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Antibiotic Allergy 
Key Messages from Practice Parameter, 
Position Paper and Experts Opinion 
Suda Sibunruang, M.D.
Objective: providing the practicing physician with 
an evidence-based approach to the diagnosis and 
management of adverse...
By the International Collaboration in Asthma, Allergy and Immunology (iCAALL), 
of which formed by EAACI, AAAAI, ACAAI, WA...
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 
pharmacologi...
Type B: unpredictable reactions 
• Drug intolerance 
• Drug idiosyncrasy 
• Drug allergy 
• Pseudoallergic (anaphylactoid)...
Drug allergy 
• an immunologically mediated response to a 
pharmaceutical and/or formulation 
(excipient) agent in a sensi...
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 exci...
Classifications of DHRs 
Mechanical 
• Allergic 
• Non-allergic 
Clinical 
Demoly P. et al. Allergy 2014; 69: 420–37
Demoly P. et al. Allergy 2014; 69: 420–37
Classifications of DHRs by clinical 
Immediate 
• typically occur within 1– 6 h after the last drug 
administration 
Non-i...
Classifications of DHRs by clinical 
Immediate 
• Urticaria, angioedema, rhinitis, conjunctivitis, 
bronchospasm, gastroin...
Bircher A. and Scherer K. Med Clin N Am 94 (2010) 711–725
Fixed drug eruption 
acute onset and appear as annular, 
edematous, sometimes blistering, 
reddish-brown to violaceous mac...
Non- immediate reactions 
• Identification of a nonimmediate reaction is 
sometimes difficult because of the 
heterogeneit...
Bircher A. and Scherer K. Med Clin N Am 94 (2010) 711–725
Demoly P. et al. Allergy 2014; 69: 420–37
Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
Clinical and biological danger signs 
suggesting severe cutaneous and/or systemic reactions 
Demoly P. et al. Allergy 2014...
Scherer K. and Bircher A. Med Clin N Am 94 (2010) 681–9
Scherer K. and Bircher A. Med Clin N Am 94 (2010) 681–9
Scherer K. and Bircher A. Med Clin N Am 94 (2010) 681–9
Algorithm for disease management of drug allergy 
Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
Algorithm for disease management of drug allergy (cont’) 
Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
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 negat...
Drug provocation test (DPT) 
• Can be performed by administering an initial 
dose of one hundredth of the therapeutic one....
Induction of drug tolerance 
• which has often been referred to as 
drug desensitization 
• temporary induction of drug to...
Drug desensitization 
• one form of induction of immune drug 
tolerance by which effector cells are rendered 
less reactiv...
Graded challenge or test dosing 
• Administration of progressively increasing 
doses of a medication until a full dose is ...
Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
Antibiotics can be classified as… 
• Beta-lactam 
• Non- Beta-lactam 
Romano A. and Caubet J. J Allergy Clin Immunol Pract...
Beta-lactam antibiotics 
2 major classes 
• Penicillins 
• Cephalosporins 
4 minor classes 
• Carbapenems 
• Monobactams 
...
Celik G., PichlerW. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
Gruchalla R. J Allergy Clin Immunol 2003;111:S548-59
Non- Beta-lactam antibiotics 
• Quinolones 
• Sulfonamides 
• Macrolides 
• Aminoglycosides 
• Rifamycins 
• Glycopeptides...
Prevalence 
• Hypersensitivity reactions to antibiotics are 
commonly reported both in adults and 
children, with a preval...
Study design: cross-sectional study (2011-2013) 
Objective: To assess the clinical characteristics and management of 
hype...
Jares E et al. Ann Allergy Asthma Immunol 113 (2014) 282-9
Jares E et al. Ann Allergy Asthma Immunol 113 (2014) 282-9
Study design: A cross-sectional descriptive study 
Method: The study was performed from January 1st, 2008 to December 31th...
Sangasapasviliya A. et al. J Med Assoc Thai 2010; 93: S106-11
Sangasapasviliya A. et al. J Med Assoc Thai 2010; 93: S106-11
Methods: retrospective study of adult inpatients between 
1992 - 2001 at KCMH 
Objective: To investigate incidence, etiolo...
Techapornroong M. et al. Asian Pac J Allergy Immunol 2010;28:262-9
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 adul...
Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
Penicillin 
• However, after complete evaluation, up to 
90% of these individuals are able to tolerate 
penicillins 
Solen...
Gruchalla R. and Pirmohamed M. N Engl J Med 2006;354:601-9
Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
Penicillin skin testing 
• Most reliable method for evaluating IgE-mediated 
penicillin allergy 
• When performed by skill...
Penicillin skin testing 
• Skin testing only with PPL and BP (without 
penicilloate or penilloate) may miss up to 20% of 
...
Penicillin skin testing 
• NPV for immediate reactions approaches 
100%, whereas the PPV is 40- 100 % 
• Patients who have...
Penicillin skin testing 
• Penicillin skin test–positive patients should 
avoid penicillin, but if they develop an 
absolu...
Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
Brockow K. et al. Allergy 2002: 57: 45–51
Torres M. and Blanca M. Med Clin N Am;2010:805–20
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 r...
Penicillin specific IgE 
• High specificity (97%-100%) but lower 
sensitivity (29%-68%) 
• Therefore, although a positive ...
Penicillin specific IgE 
• The European guidelines, also include serum-specific 
IgE assays, because cases of patients wit...
Penicillin 
• Patients with a vague and/or distant history 
of penicillin allergy may be candidates to 
receive penicillin...
Ampicillin and Amoxicillin 
• Some patients with immediate type reactions 
to amoxicillin and ampicillin have IgE 
antibod...
Ampicillin and Amoxicillin 
• Amoxicillin and ampicillin are associated with 
the development of a delayed maculopapular 
...
Cephalosporins 
Perez-Inestrosa E. et al. Curr Opin Allergy Clin Immunol 5:323–330
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 rat...
Gruchalla R. J Allergy Clin Immunol 2003;111:S548-59
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 n...
Cephalosporins 
• Patients with a history of an immediate- type 
reaction to 1 cephalosporin should avoid 
cephalosporins ...
Cephalosporin administration to patients with a 
history of penicillin allergy 
• Penicillin skin testing, when available,...
Solensky R. Med Clin N Am;2006:233–60
Cephalosporin administration to patients with a 
history of penicillin allergy 
• Skin testing to the cephalosporin follow...
Madaan A. and Li J.T.-C. Immunol Allergy Clin N Am 24 (2004) 463–76
Madaan A. and Li J.T.-C. Immunol Allergy Clin N Am 24 (2004) 463–76
Madaan A. and Li J.T.-C. Immunol Allergy Clin N Am 24 (2004) 463–76
Cephalosporin administration to patients with a 
history of amoxicillin/ampicillin allergy 
• Patients allergic to amoxici...
Monobactams (aztreonam) 
• Aztreonam is less immunogenic than penicillin 
and cephalosporins, and clinical allergic 
react...
Carbapenems 
• Limited data indicate lack of significant 
allergic cross-reactivity between penicillin 
and carbapenems 
•...
Skin-test sensitivity may decrease with time 
Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
Diagnostic evaluation of children 
• Using the same diagnostic protocol as adults 
• Several studies confirmed the safety ...
Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
Subjects with an undefined time interval 
• Subjects with an undefined time interval 
between the last drug administration...
Patients at high risk 
• If it is necessary to evaluate patients who 
experienced severe reactions (eg, SJS, TEN, AGEP, 
a...
Non- Beta-lactam antibiotics
Non- Beta-lactam antibiotics 
• Any non–-lactam antibiotic has the potential 
of causing an IgE-mediated reaction, but the...
Non- Beta-lactam antibiotics 
• Evaluation of possible allergy to these 
antibiotics should be limited to situations 
when...
Non- Beta-lactam antibiotics 
• Skin testing with nonirritating concentrations 
of non–beta lactam antibiotics is not 
sta...
Non- Beta-lactam antibiotics 
• Patients with a history of reactions to non– 
beta lactam antibiotics consistent with an I...
Quinolones 
Classified according to their generation: 
• First (cinoxacin and nalidixic acid) 
• Second (ofloxacin, norflo...
Quinolones 
• Hypersensitivity reactions to quinolones have 
been increasing over the past decade 
• Most are of the non-i...
Quinolones 
• Fixed drug eruptions, AGEP, SJS, and TEN to 
quinolones are rare 
• Immediate reactions to quinolones are le...
Quinolones 
• However, skin testing is not considered a 
completely reliable tool for diagnosing 
hypersensitivity reactio...
Macrolides 
• Classified according to the number of carbon 
atoms in their lactone ring: 
• 14 membered (erythromycin, tro...
Macrolides 
• Hypersensitivity reactions to macrolides are 
relatively uncommon (0.4%-3% of treatments) 
• Cases of immedi...
Macrolides 
• Evaluating hypersensitivity reactions to 
macrolides, the sensitivity of skin tests is low; 
therefore, DPTs...
Sulfonamides 
• e.g, sulfamethoxazole, sulfadoxine, and 
sulfapyridine) are sulfonyl arylamines, 
characterized by a sulfo...
Pichler W. and Schnyder B. J Allergy Clin Immunol 2013;256-257.e5
Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
Sulfonamides 
• Hypersensitivity reactions to sulfonamide 
antibiotics occur in approximately 2% to 4% of 
healthy persons...
Sulfonamides 
• The risk of SJS-TEN is higher for sulfonamide 
antibiotics than for other antibiotics 
• The allergic work...
Sulfonamides 
• Cross-reactivity among sulfonamide 
antibiotics has been reported 
• However, laboratory analysis of T-cel...
Solensky R. Med Clin N Am;2006:233–60
Gruchalla R. J Allergy Clin Immunol 2003;111:S548-59
Aminoglycosides 
Classified into 2 groups: 
• Streptidine group 
eg, streptomycin 
• Desoxystreptamine group 
eg, kanamyci...
Aminoglycosides 
• can cause both immediate and non-immediate 
hypersensitivity reactions 
• Immediate reactions are uncom...
Aminoglycosides 
• Other nonimmediate reactions, such as 
maculopapular rash, fixed drug eruption, and 
TEN, have been rep...
Aminoglycosides 
• Cross-reactivity among aminoglycosides is 
common, approaching 50% or more among 
those that belong to ...
Clindamycin 
• can provoke hypersensitivity reactions, mainly 
non-immediate ones, such as maculopapular 
exanthemas 
Roma...
Glycopeptides 
• The most frequent immediate reaction to 
vancomycin is the “red man syndrome,” which 
is associated with ...
Vancomycin 
• Vancomycin rarely causes IgE mediated 
reactions, but more than 50% of patients 
experience immediate cutane...
Vancomycin 
• Vancomycin also can elicit a variety of 
nonimmediate reactions, including severe 
ones, such as SJS, TEN, a...
Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
Take home messages (1) 
• Assessment of hypersensitivity reactions to 
antibiotics is clinically complex 
• The patient’s ...
Take home messages (2) 
• Skin tests have been well validated mainly for 
Beta –lactams (esp. penicillin) but less for 
ot...
Thank you for your attention
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Antibiotic allergy

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Antibiotic Allergy

Presented by Suda Sibunrueng, MD.

September12, 2014

Published in: Health & Medicine
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Antibiotic allergy

  1. 1. Antibiotic Allergy Key Messages from Practice Parameter, Position Paper and Experts Opinion Suda Sibunruang, M.D.
