Clinical Management Review

Cephalosporin Allergy: Current Understanding and

Future Challenges
David A. Khan, MDa, Aleena Banerji, MDb, Jonathan A. Bernstein, MDc, Basar Bilgicer, PhDd,
Kimberly Blumenthal, MD, MScb, Mariana Castells, MD, PhDe, Daniel Ein, MDf, David M. Lang, MDg, and
Elizabeth Phillips, MDh Dallas, Texas; Boston, Mass; Cincinnati and Cleveland, Ohio; Notre Dame, Ind; Washington, DC; and
Nashville, Tenn

INFORMATION FOR CATEGORY 1 CME CREDIT AMA PRA Category 1 CreditÔ. Physicians should claim only the credit
commensurate with the extent of their participation in the activity.
Credit can now be obtained, free for a limited time, by reading
the review articles in this issue. Please note the following List of Design Committee Members: David A. Khan, MD, Aleena
instructions. Banerji, MD, Jonathan A. Bernstein, MD, Basar Bilgicer, PhD, Kim-
berly Blumenthal, MD, MSc, Mariana Castells, MD, PhD, Daniel Ein,
Method of Physician Participation in Learning Process: The core MD, David M. Lang, MD, and Elizabeth Phillips, MD (authors);
material for these activities can be read in this issue of the Journal or Michael Schatz, MD, MS (editor)
online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The
accompanying tests may only be submitted online at www.jaci- Learning objectives:
inpractice.org/. Fax or other copies will not be accepted.
1. To appreciate the epidemiology and clinical presentations of ceph-
Date of Original Release: September 1, 2019. Credit may be obtained alosporin allergy.
for these courses until August 31, 2020.
2. To identify which beta-lactams have higher rates of cross-reactivity
Copyright Statement: Copyright Ó 2019-2021. All rights reserved. for specific cephalosporins.
Overall Purpose/Goal: To provide excellent reviews on key aspects of 3. To understand the utility of diagnostic tests in cephalosporin allergy.
allergic disease to those who research, treat, or manage allergic disease.
Recognition of Commercial Support: This CME has not received
Target Audience: Physicians and researchers within the field of external commercial support.
allergic disease.
Disclosure of Relevant Financial Relationships with Commercial
Accreditation/Provider Statements and Credit Designation: The Interests: K. Blumenthal reports a licensed clinical decision support
American Academy of Allergy, Asthma & Immunology (AAAAI) is tool that is used institutionally for inpatient beta-lactam allergy evalu-
accredited by the Accreditation Council for Continuing Medical Edu- ations at Partners HealthCare System. The rest of the authors declare
cation (ACCME) to provide continuing medical education for physi- that they have no relevant conflicts of interest. M. Schatz declares no
cians. The AAAAI designates this journal-based CME activity for 1.00 relevant conflicts of interest.

Cephalosporins are commonly used antibiotics both in allergic to cephalosporins tend to tolerate cephalosporins with
hospitalized patients and in outpatients. Hypersensitivity disparate R1 side chains but may react to other beta-lactams
reactions to cephalosporins are becoming increasingly common with common R1 side chains. Skin testing for cephalosporins has
with a wide range of immunopathologic mechanisms. not been well validated but appears to have a good negative
Cephalosporins are one of the leading causes for perioperative predictive value for cephalosporins with disparate R1 side
anaphylaxis and severe cutaneous adverse reactions. Patients chains. In vitro tests including basophil activation tests have

a
Department of Internal Medicine, Division of Allergy & Immunology, University of K. Blumenthal reports a licensed clinical decision support tool that is used institu-
Texas Southwestern Medical Center, Dallas, Texas tionally for inpatient beta-lactam allergy evaluations at Partners HealthCare
b
Department of Medicine, Division of Rheumatology, Allergy & Immunology, System. The rest of the authors declare that they have no relevant conflicts of
Massachusetts General Hospital, Boston, Mass interest.
c
Department of Internal Medicine, University of Cincinnati College of Medicine, Received for publication April 10, 2019; revised May 29, 2019; accepted for pub-
Cincinnati, Ohio lication June 2, 2019.
d
Department of Chemical and Biomedical Engineering, Notre Dame, Ind Corresponding author: David A. Khan, MD, Department of Internal Medicine, Di-
e
Department of Medicine, Division of Rheumatology, Allergy and Immunology, vision of Allergy & Immunology, University of Texas Southwestern Medical
Brigham and Women’s Hospital, Boston, Mass Center, 5323 Harry Hines Blvd, Dallas, TX 75390. E-mail: dave.khan@
f
Department of Internal Medicine, George Washington University Medical Center, utsouthwestern.edu.
Washington, DC 2213-2198
g
Department of Internal Medicine, Cleveland Clinic, Respiratory Institute, Depart- Ó 2019 American Academy of Allergy, Asthma & Immunology
ment of Allergy and Clinical Immunology, Cleveland, Ohio https://doi.org/10.1016/j.jaip.2019.06.001
h
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn
No funding was received for this study.

