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Antibiotic Allergy

This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal
guidelines, when they exist. The article ends with the authors' clinical recommendations.
A 55-year-old woman presents to the hospital with cellulitis. She reports a history of
urticaria 30 years earlier associated with taking penicillin for a respiratory tract infection. Should
cephalosporins be avoided? More generally, how should patients with a history of allergy to
antibiotics be evaluated and treated?

The Clinical Problem


Although allergic reactions to antibiotics account for only a small proportion of reported
adverse drug reactions, they are associated with substantial morbidity and mortality and
increased health care costs.1-3 Estimates of the prevalence of antibiotic allergy vary widely.1-3
Any organ may be affected, but the skin is most commonly involved. Data from the Boston
Collaborative Drug Surveillance Program1 indicate a 2.2 percent frequency of cutaneous drug
reactions among hospitalized patients, with the antibiotics amoxicillin, trimethoprim
sulfamethoxazole, and ampicillin the most commonly implicated agents. More recently, a sixmonth prospective analysis in France showed a prevalence of cutaneous drug eruptions of 3.6 per
1000 hospitalized patients; antibiotics accounted for 55 percent of cases.4

Pathogenetic Features
Allergic reactions are, by definition, immunologically mediated. A single drug may
initiate multiple immune responses, and multiple antigenic determinants may be formed from a
single drug.5,6 For instance, a major antigenic determinant and several minor determinants have
been identified for penicillin
Figure 1

General Structure of Penicillin and Important Major and Minor Allergenic Determinants.7
T cells play a predominant role in delayed hypersensitivity reactions, including antibioticinduced maculopapular eruptions
Figure 2

Maculopapular Rash Associated with Flucloxacillin Allergy.),8


whereas drug-specific IgE antibodies cause urticarial reactions
Figure 3

Urticaria Associated with Ampicillin Allergy.


A classification of drug-induced immune responses is in the Supplementary Appendix, available
with the full text of this article at www.nejm.org.

Clinical Features
The clinical features of antibiotic allergy are highly variable in terms of the type and severity of
the reaction and the organ systems affected
Table 1

Antibiotic-Induced Allergic Reactions. Factors such as the type of drug used, the nature
of the disease being treated, and the immune status of the patient are all believed to play an
important role in the clinical expression of these responses.9 The most common reactions to
antibiotics are maculopapular skin eruptions, urticaria, and pruritus.1,10 These reactions typically
occur days to weeks after initial exposure to a drug (during which sensitization occurs), although
on secondary exposure, the reaction usually occurs much sooner, sometimes within minutes to
hours.11 Occasionally, a hypersensitivity syndrome develops that is characterized by fever,
eosinophilia, and other extracutaneous manifestations.12
Some antibiotics also affect organs other than the skin. For instance, the combination of
amoxicillin and clavulanic acid can cause cholestatic liver injury, whereas hemolysis and
cytopenias, most likely caused by drug-specific antibodies, are reported with high-dose penicillin
and cephalosporin therapy.13 Severe reactions such as anaphylaxis, mediated by drug-specific
IgE antibodies, are rare. Although anaphylaxis may theoretically occur with any antibiotic, only
the frequency of penicillin-induced anaphylaxis is well described (1 in 5000 to 10,000 courses of
drug therapy).14

Special Cases
Human Immunodeficiency Virus
Patients infected with the human immunodeficiency virus (HIV) have a higher frequency
of allergic reactions to a range of antimicrobial agents (including sulfamethoxazole, amoxicillin,
clindamycin, dapsone, and amithiozone) than do persons without HIV infection.15
Hypersensitivity to trimethoprimsulfamethoxazole occurs in 20 to 80 percent of patients
infected with HIV, as compared with 1 to 3 percent of persons not infected with HIV.16 These
high rates of reaction are not well understood but may be caused by altered drug metabolism,
decreased glutathione levels, or both.15,17

Cystic Fibrosis

In approximately 30 percent of patients with cystic fibrosis, allergy develops to one or


more antibiotics.18 Piperacillin, ceftazidime, and ticarcillin have been most commonly
implicated, with the risk being higher after parenteral administration than after oral
administration. Repeated exposure to antibiotics and immune hyperresponsiveness are thought to
underlie the high prevalence of allergic reactions in patients with this disease.19

Infectious Mononucleosis
The likelihood of cutaneous reactions to penicillins and other antimicrobial agents is
increased among patients with infectious mononucleosis.20,21 Although the mechanism of these
drug reactions is not clear, the viral infection may alter the immune status of the host.22 In such
cases, the implicated agent can be readministered safely once the viral infection has resolved.23

Strategies and Evidence


Clinical Assessment
Medical history taking is critical in the evaluation of antibiotic allergy24 and in
distinguishing allergic reactions from other adverse reactions

Figure

Algorithm for the Management of Antibiotic Allergy.


