Thus, inappropriate treatment for congenital syphilis in both groups could have limited the protective effect of azithromycin on preterm delivery. In contrast to these findings, a trial in Malawi recently reported clear benefit from more frequent dosing with SP-IPTp and azithromycin. The incidence of preterm delivery was With the addition of 1 g azithromycin on two occasions to monthly SP-IPTp, the incidence of preterm delivery was lowered further to In this study, women who tested positive for syphilis were given 2.
Piperaquine may possibly be combined with azithromycin and may be better tolerated than chloroquine [ 42 ], although the two have never been tested together and the teratogenicity of piperaquine is unknown. Further investigation is needed into the prolongation of the cardiac QTc interval observed following piperaquine treatment [ 43 ]. Pyronaridine and mefloquine have each demonstrated an additive effect in vitro with azithromycin [ 17 ], although pyronaridine teratogenicity requires evaluation. Dihydroartemisinin plus azithromycin are additive to synergistic in vitro [ 44 ] whereas artesunate has shown an antagonistic effect in vitro with azithromycin [ 17 , 45 ].
This is important as it may explain the poor in vivo efficacy observed in Tanzania during a pediatric trial that combined artesunate and azithromycin [ 46 ], but not seen in trials among semi-immune adults in Thailand [ 47 ] and Bangladesh [ 48 ]. The in vitro antagonism between azithromycin and artesunate may not have been apparent in Thailand and Bangladesh because the semi-immune adults were better able to render an acquired-immune response and, thus, overcame infection despite the drug antagonism, compared with more immunologically naive pediatric patients in Tanzania.
Synthesized in the s, azithromycin is the first compound of the azalide family of antibiotics. Animal studies have shown that quantities two to four times the human daily dose do not reduce fertility nor cause fetal harm [ 49 ]. Doses up to 2 g azithromycin have been used in all trimesters of human pregnancy. Azithromycin is better tolerated than erythromycin and can be taken for shorter time periods to achieve the same therapeutic effect [ 50 ]. Long-term azithromycin chemoprophylaxis among HIV-positive patients, however, may be poorly tolerated [ 51 , 52 ].
The chemoprophylactic efficacy of azithromycin against P.
Although these studies were conducted between and , parasite sensitivity to azithromycin is likely to be the same today as the drug has not been used on any scale for malaria prevention. Azithromycin is less active against P. The trial in Indonesia described above reported A study of P. This was the first part of a two-stage trial that demonstrated in vivo synergy between azithromycin and chloroquine, and is described in greater detail within the azithromycin-chloroquine efficacy section.
Chloroquine is a 4-aminoquinoline antimalarial drug. Antenatal dosing with hydroxychloroquine throughout pregnancy has shown to have no effect on newborns up to 1 year postpartum [ 55 ]. An observational study did not detect any ophthalmo-logical abnormalities in the children born to women who used hydroxychloroquine or chloroquine for a mean of 7. The most commonly reported side effect of chloroquine in African population is pruritus which peaks 24 h after an oral dose [ 56 ]. Tolerability may vary among African populations as three times the treatment dose formerly recommended by the WHO does not appear to increase the incidence of adverse events in Guinea-Bissau [ 57 ].
Six times the therapeutic dose of mg chloroquine can produce hypotension and cardiac failure [ 58 ]. Nevertheless, chloroquine is generally well tolerated in treatment doses, can be safely administered in any trimester of pregnancy [ 13 - 16 ] and readily crosses the placenta of pregnant women without teratogenic effect [ 59 ]. Chloroquine was developed in and became the first-line treatment for all forms of malaria in the late s and s. A dose-finding study conducted during World War II reported that a regimen of mg base was used over 3 days to cure 10 Chinese and 8 American soldiers infected with P.
