Fadat, G.

Gardon, J.

Gazin, Pierre

Hengy, C.

Jambou, R.

Louis, F.J.

Louis, J.P.

Trebucq, A.

Horizon / Pleins textes

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/ *  Proposals for a new therapeutic strategy for simple ,.a 
Plasmodium falciparum malaria attacks in Cameroon - 1  
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J i? Louis', C. Hengy2, K J Louis2, I? Gazin 3, R. Jntnbou2, J Gardort3, G. Fadat2, A. Tt-ebticq 1 
' Service d'Epidémiologie, OCEAC BP 288 Yaounde-Cameroun; Service des Laboratoires, OCEAC; :a 
. I  Antenne ORSTOM auprés de I'OCEAC . 1  
Abstract 
From simplified in vivo tests, authors set up 
a cartography of the sensitivity of Plasniodim falcipanim to 
amino-4-quinolines in Cameroon; they also evaluated the 
clinical and parasitological efficacy of different therapeutic 
protocols which make use of amino-4-quinolines, quinine, 
mefloquine and halofantrine. All these drugs are adminis- 
tered orally. They recommend maintaining home medication 
with chloroquine at the dose of 25 mglkg over 3 days, con- 
serving quinine for use in the case of a possible failure. The 
use of most recent antimalarials can be proposed only as a 
last resort. 
- asymptomatic carriers on DO h a h g  a parasitaemia of Plnsmodi- ,! 
rrmfalcipanm superior or equal to 500 infested globules by mm3; a 
- Subjects who took their treatment correctly on DO, DI and D2 and 1 
who were reexamined on D3 and D7. 
1 
Introduction 
The first cases of chloroauine-resistant malaria 
in Cameroon were reported among expatriates in the South of 
the country in 1955 by Sansonetti and in the city of YaoundC by 
Hengy in 1986. 
As this situation can cast doubts on the drug 
treatment recommended at present, OCEAC (Organisation of 
Coordination for the Control of Endemic Diseases in Central 
Africa), in collaboration with the Public Health Ministry, set up 
a programme to evaluate the extensiveness of areas where there 
was resistance of Plastnodiiitn fnlcipnriim to amino-4-quino- 
lines in different bioclimatic areas of the country and the levels 
of resistance. 
- a simplified in vivo test was carried out on school children 
- this approach was followed up by a study of the efficacy 
who were asymptomatic carriers; 
of antimalarial therapy in the treatment of simple malarial 
attacks in urban clinics. 
Materials and methods 
I .  Evnliintioii of Plnsmoditim falcipanini 
sensitivity to nnzino-4-qtiinolines 
An OCEAC simplified 7-day in vivo test (Jambou et 
al., 1988) derived from the WHO 7-day in vivo test, was used. 
Accepted 3 March 1992 
..- 
, I  
_L 
In the 9 sites studied in all of Cameroon in 1989- 
1991, 7 were in areas of continuous transmission (tropical rain forest) 
and 2 (Maroua and Ngaoundere), were in savannah regions where sea- 
sonal malaria transmission is severe. 
2. Evaliiation of therapy in tirbnn clinics 
From 1957 to 1991, five surveys were carried out in 
I 
~ 
the dispensaries of Yaoundé, the capital city. 
, 
Criteria of inclusion 
- subjects 2 years of age or above were selected randomly during visits 
- fever 2 38 "C and parasite density superior to 2000 PlnsnzodÍumfnl- 
- verbal denial of antimalarial drug ingestion within the last 72 hours 
- oral consent of the patient or of a family representative in the case of 
' 
to the clinic 1 1
3 
cipnriim trophozoites per microliter of blood, 
before the consultation; 
children. 
y 
f 
Criteria of Exclusion 
- clinical signs of severity according to WHO criteria (WHO 1990); - contra-indication for the oral treatment (iterative vomiting and/or 
- 
profuse diarrhea). - P 
For each plasmodial strain studied, an in vitro sensi- 
tivity test was performed, making use of the Le Bras and Deloron 
technique (isotopic version). 
p. 
+ 
Culture microplates containing antimalarials in lyo- +- 
philized form were prepared and controlled by Centre National de 
Référence de la Chimiosensibilité du Paludisme in Paris. T~op. Med. Parasitol.43 (1992) 110-120 
