CONTENTS

• CLINICAL APPROACH 🚀
  • Allergy history
  • Antibiotic selection
• Getting started
  • Types of drug reaction
  • How allergy labels cause harm
  • Basic science of beta-lactam allergy
• Techniques for allergy management in critical care
  • (Skin testing)
  • Graded challenge
  • Desensitization
• Groups of cross-allergic antibiotics
  1. Penicillin, aminopenicillins & some G1-G2 cephalosporins
  2. Cefazolin
  3. Nafcillin
  4. Piperacillin-tazobactam
  5. Cefepime & most G3 cephalosporins
  6. Ceftazidime & aztreonam
  7. Ceftaroline
  8. Carbapenems

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clinical approach to a patient with a beta-lactam allergy

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accurate drug reaction history

[1] signs/symptoms & duration

• Swelling of the tongue, mouth, lips, or eyes?
• Dyspnea or wheeze?
• Hypotension?
• Nausea, vomiting, diarrhea, cramping?
  • Isolated gastrointestinal symptoms especially diarrhea are frequently an adverse drug reaction that doesn't reflect IgE-mediated allergy.)
  • Gastrointestinal symptoms combined with involvement of other systems (e.g., hives) indicates anaphylaxis.
• Urticaria? (Raised, erythematous, pruritic rash with each lesion typically lasting <24 hours.)
  • 1-1-1 criteria: Urticaria occurring within <1 hour after the 1st dose and lasting <1 day are likely allergic. (36415507)
• Non-IgE mediated skin reactions:
  • Mild delayed-type hypersensitivity reaction: maculopapular rash with delayed onset and no visceral organ involvement.
  • SJS/TEN may cause desquamation and ulceration of the mouth/lips/eyes, but this is uncommon with beta-lactams. (34767158)
• Organ involvement (e.g., hematologic, renal, hepatic)?

[2] how was the reaction managed?

• ? Epinephrine.
• ? Hospitalization.

[3] timing: delay to onset & duration of symptoms

• Delay to onset:
  • IgE mediated reactions occur rapidly (typically within <1 hour, and generally within <6 hours).
  • Delayed benign rash (maculopapular or urticarial): 6 hours-14 days. (34767158) 
  • AGEP (acute generalized exanthematous pustulosis): 24 hours-2 weeks. (34767158) 
  • SJS/TEN: 4 days-28 days.  (34767158) 
  • Serum sickness like reaction: 1-2 weeks. (34767158) 
  • DRESS: 2-8 weeks. (34767158) 
• Duration of symptoms:
  • Symptom duration >1 day is less likely to reflect IgE-mediated allergy. (36415507)

[4] other drugs/illnesses present?

• Pay especial attention to medications known to cause anaphylactoid reactions (e.g., IV vancomycin, IV contrast dye).
• Maculopapular rash is frequently due to a viral infection, rather than a drug reaction.

[5] time elapsed since reaction?

• Over 1 year, ~20-50% of patients may lose sensitivity. (36415507)
• Over 5 years, ~60% of patients may lose sensitivity. (36415507)
• Over 10 years, ~80% of patients with a positive skin-test reaction to penicillin will become unreactive. (30644987)
• A poorly defined childhood history of “penicillin allergy” is minimally worrisome decades later.

[6] antibiotics tolerated subsequent to reaction?

• Search the electronic medical record for prior antibiotic prescriptions: (33292466)
  • [1] Search the Epic chart for the word “antibiotic.”
  • [2] Click the “Meds” button. This will display a chronological list of all antibiotics the patient has received.

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antibiotic selection

Clinical judgement is required, but a general approach is shown below. (37068548) Note that administration of medications in the ICU will be safer than other locations, because of high-level monitoring with the immediate ability to manage anaphylaxis.

A non-severe reaction is defined as mild involvement of a single organ system, including the following: (37068548)

• Cutaneous: urticaria, erythema-warmth, pruritus, tingling, and itching of lips.
• Upper respiratory: nasal symptoms (e.g., sneezing, rhinorrhea, nasal pruritus, and/or nasal congestion), throat-clearing (itchy throat), cough not related to bronchospasm.
• Conjunctival: erythema, pruritus, or tearing.
• Maculopapular exanthema without organ involvement
• Nausea (note that severe crampy abdominal pain or repetitive vomiting would be classified as a severe reaction).

