7.1. Ampicillin Therapy for Bacterial Sepsis in Infants

Bacterial sepsis remains a leading cause of death in infants admitted to neonatal intensive care units (NICUs). The incidence of early onset sepsis (<4 postnatal days) in infants admitted to the NICU is 1.2% to 2% and for late onset sepsis (4-120 postnatal days) 14% to 36%. The incidence of late onset sepsis is higher in very low birth weight infants (VLBW, birth weight <1500 g) [1,2]. The most commonly administered medication in the NICU, with an exposure rate of 693 per 1000 NICU-discharged infants, is ampicillin [3]. Ampicillin is a beta-lactam antibiotic approved by the FDA to treat local and disseminated infections caused by susceptible organisms in patients of all age groups [4].

7.2. Ampicillin PK and Safety in Infants

The PK of ampicillin has been studied in children and adults [5-18], but data on dosing in the neonatal population are sparse. The first pharmacological studies of serum and cerebrospinal fluid concentrations after intramuscular injection of ampicillin in term and preterm (<2500 g) infants, were performed between 1967 and 1974. These studies included a combined total of 156 infants (gestational age not specified) and showed that the serum half-life of ampicillin decreases rapidly in the first two weeks of life as a result of increasing clearance. Doses studied ranged from 25-150 mg/kg, administered every 8-12 hours according to postnatal age [12-14]. A later study assessed the PK of ampicillin in 142 preterm infants with a gestational age (GA) ≥ 24 weeks. The study concluded that infants with a GA ≤ 28 weeks required a dosing interval of 18-24 hours and did not require initial dosing exceeding 50 mg/kg [15]. Current dosing regimens take into account the gestation and postmenstrual age related variation in renal drug clearance, and recommend lower doses and less frequent dosing in the most premature infants [11]. However, the available data in the literature is insufficient to support dosing of ampicillin in the most extreme premature infants (≤32 weeks gestational age at birth).

Although ampicillin is the most commonly administered medication in the NICU, its safety in the neonatal population is poorly described. Adverse events (AE) listed on the FDA label for ampicillin are not specific to the neonatal population. Ampicillin AEs are mostly due to sensitivity phenomena that are more common in people with a history of penicillin exposure. This is very uncommon in the neonatal population. In a recent study comparing clinical efficacy of ampicillin or penicillin in combination with gentamicin therapy for early onset sepsis in infants (including GA <26 weeks), both were well tolerated with no difference in AEs or laboratory abnormalities. However, the focus of this study was clinical effectiveness comparison, and not safety profiling [15]. Among the potential serious AEs in infants is the risk of ampicillin induced seizures [4]. As with other penicillin’s, β-Lactam-induced neurotoxicity is of concern if cerebrospinal fluid concentrations of ampicillin are high. This has been reported in adult case reports, but the incidence of seizures in infants, treated with ampicillin, has not been evaluated [16, 17]. Another known side-effect of ampicillin most commonly seen after repeated dosing is inhibition of the coagulation cascade. The prevalence of this AE in the neonatal population, which is at risk of coagulopathy, is unknown [18]. Overall, given the importance of safety and improved long term outcomes in the neonatal population, a more detailed description of the safety of this commonly used antibiotic is warranted.

7.3. Opportunistic Studies in Children

Studies capitalizing on standard of care procedures, such as biological sample collection from infants already receiving drugs of interest, have produced meaningful PK data resulting in improved dosing recommendations in infants and children. These studies did not administer drugs to children, but rather collected samples from children who were already receiving drugs as standard of care as prescribed per the local caregiver. In addition, preliminary data obtained through opportunistic studies has served to design phase 1-3 trials in children as well as support applications for extramural research. Through the infrastructure of the Pediatric Pharmacology Research Unit (PPRU), Wade et al. obtained timed and scavenged plasma samples to characterize the PK of fluconazole in premature infants [19]. This PK analysis led to the dose selection for a phase 3, randomized, placebo controlled trial of fluconazole prophylaxis in premature infants (clinicaltrials.gov NCT00734539). Opportunistic designs have also been successful to characterize metronidazole PK and develop piperacillin PK models in premature infants [20, 21].

7.4. Premature Infant PK Studies

The difficulties associated with infant phase 1 PK trials have forced investigators to rely upon the extrapolation of PK data obtained in older children and adults to estimate PK parameters and dosing recommendations in premature infants. However, this approach underestimates the complicated physiology of premature infants, which differs greatly from other populations. These differences include a larger extracellular fluid volume, immature renal and hepatic function, underdevelopment of metabolic enzymatic systems, and a unique blood-brain barrier, all of which can alter drug disposition significantly [17]. These infant-specific qualities result in discrepancies between adult and infant PK leading to the need for infant-derived PK assessments to better define dosing recommendations of commonly used drugs.

7.5. BPCA Drug Prioritization

NICHD developed the BPCA prioritization process to identify gaps in pediatric drugs, primarily off-patent drugs that need further study through clinical trials or other avenues of research. There are two main phases in the prioritization process. Phase 1 entails identifying therapeutic areas, which are general categories of conditions, diseases, setting of care, or populations with multiple pediatric needs to be addressed in Phase 2. Phase 2 involves determining more specific pediatric needs, including research associated with a particular drug, biologic, or device.

7.6. Data Sources

Despite the common use of ampicillin in infants admitted to the NICU, PK and safety studies to define optimal dosing are lacking. Challenges associated with clinical trials in infants limit the ability to conduct large PK and dosing trials in this population. Capitalizing on all available data sources to characterize the PK and safety of ampicillin used in infants is therefore essential. The first objective of this study was to characterize the PK of ampicillin administered to infants per standard of care as administered by their treating caregiver. PK analyses were performed on data collected for the NICHD-2011-POP01 protocol. The second objective of this study was to assess safety of ampicillin administered to infants per standard of care. Safety was primarily assessed using data from retrospective chart review of participants enrolled in a prior PPRU study and using a large epidemiological database from the Pediatrix Medical Group. Safety data collected from the NICHD-2011-POP01 study was analyzed as well.

7.7. Structure for this Clinical Study Report

As explained in Section 7.6, this report analyzes and discusses data derived from one prospective study (NICHD-2011-POP01) and two retrospective studies (PPRU study and Pediatrix epidemiological database). Sections 9, 10 and 11 of this report will cover the investigational plan, overall study population and PK analysis of data from the NICHD-2011-POP01 study. Section 12, which covers the safety analysis, will include safety data from all three studies including NICHD-2011-POP01, the PPRU study and the Pediatrix epidemiological database.