2105
2106 KHAN ET AL J ALLERGY CLIN IMMUNOL PRACT
SEPTEMBER/OCTOBER 2019

included prospective data from the Boston Collaborative Drug

Abbreviations used Surveillance Program.11 Cephalosporins were the causative drug
ADR- Adverse drug reaction class for 4% of “rash” and 5% of “hives” listed in a US-based
CF- Cystic fibrosis electronic heath record analysis.12,13 That analysis also identi-
HSR- Hypersensitivity reaction
fied cephalosporins as the causative drug class for 11% of all
RAST- Radioallergosorbent test
SCAR- Severe cutaneous adverse reaction
serum sickness-like reactions (SSLRs), 9% of all acute interstitial
SSLR- Serum sickness-like reaction nephritis, and 2.5% of angioedema reactions (Figure 1).12,13
Cephalosporin anaphylaxis incidence was 5 in 901,908
courses of oral cephalosporins and 8 in 487,630 courses for
parenteral exposures in one large US-based health plan.5 The
lower sensitivity when compared with skin testing. Rapid approximate incidence of electronic health recordedocumented
drug desensitization procedures are safe and effective and cephalosporin anaphylaxis in another US health system was 6.1
have been used successfully for immediate and some non- in 10,000 patients.14 Of 1,756,481 patients with an electronic
immediate cephalosporin reactions. Many gaps in knowledge health record report of drug-induced anaphylaxis, 1,078 (6.1%)
still exist regarding cephalosporin hypersensitivity. Ó 2019 had anaphylaxis documented from a cephalosporin antibitoic.14
American Academy of Allergy, Asthma & Immunology (J The most common cephalosporin anaphylaxis culprits in that
Allergy Clin Immunol Pract 2019;7:2105-14) population included cephalexin (1.1% of documented drug-
Key words: Cephalosporin; Penicillin; Allergy; Beta-lactam; induced anaphylaxis) and cefaclor (0.8% of documented drug-
Cross-reactivity; Skin test; Anaphylaxis induced anaphylaxis).14 Cefazolin is the most common cause
of perioperative anaphylaxis in the United States.15-17
Cephalosporins were the drug class reported to cause severe
cutaneous adverse reactions (SCARs) in 5% of possible SCAR
INTRODUCTION cases identified in the electronic health record allergy list.12,13
Cephalosporins are among the most commonly used antibi- In another US study covering more than 900,000 patients
otics for hospitalized patients in the United States and the most exposed to more than 1 million cephalosporins, there were only
common antibiotic class patients receive at discharge.1 In 3 cephalosporin-associated SCARs, and those 3 patients were
Europe, cephalosporins represent 11.4% of total outpatient an- also on other medications that also could have caused the
tibiotics, and their use has increased over time.2 Cephalosporins SCAR.5 In the largest US-based cohort of patients (n ¼ 69)
can cause a broad range of hypersensitivity reactions (HSRs) of with validated drug reaction with eosinophilia and systemic
differing immunopathology. This article will focus on our cur- symptoms syndrome, 38 had a known single causative drug
rent understanding of cephalosporin hypersensitivity, with spe- and cephalosporins were the known culprits in 5 patients
cial emphasis on immediate reactions to cephalosporins and (13%).18 Of antibiotic-induced SCARs reported to the Food
current approaches to delabeling patients. and Drug Administration’s adverse event reporting system from
2004 through 2018, ceftriaxone was the third most common
CEPHALOSPORIN ALLERGY EPIDEMIOLOGY drug reaction with eosinophilia and systemic symptoms syn-
Adverse drug reactions (ADRs) to cephalosporins are reported drome culprit (591 reported cases) and fifth most common
by 1.3% to 1.7% of US patients, with a prevalence that has been Stevens-Johnson syndrome/toxic epidermal necrolysis culprit
generally consistent over the last 20 years.3,4 The incidence of (598 reported cases) (Liqin Wang, PhD, and Li Zhou, MD,
cephalosporin ADRs was determined to be 0.80% for oral PhD, unpublished data, 2019).
cephalosporins and 0.64% for parenteral cephalosporins in one
large US health plan.5 Among inpatient allergic drug reactions in
one US hospital, a cephalosporin was the culprit drug in 4.3% in IMMUNOPATHOLOGY OF CEPHALOSPORIN
one study and 6.9% in another study.6,7 ALLERGY
Women report cephalosporin ADRs 2- to 3-fold more often Like most other drugs, cephalosporins are small molecules that
than do men.3,5 Multiple drug intolerance syndrome and mul- are not independently capable of causing an allergic reaction.19,20
tiple drug allergy syndrome are associated with cephalosporin An immune classification system provides a framework for
reactions, with approximately 15% of patients with multiple mechanistically understanding the differing clinical phenotypes
drug intolerance syndrome and multiple drug allergy syndrome of cephalosporin reactions, and models have been proposed to
counting cephalosporins as one of their culprit drug classes.8 explain how small molecules activate immune responses
The cephalosporin with the highest ADR prevalence in one (Figures 2 and 3).19,20 Cephalosporins, like penicillins, are
large northeastern US patient population was cephalexin prevalent causes of both immediate and delayed HSR pheno-
(0.6%).3 Third-generation cephalosporins (eg, ceftriaxone) and types.21 Under physiological conditions, the beta-lactam ring is
second-generation cephalosporins were the third and fourth most unstable and in the case of penicillins results in the generation of
common drug groups causing ADRs in a South Korean study of major and minor determinants that covalently bind to host
hospitalized patients.9 Ceftaroline, a newer “fifth-generation” proteins that have been well defined and used as testing strategies
parenteral cephalosporin often restricted for severe and resistant in clinical practice.22 The specific antigenic determinants of beta-
infections, has a high reported ADR incidence (up to 1 in 5).10 lactam allergy have been studied most extensively in the context
Cephalosporins can cause all HSR types, but the most of IgE-mediated reactions where it has been previously elucidated
commonly reported reaction is rash.4 There were 27 cutaneous that the antigenic determinant is predicated on the entire beta-
allergic reactions to cephalosporins among 1781 patients (1.5%; lactam and protein carrier molecule and differences in the
95% CI, 0.9%-2.1%) identified in a systematic review that class-specific side chain and R1 and R2 side chains provide the
J ALLERGY CLIN IMMUNOL PRACT KHAN ET AL 2107
VOLUME 7, NUMBER 7

