Jennifer L. Goldman

Development of biomarkers to optimize pediatric patient management: what makes children different?

Despite the frequent utilization of biomarkers in medical practice, there is a relative paucity of information regarding validated pediatric biomarkers. Frequently, biomarkers found to be efficacious in adults are extrapolated to the pediatric clinical setting without considering that the pathogenesis of many diseases is distinctly different in children, and ontogeny directly influences disease evolution and therapeutic response in children. New and innovative approaches are necessary to provide reliable, validated biomarkers that can be used to improve and advance pediatric medical care.

No Evidence of Vancomycin Minimal Inhibitory Concentration Creep or Heteroresistance Identified in Pediatric Staphylococcus aureus Blood Isolates

We evaluated vancomycin minimum inhibitory concentration (MIC) trends by 3 methods (broth microdilution, Etest and Vitek 2) in 208 Staphylococcus aureus blood isolates from 2006 to 2009 and assessed for heteroresistance. Vancomycin MICs did not increase nor was heteroresistance identified. Etest yielded higher MIC results than the other 2 methods. No MIC was >2 µg/mL by any testing method.

Pediatric Crohn Disease Presenting as Appendicitis: Differentiating Features from Typical Appendicitis

BACKGROUND The initial presentation of Crohn disease (CD) may mimic acute appendicitis, and preoperative clues may aid in recognizing patients at risk for CD. METHODS A retrospective case control study of patients presenting over 10 years compared control patients with appendicitis versus patients presenting with appendicitis who ultimately developed CD. We matched 10 patients of the same age, gender, and perforated versus nonperforated appendicitis status for each of the CD patients. Demographic, laboratory, and clinical data were compared. Additionally, appendectomy specimens of CD patients were genotyped for common NOD2 (nucleotide-binding oligomerization domain-containing protein 2) mutations. RESULTS Of 2718 patients treated for appendicitis, 8 subsequently developed CD. Compared to the matched controls, CD patients were found to have lower hemoglobin (10.4 + 1.0 vs. 13.3 + 0.2, p < 0.0001) and mean corpuscular volume (MCV) (72.5 + 3.4 vs. 84.1 + 0.5, p < 0.0001) values, and higher platelets values (444.8 + 42.2 vs. 275.6 + 8.0, p < 0.0001) at initial presentation. Anthropometric z-scores, length of stay, and antibiotic therapy duration did not significantly differ between groups. The NOD2 mutation frequency (25%) was consistent with the currently described CD population. CONCLUSIONS Preoperative findings of a low hemoglobin level and MCV count, and a high platelet count in a child presenting with appendicitis warrant further evaluation for CD, as prompt diagnosis allows for optimal treatment and quality of life for these patients.

Trends in adverse reactions to trimethoprim-sulfamethoxazole

OBJECTIVE: To examine temporal trends of adverse drug reactions (ADRs) associated with trimethoprim-sulfamethoxazole (TMP-SMX) use in children. METHODS: We performed a retrospective observational study to characterize TMP-SMX ADRs in children between 2000 and 2009. We completed a chart review at our institution by identifying children diagnosed with TMP-SMX ADRs. To compare local trends to comparable institutions, we estimated the frequency of hospitalizations for TMP-SMX ADRs at 25 tertiary pediatric hospitals utilizing the Pediatric Health Information System database. To determine whether changes in outpatient prescribing rates occurred, we used the National Ambulatory Medical Care Survey/National Hospital Ambulatory Medical Care Survey. RESULTS: At our institution, 109 children were diagnosed with a TMP-SMX ADR (5 cases from 2000 to 2004 as compared with 104 cases from 2005 to 2009). Fifty-eight percent had been treated for a skin and soft tissue infection (SSTI). A similar trend was observed nationally, where the incidence of TMP-SMX ADRs more than doubled from 2004 to 2009 at comparable pediatric hospitals (P < .001). Although national outpatient data revealed no change in overall TMP-SMX prescribing, the percentage of children prescribed TMP-SMX for SSTI sharply increased during the study period (0%–2% [2000-2004]; 9%–17% [2005–2009]). CONCLUSIONS: The majority of TMP-SMX ADRs at our institution occurred in conjunction with SSTI treatment. TMP-SMX ADRs have occurred more frequently coincident with increased prescribing for SSTI. Increased usage alone may explain the increasing trend of TMP-SMX ADRs in children; however drug–disease interaction may play a role and requires further investigation.

SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease with a high burden to individuals, their families, and society with an annual incidence of 1 to 5 per 1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017, an investigator-driven meeting was held immediately before the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN.

Safety Concerns Surrounding Quinolone Use in Children

Fluoroquinolones are highly effective antibiotics with many desirable pharmacokinetic and pharmacodynamic properties including high bioavailability, large volume of distribution, and a broad spectrum of antimicrobial activity. Despite their attractive profile as anti‐infective agents, their use in children is limited, primarily due to safety concerns. In this review we highlight the pharmacological properties of fluoroquinolones and describe their current use in pediatrics. In addition, we provide a comprehensive assessment of the safety data associated with fluoroquinolone use in children. Although permanent or destructive arthropathy remains a significant concern, currently available data demonstrate that arthralgia and arthropathy are relatively uncommon in children and resolve following cessation of fluoroquinolone exposure without resulting in long‐term sequelae. The concern for safety and risk of adverse events associated with pediatric fluoroquinolone use is likely driving the limited prescribing of this drug class in pediatrics. However, in adults, fluoroquinolones are the most commonly prescribed broad‐spectrum antibiotics, resulting in the development of drug‐resistant bacteria that can be challenging to treat effectively. The consequence of misuse and overuse of fluoroquinolones leading to drug resistance is a greater, but frequently overlooked, safety concern that applies to both children and adults and one that should be considered at the point of prescribing.

Clinical Diagnoses and Antimicrobials Predictive of Pediatric Antimicrobial Stewardship Recommendations: A Program Evaluation

BACKGROUND The number of pediatric antimicrobial stewardship programs (ASPs) is increasing and program evaluation is a key component to improve efficiency and enhance stewardship strategies. OBJECTIVE To determine the antimicrobials and diagnoses most strongly associated with a recommendation provided by a well-established pediatric ASP. DESIGN AND SETTING Retrospective cohort study from March 3, 2008, to March 2, 2013, of all ASP reviews performed at a free-standing pediatric hospital. METHODS ASP recommendations were classified as follows: stop therapy, modify therapy, optimize therapy, or consult infectious diseases. A multinomial distribution model to determine the probability of each ASP recommendation category was performed on the basis of the specific antimicrobial agent or disease category. A logistic model was used to determine the odds of recommendation disagreement by the prescribing clinician. RESULTS The ASP made 2,317 recommendations: stop therapy (45%), modify therapy (26%), optimize therapy (19%), or consult infectious diseases (10%). Third-generation cephalosporins (0.20) were the antimicrobials with the highest predictive probability of an ASP recommendation whereas linezolid (0.05) had the lowest probability. Community-acquired pneumonia (0.26) was the diagnosis with the highest predictive probability of an ASP recommendation whereas fever/neutropenia (0.04) had the lowest probability. Disagreement with ASP recommendations by the prescribing clinician occurred 22% of the time, most commonly involving community-acquired pneumonia and ear/nose/throat infections. CONCLUSIONS Evaluation of our pediatric ASP identified specific clinical diagnoses and antimicrobials associated with an increased likelihood of an ASP recommendation. Focused interventions targeting these high-yield areas may result in increased program efficiency and efficacy.

Clinical Impact of an Antimicrobial Stewardship Program on Pediatric Hospitalist Practice, a 5-Year Retrospective Analysis

BACKGROUND AND OBJECTIVES Hospitalists increasingly serve as the primary physicians for children hospitalized with infections. Consequently, hospitalists frequently interact with institutional antimicrobial stewardship programs (ASPs). Understanding how these services interact can inform ongoing practice improvement efforts. The objectives of this study were to identify factors associated with ASP recommendations among hospitalist-managed children, and to determine the association of ASP interventions with clinical outcomes for hospitalist-managed patients. METHODS We retrospectively analyzed ASP reviews of hospitalist patients from a childrens hospital from March 2008 to June 2013. Clinical factors associated with an ASP recommendation were determined. Length of stay and 30-day readmission were compared between cases of agreement and disagreement with ASP recommendations. RESULTS The ASP reviewed 2163 hospitalist patients, resulting in 350 recommendations (16.2% of reviews). Hospitalists agreed with ASP recommendations in 86.9% of cases. The odds of an ASP recommendation decreased during the study period. Ceftriaxone was the most common antibiotic associated with a recommendation (154/350, 44.0%); community-acquired pneumonia was the most common diagnosis (105/350, 30.0%). Antibiotic discontinuation was the most often recommendation; hospitalists most often disagreed with consulting infectious diseases. Disagreement with ASP recommendations was associated with a decreased length of stay of 15.4 (95% confidence interval -33.2 to 1.1) hours but not 30-day readmission prevalence. CONCLUSIONS Pediatric hospitalists and ASPs can form an effective collaboration that improves antibiotic use while providing safe care. Better characterization of the areas of disagreement between hospitalists and ASPs is needed. Future studies are needed to identify ASP strategies that will be beneficial in other hospitalist settings.

