1475-2875-7-255.fm
Review
Azithromycin-chloroquine and the intermittent preventive
treatment of malaria in pregnancy
R Matthew Chico*1, Rudiger Pittrof2, Brian Greenwood1 and
Daniel Chandramohan1
Address: 1Department of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK and 2Enfield Town Clinic, Wenlock House, 33 Eaton Road, Enfield, EN1 1NJ, UK
Email: R Matthew Chico* -
[email protected]; Rudiger Pittrof -
[email protected]; Brian Greenwood -
[email protected]; Daniel Chandramohan -
[email protected]
* Corresponding author
Published: 16 December 2008
Received: 28 July 2008Accepted: 16 December 2008
Malaria Journal 2008,
7:255
2008 Chico et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
In the high malaria-transmission settings of sub-Saharan Africa, malaria in pregnancy is an importantcause of maternal, perinatal and neonatal morbidity. Intermittent preventive treatment of malariain pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) reduces the incidence of low birth-weight, pre-term delivery, intrauterine growth-retardation and maternal anaemia. However, thepublic health benefits of IPTp are declining due to SP resistance. The combination of azithromycinand chloroquine is a potential alternative to SP for IPTp. This review summarizes key
in vitro and
invivo evidence of azithromycin and chloroquine activity against
Plasmodium falciparum and
Plasmodiumvivax, as well as the anticipated secondary benefits that may result from their combined use in IPTp,including the cure and prevention of many sexually transmitted diseases. Drug costs and thenecessity for external financing are discussed along with a range of issues related to drug resistanceand surveillance. Several scientific and programmatic questions of interest to policymakers andprogramme managers are also presented that would need to be addressed before azithromycin-chloroquine could be adopted for use in IPTp.
endemic areas, the World Health Organization (WHO)
Each year, 30 million pregnancies are at risk of malaria
recommends use of Intermittent Preventive Treatment of
infection in sub-Saharan Africa, representing a major pub-
Malaria in Pregnancy (IPTp) with sulphadoxine-
lic health problem. Malaria in pregnancy (MIP) is associ-
pyrimethamine (SP).
ated with low birth-weight (LBW-term deliveryauterine growth-retardationaternal
IPTp has two primary objectives: (1) to clear asympto-
anW is a strong predictor of infant mortality
matic peripheral and placental parasitaemia and (2) to
in sub-Saharan Africa; death within the first year of life is
provide intermittent chemoprophylaxis against malaria
three-times higher for LBW newborns compared to
infection during pregnancy. The WHO recommends
neonates of normal birth-weight]. Malaria is one of the
administration of two or three courses of SP, sulphadox-
few contributors to LBW that can be improved by specific
ine (500 mg) and pyrimethamine (25 mg), after foetal
interventi, to reduce the effects of MIP in
quickening with each course given no less than one
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Malaria Journal 2008,
7:255
month apart, and all prior to the last month of pregnancy
malaria case management, then IPTp may actually lower
larial chemoprophylaxis among paucigravi-
the selection pressure on the first-line drug by decreasing
dae increases birth-weight by an average of 127 g (95% CI
symptomatic cases that require treatment. This is particu-
88.64 to 164.75 g) and reduces, by nearly half, the inci-
larly important as countries increasingly treat pregnant
dence of LBW (RR = 0.57, 95% CI 0.46 to 0.72. It has
women with uncomplicated clinical malaria in second-
been estimated that universal coverage with IPTp would
and third-trimesters with ACTs.
reduce all-cause neonatal mortality by 32% (95% CI -1 to54
Several published reviews of drugs for IPTp have includedazithromycin and chloroquine, although only as mono-
Standard IPTp dosing does not provide the same degree of
therapw summarizes
in vitro and
in
protective efficacy for pregnant women who are HIV-pos-
vivo evidence for the therapeutic efficacy of azithromycin
itive. This can be overcome, however, by administering
and chloroquine when used alone or together and dis-
more frequent courses of SP throughout pregnancy. A
cusses the additional benefits that the combination could
study in Malawi compared monthly SP treatment versus
have on many sexually transmitted diseases and, possibly,
two courses during the antenatal period among HIV-pos-
pneumococcal infection during pregnancy. Drug costs are
itive and HIV-negative women. An estimated 7.8% of
presented along with issues related to drug resistance and
HIV-positive pregnant women had placental malaria after
surveillance. Several scientific and programmatic areas are
receiving monthly SP as compared to 21.5% of HIV-posi-
outlined, as well, that would need to be addressed for pol-
tive women who received two doses of SP (RR, 0.36 [95%
icymakers and programme managers before azithromy-
CI, 0.17–0.79]). Among HIV-negative women, 2.3% who
cin-chloroquine could be adopted for use in IPTp.
received monthly SP had placental parasitaemia in con-trast to 6.3% of HIV-negative women who received two-
Azithromycin monotherapy for treatment and prevention
dose SP (RR, 0.37 [95% CI, 0.11–1.19.
