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JAMA | Review
CONCLUSIONS AND RELEVANCE Many patients report they are allergic to penicillin but few
have clinically significant reactions. Evaluation of penicillin allergy before deciding not to use
penicillin or other β-lactam antibiotics is an important tool for antimicrobial stewardship.
A
ntibiotics are among the most commonly prescribed medi- often a rash, but that could also be nonallergic.12,13 Currently, the rate
cations across health care settings.1 A substantial portion of of IgE-mediated penicillin allergies is decreasing, potentially due to
antibiotic use is inappropriate, which contributes to antimi- the decrease in use of parenteral penicillins.14 Among 100 million
crobial resistance and a variety of adverse outcomes, including people exposed to oral amoxicillin between 1972 and 2007 in the
Clostridium difficile infection (also known as Clostridioides difficile).1-4 United Kingdom, only 1 death after anaphylaxis in association with
Expert bodies, including the World Health Organization, the Centers oral amoxicillin was identified.15
for Disease Control and Prevention (CDC), the President’s Council of Most reports of penicillin allergy describe an unknown or cuta-
Advisors on Science and Technology, and the Presidential Advisory neous reaction. Many patients with a reported penicillin allergy do
Council on Combating Antibiotic Resistant Bacteria, have all recom- not have any reaction characteristics documented in the electronic
mended implementation of policies and practices to reduce inappro- health record (EHR).16 “Unknown” is a frequently documented type
priate antibiotic use and have underscored the importance of such ef- of reaction in EHRs in cases of allergy to penicillin (26%) with other
forts for public health and patient safety. Antibiotic selection is often commonly documented reactions including rash (38%), hives (18%),
guided by a patient’s allergy history, with an allergy to penicillin com- angioedema (9%), gastrointestinal upset (6%), anaphylaxis (5%),
monly reported. About 32 million people in the United States have a and itching (5%).17 Patients presenting for penicillin allergy evalu-
documented penicillin allergy.5-7 Yet, true IgE-mediated allergies that ation have similar reported reactions, with hives and rash being the
cause anaphylaxis are uncommon. More than 95% of patients la- most common.18,19
beled as having a penicillin allergy ultimately are able to tolerate this For patients whose allergy history excludes blistering rash, he-
class of drugs.8 Most patients labeled with penicillin allergy do not molytic anemia, nephritis, hepatitis, fever, and joint pain sugges-
undergo any evaluation to determine the accuracy or persistence of tive of organ involvement or severe cutaneous adverse reactions
the allergy.9,10 This review summarizes the epidemiology of, clinical (SCAR) in response to penicillin, an allergy evaluation of some form
consequencesof,andmethodsforevaluatingpenicillinallergyandpro- is indicated. More than 95% of patients who do not have a history
vides toolkits to facilitate these evaluations. of serious penicillin allergy reactions are penicillin tolerant because8
(1) the most commonly reported penicillin hypersensitivity reac-
tion is a delayed benign rash, likely a type IV hypersensitivity reac-
tion (eTable S1 in Supplement 1) and these reactions may or may not
Methods
recur when patients are reexposed to penicillin; (2) IgE-mediated
The American Academy of Allergy, Asthma, and Immunology penicillin allergy wanes over time, with 80% of patients becoming
(AAAAI), the Infectious Diseases Society of America (IDSA), and tolerant after a decade7; and (3) many patients were never allergic,
the Society for Healthcare Epidemiology of America (SHEA) but may have had an intolerance or another cause for the symp-
boards appointed at least 1 society representative to form a writ- toms they thought represented a penicillin reaction, such as a con-
ing group. Review of the literature included a PubMed search of comitant viral infection.11,20
English-language articles published between January 1, 2005, and
September 30, 2018, using the following search terms: penicillin,
β-lactam, antibiotic, hypersensitivity, adverse reaction, allergy, skin
Clinical Consequences
test, test dose, stewardship, clinical outcome, quality improve-
ment, delabeling, antibiotic utilization, hospitalization, inpatient, The consequences of being labeled as having a penicillin allergy in-
pharmacist, surgery, emergency, oncology, nursing, and rehabilita- clude the use of alternative antibiotics that cause more treatment
tion. Relevant AAAAI, IDSA, and SHEA guidelines and articles refer- failures and adverse effects than β-lactams and contribute to anti-
enced therein were reviewed. Additional articles recommended by microbial resistance development.
