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Azithromycin for treating uncomplicated malaria

  1. Anna M van Eijk*,
  2. Dianne J Terlouw

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 16 FEB 2011

Assessed as up-to-date: 6 DEC 2010

DOI: 10.1002/14651858.CD006688.pub2


How to Cite

van Eijk AM, Terlouw DJ. Azithromycin for treating uncomplicated malaria. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD006688. DOI: 10.1002/14651858.CD006688.pub2.

Author Information

  1. Liverpool School of Tropical Medicine, Child & Reproductive Health Group, Liverpool, UK

*Anna M van Eijk, Child & Reproductive Health Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. amvaneijk@yahoo.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 16 FEB 2011

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

Interventions
Azithromycin alone, combined with another antimalarial drug, or combined with a placebo.

Control

  • 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

Primary
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.

Secondary

  • 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.

Adverse events

  • 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).

Databases
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).

Conference proceedings
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.

Reference lists
We checked the reference lists of all studies identified by the above methods.

 

Data collection and analysis

Trial selection
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.

Data extraction
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.

Data analysis
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 (Chi2 test < 0.1, I2 statistic > 50%). If we detected heterogeneity and considered it clinically meaningful to combine the trials, we used a random-effects model. We intended to explore the following potential sources of heterogeneity using subgroup analyses: participants (children versus adults, as defined by the included trials); trial setting (high versus low malaria transmission ); drug dose (total dose and division of doses over days); and presence of drug resistance to comparator drug. However, the small number of studies per comparison did not allow these analyses. They also precluded meaningful use of funnel plots and sensitivity analyses.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of ongoing 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).

 FigureFigure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
 FigureFigure 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).

 FigureFigure 3. Efficacy of azithromycin and comparison drugs for P. vivax (28 days follow up)

Abbreviations: AZ: azithromycin; CQ: chloroquine; Tetra: tetracycline; Doxy: doxycycline; Clinda: clindamycin; CI: confidence interval

*Note that in the study in India, participants were treated with primaquine from day 7 until day 20 in both arms
 FigureFigure 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).

 

P. vivax

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).

 

P. falciparum

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).

Gametocytes

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).

 FigureFigure 5. Adverse event of nausea in study arms with a sample size of 50 or more.

Abbreviations: AZ: azithromycin; CQ: chloroquine; S Am: South America; Col: Colombia; MQ: mefloquine; SP: sulphadoxine-pyrimethamine; AT/PG: atovaquone/proguanil; Art: artesunate

No information available on nausea in study using 0.5 g AZ in India, in one of the 1 g AZ studies in India, and in the 1 g AZ study in South America, or in the study using SP/CQ in India, and AT/PG in South America.

* P < 0.05 comparing the AZ 2 g study with the AZ 1 g studies
 FigureFigure 6. Adverse event of vomiting in study arms with a sample size of 50 or more.

Abbreviations: AZ: azithromycin; CQ: chloroquine; S Am: South America; Col: Colombia; MQ: mefloquine; SP: sulphadoxine-pyrimethamine; AT/PG: atovaquone/proguanil; Art: artesunate

* P < 0.05 compared to AZ 1 g placebo-controlled study in South America and AZ 1 gram open-label study in Africa
 FigureFigure 7. Adverse event of diarrhoea in study arms with a sample size of 50 or more.

Abbreviations: AZ: azithromycin; CQ: chloroquine; S Am: South America; Col: Colombia; MQ: mefloquine; SP: sulphadoxine-pyrimethamine; AT/PG: atovaquone/proguanil; Art: artesunate
 FigureFigure 8. Adverse event of pruritis in study arms with a sample size of 50 or more.

Abbreviations: AZ: azithromycin; CQ: chloroquine; S Am: South America; Col: Colombia; MQ: mefloquine; SP: sulphadoxine-pyrimethamine; AT/PG: atovaquone/proguanil; Art: artesunate

* P < 0.05 compared to all other studies

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

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.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
Download statistical data

 
Comparison 1. Overview treatment failure for AZ or AZ combination vs. control for P. falciparum

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Treatment failure on day 28, not corrected by PCR13Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 AZ vs. CQ
129Risk Ratio (M-H, Random, 95% CI)0.88 [0.53, 1.44]

    1.2 AZCQ vs. CQ (not randomized)
290Risk Ratio (M-H, Random, 95% CI)0.15 [0.01, 2.35]

    1.3 AZCQ vs. AZ monotherapy (not randomized)
177Risk Ratio (M-H, Random, 95% CI)0.05 [0.01, 0.20]

    1.4 AZCQ vs. SPCQ
2168Risk Ratio (M-H, Random, 95% CI)2.59 [1.24, 5.43]

    1.5 AZCQ vs. atovaquone-proguanil
1225Risk Ratio (M-H, Random, 95% CI)48.43 [6.80, 344.83]

    1.6 AZCQ vs. MQ
2425Risk Ratio (M-H, Random, 95% CI)2.00 [0.50, 8.07]

    1.7 AZ-artesunate vs. artesunate
1116Risk Ratio (M-H, Random, 95% CI)0.78 [0.54, 1.14]

    1.8 AZ-artesunate vs. MQ-artesunate
1110Risk Ratio (M-H, Random, 95% CI)24.00 [3.36, 171.26]

    1.9 AZ-artesunate vs. AZ-quinine (arm 1 vs. 4)
150Risk Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.55]

    1.10 AZ-artesunate vs. artemether-lumefantrine
2450Risk Ratio (M-H, Random, 95% CI)2.98 [2.03, 4.37]

    1.11 AZ-artemether vs. doxycycline-artemether
157Risk Ratio (M-H, Random, 95% CI)1.83 [1.21, 2.76]

    1.12 AZ-quinine vs. doxycycline-quinine (arm 1 vs. 4)
120Risk Ratio (M-H, Random, 95% CI)3.0 [0.14, 65.90]

 2 Treatment failure day 28, PCR corrected8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 AZCQ vs CQ
113Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.09, 14.92]

    2.2 AZCQ vs. SP
123Risk Ratio (M-H, Fixed, 95% CI)3.46 [0.95, 12.59]

    2.3 AZCQ vs. atovaquone-proguanil
1225Risk Ratio (M-H, Fixed, 95% CI)89.79 [5.60, 1440.31]

    2.4 AZCQ vs. MQ
2425Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.18, 5.87]

    2.5 AZ-artesunate vs. artemether-lumefantrine
2450Risk Ratio (M-H, Fixed, 95% CI)3.63 [2.02, 6.52]

    2.6 AZ-quinine vs. doxycycline-quinine (arm 1 vs. 4)
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.14, 65.90]

 3 Treatment failure on day 42, not corrected by PCR2445Risk Ratio (M-H, Fixed, 95% CI)1.90 [1.44, 2.49]

    3.1 AZ-artesunate vs. artemether-lumefantrine
2445Risk Ratio (M-H, Fixed, 95% CI)1.90 [1.44, 2.49]

 4 Treatment failure on day 42, (partially) corrected by PCR2445Risk Ratio (M-H, Fixed, 95% CI)2.47 [1.53, 3.99]

    4.1 AZ-artesunate vs. artemether-lumefantrine
2445Risk Ratio (M-H, Fixed, 95% CI)2.47 [1.53, 3.99]

 
Comparison 2. Overview adverse events for AZ or AZ combinations vs. control for P. falciparum

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Treatment related adverse events5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 AZ vs. CQ
132Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.46, 1.71]