The benefits of IPTp are threatened by increasing resist-
Azithromycin is a slow-acting anti-malarial macrolide
ance of
Plasmodium falciparum to SP. In many countries,
], an analogue of erythromycin with a nitrogen atom
artemisinin combination therapy (ACT) has replaced SP
inserted into the macrolide nucleus. As a result, there is
for case management, according to WHO guidelines,
enhanced penetration of drug into macrophages, fibrob-
because SP now demonstrates inadequate therapeutic effi-
lasts and polymorphonuclear neutrophils, permitting
cacy in childre]. Therapeutic efficacy of SP in chil-
greater accumulation within acidified vacuoles and
dren with clinical cases of
P. falciparum malaria does not,
extending the 1.5-hour half-life of erythromycin to 68
however, predict efficacy of IPTp. Correlation analysis
hours for azithromycin . Stable at gastric pH, azithro-
between paediatric treatment and IPTp suggests that SP
mycin has an absolute bioavailability of 37% following
may still offer some protection against MIP in geographic
oral administra accumulates in hepatic, renal,
areas where day 14 post-treatment failure rates for SP in
pulmonary and splenic ti, and gradually leaches
children are as high as 40% [tion, how-
into the bloodstream over a period of one week ild
ever, is not uniform across populations; primigravidae are
renal dysfunction and mild-to-moderate hepatic dysfunc-
particularly vulnerable to the effects of MIP and are pro-
tion do not affect excretion significantly.
tected the least by SP where sensitivity is on the decline. InGhana, where parasite sensitivity to SP remains higher
Among pregnant women, serum concentrations peak
than in east and southern Africa, uncorrected parasitolog-
within six hours of oral administration and are sustained
ical failure rates by day 28 post-treatment were 36.4% (32
for 24 hours. As the drug disperses, peak concentrations
of 88) in children, 27.1% (29 of 107) in primigravidae,
are maintained three-times longer in the placenta, myo-
6.1% (3 of 49) in secundigravidae, and 3.8% (2 of 52) in
metrial and adipose ti]; only 2.6% of a maternal
multigravidae [s, SP is already compromised and
dose, however, perfuses the placenta []. Azithromycin is
an urgent need exists to identify alternative compounds
excreted in human milk with no adverse events observed
for use in IPTp, even though SP still offers some protec-
as a consequenc].
tion up to an unknown threshold of parasite resistance.
Azithromycin targets the 70 S ribosomal subunit of the
An ideal anti-malarial drug or drug combination for IPTp
apical complex of susceptible micro-organisms including
should be safe, well tolerated, efficacious in the clearance
P. falciparum and
P. vivax . Once attached to the api-
of malaria parasites, provide a long period of chemopro-
coplasts of the parasite, azithromycin hinders polypeptide
tection and, preferably, not be deployed as the first-line
development, triggering premature detachment and
treatment for clinical malaria. If a drug or drug combina-
movement down the peptide exit tunnel. The potency of
tion used in IPTp is not simultaneously used for clinical
azithromycin, as a translation inhibitor, is greatest against
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Malaria Journal 2008,
7:255
the progeny of parasites that inherit a non-functioning
incubated between 24 and 48 hours, while its 50% inhib-
apicoplast following drug exposure, thus creating a
itory concentration values drop as low as 35 nanomolar
delayed-death effect [ory-generated
P. fal-
]. At 48-hours, azithromycin is 10-fold more active
ciparum that are resistant to azithromycin appear to accu-
than erythromycin against chloroquine-resistant
P. falci-
mulate mutations after
in vitro passage in the structural
parum; the two compounds are equipotent, however,
proteins of the ribosome []. It is unknown whether
when chloroquine-sensitive parasites are exposed to the
mutations induced by azithromycin are capable of under-
same drug concentration].
mining the inhibitory action of other drugs that also targetthe apicoplast.
Daily regimens of 250 mg with a loading dose of 500 or750 mg have shown an impressive chemoprophylactic
Safety and tolerability
effect against
P. vivax. Azithromycin had a 99% protective
Doses of azithromycin between 500 mg and 2,000 mg
effect (95% CI, 93% to 100%) among semi-immune sub-
have been used in all trimesters of human pregnancy for
jects in Indonesia over a 20-. A similar
the treatment of upper and lower respiratory tract infec-
protective efficacy, 98% (95% CI, 88% to 100%), was
tions, skin diseases,
Chlamydia trachomatis, mycoplasma
seen in Thailand [ in a semi-immune population. By
and group B streptococci infections among women aller-
comparison, the chemoprophylactic effect of azithromy-
gic to other antibiotics.
cin against
P. falciparum has shown promise, but has beenless impressive (T
Meta-analysis of eight randomized clinical trials amongpregnant women with
C. trachomatis infection found that
The first published
P. falciparum human challenge study
azithromycin was associated with fewer gastrointestinal
with azithromycin involved four non-immune volunteers
adverse events than erythromycin (OR = 0.11, 95% CI
who received a loading dose of 500 mg and 250 mg daily
0.07–0.18) and fewer total adverse events (OR = 0.11,
for three days. Subjects were then inoculated with five
95% CI 0.07–0.18) [ placebo-controlled trial, how-
Anopheles stephensi mosquitoes that had an average of 3.2
ever, suggests that azithromycin may be poorly tolerated
salivary-gland
P. falciparum sporozoites each, after which
by HIV-positive patients. Gastrointestinal effects were
they continued to receive 250 mg of azithromycin daily
reported by 78.9% of azithromycin recipients (67 of 85)
for four more days. With unquantifiable plasma concen-
and 27.5% of participants given placebo (24 of 89
trations of azithromycin, presumably due to poor absorp-
Although an unusual side-effect, case reports indicate that
tion, one of four subjects developed parasitaemia in the
HIV-positive patients may experience temporary ototoxic-
14-day post-challenge peri].
ity with azithromycin
A subsequent trial suggested that a regimen of longer
Adults treated with a 1,000 mg oral dose of azithromycin
duration might be required against
P. falciparum. Ten non-
report moderate side-effects including diarrhoea or loose
immune subjects were given a loading dose of 500 mg fol-
stools (7%), nausea (5%), vomiting (2%), and vaginitis
lowed by 250 mg daily for 2 weeks prior to parasite expo-
(2%); up to 1% of adults experience dizziness, headache,
sure. After inoculation, 250 mg was administered daily for
vertigo, and somnolen of ter-
one additional week, producing a protective effect of 40%
atogenicity in animal models, even at four-times the
(95% CI, 12% to 74%). A concurrent human challenge
study with 10 non-immune subjects was conducted usingthe same regimen, except that 250 mg was given daily for
two weeks post-exposure, rather than for just one, produc-
The
in vitro anti-malarial activity of azithromycin
ing a 100% protective effect [. This high level of protec-
increases 200-fold against
P. falciparum isolates when
Table 1: Chemoprophylactic effect of azithromycin monotherapy against Plasmodium falciparum in semi-immune non-pregnant adults.