Angioedema (n=1,022) common for these patients to tolerate cephalosporins such as

Respiratory reactions (n=737) cefazolin.34,35
Anaphylaxis (n=944) To date there have been few studies that have associated
Itching (n=1,346) variation in HLA and immediate reactions. The only HLA allele
Rash (n=10,711)
that has been significantly associated with drug-induced
Severe cutaneous adverse reaction (n=57)
anaphylaxis is HLA-DRB1*07:01 in association with aspar-
Hives/Urticaria (n=6,822)
aginase immediate reactions.36 There have been no studies that
Acute interstitial nephritis (n=27)
have been powered to specifically examine genetic risk factors for
Serum sickness (n=50)
cephalosporin allergy. In particular for IgE-mediated reactions,
where sensitivity will wane significantly over time and almost
0% 2% 4% 6% 8% 10% 12%
80% of cephalosporin-allergic individuals have lost skin-test
reactivity to the implicated drug by 5 years after the acute
FIGURE 1. Cephalosporin HSRs. This figure demonstrates the
reaction, it is assumed that HLA may be necessary but not suf-
proportion of each reported HSR in the electronic health record
ficient and subject to other ecologic and epigenetic factors.21,35
allergy module attributed to a cephalosporin antibiotic (X-axis), as
Candidate gene studies for beta-lactam allergy have demon-
determined by a large US health care system analysis that
strated the strongest associations with genetic variation in HLA
included 4,017,708 reactions reported by 2,734,506 patients.12
class II antigen presenting genes, NOD2 genes affecting class II
The HSRs are on the Y-axis, with the total number of HSRs
expression, genes involved in IgE synthesis (STAT6, IL4RA,
attributed to cephalosporin antibiotics displayed in parentheses.
IL13), expression of preformed mediators (LGALS3), and cyto-
kines (IL-4, IL-10, IL-18).37,38 For beta-lactams, a genome-wide
association study showing a signal in the class II HLA region did
antigen specificity.22,23 Unlike penicillins where the de- not reach genome-wide significance.39
terminants are stable and identifiable, determinants have not
been reliably defined for cephalosporins and the speed and effi-
ciency by which cephalosporins form hapten-protein conjugates CLINICAL PRESENTATIONS INCLUDING
is comparatively inferior to those of penicillins.24 Cephalosporins CEFAZOLIN IN PERIOPERATIVE ANAPHYLAXIS
differ from penicillins by both their 6-membered dihydrothiazine Cephalosporins are capable of causing HSRs ranging from
ring and the presence of an R2 group.21 Some evidence supports benign exanthema to anaphylaxis or SCAR. Maculopapular ex-
that the opening of the beta-lactam ring destroys the R2 side anthema are the most common form of delayed reactions. SSLRs
chain and leads to unstable conjugates and fragmented poorly may occur with many cephalosporins, but cefaclor has the
identified determinants.25,26 Although IgE antibodies can theo- highest relative risk for causing SSLR and in some series may
retically bind to the beta-lactam ring, the protein carrier, mole- represent more than 80% of antibiotic-associated SSLRs.40 The
cule, and side chains, it may be that the R1 side chain and the mechanism for cefaclor SSLR appears related to the production
remaining beta-lactam moiety covalently linking to host proteins of toxic metabolites and may have a pharmacogenetic basis, but
is central to immunogenicity. This hypothesis is supported by this has not been adequately explored.41 Although published data
in vitro as well as clinical data, which will be discussed later in the are limited, children with SSLR to cefaclor appear to tolerate
section on cross-reactivity. other cephalosporins.40 Cephalosporins are also a common cause
of antibiotic-associated SCARs.42
HSRs during the perioperative period are unpredictable and
PHARMACOGENETICS OF CEPHALOSPORIN can be life-threatening. Incidence of perioperative HSRs is likely
ALLERGY underreported but ranges in the literature from 1:1,380 to
Discovery of new HLA associations and drug hypersensitivity 1:20,000.43-45 The main etiological agents of perioperative
syndromes has been particularly impactful over the last 2 decades anaphylaxis are antibiotics and neuromuscular blocking agents,
in both improving drug safety and our understanding of the but this varies between countries. In the United States, antibi-
immunopathogenesis of these reactions.19,27-31 HLA associations otics are the most frequent cause of HSRs in the operating room,
with drug HSRs have not yet been described for most antimi- accounting for 50% of IgE-mediated perioperative HSRs.15,16
crobials including beta-lactams. The most significant associations Cefazolin, the first-line indicated perioperative antibiotic for
to date have been described between penicillins and drug- most operations, has been reported in several studies as the most
induced liver disease.28-30 For both flucloxacillin (available in common causative agent of perioperative anaphylaxis in the
Europe and Australia) and amoxicillin-clavulanate, the rarity of United States and some other countries.16,17,46,47
the drug-induced liver disease in relation to how commonly these
drugs are used has precluded translation of HLA use in screening.
There is currently not thought to be any cross-reactivity with CEPHALOSPORIN CROSS-REACTIVITY WITH
other beta-lactams for drug-induced liver disease associated with OTHER BETA-LACTAMS
either amoxicillin-clauvulanate or flucloxacillin.32 Another recent Patients with cephalosporin allergy appear to be at a higher
study found an association between the haplotype HLA- risk for a reaction to other beta-lactam antibiotics because of
DQA1*01:04/DQB1*05:03/DRB1*14:05 and drug and shared chemical structures (beta-lactam ring, R group side
nonedrug-induced interstitial nephritis.33 The specific relevance chains).48 However, patients with any reaction to a drug are at a
of this haplotype for beta-lactameassociated acute interstitial higher risk of having another reaction to a drug,8 and patients
nephritis is not known. Although semisynthetic penicillins are determined to be allergic on the basis of reactive skin test results
relatively common causes of acute interstitial nephritis, it is are not confirmed allergic with drug challenge in allergy practice
2108 KHAN ET AL J ALLERGY CLIN IMMUNOL PRACT
SEPTEMBER/OCTOBER 2019

