We found that prolonged initial empirical antibiotic therapy is associated with a two-fold higher incidence of LOS, NEC or death and a three-fold higher incidence of LOS alone. Importantly, these associations persisted after adjusting for proxy severity of illness indicators previously identified as predictors for mortality (22)
. Although administration of empirical antibiotics to preterm infants is common and is regarded to be safe, our study and others suggest that the duration of therapy is often arbitrary and the risk-benefit ratio of prolonged empirical antibiotic use may in fact be unfavorable. Cordero and Ayres reported that in their cohort of 742 extremely low birth weight (ELBW, ≤ 1000 grams birth weight) infants with initial sterile blood cultures 60% received empirical antibiotics for > 3 days(5)
. They concluded that the decision to extend the duration of empirical antibiotic therapy appeared to be an institutional decision, not one based on severity of illness. Cotten et al reported that 53% of the 4039 ELBW infant enrolled in the NICHD NRN between 1998 and 2001 received initial empirical antibiotic therapy for ≥ 5 days duration despite sterile blood cultures(8)
. In their study prolonged initial empirical antibiotic treatment of ELBW infants was associated with significantly higher rates of death and NEC or death, and a trend toward a higher rate of NEC alone even after adjusting for study center, gestational age, and other perinatal factors. A supplemental analysis of their data showed that LOS or death was significantly associated with prolonged initial empirical antibiotic therapy when organisms other than coagulase-negative Staphyococcus
caused LOS. Althoughe Cotten did not address confounding by infant feedings, we found that even though human milk feeding was independently protective, it did not confound the relationship between antibiotic therapy and adverse outcomes.
Limitations of this study are the inability to control for all factors that indicate severity of illness. Although we sought to enhance characterization of severity of illness by using established respiratory indices through day of life 7, this eliminated potential study subjects with early LOS, NEC or death. As a result our study cohort size was reduced, limiting the power to detect potential differences in death alone or NEC alone. Additionally, elimination of infants who developed early sepsis limited the utility of early leukocyte indices and acute phase reactants in identifying culture-negative infants that might benefit from a prolonged duration of antibiotics.
Prolonged initial treatment with antibiotics may be indicated for preterm newborns when the likelihood of sepsis is high; however, the broad use of prolonged antibiotics might impair important transitional events required for intestinal homeostasis. Antibiotic therapy is known to alter colonization of the gastrointestinal tract, and predispose to the emergence of pathogens and resistant organisms. Animal studies of intestinal development underscore abnormal interaction between the intestinal epithelium and the luminal microbial milieu when colonization is interrupted by housing animals in germ-free conditions or treating them with broad-spectrum antibiotics (23, 24)
. Activation of toll like receptors by commensal bacteria appears to be critical for protection against gut injury and associated mortality (25)
. The lack of bacterial species diversity and abundance of Proteobacteria species associated with widespread use of antibiotics may predispose to inflammatory stimulation that may help explain the susceptibility of premature newborns to LOS and NEC (13, 26)
Our study suggests that there may be inherent risks associated with initial empirical antibiotic treatment and that each day of antibiotic therapy increases the odds of severe outcomes. Although it may be prudent to discontinue antibiotics for many premature infants with suspected EOS when cultures are negative, we do not propose limiting antibiotic treatment duration in all premature infants because blood-sampling limitations and maternal antepartum antibiotic coverage may preclude optimal culture sensitivity (27)
. We do advocate rigorous review of ongoing empirical antibiotic treatment and prompt discontinuation of therapy if blood cultures are negative and clinical and laboratory, measurements indicate a low risk of sepsis. Automated blood culture systems now provide positive culture results within 48 hours after initiation of culture(28)
. Also, adjuvant diagnostic tests such as leukocyte indices, serum acute phase reactants, leukocyte cell surface markers, and certain pro-inflammatory cytokines may be used to estimate sepsis risk or to determine adequacy of treatment thus allowing discontinuation of antibiotic therapy (29, 30)
. Microbial molecular genetic methods under development will likely transform clinical practice early, sensitive detection of microbial pathogens and thus, prompt discontinuation of antibiotic therapy when test results are negative (29, 31)
. Finally, molecular genetic techniques now being applied to characterize the developing intestinal microbiota will enhance our understanding of the effects of antibiotic exposure on intestinal colonization and predisposition of premature infants to LOS, NEC, and death(13)
. Such knowledge may inform rational therapeutic use of antibiotics, prebiotics and probiotics.
The data from this and other retrospective studies suggests that prolonged initial empirical antibiotic treatment may predispose to adverse outcomes in premature infants. Adopting a standardized approach to empirical antibiotic prescription using clinical indicators, adjuvant diagnostic tests, and molecular techniques may enable clinicians to achieve more judicious use of antimicrobials using predefined clinical criteria. Prospective trials are needed to determine whether judicious restriction of early antibiotic treatment might reduce the risk of LOS, NEC, and death for premature infants.