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Can Fam Physician. 2006 November 10; 52(11): 1434–1438. | PMCID: PMC1783707 |
Approach to managing patients with sulfa allergy Use of antibiotic and nonantibiotic sulfonamides David Ponka, MD, CCFP(EM) OBJECTIVE To present an approach to use of sulfonamide-based (sulfa) medications for
patients with sulfa allergy and to explore whether sulfa medications are
contraindicated for patients who require them but are allergic to them. SOURCES OF INFORMATION A search of current pharmacology textbooks and of MEDLINE from 1966 to the
present using the MeSH key words “sulfonamide” and “drug sensitivity”
revealed review articles, case reports, one observational study (level II
evidence), and reports of consensus opinion (level III evidence). MAIN MESSAGE Cross-reactivity between sulfa antibiotics and nonantibiotics is rare, but on
occasion it can affect the pharmacologic and clinical management of patients
with sulfa allergy. CONCLUSION How a physician approaches using sulfa medications for patients with sulfa
allergy depends on the certainty and severity of the initial allergy, on
whether alternatives are available, and on whether the contemplated agent
belongs to the same category of sulfa medications (ie, antibiotic or
nonantibiotic) as the initial offending agent. OBJECTIF Proposer une façon d’utiliser les médicaments à base de sulfamides (sulfas)
chez les patients allergiques aux sulfas et vérifier si ces médicaments sont
contre-indiqués pour ces patients. SOURCES DE L’INFORMATION Une consultation des récents ouvrages de pharmacologie et de MEDLINE entre
1966 et aujourd’hui à l’aide des mots clés MeSH
«sulfonamide» et «drug sensitivity» a
permis de repérer plusieurs articles de revue et études de cas, une étude
d’observation et des rapports d’opinion consensuelles (preuves de niveau
III). PRINCIPAL MESSAGE Les réactions croisées entre sulfas antibiotiques et non antibiotiques sont
rares, mais elles peuvent à l’occasion affecter le traitement
pharmacologique et clinique des patients allergiques aux sulfas. CONCLUSION La façon d’utiliser les médicaments à base de sulfas chez les patients
allergiques aux sulfas dépend du degré de certitude quant à l’allergie
initiale, de la sévérité de cette condition, de la disponibilité de
médications alternatives et du fait que l’agent envisagé appartient ou non à
la même catégorie de médicament sulfamide (i.e., antibiotique ou non
antibiotique) que l’agent initialement responsable. EDITOR’S KEY POINTS- This article examines the evidence for and against prescribing sulfa
nonantibiotics to patients with a history of sulfa allergy.
- The literature search revealed many review articles and reports of consensus
opinion (level III evidence), but surprisingly, these all referred to only a
few primary studies (case reports and one observational study).
- Cross-reactivity between sulfa antibiotics and nonantibiotics is rare, but on
occasion it can affect the management of patients with sulfa allergy.
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POINTS DE REPÈRE DU RÉDACTEUR- Cet article fait le point sur les données favorables et défavorables quant à
la prescription de sulfas non antibiotiques aux patients qui ont une
histoire d’allergie aux sulfas.
- Une recherche dans la littérature a repéré plusieurs rapports de synthèse et
rapports d’opinion consensuelle (preuves de niveau III), mais étonnamment,
ils se référaient tous à un petit nombre d’études primaires (des études de
cas et une étude d’observation).
- Les réactions croisées entre sulfas antibiotiques et non antibiotiques sont
rares mais elles peuvent occasionnellement nuire au traitement des patients
allergiques aux sulfas.
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Mrs MacDonald, a 70-year-old woman, is relatively new to my practice. She
recently helped me review my understanding of what we mean by “sulfa allergy.”
(Patient’s name and age have been changed to protect her privacy.) On her
initial visit, she had a medical history of hypertension, obstructive sleep
apnea, osteoarthritis, and multiple allergies, including to “sulfa” drugs,
hydrochlorothiazide, and various environmental elements for which she received
allergy shots. Her medications included 240 mg of verapamil, 8 mg of
perindopril, and 150 mg of sulindac (a nonsteroidal anti-inflammatory drug), all
taken by mouth twice daily, and 81 mg of acetylsalicylic acid taken once daily. Her sleep apnea was well controlled with nightly use of a continuous positive
airway pressure machine set at a pressure of 5 cm of H2O. She had
never had signs of left- or right-sided heart failure. She complained of
increasing dyspnea on exertion, orthopnea, and peripheral edema. Clinical
examination, and later radiographic and echocardiographic findings, confirmed
biventricular congestive heart failure. After explaining the diagnosis and her predisposition to it, I prescribed 40 mg
of oral furosemide to be taken once daily and asked her to stop taking sulindac,
thinking it was contributing to fluid retention. I also switched her
nondihydropyridine calcium channel blocker to amlodipine (initially 5 mg by
mouth once daily), a dihydropyridine medication that contributes less to fluid
retention. I received a telephone call from the pharmacist later that day,
however, warning me that she should not take furosemide because of her history
of allergy to sulfonamide medications. Although furosemide indeed carries a
sulfa moiety, I have not in the past hesitated to prescribe it to patients who
are allergic to sulfa antibiotics because I thought cross-reactivity was very
unlikely. The pharmacist pointed out that Mrs MacDonald had reported a previous
“serious” reaction to hydrochlorothiazide (another sulfonamide nonantibiotic),
so I refrained from prescribing furosemide.
Examining the evidence Before proceeding further, and having the luxury of time as the patient was not in
any acute distress, I decided to examine the evidence for and against prescribing
sulfa nonantibiotics to patients with a history of sulfa allergy. This and similar
questions arise commonly in primary care, especially with the re-emergence of
sulfamethoxazole compounds as important first-line antibiotics in this age of
increasing resistance to them. Such compounds are also used for Pneumocystis
carinii prophylaxis for patients with HIV and AIDS. It is surprising,
therefore, that an approach to this problem is not more often discussed. I first read the relevant chapters of authoritative texts on pharmacology and the
manufacturer’s package insert for Lasix (furosemide). Although the textbooks were
not useful in answering my question, they did provide a good review of classes of
sulfa medications. The manufacturer’s package insert simply stated that patients
might be allergic to Lasix if they are allergic to “sulfonamides” without further
discussion or differentiation among various kinds of sulfonamides. I then searched MEDLINE using the MeSH keywords “sulfonamide” and “drug sensitivity”
from 1966 to the present, looking for the best available evidence to guide my
decision. Although a randomized controlled trial (level I evidence) would have been
most useful, no such evidence was found. The search did reveal many review articles
and reports of consensus opinion (level III evidence), but surprisingly, these all
referred to only a few primary studies that dealt with my question. Most of these
studies were case reports, but one was an observational study (level II
evidence). Sulfonamides are commonly used in primary care. Although
trimethoprim-sulfamethoxazole and other sulfa-antibiotic combinations are especially
widely used (sulfonamides were the first antibiotics ever introduced in 1936), this
class of medication also includes many nonantibiotic agents. Table 1 lists the most common drugs containing a sulfa
(SO 2NH 2) moiety in Canada. Several of these drugs are rarely
thought of as sulfonamides. | Table 1Commonly used sulfonamide nonantibiotic medications available in Canada |
Adverse reactions to sulfa antibiotics are relatively common compared with such
reactions to other antimicrobial agents. Adverse reactions have been estimated to
occur in 3% of courses, 1 but only 3% of these
actually are true hypersensitivity. 2
Unfortunately, hypersensitivity reactions to sulfonamides can be severe and even
life-threatening. They include immediate, immunoglobulin E–mediated
anaphylactic reactions and florid dermatologic reactions, such as Stevens-Johnson
syndrome. Hypersensitivity reactions are more commonly characterized by fever or a
maculopapular rash that develops 7 to 14 days after initiating the offending
agent. 2 There is no reliable skin test to
rule out or confirm sulfa allergy. There are important chemical differences between sulfa antibiotics and
nonantibiotics. Most authors agree that nonantibiotics are less likely to cause
severe reactions, and that the chemical differences between sulfa antibiotics and
nonantibiotics make true cross-reactivity extremely unlikely. 1-3 There is only one case
report in the literature of anaphylaxis caused by furosemide 4; the authors were unable to prove conclusively that the
allergen was in fact chemically related to the sulfa moiety. 5Perhaps the most reassuring evidence comes from Strom et al, 1 who elegantly turned the United Kingdom General Practice
Research Database into a retrospective cohort study (level II evidence) to show that
giving sulfa nonantibiotics to patients with a history of sulfa (antibiotic) allergy
carries little risk of cross-reactivity. The authors reviewed the charts of 969
patients who had had allergic reactions to sulfonamide antibiotics and of
19  257 patients who had not. All these patients subsequently received
sulfonamide nonantibiotics. For this study, “allergy” was defined very broadly and
included development of eczema and various unspecified adverse effects within a full
month of receiving the medication in question, making underreporting bias unlikely.
