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Choice of antibiotics in penicillin-allergic hospitalized patients

Authors: Kimberly G Blumenthal, MD, MSc, Roland Solensky, MD
Section Editor: Elizabeth J Phillips, MD, FRCPC, FRACP, FIDSA, FAAAAI
Deputy Editor: Anna M Feldweg, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Dec 2020. | This topic last updated: Feb 13, 2020.

INTRODUCTION

Penicillin allergy is the most common drug allergy and is reported in up to 15 percent of hospitalized patients [1]. A frequent clinical question is
whether these patients can safely receive the structurally related cephalosporins or carbapenems (monobactams [ie, aztreonam] are not cross-
reactive with penicillins and can be safely given to penicillin-allergic patients). This topic will present an approach to determining whether a
patient with reported penicillin allergy can be treated with penicillins or related beta-lactam antibiotics, with or without access to allergy
consultation. It is focused on the hospitalized patient but applies to ambulatory patients as well. The detailed allergy evaluation of a patient with
past penicillin reaction based upon penicillin skin testing and studies of cross-reactivity among beta-lactam antibiotics are reviewed elsewhere.

● (See "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam
antibiotics".)

Penicillin allergy (immediate and delayed), penicillin skin testing techniques, and rapid drug desensitization are reviewed in more detail
separately:

● (See "Penicillin allergy: Immediate reactions".)

● (See "Penicillin allergy: Delayed hypersensitivity reactions".)
● (See "Penicillin skin testing".)
● (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

IMPACT OF PENICILLIN ALLERGY ON CARE

There is morbidity, mortality, and economic cost associated with the unnecessary withholding of penicillins in patients who are labeled as allergic
on the basis of history alone. Patients with a history of penicillin allergy are more likely to be treated with broad-spectrum antibiotics, such as
quinolones or vancomycin [1-9]. There are distinct disadvantages to broad-spectrum agents, which are often more expensive, associated with
more side effects (such as Clostridioides [formerly Clostridium] difficile infection), and less effective for some infections [6,10-13]. In addition,
overuse of vancomycin and quinolones contributes to the development and spread of certain types of drug-resistant bacteria [7,14-17] (see
"Vancomycin-resistant enterococci: Epidemiology, prevention, and control", section on 'Risk factors'):

● One study assessed various risk factors for the development of vancomycin-resistant enterococcus (VRE) in a medical intensive care unit
(MICU) [17]. Among the various classes of antibiotics used prior to transfer to the MICU, quinolones had the strongest association with
subsequent development of VRE (odds ratio [OR] = 8.6), whereas treatment with penicillins/beta-lactamase inhibitors was not associated with
developing VRE [17].

● In a study of over 51,000 hospitalized patients, patients labeled as penicillin-allergic had 23 percent more C. difficile infections, 30 percent
more VRE infections than expected, 14 percent more methicillin-resistant Staphylococcus aureus (MRSA) infections, and longer hospital stays,
compared with control subjects [7]. The mechanism by which patients with a listed penicillin allergy would be at higher risk for MRSA is
unknown, although greater time in the hospital is one possibility [18].

● In a multisite, prospective cohort analysis of inpatients who received an infectious diseases consultation, patients with a history of beta-
lactam allergy who were not treated with a beta-lactam had more "adverse events" (composite outcome of readmissions for the same
infection, acute kidney injury, C. difficile infection, and drug-related adverse events) than patients with beta-lactam allergy who were treated
with a beta-lactam (adjusted OR 3.2, 95% CI 1.28-7.89) [19].

The implementation of an institutional program for addressing penicillin allergy as part of antimicrobial stewardship is a multifaceted process
involving administrators, generalists, allergists, infectious diseases specialists, pharmacists, nursing personnel, and information technology
support [20]. (See "Antimicrobial stewardship in hospital settings" and "Antimicrobial stewardship in outpatient settings".)
OUR APPROACH

Many hospitals, including all United States facilities, are mandated to establish an antimicrobial stewardship program [21]. However, access to an
allergy and immunology consult service is often lacking. This topic presents an evidence-based, pragmatic approach, which permits a large
majority of patients labeled as penicillin-allergic to receive related beta-lactam antibiotics with minimal risk of acute allergic reactions, without
the necessity of allergy consultations. The approach is based on categorization of the past reaction and for those patients with possible
immediate (eg, immunoglobulin E [IgE]-mediated) allergy, an assessment of the risk of a recurrent immediate reaction ( algorithm 1). However,
if an allergy specialist is available, consultation is strongly encouraged, especially when the algorithm suggests penicillin skin testing. (See 'Role
of the allergy specialist' below.)

Clinical history and record review — The evaluation of a patient with a history of penicillin allergy begins with the clinical history and review of
available medical records. Penicillins include the following:

● The natural penicillins – Penicillin V (oral), penicillin G (parenteral), benzathine penicillin (intramuscular), and procaine penicillin
(intramuscular)

● The antistaphylococcal penicillins – Dicloxacillin, nafcillin, oxacillin, and cloxacillin

● The aminopenicillins – Amoxicillin, amoxicillin-clavulanate, and ampicillin

● The extended-spectrum penicillins – Carbenicillin, ticarcillin, and piperacillin

Hypersensitivity reactions to any of these drugs would correctly be considered a penicillin allergy. It is useful to name the various commonly used
penicillins (ie, amoxicillin, ampicillin, specific brand names), as patients may recognize a common brand name but not realize it is a penicillin. It is
also worthwhile to ask if the patient has avoided penicillins since the reaction, because in some cases, patients had been given a penicillin again
despite a reported allergy, and if it was tolerated, then the patient is not allergic to penicillins.

Important questions — Important questions in a drug allergy history include the following ( algorithm 1):

1. What exactly were the symptoms?

● Raised, red, itchy spots with each lesion lasting less than 24 hours (hives/urticaria)?
● Swelling of the mouth, eyes, lips, or tongue (angioedema)?
● Blisters or ulcers involving the lips, mouth, eyes, urethra, vagina, or peeling skin (seen in Stevens-Johnson syndrome [SJS], toxic epidermal
necrolysis [TEN], other severe type IV reactions)?
● Respiratory or hemodynamic changes (anaphylaxis)?
● Joint pains (seen in serum sickness)?
● Did the reaction involve organs like the kidneys, lungs, liver, or lymph nodes (seen in drug rash eosinophilia systemic symptoms [DRESS, also
known as, drug-induced hypersensitivity syndrome [DiHS]), other severe type IV reactions) or were there other features such as extensive
rash (>50 percent body surface area), fever, and facial edema?

