Abstract
Non-immediate cutaneous reactions (i.e., occurring at least 1 h after the initial drug administration), particularly maculopapular exanthemas and urticarial eruptions, are common during beta-lactam treatments. A T cell-mediated pathogenic mechanism has been demonstrated in some cutaneous reactions, such as maculopapular exanthema, fixed drug eruption, acute generalized exanthematous pustulosis, and drug-induced hypersensitivity syndrome. In the diagnostic work-up, patch testing is useful, together with delayed-reading intradermal testing. Patch tests are a simple and safe diagnostic tool, which in the case of severe reactions should be used as the first line of investigation. However, patch tests are less sensitive than intradermal tests, which are preferable in subjects with mild reactions. Lymphocyte transformation or activation tests and enzyme-linked immunosorbent spot assays can be used as complementary tests. In selected cases of mild or moderate reactions, displaying negative results in the aforesaid allergy tests, a graded challenge with the implicated beta-lactam can be performed.
Similar content being viewed by others
Abbreviations
- AGEP::
-
Acute generalized exanthematous pustulosis
- AX/CLAV::
-
Amoxicillin plus clavulanic acid
- BP-OL::
-
Benzylpenicilloyl-octa-L-lysine
- CADR::
-
Cutaneous adverse drug reaction(s)
- DiHS::
-
Drug-induced hypersensitivity syndrome
- DPT::
-
Drug provocation test(s)
- DRESS::
-
Drug reaction with eosinophilia and systemic symptoms
- ELISpot::
-
Enzyme-linked immunosorbent spot
- ENDA::
-
European network for drug allergy
- FDE::
-
Fixed drug eruption(s)
- IDT::
-
Intradermal test(s)
- LTT::
-
Lymphocyte transformation test(s)
- MD::
-
Minor determinant
- MDM::
-
Minor determinant mixture
- MPE::
-
Maculopapular exanthema(s)
- PPL::
-
Penicilloyl-poly-L-lysine
- PT::
-
Patch test(s)
- SDRIFE::
-
Symmetrical drug-related intertriginous and flexural exanthema
- SJS::
-
Stevens-Johnson syndrome
- SPT::
-
Skin prick test(s)
- ST::
-
Skin test(s)
- TEN::
-
Toxic epidermal necrolysis
References
Papers of particular interest, published recently, have been highlighted as: • Of importance•• Of major importance
Romano A, Quaratino D, Di Fonso M, Papa G, Venuti A, Gasbarrini G. A diagnostic protocol for evaluating nonimmediate reactions to aminopenicillins. J Allergy Clin Immunol. 1999;103:1186–90.
Romano A, Torres MJ, Castells M, Sanz ML, Blanca M. Diagnosis and management of drug hypersensitivity reactions. J Allergy Clin Immunol. 2011;127:S67–73.
Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International consensus on drug allergy. Allergy. 2014;69:420–37.
Hunziker T, Künzi UP, Braunschweig S, Zehnder D, Hoigné R. Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey. Allergy. 1997;52:388–93.
Bigby M. Rates of cutaneous reactions to drugs. Arch Dermatol. 2001;137:765–70.
Stern RS. Clinical practice. Exanthematous drug eruptions. N Engl J Med. 2012;366:2492–501.
Roujeau JC, Haddad C, Paulmann M, Mockenhaupt M. Management of nonimmediate hypersensitivity reactions to drugs. Immunol Allergy Clin N Am. 2014;34:473–87.
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;129:169–74.
Lammintausta K, Kortekangas-Savolainen O. The usefulness of skin tests to prove drug hypersensitivity. Br J Dermatol. 2005;152:968–74.
Romano A, Gaeta F, Valluzzi RL, Caruso C, Rumi G, Bousquet PJ. The very limited usefulness of skin testing with penicilloyl-polylysine and the minor determinant mixture in evaluating nonimmediate reactions to penicillins. Allergy. 2010;65:1104–7.
•• Romano A, Gaeta F, Valluzzi RL, Caruso C, Alonzi C, Viola M, et al. Diagnosing nonimmediate reactions to cephalosporins. J Allergy Clin Immunol. 2012;129:1166–9. The largest study that evaluated subjects with non-immediate reactions to cephalosporins by performing both intradermal tests and patch tests
Hjortlund J, Mortz CG, Skov PS, Bindslev-Jensen C. Diagnosis of penicillin allergy revisited: the value of case history, skin testing, specific IgE and prolonged challenge. Allergy. 2013;68:1057–64.
Macy E, Ngor EW. Safely diagnosing clinically significant penicillin allergy using only penicilloyl-poly-lysine, penicillin, and oral amoxicillin. J Allergy Clin Immunol Pract. 2013;1:258–63.
• Romano A, Gaeta F, Valluzzi RL, Alonzi C, Maggioletti M, Zaffiro A, et al. Absence of cross-reactivity to carbapenems in patients with delayed hypersensitivity to penicillins. Allergy. 2013;68:1618–21. This study demonstrates the tolerability of imipenem/cilastatin, meropenem, and ertapenem in 204 subjects with a T cell-mediated hypersensitivity to penicillins
•• Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Caruso C, Quaratino D. Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2016;138:179–86. This study demonstrates a rate of cross-reactivity between aminopenicillins and aminocephalosporins of around 20%, as well as the tolerability of aztreonam, cefuroxime, and ceftriaxone in more than 200 subjects with a T cell-mediated hypersensitivity to penicillins
•• Pinho A, Coutinho I, Gameiro A, Gouveia M, Gonçalo M. Patch testing—a valuable tool for investigating non-immediate cutaneous adverse drug reactions to antibiotics. J Eur Acad Dermatol Venereol. 2017;31:280–7.This large study emphasizes the diagnostic value of patch tests in evaluating non-immediate reactions to antibiotics, including beta-lactams.
Ponvert C, Perrin Y, Bados-Albiero A, Le Bourgeois M, Karila C, Delacourt C, et al. Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests. Pediatr Allergy Immunol. 2011;22:411–8.
Zambonino MA, Corzo JL, Muñoz C, Requena G, Ariza A, Mayorga C, et al. Diagnostic evaluation of hypersensitivity reactions to beta-lactam antibiotics in a large population of children. Pediatr Allergy Immunol. 2014;25:80–7.
Barni S, Mori F, Sarti L, Pucci N, Rossi EM, de Martino M, et al. Utility of skin testing in children with a history of non-immediate reactions to amoxicillin. Clin Exp Allergy. 2015;45:1472–4.
Atanaskovic-Markovic M, Gaeta F, Medjo B, Gavrovic-Jankulovic M, Cirkovic Velickovic T, Tmusic V, et al. Non-immediate hypersensitivity reactions to beta-lactam antibiotics in children—our 10-year experience in allergy work-up. Pediatr Allergy Immunol. 2016;27:533–8.
Gastaminza G, Audicana MT, Fernandez E, Anda M, Ansotegui IJ. Palmar exfoliative exanthema to amoxicillin. Allergy. 2000;55:510–1.
Häusermann P, Harr T, Bircher AJ. Baboon syndrome resulting from systemic drugs: is there strife between SDRIFE and allergic contact dermatitis syndrome? Contact Dermatitis. 2004;51:297–310.
Andrade P, Brinca A, Gonçalo M. Patch testing in fixed drug eruptions—a 20-year review. Contact Dermatitis. 2011;65:195–201.
Heinzerling LM, Tomsitz D, Anliker MD. Is drug allergy less prevalent than previously assumed? A 5-year analysis. Br J Dermatol. 2012;166:107–14.
Sidoroff A. Acute generalized exanthematous pustulosis. Chem Immunol Allergy. 2012;97:139–48.
Papay J, Yuen N, Powell G, Mockenhaupt M, Bogenrieder T. Spontaneous adverse event reports of Stevens-Johnson syndrome/toxic epidermal necrolysis: detecting associations with medications. Pharmacoepidemiol Drug Saf. 2012;21:289–96.
•• Barbaud A, Collet E, Milpied B, Assier H, Staumont D, Avenel-Audran M, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions. Br J Dermatol. 2013;168:555–62. The largest study demonstrating the diagnostic value and safety of drug patch tests in AGEP, DRESS, and SJS/TEN
Kardaun SH, Sekula P, Valeyrie-Allanore L, Liss Y, Chu CY, Creamer D, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169:1071–80.
Lin YF, Yang CH, Sindy H, Lin JY, Rosaline Hui CY, Tsai YC, et al. Severe cutaneous adverse reactions related to systemic antibiotics. Clin Infect Dis. 2014;58:1377–85.
Pinto Gouveia M, Gameiro A, Coutinho I, Pereira N, Cardoso JC, Gonçalo M. Overlap between maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms among cutaneous adverse drug reactions in a dermatology ward. Br J Dermatol. 2016;175:1274–83.
Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003;139:683–93.
Schrijvers R, Gilissen L, Chiriac AM, Demoly P. Pathogenesis and diagnosis of delayed-type drug hypersensitivity reactions, from bedside to bench and back. Clin Transl Allergy. 2015 Sep 3;5:31.
Shiohara T, Kano Y. A complex inter-action between drug allergy and viral infection. Clin Rev Allergy Immunol. 2007;33:124–33.
White KD, Chung WH, Hung SI, Mallal S, Phillips EJ. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response. J Allergy Clin Immunol. 2015;136:219–34.
Romano A, Warrington R. Antibiotic allergy. Immunol Allergy Clin N Am. 2014;34:489–506. vii
Torres MJ, Romano A, Celik G, Demoly P, Khan D, Macy E, et al. Approach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America. Clin Transl Allergy. 2017;7:7.
Barbaud A, Gonçalo M, Bruynzeel D, Bircher A, European Society of Contact Dermatitis. Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions. Contact Dermatitis. 2001;45:321–8.
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.
Romano A, Blanca M, Torres MJ, Bircher A, Aberer W, Brockow K, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy. 2004;59:1153–60.
Blanca M, Romano A, Torres MJ, Férnandez J, Mayorga C, Rodriguez J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy. 2009;64:183–93.
Barbaud A. Skin testing and patch testing in non-IgE-mediated drug allergy. Curr Allergy Asthma Rep. 2014;14:442.
Liippo J, Pummi K, Hohenthal U, Lammintausta K. Patch testing and sensitization to multiple drugs. Contact Dermatitis. 2013;69:296–302.
Torres MJ, Sánchez-Sabaté E, Alvarez J, Mayorga C, Fernández J, Padial A, et al. Skin test evaluation in nonimmediate allergic reactions to penicillins. Allergy. 2004;59:219–24.
Romano A, Viola M, Gaeta F, Rumi G, Maggioletti M. Patch testing in non-immediate drug eruptions. Allergy Asthma Clin Immunol. 2008;4:66–74.
Sala Cunill A, Labrador-Horrillo M, Guilarte M, Luengo O, Cardona V. Generalised delayed desquamative exanthema after intradermal testing with betalactam antibiotics. Allergy. 2011;66:702–3.
Brajon D, Menetre S, Waton J, Poreaux C, Barbaud A. Non-irritant concentrations and amounts of active ingredient in drug patch tests. Contact Dermatitis. 2014;71:170–5.
• Brockow K, Garvey LH, Aberer W, Atanaskovic-Markovic M, Barbaud A, Bilo MB, et al. Skin test concentrations for systemically administered drugs—an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 2013;68:702–12. A European position paper giving non-irritating concentrations of the main drugs responsible for hypersensitivity reactions
Romano A, Caubet JC. Antibiotic allergies in children and adults: from clinical symptoms to skin testing diagnosis. J Allergy Clin Immunol Pract. 2014;2:3–12.
