Azithromycin for treating uncomplicated malaria

Anna M van Eijk; Dianne J Terlouw

doi:10.1002/14651858.CD006688.pub2

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Figure 1

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

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Figure 2

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

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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

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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).

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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

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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

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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

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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

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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.

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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.

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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.

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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.

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Analysis 2.1

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

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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).

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on day 28, not corrected by PCR Show forest plot	13		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 AZ vs. CQ	1	29	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.53, 1.44]
1.2 AZCQ vs. CQ (not randomized)	2	90	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.01, 2.35]
1.3 AZCQ vs. AZ monotherapy (not randomized)	1	77	Risk Ratio (M‐H, Random, 95% CI)	0.05 [0.01, 0.20]
1.4 AZCQ vs. SPCQ	2	168	Risk Ratio (M‐H, Random, 95% CI)	2.59 [1.24, 5.43]
1.5 AZCQ vs. atovaquone‐proguanil	1	225	Risk Ratio (M‐H, Random, 95% CI)	48.43 [6.80, 344.83]
1.6 AZCQ vs. MQ	2	425	Risk Ratio (M‐H, Random, 95% CI)	2.00 [0.50, 8.07]
1.7 AZ‐artesunate vs. artesunate	1	116	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.54, 1.14]
1.8 AZ‐artesunate vs. MQ‐artesunate	1	110	Risk Ratio (M‐H, Random, 95% CI)	24.00 [3.36, 171.26]
1.9 AZ‐artesunate vs. AZ‐quinine (arm 1 vs. 4)	1	50	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.15, 6.55]
1.10 AZ‐artesunate vs. artemether‐lumefantrine	2	450	Risk Ratio (M‐H, Random, 95% CI)	2.98 [2.03, 4.37]
1.11 AZ‐artemether vs. doxycycline‐artemether	1	57	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.21, 2.76]
1.12 AZ‐quinine vs. doxycycline‐quinine (arm 1 vs. 4)	1	20	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.14, 65.90]
2 Treatment failure day 28, PCR corrected Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 AZCQ vs CQ	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.09, 14.92]
2.2 AZCQ vs. SP	1	23	Risk Ratio (M‐H, Fixed, 95% CI)	3.46 [0.95, 12.59]
2.3 AZCQ vs. atovaquone‐proguanil	1	225	Risk Ratio (M‐H, Fixed, 95% CI)	89.79 [5.60, 1440.31]
2.4 AZCQ vs. MQ	2	425	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.18, 5.87]
2.5 AZ‐artesunate vs. artemether‐lumefantrine	2	450	Risk Ratio (M‐H, Fixed, 95% CI)	3.63 [2.02, 6.52]
2.6 AZ‐quinine vs. doxycycline‐quinine (arm 1 vs. 4)	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.14, 65.90]
3 Treatment failure on day 42, not corrected by PCR Show forest plot	2	445	Risk Ratio (M‐H, Fixed, 95% CI)	1.90 [1.44, 2.49]

3.1 AZ‐artesunate vs. artemether‐lumefantrine	2	445	Risk Ratio (M‐H, Fixed, 95% CI)	1.90 [1.44, 2.49]
4 Treatment failure on day 42, (partially) corrected by PCR Show forest plot	2	445	Risk Ratio (M‐H, Fixed, 95% CI)	2.47 [1.53, 3.99]

4.1 AZ‐artesunate vs. artemether‐lumefantrine	2	445	Risk Ratio (M‐H, Fixed, 95% CI)	2.47 [1.53, 3.99]

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

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment related adverse events Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 AZ vs. CQ	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.46, 1.71]
1.2 AZCQ vs. CQ	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	0.37 [0.19, 0.70]
1.3 AZCQ vs. AZ monotherapy	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.21, 0.82]
1.4 AZCQ vs. SPCQ	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.67, 3.27]
1.5 AZCQ vs. MQ	2	458	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [1.06, 1.36]
1.6 AZ‐artesunate vs. AZ‐quinine (arm 1 vs. 4)	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.05 [0.01, 0.37]
2 All adverse events (any cause) Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 AZCQ vs. SPCQ	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.75, 2.32]
2.2 AZCQ vs. atovaquone‐proguanil	1	230	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [1.09, 1.83]
2.3 AZCQ vs. MQ	2	458	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.96, 1.10]
2.4 AZ‐artemether vs. doxycycline‐artemether	1	57	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.09, 0.88]
2.5 AZ‐artesunate vs. artemether‐lumefantrine	1	261	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.81, 1.80]

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

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