2 7 9
Revista da Sociedade Br asileir a de Medicina Tr opical 3 7 ( 3 ) :2 7 9 -2 8 1 , mai-jun, 2 0 0 4
Efficacy of sulfadoxine-pyr imethamine and mefloquine for the tr eatment
of uncomplicated
Plasm odiu m falciparu m
malar ia
in the Amazon basin of Per u
Eficácia da sulfadoxina-pirimetamina e mefloquina no tratamento
de malária não-complicada por
Pla sm o dium fa lcipa rum
na bacia amazônica peruana
Alan J. Magill
1 , 2, Jor ge Zegar r a
1 , 2, Cor alith Gar cia
1 , 2, Wilmer Mar quiño
3and Tr enton K. Ruebush II
4ABSTRACT
In vi vo antimalar ial dr ug e ffic ac y studie s o f unc o mplic ate d Pla sm o d i u m f a lc i p a ru m malar ia at an iso late d site in the Amazo n b asin o f Pe r u b o r de r ing B r azil and Co lo mb ia sho we d > 5 0 % RII/RIII r e sistanc e to sulfado xine -pyr ime thamine b ut no e vide nc e
o f r e sistanc e to me flo quine .
Ke y- wo r ds: Antimalar ial dr ug r e sistanc e . Pla sm o d i u m f a lc i p a ru m. Sulfado xine -pyr ime thamine . Me flo quine . Pe r u.
RESUMO
Te ste s i n vi vo f o ra m re a li za d o s p a ra a va li a r re si stê n c i a a d ro ga s a n ti m a lá ri a , e m p e sso a s c o m m a lá ri a n ã o c o m p li c a d a , c a u sa d a p o r Plasmo dium falc ipar um, n u m a re gi ã o i so la d a d a Ba c i a Am a zô n i c a , n a f ro n te i ra c o m o Bra si l e a Co lô m b i a . Os te ste s m o stra ra m re si stê n c i a > 5 0 % RII/ RIII a su lf a d o x i n a - p i ri m e ta m i n a , m a s n ã o e vi d e n c i a ra m re si stê n c i a a m e f lo q u i n a .
Pa la vr a s- cha ve s: Re sistê nc ia a dr o gas antimalár ic a. Pla sm o d i u m f a lc i p a ru m . Sulfado xina-pir ime tamina. Me flo quina. Pe r u.
1 . Naval Me dic al Re se ar c h Ce nte r De tac hme nt Lima, Pe r u; 2 . Walte r Re e d Ar my Institute o f Re se ar c h, Silve r Spr ing, Mar yland, USA; 3 . Instituto Nac io nal de Salud, Lima, Pe r u; 4 . Natio nal Ce nte r fo r Infe c tio us Dise ase s Ce nte r s fo r Dise ase Co ntr o l and Pr e ve ntio n. US Naval Me dic al Re se ar c h Ce nte r De tac hme nt, Lima, Pe r u The studies wer e financ ed b y the US Naval Medic al Resear c h and Develo pment Co mmand, NNMC, B ethesda, MD, Wo r k Unit No . 8 4 7 7 0 5 8 2 0 0 0 2 5 GB B 0 0 1 6 GEIS Lima.
Addre ss to: Dr. Trenton K. Ruebush II. Division of Parasitic Diseases ( F-2 2 ) /Centers for Disease Control and Prevention, 4 7 7 0 B uford Highway, NE, Atlanta, GA 3 0 3 4 1 USA. Te l: 0 0 1 -7 7 0 -4 8 8 -3 6 0 4 ; Fax: 0 0 1 -7 7 0 -4 8 8 -4 2 0 3
e -mail: tk r 1 @ c dc . go v
Re c e b ido par a pub lic aç ão e m 0 4 /0 2 /2 0 0 3 Ac e ito e m: 2 0 /4 /2 0 0 4
COMUNICAÇÃO/COMMUNICATION
Altho ugh nume r o us i n vi vo antimalar ial dr ug e ffic ac y studie s have b e e n c o nduc te d in the Amazo n B asin o f So uth
Ame r ic a, the gr e at maj o r ity have b e e n c ar r ie d o ut in o r ne ar
lar ge to wns o r c itie s, suc h as Manaus, Po r to Ve lho , and I q uito s , wh e r e gr e a te r n um b e r s o f in fe c te d pa tie n ts a r e
availab le and the infr astr uc tur e ne c e ssar y to suppo r t suc h
studie s is mo r e de ve lo pe d. As a r e sult, the r e ar e lar ge ar e as
o f the Am a zo n r e gio n whe r e little o r no info r m a tio n o n
a n tim a la r ia l dr ug r e s is ta n c e is a va ila b le . We c o n duc te d studie s o f the e ffic ac y o f sulfado xine - pyr im e tham ine ( SP)
a n d m e flo q uine ( MQ) in 1 9 9 9 a nd 2 0 0 0 in the to wn o f
Caballo c o c ha, po pulatio n 3 ,3 0 0 , in the no rtheastern Peruvian
Amazo n r e gio n, lo c ate d le ss than 3 0 k m fr o m the B r azilian and Co lo mb ian b o r de r s ( Figur e 1 ) .
