In Vivo Efficacy and Tolerability of Artesunate–Azithromycin for the Treatment of Falciparum Malaria in Vietnam

Phong, Nguyen Chinh; Quang, Huynh Hong; Thanh, Nguyen Xuan; Trung, Trieu Nguyen; Dai, Bui; Shanks, G. Dennis; Chavchich, Marina; Edstein, Michael D.

doi:10.4269/ajtmh.16-0144

Cited by 8 publications

(7 citation statements)

References 22 publications

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“…As is the case with some other antibiotics, azithromycin acts against the parasite apicoplast and exerts slow antimalarial activity [6]. In clinical trials, azithromycin has been found to improve the treatment efficacy of both artesunate and chloroquine relative to each agent alone [4, 5, 11]. Azithromycin has also been shown to prevent malaria infections, although its efficacy appears to be inferior to that of doxycycline [2, 3].…”

Section: Discussionmentioning

confidence: 99%

Biannual mass azithromycin distributions and malaria parasitemia in pre-school children in Niger: A cluster-randomized, placebo-controlled trial

et al. 2019

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Background Mass azithromycin distributions have been shown to reduce mortality in preschool children, although the factors mediating this mortality reduction are not clear. This study was performed to determine whether mass distribution of azithromycin, which has modest antimalarial activity, reduces the community burden of malaria. Methods and findings In a cluster-randomized trial conducted from 23 November 2014 until 31 July 2017, 30 rural communities in Niger were randomized to 2 years of biannual mass distributions of either azithromycin (20 mg/kg oral suspension) or placebo to children aged 1 to 59 months. Participants, field staff, and investigators were masked to treatment allocation. The primary malaria outcome was the community prevalence of parasitemia on thick blood smear, assessed in a random sample of children from each community at study visits 12 and 24 months after randomization. Analyses were performed in an intention-to-treat fashion. At the baseline visit, a total of 1,695 children were enumerated in the 15 azithromycin communities, and 3,029 children were enumerated in the 15 placebo communities. No communities were lost to follow-up. The mean prevalence of malaria parasitemia at baseline was 8.9% (95% CI 5.1%–15.7%; 52 of 552 children across all communities) in the azithromycin-treated group and 6.7% (95% CI 4.0%–12.6%; 36 of 542 children across all communities) in the placebo-treated group. In the prespecified primary analysis, parasitemia was lower in the azithromycin-treated group at month 12 (mean prevalence 8.8%, 95% CI 5.1%–14.3%; 51 of 551 children across all communities) and month 24 (mean 3.5%, 95% CI 1.9%–5.5%; 21 of 567 children across all communities) than it was in the placebo-treated group at month 12 (mean 15.3%, 95% CI 10.8%–20.6%; 81 of 548 children across all communities) and month 24 (mean 4.8%, 95% CI 3.3%–6.4%; 28 of 592 children across all communities) ( P = 0.02). Communities treated with azithromycin had approximately half the odds of parasitemia compared to those treated with placebo (odds ratio [OR] 0.54, 95% CI 0.30 to 0.97). Parasite density was lower in the azithromycin group than the placebo group at 12 and 24 months (square root–transformed outcome; density estimates were 7,540 parasites/μl lower [95% CI −350 to −12,550 parasites/μl; P = 0.02] at a mean parasite density of 17,000, as was observed in the placebo arm). No significant difference in hemoglobin was observed between the 2 treatment groups at 12 and 24 months (mean 0.34 g/dL higher in the azithromycin arm, 95% CI −0.06 to 0.75 g/dL; P = 0.10). No serious adverse events were reported in either group, and among children aged 1 to 5 months, the most commonly reported nonserious adverse events (i.e., diarrhea, vomiting, and rash) were less common in the azithromycin-treated communities. Limitations of the trial include the timing of the treatments and monitoring visits, both of...

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Section: Discussionmentioning

confidence: 99%

Biannual mass azithromycin distributions and malaria parasitemia in pre-school children in Niger: A cluster-randomized, placebo-controlled trial

et al. 2019

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“…When given alone, daily azithromycin had only modest prophylactic efficacy against malaria infection in Kenyan and Indonesian adults (23,24) and against vivax malaria in Thai adults (25). Though azithromycin is not used alone for malaria treatment, its combination with chloroquine or artesunate offered excellent clinical efficacies in some trials (26,27). Both naphthoquine and azithromycin have excellent safety profiles, and their in vitro interactions on P. falciparum parasites were synergistic (28).…”

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confidence: 99%

Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia

Yang

Wang

Liu

et al. 2018

Antimicrob Agents Chemother

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New prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for 2 months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated, without any serious adverse events. Four adverse events (transient and slight elevations of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, against infections, whereas both offered 100% prophylactic efficacy against and These trials showed that NQAZ had a good safety profile, and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species.

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“…However, it has been considered as a potential candidate for combination therapy, especially in pregnant women and children, owing to its multistage targeting action with unique mechanism, attractive safety profile, and excellent pharmacological properties (20,23). AZ combination therapy with other antimalarials has been evaluated extensively in clinical trials over the past dozen years, but no reliable evidence has been found on the superiority or equivalence of AZ combination therapy with current partner drugs compared to the current first-line antimalarial combinations (22,(24)(25)(26)(27)(28)(29)(30). A more appropriate partner for AZ in combination remains to be identified.…”

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confidence: 99%

Evaluation of the Combination of Azithromycin and Naphthoquine in Animal Malaria Models

Zhao

Zhang

et al. 2020

Antimicrob Agents Chemother

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Combination therapy using drugs with different mechanisms of action is the current state of the art in antimalarial treatment. However, except for artemisinin-based combination therapies, only few other combinations are available now. The increasing concern on the emergence and spread of artemisinin resistance in Plasmodium falciparum has evoked a need for the development of new antimalarials. Moreover, the efficacy of current available chemoprophylaxis is compromised by drug resistance and noncompliance due to intolerable adverse effects or complicated dosing regimens. Therefore, new antimalarials that are more effective, safer, and more convenient are also urgently needed for malaria chemoprophylaxis. In this study, we assessed the combination of azithromycin and naphthoquine in animal malaria models. A dose-dependent interaction was observed in Peters' 4-day suppressive test on P. berghei K173 infected mice. Moreover, at inhibition levels 90% or above, synergistic effects were found for combinations at various ratios. At an optimal dose ratio of 1:1, the combination acted synergistically even after 4 weeks since first dose and provided a more effective and sustained prophylaxis than naphthoquine alone in blood stage P. berghei K173 and P. cynomolgi bastianelli L challenge models. The ability of the combination to delay and slow down resistance development in P. berghei K173 was also shown. These results showed clear evidence for the benefit of the combination therapy with azithromycin and naphthoquine in animal malaria models, providing some insight for further development of it for malaria treatment and prophylaxis.

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In Vivo Efficacy and Tolerability of Artesunate–Azithromycin for the Treatment of Falciparum Malaria in Vietnam

Cited by 8 publications

References 22 publications

Biannual mass azithromycin distributions and malaria parasitemia in pre-school children in Niger: A cluster-randomized, placebo-controlled trial

Biannual mass azithromycin distributions and malaria parasitemia in pre-school children in Niger: A cluster-randomized, placebo-controlled trial

Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia

Evaluation of the Combination of Azithromycin and Naphthoquine in Animal Malaria Models

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