Background.Interventions to reduce under-5 mortality can either target the vulnerable or include all children regardless of state of health. Here, we assess whether mass distribution of a broad-spectrum antibiotic to pre-school children reduces mortality in sub-Saharan Africa.Methods.MORDOR was a large simple trial that randomized communities in Malawi, Niger, and Tanzania to 4 biannual mass distributions of either oral azithromycin or placebo. Children aged 1-59 months were enumerated and offered treatment. Vital status was assessed at the subsequent biannual census. The primary outcome was aggregate all-cause mortality, with country-specific rates as pre-specified subgroup analyses.Results.In total, 1533 communities were randomized, 190,238 children censused at baseline, and 323,302 person-years monitored. Mean antibiotic coverage over the 4 biannual distributions was 90.4% (SD 10.4%) of the censused population. The overall annual mortality rate in placebo- treated communities was 16.5 per 1000 person-years (9.6 per 1000 person-years in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Antibiotic-treated communities had an estimated 13.5% lower mortality overall (95% CI 6.7%—19.8%, P<0.001). Mortality was 5.7% lower in Malawi (CI - 9.7%—18.9%, P=0.45), 18.1% lower in Niger (CI 10.0%—25.5%, P<0.001), and 3.4% lower in Tanzania (CI -21.2%—23.0%, P=0.77). The greatest reduction was observed in 1-5 month-old children (24.9% lower, CI 10.6%—37.0%, P=0.001).Conclusions.Mass azithromycin distribution to post-neonatal, pre-school children may reduce childhood mortality in sub-Saharan Africa, particularly in high mortality areas such as Niger. Any implementation would need to consider selection for antibiotic resistance.

SummaryBackgroundMost malaria deaths occur in rural areas. Rapid progression from illness to death can be interrupted by prompt, effective medication. Antimalarial treatment cannot rescue terminally ill patients but could be effective if given earlier. If patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate can be given before referral and acts rapidly on parasites. We investigated whether this intervention reduced mortality and permanent disability.MethodsIn Bangladesh, Ghana, and Tanzania, patients with suspected severe malaria who could not be treated orally were allocated randomly to a single artesunate (n=8954) or placebo (n=8872) suppository by taking the next numbered box, then referred to clinics at which injections could be given. Those with antimalarial injections or negative blood smears before randomisation were excluded, leaving 12 068 patients (6072 artesunate, 5996 placebo) for analysis. Primary endpoints were mortality, assessed 7–30 days later, and permanent disability, reassessed periodically. All investigators were masked to group assignment. Analysis was by intention to treat. This study is registered in all three countries, numbers ISRCTN83979018, 46343627, and 76987662.ResultsMortality was 154 of 6072 artesunate versus 177 of 5996 placebo (2·5% vs 3·0%, p=0·1). Two versus 13 (0·03% vs 0·22%, p=0·0020) were permanently disabled; total dead or disabled: 156 versus 190 (2·6% vs 3·2%, p=0·0484). There was no reduction in early mortality (56 vs 51 deaths within 6 h; median 2 h). In patients reaching clinic within 6 h (median 3 h), pre-referral artesunate had no significant effect on death after 6 h or permanent disability (71/4450 [1·6%] vs 82/4426 [1·9%], risk ratio 0·86 [95% CI 0·63–1·18], p=0·35). In patients still not in clinic after more than 6 h, however, half were still not there after more than 15 h, and pre-referral rectal artesunate significantly reduced death or permanent disability (29/1566 [1·9%] vs 57/1519 [3·8%], risk ratio 0·49 [95% CI 0·32–0·77], p=0·0013).InterpretationIf patients with severe malaria cannot be treated orally and access to injections will take several hours, a single inexpensive artesunate suppository at the time of referral substantially reduces the risk of death or permanent disability.FundingUNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases (WHO/TDR); WHO Global Malaria Programme (WHO/GMP); Sall Family Foundation; the European Union (QLRT-2000-01430); the UK Medical Research Council; USAID; Irish Aid; the Karolinska Institute; and the University of Oxford Clinical Trial Service Unit (CTSU).

BackgroundTrachoma is targeted for elimination by 2020. World Health Organization advises districts to undertake surveillance when follicular trachoma (TF) <5% in children 1–9 years and mass antibiotic administration has ceased. There is a question if other tools could be used for surveillance as well. We report data from a test for antibodies to C. trachomatis antigen pgp3 as a possible tool.MethodologyWe randomly sampled 30 hamlets in Kilosa district, Tanzania, and randomly selected 50 children ages 1–9 per hamlet. The tarsal conjunctivae were graded for trachoma (TF), tested for C. trachomatis infection (Aptima Combo2 assay: Hologic, San Diego, CA), and a dried blood spot processed for antibodies to C. trachomatis pgp3 using a multiplex bead assay on a Luminex 100 platform.Principal findingsThe prevalence of trachoma (TF) was 0.4%, well below the <5% indicator for re-starting a program. Infection was also low, 1.1%. Of the 30 hamlets, 22 had neither infection nor TF. Antibody positivity overall was low, 7.5% and increased with age from 5.2% in 1–3 year olds, to 9.3% in 7–9 year olds (p = 0.015). In 16 of the 30 hamlets, no children ages 1–3 years had antibodies to pgp3.ConclusionsThe antibody status of the 1–3 year olds indicates low cumulative exposure to infection during the surveillance period. Four years post MDA, there is no evidence for re-emergence of follicular trachoma.