Antibiotics can be divided into eight groups. Drugs within a group have similar R1-side chains and display cross-allergic reactions (whereas drugs in different groups are not cross-allergic):

1. Penicillin, aminopenicillins & selected G1-G2 cephalosporins
2. Cefazolin
3. Nafcillin
4. Piperacillin-tazobactam
5. Cefepime & most G3 cephalosporins
6. Ceftazidime & aztreonam
7. Ceftaroline
8. Carbapenems

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types of drug reaction

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Drug reactions vary greatly. Below is a description of the most commonly encountered reactions. (30558872) This chapter focuses on IgE-mediated allergic reactions. However, patients rarely may develop severe non-IgE-mediated immune drug reactions (e.g., Steven Johnson Syndrome, acute interstitial nephritis). Such patients should not be re-challenged with that drug or related agents.

true allergic reaction (Type-I hypersensitivity, IgE-mediated)

• Clinical presentation:
  • Rapid onset (generally <1 hour, especially if IV administration; possibly up to six hours).
  • Mild form: urticaria.
  • More severe: angioedema, anaphylaxis (hypotension, flushing, wheezing, nausea/vomiting, abdominal pain, stridor).
• Mechanism: IgE antibodies against drug cause mast cell degranulation
• Drugs that commonly cause this: penicillins, cephalosporins.
• Diagnosis: History, skin testing, drug challenge
• Treatment:
  • Severe: epinephrine, antihistamines, steroid.
  • Avoid drug and cross-allergic drugs in the future.
  • If use of the drug is essential, desensitization may be performed (more on this below).

anaphylactoid reaction

• Clinical presentation:
  • Nearly identical to a true allergic reaction (above), albeit less tendency to cause shock.
  • Occurs during drug infusion or immediately after administration (never a delayed reaction).
• Mechanism: Drug directly stimulates mast cells, triggering the release of inflammatory mediators.
• Drugs that commonly cause this:
  • Vancomycin (red person syndrome)
  • Fluoroquinolones
• Diagnosis:
  • Clinical diagnosis based on scenario
• Treatment:
  • Similar treatment to management of an allergic reaction, but these reactions are overall less severe and typically require only antihistamine.
  • Not a contraindication to using the drug in the future! However, the drug should be administered more slowly.

cytopenias (class II hypersensitivity reaction)

• Clinical presentation:
  • Hemolytic anemia or thrombocytopenia.
  • Typically begins in under 3 days, but can be delayed up to two weeks.
• Mechanism: IgG and complement-mediated phagocytosis or cytotoxicity.
• Drugs that commonly cause this:
  • Penicillins, cephalosporins.
  • Sulfonamides.
  • Dapsone, rifampicin.
• Treatment:
  • Steroid and/or intravenous immunoglobulin.
  • Avoid drug in the future, or agents from same class.

serum sickness like reaction (SSLR)(class III hypersensitivity reaction)

• Clinical presentation:
  • Rare in adults.
  • Fever, rash, or arthralgia.
  • Nausea, vomiting, diarrhea may occur.
  • Typically, 1-3 weeks delayed after starting drug.
  • Unlike true serum sickness, renal and hepatic involvement is rare.(33292466)
• Mechanism: Creation of antibody-antigen complexes.
• Drugs that commonly cause this:
  • Penicillin, amoxicillin, cefaclor.
  • Trimethoprim-sulfamethoxazole.
• Diagnosis: Skin biopsy.
• Treatment:
  • Steroids in severe cases.
  • Generally a benign event and future courses of medication are unlikely to lead to recurrence.(33292466)

maculopapular rash (a.k.a., benign T-cell-mediated drug reaction)

• Clinical presentation:
  • Diffuse maculopapular rash, may have associated eosinophilia.
  • Appears after days to weeks of therapy (typically ~2 weeks).
• Mechanism: Type IV cell-mediated reaction involving eosinophils
• Drugs that commonly cause this:
  • Amoxicillin
  • Sulfonamide antibiotics
• Diagnosis:
  • History and physical examination alone usually determine the diagnosis.
  • Skin biopsy, in severe or confusing cases.
• Treatment:
  • Antihistamines or topical steroid (systemic steroid in severe cases).
  • Generally benign, can re-challenge with same drug depending on scenario. In some cases, may even treat through this reaction, with careful monitoring for development of a more severe reaction.

acute interstitial nephritis (AIN)