O Georg Thieme Verlag Stuttgart. New York 
-- 
Therapeutic strategy for Plasniodiim fahiparum malaria attacks 
Table 1 Protocols of study on the efficacy of orally administered antimalarials. 
Trop. Med. Parasitol. 43 (1992) 119 
- Total N - 
I 
- - "  1987-88 Chloroquine J I  et J2: 10mglkg J3: 5mglkg 25mglkg 54 Amodiaquine 54 
1989 Chloroquine JI:  10 mglkglmatin + 5mg mg/kg/soir 35mglkg 78 
Amodiaquine J2 et J3: 5 mglkg M et S 87 
1990 Amodiaquine Id. 35mg/kg 87 
1987-88 Quinine 
Quinine 
1989 Fansidar 
Fansimef 
8 mglkg l8 h l 3  jours 
8mgIkg18hl3 jours 
lcp120 kg 
lcp120 kg 
33 
47 
46 
52 
Table1 above rougly relates to protocols for pre- gards a malabsorption or an accelerated metabolic rate was not 
scribing oral administration drugs. For each of these protocols, the first 
drug ingestion was supervised, others being administered at home. 
therefore hobm. Table 2 gives results from the 9 sites of study. 
On DO,D3 and D7, blood samples were taken by 
finger- prick. After Giemsa R.A.L.@ coloration, hematozoa were 
searched for with an optical microscope on thick and thin smears. They 
are put forward on thick smears by 100 fields examination (about 2000 
leucocytes). Parasite density was established from thick or thin smears 
for high parasitemia. Parasitic species were identified on thin smears. 
Each examination was performed by two different technicians. 
The efficacy of drug treatment was assessed on the 
7th day after the first administration of the drug: 
- the clinical criteria were disappearance of the symptomatology and 
- the parasitological criteria was absence of parasitaemia. 
return to normal of rectal temperature; 
Results 
The extensiveness of chemosensitivity of Plas- 
modium fakiparum to amino-4-quinolines in different biocli- 
matic areas in Cameroon was observed with heterogenous rate 
divisions of resistant strains, the highest rate being observed in 
areas of continuous malaria transmission. 
Roughly however, more than 80 % of circulat- 
ing strains remain sensitive to chloroquine. 
2. Eficacy of oral antimalarials 
2. I Therapeutic efficacy 
This was evaluated on the basis of clinical and 
parasitological cure, measured on the 7th day following the first 
medication and established from different protocols (Table 3). 
1. Rate vnrintions of chemoresistance 
to amino-4- quinolines Amodiaquine-base is effective at dose of 35 mg 
/kg of body weight divided over 3 days; it is likewise with 
Parasitaemia was re-examined on D3 and D7. 
It was therefore not possible to differentiate between RI and RI1 
resistance. 2.2 In vitro efficacy 
quinine and mostrecent antimalarials. 
Drug rates in the blood were not measured. The 
possible role of diminished efficacy linked to low rates as re- 
Table 2 Situation of the chemosensitivity to chloroquine (CQ) and 
amodiaquine (AQ). 
Site Test N. Total N. Inclus RI + RI1 Rill 
(%) (%) 
Edea 1989 
Maroua CQ 
M ban djoc k 
1989 
Mbebe Ja 1990 
Ju 1990 
Ja 1991 
Niete 
-LI Ngaoundere 
Nhi  
Yaounde 
Pouma 
CQ 190 68 
21 o 14 
CQ 195 86 
126 59 
CQ 122 40 
102 37 
99 19 
CQ 159 62 
AQ 151 60 
CQ ,154 15 
CQ 116 46 
CQ 140 46 
CQ 150 56 
18 
7 
9 
11 
10 
21 
16 
17 
10 
6 
13 
28 2 
28 
Plasmodial strains were tested against 
chloroquine (CQ), Monodesethylamodiaquine (MDAQ), 
Quinine (Q), Mefloquine and Halofantrine. 
Results were expressed in EC50 with limites 
defined as follows: CQ: EC50 > 100 nmol/l; MDAQ: EC50 > 60 
nmol/l; Mefloquine: EC50>26 nmol/l and Halofantrine: EC50 
>20 nmol/l; with Quinine there was a diminished sensitivity 
about a CI50>450nmol/l. . , .  
Table 3 Percentage of failure according to the current protocols. 
25mglkg 35mglkg 35mg/kg 
Chloroquine 59 50 
Amodiaquine 37 6 2 
Quinine O 4 
Fansidar@ O O 
Fansime$ O 
1987-1 988 1989 I 1990 
1988 1989 
120 Trop. Med. Pamsitol. 43 (1992) 
Table 4 Percentage of in vitro resistant strains. 
Chloroquine n = 110 n = 45 n = 83 n = 87 n = 20 
