Administration of beta lactams to a patient with a history of cephalosporin allergy

Cephalosporins are commonly-used antibiotics that can cause a variety of hypersensitivity reactions. The reactions can be broadly classified as follows:

·         Immediate reactions are reactions that develop within one hour of administration. These are usually type I, immunoglobulin E (IgE)-mediated reactions and are characterized by urticaria, angioedema, bronchospasm, and/or hypotension (refer table below for signs and symptoms of anaphylaxis).

·         Non-immediate reactions are reactions that develop >1 hour of administration, often after several hours or days. Common delayed reactions include maculopapular rashes and urticarial eruptions. Rare types of delayed reactions include serum sickness-like reactions, drug fever, and drug-induced hypersensitivity syndrome.

Signs and Symptoms of Anaphylaxis
Skin	·      Feeling of warmth ·      flushing (erythema) ·      Itching ·      Urticaria, ·      Angioedema ·      "Hair standing on end" (pilor erection)	Cardio-vascular	·      Feeling of faintness or dizziness ·      Syncope ·      Altered mental status ·      Chest pain ·      Palpitations, ·      Tachycardia, bradycardia or other dysrhythmia, ·      Hypotension ·      Tunnel vision ·      Difficulty hearing ·      Urinary or fecal incontinence ·      Cardiac arrest
Oral	·      Itching or tingling of lips, tongue, or palate ·      Edema of lips, tongue, uvula ·      Metallic taste
Ocular	·      Periorbital itching, erythema and edema ·      Tearing  ·   Conjunctival erythema
Respi-ratory	·      Nose - Itching, congestion, rhinorrhea, and sneezing ·      Laryngeal - Itching and "tightness" in the throat, dysphonia, hoarseness, stridor ·      Lower airways - Shortness of breath (dyspnea), chest tightness, cough, wheezing, and cyanosis	Neuro-logic	·      Anxiety ·      Apprehension Sense of impending doom ·      Seizures ·      Headache and confusion; ·      Young children may have sudden behavioral changes (cling, cry, become irritable, cease to play)
Gastro-intestinal	·      Nausea ·      Abdominal pain ·      Vomiting ·      Diarrhea ·      Dysphagia (difficulty swallowing)	Others	Uterine cramps in women and girls

Overall, the rate of allergic reactions to cephalosporins is approximately 10-fold lower than it is to penicillin.

Past immediate reactions to a cephalosporin

Patients with past immediate reactions to a cephalosporin can often be safely treated with other beta-lactam drugs, including structurally dissimilar cephalosporins, penicillins, carbapenems, and monobactams. However, this requires an understanding of what is known about cross reactivity patterns among cephalosporins and related drugs.

Cross reactivity among cephalosporins and between cephalosporins and penicillins commonly arises from structural similarities in side chain groups or rarely from sensitization to the core beta-lactam ring (present both penicillins and cephalosporins) or metabolites of this ring.

Patients with past immediate reactions to cephalosporins who require subsequent use of related antibiotics should be evaluated by an allergy specialist when possible. The purpose of this evaluation is to determine what other drugs may be safely administered to that patient. An algorithm depicts the approach to identifying a safe alternative cephalosporin in a patient with a past immediate cephalosporin reaction.

Most patients with immediate reactions to cephalosporins and no history of reacting to penicillins will tolerate penicillins. If a patient reacted to a cephalosporin in the past and now requires a penicillin, then penicillin skin testing is indicated to guide management.

● Negative results on penicillin skin testing indicate that the patient's reaction to the cephalosporin was probably due to a unique cephalosporin determinant. Therefore, the patient is not at increased risk for reacting to a penicillin, provided that penicillin does not share a side chain with the cephalosporin that caused the initial reaction.

● Positive results on penicillin skin testing indicate that the patient may be reactive to the beta-lactam core, provided that the penicillin and cephalosporin in question do not share similar side chains. The patient may be treated with a non beta-lactam antibiotic or desensitized to the desired penicillin.

When Penicillin Skin Testing is NOT available

If penicillin skin testing is not available, we would suggest selecting a penicillin that does NOT have a side chain similar to that on the culprit cephalosporin, and skin testing with that penicillin (in its native form). If negative, we suggest performing a graded challenge to the penicillin.

