ABROAD

Mefloquine Compared with Doxycycline for the Prophylaxis of

Malaria in Indonesian Soldiers
A Randomized, Double-Blind, Placebo-Controlled Trial
Colin Ohrt- MD; Thomas L. Richie, MD, PhD; Hendra Wldjaja. MD; G. Dcntiis Sh;mks, MD;
Januar Fitriadi, MD; David J. Fryauff, ScD; Jrg Handschin. PhD; Douglas Tang. PhD;
Bernardus Sandjaja, MD; Emiliana Tjitra. MD. MSc; Lukas Hadiarso, MD;
George Watt. MD, DTM&H; and F. Stephen Wignall. MD

Background: Mefloquine and doxycycline are the two

drugs recommended for prophylaxis of malaria for visitors
to areas where Plasmodium falciparum is resistant to chloroquine.
Objective: To compare the efficacy and tolerability of
mefloquine with those of doxycycline as prophylaxis for
malaria.
Design: Randomized, double-blind, placebo-controlled
field trial of chemoprophylaxis of malaria.
Setting: Northeastern Irian Jaya, Indonesia.
Participants: 204 Indonesian soldiers.
Intervention: After radical curative treatment, participants were randomly assigned to receive 100 mg of doxycycline per day and mefloquine placebo; 250 mg of mefloquine per week (preceded by a ioading dose of 250 mg/d
for 3 days) and doxycycline placebo; or placebos for both
drugs. Prophylaxis lasted approximately 13 weeks.
Measurements: The primary end point for efficacy was
the first occurrence of malaria, as documented by a positive malaria smear. Malaria smears were obtained weekly
and when patients had symptoms suggesting malaria. Reported symptoms were recorded daily, and an exit study
questionnaire was conducted.
Results: In the placebo group, 53 of 69 soldiers developed malaria (9.1 person-years), resulting in an attack rate
of 5.8 cases per person-year (95% CI, 4.3 to 7.7 cases per
person-year). Plasmodium falciparum accounted for 57%
of cases, and P. vivax accounted for 43% of cases. No
malaria occurred in the 68 soldiers (16.9 person-years) in
the mefloquine group; thus, the protective efficacy of
mefloquine was 100% (CI, 96% to 100%). In the doxycycline group, P. falciparum malaria occurred in 1 of 67
soldiers (16.0 person-years), yielding a protective efficacy
of 99% (CI, 94% to 100%). Both drugs were very well
tolerated.
Conclusions: Mefloquine and doxycycline were both
highly efficacious and well tolerated as prophylaxis of
malaria in Indonesian soldiers.

Ann Iiileri! Med 1997; 126:963-972.

For author affiliations and current author addresses, see end ol

alaria is a serious health risk for nonimmune

visitors to areas where malaria IVct|uently occurs ( i - 4 ) . The World Health Organization, the
U.S. Centers for Disease Control and Prevention.
the Committee to Advise on Tropical Medicine and
Travel, and the Guideline for I'ruvcicrs from Britain
all recommend meHoquine as the drug of choice for
prophylaxis of malaria in areas where Plasmodiiuu
Jiilcipaniiii is resistant to chloroquinc; doxycycline is
recommended in areas where P. fuldpuriiiu is resistant to mefloquine (5-8). The U.S. Food and Drug
Administration approved mefloquine (250 mg/\vk)
for malaria prophylaxis in 1989 and approved doxycycline (100 mg/d) for this indication in 1994 (9).
Only two studies have compared nictloquine with
doxyeyciine. A trial in Thailand (10) involved little
exposure to malaria and no placcho control, and a
recent trial in Africa (11) showed a relatively low
effieaey for each drug. Few blinded or plaeebo-controlled trials have assessed the tolerahility of lliese
drugs. Because mefloquine and doxycycline are the
agents currently recommended lor prophylaxis of
malaria, we helieved that a well-designed and carefully conducted direct comparison of the efiicacy
and tolerability of these two compounds was necessary. Distinguishing features of om' trial include I)
intense exposure to malaria; 2) nonimmune study
participants; 3) a double-hlind, plaeebo-controlled
design to permit unbiased assessment of tolerahility;
4) use of a loading dose of mefloquine; and 5)
careful monitoring of eompHance.

Methods
Study Site and Participants
This trial was eondueted from May to July 1994
in northeastern Irian Jaya, Indonesia, a lowland,
partially cleared forest area 50 km south and east of
the provincial capital, Jayapura. In this area, P. falcipanim is resistant to suifadoxine-pyrimethamine

15 June 1997 Annals of Imernul Medicine VOIUIUL- !2(I Ninnbcr 12

963

and both P. falcipani/n and P. vivax are resistant to

chloroquine (12-15). Appro.xiniately 330 soldiers
were deployed to 18 military posts; a typical post
consisted of 15 soldiers and wa.s located at a road
check point or in a local communily.
Two hundred four soldiers who met all entrance
criteria and agreed to participate were randomly assigned to one of three groups. The 14(1 soldiers
from Ambon, Indonesia, had recently arrived (before study enrollment) and had reeeived one dose
of sulfadoxine-pyrimetliamine; the 64 soldiers from
Sumatra, Indonesia, had received weekly doses of sulfadoxine-pyrimethamine in Irian Jaya for 3 months.
Before study prophylaxis began, all soldiers were
given daily prophylaxis with doxycycline tablets for 4
to 6 weeks to allow clearance of sulfadoxine and
pyrimethamine from their blood.
Our study was conducted in accordance with U.S.
Army, U.S. Navy., and Republic of Indonesia regulations governing the protection of human participants.
All volunteers gave written. nf(.)rmed consent.

