656
ria should be treated with alternative third-line drugs,
such asquinine.
Even though our sample was small, the results are an
important indicator of the current sensitivity status of P.
falciparum in the population. We recommend that, in re-
fugee situations where there is lack of a common policy
of management, drug sensitivity studies should be done
to provide guidance in developing an effective antimala-
rial policy.
Acknowledgements
We thank H. Alphonseand M. Vincent for their technical as-
sistance.
References
Baired, J. K., Bashi, H. & Jones, T. R. (1991). Resistance to
antimalarials of Plasmodium falciparum. American Journal of
Tropical Medicine and Hygiene, 44,640-644.
Bjiirkman, A. (1991). Drug resistance-changing patterns. In:
Malaria: Waiting for the Vaccine, Targett, G. A. T. (editor).
Chichester: John Wiley & Sons, pp. 105-120.
Bjorkman, A. & Phillips-Howard, P. A. (1990). The epidemio-
logy of drug-resistant malaria. Transactions of the Royal Society
of Trobical Medicine and Hveiene. 84. 177-180.
Breman, I. G. & Campbell, Cy C. (1988). Combating severema-
laria m African children. Bulletin of the World Health Organiz-
ation, 66,61 l-620.
Bruce-Chwatt, L. J. (1986). Chemotherapy of Malaria. Geneva:
World Health Organization, pp. 102-118.
Garcia-Vidal, J., Ngirabega, J. de D., Soldevila, M., Navarro,
R. & Bada, I. L. (1989).Evolution of resistanceof Plasma-
dium falciparum to antimalarial drugs in Rwanda, 1985-1987.
TRANSACTIONS
OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE (1995) 89,656-657
1Short Report 1
Vivax malaria resistant to
chloroquine: case reports from
Bombay
M. Garg, N. Gopinathan, P. Bodhe and N. A. Kshir-
sagat* Department of Clinical Pharmacology, Seth G. S.
Medical Collepe and K. E. M. HosDital. Parel. Bombav-
400 012, IndiaY
Fdrrds: malaria, Plasmodium vivax, chloroquine resistance,
Chloroquine has been the treatment of choice for vivax
malaria for more than 40 years. Lately several case re-
ports have su gested the emergenceof resistance to chlo-
roquine of P &asmodwn vivax tn Papua New Guinea and
Indonesia (MURPHY et al., 1993). In 1993 we analysed
the response of 139 casesof vivax malaria to 10 mg/kg
chloroquine+ 15 m primaquine daily for 5 d (as recom-
mended bv the a. atlonal Malaria Eradication Pro-
gramme, India) (ROY et al., 1977); 7 casesfailed to re-
spond but were successfully treated with 25 mg/kg
chloroquine (POTKAR et al., 1995).
We now report 2 cases of P. vivax infection from
Bombay, India, who failed to respond to 25 mg/kg chlo-
roquine. Both these patients presented between Decem-
ber 1994 and April 1995 to the Clinical Pharmacology
unit at the King Edward Memorial Hospital, Bombay.
Case histories
Case no. I
An 18 years old, previously healthy female presented
with a history of fever with chills and rigors for 2 d. A
*Author for correspondence.
Transactions of the Royal Society of Tropical Medicine and Hy-
giene, 83,490.
Lusty, T. & Diskett, P. (1984). Anthropometric measurements
and screening. In: Selective Feeding Programmes. Oxfam Prac-
tical Health Guide No. 1. Oxford: Oxfam Print Unit, pp. 7-
13.
Nevill, C. G. (1990). Malaria in sub-Saharan Africa. Social
Science and Medicine, 31,667-669.
Sapak, I’., Garner, I’., Baea, M., Narara, A., Heywood, P. &
Alpers, M. P. (1991). Ineffectiveness of arnodiaquine against
Plasmodium falciparum in an endemic malarious area of Pauua
New Guinea.Jo&nal of Tropical Pediatrics, 37, l-6. -
Trenholme, K. R., Kum, D. E., Raiko, A. K., Gibson, N.,
Narara, A. & Alpers, M. P. (1993). Resistance of Plasmodium
falciparum to amodiaquine in Papua New Guinea. Transactions
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of the Royal Society of Tropical Medicine and Hygiene, 87,464-
466.
Warsame, M., Wernsdorfer, W., Erikson, 0. & Bjorkman, A.