This information is important, since overdiagnosis of allergic reactions can lead to
unnecessary use of more costly antimicrobial agents and may promote the development of
resistant microorganisms.15
Table 2

Checklist for Distinguishing Immune-Mediated Reactions from Nonimmune-Mediated


Reactions. provides questions, the answers to which may help determine whether a reaction is
immunologically mediated and, if so, the type of immune mechanism responsible. Whenever
possible, patients who are being evaluated for possible antibiotic allergy should be encouraged to
provide all medical records related to previous adverse drug reactions. Table 1 summarizes the
most common reactions associated with various antibiotic classes.27

Diagnostic Tests
Skin Testing
Skin testing may be used to detect allergen-specific IgE antibodies. However, with the
exception of penicillin, the relevant immunogens (which may be derived from an unidentified
drug metabolite or degradation product) are not known for most drugs. Thus, there are no valid
in vivo or in vitro diagnostic reagents available for identifying most antibiotic-specific IgE
antibodies. Although the parent antibiotic compound may be used in testing by allergy
specialists, a negative response on a skin test cannot be interpreted to mean that IgE antibodies
are absent.28 Rather, a negative result may simply indicate insufficient sensitivity of the assay
technique or, more likely, that the appropriate drug immunogen was not used in testing.
Skin testing is highly accurate for the identification of penicillin allergy, however. The
clinically relevant antigenic determinants for penicillin are well characterized and include the
important penicillin determinant penicilloyl polylysine and multiple minor determinants. Skin
testing is performed with penicilloyl polylysine and either penicillin G diluted to 10,000 U per
milliliter or a mixture of minor determinants that usually includes a 102 M mixture of benzyl
penicilloate, benzyl penilloate, and benzyl-n-propylamine.29 Skin-prick testing with full-strength
materials is done first, and if these tests are negative at 15 minutes, they are followed by
intracutaneous testing. An increase in the wheal diameter of at least 3 mm (as compared with the
negative control) in the presence of erythema constitutes a positive test. Less than 20 percent of
patients who report a history of penicillin allergy have detectable penicillin-specific IgE

antibodies at the time of testing.30-32 Negative skin testing indicates that the previous reaction
was not IgE-mediated or that the antibodies are no longer present; in either case, penicillin can
be administered again with minimal risk of an immediate reaction (no more than 4 percent, an
incidence similar to that in the general population33,34). Although penicilloyl polylysine has
recently become unavailable commercially owing to manufacturing issues related to the
production of a low-volume product, production is expected to resume in the future.

Other Testing
Skin testing is not predictive for drug reactions that are not mediated by IgE. In such
cases, other tests may be useful but must be performed during or soon after the reaction. A
positive Coombs' test indicates cell-bound antibodies (e.g., penicillin-induced hemolytic
anemia), and low complement levels may indicate the involvement of the complement cascade
(e.g., minocycline-induced serum-sicknesslike reaction35). Levels of serum tryptase, a mastcellspecific neutral protease that indicates systemic mast-cell activation, have been shown to be
elevated for several hours after anaphylactic drug reactions.36
Drug-specific T cells, which are involved in some hypersensitivity reactions, may be
detected with the use of in vitro lymphocyte transformation tests, which are widely used in
Europe but not approved for use in the United States. This test involves mixing lymphocytes
from the patient with the drug that elicited the reaction. If drug-specific T cells are present, a
proliferative response may result; proliferation, as measured by the incorporation of tritiated
thymidine in the presence of the drug, is compared with that in the absence of the drug.37 A
positive test result indicates that the patient has been sensitized to the drug. However,
sensitization may be present even in the absence of any clinical manifestations, and positive test
results have been demonstrated in both immediate and delayed antibiotic-induced reactions
caused by -lactam drugs, sulfonamides, and quinolones.37 Until this test is further validated, it is
best considered a research tool.
Provocation testing, which involves the administration of approximately three to six
increasing doses of a drug up to the usual daily dose, may be used to confirm drug
hypersensitivity.38 However, provocation testing carries a clear risk of a reaction similar to the
previous immediate hypersensivity reaction, although subsequent reactions are generally milder
and briefer than the original reaction. In one study, the overall rate of such reactions during
provocation testing was 17.6 percent.38 Thus, such testing should be performed only by
experienced personnel in a setting in which equipment for cardiopulmonary resuscitation is
available.

Treatment
Drug Desensitization
For reactions that are presumed to be mediated by IgE, drug desensitization may be
performed if the implicated agent is required for treatment.29 Desensitization is performed by a
person with appropriate training, typically in a hospital setting. It involves the administration of
increasing amounts of the antibiotic slowly over a period of hours until a therapeutic dose is
reached. The typical starting dose is in micrograms; the route of administration may be oral or
intravenous, but the oral route appears to be associated with fewer reactions. Doses are doubled

every 15 to 30 minutes; therapeutic levels can be obtained in most cases within 4 to 5


hours.29,39 The patient is monitored closely throughout the procedure, and antihistamines and
inhaled -agonists are given for urticarial reactions and bronchospasm, respectively. If a mild
reaction (e.g., flushing or urticaria) occurs, the procedure may resume at the last tolerated dose;
if a reaction is severe (hypotension or severe bronchospasm), the procedure should be aborted
and an alternative antibiotic selected.
The mechanism by which clinical tolerance is achieved is unclear, but it is thought to involve
antigen-specific mast-cell desensitization.40 Since maintenance of a desensitized state requires
the continuous presence of the drug, desensitization must be repeated if the antibiotic is required
again later.
In a recent retrospective report,41 desensitization for IgE-mediated drug allergy was successful in
43 of 57 cases (75 percent). Eleven desensitizations (19 percent) were complicated by severe
allergic reactions, either during the procedure (anaphylaxis) or days after its completion (serum
sickness); three were terminated for reasons other than allergic reactions. In most cases of failed
desensitization, the drug reaction did not appear to be solely mediated by IgE. Desensitization
appears more likely to fail in patients with cystic fibrosis.19,41