professional society committee and board members supplemented
the literature review. Treatment Choice
The manuscript, supplement, and toolkits underwent review by β-Lactam agents, specifically penicillins and cephalosporins, are the
all 3 society boards. During the review process, additional commit- treatment of choice against many pathogens that cause common
tees provided input, including the AAAAI Practice and Policy Divi- diseases (Table 1). Often, a label of penicillin allergy alters treat-
sion, the IDSA Antimicrobial Resistance Committee, the SHEA Guide- ment decisions resulting in suboptimal treatment. Examples of these
lines Committee, and the SHEA Antimicrobial Stewardship alterations include the use of vancomycin to treat patients with meth-
Committee. The final revised manuscript was approved and en- icillin-susceptible Staphylococcus aureus bacteremia10 and avoid-
dorsed by the boards of all 3 societies. ance of cephalosporins in the management of gram-negative
bacteremia.21,22 Nafcillin and cefazolin are more effective than van-
comycin in treating patients with methicillin-susceptible S aureus
infections.23 Among S aureus strains that are sensitive to methicil-
Penicillin Allergy Epidemiology lin, up to 25% are also sensitive to penicillin. Using penicillin in cases
Penicillin is commonly associated with hypersensitivity reactions,5,6 of penicillin-susceptible S aureus infections may result in improved
most likely related to their frequent use and infection-related drug patient outcomes; however, in these cases, clinicians should con-
interactions, such as a patient developing a maculopapular rash from sider requesting β-lactamase testing to detect penicillinase
an Epstein-Barr virus infection but also given an aminopenicillin.11 production.24-27 Benzathine penicillin is the treatment of choice for
About 0.5% to 2.0% of penicillin administrations result in a reac- patients with syphilis and ceftriaxone is the treatment of choice
tion that could be consistent with a hypersensitivity reaction, most for patients with gonorrhea.28
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190 JAMA January 15, 2019 Volume 321, Number 2 (Reprinted) jama.com
interstitial nephritis), drug fever, or serum sickness, patients can Penicillins Penicillin, amoxicillin ± clavulanic acid,
ampicillin ± sulbactam, dicloxacillin, nafcillin,
be stratified into low, moderate, and high risk using the allergy oxacillin, piperacillin/tazobactam
history (Table 3). Risk stratification enables previous observa- Cephalosporins Cefazolin, cephalexin, cefoxitin, ceftriaxone,
tional studies to be applied more broadly to different patient ceftazidime, cefpodoxime, cefepime,
ceftaroline
populations and clinician groups. Based on a patient’s allergy his- Carbapenems Ertapenem, imipenem, meropenem
tory, clinicians can decide if penicillin skin testing or drug chal-
Monobactam Aztreonam
lenges are appropriate. Although many remote and minor rashes
Non–β-lactam alternatives
may be considered low risk, it is often challenging to distinguish
Fluoroquinolones Ciprofloxacin, levofloxacin, moxifloxacin
urticaria from a benign rash. Thus, considering all patients with
Macrolides Azithromycin, clarithromycin,
nonsevere cutaneous eruptions as moderate-risk may be appro- erythromycin
priate. Moreover, even in the context of a low-risk allergy history, Tetracyclines Tetracycline, doxycycline, minocycline
patients with unstable or compromised hemodynamic or respira- Aminoglycosides Gentamicin, tobramycin, amikacin
tory status and pregnant patients should be considered as having Sulfonamides Trimethoprim-sulfamethoxazole
at least a moderate-risk history because of host factors that may
Glycopeptides Vancomycin
result in poor outcomes.
Lipopeptides Daptomycin
Patients with a history of drug allergies are at a higher risk for
Oxazolidinones Linezolid
reactions than patients without them.58 The baseline risk for any re-
Lincosamides Clindamycin
action to β-lactam antibiotics is approximately 2.0%.13 Patients
with a history of penicillin allergy may react to a placebo during Nitroimidazole Metronidazole
jama.com (Reprinted) JAMA January 15, 2019 Volume 321, Number 2 191
Ambulatory practice lenge, administration of a full drug dose divided into 2 or 3 separate
Preoperative administrations with concomitant medical observation, may also be
Nursing facilities
used for patients who have low- or moderate-risk histories (Toolkit C
Intensive care units in Supplement 2). Demonstration of amoxicillin tolerance enables
Specialty units future use of all penicillin antibiotics, including aminopenicillins. Peni-
Allergy specialist office
cillin is generally not recommended for demonstrating penicillin tol-
erance because selective allergy to ampicillin and amoxicillin (ie, ami-
drug challenges; a nocebo effect has been documented in up to 10% nopenicillins) has been described, although largely in European
of drug-challenged patients.59 Individuals with underlying chronic populations.66 For patients with a history of only penicillin allergy,
urticaria do not have an increased risk for immunologically medi- after amoxicillin challenge is tolerated without an adverse reac-
ated penicillin hypersensitivity.60 tion, all β-lactams can be administered as indicated.