SummaryBackgroundWHO recommends combinations of an artemisinin derivative plus an antimalarial drug of longer half-life as treatment options for uncomplicated Plasmodium falciparum infection. In Africa, artemether–lumefantrine is the most widely used artemisinin-based combination therapy, whereas artesunate–mefloquine is used infrequently because of a perceived poor tolerance to mefloquine. WHO recommends reconsideration of the use of artesunate–mefloquine in Africa. We compared the efficacy and safety of fixed-dose artesunate–mefloquine with that of artemether–lumefantrine for treatment of children younger than 5 years with uncomplicated P falciparum malaria.MethodsWe did this multicentre, phase 4, open-label, non-inferiority trial in Burkina Faso, Kenya, and Tanzania. Children aged 6–59 months with uncomplicated malaria were randomly assigned (1:1), via a computer-generated randomisation list, to receive 3 days' treatment with either one or two artesunate–mefloquine tablets (25 mg artesunate and 55 mg mefloquine) once a day or one or two artemether–lumefantrine tablets (20 mg artemether and 120 mg lumefantrine) twice a day. Parasitological assessments were done independently by two microscopists who were blinded to treatment allocation. The primary outcome was the PCR-corrected rate of adequate clinical and parasitological response (ACPR) at day 63 in the per-protocol population. Non-inferiority was shown if the lower limit of the 95% CI for the difference between groups was greater than −5%. Early vomiting was monitored and neuropsychiatric status assessed regularly during follow-up. This study is registered with ISRCTN, number ISRCTN17472707, and the Pan African Clinical Trials Registry, number PACTR201202000278282.Findings945 children were enrolled and randomised, 473 to artesunate–mefloquine and 472 to artemether–lumefantrine. The per-protocol population consisted of 407 children in each group. The PCR-corrected ACPR rate at day 63 was 90·9% (370 patients) in the artesunate–mefloquine group and 89·7% (365 patients) in the artemether–lumefantrine group (treatment difference 1·23%, 95% CI −2·84% to 5·29%). At 72 h after the start of treatment, no child had detectable parasitaemia and less than 6% had fever, with a similar number in each group (21 in the artesunate–mefloquine group vs 24 in the artemether–lumefantrine group). The safety profiles of artesunate–mefloquine and artemether–lumefantrine were similar, with low rates of early vomiting (71 [15·3%] of 463 patients in the artesunate–mefloquine group vs 79 [16·8%] of 471 patients in the artemether–lumefantrine group in any of the three dosing days), few neurological adverse events (ten [2·1%] of 468 vs five [1·1%] of 465), and no detectable psychiatric adverse events.InterpretationArtesunate–mefloquine is effective and safe, and an important treatment option, for children younger than 5 years with uncomplicated P falciparum malaria in Africa.FundingAgence Française de Développement, France; Department for International Development, UK; Dutch Ministry of F...

BackgroundEffective and timely case management remains one of the fundamental pillars for control of malaria. Tanzania introduced artemisinin-combination therapy [ACT] for uncomplicated malaria; however, the policy change is challenged by limited availability of ACTs due to high cost. This study aimed to determine factors influencing prompt access to ACTs among febrile children in rural Kilosa, Tanzania.Methods and FindingsIn a community-based study, 1,235 randomly selected children under five were followed up weekly for six months, in 2008. Using a structured questionnaire, children's caretakers were asked about the child's febrile history in the last seven days, and treatment actions including timing, medicines used and source of care. Caretakers' knowledge about malaria and socioeconomic and demographic data were also obtained. About half of followed-up children had at least one episode of fever. Less than half (44.8%) of febrile children were taken to government facilities. Almost one-third (37.6%; 95% CI 33.1–42.1) of febrile children had prompt access to ACT. Care-seeking from a government facility was the overriding factor, increasing the likelihood of prompt access to an ACT 18 times (OR 17.7; 95% CI 10.55–29.54; adjusted OR 16.9; 95% CI 10.06–28.28). Caretakers from the better-off household (3rd–5th quintiles) were more likely to seek care from government facilities (OR 3.66; 95% CI 2.56–5.24; adjusted OR 1.80; 95% CI 1.18–2.76). The majority of antimalarials accessed by the poor were ineffective [86.0%; 295/343], however, they paid more for them (median Tsh 500) compared to the better-offs (median Tsh 0).ConclusionsPrompt access to ACT among febrile children was unacceptably low, due mainly to limited availability of subsidised ACT at the location where most caretakers sought care. There is urgent need to accelerate implementation of strategies that will ensure availability of ACT at an affordable price in remote rural areas, where the burden of malaria is highest.