Structural Determinants

of Antibiotic Allergy
Brian A. Baldo, PhD, Zhenjun Zhao, PhD, and Nghia H. Pham, PhD

Address
Molecular Immunology Laboratory, Kolling Institute of Medical
Research, Royal North Shore Hospital of Sydney, NSW 2065, Australia.
E-mail: babaldo@med.usyd.edu.au
Current Allergy Reports 2001, 1:2331
Current Science Inc. ISSN 1529-7322
Copyright 2001 by Current Science Inc.

Allergies to antibiotics, mainly the b-lactam antibiotics

(penicillins and cephalosporins), are a common, costly, and
potentially dangerous clinical problem encountered in
everyday practice. Although studies on the role of
nonb-lactam antibiotics in allergic diseases, particularly
the development of specific diagnostic tests and the
immunochemical identification of allergenic structures,
have been too few and relatively superficial, the situation
with the b-lactam antibiotics is much more advanced.
Good progress has been made in identifying the spectra of
allergenic determinants recognized by IgE antibodies in the
sera of subjects sensitized to penicillins and cephalosporins,
and this is aiding the development of an appropriate
battery of drug conjugates for use as diagnostic agents.
Patient-sensitivity responses to the b-lactam antibiotics are
frequently heterogeneous, and this factor must be taken
into account for any diagnostic strategy or future therapy
with a penicillin or cephalosporin.

Introduction
The cost of drug-related morbidity and mortality in
ambulatory care in the United States has been estimated
at $76.6 billion annually [1]. Although not all adverse
reactions to drugs are true allergic responses [2,3], reactions
to anti-infective agents, particularly a number of antibiotics,
account for a high proportion of type I, IgE-mediated
drug allergies [4,5].
Although it is approximately 80 years since Landsteiner
[6] began to research hypersensitivity, including reactions to
simple chemicals, our understanding of allergenic
molecules is still too narrow and somewhat rudimentary.
A decade ago [7], we posed the question what is the
nature and number of allergenic determinants found on
simple chemicals, and what makes a particular structure
allergenic? For the present review on antibiotic allergy, there
remains a dearth of information on well-researched cases

at the clinical and laboratory levelsof allergic responses to

nonb-lactam antibiotics. The situation is not as bad for
the b-lactam antibiotics (penicillins and cephalosporins), although sustained immunochemical investigations are needed even for these drugs.

Nonb-Lactam Antibiotics
According to Sullivan [5], among the nonb-lactam antibiotics, gentamycin and streptomycin have frequently been
implicated in provoking immediate hypersensitivity-like
reactions, whereas chloramphenicol, lincomycin, and
rifampin are occasionally responsible, and erythromycin,
kanamycin, polymixins, tetracyclines, and vancomycin are
rarely involved. With decreasing use of gentamycin and
streptomycin, allergies to these drugs [810] have become
less frequent and are now rarely encountered, and use of
other antibiotics such as lincomycin, kanamycin, and polymixins has declined.
The nonb-lactam antibiotics have been implicated in
allergic reactions much less often than have the more
frequently used penicillins and cephalosporins, and
immunochemical information, including structural detail
on allergenic determinants, is lacking. Structures of
compounds implicated in most of the reported nonblactam antibiotic allergic reactions are shown in Figure 1.
Although minocycline may induce serious adverse reactions including hypersensitivity [11], and a few cases
of anaphylactoid reactions to tetracycline and demethylchlortetracycline have been reported [12], attention has
been drawn to the comparative safety of the tetracycline
family of antibiotics (Fig. 1) [13]. Interestingly, Fawcett
and Pepys [14] suggested that after an anaphylactic
reaction to tetracycline, there is a latent period before the
reaction can be triggered again. IgE-antibody recognition
of tetracycline was recently demonstrated in some subjects
diagnosed with multiple drug allergies. In this study, the
molecular basis of drug reactions was thought to be related
to the recognition of N-alkyl groups [15].
Like the tetracyclines, allergies to macrolide antibiotics
(Fig. 1) are also rare; in a recent review of the literature,
Demoly et al. [16] state an incidence of 0.4% to 3% of
treatments. Skin tests are often negative, although a
positive prick test to spiramycin was reported by Davies
and Pepys [17]. Drug-reactive IgE antibodies have been

24

Anaphylaxis and Drug Allergy

Figure 1. Structures of some nonb-lactam antibiotics implicated in allergic reactions in humans.

