The World Health Organization (WHO) treatment guidelines for uncomplicated malaria recommend combination therapy to reduce the development of drug resistance and to improve therapeutic efficacy. Over the past decade highly efficacious artemisinin-based combination therapies (ACTs) have been implemented across the world (WHO/RBM 2006). Despite this substantial progress, there is a clear need for further antimalarial combinations, involving both candidates for the next generation of first-line antimalarials and those that address specific niches in malaria control, such as options that are safe for use during early pregnancy or that can be used for syndromic approaches that target multiple diseases.
Three antibiotic groups have been shown to have antimalarial activity in studies using experimental malaria models: tetracyclines, lincosamides, and macrolides (Pradines 2001). Antibiotics have also been used in clinical practice to enhance the effect of available antimalarials. For example, tetracycline and doxycycline (tetracyclines) and clindamycin (a lincosamide) are recommended in combination with quinine as a second-line treatment option for uncomplicated malaria following a treatment failure (WHO/RBM 2006). However, because they can disturb bone and teeth development, the tetracyclines are contraindicated among pregnant women and children, frequently the most vulnerable groups for malaria (Nosten 2006).
Azithromycin is a potential alternative treatment option. This relatively new macrolide antibiotic has a longer half-life (approximately 60 hours) and better pharmacokinetic properties (adult treatment dose for bacterial infections 500 mg orally once daily for three to seven days) compared to the macrolide erythromycin, which is widely available in developing countries (standard adult treatment dose for bacterial infections is 250 to 500 mg orally every six hours or 0.5 to 1 g every 12 hours for seven days or more). Azithromycin can treat a broad spectrum of bacterial infections; it has an attractive safety profile and could be an option for use in pregnancy, where the currently available arsenal of effective and safe antimalarials is limited (Nosten 2006). Several trials have used azithromycin to treat sexually-transmitted diseases and genital infections during pregnancy with no reports of adverse neonatal outcomes (Adair 1998; Gray 2001; Ogasawara 1999).
Studies of the efficacy of azithromycin in the treatment of uncomplicated malaria in experimental and animal models have shown that azithromycin is a relatively weak antimalarial with a slow parasite clearance rate. The treatment dose, duration of therapy, and antimalarial partner drug are reported to be important determinants of efficacy (Andersen 1995; Biswas 2001; Gingras 1992; Gingras 1993; Neerja 2004; Noedl 2001; Ohrt 2002; Puri 2000; Yeo 1995;). Results from experimental clinical studies using azithromycin (in combination or alone) for treating symptomatic malaria in Asia were inconsistent in methodology, dose used, and outcome measures (Dunne 2005a; Dunne 2005b; Krudsood 2000; Krudsood 2002; Miller 2006; Na-Bangchang 1996). In this review, we aim to summarize the available data from randomized controlled trials to assess the usefulness of azithromycin for the treatment of uncomplicated malaria and to identify its potential niche among the available antimalarial drugs.
To compare the efficacy and safety of azithromycin, alone or in combination with other antimalarial drugs, with alternative antimalarial drugs for treating uncomplicated malaria caused by Plasmodium falciparum or Plasmodium vivax.
Criteria for considering studies for this review
Types of studies
Randomized controlled trials.
Types of participants
Children and adults presenting with uncomplicated malaria (P. falciparum or P. vivax) confirmed by microscopy.
Excluded: studies in participants with signs of complicated malaria as defined by the authors (including cerebral malaria, convulsions, circulatory collapse, abnormal breathing, jaundice, macroscopic haemoglobinuria, prostration, renal impairment, severe anaemia, and hypoglycaemia) (WHO/AFRO 2001), and studies in which the participants are exclusively pregnant women.
Types of interventions
Azithromycin alone, combined with another antimalarial drug, or combined with a placebo.
- Other antimalarial drug used alone, combined with other antimalarial drugs, or combined with a placebo.
- Azithromycin alone if the intervention is azithromycin combined with another antimalarial drug.
- Azithromycin combined with another antimalarial drug if different combinations or doses of azithromycin have been used.
Types of outcome measures
Treatment failure by day 28 (unadjusted for new infections), defined as parasitological or clinical evidence of treatment failure between the start of treatment and day 28. This is equivalent to total failure defined in the current WHO guidelines (Bloland 2003) and includes new infections. Parasitological treatment failure means failure of the malaria parasite to clear from the blood during the follow-up time, or returning of malaria parasites in the blood within 28 days after initial clearance. Clinical evidence of treatment failure means parasitaemia in the presence of danger signs (vomiting, history of convulsions, inability to sit, inability to drink, lethargy); parasitaemia in the presence of symptoms of complicated malaria as described above (WHO/AFRO 2001); parasitaemia in the presence of documented fever (37.5 °C when measured axillary or 38.0 °C or more when measured rectally); or clinical treatment failure as defined by the trial authors for trials conducted before 2003.
- Treatment failure by day 28 corrected for new infections confirmed by polymerase chain reaction (PCR), defined as parasitological or clinical evidence of treatment failure between the start of treatment and day 28.
- Fever clearance time.
- Parasite clearance time.
- Presence of gametocytes on day 7, 14 or 28.
- Morbidity other than clinical malaria (eg diarrhoea, respiratory tract infections) up to 28 days.
- Serious adverse events defined as fatal, life threatening, or those that require hospitalisation.
- Adverse events that may lead to discontinuation of the drug.
- Other adverse events.
Search methods for identification of studies
We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
We searched the following databases using the search terms and strategy described in Table 1: Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; and the metaRegister of Controlled Trials (mRCT).
We searched the conference proceedings of the Multilateral Initiative on Malaria Pan-African Conferences and the Annual meetings of the American Society of Tropical Medicine and Hygiene (ASTMH) for relevant abstracts.
Researchers, organizations, and pharmaceutical companies
We contacted individual researchers working in the field, organizations including the WHO, and pharmaceutical companies (Pfizer, Sandoz) for unpublished and ongoing trials.
We checked the reference lists of all studies identified by the above methods.
Data collection and analysis
The first author screened the results of the search strategy for potentially relevant trials and retrieved the full articles of these trials. Each trial was scrutinized for multiple publications from the same study. Using an eligibility criteria form based on the inclusion criteria, two authors independently assessed the trials for inclusion in the review. Discrepancies between assessments were resolved through discussion or referred to an editor of the Cochrane Infectious Diseases Group when needed. We excluded studies that did not meet the inclusion criteria for the efficacy assessment and stated the reason for exclusion; however, we included these studies for adverse events.
We piloted the data extraction form before using it for independent data extraction. We attempted to contact the corresponding author if the available data was unclear, missing, or reported in a format that was different to the format that we required.
We extracted the number of participants analysed and the number randomized for each treatment arm and for each outcome. We calculated the percentage loss to follow-up and reported this information in the characteristics table. For continuous outcomes, we extracted the arithmetic means and standard deviations for each treatment group, together with the numbers of participants in each group. If medians were extracted, we also extracted ranges. For dichotomous outcome measures (eg treatment failure, presence of gametocytes, adverse events), we recorded the number of participants experiencing the event and the number analysed in each group. We entered the data in Review Manager 5.0.
Methodological quality assessment
We used 'The Cochrane Collaboration's tool for assessing the risk of bias' (Higgins 2008). We followed the guidance to assess whether adequate steps had been taken to reduce the risk of bias across six domains: sequence generation; allocation concealment; blinding (of participants, personnel, and outcome assessors); incomplete outcome data; selective outcome reporting; and other sources of bias (Juni 2001; Schulz 2002). We have categorized these judgments as 'yes' (low risk of bias), 'no' (high risk of bias), or 'unclear'. Where our judgement was unclear, we attempted to contact the trial authors for clarification.
We analysed the data using Review Manager 5.0 and presented all results with 95% CI. If no participants were lost to follow-up, we used an intention-to-treat analysis. For trials with loss to follow-up, we undertook an available case analysis, in which trial participants were analysed by the arm they were randomised into and participants for whom the outcome was not collected were excluded.
We compared dichotomous data using relative risks. Where data were presented using medians and ranges, we presented the data in tables only. We aimed to conduct sensitivity analyses based on allocation concealment and loss to follow-up. We did not intend to combine trials of different comparator drugs.
We assessed heterogeneity by inspecting the forest plots and assessing the heterogeneity statistics (Chi
Description of studies
We identified 19 potential studies for inclusion. Two studies were excluded because their results were not yet available: one was still ongoing at the time of the search (Pfizer 677833), and one study was completed but the analysis was not yet finished (NIAID 379821). Two other studies were excluded from the efficacy analysis because they were not randomized (Krudsood 2002; Pfizer 282919); however, these studies were included in the evaluation of adverse events. In the remaining 15 studies, 2284 participants were enrolled and 2083 (91.2%) were available for the analysis of the primary endpoint. Participants were children and adults: the lowest age for inclusion was six months (Sykes 2009). However, most studies included adolescents and adults only (13 out of the 15 studies); we estimate that 374 of the enrolled participants (16.4%) were children < 60 months and/or with a weight < 35 kg. Sixty-nine percent of participants were male and two studies included men only (Na-Bangchang 1996; Pukrittayakamee 2001); all studies excluded pregnant women. The earliest study started in 1995 and the most recent study finished in 2009. The majority of studies were funded by Pfizer alone (nine) or in combination with others (two). Six trial synopses were retrieved from the web from studies sponsored by Pfizer; the role of the funding agency was not stated in these reports.
Two studies examined P. vivax (Dunne 2005a; Pukrittayakamee 2001), whereas P. falciparum was the species of primary interest in all other studies. The early studies were conducted in Thailand (five) and India (two), whereas the more recent studies (eight) were conducted across three continents (South America, Africa, Asia). Thailand is known for its multi-resistant P. falciparum, with described resistance to chloroquine, sulphadoxine-pyrimethamine, mefloquine and quinine; malaria transmission is generally low, unstable, and seasonal. There is no malaria transmission in Bangkok, the site of three studies. Malaria transmission within the area investigated in the early Indian study was reported as "stable throughout the year" (Dunne 2005b). One of the Pfizer studies was conducted in an area of intense malaria transmission in Kenya (Pfizer 82563), but the type of malaria transmission in the areas of the other Pfizer studies was not reported. Malaria transmission was high in the study area in Tanzania (Sykes 2009), but moderate-to-low in the study area in Bangladesh (Thriemer 2010). All studies followed participants up to day 28, with seven of them reporting PCR-adjusted failure rates and seven studies continuing follow-up until day 42. However, only three studies reported day 42 results (Pfizer 84227, Sykes 2009, Thriemer 2010).
There was a wide variety in the drug combinations, doses of azithromycin and comparator drugs, and regimens used, with 41 treatment arms of the 15 studies involving 12 different antimalarials, and 28 different treatment regimens (see Characteristics of included studies or Table 2). The most common azithromycin combination was 1 g azithromycin with 0.6 g chloroquine daily for three days (1 g azithromycin/chloroquine), used in six arms. The characteristics of the included studies are given in the Characteristics of included studies table.
All studies except one (Pfizer 367653) reported excluding subjects with a recent history of intake of an antimalarial, although the period of intake could vary between the last 48 hours to 42 days prior to enrolment. In Tanzania, only subjects with a history of intake of an effective antimalarial were excluded, because local drug resistance to commonly used antimalarials such as sulfadoxine-pyrimethamine, amodiaquine and chloroquine was reported to be > 70% (Sykes 2009). Two studies used drug screening tests to confirm the absence of antimalarial metabolites (Na-Bangchang 1996; Pukrittayakamee 2001).
Risk of bias in included studies
The available information did not allow an appropriate evaluation of the quality of the data. The six trial synopses from Pfizer that were publicly available contained limited information on the methods, and did not specify randomization and allocation concealment. Baseline characteristics were broadly comparable between arms except for the baseline parasite density in the combination arm of a study in India, which was lower than the other arms (Table 4, Dunne 2005b). Four trials conducted by Pfizer included an arm with 0.5 g azithromycin and 600 mg chloroquine for three days; when one of these trials in India showed low efficacy in a second interim analysis, this arm was stopped in this and all other trials where this arm was used (Pfizer 74841, Pfizer 82576, Pfizer 84227, Pfizer 84240). Results were presented for the 59 participants in the arm for the trial in India (Pfizer 74841), but not for this arm in any of the other trials in which nine, 14, and seven participants were enrolled, respectively (Pfizer 82576, Pfizer 84227, Pfizer 84240). Two studies were reportedly terminated because of a slow rate of recruitment (Pfizer 84240, Pfizer 82563) and two arms in one trial were terminated prematurely because of a lack of efficacy (Dunne 2005b); results of the enrolled participants in these studies were included in our analyses (except for the 0.5 g azithromycin/600 mg chloroquine arm in Pfizer 84240). The comparator drugs for the studies by Pfizer in Africa, Indonesia, and South America were not the first-line drug in the respective countries.
A summary of the 'Risk of bias' assessments is presented in Figure 1 and Figure 2. Of the 15 trials included in the assessment of efficacy, the sequence generation and allocation concealment was adequate and judged to be at low risk of bias in three studies, and unknown in the remaining trials. Only five studies were judged to be at low risk of bias due to adequate blinding. Blinding of laboratory staff was conducted in five open label studies, reducing the bias for the efficacy outcome; however, adverse event reporting will remain at risk of bias in these studies.Two trials were considered to be at high risk of bias due to a moderate loss of participants (> 15%), and/or unequal distribution of loss of participants between treatment arms. We considered almost all trials at risk of selective reporting for one or more of the following reasons: the outcome assessment seemed subjective; there was no baseline data provided by treatment arm; adverse events were not reported by treatment arm; prespecified outcomes were not reported; treatment arms were included that were not randomized; only men were included; interim analyses and subsequent halting of treatment arms; and halting of complete studies before the sample size had been reached. Only one study reported that the sponsor had no role in data analysis and writing of the report (Thriemer 2010).
|Figure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
|Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
Effects of interventions
Details of how we derived estimates of total failure from the data in each trial report can be found in Table 2. Six treatment arms used the same treatment combination and dose for azithromycin (1 g of azithromycin for three days in combination with 0.6 g of chloroquine for three days); however, only three comparison regimens were the same. An overview of the RR for comparing an azithromycin-containing regimen with an alternative regimen can be seen in Table 3 (P. falciparum and P. vivax) and Analysis 1.1 (P. falciparum). A risk ratio (RR) greater than one indicates that the azithromycin regimen is more likely to result in treatment failure compared to the alternative regimen; a RR less than one indicates the opposite. The attained efficacy and 95% confidence interval for each arm, stratified by dose, is presented in Figure 3 and Figure 4, with PCR-adjusted results used for P. falciparum where available. To allow comparison and for completeness, we also show the information from the excluded trials. A meta-analysis could be conducted for the comparisons between azithromycin/chloroquine and sulphadoxine-pyrimethamine/chloroquine, azithromycin/chloroquine and mefloquine, azithromycin/chloroquine and chloroquine, and azithromycin/artesunate and artemether/lumefantrine. For the comparison between azithromycin/chloroquine and chloroquine, the chloroquine doses used differed (0.3 g on day three versus 0.6 g on day three), and the sample sizes of the second study were very small (Dunne 2005b; Pfizer 82563); for this reason, the results of the first study and not the meta-analysis have been presented where necessary (Dunne 2005b).
|Figure 4. Efficacy of azithromycin containing treatment regimens for P. falciparum (28 days follow-up)|
Abbreviations: AZ: azithromycin; CQ: chloroquine; Artm: artemether; Art: artesunate; dihydroart: dihydroartemisinin; Q: quinine; CI: confidence interval; d: days
Symbols: *: PCR-corrected; **: partially PCR-corrected; §: study conducted in an area without malaria transmission (Bangkok). The AZ dose in the combination with artemisinin 300 mg was 500 mg at start, followed by 250 mg after 24 hours and 48 hours.
An interrupted line has been drawn at the 90% efficacy level, the minimum level for the 95% confidence interval for a potentially useful drug regimen as recommended by WHO (WHO/RBM 2006).
There was no difference in total treatment failure rates for a three-day course of azithromycin monotherapy (azithromycin 0.5 g per day) compared with seven-day monotherapy courses of tetracycline, doxycycline or clindamycin in Thailand (Figure 3). In India, a three-day course of azithromycin (1 g per day) was significantly less efficacious than the standard first-line chloroquine course. In the latter study, all participants were treated with primaquine from day 7 until day 20, which may partly explain the overall higher efficacy at day 28. Compared to the other antibiotics, the time to P. vivax parasite clearance was longer with azithromycin monotherapy (Table 5).
The main meta-analyses used a fixed-effect model (except for the comparison between azithromycin/chloroquine and chloroquine) and data for participants who could be evaluated at follow-up. Because of the limited number of comparisons that could be made, no exploration of the effect of trial methodology on the estimate of treatment effect was conducted.
Total failure by day 28
Azithromycin combination therapy at a dose of 0.5 g per day in combination with chloroquine at 0.6 g per day for three days resulted in a high level of day 28 treatment failures in a study in India (Pfizer 74841) compared with a sulphadoxine-pyrimethamine/chloroquine combination (RR 6.10, 95% CI 2.21 to 16.87), and a combination of chloroquine and 1 g of azithromycin per day (RR 2.96, 95% CI 1.00 to 8.75). This led to the premature termination of the 0.5 g azithromycin/chloroquine arm in all Pfizer sponsored trials (Pfizer 82576, Pfizer 84227, Pfizer 84240) at that time. The results of the 0.5 g azithromycin/chloroquine arm from the other studies before termination were not available.
The combination of an azithromycin dose of ≤0.5 g per day for three days in combination with artesunate or artemether did not perform well. Krudsood et al (Krudsood 2000) report an increased risk of day 28 treatment failures when the combination of 0.5 g azithromycin and artesunate for three days is compared with mefloquine/artesunate (RR 24.00, 95% CI 3.36 to 171.27), but not when compared with three days of artesunate monotherapy (RR 0.78, 95% CI 0.54 to 1.14). Na-Bangchang et al report an increased risk of treatment failure when comparing the combination of azithromycin at 0.5 g for three days and artemether at 300 mg at start with doxycycline for five days and artemether in a higher dose (300 mg at start and 100 mg after 12 hours) (RR 1.83, 95% CI 1.21 to 2.76) (Na-Bangchang 1996).
Cure rates using an azithromycin dose of 0.5 mg ranged from 15% (95% CI 5% to 35%, in combination with artemether; Na-Bangchang 1996) to 66% (95% CI 53% to 78%, in combination with chloroquine; Pfizer 74841). A higher cure rate of 86% (95% CI 42% to 99%, in combination with chloroquine) was reported among seven adult participants in Africa (Pfizer 82576).
When using azithromycin doses of 1 g per day or higher, no difference was seen in treatment failures when comparing azithromycin/quinine combinations (different dose regimens for three or five days) with a doxycycline/quinine combination for seven days (Miller 2006) or azithromycin/artesunate combinations for three days (different dose regimens) (Noedl 2006) in Thailand, but sample sizes were small (< 30 participants).
Azithromycin doses of > 1 g per day for three days (1.5 g per day in Bangladesh, and 20 mg/kg/day among children in Tanzania) in combination with artesunate were associated with increased treatment failure compared to artemether-lumefantrine (pooled RR 3.08, 95% CI 2.09 to 4.55; Analysis 1.1) (Sykes 2009, Thriemer 2010).