In Vitro Hepatic Oxidative Biotransformation of Trimethoprim

Trimethoprim (TMP) has been widely used since the 1960s, both alone and in combination with sulfamethoxazole. Unfortunately, information regarding the role that cytochrome P450 enzymes (P450s) play in the formation of TMP primary metabolites is scarce. Hence, we undertook in vitro studies to identify and more fully characterize the P450s that catalyze formation of six TMP primary metabolites: TMP 1-N-oxide (1-NO-TMP) and 3-N-oxide (3-NO-TMP), 3′- and 4′-desmethyl-TMP, a benzylic alcohol (Cα-OH-TMP), and an N-acetyl cysteine (NAC) adduct of TMP (Cα-NAC-TMP). Formation kinetics for each TMP metabolite in human liver microsomes (HLMs) were consistent with single-enzyme Michaelis-Menten kinetics, and Km values were markedly above (≥10-fold) the therapeutic concentrations of TMP (50 µM). The combined results from correlation studies between rates of metabolite formation and marker P450 activities in a panel of HLMs along with inhibition studies utilizing selective P450 inhibitors incubated with pooled HLMs suggested that 1-NO-TMP, Cα-NAC-TMP, and Cα-OH-TMP were predominantly formed by CYP3A4. In contrast, 3-NO-TMP was formed predominantly by CYP1A2 in HLMs and inhibited by α-naphthoflavone. 4′-Desmethyl-TMP, which is believed to be a reactive TMP metabolite precursor, was formed by several P450s, including CYP3A4, correlated with multiple P450 activities, but was inhibited primarily by ketoconazole (up to 50%), suggesting that CYP3A4 makes a major contribution to TMP 4′-demethylation. TMP 3′-demethylation was catalyzed by multiple P450s, including CYP2C9, correlated with CYP2C9 activity, and was inhibited by sulfaphenazole (up to 40%). Overall, CYP2C9 and CYP3A4 appear to be the most significant contributors to TMP primary metabolism.

Outpatient Parenteral Antimicrobial Therapy in Pediatric Medicaid Enrollees.

Background Outpatient parenteral antimicrobial therapy (OPAT) is overused in cases where highly bioavailable oral alternatives would be equally effective. However, the scope of OPAT use for children nationwide is poorly understood. Our objective was to characterize OPAT use and clinical outcomes for a large population of pediatric Medicaid enrollees treated with OPAT. Methods We analyzed the Truven MarketScan Medicaid claims database between 2009 and 2012. An OPAT episode was identified by capturing children with claims data indicating home infusion therapy for an intravenous antimicrobial. We characterized OPAT use by describing patient demographics, diagnoses, and antimicrobials prescribed. We categorized an antimicrobial as highly bioavailable if ≥80% systemic exposure was expected from the peroral dose. We also determined the percentage of OPAT recipients in whom a follow-up healthcare encounter occurred during the OPAT episode in either the emergency department or as a hospital admission. We reviewed the primary diagnoses associated with these healthcare encounters to determine whether it was related to OPAT. Results We identified 3433 OPAT episodes in 2687 patients. A total of 4774 antimicrobials were prescribed during these episodes. Ceftriaxone and vancomycin were the most commonly prescribed antimicrobials. Highly bioavailable antimicrobials accounted for 34% of antimicrobials used for OPAT. An emergency department visit or hospital admission occurred during 38% of OPAT episodes, among which 61% were OPAT-related. Conclusions The high rate of medical encounters associated with OPAT in this cohort and the common prescribing of highly bioavailable antimicrobials underscore the opportunities for antimicrobial stewardship of pediatric OPAT.