UMEM Educational Pearls - By Matthew Poremba

Background:

The 2010 Infectious Diseases Society of America (IDSA) cystitis and pyelonephritis guidelines recommend fluoroquinolones (FQs) as first line agents for pyelonephritis treatment and also support trimethoprim-sulfamethoxazole (TMP-SMX) usage if the urinary pathogen is known to be susceptible. However, alternative regimens need to be evaluated as FQs are increasingly associated with serious adverse events, and E coli resistance rates to both FQs and TMP-SMX are rising nationally. The Cephalosporins for Outpatient Pyelonephritis in the Emergency Department (COPY-ED) study aimed to evaluate the effectiveness of oral cephalosporins in acute pyelonephritis treatment when compared to IDSA guideline-endorsed first line treatments.

Study design:

This multicenter, retrospective observational cohort study screened patients with a primary diagnosis of uncomplicated or complicated pyelonephritis using ICD-10 codes. They included all patients >18 years of age who reported symptoms of a UTI and were discharged home on oral antimicrobial therapy. Exclusion criteria included pregnancy, acute or chronic prostatitis, orchitis, epididymitis, or urinary tract surgery within 7 days prior to ED visit or surgery planned during the study period.

The primary outcome was rate of outpatient treatment failure within 14 days of discharge from the emergency department with cephalosporins compared to FQs and TMP-SMX. 

Patient Population:

• 647 patients received cephalosporins and 204 received FQs or TMP/SMX. 
• Majority female (85.9% in the cephalosporin group, 83.3% in the FQ and TMP/SMX group)
• Majority with uncomplicated pyelonephritis (72% in the cephalosporin group vs. 73% of the FQ and TMP/SMX group)
• The median age was 36 in the cephalosporin group and 33 in the FQ/TMP/SMX group.
• 60.4% of the cephalosporin group and 46.6% of the FQ + TMP/SMX group received at least one dose of an IV antibiotic prior to discharge (most commonly ceftriaxone)

Results:

Rates of treatment failure at 14 days were not statistically significant between groups, with a rate of 17.2% in the cephalosporin group and a rate of 22.5% in the FQ + TMP/SMX group. After adjusting for gender, complicated infections, previous use of intravenous or oral antibiotics, and urinary tract abnormality, the odds of treatment failure at 14 days were still not significantly different in patients who received fluoroquinolone or TMP/SMX (adjusted OR 1.275 [95% CI 0.86 to 1.9]) compared to cephalosporins.

Secondary outcomes included rates of treatment failure with first generation cephalosporins (cephalexin, cefadroxil, cefuroxime) and third generation cephalosporins (cefpodoxime, cefuroxime), rates of appropriate therapy selected based on urine culture susceptibilities, and rates of treatment failure compared to duration of treatment prescribed. None of these outcomes found statistically significant differences between groups.

Study Limitations:

• Patients could receive care at locations outside of the study sites either before or after their ED visit, which may lead to a falsely low incidence of reported treatment failure.
• Cefazolin susceptibility was used as a surrogate for all oral cephalosporin susceptibility, which may lead to underreporting of true resistance to oral first generation cephalosporins and/or overreporting incidence of resistance to third generation cephalosporins.

Key Takeaways:

• Rates of treatment failure appear to be similar between cephalosporins and guideline-endorsed treatments in pyelonephritis - though it is important to note this study predominately included younger female patients with uncomplicated pyelonephritis 
• The 2010 IDSA guideline recommendations for pyelonephritis may be outdated given changes in E Coli resistance patterns as well as increased recognition of adverse events with FQ use.

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Background:

Approximately 10% of patients presenting to the emergency department (ED) report penicillin allergies, which may lead to use of second- or third-line agents. Alternative therapies (such as aztreonam, clindamycin and fluroquinolones) carry an increased risk of mortality and complications such as Clostridioides difficile infection. Considering that less than 10% of penicillin allergies may be confirmed by formal testing results, the PEN-FAST clinical decision tool was created to identify patients with low risk of true penicillin allergy who do not require formal skin testing for rechallenging with a beta-lactam:

Though PEN-FAST has only been validated in the clinic and inpatient settings, a study from Tran et al. published this January sought to determine the safety and efficacy of utilizing this tool to assess penicillin allergies and re-challenge patients in the ED.

Study design:

This was a single-center, prospective, observational cohort study. Emergency medicine (EM) pharmacists screened patients in the ED with:

• A documented penicillin, amoxicillin or ampicillin allergy who also had an order for IV or oral clindamycin, levofloxacin or aztreonam OR
• A documented penicillin, amoxicillin or ampicillin allergy and an EM physician placed a general consult order to pharmacy requesting evaluation of antibiotic selection.