    1.2 AZCQ vs. CQ
179Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.19, 0.70]

    1.3 AZCQ vs. AZ monotherapy
179Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.21, 0.82]

    1.4 AZCQ vs. SPCQ
125Risk Ratio (M-H, Fixed, 95% CI)1.48 [0.67, 3.27]

    1.5 AZCQ vs. MQ
2458Risk Ratio (M-H, Fixed, 95% CI)1.20 [1.06, 1.36]

    1.6 AZ-artesunate vs. AZ-quinine (arm 1 vs. 4)
154Risk Ratio (M-H, Fixed, 95% CI)0.05 [0.01, 0.37]

 2 All adverse events (any cause)6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 AZCQ vs. SPCQ
125Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.75, 2.32]

    2.2 AZCQ vs. atovaquone-proguanil
1230Risk Ratio (M-H, Fixed, 95% CI)1.41 [1.09, 1.83]

    2.3 AZCQ vs. MQ
2458Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.96, 1.10]

    2.4 AZ-artemether vs. doxycycline-artemether
157Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.09, 0.88]

    2.5 AZ-artesunate vs. artemether-lumefantrine
1261Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.81, 1.80]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Appendix 1. Detailed search strategy

 

 


Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSbmRCT

1azithromycinazithromycinazithromycinazithromycinazithromycinazithromycin

2azithromycinazithromycinazithromycinERYTHROMYCINazithromycinmalaria

31 or 2ERYTHROMYCIN/ANALOGS AND DERIVATIVESERYTHROMYCIN/ANALOGS AND DERIVATIVES1 or 21 or 21 and 2

4malaria1 or 2 or 31 or 2 or 3malariamalaria-

53 and 4malariamalaria3 and 43 and 4-

6-4 and 54 and 5Limit 5 to human--



 
Footnotes

a Cochrane Infectious Diseases Group Specialized Register

b Search terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term

 

Appendix 2. Total failure (TF): method used to derive TF values from reported data

 


Trial CountryTreatment regimenRandomizedTFData to derive TFDefinitions of outcomes used in studies

 P. vivax    

Dunne 2005a

India
Azithromycin 1 g/day for 3 days

Primaquine from day 7 to 20
9812/9785/97 parasitological success (clinical response 86/97)No systematic evaluation of outcome. Parasitological failure defined as RI (recrudescence after clearance), RII (reduction in parasitaemia by > 75% of baseline without clearance, RIII (failure to reduce parasitaemia to < 25% of baseline) but no clear clinical consequence to parasitological failure (eg RII failure at day 7).  “Patients who the investigator felt were not responding to therapy were given alternative therapies at their discretion.”

Clinical response: Resolution of fever, without relapse at day 28.

Chloroquine 0.6 g on day 0 to 1, 0.3 g on day 2

Primaquine from day 7 to 20
1021/102101 parasitological success (clinical response 101/102)

Pukrittayakamee 2001

Thailand
Azithromycin 0.5 g/day for 3 days2010/18P. vivax cure: 8/18

Note: P. falciparum 6/18
Treatment failure: persistence of fever and parasitaemia for > 7 days or persistence of parasitaemia in the absence of fever for > 2 weeks. Reappearance of infection after clearance within 28 days.

Tetracycline 250 mg 4x/day for 7 days274/18P. vivax cure: 14/18

Doxycycline 200 mg/day for 7 days258/18P. vivax cure: 10/18

Clindamycin 300 mg 4x/day for 7 days205/12P. vivax cure: 7/12

 P. falciparum    

Dunne 2005b

India

 
Azithromycin 1 g/day for 3 days169/149 had RI (3), RII (3) or RIII (3) failures (5/15 clinical cure)No systematic evaluation of outcome. Treatment failure defined in terms of RI (recrudescence after clearance of parasitaemia), RII (reduction in parasitaemia to < 25% of baseline levels without clearance), and RIII (failure to reduce parasitaemia to < 25% of baseline levels), but time of evaluation and clinical consequences for type of resistance level not reported. Clinical response not defined (but one of the main outcomes). Term 'Eradication' used in table, not defined.  “Any participant who, in the opinion of the investigator, had not sufficiently improved received additional antimalarial therapy.”

Chloroquine 0.6 g on day 0 to 1, 0.3 g on day 21611/1511 had RI (9), RII (1) or RIII (1) failures (clinical cure 4/15)

Azithromycin 1 g/day for 3 days, Chloroquine 0.6 g on day 0 to 1, 0.3 g on day 2642/632 had RII (1) or RIII (1) failures (clinical cure 61/63)

Krudsood 2000

Thailand
Azithromycin 0.5 g/day, Artesunate 200 mg/day for 3 days6724/5524 RI response, 31 cure28-day cure rate used.

Sensitive: no reappearance of asexual forms of P. falciparum within 28 day follow-up. Resistance: Resistance at level I (reappearance after day 7), II (parasitaemia at day 7), and III (failure to reduce parasitaemia by > 75% of initial count or clinical deterioration after 48 hours).

Artesunate 200 mg/day for 3 days and mefloquine 10 mg/kg on day 0 to 1, 5 mg/kg on day 2671/551 RI response, 54 cure

Artesunate 200 mg/day for 3 days6834/6134 RI response, 27 cure

Miller 2006

Thailand
Azithromycin 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 3 days101/101 R1 response, 9 cureCure: clearance of P. falciparum parasitaemia without recrudescence of malaria in a 28-day period.

Azithromycin 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 5 days200/20All cure

Azithromycin 0.5 g 3x/day and quinine 10 mg/kg 3x/day for 3 days200/20All cure. Note: this arm was not randomized

Doxycycline 100 mg 2x/day for 7 days and quinine 10 mg/kg 3x/day for 7 days100/10All cure

Na-Bangchang 1996

Thailand
Azithromycin 0.5 g at start, 0.25 g at 24 and 48 hours, and artemether 300 mg at start3023/274/27 were sensitive, 23 RI responseRate of treatment failure (RI-RIII, WHO 1973).

Doxycycline 100 mg 2x/day for 5 days and artemether 300 mg at start and 100 mg after 12 hrs3014/3016/30 sensitive, 14 RI response

Noedl 2006

Thailand
Azithromycin 0.75 g 2x/day and artesunate 100 mg 2x/day for 3 days272/2523/25 cure. 2 RI28 day cure. Treatment failure divided in RI: clearance of asexual parasites within 7 days after start treatment, followed by recrudescence; RII: decrease in parasite count < 25% of baseline value within 48 hours but failure to clear parasites by day 7; RIII: failure of the parasite count to decrease to < 25% of the baseline value within 48 hours (WHO 1973).

Azithromycin 1 g/day and artesunate 200 mg/day for 3 days273/2724/27 cure, 3 RI

Azithromycin 0.75 g 2x/day and quinine 10 mg/kg 2x/day for 3 days164/1511/15 cure, 1 RI and 3 RIII

Azithromycin 0.5 g 3x/day and quinine 10 mg/kg 3x/day for 3 days272/2523/25 cure, 2 RI

Pfizer 74841

India
Azithromycin 1 g/day and chloroquine 600 mg/day for 3 days8312/7361 eradicatedOutcome: Asexual parasite clearance rate at day 28. No further definition given. Term 'eradication' used in table, not defined. 

Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 days6720/5939 eradicated

Sulfadoxine-pyrimethamine 1500mg/75 mg at start, chloroquine 0.6 g on day 0 to 1, 0.3 g on day 2794/7268 eradicated

Pfizer 82563

Kenya

 
Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 days71/51 RIII failure which cleared by day 7

(Eradication: 5/5)
Eradication: Clearance of asexual parasitaemia within 7 days of initiation of treatment, without subsequent recurrence through day 28.

Failure: RI: clearance of asexual parasitaemia before day 7, followed by recurrence on or after day 7. RII: marked reduction (< 25% of baseline) of asexual parasitaemia but no clearance prior to and up to day 7. RIII: no marked reduction ( > 25% of baseline) of parasitaemia within 48 hours. If a subject remained parasitaemic on day 7, curative treatment was provided. Terms of eradication and failure not mutually exclusive for RIII resistance: we used failure (RI-RIII) for consistency with other studies.

Chloroquine 0.6 g/day for 3 days72/71 RIII failure which cleared by day 7, and one RI failure (the other RI failure mentioned was the untreated RIII failure) (Eradication: 5/7)

PCR adjusted: 1/7

Pfizer 82576

Ghana, Kenya, Mali, Uganda, Zambia
Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 days1145/1035 late treatment failures (4.85%)

PCR adjusted: 2/103
Primary outcome table presumably PCR-adjusted; data for PCR-unadjusted results on day 28 not clearly presented. Percent early and late treatment failure used (assuming the investigators follow WHO 2003) but this may not be reliable because the trial ended at day 42. Two RIII failures in 1 g azithromycin/chloroquine arm reported, but not labelled as early treatment failures.

Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 days9 NR

Mefloquine 750 mg at start, 500 mg after 6 hours1152/1031 early treatment failure and 1 late treatment failure (1.94%)

PCR adjusted: 1/103

Pfizer 84227

Columbia/Surinam

 

 
Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 days11448/11264 eradicated 

PCR partially adjusted: 68/112 (35 analysed)
Primary endpoint asexual parasite clearance rate at day 28, not further defined. “Treatment when persistent or recurrent parasitaemia”, but time point of evaluation for treatment not defined. Used 'eradicated': asexual parasite clearance rate on day 28 among evaluable subjects.

Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 days14NR 

Atovaquone 1000 mg/day and proguanil 400 mg/day for 3 days1161/113112 eradicated

PCR adjusted: 113/113

Pfizer 84240

Indonesia
Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 days139/134 eradicated

PCR partially adjusted 4/13 eradicated (5 analysed)
Eradication: Clearance of asexual Pf parasitaemia within 7 days of initiation of treatment, without subsequent recurrence through day 28. Failure: failure to achieve clearance of Pf asexual parasitaemia within 7 days of initiation of treatment or subsequent recurrence through day 28 after achieving clearance. Subjects with persistent or recurrent parasitaemia during the follow up period were treated with antimalarial drugs and were withdrawn from further participation in the study.

Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 days7NR 

Sulfadoxine-Pyrimethamine 1500mg/75 mg at start, chloroquine 0.6 g on day 0 to 1, 0.3 g on day 2123/107 eradicated

PCR adjusted: 8/10

Pfizer 367653

Burkina Faso, Ghana, Kenya, Mali, Senegal, Zambia

 
Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 days1131/107As per correspondence with Pfizer

PCR adjusted: 0/107
Eradicated: clearance of asexual P. falciparum parasitaemia within 7 days of initiation of treatment, without subsequent recrudescence through day 28. Failure: Failure to achieve clearance of asexual P. falciparum parasitaemia within 7 days of initiation of treatment or subsequent recrudescence through day 28 after achieving initial clearance.

Mefloquine 750 mg at start, 500 mg after 6 to 10 hours1161/111As per correspondence with Pfizer

PCR adjusted: 1/111

Sykes 2009

Tanzania
Azithromycine 20 mg/kg/day and artesunate 4 mg/kg/day for 3 days12969/119Day 28 partially PCR-adjusted: 40/119 (6 not tested)

Day 42:TF 76/115, partially PCR-adjusted: 42/115 (5 not tested)
Parasitological failure: the presence of asexual malaria parasites after treatment (after day 3) on or before day 28, irrespective of symptoms.

Artemether 20 mg and lumefantrine 120 mg 2x/day for < 15 kg and 40 mg/240 mg 2x/day for ≥15 kg for 3 days13224/120Day 28 partially PCR-adjusted: 12/120 (3 not tested)

Day 42: TF 41/119, partially PCR adjusted: 17/119 (4 not tested)

Thriemer 2010

Bangladesh
Azithromycin 1.5 g/day and artesunate 200 mg/day for 3 days. Children < 35 kg: azithromycin 30 mg/kg/day, and artesunate 4 mg/kg/day for 3 days15213/142Day 28: PCR-adjusted: 8/142

Day 42: TF 22/142, PCR-adjusted: 8/142
Primary endpoint was cure: adequate clinical and parasitological response as defined by WHO criteria by day 42.

Day 28 data kindly provided by the authors.

Artemether 80 mg and lumefantrine 480 mg 2x/day for 3 days. Children < 35 kg: artemether 4 mg/kg and lumefantrine 24 mg/kg 2x/day for 3 days761/69Day 28: PCR-adjusted: 0/69

Day 42: TF 6/69, PCR-adjusted: 2/69

 Excluded studies    

Krudsood 2002

Thailand
Azithromycin 0.5 g/day and dihydroartemisinin 80 mg/day for 3 days8220/6646 cure28 day cure rate: the proportion of patients who cleared asexual parasitaemia within 7 days of initiation of treatment without subsequent recrudescence within 28 days.

Mefloquine 10 mg/kg on day 1,2; 5 mg/kg on day 3; dihydroartemisinin 80 mg/day for 3 days8868/68All cure

Pfizer 282919

India/Columbia
Azithromycin 2 g/day and chloroquine 0.6 g/day for 3 days1105/107As per presentation ASTMH December 08, New Orleans

PCR-adjusted: 3/107
Parasitological clearance day 28 (PCR unadjusted), and eradication not defined.



 
Footnotes

 

Appendix 3. Results: Treatment failure by day 28

 

 


Trial 

country
Treatment regimenBlind

ing
Total failureComparisonRisk ratio (95% CI)

(or P-value if 0 failures)
Cure day 28 (95% CI)

 P. vivax     

Dunne 2005A India1) Azithromycin 1 g/day for 3 daysP12/971 vs. 212.62 (1.67-95.22)88 (79-93)

2) Chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3P1/102  99 (94-100)

Pukrittayakamee 2001

Thailand
1) Azithromycin 0.5 g/day for 3 daysO10/18  44 (22-69)§

2) Tetracycline 250 mg 4x/day for 7 daysO4/181 vs. 22.50 (0.96-6.52)78 (52-93)§

3) Doxycycline 200 mg/day for 7 daysO8/181 vs. 31.25 (0.65-2.42)56 (31-78)§

4) Clindamycin 300 mg 4x/day for 7 daysO5/121 vs. 41.33 (0.61-2.93)58 (29-84)§

 P. falciparum     

Dunne 2005B

India

 
1) Azithromycin 1 g/day for 3 daysP9/141 vs. 20.88 (0.53-1.44)36 (14-64)

2) Chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3P11/153 vs. 2 ¶0.04 (0.01-0.18)27 (9-55)

3) Azithromycin 1 g/day for 3 days, chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3O2/633 vs. 1 ¶0.05 (0.01-0.20)97 (88-99)

Krudsood 2000

Thailand
1) Azithromycin 0.5 g/day, artesunate 200 mg/day for 3 daysO24/55  56 (42-69)§

