Faculty Bibliography

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%.

For 2013-2014, we prospectively identified US adults with flank pain, temperature >38.0°C, and a diagnosis of acute pyelonephritis, confirmed by culture. Cultures from 453 (86.9%) of 521 patients grew Escherichia coli. Among E. coli isolates from 272 patients with uncomplicated pyelonephritis and 181 with complicated pyelonephritis, prevalence of fluoroquinolone resistance across study sites was 6.3% (range by site 0.0%-23.1%) and 19.9% (0.0%-50.0%), respectively; prevalence of extended-spectrum β-lactamase (ESBL) production was 2.6% (0.0%-8.3%) and 12.2% (0.0%-17.2%), respectively. Ten (34.5%) of 29 patients with ESBL infection reported no exposure to antimicrobial drugs, healthcare, or travel. Of the 29 patients with ESBL infection and 53 with fluoroquinolone-resistant infection, 22 (75.9%) and 24 (45.3%), respectively, were initially treated with in vitro inactive antimicrobial drugs. Prevalence of fluoroquinolone resistance exceeds treatment guideline thresholds for alternative antimicrobial drug strategies, and community-acquired ESBL-producing E. coli infection has emerged in some US communities.

Background. Only half of the 3.5 million individuals with chronic hepatitis C (HCV) in the US are aware of their infection. Emergency departments (ED) provide a primary point of entry to the healthcare system for marginalized populations who are traditionally at elevated risk for HCV and are becoming an important venue for screening and linkage efforts. Optimal methods for HCV screening (universal versus targeted) in ED remain undefined. We aim to ascertain the relative prevalence of HCV infection by age and other risk factors through non-targeted screening for HCV in our high-volume urban ED. Methods. In this ongoing prospective observational cohort study, consenting adult ED patients participate in a researcher-administered structured interview and are offered a rapid HCV antibody (HCV Ab) screening test. If reactive, confirmatory serologic HCV Ab and HCV RNA are sent immediately and a clinic appointment is scheduled within 4 weeks. Participants are contacted with HCV RNA PCR results; those with detectable viral load are encouraged to attend follow-up appointment and receive a reminder call one week prior to appointment. Successful linkage to care is defined as appointment attendance. Results. A total of 2018 eligible patients were approached July 2015-April 2016. Seven hundred thirty-two participated in a structured interview. Seven hundred seven accepted an HCVAb rapid test. HCV antibody prevalence in the ED was 3.8% (0.43% in non-baby boomers without injection drug use (IDU), 7.6% in baby boomers, 34% in persons endorsing IDU). Twenty-three HCVAb-reactive participants submitted blood for confirmatory testing. A total of 12 of 23 (52%) had detectable HCV RNA, corresponding to 1.7% prevalence of chronic infection. Targeted screening of the birth cohort and those with IDU would have missed 7.4% (2 of 27) of HCVAb positive patients and 8.3% (1 of 12) with chronic infection. A total of 4 of 12 (33.3%) with chronic infection were linked to care, 2 have upcoming appointments, 1 died before appointment. Conclusion. Prevalence of HCV in our ED was higher than the national estimate of 3.4% among baby boomers used to justify national birth cohort screening. Optimal ED HCV screening methods should target baby boomers and those endorsing IDU, but a modest proportion of infections will be missed without universal screening