Azithromycin for treating uncomplicated malaria

Abstract

Background: To prevent the development of drug resistance, the World Health Organization (WHO) recommends treating malaria with combination therapy. Azithromycin, an antibiotic with antimalarial properties, may be a useful additional option for antimalarial therapy.

Objectives: To compare the use of azithromycin alone or in combination with other antimalarial drugs with the use of alternative antimalarial drugs for treating uncomplicated malaria caused by Plasmodium falciparum or Plasmodium vivax.

Search strategy: We searched the Cochrane Infectious Diseases Group Specialized Register (August 2010); CENTRAL (The Cochrane Library Issue 3, 2010); MEDLINE (1966 to August 2010); EMBASE (1974 to August 2010); LILACS (August 2010); the metaRegister of Controlled Trials (mRCT, August 2010); conference proceedings; and reference lists. We also contacted researchers and a pharmaceutical company.

Selection criteria: Randomized controlled trials comparing azithromycin, either alone or combined with another antimalarial drug, with another antimalarial drug used alone or combined with another antimalarial drug, or with azithromycin combined with another antimalarial drug if different combinations or doses of azithromycin were used. The primary outcome was treatment failure by day 28, defined as parasitological or clinical evidence of treatment failure between the start of treatment and day 28. Secondary outcomes included treatment failure by day 28 corrected for new infections confirmed by polymerase chain reaction (PCR), fever and parasite clearance time, and adverse events.

Data collection and analysis: Two people independently applied the inclusion criteria, extracted data and assessed methodological quality. We used risk ratio (RR) and 95% confidence intervals (CI).

Main results: Fifteen trials met the inclusion criteria (2284 participants, 69% males, 16% children). They were conducted in disparate malaria endemic areas, with the earlier studies conducted in Thailand (five) and India (two), and the more recent studies (eight) spread across three continents (South America, Africa, Asia). The 15 studies involved 41 treatment arms, 12 different drugs, and 28 different treatment regimens. Two studies examined P. vivax.Three-day azithromycin (AZ) monotherapy did not perform well for P. vivax or P. falciparum (Thailand: P. vivax failure rate 0.5 g daily, 56%, 95% CI 31 to 78. India: P. vivax failure rate 1 g daily,12%, 95% CI 7 to 21; P. falciparum failure rate 1 g daily, 64%, 95% CI 36 to 86.) A 1 g azithromycin and 0.6 g chloroquine combination daily for three days for uncomplicated P. falciparum infections was associated with increased treatment failure in India and Indonesia compared with the combination of sulphadoxine-pyrimethamine and chloroquine (pooled RR 2.66, 95% CI 1.25 to 5.67), and compared with the combination atovaquone-proguanil in a multicentre trial in Columbia and Surinam (RR 24.72, 95% CI 6.16 to 99.20). No increased risk of treatment failure was seen in two studies in Africa with mefloquine as the comparator drug (pooled RR 2.02, 95% CI 0.51 to 7.96, P = 0.3); the pooled RR for PCR-corrected data for the combination versus mefloquine was 1.01, 95% CI 0.18 to 5.84 (P = 1.0). An increased treatment failure risk was seen when comparing azithromycin in a dose of 1.2 to 1.5 mg in combination with artesunate (200 mg per day for three days) with artemether-lumefantrine (pooled RR 3.08, 95% CI 2.09 to 4.55; PCR-corrected pooled RR 3.63, 95% CI 2.02 to 6.52).Serious adverse events and treatment discontinuation were similar across treatment arms. More adverse events were reported when comparing the 1 g azithromycin/ 0.6 g chloroquine combination with mefloquine (pooled RR 1.20, 95% CI 1.06 to 1.36) or atovaquone-proguanil (RR 1.41, 95% CI 1.09 to1.83).

Authors' conclusions: Currently, there is no evidence for the superiority or equivalence of azithromycin monotherapy or combination therapy for the treatment of P. falciparum or P. vivax compared with other antimalarials or with the current first-line antimalarial combinations. The available evidence suggests that azithromycin is a weak antimalarial with some appealing safety characteristics. Unless the ongoing dose, formulation and product optimisation process results in a universally efficacious product, or a specific niche application is identified that is complementary to the current scala of more efficacious antimalarial combinations, azithromycin's future for the treatment of malaria does not look promising.

Figure 1

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

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 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

Figure 4

Efficacy of azithromycin containing treatment regimens for P. falciparum (28 days follow‐up) Abbreviations: AZ: azithromycin; CQ: chloroquine; Artm: artemether; Art: artesunate; dihydroart: dihydroartemisinin; Q: quinine; CI: confidence interval; d: days Symbols: *: PCR‐corrected; **: partially PCR‐corrected; §: study conducted in an area without malaria transmission (Bangkok). The AZ dose in the combination with artemisinin 300 mg was 500 mg at start, followed by 250 mg after 24 hours and 48 hours. An interrupted line has been drawn at the 90% efficacy level, the minimum level for the 95% confidence interval for a potentially useful drug regimen as recommended by WHO (WHO/RBM 2006).

Figure 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

Figure 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

Figure 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

Figure 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

Analysis 1.1

Comparison 1 Overview treatment failure for AZ or AZ combination vs. control for P. falciparum, Outcome 1 Treatment failure on day 28, not corrected by PCR.

Analysis 1.2

Comparison 1 Overview treatment failure for AZ or AZ combination vs. control for P. falciparum, Outcome 2 Treatment failure day 28, PCR corrected.

Analysis 1.3

Comparison 1 Overview treatment failure for AZ or AZ combination vs. control for P. falciparum, Outcome 3 Treatment failure on day 42, not corrected by PCR.

Analysis 1.4

Comparison 1 Overview treatment failure for AZ or AZ combination vs. control for P. falciparum, Outcome 4 Treatment failure on day 42, (partially) corrected by PCR.

Analysis 2.1

Comparison 2 Overview adverse events for AZ or AZ combinations vs. control for P. falciparum, Outcome 1 Treatment related adverse events.

Analysis 2.2

Comparison 2 Overview adverse events for AZ or AZ combinations vs. control for P. falciparum, Outcome 2 All adverse events (any cause).