FIGURE 2. Immunologic classification: Modified Gel Coombs classification of antibody-mediated and delayed T-cellemediated reactions:
Cephalosporins are associated with the full spectrum of reactions from type I (anaphylaxis)—IgE-mediated, type II (hemolytic anemia and
thrombocytopenia) to type III (serum sickness and vasculitis) as well as the full spectrum of T-cellemediated reactions (drug reaction with
eosinophilia and systemic symptoms, maculopapular eruption, Stevens-Johnson syndrome/toxic epidermal necrolysis, fixed drug erup-
tion, hepatitis, and acute generalized exanthematous pustulosis).

(because of valid safety concerns).49 Thus, precise cross-reactivity However, in the 98 patients with well-characterized severe IgE-
estimates remain unknown to date. mediated cephalosporin allergy histories, 3 patients were
In a study of 24 patients with cephalosporin reaction histories (3.1%; 95% CI, 1.0%-8.6%) skin test positive to aztreonam; the
(and a positive serum-specific IgE to cephalosporin), 2 patients remaining 95 (96.9%) tolerated aztreonam challenges.48
(8.3%; 95% CI, 2.3%-25.8%) had positive skin test results to
penicillin.50 In a study of 98 patients with well-characterized
IgE-mediated cephalosporin allergy histories and positive ceph- CROSS-REACTIVITY AMONG CEPHALOSPORINS
alosporin skin test results, 25 patients (25.5%; 95% CI, 17.9%- Several studies have suggested that cephalosporin-allergic
35.0%) had positive test results to penicillins (11 with positive subjects most often tolerate other cephalosporins with disparate
skin test results and 14 had only serum-specific IgE to penicillin R1 group side chains. The largest study to date from Romano
determinants positive).48 Among 34 hospitalized patients with et al53 evaluated 102 subjects (89 with anaphylactic histories)
cephalosporin allergy histories (not confirmed with testing) who from Italy with immediate reactions to cephalosporins who un-
received a 2-step graded challenge to penicillins, 2 patients derwent skin testing to alternative cephalosporins. They divided
(5.9%; 95% CI, 0.7%-19.7%) had an HSR.51 It thus appears subjects into 4 groups on the basis of the pattern of skin test
that cross-reactivity is likely less than 10%; the rate of reactions is reactions. Group A patients (71% of subjects) had hypersensi-
likely to be even lower in those who are unlikely to be allergic tivity to group A cephalosporins sharing a common R1
and when the cephalosporin challenged does not share the R1 methoxyamino group and included ceftriaxone, cefuroxime,
group. The generally low rate of clinical cross-reactivity observed cefotaxime, cefepime, cefodizime, and ceftazidime. Group B
between penicillins and cephalosporins that do not share the patients (13%) had hypersensitivity to group B cephalosporins
same R1 group, for both IgE- and other antibody-mediated and sharing a common R1 amino group (also shared by amoxicillin
T-cellemediated reactions, further supports the antigen speci- and ampicillin) and included cefaclor, cephalexin, and cefadroxil.
ficity of cephalosporin reactions.21 Group C patients (7%) had hypersensitivity to group C cepha-
In the cohort of 98 cephalosporin-allergic patients, 1 patient losporins that have unique R1 groups that are structurally un-
(1.0%; 95% CI, 0.0%-3.0%) had positive skin test results to related to other cephalosporins and included cefazolin,
both imipenem and meropenem.50 Among 15 hospitalized pa- cefamandole, cefoperazone, and ceftibuten. Group D subjects
tients with cephalosporin allergy histories including 3 with severe (9%) appeared to cross-react among groups with skin test reac-
IgE histories (not confirmed with testing) who received a 2-step tivity to 2 or more of groups A, B, and C. Ceftriaxone was the
graded challenge to carbapenems, 1 patient (6.7%; 95% CI, culprit cephalosporin in 60% of all patients followed by cefaclor
0.2%-32.0%) had an HSR, supporting the idea of infrequent (11.6%) and ceftazidime (8.9%). All 102 subjects tolerated 326
cross-reactivity between cephalosporins and carbapenems.51 challenges to other cephalosporin groups that were skin test
Aztreonam is less immunogenic than other beta-lactams.52 negative. This study therefore suggests that 91% of cephalo-
Patients with an allergy to cephalosporins can receive aztreo- sporin allergy is based on side-chain structure (groups A, B, and
nam (a monobactam and beta-lactam) without any concern of C) and that a negative skin test result to an alternative cepha-
cross-reactivity, except if the cephalosporin allergy is to ceftazi- losporin with a dissimilar R1 side chain predicts tolerance. Other
dime, because ceftazidime and aztreonam share a common R1 studies have confirmed side chain specificity in patients with
side chain that can result in cross-reactive allergic reactions. histories of anaphylaxis to cefazolin (cumulative total of 36
J ALLERGY CLIN IMMUNOL PRACT KHAN ET AL 2109
VOLUME 7, NUMBER 7

FIGURE 3. Models of immune activation. The hapten-prohapten model shows that the drug covalently binds to a peptide either intra-
cellularly in the endoplasmic reticulum before peptide processing and presentation or at the cell surface. The pharmacological interaction
model (p-i) shows the drug noncovalently binding to the HLA molecule and/or TCR to result in direct T-cell activation. The altered peptide
repertoire model shows a drug binding noncovalently in the HLA antigen binding cleft that alters the repertoire of self-peptide ligands,
leading to presentation of novel peptide ligands that are recognized as foreign and elicit an immune response. TCR, T-cell receptor.

patients) who have been shown to have negative skin test results test and RAST results but positive cephalosporin challenge.
and challenges to cephalosporins with different R1 side chains Romano et al57 studied 76 patients over an 8-year period at 2
including cefuroxime, ceftriaxone, ceftazidime, and cefalo- allergy clinics in Italy. Most patients (77%) had histories of
tin.47,54,55 Cefazolin has a relatively unique R1 side chain; anaphylaxis, with the remaining urticaria/angioedema. The mean
however, ceftezole (available in Asia but not the United States) time since the index reaction was 24 months. Skin test and
has an identical R1 chain and anaphylaxis has been reported to RAST were performed to injectable and oral cephalosporins,
this drug.56 Proposed cross-reactivity patterns among cephalo- with skin test concentrations of 2 mg/mL. Graded challenges
sporins are shown in Figure 4. Whether this same pattern of were performed when both test results were negative, starting
cross-reactivity occurs in other countries, particularly the United with 1/100th of the dose. Cephalosporin skin test results were
States where side chainespecific aminopenicillin reactions are positive in 72% of patients; 6.6% had negative skin test results
rare, is unknown. Overall, tolerance to cephalosporins can usu- but positive RAST results. Of those with negative IgE testing, 8
ally but not always be predicted on the basis of similarities or accepted challenges and 2 were positive. In both of the afore-
differences in R1 side chains between the cephalosporins. Con- mentioned studies, RASTs were developed in each of the
firming tolerance requires a drug challenge. research laboratories and are not commercially available. Romano
et al58 also performed skin testing in 148 children with histories
of cephalosporin allergy (43 with immediate and 105 with
DIAGNOSIS OF CEPHALOSPORIN ALLERGY
delayed reactions). In those children with immediate reactions,
Similar to evaluation of other drug-allergic patients, a careful
76.7% had positive skin test results, while none of the children
history is crucial in determining the optimal diagnostic testing
with delayed reactions had positive delayed intradermal or patch
strategy. Diagnostic tests differ between those with immediate
test results. A study from Korea using cephalosporin skin testing
versus delayed reactions to cephalosporins.
(2 mg/mL) and oral challenge in 1421 healthy controls suggested
a false-positivity rate of 5.2%.59 How commonly false-positive
SKIN TESTING skin test results occur in subjects with histories of cephalo-
Immediate reactions sporin allergy is unknown because few studies have performed
Relatively few studies have evaluated the sensitivity and challenges to patients with positive cephalosporin skin test re-
specificity of cephalosporin skin tests in patients with immediate sults. Christiansen et al60 evaluated patients with clinical histories
reactions to cephalosporins. Antunez et al50 evaluated 127 adult suggestive of cefuroxime perioperative anaphylaxis and 7 of 7
and pediatric patients from Spain over a 4-year period with a with positive skin prick test results had positive challenges. This
history suggestive of an immediate reaction to cephalosporins suggests that for patients with anaphylaxis, skin testing has a very
using skin tests, in vitro tests, and drug challenge. Fifty-one cases high positive predictive value.
(40.1%) were confirmed as allergic, with 76.4% positive by skin The ideal concentration for cephalosporin skin testing is not
tests, 5.9% with negative skin test results and positive radioal- entirely clear. Many studies have used concentrations of 2 mg/mL;
lergosorbent test (RAST) result, and 17.6% with negative skin however, nonirritating concentrations to cephalosporins have been
2110 KHAN ET AL J ALLERGY CLIN IMMUNOL PRACT
SEPTEMBER/OCTOBER 2019

