Dermatology 2013;226:347-352

Cutaneous Adverse Drug Reaction to Oral Acetazolamide and Skin Tests

Jachiet M.a · Bellon N.b · Assier H.b · Amsler E.a · Gaouar H.a · Pecquet C.a · Bourrain J.L.c · Bégon E.d · Chosidow O.b, e · Francès C.a · Ingen-Housz-Oro S.b · Soria A.a
aDepartment of Dermatology and Allergology, AP-HP, Hôpital Tenon, Paris, bDepartment of Dermatology, AP-HP, Hôpital Henri Mondor, Créteil, cDepartment of Dermatology, Hôpital A. Michallon, Grenoble, dDepartment of Dermatology, Hôpital René Dubos, Pontoise, and eUniversité Paris-Est Créteil Val de Marne, Créteil, France
email Corresponding Author


 goto top of outline Key Words

  • Acetazolamide
  • Cutaneous adverse drug reactions
  • Skin tests

 goto top of outline Abstract

Background: Few cases of cutaneous adverse drug reactions (CADR) to oral acetazolamide, a non-antimicrobial sulfonamide, have been previously reported, and the interest of acetazolamide skin tests has never been studied. Objectives: We report a series of ten patients with oral acetazolamide CADR and skin tests. Patients and Methods: The files of ten patients with CADR secondary to oral acetazolamide prescribed for cataract surgery in most cases referred between 2001 and 2011 in four French dermatology and allergy departments were retrospectively reviewed. Skin tests with acetazolamide were performed in nine patients and twelve controls. Other sulfonamides were tested in five of ten patients. Results: Seven patients developed maculopapular exanthema and four had acute generalized exanthematous pustulosis. Patch tests were positive for 8/9 patients, prick tests for 2/4 and intradermal tests for 3/3. Patch and prick or intradermal test results were concordant in 2/3 positive subjects. Patch tests for other sulfonamides were negative, as were patch tests in controls. Conclusions: We report the largest series of CADR to oral acetazolamide (maculopapular exanthema or acute generalized exanthematous pustulosis). A drug eruption after cataract surgery should be investigated for accountability of acetazolamide. In view of this retrospective study, skin tests and particularly intradermal tests appear to be an important contribution to demonstrate accountability.

© 2013 S. Karger AG, Basel

goto top of outline Introduction

Acetazolamide is a carbonic anhydrase inhibitor that belongs to the sulfonamide class. Its chemical name is N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)-acetamide. Indications for oral acetazolamide are treatment of idiopathic intracranial hypertension, hypercapnia due to chronic obstructive pulmonary disease, prevention or treatment of postoperative intraocular pressure after cataract surgery and prophylaxis of acute mountain sickness.

Whereas antimicrobial sulfonamides, especially sulfamethoxazole-trimethoprim, are strongly associated with Stevens-Johnson syndrome and toxic epidermal necrolysis, cutaneous adverse drug reactions (CADR) due to acetazolamide are rare [1]. We report a series of 10 patients with CADR with oral acetazolamide and insist on the value of skin tests.


goto top of outline Patients and Methods

goto top of outline Patients

The files of patients referred for suspected CADR secondary to oral acetazolamide between 2001 and 2011 in four French dermatology and allergy departments (Tenon, Mondor, Grenoble and Pontoise Hospital) were retrospectively reviewed. All patients were recruited in dermatology and/or allergology departments (n = 7) or were referred by dermatologists belonging to the multicenter Dermato-Allergology Franco-Belgian Group (REVIDAL-GERDA) (n = 3). For each patient, the following clinical data were collected: age, sex, past history of CADR, concomitant medications, delay between acetazolamide intake and onset of eruption, clinical aspect of the CADR, treatment and evolution. All patients were contacted by phone 1-10 years after the CADR to investigate whether other sulfonamides had been taken since acetazolamide eruption.