Dunne et al in India showed reduced treatment failure for the combination of 1 g azithromycin daily for three days and chloroquine (the standard dose of 0.6 g on day 1 and 2, and 0.3 g on day 3) versus chloroquine alone (RR 0.04, 95% CI 0.01 to 0.18) or azithromycin alone (1 g daily for three days: RR 0.05, 95% CI 0.01 to 0.20) (Dunne 2005b). A 1 g azithromycin/chloroquine combination (1 g azithromycin and 0.6 g chloroquine daily for three days) was associated with increased treatment failure in India and Indonesia compared with the combination sulphadoxine-pyrimethamine/chloroquine (pooled RR 2.66, 95% CI 1.25 to 5.67; Analysis 1.1) (Pfizer 74841, Pfizer 84240) and compared with the combination atovaquone-proguanil in a multi-site trial in Columbia and Surinam (RR 48.43, 95% CI 6.80 to 344.84) (Pfizer 84227). No increased risk on treatment failure was seen in two multi-country studies in Africa with mefloquine (750 mg at start, followed by 500 mg after six to 10 hours) as comparator drug (pooled RR 2.02, 95% CI 0.51 to 7.98, P = 0.3; Analysis 1.1) (Pfizer 82576, Pfizer 367653).
Of the seven studies that followed participants until day 42, three studies reported their day 42 results. For one study, this was not for the evaluable study population (Pfizer 84240); the results of the other two studies are presented in Analysis 1.3. The pooled RR for the combination of azithromycin and artesunate versus artemether-lumefantrine on day 42 was 1.90 (95% CI 1.44 to 2.49, Analysis 1.3).
PCR-adjusted failure rates by day 28
PCR-adjusted (partially) failure rates were available for eight studies. For the two studies in Africa comparing the 1 g azithromycin/chloroquine combination with mefloquine monotherapy, there was sufficient information to repeat the meta-analysis with PCR-adjusted data. The pooled RR was 1.01 (95% CI 0.18 to 5.87), suggesting there was no difference in treatment failure among the two treatment regimens ( Analysis 1.2; Pfizer 82576, Pfizer 367653). However, the fact that the RR decreased from 2.02 to 1.01 may indicate there were more new infections in the azithromycin/chloroquine group and that post-treatment prophylaxis is shorter with azithromycin/chloroquine than with mefloquine. For the two studies comparing azithromycin/artesunate with artemether-lumefantrine, the PCR-adjusted pooled RR on day 28 was 3.63 (95% CI 2.02 to 6.52, Analysis 1.2); on day 42 it was 2.47 (95% CI 1.53 to 3.99, Analysis 1.4).
Figure 4 shows the treatment efficacy and 95% CI for each drug regimen in order of increasing azithromycin dose, using PCR-adjusted data where available. Depending on location and combination drug, there is a tendency for improved efficacy with increasing azithromycin dose. Overall, the highest efficacy level was observed in studies in Africa with a 1.0 g azithromycin/chloroquine combination among adults. However, the only study in African children < five years so far, which used an equivalent or higher azithromycin dose in combination with artesunate, showed insufficient efficacy.
Fever and parasite clearance
Six and eight studies reported data on fever and parasite clearance, respectively, although 12 and 13 studies, respectively, mentioned that this information would be collected. The available data was insufficient for meta-analysis and is presented in Table 4 and Table 5. Drug combinations with artesunate tended to have shorter fever and parasite clearance times compared with other combinations. Asexual parasite clearance was reported to be significantly shorter for atovaquone-proguanil compared with the 1 g azithromycin/chloroquine combination but the underlying data was not provided (Pfizer 84227).
Six studies reported gametocyte outcomes; information from one study could not be interpreted (Pfizer 84240). In India, azithromycin monotherapy for P. vivax resulted in more frequent gametocytaemia at day 7 (17 out of 95) compared with chloroquine (0 out of 99, P < 0.001, Dunne 2005a). In Thailand, Noedl et al did not see a difference in the mean gametocyte clearance time among the regimens used (azithromycin/artesunate combinations and azithromycin/quinine combinations, four arms) (Noedl 2006). Gametocyte clearance was similar between a 1 g azithromycin/chloroquine combination and mefloquine monotherapy until day 28 in a study in Africa. On and beyond day 28, mefloquine showed a slightly higher gametocyte clearance rate than 1 g azithromycin/chloroquine (Pfizer 82576); unfortunately, the underlying data was not provided. No significant difference was seen in gametocyte clearance between 1 g azithromycin/chloroquine and atovaquone-proguanil in South America, although lower gametocytaemia clearance was reported with atovaquone-proguanil from week 3 onwards (Pfizer 84227). In the study among children and adults in Bangladesh, no difference in median gametocyte clearance was found between the azithromycin-artesunate and artemether-lumefantrine regimens (46.1 hours versus 97.2 hours, among 128 and 65 participants respectively; no interquartile range available) (Thriemer 2010).
Morbidity other than clinical malaria (eg diarrhoea, respiratory tract infections) up to 28 days
There was not enough systematic information in the trials to assess this secondary outcome. One trial reported a higher occurrence of upper respiratory tract infections among participants in the control group using artemether-lumefantrine compared to the azithromycin-artesunate arm (9.5% among 65 participants versus 2.3% among 128 participants respectively, P = 0.06, Thriemer 2010). Diarrhoea is discussed under specific adverse events.
Adverse events (All studies)
Details of the safety reporting methods used and the inclusion and exclusion criteria are presented in the Characteristics of included studies table. Entry criteria were rigorous for some studies, limiting the amount of adverse effects that can be expected. Ten studies excluded subjects with an allergy to study drugs, ten studies excluded persons with abnormal laboratory tests, and seven studies excluded persons with severe vomiting. As reported before, pregnant women were excluded in all studies. Three studies did not provide any baseline information. For the other studies, the presented baseline information was comparable between arms, except for the open label arm of 1 g azithromycin/chloroquine in the early study in India (Dunne 2005b), where a lower baseline parasite density was reported. Four studies did not report the procedures used to monitor adverse events. In four studies, the denominator of the study population for the evaluation of adverse events was not reported. Six studies used placebos.
Adverse events overall
The number of persons with any adverse events are presented in Table 6, and reported in terms of 'treatment related' (TR) and 'any cause' (AC) adverse events where this information was provided. TR adverse events are events which in the opinion of the investigators (of the trial) are likely, probably, or possibly related to the intervention the participant received. A participant can have more than one adverse event, and the last columns indicate the total number of adverse events which were reported by arm; the denominator here is the number of subjects, with the average number of adverse events per person in brackets.
