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Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics

Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics
Literature review current through: Jan 2024.
This topic last updated: Dec 27, 2021.

INTRODUCTION — Cephalosporins are commonly-used antibiotics that can cause a variety of hypersensitivity reactions. This topic will discuss the allergy evaluation of patients with past immediate reactions to cephalosporins, including skin testing and graded challenges. Patients with immediate reactions to a specific cephalosporin in the past may require subsequent treatment with a different cephalosporin or a related antibiotic, such as a penicillin, carbapenem, or monobactam. Approaches to these different clinical scenarios will be presented here.

The clinical manifestations and diagnosis of both immediate and delayed forms of cephalosporin hypersensitivity are discussed separately. (See "Cephalosporin hypersensitivity: Clinical manifestations and diagnosis".)

CHARACTERISTICS OF IMMEDIATE HYPERSENSITIVITY — Immediate reactions to cephalosporins are believed to be type-I, immunoglobulin E (IgE)-mediated reactions and classically begin within one hour of the last administered dose. Signs and symptoms include various combinations of flushing, urticaria, angioedema, rhinitis, bronchospasm, hypotension, and anaphylactic shock (table 1).

Natural history — Immediate hypersensitivity to cephalosporins may be lost over time, as is documented with penicillin allergy [1]. One study followed 72 patients with IgE-mediated hypersensitivity to cephalosporins prospectively over five years of follow-up and found that 68 percent of those sensitized only to cephalosporins no longer had evidence of skin test sensitization [2]. Patients who were also sensitized to penicillins were less likely to convert to negative skin tests (44 percent after five years).

ALLERGY EVALUATION — Patients with past immediate reactions to cephalosporins who require subsequent use of other cephalosporins or penicillins should be evaluated by an allergy specialist.

Goals of the evaluation — The purpose of this evaluation, which involves skin testing and graded challenge, is to determine what other drugs can be safely administered to that patient. Most patients will be able to tolerate other cephalosporins and/or penicillins. Overall <2 percent of patients allergic to cephalosporins will demonstrate clinical cross-reactivity to penicillins that do not share the same side chains. However, higher rates of skin test cross-reactivity (up to 30 percent) have been demonstrated between penicillins and cephalosporins that do share similar side chains, so it is safest to advise patients to avoid both cephalosporins and penicillins after a possible immediate cephalosporin reaction, until an allergy evaluation can be performed. (See "Cephalosporin hypersensitivity: Clinical manifestations and diagnosis", section on 'Cross-reactivity'.)

Whom to evaluate — An evaluation for immediate hypersensitivity to cephalosporins is appropriate in any patient who experienced signs of symptoms of immediate allergy shortly (within minutes to a few hours) after receiving a cephalosporin (table 1).

An allergy evaluation is also recommended for children and adults with isolated urticaria and/or angioedema, even if the onset was delayed, since urticaria and angioedema can be presentations of either immediate or delayed hypersensitivity.

Timing — Skin testing for evaluation of cephalosporin allergy is more likely to be positive the closer in time it is performed to the clinical reaction, so testing within a few months of the index reaction is ideal, although it can still be useful years later [3-7]. However, a period of at least three to six weeks should be allowed between an immediate reaction and skin testing to the suspect drug, since skin testing may be falsely negative if performed too soon [8].

ALLERGENIC COMPONENTS OF CEPHALOSPORINS — Patients may develop immunoglobulin E (IgE) antibodies against antigenic determinants that are unique to cephalosporins or to determinants that are shared with other beta-lactam drugs, particularly the penicillins [9-19].

Potential allergenic components — The core structure of both penicillins and cephalosporins contains a four-membered beta-lactam ring (figure 1).

Cephalosporins also contain a six-membered dihydrothiazine ring [14-19], which is not usually allergenic in its intact form and breaks down rapidly after administration [15,16]. In vitro studies have shown that patients may be sensitized to any of the following [10,20-24]:

The entire cephalosporin molecule that includes the cephalosporin-specific dihydrothiazine ring [11], based on a study showing that the most common pattern of reactivity was being skin-test positive to the culprit cephalosporin only and not to cephalosporins that share R1 or R2 side groups [25].

Either of the side chain groups (R1 and R2), with sensitization to R1, which comes off the shared beta-lactam ring, being significantly more common [14,17-19,26] based on studies that utilized skin testing and challenges (figure 1) [6,7,25,27].

The core beta-lactam ring or metabolites of it (uncommon) [14,17-19,26].

Side chain groups — Certain cephalosporins share structurally similar R1 side chain groups or R2 side chain groups with other cephalosporins or with specific penicillins [9,12,14,16-19,26]. Sensitization to the R1 side chain group of cephalosporins, in particular, has proved to be important in determining cross-reactivity with penicillins [2-4,6,7,27-29] and among cephalosporins [2,4,6,7,16,25,27,29-33].