Sample size
Duration of follow-up
Chemoprophylactic effect (95% CI)
750 mg loading dose and 250 mg daily
750 mg loading dose and 250 mg daily
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Malaria Journal 2008,
7:255
tion has not been replicated in the field, however, where
haemoglobin ingested by parasites, the more toxic their
multiple infections may be expected.
food vacuoles become, rapidly causing cell death. Resist-ance to chloroquine is associated with polymorphisms in
Among semi-immune populations, an equivalent or
the
P. falciparum food vacuole transporter protein (
pfcrt)
higher loading dose with the same daily regimen resulted
located on chromosome 7 [. All
pfcrt alleles from chlo-
in protective efficacies of 83% (95% CI, 69% to 91%) in
roquine-resistant strains, regardless of geographic origin,
Ke], 71% (95% CI, -14% to 94%) in Thailand
encode a conserved K76T amino acid substitution. The
d 72% (95% CI, 50% to 84%) in Indonesia
effect of
pfcrt on chloroquine pharmacokinetics remains
There were two sub-populations in the Indonesian study
disputed. Some researchers have theorized that
pfcrt ena-
which may have had slightly different degrees of acquired
bles protonated chloroquine to escape the food vacuole
immunity: the chemoprophylactic effect among soldiers
while others argue
pfcrt binds directly to chloroquine,
living for six months in the study area was 62.9% (95%
thereby inhibiting its ability to alter food vacuole ].
CI, 29.5 to 80.4) while chemoprophylactic protectionamong civilians residing in the study area for less-than 18
Safety and tolerability
months was 88.4 (95% CI, 56.6 to 97.4). The Kenyan trial
Chloroquine is safe and generally well tolerated in treat-
also evaluated weekly dosing with 1,000 mg of azithromy-
ment doses. Due to its rapid absorption, chloroquine has
cin, in contrast to a daily regimen of 250 mg, producing
a narrow therapeutic index, increasing the potential for
just 64% protective efficacy (95% CI, 47% to 77%)
toxic overdose. Hypotension and cardiac failure can be
Despite relatively poor
in vivo protection against
P. falci-
prompted by a single oral dose of 3500]. Despite
parum in field settings, the favourable safety profile of azi-
toxicity at high doses, the most commonly reported side-
thromycin in pregnant women and young children
effect in African populations is pruritus which peaks 24
prompted further investigation into molecules that might
hours after intake. Chloroquine has been used safely
be co-administered with azithromycin to improve its pro-
in all trimesters of human pregnancy for decades as both
tective effect.
a treatment and chemoprophylactic drug, crossing theplacenta without teratogenic effect
Chloroquine as monotherapy for the treatment and
prevention of malaria
Prior to establishment of IPTp in sub-Saharan Africa, chlo-
roquine was commonly given to pregnant women during
Chloroquine has been the first-line treatment of malaria
antenatal visits in sachets containing four weekly doses of
in much of the world for most of the past 60 years. Abso-
300 mg for self-administration. Compliance with chloro-
lute bioavailability is 70 to 75% while peak plasma con-
quine remained low for many reasons including pruritus
centrations are reached within two hours of oral
and its bitter taste which some women associate with
administration. A single therapeutic dose against a chloro-
medications that induce abortion [].
quine-resistant strain will persist six to 10 days in theblood, while its overall half-life is between one and two
mo]. Chloroquine accumulates extensively in
Although still a first-line treatment for
P. vivax, chloro-
the liver, connective tissue and pigmented tissue such as
quine is no longer recommended for treatment of
P. falci-
skin and retina, enabling enormous total volume distribu-
parum due to high levels of resistance. In combination
tion. Greatest concentrations are found in erythrocytes,
with another anti-malarial drug, however, chloroquine
granulocytes and platelets, and 55% is protein-bound in
might, once again, have a role in malaria control. Malawi
changed its first-line drug to SP in 1993 when chloro-quine
in vivo ]. Five
Chloroquine is active against erythrocytic life stages of
years later, chloroquine inhibited
in vitro blood schizont
Plasmodium species when haemoglobin is being actively
development in 96.5% (28 of 29) of isolates from Malawi
digested. Haem is a toxic bi-product of haemoglobin
], indicating that
pfcrt was no longer under selection
ingestion and must be eliminated through dimerization.
