Rapid Oral Desensitization to Furosemide in a Patient with Sulfonamide Allergy

1
Rapid Oral Desensitization to Furosemide in a
Patient with Sulfonamide Allergy

• Naureen Alim, MD
• Julie Patel, MD
• Baylor College of Medicine
• Houston, Texas

2
Background

• Furosemide is a commonly used loop diuretic
• Extensive reports of allergy to
  sulfonamide-containing drugs, yet rare reports of
  hypersensitivity to furosemide
• Severe reactions, including anaphylaxis, have
  been reported with furosemide
• Desensitization to furosemide described in four
  patients
• One of these was a rapid intravenous
  desensitization protocol, and other three
  patients had an oral protocol lasting 3-10 days

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Alternative treatment

• Ethacrynic acid
• Only loop diuretic without a sulfonamide molecule
• Phenoxyacetic acid derivative
• Expensive, ototoxic, and not practical for most
  patients
• Oral formulation discontinued by manufacturer
• This poses a dilemma in the outpatient management
  of patients with sulfonamide allergy who require
  a loop diuretic for heart failure etc.
• What about patients with life-threatening
  reactions to sulfonamide-containing diuretics?

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Our case

• A patient with presumed type I hypersensitivity
  to furosemide who was successfully desensitized
  with oral furosemide over the course of several
  hours
• To our knowledge this has not been described
  previously
• Provides a safe, rapid, approach to
  desensitization in patients with furosemide
  allergy who require therapy with a loop diuretic

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Case Description 1

• 44 year old woman with hypertension, mild
  intermittent asthma and chronic kidney disease
  being treated as an outpatient for volume
  overload
• Prior documented reaction to trimethoprim/
  sulfamethoxazole (rash)
• Initially started on furosemide 20mg daily
• Two weeks later, dose increased to 40mg daily
• She developed a mild erythematous rash with
  generalized pruritus which resolved spontaneously
• After two more weeks, furosemide dose increased
  to 40mg three times daily

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Case Description 2

• Patient noted immediate generalized pruritus
  followed (two days later) by a diffuse, pruritic,
  urticarial rash
• She stopped furosemide and took one dose of
  cetirizine 10mg with mild relief of symptoms
• Due to severe volume overload, she was admitted
  to the hospital for diuresis with intravenous
  ethacrynic acid
• Allergy service consulted given lack of options
  for outpatient management with an oral diuretic

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Our Approach 1

• Factors to consider in this patient
• Presumed type I hypersensitivity response to
  furosemide given clear description of urticaria
• Significant problems with volume overload
• No significant contraindications to a
  desensitization procedure
• Plan Proceed with desensitization in a monitored
  inpatient setting (done in the post-anesthesia
  care unit)

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Our Approach 2

• Design Rapid oral protocol
• Rationale
• Prior report of rapid intravenous desensitization
  had reported no adverse effects
• Restricted availability of monitored beds in a
  County Hospital
• Patient would ultimately be on oral formulation
• Additional testing not warranted
• Negative skin test would not preclude allergy
  because reaction is often to drug metabolite
• No reliable reagent available for skin testing in
  sulfonamide or furosemide allergy (immunogen not
  known)

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Table 1 Rapid oral furosemide desensitization
protocol
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Results 1

• Patient developed some generalized pruritus after
  the 1mg dose
• The 1 mg dose was repeated but after continued
  itching she received diphenhydramine 25mg
  intravenously with complete resolution of
  symptoms
• Subsequently, she continued to have mild,
  localized, self-limited pruritus after each dose
  of furosemide but did not have any rash or
  urticaria

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Results 2

• Patient successfully desensitized to a furosemide
  dose of 100mg
• Started on oral maintenance regimen furosemide
  100mg three times daily
• Observed in the hospital for another two days and
  did not have any urticaria
• She did report some mild itching after her second
  maintenance dose of furosemide, treated
  successfully with diphenhydramine

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Discussion
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Sulfonamide Allergy

• IgE-mediated reactions are rare
• Most common immune-mediated reaction is a
  non-urticarial rash (cell, IgG-, or
  IgM-mediated?)
• Other reactions
• urticaria, angioedema, anaphylaxis
• maculopapular drug eruptions, exfoliative
  dermatitis, erythema multiforme, Stevens-Johnson
  syndrome, toxic epidermal necrolysis
• allergic myocarditis
• serum-sickness, photosensitivity reactions
• Reactions appear dose-related
• Reactions may be due to hydroxylamine metabolites
  which induce in vitro cytotoxic reactions in
  peripheral blood lymphocytes of patients with
  sulfonamide hypersensitivity

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Structure of Sulfonamide antimicrobials and
non-antimicrobial drugs

• Reported association between hypersensitivity
  after the receipt of sulfonamide antibiotics and
  a subsequent allergic reaction to non-antibiotic
  drugs that contain a sulfonamide structure
• However, sulfonamide antimicrobials have an
  aromatic amine group at N4 position and a
  substituted ring at N1 position
• These groups are not found in nonantibiotic
  sulfonamide-containing drugs
• Cross-reactivity thought to be unlikely