There are several different lists and graphics in the published literature identifying groups of cephalosporins with similar or identical R1 or R2 side chains, and significant variability among the groupings. This variability has arisen from several factors, including whether the groupings are based solely on the chemical structures of the drugs or also incorporates clinical cross-reactivity (which, in turn, can be based on skin testing or challenge or both), available studies evaluating clinical relevance at the time the tables were created, and geographical differences in sensitization patterns around the world. The tables provided here should be used to select an alternative cephalosporin, which must then be evaluated with skin testing and/or challenge.

The tables can be used to choose possible alternatives to a given culprit drug:

Culprit cephalosporin was a first generation agent (table 2)

Culprit cephalosporin was a second generation agent (table 3)

Culprit cephalosporin was a third generation agent (table 4)

Culprit cephalosporin was a fourth or fifth generation agent (table 5)

The choice of alternative cephalosporins to include in skin testing is discussed further below. (See 'What to include' below.)

R1 side chains — Clinically important R1 side chain groupings include:

Drugs that have an identical R1 group and show risk for clinical cross-reactivity: Ceftriaxone, cefotaxime, cefepime, cefpodoxime, cefditoren, cefodizime, ceftizoxime, cefpirome, and cefetamet (the last five drugs are not available in the United States).

Some studies that have applied skin testing and challenge suggest cross-reactivity between the above listed cephalosporins that share the complete R1 group and cephalosporins that share the methoxyimino component in the R1 position, such as cefuroxime (figure 2) [2,4,7,16,25,30,33]. Specifically, cross-reactivity among cefuroxime, ceftriaxone, cefotaxime, cefodizime, and cefepime has been reported [2,4,7,16,25,30-33]. Sensitization to this group of cephalosporins is prevalent in some European countries (eg, Italy, Spain, and Denmark) [2-4,25,28-31,34] but appears to be less common in other parts of the world.

Ceftazidime has an R1 side chain that is slightly different from those of the aforementioned cephalosporins because it contains an alkoxyimino group instead of a methoxyimino group (figure 2). Patients sensitized to the R1 side chain of the above cephalosporins or the methoxyimino group as evidenced by cross-reactivity with cefuroxime can usually tolerate ceftazidime [33,35]. However, this is not always the case [2,4,7,25,29-31], and skin testing should be performed for the specific desired alternative cephalosporin.

All of the aminopenicillins and corresponding aminocephalosporins are potentially cross-reactive:

The following drugs share an R1 side chain group with ampicillin: Cephalexin, cefaclor, cephradine, cephaloglycin, and loracarbef (figure 3) [14,17-19]. Cross-reactivity between cephalexin or cefaclor and ampicillin has been reported [3,4,6,7,13,25,26,28,29], and cross-reactivity between cephalexin and cefaclor has also been demonstrated in cephalexin-allergic subjects [6,27,36].

The following drugs share an R1 side chain group with amoxicillin: Cefadroxil, cefatrizine, and cefprozil (figure 3) [12,14,17-19,26]. Cross-reactivity between cefadroxil and amoxicillin has been observed in subjects allergic to amoxicillin [37-39].

Amoxicillin and ampicillin and their respective R1 sharing aminocephalosporins differ from each other only by a hydroxy (-OH) group on the R1 chain. It should be assumed that a high rate of cross-reactivity exists between ampicillin and amoxicillin and that where cross-reactivity has been demonstrable between any aminopenicillin and aminocephalosporin, that this would apply to the entire group [25,35,39-43].

Cefazolin has unique side chains — Note that cefazolin, which is the most common cephalosporin to cause anaphylaxis in the United States, has unique R1 and R2 side chain groups and does not appear to cross-react with the other cephalosporins except ceftezole (a first generation agent that is only available in Italy, South Korea, and some Southeastern Asian countries) [17,18]. Ceftezole shares an identical R1 side chain and a similar R2 side chain with cefazolin [18]. Several studies suggest that skin test-positive patients with past immediate reactions to cefazolin often tolerate all other cephalosporins (except ceftezole) and other beta-lactams [6,7,25,27,44-52]. However, allergy evaluation is still advised whenever possible because there are rare exceptions.

SKIN TESTING — Multiple studies have shown that skin testing in patients with past immediate reactions to cephalosporins can be used to confirm sensitization to the suspect drug and to identify alternative cephalosporins that can then be given in challenge procedures to prove tolerance [6,7,25,27,33,35,44,46-62]. However, it is important to appreciate that cephalosporin skin testing has several limitations.