• Clinical presentation:
  • Acute kidney injury, sometimes with skin rash.
  • Typically occurs between 3 days to a month after initiation of exposure.
• Mechanism: Type IV hypersensitivity.
• Drugs that commonly cause this:
  • Semi-synthetic antistaphylococcal penicillins (e.g. nafcillin, oxacillin).
  • Fluoroquinolones, rifampicin.
• Diagnosis:
  • Active urinary sediment (e.g. with leukocyte casts).
  • Peripheral blood eosinophilia may be seen.
  • Renal biopsy is diagnostic.
• Treatment:
  • Steroid, possibly additional immunosuppressives
  • Avoid drug in the future, or agents from same class.

drug-induced liver injury (DILI)

• Clinical presentation:
  • Hepatitis (often with substantially elevated bilirubin).
  • May have rash, fever, or eosinophilia.
  • Occurs ~1-12 weeks after initiation of exposure.
• Mechanism: T-cell immunity causes lysis of hepatocytes (Class IV hypersensitivity).
• Drugs that commonly cause this:
  • Amoxicillin-clavulanate, flucloxacillin.
  • Trimethoprim-sulfamethoxazole.
  • Nitrofurantoin, minocycline, rifampicin.
• Diagnosis:
  • Laboratory evaluation for hepatitis (often diagnosis of exclusion).
  • Liver biopsy in severe cases.
• Treatment:
  • Steroid.
  • Avoid drug in the future, or agents from same class.

drug reaction eosinophilia and systemic symptoms syndrome (DRESS)

• Clinical presentation:
  • Begins 2-6 weeks after starting drug.
  • Fever, rash.
  • Peripheral eosinophilia.
  • Lymphadenopathy or organ involvement (usually liver or kidney).
• Mechanism:
  • T-cell mediated (Type-IV hypersensitivity).
• Drugs that commonly cause this:
  • Vancomycin, all beta-lactam antibiotics.
  • Sulfonamide antibiotics.
• Treatment:
  • Steroid in severe cases.
  • Avoid drug in the future, or agents from same class.

Acute Generalized Exanthematous Pustulosis (AGEP)

• Clinical presentation:
  • Begins within 48 hours of antibiotic exposure.
  • Widespread pustular eruption with non-follicular sterile pustules.
  • Fever, facial edema.
  • 25% of patients have oral involvement.
  • In severe cases can cause systemic inflammation with shock.
• Mechanism:
  • T-cell stimulated neutrophilic inflammation (Type IV hypersensitivity).
• Drugs that commonly cause this:
  • Aminopenicillins, other beta-lactams.
  • Clindamycin, vancomycin.
  • Fluoroquinolones, Sulfonamides.
• Diagnosis:
  • History, physical diagnosis, skin biopsy.
  • Labs often show neutrophilia, mild eosinophilia.
  • After recovery, patch testing can help determine the causative agent.
• Treatment:
  • Systemic steroid in severe cases.
  • Avoid drug in the future, or agents from same class.

Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN)

• Clinical presentation:
  • Occurs 4 days to a month after antibiotic initiation.
  • Desquamating rash with mucosal involvement.
  • SJS refers to more limited forms; TEN refers to patients with greater area of desquamated skin.
• Mechanism: CD8 T-cells stimulate keratinocyte death (Type IV hypersensitivity).
• Drugs that commonly cause this:
  • Sulfonamide antimicrobials.
  • Macrolides, fluoroquinolones.
  • Cephalosporins are associated with an extremely low rate of severe cutaneous adverse reactions (e.g. Steven Johnson Syndrome). (28365277)
• Diagnosis: History, physical, skin biopsy.
• Treatment:
  • Aggressive supportive care in burn unit
  • Avoid drug in the future, or agents from same class.

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why allergies cause harm

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Over 30 million Americans carry a label of “penicillin allergy.” Most of these patients (>95%) can actually tolerate penicillins. (30644987) Concern regarding antibiotic allergy causes harm in roughly two ways:

reduced antibiotic efficacy

• Beta-lactam antibiotics are often the most effective (e.g., nafcillin or cefazolin are more effective against methicillin-sensitive Staph aureus than vancomycin).
• Avoiding beta-lactam antibiotics leads to treatment with less effective antibiotics (e.g., vancomycin or clindamycin).

increased antibiotic toxicity

• Avoidance of beta-lactam antibiotics promotes the use of unnecessarily broad-spectrum agents, which usually carry higher toxicity (e.g., selection of Clostridioides difficile or methicillin-resistant staph aureus).
• Classic examples of this phenomenon:
  • Septic patient with “penicillin allergy” is treated with a triple-antibiotic cocktail (e.g. vancomycin, metronidazole, and aztreonam) instead of being treated with a single beta-lactam (e.g. piperacillin-tazobactam).
  • Patient with pneumonia and “penicillin allergy” is treated with a fluoroquinolone.

