Malaria pathogenesis and reason for drug resistantance

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1. Malaria Pathogenesis and Reason for drug resistant

2. Plasmodium species which infect humans Plasmodium vivax ( tertian ) Plasmodium ovale ( tertian ) Plasmodium falciparum ( tertian ) Plasmodium malariae ( quartian )

3. Exo- erythrocytic (hepatic) cycle Sporozoites Mosquito Salivary Gland Malaria Life Cycle Life Cycle Gametocytes Oocyst Erythrocytic Cycle Zygote Schizogony Sporogony Hypnozoites (for P. vivax and P. ovale )

4. 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

5. Components of the Malaria Life Cycle Mosquito Vector Human Host Sporogonic cycle Infective Period Mosquito bites gametocytemic person Mosquito bites uninfected person Prepatent Period Incubation Period Clinical Illness Parasites visible Recovery Symptom onset

6. 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

7. 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

8. 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

9. Exo- erythrocytic (hepatic) cycle Sporozoites Mosquito Salivary Gland Malaria Life Cycle Life Cycle Gametocytes Oocyst Erythrocytic Cycle Zygote Schizogony Sporogony Hypnozoites (for P. vivax and P. ovale )

10. 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

11. 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

12. Erythrocytic phase stages 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

13. Erythrocytic phase stages 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

14. 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

15. RESISTANCE

16. 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.

17. 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.

18. 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.

19. 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

20. 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 .

21. 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.

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

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

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

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

26. 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

27. Prevention of drug resistance Resistance develops most rapidly when a population of parasite encounters subtherapeutic concentration of antimalarial drugs. .

28. 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

29. 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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