Remarks ■ The recommendation was based on six trials of 1083 infants aged 0–59 days from Europe, Malawi, Pakistan and Türkiye, which compared third-generation cephalosporins (ceftriaxone or cefotaxime) IM/IV versus ampicillin IM/IV or penicillin IM/IV plus gentamicin IM/IV. ■ The GDG considered that third-generation cephalosporins had no clear benefits over the WHO-recommended hospital regimen of ampicillin IM/IV plus gentamicin IM/IV, that they may increase antimicrobial resistance and also had significant costs. ■ The GDG noted the increase in neurologic sequelae in the intervention (cephalosporin) group but considered the evidence to be of very low certainty. ■ The evidence was judged as low in the previous guideline and moderate in this guideline, as additional evidence was located from a large trial from Pakistan (68) which increased the precision of point estimates. ■ The GDG made this recommendation recognizing that all trials were based in tertiary hospitals except for the Pakistan trial, which was based at PHC facilities. ■ The GDG also recognized that there were limited data on antibiotic dosing. Based on the trials included in the evidence review, the GDG considered that the following antibiotic doses should be used: ampicillin IM/IV 50 mg/kg every 12 hours in the first week of life and every 8 hours after the first week of life for a total of at least 10 days plus gentamicin IM/IV 5 mg/kg once a day in the first week of life and 7.5 mg/kg once a day after the first week of life for a total of at least 10 days. ■ The GDG emphasized the importance of adjusting empiric antibiotic therapy doses during the course of the illness, as is routinely done in many hospitals. This includes targeting individual antibiotic therapy regimens based on microbiological test results, and stopping antibiotic therapy based on validated clinical and laboratory risk stratification algorithms.