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Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics

Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics
Authors:
Kimberly G Blumenthal, MD, MSc
Roland Solensky, MD
Section Editor:
N Franklin Adkinson, Jr, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Sep 2021. | This topic last updated: Sep 26, 2017.

INTRODUCTION — Penicillin allergy is the most common drug allergy reported by patients. Penicillins are one group within the family of beta-lactam antibiotics, which also includes cephalosporins, carbapenems, and monobactams. This topic will present diagnostic strategies used by allergy specialists for evaluating a patient with suspected or confirmed immediate (ie, immunoglobulin [Ig]E-mediated) allergy to penicillins. Studies of cross-reactivity between penicillins and other beta-lactam antibiotics are also reviewed.

An algorithmic approach to the use of related antibiotics, with or without access to allergy consultation and penicillin skin testing, is discussed in detail separately (algorithm 1). (See "Choice of antibiotics in penicillin-allergic hospitalized patients".)

Detailed discussions of immediate penicillin allergy and penicillin skin testing are found elsewhere. (See "Penicillin allergy: Immediate reactions" and "Penicillin skin testing".)

Delayed reactions to penicillins, ranging from maculopapular drug eruptions to severe systemic reactions, are reviewed elsewhere. (See "Penicillin allergy: Delayed hypersensitivity reactions".)

OVERVIEW — Penicillin allergy is reported by up to 10 percent of patients. However, more than 90 percent of patients with a reported penicillin allergy do not have IgE-mediated sensitivity when skin testing is performed, either because they were inappropriately labeled as allergic or because they had an earlier allergy that resolved with time [1-5]. Among patients with an IgE-mediated penicillin allergy that has been confirmed with skin testing, available studies suggest that 97 percent will tolerate cephalosporins and 99 percent will tolerate carbapenems, as reviewed in detail in this topic. However, despite these reassuring figures, beta-lactam drugs are among the leading causes of drug-induced anaphylaxis, and there are methodologic issues with the data that should be appreciated to understand the limitations of the literature.

GENERAL CONCEPTS

Features of immediate reactions — Immediate reactions to drugs typically involve flushing, pruritus, urticaria, angioedema, bronchospasm, laryngeal edema, and/or hypotension, although an array of other symptoms may be seen (table 1). Signs and symptoms usually begin within minutes to one hour or two of administration, beginning somewhat later for oral compared with intravenous medications. The clinical manifestations of these reactions are reviewed in more detail separately. (See "Penicillin allergy: Immediate reactions".)

Antigenic components of penicillins — There are multiple potentially antigenic epitopes in penicillins. Patients with IgE-mediated allergy to penicillins may be reactive to:

Allergenic epitopes arising from the core beta-lactam and adjacent ring structures, which are found in penicillins, cephalosporins, carbapenems, and monobactams (figure 1).

Allergenic epitopes arising from the R-group side chains on the aminopenicillins (ie, amoxicillin and ampicillin), which are not found in penicillin G or V or in the penicillin skin testing reagents (derived from benzylpenicillin). Patients have been described who have positive skin tests to the aminopenicillins but have negative skin testing to the penicillin G skin testing reagents, presumably (although not proven) attributable to sensitization to the R-group side chains in the aminopenicillins. These R groups are shared by certain cephalosporins (table 2). For example, amoxicillin has an R group that is identical to that in cefadroxil, cefprozil, and cefatrizine. However, selective allergy to the aminopenicillins is believed to be uncommon in most populations. (See 'Population differences' below.)

Multiple antibiotic allergy syndrome — "Multiple antibiotic allergy syndrome" is a term used to describe individuals who develop allergic reactions (either IgE- or non-IgE-mediated) to two or more non-cross-reacting antibiotics. Individuals with this syndrome have an increased propensity to react to medications in general, for reasons that are not fully understood.

In studies of patients with allergies to structurally-related antibiotics, the concept of multiple antibiotic allergy syndrome should be considered as a possible confounding factor that could overestimate cross-reactivity [6]. This was illustrated in several large studies, which yielded unexpected results attributable to multiple antibiotic allergy syndrome:

In patients with a previously documented penicillin allergic-like event, the risk ratio for an allergic-like event was higher not only for cephalosporins (10.1, CI 7.4-13.8) but also for the structurally-unrelated sulfonamides (7.2, CI 3.8-13.5) [7].

Another study evaluated the incidence of allergic reactions to antibiotics in patients who had previously undergone penicillin skin testing [1]. Among these penicillin skin test-positive patients, allergic reactions during the first post-testing antibiotic treatment occurred more frequently with non-beta-lactam antibiotics (10.8 percent) than with cephalosporins (2.4 percent) [1].

Thus, multiple antibiotic allergy syndrome may confound studies of potential cross-reactivity unless appropriate controls are included. Specifically, patients who are allergic to one drug and are challenged with a potentially related drug should theoretically also be challenged with an unrelated antibiotic. However, this is rarely done for practical reasons.

Population differences — There may be variations in patterns of sensitization in different populations, although this observation is based on very limited data. In the United States, most patients with IgE-mediated penicillin allergy are sensitive to the beta-lactam core shared by all beta-lactam drugs, and <0.5 percent are selectively allergic to aminopenicillins (ie, ampicillin and amoxicillin) [8]. In contrast, in southern Europe (eg, Spain) where amoxicillin is widely available without a prescription, up to one-third of patients are reported to be selectively allergic to the aminopenicillins [9,10]. (See 'Patients reporting a past reaction to amoxicillin or ampicillin' below.)

Side chain-specific sensitization to antipseudomonal penicillins (ie, ticarcillin and piperacillin) has been observed among patients with cystic fibrosis, who often receive frequent high-dose parenteral courses of semisynthetic penicillins [11].

Selective allergy to the aminopenicillins is presumed to be attributable to the R-group side chains, although this has not been proven conclusively. R-group side chains are implicated based on a small number of reports from investigators in Spain, in which patients with past reactions to amoxicillin or ampicillin who were tolerant to penicillin G (via skin testing, in vitro testing, or oral challenge) were challenged to cefadroxil or cephalexin, respectively (table 3). Overall, 11 of 45 (24 percent) reacted to a cephalosporin with identical R-group side chains, indicating significant cross-sensitivity between agents with identical side chains [12-14]. Patients were not challenged to cephalosporins with dissimilar side chains for comparison. These findings may not apply to countries in which amoxicillin is only available by prescription, such as the United States, although the recommended approach is still to avoid cephalosporins with identical R-group side chains in patients sensitized to aminopenicillins.

CEPHALOSPORINS — To determine if a patient with a reported immediate reaction to a penicillin can safely receive a cephalosporin, the performance of penicillin skin testing is encouraged. Because most patients have negative results, skin testing greatly simplifies future use of both penicillins and other beta-lactam drugs.

Studies evaluating cross-reactivity between penicillins and cephalosporins in various groups of patients are reviewed in this section. An algorithmic approach to the use of cephalosporins in penicillin-allergic patients is provided elsewhere. (See "Choice of antibiotics in penicillin-allergic hospitalized patients".)

Studies estimating the risk of cross-reactivity — Among patients who report penicillin reactions (but have not undergone confirmatory testing), between 0 and 8.1 percent will react if given a cephalosporin (table 4) [15-22]. The higher estimate is based upon retrospective studies in which patients with a history of penicillin allergy were treated with cephalosporins without preceding penicillin allergy testing (skin testing or in vitro testing). Such studies are the source of warnings in the package inserts of cephalosporins, which state that the risk of cross-sensitivity in penicillin-allergic patients may be as high as 10 percent. However, these studies have several limitations that may lead to an overestimation of cross-reactivity.

Among the five leading reports, two were from the 1970s, and cephalosporins produced prior to 1980 are known to have been contaminated with trace amounts of penicillin [23].