192 JAMA January 15, 2019 Volume 321, Number 2 (Reprinted) jama.com
In a study of direct drug challenges performed by allergists cillin skin testing is uninterpretable (eg, histamine-positive control
in ambulatory clinics, only 1.5% of 402 healthy young military is nonreactive; eFigure 2 in Supplement 1). Desensitization is re-
recruits with reported penicillin allergy proved to have true peni- served for scenarios in which penicillin or a penicillin-related drug
cillin allergy.67 In another study of 155 outpatients with reported is superior to alternative antibiotics. Antibiotic desensitizations are
penicillin allergy, only 2.6% were allergic to penicillin.59 Among frequently performed in hospitalized patients, often in the inten-
over 800 general pediatric patients with varied penicillin allergy sive care unit, because 1:1 nursing support is typically required. De-
histories, 94% tolerated their drug challenge.18 Similarly, drug sensitization procedures have a risk of complications and, like all
challenges have been performed on hospitalized patients by medical procedures, physicians overseeing these procedures must
nonallergist clinicians, including internists (trainees and staff), be adequately trained and credentialed and patient informed con-
nurse practitioners, and physician assistants, with results demon- sent should be obtained.
strating improved antibiotic choices and first-line therapy for
select infections.10,35,50
jama.com (Reprinted) JAMA January 15, 2019 Volume 321, Number 2 193
ing unnecessary antibiotic use and improving antibiotic choice. Am- with no apparent benefit have been observed when broader-
bulatory environments are ideal for penicillin allergy evaluation, be- spectrum antibiotics are used to manage these infections.84 Com-
cause patients are well enough to tolerate testing and, for many visits, pared with adults, when children are evaluated for penicillin al-
there is no urgent need for antibiotic therapy. lergy, less time has elapsed since the reported reaction. Despite this,
Although specialists evaluate patients with reported penicil- rashes in children are more likely a result of an infection-related ex-
lin allergy in ambulatory settings, nonspecialty ambulatory prac- anthem or a drug-infection interaction than from an immunologic
tices are encouraged to establish the infrastructure to perform response to the antibiotic. In 2 studies, 94% to 100% of infants and
low-risk amoxicillin challenges and to consider implementing children evaluated with direct amoxicillin challenge were found to
penicillin skin testing. With access to testing materials, standard be penicillin-tolerant, suggesting that a recent reaction should not
antianaphylaxis medications, and trained personnel for testing preclude a penicillin allergy evaluation in children.18,62
and monitoring, penicillin allergy evaluations can be accom-
plished in all ambulatory practices. Pregnant Patients
Antibiotics are among the most commonly prescribed medica-
Hospitalized Patients tions during pregnancy.85 Amoxicillin and cephalexin are first-line
Antibiotics are prescribed to more than half of patients admitted therapies for management of asymptomatic bacteriuria and sus-
to acute care hospitals.79 Penicillin skin testing programs imple- ceptible urinary tract infections in pregnancy.86 Penicillin in com-
mented in general medical and intensive care unit settings have bination with aminoglycoside drugs are commonly used to treat
identified benefits, such allowing narrower-spectrum antibiotics patients with chorioamnionitis.87 Syphilis in pregnancy is man-
to be chosen.52,53 Although some programs have been managed aged with penicillin. 88 Being labeled with a penicillin allergy
by nonallergy specialists,49,52,55 specialists have often assisted in during pregnancy is associated with substantial morbidity, includ-
the design or implementation of the programs.48,50 Inpatient ing increased risk of cesarean delivery, postcesarean wound com-
areas are staffed by the necessary personnel and have materials plications, and longer length of hospital stay.89,90 Although peni-
required for penicillin skin testing. Studies have identified barriers cillin skin testing is safe, it is infrequently performed during
to inpatient penicillin skin testing, including short length of stays pregnancy71; however, third trimester referral to specialists for
and inadequate time to perform penicillin skin testing in light of expectant mothers with planned cesarean delivery, group B
the many other tests performed in an inpatient setting.69 When Streptococcus colonization, and other indications are currently
penicillin skin testing is not feasible, a graded challenge can be performed at some US institutions.71
implemented for patients with moderate-risk histories after con-
sideration of potential for benefit vs potential for harm (Toolkit C Long-term Care
in Supplement 2).35,50,69 Hospitalized patients with infections may Fifty percent to 80% of older adults in long-term care facilities
benefit from challenge to specific β-lactam drugs if it is likely to cure (LTCFs) receive at least 1 course of antibiotics each year, with up to
the infection (eg, cefazolin in patients with methicillin-susceptible half of the antibiotic courses being inappropriately prescribed.91
S aureus bacteremia). This short-term solution should be followed The prevalence of reported penicillin allergy increases with age,
by penicillin allergy evaluation to potentially remove the penicillin and older adults are more likely to suffer the adverse effects associ-
allergy label if the patient can tolerate that assessment. ated with use of alternative antibiotics.92 In addition to increased
risk of C difficile infection, fluoroquinolones, a frequently employed
Periprocedure alternative antibiotic class, have significant drug-drug interactions
Evaluation of β-lactam allergy histories before elective surgical pro- with medications commonly prescribed to older adults (eg,
cedures can support decision making for the best choice of antibi- warfarin).93 Recent efforts from the Centers for Medicare & Medic-
otic prophylaxis. In general, cefazolin, or an equivalent cephalo- aid Services focus on strategies to reduce inappropriate antibiotic
sporin, is the most common first-line recommended antibiotic.32 prescribing in LTCFs. Using the same methods employed in other
Patients who report being allergic to penicillin most often receive settings, penicillin allergy evaluation could have a significant ben-
cefazolin alternatives, such as clindamycin or vancomycin. These al- efit for older adults in LTCFs.