Cephalosporin Parent Structure Penicillin Parent Structure perioperative anaphylaxis and identified an additional 27% of
O O patients when using a concentration of 20 mg/mL compared with
H H
R1 HN S R1 HN S 2 mg/mL. In the aforementioned study by Christiansen et al, they
N
R2 O
N identified 8 patients (34.8%) who were positive on challenge only;
O
O
OH however, they used a low skin test concentration of 0.5 mg/mL.
HO O
Whether skin testing with a higher concentration (eg, 2-20 mg/mL)
R1 Structure Cephalosporins with denoted R1
moiety
Penicillins with denoted R1
moiety
would have identified these “false negatives” is unknown.
Overall, we recommend using higher nonirritating skin test
Group 1
CeŌriaxone concentrations in evaluation of patients with histories of immediate
Cefotaxime reactions to cephalosporins, especially those with anaphylactic
Cefepime histories. Of note, in the United States only sterile preparations
Cefpodoxime
of drugs are used for intradermal testing; therefore, there is no
testing strategy available for aminocephalosporins such as
Cefditoren
cefadroxil, cephalexin, cefprozil, and cefaclor, which are available
(may cross react with Group 2 & 3
cephalosporins)
only in oral formulations. Other studies outside of the United
States have used 2 and 20 mg/mL of the diluted oral formulation as a
prick and intradermal testing strategy; however, this technique is
Group 2 Cefuroxime
rarely used.57
(may cross react with Group 1 & 3
cephalosporins)
Nonimmediate reactions
Skin testing using both delayed intracutaneous and patch tests
has been investigated in cases of nonimmediate cephalosporin
Group 3 CeŌazidime Aztreonam
reactions. Romano et al62 evaluated 105 patients with histories of
(may cross react with Group 1 & benign exanthema and found only 6 (5.7%) with positive
Group 2 cephalosporins)
delayed intradermal skin test results and 3 with positive patch
test results (all of whom had positive intradermal test results). Of
those with negative test results, 86 were challenged and all were
Group 4 Cefaclor Ampicillin negative. One patient had an indeterminate skin test to cepha-
A Cephalexin lexin 2 mg/mL and a positive challenge and afterwards, tests for
cephalexin, cefaclor, and cefatrizine were performed at 20 mg/mL.
A Finnish study found positive patch test results in 12 of 290
(4.1%) with cutaneous reactions to cephalosporins.63 Pinho et al64
Group 4 Cefadroxil Amoxicillin found positive patch test results in 4 of 91 (4.4%) cutaneous
B Cefprozil reactions. Positive patch test results have been rarely reported in
cases of SCARs to cephalosporins.64,65 Given the low rate of
positive skin test results, as well as the low rate of confirmed
Group 5 Cephalothin
delayed reactions, the utility of delayed cephalosporin skin tests
remains unclear.
CefoxiƟn