(1990). Isolated malaria outbreak in Somalia: role of chloro-
quine resistant Plasmodiumfalciparum demonstrated in Balcad
epidemic. Journal of Tropical Medicine and Hygiene, 93, 284-
289.
WHO (1984). Advances in Malaria Chemotherapy. Geneva:
World Health Organization, Technical Report Series, no.
711.
WHO (1990). Practical ChemotheraD of Malaria. Geneva:
World Health Organization, Technical Report Series, no.
805.
Received I February 1995; revised 21 June 1995; accepted
for publication 22June 1995
peripheral blood film revealed P. vivax (424O/pL of
blood) The patient was treated with chloroquine, 25
mg/kg over 3 d (10, 10, and 5 mg/kg on days 1, 2 and 3
respectively); the patient was observed for at least 30 min
after each dose (WHO, 1967). Following completion of
chloroquine therapy, blood was collected for a repeat
peripheral blood film and determination of chloroquine
levels in the plasma by high performance liquid chroma-
tography (HOLMBERG, 1980); the levels were within the
therapeutic range (598 pg/L) (MURPHY et al., 1993) on
day 3 but the blood film continued to show P. vivax
(144O/~L of blood). Treatment was then initiated with
sulfadoxine-pyrimethamine (500 mg+25 mg, 3 tablets
given together). The parasite count in the peripheral
blood film after this treatment was 88O/pL. At this stage,
quinine (600 mg 3 times daily) with doxycycline (100 mg
once a day) was given for 7 d. The blood films then be-
came negative and remained so on days 7 and 14 after
quinine therapy. The patient is still under observation.
Case no. 2
A 4 years old female child was brought to the Clinical
Pharmacology Unit when she remained febrile after hav-
ing received-both chloroquine (25 mg/kg) and sulfadox-
ine-pyrimethamine (1 tablet) from malaria field workers
of the Municipal Corporation of Greater Bombay. The
patient was diagnosed by blood film examination as
being infected with P. vivax (752O/uL of blood). She
was treated with supervised chloroquine (25 mg/kg) as
described above. On day 3 following this therapy, her
blood film was oositive with a narasite count of 16OO/uL
and the plasma-chloroquine level was in the therapeutic
range (240 pg/L). Since the patient had already received
sulfadoxine-nvrimetharnine. and not resoonded, and
hospital admission was refused, supervised single dose
mefloauine (15 ma/kc Lariam@ Roche) was given. The
patient became afGb&e and her blood’films were nega-
tive on days 7, 14 and 28 after therapy. The patient is
still under observation.

Discussion
Although multiresistant P. ful&zrum is an increasing
problem, reports of P. vivax resistant to chloroquine
have been few. The above case reports document the
presence of chloroquine-resistant P. vivnx in India, and
show that it may not be as rare as it is presumed to be.
Also, the number of drug resistant strains is probably in-
creasing. Antimalarial drugs other than chloro uine used
for P. vivux have limitations of their own: su?fadoxine-
pyrimethamine is not as effective as chloroquine, quinine
1s difficult to administer, and tetracyclines are contra-
indicated in children and pregnant women and are not
tolerated by many patients. Non-availability and cost
limits the use of mefloquine and halofantrine.
Further population-based epidemiological studies will
be needed to define the extent of chloroquine resistant
P. vivux and identify suitable alternative treatments. If
this problem were to becomewidespread, there would be
significant implications for the treatment and prophy-
laxis of malaria in India.