Phzer Indonesia. Two investigators randomly assigned the participants to study groups and packaged the drugs; the randomization COLIC was stored
in individual envelopes in a locked box at the study
site. All investigators and study personnel did not
have access to or know the randomization code
throughout the study. Block randomization was
used (block size, 15); participants were allocated in
equal numbers to the melloquine, doxycyciine, and
placebo groups. Drugs were packaged into weekly
zipper-lock plastic bags; each bag contained a meIloquine or meHoquine placebo tablet and a blister
pack of seven doxycycline or doxycycline placebo
capsules (double-dummy technique). During the
radieal cure, individual soldiers were assigned consecutive study drug numbers by military post and
drug packages were labeled with each soldier's
name, age, rank, post, and signature to ensure correct identification of the participant.

Prestudy Evaluation and Radical Curative

Treatment
All soldiers from military posts that were considered to have high malaria attack rates and that were
within the study area were asked to participate.
Before enrollment, volunteers had a medieal histoiy
taken and underwent physical examination and laboratory testing. Initial laboratory testing consisted o
a complete blood eount (13C CBC. Beeton Dickinson, Mountainview, California) and assessment of
glucose-6-phospliate dehydrogenase (G-6-PD) activity
(G-(>PD spot test, Sigma, St. Louis., Missouri). Participants who had a history of frequent travel, chronic
illness, allergy to one of the study drugs, or G-6-PD
delieiency were excluded from participation. Before
the study began, all participants received radical
curative treatment to clear preexisting malaria parasites from the blood and liver. Treatment consisted
of quinine sulfate (-) to 11 mg/kg of body weight
three times a day for 4 days; Danbury Pharmaceuticals), doxycyeline (101) mg twice a day tor !() days;
Pfizer Indonesia, Jakarta, Indonesia), and primaquine {30-mg base/d for 14 days; Sanofi Winthrop,
New York, New York).

The radieal curative treatment and start of study

therapy were staggered according to military post
over a 4-week period. Therapy with the study drugs
was initiated after the last dose of primaquine in the
radieal curative treatment regimen was reeeived.
Participants received 100 mg of doxycycline per day
and mefloquine placebo; 250 mg of mefloquine per
week (after a loading dose of 250 mg per day for 3
days) and doxycycline placebo; or placebos for both
drugs. A study employee visited each post every
morning. This employee identified each soldier by
name and signature, opened his packet ol" the study
drug, and watched him swallow the pill or pills and
drink water. Both the participant and the employee
signed the daily record form. Each day, this I'orm
was returned to a supervisor at the main office lor
confirmation o the soldier's and worker's signatures. All participants were eneom'aged to eat at the
lime of drug administration.
The study employee searched for any soldier who
was not present at the time of the employee's visit.
If the participant was not found, the drug packet
and a special lorni were left with the soldier's supervisor, who would later witness the drug administration. The same speeial form was used for soldiers who had planned to travel during the study
period. For unantieipated travel, soldiers were given
a standby packet of the study drug and a signature
form, were told to store these items In their travel
pack, and were instructed to provide double-signature doeumentation. Approximately eveiy week, a
supervisor and the investigators made unseheduled
visits to the posts to identity problems. For any
participant who developed malaria, records of previous drug administration were reviewed; these par-

Drug Supply, Randomization, and Packaging

Melloquine hydrochloride in 2..'iO-mg tablets that
contained a 228-mg base was provided by Hollman-La Roche in Nutley, New Jersey, Placebo tablets that were identical in appearance to the mefloquine tablets were provided by Hotfman-La Roche
in Basel, Switzerland. Doxycyciine in lOO-mg capsules and placebo capsules that were identical in
appearance but not in content to the doxycycline
capsules were provided in weekly blister packs by
9f>4

15 .Uinc

Study Initiation, Drug Dosage, and

Documentation of Compliance

Annals of Intcrniil Medicine Vokinic I2i) Niimbci 12

ticipants were carefully questioned about missed

drug doses. In situations where a doxycyciinc or
doxycycline placebo capsule was missed, two capsules were taken on the following day. If a mefloquine or mefloquine placebo tablet was missed, the
tablet was taken the following day.
End Points
The primary end point for efficacy was the first
oecurrence of malaria, as documented by a positive
malaria smear. Giemsa-stained thick and thin malaria smears were obtained weekly and when the
participants had any of the following symptoms t)f
malaria: headache, fever, chills, nausea, or vomiting.
Smears were examined by oil immersion microscopy
{magnification, XIOOO) and were considered negative if no asexual parasites were found in 200 ocular
fields of the thick film. If the initial smear was
positive, the participant was promptly visited by a
physician; a second malaria smear was obtained;
and blood was drawn for malaria culture, complete
blood eount, and measurement of drug levels. Participants with P. falcipanim malaria were treated
with quinine (9 to 11 mg/kg) three times per day for
4 days and with doxycyeline (100 mg) twice per day
for 10 days; participants with P. vivax malaria received chloroquine (600-mg base followed by 3(KI-mg
base 6 hours later and at 24 and 48 hours). After
treatment for malaria, participants were offered prophylaxis with doxycyeline {in tablet form rather than
capsules).
Later, all positive smears and a sample of negative smears were read by a senior technician who
was blinded to the initial smear result. Differences
in interpi'etation of the smears were resolved by a
third blinded reading. The randomization code was
broken after all slide diagnoses had been confirmed
and all data had been entered and checked.
Assessment of Study Drug Tolerability
Tolerability of Ihe study drugs was assessed in
five ways. In the firsl assessment, we directly compared the proportion of participants in the doxycycline and mefioquine groups who ever reported a
given symptom at any time during ihe study {participants were asked daily if they had had any symptoms). Data obtained on the first day of the study
(before the dose of the study drug) and during the
last week of the study {to eliminate symptoms of
malaria) were excluded trom the daily reporting of
symptoms in all ihree groups. In the second assessment, we compared the frequency of symptoms between the iwo drug groups and between each drug
group and tlie placebo group (background rate) by
using incidence density ratios or relative risk. This
approach corrected for unequal person-days of observation among the groups.