2. What was the timing of the reaction after taking penicillin: Minutes, hours, or days later? Did it begin after the first dose or after multiple
doses? The rapid onset of symptoms (ie, within minutes to hours) after the first dose distinguishes immediate from delayed reactions.

3. How long ago did the reaction happen? This question is most important for immediate reactions, because patients may lose the sensitivity
with time if they have no further penicillin exposures. Specifically, studies have shown that if patients with immediate penicillin allergy that was
confirmed by skin testing are retested after 10 years of penicillin avoidance, only approximately 20 percent will still have positive skin tests, while
the allergy will have resolved in 80 percent. The relevant studies demonstrating loss of immediate allergy are reviewed elsewhere (see "Penicillin
allergy: Immediate reactions", section on 'Time elapsed since the reaction'). In contrast, the natural history of serious delayed reactions is not as
well-studied.

4. How was the reaction treated? Was epinephrine (adrenaline) administered to suggest anaphylaxis? Was there a need for urgent care or
hospitalization?

5. Has the patient tolerated similar medications, such as a cephalosporin since the initial penicillin reaction? This information can be very helpful.
The information that can be deduced from various answers is reviewed separately. (See "Penicillin allergy: Immediate reactions", section on
'Exposure to related medications since the initial reaction'.)

A more detailed discussion of taking a drug allergy history is found separately. (See "An approach to the patient with drug allergy", section on
'Clinical history'.)
Categorize the past reaction — Based on the clinical history and review of the available medical record, we attempt to categorize the patient's
penicillin reaction into one of the following groups:

● Reactions that are not allergic. (See 'Reactions that are not allergic' below.)

● Possibly serious forms of delayed reactions. (See 'Possible serious delayed reactions' below.)

● Mild reactions WITHOUT features of immediate allergy. (See 'Management of mild reactions WITHOUT history of features of immediate
allergy (minimal risk of immediate allergy)' below.)

● Reactions WITH features of immediate allergy. (See 'Management of reactions WITH features of immediate allergy (some risk)' below.)

Immediate reactions typically involve some combination of pruritus, urticaria, angioedema, bronchospasm, laryngeal edema, and/or
hypotension, although an array of other symptoms may occur ( table 1). These reactions usually occur within minutes to one hour or two
of initial administration, beginning somewhat later for oral compared with intravenous medications. The most severe form of an immediate
reaction is anaphylaxis. Patients with past anaphylaxis may report that they "could not breathe," "swelled up," or "almost died," and most
patients would have required acute medical care. For the beta-lactam drugs, most immediate reactions are IgE-mediated, and the terms
"IgE-mediated" and "immediate" are used interchangeably throughout this topic review. The clinical manifestations of immediate reactions
to penicillins are reviewed in greater detail separately. (See "Penicillin allergy: Immediate reactions".)

The presence of IgE antibodies to penicillin can be reliably detected with penicillin skin testing. (See 'Penicillin skin testing' below.)

Management based upon category

Reactions that are not allergic — Some patients will describe reactions that are not allergic in nature, but instead are well-known adverse
effects (eg, diarrhea, vomiting, yeast vaginitis). It should be explained to the patient that this is not an allergy, and penicillin allergy should be
removed from the medical record or clarified to indicate that there was a side effect or intolerance. Patients with nonallergic reactions to
penicillin can receive penicillins and related medications normally, although steps should be taken to avoid the specific agent that caused the
previous adverse effect or to mitigate that adverse effect.

Family history of penicillin allergy — Other patients may never have actually taken penicillins, but are avoiding them because one or
more family members has penicillin allergy. However, penicillin allergy is not a heritable trait, and family history is not a reason to avoid penicillin.
Of note, there are drug reactions that are heavily influenced by genetics (eg, serious reactions to certain antiepileptics and antipsychotics).

Possible serious delayed reactions — A few patients may describe past reactions to penicillins that developed after days to weeks of therapy.
Serious forms of delayed reactions to penicillins include:

● Toxic epidermal necrolysis (TEN) (see "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and
diagnosis")
● Stevens-Johnson syndrome (SJS)
● Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS) (see "Drug reaction with
eosinophilia and systemic symptoms (DRESS)")
● Other exfoliating dermatoses/erythroderma (see "Erythroderma in adults")
● Serum sickness-like reactions (see "Serum sickness and serum sickness-like reactions")
● Drug-induced cytopenias (see "Drug-induced immune thrombocytopenia" and "Drug-induced hemolytic anemia" and "Drug-induced
neutropenia and agranulocytosis")
● Drug-induced renal, hepatic, or other specific organ damage (see "Clinical manifestations and diagnosis of acute interstitial nephritis" and
"Drug-induced liver injury")
● Acute generalized exanthematous pustulosis (AGEP)  

These reactions are diagnosed by historical features and review of the patient's medical record to identify objective exam, laboratory, and/or
biopsy results supportive of one of these diagnoses. Standardized diagnostic testing is not available for these types of reactions, although in vitro
testing is an active area of drug allergy research. (See "Penicillin allergy: Delayed hypersensitivity reactions".)

Evaluation — For patients suspected of having one of the serious delayed types of hypersensitivity reactions to penicillin, all future use of
penicillins should be avoided, since many of these reactions can recur (often more quickly) if the patient is exposed to the causative drug again.

Skin testing is not used in the diagnosis of these reactions, and there are no validated tests that can diagnose them retrospectively.

Future use of related antibiotics — There is very limited information in the published literature about whether patients with one of these
reactions to a penicillin will experience the same reaction to a cephalosporin or carbapenems. Therefore, most clinicians also avoid related
antibiotics in the future. However, if there is a strong indication for a cephalosporin or carbapenem, a drug allergy expert should be consulted if
available to review the details of the case and assess the risk of restarting the same or similar medication. Examples of apparent lack of cross-
reactivity with other beta-lactams in patients with delayed reactions to penicillins are reviewed elsewhere. (See "Penicillin allergy: Delayed
hypersensitivity reactions".)

Management of mild reactions WITHOUT history of features of immediate allergy (minimal risk of immediate allergy) — The majority
of patients describe mild cutaneous reactions, such as mild drug eruptions, with or without pruritus, which lack other obvious features of IgE-
mediated reactions (eg, urticaria, angioedema, bronchospasm, etc). Other symptoms, such as isolated sneezing or isolated pruritus of the eyes
or nose may be occasionally reported. Note that some caution is warranted even with mild past reactions, because the clinical history can be
inaccurate. Studies evaluating the accuracy of clinical history in penicillin allergy are reviewed elsewhere. (See "Penicillin allergy: Immediate
reactions", section on 'Clinical history'.)

Options for treatment depend upon how urgently treatment is needed and whether consultation with an allergist is readily available (
algorithm 1):

Penicillin skin testing NOT feasible — The risk of cross-reactivity between penicillins and cephalosporins is low, and the risk with
carbapenems is even lower. The best designed studies suggest that 99 percent of patients reporting a penicillin allergy (without prior penicillin
skin testing) tolerate a cephalosporin, partly because most of these patients do not have an immediate allergy to penicillin [22,23]. (See "Allergy
evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics".)

Options for treating such patients include the following (if appropriate for the infection in question):

● Give a penicillin or first- or second-generation cephalosporin using a test dose procedure. If the test dose is tolerated without symptoms, it
proves the patient does not have an immediate allergy to the antibiotic that was given. (See 'Test dose procedure (graded challenge)' below.)

● Give a third- or fourth-generation cephalosporin normally (as these are believed to be possibly less cross-reactive with penicillins compared
with early-generation cephalosporins).

● Give a carbapenem normally.

● Give aztreonam (a monobactam) or an antibiotic that is unrelated to the beta-lactams normally.

Skin testing feasible — If an allergist is available, then consultation and penicillin skin testing and challenge can determine if the patient
with a history of an IgE-mediated acute allergic reaction is currently allergic or not with certainty. Since testing is negative in the vast majority of
patients and they may subsequently receive any beta-lactams safely, this greatly simplifies future antibiotic choices. (See 'Role of the allergy
specialist' below.)

Management of reactions WITH features of immediate allergy (some risk) — Immediate reactions typically involve flushing, pruritus,
urticaria, angioedema, bronchospasm, laryngeal edema, and/or hypotension ( table 1). Patients reporting these symptoms are at some risk for
future immediate allergic reactions. Patients reporting severe or recent reactions are at higher risk than those with milder, remote reactions.

Options for treatment depend upon how urgently treatment is needed, how severe the past reaction was, and whether consultation with an
allergist is readily available ( algorithm 1):

Penicillin skin testing NOT feasible — We suggest consultation with an allergist if available. However, if this is not possible, clinicians must
attempt to identify those patients whose history suggests a past immediate reaction that was serious. The best designed cross-reactivity studies
suggest that, among patients with skin test-confirmed penicillin allergy, 97 to 98 percent of patients tolerate a cephalosporin. However, an
important limitation of these studies, which are nearly all retrospective, is the selection bias arising from the probable exclusion of patients with
the most serious past reactions by the clinicians treating them at the time.

Options for treating such patients include the following (if appropriate for the infection in question):

● Give a third- or fourth-generation cephalosporin or carbapenems using a test dose procedure. (See 'Test dose procedure (graded
challenge)' below.)

● Give aztreonam or a non-beta-lactam antibiotic normally.

Skin testing feasible — If an allergist is available, then consultation and penicillin skin testing and confirmatory challenge can determine if
the patient is allergic to penicillin with certainty, which greatly simplifies future antibiotic choices. (See 'Role of the allergy specialist' below.)

An allergy evaluation should be pursed if a penicillin or a first- or second-generation cephalosporin is indicated or superior to other antibiotics.
Either penicillin skin testing can be performed or the patient could be assumed to be allergic and receive a penicillin through an empiric (because
the patient's allergy status is unknown) desensitization protocol or receive a first-generation cephalosporin via graded challenge or empiric
desensitization. An infectious diseases consult may also be helpful to explore efficacy of different antibiotic options. (See "Rapid drug
desensitization for immediate hypersensitivity reactions".)

Management of patients with vague histories — Some patients with past drug eruptions often cannot recall enough detail for the
interviewer to make a judgment about the nature of the skin lesions (hives versus other). It is important to ascertain that the skin eruption did
not blister or peel or involve mucosal surfaces, and these are characteristics that patients generally remember. We consider reactions that are
too vague to characterize as carrying some risk of a future immediate reaction. This risk is lower if the past reaction was (possible) isolated hives
without other symptoms and occurred >10 years ago. Some experts would consider such a patient to be at minimal risk and manage them
accordingly, but this requires clinical judgement.

Safety and impact of proposed approach — A guideline nearly identical to the approach advocated in this topic was implemented at one
author's (KB) practice site (an academic tertiary care referral center) for hospitalized adults reporting a penicillin allergy who would benefit from
treatment with a beta-lactam antibiotic [24,25]. Test doses, when indicated, were administered by the medical team, whereas prior to
implementation of the guideline, all challenges had required allergy consultation. Allergy consultation was obtained if a penicillin or first- or
second-generation cephalosporin was desired in a patient with possible immediate allergy, and the patient was skin tested to penicillin (with
results guiding therapy).

The incidence of adverse drug reactions did not increase significantly after implementation, compared with the pre-guideline period, suggesting
that test dosing can be safely performed by the general medical staff with proper guidance. After implementation, there were statistically
significant reductions in the use of vancomycin, aztreonam, aminoglycosides, and fluoroquinolones. When replicated at another institution on
internal medicine inpatients, the guideline resulted in an almost twofold increase in use of favorable (ie, not antibiotic stewardship-restricted)
penicillins and cephalosporins (adjusted odds ratio [OR] 1.8, 95% CI 1.1-2.9) [26].

Based upon this initial success, the guideline was applied across a larger health care system, comprised of two academic tertiary care referral
centers and three community teaching hospitals. Sites without access to allergy/immunology and penicillin skin testing either used empiric
desensitization (ie, empiric because the patient's current sensitization status was not known) or an alternative antibiotic for inpatients with
outpatient allergy/immunology follow-up for skin testing. Test dosing was performed similarly at all sites by nonallergist providers. Since
guideline implementation, over 1000 test doses have been performed without any identified safety risks. Data collection on specific outcomes of
this approach is in progress [27].

ROLE OF THE ALLERGY SPECIALIST

If an allergy specialist is available, consultation is strongly encouraged for suspected immediate allergy, with the urgency depending upon the
clinical scenario. Allergists (or other specifically trained clinicians) can perform penicillin skin testing to determine with certainty if the patient has
an immediate penicillin allergy, which simplifies future management and may further reduce the use of broader-spectrum agents.

Penicillin skin testing — Penicillin skin testing reagents are commercially available in many countries. The performance of skin testing is
encouraged because it greatly simplifies future antibiotic choices for that patient and can reduce the use of broader-spectrum agents. The
reason for this is that the vast majority of patients turn out to be penicillin skin test-negative, and by virtue of ruling out penicillin allergy, they are
able to receive any and all beta-lactams antibiotics safely, provided they have not also reacted to cephalosporins. Penicillin skin testing is only
validated in patients with past immediate reactions to a penicillin and should not be used to screen patients who have never reacted to a
penicillin.

Skin testing takes between 30 minutes and one hour to perform, and the results are immediately available. It can be safely performed in
pregnant women and critically-ill patients when necessary. Skin testing is discussed in greater detail elsewhere. (See "Penicillin skin testing".)

Impact of proactive allergy evaluation in advance of acute need — Several groups have evaluated the impact of allergy evaluation with
penicillin skin testing or guidelines/algorithms to address the use of related antibiotics in patients reporting penicillin allergy ( table 2) [24,28-
49]. Studies performed testing in the hospital either when the need for penicillin arose or when less appropriate antibiotics were being used.
None of these studies are randomized, many are subject to selection bias, and few have a control group or control for baseline patient
differences between groups. Longer-term cost savings are more difficult to assess, as complications, suboptimal care, and antibiotic resistance
would need to be considered.

TEST DOSE PROCEDURE (GRADED CHALLENGE)

Indications and precautions — Test doses (also called graded challenges) are indicated to exclude immediate allergic reactions. Test dosing is
appropriate only when immediate allergy to the tested antibiotic is judged to be unlikely after careful consideration of the details of the
history. Test doses may be administered by an allergy specialist (preferable) or a member of the general medical team [20]. The purpose of a test
dose is to expose the patient to a small amount of drug, followed by a period of close observation, in case there is a reaction.

Because graded challenges will not prevent or circumvent an immediate allergic reaction, the clinician must be prepared to recognize and
treat such a reaction if one occurs. Diphenhydramine (oral and intravenous) and epinephrine (intramuscular) should be at the bedside. If a fixed
dose epinephrine autoinjector is not being used, the appropriate concentration and dose of intramuscular epinephrine for that patient should be
calculated in advance so that there are no delays or dosing errors if epinephrine is needed. Proper dosing of epinephrine in anaphylaxis is
described in the tables for adults ( table 3) and children ( table 4).

When test doses are given, patients are usually not pretreated with antihistamines or glucocorticoids, because antihistamines may mask early
signs of an allergic reaction. However, if a patient is already receiving a daily antihistamine for allergic rhinitis or another disorder, it is not
necessary to withhold it. Treatment with beta-adrenergic blocking medications should be withheld for 24 hours before the first dose, if feasible,
as these medications can interfere with treatment of anaphylaxis, should a reaction occur. Patients with asthma, chronic obstructive lung
disease, or other chronic pulmonary diseases should be optimally controlled prior to undergoing challenge.

At one author's (KB) institution, test doses of beta-lactam antibiotics in hospitalized patients are ordered by any clinical provider using a protocol
and administered by a nurse with a one-to-one nursing assignment for the challenge duration [20]. The patient is assessed for symptoms, and
vital signs are recorded every 30 minutes. More information about graded challenges, including interpretation of subjective symptoms, is
reviewed elsewhere. (See "Penicillin allergy: Immediate reactions", section on 'Graded challenge (test dosing)'.)

The starting dose is usually 1/10th of the full dose, but could be higher or lower, depending on the route of administration, clinical stability of the
patient, and level of certainty that the patient is not allergic to the drug.

Intravenous — In most cases, an intravenous test dose can be 1/10th (10 percent) of the final dose. If no reaction occurs, the full therapeutic
dose is administered 30 to 60 minutes later. In a study including both hospitalized patients and outpatients in an allergy/immunology clinic, a
simple two-step graded challenge in low-risk patients was as safe as three- or four-step challenges [50].

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

The test dose solution should not be significantly more dilute than the normal preparation, because patients may not react if the
concentration is dramatically altered [51,52]. Thus, the 1/10th (10 percent) dose can be withdrawn from a full-strength bag with a syringe and
administered by slow intravenous push (usually about 1 mL /min), followed in one hour (if tolerated) by the remaining 90 percent. Other
methods of administering test doses and additional safety issues surrounding test dosing policies have been described [20].

Oral — Test doses can also be given orally. An oral test dose is usually 1/4th or 1/10th of the full dose.

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

● A 1/4th dose of a pill is prepared with a pill cutter.

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

● Patients with a history of penicillin allergy are more likely to be treated with broad-spectrum antibiotics, which have distinct disadvantages,
including greater cost, more side effects, promotion of drug-resistance bacterial strains, and in some cases, reduced efficacy against certain
infections. (See 'Impact of penicillin allergy on care' above.)

● Evaluation of a patient with a reported penicillin allergy begins with a detailed history of the past reaction and a review of any relevant
medical records. The intent of these steps is categorization of the patient's past penicillin reaction and identification of serious past
reactions, particularly immediate, immunoglobulin E (IgE)-mediated reactions and serious forms of non-immediate (delayed) reactions, such
as toxic epidermal necrolysis (TEN) or drug-induced organ damage or cytopenias. (See 'Our approach' above.)
 ● Treatment options for each group of patients are shown in the algorithm ( algorithm 1).

• In some patients, the past adverse reaction to a penicillin was clearly not allergic in nature, and beta-lactam antibiotics can be given
normally. However, the adverse reaction may recur if the identical agent is used, so clinicians should be mindful of this. (See 'Reactions
that are not allergic' above.)

• In other patients, there is a convincing history of a serious type of delayed reaction, and these individuals should continue to avoid all
beta-lactam antibiotics unless the details of the case are evaluated by an allergist or other clinician with expertise in the suspected type
of reaction and it is deemed safe to use a related antibiotic. (See 'Possible serious delayed reactions' above.)

• Many patients will report mild past reactions that lacked clear features of IgE-mediated reactions ( table 1). These individuals can be
considered at minimal risk for future serious immediate reactions to beta-lactams and can receive third- or higher-generation
cephalosporins, carbapenems, or aztreonam normally (without prior penicillin skin testing). However, because the clinical history can be
unreliable, some caution with penicillins and first- and second-generation cephalosporins is still warranted, and these should be given
using a test dose procedure. Another approach is to refer such patients to an allergist for penicillin skin testing, which will conclusively
determine if the patient has an immediate penicillin allergy and simplify future management. (See 'Management of mild reactions
WITHOUT history of features of immediate allergy (minimal risk of immediate allergy)' above.)

