Guidelines for Antibiotic Allergy with special reference to Penicillin and Beta Lactam Allergy

• Allergies and anaphylaxis can occur with any medication. Allergies to antimicrobials are most likely with penicillins and cephalosporins
• Anaphylaxis to medication begins and progresses rapidly. The most common sign is severe, persistent hypotension +/- tachycardia.  Flushing, urticaria, angioedema,  pruritus and respiratory symptoms occur in many patients but may be absent. Gastrointestinal symptoms are also common. The most common causes of fatal medication-related anaphylaxis are, penicillins/cephalosporins, neuromuscular blockers radiocontrast media, and NSAIDs
• Ensuring known allergens are avoided requires patient education and prescriber caution, aided by prescription safety technology where available.Check allergy history immediately before prescribing any antimicrobial
  • Ensure you understand which antimicrobials are contra-indicated in which allergy, e.g. which products are penicillin-based
  • Ensure allergies are entered to each patient’s record and that the computer system is configured to generate automated alerts, which cannot be overridden without amending the allergy status, if there is an attempt to prescribe a known allergen,  
  • Ensure the patient understands the nature of their allergy, which medication they should not have, and that they need to communicate this to all healthcare providers.
• If a patient believes they have an allergy to an antimicrobial, but the history is inconsistent with this (see penicillin allergy section below), ensure the risks and benefits of the proposed treatments and alternatives are discussed with the patient and the patient expressly agrees to receive the proposed medication.  Update all records and ensure the patient clearly understands the change in their allergy status. 

Penicillin Allergy Summary Table

(see following text for further detail and advice)

• Penicillin Allergy is commonly reported either by patient or carer (between 10 – 20% of all patients)
• This figure grossly over-represents the true incidence of Penicillin Allergy
• Avoidance of Penicillin because of concerns regarding allergy is widespread, and in many situations unnecessary.
• Applying a label of Penicillin Allergy to a patient is a significant issue and will impose restrictions for prescribing with multiple potentially adverse outcomes (e.g.sub-optimal antibiotic effectiveness, more expensive and potentially more harmful antibiotic regimens). Caution should be taken BEFORE applying the label of Penicillin Allergy to any patient, especially when the clinical indications are tenuous. This is especially the case in young children where infectious illnesses are commonly associated with skin rashes (exanthema, and urticaria) and antibiotics used in the context of acute infection can be incorrectly labelled as the allergic trigger.
• Penicillin can provoke a number of severe and potentially fatal immune-mediated events in small numbers of patients predisposed. Presentations are variable and include anaphylaxis urticaria and angioedema occurring immediately following exposure (immediate, IgE mediated) and severe cutaneous reactions such as Acute Generalised Erythematous Pustulosis ( AGEP),  Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN) and DRESS (drug rash, often desquamating with eosinophilia and systemic symptoms, including severe hepatic dysfunction) (variable time of onset, immune-mediated, non-IgE dependent). Avoidance of Penicillin indefinitely is critically important in such patients.
• Patients who have previously tolerated Penicillin can and do react, sometimes manifesting serious and fatal reactions. Prior tolerance does not exclude risk of allergic reaction to Penicillin. Frontline healthcare personnel should know how to recognise and treat anaphylaxis.
• Cytotoxic-, immune-complex- and delayed- immune-mediated reactions including haemolytic anaemia, interstitial nephritis and pneumonitis can also be provoked by Penicillin exposure. Future use of Penicillins is best avoided.
• Non-immune mediated effects of penicillin (e.g. minor gastrointestinal upset caused by alteration of gut flora; salt and water retention in patients with renal impairment and cerebral irritation at very high doses) can lead to incorrect Penicillin Allergy labelling. Future avoidance of Penicillin is not usually necessary in these cases (but dose adjustments, in the event of renal impairment, may be required.).
• Many patients avoid Penicillin because of a family history of Penicillin Allergy or a personal history of allergy-related diseases e.g. asthma, eczema. In the absence of a suspicious clinical event, Penicillin should NOT be avoided.
  Care should be exercised with patients who report penicillin allergy but where details are vague – e.g. unknown reaction told by family member, poor recall of event, vague recollection of acute breathing, skin, CNS, GI reactions. Studies have shown little difference in the rates of test-confirmed IgE sensitivity to Penicillin in this group when compared with patients with more convincing histories of IgE mediated reactions. Do not administer Penicillin, unless or until further evaluated.
• The most common adverse event leading to a label of Penicillin allergy occurs later in or shortly after a course of Penicillin. Such reactions typically manifest with macular, papular or morbilliform skin eruptions, without systemic upset. Aminopenicillins (Ampicillin, Amoxycillin) are more commonly implicated. A number of factors other than Penicillin sensitivity should be considered. Rash in the setting of acute infection (e.g. viral exanthem) is very common, especially in children. Acute EBV infection, and less commonly HIV infection increase risk of delayed, skin-limited non-urticarial reactions with Penicillin use. Future use of Penicillin is NOT usually contraindicated in this group. It is reasonable to re-expose such patients to Penicillin again. However, there is a possibility that non-critical rashes may recur. Patient or carers should be aware of the rationale for re-exposure and the small risk of recurrence of skin rash

Penicillin Allergy Testing

• Conventional Penicillin Allergy tests will only identify IgE mediated sensitivity and are not useful in diagnosis of non-IgE based symptoms as outlined above (exanthema, SJS, TENS, DRESS, AGEP, isolated GI disturbance, seizure). The sensitivity of laboratory assays which detect IgE to Penicillin is low. For this reason, specific IgE Penicillin blood tests SHOULD NOT be used as a screening test for Penicillin Allergy and should only be interpreted in combination with other clinical information / tests by experienced specialist personnel. Testing for Penicillin Allergy requires a combination of in-vivo skin tests and in cases where these tests are negative, graded challenge / provocation tests. Testing can take anything from 1 hour to 6 hours to complete, depending on individual patient situations. Both skin testing and challenge tests can provoke systemic allergic reactions. Testing must be undertaken in a monitored hospital setting and by experienced medical personnel. Access to such services are limited in Ireland.
• IgE-based penicillin allergy tests as outlined in the section above are not helpful in evaluation of patients with late onset erythematous / morbilliform or exanthematous skin reactions, organ-specific toxic reactions (haematological, joints, kidneys) or other delayed reactions and should not be used. Direct patient testing (skin testing, penicillin challenge) must not be undertaken in patients with a history of severe cutaneous reactions such as AGEP, SJS / TEN or DRESS, where re-exposure can be fatal
• Not every patient with reported or suspected IgE-mediated Penicillin Allergy requires formal Penicillin Allergy testing. A clearcut history typical of immediate reactivity such as acute urticaria or anaphylaxis occurring in close temporal relationship to penicillin administration should be an adequate clinical indication, without further testing to avoid Penicillin in the future. A proportion of patients who have a remote history (>10 years ago) may lose Penicillin reactivity over time. Further use of Penicillin should only be undertaken if full testing indicates tolerance.
  When deciding which patients should be referred for Penicillin testing, issues to consider are:
  • Predicted future antibiotic requirements – patients with infrequent requirement for antibiotic therapy could use alternatives to Penicillin on the rare occasions when antibiotics are required. However, in patients with a high likelihood of future and regular antibiotic use e.g. Cystic Fibrosis, other chronic lung diseases, Immunodeficiency, Diabetes would benefit in having their individual circumstances with regard to Penicillin Allergy clarified.
  • A condition for which Penicillin is the best or only antibiotic of choice – e.g. Syphilis in pregnancy
  • Serious immediate hypersensitivity occurring in the setting of multiple drug exposures where Penicillin is implicated – e.g. intraoperative anaphylaxis
  • Multiple reported antibiotic sensitivities – where choices of antibiotics are highly restricted and situation with Penicillin not clearcut

Referral for Specialist Assessment

• When referring a patient for specialist assessment of suspected penicillin allergy, the following information should be collected.
  • Name, route of administration and indication for Penicillin
  • Date and time of the reaction
  • Time between commencement of the course of antibiotic and the last administered dose prior to onset of symptoms
  • Precise description of reaction – nature and severity of symptoms
  • Resolution of symptoms
  • Antibiotic usage subsequent to the event
  • Co-morbidities and other medication.
• If uncertain, discuss with a Specialist in Immunology / Allergy or with a Paediatrician with a special interest in allergy.
• Patients with true Penicillin Allergy should be informed of their sensitivity, the necessity for avoidance and the importance of advising all future healthcare personnel of the sensitivity.  All healthcare records should document the sensitivity and need for future avoidance. Patients should be advised to carry personal indicators ( e.g. alert jewellery) indicating allergy and avoidance requirements

Desensitisation of Penicillin Allergic patients is a high risk procedure and should be reserved for serious acute clinical situations where no other antibiotic choice exists and where personnel and resources to manage same are present. Desensitization, even when effective, is a transient state and does not confer longterm tolerance. Unnecessary avoidance of Penicillin can present adversity and risk to patients and is reported to increase the cost and potential for drug related adverse effects (e.g. prolonged hospitalization, less effective microbial clearance, antibiotic related side effects and secondary infections such as Clostridium difficile and VRE). Delabelling of Penicillin Allergy status in selected patient groups and particularly those indicated above where it is especially recommended has potential benefits for individual patients and for healthcare systems.

Allergy to Cephalosporins

• Allergies can occur to any medication, including all antimicrobials, and future use of that antimicrobial should be avoided in patients with a known allergy to it.
• Cephalosporin allergy. Patients should avoid all cephalosporins unless allergy testing has indicated tolerance of specific Cephalosporins. Cross-sensitivity with penicillins is possible, see below.
• Penicillin allergy and cross-sensitivity with cephalosporins - Cross sensitivity between Penicillins and Cephalosporins has been over-reported and is probably in the region of 2 – 3% for 3rd generation cephalosporins, but closer to 10% for first generation Cephalosporins.
• Cephalosporins should NOT be used  in those with known severe  Penicillin allergy ( anaphylaxis, angioedema , wheezing ,acute urticaria, severe generalised skin reactions skin reactions , haemolytic anaemia ,interstitial nephritis ,hepatitis) unless skin tests are negative and oral challenge testing is negative.
• In life-threatening situations, where non-Cephalosporin antibiotics are suboptimal, desensitization with the Cephalosporin of choice in situations where expertise is available, or if prior reported reaction with cephalosporin was not severe (late onset non-severe rash, GI upset) -  cautious administration of third generation (cefixime, cefotaxime, ceftazidime, ceftriaxone) or second generation (cefuroxime) can be considered. First generation (cefaclor, cephalexin, cephradine and cefadroxil) should be avoided.
• Patients where penicillin allergy has been outruled (see above) may receive cephalosporins if there is no specific history of reaction to cephalosporins

References:

• Penicillin Allergy – getting the label right. Drugs and Therapeutics Bulletin doi:10.1136/dtb.2017.3.0463; BMJ 2017; 358:j3402 doi:10.1136/bmj.j3402
• NICE Guideline Drug Allergy: diagnosis and management Clinical guideline [CG183] Published date: September 2014
• Irish Medication Safety Network. Briefing document: Reducing preventable harm to patients with known allergies. October 2012.

Reviewed March 2018