In vitro and skin testing studies with penicillin and cephalosporins showed a high degree of immunologic cross-reactivity, although this does not consistently translate into clinical cross-reactivity (ie, patients may have positive skin test results but not actually react to the drug) [24-28].

Most of these reports provided no information on the nature or severity of the cephalosporin reactions. In the best designed studies, there were two reactions to cephalosporins that were very questionable [15,16]. One of the reactions was an eczema exacerbation after several days of cephalosporin treatment, and the other consisted only of documentation in the anesthesia record of preoperative administration of hydrocortisone and diphenhydramine in a patient on chronic glucocorticoid treatment.

Most cephalosporin challenges in the available studies were carried out in open fashion, rather than as single- or double-blinded challenges, so cross-reactivity may have been overestimated.

In contrast, there are important factors to consider that could lead to an underestimation of the cross-reactivity:

There is a potentially strong selection bias in retrospective, real world studies, arising from the fact that the clinicians would have used clinical judgement in choosing which patients to treat with cephalosporins and which patients to treat with unrelated antibiotics. Specifically, patients who reported a recent penicillin reaction that was convincing for anaphylaxis were likely not selected to receive a cephalosporin. In the studies that provided this information, clinicians chose to use cephalosporins in 25 percent [22], 57 percent [20], and 85 percent [16] of the patients with prior penicillin allergy history, and this variability could have influenced study results.

A significant subset of the patients in these studies were likely not allergic to penicillin at the time they were treated with cephalosporins, since large studies have shown >90 percent of all patients who report a penicillin reaction in the past have negative penicillin skin test results [2,29-31]. (See "Penicillin allergy: Immediate reactions".)

Allergy evaluation and penicillin skin testing — To determine if a patient with a reported immediate reaction to a penicillin can safely receive a cephalosporin, we perform penicillin skin testing. Most patients will have negative results, which greatly simplifies future use of both penicillins and other beta-lactam drugs.

Penicillin skin testing reagents are commercially available in many countries. Skin testing should be performed by a clinician specifically trained in the technique (usually allergists). Testing protocols are discussed in greater detail elsewhere. (See "Penicillin skin testing", section on 'Procedure'.)

The results of penicillin skin testing can be used to guide management as follows:

Negative result — If penicillin skin testing is performed and is negative (no reaction), then the patient is not at substantial risk of immediate allergy to penicillins. The absence of immediate allergy should be confirmed by administering a single age-appropriate dose of the penicillin to which the patient initially reacted, followed by one to two hours of observation to ensure that an immediate reaction does not occur. This step is indicated because the negative predictive value for penicillin skin testing with the combination of penicilloyl polylysine (PPL) and penicillin G is high (about 98 percent), but not 100 percent. Also, confirming that the drug is tolerated will maximize the confidence of the patient and other clinicians with using penicillins in the future [32]. This is discussed in more detail elsewhere. (See "Penicillin skin testing", section on 'Confirmatory challenge after negative skin testing'.)

Once immediate penicillin allergy has been excluded, patients may safely receive cephalosporins as well, unless they have also reacted to a cephalosporin. If a patient has reacted in the past to a specific cephalosporin, that cephalosporin and other cephalosporins with similar R1-group side chains should be avoided, and other cephalosporins may warrant skin test evaluation if the prior reaction was severe or recent.

Positive result — If penicillin skin testing is positive, then there is a high likelihood the patient is allergic to penicillin, and 2 to 3 percent of these patients can be anticipated to react to cephalosporins. This figure is based upon studies in which patients were tested with a full panel of penicillin reagents (PPL, penicillin G, and/or the minor determinant mixture [MDM]), then challenged with cephalosporins for an overall reaction rate of 3.4 percent (table 5). If the analysis is limited to studies published after 1980 (when cephalosporins were no longer contaminated with penicillin), the reaction rate is reduced to 2 percent. Some investigators additionally performed cephalosporin skin testing (on penicillin test-positive patients) prior to cephalosporin administration and administered cephalosporins only if those tests were negative (since ethical concerns prevented cephalosporin challenges in patients with positive cephalosporin skin tests) [12,33-35].

