Oral amoxicillin plus gentamicin regimens may be superior to the procaine-penicillin plus gentamicin regimens for treatment of young infants with possible serious bacterial infection when referral is not feasible: Pooled analysis from three trials in Africa and Asia

Abstract

Background Hospital referral and admission in many- low and middle-income countries are not feasible for many young infants with sepsis/possible serious bacterial infection (PSBI). The effectiveness of simplified antibiotic regimens when referral to a hospital was not feasible has been shown before. We analysed the pooled data from the previous trials to compare the risk of poor clinical out- come for young infants with PSBI with the two regimens containing injectable procaine penicillin and gentamicin with the oral amoxicillin plus gentamicin regimen cur- rently recommended by the World Health Organization (WHO) when referral is not feasible. Methods Infant records from three individually ran- domised trials conducted in Africa and Asia were collat- ed in a standard format. All trials enrolled young infants aged 0-59 days with any sign of PSBI (fever, hypothermia, stopped feeding well, movement only when stimulated, or severe chest indrawing). Eligible young infants whose caretakers refused hospital admission and consented were enrolled and randomised to a trial reference arm (arm A: procaine benzylpenicillin and gentamicin) or two exper- imental arms (arm B: oral amoxicillin and gentamicin or arm C: procaine benzylpenicillin and gentamicin initial- ly, followed by oral amoxicillin). We compared the rate of poor clinical outcomes by day 15 (deaths till day 15, treatment failure by day 8, and relapse between day 9 and 15) in reference arm A with experimental arms and pres- ent risk differences with 95% confidence interval (CI), adjusted for trial.Results A total of 7617 young infants, randomised to arm A, arm B, or arm C in the three trials, were included in this analysis. Most were 7-59 days old (71%) and pre- dominately males (56%). Slightly over one-fifth of young infants had more than one sign of PSBI at the time of en- rolment. Severe chest indrawing (45%), fever (43%), and feeding problems (25%) were the most common signs.Overall, those who received arm B had a lower risk of poor clinical outcome compared to arm A for both per-protocol (risk difference = -2.1%, 95% CI = -3.8%, -0.4%; P = 0.016) and intention-to-treat (risk dif- ference = -1.8%, 95% CI = -3.5%, -0.2%; P = 0.031) analyses. Those who received arm C did not have an increased risk of poor clinical outcome compared to arm A for both per-protocol (risk difference = -1.1%, 95% CI = -2.8%, 0.6%) and intention-to-treat (risk difference = -0.8%, 95% CI = -2.5%, 0.9%) analyses. Overall, those who received arm B had a lower risk of poor clinical outcome compared to the combined arms A and C for both per-protocol (risk difference = -1.6%, 95% CI = -3.5%, -0.1%; P = 0.035) and inten- tion-to-treat (risk difference = -1.4%, 95% CI = -2.8%, -0.1%; P = 0.049) analyses. Conclusions Analysis of pooled individual patient-level data from three large trials in Africa and Asia showed that the WHO-recommended simplified antibiotic regimen B (oral amoxicillin and injection gen- tamicin) was superior to regimen A (injection procaine penicillin and injection gentamicin) and com- bined arms A and C (injection procaine penicillin and injection gentamicin, followed by oral amoxicillin) in terms of poor clinical outcome for the outpatient treatment of young infants with PSBI when inpatient treatment was not feasible.