and MDR strains**
Mefloquine 250 mg
1 week 4 weeks Same as above
OW
Doxycycline 100 mg Not in children< 8 yrs
1-2 days 4 weeks
OD / pregnant women
Atovaquone 250 mg + Not in children < 5kg/
proguanil 100 mg; one 1-2 days 7 days pregnant & lactating
tablet OD*** women
Terminal prophylaxis to prevent relapse of P. vivax / P. ovale
Not in pregnancy. In
14 days along with
infants, children, and
postexposure
Primaquine 30 mg OD - lactating mothers, after
prophylactics (or after
ruling out G6PD
its completion)
deficiency

OD = once daily OW = once weekly

* If not tolerated in the recommended doses, mefloquine, doxycycline or atovaquone + proguanil can
be given
** If the traveler cannot tolerate any of these regimens, Primaquine 30 mg 1-2 days before,
throughout the stay and 7 days after leaving
*** Choice for mefloquine resistant malaria in Southeast Asia (Bunna, China, Cambodia, Vietnam)

Table 56.4: Treatment of chloroquine sensitive acute malaria

In patients who can take orally:

Chloroquine (base) 600 mg followed 6 hours later by 300 mg on day one; 300 mg once daily
on days two and three.

OR

Amodiaquine (base) 600 mg followed by 200 mg (base) on day one; 400 mg once a day on
days two and three.

OR

Quinine (salt) 300 mg tablets, 6 tablets daily for three days, followed by 4 tablets daily for the
next 5-10 days.

In patients who cannot take orally:

Chloroquine IM 2.5 mg/kg every 4 hours or 3.5 mg/kg every 6 hours (total dose not to exceed
25 mg/kg base).

OR

Chloroquine IV 10 mg/kg base over 4 hours, followed by 5 mg/kg base (given in a 2 hour
infusion) every 12 hours (total dose not to exceed 25 mg/kg base).

NB: For P. falciparum infection, primaquine (gametocytocidal) 0.75 mg/kg, (maximum 45

mg) given as a single dose on first day of treatment, is a must to prevent spread.

Cerebral malaria with pronounced CNS symptoms occurs as a complication of P. falciparum

infection and carries high mortality. It needs emergency treatment with excellent nursing care
and repeated monitoring, preferably in ICU.

Currently parenteral artemether and arteether are preferred. Alternatively, quinine in high
dilution is administered by very slow infusion (see later). If there are no facilities for IV
infusion, quinine can be given in the dose of 0.25-0.5 g in 20 ml glucose saline IV, over not
less than 10 minutes by the clock. More rapid injection may cause a fall in BF, cardiac
arrhythmias and cardiac arrest. Alternatively, quinine can be given IM provided the solution
is sterile and nearly neutral in reaction.
Hypoglycemia, sometimes fatal, has been reported in patients with cerebral malaria; this
complication does not respond well to glucose by IV bolus and to glucagon. A somatostatin
analogue octreotide which inhibits the stimulatory effect of quinine on the beta cells of the
pancreas may be useful.

Chloroquine is as good as quinine for susceptible P. falciparum infection and in severe cases
it can be given IV or IM in similar way as quinine. The single average adult IV dose is 200-
300 mg of the base in a 5% solution. Intramuscular route, however, is safer and is preferred.
It can be repeated upto a total of 900 mg in 24 hours. In all these cases, oral therapy should be
started as soon as possible.

Quinidine is as effective as quinine in the treatment of malaria. If quinine is not available,

quinidine is an acceptable substitute for the emergency treatment. Doses and precautions are
the same as with quinine.

Cerebral malaria sometimes causes coma and shock. Blood pressure should be maintained by
IV fluids and dopamine. Management of coma is similar to that of coma due to other causes.
However, in some cases, lumbar puncture to reduce intra-cranial tension may cause dramatic
recovery. Convulsions are treated with diazepam.

Glucocorticoids, urea and mannitol which were used in the past to treat the cerebral edema
of falciparum malaria, are of doubtful value and in fact may have deleterious effects in these
cases; they are better avoided.

Treatment of malaria in children is essentially similar to that in adults. Quinine is better

tolerated by children but its parenteral use is associated with high toxicity. Chloroquine
injection may cause convulsions in infants and small children, and should be avoided.
Relapsing vivax attacks in small children may be treated with pyrimethamine 12.5 mg base
once a week, between the attacks. Primaquine should be avoided in the neonates for fear of
hemolysis. Mefloquine should not be used in children under 15 kg of weight. For details see
Table 56.5.

Acute malaria during pregnancy can be treated with chloroquine or quinine in the usual
doses. For chloroquine-resistant malaria, chloroquine + clindamycin combination is safe.
Table 56.5: Dosage schedule for oral treatment of moderate and severe malaria in children

Upto 1 1-3 4-6 7-11 12-14

Drug Regimen
year years years years years
Daily dose to be divided
100- 200- 300- 500- 1000-
Quinine into 3 parts and
200 300 500 1000 2000
continued for 7 days
Chloroquine 400-
75 150 300 300 i) Loading dose
(base) in mg 600
225- ii) Second-one follow 6
75 150 150 150
300 hours after first
150- iii) One dose daily on
37 75 150 150
300 day 2&3
200- 400-
Amodiaquine 50 100 150 i) Dose for first day
300 600
250- ii) Daily dose for day 2
50 50 300 50-200
400 &3
Sulfadoxine
500mg +
Single
pyrimethamine 1 tab 1 tab 2 tab
dose
12.5 mg (half
tablet)
Modified from: The Clinical Management of Acute Malaria, WHO Reg. Pub., South East
Asia Series No. 9, New Delhi.

Mefloquine is probably safe in the second and third trimesters and may be used when benefits
resistant malaria outweigh the risk. Artemisinin has no deleterious effect on the fetus and can
be considered, if the situation demands. However the data about its safety are inadequate.
Maloprim should be avoided in the first trimester but may be used in second or third trimester
with folic acid supplement. Associated anemia is treated with folic acid and iron. Primaquine,
doxycycline and malarone should be avoided.

Malaria in G6PD deficient persons: Such patients should be treated with the usual doses of
either chloroquine or quinine. If indicated, primaquine in the dose of 30-45 mg once a week
for 4-8 weeks is an acceptable treatment in areas of milder variants of G6PD deficiency.

Chloroquine resistant malaria: Chloroquine resistant P. falciparum malaria is now

widespread in many areas, including India. Chloroquine resistance should be suspected.
 In all patients with a complication of malaria such as cerebral malaria, severe anemia,
jaundice or renal failure.
In any patient who has already received a full course of chloroquine within the last one
month as that suggests the possibility of recrudescence from a resistance strain; and
When hemoglobin continues to fall in the absence of bleeding, and asexual forms of the
malarial parasite persist, along with symptoms, after 48 hours of treatment. The
persistence of gametocytes for several weeks after treatment does not represent failure of
treatment.

In patients with falciparum malaria resistant to chloroquine and sulfadoxine-pyrimethamine,

a combination therapy as the first line treatment is advocated. Artemisinin-based
combination therapy (ACT) is preferred. Table 56.6 shows the drug regimens used in the
treatment of chloroquine resistant malaria.

In ACT an artemisinin derivative is given in combination with a long acting antimalarial

(amodiaquine, lumefantrine, mefloquine or sulfadoxine-pyrimethamine) for 3 days or with
rapidly eliminated agents (tetracyclines, clindamycin) for 7 days. ACT available in India is
listed in Table 56.7, of which artesunate + sulfadoxine-pyrimethamine (SP) is used in the
National Malaria Programme of India.

Table 56.6: Treatment of chloroquine-resistant malaria

In patients who can take orally

Sodium artesunate 100mg orally 12 hrly for 3 days plus Sulfadoxine (500 mg)+
Pyrimethamine (25 mg) 3 tabs as single dose on day one

OR

Sodium artesunate 100mg orally 12 hrly for 3 days plus mefloquine 750 mg on day 2 and
then 500 mg on day 3

OR

Artmether (20 mg) + Lumefantrine (120 mg) 4 tabs twice daily for 3 days

OR

Quinine 600 mg orally t.i.d. for 5 days followed by Sulfadoxine- Pyrimethamine 3 tablets as
single dose

OR

Quinine 600 mg t.i.d. + doxycycline 100 mg b.i.d. / clindamycin 10 mg/kg b.i.d. for 7 days
OR

Sodium artesunate 100 mg orally + doxycycline 100 mg b.i.d. / clindamycin 10 mg/kg b.i.d.
for 7 days

OR

Atovaquone 250 mg+ proguanil 100 mg combination; 4 tablets ( single dose) daily for 3 days

In patients who cannot take orally

Quinine hydrochloride by IV infusion: 20 mg/kg in 500 ml of 5% dextrose-saline over 4

hours; followed by 10 mg /kg infused over 2 hours, every 8 hours, until the patient is able to
swallow and parasite density is <1%. Complete the therapy with oral quinine 600 mg t.i.d. till
total therapy is of 7days AND Tetracycline 250 mg IM 6 hourly until patients start taking
orally, followed by doxycycline 100 mg b.i.d. till total of 7 days

OR

Artemether or arteether IM (see text) AND Doxycycline OR Clindamycin

Table 56.7: Currently used antimalarial drug combinations for MDR falciparum malaria

Artesunate + SP / mefloquine/amodiaquine*
Artemether + lumefantrine*
SP + chloroquine/amodiaquine/quinine/mefloquine
Quinine + tetracycline/clindamycin
Atovaquone + proguanil
Chlorproguanil + dapsone
Sulfadoxine + pyrimethamine (SP)

*The combinations to which resistance has not been reported.

SP is always given as a single dose. All other drugs are given for 3 days, except quinine +
tetracycline combination, which is given for 7 days.

Multidrug resistant (MDR) malaria is always to be treated with drug combinations (Table
56.7).

Radical cure: Radical cure should be aimed at only in infections occurring in a nonendemic
area. Such a patient should receive primaquine in the dose of 15 mg of the base daily for 2
weeks. Simultaneously, he should continue to receive 300 mg of the chloroquine base weekly
for suppression of an overt attack. Such primaquine therapy is essential mainly in vivax
malaria.

Recrudescence: This may be due to inadequate therapy or persistence of hepatic forms. Early
recrudescence of malaria (within 28 days of anti-malarial treatment) should not be treated by
either mefloquine or halofantrine because of their enhanced cardiac toxicity. It should be
treated with artemisinin.

Adjuvant therapy in malaria: Apart from shock, severe malaria can cause renal failure leading
to oliguria, anuria and uremia. In the initial stages, the osmotic diuretic mannitol may be
useful. However, later hemodialysis or peritoneal dialysis can be life saving. It is also
important to remember the possibility of such a complication, since administration of excess
parenteral fluids during the period of unrecognised renal impairment can precipitate fatal
pulmonary edema. Falciparum malaria can cause severe hypoglycemia; this should be
remembered while treating such patients.

Chronic malaria is usually associated with iron deficiency anemia, which responds to oral
iron therapy. In severe anemia, parenteral iron and even blood transfusion may be necessary.

Immunity in malaria: Development of partial immunity is recognised in P. falciparum

infection. The immunity is basically humoral. Immune antibodies cross the placental barrier
and confer passive immunity on the foetus, who is protected for some months after birth. The
immunity operates against the erythrocytic stage, but is ineffective against other stages of the
parasite. Immunity in malaria is not only species specific, but to some extent also strain-
specific. Thus, a person who has developed immunity to a P. falciparum strain in a particular
area may get infected with a different strain when in another area. It is not absolute and
diminishes when an immune adult moves for a year to a nonendemic area. The development
of anti-malarial vaccine is still experimental.

Malaria eradication: This concept is based on the idea of completely eliminating the disease
from a particular area so as to halt its transmission completely, at the same time, preventing
the reintroduction of the disease from outside. Malaria eradication, therefore, envisages a
vigorous attack on the parasites in human patients with the suppressive, causal prophylactic
and radical curative drugs, along with eradication of the mosquitoes. Mosquitoes can transmit
malaria as well as dengue and various types of encephalitis. Eradication of mosquitoes
includes improving environmental hygiene and the use of insecticides and larvicides such as
pyrethroids, DDT and organo-phosphorous compounds. However, in practice such measures
are difficult to implement. Further mosquitoes have developed resistance to the first highly
effective, reasonably safe and cheap insecticide DDT.

Mosquito repellents: Repellents are used on the skin to prevent mosquito bites. They also
offer protection against ticks, which transmit Lyme disease. They do not kill mosquitoes but
deter them from biting. However, 100% protection against the hungry Anopheles mosquitoes
cannot be ensured. They are sold as aerosols, creams, solids (sticks), pump sprays and
liquids.

A simple remedy which acts as mosquito repellent by virtue of its fragrance has the following
composition:

Cedar wood oil: 18 ml

Citronella oil: 42 ml

Spirit of camphor to: 100 ml

Citronella oil can also be applied in the form of vanishing cream. It is non-irritant, non-toxic,
cheap and not so unpleasant. Citronella-based repellents, however, provide only a short term
protection for about 1 hr against mosquitoes and are not effective against ticks. Probably
more effective is a 35% emulsion of dimethyl phthalate (DMP) which acts as an irritant to
insect's feet. It must be rubbed into every part, avoiding eyelids, lips and scrotum.

Oil of lemon eucalyptus contains p-menthane 3, 8-diol and offer protection up to 6 hrs but it
should be avoided in children below 3 years of age. Essential oils like clove, geraniol (from
rose oil) and patchouli (from pach) in high concentrations may be used but can irritate the
skin.

Other agents used are ethohexadiol, butopyronoxyl, DEET, n-butyl acetanilide, and picaridin.
These are also irritants and have an intensely bitter taste. They can cause allergic reactions
and bronchial spasm.

DEET, N, N diethyl-m-toluamide, in concentrations of 5%-100% repels mosquitoes as well

as ticks, fleas, gnats and some flies. However, its efficacy does not increase above 50%.
DEET offers protection for 90 Olin to 12 hrs depending on the concentration. In
concentration <30%, it is probably safe in children and infants> 2 months old. No effect has
been reported on fetus when it is used by mothers during second and third trimester of
pregnancy. However, it can damage synthetic fiber containing clothes and plastics on
eyeglass frames and watch crystals.

Picaridin (5-20%) is used against mosquitoes, ticks, flies and chiggers. It appears to be as
effective as equivalent concentrations of DEET but is better tolerated on skin and does not
damage fabric or plastic.

Synthetic pyrethroids are used in antimosquito tablets and coils (Chapter 62). Permethrin-
treated clothing, shoes, bed nets, tents and sleeping bags provide protection against
mosquitoes and ticks. Permethrin repels and kills ticks, mosquitoes and other arthropods. It
remains active for several weeks even after repeated laundering. It is available in liquid and
spray forms (Chapter 62).

Highly effective, dependable and totally safe mosquito repellent is not yet available;
nevertheless use of long sleeve shirts and pants, DEET or picardin application on exposed
skin and permethrin-treated bed nets are considered the most effective existing remedies.
Chemotherapy of Amoebiasis

Amoebiasis is an infectious disease caused by the protozoan, Entamoeba histolytica. The

disease, though labelled as 'tropical', is not uncommon in temperate zones. It primarily affects
the colon, but other organs like liver, lung and brain may get secondarily involved.