We fo llo we d Wo r ld He a lth Or ga n iza tio n /Pa n Am e r ic a n He a lth Or ga n iza tio n guide lin e s fo r i n vi vo a n tim a la r ia l
dr ug e ffic ac y te sting1 4. The pr o to c o ls we r e appr o ve d b y the
Institutio nal Re vie w B o ar ds o f the U.S. Ar my, the U.S. Navy, and the Unive r sidad Caye tano He r e dia. Patie nts b e twe e n 6
mo nths and 6 0 ye ar s o f age who se thic k b lo o d sme ar s we r e
b e ing e xa m ine d a t the Ca b a llo c o c ha He a lth Ce nte r we r e
sc r e e ne d fo r malar ia par asite mia. Tho se with P. f a lc i p a ru m
mo no infec tio ns between 2 5 0 and 5 0 ,0 0 0 parasites/µl o f blo o d and an axillar y te mpe r atur e
≥
3 7 .5oC and/o r a histo r y o f fe ve rwithin the previo us 7 2 ho urs who gave info rmed c o nsent were
e nr o lle d. Sub j e c ts we r e e xc lude d if the y had sympto ms o r
2 8 0
Ma gill AJ e t al
we r e pr e gnant o r had a po sitive ur ine pr e gnanc y te st. Sample
size s we r e c alc ulate d b ase d o n an e xpe c te d r ate o f tr e atme nt
failur e in the po pulatio n o f 2 5 % fo r SP and 5 % fo r MQ with a pr e c isio n o f 5 % and a 5 % le ve l o f signific anc e .
S u b j e c ts we r e tr e a te d u n d e r s u p e r vi s i o n wi th S P
( Fansidar®; Ro c he SA, B ase l, Switze r land) , 2 5 m g/k g o f the
sulfo namide c o mpo nent in a single do se, o r MQ ( Mephaquin®,
Mepha Ltda, Aesc h-B asel, Switzerland) , 1 5 mg/k g in a single
do se . Fo r the SP tr ial, sub j e c ts we r e ask e d to r e tur n o n days
1 , 2 , 3 , 7 , and 1 4 ; fo r the MQ tr ial, additio nal fo llo w-up visits
we r e made o n days 2 1 and 2 8 . Patie nts who faile d tr e atme nt
with SP we r e tr e ate d with a 7 -day c o ur se o f q uinine plus te tr ac yc line .
Thic k b lo o d sme ar s we r e staine d with Gie msa and the
parasite density c alc ulated by c ounting the number of asexual
parasites per 3 0 0 white blood c ells, based on a manual white blood c ell c ount ( SP trial) or assuming a mean white blood
c e ll c o unt o f 6 , 0 0 0 /µl ( MQ tr ial) . Eac h b lo o d sme ar was
independently examined by two mic rosc opists. A total of 2 0 0
oil immersion fields were examined before a blood smear was
c onsidered negative. The subjec ts’ parasitologic and c linic al response to therapy were c lassified ac c ording to WHO/PAHO
guidelines1 4.
Following a major resurgence of malaria in the Amazon region
of Peru between 1 9 9 3 and 1 9 9 8 , malaria inc idenc e fell quite
dramatically in 1 9 9 9 and 2 0 0 0 , making it increasingly difficult to
identify subjects for study. As a result, we were unable to attain the
intended sample sizes. Of 1 0 0 patients with P. fa lcipa rum malaria
whose blood smears were screened over a four-week period in
1 9 9 9 , only 4 0 could be enrolled in the evaluation of SP. Fifty-four ( 9 0 %) of the 6 0 who were not enrolled were not available for
initial evaluation or follow-up because only their blood smears
had been sent to health center for review. The remaining six patients
were not enrolled because they had received prior drug therapy
( n = 3 ) , had parasitemia > 5 0 ,0 0 0 /µl ( n = 2 ) , or had only P.
fa lcipa rum gametocytes on blood smear ( n = 1 ) . The following year, a total of 9 9 9 febrile patients were screened over a 1 3 -week
period, but only 2 8 had P. fa lcipa rum malaria. Eighteen of these
were enrolled in the evaluation of MQ; the other 1 0 patients had
parasite densities < 2 5 0 /µl on their initial blood smears.
