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Background: The World Health Organization (WHO) recommends that people with uncomplicated Plasmodium falciparum malaria are treated using Artemisinin-based Combination Therapy (ACT). ACT combines three-days of a short-acting artemisinin derivative with a longer-acting antimalarial which has a different mode of action. Pyronaridine has been reported as an effective antimalarial over two decades of use in parts of Asia, and is currently being evaluated as a partner drug for artesunate., Objectives: To evaluate the efficacy and safety of artesunate-pyronaridine compared to alternative ACTs for treating people with uncomplicated P. falciparum malaria., Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; ClinicalTrials.gov; the metaRegister of Controlled Trials (mRCT); and the WHO International Clinical Trials Search Portal up to 16 January 2014. We searched reference lists and conference abstracts, and contacted experts for information about ongoing and unpublished trials., Selection Criteria: Randomized controlled trials of artesunate-pyronaridine versus other ACTs in adults and children with uncomplicated P. falciparum malaria.For the safety analysis, we also included adverse events data from trials comparing any treatment regimen containing pyronaridine with regimens not containing pyronaridine., Data Collection and Analysis: Two authors independently assessed trial eligibility and risk of bias, and extracted data. We combined dichotomous data using risk ratios (RR) and continuous data using mean differences (MD), and presented all results with a 95% confidence interval (CI). We used the GRADE approach to assess the quality of evidence., Main Results: We included six randomized controlled trials enrolling 3718 children and adults. Artesunate-pyronaridine versus artemether-lumefantrineIn two multicentre trials, enrolling mainly older children and adults from west and south-central Africa, both artesunate-pyronaridine and artemether-lumefantrine had fewer than 5% PCR adjusted treatment failures during 42 days of follow-up, with no differences between groups (two trials, 1472 participants, low quality evidence). There were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.60, 95% CI 0.40 to 0.90, two trials, 1720 participants, moderate quality evidence), but no difference was detected over the whole 42 day follow-up (two trials, 1691 participants, moderate quality evidence). Artesunate-pyronaridine versus artesunate plus mefloquineIn one multicentre trial, enrolling mainly older children and adults from South East Asia, both artesunate-pyronaridine and artesunate plus mefloquine had fewer than 5% PCR adjusted treatment failures during 28 days follow-up (one trial, 1187 participants, moderate quality evidence). PCR-adjusted treatment failures were 6% by day 42 for these treated with artesunate-pyronaridine, and 4% for those with artesunate-mefloquine (RR 1.64, 95% CI 0.89 to 3.00, one trial, 1116 participants, low quality evidence). Again, there were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.35, 95% CI 0.17 to 0.73, one trial, 1720 participants, moderate quality evidence), but no differences were detected over the whole 42 days (one trial, 1146 participants, low quality evidence). Adverse effectsSerious adverse events were uncommon in these trials, with no difference detected between artesunate-pyronaridine and comparator ACTs. The analysis of liver function tests showed biochemical elevation were four times more frequent with artesunate-pyronaridine than with the other antimalarials (RR 4.17, 95% CI 1.38 to 12.62, four trials, 3523 participants, moderate quality evidence)., Authors' Conclusions: Artesunate-pyronaridine performed well in these trials compared to artemether-lumefantrine and artesunate plus mefloquine, with PCR-adjusted treatment failure at day 28 below the 5% standard set by the WHO. Further efficacy and safety studies in African and Asian children are required to clarify whether this combination is an option for first-line treatment.

Background: Review status: Current question - no update intended. Azithromycin treatments are included in the review: Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). (Thaver D, Zaidi AKM, Critchley JA, Azmatullah A, Madni SA, Bhutta ZA. Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD004530. DOI: 10.1002/14651858.CD004530.pub3.)   This latter review is being updated, and will be published in late 2011.Enteric fever (typhoid and paratyphoid fever) is potentially fatal. Infection with drug-resistant strains of the causative organism Salmonella enterica serovar Typhi or Paratyphi increases morbidity and mortality. Azithromycin may have better outcomes in people with uncomplicated forms of the disease., Objectives: To compare azithromycin with other antibiotics for treating uncomplicated enteric fever., Search Strategy: In August 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, LILACS, and mRCT. We also searched conference proceedings, reference lists, and contacted researchers and a pharmaceutical company., Selection Criteria: Randomized controlled trials comparing azithromycin with other antibiotics for treating children and adults with uncomplicated enteric fever confirmed by cultures of S. Typhi or Paratyphi in blood and/or stool., Data Collection and Analysis: Both authors independently extracted data and assessed the risk of bias. Dichotomous data were presented and compared using the odds ratio, and continuous data were reported as arithmetic means with standard deviations and were combined using the mean difference (MD). Both were presented with 95% confidence intervals (CI)., Main Results: Seven trials involving 773 participants met the inclusion criteria. The trials used adequate methods to generate the allocation sequence and conceal allocation, and were open label. Three trials exclusively included adults, two included children, and two included both adults and children; all were hospital inpatients. One trial evaluated azithromycin against chloramphenicol and did not demonstrate a difference for any outcome (77 participants, 1 trial). When compared with fluoroquinolones in four trials, azithromycin significantly reduced clinical failure (OR 0.48, 95% CI 0.26 to 0.89; 564 participants, 4 trials) and duration of hospital stay (MD -1.04 days, 95% CI -1.73 to -0.34 days; 213 participants, 2 trials); all four trials included people with multiple-drug-resistant or nalidixic acid-resistant strains of S. Typhi or S. Paratyphi. We detected no statistically significant difference in the other outcomes. Compared with ceftriaxone, azithromycin significantly reduced relapse (OR 0.09, 95% CI 0.01 to 0.70; 132 participants, 2 trials) and not other outcome measures. Few adverse events were reported, and most were mild and self limiting., Authors' Conclusions: Azithromycin appears better than fluoroquinolone drugs in populations that included participants with drug-resistant strains. Azithromycin may perform better than ceftriaxone.

Background: Enteric fever (typhoid and paratyphoid fever) is potentially fatal. Infection with drug-resistant strains of the causative organism Salmonella enterica serovar Typhi or Paratyphi increases morbidity and mortality. Azithromycin may have better outcomes in people with uncomplicated forms of the disease., Objectives: To compare azithromycin with other antibiotics for treating uncomplicated enteric fever., Search Strategy: In August 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, LILACS, and mRCT. We also searched conference proceedings, reference lists, and contacted researchers and a pharmaceutical company., Selection Criteria: Randomized controlled trials comparing azithromycin with other antibiotics for treating children and adults with uncomplicated enteric fever confirmed by cultures of S. Typhi or Paratyphi in blood and/or stool., Data Collection and Analysis: Both authors independently extracted data and assessed the risk of bias. Dichotomous data were presented and compared using the odds ratio, and continuous data were reported as arithmetic means with standard deviations and were combined using the mean difference (MD). Both were presented with 95% confidence intervals (CI)., Main Results: Seven trials involving 773 participants met the inclusion criteria. The trials used adequate methods to generate the allocation sequence and conceal allocation, and were open label. Three trials exclusively included adults, two included children, and two included both adults and children; all were hospital inpatients. One trial evaluated azithromycin against chloramphenicol and did not demonstrate a difference for any outcome (77 participants, 1 trial). When compared with fluoroquinolones in four trials, azithromycin significantly reduced clinical failure (OR 0.48, 95% CI 0.26 to 0.89; 564 participants, 4 trials) and duration of hospital stay (MD -1.04 days, 95% CI -1.73 to -0.34 days; 213 participants, 2 trials); all four trials included people with multiple-drug-resistant or nalidixic acid-resistant strains of S. Typhi or S. Paratyphi. We detected no statistically significant difference in the other outcomes. Compared with ceftriaxone, azithromycin significantly reduced relapse (OR 0.09, 95% CI 0.01 to 0.70; 132 participants, 2 trials) and not other outcome measures. Few adverse events were reported, and most were mild and self limiting., Authors' Conclusions: Azithromycin appears better than fluoroquinolone drugs in populations that included participants with drug-resistant strains. Azithromycin may perform better than ceftriaxone.

Background: Artemisinin-based combination treatments are strongly advocated, but supplies are limited. Sulfadoxine combined with amodiaquine is an alternative non-artemisinin combination., Objectives: To compare sulfadoxine-pyrimethamine plus amodiaquine (SP plus AQ) with sulfadoxine-pyrimethamine plus artesunate (SP plus AS) for treating uncomplicated Plasmodium falciparum malaria., Search Strategy: We searched the Cochrane Infectious Diseases Group Specialized Register (October 2005), CENTRAL (The Cochrane Library 2005, Issue 4), MEDLINE (1966 to October 2005), EMBASE (1988 to October 2005), LILACS (October 2005), and reference lists. We also contacted researchers and organizations working in this field., Selection Criteria: Randomized controlled trials comparing SP plus AS with SP plus AQ for treating uncomplicated P. falciparum malaria., Data Collection and Analysis: Two authors independently applied the inclusion criteria, extracted data, and assessed methodological quality. The primary outcome measure was treatment failure (parasitological or clinical evidence of treatment failure between start of treatment and day 28). We calculated the relative risk (RR) with 95% confidence intervals (CI) for dichotomous data., Main Results: Four trials (775 participants) met the inclusion criteria. All were from areas of high and seasonal malaria transmission in Africa. Fewer participants using SP plus AQ failed treatment by day 28 (RR 0.59, 95% CI 0.42 to 0.83; 652 participants, 3 trials). Even excluding new infections, SP plus AQ performed better (RR 0.62, 95% CI 0.40 to 0.96; 649 participants, 3 trials). There was no statistically significant difference between the two treatments for treatment failure at day 14 (RR 1.14, 95% CI 0.47 to 2.78; 775 participants, 4 trials). SP plus AS was more effective at reducing gametocyte carriage at day seven (RR 2.31, 95% CI 1.36 to 3.92; 220 participants, 1 trial). One trial reported that one person - in the SP plus AQ group - developed severe malaria. Adverse events were poorly reported, but did not seem to differ in type and number between the two treatment combinations., Authors' Conclusions: SP plus AQ performed better at controlling treatment failure at day 28, but was not as good as SP plus AS at reducing gametocyte carriage at day seven. Careful consideration of local resistance patterns is required because resistance to sulfadoxine-pyrimethamine and amodiaquine are high in many areas. In order to delay development of resistance to artesunate, the combination with sulfadoxine-pyrimethamine should only be considered where both drugs are known to be effective. Data on adverse events are still lacking.

Background: Multiple-drug-resistant malaria is widespread, and in South-East Asia resistance is high against nearly all single therapy antimalarial drugs. Here, and in other areas with low malaria transmission, the combination of artesunate and mefloquine may provide an effective alternative., Objectives: To compare artesunate plus mefloquine with mefloquine alone for treating uncomplicated Plasmodium falciparum malaria., Search Strategy: We searched the Cochrane Infectious Diseases Group Specialized Register (May 2005), CENTRAL (The Cochrane Library Issue 2, 2005), MEDLINE (1966 to May 2005), EMBASE (1988 to May 2005), LILACS (May 2005), BIOSIS (1985 to June 2005), conference proceedings, and reference lists. We also contacted researchers, organizations, and pharmaceutical companies., Selection Criteria: Randomized and quasi-randomized controlled trials comparing artesunate plus mefloquine with mefloquine alone for treating uncomplicated malaria., Data Collection and Analysis: Two authors independently applied the inclusion criteria, extracted data, and assessed methodological quality. The primary outcome was treatment failure by day 28, defined as evidence of parasitaemia with or without clinical failure between days zero (start of treatment) and 28. For dichotomous data we calculated relative risks (RR) and 95% confidence intervals (CI)., Main Results: Eight trials involving 1996 participants met the inclusion criteria. All were conducted in areas with low malaria transmission, seven in South-East Asia and one in the Peruvian Amazon. The doses and dosing regimens of artesunate and mefloquine varied across trials. The trials using a total dose of 25 mg/kg mefloquine and 10 mg artesunate reported fewer treatment failures with the combination at all time points: day 28 (RR 0.17, 95% CI 0.06 to 0.47; 824 participants, 4 trials), day 42 (RR 0.23, 95% CI 0.14 to 0.39; 298 participants, 1 trial), and day 63 (RR 0.26, 95% CI 0.09 to 0.77; 501 participants, 2 trials). The results for parasitaemia showed a similar trend. Trials using a lower dose of artesunate tended to favour the artesunate plus mefloquine combination. Overall, adverse events were similar across treatment arms., Authors' Conclusions: Artesunate plus mefloquine performs better than mefloquine alone for treating uncomplicated falciparum malaria in areas with low malaria transmission. A total dose of 25 mg/kg mefloquine and at least 10 mg artesunate leads to higher cure rates. Better reporting of methods and standardisation of outcomes would help the interpretation of future trials.

Background: In Africa, malaria is often resistant to chloroquine and sulfadoxine-pyrimethamine. Chlorproguanil-dapsone is a potential alternative., Objectives: To compare chlorproguanil-dapsone with other antimalarial drugs for treating uncomplicated falciparum malaria., Search Strategy: We searched the Cochrane Infectious Diseases Group Specialized Register (May 2004), CENTRAL (The Cochrane Library Issue 2, 2004), MEDLINE (1966 to May 2004), EMBASE (1988 to May 2004), LILACS (May 2004), Biosis Previews (1985 to May 2004), conference proceedings, and reference lists, and contacted researchers working in this field., Selection Criteria: Randomized and quasi-randomized controlled trials comparing chlorproguanil-dapsone to other antimalarial drugs., Data Collection and Analysis: Two reviewers independently applied the inclusion criteria, extracted data, and assessed methodological quality. We calculated the relative risk (RR) for dichotomous data and weighted mean difference for continuous data, and presented them with 95% confidence intervals (CI)., Main Results: Six trials (n = 3352) met the inclusion criteria. Chlorproguanil-dapsone (with 1.2 mg chlorproguanil) as a single dose had fewer treatment failures than chloroquine (1 trial), but more treatment failures and people with parasitaemia at day 28 than sulfadoxine-pyrimethamine (3 trials). Two trials compared the three-dose chlorproguanil-dapsone (with 2 mg chlorproguanil) regimen with sulfadoxine-pyrimethamine in new attendees. There were fewer treatment failures with chlorproguanil-dapsone by day 7 (RR 0.30, CI 0.19 to 0.49; n = 827, 1 trial) and day 14 (RR 0.36, CI 0.24 to 0.53; n = 1709, 1 trial). Neither trial reported total failures by day 28. A further trial was carried out in participants selected because they had previously failed sulfadoxine-pyrimethamine. Adverse event reporting was inconsistent between trials, but chlorproguanil-dapsone was associated with more adverse events leading to discontinuation of treatment compared with sulfadoxine-pyrimethamine (RR 4.54, CI 1.74 to 11.82; n = 829, 1 trial). It was also associated with more red blood cell disorders (RR 2.86, CI 1.33 to 6.13; n = 1850, 1 trial)., Reviewers' Conclusions: There are insufficient data about the effects of the current standard chlorproguanil-dapsone regimen (three-dose, 2 mg chlorproguanil). Randomized controlled trials that follow up to day 28, record adverse events, and use an intention-to-treat analysis are required to inform any policy decisions.