The disease is characterised by gastrointestinal and constitutional symptoms and has a

tendency to chronicity. Acute amoebic dysentery is associated with bloody, mucoid stools,
abdominal pain and tenesmus. Chronic amoebiasis usually presents with vague symptoms
like anorexia, abdominal pain and intermittent diarrhoea or constipation. There may be
tenderness over the caecal region. Many infected persons, who pass the cystic forms of the
protozoan in feces, however, remain completely symptomless and act as 'carriers'.

E. histolytica usually lives as a harmless commensal in the lumen of human bowel, a state
which might be termed asymptomatic amoebiasis. The parasite subsists on debris and
bacteria and not on the tissues of its host. When it becomes a pathogen, the trophozoites
become larger and hematophagous, having many erythrocytes in the endoplasm, and cause
invasive amoebiasis. Invasion is mediated by the destruction of epithelial cells and killing of
neutrophils and lymphocytes.

Intestinal amoebiasis results in ulceration of the colon. The regions involved in descending
order of frequency are the caecum, the ascending colon and the rectosigmoidal area. In fatal
cases, the entire colon and even the terminal portion of the ileum may be involved leading to
acute necrotising colitis. Amoebic involvement of the caecum and appendix may cause a
clinical attack of appendicitis. A granulomatous lesion of the caecum giving rise to a lump in
that region (amoeboma), may cause obstructive symptoms.

Life cycle of E. histolytica: E. histoiytica exists in two forms:

The trophozoites, present in the intestinal lumen and in infected tissues; and
The cysts, which develop from the trophozoites within intestinal lumen.

The trophozoites with amoeboid movements are the active form. However, they die rapidly
after elimination in the stool. The cysts represent a dormant stage and are resistant to freezing
and partial drying and transmit infection from person to person.
Cysts are usually ingested following fecal contamination of water or food. Bad hygiene and
insects like flies assist in the propagation of infection. In the intestine of the host, the cyst
wall is weakened by the intestinal enzymes and the trophozoites released invade the wall of
the colon and enteroportal circulation. The organism may then find its way to the liver and
other tissues, giving rise to extra-intestinal amoebiasis.

Antiamoebic drugs:

Clinical classification

I. Drugs used only in intestinal amoebiasis (Luminal amoebicides): Halogenated

hydroxyquinolines, Diloxanide furoate, Paramomycin and Kurchi.

II. Drugs used in both intestinal and extraintestinal amoebiasis (Tissue/ mixed
amoebicides): Emetine, Dehydroemetine, Metronidazole, Tinidazole, Secnidazole.

III. Drugs used only in extra intestinal amoebiasis: Chloroquine.

Chemical classification:

I. Imidazole derivatives: Metronidazole, Tinidazole, Secnidazole.

II. Quinoline derivatives:

Halogenated hydroxyquinolines: Diiodohydroxyquinoline, Iodochlorohydroxyquinoline.

4-Aminoquinolines: Chloroquine.

III. Emetine group: Emetine, Dehydroemetine and its resinate

IV. Antibiotics: Tetracyclines, Paromomycin.

V. Miscellaneous: Diloxanide furoate, Nitazoxanide and Kurchi.

Imidazole Derivatives

Fig. 57.1: Metronidazole

METRONIDAZOLE: Metronidazole, a nitroimidazole derivative (Fig. 57.1), is the drug of
choice in most forms of amoebiasis except 10 asymptomatic cyst passers. It is:

A potent amoebicide.
Effective in both intestinal and extra-intestinal amoebiasis
Relatively less toxic and cost-effective
Also highly effective against
(1) Anaerobic protozoa (T. vaginalis, G. lamblia and Balantidium coli); and
(2) Non-sporing, anaerobic, Gram positive and negative bacilli such as bacterioides,
including the B. fragiles group, Clostridium difficile and H. pylori.

Metronidazole also has a radiosensitising effect on hypoxic tumour cells.

Mechanism of action: The susceptible organisms carry electron transport components

(ferredoxins) that donate electrons to metronidazole, which reduces the 5'-nitro group of
metronidazole; the short lived intermediates of this reaction interact with the microbial DNA
with a lethal effect. It is not activated by the aerobes and therefore does not affect them.
Resistance to metronidazole has been reported in T. vaginalis and G. lamblia but not in E.
histolytica infection.

Absorption, fate and excretion: Metronidazole is rapidly and almost completely (80%)
absorbed from the small bowel. It is, therefore, relatively ineffective in the asymptomatic
cyst-passers and in chronic intestinal amoebiasis. Food does not affect its bioavailability.
Protein binding is 20% and except for placenta, the drug diffuses into all tissues. It also
achieves concentrations lethal to the sensitive organisms in CSF, bile, bone and abscesses. It
is metabolised mainly in the liver, into a relatively inactive acid metabolite; and a hydroxy
metabolite active against anaerobes. Its t1/2 is 8 hours. The metabolites are excreted by the
kidneys, imparting a red colour to urine. Renal insufficiency does not significantly alter its
kinetics, but hepatic insufficiency prolongs its plasma t1/2. The drug is secreted in the milk.

Adverse reactions: These, as a rule, are mild and seldom necessitate discontinuation of
therapy. They include:

Common: Marked nausea, anorexia, abdominal pain and metallic taste in the mouth.
Less common: Vomiting, diarrhoea, headache, stomatitis, cystitis, dizziness, vertigo,
ataxia, urticaria, pruritus and flushing.
Rare: Muscular weakness, seizures and incoordination.
Mild blood dyscrasia in the form of neutropenia, associated with the nitro group in the
drug. It is reversible.
 Antabuse-like reactions on alcohol consumption (Chapter 6), during and for upto 3 days
of metronidazole therapy.

Possible tumorigenic and mutagenic effects occur in experimental animals but not reported
in humans.

Preparations and dosage:

(i) Tablets 200 and 400 mg for oral use.

(ii) Pediatric suspension 200 mg/5 ml.

(iii) Vaginal tablets containing 500 mg.

(iv) Rectal suppositories 1.0 and 1.5 g.

(v) Solution for IV use: For doses, see text.

Therapeutic uses:

Intestinal and hepatic amoebiasis: It is a drug of choice (See later).

Anaerobic infections: Metronidazole is effective in chemoprophylaxis and treatment of
infections due to nonsporing, Gram negative anaerobes (bacteroides) and has been used in
combination with other antimicrobials in gynecological and colorectal surgery. Initially, it
is given rectally as suppositories in the dose of 1 g eight hourly until oral feeding begins.
It is then administered orally in the dose 800 mg initially, followed by 400 mg 8 hourly
for 7-10 days. It can also be administered by IV infusion in the dose of 15 mg/kg
followed by 7.5mgl kg 6-8 hourly. Each dose is infused over a period of 1 hour. In severe
abdominal and pelvic sepsis, the combination of gentamicin with either metronidazole or
clindamycin has been shown to be synergistic. It can also be used for surgical prophylaxis
in the dose of 400 mg, 24 hours and 8 hours before surgery.
For its use in pseudomembranous colitis, see Chapter 49.
Anaerobes are implicated in a multitude of infections including those of gut, soft tissues,
skin ulcers, abscesses of the lung and brain and in septicemia, where metronidazole is
useful. It is as effective as neomycin in hepatic encephalopathy.
Ulcerative gingivitis (Vincent's stomatitis): The causative organisms are a spirochaete,
Treponema vincenti, and Gram-negative bacilli, Leptotrichia buccalis. The preferred
treatment is with penicillin G. Metronidazole orally in the dose of 200 mg thrice daily for
3-4 days is also useful. Tetracycline and clindamycin are other drugs used.
H. pylori infection ((Chapter 43)
Trichomoniasis and giardiasis (Chapter 58).
Dracunculosis: (Chapter 60)
TINIDAZOLE: This analogue of metronidazole has a longer t1/2 (13 hours) and is probably
better tolerated than metronidazole. In acute amoebic dysentery, it is given in the dose of
600-800 mg orally t.i.d. for 5 days or in the dose of 2 g (50 mg/kg in children) once daily for
3 days. In anaerobic infections, it is used orally in the dose of 2 g initially, followed by 1 g
daily (single dose) for 5-6 days. For surgical prophylaxis, it is administered in the dose of 2 g
once 12 hours before surgery.

SECNIDAZOLE: This analogue of metronidazole has a longer t1/2 and similar uses.

In acute amoebic dysentery, it is administered orally in a single dose of 2 g. In children a

single dose of 30 mg/kg is used. In hepatic amoebiasis, the dose is 1.5 g per day for five days.
In giardiasis, the single oral doses are: 2 g in adults; 500 mg in children weighing 10-15 kg;
750 mg in children weighing 16-26 kg and 1 g in those weighing over 26 kg.

ORNIDAZOLE: is an imidazole with similar properties as secnidazole. It is available as 500

mg tablets. The dose is 500 mg b.i.d. for 5-10 days. A single daily dose of 1.5 g for 3 days is
also effective.

Quinoline Derivatives

Amongst these, diiodohydroxyquinoline, iodochlorohydroxyquinoline and broxyquinoline are

halogenated hydroxyquinolines while chloroquine is a 4-aminoquinoline derivative. They act
by direct contact with the trophozoites of E. histolytica. All the halogenated oxyquinolines
also have some antibacterial and antifungal properties. The mechanism of action of
halogenated oxyquinolines is unknown.

DIIODOHYDROXYQUINOLINE: This halogenated quinoline (Fig. 57.2) is an effective

luminal amoebicide, against both motile and cystic forms of the protozoan, more so against
the former. Clearance of cysts is partially due to elimination of trophozoites. It is, however,
not effective in extraintestinal amoebiasis.

Absorption, fate and excretion: Diiodohydroxyquinoline is insignificantly absorbed from the

intestinal tract and 90% of it is excreted in feces.
Adverse reactions: These are mild and uncommon. The drug may occasionally cause
headache, nausea, vomiting and diarrhoea. Chills, fever, skin eruptions and iodine dermatitis
have been reported. It is contraindicated in patients with iodine intolerance.

Preparations and dosage: Di-iodohydroxyquinoline tablet 300 mg. Dose: 600 mg thrice daily
for 15 days. Another course may be given after 2 to 3 weeks. In infants, the drug is given in
the daily dose of 50 to 100 mg thrice daily; in children between 1 to 5 years, 150 to 300 mg 2
or 3 times daily and in those between 6 to 12 years, 300 mg thrice daily. It cannot be given as
a retention enema because of its relative insolubility in water.

IODOCHLOROHYDROXYQUINOLINE: This drug resembles di-iodohydroxyquinoline

in anti-amoebic action. It is not much absorbed from the GI tract. It is probably more useful
in cyst carriers. It also has antibacterial, antifungal and anti trichomonal actions.

Adverse reactions: These are usually mild and include diarrhoea or constipation, abdominal
pain, anal pruritus and mild iodism.

A neurological syndrome consisting of myelitis, peripheral neuritis and sometimes optic

nerve involvement (Subacute Myelo-Optic Neuropathy-SMON) has been reported in patients
receiving this drug over prolonged periods. These cases were mostly reported from Japan in
1960. They are very rarely reported from other areas. Early symptoms can improve
following the stoppage of the drug. Usually, oral daily doses of upto 750 mg for 8-10 days
are considered relatively safe in adults. Larger doses and its frequent use should be avoided.

Preparations and dosage:

(i) Iodochlorohydroxyquinoline tablets 250 mg. Dose: 750 mg daily in 3 divided doses for 10
days. The course may be repeated once after a week. It may be used along with emetine or
alternated with other drugs.

(ii) Retention enema: It is prepared by suspending 2 g of the drug in 200 ml of water. It is

instilled on alternate nights for 5 times.

(iii) Iodochlorohydroxyquinoline 3% cream for topical dermal use.

Therapeutic uses: Besides its use as luminal amoebicide, it is also used topically in fungal
infections of the skin. The major disadvantage of topical application is yellow staining of
clothes and linen.

Fig. 57.2: (a) Hydroxyquinoline nucleus

(b) Iodochlorohydroxyquinoline

(c) Di-iodohydroxyqulnoline

CHLOROQUINE: The pharmacology of chloroquine is discussed in Chapter 56. Given

orally, it is completely absorbed and concentrated in the liver. It has a minimal effect in
intestinal amoebiasis because of poor concentration in colonic lumen and wall. Its use in
hepatic amoebiasis has declined following the availability of metronidazole.

EMETINE: Emetine is an alkaloid obtained from ipecac, the root of the plant Cephalis
ipecacuanha. The other alkaloid, cephaline, though amoebicidal, is toxic for use.

Antiamoebic action: In vitro, emetine has a direct lethal effect on the trophozoites of E.
histolytica in concentrations that can be achieved in the blood. It inhibits protein synthesis in
trophozoites, which arrests their multiplication and leads to their phagocytosis. It has,
however, little effect on the cystic forms.
Absorption, fate and excretion: Emetine has a bitter taste and is absorbed from the gut but
because of its irritant nature, it is administered by deep IM injection. The drug gets
concentrated in the liver. Significant amounts are also present in the lung, kidney and spleen.
As it is slowly eliminated in urine, repeated injections can cause cumulation.

Adverse reactions: The major drawback of emetine is its toxicity. The adverse reactions are:

Local reaction: These often appear when it is administered SC but are uncommon when
the drug is given deep IM. It may cause local pain, tenderness, stiffness and weakness of
the muscles, and rarely, an abscess.
GI system: Occurrence of nausea, vomiting, diarrhoea, headache, dizziness and
prostration are common. Vomiting (hence the word "emetine") occurs both as a result of
gastric irritation and stimulation of the CTZ.
Cardiovascular system: Emetine may cause tachycardia, precordial pain, hypotension,
myocarditis and pericarditis. The ECG offers an early index of cardiotoxicity. It is
advisable to confine the patient to bed during emetine therapy and to avoid undue
exertion for three weeks thereafter. It is necessary to observe the pulse rate and BP during
the therapy; ideally, an ECG should be taken before starting the therapy, repeated after
the 5th dose and again after a week.
Miscellaneous: It may cause weakness, aching and tenderness of the muscles, especially
those of neck and limbs. The weakness is probably because of its blocking action on the
neuromuscular junction.

Emetine should be avoided in patients with cardiac or renal damage, in pregnant women, in
old people and in young children.

Preparations and dosage:

(i) Emetine hydrochloride injection, 60 mg of the salt per ml. Dose: 30 to 60 mg daily by SC
or deep IM injection.

(ii) Syrup of ipecac is the preferred agent for inducing emesis but never the liquid extract of
ipecac which is too potent. Dose: 30 ml in adults.

Therapeutic uses:

(1) As a tissue amoebicide (see later).

(2) For the treatment of Paragonimus westermanii (lung fluke) and Fasciola hepatica
infestations (Chapter 60).
(3) Ipecacuanha syrup as an emetic (Chapter 41).

DEHYDROEMETINE: This semisynthetic drug, claimed to be less toxic than emetine, is

preferred to emetine. Dehydroemetine injection contains 60 mg of the drug per ml. Dose: 1
mg per kg IM daily for 5-7 days. Dehydroemetine resinate is a slow release preparation given
orally. Dose: 50 mg daily for 10 days.

Antiamoebic Antibiotics

TETRACYCLINE: The intestinal bacteria are essential for the production of intestinal
amoebic lesions. They probably act by creating an environment congenial to the growth of
amoebae, by manufacturing certain metabolites and vitamins on which the protozoa thrive,
and by producing secondary infection.

Tetracycline, though exhibiting an antiamoebic action in vitro in large doses, probably acts in
vivo by altering the intestinal bacterial flora and creating a medium unfavourable for the
growth of amoebae. It may be administered in the dose of 0.25 g 6 hourly for 10-15 days, in
combination with metronidazole to treat amoebic liver abscess particularly when bacterial co-
infection is suspected.

PAROMOMYCIN: This aminoglycoside antibiotic (Chapter 47) given orally, is not

absorbed. In the dose of 500 mg t.i.d. for 10 days, it is effective as luminal amoebicide (cure
rate 80%). It has also been used parenterally in the treatment of leishmaniasis (Chapter 58).

Miscellaneous Agents

Fig.57.3: Diloxanide furoate

DILOXANIDE FUROATE: This potent direct amoebicidal drug (Fig 57.3) is highly
effective in chronic intestinal amoebiasis, in cyst passers and partially useful in mild acute
cases. It is of no value in extra-intestinal amoebiasis.
Given orally it is hydrolysed to diloxanide which is partly absorbed. Nonabsorbable portion
acts as a luminal amoebicide. The drug is well tolerated, safe and almost non-toxic. The
adverse effects reported are mild and include mainly GI disturbances, particularly flatulence.

Diloxanide furoate is available as 500 mg tablets and is administered orally in the dose of 500
mg 3 times daily for 5-10 days. As the drug is non-cumulative, a second course may be given
immediately following the first course.

Nitazoxanide is a prodrug. After absorption, it gets converted to an active metabolite,

tizoxanide, which is active against E. histolytica. Adverse effects are mild GI disturbances. It
is given to children in the dose of 100-200 mg b.i.d. for 3 days. It also acts against
Cryptosporidium parvum and G. lamblia (Chapter 58).

KURCHI: Kurchi consists of the dried stem bark of Holarrhena antidysenterica. Kurchi has
mild antiamoebic activity and is useful only in mild intestinal amoebiasis. It may produce
nausea and vomiting but is otherwise well tolerated. Powdered roots of this plant are used as
a household remedy in India for ages for 'abdominal pain and diarrhoea'.

Management of amoebiasis

Amoebiasis, in general, is a difficult disease to treat because of its tendency to chronicity and
the inability of various drugs to eradicate the cystic forms of the parasite completely.

The diagnosis of acute intestinal amoebiasis without demonstration of trophozoites in stools

is rarely justified. This form is most readily found in diarrhoeal stools and a saline purgative
may be used in cases with vague symptoms. Examination of the swab obtained on
sigmoidoscopic examination is also useful in clinching the diagnosis. The stools should be
examined promptly. It is important to distinguish the trophozoites from macrophages and
even experts may find it difficult to identify an active amoeba as E. histolytica when it is seen
without engulfed red blood cells.

Cysts are found in formed stools. However, the period of their fonnation varies in different
individuals. A casual failure to identify cysts does not, therefore, exclude the presence of
amoebiasis and repeated stool examination is necessary. ELISA assays that detect specific
stool antigen can distinguish between pathogenic E. histolytica from non-pathogenic E.
dispar; the latter needs no treatment.

Definitive diagnosis of amoebiasis can also be made by antigen detection by PCR and by
detection of anti-amoebic antibodies in the serum. But, these tests have limitations.

In the presence of symptoms of hepatitis, demonstration of E. histolytica in stools aids the

diagnosis. This is often not possible, particularly if the patient has received antimicrobial
therapy empirically for fever. If the patient with hepatitis is acutely ill, it is justifiable to carry
out a therapeutic test with metronidazole purely on clinical grounds. Table 57.1 summarises
the suggested treatment of amoebiasis.

Table 57.1: Summary of suggested treatment of amoebiasis

CYST PASSERS:

Diloxanide furoate 500 mg t.i.d. for 10 days.

OR

Diiodohydroxyquinoline 650 mg t.i.d. for 15 to 20 days.

OR

Iodochlorhydroxyquinoline 250 mg t.i.d. for 10 days

INVASIVE:

Metronidazole 400 to 800 mg t.i.d. for 5 days

OR

Tinidazole 2 gm daily for 2 to 3 days

OR

Secnidazole 2 gm single dose followed by a luminal amoebicide for 10 to 20 days

SEVERE CASES AND HEPATIC ABSCESS:

Metronidazole IV or Dehydroemetine IM for 5 days (See text)

Acute intestinal amoebiasis: Metronidazole in the dose of 400-600 mg (15 mg/kg in children)
three times a day for five to seven days is the treatment of choice. It is much less toxic than
emetine and is effective orally. Almost 90% of patients with moderate amoebic dysentery
respond clinically to oral metronidazole therapy. The symptoms are relieved within 24 hours.
Severe cases may need IV metronidazole or IM emetine. Additional advantage of this drug is
its effectiveness in hepatic amoebiasis which can never be entirely excluded in any case of
amoebic dysentery.

Parasites persist in the intestine in almost 30-40% of the patients who receive only
metronidazole. Therefore, metronidazole therapy should be followed by a course of a luminal
amoebicide to ensure a cure. For this purpose, diloxanide furoate 500 mg t.i.d. for 10 days or
di-iodohydroxyquinoline 600 mg b.i.d. or 50 mg t.i.d. for 15 days is used.

In patients presenting with fulminating amoebic colitis with toxic symptom, it is advisable to
use oral tetracycline in addition, to eliminate the intestinal bacteria. Emetine, though controls
symptoms rapidly, is no more recommended due to its cardiotoxicity.

Adjuvant therapy includes the use of antispasmodics for relief of colicky pain and correction
of dehydration in severe cases. A cardiac lesion should be excluded before starting emetine
and strict bed rest should be enforced during its use. None of the regimens gives entirely
satisfactory results, and relapse may occur even a month after apparent cure.

Asymptomatic cyst passers and chronic intestinal amoebiasis: The drug regimens
recommended in such cases are:

(a) Diloxanide furoate 500 mg 3 times daily for 10 days.

(b) A combination of di-iodohydroxyquinoline 1.8 g daily and tetracycline 1 g daily, in

divided doses for 10 days.

Chronic amoebic colitis is sometimes difficult to treat and usually more than one drug, given
in rotation, is needed to achieve success. It must be remembered that some of the symptoms
of colitis may be due to 'irritable colon' or certain pathological changes which may not
regress rapidly, even though the colon is cleared of pathogens. Hence, other supportive and
symptomatic therapy such as a high fibre diet and antispasmodics may be more useful.
Hepatic amoebiasis: Metronidazole is the drug of choice. Emetine hydrochloride and
chloroquine diphosphate are other alternatives.

Metronidazole (800 mg three times a day for 10 days) rapidly controls hepatic amoebiasis in
majority of cases. An alternative regime is 2.4 g (30 mg/kg) in a single daily dose for two
successive days. In this dose nausea is likely to be severe and should be prevented by
administration of metoclopramide. Metronidazole may also be administered IV in the dose of
15 mg/kg (0.75-1g for an adult) as a loading dose, followed by 7.5 mg/kg every six hours for
7-10 days. Each dose is infused slowly over one hour. Neutralised solutions should not be
refrigerated, lest precipitation occurs.

Aspiration is usually necessary in addition to chemotherapy whenever an abscess is present.

Simultaneous administration of tetracycline therapy may be beneficial.

Chloroquine diphosphate is much less potent than metronidazole. It is given in the dose of
500 mg thrice daily for 2 days followed by 250 mg twice daily for 2 to 3 weeks; however, the
relapse rate is high.

Emetine hydrochloride or dehydroemetine may be given deep IM in the dose of 1 mg per kg

of body weight for a period of 10 days. The above treatment should be followed by a course
of a luminal amoebicide.

