Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Penicillin allergy: Delayed hypersensitivity reactions

Roland Solensky, MD
Section Editor
N Franklin Adkinson, Jr, MD
Deputy Editor
Anna M Feldweg, MD


Penicillins are the medications to which allergy is most commonly reported. Penicillin allergy in all of its forms is self-reported by about 5 to 10 percent of patients [1-3]. Many of these patients have delayed forms of hypersensitivity, which typically begin more than six hours after the last administered dose and often after days of treatment. The epidemiology, risk factors, diagnosis, and management of the most common types of delayed reactions to penicillins will be discussed here.


A drug allergy (or hypersensitivity) reaction is defined as a specific immunologic reaction to a drug. The classification and pathogenesis of drug allergies are discussed in detail separately. (See "Drug allergy: Classification and clinical features" and "Drug allergy: Pathogenesis".)

The World Allergy Organization (WAO) has recommended categorizing immunologic drug reactions based upon the timing of the appearance of symptoms [4]. This system defines two general types of reactions: immediate and delayed.

Immediate reactions – Immediate reactions classically begin within one hour of the initial dose in a course or within one hour of the last administered dose. Symptoms may appear slightly later if the drug was administered orally or taken with food so that absorption is slowed. Nevertheless, the period of one hour identifies many of these reactions. When allergic sensitization first develops, the initial symptoms may appear during the latter days of treatment (ie, not following the first dose of the course) but usually within one hour of the last administered dose and then escalate rapidly. Immediate reactions to penicillins are often immunoglobulin E (IgE)-mediated, and signs and symptoms reflect widespread activation of mast cells (table 1). (See "Penicillin allergy: Immediate reactions".)