Graded Challenge
For reactions that are not considered to be mediated by IgE, management depends on the
clinical manifestations of the previous reaction. For maculopapular eruptions, the specialist may
consider a graded drug challenge, which is equivalent to provocation testing.29 Initial starting
doses are generally higher than those used for desensitization (milligrams vs. micrograms), and
the interval between doses varies, ranging from hours to days or even weeks. The patient is
monitored for adverse reactions, which are most commonly cutaneous. The decision whether to
discontinue an antibiotic if a reaction occurs depends on the nature of the reaction; bullous
lesions or those involving mucous membranes warrant withdrawal of the drug, whereas it may be
reasonable to treat through milder reactions, such as maculopapular eruptions, with the use of
antihistamines, corticosteroids, or both as needed.
During drug readministration, repeated hypersensitivity reactions (morbilliform
eruptions, fever, or both) have been noted in 58 percent of patients with the acquired
immunodeficiency syndrome who have had previous reactions to sulfamethoxazole.42 Several
graded-challenge procedures have been used successfully in such patients. An analysis of several
studies showed that readministration of sulfamethoxazole with the use of an incremental-dosing
regimen permitted the use of the drug in more than 75 percent of treated patients.43 Repeated
administration is contraindicated, however, after any life-threatening reaction that is not
mediated by IgE (e.g., drug-induced hemolytic anemia, immune-complex reactions, the Stevens
Johnson syndrome, and toxic epidermal necrolysis).

Cephalosporin in Patients with Penicillin Allergy


Penicillins and cephalosporins share a -lactam ring structure, making cross-reactivity a
concern. Although a rate of cross-reactivity of more than 10 percent has been reported, this
figure must be interpreted with caution since it is based on retrospective studies in which
penicillin allergy was not routinely confirmed by skin testing, and at least some of the reactions

were probably not immune-mediated.44 Available data, although based on small numbers,
suggest an increased risk of cephalosporin reactions among patients with positive results on
penicillin skin tests. In a review combining data from 11 studies of cephalosporin administration
in patients with a history of penicillin allergy,45 cephalosporin reactions were found to have
occurred in 6 of 135 patients with positive skin-test results for penicillin allergy (4.4 percent), as
compared with only 2 of 351 with negative skin tests (0.6 percent).
Whereas most patients who have a history of penicillin allergy will tolerate
cephalosporins, indiscriminate administration cannot be recommended, especially for patients
who have had life-threatening reactions.29 Among 12 cases of fatal anaphylaxis caused by
antibiotics in the United Kingdom from 1992 to 1997, 6 cases occurred after the first dose of a
cephalosporin, and 3 of the 6 patients were known to have penicillin allergy.46
For patients with a history of penicillin allergy who require a cephalosporin, treatment
depends on whether the previous reaction was mediated by IgE.29,47 Skin testing is warranted if
the reaction was consistent with an IgE-mediated mechanism or if the history is unclear. In one
study, one third of patients with positive results on skin tests had unclear or vague histories of
penicillin allergy.48 If testing is positive and a cephalosporin is considered necessary, then
desensitization should be performed with the use of the particular cephalosporin chosen for
treatment. A possible alternative is to perform a graded challenge with the cephalosporin,29 but
the risk of anaphylaxis, although low, must be recognized.29 If the history is inconsistent with an
IgE-mediated mechanism, it is considered safe to initiate a graded challenge without previous
skin testing.

Sulfonamide Allergy
For patients who have a history of allergy to sulfonamide antibiotics, concern has been
raised about the use of other sulfonamide-containing drugs (diuretics, sulfonylureas, and
celecoxib). However, sulfonamide antimicrobial agents (sulfamethoxazole, sulfadiazine,
sulfisoxazole, and sulfacetamide) differ from other sulfonamide-containing medications by
having an aromatic amine group at the N4 position and a substituted ring at the N1 position;
these groups are not found in nonantibiotic sulfonamide-containing drugs. Thus, despite productlabeling warnings, cross-reactivity between these two groups of sulfonamides is believed to be
unlikely.49,50
In a large observational study,51 patients with a history of allergy to sulfonamide
antibiotics had an increased risk of an allergic reaction to nonantibiotic sulfonamides, as
compared with patients without such a history (adjusted odds ratio, 2.8; 95 percent confidence
interval, 2.1 to 3.7), and were even more likely to have a reaction to penicillin (adjusted odds
ratio, 3.9; 95 percent confidence interval, 3.5 to 4.3). These results suggest that the association
between an allergy to sulfonamide antibiotics and subsequent reactions to nonantibiotic
sulfonamide drugs is probably attributable to a predisposition to allergic reactions in general, as
opposed to cross-reactivity between sulfonamide-containing antibiotics and nonantibiotic
drugs.51 However, the results must be interpreted with caution, given the retrospective design and
the use of diagnosis codes to categorize reactions, which probably resulted in some
misclassification of nonallergic reactions as allergic reactions.

Areas of Uncertainty
The mechanisms underlying antibiotic allergy have not been clearly elucidated. This
understanding is needed to facilitate the development of better diagnostic tools and drugs that are
less immunogenic. Better understanding is needed of factors mediating individual susceptibility
to allergic reactions to antibiotics. A few studies have evaluated the role of majorhistocompatibility-complex polymorphisms in the predisposition of patients to drug
reactions,52,53 but these findings need to be confirmed and expanded.
Some patients have reported adverse reactions to many chemically unrelated antibiotics.
The existence of the so-called multiple drug allergy syndrome is controversial,54,55 and accepted
diagnostic tests are needed to document drug allergy in these patients.

Guidelines
The American Academy of Allergy, Asthma and Immunology, the American College of
Allergy, Asthma and Immunology, and the Joint Task Force on Practice Parameters for Allergy
and Immunology have developed practice guidelines for the management of drug allergy29,47 on
the basis of evidence and expert opinion. The recommendations in the present review are
consistent with these guidelines.

