Antibiotic allergies – what are the guidelines?

The following are some helpful guidelines regarding antibiotic allergies. Antibiotic allergies are commonly reported by patients and are often misunderstood. This misunderstanding can lead to overuse, over-broaden, or use of classes with greater cost or toxicity. These revealing facts published by the American Academy of Allergy, Asthma and Immunology can help avoid some of those situations.

Major Recommendations

β-Lactam Antibiotics


  • Approximately 10% of patients report a history of penicillin allergy, but after complete evaluation, up to 90% of these individuals are able to tolerate penicillins. (B)
  • Treatment of patients assumed to be penicillin allergic with alternate broad-spectrum antibiotics may compromise optimal medical care by leading to multiple drug-resistant organisms, higher costs, and increased toxic effects. (C)
  • Evaluation of patients with penicillin allergy by skin testing leads to reduction in the use of broad-spectrum antibiotics and may decrease costs. (B)
  • The rate of penicillin-induced anaphylaxis after parenteral administration is approximately 1 to 2 per 10,000 treated patients. (C)
  • Penicillin is immunologically inert and haptenates proteins after undergoing spontaneous conversion under physiologic conditions to reactive intermediates. These transformation products are known as penicillin major and minor antigenic determinants. (C)
  • Penicillin skin testing is the most reliable method for evaluating IgE-mediated penicillin allergy. (B) Ideally, penicillin skin testing should be performed with both major and minor determinants. The negative predictive value of penicillin skin testing for immediate reactions approaches 100%, whereas the positive predictive value is between 40% and 100%. (B)
  • Skin testing with the major determinant and penicillin G only (without penicilloate or penilloate) may miss up to 20% of allergic patients, but data on this are conflicting. (C)
  • Penicillin G left in solution (“aged” penicillin) does not spontaneously degrade to form antigenic determinants and has no role in penicillin skin testing. (B)
  • Penicillin skin testing without the major determinant is not recommended because this would fail to identify many patients with penicillin specific IgE antibodies. (B)
  • When performed by skilled personnel using proper technique, serious reactions due to penicillin skin testing are extremely rare.(C)
  • Penicillin skin testing may be performed electively—when patients are well and not in immediate need of antibiotic therapy. Alternatively, penicillin skin testing may be performed when treatment with a penicillin compound is contemplated. (D)
  • Patients who have had negative skin test results to penicillin major and minor determinants may receive penicillin with minimal risk of an IgE-mediated reaction. Depending on the reaction history, the first dose may need to be given via graded challenge. (D)
  • Penicillin skin test–positive patients should avoid penicillin, but if they develop an absolute need for penicillin, rapid induction of drug tolerance may be performed. (B)
  • Resensitization after treatment with oral penicillin is rare, and therefore penicillin skin testing does not routinely need to be repeated in patients with a history of penicillin allergy who have tolerated 1 or more courses of oral penicillin. (B)
  • Resensitization after treatment with parenteral penicillin appears to be higher than for oral treatment, and therefore repeat penicillin skin testing may be considered in patients with a history of penicillin allergy who have tolerated a course of parenteral penicillin. (C)
  • The negative predictive value of penicillin skin testing without [penicilloyl-polylysine] is poor because many allergic patients show skin test reactivity only to the major determinant. (B)
  • When penicillin skin testing is unavailable, evaluation of penicillin allergy is based on the reaction history and likelihood of needing treatment with penicillins. (C)
  • Patients with a vague and/or distant history of penicillin allergy may be candidates to receive penicillins via graded challenge. Patients with recent or convincing reaction histories should only receive penicillins via rapid induction of drug tolerance. (C)
  • The usefulness of in vitro tests for penicillin specific IgE is limited by their uncertain predictive value. They are not suitable substitutes for penicillin skin testing. (C)

Ampicillin and Amoxicillin

  • Some patients with immediate-type reactions to amoxicillin and ampicillin have IgE antibodies directed at the R-group side chain (rather than the core penicillin determinants) and are able to tolerate other penicillin class compounds. (C)
  • Amoxicillin and ampicillin are associated with the development of a delayed maculopapular rash in approximately 5% to 10% of patients. (C) These reactions are not related to IgE-mediated allergy, and they are postulated in many cases to require the presence of a concurrent viral infection or another underlying illness. (D)


  • The overall reaction rate to cephalosporins is approximately 10-fold lower than it is for penicillin. (C)
  • Most hypersensitivity reactions to cephalosporins are probably directed at the R-group side chains rather than the core β-lactam portion of the molecule. (D)
  • Skin testing with native cephalosporins is not standardized, but a positive skin test result using a nonirritating concentration suggests the presence of drug specific IgE antibodies. (D) A negative skin test result does not rule out an allergy because the negative predictive value is unknown. (D)
  • Patients with a history of an immediate-type reaction to 1 cephalosporin should avoid cephalosporins with similar R-group side chains. (D) Treatment with cephalosporins with dissimilar side chains may be considered, but the first dose should be given via graded challenge or induction of drug tolerance, depending on the severity of the previous reaction. (D)
  • Cephalosporins and penicillins share a common β-lactam ring structure and moderate cross-reactivity has been documented in vitro. (B)

