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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 (page number not for citation purposes) 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 (page number not for citation purposes) 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 (page number not for citation purposes) 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 [ (page number not for citation purposes) 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 paet 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, (page number not for citation purposes) 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- (page number not for citation purposes) 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 thepfcrt 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 fain 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.
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