Efficacy and safety of a combination of azithromycin and chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in two multi-country randomised clinical trials in African adults

Abstract

BackgroundGiven increasing rates of resistance to existing therapy, new options for treatment and prophylaxis of malaria are needed.MethodsTwo randomised, comparative, non-inferiority studies were conducted in Africa, one double-blinded and one open-label. Adults with fever, a positive peripheral blood smear, and a positive rapid diagnostic test for Plasmodium falciparum were randomised in both studies to either azithromycin (AZ) 1,000 mg plus chloroquine (CQ) 600-mg base (AZCQ 1,000 mg) once daily for three days or mefloquine hydrochloride (MQ) 1,250 mg (split dose). In the first study, an additional regimen of AZ 500 mg plus CQ 600-mg base (AZCQ 500 mg) once daily for three days was included. All study participants were hospitalised until three consecutive daily blood smears were negative for asexual P. falciparum parasitaemia. Study participants were evaluated weekly for 42 days, with Day 28 polymerase chain reaction (PCR)-corrected parasitological clearance rate as primary endpoint.ResultsA total of 467 subjects were randomised in the two studies. At 28 days’ follow-up, PCR-corrected parasitological clearance rates in the per protocol population in the first study were 101/103 (98%) with AZCQ 1,000 mg compared with 102/103 (99%) with MQ (95% confidence interval [CI]: -5.2, 3.3). The AZCQ 500-mg regimen was stopped during an interim study review (six [86%] clearance of seven evaluable; two lost to follow-up). In the second study, clearance rates were similar: AZCQ 1,000 mg 107/107 (100%) vs MQ 111/112 (99%; 95% CI: -1.8, 3.6). Among the participating countries, in vitro CQ resistance based on pfcrt mutation frequency in the baseline isolates across both studies ranged from 20.8% (Zambia) to 96.1% (Uganda). Serious adverse events (AEs; all causality) were observed more frequently with MQ compared with AZCQ (four vs one, respectively), though discontinuations for AEs were similar (four vs three, respectively). Common AEs in the AZ-containing arms included pruritus, vomiting, dizziness, and headache.ConclusionsAmong adults with symptomatic uncomplicated falciparum malaria in Africa, the combination of AZ 1,000 mg and CQ 600-mg base once daily for three days resulted in Day 28 PCR-corrected parasitological clearance rates of ≥98% and was non-inferior to treatment with MQ. AZCQ was well tolerated.Trial registrationClinicalTrials.gov identifiers NCT00082576 and NCT00367653Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-13-458) contains supplementary material, which is available to authorized users.

Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection

“…Reassuringly, an animal model found no evidence of such an interaction, 17 and the combination has been used safely in patients with malaria. 18,19 Nevertheless, given limited experience in patients with COVID-19 and the potential for use of these drugs in patients with cardiac disease or those taking other drugs that delay repolarization, monitoring of the QTc interval at baseline and daily for the duration of treatment is advised, especially if azithromycin is coprescribed. Daily monitoring is impractical during prophylactic treatment, but assessment of the QTc interval at baseline is advised, especially for individuals with cardiac disease.…”

The return of chloroquine-susceptible Plasmodium falciparum malaria in Zambia

“…This follows a slow decline in the prevalence of chloroquine resistance in Zambia: from 95% in 2001 [24] to 26% in 2006 [25] and is now at undetectable levels. Although historical molecular data are not available specifically from Nchelenge, clinical efficacy was reported in 1986–88.…”

Falciparum Malaria Incidentally Pretreated with Azithromycin

“…Although several clinical trials have been performed to investigate the efficacy of azithromycin in the treatment of P. falciparum and P. vivax infection, there is no evidence to show that azithromycin monotherapy is sufficient to cure malaria (6,7). On the other hand, recent phase II/III studies demonstrated that a combination therapy of azithromycin and an antimalarial drug against uncomplicated P. falciparum malaria was efficacious and well tolerated (9,15). The prophylactic efficacy of azithromycin against P. vivax has been reported; however, the protective effect against P. falciparum infection is controversial (16)(17)(18).…”