Without precautions, some of these cephalosporin reactions could be severe or life-threatening. Some experts advocate more caution with the first- and second-generation cephalosporins compared with the later-generation agents, but the data are inconclusive. Therefore, options for management are:

Perform skin testing with the desired first- or second-generation cephalosporin and use the results to guide therapy. (See "Cephalosporin hypersensitivity: Clinical manifestations and diagnosis".)

Administer a cephalosporin using a test dose procedure (or graded challenge). Test dosing is usually only necessary the first time a cephalosporin is given after testing and evaluation. If the test dose elicits no symptoms, the patient is proven not allergic to cephalosporins and can receive them normally in the future. (See 'Test dosing (or graded challenge)' below.)

Administer a cephalosporin using an empiric desensitization (ie, empiric because the patient's current sensitization status is unknown). This is the most cautious approach and would usually be reserved for the patient whose past penicillin reaction was severe or who had comorbidities or acute illness that would make him/her less likely to survive an anaphylactic reaction. Desensitization techniques are reviewed separately. (See "Penicillin allergy: Immediate reactions", section on 'Desensitization'.)

If a more cautious approach is desired for a patient with positive penicillin skin testing, then first- and second-generation cephalosporins would be given by empiric desensitization, while later-generation agents could be given with a test dose procedure.

Penicillin skin testing is not available — If skin testing is not available, the clinician must estimate the risk of a serious IgE-mediated reaction to a cephalosporin using the clinical history and time elapsed since the penicillin reaction. Overall, between 90 and 99 percent of patients who undergo penicillin skin testing have been shown to tolerate penicillin without an immediate reaction and are therefore not at increased risk of immediate reactions to cephalosporins either [1-5]. An algorithm that outlines treatment options based on risk assessment is provided (algorithm 1).

Patients reporting a past reaction to amoxicillin or ampicillin — If a patient reacted specifically to amoxicillin or ampicillin (the aminopenicillins) in the past, there may be a higher risk of reaction to cephalosporins with identical R1-group side chains (table 3). For example, if a patient had an immediate reaction to amoxicillin in the past, that patient may be sensitized to the beta-lactam core in all penicillins or to amoxicillin only. Selective allergy to the aminopenicillins is believed to be uncommon in most areas of the world. (See 'Population differences' above.)

Selective allergy confirmed by skin testing — Selective allergy to amoxicillin or ampicillin can only be determined with certainty with skin testing (ie, negative skin testing with PPL, penicillin G, and penicilloate/penilloate, but positive to amoxicillin or ampicillin). Skin testing protocols are discussed separately. If skin test solutions of amoxicillin or ampicillin are not available, a selective allergy can also be diagnosed by challenging the patient with one of these drugs after negative benzylpenicillin skin testing. (See "Penicillin skin testing", section on 'Aminopenicillins'.)

Patients confirmed to be selectively allergic to amoxicillin or ampicillin should avoid cephalosporins with identical R-group side chains or receive them via a desensitization protocol (table 2). Alternatively, needed cephalosporins may be evaluated by skin testing. Such patients may receive cephalosporins with dissimilar side chains normally.

The data regarding clinical cross-reactivity among drugs with similar (but not identical) side chains are even more limited. Some investigators have proposed that patients who have reacted to a drug with a specific R group avoid all agents with similar (as opposed to identical) R groups [36], although there are no clinical data upon which to base this recommendation.

CARBAPENEMS — Carbapenems (ie, imipenem, meropenem, doripenem, and ertapenem) share a common beta-lactam ring with penicillins and hence the potential for allergic cross-reactivity (figure 1). However, accumulated data suggest that less than 1 percent of penicillin-allergic patients react to carbapenems. Despite this, many drug information systems continue to list anaphylactic reactions to beta-lactam antibiotics as a contraindication to the use of carbapenems.