Overall, 4 6 ( 8 0 .7 % ) of the 5 8 subjec ts were males; their
median age was 2 6 .4 years. Twenty-three ( 4 2 .6 %) of the subjects
had a documented fever on enrollment and 9 8 .1 % gave a history
o f fe ve r in the pr e vio us 7 2 ho ur s. Sub j e c ts had a histo r y o f
5 .3 ± 4 .0 days of fever before they were enrolled. Their geometric
mean parasite density was 5 ,8 5 6 parasites/µl.
Thir ty-fo ur ( 8 5 % ) o f the 4 0 sub j e c ts e nr o lle d in the SP
tr ial c o mple te d the 1 4 -day fo llo w-up pe r io d. Thr e e sub j e c ts
had par asite de nsitie s
≤
2 5 0 /µl o n r e -e xaminatio n o f the irday 0 b lo o d sme ar s and thr e e o the r s we r e lo st to fo llo w-up
o n days 2 , 7 , and 1 4 . Thr e e o f the 1 8 sub j e c ts e nr o lle d in the
MQ study did no t c o mple te the ir 2 8 -day fo llo w-up: o ne was
fo und to have a par asite de nsity < 2 5 0 /µl o n r e -e xaminatio n
o f he r initial b lo o d sme ar s and two we r e lo st to fo llo w-up,
o ne o n day 7 and o ne o n day 1 4 ( Tab le 1 ) . Fi gu re 1 - Ca b a llo c o c h a . No rth e a ste rn Pe ru vi a n Am a z o n Re gi o n .
Table 1 - Parasitologic and therapeutic response of Pla sm o dium fa lcipa rum to sulfadoxine-pyrimethamine or mefloquine in Caballococha, Peru, 1 9 9 9 -2 0 0 0 . Drug Parasitologic response ( %) * Therapeutic response ( %) * Drug n RIII RII RI RI/S S n ETF LTF ACR Sulfadoxine
pyrimethamine 34 24 32 6 38 - 34 18 41 41 Mefloquine 15 0 0 0 0 1 0 0 15 0 0 1 0 0
*
RIII, RII, RI = sensitive ( S) ; ETF = early treatment failure; LTF = late treatment failure; and ACR = adequate clinical response are classifications of drug efficacy ( 1 , 4 ) .
Nineteen ( 5 5 .9 % ) of the 3 4 patients in the SP trial had RII/
RIII resistanc e; 1 5 ( 4 4 .1 % ) others were c lassified as RI or RI/S.
Six ( 1 8 % ) of the subjec ts in the SP trial were c lassified as early
treatment failures ( ETF) ; 1 4 ( 4 1 % ) others had late treatment
failures ( LTF) . None of the 1 5 subjec ts in the MQ study had a
rec urrenc e of parasitemia during their 2 8 -day follow-up.
This is the fir st antimalar ial dr ug e ffic ac y study r e po r te d
fr o m the no r the aste r n Pe r uvian Amazo n r e gio n b o r de r ing
Co lo mbia and B r azil. To the best o f o ur kno wledge, no similar
studies have been c arried out in the Colombian Amazon region
o r in the ar e a o f B r azil b o r de r ing Pe r u. As in pr e vio us studie s
c o nduc te d in and ar o und the c ity o f Iquito s in Pe r u to the
so uthwe st, high le ve ls o f r e sistanc e to SP we r e fo und ( RC
Navitsk y, GM Ste nnie s: pe r so nal c o mmunic atio n, 1 9 9 9 ) , and
th e P e r u vi a n Na ti o n a l Ma l a r i a Co n tr o l P r o gr a m n o w
r e c o mme nds MQ plus ar te sunate as its fir st-line the r apy fo r
unc o mplic ate d P. f a lc i p a ru m malar ia in this ar e a.
M e f l o q u i n e a l o n e , o r i n c o m b i n a t i o n wi t h a n
2 8 1
Revista da Sociedade Br asileir a de Medicina Tr opical 3 7 ( 3 ) :2 7 9 -2 8 1 , mai-jun, 2 0 0 4
un c o m plic a te d P. f a lc i p a ru m in fe c tio n s in th e B r a zilia n
Am a zo n r e gio n3. Spo r a dic i n vi tro r e s is ta n c e to MQ h a s
b e e n r e po r te d fr o m th is a r e a s in c e th e e a r ly 1 9 8 0 s5, b ut
we ll- do c um e nte d c ase s o f the r ape utic failur e s with i n vi tro
r e sistant iso late s ar e unusual. RI i n vi vo r e sistanc e to a
single do se o f 1 5 m g/k g has o nly r e c e ntly b e e n r e c o r de d2 6.
