Review question
We reviewed available evidence on different antibiotic regimens for newborns (from birth to 72 hours of life), with early-onset sepsis (as defined by trialists).
Background
Sepsis in newborns is a severe and potential lethal condition, caused by the body's response to an infection. Neonatal sepsis is the third leading cause of neonatal death globally. Despite the high burden of sepsis in newborns, high-quality evidence in diagnosis and treatment is scarce. This Cochrane Review was originally published in 2004. To identify the most appropriate antibiotic policies for neonatal sepsis, there is a need to base these policies on an updated well-conducted review. Given the clinical importance, such a review assessing the effects of different antibiotic regimens for early-onset neonatal sepsis is needed.
Study characteristics
The evidence is current to August 2020. We included five trials randomising 865 participants. The included trials compared five different antibiotic regimens.
Key results
We included five trials: one trial compared ampicillin plus gentamicin with benzylpenicillin plus gentamicin; one trial compared piperacillin plus tazobactam with amikacin; one trial compared ticarcillin plus clavulanic acid with piperacillin plus gentamicin; one trial compared piperacillin with ampicillin plus amikacin; and one trial compared ceftazidime with benzylpenicillin plus gentamicin.
None of the five comparisons showed any difference when assessing death from all causes, serious adverse events (i.e. major complications), respiratory support, circulatory support, nephrotoxicity (toxicity in the kidneys), neurological developmental impairment (disabilities in the functioning of the brain that affect a child's behaviour, memory, or ability to learn), necrotising enterocolitis (tissues in the gut become inflamed and start to die), or ototoxicity (toxic to the ear). Current evidence cannot confirm or reject one antibiotic regimen being superior to another.
Quality of the evidence
The evidence behind our conclusions is very-low quality. The five trials had high risk of bias (i.e. the trials were conducted in a way that may have skewed results to the positive side). In addition, the five trials included few participants, making the results of this review imprecise.
Current evidence is insufficient to support any antibiotic regimen being superior to another. Large RCTs assessing different antibiotic regimens in early-onset neonatal sepsis with low risk of bias are warranted.
Neonatal sepsis is a major cause of morbidity and mortality. It is the third leading cause of neonatal mortality globally constituting 13% of overall neonatal mortality. Despite the high burden of neonatal sepsis, high-quality evidence in diagnosis and treatment is scarce. Possibly due to the diagnostic challenges of sepsis and the relative immunosuppression of the newborn, many neonates receive antibiotics for suspected sepsis. Antibiotics have become the most used therapeutics in neonatal intensive care units. The last Cochrane Review was updated in 2004. Given the clinical importance, an updated systematic review assessing the effects of different antibiotic regimens for early-onset neonatal sepsis is needed.
To assess the beneficial and harmful effects of different antibiotic regimens for early-onset neonatal sepsis.
We searched the following electronic databases: CENTRAL (2020, Issue 8); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED and Conference Proceedings Citation Index – Science on 12 March 2021. We searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs.
We included RCTs comparing different antibiotic regimens for early-onset neonatal sepsis. We included participants from birth to 72 hours of life at randomisation.
Three review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence. Our primary outcome was all-cause mortality, and our secondary outcomes were: serious adverse events, respiratory support, circulatory support, nephrotoxicity, neurological developmental impairment, necrotising enterocolitis, and ototoxicity. Our primary time point of interest was at maximum follow-up.
We included five RCTs (865 participants). All trials were at high risk of bias. The certainty of the evidence according to GRADE was very low. The included trials assessed five different comparisons of antibiotics.
We did not conduct any meta-analyses due to lack of relevant data.
Of the five included trials one trial compared ampicillin plus gentamicin with benzylpenicillin plus gentamicin; one trial compared piperacillin plus tazobactam with amikacin; one trial compared ticarcillin plus clavulanic acid with piperacillin plus gentamicin; one trial compared piperacillin with ampicillin plus amikacin; and one trial compared ceftazidime with benzylpenicillin plus gentamicin.
None of the five comparisons found any evidence of a difference when assessing all-cause mortality, serious adverse events, circulatory support, nephrotoxicity, neurological developmental impairment, or necrotising enterocolitis; however, none of the trials were near an information size that could contribute significantly to the evidence of the comparative benefits and risks of any particular antibiotic regimen.
None of the trials assessed respiratory support or ototoxicity.
The benefits and harms of different antibiotic regimens remain unclear due to the lack of well-powered trials and the high risk of systematic errors.