Cephalosporin hypersensitivity: Clinical manifestations and diagnosis

INTRODUCTION — Cephalosporins are among the most commonly used antibiotics, and their use is increasing over time [1-4]. Several types of hypersensitivity reactions have been reported with cephalosporins, ranging from mild, delayed-onset cutaneous reactions to life-threatening anaphylaxis in patients with immunoglobulin E (IgE)-mediated allergy [5-11].

This topic reviews the clinical manifestations, pathogenesis, and diagnosis of hypersensitivity reactions to cephalosporins. Issues of cross-reactivity between cephalosporins, penicillins, and related drugs, and the subsequent use of cephalosporins and related antibiotics in patients with cephalosporin or penicillin allergy, are discussed separately. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics".)

DEFINITIONS — A drug allergy may be defined as a specific immunologic reaction to a drug [12]. The classification and pathogenesis of drug allergies are discussed in detail separately. (See "Drug hypersensitivity: Classification and clinical features" and "Drug allergy: Pathogenesis".)

Immediate versus delayed reactions — The World Allergy Organization (WAO) has recommended categorizing immunologic drug reactions based upon the timing of the appearance of symptoms [12]. This system defines two broad categories of reactions: immediate and delayed. This division is intended to distinguish immunoglobulin E (IgE)-mediated (type I reactions), which account for many immediate reactions, from other types, because IgE-mediated reactions carry the risk of life-threatening anaphylaxis if the patient is re-exposed.

●Immediate reactions classically begin within one hour of the last administered dose and may begin within minutes. However, some immediate reactions appear after one hour, particularly if the drug was administered orally or taken with food. For these reasons, some guidelines include reactions beginning up to six hours after the last administered dose in the immediate category [13-16]. Nevertheless, the period of one hour identifies most immediate reactions associated with cephalosporins and other beta-lactam antibiotics. When sensitization (ie, formation of IgE) to a drug first develops, the initial symptoms may appear towards the end of a course of treatment but usually within one hour of the last administered dose and then typically escalate rapidly with any successive doses. Another common pattern is for symptoms to appear rapidly after the first dose of a subsequent course.

●Delayed (or nonimmediate) reactions occur more than one hour after the initial drug administration [14-16]. Most delayed reactions begin after six hours and typically after days of treatment. Delayed reactions are more common than immediate reactions. They may be caused by several different mechanisms, but generally they are not IgE-mediated.

The classification and pathogenesis of allergic drug reactions are presented in detail separately. (See "Drug hypersensitivity: Classification and clinical features" and "Drug allergy: Pathogenesis".)

CLINICAL HISTORY — The primary aims of the clinical history are to assess what type of reaction the patient likely experienced in the past, and to detect severe drug reactions, such as anaphylaxis (immediate), or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) (delayed). The history of a drug reaction should ascertain the following:

●Each exact agent reportedly associated with a reaction, and how it was administered (parenterally or orally) (table 1).

●The indication for its use (to make sure the reported drug is consistent with the indication).

●The signs and symptoms of the reaction.

●How long ago the reaction occurred (patients with more recent reactions are at higher risk for recurrence). (See 'Natural history' below.)

●The timing of onset of the reaction (both from the precipitating dose, as well as from the initiation of that course of therapy).

●Any treatment given and response to that treatment (including the duration of the reaction).

●Other concurrent medications, especially if they were new or temporary.

●Any prior or subsequent history of exposure to the same drug or structurally similar drugs, with or without reactions. The source of this clinical history may be the patient, the medical record, a relative, the primary care physician, or a combination of sources.

IMMEDIATE REACTIONS — Immediate reactions are characterized by various combinations of flushing, urticaria, angioedema, rhinitis, bronchospasm, hypotension, and anaphylactic shock, usually developing within an hour of the last administered dose (table 2).

Signs and symptoms

Urticaria with or without angioedema — Many immediate reactions involve urticaria or hives, which are intensely pruritic, erythematous, cutaneous plaques or papules (picture 1A-C). Individual urticarial lesions resolve over the course of hours without residual markings, and then reappear elsewhere. Angioedema of the face, hands, or other areas may also be present, which develops within an hour or two of administration and resolves gradually over one to five days, depending upon severity. Careful attention should be paid to the patient's skin, both at the time of evaluation and when recording the details of the reaction in the patient's medical record, since accurate and detailed information can greatly facilitate later diagnosis and management.