Limitations — Skin testing with cephalosporins is not as well-validated as penicillin skin testing for the following reasons:

The allergenic determinants of cephalosporins have not been well-defined, unlike those for penicillins.

Reagents are not commercially available for testing to cephalosporin-protein conjugates, as they are for penicillins.

The positive and negative predictive values of testing have not been fully established.

There are regional differences in patterns of sensitization to cephalosporins around the world, such that research findings from one area may not be generalizable to other populations. (See 'Groups of cephalosporins less likely to cross react' below.)

In the United States, only cephalosporins that already come as a sterile parenteral formulation are used for skin testing, limiting the scope of the evaluation. However, other countries have additional options. (See 'Preparation of reagents' below.)

Technique — Prick/puncture technique is performed first. If prick/puncture tests are negative, then intradermal testing is performed [8,63-66]. A general discussion of skin testing techniques, including preparation of the patient and contraindications, is found separately. (See "Overview of skin testing for IgE-mediated allergic disease".)

The author's approach is to spread testing over three separate days to reduce the risk of inducing systemic reactions. Testing with penicillin reagents is performed on one day, amoxicillin and ampicillin on another, and testing to cephalosporins on a third day [3,4]. However, this may not be feasible in most settings. Therefore, skin tests with all reagents can be performed on one day. Both approaches are safe, and systemic reactions to the testing itself are rare.

What to include — To perform a comprehensive evaluation of a suspected immediate cephalosporin allergy, we suggest prick/puncture skin testing, followed if negative by intradermal skin testing to all of the following:

Positive histamine and negative saline controls to ensure normal skin reactivity.

The cephalosporin(s) implicated in the past reaction. A complete listing of parenteral and oral cephalosporins is shown in the table (table 6). Only parenteral drugs are used for skin testing in the United States. (See 'Preparation of reagents' below.)

One or more alternative cephalosporins with dissimilar side chains, especially in the R1 position, that the patient could potentially receive instead, which can be selected using the tables below.

Culprit cephalosporin was a first generation agent (table 2)

Culprit cephalosporin was a second generation agent (table 3)

Culprit cephalosporin was a third generation agent (table 4)

Culprit cephalosporin was a fourth or fifth generation agent (table 5)

(See 'Groups of cephalosporins less likely to cross react' below.)

The classic penicillin reagents: the major determinant (penicilloyl-polylysine [PPL] or benzylpenicilloyl-octa-L-lysine), the minor determinant mixture (MDM) or a minor determinant (MD; sodium benzylpenilloate) if available, and benzylpenicillin (also called penicillin G). Note that it would not be necessary to include these if the patient has tolerated penicillins or amoxicillin since the cephalosporin reaction.

Ampicillin and amoxicillin (where parenteral formulations are available for use in testing): The aminopenicillins are included to detect patients who are sensitized to side chain groups that are shared by these and some cephalosporins (figure 3). If the patient tests positive to one or both of these, then the related antibiotics should be excluded from the list of potential alternative cephalosporins for evaluation. Alternatives drugs should be chosen instead from one of the following: ceftriaxone, cefuroxime, cefotaxime, cefepime, cefodizime, or ceftazidime.

The full panel of tests may not be clinically indicated in all situations. For example, if a patient developed hives to cefpodoxime but had no known adverse reaction to penicillin, and the clinician simply wanted to determine if it was safe to treat the patient with penicillins in the future, then it might be sufficient just to skin test with the classic penicillin reagents. Approaches to common clinical scenarios are discussed below. (See 'Use of related antibiotics in cephalosporin-allergic patients' below.)

Concentrations for skin testing — For most cephalosporins, 20 mg/mL is a non-irritating concentration [25,44,67-70], which is endorsed by European position papers for testing of cephalosporin and other beta-lactam allergy [8,68,71]. An exception is cefepime, for which we propose a skin testing solution of 2 mg/mL, as higher concentrations can be irritating. For patients with prior severe anaphylaxis to a cephalosporin, prick testing is always performed first, and solutions for initial intradermal testing can be diluted 10- to 1000-fold further, to reduce the risk of inducing a systemic reaction.

Preparation of reagents — Testing solutions of cephalosporins (and penicillins) should be freshly prepared on the day of testing [3,4,25,30,69].

For injectable cephalosporins, the intravenous formulation is used (table 6). In the United States, intravenous preparations of cephalosporins are the only form used for skin testing, because intradermal skin testing using solutions prepared from oral tablets or capsules is not generally performed outside of research settings. In addition, oral liquid suspensions are not appropriate for intradermal skin testing.

In many other countries, oral cephalosporins are solubilized and filter-sterilized for use in skin testing. The powder contained in capsules or obtained by removing the external layer of tablets with a scalpel can be used. After weighing the powder, solutions are prepared under a laminar flow hood [72,73] and are filter-sterilized through single-use devices (0.20 micrometer syringe filter) [4,6]. These approaches have not been standardized, and studies suggest that the negative predictive value is significantly less than 100 percent for oral aminocephalosporins prepared in this way [6].

Interpretation

Positive results — A positive skin test (on the volar forearm) to a cephalosporin drug may be defined as a wheal >3 mm in diameter for skin prick testing, or any increase by 3 mm or more in the diameter of the wheal produced by the injection for intradermal testing, with surrounding erythema, that develops within 20 minutes of placement [4,8,73]. A positive skin test result implies the presence of drug-specific immunoglobulin E (IgE) antibodies and potential clinical allergy. Cephalosporins that yield positive skin tests should not be given except through a desensitization protocol.

As with skin testing for most drugs, the positive predictive value has not been precisely defined, because this would require administering the drug to large numbers of skin test-positive patients with no personal benefit to confirm that they are truly reactive, which has been generally avoided for ethical reasons.

The sensitivity of skin testing with cephalosporins has been estimated in some studies involving children [3,74], both children and adults [31], and adults [4,6,7], with histories of immediate reactions to these beta-lactams. The rate of positive responses to cephalosporin skin tests ranged from 8.9 percent (22 of 245 subjects) [7] to 72.1 percent (31 of 43) [3], although patients with positive test results were not challenged to confirm if these were true positives (for the ethical reasons just mentioned). The highest rate was found in a study from the author's center [3], in which 30 (70 percent) of the 43 children with immediate reactions to cephalosporins had experienced anaphylaxis.

Negative results — If prick/puncture and intradermal test responses are negative, it does not conclusively prove that the patient does not have specific IgE antibodies to the cephalosporin in its native state [4]. In addition, the patient could still have IgE antibodies against a metabolite or metabolite-protein complex not detected by the testing, and the negative predictive value of cephalosporin skin testing is not well-defined. Therefore, in patients with a history suggestive of a higher risk or IgE-mediated reaction, negative skin testing should be followed by graded challenge before the patient can be advised that it is safe to receive that cephalosporin again.

IN VITRO TESTING — In vitro assays for cephalosporin-specific immunoglobulin E (IgE) are not commonly used, because they are less sensitive than skin testing and not widely available [4,8,64]. The only commercially-available cephalosporin-specific IgE test is for cefaclor, and that is rarely obtained because cefaclor is not widely used in the United States, and because of the negative predictive value of cefaclor IgE for both cefaclor and related aminocephalosporins, such as cephalexin, is not high.

In a series of the author's concerning 59 subjects (31 adults and 28 children) with histories of immediate reactions to cefaclor, the ImmunoCAP was positive in only 16 subjects (12 adults and 4 children), whereas skin tests were positive in 44 (22 adults and 22 children). Of the 16 subjects positive to cefaclor ImmunoCAP, 14 were also skin test positive; the remaining 2 (both adults) were skin test negative [75]. A few studies have performed investigational assays for IgE to cephalosporins other than cefaclor in samples larger than 10 patients [4,10,20,21,29,30,34,76,77].

In some centers, flow cytometric basophil activation tests (BAT) for drug allergy are performed [50,51,78-84]. This is not widely available in the United States, and additional comprehensive studies in large samples are required in order to further validate the technique and provide a definitive assessment of its sensitivity [85].

GRADED CHALLENGE (TEST DOSING) — A graded challenge, also called a test dose, does not modify a patient's response to a drug, so patients who tolerate challenge prove that they are not allergic to the drug in question. Graded challenges often require experience to interpret properly, because patients can develop nonspecific or anxiety-related symptoms.

Indications and precautions — Graded challenge is appropriate only when immediate allergy to the tested drug is judged to be unlikely after careful consideration of the details of the history [36,66,86]. In the United States, graded challenges are used to confirm tolerance, whereas European guidelines also emphasize a role for graded challenge in establishing a firm diagnosis of beta-lactam hypersensitivity in selected cases of patients with negative skin tests and reliable in vitro tests [8,63,64,87]. Note that challenges with cephalosporins can reasonably be expected to elicit reactions more often than challenges with penicillins, because the negative predictive value of cephalosporin skin testing is not as well-defined and likely lower than that of penicillin skin testing. For cephalosporins, a drug is most likely to be tolerated on challenge if it has different R1 and R2 side chains from the cephalosporin that caused the index reaction and yielded negative results on skin testing. All challenges in patients with a higher-risk history should be confirmed by a graded rather than single-dose challenge. (See 'Technique' below.)

Test doses may be administered by an allergy specialist (preferable) or a member of the general medical team [88]. 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.

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. An H1 antihistamine (eg, cetirizine 10 mg orally) and epinephrine for intramuscular injection should be available, preferably in the form of an autoinjector to ensure the appropriate dose is given. If a fixed-dose epinephrine autoinjector is not being used, 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 epinephrine is needed. Proper dosing of epinephrine and anaphylaxis management is described in the tables for adults (table 7) and children (table 8).

Technique — Prior to graded challenges, patients are usually not pretreated with antihistamines or glucocorticoids, because antihistamines may mask early signs of an allergic reaction. However, if a patient is already receiving a daily antihistamine for allergic rhinitis or another disorder, it is not necessary to withhold it (unless skin testing is being performed prior to challenge). We usually withhold beta-adrenergic blocking medications for 24 hours before the first dose, if feasible, as these medications can interfere with treatment of anaphylaxis, should a reaction occur. Patients with asthma, chronic obstructive lung disease, or other chronic pulmonary diseases should be optimally controlled prior to undergoing challenge.

The patient is assessed for symptoms, and vital signs are recorded every 30 minutes. More information about graded challenges, including interpretation of subjective symptoms, is reviewed separately. (See 'Graded challenge (Test dosing)' above.)

Patients who develop symptoms consistent with an immunoglobulin E (IgE)-mediated reaction during or shortly after the graded challenge (within a few hours of receiving the full dose) should be treated appropriately and should not receive further drug. These patients should be considered allergic to that agent and it should be avoided. If that specific drug is critical and there is no equivalent alternative, it can be administered using a desensitization protocol. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

Oral protocols — Most graded challenges in the outpatient setting are performed with oral cephalosporins. A typical oral challenge consists of two steps. In a study including both hospitalized patients and outpatients in an allergy/immunology clinic, a simple two-step graded challenge in low-risk patients was as safe as three- or four-step challenges [89].

The first step is to administer 1/4th of a full dose (can be prepared with a pill cutter) or 1/10th (usually prepared with the liquid oral suspension) of the full dose. If no reaction occurs, the full therapeutic dose is administered 30 to 60 minutes later.

An example of an oral test dose to cephalexin starting with 1/10th of a dose would be the following: Give 25 mg (ie, 0.5 mL of the 250 mg/5 mL suspension, given with a glass of water), followed by one hour of observation. If no symptoms, give 250 mg, followed by one hour of observation.

Intravenous or intramuscular protocols — Intravenous (IV) or intramuscular graded challenges are used less often. In most cases, a test dose can be 1/10th (10 percent) of the full therapeutic dose for that patient. If no reaction occurs, the full therapeutic dose (or 9/10th of the full dose) is administered 30 to 60 minutes later.

An example of an IV test dose to ceftazidime starting with 1/10th of a dose would be the following: Give 100 mg, followed by one hour of observation. If no symptoms, give 1000 mg, followed by one hour of observation. The next dose after that is given normally when it is due.

For IV challenges, the test dose solution should not be significantly more dilute than the normal preparation, because patients may not react if the concentration is dramatically altered [36,90]. Thus, the 1/10th (10 percent) dose can be withdrawn from a full-strength bag with a syringe and administered by slow IV push (usually about 1 mL/min), followed in one hour (if tolerated) by the remaining 90 percent. Other methods of administering test doses and additional safety issues surrounding test dosing policies have been described [88].

If it is necessary to perform challenges with the culprit cephalosporins in high-risk subjects (eg, those who experienced severe reactions), an initial dose of 1/100th of the therapeutic one is administered. In cases with negative results, one hour later a dose of 1/10th and, if the result is again negative, after another hour a full therapeutic dose [4]. Note that a 2020 European position paper suggests using different challenge protocols depending on the patient's risk profile [8].

Risk of resensitization — Questions sometimes arise about the risk of resensitizing a patient as a result of an oral challenge or treatment with a full course of oral antibiotics. Studies suggest that resensitization occurs in <1 percent of patients exposed through oral administration and doesn't always correlate with clinical reactivity, and so the practice of retesting patients following negative oral challenge or oral treatment is not standard. However, there may be certain high-risk groups of patients, such as patients with cystic fibrosis who receive multiple courses of intravenous antibiotics, in whom patients with past severe anaphylaxis might become resensitized after treatment. The author usually retests patients who experienced severe reactions after four weeks to determine if there has been resensitization after previous loss of sensitivity [4,8,63,64]. This issue has been studied more extensively in penicillin-allergic patients. (See "Penicillin skin testing", section on 'Resensitization'.)

USE OF RELATED ANTIBIOTICS IN CEPHALOSPORIN-ALLERGIC PATIENTS — The groups of antibiotics that are related to cephalosporins are penicillins, carbapenems, and monobactams (figure 4). An approach for the use of each of these related drugs in a cephalosporin-allergic patient is outlined below.

