Background: Inappropriate antibiotic prescriptions are a known driver of antimicrobial resistance in settings with limited diagnostic capacity. This study aimed to assess the impact of diagnostic algorithms incorporating rapid diagnostic tests on clinical outcomes and antibiotic prescriptions compared with standard-of-care practices, of acute febrile illness cases at outpatient clinics in Shai-Osudoku and Prampram districts in Ghana. Methods: This was an open-label, centrally randomized controlled trial in 4 health facilities. Participants aged 6 months to <18 years of both sexes with acute febrile illness were randomized to receive a package of interventions to guide antibiotic prescriptions or standard care. Clinical outcomes were assessed on day 7. Results: In total, 1512 patients were randomized to either the intervention (n = 761) or control (n = 751) group. Majority were children aged <5 years (1154 of 1512, 76.3%) and male (809 of 1512, 53.5%). There was 11% relative risk reduction of antibiotic prescription in intervention group (RR, 0.89; 95% CI,. 79 to 1.01); 14% in children aged <5 years (RR, 0.86; 95% CI,. 75 to. 98), 15% in nonmalaria patients (RR, 0.85; 95% CI,. 75 to. 96), and 16% in patients with respiratory symptoms (RR, 0.84; 95% CI,. 73 to. 96). Almost all participants had favorable outcomes (759 of 761, 99.7% vs 747 of 751, 99.4%). Conclusions: In low- and middle-income countries, the combination of point-of-care diagnostics, diagnostic algorithms, and communication training can be used at the primary healthcare level to reduce antibiotic prescriptions among children with acute febrile illness, patients with nonmalarial fevers, and respiratory symptoms. Clinical Trials Registration: NCT04081051.