Urticaria and angioedema developing rapidly after administration is considered an immediate reaction. However, urticaria and angioedema that develop later in the course of treatment may represent a form of delayed drug reaction, and these two reactions can be difficult or impossible to distinguish without an allergy evaluation if the clinical history is vague. (See 'Delayed-onset urticaria/angioedema' below.)

Occasionally, the diagnosis of potential drug allergy and the timing of a potential reaction is confused by an individual's underlying tendency to chronic urticaria. Patients should be asked if they are prone to developing urticaria in other situations, and whether they have ever had prolonged or unexplained episodes of urticaria and/or angioedema.

Anaphylaxis — Anaphylaxis, the most severe and potentially fatal form of immunoglobulin E (IgE)-mediated reaction, may present with a spectrum of possible signs and symptoms affecting multiple organ systems (table 2) [17-27]. A typical presentation of drug-induced anaphylaxis would be rapid onset of urticaria, accompanied by pruritus, flushing, throat tightness, chest tightness or cough, possibly progressing to hypotension or shock. (See "Anaphylaxis: Acute diagnosis" and "Anaphylaxis: Emergency treatment".)

Some anaphylactic reactions to cephalosporins, such as ceftazidime, ceftriaxone, cefazolin, and cefuroxime, have caused a special type of vasospastic myocardial ischemia or infarction called Kounis syndrome [27-37], in which vasospasm of epicardial coronary arteries can occur in response to increased inflammatory mediators released during a hypersensitivity reaction [38].

The incidence of cephalosporin-induced anaphylaxis ranges from 0.6 to 6.8 cases per 100,000 exposures [9,10,39,40]. A particularly high incidence (6.8 cases per 100,000 exposures) was found in a Korean study [10], in which the incidence of fatal anaphylaxis was 0.1 cases per 100,000 exposures. In an American study, 33 (9 percent) of 368 fatalities, in which a culprit drug class could be identified, were due to cephalosporins [41].

An increasing number of anaphylactic reactions to cephalosporins have been reported in the last decade [10,41-67]. In a study recorded by the French Allergy Vigilance Network, cephalosporins were responsible for 12 percent of severe drug-induced anaphylaxis [42], whereas, in a Chinese study, they accounted for the majority (34.5 percent) of 467 antibiotic-induced anaphylaxis [48]. In a study of reported drug-induced anaphylaxis in the electronic health records of a large United States health care system, the prevalence of cephalosporin anaphylaxis was 6.1 per 10,000 [49].

Any cephalosporin can cause anaphylaxis [10,17-37,40,42-58,61-146], although cefazolin, cefaclor, cefuroxime, and ceftriaxone have been reported more often [19,20,22,24,26,28-37,40,42-56,58,61-64,66-81,83-98,110,111,113,114,119-125,128-136,138,139,141-144,146]. Parenterally-administered drugs may be more commonly implicated. Cases of anaphylaxis due to an occupational exposure to cephalosporins (eg, cefotiam and cefuroxime) have also been reported [101,106,109,125-127,147].

Management of acute reactions — The suspect cephalosporin should be discontinued and symptomatic treatments administered:

●Anaphylaxis is treated with intramuscular epinephrine, as described in detail separately. (See "Anaphylaxis: Emergency treatment".)

●Antihistamines are given for urticaria. Angioedema also responds to antihistamines, and glucocorticoids can be added for severe symptoms. Specific agents and dosing are discussed in detail separately. (See "New-onset urticaria", section on 'Treatment'.)

Photos of the reaction should be obtained by the patient or clinician and added to the patient's medical record for future reference. The causative drug should be listed as an allergy, with a description of the reaction and timing relative to the last administered dose.

The patient should be told to avoid all cephalosporins and penicillins until evaluated by an allergist, particularly if the reaction was anaphylaxis. Among patients with an immediate allergy to cephalosporins, less than two percent will react to penicillins, but immediate reactions can be dangerous. In addition, there may be higher rates of cross-reactivity between cephalosporins and penicillins that share common side chain groups, and an understanding of these patterns is important for choosing alternative drugs that are more likely to be tolerated. Referral to an allergist should be arranged whenever possible, because it is likely that the patient can be cleared to take penicillins and other cephalosporins. (See 'Referral to an allergy specialist' below.)

