antibiotic allergy

Antibiotic AllergyKey Messages from Practice Parameter,

Position Paper and Experts Opinion

Suda Sibunruang, M.D.

Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73

Objective: providing the practicing physician with an evidence-based approach to the diagnosis and

management of adverse drug reactions

Demoly P. et al. Allergy 2014; 69: 420–37

By the International Collaboration in Asthma, Allergy and Immunology (iCAALL), of which formed by EAACI, AAAAI, ACAAI, WAO Obj: highlight the key messages that are common to the existing guidelines

Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12

Adverse drug reactions (ADRs)

Type A: predictable reactions• Usually dose dependent, related to the known

pharmacologic actions of the drug, occur in otherwise healthy individuals

• Approximately 80% of all ADRsType B: unpredictable reactions• Dose independent, unrelated to the pharmacologic

actions of the drug, occur only in susceptible individuals• Unintended response to a drug taken at a dose

normally used in humansDemoly P. et al. Allergy 2014; 69: 420–37


Type B: unpredictable reactions

• Drug intolerance• Drug idiosyncrasy• Drug allergy• Pseudoallergic (anaphylactoid) reactions


Drug allergy

• an immunologically mediated response to a pharmaceutical and/or formulation (excipient) agent in a sensitized person


Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95

Drug hypersensitivity reactions (DHRs)

• Adverse effects of pharmaceutical formulations (including active drugs and excipients) that clinically resemble allergy

• Drug allergies are DHRs for which a definite immunological mechanism is demonstrated

• For general communication, when a drug allergic reaction is suspected, DHR is the preferred term, because true drug allergy and nonallergic DHR may be difficult to differentiate based on the clinical presentation alone


Classifications of DHRsMechanical• Allergic• Non-allergicClinical


Classifications of DHRs by clinical

Immediate• typically occur within 1– 6 h after the last drug

administrationNon-immediate • occur at any time as from 1 h after from the

initial drug administration


Classifications of DHRs by clinical

Immediate• Urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm,

gastrointestinal symptoms [nausea, vomiting, diarrhea, abdominal pain], anaphylaxis, anaphylactic shock

Non-immediate • Delayed urticaria, maculopapular eruptions, fixed drug

eruptions, vasculitis, TEN/SJS, DRESS, AGEP, symmetrical drug-related intertriginous and flexural exanthemas (SDRIFE)

• Hepatitis, renal failure, pneumonitis, anemia, neutropenia, thrombocytopenia


Bircher A. and Scherer K. Med Clin N Am 94 (2010) 711–725

Sousa I. N Engl J Med 2011;365:6

acute onset and appear as annular, edematous, sometimes blistering, reddish-brown to violaceous macules orplaques

Hallmarks include residual hyperpigmentation after healingand recurrence at previously affected sites, with subsequent antigenic challenges

Fixed drug eruption

Non- immediate reactions

• Identification of a nonimmediate reaction is sometimes difficult because of the heterogeneity of the clinical manifestations, which can be quite similar to the symptoms of infectious diseases

• Moreover, these reactions may be favored by a concomitant viral infection, such as those caused by HIV,CMV, HHV-6, or EBV


Bircher A. and Scherer K. Med Clin N Am 94 (2010) 711–725


Clinical and biological danger signs suggesting severe cutaneous and/or systemic reactions

Scherer K. and Bircher A. Med Clin N Am 94 (2010) 681–9


Algorithm for disease management of drug allergy


Algorithm for disease management of drug allergy (cont’)

Romano et al. J Allergy Clin Immunol 2011;127:S67-73

Drug provocation test (DPT)

• Gold standard to establish a firm diagnosis in subjects with clear-cut histories and negative allergy tests

• Is intended for patients who, after a thorough evaluation, are unlikely to be allergic to the given drug


Drug provocation test (DPT)

• Can be performed by administering an initial dose of one hundredth of the therapeutic one.

• In patients with negative results, a one-tenth dose is administered 1 hour later

• If the result is again negative, then a full dose is administered after another hour


Induction of drug tolerance

• which has often been referred to as drug desensitization• temporary induction of drug tolerance involve

administration of incremental doses of the drug

• involve IgE immune mechanisms, non- IgE immune mechanisms, pharmacologic mechanisms, and undefined mechanisms


Drug desensitization

• one form of induction of immune drug tolerance by which effector cells are rendered less reactive or nonreactive to IgE-mediated immune responses by rapid administration of incremental doses of an allergenic substance


Graded challenge or test dosing

• Administration of progressively increasing doses of a medication until a full dose is reached

• The medication is introduced in a controlled manner to a patient who has a low likelihood of reacting to it. Unlike procedures that induce drug tolerance, graded challenges usually involve fewer doses, are of shorter duration, and are not intended to induce drug tolerance


Antibiotics can be classified as…

• Beta-lactam• Non- Beta-lactam


Beta-lactam antibiotics

2 major classes• Penicillins • Cephalosporins4 minor classes• Carbapenems• Monobactams• Oxacephems• Clavams


Gruchalla R. J Allergy Clin Immunol 2003;111:S548-59

Non- Beta-lactam antibiotics

• Quinolones • Sulfonamides• Macrolides• Aminoglycosides• Rifamycins• Glycopeptides• Clindamycin


Prevalence

• Hypersensitivity reactions to antibiotics are commonly reported both in adults and children, with a prevalence of approximately 10%

• In U.S., antibiotic-associated adverse events have been implicated in 19.3% of all emergency department visits for drug-related adverse events

Legendre D. et al. Clin Infect Dis 2013:1-9Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12

Jares E et al. Ann Allergy Asthma Immunol 113 (2014) 282-9

Study design: cross-sectional study (2011-2013)Objective: To assess the clinical characteristics and management of hypersensitivity drug reactions in different Latin American countries.Methods: An European Network of Drug Allergy questionnaire survey was implemented in 22 allergy units in 11 Latin American countries Results: 868 hypersensitivity drug reactions in 862 patients.71% of adults and elderly patients were women and 51% of children were girls. Children presented with less severe reactions than adults

Jares E et al. Ann Allergy Asthma Immunol 113 (2014) 282-9

Sangasapasviliya A. et al. J Med Assoc Thai 2010; 93: S106-11

Study design: A cross-sectional descriptive study

Method: The study was performed from January 1st, 2008 to December 31th, 2008.

Data were collected from records of in-patients and out-patients

Objective: To evaluate the prevalence of drug hypersensitivity, clinical manifestations,

type of drugs involved, severity, and patients demographic data

Results: A total of 140 patients, most common manifestration of drug allergy was maculopapular

rash (34.99%). Majority (80.71%) of drug hypersensitivity was mild in severity

Sangasapasviliya A. et al. J Med Assoc Thai 2010; 93: S106-11

Techapornroong M. et al. Asian Pac J Allergy Immunol 2010;28:262-9

Methods: retrospective study of adult inpatients between

1992 - 2001 at KCMH

Objective: To investigate incidence, etiology, clinical manifestations, management

and outcome of patients with anaphylaxis

Results: Of 448,211 admissions, 80 events of anaphylaxis in 79 patients (0.017%)

were found

Techapornroong M. et al. Asian Pac J Allergy Immunol 2010;28:262-9

Beta-lactam antibiotics

Penicillin

• Penicillin allergy is the most commonly reported drug allergy, with a prevalence rate of 5% to 10% in adults and children


Penicillin

• However, after complete evaluation, up to 90% of these individuals are able to tolerate penicillins


Gruchalla R. and Pirmohamed M. N Engl J Med 2006;354:601-9

Penicillin skin testing

• Most reliable method for evaluating IgE-mediated penicillin allergy

• When performed by skilled personnel using proper technique, serious reactions are extremely rare

• Ideally, penicillin skin testing should be performed with both major and minor determinants



• Skin testing only with PPL and BP (without penicilloate or penilloate) may miss up to 20% of patients with penicillin allergy, but these data are controversial

• Several studies, including DPTs, have shown a similar rate of reactions in patients who display negative skin prick tests to PPL and BP compared with patients with negative skin prick tests to the full set of major and minor penicillin determinants



• NPV for immediate reactions approaches 100%, whereas the PPV is 40- 100 %

• Patients who have had negative skin test results to penicillin major and minor determinants may receive penicillin with minimal risk of an IgE-mediated reaction. Depending on the reaction history, the first dose may need to be given via graded challenge



• Penicillin skin test–positive patients should avoid penicillin, but if they develop an absolute need for penicillin, rapid induction of drug tolerance may be performed


Brockow K. et al. Allergy 2002: 57: 45–51

Torres M. and Blanca M. Med Clin N Am;2010:805–20

Resensitization

• Resensitization after parenteral penicillin appears to be higher than for oral treatment, therefore repeat penicillin skin testing may be considered in patients with a history of penicillin allergy who have tolerated a course of parenteral penicillin


Penicillin specific IgE

• High specificity (97%-100%) but lower sensitivity (29%-68%)

• Therefore, although a positive in vitro test result for penicillin specific IgE is highly predictive of penicillin allergy, a negative in vitro test result does not adequately exclude penicillin allergy


Penicillin specific IgE• The European guidelines, also include serum-specific IgE

assays, because cases of patients with clear-cut histories of immediate hypersensitivity reactions to Beta-lactams that display negative results in skin tests and positive ones in such assays have been reported

• Moreover, these guidelines suggest to perform in vitro tests before skin testing in subjects with a history of severe anaphylaxis to reduce the risk of systemic reactions to skin prick tests

• Another option for increased safety (instead of in vitro testing) is starting skin testing with diluted reagents


Penicillin

• Patients with a vague and/or distant history of penicillin allergy may be candidates to receive penicillins via graded challenge

• Patients with recent or convincing reaction histories should only receive penicillins via rapid induction of drug tolerance


Ampicillin and Amoxicillin

• Some patients with immediate type reactions to amoxicillin and ampicillin have IgE antibodies directed at the R-group side chain (rather than the core penicillin determinants) and are able to tolerate other penicillin class compounds


Ampicillin and Amoxicillin

• Amoxicillin and ampicillin are associated with the development of a delayed maculopapular rash in approximately 5% to 10% of patients

• These reactions are not related to IgE-mediated allergy, and they are postulated in many cases to require the presence of a concurrent viral infection or another underlying illness


Cephalosporins

Perez-Inestrosa E. et al. Curr Opin Allergy Clin Immunol 5:323–330

Torres M. and Blanca M. Med Clin N Am;2010:805–20

Cephalosporins

• Most hypersensitivity reactions to cephalosporins are probably directed at the R-group side chains rather than the core beta-lactam portion of the molecule


Pichichero M.E. and Zagursky R. Ann Allergy Asthma Immunol 112 (2014) 404-12

Cephalosporins

• Skin testing with native cephalosporins is not standardized, but a positive skin test result using a nonirritating concentration suggests the presence of drug specific IgE antibodies

• A negative skin test result does not rule out an allergy because the negative predictive value is unknown


Cephalosporins

• Patients with a history of an immediate- type reaction to 1 cephalosporin should avoid cephalosporins with similar R-group side chains

• Treatment with cephalosporins with dissimilar side chains may be considered, but the first dose should be given via graded challenge or induction of drug tolerance, depending on the severity of the previous reaction


Cephalosporin administration to patients with ahistory of penicillin allergy

• Penicillin skin testing, when available, should be considered before administration of cephalosporins

• Patients who have a history of a possible IgE-mediated reaction to penicillin, regardless of the severity of the reaction, may receive cephalosporins with minimal concern about an immediate reaction if skin test results for penicillin major and minor determinants are negative


Solensky R. Med Clin N Am;2006:233–60

Cephalosporin administration to patients with ahistory of penicillin allergy

• Skin testing to the cephalosporin followed by graded challenge appears to be a safe method for administration of some cephalosporins in penicillin allergic patients

• If penicillin and cephalosporin skin testing is unavailable, depending on the reaction history, cephalosporins may need to be given via graded challenge or rapid induction of drug tolerance


Madaan A. and Li J.T.-C. Immunol Allergy Clin N Am 24 (2004) 463–76

Cephalosporin administration to patients with ahistory of amoxicillin/ampicillin allergy

• Patients allergic to amoxicillin should avoid cephalosporins with identical R-group side chains (cefadroxil, cefprozil, cefatrizine) or receive them via rapid induction of drug tolerance

• Patients allergic to ampicillin should avoid cephalosporins and carbacephems with identical R-group side chains (cephalexin, cefaclor, cephradine, cephaloglycin, loracarbef) or receive them via rapid induction of drug tolerance


Monobactams (aztreonam)

• Aztreonam is less immunogenic than penicillin and cephalosporins, and clinical allergic reactions to aztreonam are less common than other beta–lactam antibiotics

• Aztreonam does not cross-react with other beta-lactams except for ceftazidime, with which it shares an identical R-group side chain


Carbapenems

• Limited data indicate lack of significant allergic cross-reactivity between penicillin and carbapenems

• Penicillin skin test–negative patients may safely receive carbapenems

• 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



Skin-test sensitivity may decrease with time

Diagnostic evaluation of children

• Using the same diagnostic protocol as adults• Several studies confirmed the safety of skin

tests in children, with a rate of 1% to 3% of systemic reactions to skin testing

• Negative predictive value of the DPT has been shown to be high, and retesting has been suggested to be reserved only to patients with severe reactions


Subjects with an undefined time interval

• Subjects with an undefined time interval between the last drug administration and the hypersensitivity reaction can be considered as non-immediate reactors


Patients at high risk

• If it is necessary to evaluate patients who experienced severe reactions (eg, SJS, TEN, AGEP, and DRESS)

• Patch tests should be used as the first line of investigation with BP, AM, AX, and any suspect Beta-lactam

• In case of positive results, skin prick tests should be avoided

• In case of negativity, for intradermal testing, the drug should be initially tested with the highest dilution



• Any non–-lactam antibiotic has the potential of causing an IgE-mediated reaction, but these appear to occur less commonly than with Beta- lactam antibiotics

• There are no validated diagnostic tests for evaluation of IgE-mediated allergy to non–beta-lactam antibiotics



• Evaluation of possible allergy to these antibiotics should be limited to situations when treatment with the drug is anticipated (rather than electively as for penicillin)



• Skin testing with nonirritating concentrations of non–beta lactam antibiotics is not standardized.

• A negative skin test result does not rule out the possibility of an immediate-type allergy

• A positive skin test result suggests the presence of drug specific IgE antibodies, but the predictive value is unknown



• Patients with a history of reactions to non–beta lactam antibiotics consistent with an IgE mediated mechanism should only receive them if an alternate agent cannot be substituted and only via rapid induction of drug tolerance


QuinolonesClassified according to their generation:• First (cinoxacin and nalidixic acid)• Second (ofloxacin, norfloxacin,ciprofloxacin,

and enoxacin)• Third (levofloxacin)• Fourth (gemifloxacin and moxifloxacin)


Quinolones• Hypersensitivity reactions to quinolones have been

increasing over the past decade• Most are of the non-immediate type• Most frequent manifestation being maculopapular

rash• The estimated incidence of skin rashes varies

between different quinolones, which range from 1- 7%, gemifloxacin being associated with a higher incidence of skin rashes (particularly in female patients younger than 40 years old)


Quinolones• Fixed drug eruptions, AGEP, SJS, and TEN to

quinolones are rare• Immediate reactions to quinolones are less

frequent than non-immediate ones, with a reported incidence between 1:1000 and 1:1,000,000


Quinolones• However, skin testing is not considered a

completely reliable tool for diagnosing hypersensitivity reactions to quinolones, mainly because it can induce both false-positive and false-negative results

• DPTs are considered the gold standard• Cross-reactivity is common between first- and

second generation quinolones, and, to a lesser extent, between the third and fourth generations


Macrolides• Classified according to the number of carbon

atoms in their lactone ring:• 14 membered (erythromycin, troleandomycin,

roxithromycin, dirithromycin, and clarithromycin),

• 15 membered (azithromycin)• 16 membered (spiramycin,rokitamycin,

josamycin, and midecamycin)


Macrolides• Hypersensitivity reactions to macrolides are

relatively uncommon (0.4%-3% of treatments)• Cases of immediate reactions in the form of

urticaria and/or angioedema, rhinoconjunctivitis, and anaphylaxis; and non-immediate reactions, such as maculopapular rash, delayed appearing urticaria, contact dermatitis, fixed drug eruptions, and TEN, have been reported in children and adults.


Macrolides• Evaluating hypersensitivity reactions to

macrolides, the sensitivity of skin tests is low; therefore, DPTs often are necessary

• Macrolide hypersensitivity is unlikely to be a class hypersensitivity


Sulfonamides• e.g, sulfamethoxazole, sulfadoxine, and

sulfapyridine) are sulfonyl arylamines, characterized by a sulfonamide (SO2-NH2) moiety directly attached to a benzene ring, which carries an unsubstituted amine (-NH2) at the N4 position


Pichler W. and Schnyder B. J Allergy Clin Immunol 2013;256-257.e5

Sulfonamides• Hypersensitivity reactions to sulfonamide

antibiotics occur in approximately 2% to 4% of healthy persons but in as many as 50% to 60% of patients with AIDS

• Immediate reactions are rare• are more frequently associated with non-immediate

manifestations, such as maculopapular rashes and fixed eruptions

• More serious hypersensitivity reactions, such as SJS, TEN, and DRESS, also have been reported


Sulfonamides• The risk of SJS-TEN is higher for sulfonamide

antibiotics than for other antibiotics• The allergic workup includes both skin tests and

DPTs• Intradermal tests may be helpful in both

immediate and non-immediate reactions• Patch testing is used in Europe in nonimmediate

reactions; however, its sensitivity seems to be lower than delayed-reading intradermal tests


Sulfonamides• Cross-reactivity among sulfonamide

antibiotics has been reported• However, laboratory analysis of T-cell

reactions and clinical data indicate that non-antibiotic sulfonamides, such as glibenclamide, furosemide, and celecoxib, are not stimulatory and are tolerated by patients allergic to sulfonamide antibiotics


Solensky R. Med Clin N Am;2006:233–60

AminoglycosidesClassified into 2 groups: • Streptidine group eg, streptomycin • Desoxystreptamine group eg, kanamycin, amikacin, gentamicin, tobramycin, and neomycin


Aminoglycosides• can cause both immediate and non-immediate

hypersensitivity reactions• Immediate reactions are uncommon• Contact dermatitis is the most frequent non-

immediate reaction to aminoglycosides, and neomycin is the most common sensitizer among topical medications


Aminoglycosides• Other nonimmediate reactions, such as

maculopapular rash, fixed drug eruption, and TEN, have been reported

• Patch tests are recommended for the diagnosis of non-immediate reactions, especially for contact dermatitis


Aminoglycosides• Cross-reactivity among aminoglycosides is

common, approaching 50% or more among those that belong to the desoxystreptamine group

• Streptomycin does not share common antigenic structures with other aminoglycosides that belong to the desoxystreptamine group, and cross-reactivity to the latter has not been reportedRomano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12

Clindamycin• can provoke hypersensitivity reactions, mainly

non-immediate ones, such as maculopapular exanthemas


Glycopeptides • The most frequent immediate reaction to

vancomycin is the “red man syndrome,” which is associated with its rapid intravenous administration and is characterized by flushing, warmth, pruritus, and hypotension


Vancomycin

• Vancomycin rarely causes IgE mediated reactions, but more than 50% of patients experience immediate cutaneous erythema, flushing, and pruritus (red man syndrome), which is the result of non–IgE-mediated histamine release

• Prevention by slowing the rate of infusion and premedicating with H1-antihistamines


Vancomycin • Vancomycin also can elicit a variety of

nonimmediate reactions, including severe ones, such as SJS, TEN, and DRESS


Take home messages (1)

• Assessment of hypersensitivity reactions to antibiotics is clinically complex

• The patient’s history is fundamental• Allergic examination is based mainly selected

on the basis of the clinical features and the type of reaction

Take home messages (2)

• Skin tests have been well validated mainly for Beta –lactams (esp. penicillin) but less for other classes of antibiotics

• DPT remains an essential diagnostic tool

Thank you for your attention

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