ternatives are considered less effective antibiotics for managing pro-
phylaxis and are associated with an increased risk of SSIs17 and, pos- Oncology
sibly, C difficile infection.80 In addition, given the logistical challenges Patients with cancer are commonly prescribed antibiotics for both
of completing vancomycin infusion (1 to 2 hours depending on the prophylaxis and treatment and have a higher prevalence than the
dose) within the recommended time frame (1 to 2 hours prior to in- general population of reported antibiotic allergy.94 For example,
cision), insufficient antibiotic may be present in the tissues at the β-lactam antibiotics are important for management of common
critical time of skin incision.17 Preoperative penicillin allergy evalu- infectious syndromes, such as fever and neutropenia.95 Patients
ation has been successful for general,70 cardiac,81 and orthopedic with cancer are at a high risk for developing resistant organisms
surgical procedures.82 A study showed that 300 patients with low- and complications, such as C difficile infection.96,97 Thus, efforts to
and moderate-risk penicillin allergy histories received cephalo- evaluate reported penicillin allergy in patients with cancer may
sporins (largely cefazolin) and there was only 1 possible reaction.83 improve treatment decisions and potentially affect outcomes, such
as hospital length of stay.94 Interventions for clinical evaluation
Pediatric Patients implemented in either outpatient or patient settings, ideally before
Common childhood infections, such as otitis media and pharyngi- the initiation of chemotherapy or bone marrow transplant, may
tis, are often managed with penicillins. Higher rates of adverse events improve outcomes. Patients receiving immunosuppressant agents
194 JAMA January 15, 2019 Volume 321, Number 2 (Reprinted) jama.com
Possible systemic (anaphylactic) reaction Assess airway, breathing, circulation Patient labeled as penicillin-allergic
Typically involves ≥2 organ systems Obtain vital signsa Consider specialty evaluation
Cutaneous: pruritus, flushing, rash, urticaria, or swelling Place patient in supine position and elevate legs
Respiratory: nasal congestion, runny nose, cough, If automated external defibrillator is available, retrieve and bring
shortness of breath, chest tightness, wheezing to bedside
Cardiovascular: faintness, tachycardia, tunnel vision, Administer intramuscular epinephrineb mid-upper outer thigh;
chest pain, hypotension, sense of impending doom, repeat every 5-15 min as needed
loss of consciousness Call 911
Gastrointestinal: nausea, vomiting, cramping, diarrhea Administer oxygen and intravenous fluids, if available
Hypotension alone in the setting of a known allergen Administer adjunctive treatments such as antihistamine, steroids,
exposure is also considered anaphylaxis and bronchodilatorsb
a Vital signs should be checked every 15 minutes, but patients do not typically require continuous pulse oximetry or cardiac monitoring.
b Medication and dosages are provided in Toolkit E.