I n th e r e po r t b y Ce r utti e t a l2, o n ly o n e o f 9 4 pa tie n ts wa s
c la s s ifie d a s a R I fa ilur e with r e c ur r e n c e o f s ym p to m s
a n d pa r a s ite m ia o n da y 2 7 . Th is pa tie n t h a d a s ub - o ptim a l
MQ b l o o d l e ve l c o m b i n e d wi th a n i n c r e a s e d I C5 0 fo r
m e fl o q u i n e i n th e r e c r u d e s c e n t i s o l a te . We fo u n d n o
e vi de n c e o f r e s i s ta n c e to MQ a t o u r s tu dy s i te i n th e
n o r th e a s te r n Pe r uvia n Am a zo n r e gio n , b ut o uts ide th e
Min is tr y o f He a lth , th is dr ug c a n o n ly b e fo un d in a fe w
ph a r m a c ie s , a n d its c o s t o f a ppr o xim a te ly $ 4 . 7 0 pe r ta b le t
m a k e s it to o e xpe n s ive fo r m o s t pa tie n ts .
In ge ne r al, patte r ns o f antimalar ial dr ug r e sistanc e te nd
to b e similar in c o ntiguo us ge o gr aphic al ar e as whe r e the
e pide mio lo gy o f malar ia is unifo r m and the r e ar e no maj o r
to po gr aphic al b ar r ie r s. This study, fr o m a r e lative ly iso late d
ar e a o f the Pe r uvian Am azo n r e gio n, pr o vide s additio nal
e vide nc e fo r this state me nt and mak e s it lik e ly that similar
patte r ns o f r e sistanc e will b e fo und if studie s ar e do ne o n the
B r azilian o r Co lo mb ian sides o f the b o r der, given the fr equent
m o ve m e nt o f r e s ide nts a lo ng the Am a zo n Rive r b e twe e n
B r azil, Co lo mb ia, and no r the aste r n Pe r u.
ACKNOWLEDGEMENTS
The authors would like to thank the staff of the Caballoc oc ha
Health Center and Rebec a Carrion, Dolores Rimarac hin, and Julio Figueroa for their help during the two studies.
REFERENCES
1 . B r uc e - Chwatt LJ , B lac k RH, Canfie ld CJ , Clyde DF, Pe te r s W, We r nsdo r fe r WH. Che m o the r apy o f Malar ia. Wo r ld He alth Or ganizatio n Mo no gr aph Se r ie s No 2 7 , Wo r ld He alth Or ganizatio n, Ge ne va, 1 9 8 6 .
2 . Ce r utti C, Dur lac he r RR, Ale nc ar FEC, Se gur ado AAC, Pang LW. In vi vo
e ffic ac y o f me flo q uine fo r the tr e atme nt o f falc ipar um malar ia in B r azil.
Jo ur nal o f Infe c tio us Dise ase s 1 8 0 : 2 0 7 7 -2 0 8 0 , 1 9 9 9 .
3 . Fundaç ão Nac io nal de Saúde. Manual de Ter apêutic a de Malár ia. Ministér io da Saúde . B r asilia, 2 0 0 1 .
4 . Pan Amer ic an Health Or ganizatio n. Evaluatio n o f the Ther apeutic Effic ac y o f Drugs fo r the Treatment o f Unc o mplic ated Pla sm o di u m f a lc i pa ru m Malaria in the Amer ic as. OPS/HCP/HCT/1 1 3 /9 8 , Washingto n DC, 1 9 9 8 .
5 . So uza JM. A phase II c linic al tr ial o f me flo q uine in B r azilian male sub j e c ts. B ulle tin o f the Wo r ld He alth Or ganizatio n 6 1 : 8 1 5 - 8 2 0 , 1 9 8 3 . 6 . Salc e do JMV, Camar go LMA, B r aga MFV, Mar ia PS, Mac ê do VO. Avaliaç ão
da e fi c á c i a e to l e r â n c i a do a r te s u n a to a s s o c i a do á te tr a c i c l i n a n a te r apê utic a da m alár ia falc ipar um . Re vista da So c ie dade B r asile ir a de Me dic ina Tr o pic al 3 0 : 2 5 1 - 2 5 7 , 1 9 9 7 .