The following studies support a low rate of clinical cross-reactivity between penicillin and carbapenems:

An early study of 40 patients found a relatively high rate of skin test cross-reactivity between carbapenems and penicillins. However, patients were not challenged to confirm allergy (ie, clinical cross-reactivity was not demonstrated), and the method of skin testing to carbapenems used in this early paper has not been validated [37].

A 2014 systematic review found that among 854 patients with past penicillin reactions (including proven, suspected, or possibly IgE-mediated), 4.3 percent experienced any type of hypersensitivity reaction to a carbapenem [38]. Of the 295 patients with positive skin tests to penicillin, only 1 individual (0.3 percent) had a reaction that was possibly IgE-mediated to a carbapenem.

In several studies, collectively including more than 500 adults and children, penicillin sensitization was confirmed with skin testing, and patients were then skin tested to imipenem or meropenem. If skin testing to the carbapenem was negative, a challenge with that carbapenem was performed [39-42]. Just one percent of the total group had positive carbapenem skin tests and were not challenged. The remaining 99 percent had negative carbapenem skin tests and tolerated the carbapenem.

In a study of 212 patients, among whom there was a relatively high rate of anaphylaxis, penicillin (or amoxicillin) allergy was confirmed by clinical history plus positive skin testing, and all patients were then skin tested with imipenem (maximum intradermal concentration 0.5 mg/mL), meropenem (1 mg/mL), and ertapenem (1 mg/mL) [43]. None had positive skin tests to the carbapenems. Of the 212 patients, 211 consented to graded challenges with each carbapenem, and all patients tolerated all three drugs.

Recommended approach — Based on these data, we recommend an approach to patients with a history of penicillin allergy who require treatment with carbapenems that is analogous to that described above for cephalosporins:

If penicillin skin testing is available and is negative, patients may safely receive carbapenems.

If penicillin skin testing is positive, the patient's chance of reacting to the carbapenem is <1 percent, and the carbapenem may be administered via a test dose procedure. One expert prefers the approach of skin testing to penicillin as well as carbapenems, and if penicillin testing is positive and carbapenem testing is negative, then the carbapenem of choice can be given without a test dose [43].

If penicillin skin testing is unavailable, then carbapenems can either be given normally if the patient's reaction to penicillin was mild or remote or the carbapenem may also be administered via graded challenge if the penicillin reaction was more severe.

MONOBACTAMS (AZTREONAM) — Aztreonam is the only clinically available monobactam, and it has a monocyclic beta-lactam structure (figure 1). In vitro studies and skin testing studies demonstrated no immunologic cross-reactivity between penicillin and aztreonam [44,45]. Likewise, aztreonam challenges of penicillin skin test-positive patients revealed no reactions [46-48]. Based on this evidence, patients with a history of penicillin allergy may safely receive aztreonam [49].

Of note, cross-reactivity between aztreonam and the third-generation cephalosporin ceftazidime has been reported, presumably related to their identical side chains. This is discussed separately. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Carbapenems and monobactams'.)

TEST DOSING (OR GRADED CHALLENGE) — Test doses (also called graded challenges) are indicated to exclude immediate allergic reactions. The purpose of a test dose is to expose the patient to a small amount of drug, followed by a period of close observation, in case there is a reaction.

Indications and precautions — Test dosing is appropriate only when immediate allergy to the tested antibiotic is judged to be unlikely after careful consideration of the details of the past reaction. Examples include the following:

Patients who had a mild past reaction to penicillin that lacked features of an IgE-mediated allergy (table 1).

Patients who had a mild past reaction to penicillin that occurred more than 10 years ago, even if it involved hives or angioedema, since approximately 80 percent of patients with IgE-mediated penicillin allergy have lost the sensitivity after 10 years. (See "Penicillin allergy: Immediate reactions", section on 'Time elapsed since the reaction'.)

In contrast, if a patient's history is vague but some element of it suggests a serious IgE-mediated reaction (eg, "My mother said that I could not breathe"), then the more cautious approach of performing a rapid empiric drug desensitization is warranted (assuming skin testing is not available). (See "Penicillin allergy: Immediate reactions", section on 'Desensitization'.)

Most graded challenges can safely be carried out in an office without intravenous access. H1 antihistamines and epinephrine (intramuscular) should be readily available. Because graded challenges will not prevent or circumvent an immediate allergic reaction, the clinician must be prepared to recognize and treat such a reaction if one occurs. If an epinephrine autoinjector is not available, the appropriate concentration and dose of intramuscular epinephrine for that patient should be calculated in advance so that there are no delays or dosing errors if it is needed. (See "Anaphylaxis: Emergency treatment", section on 'Epinephrine'.)

Treatment with beta-adrenergic blocking medications should be withheld for 24 hours before challenge if feasible, as these medications can interfere with treatment of anaphylaxis should a reaction occur. Patients with asthma, chronic obstructive lung disease, or other pulmonary diseases should be optimally controlled prior to undergoing challenge.

Procedure — When graded challenges are performed to exclude immediate allergic reactions, patients should not be pretreated with antihistamines or glucocorticoids because these agents may mask early signs of an allergic reaction.

Challenges to exclude immediate reactions can be performed in a variety of ways. The starting dose is usually 1/4th or 1/10th of the full dose. The patient is observed for 30 to 60 minutes after this initial dose, then if no symptoms develop, a full dose is given and the patient is observed for another 30 to 60 minutes.

As an example, a test dose for oral cephalexin could be performed as follows, using a standard oral suspension (250 mg/5 mL): Give 1/10th of a dose (25 mg or 0.5 mL of the full strength suspension, given with a glass of water), followed by 60 minutes of observation. If no symptoms, give 250 mg, followed by 60 minutes of observation.

Interpretation — Although simple in theory, graded challenges can require experience to interpret. A minority of patients develop nonspecific symptoms during the procedure, which can mimic symptoms of true allergy [50]. Most commonly, these include perioral tingling, pruritus without urticaria, throat and lip discomfort, headache, tachycardia, and nausea. These may be anxiety-related, and spending time with the patient explaining the safety of challenge procedures in advance may help to reduce the incidence of these nonspecific reactions.

If the patient develops convincing signs and symptoms consistent with an immediate reaction during or shortly after the graded challenge (within a few hours of receiving the full dose), no further drug should be given, and symptoms should be treated appropriately. These patients should be diagnosed with IgE-mediated allergy. If they require the drug in question in the future, it should be administered via a formal desensitization protocol. (See "Penicillin allergy: Immediate reactions", section on 'Desensitization'.)

If only subjective symptoms are reported, repeat challenge including placebo controls and masked observations may occasionally be warranted.

Patients with a negative challenge may still develop delayed reactions to the drug in question, but these should not be serious. This was illustrated in a multicenter study of 118 history-positive patients who had both negative skin tests and negative challenges to beta-lactams and were subsequently treated with a beta-lactam [51]. The negative predictive value of the evaluation was 94 percent for any type of reaction. Nine patients experienced symptoms with re-exposure, all of which were mild and delayed (beginning >1 hour after administration). Symptoms consisted of urticaria in five patients, exanthema in three, and one undefined cutaneous reaction.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topic (see "Patient education: Allergy to penicillin and related antibiotics (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Penicillin-allergic patients can often be treated with cephalosporins and carbapenems, although safe administration requires an understanding of what is known about cross-reactivity patterns among different beta-lactams. More than 90 percent of patients with a reported penicillin allergy do not have immunoglobulin (Ig)E-mediated sensitivity when skin testing is performed, either because they were inappropriately labeled as allergic or because they had an earlier allergy that resolved with time. Even among patients with an IgE-mediated penicillin allergy that has been confirmed with skin testing, available studies suggest that 97 percent will tolerate cephalosporins and 99 percent will tolerate carbapenems. Still, beta-lactam reactions can be severe, and the goal of an allergy evaluation is to clarify that individual's specific risk, based upon available data and the details of the patient's past reaction(s). (See 'Overview' above.)

Immediate reactions to drugs typically involve flushing, pruritus, urticaria, angioedema, bronchospasm, laryngeal edema, and/or hypotension, although an array of other symptoms may be seen (table 1). Signs and symptoms usually begin within minutes to one hour or two of administration. The allergens that are believed important for these reactions arise from the core beta-lactam ring structure, which is common to penicillins, cephalosporins, carbapenems, and monobactams (figure 1). However, patients may also react selectively to the aminopenicillins (amoxicillin and ampicillin), although this has largely been described in Spain and may not be a widespread phenomenon. (See 'General concepts' above.)

To determine if a patient with a reported immediate reaction to a penicillin can safely receive a cephalosporin, the performance of penicillin skin testing is encouraged. (See 'Cephalosporins' above.)

If penicillin skin testing is negative (no reaction), then the patient is not at substantial risk of immediate allergy to penicillins or cephalosporins, unless he/she has also reacted to a cephalosporin, in which case that cephalosporin and others with identical side chains should be avoided. Demonstrating that the patient has a negative skin test to the desired cephalosporins further increases safety. (See 'Negative result' above.)

If penicillin skin testing is positive, then there is a high likelihood that the patient is allergic to penicillin, and 2 to 3 percent of these patients can be anticipated to react to cephalosporins. Without precautions, some of these reactions could be severe or life-threatening. The patient should either be treated with an unrelated antibiotic or if a cephalosporin is strongly indicated, it should be given by a test dose procedure or by empiric desensitization, depending upon the severity of the previous penicillin reaction and other factors. Demonstrating that the patient has a negative skin test to the desired cephalosporin further increases safety. (See 'Positive result' above.)

If skin testing is not available, the clinician must estimate the risk of a serious IgE-mediated reaction to a cephalosporin using the clinical history and time elapsed since the penicillin reaction. The best designed studies suggest that 90 to 99 percent of all patients reporting a penicillin allergy (who do not undergo skin test evaluation) will tolerate a cephalosporin. An approach based on risk assessment is shown in the algorithm (algorithm 1).

Patients who reacted initially to amoxicillin or ampicillin should undergo the same risk assessment as penicillin-allergic patients. In addition, if the patient lives in an area of the world (eg, southern Europe) in which selective allergy to amoxicillin or ampicillin is relatively common, they should avoid cephalosporins with identical R-group side chains if they have positive skin tests to aminopenicillins or receive these cephalosporins via graded challenge or desensitization (table 2). (See 'Patients reporting a past reaction to amoxicillin or ampicillin' above.)

To determine if a patient with a reported immediate reaction to a penicillin can safely receive a carbapenem, the approach is similar to that for cephalosporins, although the rate of cross-reactivity is lower, and there are no additional concerns related to side chains. (See 'Carbapenems' above.)

If penicillin skin testing is available and is negative, patients may safely receive carbapenems.

If penicillin skin testing is positive or unavailable, the carbapenem may be administered via a test dose procedure.

Aztreonam is the only monobactam available for clinical use. There is no evidence of immunologic cross-reactivity between penicillins and monobactams, and penicillin-allergic patients may receive aztreonam normally. (See 'Monobactams (aztreonam)' above.)

Test doses (also called graded challenges) are indicated to exclude immediate allergic reactions when a reaction is believed to be unlikely and skin testing is not available or does not fully answer the clinical question. The purpose of a test dose is to expose the patient to a small amount of drug, followed by a period of close observation, in case there is a reaction. (See 'Test dosing (or graded challenge)' above.)

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Topic 2087 Version 22.0

References

1 : Oral antibiotic adverse reactions after penicillin skin testing: multi-year follow-up.