No clear difference in frequency of adverse events was detected in studies involving P. vivax (Table 6); in one study the frequency of adverse events tended to be lower in the azithromycin arm (Dunne 2005a), whereas in the other study they tended to be higher (Pukrittayakamee 2001).
The open label arm of the 1 g azithromycin/chloroquine combination in the early study in India reported less adverse events compared to the (blinded) chloroquine (RR 0.37, 95% CI 0.19 to 0.70) or azithromycin (RR 0.41, 95% CI 0.21 to 0.82) monotherapy arms (Dunne 2005b). The azithromycin/artesunate combinations had less TR adverse events compared to the azithromycin/quinine combinations in Thailand (Noedl 2006); the azithromycin/artemether combination had less AC adverse events compared to doxycycline/artemether in the same country (Na-Bangchang 1996). No difference was seen in adverse events when the 1 g azithromycin/ chloroquine combination was compared with sulphadoxine-pyrimethamine/chloroquine; however, the information on adverse events in studies using sulphadoxine-pyrimethamine/chloroquine was very limited (Pfizer 74841, Pfizer 84240). More adverse events were reported in the 1 g azithromycin/chloroquine combination arm compared with mefloquine (RR 1.26, 95% CI 1.06 to 1.50; Pfizer 82576) or atovaquone-proguanil (RR 1.41, 95% CI 1.09 to 1.83; Pfizer 84227) in placebo-controlled studies. This was not seen in the open-label study comparing 1 g azithromycin/chloroquine to mefloquine (RR 1.14, 95% CI 0.95 to 1.37; Pfizer 367653). The pooled RR for TR adverse events when comparing the 1 g azithromycin/chloroquine combination with mefloquine was 1.20, 95% CI 1.06 to 1.36 (Analysis 2.1, Pfizer 82576, Pfizer 367653). No difference in adverse events was detected in the studies comparing azithromycin/artesunate versus artemether-lumefantrine.
Serious adverse events and discontinuations
Serious adverse events and discontinuations are presented in Table 7, with a distinction between TR adverse events and AC adverse events, where this information was provided. We also included any other adverse events reported for laboratory tests or physical examination. Types of serious adverse events are presented in the last column. There were no deaths, and no significant differences between regimens for serious adverse events and discontinuations. Some laboratory abnormalities were reported, but these all seemed transient.
Specific adverse events
Where this information was available, we summarized findings for specific adverse events in Table 8. Because different doses of azithromycin were used over the different trials, we assessed the occurrence of a dose-response relationship for azithromycin. We were able to explore this for nausea (Figure 5), vomiting (Figure 6), diarrhoea (Figure 7), and pruritis (Figure 8). A higher prevalence of nausea (33.0% or 33/100) was reported among participants using 2 g azithromycin/chloroquine (open label study in Columbia/India) compared to participants using 1 g azithromycin/chloroquine (9.6% or 11/114 in placebo controlled trial, RR 3.1, 95% CI 1.7 to 5.8, and 11.5% or 13/113 in open label trial, RR 2.6, 95% CI 1.5 to 4.7, comparing 2 g versus 1 g azithromycin dose). No consistent difference was detected for the other adverse events examined. Although Figure 5 suggested there might be an association between azithromycin dose and nausea, this did not seem to translate into vomiting (Figure 6). No dose-response relationship was apparent for diarrhoea (Figure 7), and pruritis was mainly reported in studies in Africa and South America (Figure 8).
This review covers azithromycin efficacy and safety data for uncomplicated malaria among participants from controlled trials across malaria endemic regions in Africa, South America, and Asia conducted over a 14-year period. Overall, the reviewed studies show the evidence is scattered, variable in quality, and with a considerable risk of bias; additionally, there are substantial gaps in knowledge.
For P. vivax there is simply insufficient data, with only two studies available. From the evidence provided, azithromycin is inadequate as a monotherapy for P. vivax using a dose of 0.5 to1 g per day for three days, and, like other antimalarial antibiotics, has no apparent effect on the P. vivax hypnozoites.
For uncomplicated P. falciparum malaria, the evidence covered a wide variety of dose regimens, partner drugs, and comparators, although the varied reporting quality and low adherence to the widely recommended CONSORT guidelines for the reporting of clinical trials complicated assessment of the evidence (Hopewell 2008). The available data suggest that azithromycin has weak dose-dependent antimalarial activity and is not efficacious as a monotherapy. The current evidence does not support firm conclusions about the use of azithromycin as part of combination therapy for treating uncomplicated P. falciparum. The wide variety of involved treatment arms limited meta-analyses, but individual trial results showed that the efficacy of a combination of 1 g azithromycin/chloroquine for three days was significantly lower when compared with sulphadoxine-pyrimethamine/chloroquine in Asian adults or atovaquone-proguanil in South American adults, and equivalent when compared to mefloquine in African adults. Compared with artemether-lumefantrine, one of the WHO recommended ACTs (WHO/RBM 2006), a higher dose of azithromycin (1.1 to 1.5 g/day for three days) in combination with artesunate was inadequate among African children and inferior among adults in Bangladesh. Only studies of the azithromycin/chloroquine combination among adults in Africa (Pfizer 367653) and one study in India/Colombia had an efficacy level > 95% and a lower 95% CI limit of 90% or above, which is the recommended cure rate for a new antimalarial medicine to be considered for policy (Figure 3, WHO/RBM 2006). For the azithromycin/chloroquine combination, 2 g azithromycin per day for three days may be needed to reach universal cure rates in excess of 90%, but this may not be as well tolerated as 1 g/day.
There were no differences in serious adverse events among the regimens used. There was no difference in adverse events overall when comparing azithromycin/chloroquine with sulphadoxine-pyrimethamine/chloroquine (Asia), but there were significantly more adverse events when comparing azithromycin/chloroquine with mefloquine (Africa) or atovaquone/proguanil (South America). Higher doses of azithromycin may result in nausea, but not necessarily vomiting (Figure 5 and Figure 6). However, a note of caution should be mentioned, because different studies have different systems and rigor regarding the detection of adverse events and so comparing adverse events between studies is not as reliable as comparing adverse events between different arms of the same study.
Besides the standard challenges to meta-analysis in Cochrane reviews related to variations in definitions, endpoints and study design between reviewed studies, two issues deserve specific mention. Over the past few years the assessment of efficacy of antimalarials with longer half-lives has moved towards the use of day 42 PCR-adjusted findings as the primary endpoint of interest (Stepniewska 2004). PCR-adjustment is particularly important in areas of high malaria transmission, where on the one hand a high rate of re-infection may mask successful clearance of the original infection, while on the other a higher background immunity of older children or adult participants may complement the drug treatment and may mask a low-grade level of drug resistance (White 2002). Of the 13 randomized trials for P. falciparum, three were conducted in an area without malaria transmission (Bangkok, Thailand), while (partial) PCR adjustment for day 28 was available for eight trials, including trials in Africa that were presumably conducted in areas of higher transmission. Although seven studies reportedly followed patients until day 42, those outcomes were not presented in the publications for five of these studies.The half life of azithromycin (approximately 60 hours or 2.5 days) suggests that treatment failures are likely to occur by day 28, but the day 28 PCR-adjusted rates may underestimate the true failure rates. The RR for the azithromycin-combination compared with a comparator drug may also depend on the pharmacokinetic qualities of the comparator drug, eg if this is a short-acting or a long-acting drug, or a drug with a post-treatment prophylactic effect.
This review is also defined by the fact that almost half of the reviewed trial information originated from publicly-available trial synopses prepared by the manufacturer Pfizer. The company has made a commendable effort to provide public access to their unpublished research findings on azithromycin, allowing us to include the majority of relevant azithromycin treatment trials in this review. Although these synopses are limited in the amount of detail and did not go through the standard peer review process, they make up a substantial proportion of the available 'azithromycin for malaria' literature. The reported methodology sections in the manuscripts and trial synopses frequently lacked the required level of detail to assess the quality of the trials. Pfizer and authors of non-Pfizer-related articles were contacted for additions, clarification and verification of the quality, methods and data where needed, which was partially obtained.
One study, conducted between 1998 and 2001, needs specific mention from a methodological perspective. The promising results of this study for the 1 g/day azithromycin dose in combination with chloroquine (Dunne 2005b) likely guided Pfizer’s subsequent efforts to assess the antimalarial properties of azithromycin, but we had serious quality concerns: the azithromycin/chloroquine combination arm was not blind and was not conducted concurrently with the other arms. This suggests that randomization may not have occurred for this last arm, and technically this arm could be excluded from this review. Results may indeed have been somewhat biased, as the enrolment parasitaemia of the last arm was lower compared to the other arms and enrolment parasite density is a well-known determinant of treatment outcome (Stepniewska 2004). In addition, the outcome assessment appeared subjective ("Any participant who, in the opinion of the investigator, had not sufficiently improved received additional antimalarial therapy"). This may have contributed to the higher efficacy level observed in the initial study in India compared to the later study in the same country.
The variation in assessed azithromycin doses and treatment arms for the azithromycin-chloroquine combinations that followed the initial Indian study in part depicts the product development and dose-optimisation process Pfizer undertook to adapt a widely used antimicrobial for an antimalarial application. Unfortunately, although there are guidelines for assessing drug efficacy, there are no clear guidelines for the development and field assessment of optimal antimalarial doses and dose regimens for programmatic conditions, taking into account efficacy and safety as well as costs, user-friendliness, and long-term prospects, particularly the potential for drug resistance (Barnes 2008). It is increasingly being recognized that new antimalarial candidates may not achieve their full potential in terms of impact and useful life-span because of a lack of attention to dose-optimization, and a tendency to select, register and market doses at the lower end of the therapeutic range, which before long fuel the development of resistance.
The assessed azithromycin doses, observed dose-dependency, and regional variation in efficacy illustrate this issue (Figure 2). Sub-optimal results were obtained among adults in India, Colombia, Surinam, and Indonesia when a 1 g azithromycin/chloroquine combination was used; however, this same dose and combination performed well in Africa, where a higher level of pre-existing antimalarial immunity in adult study participants may have contributed to high clearance rates. A relatively high dose of 1.2 g azithromycin per day in combination with artesunate was insufficient for African children, confirming the likely role of pre-existing immunity in the observed difference in parasite clearance. The level of background chloroquine resistance in the study area will also have contributed to the difference in the azithromycin/chloroquine combination; in areas with a high level of chloroquine resistance, the combination is effectively reduced to an azithromycin monotherapy. In addition, the effect of dose may depend on a patient's weight, with higher treatment failure rates reported in heavier subjects in two studies (Pfizer 74841, Pfizer 82576). A recent single arm study using a high dose of azithromycin (2 g/day for three days) in combination with chloroquine did show a higher efficacy in a multi-site study in adults in India and Columbia (Pfizer 282919), suggesting that a 2 g azithromycin dose may be needed to achieve universal high efficacy. This higher azithromycin dose seemed less well tolerated, however, and was associated with an increased risk of nausea, but not vomiting or diarrhoea (Figures 3 to 5). The reported incidence of nausea and vomiting with 2 g azithromycin/chloroquine (30% and 18%, respectively) was higher than in a study using a single 2 g dose of azithromycin for community-based pneumonia or acute sinusitis among adults (4% and 1%, respectively) (Pfizer 2008). Apart from differences in monitoring, it is possible that the duration of therapy and the malarial illness may have contributed to the higher occurrence of these adverse events.
A cumulative dose of 3 to 6 g of azithromycin is relatively high compared with other applications of azithromycin. Lower doses are used for bacterial infections (eg 500 mg per day for three days) and single treatments of azithromycin with 1 to 2 g have been used successfully for treating otitis media among children (a dose of 30 mg/kg once up to a maximum of 2 g), community-acquired pneumonia among adults (one single dose of 2 g), acute bacterial sinusitis among adults (one single dose of 2 g), and sexually-transmitted diseases (one single dose of 1 g) (Pfizer 2008). In bacteria, macrolides such as azithromycin and erythromycin bind to the 50S ribosomal subunit and inhibit protein synthesis, causing premature detachment of incomplete peptide chains and subsequent cell death (Retsema 2001). In bacterial infections, azithromycin works effectively because it concentrates in tissues and white blood cells; neutrophils can become vehicles for drug delivery at a site of infection and a higher dose can enhance drug efficacy (Blumer 2005; Retsema 2001). For malaria, higher and longer treatment doses are needed because of a different mechanism of action: azithromycin affects the 'house keeping' function of the apicoplast in the progeny, causing 'delayed death' (Dahl 2008). The apicoplast is an organelle in the plasmodium; its function is currently unclear , but it is thought to have an origin in prokaryotes. Although malaria parasites directly exposed to azithromycin do not seem to be functionally affected, and can go on to invade an erythrocyte and develop into a schizont, these schizonts are unable to form functional merozoites and will subsequently die (Dahl 2008). A higher efficacy of azithromycin can be expected when at least two asexual cycles (approximately 96 hours) have occurred (Biswas 2001), which might translate into a four-day course of azithromycin. Given the relatively slow and weak antimalarial action of azithromycin, the use of this drug for case-management would need to rely heavily on combination with a fast-acting efficacious antimalarial such as a member of the artemisinin group (Noedl 2001).