Acknowledgements
We thank the Dean, Dr P. M. Pai, for permission and sup-
port to carry out these studies. We acknowledge Dr Alka Ka-
rande, Executive Health Officer, and the Public Health
Department of the Municipal Corporation of Greater Bombay
for help rendered and we especially thank malaria inspector Mr
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL. MEDICINE AND HYGIENE (1995) 89,657-658
-1
Activity in vitro of chloroquine,
cycloguanil, and mefloquine against
African isolates of Plasmodium
falciparum: presumptive evidence for
chemoprophylactic efficacy in Central
and West Africa
Leonardo K. Bascol’, Pascal Ringwald**‘, Rasoka
Thor*. lean-Claude Do14 and lacaues Le Bras’
KZentr~ i?lationul de RifkrenEe de la -Chi&osensibilid du
Puludisme, Laboratoire de Purusitologie, H6pitul Bichut-
Claude Bernard, 75877 Paris, France; Vnstitut de
MLdecine Tropicule du Service de SunJ des Armies, Part
du Phuro, Marseille, France
Keywords: malaria,Plasmodiumfalciparum, chloroquine, cyclo-
guanil, mefloquine,activity in v&o, CentralandWest Africa
Antimalarial chemoprophylaxis is one of the important
means to protect nommmune travellers visiting malaria
endemic areas. At present, there is no consen& on the
prophylactic regimens, especially for West and Central
Africa, where chloroquine resistance is present but is
nenerallv of low level (tvne RI and RII). The World
health i)rganization (WKO) and the Am&ican Centers
for Disease Control recommend mefloquine for most of
sub-Saharan Africa (CDC, 1990; WHO, 1995). Euro-
pean experts generally recommend either mefloquine or
chloro uine lus propanil, on a case-to-casebasis, for
Centra 7 and -6 est Africa (BRADLEY & WARHURST, 1995;
CSHP, 1995). For East Africa, it is generally agreed that
mefloquine is the drug of choice. Whether chloroquine
plus proguanil or mefloquine should be prescribed for
Central and West Africa is still debated, largely because
*Author for correspondence.
**Present address: ORSTOMIOCEAC, B. P. 288, YaoundC, Cam-
eroon .
657
S. Pawar for his untiring efforts in follow-up and MS A. Ghoti-
kar for blood film examination.
References
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tion of chloroquine and its metabolite desethyl chloroquine
in human plasma and urine by high performance liquid
chromatography.Jourl of Chromatography,221,119-127.
Muruhv, G. S.. Pumomo. H. B.. Andersen. E. M.. Banes.M.
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(1993). Vi&x malaria >esi&ant to treatment and prophylaxis
with chloroauine. Lancet. 341.96100.
Potkar, C. N., i(athuria, R. h Kshrisagar, N. A. (1995). Resur-
gence of malaria and drug resistance in P. fukiparum and P.
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vivax species in Bombay. Journal of Associationof Physicians
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Roy, R. G., Chakrapani, K. P., Dhinagaran, D., Sitaraman, N.
-L. & Ghosh, RI B. (1977): Efficacy of Kay radical &eat-
ment of P. vivax infection in Tamil Nadu. IndianJournal of
MedicalResearch, 65,652-i%.
WHO (1967). Chemotherapyof Malaria. Report of a WHO Scien-
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Report Series, no. 375.
Received 30 May 1995; revised 28 June 1995; accepted for
publication 28June 1995
no randomized, prospective study on the effectiveness of
these 2 regimens has been conducted.
Previous studies have been based on retrospective
questionnaires distributed to returning travellers or
PeaceCorps volunteers (LOBEL et al., 1%3; STEFFEN et
al.. 19931.These investieators have concluded that me-
floquine is well tolerated&d more effective than chloro-
quine plus proguanil for chemoprophylaxis in travellers
visiting Africa. However, the design of these studies can-
not lead to firm conclusions due to the subjective answers
of the tourists to questionnaires concerning compliance,
tolerance, and effectiveness and the statistical bias in-
volving a significantly smaller sample size for the chloro-
quine-proguanil group.
Another indirect approach to evaluate the efficacy of
antimalarial drugs is the determination of their activity in
vitro against fresh clinical isolates of Plasmodium fulcipa-
rum. Between 1992 and 1994, we have analysed the drug
sensitivity patterns of more than 300 isolates obtained
from malaria-infected travellers returning to France from
sub-saharan Africa, mostly from the francophone coun-
tries in central and western parts of the continent. The
activity in vitro of chloroquine, cycloguanil (biologically
active metabolite of proguanil), and mefloquine was
determined using the isotopic semi-microtest (BASCO et
al., 1994). Based on previous in vitro/in vivo correlation
studies (LE BRAS & RINGWALD, 1990), the threshold
50% inhibitory concentration (I&)) value for resistance
to chloroquine was set at 100 no. The threshold vahte
for cycloguanil resistance was fixed at 50 nM (BASCO et
al., 1994). Most malaria-infected patients receiving cor-
rect chloroquine-proguanil prophjrlaxis provide isolates
with cvcloguanil ICso values above this threshold value.
The &t-off value for mefloquine resistance was esti-
mated to be >30 IBM,basedon the analysis of drug sensi-
Table. Proportion of drug-resistant Plasmohm fdcipanun
isolates from sub-Saharan Africa between 1992and 1994
Resistanceto Central Africa West Africa
Chloroquine and cycloguanil 32/143 (22%)