goto top of outline Patch Tests, Prick Tests and Intradermal Tests

All skin tests were performed at least 2 months after skin adverse events. Acetazolamide patch tests were freshly prepared, with commercial acetazolamide (Diamox®, Sanofi, France), diluted at 30% in petrolatum. Test materials used were IQ Ultra Chambers or Finn Chambers (Destaing, France) covered on the upper back with Mefix® (Molnlycke Health Care, Sweden). The patches were removed on day 1 (D1) or day 2 (D2). Readings were performed between D1 and D4 according to clinical practice of each center and to the ICDRG criteria [2]. In comparison, 12 controls, i.e. 10 patients who had never received acetazolamide and 2 controls who had previously received acetazolamide without developing any reaction, were tested with acetazolamide patch tests.

Commercial preparations with acetazolamide were freshly prepared ‘as is' (10 mg/ml) for prick test, and diluted at 1 mg/ml in 0.9% sterile serum saline for intradermal tests. 0.04 ml was injected on the forearm with a negative (serum saline) and positive control (10 mg/ml histamine chlorhydrate). Prick and intradermal tests were read after 20 min, 2 and 4 days.

According to European guidelines on delayed readings, intradermal tests were considered positive when there was an infiltrated and erythematous reaction. To determine the absence of irritancy of positive patch tests, results from 12 controls tested with the same methods were performed with acetazolamide [3,4]. All other drugs used concomitantly by the patients were also tested.

This study received local institutional review board agreement.


goto top of outline Results

goto top of outline Patients

The main clinical characteristics of the patients are summarized in table 1. Seven patients developed maculopapular exanthema (MPE) and four patients had acute generalized exanthematous pustulosis (AGEP) (fig. 1). Patient 4 experienced first MPE 24 h after right eye cataract surgery with oral acetazolamide administration and AGEP 6 h after rechallenge of the drug, 10 days after, for left eye cataract surgery. Two patients had mucosal involvement, with oral (2/2) and nasal (1/2) ulcerations. In all cases except one, the time lag of appearance of the drug reaction was short, ranging from 6 to 48 h; for one patient it was 5 days. Two patients had a previous clinical history of skin adverse events with other drugs: patient 1 with venlafaxine, and patient 4 with sulfamethoxazole-trimethoprim and sulfadoxine-pyrimethamine. For the others, data about previous sensitization were missing. Six patients were treated with topical steroids and three patients with oral antihistamines. Three patients required systemic steroids due to severe mucosal or skin involvement. Time lag to recovery ranged between 5 days and 1 month. None of the patients contacted by phone had been rechallenged with sulfonamide after the CADR.

Table 1. Clinical characteristics of patients with CADR with oral acetazolamide

Fig. 1. AGEP (patient 9).

goto top of outline Skin Tests

Nine patients were tested with acetazolamide skin tests and were all positive (summarized in table 2).

Table 2. Skin test results with acetazolamide (patch tests, prick tests and intradermal tests) and others drugs

All skin tests were performed with a delay ranging from 8 weeks to 3 years after the CADR. Patch tests were read on D1 (1/9), D2 (6/9), D3 (1/9) or D5 (1/9). Other sulfonamides were tested in five of ten patients. Patch tests were performed in nine cases and were positive in eight cases: on D2 for six patients with an early reading on D1 for one of them, and on D3 and D5 for two patients.

Four patients also had prick test (10 mg/ml) and three patients had intradermal tests (0.01, 0.1 and 1 mg/ml). Prick tests were positive at late reading (D2) for two patients. Acetazolamide intradermal tests were positive on D1 in one case and on D2 and D4 in all three patients tested (fig. 2). Both the patch test and intradermal tests were positive in 2/3 patients. Patient 4 had a negative patch test with positive pustulosis prick and intradermal tests on D2 and D4.

Fig. 2.a Positive acetazolamide prick test (10 mg/ml). b, c Intradermal test (b 0.1 mg/ml, c 1 mg/ml) on D2 (patient 4).

No side effects or reactivation of the CADR were observed with skin tests. Patch tests for other sulfonamides were negative (patient 5, 6, 8 and 10). Furosemide prick and intradermal tests were negative (patient 2) on D2 and D4. Details concerning tests with other putative drugs and other sulfonamides are summarized in table 2.

A histological analysis of acetazolamide patch test on D2 (patient 2) showed an eczematous pattern characterized by dissociated epidermis with extensive spongiosis, keratinocytes necrosis and dermal perivascular inflammatory infiltrate (lymphocytes, eosinophils and neutrophils).

All other drugs concomitantly administrated with acetazolamide and other sulfonamides were tested and remained negative. All twelve control patients had negative acetazolamide patch tests.


goto top of outline Discussion

Only a few cases of CADR with oral acetazolamide have been previously reported [5,6,7] (table 3). All these cases were severe CADR (AGEP, Stevens-Johnson syndrome). Furthermore, some cases of contact dermatitis, either eczema or MPE, have been reported with topical acetazolamide [8]. We report herein a series of ten cases of CADR to oral acetazolamide, prescribed for cataract surgery in most cases (7/10), as a prevention of peri- and postoperative ocular hypertension. With the aging of the population, cataract surgery is more and more common. Consequently, even if not systematically recommended for that surgery, the use of systemic acetazolamide is expected to increase, and ophthalmologists should be aware of the risk of some severe CADR with this drug.

Table 3. Previously published cases of CADR to acetazolamide

Most of the patients developed the CADR within a short time after acetazolamide intake, while there were no data about previous exposure, and four patients had a clinical presentation of typical AGEP.

Eight patients had positive patch tests for the putative drug. As previously reported, patch tests are frequently positive in AGEP, especially with numerous causative drugs as antibiotics, immunosuppressive therapies and analgesics [9,10]. To our knowledge no positive patch test has been reported with acetazolamide.

Even though the sensitivity of patch tests in AGEP seems to be high, up to 50% in the study by Wolkenstein et al. [11], the sensitivity of skin tests and especially prick and intradermal tests with delayed reading is unknown. Moreover the diagnostic value of acetazolamide skin tests is unknown. In our series, the patient who experienced two episodes of CADR due to acetazolamide had positive delayed prick and intradermal test results with local pustulosis. According to our results, we could hypothesize that delayed reading intradermal tests are sensitive to diagnose delayed hypersensitivity to acetazolamide as already reported for others drugs [12]. None of our patients experienced a relapse of the cutaneous eruption secondary to the skin tests. Positive patch tests seem to be specific regarding the negative results observed in the control group.

Cross-reactivity between antimicrobial and non-antimicrobial sulfonamides has already been discussed; some studies conclude to a predisposition to allergic reactions rather than to a cross-reactivity between sulfonamide-based drugs [13,14,15]. In our cases, one patient (patient 4) had a history of CADR with two sulfonamide family drugs, sulfamethoxazole-trimethoprim and sulfadoxine-pyrimethamine, but no test has been performed with these drugs in this patient. As regards this case, we should remain cautious, especially for drugs that may be responsible for severe CADR such as AGEP or Stevens-Johnson/Lyell syndrome.

Although no immune-mediated mechanism has been shown for this hypersensitivity, it has been hypothesized that the arylamine group, present in antimicrobial sulfonamide, is critical in producing hypersensitivity reactions [16]. Only few cases have been documented with cross-reactivity between sulfonamide medications [17].

However, for all other patients who were tested with a wide spectrum of other sulfonamides and who had never previously received those drugs, results were negative. We did not contraindicate sulfonamides other than acetazolamide to these patients. In contrast, all forms of acetazolamide (oral and eye drops) were definitively contraindicated.


goto top of outline Conclusion

We report the largest series of CADR, MPE and AGEP, to oral acetazolamide. Skin tests and particularly intradermal tests with acetazolamide were useful to confirm the diagnosis either by patch test and if negative by intradermal test with delayed readings. A drug eruption after cataract surgery should be investigated for the accountability of acetazolamide. In view of this retrospective study, skin tests appeared to be an important contribution to demonstrate accountability. Cross-reactivity between acetazolamide and other sulfonamide drugs remains to be evaluated.


goto top of outline Disclosure Statement

The authors declare no conflicts of interest.

 goto top of outline References
  1. Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al: Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333:1600-1607.
  2. Wilkinson DS, Fregert S, Magnusson B, Bandmann HJ, Calnan CD, Cronin E, et al: Terminology of contact dermatitis. Acta Derm Venereol 1970;50:287-292.