Geographical differences — Cefazolin has been responsible mainly for perioperative anaphylactic reactions worldwide, especially in North America [26,33-35,37,40,42,44,46-48,52,54-56,58,62,63,65,67,97,110,111,113,114,130-132,134-136,138,139,142-144]. Anaphylactic reactions to other cephalosporins, such as cefaclor, cefuroxime, ceftazidime, cefotaxime, and ceftriaxone, have also been reported worldwide, but mainly in European countries, such as Italy, Spain, and France [19,20,22-24,27-32,36,40,42-45,47-51,53,58,62-64,66-98,116-125,128,129,133,141,145,146]. Several anaphylactic reactions to cefaclor have been reported in Korea [53,61,133]. In China and Iran, ceftriaxone has been responsible for many deaths [50,51]. Ceftriaxone was also associated with the highest number of fatalities in an analysis of an Italian database [141]. Anaphylactic reactions to cefotiam, cefotetan, and cefoperazone have been reported almost exclusively in Japan, Korea, and China [10,21,25,48,101,109,112,126,127,137,140].

Pathophysiology — Immediate reactions occur in patients who have formed IgE antibodies against specific allergenic epitopes of a cephalosporin molecule, or a metabolite of the molecule, or the combination of the drug/metabolite conjugated to serum proteins. These reactions are classified as type I reactions in the Gell and Coombs system of immunologic reactions (table 3). If a patient with these antibodies receives the same drug again, the drug (or its metabolite, etc) reacts with IgE bound to the surface of mast cells and basophils and leads to the wide-spread activation, degranulation, and release of vasoactive mediators from these cells. These mediators cause the signs and symptoms of immediate reactions.

Possible allergens — Patients may develop IgE antibodies against antigenic determinants that are unique to cephalosporins or to determinants that are shared with other beta-lactam drugs, particularly the penicillins [148-153]. The core structure of both penicillins and cephalosporins contains a four-membered beta-lactam ring (figure 1). Patients may become sensitized to the entire cephalosporin molecule (most common), the side chain groups, or to the beta-lactam core or its metabolites (least common), as discussed in more detail separately. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Potential allergenic components'.)

The significance of side chain groups — Penicillins and cephalosporins can be grouped according to similarities in the structures of side chain groups [153-157]. There are data to support side chain cross-reactivity within the same class of beta-lactams (eg, cephalosporins), as well as across different beta-lactam classes (eg, aztreonam and ceftazidime). However, the clinical relevance of these groupings and epidemiologic differences related to antibiotic use across populations has not been adequately studied. Thus, both of the following statements are accurate:

●It is not necessarily true that patients who have had an allergic reaction to a given cephalosporin will also react adversely to other cephalosporins or penicillins with identical or similar side groups.

●Conversely, clinicians must not falsely assume that a cephalosporin-allergic patient will not react to another cephalosporin solely because it has a different side chain group from the culprit cephalosporin. Instead, it is better to be cautious and consult an allergy specialist for assistance with patients with severe past reactions.

Issues of cross-reactivity among cephalosporins and between cephalosporins and penicillins, carbapenems, and monobactams are discussed in more detail separately. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics".)

Cross-reactivity — Patients with a possible immediate allergy to a cephalosporin should be advised to avoid all cephalosporins and penicillins until evaluated by an allergy specialist, particularly if the reaction was serious. In reality, such individuals may be able to receive other cephalosporins [34,44,46,56,62,66,67,97,144] and/or other beta-lactams including penicillins safely [34,46,47,62,63,66,67,92,97,144], although this is best determined through an allergy evaluation. (See 'Referral to an allergy specialist' below.)

Among cephalosporins — A significant percentage (ie, up to 43 percent in large studies) of patients who react to one cephalosporin will react to other cephalosporins and particularly those cephalosporins that have a shared R1 group [44,67,74,81,89,92]. One possible but important exception to this general statement may be patients with immediate reactions to cefazolin, which has R1 and R2 groups that are distinct from all other currently marketed beta-lactams, except ceftezole, a first generation cephalosporin that shares an identical R1 side chain and a similar R2 side chain with cefazolin [155]. Ceftezole, which is marketed under different trade names, is available in Italy, South Korea, and some Southeastern Asian countries. Several studies suggest that skin test-positive patients with past immediate reactions to cefazolin often tolerate other cephalosporins (except ceftezole) and other beta-lactams [34,35,44,46,56,62,67,97,136,142-144]. However, allergy evaluation is still advised whenever possible.