This chapter will explore ways to safely utilize antibiotics in patients with a history of allergy. However, it's important to realize that the risk of an anaphylactic reaction is never zero. Patients with a history of anaphylaxis to one medication may be more likely to develop anaphylaxis to other medications in general. As is often the case in medicine, our task is to minimize risk as much as possible – but we can never get to zero risk. In fact, attempting to achieve zero risk could merely lead to more harms (e.g., placing the patient on a regimen of vancomycin, aztreonam, and levofloxacin – which likely increases their overall risk of being harmed by a medication side-effect!).

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basic science & R1-chains

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good news: IgE-mediated allergy to “beta-lactam antibiotics” doesn't exist

• Previously, it was believed that patients were allergic to the core beta-lactam ring structure. An allergy to the core beta-lactam ring would be extremely problematic, because this would imply that the patient would be allergic to all beta-lactam antibiotics.
• Fortunately, allergic reactions to the core beta-lactam ring structure don't seem to exist. Therefore, if a patient is allergic to one beta-lactam, this doesn't mean that they will necessarily be allergic to all drugs in this class.

IgE-mediated allergies occur to R1-side chains

• Patients are actually allergic to the R1-side chain of individual beta-lactam antibiotics.
  • Beta-lactams are too small to bind to IgE. In order to be recognized by the immune system, they must stick to proteins.
  • When a beta-lactam is attached to a protein, the R1-side chain sticks out. It plays a key role in binding to antibodies, and thereby driving allergic reactions.
• This can be a bit confusing:
  • Allergy to certain antibiotics will cross-react with antibiotics which have similar R1-side chain (e.g., ampicillin is cross-allergic with some first-generation cephalosporins).
  • Some antibiotics have side-chains which are unique and not cross-allergic with other drugs (e.g. cefazolin and ceftaroline).
• The key to determining cross-allergy is structural similarity between R1-side chains (not necessarily how a specific antibiotic is classified). For example, aztreonam and ceftazidime have identical R1 side-chains and are cross-allergic (despite belonging to different classes of beta-lactams).
• The R1-side chains of many beta-lactams are shown below. This provides a background for understanding the cross-reactivity of various beta-lactams.

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penicillin skin testing

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drawbacks of skin testing in critical care medicine

• [1] Skin tests are clinically validated only for penicillin allergy (not for other antibiotics).
  • A negative penicillin allergy doesn't exclude allergies to structurally unrelated beta-lactams (e.g., aminopenicillins, cephalosporins, or piperacillin). (17620077)
  • The only benefit of skin testing is helping to remove the label of “penicillin allergic.”
• [2] Penicillin skin testing is increasingly irrelevant, as we recognize that natural penicillins are actually cross-allergic with very few antibiotics.
  • For example, preoperative skin testing has been touted as a way to allow patients to receive cefazolin for perioperative prophylaxis.(28965632) But cefazolin isn't cross-allergic with penicillin! So you don't need a skin test – you can just give cefazolin.
• [3] Necessary materials and trained staff are unavailable at most hospitals.
• [4] Skin testing causes a time delay before antibiotic administration.
• [5] A negative skin test doesn't completely exclude allergy (a ~5% risk of reaction may remain, despite a negative skin test).
• [6] A positive skin test doesn't necessarily mean that the patient cannot tolerate penicillin.  Among patients with a positive result, as many as 50% may actually be able to tolerate penicillin. (29304914)

bottom line?

• Skin testing isn't a logistically viable solution for critically ill patients with acute infection.

