798 infection control & hospital epidemiology july 2018, vol. 39, no. 7 Pediatric hematopoietic cell transplant (HCT) patients are


at high risk for infection, particularly during the immuno- suppression and neutropenia immediately posttransplant. Establishing appropriate antibiotic utilization benchmarks will help to optimize days of antibiotic exposure at this critical stage. This effort is particularly important in patients post- transplant. Decreasing antibiotic exposure will not only limit pressure on resistance evolution and curtail healthcare costs but also may reduce adverse clinical outcomes such as mortality,11 graft-versus-host disease (GVHD),11,12 Clostridium difficile infection,13 and acute kidney injury,14 which have been linked to broad-spectrum antibiotic use. While survey-based studies of prophylaxis in HCT patients have identified differences in practice by center,15,16 variability in broad-spectrumantibiotic utilization in this population has not been evaluated. We aimed to describe and compare antibiotic utilization for


children undergoing HCT during the neutropenic period immediately posttransplant. We hypothesized that despite the homogeneity of this patient population and the existence of practice guidelines for antibiotic administration,17 across- hospital variability would exist. We also sought to explore patient-level and hospital-level factors that contribute to this variability.


methods Study Design and Setting


We performed a retrospective cohort study with data merged from 2 distinct data sources: the Pediatric Health Information System (PHIS) and the Center for International Blood and Marrow Transplantation Research (CIBMTR). PHIS is an administrative and clinical database with inpatient data from freestanding children’s hospitals associated with the Child Health Corporation of America. Data elements include demographics, dates of admission and discharge, diagnosis and procedure codes, and adjusted hospital charges. This database also contains billing data corresponding to specific resources utilized, including inpatient pharmaceutical agents with medication name and dates of administration. The CIBMTR registry represents an international network


of >450 centers that contribute observational data on patients undergoing transplant. The registry captures basic data on all allogeneic transplants in the United States18 and contains information on transplant characteristics, clinical history, and post-HCT outcomes.


Study Population and Cohort Assembly


The cohort assembly process is depicted in Figure 1. The PHIS database was screened for patients with acute leukemia who underwent HCT based on an admission with the following characteristics: (1) ICD-9 discharge diagnosis denoting acute leukemia (204.xx or 205.xx); (2) code suggesting HCT,


including procedure code (41.xx), clinical service code (531537, 531527, 531533, 531531), or pharmaceutical codes (busulfan or cyclophosphamide plus tacrolimus or cyclos- porine); (3) admission between 2004 and 2011; and (4) age <21 years at admission. Next, the CIBMTR database was queried for similar criteria: (1) children <21 years of age undergoing first allogeneicHCT for acute leukemia, (2) year of transplant between 2004 and 2011, and (3) consent for parti- cipation in the registry with research level data through 100 days posttransplant. Lastly, patients identified from the 2 data sources were merged using the following common data elements: sex, underlying disease, date of birth, date of trans- plant, and location of transplant.19 Patients common to both datasets were included in subsequent data analyses. Hospitals with <10 patients in the merged dataset were excluded because we considered it too difficult to generalize practice patterns based on such limited patient numbers.


Outcome: Antimicrobial Use


The primary outcome was antibiotic utilization rate defined as days of antibiotic therapy (DOTs) per 1,000 neutropenic days. Utilization rates were calculated for each hospital for specific antibiotic groups. The DOTs can be >1,000 if patients receive multiple agents in the class of interest on the same day. We focused on the following groups of antibiotics: (1) anti- pseudomonal antibiotics recommended for empiric treatment of febrile neutropenia including cephalosporins (cefepime, ceftazidime), penicillins (piperacillin-tazobactam and ticarcillin- clauvulanate), and carbapenems (meropenem, imipenem- cilastin, ertapenem, and doripenem)17 and (2) broad-spectrum gram-positive antibiotics (vancomycin, linezolid, and daptomy- cin).We also analyzed carbapenem utilization separately because this class is a mainstay of therapy for drug-resistant infections and is also a Centers for Disease Control and Prevention target for antibiotic stewardship.20 The primary analysis evaluated antibiotic exposures


between day of transplant and time of neutrophil engraftment or death (if the patient died prior to engraftment). Time to engraftment is defined as the first of 3 laboratory values in which the absolute neutrophil count is ≥ 500 cells/mm3. If the patient failed to engraft, follow-up time was limited to 30 days after transplant to capture a uniform period of posttransplant care before additional interventions.


Covariate Definitions


Patient-level demographics and transplant characteristics. Patient-level demographic variables and transplant characteristics were captured from CIBMTR data. Demographic variables, including age, sex, and race (white or nonwhite), were summarized by hospital. Similarly, transplant characteristics including underlying disease (acute myeloid leukemia, acute lymphoblastic leukemia), disease status at


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