2) Artesunate 200 mg/day for 3 days, mefloquine 10 mg/kg on day 1 to 2, 5 mg/kg on day 3O1/551 vs. 224.00 (3.36-171.27)98 (89-100)§

3) Artesunate 200 mg/day for 3 daysO34/611 vs. 30.78 (0.54-1.14)44 (32-57)§

Miller 2006

Thailand
1) Azithromycin 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 3 daysO1/101 vs. 2

1 vs. 3 ¶

1 vs. 4
P=0.33 (Fisher)

P=0.33 (Fisher)

P=1.0 (Fisher)
90 (54-99)*

2) Azithromycin 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 5 daysO0/202 vs. 1

2 vs. 3 ¶

2 vs. 4
P=0.33 (Fisher)

P=1.0 (Fisher)

P=1.0 (Fisher)
100 (80-100)

3) Azithromycin 0.5 g 3x/days and quinine 10 mg/kg 3x/day for 3 daysO0/203 vs. 1 ¶

3 vs. 2 ¶

3 vs. 4 ¶
P=0.33 (Fisher)

P=1.0 (Fisher)

P=1.0 (Fisher)
100 (80-100)

4) Doxycycline 100 mg 2x/day and quinine 10 mg/kg 3x/day for 7 daysO0/10  100 (66-100)

Na-Bangchang 1996

Thailand
1) Azithromycin 0.5 g at start, 0.25 g at 24 and 48 hrs, and artemether 300 mg at startO23/271 vs. 21.83 (1.21-2.76)15 (5-35)

2) Doxycycline 100 mg 2x/day for 5 days and artemether 300 mg at start and 100 mg after 12 hoursO14/30  53 (35-71)

Noedl 2006

Thailand
1) Azithromycin 0.75 g 2x/day and artesunate 100 mg 2x/day for 3 daysO2/251 vs. 2

1 vs. 3

1 vs. 4
0.72 (0.13-3.96)

0.30 (0.06-1.44)

1.00 (0.15-6.55)
92 (73-99)§

2) Azithromycin 1 g/day and artesunate 200 mg/day for 3 daysO3/272 vs. 1

2 vs. 3

2 vs. 4
1.39 (0.25-7.64)

0.42 (0.11-1.62)

1.39 (0.25-7.64)
89 (70-97)§

3) Azithromycin 0.75 g 2x/day and quinine 10 mg/kg 2x/day for 3 daysO4/153 vs. 1

3 vs. 2

3 vs. 4
3.33 (0.69-16.06)

2.40 (0.62-9.33)

3.33 (0.69-16.06)
73 (45-91)§

4) Azithromycin 0.5 g 3x/day and quinine 10 mg/kg 3x/day for 3 daysO2/254 vs. 1

4 vs. 2

4 vs. 3
1.00 (0.15-6.55)

0.72 (0.13-3.96)

0.30 (0.06-1.44)
92 (73-99)§

Pfizer74841

India

 
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP/O12/731 vs. 2

1 vs. 3
0.48 (0.26-0.91)

2.96 (1.00-8.75)
84 (73-91)

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysP20/592 vs. 1

2 vs. 3
2.06 (1.10-3.86)

6.10 (2.21-16.87)
66 (53-78)

3) Sulfadoxine-pyrimethamine 1500 mg/75 mg at start, chloroquine 600 mg on day 1 to 2, 300 mg on day 3O4/72  94 (86-98)

Pfizer 82563

Kenya
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP1/51 vs. 20.70 (0.09-5.76)80 (30-99)

2) Chloroquine 0.6 g/day for 3 daysP2/7  86 (42-99)*

Pfizer 82576

Ghana, Kenya, Mali, Uganda, Zambia
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP5/1031 vs. 32.50 (0.50-12.59)98 (92-100)*

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysPNR  

3) Mefloquine 750 mg at start, 500 mg after 6 hoursP2/103  99 (94-100)*

Pfizer 84227

Colombia/Surinam
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP48/1121 vs. 348.43 (6.80-344.84)61 (51-70)**

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysPNR   

3) Atovaquone 1000 mg/day and proguanil 400 mg/day for 3 daysP1/113  100 (96-100)*

Pfizer 84240

Indonesia
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP9/131 vs. 32.31 (0.84-6.36)31 (10-61)**

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysPNR   

3) Sulfadoxine-pyrimethamine 1500 mg/75 mg at start, chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3P3/10  80 (44-96)*

Pfizer 367653

Burkina Faso, Ghana, Kenya, Mali, Senegal, Zambia
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysO1/1071 vs. 21.05 (0.07-16.52)100 (96-100)*

2) Mefloquine 750 mg at start, 500 mg after 6to 10 hoursO1/112  99 (94-100)*

Sykes 2009

Tanzania
1) Azithromycine 20 mg/kg/day and artesunate 4 mg/kg/day for 3 daysO69/1191 vs. 22.90 (1.96-4.28)66 (57-75)**

2) Artemether 20 mg and lumefantrine 120 mg 2x/day for < 15 kg and 40 mg/240 mg 2x/day for ≥15 kg for 3 daysO24/12090 (93-95)**

Thriemer 2010

Bangladesh
1) Azithromycin 1.5 g/day and artesunate 200 mg/day for 3 days. Children < 35 kg: azithromycin 30 mg/kg/day, and artesunate 4 mg/kg/day for 3 days.O13/1421 vs. 26.32 (0.84-47.31)94 (89-97)*

2) Artemether 80 mg and lumefantrine 480 mg 2x/day for 3 days. Children < 35 kg: artemether 4 mg/kg and lumefantrine 24 mg/kg 2x/day for 3 daysO1/69100 (93-100)*

 Excluded studies (P. falciparum)     

Krudsood 2002

Thailand
1) Azithromycin 0.5 g/day and dihydroartemisinin 80 mg/day for 3 daysO46/661 vs. 2P < 0.001 (Fisher)70 (57-80)§

2) Mefloquine 10 mg/kg on day 1 and 2, and 5 mg/kg on day 3, and dihydroartemisinin 80 mg/day for 3 daysO0/68  100 (93-100)§

Pfizer 282918

India, Colombia
1) Azithromycin 2 g/day and chloroquine 600 mg/day for 3 daysO5/107  97 (91-99)*



 
Footnotes

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)

* PCR-adjusted

** Partially PCR-adjusted. Pfizer 84227: 35/49 infections analysed, 4 reinfection. Pfizer 84240: 5/9 treatment failures analysed, all recrudescent.