Conclusions and Recommendations


Patients who report a history of antibiotic allergy require a careful assessment of the
nature of the reaction to determine the likelihood that it was immunologically mediated. For
patients whose history suggests an IgE-mediated reaction to penicillin, such as the case described
in the vignette, skin testing is indicated, if available, before they receive another -lactam
antibiotic. If test results are negative, the -lactam agent may be administered. If test results are
positive or testing cannot be done, the drug should be avoided or a desensitization procedure
should be performed.

Source Information
From the University of Texas Southwestern Medical Center, Dallas (R.S.G.); and the
Department of Pharmacology, University of Liverpool, Liverpool, United Kingdom (M.P.).
Address reprint requests to Dr. Gruchalla at the University of Texas Southwestern
Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8859, or at
rebecca.gruchalla@utsouthwestern.edu.

References
1. Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions: a report
from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive
inpatients, 1975 to 1982. JAMA 1986;256:3358-3363
CrossRef | Web of Science | Medline
2. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in
hospitalized patients: a meta-analysis of prospective studies. JAMA
1998;279:1200-1205
CrossRef | Web of Science | Medline
3. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of
admission to hospital: prospective analysis of 18,820 patients. BMJ 2004;329:1519
CrossRef | Web of Science | Medline
4. Fiszenson-Albala F, Auzerie V, Mahe E, et al. A 6-month prospective survey of
cutaneous drug reactions in a hospital setting. Br J Dermatol 2003;149:1018-1022
CrossRef | Web of Science | Medline
5. Park BK, Pirmohamed M, Kitteringham NR. Role of drug disposition in drug
hypersensitivity: a chemical, molecular, and clinical perspective. Chem Res
Toxicol 1998;11:969-988
CrossRef | Web of Science | Medline
6. Schnyder B, Mauri-Hellweg D, Zanni M, Bettens F, Pichler WJ. Direct, MHCdependent presentation of the drug sulfamethoxazole to human alpha/beta T cell
clones. J Clin Invest 1997;100:136-141
CrossRef | Web of Science | Medline
7. Weltzien HU, Padovan E. Molecular features of penicillin allergy. J Invest
Dermatol 1998;110:203-206
CrossRef | Web of Science | Medline
8. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med
2003;139:683-693
Web of Science | Medline
9. Adkinson NF Jr. Drug allergy. In: Adkinson NF Jr, Yunginger J, Busse W,
Bochner B, Holgate S, Simons F, eds. Middleton's allergy: principles and
practice. Philadelphia: Mosby, 2003:1679-94.
10. Lee CE, Zembower TR, Fotis MA, et al. The incidence of antimicrobial allergies
in hospitalized patients: implications regarding prescribing patterns and emerging
bacterial resistance. Arch Intern Med 2000;160:2819-2822
CrossRef | Web of Science | Medline
11. Pirmohamed M, Breckenridge AM, Kitteringham NR, Park BK. Adverse drug
reactions. BMJ 1998;316:1295-1298
CrossRef | Web of Science | Medline
12. Sullivan JR, Shear NH. The drug hypersensitivity syndrome: what is the
pathogenesis? Arch Dermatol 2001;137:357-364
Web of Science | Medline
13. Pirmohamed M, Kitteringham NR, Park BK. The role of active metabolites in
drug toxicity. Drug Saf 1994;11:114-144
CrossRef | Web of Science | Medline

14. Rudolph AH, Price EV. Penicillin reactions among patients in venereal disease
clinics: a national survey. JAMA 1973;223:499-501
CrossRef | Web of Science | Medline
15. Pirmohamed M, Park BK. HIV and drug allergy. Curr Opin Allergy Clin
Immunol 2001;1:311-316
CrossRef | Medline
16. van der Ven AJAM, Koopmans PP, Vree TB, van der Meer JW. Adverse
reactions to co-trimoxazole in HIV infection. Lancet 1991;338:431-433
CrossRef | Web of Science | Medline
17. Farrell J, Naisbitt DJ, Drummond NS, et al. Characterization of sulfamethoxazole
and sulfamethoxazole metabolite-specific T-cell responses in animals and
humans. J Pharmacol Exp Ther 2003;306:229-237
CrossRef | Web of Science | Medline
18. Wills R, Henry RL, Francis JL. Antibiotic hypersensitivity reactions in cystic
fibrosis. J Paediatr Child Health 1998;34:325-329
CrossRef | Web of Science | Medline
19. Burrows JA, Toon M, Bell SC. Antibiotic desensitization in adults with cystic
fibrosis. Respirology 2003;8:359-364
CrossRef | Web of Science | Medline
20. Andersen Lund B, Bergan T. Temporary skin reactions to penicillins during the
acute stage of infectious mononucleosis. Scand J Infect Dis 1975;7:21-28
Web of Science | Medline
21. Pullen H, Wright N, Murdoch JM. Hypersensitivity reactions to antibacterial
drugs in infectious mononucleosis. Lancet 1967;2:1176-1178
CrossRef | Web of Science | Medline
22. Levy M. Role of viral infections in the induction of adverse drug reactions. Drug
Saf 1997;16:1-8
CrossRef | Web of Science | Medline
23. Nazareth I, Mortimer P, McKendrick GD. Ampicillin sensitivity in infectious
mononucleosis -- temporary or permanent? Scand J Infect Dis 1972;4:229-230
Medline
24. Gruchalla RS. Clinical assessment of drug-induced disease. Lancet
2000;356:1505-1511[Erratum, Lancet 2001;357:724.]
CrossRef | Web of Science | Medline
25. Mori K, Maru C, Takasuna K. Characterization of histamine release induced by
fluoroquinolone antibacterial agents in vivo and in vitro. J Pharm Pharmacol
2000;52:577-584
CrossRef | Web of Science | Medline
26. Veien M, Szlam F, Holden JT, Yamaguchi K, Denson DD, Levy JH. Mechanisms
of nonimmunological histamine and tryptase release from human cutaneous mast
cells. Anesthesiology 2000;92:1074-1081
CrossRef | Web of Science | Medline
27. Litt JZ. Litt's drug eruption reference manual: including drug interactions. 10th
ed. London: Taylor & Francis, 2004.
28. Empedrad R, Darter AL, Earl HS, Gruchalla RS. Nonirritating intradermal skin
test concentrations for commonly prescribed antibiotics. J Allergy Clin Immunol
2003;112:629-630
CrossRef | Web of Science | Medline

