Review question
We reviewed the available evidence on different antibiotic regimens for newborns (from 72 hours of life to one month of life) with late-onset sepsis.
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 this high burden of sepsis in newborns, high-quality evidence in diagnosis and treatment is scarce. This Cochrane Review was originally published in 2005. To identify the most appropriate antibiotic policies for neonatal sepsis, there is a need to base these policies on an updated well-conducted review. Therefore, there is a need for such a review assessing the effects of different antibiotic regimens for late-onset neonatal sepsis.
Study characteristics
The evidence is current to March 2021. We included five trials randomising 580 participants. The five trials compared five different antibiotic regimens.
Key results
We included five trials: one trial compared cefazolin plus amikacin with vancomycin plus amikacin; one trial compared ticarcillin plus clavulanic acid with flucloxacillin plus gentamicin; one trial compared cloxacillin plus amikacin with cefotaxime plus gentamicin; one trial compared meropenem with standard care (ampicillin plus gentamicin or cefotaxime plus gentamicin); and one trial compared vancomycin plus gentamicin with vancomycin plus aztreonam.
None of the five antibiotic comparisons showed that the choice of antibiotics influenced the effects on death from all-causes, serious adverse events (i.e. major complications), 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), or necrotising enterocolitis (tissues in the gut become inflamed and start to die). Current evidence cannot confirm or reject, one antibiotic regimen being superior to another due to scarce data.
Quality of the evidence
Our conclusions are based on very low-quality evidence. The five trials were at 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. RCTs assessing different antibiotic regimens in late-onset neonatal sepsis with low risks 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. 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, and observational studies in high-income countries suggest that 83% to 94% of newborns treated with antibiotics for suspected sepsis have negative blood cultures. The last Cochrane Review was updated in 2005. There is a need for an updated systematic review assessing the effects of different antibiotic regimens for late-onset neonatal sepsis.
To assess the beneficial and harmful effects of different antibiotic regimens for late-onset neonatal sepsis.
We searched the following electronic databases: CENTRAL (2021, Issue 3); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED and Conference Proceedings Citation Index – Science on 12 March 2021. We also 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 late-onset neonatal sepsis. We included participants older than 72 hours of life at randomisation, suspected or diagnosed with neonatal sepsis, meningitis, osteomyelitis, endocarditis, or necrotising enterocolitis. We excluded trials that assessed treatment of fungal infections.
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 (580 participants). All trials were at high risk of bias, and had very low-certainty evidence.
The five included trials assessed five different comparisons of antibiotics.
We did not conduct a meta-analysis due to lack of relevant data.
Of the five included trials one trial compared cefazolin plus amikacin with vancomycin plus amikacin; one trial compared ticarcillin plus clavulanic acid with flucloxacillin plus gentamicin; one trial compared cloxacillin plus amikacin with cefotaxime plus gentamicin; one trial compared meropenem with standard care (ampicillin plus gentamicin or cefotaxime plus gentamicin); and one trial compared vancomycin plus gentamicin with vancomycin plus aztreonam.
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.