S
IN VITRO TESTING FOR CEPHALOSPORINS
Group 6 Cefazolin
Current standardized serologic testing for cephalosporins is
CeŌezole*
N lacking. Having reliable serologic testing for these agents would
N
N
N be ideal for helping to validate cephalosporin skin testing results
or for providing an alternative approach for diagnosing cepha-
losporin allergy when skin testing is not possible (ie, in patients
FIGURE 4. Sharing of R1 side chains between cephalosporins and with dermotographism or taking medications that have antihis-
other beta-lactams. Cephalosporin immunogenicity and cross- tamine receptor 1 activity) or not feasible (eg, no allergist access
reactivity appears to be largely dictated by R1 side chains. The or availability). Several studies have evaluated specific cephalo-
group numbers have been labeled for the purpose of illustrating sporin IgE assays that have been correlated with cephalosporin
differing R1 side chains. Colored shading represents shared struc- skin testing and challenge results, which have been helpful for
tures with clinical cross-reactivity described. The R1 side-chain providing data on their potential positive and negative predictive
chemical structure names are as follows: group 1 (2-amino-N- values in the diagnosis of cephalosporin allergy. The
methoxythiazole-4-carbimidoyl); group 2 (N-methoxyfuran-2- immunoassay methods used to detect specific IgE have been
carbimidoyl); group 3 ((E)-2-((((2-aminothiazol-4-yl)methylene) radioimmunoassay, ELISA, and fluorescent enzyme immuno-
amino)oxy)-2-methylpropanoic acid); group 4A (phenylmethan- assay.48,50,53,66,67 The cephalosporin conjugates used for these
amine); group 4B (4-(aminomethyl)phenol); group 5 (thiophene); assays have been synthesized essentially using the same methods
group 6 (tetrazole). *Ceftezole is not available in the United States. used for synthesizing penicillin conjugates.67 However, these
assays have been limited to only a few cephalosporins used pri-
shown to range from 10 to 33 mg/mL.61 The exception was marily for research due to their poor sensitivity compared with
cefepime, which was shown to be irritating in concentrations of skin testing and lack of availability.50 In fact, the only
20 mg/mL. Uyttebroek et al54 evaluated patients with cefazolin commercially available in vitro test is a fluorescent enzyme
J ALLERGY CLIN IMMUNOL PRACT KHAN ET AL 2111
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TABLE I. Desensitization protocol for cefepime78

Name of medication: Cefepime
Total mg per bag Amount of bag infused (mL)
Solution 1 20 mL of 0.100 mg/mL 2.00 1.87
Solution 2 20 mL of 1.000 mg/mL 20.00 3.75
Solution 3 20 mL of 10.000 mg/mL 200.30 7.50
Solution 4 20 mL of 96.053 mg/mL 1921.30 20.00
Step Solution Rate (mL/h) Time (min) Volume infused per step (mL) Dose administered with this stem (mg) Cumulative dose (mg)

1 1 0.5 15 0.12 0.013 0.013

2 1 1 15 0.25 0.025 0.038
3 1 2 15 0.50 0.050 0.088
4 1 4 15 1.00 0.100 0.188
5 2 1 15 0.25 0.250 0.438
6 2 2 15 0.50 0.500 0.938
7 2 4 15 1.00 1.000 1.938
8 2 8 15 2.00 2.000 3.938
9 3 2 15 0.50 5.000 8.938
10 3 4 15 1.00 10.000 18.938
11 3 8 15 2.00 20.000 38.938
12 3 16 15 4.00 40.000 78.938
13 4 4 15 1.00 96.053 174.991
14 4 10 15 2.50 240.133 415.123
15 4 20 15 5.00 480.266 895.389
16 4 40 17.25 11.50 1104.611 2000.000
Total time ¼ 242.25 min (4 h 2 min)

immunoassay IgE immunoassay for cefaclor (ImmunoCAP, remarkable wheal/flare reaction to a cephalosporin drug, challenge
Phadia, Uppsala, Sweden). with the culprit cephalosporin drug is recommended to definitively
A study evaluating 102 patients with a history of cephalo- rule out cephalosporin allergy.71 As has been observed for penicillin,
sporin allergy using skin testing and an in vitro cefaclor (an in patients with histories of cephalosporin allergy clearly compatible
aminocephalosporin) immunoassay found that 16 had a positive with IgE-mediated pathogenesis, the likelihood of negative skin test
skin test result whereas only 8 of 16 subjects had a positive results and cephalosporin tolerance increases the more time has
in vitro sIgE test result to cefaclor.53 The results indicate that a elapsed since the adverse reaction occurred.72 Thus, patients with
patient reacting to a cephalosporin that shares a similar or negative skin test results and a history compatible with an IgE-
identical side chain with penicillin has a relative risk ratio of mediated reaction, who have experienced an adverse reaction
cross-reacting with at least 1 penicillin of 2.89 (95% CI, 1.37- within the previous 6 months, may be regarded as being at elevated
6.11).53 However, this study and others have demonstrated risk and considered as candidates for safeguards such as a graded-
significant heterogeneity in cross-reactivity between penicillins dose challenge beginning at a lower dose (eg, 1/100th-1/10th of
and cephalosporins as well as between cephalosporin groups, the full dose).
indicating the need for a broader array of cephalosporin reagents The positive predictive value of cephalosporin skin testing has
to adequately assess for cephalosporin sIgE using in vitro also not been established; however, false-positive skin test results
assays.48,53,68 to cephalosporin antibiotics may be encountered.59 Limited
Another assay that may be useful for assessing cephalosporin retrospective data suggest that adverse reactions on challenge will
hypersensitivity is the basophil activation test, which measures be observed in approximately one-third to one-half of patients
surface CD63 or CD203c expressed on basophils after stimula- with positive skin test results to penicillin.73 Similarly, because
tion with the culprit drug. In general, its specificity is greater such reactions may be serious or even life-threatening, should a
than the sensitivity (sensitivity, 50%-60%; specificity, >90%), cephalosporin drug to which a positive skin test result is observed
but there is limited information available on using this assay for be clearly indicated, without an equally efficacious alternative
assessing cephalosporin allergy.69 A study of 18 patients with that can be used, desensitization should be performed.
cefazolin perioperative anaphylaxis confirmed by intradermal
skin tests found that basophil activation test using CD63 or
CD203c was 38% to 75% sensitive, respectively.70 RAPID DRUG DESENSITIZATION
Because of frequent and repeated antibiotic exposures, there is
a higher prevalence of cephalosporin allergy and anaphylaxis in
CEPHALOSPORIN CHALLENGE targeted populations such as patients with cystic fibrosis (CF),
As indicated above, the negative predictive value associated with immunodeficiencies, and spina bifida. In these populations and
immediate hypersensitivity skin testing to cephalosporins has not in patients with severe reactions to cephalosporins, for which
been established. For this reason, when skin testing does not reveal these antibiotics are considered first-line therapy, rapid drug
2112 KHAN ET AL J ALLERGY CLIN IMMUNOL PRACT
SEPTEMBER/OCTOBER 2019

