Malaria pathogenesis and reason for drug resistantance

Malaria Pathogenesis and Reason for drug resistant

Plasmodium species which infect humans

Plasmodium vivax (tertian)

Plasmodium ovale (tertian)

Plasmodium falciparum (tertian)

Plasmodium malariae (quartian)

Exo-erythrocytic (hepatic) cycle

Sporozoites

Mosquito Salivary Gland

Malaria Life CycleLife Cycle

Gametocytes

Oocyst

Erythrocytic Cycle

Zygote

Schizogony

Sporogony

Hypnozoites(for P. vivax and P. ovale)

Malaria Transmission Cycle

Parasite undergoes sexual reproduction in the mosquito

Some merozoites differentiate into male or female gametocyctes

Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts

Dormant liver stages (hypnozoites) of P. vivax and P. ovale

Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood

MOSQUITO HUMAN

Sporozoires injected into human host during blood meal

Parasites mature in mosquito midgut and migrate to salivary glands

Components of the Malaria Life Cycle

Mosquito Vector

Human Host

Sporogonic cycle

Infective Period

Mosquito bitesgametocytemic person

Mosquito bitesuninfected person

Prepatent Period

Incubation Period

Clinical Illness

Parasites visible

Recovery

Symptom onset

Exo-erythrocytic (tissue) phase

Blood is infected with sporozoites about 30 minutes after the mosquito bite

The sporozoites are eaten by macrophages or enter the liver cells where they multiply – pre-erythrocytic schizogeny

P. vivax and P. ovale sporozoites form parasites in the liver called hypnozoites

Exo-erythrocytic (tissue) phase

P. malariae or P. falciparum sporozoites do not form hypnozites, develop directly into pre-erythrocytic schizonts in the liver

Pre-erythrocytic schizogeny takes 6-16 days post infection

Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver

Relapsing malaria

P. vivax and P. ovale hypnozoites remain dormant for months

They develop and undergoes pre-erythrocytic sporogeny

The schizonts rupture, releasing merozoites and produce clinical relapse

Exo-erythrocytic (hepatic) cycle

Sporozoites

Mosquito Salivary Gland

Malaria Life CycleLife Cycle

Gametocytes

Oocyst

Erythrocytic Cycle

Zygote

Schizogony

Sporogony

Hypnozoites(for P. vivax and P. ovale)

Exo-erythrocytic (tissue) phase

P. vivax and P. ovale hypnozoites remain dormant for months

They develop and undergoes pre-erythrocytic sporogeny

The schizonts rupture, releasing merozoites and producing clinical relapse

Erythrocytic phase

Pre-patent period – interval between date of infection and detection of parasites in peripheral blood

Incubation period – time between infection and first appearance of clinical symptoms

Merozoites from liver invade peripheral (RBC) and develop causing changes in the RBC

There is variability in all 3 of these features depending on species of malaria

Erythrocytic phasestages of parasite in RBC

Trophozoites are early stages with ring form the youngest

Tropohozoite nucleus and cytoplasm divide forming a schizont

Segmentation of schizont’s nucleus and cytoplasm forms merozoites

Schizogeny complete when schizont ruptures, releasing merozoites into blood stream, causing fever

These are asexual forms

Erythrocytic phasestages of parasite in RBC

Merozoites invade other RBCs and schizongeny is repeated

Parasite density increases until host’s immune response slows it down

Merozoites may develop into gametocytes, the sexual forms of the parasite

Schizogenic periodicity and fever patterns

Schizogenic periodicity is length of asexual erythrocytic phase 48 hours in P.f., P.v., and P.o. (tertian) 72 hours in P.m. (quartian)

Initially may not see characteristic fever pattern if schizogeny not synchronous

With synchrony, periods of fever or febrile paroxsyms assume a more definite 3 (tertian)- or 4 (quartian)- day pattern

RESISTANCE

DEFINITION

Drug resistance is the ability of the parasite species to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance.

The important factors that are associated with resistance are

Longer half-life. Single mutation for resistance. Poor compliance Host immunity. Number of people using these

drugs.

The characteristics of a drug that make it vulnerable to the development of resistance are:

a long terminal elimination half-life a shallow concentration-effect

relationship mutations that confer marked

reduction in susceptibility.

Drug resistance is most commonly seen in P. falciparum.

Only sporadic cases of resistance have been reported in vivax malaria.

Resistance to chloroquine is most prevalent

Degree of resistance

WHO has developed a simple scheme for estimating the degree of resistance that involves studying the parasitemia over 28 days.

Smears on day 2, 7 and 28 are done to grade the resistance as R1 to R3. In a case of normal response parasite count to fall to 25% of pre-treatment value by 48 hours and smear should be negative by 7 days.

Sensitive (S)

The asexual parasite count reduces to 25% of the pre-treatment level in 48 hours after starting the treatment and complete clearance after 7 days, without subsequent recrudescence - Complete Recovery.

RI, Delayed Recrudescence

The asexual parasitemia reduces to < 25% of pre-treatment level in 48 hours, but reappears between 2-4 weeks.

RI, Early Recrudescence

The asexual parasitemia reduces to < 25% of pre-treatment level in 48 hours, but reappears earlier.

RII Resistance

Marked reduction in asexual parasitemia (decrease >25% but <75%) in 48 hours, without complete clearance in 7 days.

RIII Resistance

Minimal reduction in asexual parasitemia, (decrease <25%) or an increase in parasitemia after 48 hours.

This classification however has some limitations

1. In endemic areas it is not easy to differentiate recrudescence from re-infection.

2. Recrudescence can occur beyond 28 days also.

3. Therapeutic failure could be due to other causes also.

4. RII is a very broad category. 5. Practical difficulties in following the patient

for 28 days. 6. Intermittent nature of parasitemia in the

blood

Prevention of drug resistance

Resistance develops most rapidly when a population of parasite encounters subtherapeutic concentration of antimalarial drugs.

.

The following points will be helpful in reducing the emergence of resistance:

Selection of drugs - Use conventional drugs first in uncomplicated cases. Greater the exposure, higher will be the emergence of resistance.

Avoid drugs with longer half-life if possible

Ensure compliance

Avoid basic antimalarials for non-malarial indications (e.g. Chloroquine for rheumatoid arthritis in a malarial endemic area).

Monitoring for resistance and early treatment of these cases to prevent their spread.

Clear policy of using newer antimalarials. Use of combinations to inhibit emergence

of resistance

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