Anticonvulsant Hypersensitivity Syndrome

  • General Information
    • Drug-induced, multiorgan syndrome – potentially fatal.
    • Reported with anticonvulsants such as carbamazepine, phenytoin, phenobarbital and lamotrigine
    • Other medicines, such as sulphonamides, sulphones, allopurinol and NSAIDs
  • Clinical Diagnosis
    • Triad: fever, rash, and organ involvement (i.e. hepatitis)
      • Fever: 90-100% of cases – characteristically high, spiking fevers. May persist for weeks after the offending drug is discontinued. The fever may precede or be concurrent with the cutaneous eruption.
      • Rash: 90% of cases – typically macular erythema that becomes confluent and may generalize into erythroderma. The face, trunk and upper limbs are the first to be involved, followed by the lower limbs. The rash may spare the face. Desquamation occurs with resolution. Periorbital and facial edema may be severe and occurs in 25% of cases. Blistering may be seen over edematous areas.
      • Organ Involvement:
        • Hepatitis: 50% of cases – usually mild, but can be severe. The mortality rate is between 18 and 40% if hepatitis is present. Liver function tests may be grossly elevated and continue to rise after the drug has been discontinued. Return of liver function tests to normal may take up to a year.
        • Tender lymphadenopathy: occurs in 70% of cases and may be either local or generalized.
        • Splenomegaly: may also be seen, but is less common.
      • Hematologic abnormalities: 50% of cases – Leukocytosis with atypical lymphocytes and eosinophilia (only in 20%)  can be seen. Coagulopathy may also occur.
    • Each clinical feature may be of variable onset, leading to confusion and delay in diagnosis
    • Interval between first drug exposure and symptoms is usually 2-4 weeks, but has been reported in individuals receiving anticonvulsants for 3 months.
    • Syndrome is more severe in previously sensitized individuals.
  • Mechanism
    • Some features to suggest that it is a form of allergic hypersensitivity.
    • Phenytoin is metabolized by cytochrome P-450 to intermediate metabolites, known as arene oxides. Arene oxides can contribute to an immunological response or even cause cell death.
    • Usually detoxified by epoxide hydroxylase, but those who develop AHS may have decreased enzyme function.
  • Treatment
    • Treatment of AHS is largely symptomatic.
    • The offending medicine should be immediately discontinued.
    • Topical steroids and antihistamines are helpful in controlling symptoms associated with the rash.
    • Systemic corticosteroids are often used, although there have been no trials to assess the efficacy of this treatment.
    • Relapse of the condition is often seen; thus, patients who have experienced AHS should avoid arene oxide anticonvulsants (carbamazepine, phenytoin and phenobarbital) in the future.

Answer to Case Challenge #2

Case Challenge #2 presented a 42 yo female with fever, LAD, macular rash, and elevated LFTs after the recent intiation of phenytoin for new onset seizures.

CC2

What is the best management step?

D) Stop phenytoin – the patient has Anticonvulsant Hypersensitivity Syndrome

  • Starts within 2-4 weeks of starting anti-epileptics with aromatic benzene rings (subset of DRESS)
  • Main culprits: Carbamazepine, Phenytoin, Primidone, Phenobarbital
  • Stop drug and avoid repeat exposure to similar drugs
  • Buzz words: Rash, LAD, hepatitis, renal failure in person on offending agent
  • Eosinophilia only seen in about 20% of cases

Look forward to a more extensive review of Anticonvulsant Hypersensitivity Syndrome. There will be a new case challenge next week!

Vancomycin shortage

You read that correctly, folks. As you may already know, there is a nation-wide shortage of vancomycin, in part due to increasing demand. Before starting the medication empirically, it may be important to review the indications, spectrum, dosing, and  pharmacokinetics of this antibiotic titan.

Vancomycin

– Indications:
  • Documented methicillin-resistant staphylococcus aureus infections
  • Treatment of gram-positive infections in patients with serious B-lactam allergies
  • Empiric treatment for patients at risk for MRSA (prior documented infection, prior antibiotic therapy, indwelling catheter, prolonged hospitalization/nursing home, high prevalence of community-acquired MRSA)
  • Treatment of ampicillin-resistant enterococcal infections (if vancomycin susceptible)
  • Treatment of community-acquired meningitis (in addition to ceftriaxone) and post-neurosurgical meningitis (in addition to cefepime or meropenem)
  • Surgical prophylaxis for procedures involving implantation of prostheses in patients allergic to B-lactams
– Spectrum:
  • Aerobic gram-positive cocci: bactericidal against staphylococcal and non-enterococcal streptococci
  • Enterococcal infections, if systemic, may require synergistic treatment with gentamicin
  • Gram-positive bacilli: diptheroids, Clostridium spp, Bacillus spp
– MIC and Resistance patterns
  • Resistant gram-positives: some Lactobacillus spp, Erysipelothrix spp, Pediococcus spp
  • MRSA: MIC ≤ 2 = sensitive; MIC ≥ 16 = resistant
  • Streptococci: MIC ≤ 1 = sensitive
  • Other: MIC ≤ 4 = sensitive; MIC ≥ 32 = resistant
– Dosing:
  • CrCl > 60 ml/min: 10-15 mg/kg q12h
  • 40-60 ml/min: 10-15 mg/kg q12-24h
  • 20-40 ml/min: 5-10 mg/kg q24h
  • 10-120 ml/min: 5-10 mg/kg load, then 500mg IV post HD only
  • Single dose should not exceed 2 grams
– Pharmacokinetics
  • Half-life 6-8 hours in adults with normal renal function
  • For renal insufficiency, see dosing recommendations above
  • Trough levels:
    • goal 10-15 for most cases
    • goal 15-20 for for CNS infections, endocarditis, VAP, or osteomyelitis
    • Patients at risk for nephrotoxicity at higher trough levels
  • To reduce the risk of the Red Man Syndrome (a histamine response that causes flushing, tachycardia, and hypotension), doses should be infused slowly

For more about the vancomycin shortage, check out the links below:

Solvadi earns Gilead over $10 billion!

Several days ago, Gilead Sciences announced that it earned over $10.3 billion dollars in sales of its hepatitis C drug, Solvadi. In addition to Solvadi, Gilead Sciences earned over $2 billion in sales of another hepatitis C drug which was recently approved for sale, Harvoni. The recent wave of new hepatitis C medications has garnered a lot of attention given its more tolerable side effects and efficacy in treating hepatitis C. However, in the United States each Solvadi pill is priced at $1,000 and a three month regimen can cost up to $84,000.

In addition to this announcement, NPR Morning Edition recently highlighted Gilead Sciences efforts to reduce the cost of Solvadi in lower income countries. However, this has come under scrutiny as the cheaper cost is still considered relatively expensive for many of these countries.

Check out the articles below!

http://www.nytimes.com/2015/02/04/business/sales-of-sovaldi-new-gilead-hepatitis-c-drug-soar-to-10-3-billion.html?_r=0

http://www.npr.org/blogs/health/2014/02/06/272519954/maker-of-1-000-hepatitis-c-pill-looks-to-cut-its-cost-overseas