Model Based Evaluation of Hypersensitivity Adverse Drug Reactions to Antimicrobial Agents in Children

Abstract

Drug use in children is–in most cases–supported by extrapolation of data generated from clinical trials in adult populations. This puts children at higher risk of developing adverse drug reactions (ADRs) due to “off-label” use of drugs and dosing issues. Major types of ADRs are drug hypersensitivity reactions, an idiosyncratic type of ADRs that are largely unpredictable and can cause high morbidity and mortality in a hard-to-identify specific population of patients. Lack of a complete understanding of the pathophysiology of DHRs and their unpredictive nature make them problematic in clinical practice and in drug development. In addition, ethical and legal obstacles hinder conducting large clinical trials in children, which in turn make children a “therapeutic orphan” where clear clinical guidelines are lacking, and practice is based largely on the personal experience of the clinician, hence making modeling desirable. This brief review summarizes the current knowledge of model-based evaluation of diagnosis and management of drug hypersensitivity reactions (DHRs) to antimicrobial drugs in the pediatric population. Ethical and legal aspects of drug research in children and the effect of different stages of child development and other factors on the risk of DHRs are discussed. The role of animal models, in vitro models and oral provocation test in management of DHRs are examined in the context of the current understanding of the pathophysiology of DHRs. Finally, recent changes in drug development legislations have been put forward to encourage drug developers to conduct trials in children clearly indicate the urgent need for evidence to support drug safety in children and for modeling to guide these clinical trials.

Comparison of the Liverpool Causality Assessment Tool vs. the Naranjo Scale for predicting the likelihood of an adverse drug reaction: A retrospective cohort study

“…This study was conducted to examine the value of screening suspected ADR cases prior to any investigations using history and clinical presentation alone in an ambulatory care setting and to compare the Naranjo Scale to the Liverpool Causality Assessment. The 2 published assessment tools: the older Naranjo Scale and newly developed tool by the Liverpool group were correlated with well‐studied diagnostic tests such as the allergy skin test, lymphocyte toxicity assay, in vitro platelet toxicity assay, radioallergosorbent test and oral challenge 22–25 …”

“…The 2 published assessment tools: the older Naranjo Scale and newly developed tool by the Liverpool group were correlated with wellstudied diagnostic tests such as the allergy skin test, lymphocyte toxicity assay, in vitro platelet toxicity assay, radioallergosorbent test and oral challenge. [22][23][24][25] Both assessment tools have a high sensitivity in predicting ADR cases but poor specificity. Liverpool Causality Assessment Tool (97.2 ± 2.4%) proved to be the more sensitive tool compared with its predecessor, Naranjo Scale (81.2 ± 5.69%).…”

The Psychological Relieving Effect of Drug Provocation Test in Drug Hypersensitivity

“…Adverse drug reactions account for 3–6% of all hospital admissions and occur in 10–15% of hospitalized patients. 1 , 2 Drug hypersensitivity reactions represent approximately one-third of all adverse drug reactions, 3 and epidemiological studies have shown that approximately 7% of the population experience drug hypersensitivity reactions at least once in their lives. 4 Drug hypersensitivity is considered a public health problem owing to the associated morbidity and socioeconomic costs worldwide.…”

“…4 Drug hypersensitivity is considered a public health problem owing to the associated morbidity and socioeconomic costs worldwide. [1][2][3][4] Patients with drug hypersensitivity experience a sensation of anxiety, fear, and tension, which can influence their quality of life and disrupt daily performance. Previously, studies have been conducted on the quality of life and psychology in patients with drug hypersensitivity, [5][6][7] but many aspects remain to be elucidated.…”