Screened patients were excluded from the study if orders were placed by a non-EM physician, if they previously tolerated a penicillin/cephalosporin within the healthcare system of the study site, if they were unable to participate in bedside interview, if the antibiotics selected were appropriate despite the penicillin allergy or if there were time constraints that would delay care if the PEN-FAST assessment needed to be completed. 

Study Intervention:

EM pharmacists completed the PEN-FAST assessment for all included patients. They recommended rechallenging with an appropriate beta-lactam for patients with a score of 0-2, recommended to consider rechallenging for patients scoring 3, and did not recommend rechallenging for scores of 4-5 or if it was confirmed patients previously experienced anaphylaxis, angioedema or severe cutaneous reactions with a beta-lactam. Orders for any change in therapy were only placed with discussion and agreement from EM physicians. Rechallenged patients were assessed at bedside for any immune-mediated reactions 45 to 75 minutes after initiation of antibiotics. The primary outcome was the percent of patients with a PEN-FAST score of 0-2 who tolerated a beta-lactam after being rechallenged.

Patient Characteristics:

After screening, one hundred patients were included in this study.

• Median age: 72 [IQR 59-81]
• Penicillin Allergy Label:
  • Penicillin VK, G or unspecified = 88%
  • Amoxicillin or ampicillin = 11%
  • Combined amoxicillin/clavulanate = 1%
• Calculated PEN-FAST scores:
  • 0 = 31%
  • 1 = 26%
  • 2 = 4%
  • 3 = 30%
  • 4 = 3%
  • 5 = 6%

Results:

Primary Outcome: 

• Out of 61 patients with a PEN-FAST score of 0-2, 52 patients were rechallenged. All 52 patients (100%) tolerated rechallenge with a beta-lactam.

Secondary Outcomes:

• Out of 30 patients with a PEN-FAST score of 3, six patients were rechallenged. All six patients (100%) tolerated rechallenge with a beta-lactam.
• The number of immune mediated reactions among all patients rechallenged was 0.
• Median time from initial order entry to entry of new antibiotic order for patients who were re-challenged was 17 minutes (IQR 10-23)
• Median time from initial order to antibiotic administration for patients who were re-challenged was 41 minutes (IQR 29-65)

Key Takeaways:

• The PEN-FAST decision tool was able to safely identify and risk-stratify eligible patients for beta-lactam rechallenge in the ED in this exploratory study.
• Prudent antibiotic selection is of particular significance in the ED, given that antibiotic therapy initiated in the ED influences inpatient ordering.

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Background:

Epinephrine administration is a critical component of treating severe allergic reactions, and delayed administration is associated with increased morbidity and mortality. Epinephrine auto-injectors are the current standard of care and allow for rapid administration in all care settings, but compliance issues can limit their use. The most common reason patient’s site for failure to administer or delayed administration of auto-injectors is needle phobia (particularly with pediatric patients). This has led to interest in developing needle-free epinephrine delivery devices that are easy to administer.

New Drug Approval:

This August, the FDA approved an epinephrine nasal spray (brand name: Neffy) for use as emergency treatment for Type 1 allergic reactions, including life-threatening anaphylaxis. The approval was based on four studies, including 175 total patients, comparing epinephrine 2 mg nasal spray with an epinephrine 0.3 mg intramuscular injection in healthy adults and children. These studies showed similar blood concentrations of epinephrine between treatment arms through 60 minutes after administration. In addition, both treatment arms showed similar elevations in heart rate and systolic blood pressure.

• Who is it for?
  • Epinephrine 2 mg nasal spray is approved for all adult and pediatric patients who weight more than 30 kg (66 lbs).
• How is it supplied?
  • Epinephrine 2 mg nasal spray comes in single-use devices, as a unit-dose spray. This is the same device that is used for many other commercially available internasal products, including Narcan (naloxone) nasal spray.
• How it is given?
  • Epinephrine 2 mg nasal spray device should be fully inserted into one nostril pointing straight into the naris, and then the plunger should be depressed. If symptoms do not improve or worsen after the first dose, a second dose of epinephrine 2 mg nasal spray should be given into the same nostril.
• Common side effects?
  • The most common side effects are throat irritation, intranasal paresthesia, headache, nasal discomfort, feeling jittery, paresthesia, fatigue, tremor, rhinorrhea, nasal pruritis, sneezing, abdominal pain, gingival pain, oral hypoesthesia, nasal congestion, dizziness, nausea and vomiting. 

Bottom Line:

Epinephrine nasal spray is a newly approved option for the treatment of severe allergic reactions and anaphylaxis. While this approval was based on studies in healthy adults and children who did not currently have anaphylaxis, this medication may be worth considering for patients who have issues or concerns about using an injectable device to administer epinephrine.

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A panel comprised of 21 participants selected by four clinical toxicology societies (America’s Poison Centers, American Academy of Clinical Toxicology, American College of Medical Toxicology, and Canadian Association of Poison Control Centers) sought to develop consensus guidelines for management of acetaminophen poisoning in the US and Canada. Highlights from this framework include:

Acetylcysteine Stopping Criteria

A common misconception is that acetylcysteine is administered for 21 hours then discontinued. The consensus statement codifies the practice of reassessing the patient at the end of the acetylcysteine infusion and only stopping acetylcysteine if all of the following criteria are met:

• Acetaminophen concentration <10 mcg/mL
• INR <2.0
• ALT/AST normal for patient or if elevated have decreased from peak (25%-50%)
• Patient is clinically well

Ingestion of Extended-Release Acetaminophen Products

Extended release acetaminophen products are available on the US market. Management is largely the same as for instant release acetaminophen except for several exceptions:

• Activated charcoal may be useful >4 hours after ingestion if acetaminophen concentration is rising (indicating ongoing absorption)
• If a concentration drawn 4-12 hours after ingestion is >10 mcg/mL but below the Matthew-Romack treatment line, a second level should be drawn in four to six hours

Management of Repeated Supratherapeutic Acetaminophen Ingestion

When a patient presents following repeated acetaminophen ingestions over a period of greater than 24 hours the Matthew-Romack nomogram is no longer applicable for guiding decisions regarding treatment with acetylcysteine. The consensus statement recommends initiating treatment in this scenario if the patient’s acetaminophen concentration is > 20 mcg/mL or if patient’s AST/ALT are abnormal.

Final Thoughts:

These guidelines will function as a useful reference and officially codify a general framework with evidence-based recommendations for the management of acetaminophen poisoning. As always, a poison center or clinical toxicologist should be consulted for any complicated or serious acetaminophen poisoning.

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Empiric antimicrobial treatment for necrotizing soft tissue infections (NSTIs) should include coverage of a wide range of pathogens including Staphylococcus spp, Streptococcus spp, anaerobic bacteria and gram negative bacteria. Treatment should also include an agent that suppresses toxin production by group A Streptococcus (GAS), with the Infectious Diseases Society of America (IDSA) guidelines recommending clindamycin plus penicillin for treatment of GAS causing necrotizing fasciitis and toxic shock syndrome. A typical empiric NSTI regimen would be vancomycin plus clindamycin plus piperacillin-tazobactam. 

Linezolid is an appealing alternative to clindamycin and vancomycin, as it has anti-toxin effects via inhibition of exotoxin expression, potent in vitro activity against Streptococcus spp, activity against methicillin-resistant Staphylococcus aureus (MRSA), and potential for less adverse effects than clindamycin plus vancomycin. Several recent studies have looked at using linezolid in lieu of clindamycin plus vancomycin when treating NSTIs.

Published Studies:

Dorazio and colleagues published a retrospective single center study compared 62 matched pairs of patients who received linezolid vs. clindamycin plus vancomycin as part of their NSTI treatment.

• Primary outcome was mortality at 30 days and secondary outcomes were the rates of C. difficile infection and rates of acute kidney injury (AKI). 
• No statistically significant difference in any primary or secondary outcomes noted, although there was a trend towards more AKI with clindamycin plus vancomycin versus linezolid 
  • AKI rates: 9.68% in the clindamycin + vancomycin group vs 1.61% in the linezolid group; HR 6 [95% CI .73-276]

Heil and colleagues published a retrospective single center cohort study examined patients who received either linezolid (n = 29) or clindamycin (n = 26) for treatment invasive soft tissue infection or necrotizing fasciitis with GAS isolated from blood and/or tissue.

• There was no difference in any primary or secondary outcomes, which included inpatient mortality, duration of vasopressor requirement, hospital length of stay, rates adverse drug events and change in Sequential Organ Failure Assessment score from baseline through 72 hours of hospitalization.

Lehman and colleagues published a retrospective single center study compared patients who received linezolid (n = 21) versus clindamycin plus vancomycin (n = 28) in addition to gram-negative and anaerobic coverage for empiric treatment of NSTIs.