• Patients who describe past reactions with features of IgE-mediated allergy are at some risk for similar reactions in the future, and the
risk is greatest in patients with severe and recent reactions. We also consider patients to be at risk if the history is too vague to
categorize (eg, the clinician cannot tell if skin lesions were hives or something else). A more cautious approach is warranted for this
group of patients: Third- and higher-generation cephalosporins and carbapenems can be given using a test dose procedure. If a
penicillin or a first- or second-generation cephalosporin is strongly indicated, infectious diseases and allergy specialists should be
consulted to confirm the need for these antibiotics and safe administration, respectively. Penicillin skin testing can be performed to
clarify the patient's status or the patient can be assumed to be allergic and receive a penicillin or early-generation cephalosporin using a
rapid "desensitization" protocol. (See 'Management of reactions WITH features of immediate allergy (some risk)' above.)

● The performance of penicillin skin testing is encouraged because more than 90 percent have negative results (ie, no evidence of allergy),
which greatly simplifies future antibiotic choices for that patient and can reduce the use of broader-spectrum agents. Skin testing takes one
to three hours to perform and should be done by specifically trained personnel. (See 'Role of the allergy specialist' above.)

● Test doses (also called graded challenges) to exclude immediate allergic reactions are appropriate only when immediate allergy to the
tested antibiotic is judged to be unlikely after careful consideration of the details of the history. The purpose of a test dose is to
expose the patient to a small amount of drug initially, followed by a period of close observation, in case there is a reaction. Because test
dosing will not prevent or circumvent symptoms, the clinician must be prepared to recognize and treat an allergic reaction if one occurs. (See
'Test dose procedure (graded challenge)' above.)

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12. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high
morbidity and mortality. N Engl J Med 2005; 353:2442.

13. Jeffres MN, Narayanan PP, Shuster JE, Schramm GE. Consequences of avoiding β-lactams in patients with β-lactam allergies. J Allergy Clin
Immunol 2016; 137:1148.

14. Bonafede M, Rice LB. Emerging antibiotic resistance. J Lab Clin Med 1997; 130:558.

15. Murray BE. Vancomycin-resistant enterococcal infections. N Engl J Med 2000; 342:710.

16. Rao GG. Risk factors for the spread of antibiotic-resistant bacteria. Drugs 1998; 55:323.

17. Martínez JA, Ruthazer R, Hansjosten K, et al. Role of environmental contamination as a risk factor for acquisition of vancomycin-resistant
enterococci in patients treated in a medical intensive care unit. Arch Intern Med 2003; 163:1905.

18. Solensky R. Penicillin allergy as a public health measure. J Allergy Clin Immunol 2014; 133:797.

19. MacFadden DR, LaDelfa A, Leen J, et al. Impact of Reported Beta-Lactam Allergy on Inpatient Outcomes: A Multicenter Prospective Cohort
Study. Clin Infect Dis 2016; 63:904.

20. Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing inpatient beta-lactam allergies: A multi-hospital implementation. J Allergy Clin
Immunol Pract 2017.

21. Joint Commission on Hospital Accreditation. APPROVED: New Antimicrobial Stewardship Standard. Jt Comm Perspect 2016; 36:1, 3.

22. Daulat S, Solensky R, Earl HS, et al. Safety of cephalosporin administration to patients with histories of penicillin allergy. J Allergy Clin
Immunol 2004; 113:1220.

23. Goodman EJ, Morgan MJ, Johnson PA, et al. Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic
response. J Clin Anesth 2001; 13:561.

24. Blumenthal KG, Shenoy ES, Varughese CA, et al. Impact of a clinical guideline for prescribing antibiotics to inpatients reporting penicillin or
cephalosporin allergy. Ann Allergy Asthma Immunol 2015; 115:294.

25. Blumenthal KG, Shenoy ES, Hurwitz S, et al. Effect of a drug allergy educational program and antibiotic prescribing guideline on inpatient
clinical providers' antibiotic prescribing knowledge. J Allergy Clin Immunol Pract 2014; 2:407.

26. Blumenthal KG, Wickner PG, Hurwitz S, et al. Tackling inpatient penicillin allergies: Assessing tools for antimicrobial stewardship. J Allergy
Clin Immunol 2017.

27. Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing Inpatient Beta-Lactam Allergies: A Multihospital Implementation. J Allergy Clin
Immunol Pract 2017; 5:616.

28. Macy E, Burchette RJ. Oral antibiotic adverse reactions after penicillin skin testing: multi-year follow-up. Allergy 2002; 57:1151.

29. Rimawi RH, Cook PP, Gooch M, et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med 2013;
8:341.

30. Assem ES, Vickers MR. Tests for penicillin allergy in man. II. The immunological cross-reaction between penicillins and cephalosporins.
Immunology 1974; 27:255.

31. Girard JP. Common antigenic determinants of penicillin G, ampicillin and the cephalosporins demonstrated in men. Int Arch Allergy Appl
Immunol 1968; 33:428.
 32. Audicana M, Bernaola G, Urrutia I, et al. Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation
of cross-reactivity with cephalosporin. Allergy 1994; 49:108.

33. Romano A, Guéant-Rodriguez RM, Viola M, et al. Cross-reactivity and tolerability of cephalosporins in patients with immediate
hypersensitivity to penicillins. Ann Intern Med 2004; 141:16.

34. Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp Allergy
2001; 31:438.

35. Warrington RJ, Simons FE, Ho HW, Gorski BA. Diagnosis of penicillin allergy by skin testing: the Manitoba experience. Can Med Assoc J 1978;
118:787.

36. Forrest DM, Schellenberg RR, Thien VV, et al. Introduction of a practice guideline for penicillin skin testing improves the appropriateness of
antibiotic therapy. Clin Infect Dis 2001; 32:1685.

37. Arroliga ME, Radojicic C, Gordon SM, et al. A prospective observational study of the effect of penicillin skin testing on antibiotic use in the
intensive care unit. Infect Control Hosp Epidemiol 2003; 24:347.

38. Wall GC, Peters L, Leaders CB, Wille JA. Pharmacist-managed service providing penicillin allergy skin tests. Am J Health Syst Pharm 2004;
61:1271.

39. Park MA, McClimon BJ, Ferguson B, et al. Collaboration between allergists and pharmacists increases β-lactam antibiotic prescriptions in
patients with a history of penicillin allergy. Int Arch Allergy Immunol 2011; 154:57.

40. King EA, Challa S, Curtin P, Bielory L. Penicillin skin testing in hospitalized patients with β-lactam allergies: Effect on antibiotic selection and
cost. Ann Allergy Asthma Immunol 2016; 117:67.

41. Heil EL, Bork JT, Schmalzle SA, et al. Implementation of an Infectious Disease Fellow-Managed Penicillin Allergy Skin Testing Service. Open
Forum Infect Dis 2016; 3:ofw155.