The determination to challenge with penicillin or amoxicillin/ampicillin may be based on the patient’s history and/or the drug that may need to be administered immediately or prescribed in the future. Patients should be observed as long as severe exposure-related reactions are anticipated.  This recommendation depends on the type of previous drug reaction, the drug under investigation, and the patient’s individual condition.  While the majority of Committee members advocate 60 minutes of observation following the final oral provocation dose, some judge 30 minutes to be adequate for many patients. For this reason, we encourage the allergist to tailor the observation time from 30 to 60 minutes, as they deem most appropriate. 

A commonly used protocol is the administration of full dose oral beta lactam with monitoring for 30-60 minutes, but an alternative and more cautious protocol may be used that entails:

• A “test dose” (e.g, 10-25% of the  full oral dose), observation for 30 minutes, followed by the remaining or full oral dose with monitoring for 30-60 minutes. ^{(ACAAI 2010)}

OR

• A starting dose that is usually 1/100 or 1/10 of the full dose. Ten-fold increasing doses are administered every 30 to 60 minutes until the full therapeutic dose is reached.^{(UptoDate 2014)}

The reference tables above are reproduced from the 2010 Drug Allergy Practice Parameter

Reference tables of β-lactam antibiotics classified according to R1- and R2- side chains.

*Note from Joint Task Force on Practice Parameters⁴

Patients with a history of an immediate-type allergic reaction to a cephalosporin who require penicillin should undergo penicillin skin testing. However, if penicillin skin testing is unavailable, because the likelihood of reaction is low, cautious graded challenge with penicillin may be considered in patients with a history of immediate-type allergy to cephalosporins. 

Use of the same cephalosporin that caused a previous reaction —Rarely, a patient requires the same cephalosporin to which there is evidence of IgE-mediated allergy. A formal desensitization protocol should be performed in this situation. The procedure described for penicillin desensitization would be appropriate. 

Carbapenems and Monobactam

Patients with immediate cephalosporin allergy usually tolerate carbapenems (e.g., imipenem/cilastatin, meropenem, ertapenem, and doripenem). In the largest study available (Romano A et al. 2010), 98 patients with convincing histories of immediate cephalosporin reactions and positive skin tests to the culprit cephalosporin underwent allergy evaluation and graded challenge with several related medications. Overall, fewer than 5 percent had positive skin tests to carbapenems or monobactams. Penicillin skin test–positive patients and patients with a history of penicillin allergy who do not undergo skin testing should receive carbapenems via graded challenge.

Aztreonam is the only monobactam available for clinical use. There is no evidence of immunologic cross reactivity between the core cephalosporin structure and monobactams, so most cephalosporin-allergic patients may receive aztreonam normally. An exception is the patient with a past immediate reaction to ceftazidime, because aztreonam and ceftazidime share an identical side chain, and cross reactivity between the two drugs is reported. Therefore, penicillin and cephalosporin allergic patients may safely receive aztreonam, with the exception of patients who are allergic to ceftazidime.

Past non-immediate reactions to a cephalosporin

• Structural similarities among drugs might predict the recurrence of non-immediate reactions. Cross reactivity between aminopenicillins (eg, ampicillin, amoxicillin, and bacampicillin) and aminocephalosporins, like cephalexin has been reported. 
• Management options depend upon the type of reaction that occurred. 
• If a patient has a history of a non–IgE-mediated reaction to cephalosporin (other than serious reactions such as SJS or TEN) and re quires penicillin, a graded challenge with penicillin may be performed and skin testing is not indicated.⁴
• The presence of fever, mucosal involvement, or systemic symptoms should be interpreted as a more severe type of drug reaction and the culprit cephalosporin should not be given again.

References:

1. Beta-lactam antibiotic skin testing and oral challenge (ACAAI 2015 Drug Allergy and Anaphylaxis Committee).
2. UptoDate: Cephalosporin-allergic patients: Subsequent use of cephalosporins and related antibiotics [Accessed  26 Dec 2018]
3. Sampson H.A. et al.. Second symposium on the definition and management of anaphylaxis: Summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. (J Allergy Clin Immunol 2006;117:391-7.
4. Joint Task Force on Practice Parameters, American Academy of Allergy A, Immunology, American College of Allergy A, Immunology, Joint Council of Allergy A, et al. Drug allergy: an updated practice parameter. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2010;105(4):259-73.