TABLE II. Future needs in cephalosporin hypersensitivity with CF is due to a better management of infections with anti-
 Improved cephalosporin epidemiology studies with well-defined biotics.84 Unfortunately, penicillin skin testing is underused in
phenotypes and clinical risk factors the population with CF.85
 Identification of relevant cephalosporin antigenic determinants The most common symptoms of beta-lactam allergy in pa-
 US studies with adequate power to evaluate genetic risk factors for tients with CF are pruritus and rash.80 Koch et al86 studied 121
cephalosporin allergy patients with CF and found that 4.5% of the courses were
 Precise determination of risk of administration of cephalosporins to associated with adverse reactions. However, most of these re-
patients with well-defined penicillin allergy histories actions were nonimmediate, such as maculopapular rashes and
 Cross-reactivity patterns of cephalosporins in non-European populations drug fever. Piperacillin and ceftazidime accounted for most re-
 Ideal concentration for immediate hypersensitivity cephalosporin skin actions. Wills et al79 also reported that nonimmediate reactions
tests were seen commonly (34% of all reactions) in 53 patients with
 Diagnostic test characteristics of immediate and delayed skin tests for CF.
cephalosporin allergy Skin testing and drug challenges, as described earlier, are well
 Accuracy of in vitro tests for cephalosporin allergy studied and protocols should be used for routine evaluation in
 Development of novel diagnostic tests for cephalosporin allergy patients with conditions such as CF and common variable im-
munodeficiency. In addition to immediate reactions discussed
previously, rapid desensitizations have been used successfully for
nonimmediate reactions to ceftazidime in patients with CF.87
desensitization should be considered as a therapeutic approach.74
Patients with positive cephalosporin skin test results and/or FUTURE CHALLENGES
anaphylactic histories are good candidates for rapid intravenous Although our knowledge of cephalosporin hypersensitivity
or oral cephalosporin desensitization.75 Protocols for cephalo- and management is advancing, there are still several areas that
sporin rapid drug desensitization include choosing a safe starting need further research (Table II). The lack of knowledge regarding
dose, typically 1/10,000th to 1/1,000,000th of the target dose, cephalosporin antigenic determinants is a hindrance to the
doubling steps, and allowing for a minimum of 15 minutes development of improved in vivo and in vitro diagnostic tests.
between steps.76,77 Volumes for desensitization should match the Adequately powered studies to assess the diagnostic utility of skin
volumes for regular administration of cephalosporins.78 Because and in vitro tests have not been performed, which limit the cli-
cephalosporins are dosed daily, patients are desensitized only nician’s interpretation of positive or negative skin test results.
once and subsequent doses are managed as regular administra- Novel methods such as the use of nanoallergen platforms, pre-
tion. Although patients with CF are high-risk desensitization viously used in platin hypersensitivity, may provide mechanistic
candidates due to severe respiratory symptoms and low FEV1, and diagnostic insights.88 The epidemiology of beta-lactam hy-
there is no formal contraindication for desensitization. In an persensitivity is poorly defined in large data sets in the United
earlier study, 52 desensitization procedures were done on 15 States, and to date, allergy referral population epidemiology ap-
patients with CF (FEV1 ¼ 11%-77% predicted).78 Either a 12- pears different in the United States compared with Europe where
step or 16-step desensitization protocol with cephalosporins most cephalosporin hypersensitivity studies were conducted.
including ceftazidime and cefepime was used (Table I). All pa- Hence, the generalizability of practices and approaches for
tients completed the desensitization; 96.2% had no severe cephalosporin hypersensitivity may not apply across different
adverse events, and minor reactions occurred in 9.6% of patients. populations. Despite these knowledge gaps, a rational and risk-
based approach to patients presenting with cephalosporin hy-
SPECIAL GROUPS: PATIENTS WITH CF AND persensitivity exists today, but will be refined over time as more
IMMUNODEFICIENCY clinicians and researchers work to define optimal testing strate-
Antibiotic hypersensitivity is a major complication in the gies for the growing population reporting a cephalosporin allergy.
treatment of patients with chronic conditions such as CF and
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