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graded challenge

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general concept

• Graded challenge may be used in situations where an anaphylactic reaction is possible, but unlikely to occur. Depending on patient specifics, examples could include:
  • [1] Non-severe reaction to the medication (e.g., hives) within <5 years.
  • [2] Severe reaction to the medication >10 years previously.
• The patient is first exposed to a small dose of the drug and, if this is tolerated, escalating doses are administered.
• This can be performed with any intravenous antibiotic (unlike penicillin skin testing).
• ICU admission represents an excellent opportunity to perform a graded challenge, since the patient is being intensely monitored with the ability to immediately treat anaphylaxis.
• Graded challenge is easily performed at no additional cost to the patient.

how to perform a graded challenge in the ICU

• Epinephrine must be immediately available at the bedside. If an allergic reaction occurs, treat it and hold any additional antibiotic.
  • Cutaneous reactions (e.g., hives) may be treated with diphenhydramine.
  • Anaphylaxis or angioedema should be treated with epinephrine.
• General protocol for graded challenge:
  • [1] Give 1% of the dose as a slow IV push.
  • [2] Observe for 30 minutes.
  • [3] Give 10% of the dose as a slow IV push.
  • [4] Observe for 30 minutes.
  • [5] Give the remainder of the antibiotic dose at the usual rate. (36122788, 37588449)

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desensitization

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what is desensitization?

• Patient with a known IgE-mediated allergy (or highly suspected allergy) is gradually exposed to escalating doses of drug.
• An allergic reaction occurs and is managed medically.  After controlling the allergic reaction, more drug is given!
  • Desensitization:  Intentionally provoke an allergic reaction and treat through it.
  • Graded challenge:  Test for allergic reaction and stop drug administration if a reaction occurs.
• Eventually, IgE antibodies against the drug are depleted and the reaction subsides.  Now the patient is able to tolerate the drug.
  • However, the drug must be continually administered to the patient in order for desensitization to work. If the patient stops being exposed for a long period of time, re-exposure may cause anaphylaxis.
• ⚠️ Desensitization should not be used for non-IgE mediated drug reactions (e.g., SJS/TEN, DRESS, AGEP, drug-induced nephritis). (34767158)

how to perform desensitization

• Rigorous, validated protocols must be followed carefully.
• Initially a very tiny antibiotic dose is administered, and this is gradually increased over time (e.g., over a period of 6-12 hours).
• If allergic reactions occur, antibiotic administration is temporary held and the reaction is treated. Once the reaction subsides, additional antibiotic is administered.
• Desensitization should be performed in an ICU/ED with the capacity to immediately treat anaphylaxis or angioedema.

role of desensitization

• Occasionally used in situations where a specific antibiotic is uniquely useful.
• With increasing understanding about the lack of cross-reactivity between most antibiotics, this is rarely required currently.

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groups of cross-allergic antibiotics

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Antibiotics relevant to the ICU may be broken down into eight groups of cross-allergic antibiotics, listed below. If a patient has an IgE-mediated allergy to an antibiotic in one group, then drugs from a different group can be utilized.

1. Penicillin, aminopenicillins, and select G1-G2 cephalosporins
2. Cefazolin
3. Nafcillin
4. Piperacillin-tazobactam
5. Cefepime & most G3 cephalosporins
6. Ceftazidime & aztreonam
7. Ceftaroline
8. Carbapenems

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penicillin, aminopenicillins, and select G1-G2 cephalosporins

medications in this group

• Penicillin G (included here out of an abundance of caution, but in reality penicillin G has a different structure and may not truly belong here). (28483315, 33500632) For example, there are many patients who are allergic to aminopenicillins, but not Penicillin G.(31826341)
• Ampicillin, Amoxicillin.
• Some G1 cephalosporins, e.g.:
  • Cefadroxil.
  • Cefatrizine.
  • Cephalexin.
• Some G2 cephalosporins, e.g.:
  • Cefaclor.
  • Cefprozil.
  • Loracarbef.

comments

• This group might actually include 2-3 subgroups that display cross-allergic reactions. For example, penicillin has a unique structure as compared to cephalosporins and a low rate of cross-reactivity with cephalosporins. However, it is probably prudent to consider these antibiotics as a single cross-allergic group.

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cefazolin

medications in this group

• Cefazolin.
• Ceftezole (not available in the United States)

comments

• Cefazolin has a unique R-side chain that is not cross-allergic with other beta-lactams available in the United States. (30916014)
• Cefazolin is safe in patients with penicillin allergy (or, at least as safe as any other antibiotic; patients with a penicillin allergy are more likely to be allergic to any antibiotic). (31362351)

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nafcillin

medications in this group

• Nafcillin.

comments:

• Nafcillin seems to be a uniquely non-allergic medication. There are hardly any reports of anaphylaxis against it at all (perhaps only one). (6465179)
• Structurally, the R1 side-chain of nafcillin is rather unique, and unlike other beta-lactams. Nafcillin does not appear to be cross-allergic with penicillin G or aminopenicillins.
• It remains unclear whether nafcillin may be cross-allergic with other semisynthetic penicillins (e.g., oxacillin, flucloxacillin). Based on its unique structure, nafcillin probably isn't cross-allergic with these agents (figures below).

