Zaidi 2012.
| Methods | This study was a randomised controlled trial conducted from November 2003 to December 2005. The study took place in three low‐income communities in and around Karachi, Pakistan. The nearest hospital with neonatal services was located within 45 to 60 minutes driving distance. Community health workers visited newborns at home at regular intervals and referred potentially eligible infants to a nearby primary health care clinic. At the clinic, study physicians determined eligibility and administered injectable antibiotics. Oral antibiotics were administered by the mother at home. | |
| Participants | Eligible infants were 0 to 59 days of age, met criteria for a PSBI and whose parents refused hospital referral. PSBI was present if infants had any one of the following: apnoea/poor respiratory effort, seizures observed by doctors, bulging fontanelle, temperature > 38.5°C or < 35.5°C, severe lethargy/floppy baby, capillary refill more than two seconds, severe chest indrawing or grunting. PSBI was also present if any three of the following were present: respiratory rate > 60/min, feeding difficulty/poor suck, temperature 37.5°C to 38.5°C or 35.5°C to 36.0°C, lethargy, excessive crying/irritability, weak/abnormal/absent cry, abdominal distension, hypoglycaemia, history of seizures, presence of skin/eye/umbilical infection, any maternal infectious risk factor. Infants were excluded from the trial if the family refused injectable therapy, if signs of severe jaundice or clinically obvious meningitis were present, or if the patient had been previously enrolled in the same trial. | |
| Interventions | Infants who met the eligibility criteria were randomly assigned to receive one of three treatment regimens at the clinics: procaine penicillin 50,000 units/kg/day once daily and gentamicin 5 mg/kg day once daily, both by intramuscular injections for seven days; ceftriaxone 50 mg/kg/day once daily by intramuscular injection for seven days; or oral TMP‐SMX 10 mg/kg divided in twice‐daily doses and gentamicin 5 mg/kg day once daily intramuscular injection for seven days | |
| Outcomes |
Primary outcome: treatment failure, defined as: (1) death at any time during the seven‐day treatment period, (2) deterioration in clinical condition at any time after the start of therapy, or (3) no improvement after 2 days of therapy, necessitating antibiotic change Secondary outcomes: case fatality rates at 7 and 14 days after enrolment, relapse, withdrawal, therapy completion rates and adverse events |
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| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Block randomization in varying multiples of 3 stratified by site was done with a computer‐generated list" Comment: there was appropriate random sequence generation |
| Allocation concealment (selection bias) | Low risk | Quote: "...treatment group assignment was placed in opaque sealed envelopes that were opened sequentially by study physicians" Comment: there was appropriate allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quot: "Blinding of therapy was not possible because of the observable differences in delivery of the 3 regimens." 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 | Quote: "The treating physician was also the assessor of treatment failure outcomes because we thought that he/she was the best judge of whether the baby had improved with therapy" Comment: personnel assessing the outcomes were not sufficiently blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "There was no significant difference among 7‐day therapy completion rates in the 3 groups, with 84 of 143 (59%) completing 7 days of penicillin and gentamicin, 80 of 142 (56%) completing 7 days of ceftriaxone and 83 of 137 (61%) completing 7 days of TMP‐SMX and gentamicin." "In a modified per‐protocol analysis, excluding all withdrawals and the infant with protocol violation, the TMP‐SMX plus gentamicin group still had a higher treatment failure rate than the penicillin plus gentamicin group after 7 days of therapy (RR 1.84, 95% CI 0.98 to 3.44), but did not reach statistical significance." Comment: the rates of attrition were similar for the intervention and control groups |
| Selective reporting (reporting bias) | Low risk | Comment: the trial was registered with a clinical trials registry and reported the outcomes identified in the study protocols Clinicaltrials.gov registry number: 00189384 |
| Other bias | High risk | Response bias Quote: "Another limitation is that use of TMP‐SMX was ascertained by mother/family member report when the baby was brought to the clinic, not directly observed." |
IMCI: Integrated Management of Childhood Illness IMNCI: Integrated Management of Neonatal and Childhood Illness NGO: non‐governmental organisation PSBI: possible serious bacterial infection TMP‐SMX: trimethoprim‐sulphamethoxazole UNICEF: United Nations International Children's Emergency Fund WHO: World Health Organization