§ Study follow-up conducted in area without malaria transmission

¶ Treatment arms not conducted at the same time period

 

Appendix 4. Results: Fever clearance time

 


StudyDefinitionTreatmentNMedian, hrsMean (SD), hrsRange, hrs

 P. vivax     

Pukrittayakamee 2001Time taken for body temperature to fall below 37.5 °C and remain below this value for > 48 hoursAZ2061 4-156

TET2757 4-125

DX2568 6-128

CL2043 4-110

 P. falciparum     

Krudsood 2000Time from the start of treatment until the oral temperature fell to ≤37.5 ºC and remained below that level for the next 48 hoursAZ+AT67 33.6 (27.2)0-120

AT+MQ67 38.8 (32.1)0-152

AT68 37.9 (29.0)0-152

Miller 2006Time (in hours) until temperature was ≤37.4 °C and remained there for at least an additional 48 hoursAZ3+Q10 52.5 (42.0)-

AZ5+Q20 41.5 (30.9)-

AZ4.5+Q20 49.8 (44.0)-

Q+DX10 52.8 (42.0)-

Na-Bangchang 1996The time taken for the temperature to return to normal i.e. below 37.3 °C and remain at that value for at least 24 hoursART+AZ2720 8-35

ART+DX3026.5 3-63

Noedl 2006Time from initiation of treatment until oral temperature decreased to < 37.5°C and remained at less than this temperature for the next 48 hoursAZ4.5+AT25 23.4 (22.5)0.0-76.2

AZ3+AT27 16.7 (16.2)0.0-61.3

AZ4.5+60Q15 51.4 (32.8)0.0-114.0

AZ4.5+90Q25 38.1 (38.3)0.0-140.0

Thriemer 2010Interval from start of treatment until the axillary temperature decreased to < 37.5°C and remained below this temperature for the next 48 hoursAZ4.5+AT1286.3

(19.3)*
IQR:

0.0-19.6

(16.2-21.5)*

AL653.4

(18.5)*
0.0-19.1

(6.5-28.2)*



 
Footnotes

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

 


StudyDefinitionTreatmentNMedian, hrsMean (SD), hrsRange, hrs

 P. vivax     

Dunne 2005aTime to clearance of parasitaemiaAZ9755 NR

CQ10220 NR

Pukrittayakamee 2001Time to fall below detectable levels in a peripheral blood smear.AZ20 146 (65) 

TET27 131 (35) 

DX25 145 (45) 

CL20 110 (42) 

 P. falciparum     

Dunne 2005bTime at resolution of parasitaemiaAZ1696 NR

CQ1657 NR

AZ/CQ6336 NR

Krudsood 2000Time from the start of treatment until the first negative blood film, which remained negative for the next 24 hoursAZ+AT67 43.5 (17.3)5-103

AT+MQ67 45.3 (14.7)11-97

AT68 43.7 (13.6)21-80

Miller 2006Time from the start of treatment until the first negative blood smear for asexual stages, which remained negative for an additional 24 hoursAZ3+Q10 78.9 (25.8)-

AZ5+Q20 77.7 (21.4)-

AZ4.5+Q20 77.7 (23.1)-

Q+DX10 68.8 (23.1)-

Na-Bangchang 1996Time taken for the parasite count to fall below the level of microscopic detectionART+AZ2728 18-48

ART+DX3031 8-54

Noedl 2006Time from initiation of treatment until the first time that blood films were negative for asexual parasites of P. falciparum and remained negative for the next 48 hoursAZ4.5+AT25 33.1 (15.3)8.8-79.1

AZ3+AT27 35.7 (10.5)18.2-55.6

AZ4.5+60Q15 93.1 (32.0)37.0-149.1

AZ4.5+90Q25 62.9 (26.1)14.5-115.5

Thriemer 2010The interval from the start of the treatment until the first time a blood smear was negative for asexual P. falciparum and two consecutive smears were negative.AZ4.5+AT12825.1IQR

18.5-30.3

AL6527.218.3-30.2



 
Footnotes

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

 

 


Trial 

country
Treatment regimenBlindingAE treatment related (TR)

(%)
Risk ratio AE*   (95% CI)AE any cause (AC) (%)Number AE

TR

(average AE/person)
AC

(average AE/person)

 P. vivax      

Dunne 2005A India1) Azithromycin 1 g/day for 3 daysP13/97 (13.4)0.57 (0.31-1.05) 15/97 (0.2) 

2) Chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3P24/102 (23.5)Reference 35/102 (0.3) 

Pukrittayakamee 2001

Thailand
1) Azithromycin 0.5 g/day for 3 daysO6/18 (33.3)^P = 0.06 (Fisher)   

2) Tetracycline 250 mg 4x/day for 7 daysO0/18 (0.0)    

3) Doxycycline 200 mg/day for 7 daysO0/18 (0.0)    

4) Clindamycin 300 mg 4x/day for 7 daysO0/12 (0.0)Reference   

 P. falciparum      

Dunne 2005B

India

 
1) Azithromycin 1 g/day for 3 daysP8/16 (50.0)0.78 (0.42-1.46) 8/16 (0.5) 

2) Chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3P9/16 (56.3)Reference 10/16 (0.6) 

3) Azithromycin 1 g/day for 3 days, chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3O13/63 (20.6)0.37 (0.19-0.70) 18/63 (0.3) 

Krudsood 2000

Thailand
1) Azithromycine 0.5 g/day, Artesunate 200 mg/day for 3 daysONR"Most adverse events were mild to moderate severity, difficult to distinguish from complaints of malaria, and disappeared within a week after the drugs were administered."  

2) Artesunate 200 mg/day for 3 days, mefloquine 10 mg/kg on day 1 to 2, 5 mg/kg on day 3ONR  

3) Artesunate 200 mg/day for 3 daysONR  

Miller 2006

Thailand
1) Azithromycin 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 3 daysO10/10

(100)
  16/10 (1.6)32/10 (3.2)

2) Azithromycin 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 5 daysO20/20 (100)  28/20 (1.4)45/20 (2.3)

3) Azithromycin 0.5 mg 3x/day and quinine 10 mg/kg 3x/day for 3 daysO21/21 (100)  32/21 (1.5)55/21 (2.6)

4) Doxycycline 100 mg 2x/day and quinine 10 mg/kg 3x/day for 7 daysO10/10 (100)  20/10 (2.0)31/10 (3.1)

Na-Bangchang 1996

Thailand
1) Azithromycin 0.5 g at start, 0.25 g at 24 hours and 48 hours, and artemether 300 mg at startONR0.28 (0.09-0.88)3/27 (11.1)  

2) Doxycycline 100 mg 2x/day for 5 days and artemether 300 mg at start and 100 mg after 12 hoursONRReference12/30 (40.0)  

Noedl 2006

Thailand
1) Azithromycin 0.75 g 2x/day and artesunate 100 mg 2x/day for 3 daysO1/27 (3.7)0.05 (0.01-0.37)26/27 (96.3) 113/27(4.2)

2) Azithromycin 1 g/day and artesunate 200 mg/day for 3 daysO3/27 (11.1)0.16 (0.05-0.47)27/27 (100) 154/27 (5.7)

3) Azithromycin 0.75 g 2x/day and quinine 10 mg/kg 2x/day for 3 daysO8/16 (50.0)0.71 (0.41-1.23)16/16 (100) 102/16 (6.4)

4) Azithromycin 0.5 g 3x/day and quinine 10 mg/kg 3x/day for 3 daysO19/27 (70.4)Reference27/27 (100) 169/27 (6.3)

Pfizer74841^^

India

 
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP/ONR  7/83 (0.1)24/83 (0.3)

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysPNR  2/67 (0.03)20/67 (0.3)

3) Sulfadoxine-pyrimethamine 1500 mg/75 mg at start, chloroquine 600 mg on day 1 to 2, 300 mg on day 3ONR  3/80 (0.04)22/80 (0.3)

Pfizer 82563

Kenya
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP  7/7 (100)7/7 (1.0) 

2) Chloroquine 0.6 g/day for 3 daysP  7/7 (100)18/7 (2.6) 

Pfizer 82576

Ghana, Kenya, Mali, Uganda, Zambia
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP89/114 (78.1)1.26 (1.06-1.50)106/114 (93.0)175/114 (1.5)327/114 (2.9)