This algorithm provides the suggested management for reactions precipitated epinephrine. Antihistamines and corticosteroids may be used for symptom
by drug challenges in ambulatory settings. The most common reactions will be control and corticosteroids may be used to inhibit a biphasic anaphylactic
subjective symptoms and minor cutaneous reactions. Rarely, reactions that are reactions, but these are adjunctive treatments only. Anaphylaxis guidance for
anaphylactic may be encountered. Anaphylaxis requires timely treatment with emergency and acute care settings exists.100
can be skin tested, although they may have increased likelihood of antihistamine (eg, cetirizine, fexofenadine) rather than a sedating
a nonreactive histamine. antihistamine (eg, diphenhydramine). Epinephrine may also be used
for more diffuse urticaria. Rarely (<1 in 500), patients may develop
Sexually Transmitted Infection Clinics anaphylaxis, a systemic reaction. Anaphylaxis often includes a cu-
β-Lactam antibiotics are first-line treatment for patients with syphi- taneous sign or symptom (eg, pruritus, urticaria, flushing) as well as
lis and gonorrhea, with no equivalently efficacious alternative anti- other organ system involvement (eFigure 1 in Supplement 1). For ex-
biotics for patients with severe penicillin allergy.28 Approximately ample, respiratory system involvement may be manifested as wheez-
15% of patients evaluated in a sexually transmitted infection (STI) ing, dyspnea, or coughing. Gastrointestinal system involvement may
clinic reported a penicillin allergy.98 Treatment of STIs in patients be manifested as abdominal pain, diarrhea, or vomiting. Timely rec-
with a penicillin allergy is particularly challenging because many STI ognition and management of anaphylaxis, including the adminis-
clinics may not have the resources to offer skin testing; however, tration of intramuscular epinephrine, can be lifesaving, and a delay
direct challenges should be considered. Guidelines recommend ini- of administration of epinephrine can be fatal. An anaphylaxis and ad-
tiation of STI treatment at the clinic visit with direct observation of junctive treatment kit is useful for all settings to allow for immedi-
the patient by the clinic staff to minimize the risk for curative ate treatment of allergic reactions (Toolkit E in Supplement 2).
therapy not being administered.28,99
jama.com (Reprinted) JAMA January 15, 2019 Volume 321, Number 2 195
risk of hypersensitivity reaction.101,102 Some institutions have used result, or is erroneously re-entered at a later date, the benefits of
wallet cards or apps to allow patients to maintain their active the clinical evaluation will not be achieved. Unfortunately, failure
allergies.103 Active allergy lists should be communicated to all care to modify the allergy history listing may occur in more than 1 in 5
providers and pharmacies. Amoxicillin challenges virtually exclude tested patients.68,106
IgE-mediated allergies, but patients may experience other, benign Evaluation of penicillin allergy has substantial benefits for
skin rashes at an incidence similar to the general population.104 To patients by allowing improved antimicrobial choice for treatment
completely exclude benign delayed rashes, a longer course of anti- and prophylaxis. As a component of antimicrobial stewardship
biotics is required, but this is not recommended because it exposes efforts, evaluation of penicillin allergy leads to more appropriate
patients to unnecessary antibiotics.104 antibiotic administration and may reduce antimicrobial resistance
EHRs can accommodate a large amount of information in the and cases of C difficile infection. Testing for penicillin allergy is rec-
allergy module, including the allergen (drug), reaction, reaction type ommended by the CDC and multiple professional societies.37,107-109
(eg, intolerance, allergy), date noted, and comments. However, al- Antibiotic challenge procedures are gaining acceptance, but
lergy documentation is often vague, with up to 80% of allergies lack- many clinicians do not know how to perform these procedures.
ing descriptions of the reactions.16 Many entries may be inaccu- Beyond infrastructure and resources, the major barrier to evalua-
rate; in 1 study, only one-third of entries were confirmed by tion of penicillin allergy is clinician knowledge and comfort.110
patients.105 While nonclinicians may enter patient-reported aller- Specialists cannot address this problem alone, but should be
gies, clinicians should assess whether the entry has clinical utility and, engaged directly or through collaborations with clinicians across
if so, enter additional reaction details. the care continuum to address this problem. Practical educational
After allergy evaluations, proper updating regarding allergy materials and testing procedures are provided with this review to
information should be performed. EHR allergy modules often facilitate implementation of penicillin allergy assessment.
include historical allergies that have been added, modified,
or deleted over time. When penicillin is tolerated in a patient with
a history of penicillin allergy, the active penicillin allergy should
Conclusions
be deleted from the EHR. When it is not appropriate to remove
or delete the allergy, qualifying comments should be added in Many patients report they are allergic to penicillin, but few have
to provide detail. For example, "penicillin skin test positive" or clinically significant reactions. Evaluation of penicillin allergy before
"tolerates cephalexin" can inform future care. If the allergy is not deciding not to use penicillin or other β-lactam antibiotics is an
removed from the record after a negative penicillin skin testing important tool for antimicrobial stewardship.
ARTICLE INFORMATION reactions and has served on clinical trial safety and REFERENCES
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