29. Bernstein I, Gruchalla RS, Lee R, Nicklas R, Dykewicz M. Executive summary of


disease management of drug hypersensitivity: a practice parameter. Ann Allergy
Asthma Immunol 1999;83:665-700
CrossRef | Medline
30. Gadde J, Spence M, Wheeler B, Adkinson NF Jr. Clinical experience with
penicillin skin testing in a large inner-city STD clinic. JAMA 1993;270:24562463
CrossRef | Web of Science | Medline
31. Mendelson LM, Ressler C, Rosen JP, Selcow JE. Routine elective penicillin
allergy skin testing in children and adolescents: study of sensitization. J Allergy
Clin Immunol 1984;73:76-81
CrossRef | Web of Science | Medline
32. Sogn DD, Evans R III, Shepherd GM, et al. Results of the National Institute of
Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive
value of skin testing with major and minor penicillin derivatives in hospitalized
adults. Arch Intern Med 1992;152:1025-1032
CrossRef | Web of Science | Medline
33. Lin RY. A perspective on penicillin allergy. Arch Intern Med 1992;152:930-937
CrossRef | Web of Science | Medline
34. Macy E, Mangat R, Burchette RJ. Penicillin skin testing in advance of need:
multiyear follow-up in 568 test result-negative subjects exposed to oral
penicillins. J Allergy Clin Immunol 2003;111:1111-1115
CrossRef | Web of Science | Medline
35. Malakar S, Dhar S, Shah Malakar R. Is serum sickness an uncommon adverse
effect of minocycline treatment? Arch Dermatol 2001;137:100-101
Web of Science | Medline
36. Ordoqui E, Zubeldia J, Aranzabal A, et al. Serum tryptase levels in adverse drug
reactions. Allergy 1997;52:1102-1105
CrossRef | Web of Science | Medline
37. Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug
hypersensitivity. Allergy 2004;59:809-820
CrossRef | Web of Science | Medline
38. Messaad D, Sahla H, Benahmed S, Godard P, Bousquet J, Demoly P. Drug
provocation tests in patients with a history suggesting an immediate drug
hypersensitivity reaction. Ann Intern Med 2004;140:1001-1006
Web of Science | Medline
39. Solensky R. Drug desensitization. Immunol Allergy Clin North Am 2004;24:425443
CrossRef | Web of Science | Medline
40. Naclerio R, Mizrahi E, Adkinson NF Jr. Immunologic observations during
desensitization and maintenance of clinical tolerance to penicillin. J Allergy Clin
Immunol 1983;71:294-301
CrossRef | Web of Science | Medline
41. Turvey SE, Cronin B, Arnold AD, Dioun AF. Antibiotic desensitization for the
allergic patient: 5 years of experience and practice. Ann Allergy Asthma Immunol
2004;92:426-432
CrossRef | Web of Science | Medline

42. Carr A, Penny R, Cooper DA. Efficacy and safety of rechallenge with low-dose
trimethoprim-sulphamethoxazole in previously hypersensitive HIV-infected
patients. AIDS 1993;7:65-71
CrossRef | Web of Science | Medline
43. Rich JD, Sullivan T, Greineder D, Kazanjian PH. Trimethoprim/sulfamethoxazole
incremental dose regimen in human immunodeficiency virus-infected persons.
Ann Allergy Asthma Immunol 1997;79:409-414
CrossRef | Web of Science | Medline
44. Saxon A, Beall GN, Rohr AS, Adelman DC. Immediate hypersensitivity reactions
to beta-lactam antibiotics. Ann Intern Med 1987;107:204-215
Web of Science | Medline
45. Kelkar PS, Li JT. Cephalosporin allergy. N Engl J Med 2001;345:804-809
Full Text | Web of Science | Medline
46. Pumphrey RS, Davis S. Under-reporting of antibiotic anaphylaxis may put
patients at risk. Lancet 1999;353:1157-1158
CrossRef | Web of Science | Medline
47. Lieberman P, Kemp S, Oppenheimer J, Lang D, Bernstein I, Nicklas R. The
diagnosis and management of anaphylaxis: an updated practice parameter. J
Allergy Clin Immunol 2005;115:Suppl:S483-S523
CrossRef | Medline
48. Solensky R, Earl HS, Gruchalla RS. Penicillin allergy: prevalence of vague
history in skin test-positive patients. Ann Allergy Asthma Immunol 2000;85:195199
CrossRef | Web of Science | Medline
49. Brackett CC, Singh H, Block JH. Likelihood and mechanisms of crossallergenicity between sulfonamide antibiotics and other drugs containing a
sulfonamide functional group. Pharmacotherapy 2004;24:856-870
CrossRef | Web of Science | Medline
50. Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients
who are allergic to sulfonamides? Revisiting the meaning of `sulfa' allergy. Drug
Saf 2001;24:239-247
CrossRef | Web of Science | Medline
51. Strom B, Schinnar R, Apter A, et al. Absence of cross-reactivity between
sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med
2003;349:1628-1635
Free Full Text | Web of Science | Medline
52. O'Donohue J, Oien KA, Donaldson P, et al. Co-amoxiclav jaundice: clinical and
histological features and HLA class II association. Gut 2000;47:717-720
CrossRef | Web of Science | Medline
53. Romano A, De Santis A, Romito A, et al. Delayed hypersensitivity to
aminopenicillins is related to major histocompatibility complex genes. Ann
Allergy Asthma Immunol 1998;80:433-437
CrossRef | Web of Science | Medline
54. Macy E. Multiple antibiotic allergy syndrome. Immunol Allergy Clin North Am
2004;24:533-543
CrossRef | Web of Science | Medline