42. Solley GO, Gleich GJ, Van Dellen RG. Penicillin allergy: clinical experience with a battery of skin-test reagents. J Allergy Clin Immunol 1982;
69:238.

43. Saxon A, Beall GN, Rohr AS, Adelman DC. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987; 107:204.

44. Blanca M, Fernandez J, Miranda A, et al. Cross-reactivity between penicillins and cephalosporins: clinical and immunologic studies. J Allergy
Clin Immunol 1989; 83:381.

45. Shepherd GM, Burton DA. Administration of cephalosporin antibiotics to patients with a history of penicillin allergy. J Allergy Clin Immunol
1993; 91:262.

46. Pichichero ME, Pichichero DM. Diagnosis of penicillin, amoxicillin, and cephalosporin allergy: reliability of examination assessed by skin
testing and oral challenge. J Pediatr 1998; 132:137.

47. Greenberger PA, Klemens JC. Utility of penicillin major and minor determinants for identification of allergic reactions to cephalosporins. J
Allergy Clin Immunol 2005; 115:S182.

48. Park MA, Koch CA, Klemawesch P, et al. Increased adverse drug reactions to cephalosporins in penicillin allergy patients with positive
penicillin skin test. Int Arch Allergy Immunol 2010; 153:268.

49. Ahmed KA, Fox SJ, Frigas E, Park MA. Clinical outcome in the use of cephalosporins in pediatric patients with a history of penicillin allergy.
Int Arch Allergy Immunol 2012; 158:405.

50. Iammatteo M, Blumenthal KG, Saff R, et al. Safety and outcomes of test doses for the evaluation of adverse drug reactions: a 5-year
retrospective review. J Allergy Clin Immunol Pract 2014; 2:768.

51. Khan DA, Solensky R. Drug allergy. J Allergy Clin Immunol 2010; 125:S126.

52. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and
Immunology, Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol
2010; 105:259.

Topic 111361 Version 5.0

GRAPHICS

Approach to the patient with a past penicillin reaction who requires antibiotics

This algorithm is intended for use in conjunction with the UpToDate content on choice of antibiotics in penicillin-allergic hospitalized patients. It is oriented toward hospitalized patients but also applies t
procedures can be performed in an appropriately monitored setting with the staff and equipment needed to manage allergic reactions, including anaphylaxis.

IgE: immunoglobulin E.
* Ask the following:
1. What exactly were the symptoms?
Raised, red, itchy spots with each lesion lasting less than 24 hours (hives/urticaria)?
Swelling of the mouth, eyes, lips, or tongue (angioedema)?
Blisters or ulcers involving the lips, mouth, eyes, urethra, vagina, or peeling skin (seen in SJS, TEN, other severe type IV reactions)?
Respiratory or hemodynamic changes (anaphylaxis)?
Joint pains (seen in serum sickness)?
Did the reaction involve organs like the kidneys, lungs, or liver (seen in DRESS, other severe type IV reactions)?
2. What was the timing of the reaction after taking penicillin: Minutes, hours, or days later? Was it after the first dose or after multiple doses?
3. How long ago did the reaction happen? (After 10 years of avoidance, only 20% of patients with IgE-mediated penicillin allergy will still be allergic).
4. How was the reaction treated? Was there a need for urgent care or was adrenaline/epinephrine administered?
5. Has the patient tolerated similar medications, such as ampicillin, amoxicillin, or cephalexin since the penicillin reaction?
¶ Isolated mild hives, without other symptoms of an IgE-mediated reaction, can often occur in the setting of an infection. Patients with this history, especially if it occurred in childhood or >10 years ago, may also be c
for a recurrent serious reaction.
Δ This algorithm is intended for use in conjunction with additional UpToDate content. For a description of how to safely perform a TEST DOSE PROCEDURE, refer to the UpToDate topic on choice of antibiotics in penici
◊ Consult allergist to perform skin testing. If skin testing is not possible, patient may still be able to receive penicillins or first- or second-generation cephalosporins using a desensitization (also known as tolerance ind
UpToDate topic on rapid drug desensitization for immediate hypersensitivity reactions.

Original figure modified for this publication. Blumenthal KG, Shenoy ES, Varughese CA, et al. Impact of a clinical guideline for prescribing antibiotics to inpatients reporting penicillin or cephalosporin allergy. Ann Allergy Asthma I
used with the permission of Elsevier Inc. All rights reserved.

Graphic 112936 Version 5.0

Immediate allergic reactions to drugs (IgE-mediated or non-IgE-mediated): Possible signs and symptoms

Skin

Itching*
Urticaria*
Angioedema*
Warmth
Flushing
Other exanthema

Eyes, ears, nose

Periorbital edema*
Rhinorrhea*
Nasal itching*
Nasal congestion*
Ocular itching
Tearing
Conjunctival injection and/or edema
Sneezing

Mouth

Itching or tingling of lips, tongue, oral mucosa*

Angioedema of lips, tongue, or uvula*
Metallic taste

Throat

Itching*
Sense of constriction or swelling in throat*
Change in voice quality*
Difficulty swallowing*
Stridor*
Hoarseness
Drooling

Lungs

Shortness of breath*
Chest tightness*
Repetitive cough*
Wheezing*
Drop in oxygen saturation, cyanosis

Cardiovascular

Lightheadedness/faintness/dizziness*
Tachycardia or occasionally, bradycardia*
Hypotension*
Syncope/loss of consciousness
Palpitations
Tunnel vision
Difficulty hearing
Urinary or fecal incontinence
Cardiac arrest

Gastrointestinal

Nausea
Vomiting
Abdominal cramping or pain
Diarrhea

Gynecologic

Vaginal itching
Uterine cramping or bleeding

Neurologic

Anxiety
Sense of impending doom
Altered mental status/confusion
Seizures

Immediate reactions to drugs often present with combinations of the signs and symptoms listed in the table. Those bolded and marked with an asterisk (*) are more consistent and representative
than the others, and one or more of these should be present to consider the reaction immediate.

IgE: immunoglobulin E.

Graphic 100732 Version 5.0

Studies of proactive penicillin skin testing in hospitalized patients

Patients Penicillin skin testing Use of beta-lactam antibiotics as a

Study Study details/comments
enrolled/tested (PST) results result of PST

Arroliga (2003) [1] 100/96 1 positive 38 patients received antibiotics Intensive care unit patients.
10 nondiagnostic 31 of 38 received beta-lactams
85 negative

Wall (2004) [2] 26/23 1 indeterminate 26 of 26 received a beta-lactam antibiotic PST performed by allergist-trained pharmacist. Almost all
22 negative patients (n = 22) were referred for evaluation by infectious
diseases consultation.