in the third assessment, we compared the proportions of participants who had a symptom during
the first week of the study, when nearly equal numbers of participants were present in all three groups
and when the risk for intolerability of the study
drugs was believed to be highest (during and after
the administration of the mefloquine loading dose).
The fourth assessment, an exit questionnaire, was
performed by one investigator during the last month
of the study to specifically ask about known or
suspected intoicrability to the study drugs. Only
data from persons who were still receiving the study
drug at the time of questioning were included. Participants were asked whether they felt healthier after participating in the study; which symptoms they
thought were related to the study drug; whether
they had dizziness, nausea, diarrhea, dilieulty sleeping, and dreams; and whether they had regularly
taken the drug with water and food. In the fifth
assessment, participants who required discontinuation of study therapy or dose adjustment because of
possible side effects were deseribed in detail.
Statistical Analysis
Incidence rates {incidence density) for all cases
of malaria and for cases of malaria caused by either
P. falcipaniin or P. vivax were calculated for each
group as the number of cases of malaria divided by
total person-years of follow-up. Each soldier's person-time was included until the soldier left the
study. Cumulative risk was calculated as the number
of cases divided by the number of participants beginning study prophylaxis. Participants who did not
complete the radical cure were excluded from the
analysis. In the efficacy analyses, a mixed infection
was considered to have been caused by /*. falcipunini. Protective efficacy was defined as the percentage reduction in the occurrence of malaria and was
calculated as (1 - the relalive risk) x 100. where
the relative risk was denned as the ratio (drug:
placebo) of either incidence rates or cumulative
risks. Koopman method was used to obtain CIs for
the ratio of two proportions (16) to calculate CIs
for protective efficacy based on relative risk. Exact
CIs for incidence density rates {cases/person-time)
were based on the Poisson distribution. The exact
conditional distribution (binomial distribution) was
used to calculate CIs for protective efficacy on the
basis of the incidence density ratio (17). For the placebo group, the Kaplan-Meier pnxluct-llmit method was used to estimate the cumulative probability
of remaining free of malaria during follow-up for all
cases of malaria combined and for cases of malaria
caused by either P. falcipariim or P. vhuy (at the
time when one type of malaria occurred, the other
type was considered censored) (IS). The Fisher exact test was used to compare proportions ol' spon-

t5 June 19'>7 Annals of mental Medicine Volume t26 Number 11

965

taneously reported symptoms. Unpaired Mests were

used to compare mean values of continuous outcome variables. Unless otherwise noted, all reported
CIs are 95% CIs and all reported P values are
two-sided. Epi Info 6.02 (Centers for Disease Control and Prevention, Atlanta, Georgia) and SPSS 6.1
for Windows {SPSS Inc., Chicago, Illinois) were used
for both data management and standard statistical
analyses.
Role of Funding Sources
Co-investigators from the Tropical Medicine Unit
of F. Hoffmann-La Roehe Ltd. in Basel. Switzerland,
assisted with protocol design, regulatory issues, and
quality assurance. Neither of the pharmaceutical companies tiiat provided support played any role in
gathering, analyzing, or interpreting the data.

Results
Study Participants, Compliance Documentation,
and Follow-up
Three hundred thirty-one soldiers were deployed
to the study area. Of these, 53 (16%) were not
asked to participate because their military post was
in an area of low transmission of malaria organisms,
34 (l.3%) refused to participate or to have blood
drawn, and 40 (12.1%) were excluded from participation for the following reasons: Eleven were
G-6-PD deficient, 6 frequently traveled., 5 had an
underlying illness, 1 was allergic to the study drug,
11 were Intolerant to quinine during radical curative
treatment, and 6 left the area. Of the 331 soldiers,
204 (61%) met all entrance eriteria and were randomly assigned to one of the three study groups (67
to the doxycycline group, 68 to the mefloquine
group, and 69 to the placebo group). Sixteen of the
204 participants (7.8%) did not complete the study.
Five doxycyeline recipients (7.4%) withdrew from
the study (3 because of travel from the area, I
Table 1. Participant Characteristics
Characteristic

Doxycycline
Group
(n = 67)

Mean age SD, y

Mean weighl SD, kg
Mean time betvi/een arrival
in Irian Jaya, Indonesia,
and study entry, d
Splenomegaly, %
Mean hematocrtt SD
History of maiaria, %
Median lifetime episodes of
malaria, n
Median time since most
recent case of malaria, y'

26.0 3.9
59.5 6.5

25.9 4.2
57.9 4.2

25.7 4 . 1
59,0 4,8

62.0
3
0.45 0.03
59

69.0
0
0.45 0.03
61

65.0
1
0.44 0.03
62

Seiare nrnvng in Irian Jaya. lndonei.id

966

Mefloquine
Group
(n = 68)

Placebo
Group
in = 69)