A recent systematic review of studies shows that chloroquine still has an APR of Treatment failures, however, have been on the rise over the past 5 years [ 63 ] with the primary foci of resistance in Indonesia, Papua New Guinea, Timor-Leste and other parts of Oceania [ 64 ]. Reports of chloroquine resistance have also come from India [ 65 ] and South America [ 66 , 67 ]. Although chloroquine remains available at the community level in many settings, it is no longer recommended for the treatment of uncomplicated P. Prior to the introduction of SP-IPTp, pregnant women commonly received sachets of chloroquine chemoprophylaxis during antental consultations, each containing four weekly doses of mg for self-administration [ 68 ].
Even today, chloroquine may offer modest chemoprophylactic effect against low birth weight among pregnant women in West Africa [ 69 ], although this may be limited to multigravidae [ 70 ]. Table 2 contains efficacy data of four studies that included chloroquine monotherapy arms, two being pediatric treatment trials of particular note.
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These are described within their national contexts below. Efficacy of azithromycin, chloroquine or the combination against P. Falciparum infection observed among non-pregnant adults and children in recent studies.
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Malawi was the first country in sub-Saharan Africa to abandon chloroquine in favor of SP for the treatment of uncomplicated malaria. In , chloroquine treatment failure rates had been as high as Five years later, chloroquine in vitro testing inhibited blood schizont development in Genetic analysis of P.
Nevertheless, perpetuating chloroquine-resistant polymorphisms comes with a high fitness cost for P. Plasmodium falciparum resistance to chloroquine was first reported in Guinea-Bissau in [ 77 ]. Among these strains, pfcrt 76T was associated with resistance but pfmdr 1 86Y was not. In addition, the prevalence of single-nucleotide polymorphisms at pfcrt positions 76, and , and pfindrl position 86 did not change significantly [ 78 ]. Although the treatment efficacy was not reported, it appears as though a regimen with 2. This suggests that chloroquine resistance, while widespread, is not particularly potent [ 80 ].
Reinforcing this are data from a recent pediatric trial in Guinea-Bissau. No severe drug-related adverse events were reported, although pruritus was reported in Data available on the safety and tolerability of azithromycin plus chloroquien are limited. No other dose-response relationships were observed, although chloroquine-associated pruritus was common in sub-Saharan Africa studies where the prevalence ranged from Data are not disaggregated by country or study site, but as previously noted, evidence from a study among children in Guinea-Bissau suggests that some African populations tolerate chloroquine better than others [ 79 ].
A placebo-controlled two-arm trial followed by an open-label single-arm study in India demonstrated in vivo synergy using the combination of azithromycin plus chloroquine [ 18 ]. In the placebo-controlled trial, 32 semi-immune subjects were treated for uncomplicated P. In the second open-label study, 64 semi-immune subjects with P.
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By day 28, azithromycin had continued to suppress fever and parasites in only These outcomes were in contrast to the treatment effect reported among subjects who received combination therapy. ACPR at day 7 was It is also likely that women in sub-Saharan have greater acquired immunity than their Indian counterparts. Thus, the synergy between azithromycin and chloroquine observed in the Indian studies may be replicable elsewhere among pregnant women whose parasite densities at the time of treatment are equal to or lower than levels reported in the Indian study population.
The results of several published clinical trials, conference presentations and data from a recently published Cochrane review are consolidated in Table 2 , while important contextual factors are discussed below. Studies investigating azithromycin plus chloroquine involved only non-pregnant adults with P.
The first study of azithromycin plus chloroquine in sub-Saharan Africa was a small two-arm placebo-controlled trial in a high-transmission area of western Kenya that was suspended prematurely due to logistical issues. Nevertheless, a regimen of 1 g azithromycin plus mg chloroquine daily for 3 days was able to achieve parasite eradiation in five of five subjects by day 28; one treatment failure RIII was reported that cleared by day 7 and did not recur through day 28 [ 81 ]. This was followed up by a multicenter, multicountry, placebo-controlled trial in sub-Saharan Africa that compared two regimens of azithromycin 1 g vs.
The study arm of mg azithromycin was suspended early based on the data from South America and India; no data were reported. However the day PCR-adjusted APR for the group given three doses of 1 g azithromycin plus mg chloroquine was Of particular interest is the sub-analysis of APR by pfcrt prevalence by the study site. Several studies of azithromycin-chloroquine have been conducted outside of sub-Saharan Africa and are included in Table 2. A multicenter study in India and Colombia evaluated a combination of 2 g azithromycin with mg chloroquine base once daily for 3 days; the PCR-adjusted day efficacy was Azithromycin is an analog of erythromycin, modified by the insertion of a nitrogen atom into the macrolide nucleus.
It is stable at gastric pH with a high affinity for tissue due to the presence of two basic tertiary amine groups which enhance its amphiphilic properties [ 85 ]. Azithromycin targets the S ribosomal subunit of the apical complex in susceptible microorganisms including P.
Once attached, azithromycin hinders polypeptide development by triggering premature detachment and movement along the peptide exit tunnel. Azithromycin accumulates in hepatic, renal, pulmonary and splenic tissue [ 90 ], slowly reaching the circulatory system over a 1-week period [ 86 ]. Less than 3. Azithromycin is not known to cause any clinically significant interactions [ 95 ]. A study of 20 pregnant women showed that maternal serum concentrations peak within 6 h of dosing and high serum concentrations are sustained for 24 h [ 96 ].
Compared with serum, azithromycin achieves high and sustained concentrations in the body tissues. In the above study, the concentrations were seven, six and three times higher in placental, myometrial and adipose tissues, respectively. Figure 1 illustrates the concentration-time profile of azithromycin over time in serum and tissues. A more recent pharmacokinetic study of azithromycin two 2 g doses 24 h apart plus chloroquine mg base daily for 3 days given to 31 pregnant and 29 non-pregnant women in Papua New Guinea showed that plasma concentrations of azithromycin differ between groups within the first 48 h of dosing.
The pharmacokinetic profiles were similar between groups, indicating that dose adjustments may not be necessary among pregnant women, even in the presence of parasitemia [ 97 ]. Chloroquine pharmacokinetic end points were not reported. Adapted from [ 96 ]. Chloroquine is quickly absorbed and reaches high concentrations in the digestive vacuoles of malaria parasites.
Once there, chloroquine forms a complex with ferriproporphyrin IX FP , a major toxic by-product of parasitic hemoglobin digestion, preventing parasites from polymerizing FP into harmless hemozoin and expelling it through their digestive vacuoles. As a result, parasite membranes become highly permeable, causing rapid death [ 98 ]. As discussed previously, resistance to chloroquine is associated with parasite protein pfcrt mutant alleles K76T or, in two single cases, K76N or K76I [ 99 ]. These are located in the digestive membrane of the food vacuole [ , ]. Some researchers suspect that pfcrt enables protonated chloroquine to escape the food vacuole whereas others postulate that pfcrt binds directly to chloroquine, inhibiting its ability to alter vacuole pH [ ].
Chloroquine accumulates extensively in hepatic, connective and pigmented tissues [ ]. Its half-life is 1 - 2 months [ , ]. Known pharmacokinetic interactions of chloroquine are presented in Table 3. Praziquantel is the first-line anti-schistosomal therapy recommended by the WHO for use among pregnant women in endemic areas [ ]. However, pregnancy did not alter overall pharmacokinetics and researchers concluded that no adjustment in regimen would be required for pregnancy [ ]. The results of another pharmacokinetic study in Papua New Guinea involving 30 pregnant and 30 non-pregnant indicate otherwise.
Women were given a daily dose of mg chloroquine base for 3 days along with SP-IPTp per national policy. Chloroquine and related metabolites were still present 42 days later, but plasma concentrations were significantly lower in pregnant women.
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This may explain treatment outcomes among those with asymptomatic parasitemia at enrollment. In total, By day 28, P. Table 4 combines key pharmacokinetic results from the two Papua New Guinea studies, comparing selected end points for chloroquine [ ] and azithromycin [ 97 ].
A separate clinical trial being conducted in parallel at the same sites will evaluate the parasite clearance rates and pharmacokinetics of the same fixed-dose combination regimen in pregnant women with P.
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