Drug-Resistant Malaria - libdoc.who.int - World Health Organization

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64 / CONTROL may develop from any surviving individual asexual forms. When any of these compounds are used for the treatment of established infections (in practice this will usually only refer to chloroquine), far larger numbers of asexual parasites will be exposed to them. Ultimately the number of parasites exposed to a drug is the product of the number of people taking the drug multiplied by the mean number of parasites per individual. Frequency of Resultant Mutants in Parasite Populations Various estimates have been made of the frequency with which mutants resistant to various antimalarial drugs occur in different species of malaria parasites of birds and of rodents, but no good estimates are available for P.falciparum. While the frequency of mutations resulting in parasites resistant to DHFR inhibitors appears to be greater than that for chloroquine, this depends very much on the parasite species. Estimates for pyrimethamine seem to su§gest that resistant mutants are present in the order of 1 in 10 parasites or less in natural populations of both P.gallinaceum and P.falciparum. While no estimate is available for chloroquine, the relative frequencies would appear to be P.berghei > P.falciparum>,,>P.gallinaceum»P.vivax. Moreover, there seems to be a geographical variation in the mutation rate in P. falciparum as regards resistance to chloroquine, the rate being apparently higher in South-East Asia and South America than 1n Africa. However, host as well as parasite factors must play a role in the ease of manifestat ion of chloroquine resistance, and this may well account for the long delay before this phenomenon has become apparent on the African continent. Influence of Drugs on Parasite Transmission While antifols have a sporontocidal action against drugsensitive strains of P.falciparum, this "action is lost in parallel with decreasing sensitivity of the asexual stages. Chloroquine which has neither a sporontocidal action nor any action against mature gametocytes even of drug-sensitive strains of P.falciparum, appears to have a paradoxical action on the transmission of chloroquine-resis.ant parasites, and may actually enhance their infec t i vity to vec tor anophe lines. However, this may be re lated to the biological advantage of chloroquine-resistant P.falciparum. Primaquine which is, of course, not used for the prophylaxis or therapy of falciparum malaria, possesses a potent gametocytocidal action against both chloroquine or antifol-sensitive or -resistant parasites. Antimalarial Drugs Available and Their Roles Table 8 shows drugs or combinations 1n current use (see Appendix 5 for further details)
CONTROL / 65 Table 8. Drugs or Combinations 1n Current Use --N-a-m-;--- -----Type-----r---·~-----------P;:oblems ------ Proguani~--- DHFR inhibitor (an t i f 01) Prophylaxi-s-- Resistance common (P.f. and P.v.) Pyrimethamine! suI fadoxine (Fansidar) DHF"RInhibito':--- Prophylaxis --- (an t if~~ ___ -+_= _______ _ DHFR and DHPS inhibitors Therapy of chloroquineresistant P.f. Resistance appearing in parts of Brazil, Kampuchea J Thailand and elsewhere Pyrimethamine/ dapsone (Maloprim) DHFR and DHP S inhibitors Prophylaxis of chloroquineresistant P.f. May cause agranulocytosis Chlo-;~qu~ 4- aminoquinoline blood schizontocide Prophylaxis -- Therapy Resistanc~-wide;Pread -in P-.-f-.- except in Western Asia an-d- large parts of Africa 4-amTnoquino 1 i ne blood schizontocide - Prophylaxis-- Therapy Resist;~~-;-sTrghtly-Iess P. f .. as compared to chloroquine io-- Quini ne Blo~---- schizontoc ide Therapy of mu1tipleresistant P. f. Expensive~ativery-toxIC- -AntIr;;-i:l p s;':-- in P.v. Garnet ocytoc ide in P. f. --T~;;-i;:-;:Spec ra-fly-in G-6-PD---- deficient subjects when used in daily administration for anti relapse treatment Qu i nOli ne -me t I;~anol blood schizontocide ~;;:~p~f---- multip1eresistant P.f. --cli~ic~~;ials-n~-y~t-------- completed (see Annex 11) Tetracyc li ne Antibiotic blood schizontocide Therapy of multiple-resistant P. f. Slow action. Usually given concurrently with or subsequent to quinine administration Note: P.f: Plasmodium falciparum; P.v. glucose-6-phosphate dehydrogenase Plasmodium vivax; G-6-PD:
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Drug-Resistant Malaria The Report o
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Foreword A meeting on drug-resistan
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CONTENTS Page Drug Pressure and Res
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2 / INTRODUCTION Differences in dru
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II. Opening Address and Messages Ol
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OPENING ADDRESS / 7 phical boundari
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OPENING ADDRESS / 9 to preserve for
Page 19 and 20:
OPENING ADDRESS / 11 is also here a
Page 21 and 22: Ill. Review of Drug Resistance in P
Page 23 and 24: REVIEW I 15 Table 1. Sensitivity Te
Page 25 and 26: REVIEW / 17 Other Studies Validatio
Page 27 and 28: Distribution of Chloroquine-Resista
Page 29 and 30: REVIEW I 21 are signs to suggest th
Page 31 and 32: REVIEW / 23 (h) specialized investi
Page 33 and 34: REVIEW / 25 TABLE 3~ Comparison of
Page 35 and 36: REVIEW / 27 Of 22 mefloquine in vit
Page 37 and 38: REVIEW / 29 operational conditions
Page 39 and 40: REVIEW / 31 the possible influence
Page 41 and 42: IV. Monitoring of Drug Response of
Page 43 and 44: MONITORING / 35 during recent years
Page 45 and 46: MONITORING / 37 India, Sri Lanka an
Page 47 and 48: Table 4. Results of Micro In Vitro
Page 49 and 50: MONITORING / 41 The superiority of
Page 51 and 52: MONITORING / 43 input of the result
Page 53 and 54: MONITORING / 45 table time 1ag and
Page 55 and 56: Table 6. Probability of Detecting t
Page 57 and 58: MONITORING / 49 prevalence = 10% an
Page 59: MONITORING / 51 TDR. At the end of
Page 62 and 63: 54 / RESEARCH RESULTS characteristi
Page 64 and 65: 56 / RESEARCH RESULTS EXO-ERYTHROCY
Page 67 and 68: VI. Control of Drug-Resistant P. fa
Page 69 and 70: CONTROL / 61 DRUG USE AIMING AT PRE
Page 71: Table 7. Specific Actions for the C
Page 75 and 76: Table 9. Suggested Use of Antimalar
Page 77 and 78: Table 9. Suggested Use of Antimalar
Page 79 and 80: CONTROL / 71 Radical therapy of mic
Page 81 and 82: CONTROL / 73 Tanzania several years
Page 83 and 84: VII. Field and Laboratory Research
Page 85 and 86: RESEARCH FOR CONTROL / 77 In vivo a
Page 87 and 88: RESEARCH FOR CONTROL / 79 migrants
Page 89 and 90: RESEARCH FOR CONTROL / 81 and Phase
Page 91: RESEARCH FOR CONTROL / 83 (b) Metho
Page 94 and 95: 86 / RECOMMENDATIONS and sulfonamid
Page 96 and 97: 88 / RECOMMENDATIONS (xiii) Simple
Page 99 and 100: IX. Summary The Meeting on Drug-Res
Page 101 and 102: APPENDIX 1 List of Participants, Ob
Page 103 and 104: APPENDICES / 95 Sri Lanka Dr M.K. B
Page 105 and 106: APPENDICES / 97 Papua New Guinea Dr
Page 107 and 108: APPENDICES / 99 TEMPORARY ADVISERS
Page 109 and 110: APPENDICES / 101 Dr L.E. Molineaux
Page 111 and 112: APPENDIX 2 List of Documents A. WOR
Page 113 and 114: APPENDICES / 105 Comparative study
Page 115 and 116: APPENDIX 3.1 I 107 RESPONSE OF Plas
Page 117: APPENDIX 3.2 / 109 RESPONSE OF P. F
Page 120 and 121: 112 / APPENDICES 0.25 0.50 0.75 1.0
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114 / APPENDICES Chloroquine is eff
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116 / APPENDICES 1.4 Sulfonamide pl
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118 / Various tetracycline analogs
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120 / APPENDICES A loading dose on
Page 130 and 131:
122 / APPENDICES The drug should be
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124 / APPEND ICE S 2. INDICATIONS f
Page 134 and 135:
126 / APPENDICES they are already r
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128 / APPENDICES 5.2 In suppressive
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130 / APPENDICES Outline research p
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132 / APPENDICES Long-term To preve
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APPENDIX 8 Considerations Related t
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APPENDICES / 137 4. Screening point
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