UMEM Educational Pearls - Pharmacology & Therapeutics

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Steroids induce leukocytosis through the release of cells from bone marrow and the inhibition of neutrophil apoptosis.   This effect typically occurs within the first two weeks of steroid treatment. 

Leukocyte elevation is commonly used in the diagnosis of septic patients; however, this can be hard to discern in patients on concomitant steroid therapy.

A retrospective cohort study of adult patients presenting with fevers and a diagnosis of pneumonia, urinary tract infection, bacteremia, cellulitis, or COPD exacerbation was conducted to determine the maximal level of WBC within the first 24h of admission between patients on acute, chronic, or no steroid treatment.

Results: maximal WBC levels (p< 0.001)

·        Acute steroid therapy: 15.4 ± 8.3 x 10 ⁹/L

·        Chronic steroid therapy: 14.9 ± 7.4 x 10 ⁹/L

·        No steroid therapy: 12.9 ± 6.4 x 10 ⁹/L

An increase in WBC of 5 x 10 ⁹/L can be found in acute and chronic steroid use when presenting with an acute infection and fever.

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Fosfomycin is an antibiotic infrequently used for the treatment of urinary tract infections (UTIs). It has a broad spectrum of activity that covers both gram-positive (MRSA, VRE) and gram-negative bacteria (Pseudomonas, ESBL, and carbapenem-resistant Enterobacteriaceae), which is useful in the treatment of multidrug-resistant bacteria. 

Fosfomycin is FDA approved for the treatment of uncomplicated UTIs in women due to susceptible strains of Escherichia coli and Enterococcus faecalis (3g oral as a single dose). Data has also demonstrated that it can be used for complicated UTIs; however, dosing is different in this population (3 g oral every 2-3 days for 3 doses).  Fosfomycin is not recommended for pyelonephritis.

The broad spectrum of activity, in addition to only needing a single dose in most cases, makes fosfomycin an attractive option; however, it should be reserved for use in certain circumstances.  Fosfomycin should not be considered as a first-line option.  It is also more expensive than other medications (~$100/dose) and in countries with high rates of utilization bacteria are developing resistance to fosfomycin.  In addition, most outpatient pharmacies do not keep this medication in stock.

Take-Home Point:

Fosfomycin should be reserved for multidrug-resistant UTIs in which other first-line options have been exhausted.

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Question

Patients with severe asthma exacerbations that are unresponsive to inhaled beta-agonists may require the use of epinephrine to control their symptoms.  When patients get to this point what route of administration should be used for the administration of epinephrine?

The most recent asthma guidelines (published in 2007) recommend the use of SubQ epinephrine 0.3-0.5 mg every 20 minutes for 3 doses.  Drug references typically list SubQ or IM epinephrine 0.01 mg/kg (~0.3-0.5 mg) every 20 minutes as appropriate routes of administration.  There is currently no data demonstrating that one route of administration is better than the other in patients with asthma; however, in other disease states, such as anaphylaxis, IM epinephrine is preferred due to the more rapid and reliable absorption over SubQ administration.

Auto-injectors that administer IM epinephrine 0.3 mg are available.  These auto-injectors may decrease the risk of medications error; however, they can be expensive.  SubQ administration requires the use of a syringe and a vial/ampule of 1 mg/mL epinephrine.

Bottom Line: Either SubQ or IM epinephrine administration is appropriate for patients with severe asthma exacerbations.  The preferred method at a given institution will be dictated by historical practice, risk of medication dosing errors, and drug cost.

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Insulin mechanism of action for hyperkalemia:

· Binds to skeletal muscle receptors

· Increased activity of the sodium-potassium adenosine triphosphatase and glucose transporter GLUT4

· Glycemic response occurs at lower levels of insulin

· Potassium transport activity increases as insulin levels increase

Patients with insulin resistance due to type-2 diabetes do not become resistant to the kalemic effects of insulin.

Hypoglycemia following insulin administration for hyperkalemia:

· Occurs 1-3 hours post dose, even with initial bolus of dextrose

· The amount of glucose is insufficient to replace the glucose utilized in response to the administered dose of insulin

· Insulin’s half-life is increased in ESRD leading to longer duration of action

A systematic review of 11 studies regarding insulin dosing for hyperkalemia:

· 22 patients (18%) experienced hypoglycemia

· Studies that only gave 25 grams (1 amp) of dextrose had the highest incidence of hypoglycemia (30%)

Tips:

· Consider insulin dose reduction in patients with renal failure

· Use an order set to ensure patients receive appropriate POC glucose monitoring to detect delayed onset of hypoglycemia

· Dextrose 50% (25 grams) should be given to all patients with pre-insulin BG <350 mg/dL

Subsequent PRN dextrose 50% (25 grams) should be used to maintain BG >100 mg/dL after insulin administration

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Fever occurs in 40% of patients with sepsis.  Historically, there has been conflicting evidence of whether patient outcomes improve with antipyretic therapy.

A recent large meta-analysis assessed the effect of antipyretic therapy on mortality of critically ill septic patients.  The analysis included 8 randomized studies (1,531 patients) and 8 observational studies (17,432 patients) that assessed mortality of septic patients with and without antipyretic therapy.

The authors found no difference in mortality at 28 days or during hospital admission.  There was also no difference in shock reversal, heart rate, or minute ventilation.

As expected, they found a statistically significant reduction in posttreatment body temperature (-0.38°C, 95% IC -0.63 to -0.13) in patients who received antipyretic therapy.  NSAIDs and cooling therapies were more effective than acetaminophen, however no agent or dosing information was provided and only one study included physical cooling therapies.

Bottom Line: Antipyretic therapies do not reduce mortality in patients with sepsis, but they may improve patient comfort by reducing body temperature.

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Question

Alpha-blockers (tamsulosin, alfuzosin, doxazosin, and terazosin) are antagonists of alpha1A-adrenoreceptors, which results in the relaxation of ureteral smooth muscle.    Current evidence suggests alpha-blockers may be useful when ureteral stones are 5-10 mm; however, there is no evidence to support the use of alpha-blockers with stones <5 mm.  Patients with ureteral stones >10 mm were excluded from studies utilizing these medications.

The size of most ureteral stones will be unknown due to the lack of need for imaging able to measure stone size. Given that the median ureteral stone size is <5 mm, most patients will not benefit from the use of an alpha-blocker.

Also, keep in mind that the data for adverse events with alpha-blockers used for ureteral stones is limited and that these medications have a risk of hypotension.

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Question

When you look up dosing for levofloxacin for community acquired pneumonia (CAP), you will find that both of the following options are approved:

• Levofloxacin 500 mg IV/PO daily x 7-14 days
• Levofloxacin 750 mg IV/PO daily x 5 days

This is based on a multicenter, randomized, double-blind, active treatment trial comparing these two regimens in CAP (mild to severe). This non-inferiority trial shows that the 750 mg dose of levofloxacin for 5 days is "at least as effective and well tolerated" as the 500 mg dose of levofloxacin for 10 days.

So why should you choose the 750 mg daily x 5 day regimen?

• Higher doses maximize the concentration-dependent pharmacokinetic profile of the drug
• Higher doses and shorter duration may be associated with less drug resistance
• Patients subjectively report feeling better at day 3 with the higher dose regimen

As alway with levofloxacin, don't forget to renally dose adjust subsequent doses when writting a script or scheduled inpatient order for patients with reduced creatinine clearance! 

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• The incidence of Staphylococcus aurea as a urinary pathogen is increasing, however, this finding may represent more than a simple urinary tract infection.
• One review found an 8-21%rate of association between S. aureus in the urine with bacteremia.
• Additional work up, including blood cultures, may be warranted in patients with systemic symptoms, lack of access to follow up, and no urinary tract pathology or instrumentation.

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Linezolid is a weak, nonselective monoamine oxidase inhibitor (MAOI). A recent FDA Drug Safety Communication released in March 2016 noted reports of serotonin syndrome associated with certain opioids, particularly fentanyl and methadone. Development of serotonin syndrome after concomitant administration of linezolid with other serotonergic agents has been reported. Due to a potential risk of serotonin syndrome, a patient on chronic methadone should not be started on concomitant linezolid unless they will be monitored.

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The addition of diazepam to naproxen for patients with acute, nontraumatic, nonradicular lower back pain did not improve pain or functional outcomes at 1 week or 3 months after ED discharge compared to placebo.

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Below is a list of pharmacy-related pearls from the 2016 Surviving Sepsis Guidelines:

• Fluid resuscitation: 30 mg/kg IV crystalloids within 3 hours (strong recommendation, low quality evidence)
• Vasopressors:
  • MAP target 65 mm Hg (strong recommendation, low quality evidence)
  • Norepinephrine 1st line (strong recommendation, moderate quality evidence). Epinephrine (weak recommendation, low quality evidence) or up to 0.03 Units/min vasopressin (weak recommendation, moderate quality evidence) may be added to NE.
• Antibiotics:
  • Obtain blood cultures prior to administration, but do not delay antibiotics (best practice)
  • Initiate empiric broad-spectrum antibiotics within 1 hour (strong recommendation, moderate quality evidence)
  • Consider double gram-negative coverage in patients with septic shock at high risk of multidrug-resistant pathogen
  • Risk factors for invasive Candida infection: immunocompromised state, TPN, necrotizing pancreatitis, recent major abdominal surgery, recent fungal infection
  • Optimize pharmacokinetic/pharmacodynamic properties- e.g., IV loading dose of vancomycin of 25-30 mg/kg is favored (best practice)
• Corticosteroids: IV hydrocortisone 200 mg per day if hemodynamic stability is not achieved through crystalloids and vasopressors (weak recommendation, low quality evidence)

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In a study comparing ketorolac IV doses of 10 mg, 15 mg, and 30 mg, no difference in pain score reduction or need for rescue analgesia was observed.

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Consider esmolol IV 500 mcg/kg loading dose followed by a continuous infusion of 0-100 mcg/kg/min for patients in refractory ventricular fibrillation 

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Do you have a patient with renal insufficiency who is in need of an anticoagulation bridge to warfarin? Subcutaneous unfractionated heparin (UFH) as an initial dose of 333 Units/kg subcutaneously followed by a fixed dose of 250 Units/kg (actual body weight) every 12 hours may be an alternative to admission for heparin infusion with monitoring.

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What they did:

• End stage renal disease (ESRD) patients presenting to the ED for emergent hemodialysis (HD) with baseline QTc prolongation (>450 msec in men and >470 msec in women) were given antiemetics or antihistamines for symptomatic relief of nausea and pruritis. A repeat ECG was obtained 2 hours after medications were given.
• Most patients received oral or intravenous promethazine 25 mg, ondansetron 4-8 mg, or diphenhydramine 25-50 mg.

What they found:

• 44 patients had a mean initial QTc of 483.7 msec (SD 18.4). Two hours after medication administration, the mean QTc was 483.8 msec (SD 20.0).
• Among 13 patients with initial QTc intervals >500 msec, 9 had an increased QTc interval after medication administration (average increase 11.8 msec, SD 6.7 msec).
• 8 patients with baseline QTc <500 msec had QTc >500 msec after medication administration.
• No patients experienced dysrhythmias, death, or were admitted for dysrhythmia or syncope 1 week after medication administration.

Application to clinical practice:

• While the mean QTc did not change, the proportion of individuals who experienced an increase in QTc interval is not reported.
• Although greatly limited by a small sample size, this study suggests that usual doses of promethazine, ondansetron, or diphenhydramine in patients presenting for emergent HD with baseline QTc prolongation may be safe.
• Additional studies, especially in patients with QTc prolongation >500 msec, are warranted.

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Prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP) are used for INR reversal in patients on vitamin K antagonists (VKA) (e.g., warfarin) with life-threatening bleeding. Guidelines from the Neurocritical Care Society and Society of Critical Care Medicine recommend using PCC over FFP for patients with VKA-associated hemorrhage and an INR >=1.4.

New study-INCH trial:

• Multi-center, prospective, randomized, open-label trial comparing FFP IV 20 ml/kg + phytonadione IV 10 mg versus 4-factor PCC IV 30 IU/kg + phytonadione IV 10 mg
• Adult patients on VKA with intracerebral or subdural hemorrhage with INR >=2.0 were included. Patients with traumatic intracranial hemorrhage were excluded.

What they found:

• Analysis included 50 (23 FFP and 27 PCC) patients (trial was stopped early after a safety analysis)
• 2 (9%) patients in the FFP group and 18 (67%) patients in the PCC group achieved an INR <=1.2 within 3 hours (adjusted OR 30.6, 95% CI 4.7-197.9; p=0.0003)
• Hematoma expansion at 3 hours was higher in those treated with FFP than PCC (adjusted difference 16.9 ml, 95% CI 2.5-31.3; p=0.023)
• Time until INR <=1.2 was longer in the FFP group than the PCC group (1482 vs 40 minutes; p=0.050)

Application to clinical practice:

• Of note, FFP 30 ml/kg has been suggested to provide more complete coagulation factor correction (this trial used 20 ml/kg), and package inserts for PCCs recommend doses based on INR and weight (this trial used 30 IU/kg for all patients)
• Although the sample size was small, this study suggests that in patients with VKA-associated non-traumatic intracranial hemorrhage and an elevated INR, PCC may provide faster INR correction than FFP, and may additionally be associated with a smaller degree of hematoma expansion.

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Amiodarone 150 mg IV over 10 minutes and procainamide IV 20-50 mg/min (up to 17 mg/kg) are two antiarrhythmic medications recommended in the American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care for stable wide QRS complex tachycardia. [1]

What they did:

Multi-center, prospective, randomized, open-label trial comparing the incidence of major cardiac events in the acute treatment of hemodynamically stable patients with wide QRS monomorphic tachycardia (presumed to be VT) using amiodarone 5 mg/kg IV infused over 20 minutes versus procainamide 10 mg/kg IV infused over 20 minutes. [2] The study period was 40 minutes, starting from the beginning of the infusion.

What they found:

• Analysis included 62 (n=33 procainamide, n=29 amiodarone) patients from 16 hospitals
• Fewer patients treated with procainamide experienced major cardiac events during the study period compared to those who received amiodarone (9% vs 41%; OR =0.1, 95% CI 0.03-0.6; P=0.006). The most frequent adverse cardiac event was severe hypotension requiring electrical cardioversion.
• Termination of VT occurred more frequently in patients treated with procainamide (67% vs 38%; OR =3.3, 95% CI 1.2-9.3; P=0.026).

Application to clinical practice:

• Medication doses and patient weights are not reported in the results. A comparison of the doses used in the PROCAMIO study to those recommended in the AHA guidelines for a 70 kg and 100 kg patient are as follows:
  • Procainamide:
    • 70 kg patient would receive procainamide 35 mg/min for 20 minutes. This is in the middle of the dose range recommended by the AHA.
    • 100 kg patient would receive procainamide 50 mg/min for 20 minutes. This is the upper limit of the dose range recommended by the AHA.
  • Amiodarone:
    • 70 kg patient would receive amiodarone 350 mg over 20 minutes. This is approximately equal to administering 2 doses of 150 mg at the infusion rate recommended in the AHA guidelines.
    • 100 kg patient would receive amiodarone 500 mg over 20 minutes. This is approximately equal to administering 3 doses of 150 mg at an infusion rate over 1.5 times higher than that recommended in the AHA guidelines.

• The study size was small, and depending on patient weights, it is possible that amiodarone dosing was more aggressive compared to doses commonly used in the US. However, the results suggest that procainamide could offer improved safety and efficacy over amiodarone for stable wide QRS tachycardia.

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Fluoroquinolone antibiotics are used to treat a wide range of infections and as prophylaxis against infection in certain immune compromised patients. In 2008 the FDA issued a boxed warning for tendonitis and tendon rupture for the fluoroquinolone antibiotic class, and in May 2016 a statement recommending the use of alternate therapies for uncomplicated UTIs and upper respiratory infections was issued. The mechanism by which fluoroquinolones causes tendon injury has not been elucidated, but may be related to oxidative stress caused by the overproduction of reactive oxygen species in tenocytes.

Adverse event reporting to the FDA is performed voluntarily by healthcare professionals and consumers through MedWatch. An analysis of tendon rupture events associated with fluoroquinolone use reported to the FDA’s Adverse Event Reporting System (FAERS) database was recently published.

What they found:

• 2495 reported cases of tendon rupture associated with fluoroquinolones
• Most cases involved levofloxacin (n=1555), ciprofloxacin (n=606), or moxifloxacin (n=230).
• Concomitant corticosteroids were administered in 21.2% of cases.
• The mean age was approximately 60 +/- 5 years.
• The ratio of men:women was 1.16:1.
• Renal function was not reported in this study.

Application to clinical practice:

• There is a risk of tendonitis/tendon rupture with administration of fluoroquinolone antibiotics.
• Risk factors for fluoroquinolone-associated tendinopathies may include advanced age, impaired renal function, and use of concomitant corticosteroids.
• Alternatives to fluoroquinolone antibiotics should be considered for patients with tendinopathy risk factors.
• When indicated, fluoroquinolones should be used at the lowest effective dose for the shortest possible time period to minimize exposure.

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