Between cephalosporins and penicillins — Most patients with immediate reactions to cephalosporins are allergic only to cephalosporins and not to penicillins [34,46,47,62,63,66,67,92,97,144]. 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, such as the aminocephalosporins (cephalexin, cefadroxil, and cefaclor) and the aminopenicillins (amoxicillin, ampicillin, bacampicillin), which are most commonly used in outpatient practice [47,158]. Studies showing these higher rates evaluated mainly European populations, and the corresponding rates in other populations are less well defined. In a study of Australian and American adults with histories of hypersensitivity reactions to cephalosporins and/or penicillins , 11 (6.3 percent) of the 174 patients who were initially labeled as allergic to aminocephalosporins had positive skin tests to ampicillin; all 11 patients had been labeled as allergic to cephalexin [67]. As had been seen in previously published studies This apparent aminopenicillin and aminocephalosporin cross-reactivity predominated in the Australian cohort of this study, as had been seen in previously published studies [159]. Therefore, because cross-reactivity between penicillins and cephalosporins does occur, allergy evaluation is advised whenever possible.

With other beta-lactam drugs — Patterns of cross-reactivity among different beta-lactam antibiotics, including carbapenems and monobactams, are summarized in the figure and discussed in further detail separately (figure 2). (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Use of related antibiotics in cephalosporin-allergic patients'.)

Natural history — IgE-mediated allergy to beta-lactams, including cephalosporins, can resolve over time in patients who successfully avoid further exposure [160,161]. This is discussed in more detail separately. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Natural history'.)

Evaluation and diagnosis — The diagnosis of an immediate cephalosporin reaction that occurred in the past is based upon the clinical history, skin testing, and graded challenge (when appropriate) [15,16,162,163]. Skin testing and graded challenges are usually performed by allergy specialists, or other clinicians specifically trained in these techniques. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics".)

As with other drug allergies, skin testing is not a reliable way to screen for cephalosporin allergy in a patient who never received a cephalosporin or who received one without an adverse reaction [164].

Referral to an allergy specialist — Patients with past reactions to cephalosporins that are suspected to have been immediate reactions and who require subsequent use of other cephalosporins or penicillins should be evaluated by an allergy specialist. Isolated urticaria, with or without angioedema, can represent either an immediate or a delayed drug reaction, and it is difficult to distinguish the two based on clinical history alone because patients may not be clear about the timing of symptom onset. Therefore, we suggest allergy evaluation for these patients also. The purpose of this evaluation, which usually involves skin testing and graded challenge, is to determine what other drugs may be safely administered to that patient. Most patients will be able to tolerate other cephalosporins and/or penicillins [34,44,46,47,56,62,63,66,67,92,97,144].

If referral is not feasible — If referral to an allergist in the outpatient setting is not feasible or possible in a timely fashion, patients with suspected past immediate reactions should avoid all cephalosporins and penicillins if there are alternative antibiotics that can be used. However, if a cephalosporin or penicillin is considered the best option for a serious infection and there is no equivalent alternative antibiotic, then a graded challenge with an alternative cephalosporin or a penicillin can be performed, followed by formal outpatient allergy evaluation in the future. The choice of an alternative cephalosporin is discussed separately. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Graded challenge (Test dosing)'.)

NONIMMEDIATE REACTIONS — A large percentage of cephalosporin reactions are nonimmediate (or delayed) and consist of signs and symptoms limited to the skin. Most of these reactions will not recur upon re-exposure. Nonimmediate reactions most often consist of maculopapular or morbilliform cutaneous eruptions or delayed-onset urticaria and/or angioedema. In a pediatric series of 105 patients with nonimmediate/delayed reactions to cephalosporins, 58 demonstrated urticaria, 29 had maculopapular rash, 13 had erythema, 8 had both urticaria and angioedema, and 8 had isolated angioedema [68].

The pathogenesis of nonimmediate reactions seems to be heterogeneous and is not completely understood:

●Clinical and immunological studies suggest that a type IV (cell-mediated) pathogenic mechanism may be involved in some nonimmediate reactions, such as maculopapular, pustular, and bullous exanthemas (table 3) [165-167].

●Some nonimmediate cutaneous reactions may not represent drug hypersensitivity at all, but may simply be manifestations of the underlying viral infection itself or an interaction between the drug and the virus [168]. Similar to the known interaction with aminopenicillins, concomitant infection with certain viruses, such as Epstein-Barr virus (EBV), may predispose patients receiving cephalosporins to develop delayed cutaneous reactions [169-172].