55. Warrington R. Multiple drug allergy syndrome. Can J Clin Pharmacol 2000;7:1819
Medline

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6. Fotini D Kavadas, Anna Kasprzak, Adelle R Atkinson. (2013) Antibiotic skin testing
accompanied by provocative challenges in children is a useful clinical tool. Allergy,
Asthma & Clinical Immunology 9:1, 22
CrossRef
7. Aaron Fay, Nambi Nallassamy, John D. Pemberton, Allison Callahan, Edward J. Wladis,
John Nguyen, Marlene L. Durand. (2013) Prophylactic Postoperative Antibiotics for
Enucleation and Evisceration. Ophthalmic Plastic and Reconstructive Surgery 29:4, 281285
CrossRef
8. William J. Peppard, Sarah R. Peppard, Lewis Somberg. (2012) Optimizing Drug Therapy
in the Surgical Intensive Care Unit. Surgical Clinics of North America 92:6, 1573-1620
CrossRef
9. Christopher Chang, Mubashar M. Mahmood, Suzanne S. Teuber, M. Eric Gershwin.
(2012) Overview of Penicillin Allergy. Clinical Reviews in Allergy & Immunology 43:12, 84-97
CrossRef
10. Stacey Singer-Leshinsky. (2012) CME ARTICLE Pathogenesis, diagnostic testing, and
management of mononucleosis. Journal of the American Academy of Physician
Assistants 25:5, 58-62
CrossRef
11. P. Bro, Th. Harr, C. Hecking, L. Grize, K. Scherer, K. A. Jaeger, A. J. Bircher. (2012)
Nonirritant intradermal skin test concentrations of ciprofloxacin, clarithromycin, and
rifampicin. Allergyn/a-n/a
CrossRef
12. Javier Iglesias-Souto, Ruperto Gonzlez, Paloma Poza-Guedes, Inmaculada SanchezMachn, Victor Matheu. (2012) Accuracy in diagnosis of allergy to -lactams. Critical
Care 16:2, 414
CrossRef

13. Tory L. McJunkin, Paul J. Lynch, Elizabeth Srejic. Complications of Peripheral Nerve
Stimulation. In: Reducing Risks and Complications of Interventional Pain Procedures.
Elsevier, 2012:11-18.
CrossRef
14. Madeleine Duvic. Urticaria, Drug Hypersensitivity Rashes, Nodules and Tumors, and
Atrophic Diseases. In: Goldman's Cecil Medicine. Elsevier, 2012:2532-2543.
CrossRef
15. Leslie C. Grammer. Drug Allergy. In: Goldman's Cecil Medicine. Elsevier, 2012:16381640.
CrossRef
16. Aristo Vojdani, Jama Lambert. (2012) The Onset of Enhanced Intestinal Permeability
and Food Sensitivity Triggered by Medication Used in Dental Procedures: A Case
Report. Case Reports in Gastrointestinal Medicine 2012, 1-3
CrossRef
17. Mamta Sharma, Pramodini B. Kale-Pradhan, Jason Taylor, Riad Khatib. (2011)
Cephalosporins for Patients With a History of Penicillin Allergy: The Safety of an Oral
Test Dose. Hospital Pharmacy 46:12, 952-955
CrossRef
18. Cornelia S. Seitz, Eva-B. Brcker, Axel Trautmann. (2011) Suspicion of macrolide
allergy after treatment of infectious diseases including Helicobacter pylori: Results of
allergological testing. Allergologia et Immunopathologia 39:4, 193-199
CrossRef
19. Cornelia S. Seitz, Eva-B. Brcker, Axel Trautmann. (2011) Diagnosis of drug
hypersensitivity in children and adolescents: Discrepancy between physician-based
assessment and results of testing. Pediatric Allergy and Immunology 22:4, 405-410
CrossRef
20. Firas Al-Niaimi. (2011) Drug eruptions in dermatology. Expert Review of Dermatology
6:3, 273-286
CrossRef
21. Merritt L. Fajt, Andrej A. Petrov. (2011) Outpatient Aspirin Desensitization for Patients
With Aspirin Hypersensitivity and Cardiac Disease. Critical Pathways in Cardiology: A
Journal of Evidence-Based Medicine 10:1, 17-21
CrossRef
22. Carey C. Linden, Rana T. Misiak, Ganesa Wegienka, Suzanne Havstad, Dennis R.
Ownby, Christine C. Johnson, Edward M. Zoratti. (2011) Analysis of allergen specific
IgE cut points to cat and dog in the Childhood Allergy Study. Annals of Allergy, Asthma
& Immunology 106:2, 153-158.e2
CrossRef
23. Mark Boguniewicz, Donald Y.M. Leung. Adverse Reactions to Drugs. In: Nelson
Textbook of Pediatrics. Elsevier, 2011:824-828.e1.
CrossRef
24. P. Chaves, M. J. Torres, A. Aranda, S. Lopez, G. Canto, M. Blanca, C. Mayorga. (2010)
Natural killer-dendritic cell interaction in lymphocyte responses in hypersensitivity
reactions to betalactams. Allergy 65:12, 1600-1608
CrossRef
25. Alma Chavez, Amir Mian, Amy M. Scurlock, Douglas Blackall, Gulnur Com. (2010)
Antibiotic hypersensitivity in CF: Drug-induced life-threatening hemolytic anemia in a

