From the CLINIcAL InQUiRiES Family Physicians Inquiries Network Ron Healy, MD University of Washington, Which diuretics are safe Seattle; Alaska Family Medicine Residency, Anchorage and effective for patients Terry Ann Jankowski, MLS University of Washington, Seattle with a sulfa allergy? Evidence-based answer Diuretics that do not contain a sulfonamide subsequent allergic reactions to commonly group (eg, amiloride hydrochloride, used sulfonamide-containing diuretics eplerenone, ethacrynic acid, spironolactone, (eg, carbonic anhydrase inhibitors, loop and triamterene) are safe for patients with an diuretics, and thiazides) (strength of allergy to sulfa. The evidence is contradictory recommendation: C, based on case series ® as to whether a history Dowdenof allergy to Healthand poor Media quality case-control and cohort sulfonamide antibiotics increases the risk of studies). Copyright Clinical commentaryFor personal use only Are all sulfa drugs created equal? agents and off-patent, with no company Historical bromides commonly fall by the to take up their cause, no one has been FAST TRACK wayside as better evidence becomes willing to challenge outdated package Reasonable available. Who would have thought 15 insert warnings. years ago that we would be promoting As clinicians who regularly work evidence supports beta-blockers for patients with congestive without a net, we are accustomed to what many of us heart failure? prescribing medications in less than ideal are doing: Using Likewise, with closer inspection, we circumstances. Thankfully, reasonable cheap thiazides have learned that not all sulfa drugs are evidence is available to support what many created equal. The stereospecificity due of us are already doing—using cheap for patients to the absence of aromatic amines in thiazides for patients despite a history of with a history common diuretics means they are safe sulfa allergy. for patients with known sulfa antibiotic Brian Crownover, MD, FAAFP of sulfa allergy 96 MDG Family Medicine Residency, allergies. Given that diuretics are older Eglin Air Force Base, Fla z Evidence summary hydrochlorothiazide, and indapamide). Little research has been performed Hypersensitivity reactions occur when on sulfonamide antibiotic and sulfon- the aromatic amine group is oxidized amide diuretic allergic cross-reactivity. into hydroxylamine metabolites by the What we do know is that there are 2 liver. Sulfonamides that do not contain classes of sulfonamides—those with an this aromatic amine group undergo dif- aromatic amine (the antimicrobial sul- ferent metabolic pathways, suggesting fonamides) and those without (eg, the that allergic reactions that do occur in diuretics acetazolamide, furosemide, this group are not due to cross-reactivity 488 VOL 56, NO 6 / JUnE 2007 THE JOURNAL OF FAMILY PRACtICE For mass reproduction, content licensing and permissions contact Dowden Health Media. Diuretics for patients with sulfa allergy in sulfa-allergic patients. But that point When the results were adjusted for is far from settled by the research. age, sex, history of asthma, use of medi- cations for asthma or corticosteroids, the On one side, a large cohort study adjusted odds ratio for individuals ex- shows some cross-reactivity periencing an allergy to a nonantibiotic A large retrospective cohort study us- sulfonamide in those persons with a his- ing Britain’s General Practice Research tory of allergy to a sulfonamide antibiotic Database identified 20,226 patients seen was 2.8 (95 % CI, 2.1–3.7). Of note, the from 1987 through March 1999 who adjusted odds ratio for the occurrence were prescribed a systemic sulfonamide of a penicillin allergy in a patient with a antibiotic, and then at least 60 days later history of sulfonamide antibiotic allergy received a nonantibiotic sulfonamide (eg, was significantly higher at 3.9 (95% CI, thiazide diuretic, furosemide, oral hypo- 3.5–4.3). glycemic).1 Researchers reviewed records Some limitations of the study includ- to determine whether patients described ed uncertainty of cause and effect of pre- as having an allergic reaction to a sulfon- scribed medications and subsequent reac- amide antibiotic were at increased risk of tions, possible inconsistency of physician having a subsequent allergic reaction to diagnosis and coding, and lack of precision a sulfonamide nonantibiotic. in the diagnosis of allergic reactions. There Patients were identified as being al- is also the possibility of “suspicion bias,” lergic using both narrow definitions where patients with a history of allergies (anaphylaxis, bronchospasm, urticaria, may be more closely monitored for subse- laryngospasm, or angioedema) and quent reactions than nonallergic patients. broad ones. As only 18 patients out of the 