pressure. In 2001, field sampling failed to find parasites
Under normal circumstances, parasites bio-crystallize
carrying the
pfcrt mutation associated with resistance
haem to form haemozoin, the iron-containing pigment
and a clinical trial using chloroquine monotherapy was
that accumulates as non-toxic cytoplasmic granules. Chlo-
100% efficacious (63 of 63) among asymptomatic semi-
roquine prevents this process by concentrating at
immune adults who received 600 mg on day 0 and day 1,
nanomolar levels outside parasites (10-9) and one million
and 300 mg on day 2 [. Most recently, a study in 2005
times higher (10-3) in parasite food vacuoles of infected
showed chloroquine to clear parasite infection in 98.8%
erythrocyt. Inside parasite vacuoles, chloroquine
(79 of 80) of Malawi children with uncomplicated
P. fal-
binds to haem, preventing its expulsion. Thus, the more
ciparum malaria [
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Malaria Journal 2008,
7:255
The re-emergence of high
in vitro sensitivity to chloro-
Azithromycin and chloroquine do not exhibit any clini-
quine in Malawi – within just five years – suggests the
pfcrt
cally relevant pharmacokinetic interactio
resistance mutation involves considerable fitness cost to
chloroquine resistance is reversible with calcium channel
P. falciparum -]. This micro-evolutionary reversal is
blockers, such as verapamil and desipramine, that inhibit
all the more remarkable because it occurred despite the
p-glycoprotein-m,]. Azithromycin is a
continued availability of chloroquine in the formal and
p-glycoprotein subs which may suggest the pres-
informal private sector. It is likely that
P. falciparum sensi-
ence of a metabolic mechanism for synergy. Whether
tivity will return elsewhere in the region, if it has not
additive or synergistic, complete parasitological clearance
already, with the declining chloroquine use.
using the combination would not be expected in less than48 hours, the equivalent of two schizogenesis cycles. Thus,
Chloroquine monotherapy continues to demonstrate
a conservative approach to
in vivo dosing may require a
modest therapeutic utility in west Africa. A recent observa-
three-day regimen to realize the full benefits of the azi-
tional study in Benin examined the effect of self-adminis-
thromycin-chloroquine combination against
P. falciparum
tered chloroquine chemoprophylaxis among pregnant
while minimizing the opportunity for survival of wild-
women (N = 1090), comparing self-reported dosing over
type progeny.
pregnancy with birth weights. An estimated 49.9% ofwomen reported taking weekly chloroquine in the first tri-
Evidence for synergy of the combination in vivo
mester, increasing to 92% of women in the second trimes-
A two-stage trial in India demonstrated
in vivo synergy
ter and 97.5% in the final trimester. Random testing of
between azithromycin and chloroquine against
P. falci-
urine samples at delivery established a point-prevalence
parum infection. The first stage, which was double-
for chloroquine use. In total, an estimated 99% of women
blinded, included 32 semi-immune subjects treated for
had ingested chloroquine (N = 166); of these, 72% had
uncomplicated
P. falciparum malaria with either azithro-
levels consistent with consuming 300 mg in the previous
mycin (1,000 mg) plus chloroquine placebo on days 0, 1
seven days. Subjects with self-reported chemoprophylac-
and 2, or chloroquine (600 mg) on days 0, 1 and 300 mg
tic use for seven or more months were four times more
on day 2 plus azithromycin placebo on days 0, 1 and 2.
likely to give birth to child of normal birth weight (> 2500
The second stage of the trial was open label and included
grams) than women who used chemoprophylaxis for less
64 semi-immune subjects who received the azithromycin-
than four months (adjusted OR = 3.96; 95% CI = 1.9 to
chloroquine combination therapy in doses equal to stage
8.28; p =< 0.001) [.
one. Treatment response rates at day 28 showed
in vivosynergy: 33% of those who received azithromycin mono-
Parasitological evidence of chloroquine efficacy was
therapy remained free of fever by day 28 compared to
reported, as well, in a recent four-arm clinical trial con-
27% in the chloroquine-treatment group. In contrast,
ducted in Ghana among pregnant women with asexual
P
97% of patients who received drugs co-administered had
falciparum stage parasitaemia. Women randomized to a
resolved fever and parasitaemia by day 7 with no observed
chloroquine treatment group (N = 225) received 600 mg
recrudescence by day 28. Parasitological responses by
for 2 days and 300 mg on the third day. The uncorrected
treatment group mirrored the synergy of clinical observa-
day-28 treatment failure rate was 30% (62 of 208).
tions. Azithromycin monotherapy eradicated parasites in
Polymerase chain reaction (PCR) analysis confirmed that
19% of subjects (3 of 16) by day 3, increasing to 63% of
14% (30 of 208) were treatment failures while 6% (11 of
subjects (10 of 16) by day 7, and dropping to 36% at day
208) were re-infections. PCR was unable to distinguish
28. As would be expected, chloroquine monotherapy was
cases of recrudescence from new infection in the remain-
faster-acting than azithromycin alone, but it also demon-
ing 10% (21 of 20.
strated an increase in failures by day 28. Specifically, 56%of subjects (9 of 16) were free of parasites at day 3, fol-
Potential for azithromycin and chloroquine when used in
lowed by 88% (14 of 16) at day 7 and, finally, 27% (4 of
combination for the prevention of malaria
15) by day 28. For subjects receiving azithromycin-chloro-
Evidence for synergy of the combination in vitro
quine combination treatment, however, 97% parasitolog-
An additive effect between azithromycin and chloroquine
ical eradication was achieved by day 3 and sustained
has been shown in sensitivity testing conducted over a 48-
through day 7 and day 28 [
hour period. When incubation is extended to 68 hours,drug synergy has been seen against chloroquine-resistant
Treatment trials with the azithromycin-chloroquine
isolates; the combination remains additive, however,
combination in Africa
against chloroquine-sensitive pa
et al in
A double-blinded multi-centre trial was held in Burkina
contrast, observed an additive effect at 96 hours of incu-
Faso, Ghana Mali, Kenya, Uganda, and Zambia to com-
bation against chloroquine-resistant isol].
pare the therapeutic efficacy and tolerability of azithromy-cin-chloroquine with that of mefloquine ]; a second,
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Malaria Journal 2008,
7:255
open-label, confirmatory trial was conducted in the same
discrete treatment periods using pre-packaged sachets
countries, with the addition of Senegether,
labeled with pictogram instructions that are explained
these studies established an efficacious treatment course
during initial consultaEven so, achieving
for azithromycin-chloroquine against uncomplicated
P.
high rates of adherence to a three-day azithromycin-chlo-
falciparum infection: a fixed daily dose of 1,000 mg of azi-
roquine regimen – administered two or three times during
thromycin and 600 mg of chloroquine taken for three
pregnancy – would likely be a challenge. Public education
days. This treatment regimen represents a slightly higher
campaigns in recent years have discouraged chloroquine
dose of chloroquine than has been commonly adminis-
use. Thus, community acceptance, even in a new combi-
tered. Most often, 25 mg of chloroquine is provided per kg
nation, would require innovative packaging and market-
of body weight over a three-day period: 10 mg per kg on
ing. Adherence could be improved if a three-dose
days 1 and 2 with 5 mg per kg on day 3. The azithromycin-
azithromycin-chloroquine fixed-dose formulation is
chloroquine fixed dose contains a total of 1,800 mg of
designed specifically for IPTp. In countries currently
chloroquine, an amount that would typically be given to
implementing Home-based Management of Malaria and/
a person weighing 72 kg. The average weight of pregnant
or the community component of the Integrated Manage-
women in the Ghana efficacy as 55.9 kilo-
ment of Childhood Illness, adherence to IPTp could be
grams. Thus, 600 mg per day over three days is 22.4%
improved further with community health workers making
more chloroquine than is in the typical treatment course.
house visits on days following antenatal consultations toverify self-treatment while taking the opportunity to
Mefloquine was an appropriate comparator in these sub-
develop or review an individualized perinatal plan in the
Saharan studies because it has not been used regularly in
the region and parasite sensitivity is likely quite high.
Mefloquine is also a potential candidate to replace SP in
Azithromycin plus SP is another option for IPTp which
IPTp. Preliminary results suggest that azithromycin-chlo-
would not present the disadvantage chloroquine-associ-
roquine is non-inferior to mefloquine with
P. falciparum
ated pruritus. However, SP may have surpassed a resist-
clearance rates comparable to those observed in India.
ance threshold which would make it an ineffective partner
The azithromycin-chloroquine combination warrants fur-
drug. Alternatively, azithromycin could be combined with
ther investigation and may also offer particular advan-
piperaquine to improve adherence; piperaquine is at least
tages in settings where mixed infections of
P. falciparum
as effective as, and better tolerated than, chloroquine
and
P. vivax predominate.
against
P. falciparum and
P. vivax ine isanother potential partner drug, shown to have additive
The azithromycin-chloroquine combination for IPTp
properties with azithrom. Mefloquine, despite
some important issues of tolerability, has the advantage
If azithromycin and chloroquine are used together in
that it can be administered as a single, observed dose.
IPTp, then an initial priority should be to identify themost suitable dose of the combination. It seems likely that
Optimal timing
a three-day treatment regimen will be needed to ensure
SP is contraindicated prior to quickening due to its tera-
complete parasitological clearance while minimizing
togenic risk and, again, one month prior to delivery
selection for resistant genotypes. Thus, as an initial inves-
because of possible drug-induced kernicterus. Thus, pro-
tigation, it would be appropriate to give women two or
viding IPTp with SP requires estimating gestational age
three courses of IPTp during the antenatal period in a reg-
and delivery date with some accuracy. In contrast, there
imen of 1,000 mg of azithromycin plus 600 mg chloro-
are no known contraindications for azithromycin-chloro-
quine base, once daily for three days. Because rates of drug
quine at any gestational age. This is important because
absorption, distribution and excretion are commonly
current IPTp guidelines are currently based on operational
altered during pregnancy, pharmacokinetic investigations
convenience rather than the natural course of MIP ].
should be conducted as part of, or in parallel to, a clinical
Earlier IPTp administration may be important as maternal
parasite densities peak between nine and 16 wtapering until term. IPTp administration in the last month
Acceptance and adherence
of pregnancy may be of considerable value, too, increas-
Acceptance of and adherence to a three-day regimen of
ing foetal weight gain during final stages of accelerated
azithromycin-chloroquine would be needed. In most
growth
in utero
operational settings, the first dose of azithromycin-chlo-roquine can be administered as directly observed therapy
Mefloquine may also be suitable for administration ear-
during antenatal visits, but doses on the following two
lier and later in pregnancy than SP. Based, in part, on post-
days would require self-administration. Improvements in
marketing surveys and retrospective studies which include
adherence to multi-day regimens have been shown for
1271 first-trimester pregnancies, the US Centers for Dis-
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Malaria Journal 2008,
7:255
ease Control and the UK Health Protection Agency recom-
least one STI on any given day –
Treponema pallidum, N.
mend mefloquine chemoprophylaxis for pregnant
gonorrhoea, C. trachomatis, or
Trichomonas vaginalis. While
women in any trimester when travelling to areas of high
this prevalence may be higher than in some other parts of
malaria transmission. Overall experience does not suggest
sub-Saharan Africa, of particular concern is that 48% of
that mefloquine is teratogenic [inistration in
these infections are asymptomatic. In addition, just 2% of
the first trimester, however, may warrant caution in light
women with symptomatic STIs ever seek treatment in Hla-
of two retrospective studies that found associations
bisa, and when they do, only 65% of them receive ade-
between mefloquine exposure and spontaneous abortion
quate care. Pregnant women are less likely to have
asymptomatic STIs compared to non-pregnant women(17% vs. 59%), but the age-specific prevalence of infec-
ACTs are associated with embryotoxicity over a narrow
tion is often twice as high for pregnant wo]. This
dose range in animal models of early pregnancy with
level of disease prevalence, symptomatic and asympto-
some additional evidence of lethality in second and third
matic, suggests a role for mass treatment during preg-
trimesters this reason, the WHO recommends
ACTs for curative purposes only during the second- andthird-trimesters if other treatments have been considered
The presumptive treatment of STIs in pregnancy improved
unsuitable. First-trimester administration is contraindi-
maternal health and birth outcomes in a randomized clin-
cated unless treatment is considered life-saving for the
ical trial involving 4,033 pregnancies in Ugandaag-
inal infections were significantly lower in women whoreceived a one-time dose of azithromycin (1,000 mg),
Potential additional benefits of azithromycin-chloroquine
metronidazole (2,000 mg) and cefixime (400 mg) com-
when used for IPTp
pared to women who received iron/folate and low-dose
Use of the azithromycin-chloroquine combination in
multivitamins. In the treatment group, the relative risk
IPTp may offer several additional public health benefits
(RR) of
T. vaginalis was 0.28 (95% CI, 0.18–0.49), the RR
over other possible replacements for SP.
of bacterial vaginosis was 0.78 (95% CI, 0.69–0.87), andthe RR of infant ophthalmia was 0.37 (95% CI, 0.20–
Reduction of sexually transmitted infections
0.70). The incidence of LBW was substantially reduced in
Sexually transmitted infections (STI) adversely affect preg-
the intervention group (RR, 0.68; 95% CI, 0.53–0.86) as
nancy and contribute to pre-term delivery, LBW, intrauter-
was early neonatal mortality (25.4 per 1,000 live births),
ine growth-retardation, spontaneous abortion, stillbirth,
when compared to the control group (29.1 per 1,000 live
newborn morbidity and mortalitaternal health is
also jeopardized by STIs with potential complicationsincluding pelvic inflammatory disease, ectopic pregnancy
While difficult to attribute specific beneficial outcomes to
and infePrevalence estimates of symptomatic
each compound, azithromycin probably had a considera-
STIs at antenatal clinics in sub-Saharan Africa range
ble effect. An oral dose of 1,000 mg of azithromycin clears
between 2.5 and 17% for ], 1.7 and 7% for
more than 90% of cervical infections due to
N. gonorrhoea
Neisseria gonorrhoea - to 20.8% for
C. tra-
and
C. trachomatis [e same dose will cure and pro-
chomatis ] and 7.3% to 62% for chancroid
vide chemoprophylaxis against chancroid and syphilis.
Studies in Uganda and Tanzania ] have shownthat azithromycin, 1,000 mg and 2,000 mg respectively, is
In resource-limited settings, testing women for STIs dur-
equally effective as benzathine penicillin G in treating
ing antenatal consultations and providing appropriate
syphilis among non-pregnant adults. If untreated in preg-
care has been a public health challenge for decades. To
nancy, one-third of women will develop congenital syph-
assist countries, the WHO has developed syndromic-
ilis, carrying major risk for the foetus. One study in
based algorithms for the detection of STIs. In high-trans-
Tanzania found unscreened congenital syphilis associated
mission areas, the method is reliable for men, but much
with 51% of stillbirths, 24% of pre-term live births and
less so for women. Syndromic diagnosis of
N. gonorrhoea
17% of adverse pregnancy events er trial in
and
C. trachomatis among women has a sensitivity of 30 to
Zambia implicated maternal syphilis in 42% of spontane-
80% and a specificity of 40 to 80%; rarely does the sum of
ous abortionsspite the high cure rates observed
the two exceed 120% [. An additional shortcom-
in the clinical trials of Uganda and Tanzania, 1,000 mg
ing is that asymptomatic infection, a substantial portion
and 2,000 mg of azithromycin given to five pregnant
of disease burden, remains undetected and, thus,
women with syphilis in China did not prevent trans-pla-
cental infection []. Thus, IPTp with azithromycin-chloroquine should not be viewed as a replacement for
In South Africa's largest district, Hlabisa, 24.9% of females
benzathine penicillin G in the prevention of congenital
between 15 and 49 years of age are estimated to have at
disease. However, azithromycin-chloroquine adminis-
(page number not for citation purposes)
Malaria Journal 2008,
7:255
tered in IPTp may improve outcomes for the majority
three times would cost between US $14.00 and $21.00 per
women whose syphilis infections, both symptomatic and
pregnancy. This is prohibitively expensive for national
asymptomatic, that are currently undiagnosed and
malaria control programmes in most endemic countries
in Africa. Thus, external funding would be required forwidespread implementation of the combination in IPTp.
The extent to which the control of STIs can prevent the
This could take many forms: a direct donation from the
spread of HIV remains unknown. Observational studies
pharmaceutical industry, and/or a financing mechanism
associate treatment of ulcerative STIs with reductions in
modelled after the Global ACT Subsidy or the Interna-
HIV transmission, particularly among men], and yet
tional Financing Facility for Immunization.
a systematic review of eight clinical trials failed to find thesame relationship in seven of th]. It is possible
Azithromycin and selection for resistance
that two or three IPTp treatments with azithromycin-chlo-
There are concerns that use of azithromycin-chloroquine
roquine could offer women some protection against HIV
for IPT could encourage the emergence and spread of
infection in pregnancy, but the observable difference may
resistance to a variety of organisms. Pathogens that need
be undetectable due to sample size limitations in most
to be considered include malaria parasites, organisms
clinical trials, especially in areas with low HIV prevalence
causing STIs, and the pneumococcus.