In patients in whom the diagnosis between amoebic and pyogenic liver abscess is not certain,
metronidazole alone should be avoided because a pyogenic liver abscess may temporarily
respond to metronidazole.

Other forms of extra-intestinal amoebiasis: These respond well to metronidazole.

Criteria for cure of amoebiasis: Failure to detect E. histolytica in stool specimens obtained at
regular intervals for next 2 years is taken as the criterion for cure of amoebic infection.
Clinical cure does not signify cure of the disease and relapses can occur.

Prevention: The cysts responsible for propagation of the disease are resistant to the agents
routinely used to purify water. Chlorine, in the concentration employed to purify water, fails
to kill them. It is, therefore, necessary to avoid fecal contamination of water by sanitary
disposal of feces. Fly control and detection and treatment of carriers are equally important.
The surest way to eliminate cysts from water is to boil it. There is no effective prophylactic
therapy. Prophylactic use of small doses of luminal amoebicides has been tried. Although
they have been claimed to be useful, such a procedure will have limited application,
particularly in those areas where possibility of frequent reinfection is always present.
Chemotherapy of Other Protozoal Infections

Leishmaniasis is a vector-borne infection caused by intracellular protozoa of the genus

Leishmania. Nearly 10% of world population is at risk of acquiring leishmaniasis. It presents
as several clinical syndromes. The most common are:

(a) Visceral leishmaniasis (VL),

(b) Cutaneous leishmaniasis (CL) and

(c) Mucocutaneous (MCL) leishmaniasis, resulting from pathological changes in

reticuloendothelial organs, dermis and muco-oropharynx respectively.

Nearly 90% of cases worldwide are reported from India, Bangladesh, Nepal, Sudan and
Brazil. From 30 mammalian infecting species of leishmania, 21 are responsible for human
disease.

Visceral Leishmaniasis or Kala-azar

This form of the disease, produced by Leishmania donovani and L. infuntum (India, Nepal,
Bangladesh and Sudan) and L. chagasi (Latin America) is transmitted by Phlebotomus
sandflies. In most leishmania infections, dogs and rodents act as reservoir. Only patients with
post-kala-azar dermal leishmaniasis (PKDL) and those with CL act as human reservoir for L.
donovani and L. tropica respectively. In India, VL is found predominantly in Bihar, Assam,
W. Bengal and Orissa.

VL can be asymptomatic, sub clinical and self-resolving or it can run an aggressive fatal
course. Clinically, it is characterised by weight loss, hepatosplenomegaly, irregular fever,
anemia, leukopenia and hypergamma-globulinemia and suppressed cellular immunity.

PKDL is sometimes observed as a syndrome after inadequate or early cessation of treatment

of VL. The dermal lesions act as a source of reservoir for L. donovani spread.

Life cycle: During its life cycle, the protozoan exists in two forms:

(1) Leishmania forms, (amastigotes) found within the reticuloendothelial cells of the liver,
spleen and lymph nodes, and within the macrophages of the infected person; and
(2) Motile flagellated leptomonad forms (promastigotes) which develop from the
leishmania forms within the digestive tract of the sandfly, after it has fed on the blood of an
infected individual. The development of the leptomonad forms within the sandfly takes about
10 days. They are injected by the sandfly into man during its bite, whereupon they attack the
reticuloendothelial cells, are phagocystosed by macrophages and get transformed into the
leishmania forms.

Diagnosis of kala-azar depends upon the demonstration of the leishmania forms in the
peripheral blood or in the aspirate obtained by sternal, splenic, liver or lymph node puncture.
Blood culture is a more certain but time consuming method of diagnosis.

The drugs used in leishmaniasis are:

I. Pentavalent antimony compounds: Sodium stibogluconate and Meglumine antimonate.

II. Diamidine derivatives: Dihydroxystibamidine isethionate and Pentamidine isethionate.

III. Miscellaneous: Amphotericin B, Aminocidin, Paramomycin, Miltefosine.

Table 58.1: Drugs for leishmaniasis

Drug Dose (adults and children)

Sodium stibogluconate
Meglumine antimonate
Amphotericin B
Liposomal amphotericin B
Pentamidine
Miltefosine
20 mg of Sb/kg/day, IV slowly over 5 min or IM for 28-30
days
Same as above
0.5 to 1.0 mg/kg IV, every second day for 15 infusions
3 mg/kg/day on days 1-5, 14 and 21 (Total 21 mg/kg)
2-4 mg/kg daily or every second day IV or IM upto 15 doses.
2.5 mg/kg/day for 4 weeks.

I. Pentavalent antimony compounds: The pentavalent antimony compounds, discovered in

1912, exhibit little activity against the leptomonad forms of Leishmania in vitro. Their
efficacy in vivo suggests their reduction into trivalent antimony compounds in the body.

SODIUM STIBOGLUCONATE: This is the drug most preferred for the treatment of
leishmaniasis. It acts by suppressing both glycolysis and fatty acid metabolism and by
diminishing the net generation of ATP and GTP in the amastigotes. Given IV/IM, it is
excreted in two phases: a short phase with t1/2 of 2 hours and long phase with t1/2 of more than
24 hours (33-76 hours). The latter reflects slow release of trivalent antimony from the tissues,
which contributes to prolonged effects of the drug. Leishmania can develop resistance to
antimonials and high degree of resistance has been reported from Bihar in India.

Adverse reactions: The common adverse effects include a metallic taste in mouth, nausea,
vomiting, diarrhoea, giddiness and local thrombosis. Myalgias, arthralgia, hepatitis,
pancreatitis and rarely arrhythmia may occur. ECG may show flattening or inversion of T
waves, and prolongation of QT interval. A few cases of anaphylactoid shock and renal failure
have been reported.

II. Diamidine derivatives: These drugs are more potent but more toxic than the pentavalent
antimony compounds. However, they are not so effective in Indian Kala-azar. The
mechanism of action is not known. They interfere with amino acid transport, disrupt the
mitochondria and inhibit the transformation of amastigotes to promastigotes. They are also
useful for prophylaxis against T. gambiense and in the treatment of early Gambian and
Rhodesian trypanosomiasis.

PENTAMIDINE: Two pentamidine salts are available, isethionate (Pentamidine) and

mesylate (Lomidine). They are administered IM. It is concentrated in the liver; very little gets
into the brain tissue. The drug can be detected in the urine for 6-8 weeks.

Adverse reactions: Following the IM injection, it may cause local irritation, breathlessness,
nausea, vomiting, facial flushing, pruritus, arthralgia, myalgia, tachycardia, arrhythmia and
hypotension. The systemic toxicity includes hepatotoxicity, leukopenia, thrombocytopenia
and nephrotoxicity. About 5% of patients may develop insulin dependent diabetes mellitus. It
appears to have a direct action on the pancreatic beta cells, resulting in initial insulin release
followed by impaired insulin secretion.

Therapeutic uses

Visceral and mucocutaneous leishmaniasis resistant to pentavalent antimony therapy are

treated with a course of pentamidine or amphotericin B.
Pneumocystis jiroveci pneumonia: Although cotrimoxazole is highly effective in P.
jiroveci pneumonia, its increased toxicity in patients with AIDS makes some physicians
prefer pentamidine. It is also used for prophylaxis. A dose of 300 mg aerosolised, given
once every 4 weeks, appears to be 60-70% effective in preventing the first episode of
pneumonia in patients with AIDS. The other drugs used for the same purpose are daily
cotrimoxazole and weekly combination of sulfadoxine and pyrimethamine, (Chapter 56).
Trypanosomiasis: See later.
DIHYDROXYSTILBAMIDINE ISETHIONATE: This is given IV in the dose of 250 mg
daily for 10 days. The course may be repeated after an interval of 2 weeks and a total dose of
7.5g, should be given over a period of 4 to 5 weeks. Its toxicity is similar to that of
pentamidine.

III. Miscellaneous:

AMPHOTERICIN B: This antifungal antibiotic, (Chapter 50) is useful in patients not

responding to antimony compounds. However, it is expensive, toxic and not easily available.
The doses vary in different regions probably because differences in leishmania species and
their susceptibility.

Amphotericin damages an ergosterol-like membrane steroid of leishmania. It is considered

the drug of choice for Indian Kala-azar. The disease can relapse but responds to repeat
therapy. Freedom from relapse for 6 month indicates cure.

Preparations:

(i) Conventional amphotericin B (complexed with bile salt deoxycholate),

(ii) Amphotericin B colloidal dispersion

( iii) Amphotericin B lipid complex and

(iv) Liposomal preparations. The latter are less toxic as they are targeted specifically toward
macrophages, and may be preferred.

MILTEFOSINE: This phosphocholine derivative has been reported to be highly effective

orally particularly in Indian visceral and cutaneous leishmaniasis. It acts by interfering with
cell signaling pathways. This possibly results in altered lipid metabolism, inhibition of
mitochondrial function, modulation of macrophage response and induction of apoptosis. It is
administered as 50 mg b.i.d. for 4 weeks. For those with weight more than 50 kg, 50 mg t.i.d.
is recommended.

Response rate to miltefosine is variable (60-90%). It is metabolized by the liver and has a t1/2
of 6-9 days. Adverse effects reported are vomiting, diarrhoea and transient hepatic and renal
damage. It is teratogenic and should be avoided in pregnancy. Rapid development of drug
resistance is a major disadvantage.
AMINOCIDIN (Paromomycin): This aminoglycoside antibiotic has been claimed to be
useful in the treatment of visceral leishmaniasis. It is given in the dose of 15-20 mg/kg/day, in
3 divided doses 1M, for 21 days. It needs further evaluation. (Chapter 47).

Oriental Sore

This condition is caused commonly by Leishmania tropica (L. major). The parasite is
transmitted by another species of sandfly. It is characterised by nodular skin lesion that later
ulcerates. Mild lesions may be left to heal by themselves. More severe cases require local as
well as systemic antimonial therapy. Ketoconazole in the dose of 200-400 mg/day for 4-6
weeks may be useful.

Sores on the face and hands often get secondarily infected and tend to become chronic. This
would need additional antibiotic therapy.

American Mucocutaneous Leishmaniasis

It is caused by Leishmania brasiliensis and L. mexicana. It is characterised by skin

granulomas and ulcerative lesions of the nose, mouth and pharynx. The treatment is similar to
that of visceral leishmaniasis. However, the disease is relatively resistant to antimonials.
Amphotericin B is perhaps the best alternative.

Currently used drugs for leishmaniasis are generally toxic, need to be given for long time and
do not eliminate persistent forms of the parasite from the host. There is a variation in
therapeutic response depending on the leishmanial species. Organisms can develop
resistance.

Trypanosomiasis

This disease, caused by parasites of the genus Trypanosoma, is characterised by chronic

irregular fever, skin eruptions, lymphadenitis, and physical and mental lethargy. It can be
divided into:

(1) African trypanosomiasis (Sleeping sickness) is caused by Trypanosoma gambiense and

Trypanosoma rhodesiense transmitted by tse-tse and open woodland flies respectively.

(2) South American trypanosomiasis caused by Trypanosoma cruzi transmitted by blood

sucking Reduviid bugs.
African trypanosomiasis: Therapeutic response is better if the treatment of sleeping sickness
is undertaken in its earlier stage when the parasite has not invaded the CNS.

SURAMIN SODIUM: This drug, a complex organic urea compound, is particularly useful
in treating the more acute rhodesian form of African trypanosomiasis and early infections
with T. gambiense. It is also a useful prophylactic agent but has now been replaced by
pentamidine for this purpose.

The mechanism of action is not clear. Parasites treated with the drug lose their infectivity but
still survive in vitro for over U hours after exposure. In addition to trypanocidal activity, the
drug is effective against the adult forms of Onchocerca volvulus.

Absorption, fate and excretion: Suramin is administered IV as the drug is not adequately
absorbed from the gut; IM administration is painful. It gets extensively bound to plasma
proteins and persists in the plasma for as long as 3 months after a single dose. It does not
cross the blood brain barrier and is, therefore, useless in the encephalitic stage of the
disease. The drug is excreted in urine.

Adverse reactions: These include nausea, vomiting, dermatitis, chills, fever, pruritus,
paraesthesias, photophobia, polyuria and sometimes loss of consciousness. Blood dyscrasias
may develop occasionally. The drug is nephrotoxic and may give rise to cylindruria,
albuminuria and hematuria.

Preparations and dosage: A freshly prepared 10% solution in distilled water is given IV at
intervals of 5 to 7 days for 5-6 injections. The initial dose is 0.5 g followed by 1 g in
subsequent injections. A child under 3 years is usually given 0.25 g, from 3 to 10 years 0.5 g
and those above ten years 1 g. As the drug is nephrotoxic, urine should be examined before
each injection. For use of suramin in onchocerciasis (Chapter 60).

PENTAMIDINE ISETHIONATE: This drug may be used as a substitute for suramin. It is

administered IV in the dose of 3 to 4 mg of the base per kg of body weight, on every alternate
day for 10 doses. A single IM dose (300-400 mg) once every 6 months has been shown to
protect against the Gambian but not the Rhodesian disease. Hypotension and hypoglycemia
are common adverse effects. The drug doses not cross the BBB.
The organic arsenical compounds used in African trypanosomiasis are Mel B and Mel W.
These compounds are toxic and are mainly used to treat meningo-encephalitic stage of the
disease.

MELARSOPROL (Mel B): This trivalent organic arsenical, dissolved in propylene glycol,
is administered IV, slowly, in increasing doses of 0.36-3.6 mg per kg (upto a maximum of
200 mg). The injection is given on alternate days for 3 days. The course may be repeated
after an intermission of 3 weeks in cases with involvement of the CNS. Nearly 95% of the
patients can be cured without serious complication, whereas 1-5% die during treatment. The
toxic manifestations include vomiting, abdominal colic, proteinuria, neuritis, blood
dyscrasias, myocardial damage and arsenical encephalopathy. Mel B is contraindicated in
severely debilitated patients and in those with hepatic and/or renal damage.

MELARSONYL POTASSIUM (Mel W): This water soluble derivative of Mel B is given
as a 5% solution, by IM injection. The first dose is 2 mg per kg; then 4 mg per kg given daily
for 3 days. In severe cases, another course of 4 mg per kg daily for 4 days may be given after
a week. The preparation is probably less toxic but also less effective than the parent
compound in advanced T. rhodesiense infection, but may be equally effective in T.
gambiense infection. The drug is also useful in onchocerciasis.

NITROFURAZONE: The drug has been employed for trypanosomiasis in patients who
have relapsed after other forms of treatment. It is given orally in doses of 500 mg t.i.d. for 7
to 10 days. For children, a dose of 30 mg per kg is recommended. The adverse manifestations
include GI disturbances, peripheral neuritis, seizures and hemolysis in G6PD deficient
patients.

EFLORNITHINE HYDROCHLORIDE (Difluoromethylornithine, DFMO) has been

shown to give high cure rates in late stages of gambian trypanosomiasis. It causes irreversible
inhibition of synthesis of polyamines required for cell division and differentiation. The drug
can cause headache, alopecia, diarrhoea, anemia, leucopenia and thrombocytopenia.
Hallucinations, convulsions and hearing loss may occur. It is teratogenic.

It is administered by IV infusion in the dose of 400 mg/kg/day in four divided doses for 14
days. It should be considered as an alternative in patients who relapse after melosoprol.
Eflorinthine cream has been found useful in reducing the rate of growth of facial hair in
women; however it needs to be used for prolonged period (Chapter 69).

South American Trypanosomiasis (Chagas' disease)

There is no effective and safe agent available for the treatment of this condition. Two drugs
nifurtimox and benznidazole, effective orally, appear to kill circulating trypanosomes.

Nifurtimox is given orally in a dose of 8 to 10 mg/kg per day in 4 divided doses, for 90 to 120
days. The drug may cause GI disturbances, weight loss, insomnia, arthralgia, neuropathy,
leucopenia and seizures.

Benznidazole is administered in a dose of 5-10 mg/kg/day in two divided doses for 60 days.
Generally it is well tolerated. It can cause GI disturbances, polyneuropathy and bone marrow
suppression. They are not useful in chronic disease.

A variety of other drugs, including pyrimethamine, nitrofurans, amphotericin Band

puromycin have been given a trial. None ofthese gives complete cure. They only cause a
transient disappearance of parasitemia.

Toxoplasmosis

Toxoplasmosis is a common disease of birds and mammals, caused by infection with the
obligate intracellular protozoan Toxoplasma gondii. The organisms are arc shaped
(toxon=arc; gondii=the name of a North American rodent). Infection in the animal world
occurs by ingestion of cysts that contain sporulated oocytes (bradyzoites) by an intermediate
host such as the rat or the sheep. The bradyzoites released in the gut enter the epithelium of
the small intestine and transform into rapidly dividing tachyzoites, which can infect all
mammalian cells except the RBCs. Seven to 10 days after the tachyzoite infection, tissue
cysts containing many tachyzoites are formed. The parasites in sexual phase (feline phase)
takes place in the definitive host like the cat which ingests the infected rats. The infected cats
may excrete millions of sporozoites containing oocytes which may remain viable for many
years in the soil. Human infection occurs following ingestion of either soil contaminated with
sporulated oocytes or undercooked meat containing tachyzoites. Cysts are commonly found
in tissues such as the brain, and skeletal muscles.
Toxoplasmosis is largely asymptomatic and self-limiting, but a small percentage of patients
get lymphadenopathy, fever and malaise. Retinochoroiditis forms an important manifestation
(25-35%) in children but is rare in adults.

Encephalitis, myocarditis and pneumonitis can occur. Repeated abortions can occur in
infected women. There is no drug which will kill the trophozoites or eradicate the cysts.
Spontaneous cure is known. No treatment is recommended for asymptomatic infection in
immunocompetent subjects.

A combination of pyrimethamine and sulfadiazine is effective in inhibiting the trophozoites.

Pyrimethamine, a DHF reductase inhibitor, is given orally in the initial dose of 75 mg. daily,
followed by 25-50 mg daily. Sulfadiazine is used in the dose of 2 gm followed by 0.5-1.0 g
orally every six hours. The combination treatment is given for 4-6 weeks. Pyrimethamine can
also be combined with clindamycin or azithromycin. The other drugs used are cotrimoxazole,
atovaquone, spiramycin and clarithromycin.

The regimen recommended in affected, pregnant women is spiramycin, a macrolide, in the

dose of 1 g t.i.d. orally continued throughout pregnancy. In all cases, folic acid supplement
should be given. Monthly ultrasonography is suggested to detect any fetal abnormality. The
presence of hydrocephalus is an indication to terminate pregnancy.

Congenitally infected neonates are treated aggressively with oral pyrimethamine (0.5 to 1.0
mg/kg/day) and sulfadiazine (100 mg/kg/day) along with folic acid for one year. Spiramycin
(100 mg/kg/day) may also be useful. However, a macrolide alone may not be beneficial
unless combined with pyrimethamine. Clindamycin can be substituted for sulfadiazine in
patients allergic to sulfonamide.

Trichomoniasis

Vaginal discharge is a common complaint in general practice. It must be emphasised that

many discharges are non-infective and hence it is wrong and may even be harmful to use
systemic or local antimicrobial drugs unless proper diagnosis is made.

In women of the child-bearing age excessive vaginal discharge (leucorrhoea) may simply be
due to pelvic congestion or increased secretion of the cervical glands as in cervical erosion or
during oral contraceptive medication. In such cases bacteriological examination is negative
and no drugs are indicated. What is needed is reassurance and advice on simple hygiene and
cauterisation of the cervical erosion.

Vaginal discharge due to infection should be treated according to the causative organism.
Trichomonas vaginalis is by far the commonest one, followed by C. albicans. Typically,

(a) Trichomoniasis presents as an intense vaginitis with a purulent, greenish yellow profuse,
frothy, offensive discharge. Other symptoms include pruritus, burning, edema, dyspareunia
and urinary frequency.

(b) Candidial vaginitis is less intense with thin and curd like or 'cheesy' discharge and
adherent plaques on the vaginal wall.

Trichomonas vaginalis is the infectious protozoan most commonly associated with

vulvovaginitis during reproductive years. Infection in males is often symptomless. The
condition is diagnosed by microscopic examination of fresh material from the vagina, of
semen, of prostatic fluid obtained by massage and of urinary sediment. The flagella of the
protozoan can be identified in a wet smear.

Drugs for local treatment: They are useful when extravaginal sources of reinfection are not
present. They include:

(a) Halogenated hydroxyquinolines like lodochlorohydroxyquinoline,

Diiodohydroxyquinoline;

(b) Agents like Furazolidone, surfactants like Sodium lauryl sulfate, Dioctyl sodium
sulfosuccinate, Triclobisonium and Povidone iodine.

These drugs are discussed elsewhere. They are often combined with deodorizers like thymol,
menthol, or eucalyptol. Other local agents like vinegar, boric acid and lactic acid are used to
lower the vaginal pH to its usual acidity (3.5 to 4.5). This facilitates the growth of the normal
vaginal flora and results in suppression of the trichomonal infection.

Drug for systemic therapy: Oral metronidazole is the drug of choice for trichomoniasis
(Chapter 57).

Trichomoniasis responds well to oral metronidazole 400 mg twice daily for 7 days. A second
course may be instituted after 4-6 weeks. A single dose of 2 g has also been reported to give
equally good results. Since trichomoniasis is a urogenital infection, simply using local
pessaries without systemic therapy is unsatisfactory. However, addition of topical treatment
to systemic therapy increases local concentration, which may be beneficial in refractory
cases.

Trichomoniasis is sexually transmissible and it is advisable to administer a course of

metronidazole to the sexual consorts of the infected persons. It is advisable to avoid sexual
intercourse until cure bas been confirmed. Infections due to C. albicans and gonococcal and
puerperal infections need appropriate antibiotic therapy (Chapter 53).

Metronidazole, given in the dose of 400 mg twice daily for 7 days, is also useful in the
treatment of mixed vaginitis (non-specific vaginitis) due to an aerobe (Gardnerella vaginalis)
and anaerobes. The infection causes a malodorous, off-white, vaginal discharge of high pH,
giving a positive amine test. There is no inflammation of the vaginal wall.

Tinidazole and Secnidazole: These imidazoles are effective in a single oral dose of 2 g in
the treatment of vaginal trichomoniasis and giardiasis (Chapter 57).

Giardiasis

Giardia lamblia is a flagellate protozoan parasite of the small intestine. Like E. histolytica, it
has no animal host and is transmitted from man to man by fecal contamination of food and
water. It can cause diarrhoea, anorexia, nausea, vomiting, abdominal pain and weight loss.
Both the cysts and trophozoites may be found in the stools. Giardiasis is quite common and
often exists in association with E. histolytica infection.

Metronidazole is the drug of choice in giardiasis. It is given in the dose of 200 mg t.i.d. for 5
days in adults and 15 mg/kg/day in 3 divided doses for 5 days in children.

Nitazoxanide is effective against metronidazole resistant G. lamblia. Other drugs used are
tinidazole, 2 g single dose, furazolidone (100 mg q id for 7 days) and paramomycin.