20,226 patients were reported as On the other side, small studies having an allergic reaction using the nar- reveal little risk of cross-reaction row definition, analysis was based on Researchers involved in a retrospective the broad definition. Added to the broad study of 363 hospital charts examined category were asthma, eczema, and oth- 34 patients with a self-reported history of FAST TRACK er “adverse” drug effects that were not sulfa allergy who were subsequently giv- The odds of specified by the author. en acetazolamide (a carbonic anhydrase Using this broad definition, research- inhibitor), furosemide (a loop diuretic), an allergy to ers identified allergies to sulfonamide an- or both.2 The nature of the self-reported a nonantibiotic tibiotics in 969 patients. Of this group, 96 sulfa allergic reaction was documented sulfonamide more patients (9.9%) had a subsequent reaction in 79% of the 34 patients. These re- than doubled to a sulfonamide nonantibiotic, which in- ported reactions included urticarial rash, cluded drugs from the loop and thiazide nonspecified rash, dyspnea, swelling, if the patient had diuretic classes (including bumetanide, nausea or vomiting, throat swelling, red a history of allergy chlorothiazide, furosemide, hydrochloro- eyes, and bullae. Two patients who were to a sulfonamide thiazide, indapamide, and torsemide). It given acetazolamide developed urticaria. was unclear if any patients taking a car- No allergic reactions occurred for those antibiotic bonic anhydrase inhibitor experienced patients given furosemide. an allergic reaction. For comparison pur- The researchers concluded that there poses, of the 19,257 patients who were was little clinical or pharmacological not identified as having an allergy to a evidence to suggest that a self-reported sulfonamide antibiotic, again using the sulfa allergy was likely to produce a life- broad definition, 315 (1.6%), had a sub- threatening cross-reaction with acetazol- sequent allergic reaction to a sulfonamide amide or furosemide. Small numbers and nonantibiotic, for an unadjusted odds ra- the lack of a standard definition for an tio of 6.6 (95% confidence interval [CI], allergic reaction limited the strength of 5.2–8.4). their conclusion. C O NTIN UE D www.jfponline.com VOL 56, NO 6 / JUnE 2007 489 ES i R i QU n I A small single-blind study of 28 pa- A literature review of Medline from tients with a history of fixed drug erup- 1966 to early 2004 revealed 21 case se- AL c tion to sulfonamide antibiotics examined ries, case reports, and “other articles” the usefulness of patch testing as an al- that evaluated the presence of cross-reac- ternative to controlled oral challenge test- tivity.4 When the authors of this literature CLINI ing.3 Before patch testing, a sulfonamide reviewed drilled down to diuretics, they antibiotic allergy was confirmed by each found 5 case reports for cross-reactivity patient with an oral challenge of sulfa- to acetazolamide, 2 case reports for furo- methoxazole, sulfadiazine, or sulfameth- semide, 1 case series, and 2 case reports azole. Potential cross-reactivity to several for indapamide (a thiazide diuretic). nonantibiotic sulfonamides (including After reviewing the studies, the authors furosemide) was also investigated using concluded that little evidence suggested a controlled oral challenge testing of these problem with cross-reactivity either with agents. Every patient tolerated a subse- acetazolamide or furosemide and that quent oral challenge with furosemide. there may be an association of cross- reactivity between sulfonamide antibi- Literature reviews limited otics and indapamide. This study was by small numbers limited by its small numbers and lack of Two literature reviews examined the small explicit critical appraisal. number of case series, case reports, and In another literature review—in “other articles” and concluded little evi- which the main focus was cross-reac- dence supports the presence of cross-re- tivity between sulfonamide antibiotics activity between sulfonamide antibiotics and celecoxib—the authors concluded and non-sulfonamide antibiotics.4,5 These that little evidence supported definitive reviews were limited by their search crite- cross-reactivity between sulfonamide ria and lack of explicit critical appraisal. antibiotics and diuretics.5 The limita- tions of this study were similar to those of the previous study. Recommendations from others The manufacturer insert for furosemide states, under the heading “General Pre- cautions,” that “patients allergic to sul- fonamides may also be allergic to furo- semide.”6 A similar warning occurs for hydrochlorothiazide under the heading “Contraindications.”7 n References 1. Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics