UMEM Educational Pearls - Pharmacology & Therapeutics

When patients with severe allergies to penicillin (urticarial, bronchospasm, anaphylaxis, angioedema) are excluded, the cross reactivity to cephalosporins is very low (approximately 0.1%)

The reaction is related to structures in the side chain, not the cyclical structure as thought in the past.

There are several cephalosporins with IDENTICAL side chains that should not be given to patients with allergies to specific penicillins, namely:

• Penicillin:   do not give cefoxitin
• Ampicillin:   do not give cefaclor or cephalexin
• Amoxicillin: do not give cefadroxil or cefprozil

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A recent meta-analysis has called into question whether contrast-induced AKI even occurs after an IV dye load for radiologic imaging. [1] This conclusion is most certainly up for debate.

Irrespective of that conclusion, prevention of contrast-induced nephropathy is still important. Is there any benefit to using N-acetylcysteine over normal saline in the ED? Probably not according to a new study. [2]

• The primary outcome was contrast-induced nephropathy, defined as an increase in creatinine level of 25% or 0.5 mg/dL, measured 48 to 72 hours after CT.
• The authors found no reduction in contrast-induced nephropathy in patients who received NAC vs normal saline (about 7% in each group).
• The important finding is that the contrast-induced nephropathy rate in patients receiving less than 1 L IV fluids in the ED was 13% compared to 3% for more than 1 L.

Conclusions

1. Contrast-induced AKI does happen after emergency CT.
2. NAC does not provide additional benefit over saline alone.
3. Giving more than 1 L of normal saline markedly reduces the risk.

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Treatment of patients with HIV/AIDS can frequently mean consideration for, and need to treat cryptoccocal meningitis.

Since 1997, studies have demonstrated that high-dose Amphotericin B combined with flucytosine has improved outcomes compared to low dose treatment or monotherapy.

A recent 2013 study reiterated this approach, showing significant decrease in deaths at 70 days post-treatment and increased rates of yeast clearance with combination therapy of Amphotericin B plus flucytosine. 

Recommendation:

Antifungal treatment of cryptococcal meningitis should start with Amphotericin B at 0.7-1 mg/kg IV daily plus concurrent flucytosine 25 mg/kg orally q6 hours. Fluconazole can be substituted in place of flucytosine if it is not available or not tolerated.

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ACLS recommendation for procainamide in tachycardic rhythms is:

Loading dose 20 mg/minute (up to 50 mg/minute for more urgent situations) until:

• Arrhythmia is controlled
• Hypotension occurs
• QRS complex widens by 50% of its original width
• or total of 17 mg/kg is given

Maintenance infusion is 1 to 4 mg/min.

An easier method for dosing acute onset atrial fibrillation in stable patients was used in the Ottawa Aggressive Protocol, in which they administered 1 gm over 60 min, which was interrupted if BP < 100 mmHg; if corrected by a 250 ml IV bolus, the infusion was resumed. This was not used, however if the patient was to be admitted.

A strategy for treating stable monomorphic VT with procainamide used:

100 mg IV over 1-2 minutes, repeat as necessary until an endpoint of

• Termination of tachycardia
• Drug induced hemodynamic deterioration
• Completion of 800 mg maximal dose

If no slowing of the tachycardia occurred with a dose of 400 mg, the administration was ceased.

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Although there is a paucity of data to guide dosing of antimicrobials in the critically ill obese patient, we can draw some conclusions from existing kinetic studies. Assuming normal renal and hepatic function, here's what to do:

Penicillins: Use the high end of dosing range. For example, if the plan is to use piperacillin/tazobactam 3.375 gm IV every 6 hours for a complicated intra-abdominal infection, use 4.5 gm instead.

Cephalosporins: Use the high end of the dosing range.

Carbapenems: Use the high end of the dosing range.

Quinolones: Use the high end of the dosing range.

Aminoglycosides: Dose using adjusted body weight. ABW (kg) = IBW + 0.4 X (actual body weight - IBW)

Vancomycin: 15-20 mg/kg actual body weight every 8 to 12 hours. Adjust based on trough level.

When dosing most antibiotics in critically ill obese patients, use the high end of the dosing range (if not more).

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A recent review identified 5 key points to consider when prescribing fluids.

1. Fluids should be prescribed as drugs, recognizing that any fluid can be harmful if dosed incorrectly.
2. The differences in efficacy between administering a 'crystalloid versus colloid' are modest; however, the cumulative differences in safety appear more significant.
3. The qualitative toxicity associated with hydroxyethyl starch (HES) and isotonic saline remains a concern.
4. The differences in chloride load and strong ion difference between cystalloid solutions, such as isotonic saline compared with physiologically more balanced solutions, appear to have clinical relevance.
5. The 'default' resuscitation fluid for acutely ill patients should likely be physiologically balanced crystalloid solutions (eg, PlasmaLyte or Ringer's lactate ).

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A recent, randomized study evaluated two approaches for treating acute pain in an inner-city ED.

• Group 1 received hydromorphone 2 mg. Group 2 received hydromorphone 1 mg (with the option of a second 1 mg dose 15 minutes later).
• 1 hour after the dose, patients were asked if they wanted more pain medication.
• Both groups had an equal proportion of patients decline more pain medication at one hour (67%). 61% of patients in the 1 + 1 group only needed the initial dose of hydromorphone!
• Secondary outcomes and safety measures were also similar between the groups.
• Patients with chronic pain, age >64, weight <150 pounds, or opioid use within last 7 days were excluded. 

Application to clinical practice: For most patients with acute, severe pain in the ED, start with hydromorphone 1 mg. It may be all the patient needs and can potentially avoid giving them extra opioid they don't need.

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• Hold metformin if the patient is at risk for dehydration (eg. vomiting, diarrhea) due to the risk of lactic acidosis
• Medications that stimulate insulin secretion (eg. sulfonylureas, repaglinide, or nateglinide) should be held if the patient is at risk for hypoglycemia
• Patients usually should continue their basal insulin, but may decrease or hold their bolus dosing.
• Finger sticks should be checked every 2-4 hours for those on insulin, or 2-4 times per day for type II diabetics not on insulin.

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Background

In the current era of community-acquired MRSA (CA-MRSA), most of our outpatient treatment options for cellulitis aim to cover MRSA. Choices include sulfamethoxazole/trimethoprim (SMZ-TMP), doxycycline, linezolid, and clindamycin (depending on local susceptibility patterns).

A New Study

• In a double-blind, placebo-controlled trial 146 patients with cellulitis were randomized to receive cephalexin alone or cephalexin + SMZ-TMP for 7-14 days
• Lots of exclusion criteria basically narrowed the patient population to uncomplicated cellultits with no history of diabetes or other immunocompromising conditions
• Cure rates up to 30 days post-treatment were the same between the two groups (>80%)

Take Home Clinical Points

• Even in communities with high prevalence of MRSA, uncomplicated cellulitis cases without pus generally seem to be strep species.
• Therefore, make sure to include an anti-streptococcal component (such as cephalexin) to the MRSA agent (doxycycline or SMZ-TMP). Clindamycin has sufficient strep coverage by itself (but may not adequately cover MRSA).
• Given the potential for MRSA infections to deteriorate quickly and the inability to differentiate staph from strep without cultures, MRSA coverage should still be considered.

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Introduction

Fosphenytoin is a prodrug and is metabolized quickly to phenytoin after administration. The conversion of fosphenytoin to phenytoin involves the release of phosphate. In fact, each mmol of fosphenytoin releases 1 mmol of phosphate.

Clinical Question

Are patients at risk for hyperphosphatemia after fosphenytoin loading?

Data

There are only two cases of reported hyperphosphatemia.

• A 17-year old African-American male with end-stage renal disease developed acute hyperphosphatemia to 3.9 mmol/L (12.1 mg/dL) following the IV administration of 1000 mg of fosphenytoin for an idiopathic complex partial seizure
• An infant in status epilepticus had marked hyperphosphatemia 8.4 mmol/L (25.9 mg/dL) after a 5-10 fold dosing error.

Bottom Line

Despite the phosphate load from fosphenytoin administration, hyperphosphatemia is very rare and probably associated with renal insufficiency and dosing errors.

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• Prothrombin Complex Concentrate (PCC) Kcentra™ has been approved for urgent reversal of major bleeding in patients taking vitamin K antagonists (e.g. warfarin).

• It contains factors 2,7,9 and 10, and antithrombotic Proteins C and S.

• Both fatal and non-fatal arterial and venous thromboembolic complications have occurred with Kcentra™. Thrombotic events occurred more frequently in the PCC group compared to plasma, although the differences were not statistically significant.

• Volume overload occurred less frequently in the PCC group, as there is a smaller volume  administered with PCC compared to that of plasma.

• Percentage of INR ≤ 1.3 at 30 minutes was 62% in the PCC group and 9.6% in the plasma group.

Approval of Kcentra™ may open the door for studying treatment of the bleeding patient on newer oral anticoagulants.

A new recommendation in the 2013 Ischemic Stroke Guidelines provides guidance on what to do in patients taking new oral anticoagulants who are deemed eligible for IV fibrinolysis. Here is what the guidelines say:

• The most helpful lab tests are not widely available.
• A detailed history is important, but not always obtainable.

Until further data are available, a history consistent with recent use of new oral anticoagulants generally precludes use of IV tPA.

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• Although Keppra has been used more frequently in clinical practice, there is little evidence for its use in status epilepticus.
• It has a wide spectrum of action and few drug interactions.
• Initially, case series appeared to be highly successful in terminating seizures as an add-on agent.
• A review of 2 prospective studies found efficacies of 44% as an add- on agent, and 75% as a primary agent. The studies had markedly different populations.
• In a retrospective study, the treatment failure rates were 3X higher than that of intravenous valproic acid as an add-on agent in terminating status epilepticus.
• Therefore, although it is used frequently, the evidence for use is limited and inconclusive in terminating status epilepticus.

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• A recent Cochrane review examined the use of early statin therapy in patients with ACS.

• They evaluated 18 studies (14,303 patients), which compared early statin therapy (within 14 days) to placebo or usual care.

• The conclusion was that initiation of early statin therapy does not reduce death, myocardial infarction of stroke up to four months, but reduces the occurrence of unstable angina by 24% at 4 months following ACS.

• Many smaller studies previously noted benefits with early statin initiation prior to this meta-analysis.

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The newest iteration of 'Guidelines for the Early Management of Patients with Acute Ischemic Stroke' was recently published. Here are the key revisions specific to blood pressure management:

• In patients with markedly elevated blood pressure who do not receive fibrinolysis, a reasonable goal is to lower blood pressure by 15% during the first 24 hours after onset of stroke. The level of blood pressure that would mandate such treatment is not known, but consensus exists that medications should be withheld unless the systolic blood pressure is >220 mmHg or the diastolic blood pressure is >120 mmHg (Class I; Level of Evidence C).
• No data are available to guide selection of medications for the lowering of blood pressure in the setting of acute ischemic stroke. Labetalol and/or nicardipine are listed as preferred, but other options can be used (Class IIa; Level of Evidence C).
• Restarting antihypertensive medications is reasonable after the first 24 hours for patients who have preexisting hypertension and are neurologically stable (Class IIa; Level of Evidence B).

If administering rtPA, blood pressure needs to be <185/110 mm Hg. That recommendation didn't change.

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Intraosseus (IO) access has become quite popular in critically ill patients requiring immediate resuscitation. In a patient responsive to pain, however, pain and discomfort is associated with the force of high-volume infusion through the established line.

• Before flushing the line, consider administering preservative-free 2% lidocaine (without epinephrine) for patients responsive to pain prior to flush.

• The suggested dose is 20-40 mg (1-2 mL) of the 2% lidocaine, followed by the 10 mL saline flush.

If preservative-free 2% lidocaine is not stocked in your ED, now is the time to consider adding it.

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The two available Tetanus/reduced diphtheria toxoid/acellular pertussis (Tdap) vaccine products in the U.S. are Boostrix and Adacel. Neither were originally approved in older adults age 65 and older. Boostrix received FDA-approval for use in this age group in July 2011, but Adacel never has.

However, in June 2012 ACIP issued new guidance recommending Tdap for all adults age 65 years and older. 

"When feasible, Boostrix should be used for adults aged 65 years and older; however, ACIP concluded that either vaccine administered to a person 65 years or older is immunogenic and would provide protection. A dose of either vaccine may be considered valid."

Bottom line: Regardless of which Tdap product is stocked at your institution, both are considered safe to use in adults 65 years and older.

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In the rare circumstance you need to treat a patient with suspected PID and an allergy to doxycycline, what is the alternative?

For oral regimens, azithromycin is an option in place of doxycycline.

• In one randomized trial, azithromycin demonstrated short-term effectiveness when given 500 mg X 1, followed by 250 mg/day for 6 days.
• In another randomized study, the combination of ceftriaxone 250 mg IM single dose and azithromycin 1 g orally once a week for 2 weeks was effective.

Suggested regimen for PID with doxycycline allergy:

• Ceftriaxone 250 mg IM X 1
• Azithromcyin 500 mg IV/PO X 1, then 250 mg PO daily for 6 days
• plus/minus Metronidazole 500 mg PO twice daily for 14 days

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It seems we've finally put to bed the myth that 10% of penicillin-allergic patients will also react to cephalosporins. Dr. Campagna, et al. recently published a review article concluding that the true cross-reactivity is negligible except when side-chains are similar [PMID 21742459]. 

This topic was also the subject of a recent post on the Academic Life in EM blog (http://academiclifeinem.blogspot.com/2012/08/busting-myth-10-cephalosporin.html).

But what about the reverse question? Can I give a penicillin to a cephalosporin-allergic patient?

Dr. Romano's group tested 98 patients with skin-test postitive cepahlosprin allergy (mostly IgE -mediated anaphylaxis). Patients were then skin tested for penicillin allergy. Those testing negative were challenged with a penicillin.

• 25% of patients reacted to the penicillin

• Similar side-chain was a strong predictor of cross-reactivity

​A Letter to the Editor response to this study pointed out that the authors used a smaller-than-standard size threshold for a positive response to the penicllin AND used a higher-than-standard dose of amoxicillin for testing. In light of this, the rate of subjects with cephalosporin allergy who do not have a history of penicillin allergy but with true IgE-mediated allergy to penicillin might be much closer to 5%.

Bottom line: The cross-reactivity of penicillins in cephalosporin-allergic patients is somewhere between 5-25%.

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A slight correction: The correct AUTHOR in the referenced article is:

Wilkerson, R. Gentry, MD. Angioedema in tthe Emergency Department: An Evidence-Based Review. Emergency Medicine Practice, Nov 2012;14(11).