Transitioning to Oral Antibiotics for Young Infants: Overcoming a Historical Hesitancy Free

Intravenous (IV) antibiotics are commonly used in hospital settings, although often without clear supporting evidence. In cases of oral intolerance, IV antibiotics allow physicians to bypass the enteral system and administer necessary medications. However, IV antibiotics are frequently used over oral antibiotics because of presumed improved source penetration or bioavailability, although many recommendations are based on expert consensus rather than proven clinical superiority.^1,2  Although there are fewer randomized control trials in pediatrics compared with adults on the conversion of IV to oral antibiotics, observational studies in children have led to earlier transition from IV to oral antibiotics for several conditions. Most notably, large multicenter retrospective cohort studies on the safe transition from IV to oral antibiotics for children with acute osteomyelitis,³  complicated appendicitis,⁴  and complicated pneumonia⁵  have revealed no increase in the rate of treatment failure for children transitioned to oral antibiotics before discharge. Subsequently, after publication of these studies, nationwide reductions were seen in the use of post-discharge IV antibiotic therapy for these 3 conditions.⁶ 

In this issue of Hospital Pediatrics, Chang et al present a single-center quality improvement intervention seeking to decrease IV antibiotic duration for infants <29 days of age admitted with urinary tract infections (UTIs),⁷  for which their initial clinical pathway recommendation was 7 days of IV antibiotics. Through clinical pathway change and educational interventions, the authors decreased IV antibiotic duration from 4.7 days to 3.1 days over 2 years. Length of stay also decreased from 5.4 to 3.6 days, without a difference in 30-day readmissions for recurrent UTI. Although further studies are needed to examine the effectiveness of early transition to oral antibiotics for UTIs in premature infants and infants with genitourinary anomalies, this study represents a major step forward in improving IV antibiotic stewardship, specifically in neonates.

Although pediatricians have adopted earlier transition from IV to oral antibiotics for some conditions, concern around the use of oral antibiotics in neonates and young infants remains. Young infants are commonly administered prolonged IV antibiotic courses over oral antibiotics, which can lead to prolonged hospitalization, IV-related complications, and overall increased hospital costs.^1,8  This likely stems from a concern for immature immune response and fear of inadequate absorption and bioavailability.^8,9  Neonatal gastrointestinal physiology differs from that of older children because of slower gastric emptying time, higher gastric pH, and concern for reduced volume of distribution of lipophilic antibiotics.⁹ 

Despite this known pathophysiology, there is abundant pharmacokinetic evidence suggesting efficacy of oral antibiotics in neonates and young infants. For our most commonly used antibiotics, antimicrobial killing is dependent on the period of time in which antibiotic levels are above the minimum inhibitory concentration.¹⁰  The authors of one systematic review found that although oral antibiotics take longer to reach maximum serum concentration in neonates, they eventually reach adequate serum concentrations as determined by the minimum inhibitory concentration of relevant organisms.²  Another study of term neonates with early onset group B streptococcal disease revealed that switching to extra-high-dose oral amoxicillin after 48 hours of IV therapy maintained therapeutic serum amoxicillin concentrations.¹¹  The authors of a pooled population study evaluating the pharmacokinetic profiles of 261 preterm and term neonates similarly found that young infants treated with oral amoxicillin reached adequate serum levels using a twice-daily high-dose regimen.¹²  These data support the use of IV antibiotics initially to ensure that maximum serum concentration is quickly reached, with safe transition to oral antibiotics in term infants who have clinically improved. However, caution should be exercised with premature infants because most pharmacokinetic studies and clinical effectiveness studies are limited to term (≥37 weeks’ gestation) infants, and functional maturation of the gastrointestinal tract appears in general at ∼32 to 34 weeks’ gestation.⁹ 

The work by Chang et al highlights an area that has gained traction toward shorter IV courses in young infants (≤90 days of age), specifically UTIs. Observational data have revealed that infants with UTIs who transition to oral antibiotics earlier do not have worse outcomes,^13–15  even in cases with concomitant bacteremia.^16,17  One study of infants <60 days of age revealed that 85% of patients had clinical improvement after the first 24 hours of antibiotics,¹³  and another revealed no differences in treatment failure, relapse, or renal scarring based on the duration of IV antibiotics for neonates (≤31 days of age) treated with initial IV antibiotic therapy who transitioned to complete their course with oral antibiotics.¹⁴  However, data from randomized studies are sparse.

Recent data also support the use of oral antibiotics in neonates (<29 days old) with other infectious diagnoses outside of UTI. In a randomized trial of neonates with probable bacterial infection, Keij et al demonstrated the noninferiority of an early IV to oral antibiotic switch therapy compared with a full course of IV antibiotics.⁸  An observational study of neonates with uncomplicated skin and soft tissue infections revealed no association between treatment failure and IV antibiotic regimen.¹⁸  Similarly, the authors of a multicenter retrospective cohort study of shortened IV antibiotic therapy for neonates and young infants with uncomplicated, late-onset group B Streptococcus bacteremia found no difference in recurrence of disease or treatment failure.¹⁹  These data support earlier transition to oral antibiotics for neonates and young infants.

With the current evidence, shorter IV antibiotic courses for certain neonatal infections may be considered. Doing so requires physicians to use frameworks based on existing guiding principles of IV to oral transitions. Generally, transition to oral therapy is appropriate when a patient is clinically stable with evidence of clinical improvement (eg, resolving fever), has no signs of severe sepsis or persistent bacteremia, and is able to tolerate oral medication, as well as when an appropriate oral agent with antibiotic susceptibility confirmation is available.^1,20  Because neonates have an increased risk of bacterial meningitis and other invasive infections, additional considerations may include normal cerebrospinal fluid cell counts with negative cerebrospinal fluid culture results and no evidence of complicated or disseminated infection with foci distant to the primary site of infection.²⁰ 

This study by Chang et al⁷  adds much value to our continued discussions regarding the transition from IV to oral antibiotics in neonates. Although one may argue Chang and colleagues were premature in their quality efforts because of a lack of age-specific data or randomized trials in this area, given the lack of existing evidence to support long IV antibiotic courses for neonates with UTI, it is likely reasonable to move forward with responsible improvement efforts in this and similar areas, particularly in the presence of reassuring bodies of well-conducted observational studies. Future quality improvement initiatives of neonates should have robust processes for measuring outcome and balance measures. Additionally, as suggested by Chang et al,⁷  future studies on the total duration of antibiotic treatment of UTIs would be another fruitful area of work for antibiotic stewardship efforts to promote reductions in antimicrobial resistance.