Malaria parasites
Chloroquine may offer its own protection against HIV
Apart from clinical trials, azithromycin has never been
transmission. Cord blood containing high levels of chlo-
used operationally for treatment or prevention of malaria.
roquine has been associated with a reduced risk of
The susceptibility of azithromycin-chloroquine for select-
mother-to-child transmission (MTCT) of HIV ]. In
ing parasites resistant to azithromycin is, therefore,
addition, viral shedding in breast milk has been lowered
unknown. The declining use of chloroquine throughout
among HIV-positive women who received three days of
sub-Saharan Africa is likely to lead to reversal of resistance
600 mg chloroquine as an anti-malarial chemoprophylac-
as witnessed in Malawi where parasite sensitivity returned
tic []. It is unknown whether this reduction in viral
five years after suspending its use. It is possible the re-
load is sufficient to prevent HIV transmission among
introduction of chloroquine with azithromycin as a part-
mothers who choose to breastfeed.
ner drug may prevent re-selection of parasites carrying the
pfcrt resistance mutation. However, rigorous surveillance
Prevention of pneumococcal infection in pregnancy
would be needed to verify this assumption.
Pneumonia is not a common focus of maternal healthpackages in most resource-limited settings because the
Organisms causing STIs
incidence in pregnancy is not appreciably higher than in
Azithromycin sensitivity patterns in high-income coun-
non-pregnant women [ progression, how-
tries do not suggest that its use in IPTp would rapidly
ever, is substantially more virulent during gestation
induce resistance in
N. gonorrhoea or
C. trachomatis. Sensi-
]. There are old data from Ibadan, Nigeria, that suggest
tivity of the gonococcus remains relatively high, even in
the incidence of pneumococcal meningitis may increase
the presence of growing penicillin resistance. In the
during pregnancy and puerperal pe
United States, minimum inhibitory concentrations
records between 1958 and 1962 revealed that 86% (26 of
(MICs) of azithromycin exposed to gonococcal isolates
31) of women with pneumococcal meningitis were preg-
have increased modestly since 1992 when tracking began.
nant (15) or had recently delivered (11). By comparison,
In 2006, 0.2% (14 of 6,089) of isolates provided through
disproportionately fewer pregnant or early postpartum
a national network were resistant to azithromycin with a
women, 22% (7 of 32) in total, were diagnosed with other
MIC > 2.0 μg/ml, representing a slight decrease from 0.6%
types of meningitis. It is uncertain whether this enhanced
(35 of 6,199) of isolates in 200]. In the case of
C.
risk in pregnancy occurs in other parts of Africa. If so, then
trachomatis, the most recent meta-analysis of 12 trials
it is conceivable that IPTp with azithromycin might pro-
involving 1,543 patients estimates cure rates to be 97%
vide some protection against this uncommon but very
with a single 1,000 mg dose of azithromycin].
serious infection.
There is greater concern regarding syphilis. Azithromycin
has been used, for example, since 1999 in San Francisco
The cost of 1,800 mg of chloroquine (600 mg per day for
(USA) for chemoprophylactic (1,000 mg) and curative
three days) ranges between US $0.10 and $0.20, while
(2,000 mg) purposes against syphilis. By 2004, a muta-
3,000 mg of azithromycin (1,000 mg per day for three
tion associated with
T. pallidum resistance to macrolides at
days) is approximately US $6.80 ]. Thus, an azithro-
the A2058 position in the 23S rRNA gene was found in
mycin-chloroquine IPTp regimen administered two or
56% blood samples from the main metropolitan sexual
(page number not for citation purposes)
Malaria Journal 2008,
7:255
health centre. All isolates were from men who have sex
not earlier, as might be expected with a treatment-induced
with men, 31% of which were from HIV-infected men
e in sensitivity is likely attributable,in large part, to underlying erythromycin resistance which
Ways to reduce opportunity for resistance
has been in general use for over 50 years. Erythromycin-
A number of steps could be taken to reduce the chances
resistant
T. pallidum isolates with mutation at the A2058
that azithromycin use in IPT might enhance macrolide
position confer resistance to macrolide antibiotics and are
resistance in bacteria responsible for several major infec-
associated with treatmen]. Indeed, a
tions. Considerations include the following:
risk factor for being infected with azithromycin-resistantsyphilis is having used azithromycin or other macrolides
Setting dose and duration above resistance breakpoint
in the rece].
A counter-selective dose – the minimum dosage necessaryto prevent the emergence of drug resistance – can be used
The potential for rapid induction of
T. pallidum resistance
instead of the conventional minimum required dose to
in Africa is difficult to estimate since molecular analyses of
achieve adequate clinical and parasitological cure. Such a
the A2058 region have not been included in most syphilis
dose, set just above the resistance breakpoint of target
studies of the region. In Madagascar, the mutation was not
micro-organisms, would suppress most pathogens during
found in analysis of 103
T. pallidum isolates and no azi-
initial drug exposure and sustain concentrations sufficient
thromycin treatment failures have been reported in coun-
to inhibit mutant progeny that might survive and select
tr]. Because neither macrolide has been
for resistance. Breakpoints and a counter-selective dose for
deployed on any scale in focus countries of IPTp, azithro-
azithromycin-chloroquine can be modelled using phar-
mycin may be less vulnerable to rapid loss of sensitivity as
macokinetic and pharmacodynamic parameters in IPTp
has been witnessed in high-income countries.
target countries. While there will always be the potentialfor inducing resistance, a multi-national, multi-centre sur-
The pneumococcus
veillance study over 10 years has shown that treatment of
Pneumococcal resistance to macrolides occurs by two pri-
respiratory tract infections to the point of bacterial eradi-
mary mechanisms, each with distinct genetic markers:
cation minimizes potential for selecting and maintaining
ribosomal methylation (
ermB or
ermA genes) and efflux
resistant strains].
