Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): a randomised controlled trial

Background: The early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, were single centre or country, insufficiently powered, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad spectrum antibiotic is superior to standard of care regimen (SOC) in empiric treatment of LOS and thus aimed to compare the efficacy and safety of meropenem to SOC in infants aged 44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or SOC (ampicillin+gentamicin or cefotaxime+gentamicin) for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients (full analysis set) and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3rd 2012 to November 30th 2014, in total 136 patients in each arm were randomized; 140 (52%) were culture positive. Success at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p=0.087); 17/63 (27%) vs. 10/77 (13%) in patients with positive cultures (p=0.022). The main reason of failure was modification of allocated therapy. Adverse events occurred in 72% and serious adverse events in 17% of patients, the mortality rate was 6% with no differences between study arms. Cumulative acquisition of CRGNO by day 28 occurred in 4% in the meropenem and 12% in the SOC arm (p=0.052). Conclusions: Meropenem was not superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality and did not outselect colonization with CRGNOs. Meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing ESBL and AmpC beta-lactamases are circulating. Clinical trial registration ID# NCT01551394