Original Article

Adverse Events in Pediatric Patients Receiving Long-Term Outpatient Antimicrobials Scott C. Olson,1,2 Sherilyn Smith,1,2,3 Scott J. Weissman,1,2,4 and Matthew P. Kronman1,2,3 1

Department of Pediatrics; 2Division of Infectious Diseases, University of Washington, Seattle; 3Center for Clinical and Translational Research; and 4Center for Global Infectious Disease Research, Seattle Children’s Hospital Research Institute, Washington

Corresponding Author: Matthew P. Kronman, MD, MSCE, Seattle Children’s Hospital, Division of Infectious Diseases, 4800 Sandpoint Way NE, Mailstop MA.7.226, Seattle, WA 98105. E-mail: [email protected]. Received January 13, 2014; revisions received April 4, 2014; accepted April 5, 2014; electronically published April 30, 2014.

Background. Although long treatment courses of outpatient antimicrobials are often used in pediatric patients, few data exist regarding the frequency of adverse events (AEs) associated with these medications. Methods. We performed a retrospective cohort study of all patients seen in the Infectious Diseases clinic at a tertiary referral children’s hospital from August 1, 2009 to August 1, 2011. We included patients who received 14 days of oral or intravenous antibiotic, antiviral, or antifungal medications. Patients receiving only prophylactic medications or human immunodeficiency virus treatment were excluded. Results. Three hundred thirty-five subjects met inclusion criteria, with a median age of 7.4 years at start of therapy. The cohort was predominantly male (60%), white (54%), and previously healthy (59%). A majority (88.4%) of subjects were treated for bacterial infections. β-Lactam agents were the most commonly used antimicrobial class (210 subjects; 62.7%), followed by clindamycin (86; 25.7%), rifampin (76; 22.7%), and vancomycin (62; 18.5%). Overall, 107 (31.9%) subjects experienced 151 distinct AEs. The most common individual AE noted was diarrhea (44; 29.1% of all AEs). Serious AEs developed in 42 (12.5%) subjects, including allergic reactions (15; 11.3% of all AEs), venous catheter-related complications (14; 13.0% of those with catheters), neutropenia (9; 3.0%), renal insufficiency (7; 2.5%), and hepatotoxicity (3; 1.1%). Rates of AEs were similar between those on oral and intravenous antimicrobials. Conclusions. In our study population, patients on prolonged oral or intravenous outpatient antimicrobials experienced AEs frequently. These findings support the need for close monitoring of pediatric patients on prolonged antimicrobial therapy and vigilance for unwanted effects of these medications. Key words.

adverse events; antimicrobial stewardship; antimicrobials; outpatient; pediatrics

BACKGROUND Many serious pediatric infections are initially evaluated and diagnosed during an acute hospitalization, with directed antimicrobial therapy begun in the inpatient setting. Because adverse events (AEs) may be associated with prolonged hospitalizations (such as the psychologic effects of hospitalization on children, increased risk for nosocomial infections, or the expense of inpatient care), prolonged antimicrobial courses are often completed in the outpatient setting [1]. Although most severe infections in pediatric patients were historically managed with parenteral antimicrobials, prolonged oral treatment is increasingly used, because studies have shown both safety and efficacy in diseases such as osteomyelitis [2]. Despite the frequency of prolonged outpatient antimicrobial therapy, there remains a paucity of data evaluating

the safety of, and appropriate monitoring for, long-term intravenous and oral antimicrobial treatment in the pediatric population [3]. Knowing the rate of overall AEs, frequency of specific AEs, and whether certain antimicrobial classes are associated with specific AEs would aid clinicians in monitoring children on long-term antimicrobials and would guide follow-up scheduling and choice of monitoring studies. Guidelines exist for management and monitoring of outpatient parenteral antimicrobials in adult patients [3], but pediatric practice is currently mainly driven by opinion and personal experience. In previous studies, the safety of prolonged intravenous therapy [2, 4–6] or prolonged antimicrobials in specific infectious processes [7, 8] were evaluated; but no studies to date have examined long-term oral antimicrobial therapy in children to assess AEs. We aimed to characterize the

Journal of the Pediatric Infectious Diseases Society, Vol. 4, No. 2, pp. 119–25, 2015. DOI:10.1093/jpids/piu037 © The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: [email protected].

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associated rate and impact of AEs in children treated with prolonged outpatient oral or intravenous antimicrobial therapy at a single, academic Pediatric Infectious Diseases clinic over a 2-year period. METHODS Design and Data Source

We conducted a retrospective cohort study of all children seen in the Infectious Diseases clinic at Seattle Children’s Hospital (SCH) between August 1, 2009 and August 1, 2011. Seattle Children’s Hospital is a tertiary care pediatric hospital with a broad geographic referral base; the outpatient Infectious Diseases clinic typically occurs 1–2 times per week and is staffed by physicians, nurse practitioners, and learners including medical students, pediatric residents, and pediatric infectious diseases fellows. A custom electronic data query identified all patients who visited the clinic during the study period. Patient charts were reviewed using the computerized medical record system (CIS, Cerner), which was used continuously during the study period. Two authors performed chart reviews (S. C. O., M. P. K.), and data were collected using a standardized electronic chart abstraction tool. We included subjects who received 14 days of oral or intravenous antibiotic, antiviral, or antifungal medications. We excluded subjects whose medication was given for prophylactic purposes only (eg, longstanding trimethoprimsulfamethoxazole for Pneumocystis carinii prophylaxis in a heart transplantation patient), for treatment of human immunodeficiency virus, or if the infection was managed at other hospitals or remote clinics (because of lack of follow-up data in the SCH electronic medical record). Antimicrobial Exposures

We recorded all systemic antimicrobial medications administered during the treatment period and recorded start and stop dates for each medication administered. When a medication was stopped, the reason for discontinuation was recorded. The infectious diseases practitioners make medication changes during clinic visits; we also recorded when these were made by telephone. Because patients are not routinely monitored in the clinic after discontinuation of antimicrobial therapy, subjects’ time in the cohort was censored at the end of their antimicrobial therapy. Outcomes

We used predefined AE categories. Adverse events based on clinical evaluation (eg, rash or diarrhea) were collected from clinical notes, and the date of events were recorded. Laboratory outcomes of interest and their dates were recorded; all laboratory values occurring during antimicrobial therapy were captured, whether ordered by the infectious diseases physicians or other practitioners. Routine

practice in the Infectious Diseases clinic is to monitor complete blood count, creatinine, and liver function tests for most patients on prolonged antimicrobials weekly. Most subjects (303; 90.5%) received laboratory monitoring. We defined neutropenia as an absolute neutrophil count

Adverse Events in Pediatric Patients Receiving Long-Term Outpatient Antimicrobials.

Although long treatment courses of outpatient antimicrobials are often used in pediatric patients, few data exist regarding the frequency of adverse e...
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