Hi, my name is Anne Liu. I'm jointly appointed through allergy, immunology, and infectious diseases, and it's my pleasure today to speak to you about antibiotic allergies. Antibiotic allergies are a common reason for giving patients second or third line antibiotics, and for administration of antibiotics that are more expensive and unnecessarily broad in spectrum for the patient's infection. Being labeled with a penicillin allergy has been shown to be associated with longer hospitalizations and increased rates of serious drug resistant infections as well as delays in resolution of infection symptoms. The American Board of Internal Medicine has recommended against overuse of non beta-lactam antibiotics in patients who carry a history of beta-lactam allergy without appropriate evaluation of that allergy. Evaluation of antibiotic allergies and drug allergies in general requires a detailed history. If assessing current risk based on a prior reaction, these following elements should be elicited: knowing the source of information, whether the patient, the patient's parents or a physician who observed the reaction is important; next, a timeline is essential in reaction classification, including start and end of possibly related medications, onsets and evolution of the reaction and timing and response to any treatments attempted; a detailed description of the reaction should be elicited, including any skin manifestations in their duration; knowing what concurrent illnesses were present at the time of the purported reaction, such as a viral infection with an amoxicillin-related rash also contributes to sorting out the likelihood of a true allergy; data from the time of a reaction and any provocation testing afterwards, including labs, histology, skin biopsies, skin testing, challenges, test dosing and desensitization can also inform your assessment of whether the patient had a true immunologically mediated hypersensitivity reaction versus a side effect, intolerance or other type of reaction; eliciting whether the patient has had any subsequent accidental exposures can also be very helpful retrospectives knowledge; if you are assessing an ongoing reaction, similar elements are needed but it can be more accurate as the information is more readily available and verifiable. A reaction timeline, reaction description, diagnostic workup and concurrent illnesses and medications can also be corroborated by an examination and skin inspection. Rashes are part of many antibiotic reactions and characterizing them as accurately is hugely helpful in risk stratification for future administration. Many patients will call any sort of itchy rash, hives, but there are many types of drug rashes that are not hives. An immediate onset urticarial eruption with angioedema should be viewed differently from a mild maculopapular rash that gradually resolved without any medical attention, although both may be labeled in the chart as hives. To allergists, hives are urticaria which implies a specific immunologic pathway distinct from a maculopapular rash a bullous eruptions such as Stevens-Johnson or toxic epidermal necrolysis, serum sickness, fixed drug eruption, drug reaction with eosinophilia and systemic symptoms and many, many others. An accurate classification has substantial implications for whether and how to rechallenge. A history of DRESS, or TEN, or SJS is a contraindication to rechallenge with the culprit drug. So, why do we want to revisit histories of antibiotic adult allergies when there can be alternatives? As I mentioned earlier, one of the most pressing reasons is the poor efficacy of alternatives. For example, use of vancomycin for methicillin susceptible staphorious when cefazolin and nafcilin are known to be more effective. Drug resistance can also limit the use of alternatives, both in treating a current infection and future infections. The exposure to a broader than necessary antibiotic maybe reflected in future resistance patterns. Intolerances and drug-drug interactions may also limit use of alternatives such as gastrointestinal side effects with macrolides. Alternatives may also be contraindicated, for example, we cannot use doxycycline for pregnancy-related syphilis, penicillin must be used. Other factors such as bioavailability, route of administration as well as cost should be taken into consideration. Although cost is not the first factor in antibiotic choice, it is one of the central concerns in antimicrobial stewardship. Diagnostic testing for antibiotic allergies can be employed for specific scenarios: Tryptase can be measured in the serum and should be drawn if anaphylaxis is suspected, but must be done in a specific timeframe. It peaks about one hour after the onset of an immediate type hypersensitivity reaction and thereafter declines over several hours, so it's not helpful when checked further out from a reaction. Tryptase is released by mast cells along with other mediators that account for a lot of the symptoms around immediate hypersensitivity reactions, including itching, swelling, or urticaria, bronchospasm and hypotension. For retrospective evaluations, skin testing can be placed and interpreted by an allergist and can be done with several antibiotics, primarily when suspecting or trying to rule out an immediate type hypersensitivity. Recent anaphylaxis, antihistamines and some other medications may produce false negatives. And negative skin testing must be followed by a confirmatory challenge either oral or IV to make any conclusions. Desensitization as a method of administering an antibiotic or any other medication to a patient who is thought to have a high likelihood or a known allergy, particularly an immediate type hypersensitivity. We recommend that a desensitization be done under the supervision of an allergist. The exact protocol depends on the nature of the prior reaction and the acuity of the patient. It is a temporary state that is maintained only as long as the drug is in the system. Redesensitization is required if doses are missed. Subsequent courses must be done by desensitization. And challenges, in contrast, are done in patients who have a low likelihood of a true allergy, and are done to demonstrate the absence of an allergy. The protocol also depends on the reaction history and the acuity of the patient. This should be done with caution and specific circumstances. The decision to desensitize or challenge should be based on multiple elements which may include skin testing. With regard to common antibiotic allergies, penicillin is one of the most common causes of antibiotic reactions, and about 10 percent of those patients will report a history of penicillin allergy. Of these, about 90 percent will actually be able to tolerate penicillin. Penicillin skin testing is well validated and is FDA approved, and has a negative predictive value of around 95 percent. Because it is the metabolites of penicillin that elicit most reactions, skin testing is done with Pre-PEN and pennicillin G as major and minor determinants, respectively, which tests for immediate type hypersensitivities. It is not used to detect a delayed type reactions, side effects and intolerances. In vitro penicillin IgE testing is available, but it carries in low negative predictive value, so is inferior to skin testing. Aminopenicillins include amoxicillin and ampicillin. These can produce allergies in patients who are penicillin-tolerant, is mediated by structural side chains rather than the beta-lactam ring. Aminopenicillins can be cross-reactive with cephalosporins with similar side chain. Most commonly though, amoxicillin is associated with a higher rate of delayed maculopapular rashes usually in the setting of a concurrent viral infection. Cephalosporins are less likely to cause allergy than penicillins. And when they do cause an immediate hypersensitivity, it is to the R-group side chain. It is reasonable to avoid cephalosporins with similar R-groups, but cephalosporins with unrelated side group structures can be given by graded challenge. Skin testing of cephalosporins is not standardized but can be useful in certain specific settings. Many people have heard of cross-reactivity among beta-lactams, especially between penicillins and cephalosporins. In a patient with a history of penicillin reaction, the likelihood of being able to safely administer a cephalosporin depends on the type of penicillin reaction, results of the penicillin skin testing, and the cephalosporin generation. Sulfonamides rarely cause IgE mediated reactions, and much more commonly cause delayed maculopapular exanthems. Amongst sulfonamides, there's no specific cross reactivity between antibiotics and nonantibiotics, such as furosemide. Sulfonamide skin testing should be reserved for select circumstances, and slow oral desensitization to bactrim is a useful tool for sulfonamide -sensitive patients. Vancomycin most commonly produces Red Man syndrome caused by nonspecific muscle activation with histamine release and symptomatically mimics a hypersensitivity reaction. True IgE mediated hypersensitivity to vancomycin is rare but it does happen. So, desensitization can be done if necessary. Usually, premedication with antihistamines, holding opiates and reducing the infusion rate to 30 to 50 percent are sufficient to overcome Red Man syndrome. Allergy evaluations to delabel antibiotic allergies are a powerful tool for antimicrobial stewardship programs. A number of studies have demonstrated substantial cost savings and increased use of optimal antibiotics from antibiotic allergy evaluations primarily in patients with a history of penicillin allergy as well as other beneficial outcomes. Some institutions have decision pathways that empower the treating physician to determine whether to do graded challenge or to consult allergy with positive outcomes. Partnering with allergists trained in these evaluations can remove a lot of the mystery that surrounds antibiotic allergies. I hope this has been helpful, and thank you for your attention.