pediatric patient. Journal of Cystic Fibrosis 9:6, 433-438


CrossRef
26. Nithya Swamy, Scot A. Laurie, Ernesto Ruiz-Huidobro, David A. Khan. (2010)
Successful Clarithromycin Desensitization in a Multiple MacrolideAllergic Patient.
Annals of Allergy, Asthma & Immunology 105:6, 489-490
CrossRef
27. Amitava Ganguli, Munir Pirmohamed. Drug allergy in lung disease. In: Drug-induced
and Iatrogenic Respiratory Disease. CRC Press, 2010.
CrossRef
28. D. Picard, B. Janela, V. Descamps, M. D'Incan, P. Courville, S. Jacquot, S. Rogez, L.
Mardivirin, H. Moins-Teisserenc, A. Toubert, J. Benichou, P. Joly, P. Musette. (2010)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A Multiorgan
Antiviral T Cell Response. Science Translational Medicine 2:46, 46ra62-46ra62
CrossRef
29. J. Luis Castrejon, Neil Berry, Sabah El-Ghaiesh, Basil Gerber, Werner J. Pichler, B.
Kevin Park, Dean J. Naisbitt. (2010) Stimulation of human T cells with sulfonamides and
sulfonamide metabolites. Journal of Allergy and Clinical Immunology 125:2, 411-418.e4
CrossRef
30. So Hee Lee, Heung Woo Park, Sae Hoon Kim, Yoon Seok Chang, Sun Sin Kim, Sang
Heon Cho, Kyung Up Min, You Young Kim. (2010) The Current Practice of Skin
Testing for Antibiotics in Korean Hospitals. The Korean Journal of Internal Medicine
25:2, 207
CrossRef
31. HENRY F. CHAMBERS. Penicillins and -Lactam Inhibitors. In: Mandell, Douglas, and
Bennett's Principles and Practice of Infectious Diseases. Elsevier, 2010:309-322.
32. Naureen Alim, Julie Y. Patel. (2009) RAPID ORAL DESENSITIZATION TO
FUROSEMIDE. Annals of Allergy, Asthma & Immunology 103:6, 538
33. Tatiana Tchen, Zad Reguia, Fabien Vitry, Elizabeth Arnoult, Anne Grange, Grange
Florent, Phillipe Bernard. (2009) Usefulness of skin testing in cutaneous drug eruptions
in routine practice. Contact Dermatitis 61:3, 138-144
34. Yuan-Pin Hung, Nan-Yao Lee, Chia-Ming Chang, Hsin-Chun Lee, Chi-Jung Wu, Po-Lin
Chen, Ching-Chi Lee, Chih-Huan Chung, Wen-Chien Ko. (2009) Tolerability of
teicoplanin in 117 hospitalized adults with previous vancomycin-induced fever, rash, or
neutropenia: A retrospective chart review. Clinical Therapeutics 31:9, 1977-1986
35. Christopher H. LeMaster, David F.M. Brown, Eric S. Nadel. (2009) Progressive Rash
After Recent Antibiotic Exposure. The Journal of Emergency Medicine 37:2, 160-162
36. Daniel A. Hatef, Patrick Cole, Lior Heller. (2009) Pedicled TRAM flap unaffected by
clindamycin hypersensitivity reaction. Journal of Plastic, Reconstructive & Aesthetic
Surgery 62:7, e238-e239
37. M.G. Canto, M.J. Torres. (2009) Urticaria, angioedema, alergia a medicamentos.
Medicine - Programa de Formacin Mdica Continuada Acreditado 10:34, 2249-2256
38. A.T. Nagao-Dias, F.M. Teixeira, H.L.L. Coelho. (2009) Diagnosing immune-mediated
reactions to drugs. Allergologia et Immunopathologia 37:2, 98-104
39. Cristina Surez, Francesc Gudiol. (2009) Antibiticos betalactmicos. Enfermedades
Infecciosas y Microbiologa Clnica 27:2, 116-129
40. Infectious diseases, tropical medicine and sexually transmitted infection. In: Kumar and
Clark's Clinical Medicine. Elsevier, 2009:79-206.
41. Anne Yates. (2008) The Reply. The American Journal of Medicine 121:12, e13