5.0

4.8

3.8

because of noncomplianee with the study protocol,

and I because of a false-positive malaria smear with
concurrent illness); 7 mefloquine recipients (10.3%)
withdrew (4 because of travel from the area, 2 because
of noncompliance with study protocol, and I because
of eoncurrent illness); and 4 recipients of both placebos (5.8%) withdrew (3 because of travel from
the area and 1 beeause of a false-positive malaria
smear).
The partieipants' baseline characteristics and history of malaria are summarized in Table 1. The
groups were well balanced with regard to baseline
variables and possible risk factors. Troops from Sumatra had baseline malaria smear evaluations while
receiving prophylaxis with sulfadoxine-pyrimethamine: Five percent of these soldiers (3 of 64) were
positive for P. faldparum and 30%- (19 of 64) were
positive for P. vivax; most were asymptomatic. The
140 men in the battalion from Ambon had been
receiving prophylaxis with doxycycline for 10 days
before we were given permission to collect baseline
smears; none of these participants was positive for
either organism.
Signature documentation of the 15 221 doses of
the study drug was as follows: member of research
team plus participant, 95.5% (14 542 doses): participant plus other witness (usually the post supeiTisor), 2.7%. (416 doses); participant only, 1.3% (203
doses); no dose taken, 0.3% (48 do.ses); and no documentation, 0.1% (12 doses). No signilicant dilerenees were seen in numbers of witnessed or missed
doses between the study groups (data not shown).
Initially enrolled participants who did not develop malaria or who dropped out of the study were
followed for a mean of 13.5 weeks (range, 12.7 to
14.6 weeks). An additional seven participants who
were stationed at a post that enrolled late and who
did not develop malaria were followed for a mean
of 9.4 weeks.
Protective Efficacy
Table 2 shows the attack rate (per person-year)
and protective efficacies of mefloquine and doxycycline relative to placebo. In the placebo group, 53
(77%) of the partieipants developed malaria (9.1
person-years), resulting in an attack rate of 5.8 cases
per person-year (95% CI, 4.3 to 7.7 cases per person-year). Of these eases, 57% were caused by P. falcipanim and 44%. were eaused by P. vivax. One
mixed infection occurred; this infection was considered to have been eaused by P. faldparum. In the
placebo group, the first cases of P. faldparum and
P. I'/Vav malaria occurred 13 and 11 days, respectively, after the last dose of priniaquine (Figure).
No eases of malaria developed in the mefloquine
group (16.9 person-years). On the basis of the reduction in incidence density, this yields protective

t5 June t997 Annals of Internal Medicine Volume 126 Number 12

Table 2.
study
Group

Efficacy of Prophylaxis for All Cases of Malaria

Participants

Plasmodium Species
Causing Malaria

Ca5es of
Malaria

Follow-up

Incidence
Density

personyears

cases/
personyear

16.9
16.9
16.9
16,0
16.0
16,0
9.1
9.1
9.1

0.00
0.00
0.00
0.063
0.00
0.063
3.30
2.53
5.82

Mefloquine

68

Doxycycline

67

Placebo

69

Plasmodium falciparum
P. vivax
Ail species
P. falciparum
P. vivax
All species
P. falciparum
P. vivax
All species

0
0

1
0
1
30
23
53

Protective Eflicaty
Calculated as
Reduction in
Cumulative Risk
(95% CI)

Protective Efficacy
Calculated as
Reduction in
Incidence Density
(95% CD
'o

100(87-100)
100(83-100)
100(93-100)
96.5(81-100)
100(83-100)

100(93-100)
100(91-100)
100(96-100)
98(88-100)
100(90-100)
99(94-100)
-

98,0(89-100)
-

Cumulative risk and CIs unchanged if risk is based on Ihe number of participants completing study.

efficacies of 100% (CI, 96% to 100%) for aU cases

of malaria, 100% {CI, 93% to 100%) for cases
caused by F. fakipamm. and 100% (CI, 91% to
100%) for cases caused by F. vivux. One case of
malaria occurred in the doxycycline group (16.0 person-years), yielding protective efficacies of 99% (CI,
94% to 100%) for all cases of malaria, 98% (CI, 88%
to 100%) for cases caused by F. facipamnu and 100%
(CI, 90% to 100%) for cases caused hy F vivax.

doxycycline and mefloquine groups who had reported a symptom at any time during the study
(Table 3, columns ! and 2). Unlike the placebo
group, the doxycycline and mefloquine groups had a
similar number of participants throughout the surveillance period; Ihis minimized the bias introduced
by differences in observation time. We found that
significantly fewer soldiers in the doxycycline group
reported any gastrointestinal symptoms, anorexia, any
neurologic symptoms, dizziness, headache, and subjective fever than did soldiers in the niefioquine group.
Cough was reported by more participants in the doxycycline group. Table 3 lists 20 symptom categories:

Study Drug Tolerability and Laboratory Data

In the first assessment of tolerability, we directly
compared the proportion of participants in the
100

-^
_^
CO

80

O
CD
CD
^_
LL

60

40
All

.9CO
_

20

P falciparum malaria
P. vivax malaria

10

11

12

13

14

15

Time, wk
Figure. Kaplan-Meier plot (survival curve) of estimated cumulative probability of remaining free of malaria in 69 placebo recipients. Plots
are for all cases of malaria (53 cases), cases of malaria caused by Plasmodium falciparum (30 cases), and cases of malaiia caused by P. vivax {23 cases). The
species-specific curves consider the other species as censored (removed) at the time of occurrence ot malaria The mefloquine and doxycycline groups were
excluded from this plot for clarity. Short vertical bars represent the four participants who dropped out of the study: numbers in parentheses are the numbers
of participants at risk.

15 June 1997 Anmds of Inlcnud Medicine Voltmic 126 Nuiiil-icr I,

967

Table 3.

Spontaneously Reported Symptoms

Symptom

Doxycycline
Group
(n - 67)*

Mdioquine
Group
(n = 68)*

Reiative Riskt
Doxyeyciine Compared
with Mefloquine

Doxycycline Compared
with Piacebo

Mefloquine Compared
with Piacebo

n
All gastrointestinal symptoms
Nausea
Vomiting
Abdominal pain
Diarrhea
Constipation
Anorexia
Ali neurologic symptoms
insomnia
Somnolence
Dreams
Dizziness
Headache
Palpitations
Sexual dysfunction
Other symptoms
Fever
Malaise
Skin-related
Cough
Ali symptoms

16*
3
1
8
4
1
4t
22*
4
1
1
6

29*
8
2
13
7
2
14*
34*
8
2

n
1

1
5*

7
22
21*
58

0.78
0.39

25
2
3

0.83
0,28*
0,52
0.98
0.69
0,52
1.15
0,2911
0.41
0.52
1.03
0.23I
0.2911
0.34
0.26

14*
14
22
11*
58

0.3
0,52
1.58*
3.3711
0.81

1
18

0.94
1,38

0,85
1.56
0.26
0,76
0,2511
0.1611
0.09
0.52
0,33*
0.31

0.87
2.26
0,50
0.66
0,87
0,39*
0.17*
0.50
1.42
1.05

0.10*

0.40

0,35
0,94
1,29
1.24
0.6411

1.17
1.81
0.81
0.3711
0.791

' SlatiSliCi romiiririsons beiwei?n the number ol participanls m liie dtjxycycline iroup and the number ol partit.ipanls in ihe metloquine group only (coluinris 1 and 2, Fisher exact test)
The placebo group wds excluded because of shorter (ollow-jp. P values not corrected lor multiple comparFSOiis,
1 Relative nsk wd$ used to compaie aaivB drugs with placebo because of shorter follow-up in the placebo group. Relative risk was calculated as incidence density ratios [(number ol
symptoms/total person-yea rs|/I number of symptoms/total person-yea rs|) In column 3, a relative risk less than 1 represent better tolerability of doxycycline compared with medoquine.
in columns 4 and 5, a relative risk less than 1 represents better tolerability of doxycycline and mefloquine relative to placebo.
* P < ; 0.05
& P < 0.01
UP< 0.001

Fewer doxycycline recipients ihyn mefloquine recipients had symptoms in 16 categories; ihe same number
of parlicipants n holh groups had symptoms in 3
categories; and more do?^cyeline recipients than mefloquine recipients had symptoms in 1 categoiy.
In the second assessment, we compared the frequency of symptoms between the two drug groups
and between each drug group and the placebo
group (background rate) by using incidence density
ratios or relative risk (Table 3, la.st 3 columns). By
using this method to determine the total number of
reported symptoms, we noted that both doxycycline
and meoquinc were significantly better tolerated than
placebo {P < (l.OI and P= .J5, respectively) and
that doxycycline was better tolerated than mefloquine {P = 0.006). No symptom occurred significantly more frequently in either the doxycycline or
melloquine group than in the plaeebo group.
During the first week of the study, a symptom
was spontaneously reported by 69 (M%) participants: 30'.'^ of those reeeiving doxycycline (20 of 66;
P > 0.2 [relative to placebo]), 37% of those reeeiving mefloquine (25 of 68; P> 0.2). and 35% of
those receiving plaeebo (24 of 68). Gastrointestinal
symptoms were reported by 22 (11%) participants
during the Hrst week of the study: 9.1% {P> 0.2
[relative to plaeebo]) of the doxycycline group,
16.2% {P = 0.09) of the mefloquine group, and
7.4% of the placebo group. No statistically signifi968

cant differences were seen in the first week for any

symptom, including neurologic symptom.
An exit quesiionnaire was conducted during the
last month of the study. The only statistically significant finding was that more doxyeyciine recipients
noted nausea if they did not take the drug with
food: Twenty-two (35%) doxycycline recipients compared with 9 (14%) mefloquine recipients {P =
0.003) and 2 (11%) placebo recipients {P = 0.03)
noted this symptoms.
Two soldiers were removed from the study because of illness: one (a doxycycline recipient) because of a serious neurologie event (acute hysteria)
and a false-positive malaria smear and the other (a
mefioquine recipient) because of a febrile illness of
uncertain origin. An additional mefloquine reeipient
who had a histoiy of head trauma and strabismus
refused to take the drug for several days because of
headaehes and an increase in visual ditfieulty. At the
time of evaluation, his symptoms were considered to
be unrelated to the study drug. When his symptoms
resolved, therapy with the study drug was resumed,
and he successfully eonipleted the study. No participant was withdrawn from the study because of intolerance to the study drugs or adverse effects thai
.seemed to be related to the study drugs.
Complete blood counts obtained before and after
the study revealed a signifieant increase in hematoerit
in the doxycycline group (increase. 0.0147) when com-

15 .lunc I'W7 Annuls of Inwrnai Medieine Volumu 126 Number 12

pared with changes in hematocrit in the mefloquine

group (deerease, O.()()5(}; P = 0.005) and the plaeeho
group (decrease, 0.0055; P = 0.002). The total Icukoeyte eount, the ditt'erential, and the platelet eount
did not ehange significantly in any study group.

D5cu5sion
This randomized, double-blind, placebo-controlled
comparison of melloquine and doxycyeline showed
that both agents were hlglily etticacious as prophyliLxis
for chloroquine-resistant P. j'ccipanin and P. vivax
malaria in a largely nonimmune population. Only one
case of malaria oeciu'red in the doxyeycliiie group, and
no cases occurred in the meoquine group. However,
in the placebo group, malaria developed in more than
50% of the participants during the first 6 weeks of the
study and had developed in 11% by the end of the
study. These results yield high protective efficacies with
narrow 95% CIs. Our study also confirms that both
drugs are very well tolerated.
Effieaey in this trial was as good as or better than
efficacy in previous trials that evaluated mefloquine
or doxycyciine. Initial field trials of prophylaxis with
meoquine in semi-immune Thai villagers in 1977
showed that weekly (ISO or 360 mg) and cvcryother-week (360 mg) regimens had high effieaey
(19). Since 1977, six studies have been performed
near the border areas of Thailand; these studies
used weekly melloquine or mefloquine-sulfadoxinepyrimethamine (20-25). All but one of these studies
showed 70% to 90%' proteetive efficacy or effectiveness (efficacy refers to monitored compliance; effectiveness refers to unmonitored compliance) against
P. falciparum malaria. Lobel and colleagues (26)
found that weekly mefloquine had an effeetiveness
of 94% (Cl, 86% to 97%; calculated as the percentage reduetion in incidence density) compared with
chloroquine in Peace Corps volunteers working in
sub-Saharan Africa. In a large cohort study of travelers returning from East Africa, Steffen and colleagues (27) found that the prophylactic effectiveness of mefloquine was 91% (CI, 85% to 94%;
calculated as the percentage reduction in incidence
density).
Four controlled field trials evaluated the prophylactic efficacy or effectiveness of doxycycline in Thailand from 1985 to 1988. In 1985-1986^ Pang and coworkers (28) showed that investigator-witnessed daily
administration of doxycycline (at a dose equivalent
to the 100-mg adult dose) eompared with chioroquine yielded a proteetive efficacy of 87% (CI, 66%
to 9(-)%\ calculated as the percentage reduction in
incidence density) for /'. falcipafiiin malaria in semiimmune adolescent children. In a follow-up placebocontrolled trial in the same study sample (29), doxy-

cycline (100-mg adult equivalent dose) provided

proteetive elficacics of 89% (CI, 5 1 % to 96%) for
P falciparum malaria and 96%.' (CI, S5%. to 98%;
calculated as the percentage reduction in incidence
density) for P. VIVCLK malaria. In 1986-1987, a doubleblind, placebo-controlled cohort study of Thai soldiers (30) found thai 100 mg of doxycycline per day
provided protective efficacies of 98% (CI, 92% to
99%) for P. falciparum malaria and 81%^ (CI. - 1 2 %
to 98%.'; calculated as the percentage reduction in
incidence density) for P. vivax malaria. In 198719SS. a follow-up randomized trial of effectiveness
(73%' compliance with doxycycline) in Thai soldiers
(31) showed a protective effeetiveness of 64% (Cl,
36%. to 79%) for P. fakiparum malaria and 64%
(CI. 44% to 76%; calculated as the perecntagc reduction in cumulative risk) for P. vivax malaria, relative to pyrimethamine-dapsone.
In addition, the effieaey of doxycycline has been
assessed in two studies done in East Africa. A randomized, piacebo-conlrollcd clinical trial performed in
semi-immune adolescent Kenyan children (II) found
protective efficacies of 77% (CI, 55% to 88%) with
mefloquine and 84% (CI, 66% to 92%; calculated
as the percentage reduetion in incidenee density)
with doxyeyeline. In a recent double-blind, placebocontrolled trial comparing azithromycin wilh doxycyeline in semi-immune Kenyan adults, the proteetive efficacy of doxyeyeline was 93% (CI, 80% to
97%'; calculated as the percentage reduetion in cumulative risk) (Shanks GD. Personal communication).
Our report is a new contribution to the literature
on the efficacy of doxycycline and mefloquine beeause our trial directly compared these di'ugs and
showed that high efficacy is achievable. The high
effieaey that we obsewed probably reflects that our
participants were motivated to take prophylaxis, that
compliance was closely monitored, that a loading
dose of mefloquine was used, and that parasites
were sensitive to the study drugs. In addition, if a
doxycycline dose was missed, two doses were taken
the following day.
The gcneralizability of findings from prophylaxis
trials for malaria prevention is limited by three factors; parasite resistance patterns, imnnmity of study
participants, and problems with compliance. In Irian
Jaya. resistance to antimalaria! drugs seems to be as
great as or greater than the resistance seen in most
malarious aieas in the world. Tn this area, /-*. faiciparum is resistant to sulfadoxine-pyrimethamine
and both /'. falcipamm and 7^. vivax are resistant to
chloroquine (12-15). The high efficacy of mefioquine seen in our study, however, is not generalizable to areas where P. falciparum is highly resistant
to mefloquine (for example, the Thai-Burmese and
Thai-Cambodian border areas) (32-34).
Results of prophylaxis studies in semi-immune

15 June 1997 Annals of internal Medicine Volume 126 Nuinhcr 12

969

persons may not be generalizable to nonimmune

populations. We believe that our sample is best classified as nonimmunc to malaria. Immunity to malaria gradually develops after several exposures, is
incomplete, and is lost after exposure stops (35). A
semi-immune state is rejected by decreased frequency and levels ol parasitemia, as v^el! as by parasitemia in the absence of clinical symptoms. The
baseline characteristics of our participants (Table 1)
suggest little recent exposure to malaria, as shown
by medical histories, infrequency of splenomegaly,
and normal hematocrits. Transmission of malaria organisms is very low in the areas from which the
troops in our study originated (Baird K. Personal communication; Ambon, Indonesian Ministiy of Health.
Personal communication). As shown by their initial
malaria smears, troops from Sumatra (64 of 204 participants) had been exposed to malaria for 3 months
before the study while receiving sulfadoxine-pyrimethamine. We believe that any low-level clinical
immunity present in this subset as a result of brief
exposure to malaria did not influence outcome;
thus, the results of our trial should be generalizable
to travelers who have never had malaria. The fact
that 49 of the 53 placebo recipients who developed
malaria had two or more symptoms typical of malaria at the time of a positive smear during active
case detection supports the classification of these
recipients as nonimmune.
Doxycycline, with its daily dosing requirement,
may be relatively less effective than mefloquine because of problems with compliance. To address this
question, we followed an additional group of soldiers for 13.2 person-years {ii = S3: 36 persons who
did not participate in our study and 47 study participants in whom malaria had been treated). Our
study team diagnosed all cases of malaria and provided all treatment but did not enforce compliance.
Eight cases of malaria occurred (four caused by
F. falcipanim and four eaused by P. vivax); this
yielded a protective effectiveness of 89% (Cl, 78%
to 96%) for all cases of malaria and a protective
eflFectiveness of 89% (CI, 73% to 98%0 for cases
caused by either P. falcipanim or P. vivax. Overall,
participants in this group were more likely to be
exposed to malaria (many had previously developed
malaria while in the placebo group of our study)
and were less likely to be compliant (several did not
wish to participate in the study) than the average
participant. Effectiveness decreased in the group.,
but by less than we had anticipated.
Concern exists about the time required to
achieve adequate mefloquine plasma concentrations
after initiation of weekly prophylaxis (7 weeks) (36,
37). Boudreau and colleagues (36) found that a
3-day mefloquine loading dose was well tolerated in
U.S. soldiers and thai this dose rapidly produced
970

steady-state plasma mefloquine concentrations. Our

trial and a large cohort study of Dutch soldiers
deployed to Cambodia (32, 38) have confirmed that
this regimen is very well tolerated.
None of the studies described above has identified significant problems with the tolerability of
doxycyciinc or mciloquinc. Gastrointestinal intolerance (especially when doxycycline is taken on an
empty stomach), sensitivity to the sun, and vaginitis
are the adverse etfects most commonly associated
with doxycycline (7). Esophageal erosions may be
an underappreciated adverse effect of doxycycline
(39, 40). Gastrointestinal intolerance, dizziness, and
sleep disturbance have been most commonly reported with mefioquine (7, 36). Cases of serious
neuropsychiatrie disorders (seizures, acute psychoses, and neurosis) have been reported in persons
receiving mefioquine (27, 41-43). A randomized,
double-blind field trial directly compared the tolerability of mefioquine and doxycycline in U.S. soldiers deployed to Thailand (10, 44). No differences
in tolerability or gastrointestinal palhogens were
found. Large cohort studies and a recent doubleblind comparison have largely failed to demonstrate
a difference in frequency of adverse effects with
mefioquine and chloroquine (26, 27, 36).
Our trial is the first double-blind, placebo-controlled assessment of mefloquine and doxycycline
tolerability. The five methods of assessment consistently showed that both drugs were veiy well tolerated. We witnessed one serious neuropsychiatrie
event in a doxycycline recipient but doubt that this
event was associated with doxycycline. No participant was removed from the study because of a
possible drug-related side effect. We found the relative risk for neurologic symptoms with mefioquine
to be similar to or less than the risk scon with
placebo in all categories except dizziness (relative
risk, 1.42: P> 0.2). Fewer neurologic, gaslrointestinal, and overall symptoms were reported in the
doxycycline group than in the mefloquine and placebo groups. A possible explanation for this finding
is that doxycycline prevented the occurrence of
other infectious diseases. This explanation is further
supported by the significantly increased hematocrit
in the doxycycline group. In addition, toicrability
was probably improved because we encouraged all
participants to take the study drug with food.
The gencralizabilily of our data on tolerability is
limited by three factors: the study sample (young,
healthy Asian men), the sample size (uncommon
events were not detectable), and the geographic
location (an area where infectious diseases are prevalent). It is possible but unlikely that bias was introduced 1) when soldiers were exposed to quinine
and doxycycline before the study or 2) because of
the nonidentical contents of the doxyeycline study

15 June 1997 Annals of hncrnat Medicine Vokimc 126 Numhcr 12

capsules. In addition, incidence density data are misleading when Ihe frequency of side effects is not
constant with time and the study groups have different durations of follow-up. In our study, the total
number of symptoms plotted by study week was
fairly constant (data not shown). The best way to
draw conclusions from data on tolerability is to seek
consistent findings across methods of assessment.
We included a placebo group to determine the
aetual malaria attack rate. The use of the placebo
group was deemed ethical because soldiers deployed
to Irian Jaya usually receive only sulfadoxine-pyrimethamine or chloroquine prophylaxis for 3 months
and then receive no prophylaxis. We provided 24hour radio support and standby quinine that could
be used to begin treating malaria if symptoms occurred and a microscopic diagnosis was not immediately available.
Our data suggest that both mefloquine and doxycycline, when taken as directed, are highly effective
in preventing malaria in visitors traveling to areas
where parasites are sensitive to these drugs. We
suggest the mefloquine loading-dose regimen for
persons who will enter a malarious area sooner than
I week after initiation of prophylaxis and who do
not have a contraindication to mefloquine. We believe that dox7cyciine should be reeomniended for
persons who are likely to be compliynt, who do not
have a eontraindieation to the drug, who cannot
tolerate mefloquine, or who are traveling in an area
of mefloquine resistance. Doxycycline must be consumed with food to prevent gastrointestinal intolerance. Esophageal ulcers may be prevented if water
and food are consumed after intake of the drug and
if persons do not lie supine. Both doxycycline and
mefloquine should be prescribed only for persons
traveling to an area where malaria occurs, and both
must be taken for 4 to weeks after departure from
the malarious area. Finally, physicians can reassure
patients that intoleranee to both drugs is uncommon.
Disclaimer: The views expressed here art' those of the authors
und not necossarily those ol" Ihe U.S. Army, the U.S. Niivy. the
U.S. Department of Defense, or Uie Indtinesian Army.

Appendix: Research Working Group

U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bttngkok. Thailand:
Colin Ohrt. MD, George Walt, MD. DTM&H.
U.S. Naval Medical Research Unit 2. Jayapura and
Jakarta. Indonesia: Thomas L. Richie. MD. PhD; Hendra
Widjaja. MD; David J. Fryauff, ScD; Hasan Basri, MD; J.
Kevin Baird, PhD; Purnomo, MSc; M. Awalludin Sutamihardja; Suradi; F. Stephen Wignall, MD.

Naval Medical Research Institute, Bethesda, Maryland: Stephen L. Hoffman, MD.

District Military Health Services. Jayapura, Irian Jaya.
Indonesia; Januar Fitriadi, MD; Budi Santoso. MD; Lukas Hadiarso, MD.
Army Malaria Research Unit, Ingleburn. Australia: Ci.
Dennis Shanks, MD.
Center lor Health Research and Development, National Institutes of Health, Jakarta, Indonesia; Emiliana
Tjitra, MD, MSe; Suriadi Gunawan, MD. DPH; Harijani
Marwoto, MSc; Sri Oemijati. MD. DR; and P.R. Arbani,
MD, MPH.
Battalions 143 and 731, Indonesian Army, Irian Jaya,
Indonesia; Wendy Budiawan, MD; Bambang Sukanto, M D .
F. Hoffmann-La Roche Ltd.. Basel, Switzerland: Jrg
Handscliin, P h D ; Dieler Stiirchler. M D .
Provincial Health Ser\it:e, Jayapitra, Indonesia; Bernardus Sandjaja. M D ; Slamet Harjo.suwiirno. M D . M P H ;
Budi Suhianto. M D .
Walter Reed Army Instiiutc of Research, Washington,
DC; Douglas Tang. P h D .
Acknowlcdf-menis: The authors thank many olHcials oi' the Indonesian Army, Provincial Health Serviee. Ministry of Health, lor
assistance: the staff oi" Piizer Indonesia for providing the weekly
blister packs ol" doxycyline: and ihe commanders and soldiers of
battalion.'^ 143 and 731 "or their support and cooperation. They
iilso Ihiink the field workersSyaiful Uniawim. Dewa Put Budi
Wilantara. Frans Subawa. Imanuddin. Jumiati. Khamdi. I. Nyoman Bonder, t. Gusti Nyoman Parwala. Ujang Jaenuddin. and
Nurslinwho were key to the success of ihis .'^tudy.
Griini Supporl: lu part by F. Hotlhi;inn-La Roehe. Basel. Switzerland: U.S. Army Medical Research and Material Connnand:
and U.S. Naval Medieal Research and Development CommaniJ.
Doxyeycline and doxycycline placeLx) were provided tree of
eliLtrge by Pl'tzer Indonesia; meHoquine hydrochloride was provided free of charge by F. t^offmann-Lit Roehe. Nutley. New
Jersey; and melloquine placebo was provided by F. MolTmann-La
Roche, Basel, Switzerland.
Requests for Reprinis: Colin Ohrt. MD. Dcpartnienl of Clinical
Pharmaeokigy, Division of Experimental Therapeutics. Waller
Reed Army^Institutc of Research, Washington. DC 20307-5100.
Current Author Addresses: Dr. Ohrt: Department of Clinieal Pharmacology. Division of Experimental Therapeuties. Waller Reed
Army Institute of Research. Washingtt>n. DC 20307-5 UK).
Drs. Richie, Widjaja, and F-ryauff: U.S. Embassy, Altn: U.S.
NAMRU-2/(PFRSON"S NAME), Box 3 Unit 8132, APO AP
96211-.S132. United States.
Dr. Fitriadi: Office of Military Command VIIlTrikora, (KESDAM
VIII Trikora). Jrilur Gura Besi. .layapura W i l l . Irian Jaya. Indonesia.
Dr. Hadiarso: Sub-Directorate of Preventive Medicine, The Indonesian Army Directorate of Health. Jiilur Abdul Rahman
Saleh No. 20, Jakarta Pusat. Indonesia.
Dr. Tjitra: Infectious Diseases Research Center, National Institute of Health Research Division, Ministiy of Health. Jalur Percetakiin Negara no. 2y. Jakarta 10560. Indonesia.
Dr. Shanks: U.S. Army Medical Research Unil, Unit (i4IO') Nirobi. APO AE (W83l-.5O(IO.
Dr. Handschin: Pharma Business Development and Strategic
Marketing, F. Honiann-La Roche Ltd, Pharmiicuetieals Division, CH-4070 Basel, Switzerland.
Dr. Sandjaja: Health Training Center (Balai Pelatihan Kesehata),
Jalur Kesehatan No. 1, Abepura, Jayapura yy351, Irian Jaya,
Indonesia.
Dr. Tang: Division of Biotnctrics. Department of Biostatistics,
Walter Reed Army Insiituie of Research. Walter Reed Army
Medical Center. Washington. DC 20307-5IOO.

15 June 1997 Annals of Internal Medicine Volume 126 Number 12

971

Dr. Watt: U.S. Army Medical Component. Armed Forces Research Itistitule of Medical Science. APO AP ^01546, Uniletl
States.
Dr, Wignali: Freeport Malaria Control, I'O Box 61982. New
Orleans. LA 7(llhl-l')82.

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