Faculty Bibliography

Introduction: Management of acetaminophen (APAP) toxicity is heavily reliant on the plasma or serum concentration. We sought to determine the analytical characteristics of past and current commercial APAP assays in the United States.
Method(s): We systematically reviewed the analytical characteristics of APAP assays cleared by the Food and Drug Administration's (FDA) 510(k) premarket notification process by searching the Clinical Laboratory Improvement Amendments (CLIA) database. If no analytical data were available, we contacted the manufacturer directly and searched for peer reviewed reports. We excluded non-blood assays, qualitative assays, and assays for which precision data were not available. We collected the following data where available: test principle, precision near 10mg/L, precision near 150 mg/L, limits of detection, and limits of quantitation. Accuracy and specificity were not routinely reported and outside the scope of this study.
Result(s): From 212 search results, we identified 19 different assays derived from 15 parent devices (Figure 1). All extracted analytical characteristics are shown in Table 1. Twelve were enzymatic while 7 were immunoassays. For all assays, absolute analytical precision decreased as analyte concentration increased (Figure 1). Near [APAP]=10mg/L, the most precise assays had a standard deviation (SD) of 0.2 mg/L or coefficient of variation (CV=SD/mean) of 1% and the least precise assays had a SD of range of 1.8mg/L or a CV of 10%. Near [APAP]=150 mg/L, the most precise assay had a SD of 1.4 mg/L or CV of 0.9% and the least precise assays had a SD of 7.4mg/L or a CV of 4.9%. Some manufacturers failed to validate assay precision at or near clinically- relevant [APAP]: two assays did not have precision data for [APAP]<40 mg/L, eight assays did not have precision data for [APAP]>150mg/L. The limit of detection ranged from 0.1- 2.4mg/L. The lower limit of quantitation ranged from 0.6-10mg/ L. The upper limit of quantitation ranged from 200-380 mg/L, before dilution.
Conclusion(s): APAP assays uncovered by our search had good analytical precision with improvement over time. The failure of some manufacturers to validate precision near treatment thresholds is concerning. Newer APAP assays could quantify lower [APAP], raising the likelihood of overdiagnosis and subsequent overtreatment. The FDA CLIA database for 510(k) devices is limited by redundant entries and incomplete data but remains a freely accessible starting point for clinicians to learn about many toxicologic assays. These data are not a substitute for independent laboratory optimization and validation.

Objective: Metaxalone is a central nervous system depressant utilized in the treatment of acute skeletal muscle pain. The exact mechanism of action has not been established but large ingestions have been associated with serotonin toxicity. We report on a patient who expired from complications of serotonin toxicity induced by massive metaxalone ingestion. Case report: A 20-year-old female with a prior history of depression presented to the emergency department unresponsive. History was unclear, however, her mother reported that the patient had access to her medications which included metaxalone, duloxetine, gabapentin, acetaminophen and oxycodone. She was intubated immediately and was found to be rigid with hyperreflexia and clonus. Initial vital signs were blood pressure 141/76 mmHg, heart rate 171 beats/minutes, respiratory rate 9/ minute, temperature 41.6 degreeC, oxygen saturations 98% (on supplemental oxygen). Initial venous blood gas showed pH 7.19, PCO2 23 mmHg, and lactate 1.2mmol/L. Initial blood tests revealed sodium 144mmol/L, potassium 2.6mmol/L, chloride 122mmol/L, bicarbonate 8 mmol/L, blood urea nitrogen 21mmol/L, creatinine 244 mumol/L, glucose 8.82 mmol/L and an acetaminophen concentration 662 mumol/L with an unknown time of ingestion. Despite supportive measures, external cooling, intravenous benzodiazepines and N-acetylcysteine therapy she developed multiorgan failure, cerebral edema and expired on day 3 of admission. High performance liquid chromatography/tandem mass spectrometry of admission blood samples revealed a serum metaxalone of 59 mg/dL (therapeutic less than 29.6 mg/dL) in addition to detectable dextromethorphan, diphenhydramine and gabapentin concentrations but no detectable serum duloxetine.
Conclusion(s): Metaxalone is an oxazolidinone analog which is a class that was initially developed as potential antidepressant (toloxatone) and antimicrobial agents (linezolid). Based on the structure, metaxalone is expected to have monoamine oxidase inhibitor activity and may cause serotonin toxicity by itself or in conjunction with additional serotonergic medications [1]. Here we present a severe case of serotonin toxicity associated with death of a young patient with confirmed elevated metaxalone concentrations

Background: Many interventions in medical toxicology are initiated once the serum drug or metabolite concentration exceeds a threshold value. However, toxicologists may be uninformed or misinformed about the precision of their laboratory assays. Differences in instrument precision may be an underrecognized source of harm when it comes to managing the poisoned patient.
Method(s): We accessed the Food and Drug Administration's (FDA) Clinical Laboratory Improvement Amendments database and manufacturer websites to obtain data on the analytical precision of all instruments which measure the following: acetaminophen, salicylate, iron, lead, lithium, and lactate. These measurands were chosen because there exist agreed-upon serum threshold concentrations which trigger costly or high-risk clinical actions (e.g. hemodialysis for serum [salicylate] > 100 mg/dL, chelation for serum [lead] > 50 ug/L). All instrument manufacturers must perform precision testing and provide the "total run" standard deviation (SD) of an instrument before seeking FDA approval. The total run SD is obtained for multiple measurand concentrations by analyzing a reference standard of known concentration over multiple days on the same instrument, then aggregating the error. We systematically collected the total run SD at the highest and lowest measurand concentrations reported for each instrument. We used these data to calculate 95% confidence intervals (95% CI) based on a single patient measurement to render them clinically meaningful.
Result(s): Precision data were available for between 2-5 instruments per measurand (Figure 1). Precision decreased with increasing measurand concentration for all instruments. Near the 10 ug/mL threshold for acetaminophen, the most precise instrument (Siemens, Advia) had a 95% CI range of 0.7 ug/mL while the least precise instrument (Beckman, EMIT) had a 95% CI range of 18 ug/mL. We observed that many manufacturers did not validate instrument precision at measurand concentrations near threshold values: all five salicylate assays failed to report precision data for serum concentration above 100 mg/ dL. It is likely that measurand concentrations near these thresholds in clinical practice are less precise than even our data suggest. Low precision in this context will lead to both systematic overtreatment and undertreatment of patients (Figure 2). Reassuringly, instrument precision has improved with time. The Abbott AxSYM and Fisher DRI platforms were the oldest and consistently had the lowest precision while the current generation Abbott ARCHITECT platform had the highest precision across multiple measurands.
Conclusion(s): Our study highlights the importance of contextualizing laboratory test results within the overall evaluation of the poisoned patient, particularly when those results are near a threshold value which requires high-risk interventions. Although results are reported without confidence intervals in the clinical setting, all measurements are inherently imprecise. We recommend that toxicologists collaborate with institutional laboratory services to determine the instrument-specific precision of frequently ordered toxicologic tests

Staphylococcus aureus is an opportunistic pathogen that causes a range of serious infections associated with significant morbidity, by strains increasingly resistant to antibiotics. However, to date all candidate vaccines have failed to induce protective immune responses in humans. We need a more comprehensive understanding of the antigenic targets important in the context of human infection. To investigate infection-associated immune responses, patients were sampled at initial presentation and during convalescence from three types of clinical infection; skin and soft tissue infection (SSTI), prosthetic joint infection (PJI) and pediatric hematogenous osteomyelitis (PHO). Reactivity of serum IgG was tested with an array of recombinant proteins, representing over 2,652 in-vitro-translated open reading frames (ORFs) from a community-acquired methicillin-resistant S. aureus USA300 strain. High-level reactivity was demonstrated for 104 proteins with serum IgG in all patient samples. Overall, high-level IgG-reactivity was most commonly directed against a subset of secreted proteins. Although based on limited surveys, we found subsets of S. aureus proteins with differential reactivity with serum samples from patients with different clinical syndromes. Together, our studies have revealed a hierarchy within the diverse proteins of the S. aureus "immunome", which will help to advance efforts to develop protective immunotherapeutic agents.

Objective: Both acute and chronic salicylism constitute a significant cause of mortality and morbidity in poisoned patients. While some authors have suggested that there is no need to screen for salicylate toxicity in the absence of a history or an anion gap acidosis, here we present a case of non-anion gap acidosis in a patient with significant salicylate poisoning. Case report: A 59-year-old man with no known significant past medical history was brought to the Emergency Department with depressed mental status. On arrival, he was tachypneic (26/ minutes) with shallow respirations, temperature of 37.3 degreeC, blood pressure 129/79 mmHg, heart rate 81 bpm, and oxygen saturation 94% on room air. Venous blood gas analysis showed: pH 7.4 and pCO2 28mmHg. Initial blood tests revealed: sodium 135 mmol/L, potassium 4.6mmol/L, chloride 105 mmol/L, bicarbonate 19mmol/L, blood urea nitrogen 19 mmol/L, creatinine 132 mumol/ L, glucose 6.7mmol/L, and anion gap 11 mmol/L (normal range 8-16 mmol/L). He was intubated and a subsequent arterial blood gas showed: pH 7.14 and pCO2 77 mmHg. Blood salicylate concentration obtained on initial screening was 0.61 mmol/L (therapeutic < 0.22 mmol/L). Intravenous bicarbonate infusion was started, he was given multi-dose activated charcoal and hemodialysis performed. He was extubated five days after admission and medically cleared on day 7 of admission. Conclusion: Significant salicylate ingestion is a well-recognized cause of elevated anion gap metabolic acidosis. Sporer et al. suggested that there is no need to screen for salicylate ingestion in the absence of anion gap acidosis [1]. However, here we demonstrate the presence of a non-anion gap metabolic acidosis associated with a clinically severe salicylate ingestion. There are multiple explanations for this phenomenon. Multiple chemistry analyzers including the one used at our hospital uses a proprietary ion-sensitive chloride electrode. With this analyzer, salicylate concentrations of 0.145 mmol/L and more than 0.43 mmol/L are known to cause a 4% and 15% false increase in chloride concentrations, respectively. This can erroneously cause a normal or even negative anion gap. In addition, acute salicylism occasionally causes proximal renal tubular dysfunction that can contribute to a non-anion gap acidosis. Clinicians should be compulsive about screening for salicylates in undifferentiated poisoned patients as routine chemistry tests may be insufficient to show salicylate toxicity

STUDY OBJECTIVE/OBJECTIVE:The incidence of Clostridium difficile infection has increased and has been observed among persons from the community who have not been exposed to antibiotics or health care settings. Our aims are to determine prevalence of C difficile infection among emergency department (ED) patients with diarrhea and the prevalence among patients without traditional risk factors. METHODS:We conducted a prospective observational study of patients aged 2 years or older with diarrhea (≥3 episodes/24 hours) and no vomiting in 10 US EDs (2010 to 2013). We confirmed C difficile infection by positive stool culture result and toxin assay. C difficile infection risk factors were antibiotic use or overnight health care stay in the previous 3 months or previous C difficile infection. We typed strains with pulsed-field gel electrophoresis. RESULTS:Of 422 participants, median age was 46 years (range 2 to 94 years), with median illness duration of 3.0 days and 43.4% having greater than or equal to 10 episodes of diarrhea during the previous 24 hours. At least one risk factor for C difficile infection was present in 40.8% of participants; 25.9% were receiving antibiotics, 26.9% had health care stay within the previous 3 months, and 3.3% had previous C difficile infection. Forty-three participants (10.2%) had C difficile infection; among these, 24 (55.8%) received antibiotics and 19 (44.2%) had health care exposure; 17 of 43 (39.5%) lacked any risk factor. Among participants without risk factors, C difficile infection prevalence was 6.9%. The most commonly identified North American pulsed-field gel electrophoresis (NAP) strains were NAP type 1 (23.3%) and NAP type 4 (16.3%). CONCLUSION/CONCLUSIONS:Among mostly adults presenting to US EDs with diarrhea and no vomiting, C difficile infection accounted for approximately 10%. More than one third of patients with C difficile infection lacked traditional risk factors for the disease. Among participants without traditional risk factors, prevalence of C difficile infection was approximately 7%.