Previous studies have demonstrated the high frequency of bacterial sepsis in neonates and infants admitted to neonatal intensive care units (NICU), often assiciated with serious complications or death. Many pathogens capable of causing nosocomial bacterial sepsis in neonates and young infants have developed resistance to the antibiotics considered of choice for treatment. Meropenem is an antibiotic that can overcome antimicrobial resistance, generally being safe and well tolerated with very good pharmacokinetic (PK) and pharmacodynamic characteristics. However, it has not yet been registered in neonates and infants aged <3 months due to limited data on its PK characteristics activity and safety. Core objectives of HEAD-PM are to evaluate the PK, safety and efficacy of meropenem in comparison to standard care in neonates and infants aged <3 months suffering from late -onset sepsis and describe PK and safety in bacterial meningitis (BM). To achieve these aims, clinical trial on meropenem use for late-onset sepsis and BM will be developed. Using previously published PK models, a sampling scheme will be designed and population PK analysis used to identify relevant PK parameters. Safety will be evaluated through analysis of haematological and biochemical parameters and monitoring adverse events. Appearance of resistant bacteria will be monitored through regular cultures during therapy. Clinical assessments including neurological and developmental evaluations (Bayley Scales) will be conducted during two years after enrolment. Immunologic and genetic studies will also be performed to evaluate predictors of susceptibility to infections and response to therapy. In addition, resistant bacterial isolates will be studied to elucidate the mechanism of resistance and sensitive PCR assays will be used to test culture negative samples. A Paediatric Investigation Plan will be developed and submitted to the EMEA. The results of this study will then be used to develop a PUMA.

The core strategy of the project includes the combination of the following two clinical trials:

• HEAD-PM1: An open label, randomised, multicenter, comparator-controlled study to evaluate the PK, efficacy and safety of meropenem as compared with standard antibiotic therapy in neonates and infants aged < 3 months treated in neonatal intensive care units (NICU) for late onset sepsis (LOS) defined as sepsis appearing after 72 hrs from birth.
• HEAD-PM2: An open label, multicenter, observational study to evaluate the PK and safety of meropenem in neonates and infants aged < 3 months with bacterial meningitis admitted to NICUs.