Delayed (nonimmediate) reactions – Delayed (nonimmediate) reactions usually appear after more than one dose of drug and typically after days of treatment. For example, delayed cutaneous maculopapular eruptions to amoxicillin classically start on day 7 to 10 of treatment and may even begin 1 to 3 days after cessation of treatment. The symptoms typically begin several hours after the last administered dose, although the timing relative to the last administered dose is variable. However, symptoms should not begin within one hour of the initial dose of a medication. There are different mechanisms underlying various forms of delayed reactions, but they are not IgE-mediated.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Aug 31, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Lee CE, Zembower TR, Fotis MA, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med 2000; 160:2819.
  2. Park M, Markus P, Matesic D, Li JT. Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy Asthma Immunol 2006; 97:681.
  3. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol 2010; 105:259.
  4. Demoly P, Adkinson NF, Brockow K, et al. International Consensus on drug allergy. Allergy 2014; 69:420.
  5. Blanca-López N, Zapatero L, Alonso E, et al. Skin testing and drug provocation in the diagnosis of nonimmediate reactions to aminopenicillins in children. Allergy 2009; 64:229.
  6. Romano A, Blanca M, Torres MJ, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy 2004; 59:1153.
  7. Cohen AD, Friger M, Sarov B, Halevy S. Which intercurrent infections are associated with maculopapular cutaneous drug reactions? A case-control study. Int J Dermatol 2001; 40:41.
  8. Bass JW, Crowley DM, Steele RW, et al. Adverse effects of orally administered ampicillin. J Pediatr 1973; 83:106.
  9. Ibia EO, Schwartz RH, Wiedermann BL. Antibiotic rashes in children: a survey in a private practice setting. Arch Dermatol 2000; 136:849.
  10. Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256:3358.
  11. Arndt KA, Jick H. Rates of cutaneous reactions to drugs. A report from the Boston Collaborative Drug Surveillance Program. JAMA 1976; 235:918.
  12. Caubet JC, Kaiser L, Lemaître B, et al. The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. J Allergy Clin Immunol 2011; 127:218.
  13. Mirakian R, Leech SC, Krishna MT, et al. Management of allergy to penicillins and other beta-lactams. Clin Exp Allergy 2015; 45:300.
  14. Yawalkar N. Drug-induced exanthems. Toxicology 2005; 209:131.
  15. Segal AR, Doherty KM, Leggott J, Zlotoff B. Cutaneous reactions to drugs in children. Pediatrics 2007; 120:e1082.
  16. Shear NH, Knowles SR, Shapiro L. Cutaneous reactions to drugs. In: Fitzpatrick's Dermatology in General Medicine, 7th ed, Wolff K, Goldsmith LA, Katz SI, et al (Eds), McGraw Hill, New York 2008. p.355.
  17. Solensky R. Drug desensitization. Immunol Allergy Clin North Am 2004; 24:425.
  18. Patel BM. Skin rash with infectious mononucleosis and ampicillin. Pediatrics 1967; 40:910.
  19. Pirmohamed M, Park BK. HIV and drug allergy. Curr Opin Allergy Clin Immunol 2001; 1:311.
  20. Park BK, Pirmohamed M, Kitteringham NR. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol 1992; 34:377.
  21. Mayorga C, Celik G, Rouzaire P, et al. In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2016; 71:1103.
  22. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331:1272.
  23. Ponvert C, Weilenmann C, Wassenberg J, et al. Allergy to betalactam antibiotics in children: a prospective follow-up study in retreated children after negative responses in skin and challenge tests. Allergy 2007; 62:42.
  24. Mattheij M, de Vries E. A suspicion of antibiotic allergy in children is often incorrect. J Allergy Clin Immunol 2012; 129:583; author reply 583.
  25. Mori F, Cianferoni A, Barni S, et al. Amoxicillin allergy in children: five-day drug provocation test in the diagnosis of nonimmediate reactions. J Allergy Clin Immunol Pract 2015; 3:375.
  26. Mill C, Primeau MN, Medoff E, et al. Assessing the Diagnostic Properties of a Graded Oral Provocation Challenge for the Diagnosis of Immediate and Nonimmediate Reactions to Amoxicillin in Children. JAMA Pediatr 2016; 170:e160033.
  27. Vyles D, Adams J, Chiu A, et al. Allergy Testing in Children With Low-Risk Penicillin Allergy Symptoms. Pediatrics 2017; 140.
  28. Vyles D, Chiu A, Simpson P, et al. Parent-Reported Penicillin Allergy Symptoms in the Pediatric Emergency Department. Acad Pediatr 2017; 17:251.
  29. Confino-Cohen R, Rosman Y, Meir-Shafrir K, et al. Oral Challenge without Skin Testing Safely Excludes Clinically Significant Delayed-Onset Penicillin Hypersensitivity. J Allergy Clin Immunol Pract 2017; 5:669.
  30. Hjortlund J, Mortz CG, Skov PS, et al. One-week oral challenge with penicillin in diagnosis of penicillin allergy. Acta Derm Venereol 2012; 92:307.
  31. Coskey RJ, Bryan HG. Letter: Fixed drug eruption due to penicillin. Arch Dermatol 1975; 111:791.
  32. Santosa A, Teo BW, Shek LP. Fixed drug eruption caused by piperacillin-tazobactam. J Investig Allergol Clin Immunol 2013; 23:132.
  33. Ponce Guevara LV, Yges EL, Gracia Bara MT, et al. Fixed drug eruption due to amoxicillin and quinolones. Ann Allergy Asthma Immunol 2013; 110:61.
  34. Pérez-Ezquerra PR, Sanchez-Morillas L, Alvarez AS, et al. Fixed drug eruption caused by amoxicillin-clavulanic acid. Contact Dermatitis 2010; 63:294.
  35. Rahman MH. Fixed drug eruption in Bangladeshi population: confirmed by provocative test. Int J Dermatol 2014; 53:255.
  36. Matsumoto Y, Okubo Y, Yamamoto T, et al. Case of acute generalized exanthematous pustulosis caused by ampicillin/cloxacillin sodium in a pregnant woman. J Dermatol 2008; 35:362.
  37. Talati S, Lala M, Kapupara H, Thet Z. Acute generalized exanthematous pustulosis: a rare clinical entity with use of piperacillin/tazobactam. Am J Ther 2009; 16:591.
  38. Riten K, Shahina Q, Jeannette J, Palma-Diaz MF. A severe case of acute generalized exanthematous pustulosis (AGEP) in a child after the administration of amoxicillin-clavulanic acid: brief report. Pediatr Dermatol 2009; 26:623.
  39. Jurado-Palomo J, Cabañas R, Prior N, et al. Use of the lymphocyte transformation test in the diagnosis of DRESS syndrome induced by ceftriaxone and piperacillin-tazobactam: two case reports. J Investig Allergol Clin Immunol 2010; 20:433.
  40. Ferrandiz-Pulido C, Garcia-Patos V. A review of causes of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Arch Dis Child 2013; 98:998.
  41. Tatum AJ, Ditto AM, Patterson R. Severe serum sickness-like reaction to oral penicillin drugs: three case reports. Ann Allergy Asthma Immunol 2001; 86:330.
  42. Clark BM, Kotti GH, Shah AD, Conger NG. Severe serum sickness reaction to oral and intramuscular penicillin. Pharmacotherapy 2006; 26:705.
  43. Linares T, Fernández A, Soto MT, et al. Drug fever caused by piperacillin-tazobactam. J Investig Allergol Clin Immunol 2011; 21:250.