In vitro studies have produced conflicting results for interactions of azithromycin combinations: Edgie-Mark et al (2009) reported indifference between azithromycin and chloroquine, whereas others indicated that there may be an additive or synergistic effect of the combination (Edgie-Mark 2009; Nakornchai 2006; Noedl 2007; Ohrt 2002 ). But the level of azithromycin-chloroquine interaction may depend on the background resistance level of the P. falciparum strain to chloroquine (Ohrt 2002). For the azithromycin-artesunate combination, antagonism has been reported (Nakornchai 2006), whereas an additive to synergistic interaction was reported for azithromycin-dihydroartemisinin by Noedl et al (2007) and an additive with a trend for antagonism was reported by Ohrt et al (2002) (Noedl 2007; Ohrt 2002). An additive effect has been reported for azithromycin-mefloquine (Nakornchai 2006), and an additive to synergistic effect for azithromycin-quinine, azithromycin-pyroniradine, azithromycin-tafenoquine, and azithromycin-primaquine (Nakornchai 2006; Noedl 2007; Ohrt 2002). Thus far, azithromycin has mainly been combined with chloroquine. A few studies in Thailand assessed other azithromycin combinations for P. falciparum, but, except for the study by Krudsood and colleagues, these had relatively small sample sizes (30 participants or less per arm) (Krudsood 2000; Miller 2006; Na-Bangchang 1996; Noedl 2006 ). The studies where azithromycin was combined with artesunate did not show promising results compared with artemether-lumefantrine.
Given the weak antimalarial properties and low prospects as a competitor drug for the current range of ACTs, the remaining interest in an azithromycin combination seems mainly based on its appealing safety profile. This would allow two potential niche applications among pregnant women and children: intermittent preventive treatment (IPT) and use as a potential syndromic treatment, eg for malaria and respiratory tract infections in children and malaria and sexually-transmitted diseases in pregnant women (Chico 2008). Findings in this review were mainly based on adult males and care should be taken when extrapolating efficacy and tolerability findings from adults to a paediatric or pregnant population, whose different pharmacokinetic profiles may require different doses. However, the two studies which included children and compared an azithromycin/artesunate combination with an azithromycin dose of > 1 g per day with artemether-lumefantrine showed that the azithromycin/artesunate combination was three times more likely to result in failure ( Analysis 1.1). Two more paediatric studies are in analysis or ongoing in African countries (Pfizer 677833: Burkina Faso, Cote d'Ivoire, Ghana, Kenya, Mali, Zambia, a comparison of fixed-dose azithromycin/chloroquine versus artemether-lumefantrine; NIAID 379821: Malawi, comparison of azithromycin/chloroquine versus chloroquine alone, chloroquine and artesunate, and chloroquine and malarone), assessing azithromycin doses ranging from 20 to 30 mg/kg/day for three days. This is equivalent to 1.2 to 1.8 g in a person of 60 kg. Findings from these studies will be included in a future update of this review.
A small study in Malawi evaluated the usefulness of sulphadoxine-pyrimethamine in combination with 1 g azithromycin per day for two days for treating uncomplicated malaria in pregnancy (Kalilani 2007). This combination resulted in fewer recrudescent episodes when compared to sulphadoxine-pyrimethamine monotherapy, but the authors reported one abortion that was possibly related to treatment, four days after exposure (Kalilani 2007). Azithromycin monotherapy has been evaluated for malaria prophylaxis among healthy, non-pregnant, semi-immune adults in doses ranging from 250 mg daily to 1000 mg weekly. The reported prophylactic efficacy ranged from 98% to99% for P. vivax in two studies with a total of 327 participants (Heppner 2005; Taylor 1999), and 64% to 83% for P. falciparum in three studies with a total of 444 participants (Andersen 1998; Heppner 2005; Taylor 1999). For P. vivax, the results were better than the treatment results of azithromycin monotherapy for clinical malaria. When considering the drug for IPT in pregnancy, azithromycin is not optimal given the need for a longer duration of treatment. This may cause substantial challenges for adherence, driving resistance. In addition, the combination of azithromycin with chloroquine is not ideal for IPT, given the efforts by countries to remove chloroquine from the national shelves in favour of ACTs (Sipilanyambe 2008; WHO 2008), and the problems with adherence and adverse events such as pruritis, which are well-described in the African region (Taylor 2004). As resistance to sulphadoxine-pyrimethamine is increasing and the effective lifespan of IPT with sulphadoxine-pyrimethamine may be coming to an end (Ter Kuile 2007), plans are underway to test a 1 g azithromycin/chloroquine combination as a fixed-dose option for IPTp (IPT for pregnant women) in Africa (Dr. Chandra, personal communication, Chico 2008). Given the above dose-dependent data in non-pregnant adults, and the challenges to successful implementation, this may not be a potential niche product just yet.
Implications for practice
The available evidence suggests that azithromycin has relatively weak antimalarial activity.
Given the availability of highly efficacious and cheaper first and second line antimalarials, there does not seem to be a place for wide-scale programmatic use of the assessed azithromycin-chloroquine combinations and the azithromycin-artesunate combination for case-management of uncomplicated P. falciparum malaria (WHO/RBM 2006); there is insufficient data available on the use of azithromycin with other partner drugs.
The available evidence is very limited. The main reasons for this are the small number of studies using the same treatment combination, azithromycin dose and comparison group; uncertainty over trial methodological quality; the sub-optimal results reported so far, mainly with chloroquine; and the availability of superior alternatives in the form of ACTs. In addition, the current cost of azithromycin would be a barrier as well: a treatment course of 1 g azithromycin/0.6 g chloroquine for three days was estimated at $7 (Chico 2008).
Implications for research
While the current evidence is insufficient for policy makers, the fact that azithromycin has a different mechanism of action to other antimalarials, together with its safety profile, may offer treatment options for pregnant women and children; for example, there may be opportunities to use it for a syndromic approach that could be explored further.
We also understand that Pfizer is working on optimizing the drug formulation in order to overcome some of the described challenges. Unless those efforts are fruitful, however, the current move towards a ‘low’ 1 g dose azithromycin/chloroquine fixed-dose product focusing on IPTp may be somewhat impetuous. Furthermore, the need for a treatment course lasting several days (and the potential for pruritis when combined with chloroquine) poses a considerable challenge for wide-scale use as IPTp.
Given the limited data, and the potential further improvements in drug formulation, it remains important to explore further the use of azithromycin in combination with fast-acting drugs with different mechanisms of action for case management, or in combination with other medium/long-acting drugs for IPT, or at higher daily doses. For case management, exploration of a twice daily versus once daily regimen may be worthwhile to assess if such a regimen would reduce nausea when used in combination with other antimalarials.
In conclusion, azithromycin is a weak antimalarial with some appealing characteristics. Unless it overcomes some of the highlighted challenges and finds a specific niche that is complementary to the current scala of more efficacious antimalarial combinations, its future as an antimalarial does not look promising.
A M van Eijk was awarded a Reviews for Africa Programme Fellowship (www.mrc.ac.za/cochrane/rap.htm), funded by a grant from The Nuffield Commonwealth Programme, through The Nuffield Foundation. D J Terlouw received financial support from the Centers for Disease Control. The editorial base for the Cochrane Infectious Diseases Group is funded by the UK Department for International Development for the benefit of developing countries.
We are grateful to Dr R Chandra from Pfizer for additional information on Pfizer-led trials, and to Dr Noedl and Dr Thriemer for their kind assistance in providing additional information. We thank Dr Gertrude Kalanda for her help in verifying trial information, and Professor F ter Kuile for his review of the manuscript.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. Detailed search strategy
Appendix 2. Total failure (TF): method used to derive TF values from reported data
Appendix 3. Results: Treatment failure by day 28
Abbreviations:CI: confidence interval; NR: not reported; O: open Label; P: use of placebo. Significant risk ratios printed in bold
Calculations of risk ratios and cure with 95% confidence intervals using Epicalc 2000 version 1.02 (Gilman & Myatt: http://www.brixtonhealth.com/epicalc.html)
¶ Treatment arms not conducted at the same time period
Appendix 4. Results: Fever clearance time
Abbreviations: AZ: azithromycin; TET: tetracycline; DX: doxycycline; CL: clindamycin; AT: artesunate; Q: quinine; MQ: mefloquine; ART: artemether; AL: artemether-lumefantrine; SD: Standard deviation; hrs: hours, IQR: inter-quartal range. The numbers in the treatment column indicate the full treatment course dose in g for azithromycin and mg/day for quinine.
*Only patients included who were febrile at enrolment
Appendix 5. Results: Parasite clearance time
Abbreviations: AZ: azithromycin; TET: tetracycline; DX: doxycycline; CL: clindamycin; AT: artesunate; Q: quinine; MQ: mefloquine; ART: artemether; AL: artemether-lumefantrine, SD: Standard deviation; hrs: hours; NR: not reported, IQR: inter-quartal range. The numbers in the treatment column indicate the full treatment course dose in g for azithromycin and mg/day for quinine.
Appendix 6. Results: Adverse events, treatment related and all cause
Abbreviations: AE: adverse events; TR: treatment related; AC: any cause; CI: confidence interval; NR: not reported; O: open label; P: use of placebo
Total number of adverse events reported as number of adverse events/number of participants.
Calculations of risk ratios and cure with 95% confidence intervals using Epicalc 2000 version 1.02 (Gilman & Myatt: http://www.brixtonhealth.com/epicalc.html)
*Risk ratio for treatment-related adverse events if data is available, otherwise risk ratio for adverse events of 'any cause'
^Only delayed appearance of P. falciparum reported as adverse events
^^Only frequent adverse events (eg 2% to 3% or more) reported
Appendix 7. Results: Serious adverse events (SAE), discontinuations and other adverse events (laboratory, ECG, physical examination
Abbreviations: SEA: serious adverse event; AE: adverse event; TR: treatment related; AC: any cause; NR: not reported; O: open label; P: use of placebo
There were no significant differences for SEA and discontinuations among treatment arms
Appendix 8. Common side effects among studies with detailed reporting of adverse events
Abbreviations: AZ: azithromycin; CQ: chloroquine; NR: not reported. If both 'All cause' and 'treatment related' adverse events were reported, we included 'All cause' adverse events.
*In the study by Thriemer et al, nausea defined as abdominal pain and discomfort, and diarrhoea defined as loose stools.
- Azithromycin arms: Nausea: Pfizer 282919 versus 82576: RR 3.11, 95% CI 1.66 to 5.84; Pfizer 282919 versus 367653: RR 2.61, 95% CI 1.45 to 4.68; Pfizer 282919 versus Dunne 2005b: RR 4.72, 95% CI 1.75 to 12.72;
- Azithromycin arms: Vomiting: Pfizer 282919 versus 367653: RR 4.11, 95% CI 1.6 to 10.6; Pfizer 282919 versus 84227: RR 2.96, 95% CI 1.30 to 6.72
- Azithromycin arms: Diarrhoea: No significant differences
- Azithromycin arms: Pruritis: Pfizer 82576 versus 84227: RR 2.03, 95% CI 1.42 to 2.92 (Pruritis in AZ/CQ arm in Pfizer 82576 also significant higher versus AZ regimens in other studies which reported on pruritis)
Last assessed as up-to-date: 6 December 2010.
Protocol first published: Issue 3, 2007
Review first published: Issue 2, 2011
Contributions of authors
AM van Eijk wrote the protocol and review. DJ Terlouw edited the protocol and review, and assisted with the gathering of data.
Declarations of interest
Sources of support
- No sources of support supplied
- Nuffield Commonwealth Foundation, UK.
- Department for International Development (DFID), UK.
- Liverpool School of Tropical Medicine, UK.
Differences between protocol and review
Although we initially intended to assess the possibility of subgroup analysis by species of malaria, it proved irrelevant to compare studies for P. vivax directly with studies for P. falciparum given the different efficacy of the drugs used for these species. We decided instead to keep all data stratified by malaria species. The trials excluded for meta-analyses were included in the assessment of adverse events and drug efficacy, because they provided valuable information for these outcomes. We believe that excluding these trials would deprive the reader of a complete overview of the topic. This review was conducted over several years and because of the adoption of new methods by the Cochrane group for assessing risk of bias, we changed our assessment accordingly using the revised guidelines in 2008.
Medical Subject Headings (MeSH)
Antimalarials [*therapeutic use]; Artemisinins [therapeutic use]; Atovaquone [therapeutic use]; Azithromycin [*therapeutic use]; Chloroquine [therapeutic use]; Drug Combinations; Drug Therapy, Combination; Ethanolamines [therapeutic use]; Fluorenes [therapeutic use]; Malaria, Falciparum [*drug therapy]; Malaria, Vivax [*drug therapy]; Mefloquine [therapeutic use]; Proguanil [therapeutic use]; Pyrimethamine [therapeutic use]; Randomized Controlled Trials as Topic; Sulfadoxine [therapeutic use]; Treatment Failure
MeSH check words
Female; Humans; Male