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysP4/9 (44.4)0.72 (0.34-1.52)6/9 (66.7)7/9 (0.8)11/9 (1.2)

3) Mefloquine 750 mg at start, 500 mg after 6 hoursP71/115 (61.7)Reference107/115 (93.0)150/115 (1.3)337/115 (2.9)

Pfizer 84227^^

Colombia/Surinam
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysPNR1.41 (1.09-1.83)68/114 (59.6)  

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysPNR1.52 (0.98-7.80)9/14 (64.3)  

3) Atovaquone 1000 mg/day and proguanil 400 mg/day for 3 daysPNRReference49/116 (42.2)  

Pfizer 84240

Indonesia
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP8/13 (61.5)1.48 (0.67-3.27)10/13 (76.9)22/13 (1.7)46/13 (3.5)

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysP6/7 (85.7)2.06 (0.99-4.29)7/7 (100)12/7 (1.7)26/7 (3.7)

3) Sulfadoxine-Pyrimethamine 1500mg /75 mg at start, chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3P5/12 (41.7)Reference7/12 (58.3)8/12 (0.7)18/12 (1.5)

Pfizer 367653

Burkina Faso, Ghana, Kenya, Mali, Senegal, Zambia
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysO80/113 (70.8)1.14 (0.95-1.37)95/113 (84.1)173/113 (1.5)264/113 (2.3)

2) Mefloquine 750 mg at start, 500 mg after six to10 hoursO72/116 (62.1)Reference92/116 (79.3)175/116 (1.5)281/116 (2.4)

Sykes 2009

Tanzania
1) Azithromycine 20 mg/kg/day and artesunate 4 mg/kg/day for 3 daysO1.21 (0.81-1.80)39/129 (30.2)44/129 (0.3)

2) Artemether 20 mg and lumefantrine 120 mg 2x/day for < 15 kg and 40 mg/240 mg 2x/day for ≥15 kg for 3 daysOReference33/132 (25.0)38/132 (0.3)

Thriemer 2010

Bangadesh
1) Azithromycin 1.5 g/day and artesunate 200 mg/day for 3 days. Children <35 kg: azithromycin 30 mg/kg/day, and artesunate 4 mg/kg/day for 3 days.O27/128 (0.2)

2) Artemether 80 mg and lumefantrine 480 mg 2x/day for 3 days. Children <35 kg: artemether 4 mg/kg and lumefantrine 24 mg/kg 2x/day for 3 daysO33/65 (0.5)

 Excluded studies (P. falciparum)      

Krudsood 2002

Thailand
1) Azithromycin 0.5 g/day and dihydroartemisinin 80 mg/day for 3 daysONR"Regarding safety, it was difficult to distinguish between symptoms of acute malaria and drug-related effects. All signs and symptoms and parasitaemia simultaneously disappeared within few days."  

2) Mefloquine 10 mg/kg on day 1 and 2, and 5 mg/kg on day 3, dihydroartemisinin 80 mg/day for 3 days

Pfizer 282918

India, Colombia
1) Azithromycin 2 g/day and chloroquine 0.6 g/day for 3 daysO48/110 (43.6) NR 78/110 (0.7)



 
Footnotes

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

 

 


Trial 

country
Treatment regimenBlindingSAEDiscontinuationLab and otherNotes


TRACTRAC

 P. vivax       

Dunne 2005a India1) Azithromycin 1 g/day for 3 daysP000NRNR2 discontinued in arm 2 because of pruritis (1) and maculopapular rash (1)

2) Chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3P002NRNR

Pukrittayakamee 2001

Thailand
1) Azithromycin 0.5 g/day for 3 daysO00NRNR "None of the patients developed serious adverse effects as monitored by clinical symptoms and laboratory data."

2) Tetracycline 250 mg 4x/day for 7 daysO00NRNR 

3) Doxycycline 200 mg/day for 7 daysO00NRNR 

4) Clindamycin 300 mg 4x/day for 7 daysO00NRNR 

 P. falciparum       

Dunne 2005b

India

 
1) Azithromycin 1 g/day for 3 daysP0000NR 

2) Chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3P0000NR 

3) Azithromycin 1 g/day for 3 days, chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3O0000NR 

Krudsood 2000

Thailand
1) Azithromycin 0.5 g/day, artesunate 200 mg/day for 3 daysO00NRNR"Several patients had abnormal haematology and biochemistry at the beginning, but all of these improved a few weeks after treatment." 

2) Artesunate 200 mg/day for 3 days, mefloquine 10 mg/kg on day 1 to 2, 5 mg/kg on day 3O00NRNR 

3) Artesunate 200 mg/day for 3 daysO00NRNR 

Miller 2006

Thailand
1) Azithromycin 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 3 daysO00NRNRElevated ALT level (1 in each group). Resolved within 10 days of completion of therapy.Most side effects related to quinine (tinnitus, prolonged QTc)

2) Azithromycin 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 5 daysO00NRNR

3) Azithromycin 0.5 g 3x/day and quinine 10 mg/kg 3x/day for 3 daysO00NRNR

4) Doxycycline 100 mg 2x/day and quinine 10 mg/kg 3x/day for 7 daysO00NRNR

Na-Bangchang 1996

Thailand
1) Azithromycin 0.5 g at start, 0.25 g at 24 hours and 48 hours, and artemether 300 mg at startO00NRNRNR"Transient mild nausea, abdominal discomfort and loss of appetite were common adverse effects." 

 

2) Doxycycline 100 mg 2x/day for 5 days and artemether 300 mg at start and 100 mg after 12 hoursO00NRNRNR

Noedl 2006

Thailand
1) Azithromycin 0.75 g 2x/day and artesunate 100 mg 2x/day for 3 daysO0000NROne participant with food poisoning withdrawn in arm 4.

2) Azithromycin 1 g/day and artesunate 200 mg/day for 3 daysO0000NR

3) Azithromycin 0.75 g 2x/day and quinine 10 mg/kg 2x/day for 3 daysO0000ECG: quinine groups significant prolongation of QT interval.

4) Azithromycin 0.5 g 3x/day and quinine 10 mg/kg 3x/day for 3 daysO0100

Pfizer74841

India

 
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP/O0/835/83 (6.0%)03/83 (3.6%)“No clinical significant laboratory findings or changes in vital signs."SEA any cause: arm 1: cerebral malaria (1), fever (4); arm 2:  fever (3), convulsion (1), pneumonia (1); arm 3: fever (2), abnormal behaviour (1, TR).

2) Azithromycin  0.5 g/day and chloroquine 0.6 g/day for 3 daysP0/675/67 (7.5%)00/67Discontinuations: 1 cerebral malaria and 2 malarial fever in arm 1, and 1 malarial fever in arm 3.

3) Sulfadoxine-pyrimethamine 1500mg /75 mg at start, chloroquine 0.6 g on day 1 to 2, 0.3 mg on day 3O1/80 (1.3%)3/80 (3.8%)01/80 (1.3%)

Pfizer 82563

Kenya
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP01/6 (16.7%)00Similar incidence of lab abnormalities in both groups. "None were unexpected for this population."

Vital signs: larger mean decrease in BP and larger mean increase in heart rate from baseline in group 2.
One SEA in group 1 (seizures) in a person with a history of seizures.