pump mutation (
mefA or
mefE genes). Based on experi-ence in mass treatment of trachoma with azithromycin,
there is concern that use of the azithromycin-chloroquine
If azithromycin-chloroquine is limited to IPT, made avail-
combination for IPTp might increase the prevalence of
able only through health facilities, and not simultane-
azithromycin- and erythromycin-resistant pneumococci.
ously used for treatment purposes, then drug pressure can
Trachoma eradication campaigns using azithromycin
be kept to a minimum.
among vulnerable groups of children in Australia andNepal found that one-time treatment may select mac-
Monitoring sensitivity of pneumococci
rolide-resistant pneumococcal strains in the nasopharynx
Coordinated resistance surveillance of pneumococci
] and conjunctiva [election, however, was
should become a regional objective if countries choose to
transient. In Australia, 98.7% (78 of 79) of nasopharyn-
adopt azithromycin-chloroquine for IPT. Regional net-
geal pneumococcal isolates collected at baseline were sen-
works already exist for monitoring malaria and pneumo-
sitive to azithromycin, decreasing to 84.2% (32 of 38)
coccal resistance, and could collaborate on this objective.
between two to three weeks, and then 73% (27 of 37) at
Monitoring, however, can be a source of controversy as
two months. By six months, 94.9% of isolates were sensi-
the relevance of
in vitro macrolide sensitivity to clinical
tive to azithromycin]. One-year after a trachoma
outcomes is not well established. There has not been a
campaign in Nepal, 86% (50 of 57) of randomly collected
concomitant rise in
S. pneumoniae case-mortality rates as
isolates were positive for
S. pneumoniae, and 100% (50 of
increasing macrolide resistance has been observed
in vitro
50) were azithromycin seelection of azi-
]. A similar paradox has been seen with penicillin-
thromycin-resistant strains, however, has not always fol-
resistant
S. pneumoniae ]. Multiple reasons may
lowed trachoma treatment campaigns. Very high
contribute to these discordant trends. In the case of newer
macrolide sensitivity of nasopharyngeal pneumococci
macrolides, including azithromycin, drug concentrations
was observed in Tanzania when samples were obtained at
are able to reach higher levels in the intracellular tissue
three weeks, two months and six months post-treatment.
and in the epithelial lining fluid of the lung than concen-
Of 4,782 pneumococcal swabs tested, only one demon-
trations measured in blood ]. Azithromycin,
strated pneumococcal resistance to azithromycin. Curi-
therefore, may have superior pharmacokinetics
in vivo to
ously, the resistant sample was collected at six months,
inhibit
S. pneumoniae infection, safeguarding favourabletreatment outcomes in the face of increasing macrolide
(page number not for citation purposes)
Malaria Journal 2008,
7:255
resistance as measured
in vitro. However, macrolide efflux
MTCT or post-partum transmission among sero-positive
pump mutations have been identified in
S. pneumoniae
women who choose to breastfeed?
isolates with erythromycin MICs of at least 8 μg/mL – con-centrations of azithromycin that have been associated
with clinical fa
in vitro-in vivo paradox
Azithromycin-chloroquine is a potential alternative to SP
may be better understood with improved surveillance that
for use in IPTp. The combination has demonstrated syner-
involves analysis of
in vitro MICs and
in vivo treatment
gism
in vivo against
P. falciparum in India. Preliminary
outcomes that include morbidity markers – not just mor-
results of studies in non-pregnant adults in sub-Saharan
bidity rates – which may be more sensitive in detecting the
Africa have shown that azithromycin-chloroquine is not
effect of
in vitro changes in macrolide resistance on clinical
inferior to mefloquine, a compound currently under con-
sideration for IPTp. The azithromycin-chloroquine com-bination may be safely administered at any time in
Key scientific and programmatic questions
pregnancy. The secondary benefits of the combination,
Evidence to date suggests that azithromycin-chloroquine
clearing of symptomatic and asymptomatic STIs, may be
is a potential alternative for SP for IPTp and its evaluation
as important to maternal, foetal and neonatal health as
in clinical trials is warranted. Several scientific and pro-
the clearance and prevention of malaria. Innovative pric-
grammatic questions need to be addressed, however, so
ing mechanisms would be required to introduce azithro-
that policymakers and programme managers are able to
mycin-chloroquine for IPTp since the drug cost per
consider the merits of azithromycin-chloroquine in IPTp.
pregnancy would otherwise be US $14.00 to $21.00 for
Key questions include:
two or three courses. Close monitoring of antibiotic resist-ance markers would need to be an essential part of any
1) Is azithromycin-chloroquine superior to SP and other
IPTp programme using azithromycin-chloroquine.
candidate replacements for IPTp in reducing LBW, mater-nal anaemia and parasite clearance?
Competing interests
The authors declare that they have no competing interests.
2) How much of the IPTp effect on birth weight, using azi-thromycin-chloroquine, may be due to a reduction in
STIs, and what might be the savings, human and financial,
MC structured the review and wrote the paper. RP
due to reduced STIs in pregnancy that could result?
reviewed the early manuscript and contributed to the writ-ing of the paper. BG reviewed the early manuscript and
3) Might administration of azithromycin-chloroquine
contributed to the writing of the paper. DC refined the
prior to quickening and within the last month of gestation
structure of the review and contributed to the writing of
– periods contraindicated with SP – have additional effect
the paper. All authors read and approved the final version.
on LBW, maternal anaemia and parasite clearance?
4) Would the use of azithromycin-chloroquine for IPTp
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