Hjortlund J, Mortz CG, Skov PS, Eller E, Poulsen JM, Borch JE, et al. One-week oral challenge with penicillin in diagnosis of penicillin allergy. Acta Derm Venereol. 2012;92:307–12.
Demoly P, Romano A, Botelho C, Bousquet-Rouanet L, Gaeta F, Silva R, et al. Determining the negative predictive value of provocation tests with beta-lactams. Allergy. 2010;65:327–32.
Rozieres A, Hennino A, Rodet K, Gutowski MC, Gunera-Saad N, Berard F, et al. Detection and quantification of drug-specific T cells in penicillin allergy. Allergy. 2009;64:534–42.
Romano A, Di Fonso M, Pietrantonio F, Pocobelli D, Giannarini L, Del Bono A, et al. Repeated patch testing in delayed hypersensitivity to beta-lactam antibiotics. Contact Dermatitis. 1993;28:190.
Patriarca G, Schiavino D, Nucera E, Milani A. Positive allergological tests may turn negative with no further exposure to the specific allergen: a long-term, prospective, follow-up study in patients allergic to penicillin. J Investig Allergol Clin Immunol. 1996;6:162–5.
Romano A, Viola M, Bousquet PJ, Gaeta F, Valluzzi R, Caruso C, et al. A comparison of the performance of two penicillin reagent kits in the diagnosis of beta-lactam hypersensitivity. Allergy. 2007;62:53–8.
Pinho A, Marta A, Coutinho I, Gonçalo M. Long-term reproducibility of positive patch test reactions in patients with non-immediate cutaneous adverse drug reactions to antibiotics. Contact Dermatitis. 2017;76:204–9.
Aberer W, Bircher A, Romano A, Blanca M, Campi P, Fernandez J, et al. Drug provocation testing in the diagnosis of drug hypersensitivity: general considerations. Allergy. 2003;58:854–63.
• Mayorga C, Celik G, Rouzaire P, Whitaker P, Bonadonna P, Rodrigues-Cernadas J, et al. In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 2016;71:1103–34. A European position paper providing information on indications and limits of in vitro tests for evaluating subjects with hypersensitivity reactions to drugs
Schnyder B, Pichler WJ. Skin and laboratory tests in amoxicillin- and penicillin-induced morbilliform skin eruption. Clin Exp Allergy. 2000;30:590–5.
Luque I, Leyva L, José Torres M, Rosal M, Mayorga C, Segura JM, et al. In vitro T-cell responses to beta-lactam drugs in immediate and nonimmediate allergic reactions. Allergy. 2001;56:611–8.
Trautmann A, Seitz CS, Stoevesandt J, Kerstan A. Aminopenicillin-associated exanthem: lymphocyte transformation testing revisited. Clin Exp Allergy. 2014;44:1531–8.
Hari Y, Frutig-Schnyder K, Hurni M, Yawalkar N, Zanni MP, Schnyder B, et al. T cell involvement in cutaneous drug eruptions. Clin Exp Allergy. 2001;31:1398–408.
Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy. 2004;59:809–20.
Khalil G, El-Sabban M, Al-Ghadban S, Azzi S, Shamra S, Khalifé S, et al. Cytokine expression profile of sensitized human T lymphocytes following in vitro stimulation with amoxicillin. Eur Cytokine Netw. 2008;19:131–41.
Polak ME, Belgi G, McGuire C, Pickard C, Healy E, Friedmann PS, et al. In vitro diagnostic assays are effective during the acute phase of delayed-type drug hypersensitivity reactions. Br J Dermatol. 2013;168:539–49.
Tanvarasethee B, Buranapraditkun S, Klaewsongkram J. The potential of using enzyme-linked immunospot to diagnose cephalosporin-induced maculopapular exanthems. Acta Derm Venereol. 2013;93:66–9.
Solensky R, Khan DA, Bernstein IL, Bloomberg GR, Castells MC, et al. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105:259–73.
Torres MJ, Blanca M, Fernandez J, Romano A, Weck A, Aberer W, et al. Diagnosis of immediate allergic reactions to beta-lactam antibiotics. Allergy. 2003;58:961–72.
Bourke J, Pavlos R, James I, Phillips E. Improving the effectiveness of penicillin allergy de-labeling. J Allergy Clin Immunol Pract. 2015;3:365–34.e1.
Yesudian PD, King CM. Occupational allergic contact dermatitis from meropenem. Contact Dermatitis. 2001;45:53.
Noguerado-Mellado B, Pinto Fernández C, Pineda-Pineda R, Martínez Lezcano P, Álvarez-Perea A, De Barrio Fernández M. Cross-reactivity between carbapenems: two case reports. J Allergy Clin Immunol Pract. 2014;2:816–7.
Bonadonna P, Schiappoli M, Senna G, Passalacqua G. Delayed selective reaction to clavulanic acid: a case report. J Investig Allergol Clin Immunol. 2005;15:302–4.
Kamiya K, Kamiya E, Kamiya Y, Niwa M, Saito A, Natsume T, et al. Drug eruption to clavulanic acid with sparing of cellulitis-affecting site. Allergol Int. 2015;64:280–1.
Rubio M, Bousquet PJ, Gomes E, Romano A, Demoly P. Results of drug hypersensitivity evaluations in a large group of children and adults. Clin Exp Allergy. 2012;42:123–30.
Fox SJ, Park MA. Penicillin skin testing is a safe and effective tool for evaluating penicillin allergy in the pediatric population. J Allergy Clin Immunol Pract. 2014;2:439–44.
Caubet JC, Kaiser L, Lemaitre B, Fellay B, Gervaix A, Eigenmann PA. The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. J Allergy Clin Immunol. 2011;127:218–22.
Fernandez TD, Mayorga C, Ariza A, Corzo JL, Torres MJ. Allergic reactions to antibiotics in children. Curr Opin Allergy Clin Immunol. 2014;14:278–85.
Caubet JC, Frossard C, Fellay B, Eigenmann PA. Skin tests and in vitro allergy tests have a poor diagnostic value for bening skin rashes due to β-lactams in children. Pediatr Allergy Immunol. 2015;26:80–2.
Marrs T, Fox AT, Lack G, du Toit G. The diagnosis and management of antibiotic allergy in children: systematic review to inform a contemporary approach. Arch Dis Child. 2015;100:583–8.
Romano A, Gaeta F, Arribas Poves MF, Valluzzi RL. Cross-reactivity among beta-lactams. Curr Allergy Asthma Rep. 2016;16:24.
Phillips E, Knowles SR, Weber EA, Blackburn D. Cephalexin tolerated despite delayed aminopenicillin reactions. Allergy. 2001;56:790.
Trcka J, Seitz CS, Bröcker EB, Gross GE, Trautmann A. Aminopenicillin-induced exanthema allows treatment with certain cephalosporins or phenoxymethyl penicillin. J Antimicrob Chemother. 2007;60:107–11.
Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: a cohort study. J Allergy Clin Immunol. 2014;133:790–6.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Drs. Romano, Valluzzi, Caruso, Maggioletti, and Gaeta declare no conflicts of interest relevant to this manuscript.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Allergic Skin Diseases
Rights and permissions
About this article
Cite this article
Romano, A., Valluzzi, R.L., Caruso, C. et al. Non-immediate Cutaneous Reactions to Beta-Lactams: Approach to Diagnosis. Curr Allergy Asthma Rep 17, 23 (2017). https://doi.org/10.1007/s11882-017-0691-4
Published:
DOI: https://doi.org/10.1007/s11882-017-0691-4