  2. 2. Objective: providing the practicing physician with an evidence-based approach to the diagnosis and management of adverse drug reactions Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  3. 3. 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 Demoly P. et al. Allergy 2014; 69: 420–37
  4. 4. Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  5. 5. 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 ADRs Type 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 humans Demoly P. et al. Allergy 2014; 69: 420–37 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  6. 6. Type B: unpredictable reactions • Drug intolerance • Drug idiosyncrasy • Drug allergy • Pseudoallergic (anaphylactoid) reactions Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  7. 7. Drug allergy • an immunologically mediated response to a pharmaceutical and/or formulation (excipient) agent in a sensitized person Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  8. 8. Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
  9. 9. 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 Demoly P. et al. Allergy 2014; 69: 420–37
  10. 10. Classifications of DHRs Mechanical • Allergic • Non-allergic Clinical Demoly P. et al. Allergy 2014; 69: 420–37
  11. 11. Demoly P. et al. Allergy 2014; 69: 420–37
  12. 12. Classifications of DHRs by clinical Immediate • typically occur within 1– 6 h after the last drug administration Non-immediate • occur at any time as from 1 h after from the initial drug administration Demoly P. et al. Allergy 2014; 69: 420–37
  13. 13. 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 Demoly P. et al. Allergy 2014; 69: 420–37
  14. 14. Bircher A. and Scherer K. Med Clin N Am 94 (2010) 711–725
  15. 15. Fixed drug eruption acute onset and appear as annular, edematous, sometimes blistering, reddish-brown to violaceous macules or plaques Hallmarks include residual hyperpigmentation after healing and recurrence at previously affected sites, with subsequent antigenic challenges Sousa I. N Engl J Med 2011;365:6
  16. 16. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  17. 17. Bircher A. and Scherer K. Med Clin N Am 94 (2010) 711–725
  18. 18. Demoly P. et al. Allergy 2014; 69: 420–37
  19. 19. Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
  20. 20. Clinical and biological danger signs suggesting severe cutaneous and/or systemic reactions Demoly P. et al. Allergy 2014; 69: 420–37
  21. 21. Scherer K. and Bircher A. Med Clin N Am 94 (2010) 681–9
  22. 22. Scherer K. and Bircher A. Med Clin N Am 94 (2010) 681–9
  23. 23. Scherer K. and Bircher A. Med Clin N Am 94 (2010) 681–9
  24. 24. Algorithm for disease management of drug allergy Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  25. 25. Algorithm for disease management of drug allergy (cont’) Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  26. 26. Romano et al. J Allergy Clin Immunol 2011;127:S67-73
  27. 27. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  28. 28. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  29. 29. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  30. 30. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  31. 31. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  32. 32. Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
  33. 33. Antibiotics can be classified as… • Beta-lactam • Non- Beta-lactam Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  34. 34. Beta-lactam antibiotics 2 major classes • Penicillins • Cephalosporins 4 minor classes • Carbapenems • Monobactams • Oxacephems • Clavams Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  35. 35. Celik G., PichlerW. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
  36. 36. Gruchalla R. J Allergy Clin Immunol 2003;111:S548-59
  37. 37. Non- Beta-lactam antibiotics • Quinolones • Sulfonamides • Macrolides • Aminoglycosides • Rifamycins • Glycopeptides • Clindamycin Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  38. 38. 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 2013:1-9 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  39. 39. 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
  40. 40. Jares E et al. Ann Allergy Asthma Immunol 113 (2014) 282-9
  41. 41. Jares E et al. Ann Allergy Asthma Immunol 113 (2014) 282-9
  42. 42. 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
  43. 43. Sangasapasviliya A. et al. J Med Assoc Thai 2010; 93: S106-11
  44. 44. Sangasapasviliya A. et al. J Med Assoc Thai 2010; 93: S106-11
  45. 45. 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%) Techapornroong M. et al. Asian Pac J Allergy Immunol 2010;28:262-9 were found
  46. 46. Techapornroong M. et al. Asian Pac J Allergy Immunol 2010;28:262-9
  47. 47. Techapornroong M. et al. Asian Pac J Allergy Immunol 2010;28:262-9
  48. 48. Beta-lactam antibiotics
  49. 49. Penicillin • Penicillin allergy is the most commonly reported drug allergy, with a prevalence rate of 5% to 10% in adults and children Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  50. 50. Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
  51. 51. Penicillin • However, after complete evaluation, up to 90% of these individuals are able to tolerate penicillins Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  52. 52. Gruchalla R. and Pirmohamed M. N Engl J Med 2006;354:601-9
  53. 53. Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
  54. 54. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  55. 55. Penicillin skin testing • 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  56. 56. Penicillin skin testing • 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  57. 57. Penicillin skin testing • 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  58. 58. Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
  59. 59. Brockow K. et al. Allergy 2002: 57: 45–51
  60. 60. Torres M. and Blanca M. Med Clin N Am;2010:805–20
  61. 61. Torres M. and Blanca M. Med Clin N Am;2010:805–20
  62. 62. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  63. 63. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  64. 64. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  65. 65. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  66. 66. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  67. 67. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  68. 68. Cephalosporins Perez-Inestrosa E. et al. Curr Opin Allergy Clin Immunol 5:323–330
  69. 69. Cephalosporins Perez-Inestrosa E. et al. Curr Opin Allergy Clin Immunol 5:323–330
  70. 70. Torres M. and Blanca M. Med Clin N Am;2010:805–20
  71. 71. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  72. 72. Gruchalla R. J Allergy Clin Immunol 2003;111:S548-59
  73. 73. Pichichero M.E. and Zagursky R. Ann Allergy Asthma Immunol 112 (2014) 404-12
  74. 74. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  75. 75. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  76. 76. Cephalosporin administration to patients with a history 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. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  77. 77. Solensky R. Med Clin N Am;2006:233–60
  78. 78. Cephalosporin administration to patients with a history 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  79. 79. Madaan A. and Li J.T.-C. Immunol Allergy Clin N Am 24 (2004) 463–76
  80. 80. Madaan A. and Li J.T.-C. Immunol Allergy Clin N Am 24 (2004) 463–76
  81. 81. Madaan A. and Li J.T.-C. Immunol Allergy Clin N Am 24 (2004) 463–76
  82. 82. Cephalosporin administration to patients with a history 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  83. 83. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  84. 84. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  85. 85. Skin-test sensitivity may decrease with time Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  86. 86. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  87. 87. Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  88. 88. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  89. 89. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  90. 90. Non- Beta-lactam antibiotics
  91. 91. Non- Beta-lactam antibiotics • 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  92. 92. 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) Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  93. 93. Non- Beta-lactam antibiotics • 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  94. 94. Non- Beta-lactam antibiotics • 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  95. 95. Quinolones Classified according to their generation: • First (cinoxacin and nalidixic acid) • Second (ofloxacin, norfloxacin,ciprofloxacin, and enoxacin) • Third (levofloxacin) • Fourth (gemifloxacin and moxifloxacin) Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  96. 96. 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) Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  97. 97. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  98. 98. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  99. 99. 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) Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  100. 100. 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. Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  101. 101. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  102. 102. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  103. 103. Pichler W. and Schnyder B. J Allergy Clin Immunol 2013;256-257.e5
  104. 104. Celik G., Pichler W. and Adkinson F. Middleton’s Allergy 8th edition,1274-95
  105. 105. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  106. 106. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  107. 107. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  108. 108. Solensky R. Med Clin N Am;2006:233–60
  109. 109. Gruchalla R. J Allergy Clin Immunol 2003;111:S548-59
  110. 110. Aminoglycosides Classified into 2 groups: • Streptidine group eg, streptomycin • Desoxystreptamine group eg, kanamycin, amikacin, gentamicin, tobramycin, and neomycin Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  111. 111. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  112. 112. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  113. 113. 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 reported Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  114. 114. Clindamycin • can provoke hypersensitivity reactions, mainly non-immediate ones, such as maculopapular exanthemas Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  115. 115. 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 Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  116. 116. 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 Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
  117. 117. Vancomycin • Vancomycin also can elicit a variety of nonimmediate reactions, including severe ones, such as SJS, TEN, and DRESS Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  118. 118. Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
  119. 119. 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
  120. 120. 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
  121. 121. Thank you for your attention

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