Other cephalosporins — Most patients with past cephalosporin reactions can receive other cephalosporins safely. Although the side chain groups of cephalosporins are believed to be important in determining cross-reactivity, it is important for clinicians to appreciate that side chain similarities alone cannot be relied on to predict cross-reactivity accurately [2,4,6,7,16,25,27,29-31,33,48]. Rather, in studies of at least five cephalosporin-allergic subjects [6,7,25,27,35,44,48,49,51], these similarities are best used to select structurally different cephalosporins from the one that caused the initial reaction, which are then evaluated with skin testing and challenge to determine patient tolerance.

Algorithmic approach — An abbreviated algorithm, which does not require testing to the full panel of penicillin and cephalosporin reagents but instead focuses on identifying an alternative cephalosporin that the patient can safely receive, is shown (algorithm 1):

The clinician should choose one or more alternative cephalosporins that have different side chains, especially in the R1 position, from the cephalosporin that caused the past reaction. However, a similar side chain should not absolutely exclude a drug from consideration if it is the most appropriate drug for the clinical situation [35].

Skin testing should be performed to the desired cephalosporin. (See 'Skin testing' above.)

If the results are positive, then the patient should be assumed to be allergic to the desired cephalosporin and it should only be administered using a desensitization protocol.

If the results are negative, then the desired cephalosporin can be administered by graded challenge to confirm that the drug is tolerated. (See 'Graded challenge (Test dosing)' above.)

According to the American practice parameter, an alternative approach is giving the selected cephalosporin via a graded challenge, without performing any skin tests [36]. (See 'Graded challenge (Test dosing)' above.)

Groups of cephalosporins less likely to cross react — In a study from the author's center that assessed cross-reactivity among cephalosporins, groupings of cephalosporins were identified that were useful for selecting alternative cephalosporins that patients are likely to tolerate [25]. In this study, 102 cephalosporin-allergic adults underwent extensive cephalosporin skin testing (and cefaclor-specific immunoglobulin E [IgE] assays), followed by 323 challenges with different cephalosporins to determine patterns of tolerance. Four groups were identified:

Group A (73 subjects) consisted of patients with positive skin tests to one or more of the cephalosporins with methoxyimino groups in the R1 position (ceftriaxone, cefuroxime, cefotaxime, cefepime, cefodizime) or ceftazidime (figure 2). These patients underwent skin tests and, in case of negative results, challenges with cefaclor, cefazolin, and ceftibuten. All patients tolerated these alternative cephalosporins using this approach. In this group, 32 of 73 patients had positive skin testing to more than one of the group A cephalosporins (ie, the culprit group A cephalosporin and another one that shared a methoxyimino group). Note that despite the different R1 group of ceftazidime, a similar pattern of tolerance with cefaclor, cefazolin, and ceftibuten was observed. The frequency of sensitization to the group A cephalosporins in the United States appears to be lower than that in Europe.

Group B (13 subjects) consisted of patients with positive skin tests to the aminocephalosporins cephalexin, cefaclor, or cefadroxil (figure 3). These patients underwent skin tests and, in case of negative results, challenges with ceftriaxone, cefuroxime, cefazolin, and ceftibuten. All patients tolerated ceftriaxone and cefuroxime (both in group A), as well as cefazolin and ceftibuten. In this group, only 2 of 13 patients had positive skin testing to more than one of the group B aminocephalosporins.

Group C (7 patients) tested positive to cephalosporins other than those belonging to the aforementioned groups (ie, cefoperazone, cefamandole, and cefazolin) (figure 5). One subject who had reacted to cefoperazone tested positive to both cefoperazone and cefamandole, which share an identical R2 side chain. These patients were then challenged with cephalosporins to which they were skin test negative and no reactions occurred.

Group D (9 participants) tested positive to cephalosporins belonging to two different groups. These patients were also challenged with cephalosporins to which they were skin test negative and no reactions occurred.

The groupings described above have been observed in several European countries. Similar studies have been performed very rarely in North American populations or in other parts of the world [7], so clinicians should only use these groupings to choose alternative agents that are then evaluated with skin testing or challenge to determine if the patient can tolerate them.