Cephalosporin Administration to Patients with a History of Penicillin Allergy

  • Since 1980, studies show that approximately 2% of penicillin skin test–positive patients react to treatment with cephalosporins, but some of these reactions may be anaphylactic reactions. (C)
  • Without preceding penicillin skin testing, cephalosporin treatment of patients with a history of penicillin allergy, selecting out those with severe reaction histories, [shows] a reaction rate of 0.1% based on recent studies. (C)
  • Penicillin skin testing, when available, should be considered before administration of cephalosporins in patients with a history of penicillin allergy. (E)
  • Patients who have a history of a possible IgE-mediated reaction to penicillin, regardless of the severity of the reaction, may receive cephalosporins with minimal concern about an immediate reaction if skin test results for penicillin major and minor determinants are negative. (B)
  • Treatment options for penicillin skin test–positive patients include (1) administration of an alternate (non–β-lactam) antibiotic, (2) administration of cephalosporin via graded challenge, or (3) administration of cephalosporin via rapid induction of drug tolerance.(E)
  • Skin testing to the cephalosporin followed by graded challenge appears to be a safe method for administration of some cephalosporins in penicillin allergic patients. (B)
  • If penicillin and cephalosporin skin testing is unavailable, depending on the reaction history, cephalosporins may need to be given via graded challenge or rapid induction of drug tolerance. (E)

Penicillin Administration to Patients with a History of Cephalosporin Allergy

  • Patients allergic to amoxicillin should avoid cephalosporins with identical R-group side chains (cefadroxil, cefprozil, cefatrizine) or receive them via rapid induction of drug tolerance. (C) Similarly, patients allergic to ampicillin should avoid cephalosporins and carbacephems with identical R-group side chains (cephalexin, cefaclor, cephradine, cephaloglycin, loracarbef) or receive them via rapid induction of drug tolerance. (C)
  • Patients with a history of an immediate-type reaction to a cephalosporin should undergo penicillin skin testing, if available, before treatment with penicillin. (E) If test results are negative, they may safely receive penicillins. (B) If test results are positive, an alternate drug should be used or they should undergo rapid penicillin induction of drug tolerance. (B) If penicillin skin testing is unavailable, penicillin may be administered via cautious graded challenge. (C)

Monobactams (Aztreonam)

  • Aztreonam is less immunogenic than penicillin and cephalosporins, and clinical allergic reactions to aztreonam are less common than other β-lactam antibiotics. (C)
  • Aztreonam does not cross-react with other β-lactams except for ceftazidime, with which it shares an identical R-group side chain.(B)


  • Limited data indicate lack of significant allergic cross-reactivity between penicillin and carbapenems. (B) Penicillin skin test–negative patients may safely receive carbapenems. (C) Penicillin skin test–positive patients and patients with a history of penicillin allergy who do not undergo skin testing should receive carbapenems via graded challenge. (C)

Non–β-Lactam Antibiotics

  • Any non–β-lactam antibiotic has the potential of causing an IgE-mediated reaction, but these appear to occur less commonly than with β-lactam antibiotics. (C)
  • There are no validated diagnostic tests for evaluation of IgE-mediated allergy to non–β-lactam antibiotics. (C) Evaluation of possible allergy to these antibiotics should be limited to situations when treatment with the drug is anticipated (rather than electively as for penicillin). (D)
  • Skin testing with nonirritating concentrations of non–β-lactam antibiotics is not standardized. A negative skin test result does not rule out the possibility of an immediate-type allergy. A positive skin test result suggests the presence of drug specific IgE antibodies, but the predictive value is unknown. (D)
  • Patients with a history of reactions to non–β-lactam antibiotics consistent with an IgE-mediated mechanism should only receive them if an alternate agent cannot be substituted and only via rapid induction of drug tolerance. (D)
  • Sulfonamide antibiotics rarely cause IgE-mediated reactions and more commonly result in delayed maculopapular rashes, particularly in HIV–positive patients. (C)
  • There is no evidence to suggest allergic cross-reactivity between sulfonamide antibiotics and nonantibiotic sulfonamides. (C)
  • Vancomycin rarely causes IgE-mediated reactions, but more than 50% of patients experience immediate cutaneous erythema, flushing, and pruritus (red man syndrome), which is the result of non–IgE-mediated histamine release. (C)
  • Red man syndrome reactions can be prevented by slowing the rate of infusion and premedicating with histamine1 receptor antihistamines. (C)
  • Aminoglycosides rarely cause drug allergic reactions, including IgE-mediated systemic reactions. (C)
  • IgE-mediated and non–IgE-mediated anaphylactic reactions have been reported with quinolones. In vitro studies suggest a large extent of allergic cross-reactivity among quinolones, but there are no clinical studies to confirm this. (C)

Rating Scheme for the Strength of the Recommendations

Strength of Recommendation

  • A Directly based on category I evidence
  • B Directly based on category II evidence or extrapolated from category I evidence
  • C Directly based on category III evidence or extrapolated from category I or II evidence
  • D Directly based on category IV evidence or extrapolated from category I, II, or III evidence
  • E Based on consensus of the Joint Task Force on Practice Parameters


  1. Drug Allergy an Updates Practice Parameter: Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology; ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY; VOLUME 105, OCTOBER, 2010
  2. National guideline clearinghouse; AHRQ