Australian Doctor 15th September 2023 AD 15th Sept Issue | Page 16

15 SEPTEMBER 2023 ausdoc . com . au tetracyclines ( 0.8 %), quinolones ( 0.6 %) and glycopeptides ( 0.5 %). 4

Patient-reported penicillin allergy is associated with increased methicillin-resistant Staphylococcus aureus ( MRSA ) and Clostridium difficile infection ( CDI ), surgical site infections , delayed time to antibiotic therapy , inappropriate antibiotic utilisation , increased length of stay , ICU admission and outpatient mortality . 4 , 6-11

Addressing antibiotic allergies in healthcare has become the target for community and hospital antimicrobial stewardship programs ( ASP ). 12

Antibiotic allergy ‘ delabelling ’

Delabelling is defined as the removal of a patients penicillin allergy via allergy testing ( which may involve skin testing ) or medical reconciliation . 12 Skin testing includes skin prick testing ( SPT ) and intradermal testing ( IDT ), usually performed by allergists / immunologists or those with specialist training . An oral challenge ( test dose ) remains the gold standard allergy test and must follow negative skin testing to truly ensure a patient is ‘ delabelled ’. While the term delabelling was introduced in 2013 , antibiotic allergy testing in both the in- and outpatient has been performed for more than 40 years ago . 13 , 14 Antibiotic allergy delabelling is now incorporated into hospital in- and outpatient ASP in some centres , and increasingly in multidisciplinary settings , to reduce the prevalence and impact . 15-17

The traditional approach of skin testing followed by oral challenge is being increasingly reserved for moderate to severe penicillin allergies , with direct oral challenge ( that is , single or multi-step test dose without skin testing ) a guideline-supported practice . 18 , 19 For antibiotic allergies other than penicillin , delabelling remains predominantly skin testing before oral challenge in specialist centres . The successful use of direct oral challenge in sulphonamide allergies has also been increasing reported in Australian and international settings .

20 , 21

Direct delabelling ( the removal of an antibiotic allergy via medical reconciliation only ) has also been increasingly deployed by non-allergists , in particular pharmacists , as a primary method for removing allergies that are not immunologically mediated ( for example , nausea , vomiting , headache , family history alone ); this can be deployed for any antibiotic allergy after careful history taking . 22 The approaches to low , moderate and high-risk allergies are described later .

The removal of an antibiotic allergy leads to reduction in inappropriate antibiotic use , restricted antibiotic use ,

3 , 16 , 17 , 23 length-of-stay and hospital costs .

Evidence exists to enable the allergist and non-allergist to perform penicillin allergy risk assessment to appropriately match the resultant phenotype with an appropriate delabelling plan .

Antibiotic allergy risk assessment

Careful assessment of an antibiotic allergy is required before assigning the correct management ( both testing and prescribing ). There are several assessment tools or algorithms to assist clinicians in assessing antibiotic allergies , in particular beta-lactam allergies ( see table 2 ).

Clinical decision rules allow prompt risk-stratification of patients at pointof-care , using the smallest number of

Table 1 . Allergic immediate and delayed reactions according to Gell and Coombs

Immune mechanism

Type 1 Type 2 Type 3 Type 4

key signs or symptoms . Two Australian-derived tools can be implemented for this process . PEN-FAST ( see box 2 ) is an internationally validated clinical decision rule . A cut-off of less than 3 points for PEN-FAST indicates a low risk of penicillin allergy . Stevenson et al , from a retrospective cohort of 447 Australian patients with a penicillin allergy , also identified benign rash more than one year previously as a lowrisk criterion . 24 The Australasian Society of Clinical Immunology and Allergy

( ASCIA ) also provides algorithms for the assessment of low and high-risk penicillin allergies .

Risk-based approaches to antibiotic allergy testing

Box 3 outlines an approach to delabelling that can be deployed for a range of antibiotic allergy phenotypes . While the predominant literature concerns penicillin allergy , some recommendations may be applied to other antibiotic allergies . Also see Devchand et al ’ s 2019 guideline on assessment and testing for primary care physicians . 27

Antibiotic prescribing in key allergy classes

BETA-LACTAMS The Australian Therapeutic Guidelines provides an overview of appropriate prescribing of beta-lactams in patients reporting a primary penicillin , cephalosporin or carbapenem allergy . 33 The rates of cross-reactivity between penicillins and cephalosporins in the modern literature are quoted as less than 2 % ( see figure 4 ). 34 , 35 There are higher rates of cross-reactivity when penicillins and cephalosporins with the same side chain ( R1 ) are prescribed ; the most common example is aminopenicillins ( amoxicillin , ampicillin ) and aminocephalosporins ( cephalexin , cefaclor ), see table 3 . 3 , 27

Non-cross-reactive beta-lactams can be used in patients with low-moderate risk allergy phenotypes ( for example , childhood rash , delayed benign rash ) who report a primary beta-lactam allergy . Do not use nonbeta-lactams in patients with high-risk allergy phenotype ( for example , anaphylaxis or SCAR ) unless under specialist advice or critical need .

MACROLIDES While antibiotic allergies to macrolides are frequently reported , many are drug intolerances ( Type A ADRs ) and can be removed via direct delabelling .

In cases of presumed immune mediated allergies ( for example , rash , anaphylaxis ), there is limited

T-cell mediated

Type Immediate reaction Delayed Delayed Delayed

Clinical presentations

Treatment

Boussetta N et al . Intern Med 2017 / CC BY / bit . ly / 43cd1KK

Figure 1 . Angioedema of the face .

Figure 2 . Urticaria .

Mild to moderate : immediate urticaria , angioedema ( see figure 1 ), rhino-conjunctivitis , gastrointestinal symptoms

Severe : anaphylaxis , bronchospasm , anaphylactic shock

STOP THE CULPRIT ANTIBIOTIC

Mild-moderate : antihistamines ( non-drowsy )

Severe : adrenaline , bronchodilators

Severe : haemolytic anaemia , thrombocytopenia

STOP THE CULPRIT ANTIBIOTIC Transfer to specialist care

James Heilman , MD / CC BY-SA 3.0 / bit . ly / 3pRhGn8

Severe : serum sickness-like illness , typically one week after exposure to drug ; high-grade fever , malaise , arthralgia , skin rash , jaw claudication , high inflammatory markers ( CRP ) and complement consumption ( low C3 and C4 )

STOP THE CULPRIT ANTIBIOTIC Transfer to specialist care

Box 2 . PEN-FAST penicillin allergy risk tool

Mild to moderate : has only skin involvement , with delayed urticaria ( see figures 2 and 3 ), maculopapular rash , exanthema , fixed drug eruption

Severe with skin involvement / severe cutaneous adverse reaction ( SCAR ): Stevens-Johnson syndrome ( SJS ), toxic epidermal necrolysis ( TEN ), drug reaction with eosinophilia and systemic symptoms ( DRESS ), acute generalised exanthematous pustulosis ( AGEP ), vasculitis

Severe other : drug-induced liver or kidney injury , vasculitis

STOP THE CULPRIT ANTIBIOTIC

Mild-moderate : antihistamines ( non-drowsy ) for pruritus , topical and short course of oral corticosteroids

Severe : transfer to specialist care immediately

This requires three clinical criteria , from which the risk of a positive penicillin allergy test can be accurately predicted :

Clinical criteria PEN – Penicillin allergy reported by patient F – Five years or less since reaction ( major criterion ) 2

A – Anaphylaxis or angioedema or S – Severe cutaneous adverse reaction ( major criterion )

T – Treatment required for reaction 1

0 points – Very low risk of positive penicillin allergy test < 1 % 1-2 points – Low risk of positive penicillin allergy test 5 % 3 points – Moderate risk of positive penicillin allergy test 20 % 4 points – High risk of positive penicillin allergy test 50 %

Source : Trubiano JA et al 2020 25 value in skin testing because of poor sensitivity and specificity . Further the data on cross-reactivity between macrolides is limited . 36 Consider an alternative macrolide in patients with low-risk allergy phenotypes to an individual macrolide . Avoid the macrolide class in patients with a moderate-high risk phenotype and seek specialist advice .

GLYCOPEPTIDES Glycopeptides infrequently cause true immune-mediated reactions . The most commonly used glycopeptide in the community is oral vancomycin and , in the hospital setting , the IV preparation . IV vancomycin infusion-related reactions , previously defined as “ red man syndrome ”, result from non-IgE-mediated mast cell activation . 37 IgE immune-mediated reactions to glycopeptides are rare , while T-cell-mediated ( delayed hypersensitivity ) are more frequently reported , in particular vancomycin DRESS . 38 Vancomycin is the single leading cause of DRESS in Australia , and is tightly associated with a new genomic association — HLA-A * 32:01 . 39 Testing for this HLA type before the use of vancomycin is not currently recommended , with 75 patients requiring testing to prevent one case . 38

Avoid rechallenge and seek specialist advice in patients reporting phenotypes not consistent with vancomycin infusion syndrome .

SULFONAMIDES Sulfonamide allergies are

Points

2

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