42. Weekitt Kittisupamongkol. (2008) Lower Incidence of Cross-reactions. The American


Journal of Medicine 121:12, e11
43. Dave M Lutomski, Jennifer A LaFollette, Michael A Biaglow, Lisa A Haglund. (2008)
Antibiotic Allergies in the Medical Record: Effect on Drug Selection and Assessment of
Validity. Pharmacotherapy 28:11, 1348-1353
44. Jeffrey A. Linder. (2008) Editorial Commentary: Antibiotics for Treatment of Acute
Respiratory Tract Infections: Decreasing Benefit, Increasing Risk, and the Irrelevance of
Antimicrobial Resistance. Clinical Infectious Diseases 47:6, 744-746
45. Michael James, Elizabeth A. Martinez. (2008) Antibiotics and perioperative infections.
Best Practice & Research Clinical Anaesthesiology 22:3, 571-584
46. Natasha E. Holmes, Marisa Hodgkinson, Claire Dendle, Tony M. Korman. (2008) Report
of oral clarithromycin desensitization. British Journal of Clinical Pharmacology 66:2,
323-324
47. G. Karakaya, S.R. Isik, A.F. Kalyoncu. (2008) Determining safe antibiotics for drug
hypersensitive patients with the alternative method of double-triple test. Allergologia et
Immunopathologia 36:5, 264-270
48. P. Demoly, W. Pichler, M. Pirmohamed, A. Romano. (2008) Important questions in
Allergy: 1 - drug allergy/hypersensitivity. Allergy 63:5, 616-619
49. Heidi M. Bauer, Dan Wohlfeiler, Jeffrey D. Klausner, Sarah Guerry, Robert A. Gunn,
Gail Bolan. (2008) California Guidelines for Expedited Partner Therapy for Chlamydia
trachomatis and Neisseria gonorrhoeae. Sexually Transmitted Diseases 35:3, 314-319
50. Jerrold H. Levy, N Franklin Adkinson. (2008) Anaphylaxis During Cardiac Surgery:
Implications for Clinicians. Anesthesia & Analgesia 106:2, 392-403
51. Amanda Lam, Inderpal Randhawa, William Klaustermeyer. (2008) Cephalosporin
Induced Toxic Epidermal Necrolysis and Subsequent Penicillin Drug Exanthem.
Allergology International 57:3, 281-284
52. Arnon Goldberg, Ronit Confino-Cohen. (2008) Skin testing and oral penicillin challenge
in patients with a history of remote penicillin allergy. Annals of Allergy, Asthma &
Immunology 100:1, 37-43
53. U. Jappe. (2007) Amoxicillin-induced exanthema in patients with infectious
mononucleosis: allergy or transient immunostimulation?. Allergy 62:12, 1474-1475
54. Antonino Romano, Pascal Demoly. (2007) Recent advances in the diagnosis of drug
allergy. Current Opinion in Internal Medicine 6:5, 443-447
55. Karim Lakhal, Brice Lortat-Jacob, Catherine Neukirch, Olivier Pajot, Michel Wolff.
(2007) Safe Use of Meropenem in a Patient with a Possible Nonimmediate Allergy to
Imipenem. Pharmacotherapy 27:9, 1334-1338
56. Soledad Lopez, Natalia Blanca-Lopez, Jose Antonio Cornejo-Garcia, Gabriela Canto,
Maria Jose Torres, Cristobalina Mayorga, Miguel Blanca. (2007) Nonimmediate
reactions to betalactams. Current Opinion in Allergy and Clinical Immunology 7:4, 310316
57. Jeremy A Schafer, Noe Mateo, Garry L Parlier, John C Rotschafer. (2007) Penicillin
Allergy Skin Testing: What Do We Do Now?. Pharmacotherapy 27:4, 542-545
58. Stefan Whrl. (2007) Clinical work-up of adverse drug reactions. Expert Review of
Dermatology 2:2, 217-231
59. Albert Finn. Immunoglobulin E-Mediated (Immediate) Hypersensitivity. In: Medical
Immunology, Sixth Edition. CRC Press, 2007:295-308.

60. Frederick A. Pereira, Adarsh Vijay Mudgil, David M. Rosmarin. (2007) Toxic epidermal
necrolysis. Journal of the American Academy of Dermatology 56:2, 181-200
61. (2007) Lost in Transcription. New England Journal of Medicine 356:3, 311-311
62. Laurence Valeyrie-Allanore, Bruno Sassolas, Jean-Claude Roujeau. (2007) Drug-Induced
Skin, Nail and Hair Disorders. Drug Safety 30:11, 1011-1030
63. Prakash Manoharan, Douglas Fullen, Anca Avram. (2006) Neutrophilic urticaria: wholebody 111In-leukocyte scan and histological correlation. European Journal of Nuclear
Medicine and Molecular Imaging 33:12, 1523-1524
64. Burke A. Cunha. (2006) Antibiotic Selection in the Penicillin-Allergic Patient. Medical
Clinics of North America 90:6, 1257-1264
Philippe Bonniaud, Clio Camus, Ahmad Jibbaoui, Kabeya Kazambu, Nicolas Baudouin,
Pascal Foucher, Philippe Camus. Drug-induced respiratory emergencies. In: Respiratory
Emergencies. CRC Press, 2006:269-290.
65. Judith Sendzik, Ralf Stahlmann. (2006) Unerwnschte Wirkungen der -LactamAntibiotika: Widerspruch zu Ehrlichs Paradigma der selektiven Toxizitt. Pharmazie in
unserer Zeit 35:5, 432-437
66. (2006) Antibiotic Allergy. New England Journal of Medicine 354:21, 2293-2294
67. Joyce A. Generali. (2006) Hospital Pharmacy Pulse - Recent Publications on Medications
and Pharmacy. Hospital Pharmacy 41:5, 484-486

Jurnal Penyakit Kulit dan Kelamin

Antibiotic Allergy

Nama : Nurul Ratna Sari


NIM : 10542 0110 09

FAKULTAS KEDOKTERAN
UNIVERSITAS MUHAMMADIYAH
MAKASSAR