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piperacillin-tazobactam

medications in this group

• Piperacillin-Tazobactam.
• ? Sulbactam.
• ? Clavulanate (less structural similarity).

comments

• The structure of piperacillin-tazobactam is quite distinct from aminopenicillins or cephalosporins (figure below). This predicts a lack of cross-allergy. About 15% of patients with verified allergies to piperacillin-tazobactam are also allergic to penicillin, likely due to the coexistence of multiple independent drug allergies. Most patients with penicillin allergy can likely tolerate piperacillin-tazobactam. (33444815, 33474862, 32320796).
• ⚠️ It is unclear whether tazobactam could be cross-allergic with sulbactam or clavulanate. Structurally, tazobactam and sulbactam are quite similar. Caution should be exercised for patients with a history of severe allergy to ampicillin-sulbactam or amoxicillin-clavulanate. (31261671, 33444815)

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cefepime and most G3 cephalosporins

medications in this group

• Most G3 cephalosporins except ceftazidime, for example:
  • Ceftriaxone.
  • Cefotaxime.
  • Cefpodoxime.
  • Cefditoren.
  • Cefodizime.
  • Ceftizoxime
  • Cefetamet.
• G4 cephalosporins: Cefepime.

comments

• It is increasingly recognized that different groups of cephalosporins are not cross-allergic. (25930196)

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ceftazidime and aztreonam

medications in this group

• Ceftazidime (G3 cephalosporin).
• Aztreonam.
• Cefiderocol (G5 cephalosporin).

comments

• Ceftazidime and aztreonam have the same R1 side chain. This makes them cross-allergic, even though they are in different sub-classes of beta-lactam antibiotics.
• Aztreonam has historically been regarded as safe in “beta-lactam allergy,” but it is actually cross-reactive with ceftazidime. Nonetheless, aztreonam does have a proud track record of being safely employed in patients with allergy to a variety of other beta-lactam antibiotics.
• Ceftazidime or aztreonam may be options for patients unable to tolerate cefepime or most other G3 cephalosporins. (11167362, 31479769)

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ceftaroline

medications in this group

• Ceftaroline (G5 cephalosporin).

comments

• To date there aren't many reports of anaphylaxis from ceftaroline. However, a recent retrospective case series suggested that ceftaroline may cause unusually high rates of T-cell mediated hypersensitivity reactions (e.g., cytopenias, hepatitis, nephritis, desquamating skin rash).(27130709)

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carbapenems

medications in this group

• Ertapenem.
• Meropenem.

comments

• Meropenem, ertapenem, and imipenem all have the same R1-side chain (figure below).
• Meropenem seems nearly incapable of eliciting anaphylactic reactions.
  • Structurally, meropenem has a stubby and nearly nonexistent R1 side-chain (image below). This explains why it doesn't cause allergy.
  • Evidence supports the use of meropenem in patients with a history of anaphylaxis to aminopenicillins. (17696578, 25048853, 18467251, 25566799)
  • Meropenem can be a safe option for broad-spectrum coverage in patients with a myriad of antibiotic allergies.
• Imipenem-cilastatin may cross-react with some beta-lactam antibiotics, most likely due to the cilastatin component.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Being misled by the terms “penicillin allergy” and “cephalosporin allergy,” which should be eliminated.
• Failure to obtain a thorough allergy history that documents the exact nature of the drug reaction.
• Failure to realize that for patients with allergy to one beta-lactam, a non-cross-allergic beta-lactam can usually be used safely.
• Under-utilization of graded challenge to disprove allergic reactions. The best time to perform a graded challenge is when the patient is being intensively monitored in an ICU or ED.

Guide to emoji hyperlinks

• = Link to online calculator.
• = Link to Medscape monograph about a drug.
• = Link to IBCC section about a drug.
• = Link to IBCC section covering that topic.
• = Link to FOAMed site with related information.
• = Link to supplemental media.