Variability in Antibiotic Use at Children's Hospitals

DISCUSSION

To our knowledge, this study is the first to compare antibiotic use across children's hospitals. We found that 60% of hospitalized children are prescribed at least 1 antibiotic, and that antibiotics were given for an average of 468 of 1000 inpatient-days. When examined by hospital, however, significant variability in antibiotic use becomes apparent: after extensive adjustment for both patient and hospital level characteristics, children at some institutions were 44% more likely to receive antibiotics or, using an alternative metric, were exposed to antibiotics for 37% more days when compared with other institutions.

Although outpatient antibiotic-prescribing has been relatively well characterized,^20,–,25 the data that describes inpatient antibiotic use are limited. Antibiotic use has been measured among networks of hospitals, including Centers for Disease Control and Prevention initiatives such as the National Nosocomial Infection Surveillance System²⁶ and Project Intensive Care Antimicrobial Resistance Epidemiology;²⁷ however, these programs analyzed exclusively ICU admissions and a relatively small proportion of children. In addition, antibiotic use in these reports is quantified as “defined daily doses” per 1000 patient-days, a metric unsuitable for children because children's medications are dosed on the basis of weight. More recently, the number of days of therapy (DOT) has been proposed as an alternative measure of antimicrobial use that may allow more appropriate comparisons of antimicrobial use between adults and children.¹ Adopting this approach, investigators found that 60% of hospitalized adults received at least 1 dose of antibiotic therapy and that inpatients received an average of 776 per 1000 patient-days of therapy. Comparing use across these hospitals in a subsequent analysis, the same group reported that the proportion of inpatients who received at least 1 dose of an antibiotic agent during their hospitalization demonstrated a range across hospitals of 44.4% to 73.6%, whereas the mean total rate of antibiotic use ranged between 454 and 1153 per 1000 patient-days (multiple antibiotics on the same day each count individually as 1 DOT, which allows the total DOT numerator to exceed 1000).² Again, however, these studies analyzed adult patients without subset analyses of children.

Only 2 studies have focused exclusively on antibiotic use in hospitalized children. A point prevalence survey, which included only ICU patients, identified that ∼71% of NICU patients and 43% of PICU patients were receiving antibiotics at the time of the survey.²⁸ The authors of the lone pediatric-specific study of all hospitalized children (not confined to the ICU) described discharges from 20 academic hospitals throughout the United States.²⁹ This study identified a mean of 33% of children as exposed to at least 1 antibiotic during their hospitalization and ∼550 DOT per 1000 patient-days. These academic hospitals, however, served primarily adult patients and, after excluding adults from the analysis, there were 30-fold fewer children per year than were included in our study of 40 freestanding children's hospitals. In addition, the analysis did not compare antibiotic use between institutions.

The striking variability in antibiotic use revealed by our analysis persisted despite adjustment for patient characteristics associated with an increased need for antibiotic therapy or prophylaxis (infection diagnosis, surgical procedures, ICU stay, ventilator days, and underlying chronic conditions) as well as for hospital characteristics (summarized by the CMI), suggestive of an institution that may provide more advanced care to a generally sicker population and, therefore, require more empiric or targeted antibiotic therapy. In addition, our analysis included children who were admitted to exclusively freestanding children's hospitals throughout an entire year, representing a relatively homogeneous group of centers with respect to the need and expertise available for the treatment of infectious diseases. In addition, hospitals that exposed a higher proportion of patients to antibiotics also used more days of therapy, a relationship inconsistent with the notion that institutions at which more patients are exposed to antibiotics use these drugs for shorter periods of time, or vice versa. Also, hospitals that used more antibiotics, measured either by overall use or days of therapy, tended to (aggregately) use more vancomycin, cefepime, piperacillin/tazobactam, ticarcillin/clavulanate, carbapenems, fluoroquinolones, and linezolid as a proportion of total antibiotic use than did lower-using centers, negating the possibility that antibiotic quantity was generally offset by limiting patient exposure to these broad-spectrum drugs (and the associated increased antibiotic resistance pressure and cost).

Although it is unclear what factors specifically drove increased antibiotic use within higher-using hospitals, variability was apparent in both the percentage of children who received an antibiotic agent at any time during their hospitalization as well as in total days of antibiotics received. Thus, either a lower threshold to institute treatment with antibiotics or a longer length of therapy for a given condition (or both) could have contributed. Notably, many children who received antibiotic agents did not have a diagnosis code for infection. Although some of these patients may have received appropriate surgical prophylaxis, variability in the threshold to begin (or continue) antibiotics for conditions ultimately not diagnosed as infectious could account for this phenomenon.

Although not surprising, such profound variability in antibiotic use is troubling. If variability remains after normalizing for differences in illness severity and patient complexity, it follows that either children at some hospitals are undertreated with antibiotics and, therefore, are unnecessarily at risk of treatment failure or, the more likely alternative, that some hospitalized children receive excessive antibiotic therapy and therefore are unnecessarily at risk of developing antibiotic-resistant infections and drug-related adverse effects while incurring inappropriate hospital costs. In addition to highlighting the need to establish effective antibiotic stewardship programs in children's hospitals, a setting in which there remains considerable opportunity for improvement,³⁰ these data provide further impetus to perform comparative effectiveness studies to determine the appropriate therapy, particularly with respect to duration of antibiotic therapy, for common pediatric infections.³¹ More detailed analyses of these data to identify specific agents and indications associated with the greatest variability will provide high-impact targets for improvement.

Our study has limitations. The PHIS database offers the unique advantage of detailed, national-level, pediatric data from the majority of US metropolitan areas. PHIS provides up to 21 diagnosis codes per hospitalization, which provides more diagnosis data per patient than most administrative data sets. This database, however, may not be generalizable to nontertiary care, freestanding children's hospitals. For example, because of referral bias, PHIS may overrepresent the true incidence of some medically complicated or severe infections. Also, administrative data sources such as PHIS are limited with specific regard to the possibility of miscoded or inaccurate information. Although generally specific, identification based on ICD-9 Clinical Modification may not have ideal sensitivity. In this study, however, we did not rely heavily on ICD-9-based coding, including the dependent and the majority of independent variables, and the use of ICD-9 codes to identify chronic complex conditions has been validated.¹⁹ In addition, all data benefited from an established mechanism of validity and reliability checks performed by the data vendor. Antibiotic use data are derived from antibiotic orders; therefore, any drugs that were ordered and not administered to children would misclassify those children with respect to antibiotic use.