Common reactions (usually mild) — The two most common types of nonimmediate reactions to cephalosporins are cutaneous maculopapular eruptions and delayed-onset urticaria and/or angioedema.

Cutaneous maculopapular eruption — Maculopapular or morbilliform eruptions are common adverse reactions to cephalosporins in both children and adults (picture 2 and picture 3) [68,173-175]. These are mostly mild and self-limited and are typically delayed in onset by several hours to days after the initiation of therapy [68,173-175]. The lesions of maculopapular drug eruptions are relatively fixed and last for several days, in contrast to urticarial lesions (which are transient, appear in crops, and then resolve within hours). (See "Exanthematous (maculopapular) drug eruption".)

Acute management — Acute management involves discontinuing the causative drug and symptomatic treatment if needed (see "Exanthematous (maculopapular) drug eruption", section on 'Management'). Photos of the reaction should be obtained by the patient or clinician and added to the patient's medical record for future reference. The causative drug should be listed as an allergy with a description of the reaction and its timing of onset relative to the last dose. The patient should be told to avoid the causative drug in the future, but other cephalosporins will likely be tolerated, as discussed below. Patients with delayed maculopapular eruptions to a cephalosporin generally do not need to avoid penicillins or other beta-lactams. (See 'Evaluation and diagnosis' below.)

Delayed-onset urticaria/angioedema — Urticaria and/or angioedema that appear several hours or days after the last administered dose are another common presentation of delayed cephalosporin reactions, in both children and adults [68,173-175]. In the pediatric series of 105 patients mentioned above, 58 of 116 nonimmediate reactions to cephalosporins in otherwise healthy children were urticarial eruptions [68]. Features that help distinguish these reactions from immediate reactions include the delayed onset of symptoms and the absence of other signs or symptoms of anaphylaxis, such as bronchospasm or hypotension. However, in reality, it can be difficult or impossible to determine from history alone if urticaria and angioedema resulted from a delayed or an immediate cephalosporin reaction. Because immediate allergy can progress to anaphylaxis with re-exposure, these patients should be evaluated for immediate allergy before they are given cephalosporins again [68,174]. (See 'Referral to an allergy specialist' above.)

Acute management — Management involves discontinuing the causative drug and symptomatic treatment if needed (see "New-onset urticaria", section on 'Treatment'). Photos of the reaction should be obtained by the patient or clinician and added to the patient's medical record for future reference. The causative drug should be listed as an allergy, with a description of the reaction and its timing relative to the last dose. The patient should be told to avoid all cephalosporins and penicillins until evaluated by an allergist, as described in the next section.

Evaluation and diagnosis — The diagnosis of a mild nonimmediate cephalosporin reaction is based upon the clinical history and physical exam (if signs or symptoms are still present). Further evaluation depends upon the presence of hives or angioedema:

●If the nonimmediate reaction involved hives or angioedema, we advocate evaluating for immunoglobulin E (IgE)-mediated allergy to the cephalosporin that caused the reaction, an alternative cephalosporin that is likely to be useful in the future, and penicillin. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics".)

●If the patient's past reaction did not involve hives or angioedema and was mild (eg, maculopapular rash lasting less than one week and without systemic symptoms), then a graded challenge to the desired cephalosporin can be performed. We generally avoid the same drug that caused the index reaction, but that drug can be used if it is superior for the treatment of a specific infection.

The utility of other types of testing for the diagnosis of nonimmediate reactions is debated and practice differs between European and American allergists [166]. Centers in Europe and Australia evaluate nonimmediate reactions with delayed reading of intradermal tests and/or patch testing followed by challenge if testing is negative and the index reaction was mild [67,68,166,173-177]. However, when delayed readings of intradermal tests and patch testing have been performed, the results are negative in most patients [67,173-175]. This may be particularly true in children, in whom delayed rashes temporarily associated with cephalosporins and other beta-lactams may be the result of a viral exanthem or a drug-infection interaction that does not reproduce on re-exposure. According to a 2020 European position paper, direct challenges (ie, without previous skin testing) with suspected cephalosporins or penicillins can be performed in children with mild maculopapular exanthemas (ie, limited or widespread rash; <1-week duration, without systemic involvement) [15]. The following studies are representative:

●In a study from the author's center of 105 children with delayed reactions to cephalosporins, all had negative reactions to delayed readings of intradermal testing [68]. One hundred and four children with negative tests were offered challenge with the cephalosporin that caused the index reaction, 95 accepted, and all tolerated the drug. One patient developed hives to a suspension of the drug, but tolerated it in capsules, indicating that the reaction was due to an excipient [68].

●In a similar study of 105 adults with nonimmediate reactions, only five patients demonstrated positive responses to delayed-reading intradermal tests with the responsible cephalosporins [174]. Of those with negative delayed readings, 86 agreed to be challenged, and all tolerated the drug.

●In the aforementioned study of Australian and American adults, 7 (8.4 percent) of the 83 adults with histories of nonimmediate reactions to cephalosporins had positive delayed-reading intradermal tests to a cephalosporin [67]. Another study evaluated 91 patients ranging from 12 to 93 years with such histories by performing patch tests; 4 subjects (4.4 percent) were positive [175].

The author's approach to diagnosis in patients with mild nonimmediate cutaneous reactions to a specific cephalosporin, and where a sterile injectable preparation of the drug is available, is to perform delayed-reading intradermal skin testing, and if this is negative, graded challenge is performed [178]. The argument in favor of performing delayed-reading skin testing is that it can further improve the safety of graded challenge.

In the United States, the more common approach is to base the diagnosis on clinical features, with skin testing to exclude immediate allergy if the index reaction involved urticaria and angioedema, and challenge to prove tolerance. However, an increasing number of allergy and dermatology specialist centers are performing delayed-readings of intradermal skin testing and patch testing [67,166,179].

Challenge procedures — For patients with past nonimmediate (delayed) index reactions that were mild (exanthem [rash], isolated urticaria and/or angioedema) who subsequently require a cephalosporin, challenge procedures are not standardized and different experts have distinct approaches. The optimal approach is not known, and the issues with such challenges are described in this section. The limitations of challenges should be explained to patients.

In general, challenge (also called test dosing) protocols are based upon the time course of the patient's reaction and the pharmacology of the drug involved. Many different protocols have been described, ranging from graded challenge, to full single-dose challenge, to multiple-day procedures, although multiple-day challenges are not commonly done outside of specialty drug allergy centers. Of note, the lack of a response to a challenge may not preclude a recurrent nonimmediate reaction with full therapeutic treatment. Specifically, studies of penicillin reactions have documented that some delayed reactions only develop after several days of a full therapeutic dose or only in the presence of a concomitant viral infection [180-182].  

Regional differences in practice exist, although a common and pragmatic approach to challenge in patients whose index reactions were mild and delayed is to administer 1/10^th of a full therapeutic dose, and if there is no reaction within one hour, to give a full dose, followed by another hour of observation. Another common approach is to administer the full dose as a single-step challenge and observe for one hour. Delayed reactions can occur up to 48 hours later (and up to eight days later, in rare cases), and the patient should be informed about this, although these reactions are generally mild [183].

●In one study of patients who had negative allergy evaluations followed by a one-day, full-dose challenge, subjects were investigated with a questionnaire to determine if they had subsequently taken the beta-lactam antibiotic in question again [183]. Among the 371 subjects with nonimmediate index reactions, the one-day challenge had a negative predictive value (NPV) of 94.9 percent.

●The author's approach to challenging adults with past mild delayed reactions and negative delayed-reading intradermal tests is to give 1/10^th of the maximum single unit dose and, if tolerated, to administer a full dose one to seven days after, depending on the time interval of the index reaction [15,174]. However, this approach may not be practical in many settings.

●According to a European position paper, if the patient requires therapy at the time of the challenge, the one-tenth dose (if tolerated) should be followed one hour later by a full dose [15]. If a full dose is tolerated, a normal course of the drug can be administered.

Uncommon reactions (more severe) — Cephalosporins have been associated with other types of nonimmediate hypersensitivity reactions that can be severe and even life-threatening, including the following:

●Severe blistering cutaneous reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) [51,184-187], acute generalized exanthematous pustulosis (AGEP) [176,187-192], and erythroderma [193,194]. Patients with these severe reactions should never be exposed to the causative drug again. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Acute generalized exanthematous pustulosis (AGEP)".)

●Acute localized exanthematous pustulosis [195,196]. (See "Acute generalized exanthematous pustulosis (AGEP)".)