2) Chloroquine 0.6 g/day for 3 daysP0000

Pfizer 82576

Ghana, Kenya, Mali, Uganda, Zambia
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP01/114 (0.9%)2/114 (1.8%)3/114 (2.6%)"The incidence of laboratory abnormalities was similar in arm 1 and arm 3."SEA: Dyspnoea and confusional state in arm 1, mental disorder and nephritic syndrome in arm 3 (TR)

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysP0000Discontinuations: arm 1: confusion 1, vomiting 2 (TR), arm 3: vomiting 2, (1 TR), jaundice 1, fever 1 (TR)

3) Mefloquine 750 mg at start, 500 mg after 6 hoursP2/115 (1.7%)2/115 (1.7%)2/115 (1.7%)4/115 (3.5%)

Pfizer 84227

Colombia/Surinam
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysPNR3/114 (2.6%)NR6/114 (5.3%)NRSEA: Arm 1: complicated malaria, progressive renal failure, sepsis; arm 2: enterocolitis; arm 3: diabetic neuropathy, progressive severe anaemia.

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysPNR1/14 (7.1%)NRNRNRDiscontinuations:

Arm 1: vomiting 2, infection 2, sepsis 1, electrolyte imbalance 1; arm 3: infection 1.

3) Atovaquone 1000 mg/day and proguanil 400 mg/day for 3 daysPNR2/116 (1.7%)NR1/116 (0.9%)NR

Pfizer 84240

Indonesia
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysP01/13 (7.7%)00"All treatment groups showed a similar incidence of laboratory abnormalities (1 subject in each group) with regard to normal baseline. None of the laboratory abnormalities was unexpected for this disease population."SEA  arm 1: recurrent malaria; arm 2: appendicitis

2) Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 daysP01/7 (14.3%)00

3) Sulfadoxine-Pyrimethamine 1500 mg/75 mg at start, chloroquine 0.6 g on day 1 to 2, 0.3 g on day 3P00/1200 

Pfizer 367653

Burkina Faso, Ghana, Kenya, Mali, Senegal, Zambia
1) Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 daysO0/1130/113NR1/113 (0.9%)"No subjects were discontinued from the study due to abnormal laboratory test results."SEA: dizziness and intentional self injury

2) Mefloquine 750 mg at start, 500 mg after 6 to 10 hoursO1/116 (0.9%)2/116 (1.7%)NR0/116Discontinuation in arm 1 because of pruritis

Sykes 2009

Tanzania
1) Azithromycine 20 mg/kg/day and artesunate 4 mg/kg/day for 3 daysO1/120Lab-abnormalities on day 14:

18/120

2) Artemether 20 mg and lumefantrine 120 mg 2x/day for <15 kg and 40 mg/240 mg 2x/day for ≥15 kg for 3 daysO9/129Lab-abnormalities on day 14:

22/121

Thriemer 2010

Bangladesh
1) Azithromycin 1.5 g/day and artesunate 200 mg/day for 3 days. Children < 35 kg: azithromycin 30 mg/kg/day, and artesunate 4 mg/kg/day for 3 days.O08NRDiscontinuations: Development of P. vivax ≥ day 21

2) Artemether 80 mg and lumefantrine 480 mg 2x/day for 3 days. Children < 35 kg: artemether 4 mg/kg and lumefantrine 24 mg/kg 2x/day for 3 daysO04NR

 Excluded studies (P. falciparum)       

Krudsood 2002

Thailand
1) Azithromycin 0.5 g/day and dihydroartemisinin 80 mg/day for 3 daysO0000"Some baseline laboratory parameters were affected by disease status. However, they all returned to normal within 1-2 weeks." 

2) Mefloquine 10 mg/kg on day 1 and 2, and 5 mg/kg on day 3, dihydroartemisinin 80 mg/day for 3 days 0000 

Pfizer 282919

India, Colombia
1) Azithromycin 2 g/day and chloroquine 0.6 g/day for 3 daysO0 NR0 NR  



 
Footnotes

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

 


StudyTreatment regimesBlindingNauseaVomitingDiarrhoeaPruritisDizziness





%n/N%n/N%n/N%n/N%n/N

Dunne 2005a

India
1) AZ 1 g/day for 3 daysP0.00/970.00/970.00/971.01/97NR 

2) CQ 0.6 g on day 1 to 2, 0.3 g on day 3P4.95/1027.88/1020.00/1027.88/102NR 

Dunne 2005b

India
1) AZ 1 g/day for 3 daysP0.00/160.00/1612.52/166.31/166.31/16

2) CQ 0.6 g on day 1 to 2, 0.3 g on day 3P0.00/160.00/166.31/1618.83/1618.83/16

3) AZ 1 g/day for 3 days, CQ 0.6 mg on day 1 to 2, 0.3 g on day 3O6.34/637.95/633.22/631.61/630.00/63

Miller 2006

Thailand
1) AZ 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 3 daysONR 10.01/1020.02/10NR 100.010/10

2) AZ 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 5 daysONR 20.02/2015.03/20NR 100.020/20

3) AZ 0.5 g 3x/day and quinine 10 mg/kg 3x/day for 3 daysONR 19.04/219.52/21NR 90.519/21

4) Doxycycline 100 mg 2x/day and quinine 10 mg/kg 3x/day for 7 daysONR 40.04/1010.01/10NR 100.010/10

Pfizer74841§

India

 
1) AZ 1 g/day and CQ 0.6 g/day for 3 daysP/ONR 14.512/834.84/832.42/83NR 

2) AZ 0.5 g/day and CQ 0.6 g/day for 3 daysPNR 13.49/676.04/673.02/67NR 

3) SP 1500 mg/75 mg at start, CQ 0.6 g on day 1 to 2, 0.3 g on day 3ONR 18.815/801.31/800.00/80NR 

Pfizer 82576

Ghana, Kenya, Mali, Uganda, Zambia
1) AZ 1 g/day and CQ 0.6 g/day for 3 daysP9.611/11418.421/11412.314/11451.859/11416.719/114

2) AZ 0.5 g/day and CQ 0.6 g/day for 3 daysP0.00/922.22/90.00/922.22/90.00/9

3) Mefloquine 750 mg at start, 500 mg after 6 hoursP17.420/11525.229/11510.412/1159.611/11533.939/115

Pfizer 84227

Colombia/Surinam
1) AZ 1 g/day and CQ 0.6 g/day for 3 daysPNR 6.17/1145.36/11425.429/114NR 

2) AZ 0.5 g/day and CQ 0.6 g/day for 3 daysPNR 14.32/140.00/1428.64/14NR 

3) Atovaquone 1000/proguanil 400 mg/day for 3 daysPNR 4.35/1164.35/1162.63/116NR 

Pfizer 84240

Indonesia
1) AZ 1 g/day and CQ 0.6 g/day for 3 daysP53.87/1330.84/137.71/13NR 15.42/13

2) AZ  0.5 g/day and CQ 0.6 g/day for 3 daysP28.62/742.93/714.31/7NR 28.62/7

3) SP 1500 mg/75 mg at start, CQ 0.6 g on day 1 to 2, 0.3 g on day 3P16.72/1216.72/1216.72/12NR 8.31/12

Pfizer 367653

Burkina Faso, Ghana, Kenya, Mali, Senegal, Zambia
1) AZ 1 g/day and CQ 0.6 g/day for 3 daysO11.513/1134.45/11312.414/11328.332/11319.522/113

2) Mefloquine 750 mg at start, 500 mg after 6 to 10 hoursO15.518/11625.029/1165.26/1161.72/11623.327/116

Sykes 2009

Tanzania
1) Azithromycine 20 mg/kg/day and artesunate 4 mg/kg/day for 3 daysONR7.810/129NR5.47/1291.62/129

2) Artemether 20 mg and lumefantrine 120 mg 2x/day for < 15 kg and 40 mg/240 mg 2x/day for ≥15 kg for 3 daysONR1.52/132NR3.04/1320.81/132

Thriemer 2010*

Bangladesh
1) Azithromycin 1.5 g/day and artesunate 200 mg/day for 3 days. Children < 35 kg: azithromycin 30 mg/kg/day, and artesunate 4 mg/kg/day for 3 days.O7.810/1286.38/1283.95/128NRNR

2) Artemether 80 mg and lumefantrine 480 mg 2x/day for 3 days. Children < 35 kg: artemether 4 mg/kg and lumefantrine 24 mg/kg 2x/day for 3 daysO18.512/653.12/6500/65NRNR

 Excluded studies           

Pfizer 282919

India, Colombia
1) AZ 2 g/day and CQ 0.6 g/day for 3 daysO30.033/11018.220/11011.813/1103.64/110NR 



 
Footnotes

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)

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 6 December 2010.