    External Resources

  3. Barbaud A, Gonçalo M, Bruynzeel D, Bircher A: Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions. Contact Dermatitis 2001;45:321-328.
  4. Brockow K, Romano A, Blanca M, Ring J, Pichler W, Demoly P: General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 2002;57:45-51.
  5. Ogasawara K, Tomitsuka N, Kobayashi M, Komoribayashi N, Fukuda T, Saitoh H, et al: Stevens-Johnson syndrome associated with intravenous acetazolamide administration for evaluation of cerebrovascular reactivity. Case report. Neurol Med Chir (Tokyo) 2006;46:161-163.
  6. Sud RN, Grewal SS: Stevens Johnson syndrome due to Diamox. Indian J Ophthalmol 1981;29:101-103.

    External Resources

  7. Ogoshi M, Yamada Y, Tani M: Acute generalized exanthematic pustulosis induced by cefaclor and acetazolamide. Dermatology 1992;184:142-144.
  8. Daveluy A, Vial T, Marty L, Miremont-Salamé G, Moore N, Haramburu F: Contact dermatitis caused by acetazolamide under occlusion (in French). Presse Med 2007;36:1756-1758.

    External Resources

  9. De Thier F, Blondeel A, Song M: Acute generalized exanthematous pustulosis induced by amoxycillin with clavulanate. Contact Dermatitis 2001;44:114-115.
  10. Barbaud A: Drug patch tests in the investigation of cutaneous adverse drug reactions (in French). Ann Dermatol Venereol 2009;136:635-644.
  11. Wolkenstein P, Chosidow O, Fléchet ML, Robbiola O, Paul M, Dumé L, et al: Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis 1996;35:234-236.
  12. Romano A, Viola M, Mondino C, Pettinato R, Di Fonso M, Papa G, et al: Diagnosing nonimmediate reactions to penicillins by in vivo tests. Int Arch Allergy Immunol 2002;129:169-174.
  13. 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.
  14. Hoigné R, Schlumberger HP, Vervloet D, Zoppi M: Epidemiology of allergic drug reactions. Monogr Allergy 1993;31:147-170.

    External Resources

  15. Johnson KK, Green DL, Rife JP, Limon L: Sulfonamide cross-reactivity: fact or fiction? Ann Pharmacother 2005;39:290-301.
  16. Tilles SA: Practical issues in the management of hypersensitivity reactions: sulfonamides. South Med J 2001;94:817-824.

    External Resources

  17. Knowles S, Shapiro L, Shear NH: Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of ‘sulfa' allergy. Drug Saf 2001;24:239-247.

 goto top of outline Author Contacts

Dr. Angèle Soria
Department of Dermatology and Allergology, Hôpital Tenon - AP-HP
4 rue de la Chine
FR-75020 Paris (France)

 goto top of outline Article Information

M. Jachiet and N. Bellon contributed equally to this work. C. Pecquet and J.L. Bourrain are members of the Dermato-Allergology Franco-Belgian Group (REVIDAL-GERDA).

Received: January 21, 2013
Accepted after revision: March 18, 2013
Published online: June 29, 2013
Number of Print Pages : 6
Number of Figures : 2, Number of Tables : 3, Number of References : 17

 goto top of outline Publication Details


Vol. 226, No. 4, Year 2013 (Cover Date: September 2013)

Journal Editor: Saurat J.-H. (Geneva)
ISSN: 1018-8665 (Print), eISSN: 1421-9832 (Online)

For additional information:

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.