Month: November 2012

One and Done: Single-Dose Antimicrobials in the ED

by Nadia I. Awad, posted in EM PharmD Blog

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:

Infection
Single-Dose Antimicrobial Treatment
Chlamydia
Azithromycin 1 g PO
Gonorrhea
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.

Vancomycin Loading Dose In The ED

by empharmd, posted in EM PharmD Blog

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 oneof the following:
o   WBC 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

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

by Nadia I. Awad, posted in EM PharmD Blog

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.