DateEventDescription

14 March 2011AmendedAdditional tables moved to appendices to aid readability



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Protocol first published: Issue 3, 2007
Review first published: Issue 2, 2011


DateEventDescription

18 July 2008AmendedConverted to new review format.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Nuffield Commonwealth Foundation, UK.
  • Department for International Development (DFID), UK.
  • Liverpool School of Tropical Medicine, UK.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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.

 

Index terms

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

References

References to studies included in this review

  1. Top of page
  2. AbstractResumenRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to ongoing studies
  21. Additional references
Dunne 2005a {published data only}
  • Dunne MW, Singh N, Shukla M, Valecha N, Bhattacharyya PC, Patel K, et al. A double-blind, randomized study of azithromycin compared to chloroquine for the treatment of Plasmodium vivax malaria in India. American Journal of Tropical Medicine and Hygiene 2005;73(6):1108-11.
Dunne 2005b {published data only}
  • Dunne MW, Singh N, Shukla M, Valecha N, Bhattacharyya PC, Dev V, et al. A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. Journal of Infectious Diseases 2005;191(10):1582-8.
Krudsood 2000 {published data only}
  • Krudsood S, Silachamroon U, Wilairatana P, Singhasivanon P, Phumratanaprapin W, Chalermrut K, et al. A randomized clinical trial of combinations of artesunate and azithromycin for treatment of uncomplicated Plasmodium falciparum malaria in Thailand. Southeast Asian Journal of Tropical Medicine and Public Health 2000;31(4):801-7.
Krudsood 2002 {published data only}
  • Krudsood S, Buchachart K, Chalermut K, Charusabha C, Treepasertsuk S, Haoharn O, et al. A comparative clinical trial of combinations of dihydroartemisinin plus azithromycin and dihydroartemisinin plus mefloquine for treatment of multidrug resistant falciparum malaria. Southeast Asian Journal of Tropical Medicine and Public Health 2002;33(3):525-31.
Miller 2006 {published data only}
  • Miller RS, Wongsrichanalai C, Buathong N, McDaniel P, Walsh DS, Knirsch C, et al. Effective treatment of uncomplicated Plasmodium falciparum malaria with azithromycin-quinine combinations: a randomized, dose ranging study. American Journal of Tropical Medicine and Hygiene 2006;74(3):401-6.
Na-Bangchang 1996 {published data only}
  • Na-Bangchang K, Kanda T, Tipawangso P, Thanavibul A, Suprakob K, Ibrahim M, et al. Activity of artemether-azithromycin versus artemether-doxycycline in the treatment of multiple drug resistant falciparum malaria. Southeast Asian Journal of Tropical Medicine and Public Health 1996;27(3):522-5.
Noedl 2006 {published and unpublished data}
  • Noedl H, Krudsood S, Chalermratana K, Silachamroon U, Leowattana W, Tangpukdee N, et al. Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: A randomized, phase 2 clinical trial in Thailand. Clinical Infectious Diseases 2006;43:1264-71.
Pfizer 282919 {published and unpublished data}
  • Pfizer Inc. A three day trial of azithromycin plus chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria. http://www.clinicaltrials.gov/ct/show/NCT00282919 2008.
Pfizer 367653 {published and unpublished data}
  • Pfizer Inc. A phase-3, randomized, open-label, comparative trial of azithromycin plus chloroquine versus mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria in Africa. http://pdf.clinicalstudyresults.org/documents/company-study_4619_0.pdf 2008.
Pfizer 74841 {published and unpublished data}
  • Pfizer Inc. A phase 2/3 randomized, comparative trial of azithromycin plus chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in India. http://pdf.clinicalstudyresults.org/documents/company-study_1101_0.pdf 2007.
Pfizer 82563 {published and unpublished data}
  • Pfizer Inc. A phase 2, double blind, randomized, comparative trial of azithromycin in combination with chloroquine versus chloroquine in the eradication of asymptomatic Plasmodium falciparum infection in semi-immune adults. http://pdf.clinicalstudyresults.org/documents/company-study_1764_0.pdf 2007.
Pfizer 82576 {published and unpublished data}
  • Pfizer Inc. A phase 2/3, randomized, double-blind, comparative trial of azithromycin plus chloroquine versus mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria in Africa. http://pdf.clinicalstudyresults.org/documents/company-study_2362_0.pdf 2007.
Pfizer 84227 {published and unpublished data}
  • Pfizer Inc. A phase 2/3, randomized, double blind, comparative trial of azithromycin plus chloroquine versus atovaquone-proguanil for the treatment of uncomplicated Plasmodium falciparum malaria in South America. http://pdf.clinicalstudyresults.org/documents/company-study_1770_0.pdf 2007.
Pfizer 84240 {published and unpublished data}
  • Pfizer Inc. A phase 2/3, randomized, comparative, double blind trial of azithromycin plus chloroquine versus sulfadoxine-pyrimethamine plus chloroquine for the treatment of uncomplicated, symptomatic falciparum malaria in Southeast Asia. http://pdf.clinicalstudyresults.org/documents/company-study_1765_0.pdf 2007.
Pukrittayakamee 2001 {published data only}
  • Pukrittayakamee A, Clemens R, Chantra A, Nontprasert A, Luknam T, Looareesuwan S, et al. Therapeutic responses to antibacterial drugs in vivax malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 2001;95:524-8.
Sykes 2009 {published and unpublished data}
  • Sykes A, Hendriksen I, Mtove G, Mandea V, Mrema H, Rutta B, et al. Azithromycin plus artesunate versus artemether-lumefantrine for treatment of uncomplications malaria in Tanzanian children: a randomized, controlled trial. Clinical Infectious Diseases 2009;49:1195-1201.
Thriemer 2010 {published and unpublished data}
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References to ongoing studies

  1. Top of page
  2. AbstractResumenRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to ongoing studies
  21. Additional references
NIAID 379821 {published and unpublished data}
  • National Institute of Allergy and Infectious Diseases. Chloroquine alone or in combination for malaria in children in Malawi. http://www.clinicaltrials.gov/ct/show/NCT00379821. 2006.
Pfizer 677833 {published data only}
  • Pfizer Inc. Azithromycin plus chloroquine versus artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria in children in Africa. http://www.clinicaltrials.gov/ct/show/NCT00677833. 2008.

Additional references

  1. Top of page
  2. AbstractResumenRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to ongoing studies
  21. Additional references
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