Although Strom and colleagues found that patients allergic to sulfonamide
antibiotics were more likely than nonallergic patients to react to sulfonamide
nonantibiotics (9.9% vs 1.1%), they also found that the rate of reaction was even
greater among patients allergic to penicillin who received sulfonamide
nonantibiotics (14.2%). Penicillins do not have a sulfonamide moiety, so the
researchers argued that any sulfonamide cross-reactivity appears predominantly
related to a greater predisposition to allergic reactions in general among patients
allergic to sulfonamide antibiotics, rather than to a specific sulfa
hypersensitivity. In our case, our patient’s previous reactions to “sulfa” drugs and
hydrochlorothiazide were not well documented, and neither she nor the pharmacist
could recall the specific nature of the reactions. Since the patient thought that
her reactions were serious, and because her allergy extended to both antibiotic and
nonantibiotic sulfonamides, I was compelled to find an alternative to furosemide. A look at Table 1 shows that most diuretic agents are sulfonamide derivatives. The only
diuretics that are not are the potassium-sparing diuretics (triamterene,
spironolactone, and amiloride) and ethacrynic acid. 6 At the time, the pharmacist informed me that they did not have any
ethacrynic acid in stock, so I chose amiloride. I realized that it did not have the
same natriuretic effect as ethacrynic acid, the agent of choice in this case, and
that she needed close follow-up as she was also taking an angiotensin-converting
enzyme inhibitor. Some might argue that spironolactone, a potassium-sparing agent
with strong anti-aldosterone activity, would be preferable based on the landmark
Randomized Aldactone Evaluation Study 7 that
showed improved survival among patients with severe (class III or IV) congestive
heart failure using it. My patient, however, did not have this degree of illness.
Several weeks after starting amiloride (10 mg by mouth daily), Mrs MacDonald
developed hyperkalemia (K+ = 6.3 mmol/L). By this time,
however, the pharmacy had received ethacrynic acid tablets, and my patient is now
doing well on this medication at a dose of 50 mg daily and is no longer complaining
of dyspnea or edema. This case and the literature review I did for it illustrate that, although
cross-reactivity between sulfa antibiotics and nonantibiotics is rare, certain
situations warrant prudence. A difficult decision would await her physician should
Mrs MacDonald’s condition deteriorate. Would furosemide continue to be
contraindicated if she developed acute pulmonary edema? After some reflection and
discussion with my patient, I believe that, considering her history of serious
reaction to hydrochlorothiazide, all possible alternatives should be explored before
using another sulfonamide diuretic, such as furosemide. Alternatives would include
using parenteral ethacrynic acid and a bilevel positive airway pressure mask. For most patients with sulfa allergy who have no history of life-threatening
reactions and are not allergic to more than one class of sulfonamides, however,
available evidence suggests that furosemide can be used safely in an emergency.
Further research that would help clinicians with this decision should include level
I evidence from a randomized controlled trial or at least a prospective study. When prescribing furosemide or other sulfonamide nonantibiotics to patients with
sulfa allergy, it would be prudent to administer a test dose, orally if possible and
in a monitored environment. Specialist consultation might also be helpful, as
several desensitization protocols for sulfonamides are described in the
literature. 2,8 A comprehensive approach to difficult cases involving sulfa
allergies is shown in . I asked Mrs MacDonald to obtain a MedicAlert bracelet and will refer her to an
allergist for advice regarding future use of diuretics in emergencies. Family
physicians need to be especially attentive to the relatively common scenario in
which a patient with a history of allergy to a sulfonamide antibiotic presents with
congestive heart failure. The presence of allergies to other sulfonamides and the
seriousness of these allergies, as well as the acuity of the patient’s presentation,
should all be taken into account when deciding on clinical management. Finally, the
most important lesson from this case might be that family physicians can have a
critical role in documenting and reporting allergic reactions properly and in
anticipating possible clinical dilemmas in patients with multiple drug
allergies. | • | Dr Ponka is an Assistant Professor and Unit Residency Program Director at
the Civic Campus site of the Department of Family Medicine at the
University of Ottawa in Ontario. |
1. Strom BL, Schinnar R, Apter AJ, Margolis DJ, Lautenbach E, Hennessy S, et al. Absence of cross-reactivity between sulfonamide antibiotics and
sulfonamide nonantibiotics. N Engl J Med. 2003;349:1628–1635. [PubMed] 2. Slatore CG, Tilles SA. Sulfonamide hypersensitivity. Immunol Allergy Clin N Am. 2004;24:477–490. 3. Johnson KK, Green DL, Rife JP, Limon L. Sulfonamide cross-reactivity: fact or fiction? Ann Pharmacother. 2005;39:290–301. [PubMed] 4. Hansbrough JR, Wedner HJ, Chaplin DD. Anaphylaxis to intravenous furosemide. J Allergy Clin Immunol. 1987;80:538–541. [PubMed] 5. Sullivan TJ, Blobstein SH. Cross-reactions among furosemide, hydrochlorothiazide, and
sulfonamides. JAMA. 1991;265:120–121. [PubMed] 6. Ives HE. Diuretic agents. In: Katzung BG, editor. Basic and clinical
pharmacology. 9th ed. New York, NY: Lange Basic Science; 2004. pp. 241–259. 7. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in
patients with severe heart failure. Randomized Aldactone Evaluation Study
Investigators. N Engl J Med. 1999;341:709–717. [PubMed] 8. Tilles SA. Practical issues in the management of hypersensitivity reactions:
sulfonamides. South Med J. 2001;94:817–824. [PubMed]
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