CI 50 > 100 nmol 60 60 55 52 55 
Amodicaquine n = 70 n = 42 n = 62 n = 87 n = 18 
CI 50 > 60 nmoi 24 26 34 13 1 1  
Quinine n = 81 n = 44 n = 79 n = 87 n = 18 
CI 50 > 450 nmol 1 2 9 3 O 
Mefloquine n = 26 n = 20 n = 22 n = 12 
CI 50 > 26 nmol O 5 5 8 
Halofantrine n = 20 
CI 50 20 nmol O 
1 I? Louis, C. Hengy, B J Louis et al. - 
5.- 
1987 1988 1989 I 990 1991 
1987 1988 1989 1990 1991 
. -  
Results are &en in Table 4 where they are 
expressed in percentage of resistant strains. 
Discussion 
The resistance of Plasmodium falcipanrm to 
amino-4- quinolines was observed for the first time in the South 
of Cameroon, in Limbe, in 19S5, among children of expatriates. 
It rapidly reached the Capital City, Yaoundé and is spreading 
now at different rates in through whole country. However 80 % 
of circulating plasmodial strains remain sensitive to chloro - 
quine. 
Studies made on patients with a parasitologi- 
cally confirmed clinical malaria show a very high rate of failure 
with chloroquine, in whatever dosages are used, either 25 or 
35 mg/kg of body weight. 
If on the one hand a very high rate of failure is 
recorded in the use of amiodaquine-base at a dose of 25 mg/kg, 
on the other hand, administration of 35mg/kg over 3 days of 
amodiaquine is found to be perfectly efficient, thus confirming 
the works of Macaigne et al. (1989), and that of Hengy et al. 
(1989). 
All other antimalarials studied maintain the 
whole of their efficacy; it is however prudent to be vigilant, 
since in vitro tests are showing warning signs (Table 4). 
These results enables us to propose the follow- 
ing recommendations: 
1. It is necessary to keep promoting oral therapies whose ad- 
vantages cannot be overemphasized. 
2. For presumptive home treatment of febrile attacks, chloro- 
quine remains a first choice at a dose of 25 mg/kg of body 
weight over 3 days. 
3. On the contrary, at clinics where these home treatments are 
ending up in failure, it would be preferable to prescribe 
amodiaquine-base for the first choice treatment at a dose 
of 35 mglkg of body weight over 3 days, once the parasito- 
logical diagnosis is made. 
4. For the second choice treatment, one can continue to use 
quinine, which would conserve the use of most recent anti- 
malarials. 7 
- -  
*** \ 
1.) 
1 *'i 
These proposals are appropriate only in the ' f  
hypothesis that surveillance of the chemosensitivity of Plasmo- y,' 
diilni falcipariim to antimalarials is maintained. 1 
Sansonetti, I! I!, J: Le Bras, E Verdier, G. Charmof, B. Dupont, C. La- 
presle: Chloroquine-resistant Plasmodiiim falcipanim in 
Cameroon. Lancet (1985) i, 1154-1155 
Hengy, C., E Eberle, A. Arrive, D. Koiika-Bemba, I! Gazin, R. Jnniboii: 
Accès palustres simples en zone de haut niveau de résistance à la 
Chloroquine. Bull. Soc. Path. Ex. 83 (1990) 53-60 
Jambou, R., II Gnzin, N A. Ghogomii, D. hgonfii, A. Trebiicq, C Hengy: 
Proposition de protocole-test in vivo simplifié sur 7 jours. Bull. 
liais. doc. OCEAC 86 (1988) 4 1-42 
W O :  Division of control of tropical diseases.Severe and complicated 
malaria. Trans of Royal Soc. Trop. Med. Hyg. 84 (1990) 2, 1-65 
Le Bras, 1, I! Deloron: In vitro study drug sensibility of Plasmodium 
falcipariim, evaluation of a new semi-microtest. Am. J. Trop Med. 
Macaigne, E, A. Combe, II Vincetideair, J: K. Eboiimboii, 2: Carniec 
R. hlichel, C. Ripert: Sensibilité in vivo de Plasmodium fnlci- 
panini à ¡'amodiaquine dans la ville d'Ed&, Cameroun. Bull. Soc. 
Path Ex. 82 (1989) 208-216 
Hyg. 32 (1983) 447-451 
DE J: I? Louis 
Service d'Epidémiologie, Organisation de coordination pour 
la lutte contre les endemies en afrique centrale (OCEAC) 
PB 288 Yaounde-Cameroun - * <  :r 
T i  


Proposals for a new therapeutic strategy for simple Plasmodium falciparum malaria attacks in Cameroon

Proposals for a new therapeutic strategy for simple Plasmodium falciparum malaria attacks in Cameroon

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