2 : Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy.

3 : Penicillin skin testing in patients with a history of beta-lactam allergy.

4 : The impact of penicillin skin testing on clinical practice and antimicrobial stewardship.

5 : The use of penicillin skin testing to assess the prevalence of penicillin allergy in an emergency department setting.

6 : Detection of patients with multiple drug allergy syndrome by elective tolerance tests.

7 : Is there cross-reactivity between penicillins and cephalosporins?

8 : Is there cross-reactivity between penicillins and cephalosporins?

9 : Importance of mixture of minor determinants and benzylpenicilloyl poly-L-lysine skin testing in the diagnosis of beta-lactam allergy.

10 : Benzylpenicillin skin testing is still important in diagnosing immediate hypersensitivity reactions to penicillins.

11 : Allergy to semisynthetic penicillins in cystic fibrosis.

12 : Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin.

13 : Cross-reactivity between a penicillin and a cephalosporin with the same side chain.

14 : Clinical cross-reactivity between amoxicillin and cephadroxil in patients allergic to amoxicillin and with good tolerance of penicillin.

15 : Safety of cephalosporin administration to patients with histories of penicillin allergy.

16 : Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic response.

17 : Immunologic cross-reactivity between penicillins and cephalosporins: a review.

18 : Penicillin allergy and the cephalosporins.

19 : Adverse drug reactions to a cephalosporins in hospitalized patients with a history of penicillin allergy.

20 : Anaesthetist's responses to patients' self-reported drug allergies.

21 : Allergic Reactions in Hospitalized Patients With a Self-Reported Penicillin Allergy Who Receive a Cephalosporin or Meropenem.

22 : Penicillin allergy and surgical prophylaxis: Cephalosporin cross-reactivity risk in a pediatric tertiary care center.

23 : Cephalothin in the treatment of penicillin sensitive patients

24 : Immunohaematological cross-allergenicity between penicillin and cephalothin in humans.

25 : Tests for penicillin allergy in man. II. The immunological cross-reaction between penicillins and cephalosporins.

26 : The immunogenicity of cephalosporin derivatives and their cross-reaction with penicillin.

27 : Antigenicity and cross-reactivity of penicillins and cephalosporins.

28 : Common antigenic determinants of penicillin G, ampicillin and the cephalosporins demonstrated in men.

29 : Routine elective penicillin allergy skin testing in children and adolescents: study of sensitization.

30 : Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults.

31 : Clinical experience with penicillin skin testing in a large inner-city STD clinic.

32 : The value of routine penicillin allergy skin testing in an outpatient population.

33 : Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins.

34 : Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins.

35 : Diagnosis of penicillin allergy by skin testing: the Manitoba experience.

36 : A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients.

37 : Imipenem cross-reactivity with penicillin in humans.

38 : A systematic review: can one prescribe carbapenems to patients with IgE-mediated allergy to penicillins or cephalosporins?

39 : Tolerability of meropenem in children with IgE-mediated hypersensitivity to penicillins.

40 : Brief communication: tolerability of meropenem in patients with IgE-mediated hypersensitivity to penicillins.

41 : Imipenem in patients with immediate hypersensitivity to penicillins.

42 : Tolerability of imipenem in children with IgE-mediated hypersensitivity to penicillins.

43 : Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins.

44 : Investigation into the immunologic cross-reactivity of aztreonam with other beta-lactam antibiotics.

45 : Cross-allergenicity and immunogenicity of aztreonam.

46 : Immunogenicity and cross-allergenicity of aztreonam.

47 : Tolerance to aztreonam in patients allergic to beta-lactam antibiotics.

48 : Tolerability of aztreonam in patients with IgE-mediated hypersensitivity to beta-lactams.

49 : Drug allergy: an updated practice parameter.

50 : Evaluation of the nocebo effect during oral challenge in patients with adverse drug reactions.

51 : Determining the negative predictive value of provocation tests with beta-lactams.