• The primary outcome of duration of MRSA-active therapy was 2.9 days in the linezolid group versus 3.9 days in the vancomycin group (p = 0.04)
• The only secondary outcome that reached statistical significance was new-onset AKI, with a rate of 38.1% in the vancomycin plus clindamycin group versus 0% in the linezolid group (0%)

Bottom Line:

When added to an agent with good gram negative and anaerobic coverage (i.e. piperacillin-tazobactam), linezolid may be a more viable option for coverage of MRSA and GAS toxin production during empiric NSTI treatment when compared to clindamycin plus vancomycin. This is largely due to a more favorable side effect profile.

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Nitroglycerin easily migrates into polyvinyl chloride (PVC), a plastic commonly used in intravenous tubing due to its flexibility and low cost. A slow rate of flow and long tubing length increase the loss of nitroglycerin. While using less absorptive tubing (i.e. polyethylene or polypropylene) when administering nitroglycerin is recommended, most published clinical studies looking at nitroglycerin have used PVC tubing.

A 1989 study compared nitroglycerin delivery through PVC tubing and low sorbing tubing at various concentrations and flow rates.¹ Samples were obtained from the nitroglycerin bottle and the distal end of the tubing at several time points. 

• An average of 39.7% (SD 12.7) of nitroglycerin was lost at the distal end of PVC tubing, while an average of 2.3% (SD 9.3) of nitroglycerin was lost with low sorbing tubing.

A 2018 study enrolled 8 volunteers to receive nitroglycerin infusions through PVC tubing and low sorbing polyolefin tubing.² 

• The average max plasma concentration of nitroglycerin was 0.33 ng/ml (SD 0.19) in the PVC group, compared to 1.37 ng/ml (SD 0.89) with low sorbing tubing. 
• This small study showed a trend towards greater lowering of mean arterial pressure from baseline with low sorbing tubing when compared to the PVC group, although this was not statistically significant.

Bottom Line: Most studies evaluating nitroglycerin use in various clinical scenarios have used PVC tubing. Doses based on use with PVC tubing may be too high when using less absorptive tubing. Employing more conservative dosing strategies when using low sorbing tubing can help mitigate the risk of adverse effects (i.e. hypotension, headache).

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Myasthenia gravis is an autoimmune disease of the neuromuscular junction, most commonly due to antibodies attacking acetylcholine receptors in the postsynaptic membrane. Up to 30% of patients with myasthenia gravis will experience a myasthenic crisis during their disease course. If rapid sequence intubation is indicated, the unique characteristics of this patient population must be considered in the event use of a paralytic is necessary. All paralytic agents can be expected to last significantly longer, and an unpredictable response may be seen with depolarizing agents - therefore non-depolarizing agents are preferred in this population.

Non-Depolarizing Agents (Rocuronium, Vecuronium)

• MG patients have increased sensitivity to non-depolarizing agents and require lower doses than typically used
• It is reasonable to dose non-depolarizing agents at one-half the standard dose used. For example, rocuronium would be dosed at 0.5-0.6 mg/kg instead of the standard 1-1.2 mg/kg

Depolarizing Agents (Succinylcholine)

• MG patients have decreased expression of normal acetylcholine receptors which are required for depolarizing agents to work effectively and require higher doses than typically used
• Succinylcholine is typically dosed at 1.5-2.0 mg/kg (roughly double the dose used in other patient populations)

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Magnesium has been associated with function of serotonin and vascular tone regulation, both of which are mechanisms that implicate there may be a role in treatment of migraine. As this is a well-tolerated medication with a good safety profile, there is interest in utilizing this medication in the treatment of migraines. However, studies comparing magnesium to standard migraine treatments are lacking.

A recent single-center, double-blinded, randomized controlled trial compared magnesium, metoclopramide and prochlorperazine for treatment of migraine in the ED. Patients received either magnesium sulfate 2 grams, metoclopramide 10 mg or prochlorperazine 10 mg intravenously over 20 minutes. Adjunctive and rescue medications could be used at the providers discretion.

Pain was assessed with the 11-point Numeric Rating Scale at baseline and at several timepoints after completion of the infusion. Median change in pain score was found to be -3 in all groups at 30 minutes. Post-hoc analysis found magnesium to be non-inferior to prochlorperazine and metoclopramide at this time point. No difference in ED length of stay was found between groups. Adverse events were reported in 5% of patients receiving magnesium, 4.5% in patients receiving metoclopramide and 11.5% in prochlorperazine patients (p = 0.51). The most common adverse events were dizziness, akathisias, and anxiety.

Bottom Line: Magnesium can be used as an adjunctive agent in the treatment of migraines, and may also be considered as an alternative agent when other options such as prochlorperazine and metoclopramide are not appropriate. A reasonable dose would be 2 grams IV infused over 20 minutes. The team should follow-up 30-60 minutes after infusion to assess response to therapy.

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