●Isolated fever [197,198] and isolated eosinophilia [199,200]. (See "Drug fever" and "Approach to the patient with unexplained eosinophilia", section on 'Causes of eosinophilia'.)

●Drug reaction with eosinophilia and systemic symptoms (DRESS), also called drug-induced hypersensitivity syndrome (DiHS) [51,175,176,187,192,201-209]: DRESS/DiHS can be associated with involvement of internal organs such as hepatitis or interstitial nephritis and rarely can occur in association with cephalosporins in the absence of skin involvement or other features of DRESS. (See "Drug hypersensitivity: Classification and clinical features", section on 'Type IV reactions'.)

●Serum sickness-like reactions (SSLRs), present with fever, arthralgias, and rash (eg, painful urticarial plaques) [210]: Cefaclor, in particular can cause SSLRs in children, possibly due to a genetic defect in metabolism of this specific drug [211]. Serum sickness-like reactions to cephalosporins (especially cefaclor and cefprozil) are thought to be due to altered drug metabolism, rather than antibody formation [212]. Patients with cefaclor-associated SSLR can receive other cephalosporins normally in the future, including the structurally similar agent loracarbef [213]. (See "Serum sickness and serum sickness-like reactions".)

●Linear immunoglobulin A (IgA) bullous dermatosis [214]: Linear IgA bullous dermatosis is classically associated with vancomycin, although it may occur with beta-lactams and other antibiotics. It may present with lesions on the skin, on the mucous membranes, or in both locations. (See "Linear IgA bullous dermatosis".)

●Fixed drug eruptions (FDE) [215,216]: Cephalosporins are an uncommon cause of fixed drug eruption, which typically present with solitary round to oval, dusky red to brown/black macules that may evolve into edematous plaques or bullae (picture 4A-C). Sites of predilection include the lips, genitalia, perianal area, and extremities. Acute lesions usually develop 30 minutes to 8 hours after drug administration and resolve spontaneously in 7 to 10 days. Severe forms like generalized bullous FDE, which can share features of SJS, have also been reported [217]. (See "Fixed drug eruption".)

Use of related drugs following a severe delayed reaction — Individuals with a history of SJS/TEN or DRESS/DiHS while taking a cephalosporin should avoid all cephalosporins, and especially avoid those cephalosporins that share R1 or R2 side chain with the culprit cephalosporin, unless there is a critical clinical indication such that the potential benefit outweighs any risk. This cautious approach is appropriate because re-exposure in a patient with SJS/TEN or DRESS carries the risk of reactivation of the reaction, which can cause significant short- and long-term morbidity or death. The same approach applies to AGEP, although cross-reactivity patterns have not been well-established, and AGEP is not associated with any known mortality or long-term morbidity. However, a cautious approach is appropriate in most situations involving these severe reactions, until more data are available.  

In patients with SJS/TEN, DRESS/DiHS, and AGEP to a cephalosporin, it is usually prudent to avoid penicillins also, particularly those containing the same side chains (eg, aminopenicillins) and other beta-lactams sharing side chains with the culprit drug (eg, aztreonam if the culprit was ceftazidime). In contrast, carbapenems are generally considered safe in the setting of severe cutaneous adverse drug reactions or organ-specific hypersensitivity to cephalosporins, due to very low cross-reactivity, and aztreonam could be used if ceftazidime was not the culprit. A few studies have evaluated the safety of using aztreonam [192,218] or carbapenems [219] in patients with past severe reactions to penicillins. In a study from the author's center [218], seven patients with severe T cell-mediated hypersensitivity to aminopenicillins (five with TEN and two with AGEP) were negative to aztreonam skin tests and tolerated aztreonam challenges. In another study from the same center [219], four patients with TEN and three with AGEP tolerated carbapenems (ie, imipenem/cilastatin, meropenem, and ertapenem) found negative in skin testing.

Research is ongoing into the evaluation of these severe delayed reactions and the safety of using related beta-lactams in the future. In European centers, patients with severe nonimmediate reactions, such as SJS/TEN, DRESS/DiHS, and AGEP are evaluated by both patch tests and delayed-reading intradermal tests [15,176,177,192,218,220]. In patients with more significant reactions, such as DRESS/DiHS, it is recommended that this type of testing be delayed at least six months after the acute reaction has subsided to avoid confusion with DRESS/DIHS relapse should a recurrence of symptoms occur. Patch tests are performed first (ie, prior to intradermal tests) and, if positive, intradermal tests are avoided. The sensitivity of patch testing for most types of drug-induced SJS/TEN is <40 percent [166,221]. If patch tests are negative, intradermal tests are performed using higher drug dilutions [15,220]. However, the positive and negative predictive values of patch tests or intradermal tests have not been fully defined, because in many studies, challenges to confirm true reactivity are not performed given the severity of these reactions [15,176,222].

Milder reactions — Milder reactions, such as serum sickness-like reactions (SSLRs), occur with both aminopenicillins and aminocephalosporins and are not a reason to avoid implicated or cross-reactive drugs indefinitely in the future. Studies on SSLR suggest that these reactions are less likely to recur with time and often do not recur on rechallenge in older children [223]. Similarly, single lesion, non-bullous, FDEs are milder reactions that may not preclude rechallenge with the implicated or potentially cross-reactive cephalosporins if there is clear benefit to treatment.  

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

●Use of cephalosporins is increasing, and this class of antibiotics can cause a range of hypersensitivity reactions. Drug hypersensitivity reactions may be broadly divided into immediate reactions, which develop rapidly (ie, within minutes to six hours) following administration, and nonimmediate (or delayed) reactions, which begin hours to days into a course of treatment. (See 'Definitions' above.)

●Immediate reactions to cephalosporins are primarily immunoglobulin E (IgE)-mediated reactions, such as urticaria, angioedema, or anaphylaxis (table 2). Patients with a possible immediate allergy to a cephalosporin should be advised to avoid all cephalosporins and penicillins until evaluated by an allergy specialist, particularly if the reaction was serious. In reality, such individuals may be able to receive other cephalosporins and/or other beta-lactams (including penicillins) safely, although this is best determined through an allergy evaluation. (See 'Immediate reactions' above.)

●The diagnosis of IgE-mediated immediate allergy to cephalosporins involves clinical history, skin testing to cephalosporins and penicillin determinants, and a challenge procedure when possible. Referral to an allergist is indicated if the patient is likely to require therapy with cephalosporins or penicillins in the future. (See 'Evaluation and diagnosis' above and "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Skin testing'.)

•Isolated urticaria and/or angioedema can represent either an immediate or a nonimmediate reaction. Therefore, all patients with urticaria and/or angioedema, regardless of the timing of onset, should undergo an evaluation for IgE-mediated allergy. (See 'Evaluation and diagnosis' above.)

•If referral to an allergist is not possible, and a cephalosporin or penicillin is considered the best option for a serious infection and there is no equivalent alternative antibiotic, then a graded challenge with an alternative cephalosporin or penicillin with different side chain structures can be performed, followed by formal outpatient allergy evaluation in the future. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Graded challenge (Test dosing)'.)

●Nonimmediate (delayed) reactions include common, mild reactions limited to the skin, such as maculopapular rash and delayed-onset urticaria and/or angioedema. The mechanisms involved in these reactions are not completely understood, but most of them will not recur upon re-exposure. The specific drug that caused the reaction is usually avoided in the future, although other cephalosporins with different side chain structures can be used. However, even the causative drug can be readministered using a challenge procedure if it is superior for the treatment of a specific infection. (See 'Common reactions (usually mild)' above and 'Evaluation and diagnosis' above.)

•Delayed urticaria and/or angioedema can be difficult or impossible to differentiate from immediate reactions if the timing of onset is unclear or the reaction occurred during the patient's first exposure to a drug. For this reason, we suggest that patients with delayed urticaria and/or angioedema undergo evaluation to exclude IgE-mediated immediate hypersensitivity, including skin testing and ingestion challenge. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Graded challenge (Test dosing)'.)

•For patients with delayed maculopapular rash, skin testing for immediate hypersensitivity is not necessary, although European centers often evaluate these reactions with delayed readings of intradermal testing, patch testing, or both. These forms of testing are not standard practice in the United States, where delayed exanthema are diagnosed clinically. (See 'Evaluation and diagnosis' above.)

●Cephalosporins can also cause serum sickness-like reaction and more severe delayed reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and rarely single organ involvement such as drug-induced liver disease. Patients with these types of severe reactions to cephalosporins benefit from assessment by a specialist, such as an allergist and immunologist or dermatologist for information on the safety of future antibiotic use. In some cases, avoidance of all cephalosporins and often related penicillins and beta-lactams is warranted, although there are exceptions. (See 'Uncommon reactions (more severe)' above.)