Mir 2017.

Methods	The study was a randomised controlled trial from January 2010 to December 2013. The study took place in five low‐income settlements in coastal Karachi, Pakistan (Rehri Goth, Ibrahim Hyderi, Ali Akbar Shah Goth, Bhains colony, and Bilal colony). Infants from the catchment area were either referred to a study clinic by community health workers during routine household surveillance or presented with their family at one of the five primary healthcare clinics, at which study clinicians screened them for eligibility to participate in the trial. Paramedics or study clinicians administered all intramuscular injections at study clinics; study personnel gave the morning dose of oral antibiotic at the clinic, and a community health worker visiting the child's household administered the evening dose.
Participants	Inclusion criteria: aged 0 to 59 days, living in the catchment area, refusal by family to be admitted to hospital, and at least one of any of the following signs of clinical severe infection: movement only when stimulated; not feeding well on observation; temperature ≥ 38°C or < 35·5°C; severe chest indrawing. Exclusion criteria: infants were excluded from the study if their family agreed to admission, weight at presentation < 1500 grams, major congenital malformations or suspected chromosomal abnormalities were present, surgical conditions needed hospital referral, they had been admitted for illness in the past two weeks, they had been included previously in the study, or they had one or more signs of critical illness (unconsciousness; convulsions; inability to feed; apnoea; inability to cry; cyanosis; bulging fontanelle; active bleeding needing transfusion; persistent vomiting)
Interventions	The reference treatment regimen was procaine benzylpenicillin (40,000 mg/kg to 60,000 units/kg) and gentamicin (4 mg/kg to 6.5 mg/kg), each administered intramuscularly once daily for seven days. The second regimen was gentamicin administered intramuscularly once daily and amoxicillin (75 mg/kg/day to 100 mg/kg/day) administered orally twice daily for seven days. The third regimen was procaine benzylpenicillin and gentamicin administered intramuscularly once daily for two days followed by amoxicillin administered orally twice daily for five days.
Outcomes	Primary outcome: treatment failure within seven days of enrolment, which we defined as either: death; admission; clinical deterioration; change in antibiotic regimen because of infectious comorbidity; serious adverse event; occurrence of a new sign of clinical severe infection on or after day three; persistence of presenting signs at day four; or recurrence of initial signs of sepsis on or after day five Among young infants who had treatment failure, secondary outcomes were: death within seven days of enrolment; death at any time before the day 14 to 15 assessment; and admission for any reason at any time within seven days of enrolment Among children who did not have treatment failure, secondary outcomes were: admission at any time between the day eight and day 14 to 15 visits; death at any time between the day eight and day 14 to 15 visits; and non‐fatal relapse at any time between the day eight and day 14 to 15 visits
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "We used a site‐specific and age‐specific (< 7 days and 7 to 59 days) randomization sequence list generated by the London School of Hygiene & Tropical Medicine." Comment: there was appropriate random sequence generation
Allocation concealment (selection bias)	Low risk	Quote: "The allocation sequence for every site and age group was placed in serially numbered, sealed, opaque envelopes by the Data Management Unit at Aga Khan University and delivered to every site. Study clinicians selected the next envelope and the treatment corresponding to the allocation code printed within was assigned to the infant." Comment: there was appropriate allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Study participants' families and study clinicians were not blinded to treatment allocation because giving placebo injections to sick young infants was judged unethical" Comment: the nature of the intervention made blinding of participants and personnel not feasible, but the outcome is not likely to be influenced by the lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	High risk	Comment: The clinicians who delivered the intervention were also responsible for being the primary assessors of the outcome
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: of the 820 infants allocated to procaine benzylpenicillin and gentamicin, 9% (73) had inadequate follow‐up and/or inadequate treatment and were excluded from analysis. Of the 816 allocated to amoxicillin and gentamicin 8% (65) had inadequate follow‐up and/or inadequate treatment and were excluded from analysis. Of the 817 allocated to procaine benzylpenicillin, gentamicin and amoxicillin 8% (64) had inadequate follow‐up and/or inadequate treatment and were excluded from analysis. Thus, all groups had similar rates of attrition.
Selective reporting (reporting bias)	Low risk	Comment: the trial was registered with a clinical trials registry. In addition, the study protocol was published in Pediatric Infectious Disease Journal in 2013. The authors reported all outcomes described in the protocol Clinicaltrials.gov registry number: NCT01027429
Other bias	Low risk	Response bias: all doses of both oral and injectable medications were administered and observed by health providers