Thursday, November 29, 2012

One and Done: Single-Dose Antimicrobials in the ED

We are all familiar with this label on the vials and packages of antimicrobials that have been prescribed to us over the course of the years:

How often is this to likely occur among patients discharged from the emergency department? The most challenging part of providing patients with prescriptions for antimicrobials to be filled once they are discharged from the emergency department is the fact that (a) there is no guarantee that the prescription will be filled; and (b) even if the prescription is filled, as soon at the patient starts to recover from their infection, he or she may discontinue the agent. This can lead to a return visit to the ED, especially if the patient's condition fails to improve or worsens, and potentially increased costs to the healthcare system. Even if the patient is compliant with the treatment prescribed, antimicrobial resistance may increase, especially in cases where the outpatient treatment is suboptimal with poor penetration to the affected area and the course of therapy is unnecessarily prolonged.

So the question is: are there certain infectious conditions where we as clinicians can get away with administering a single dose of an antimicrobial agent to a patient in the emergency department and be safe to say that the patient has been effectively treated? In other words, is the concept of "one [dose of an antimicrobial agent] and done" adequate and effective?

The answer: yes, I believe there are. The advantages are quite obvious. There is direct observation of the patient actually receiving treatment; compliance with treatment is essentially not something that we need to be concerned about; and high concentrations of the antimicrobial agent may be reached to effectively cure the infection.

Before delving into specific infectious diseases, there are some criteria that should be fulfilled prior to making the decision that a patient's condition allows for administration of a single dose of an antimicrobial agent in the emergency department (adapted and modified from Singer and colleagues):
  • Availability of the antimicrobial agent and any equipment required for administration
  • Time required for administration by the ED physician and/or nurse 
  • Cost-effectiveness of the therapeutic agent 
  • Feasible route of administration with acceptable adverse effects associated with the agent 
  • Sufficient tissue penetration to allow for effective kill
  • Acceptability of potential failure rate associated with the infection (i.e. infection should not be severe or life-threatening to consider single-dose antimicrobial therapy) 
  • Sufficient data in the literature exists to support the use of single-dose antimicrobial therapy for a particular condition
  • Tolerability to treatment based on allergy status
  • Immune status of the patient (i.e. patients with immunocompromised conditions and/or significant comorbidities may not be ideal candidates for single-dose antimicrobial therapy)
Listed below are the infectious conditions where single-dose antimicrobial therapy may be utilized along with the recommended dosing strategy:

Single-Dose Antimicrobial Treatment
Azithromycin 1 g PO
Ceftriaxone 250 mg IM
Primary, secondary, or early latent syphilis
Benzathine penicillin G 2.4 million units IM
Vaginal trichomoniasis
Metronidazole 2 g PO OR Tinidazole 2 g PO
Vulvovaginal candidiasis
Fluconazole 150 mg PO
Acute otitis media
Ceftriaxone 50 mg/kg IM OR Azithromycin 30 mg/kg PO
Streptococcal pharyngitis
Benzathine penicillin G:
< 27 kg: 600, 000 units IM
> 27 kg: 1.2 million units IM

I would like to thank Patrick Bridgeman, Pharm.D., BCPS, for providing me with the inspiration to write about this topic.

Monday, November 26, 2012

Vancomycin Loading Dose In The ED

Vancomycin dosing in EDs has been on a journey from “a gram” for everyone towards a weight based dosing scheme.  This shift has been driven by a number of sources, but namely by the Infectious Disease Society of America, American Society of Health-System Pharmacists and Society of Infectious Disease Pharmacists' (IDSA/ASHP/SIDP) guideline recommendations for vancomycin therapeutic monitoring.1
The change in dosing strategy is similar to other ID discussion nowadays; resistance and multidrug resistant pathogens are the impetus for pushing the envelope when it comes to antimicrobial dosing.  Usually this discussion involves gram-negative pathogens and their antimicrobial counterparts.  But, S. aureus, particularly MRSA (both community and hospital organisms) is becoming more resistant to vancomycin.  Resistant pathogens like hVISA and VRSA, although rare, are starting to pop up in the US.
In a collaboration of ID docs and ID pharmacists, these guidelines bring to light the importance of utilizing the pharmacokinetics of vancomycin to improve our dosing practices. Since the conventional dosing strategies (i.e., vancomycin 1g every 12 hours) were not developed to reach the target therapeutic troughs (15 – 20 mg/dL) more aggressive, weight based doses are recommended (IIIB). The recommended strategies to achieve target trough concentration consist of employing a loading dose (25 - 30 mg/kg) followed by a maintenance dose (15 – 20 mg/kg/dose divided every 8 to 12 hours).1 These strategies make sense; with linear pharmacokinetics more drug equals higher concentration. Unfortunately, there is little prospective evidence to support the safety and efficacy of vancomycin loading doses, reflected by a IIIB recommendation. 
For us in the ED, identifying who should receive vancomycin loading doses can be challenging. Striking a balance between achieving a therapeutic trough and safety (particularly nephrotoxicity) is a constant experiment.  I think it is clear that the higher we push vancomycin dosing, the risk of nephrotoxicity increases.  Selecting the patients who are thought to have a benefit from higher dosing mirrors the population who is at highest risk of nephrotoxicity. Through retrospective data (again) independent risk factors associated with vancomycin nephrotoxicity include: total daily doses >4g, actual body weight >101.4kg, GFR < 86.6mL/min and admission to an intensive care unit. 2,3,4
We can however, limit the risk of toxicity by creating a threshold of the total daily dosing to < 4g and no more than 2g/dose, using adjusted body weight for obese patients to avoid overdosing and employing intensive therapeutic monitoring.  But what by way of efficacy are we sacrificing while adjusting for this risk?
While I hope to see prospective data on the efficacy and safety of these vancomycin-dosing strategies, I am not holding my breath.  Fortunately there are alternatives out there. Similar to the fosphyenytoin/phenytoin discussion vancomycin alternatives like linezolid, tigecycline, ceftaroline and daptomycin are expensive… for now.  Sure one agent alone cannot replace vancomycin, but using each in their own niches is certainly plausible. 
But for now, this is how I try to determine who is a candidate for vancomycin loading doses:
·       Age > 18 years
·       Creatinine clearance > 86.6 mL/min
·       Patients with suspected or proven infection caused by S. aureus
o   Bacteremia, endocarditis, osteomyelitis, meningitis, HCAP/HAP
·       With one of the following:
o   WBC < 4,000 cells/mm3, or > 12,000 cells/mm3, or > 10% bands
o   Temperature < 97 °F, or > 100.4 °F
o   Heart rate > 90 bpm
o   Respiratory rate > 20 bpm or PaCO2 < 32 mmHg

1.     Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American society of health-system pharmacists, the infectious disease society of American, and the society of infectious disease pharmacists. CID 2009;49:325-7
2.     Hidayat LK, Hsu DI, Quist, et al. High-Dose Vancomycin Therapy for Methicillin-Resistant Staphylococcus aureus Infections: Efficacy and Toxicity. Arch Intern Med, 2006:166:2138-2144
3.     Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrobial agents and chemotherapy, 2008;52(4):1330-36
4.     Lodise TP, Patel N, Lomaestro GM, et al. Relationship between Initial Vancomycin Concentration-Time Profile and Nephrotoxicity among Hospitalized Patients. Clinical Infectious Diseases 2009;49:507-14
5.     Wang JT, Fang CT, Chen YC, Chang SC. Necessity of a loading dose when using vancomycin in critically ill patients. J Antimicrobe Chemother 2001; 47:246

Thursday, November 22, 2012

Silibinin for Amatoxin Poisoning: Preventing the Last [Thanksgiving] Supper?

Ingestion of cyclopeptide mushrooms can lead to irreversible hepatotoxicity that may potentially be life-threatening. The mechanism by which hepatotoxicity occurs is through the activity of α-amanitin, which is taken up by hepatocytes and inhibits DNA-dependent RNA polymerase II, preventing DNA transcription into mRNA, which consequently halts the process of protein production. This causes injury of organ systems that are highly dependent on protein synthesis, such as the gastrointestinal mucosa, kidneys, and liver, which eventually leads to tissue necrosis. In addition, it is hypothesized that the activity of this toxin can lead to the production of free oxygen radicals that further exacerbate hepatocellular necrosis. It is reported that the lethal dose of α-amanitin in humans is 0.1 mg/kg body weight, which is equivalent to as little as one fresh mushroom (30 to 50 grams).

The most difficult part in terms of the management of cyclopeptide mushroom poisoning is the fact that there is no standard antidote that has been proven to be effective, and in many instances, their use is somewhat controversial. Those that have been tried include activated charcoal, high doses of intravenous penicillin G, intravenous N-acetylcysteine, intravenous cimetidine, and hemoperfusion. Aggressive hydration is indicated to prevent injury to the kidneys. In cases of severe cyclopeptide mushroom poisoning, liver transplantation may be warranted.

Quite recently, however, there has been some talk regarding silibinin, a water-soluble derivative of silymarin (milk thistle), as an antidote for the treatment of cyclopeptide mushroom poisoning. It has been used in Europe for decades for the treatment of acute amatoxin poisoning, and is currently being investigated as a study drug in the United States for the same indication. It is thought to act through competitive inhibition of the transporter system that is necessary for uptake of amatoxin into hepatocytes. Not only does this interrupt primary circulation of amatoxin, but it also disrupts enterohepatic recirculation of the toxin as well, the latter process being relevant to toxicity since many patients present long after complete absorption of the cyclopeptide. Silibinin seems to also possess anti-inflammatory and antioxidant properties, preventing injury and oxidative stress to the liver in the setting of amatoxin poisoning; it may also stimulate protein synthesis, thereby preventing further damage to the liver, allowing for regeneration of injured tissue within the liver and restoration of hepatic function.
The dosing schedule for silibinin as an investigational antidote for highly suspected or confirmed amatoxin ingestion in patients at least two years of age is as follows:
  • Loading dose of 5 mg/kg IV infused over one hour followed by a maintenance infusion of 20 mg/kg/day 
  • Infusion is to be continued until coagulopathy has resolved and liver function tests normalize
At this point, you may be asking where the evidence is to show that silibinin improves long-term clinical outcomes in patients with amatoxin poisoning. The short answer is that there is not a whole lot of evidence to support this hypothesis. Although there are plenty of published case reports that show its potential benefit in acute toxicity, a retrospective study conducted by Zilker and colleagues (Clin Toxicol 2005; 43:438) demonstrated that there are simply not enough cases of amatoxin poisoning to draw a meaningful conclusion regarding the effectiveness of silibinin when compared to other therapies.

Some logistical issues regarding drug procurement include the following:
  • Because this is a study drug, in the setting where ingestion of amatoxin is highly suspicious, consultation with the toxicology service and/or local poison control center is necessary.
  • Contact would need to be made with the principal investigator of the open-label multicenter study in order to enroll the patient(s) into the study and retrieve the drug.
  • Arrangements would have to be made to have the drug flown in and couriered to the institution.
  • An emergency investigational new drug application with the study protocol would need to be completed and approved by an institutional review board prior to administration of the agent.
These factors are important to consider because a delay in treatment with silbinin for amatoxin poisoning by more than 48 hours has been shown to be associated with a more severe course of coagulopathy and hepatic injury.

Since a trial is ongoing in the United States and the adverse events associated with treatment are relatively benign (facial flushing and rash), the potential benefits of silibinin do seem to outweigh the risks associated with treatment. Perhaps the results of the trial may shed some light regarding its place in therapy for amatoxin poisoning.

Monday, November 19, 2012

Aminophylline and Bradyasystolic Cardiac Arrest

When it comes to drug therapy in cardiac arrest, we just can’t get it right.  Granted, the heterogeneity of the causes of cardiac arrest as well as patient population characteristics make it difficult to find a drug (or combination of drugs) that will improve survival.  But that doesn’t stop us from looking for one.  Take for instance, aminophylline. Yes, aminophylline.

The ethylenediamine salt of theophylline, aminophylline is thought to counteract the effects of adenosine on the heart (and lungs) by antagonizing the A1 receptor.  While various other mechanism of modulating inflammation exist, the PDE inhibiting effects of aminophylline leads to increases in cAMP and cGMP concentrations and has the potential to exert synergistic effects when given with beta-agonists though augmented cAMP concentrations. [1] These mechanisms provide bronchodilation during asthma exacerbations, and are thought to also produce favorable effects in bradyasystolic cardiac arrest.

Initial case reports and small trials suggested promising ROSC outcomes in patients who received aminophylline after other efforts in CPR failed. [2, 3, 4] These initial findings and theoretical benefits in cardiac arrest were put to the test in a large trail (N=971) in Canada [5]. In this study, patients who suffered an out-of-hospital cardiac arrest with asystole or pulseless electrical activity and who were unresponsive to initial treatment with epinephrine and atropine were randomized to blinded aminophylline or placebo. Aminophylline was administered as a 250mg IV bolus, which could be repeated after 90s for a total dose of 500mg (94% of patients received 500mg). Aminophylline did not improve any outcomes including ROSC or survival to hospital discharge.

Aside from other methodological limitations with this study, the use of aminophylline requires more attention.  When one considers aminophylline essentially as theophylline, nightmares of pharmacokinetics should swiftly come back to haunt the mind. The pharmacokinetics of theophylline varies widely between patients and cannot be predicted by age, body weight, sex or virtually any other characteristic. Dosing aminophylline at 500mg (typical dose used for asthma is 6mg/kg) will likely achieve a concentration of about 15 mcg/mL – the upper limit of the therapeutic window (5-15mcg/mL).  Not forgetting the complex kinetics (again), this concentration could be much higher, or much lower. Above the therapeutic window, seizures can occur though central A1 antagonism. Below the therapeutic window, the beneficial effects on the heart and lungs may not occur. The balancing of these effects and the drug interactions causing both decreased clearance and increased clearance make it difficult to dose safely and a less than ideal agent to use as a one-dose-fits-all strategy.

It seems that the search continues for a drug that will join the ranks of good quality early chest compressions and defibrillation.  Let’s move on and remember aminophylline as one of the many the cautionary tales of pharmacokinetics.

1. Barnes PJ. Chapter 36. Pulmonary Pharmacology. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. Accessed November 17, 2012.

2. Mader TJ, Gibson P. Adenosine receptor antagonism inrefractory asystolic cardiac arrest: results of a human pilot study. Resuscitation1997;35:3–7
3. Mader TJ, Smithline HA, Gibson P. Aminophylline in undifferentiated out-of-hospital asystolic cardiac arrest. Resuscitation 1999;41:39–45.
4. Mader TJ, Sminthline HA, Durkin L, et al. A randomized controlled trial of intravenous aminophylline for atropine-resistant out-of-hospital asystolic cardiac arrest. Acad Emerg Med 2003;10:192–7.

5. Abu-Laban RB, McIntyre CM, Christenson JM, et al. Aminophylline in bradyasystolic cardiac arrest: a randomised placebo-controlled trial. Lancet 2006;367:1577–84.

Thursday, November 15, 2012

Immunogenicity of Alteplase: Never Say Never

A few weeks ago, we received an interesting question from one of the ED attending physicians regarding the immunogenicity of alteplase. Providing him with an answer made me realize to not take for granted the information available regarding the differences between the various thrombolytic agents, and reading more about this topic made me a bit humbled by the years of research and clinical experience that went into what we currently know today about these agents.

Streptokinase was developed in the 1930s as a product derived from various polypeptide chains that originated from beta-hemolytic streptococci. Shortly after its discovery, it was found that patients with recent streptococcal infections may develop antibodies against streptokinase, causing an immune complex to form between the circulating antibodies and streptokinase. This may potentially invoke an immune system response characterized as a type III allergic reaction, especially with frequent administration of streptokinase. In addition, a type I IgE-mediated reaction to steptokinase may develop within minutes of its infusion that can manifest as a full-blown anaphylactic reaction. Because streptokinase is not fibrin-specific, its infusion can induce rapid activation of plasminogen to plasmin, which can lead to generalized depletion of plasminogen, leading to histamine release secondary to activation of the complement cascade and production of bradykinin; this may induce marked facial flushing and hypotension. The rate of immunogenicity in patients who receive streptokinase is reported as upwards of 6%, based on the results of the GUSTO-I trial.

The search began for the ideal thrombolytic agent that was less likely to induce an immunogenic response and possess more specificity for fibrin, and decades later, alteplase was developed. Because alteplase is a genetically engineered version of endogenous human tissue plasminogen activator obtained from the human melanoma cell line produced via recombinant DNA technology, the likelihood of it inducing an immunogenic response in patients receiving the product should theoretically be lower than streptokinase. In addition, because alteplase is more specific for the activation fibrin-bound plasminogen to fibrin-bound plasmin, this allows for local fibrinolysis while minimizing bradycardia and hypotension.

This all sounds good and well for alteplase...until further research in the literature regarding the actual incidence of immunogenic reactions is done. Somewhat surprisingly, the incidence of an immunogenic response associated with alteplase is reported to be 0.1 to 2%. The type of response seen in published case reports has widely varied and includes urticaria, rash, hypotension, oropharyngeal swelling, and facial angioedema. Even more interesting is the fact that it has been hypothesized that because angiotensin-converting enzyme (ACE) inhibitors inhibit the action of kininases that normally break down bradykinin, these agents may exacerbate angioedema that occurs in the setting of alteplase infusion.

What is one to do? In most of the case reports, patients were adequately managed with the administration of fluids, antihistamine, corticosteroid, and/or vasopressor therapy; however, in nearly half of all reported cases, emergent intubation was necessary as a life-saving intervention. Simply put, be on the lookout for this as a possible complication of alteplase (not to mention the risk for bleeding). Should a patient begin to experience respiratory distress, facial angioedema, or other clinical signs and symptoms suggestive of anaphylaxis with the administration of alteplase, immediate management of the immunogenic reaction should be instituted as appropriate and a decision of whether or not the infusion is to be continued should be determined on a case-by-case basis.

I would like to acknowledge the efforts of Rana Abdeljabbar, Pharm.D. Candidate 2013 and John Youhanna, Pharm.D. Candidate 2013 for their contributions to this blog post.

Monday, November 12, 2012

Pharmacy Consult: Nitroglycerin Paste to IV Conversion

While I’m not a huge fan of nitroglycerin paste, I understand it’s clinical usefulness. The ability of slapping on an inch of paste to relieve chest discomfort is certainly non-invasive and can achieve effective results.  With this simplicity, a degree of randomness exists with regard to the ability to titrate the dose.  If the desired clinical effect is not achieved, how much more can we apply safely? Conversely, if hypotension results, how long will the effects last after the paste is wiped off?

Though more invasive, IV nitroglycerin provides greater control and titratablility and one study suggests a dose conversion between the dosage forms. (Am J Crit Care. 1998 Mar;7(2):123-30)

The conversion from IV to PASTE is relatively straightforward. Apply the appropriate amount of PASTE, and then stop the infusion of nitroglycerin 30 minutes later. (see table below for conversions)

Converting from PASTE to IV is a little more difficult (and has not been studied).  After removal of the nitropaste, the duration of effect of nitroglycerin is anywhere from 2 hours to 12 hours. So titration to IV will be more difficult and require close attention. It would therefore make more sense to target the lower end of the conversion range. For example, if 1 inch was applied and the conversion range is 10-39 mcg/min, the IV rate should be started at 10 mcg/min about 1 hour after the paste is removed and subsequently titrated.

Of course if the decision to convert to IV was because the paste is not achieving the desired effect, the infusion could be started earlier, but still targeting the lower dose range.

5 mcg/min
10 – 39 mcg/min
40 – 59 mcg/min
60 – 100 mcg/min

Thursday, November 8, 2012

Playing the Cards Right with Nicardipine

Since starting my residency, nicardipine has become one of the drugs that I have grown to love…maybe even becoming one of my favorite drugs to use for blood pressure control, especially in neurological emergencies such as acute ischemic stroke and subarachnoid hemorrhage. Time and time again, it has never failed me in these settings. It’s like a best friend who shows up at the right place and at the right time who knows exactly what to do in a difficult situation and does it right.

Nicardipine is a dihydropyridine calcium channel blocker that exerts its physiological effect by relaxing the vascular smooth muscle, leading to vasodilation and reduced systemic blood pressure. The great thing about it in the setting of neurological emergencies is that it has the added benefit of crossing the blood-brain barrier, allowing for relaxation of the smooth muscle within the cerebral vasculature. Its onset of action is anywhere from 5 to 15 minutes, and it has a predictable dose-response relationship. The other property that nicardipine has that makes it an ideal parenteral antihypertensive agent to use is its ease of dose titration, which is illustrated below:
  • Starting dose: 5 mg/hr
  • Titrate upward by 2.5 mg/hr every 5 to 15 minutes based on observed blood pressure response
  • Maximum dose: 15 mg/hr
  • Decrease rate by 2.5 mg/hr increments every 15 minutes if blood pressure is overcorrected until target blood pressure is reached

In my own personal experience, however, for some reason, EM attending physicians and EM residents resort to other parenteral antihypertensive medications first. As long as the pulse of the patient can tolerate it, the agent that is chosen first by most of the physicians that I work with is typically labetalol, which in many cases ends up not sufficiently reducing the blood pressure to our target. We usually end up switching to a nicardipine drip anyway. As this study demonstrated for a variety of hypertensive crises, many clinicians ultimately use nicardipine when labetalol fails due to the fact that nicardipine provides more dependable control of blood pressure. Speaking to some of the clinicians at my own institution, they tend to favor nicardipine as well due to the fact that there is a lesser incidence of bradycardia and hypotension compared to labetalol. The one thing that tends to be cumbersome for them with nicardipine is the fact that if a peripheral IV is used to infuse the drug, the line must be changed every 12 hours as long as the infusion is running to minimize irritation of the peripheral veins.

Granted, it may take some time for the nicardipine drip to be made and to program the infusion pump to deliver the medication, but this should not be a limiting factor in not using the medication at all. In fact, it does come in a premixed bag ready for use, so this can certainly reduce some time associated with preparing the product; in addition, the premixed formulation of nicardipine demonstrated greater benefit in controlling blood pressure for patients in the emergency department in comparison to labetalol in the CLUE study.

For neurological emergencies, I recommend the use of nicardipine over labetalol. It is important to remember that in this setting, the blood pressure should not be overcorrected too rapidly; this can be achieved by maintaining the systolic blood pressure between 140 and 160 mmHg. With this kind of control, the cards are indeed played right with nicardipine.

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