Park (2011) [3] 503/71 4 positive 29 of 71 received a beta-lactam Pharmacist screened all patients and recommended
67 negative Patients enrolled but not evaluated allergy consultation for PST in select patients.
54 (26%) received a beta-lactam

Rimawi (2013) [4]
482/146 1 positive 145 received beta-lactam antibiotics Most inclusive study with about one-third of inpatients
145 negative with penicillin allergy included in study. Beta-lactam
antibiotics used were predominantly broad-spectrum,
including piperacillin-tazobactam (n = 42), ceftriaxone (n =
27), and cefepime (n = 23). In this study, 217 patients were
excluded because of uncertain allergy history, but were
PST-eligible.

King (2016) [5] NA/50 50 negative 37 of 50 were changed to beta-lactam Patients were highly selected, including screened for skin
antibiotic test eligibility and already prescribed a broad-spectrum
antibiotic.

Heil (2016) [6] 90/76 64 negative 54 of 64 had changed to antibiotic therapy Skin testing service run by infectious diseases fellows and
9 nondiagnostic (34 of 54 more narrow spectrum, 43 of 54 patients were highly selected through antibiotic
3 positive more effective therapy, 33 of 54 less costly stewardship team referral, infectious diseases consultation
therapy) service, or the direct request of hospital team.

Chen (2016) [7] 252/228 223 negative 49 patients were on a penicillin or Electronic health record screened 1203 patients with
PST was completed in 19% 5 positive cephalosporin before PST versus 77 after penicillin allergy. Pharmacist prioritized based on patient
of penicillin-allergic (5 negative history only) Active orders for broad-spectrum antibiotics length of stay, antibiotic therapy, and comorbidities.
inpatients decreased (vancomycin decreased 33%,
clindamycin decreased 61%, quinolones
decreased 36%, carbapenems decreased
50%, and aztreonam decreased 68%)

Blumenthal (2017) [8]
278/42
Included all internal
medicine patients at a
tertiary care academic
medical center with
penicillin allergy being
treated for an infection
43 negative For all enrolled patients: Odds of receiving a Only study that provides insight into policy impact of
penicillin or cephalosporin as an inpatient proactive PST with adjusted analyses.
were not increased as a result of this policy
(adjusted odds ratio [OR] 1.3 [0.8, 2.0])
In the subgroup of patients who were skin
tested (43): Odds of receiving a penicillin or
cephalosporin as an inpatient (adjusted OR
5.6 [2.5, 12.4]) and on discharge (adjusted OR
2.5 [1.04, 6.2]) were both increased

PST: penicillin skin testing; NA: not available.

References:
1. Arroliga ME, Radojicic C, Gordon SM, et al. A prospective observational study of the effect of penicillin skin testing on antibiotic use in the intensive care unit. Infect Control Hosp Epidemiol 2003; 24:347.
2. Wall GC, Peters L, Leaders CB, Wille JA. Pharmacist-managed service providing penicillin allergy skin tests. Am J Health Syst Pharm 2004; 61:1271.
3. Park MA, McClimon BJ, Ferguson B, et al. Collaboration between allergists and pharmacists increases beta-lactam antibiotic prescriptions in patients with a history of penicillin allergy. Int Arch Allergy Immunol 2011;
154:57.
4. Rimawi RH, Cook PP, Gooch M, et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med 2013; 8:341.
5. King EA, Challa S, Curtin P, Bielory L. Penicillin skin testing in hospitalized patients with beta-lactam allergies: Effect on antibiotic selection and cost. Ann Allergy Asthma Immunol 2016; 117:67.
6. Heil EL, Bork JT, Schmaizie SA, et al. Implementation of an infectious disease fellow managed penicillin allergy skin testing service. Open Forum Infect Dis 2016; 3:ofw155. eCollection 2016.
7. Chen JR, Tarver SA, Alvarez KS, et al. A proactive approach to penicillin allergy testing in hospitalized patients. J Allergy Clin Immunol Pract 2016.
8. Blumenthal KG, Wickner PG, Hurwitz S, et al. Tackling inpatient penicillin allergies: Assessing tools for antimicrobial stewardship. J Allergy Clin Immunol 2017.

Graphic 111029 Version 2.0

Rapid overview: Emergency management of anaphylaxis in adults

Diagnosis is made clinically:

The most common signs and symptoms are cutaneous (eg, sudden onset of generalized urticaria, angioedema, flushing, pruritus). However, 10 to 20% of patients have no skin findings.

Danger signs: Rapid progression of symptoms, respiratory distress (eg, stridor, wheezing, dyspnea, increased work of breathing, persistent cough, cyanosis), vomiting, abdominal pain,
hypotension, dysrhythmia, chest pain, collapse.

Acute management:
The first and most important treatment in anaphylaxis is epinephrine. There are NO absolute contraindications to epinephrine in the setting of anaphylaxis.

Airway: Immediate intubation if evidence of impending airway obstruction from angioedema. Delay may lead to complete obstruction. Intubation can be difficult and should be performed by the most
experienced clinician available. Cricothyrotomy may be necessary.

Promptly and simultaneously, give:

IM epinephrine (1 mg/mL preparation): Give epinephrine 0.3 to 0.5 mg intramuscularly, preferably in the mid-outer thigh. Can repeat every 5 to 15 minutes (or more frequently), as needed. If
epinephrine is injected promptly IM, most patients respond to one, two, or at most, three doses. If symptoms are not responding to epinephrine injections, prepare IV epinephrine for infusion.

Place patient in recumbent position, if tolerated, and elevate lower extremities.

Oxygen: Give 8 to 10 L/minute via facemask or up to 100% oxygen, as needed.

Normal saline rapid bolus: Treat hypotension with rapid infusion of 1 to 2 liters IV. Repeat, as needed. Massive fluid shifts with severe loss of intravascular volume can occur.

Albuterol (salbutamol): For bronchospasm resistant to IM epinephrine, give 2.5 to 5 mg in 3 mL saline via nebulizer, or 2 to 3 puffs by metered dose inhaler. Repeat, as needed. 

Adjunctive therapies:

H1 antihistamine*: Consider giving cetirizine 10 mg IV (given over 2 minutes) or diphenhydramine 25 to 50 mg IV (given over 5 minutes) - for relief of urticaria and itching only.

H2 antihistamine*: Consider giving famotidine 20 mg IV (given over 2 minutes).

Glucocorticoid*: Consider giving methylprednisolone 125 mg IV.

Monitoring: Continuous noninvasive hemodynamic monitoring and pulse oximetry monitoring should be performed. Urine output should be monitored in patients receiving IV fluid resuscitation for
severe hypotension or shock.

Treatment of refractory symptoms:

Epinephrine infusion ¶: For patients with inadequate response to IM epinephrine and IV saline, give epinephrine continuous infusion, beginning at 0.1 mcg/kg/minute by infusion pump Δ.
Titrate the dose continuously according to blood pressure, cardiac rate and function, and oxygenation.

Vasopressors ¶: Some patients may require a second vasopressor (in addition to epinephrine). All vasopressors should be given by infusion pump, with the doses titrated continuously according to blood
pressure and cardiac rate/function and oxygenation monitored by pulse oximetry.

Glucagon: Patients on beta-blockers may not respond to epinephrine and can be given glucagon 1 to 5 mg IV over 5 minutes, followed by infusion of 5 to 15 mcg/minute. Rapid administration of
glucagon can cause vomiting.

Instructions on how to prepare and administer epinephrine for IV continuous infusions are available as separate tables in UpToDate.

IM: intramuscular; IV: intravenous.

* These medications should not be used as initial or sole treatment.
¶ All patients receiving an infusion of epinephrine and another vasopressor require continuous noninvasive monitoring of blood pressure, heart rate and function, and oxygen saturation.
Δ For example, the initial infusion rate for a 70 kg patient would be 7 mcg/minute. This is consistent with the recommended range for non-weight-based dosing for adults, which is 2 to 10 mcg/minute. Non-
weight-based dosing can be used if the patient's weight is not known and cannot be estimated.

Adapted from: Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010; 125:S161.

Graphic 58346 Version 32.0

Rapid overview: Emergency management of anaphylaxis in infants and children*

Diagnosis is made clinically:

The most common signs and symptoms are cutaneous (eg, sudden onset of generalized urticaria, angioedema, flushing, pruritus). However, 10 to 20% of patients have no skin findings.

Danger signs: Rapid progression of symptoms, evidence of respiratory distress (eg, stridor, wheezing, dyspnea, increased work of breathing, retractions, persistent cough, cyanosis), signs
of poor perfusion, abdominal pain, vomiting, dysrhythmia, hypotension, collapse.

Acute management:
The first and most important therapy in anaphylaxis is epinephrine. There are NO absolute contraindications to epinephrine in the setting of anaphylaxis.

Airway: Immediate intubation if evidence of impending airway obstruction from angioedema. Delay may lead to complete obstruction. Intubation can be difficult and should be performed by the most
experienced clinician available. Cricothyrotomy may be necessary.

IM epinephrine (1 mg/mL preparation): Epinephrine 0.01 mg/kg should be injected intramuscularly in the mid-outer thigh. For large children (>50 kg), the maximum is 0.5 mg per dose. If there is no
response or the response is inadequate, the injection can be repeated in 5 to 15 minutes (or more frequently). If epinephrine is injected promptly IM, patients respond to one, two, or at most, three
injections. If signs of poor perfusion are present or symptoms are not responding to epinephrine injections, prepare IV epinephrine for infusion (see below).

Place patient in recumbent position, if tolerated, and elevate lower extremities.

Oxygen: Give 8 to 10 L/minute via facemask or up to 100% oxygen, as needed.

Normal saline rapid bolus: Treat poor perfusion with rapid infusion of 20 mL/kg. Re-evaluate and repeat fluid boluses (20 mL/kg), as needed. Massive fluid shifts with severe loss of intravascular
volume can occur. Monitor urine output.

Albuterol: For bronchospasm resistant to IM epinephrine, give albuterol 0.15 mg/kg (minimum dose: 2.5 mg) in 3 mL saline inhaled via nebulizer. Repeat, as needed.

H1 antihistamine: Consider giving diphenhydramine 1 mg/kg (max 40 mg IV, over 5 minutes) or cetirizine (children aged 6 months to 5 years can receive 2.5 mg IV, those 6 to 11 years of age can
receive 5 or 10 mg IV, over 2 minutes).

H2 antihistamine: Consider giving famotidine 0.25 mg/kg (max 20 mg) IV, over at least 2 minutes.

Glucocorticoid: Consider giving methylprednisolone 1 mg/kg (max 125 mg) IV.

Monitoring: Continuous noninvasive hemodynamic monitoring and pulse oximetry monitoring should be performed. Urine output should be monitored in patients receiving IV fluid resuscitation for
severe hypotension or shock.

Treatment of refractory symptoms:

Epinephrine infusion ¶: In patients with inadequate response to IM epinephrine and IV saline, give epinephrine continuous infusion at 0.1 to 1 mcg/kg/minute, titrated to effect.

Vasopressors ¶: Patients may require large amounts of IV crystalloid to maintain blood pressure. Some patients may require a second vasopressor (in addition to epinephrine). All vasopressors should
be given by infusion pump, with the doses titrated continuously according to blood pressure and cardiac rate/function monitored continuously and oxygenation monitored by pulse oximetry.

IM: intramuscular; IV: intravenous.

* A child is defined as a prepubertal patient weighing less than 40 kg.
¶ All patients receiving an infusion of epinephrine and/or another vasopressor require continuous noninvasive monitoring of blood pressure, heart rate and function, and oxygen saturation. We suggest that
pediatric centers provide instructions for preparation of standard concentrations and also provide charts for established infusion rate for epinephrine and other vasopressors in infants and children.

Graphic 74242 Version 35.0

Contributor Disclosures
Kimberly G Blumenthal, MD, MSc Other Financial Interest: Licensed clinical decision support tool related to beta-lactam allergy evaluation. Roland Solensky,
MD Grant/Research/Clinical Trial Support: Stallergenes Greer [Allergic rhinitis]; ALK [Allergic rhinitis]. Consultant/Advisory Boards: ALK [Allergic
rhinitis]. Elizabeth J Phillips, MD, FRCPC, FRACP, FIDSA, FAAAAI Equity Ownership/Stock Options: IIID Pty Ltd [HLA-B*5701 testing for abacavir hypersensitivity].
Patent Holder: IIID Pty Ltd [HLA-B*5701 testing for abacavir hypersensitivity]; [Detection of HLA-A*32:01 in connection with determining DRESS and methods of
treating bacterial infection in vancomycin-induced DRESS]. Grant/Research/Clinical Trial Support: National Institutes of Health [Drug hypersensitivity]; National
Health and Medical Research Council of Australia. Consultant/Advisory Boards: BioCryst [Hereditary angioedema]. Anna M Feldweg, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review
process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy