This document discusses antibiotic allergy and provides key messages from several guidelines and expert opinions on the diagnosis and management of adverse drug reactions. It defines different types of drug hypersensitivity reactions and classifications. It also discusses approaches to evaluating antibiotic allergies, including skin testing and drug provocation tests. Specific sections focus on penicillin allergy testing and management. The document is a comprehensive review drawing from multiple guidelines and studies.

1. Antibiotic Allergy
Key Messages from Practice Parameter,
Position Paper and Experts Opinion
Suda Sibunruang, M.D.

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

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

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. Classifications of DHRs
Mechanical
• Allergic
• Non-allergic
Clinical
Demoly P. et al. Allergy 2014; 69: 420–37

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

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

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

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

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

20. Clinical and biological danger signs
suggesting severe cutaneous and/or systemic reactions
Demoly P. et al. Allergy 2014; 69: 420–37

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

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

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

24. Algorithm for disease management of drug allergy
Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73

25. Algorithm for disease management of drug allergy (cont’)
Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73

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

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

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

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

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

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

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

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

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

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

48. Beta-lactam antibiotics

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

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

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

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

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

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

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

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

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

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

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

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

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. 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. 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. Solensky R. Med Clin N Am;2006:233–60

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

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

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

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. 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. 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. Skin-test sensitivity may decrease with time
Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12

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

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. 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. Non- Beta-lactam antibiotics

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

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

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. 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. 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. Solensky R. Med Clin N Am;2006:233–60

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

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

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. 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. Thank you for your attention