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Figure 1 Chemical structure of sulfonamide
antimicrobials
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Figure 1 Chemical Structures of the Loop
Diuretics
A Torsemide B Furosemide C
Bumetanide D Ethacrynic acid
Wall, GC et al. Ethacrynic Acid and the
Sulfa-Sensitive Patient. Arch Intern Med 2003
163116-7
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Cross-reactivity of Sulfonamide
antimicrobials/non-antimicrobials

• Large retrospective cohort study
• Patients with sulfonamide antibiotic allergy had
  an increased risk of an allergic reaction to
  nonantibiotic sulfonamides, as compared with
  patients without this history (adjusted OR, 2.8
  95 CI 2.1 to 3.7)
• BUT, they were even more likely to react to
  penicillin (adjusted OR, 3.9 95 CI 3.5 to 4.3)
• This may reflect a predisposition to allergic
  reactions rather than cross-reactivity between
  sulfonamide-based antimicrobial and
  non-antimicrobial drugs

Strom BL. et al. Absence of Cross-Reactivity
between Sulfonamide Antibiotics and Sulfonamide
Nonantibiotics. N Engl J Med 2003 3491628-35
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Sulfamethoxazole in HIV- positive patients

• Hypersensitivity occurs in 20-80 of patients
  with HIV versus 1-3 of non-infected patients
• Mechanism ?glutathione deficiency, altered
  hepatic metabolism and production of reactive
  intermediates
• HIV-infected patients can usually be rechallenged
  with sulfamethoxazole
• This may be due to fluctuating differences in
  oxidative metabolism, or reductive capacity, at
  various stages of AIDS

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Skin Testing

• Used to detect allergen-specific IgE antibodies
• Relevant immunogen is not known for most drugs
• What about the use of parent antibiotic compound
  for skin test?
• A negative skin test cannot be interpreted to
  mean that IgE antibodies are absent
• May just mean that the relevant immunogen was not
  used in test

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Skin Testing

• In prior case report of anaphylaxis to
  furosemide, the patient had demonstrated positive
  intradermal skin tests to furosemide,
  chlorothiazide, bumetanide and sulfamethoxazole/
  trimethoprim (using dilutions of
  pharmaceutic-grade solutions)
• Despite this, there are numerous studies in the
  literature of negative skin tests when the free
  drug sulfamethoxazole is used
• Low molecular weight drugs may be incapable of
  inducing an immune response in their free state
  and require conjugation with a carrier. This may
  explain prior lack of success

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Desensitization or Graded Challenge?

• DESENSITIZATION
• For IgE mediated reactions, desensitization may
  be performed
• Involves administration of increasing amounts of
  antibiotic over a period of hours until
  therapeutic dose reached
• Starting dose typically in micrograms
• Mechanism for tolerance thought to involve
  antigen-specific mast-cell desensitization

• GRADED CHALLENGE
• For non-IgE mediated reactions that are not
  life-threatening, consider graded challenge
• Intervals between doses ranges from hours to days
  or weeks
• Starting dose typically higher (milligrams)

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Furosemide Desensitization

• Desensitization to furosemide is uncommon
• Oral protocols previously described took 3-10
  days (graded challenge vs. desensitization)
• Oral protocols were performed in patients with
  pancytopenia and pancreatitis (non-type I
  hypersensitivity reactions) and urticaria
  (presumed type-I reaction)
• The patient who underwent an intravenous
  desensitization protocol had facial edema with
  rash but a negative intradermal skin test to 1
  furosemide

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Advantages of Our Protocol

• Oral desensitization is safer than intravenous
  desensitization
• Use of a rapid protocol is more cost-effective in
  terms of requirements for a monitored bed and
  staff resources and may be possible to perform
  in the outpatient setting
• We propose our protocol as a novel approach to
  loop diuretic desensitization
• This may offer a possible therapy for patients
  with non-life-threatening reactions to furosemide

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Future Directions

• IgE antibodies to sulfamethoxazole demonstrated
  in sulfonamide-allergic patients by in vitro
  assays and in vivo by skin testing but no tests
  available
• Need to look for IgE antibodies to furosemide
• RAST testing
• Skin testing to free drug at various
  concentrations using skin prick or intradermal
  techniques
• Skin testing to drug conjugated to a carrier
• Identification of the major antigenic
  determinants of various sulfonamide drugs with
  standardization of skin testing technique as was
  done with penicillin

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References

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  Challenge in Patients with Heart Failure and
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• Hansbrough JR, Wedner J, Chaplin DD. Anaphylaxis
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• Juang P. et al. A Successful Rapid
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• Strom BL. et al. Absence of Cross-Reactivity
  between Sulfonamide Antibiotics and Sulfonamide
  Nonantibiotics. N Engl J Med 2003 349 1628-35
• Wall, GC et al. Ethacrynic Acid and the
  Sulfa-Sensitive Patient. Arch Intern Med 2003
  163116-7