The same cephalosporin that caused the reaction — Rarely, a patient requires the same cephalosporin to which there is evidence of IgE-mediated allergy. A formal desensitization protocol should be performed in this situation. The procedure described for penicillin desensitization would be appropriate. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

Penicillins — Most patients with immediate reactions to cephalosporins and no history of reacting to penicillins will tolerate penicillins. However, there are patients who react to both groups of drugs and there are at least three allergenic determinants that are shared by penicillins and cephalosporins that may be responsible for this cross-reactivity:

Side chain groups – Side chain groups may be the most common source of cross-reactivity between cephalosporins and penicillins. In one study, patients with past reactions to cephalosporins with similar or identical side chains with penicillins demonstrated a threefold increased incidence of positive results on allergy tests (skin testing or in vitro testing) with that penicillin [28]. Amoxicillin has the same side chain as cefadroxil, cefprozil, and cefatrizine [12,14,17-19,26]. Ampicillin has the same side chain as cefaclor, cephalexin, cephradine, cephaloglycin, and loracarbef (no longer available in the United States) [14,17-19,26].

Small moieties – Small moieties shared by cephalosporins and penicillins can also be allergenically important. In one study, a population of IgE antibodies recognizing a methylene group present in both cephalothin and benzylpenicillin was identified in patient sera [20]. Positive skin tests to both benzylpenicillin and cephalothin have been observed in such patients.

Beta-lactam ring – A very small percentage of patients with primary cephalosporin reactions may be sensitized to the beta-lactam core that is common to cephalosporins, penicillins, monobactams, and carbapenems (figure 4) [28]. Patients with this type of allergy would have positive allergy tests to all beta-lactams [28,42,91].

Algorithmic approach — If a cephalosporin-allergic patient requires a penicillin, then penicillin allergy testing is indicated to guide management as follows (algorithm 2):

Negative results on penicillin skin testing indicate that the patient's reaction to the cephalosporin was probably due to a unique cephalosporin determinant. Therefore, the patient is not at increased risk for reacting to a penicillin, provided that penicillin does not share a side chain with the cephalosporin that caused the initial reaction.

Positive results on penicillin skin testing indicate that the patient may be reactive to the beta-lactam core, provided that the penicillin and cephalosporin in question do not share similar side chains. Because selective recognition by IgE antibodies of the beta-lactam ring is very rare [14], the clinical history and risk stratification should be taken into account in this situation. The possibility of a separate but concomitant sensitization to both the culprit cephalosporin and the selected penicillin should also be taken into account [14]. Thus, the patient should undergo skin tests with aztreonam and/or carbapenems and, if negative, she/he can be treated with these alternative beta-lactams. In case of positive results, she/he can be treated with a non-beta-lactam antibiotic or desensitized to the desired penicillin. (See "Penicillin allergy: Immediate reactions", section on 'Desensitization'.)

If penicillin skin testing is not available, the American practice parameter suggests that the selected penicillin can be given using a graded challenge [36]. (See 'Graded challenge (Test dosing)' above.)

Note that it is the author's approach to first (before penicillin skin testing) obtain drug-specific IgE to penicillins (penicillin G, penicillin V, amoxicillin, and ampicillin) and cefaclor in subjects who experienced a severe anaphylactic reaction to a cephalosporin, especially cephalothin, cefamandole, cephalexin, cefadroxil, and cefaclor, which share similar or identical side chains with penicillins. If these are positive, then skin testing is not performed and alternative antibiotics, including beta-lactams other than penicillins and culprit cephalosporins (eg, carbapenems, aztreonam, and group A cephalosporins), can be used after an appropriate allergy workup, or the patient can be desensitized. If the penicillin-specific IgE is negative, penicillin skin testing is then performed. However, IgE immunoassays are rarely used in the United States.

In studies where penicillins were administered to cephalosporin-allergic subjects presenting negative results in penicillin allergy tests , all individuals tolerated the penicillins concerned (eg, benzylpenicillin, penicillin VK, amoxicillin, and flucloxacillin) [6,7,27,28,31,35,44,48,51,92]. The safety and feasibility of amoxicillin challenges without penicillin skin tests was assessed in 40 patients with anaphylactic reactions to cefazolin and positive skin tests to it [92]. All 40 patients underwent a three-day amoxicillin challenge without reporting immediate reactions. One patient experienced a delayed benign rash at 24 hours and ceased amoxicillin.

Carbapenems and monobactams — Patients with immediate cephalosporin allergy usually tolerate carbapenems (eg, imipenem, meropenem, ertapenem, and doripenem) and monobactams (ie, aztreonam) [28,93]. In the largest study available, 98 patients with convincing histories of immediate cephalosporin reactions and positive skin tests to the culprit cephalosporin underwent allergy evaluation and graded challenge with several related medications. Overall, fewer than 5 percent had positive skin tests to carbapenems or monobactams [28]. For ethical reasons, patients with positive skin tests were not challenged to determine if the positive results were true.

Carbapenems share a common four-membered beta-lactam ring with cephalosporins (and penicillins) and hence the potential for cross-sensitization, although clinical cross-reactivity with cephalosporins appears to be rare (figure 4). In the study mentioned above, only 1 of 98 subjects was skin test positive to both cephalosporins and carbapenems (both meropenem and imipenem), and this patient also tested positive to penicillin reagents and aztreonam. Therefore, his IgE antibodies were probably directed against the beta-lactam ring that is shared by all beta-lactams [28]. In the 97 subjects with negative skin tests to carbapenems, graded challenges were performed with meropenem and imipenem and were well-tolerated by 96 patients. The one remaining subject developed a mild urticarial eruption 30 minutes after the full dose of imipenem.

The author's recommended approach to patients with a history of an immediate reaction to a cephalosporin, who now require a carbapenem, is to perform skin testing with the carbapenem in question. The concentrations used in the study above were meropenem at 1 mg/mL and imipenem at 0.5 mg/mL for each component [28].

If skin tests are negative, the carbapenem can be given by graded challenge.

If skin tests are positive, the carbapenem should be given only if there is no alternative drug and then using a desensitization protocol. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

Aztreonam is the only monobactam clinically available. Although it contains a monocyclic beta-lactam core, with very rare exceptions [14,91], it does not pose a risk to patients allergic to penicillin. It also does not pose a risk to patients allergic to cephalosporins other than ceftazidime. However, clinical cross-reactivity has been reported between aztreonam and ceftazidime, which share an identical R1 side chain group [28,94,95]. Despite the similarity in side chain groups, not all ceftazidime-allergic patients react to aztreonam [28,96], and not all aztreonam-allergic patients react to ceftazidime [97]. Therefore, we suggest that patients who experienced immediate reactions to ceftazidime in the past and now require aztreonam be skin tested to aztreonam at concentrations up to 20 mg/mL [70].

If aztreonam skin test results are negative, the patient can receive it by graded challenge.

If aztreonam skin tests to aztreonam are positive and the patient has a particular need for this drug, then it should be administered using a rapid desensitization protocol. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

If an allergy evaluation is not possible, then we suggest informing the patient with a past reaction to ceftazidime that the risk of reacting to aztreonam is estimated at less than 5 percent [28] and then performing a graded challenge.

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".)

SUMMARY AND RECOMMENDATIONS

An evaluation for immediate hypersensitivity to cephalosporins is appropriate in any patient who experienced signs of symptoms of immediate allergy shortly (within minutes to a few hours) after receiving a cephalosporin (table 1), as well as patients with isolated urticaria or angioedema regardless of the timing of onset. If the immediate allergy is confirmed, it is still likely that the patient can be demonstrated (through skin testing and graded challenge) to tolerate other beta-lactam drugs, including structurally dissimilar cephalosporins, penicillins, carbapenems, and monobactams. (See 'Allergy evaluation' above.)

Cross-reactivity among cephalosporins and between cephalosporins and penicillins commonly arises from structural similarities in side chain groups or rarely from sensitization to the core beta-lactam ring (present in both penicillins and cephalosporins) or metabolites of this ring (figure 1). (See 'Allergy evaluation' above.)

The allergy evaluation is similar to that for immediate penicillin allergy and is based on skin testing and graded challenge. However, testing for immediate cephalosporin allergy is not as well-validated and reliable as testing for penicillin allergy, for several reasons. In vitro immunoglobulin E (IgE) assays specific to cephalosporins are used in some countries but not in the United States. (See 'Skin testing' above and 'Graded challenge (Test dosing)' above and 'In vitro testing' above.)

An algorithm depicts the approach to identifying a safe alternative cephalosporin in a patient with a past immediate cephalosporin reaction (algorithm 1). (See 'Other cephalosporins' above.)

Most patients with immediate reactions to cephalosporins and no history of reacting to penicillins will tolerate penicillins. If a patient reacted to a cephalosporin in the past and now requires a penicillin, then penicillin allergy testing is indicated to guide management as shown (algorithm 2). (See 'Penicillins' above.)

Patients with immediate cephalosporin allergy usually tolerate carbapenems (eg, imipenem, meropenem, ertapenem, and doripenem). An approach to evaluating such patients, which involves carbapenem skin testing, is described. (See 'Carbapenems and monobactams' above.)

Aztreonam is the only monobactam available for clinical use, and there is no evidence of immunologic cross-reactivity between the core cephalosporin structure and monobactams, so most cephalosporin-allergic patients may receive aztreonam normally. An exception is the patient with a past immediate reaction to ceftazidime, because aztreonam and ceftazidime share an identical side chain, and cross-reactivity between the two drugs is reported. An approach to evaluating such patients, which involves aztreonam skin testing, is described. (See 'Carbapenems and monobactams' above.)

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Topic 13536 Version 17.0

References

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