Structural Determinants of Antibiotic Allergy Baldo et al.

detected, in particular by Pascual et al. [18], who also

demonstrated inhibition of antibody binding in vitro
with erythromycin and diacetylmidecamycin.
Rifamycins are a group of structurally similar macrocyc lic ant ibiot ics (Fig. 1) whos e us e va rie s f rom
tuberculosis therapy to local application to infected wounds.
Reactions to these drugs are poorly documented, but
systemic reactions to rifamycin SV have been reported
[19,20]. The structural similarity of this group of drugs
suggests that cross-reactions to other members of the
family are highly likely. The presence of IgE antibodies to
rifampicin in patients with systemic reactions to the drug has
been suggested by positive skin test responses and a positive
radioallergosorbent test [21]. Again, immunochemical
results on allergenic determinants are lacking, but an early
study identified cross-reactive IgE antibodies that recognized
the rifampicin nucleus but not the side chain [22].
Rashes, pruritis, hypotension, shock, and angioedema
are well-known adverse effects of vancomycin [23].
The structurally and therapeutically similar glycopeptide
antibiotic, teicoplanin (Fig. 1), shows a similar spectrum of
adverse effects but appears to be less toxic. Despite the
chemical similarity of the two compounds and some reports
of cross-reactions [24], teicoplanin has been suggested as a
substitute for patients intolerant to vancomycin [25].
Most allergic responses to chloramphenicol (Fig. 1)
appear to occur after topical application, but reactions,
including anaphylaxis, following oral and parenteral
administration and application of chloramphenicol eye
ointment have been reported [26,27]. Apart from some
early studies designed to detect antichloramphenicol
human serum albumin conjugate [28], immunologic
studies on allergies to this antibiotic are seriously lacking.
Reported cross-sensitization between chloramphenicol
and dinitrochlorobenzene has not been firmly established.

b-Lactam Antibiotics

All penicillins and cephalosporins contain a b-lactam ring

attached to a thiazolidine (penicillins) or dihydrothiazine
(cephalosporins) ring. Individual drugs are distinguished
by the group attached via an amide linkage to the b-lactam
ring and, additionally in cephalosporins, a substituent at
the 3-position on the dihydrothiazine ring (Fig. 2).

The entire hapten and major-minor

views of penicillin antigens
Over more than two decades, investigators produced a
detailed definition of the complexity of penicillin
antigens and their putative roles in hypersensitivity [29].
This large body of research built on and vastly extended the
foundation of our understanding of hypersensitivity to
small molecules, which was laid down by Landsteiner [6]
and is widely seen as a model system for drug allergy. Even
so, the picture of penicillin antigens provided by this
research has restricted our view of the fine structural

25

specificity of not only penicillins but also other drug

allergenic determinants.
In the prevailing view of penicillin antigens, antigenic (or allergenic) determinants are viewed as whole
hapten molecules attached to a protein carrier, and antigenic differences are seen to be due to the location of the
hapten-protein linkage and the ring modifications
arising from the linkage. Although knowledge of the
hapten-protein linkage is important, it is usually not
sufficient to identify the precise allergenic determinant
structures. Clinical, immunoassay, quantitative inhibition, and prick-test findings have established that sidechain structures on penicillins, without the participation
of the b-lactam and thiazolidine rings, may be allergenic
and responsible for allergic reactions [3033]. Earlier
skin test findings by Solley et al. [34] and Moss et al. [35]
agree with this view.
Recognition of side-chain groups on different
penicillins presumably could occur when the groups are
part of the major, or penicilloyl, determinant, which is
linked to a protein carrier via opening of the b-lactam ring.
Also, recognition presumably could occur if the groups are
part of minor determinants such as penicillanyl or
penicillenate antigens, which are linked through the
thiazolidine ring carboxyl and sulfur atom, respectively. In
other words, from the viewpoint of immunologic
recognition, the nature of the hapten-protein linkage is less
informative than the precise structures complementary to
the antibody and T-cell receptor sites.

Heterogeneity of b-lactam allergenic determinants

The major-minor determinant view of penicillin
antigens and the emphasis on the differently linked
penicillin molecule do not take into account the fine
structural heterogeneity of allergenic determinants of the
whole range of b-lactam antibiotics. Our detailed
quantitative hapten-inhibition studies reveal a spectrum
of IgE-binding determinants extending from one side of
penicillin and cephalosporin molecules to the other.
These determinants range in specificity from side-chain
or thiazolidine/dihydrothiazine ring only to compound
determinants involving one or both of these structures
with the b-lactam ring (Fig. 2) [3133,36].
Such heterogeneity of allergenic determinants can
be demonstrated at the immunochemical level, as
shown by Harle and Baldo [31] and Pham and Baldo
[36], and in serologic recognition patterns of penicillinand cephalosporin-reactive IgE antibodies detected
in routine laboratory testing of sera from subjects
with suspected allergies to b-lactam antibiotics. Examples
of IgE-antibodyb-lactam recognition patterns from
studies of over 1600 patients with suspected allergy to
penicillins, cephalosporins, or both are shown in Table 1.
Selected examples demonstrated that, even at the serologic level, heterogeneity of recognized allergenic
structures is apparent.

26

Anaphylaxis and Drug Allergy

Figure 2. Structures of penicillins and cephalosporins and spectra of allergenic determinants recognized by sera from sensitive patients.

Structural Determinants of Antibiotic Allergy Baldo et al.

27

Table 1. Examples of drug recognition patterns by -lactamreactive IgE antibodies in the sera
of subjects with suspected allergic sensitivity
Scores for detection of specific IgE antibodies*
Subjects

BPO AmoxO AmpiO

A61
9986
A1155
A2165
A1378
A450
A1583
A162
A2149
A2226
A2022
A1878
A2143

4+
1+
4+
3+
4+

4+
3+
1+
3+
-

PMPO

4+
2+
4+

2+
1+
3+

BPA AmoxA AmpiA

3+
1+
2+
1+

4+
3+
3+

1+
1+
3+

4+
3+

PMPA

1+
1+
3+

Flu
-

4+
1+
-

2+
2+

Cein Ceclor Celex

1+
1+
2+
2+

3+
1+

4+
4+
4+

4+
1+
4+
3+
3+
-

1+
1+
4+
1+

3+
-

*Antibodies detected by determining percentage radioactive uptake of 125Iantihuman-IgE in solid-phase

radioimmunoassays. Scoring system for antibody reactivity: -, negative (radioactive uptake < 1%);
, equivocal (1%1.5%); 1+, weak positive (1.6%5%); 2+, moderate positive (5.1%10%); 3+, strong positive (10.1%20%);
4+, very strong positive (> 20%).
AmoxAamoxicillanyl; AmoxOamoxicilloyl; AmpiAampicillanyl; AmpiOampicilloyl; BPAbenzylpenicillanyl; BPObenzylpenicilloyl;
Ceclorcephacloroyl; Ceincephalothoyl; Celexcephalexoyl; Fluflucloxacilloyl; PMPAphenoxymethylpenicillanyl;
PMPOphenoxymethylpenicilloyl.

Antibodies detect a variety of structures ranging from

side-chain groups to an entire penicillin or cephalosporin
molecule. In our solid-phase radioimmunoassay studies,
we employed penicilloyl- and cephalosporoyl-polylysine
together with some different penicillanyl-polylysines,
minor determinants that appear to have good diagnostic
potential [37,38]. The preparation of these two types of
antigen conjugates is summarized in Figure 3.
IgE antibodies from some subjects recognized only -oyl
(sera A61 and 9986) or -anyl (A1155 and A2165) specificities, whereas others reacted with both determinants (A1583
and A1878), and still others demonstrated clear side-chain
specificity by reacting with only one penicillin (eg, A450 with
flucloxacillin). Because penicillins and cephalosporins share
some structural features, antibody recognition within and
between the two families of drugs might be expected,
and in fact this is seen. Although some sera reacted only
with penicillins (eg, A61 and A1583) or only with cephalosporins (A162), others reacted across the range of drugs in
both families (A1878), and still others (A2143) recognized
only a single member from each family.
As with the penicillins, IgE antibodies from some
cephalosporin-sensitive subjects reacted with only
one member of the group (A2149 and A2226). Clear
recognition of a number of different cephalosporins,
together with selective recognition of only the -anyl
derivatives of benzylpenicillin and amoxicillin (A2165), is
another example of extreme heterogeneity of the IgE-antibodyb-lactam recognition profile. The recognition profile
shown by serum A2022 is an example of the extraordinary
selectivity of allergenic recognition that may occur at the

fine structural level. Despite the extremely broad

recognition of different penicillins and cephalosporins,
including the amoxicillanyl determinants, IgE antibodies
from this patient did not react with the amoxicilloyl
determinant. Antibody recognition patterns such as the
examples outlined here suggest that, in at least some
sensitive subjects, more than one population of b-lactam
reactive IgE antibodies is present.

Allergenic specificities and the diagnosis

of b-lactam antibiotic allergies
At present, diagnostic testing for penicillin allergies is
inadequate, and, when it is done at all, the small
number of antigens available are lacking in diagnostic
range and chemica l characterization. The current
selection of test reagents is usually based on benzylpenicillin only and includes the penicilloyl (major)
determinant and a number of minor determinants
thought to be important clinically: free benzylpenicillin,
penicilloic acid, penicillenate, penicillanyl, penamaldate,
penaldate, D-penicillamine, and penicoyl. Such a list
of minor determinants is rarely if ever available for
diagnosis in vivo or in vitro. The situation is even less
developed for the cephalosporins, with cephalosporoyl
derivatives of the most frequently prescribed members of
the family unavailable.
With this in mind, -oyl and -anyl derivatives of the
penicillins and cephalosporins most frequently implicated
in allergic reactions were prepared and employed in vitro in
solid-phase radioimmunoassays for the detection of drugreactive IgE antibodies in the sera of subjects with suspected

28

Anaphylaxis and Drug Allergy

Figure 3. General methods for preparation and structures of A, penicilloyl and cephalosporoyl (major) determinants and B,
penicillanyl and cephalosporanyl (minor) determinants.

b-lactam antibiotic allergic sensitivity. In tests on 1682

subjects, 433 (25.7%) had serum IgE antibodies that reacted
with at least one penicillin or cephalosporin. Of these, 397
subjects (23.6%) had IgE antibodies to at least one cephalosporin, whereas only 248 (14.7%) had antibodies to at
least one penicillin. Two hundred and twelve (12.6%) of the
sera contained IgE antibodies to both drugs, whereas 185
(11%) were positive only to one or more cephalosporins,
and 36 (2.1%) were positive only to one or more penicillins.
Results with the most frequently prescribed penicillin,
amoxicillin, indicated that serologic cross-reactivity often
occurs with benzylpenicillin. Of 1627 patients sera examined, 128 (7.9%) tested positive to both drugs, but only 25
(1.5%) were positive to benzylpenicillin and negative to
amoxicillin. Superiority of the -anyl form of both drugs
was clearly demonstrated, with 69 subjects (4.2%) positive to
benzylpenicillanyl and negative to benzylpenicilloyl and

114 (7%) positive to amoxicillanyl and negative to amoxicilloyl. On the other hand, only five sera (0.3%) reacted to the
-oyl but not the -anyl form of benzylpenicillin, and 35
(2.2%) were positive to the -oyl but not the -anyl form of
amoxicillin.

Preparation and characterization

of b-lactam conjugates for diagnosis
Methodology for the preparation and characterization of
benzylpenicilloyl-protein conjugates is well established and
described [37,39,40]. Data is needed for other penicillins
including the frequently prescribed aminobenzyl compounds, for which some studies have been undertaken [39]
and for the cephalosporins, especially in relation to stability
and possible degradation and polymerization products.
The penamaldate assay for the quantitation of
penicilloic acid and penicilloyl derivatives described by

Structural Determinants of Antibiotic Allergy Baldo et al.

29

Figure 4. 1H nuclear magnetic resonance

spectra of A, benzylpenicilloyl-polylysine
and B, benzylpenicillanyl-polylysine.
(From Zhao et al. [37]; with permission.)

Rolli and Schneider [40] remains a valuable method for

characterization of conjugates to be used for skin and
laboratory-based IgE testing. Bearing in mind the usual
difficulty of characterizing hapten-protein conjugates in
terms of number of hapten groups per mole and precise
chemical linkages, presence of possible fission products,
and so forth, there is a clear need for the employment of
more exact and powerful analytic methodologies. Recent
applications of 1 H nuclear magnetic resonance (NMR)
spectroscopy for the characterization of penicilloyl
and penicillanyl conjugates [37,41,42] is a step in this
direction. This analytic instrumental approach is a useful
and convenient method for estimating the degree of
substitution of carrier (L-polylysine) conjugates and has
the advantage that it measures the number of substituted
and unsubstituted lysine residues directly [37].
Figure 4 shows the 1H NMR spectra of benzylpenicilloyl-polylysine and benzylpenicillanyl-polylysine [37]. In
the benzylpenicilloyl-polylysine spectrum, broad peaks for
the Ha, Hb, Hg, and Hd protons of polylysine were seen at
4.30, 1.67 to 1.77, 1.40, and 1.67 ppm, respectively. At pH
5.65, the He resonances occurred at 2.95 (unsubstituted)
and 3.11 ppm (substituted). When the pH was increased to
11.8, the peak produced by unsubstituted residues moved
upfield by 2.58 ppm while the position of the He peak for
substituted residues remained unchanged. A comparison of
the areas of these peaks provides a direct measurement of
the derivatization of the lysine residues. Benzylpenicilloyl
showed methyl resonances at 1.24 and 1.57, H2 at 3.47,
benzylic CH 2 at 3.64, and aromatic hydrogens near 7.3
ppm. The H6 proton was seen as a doublet at 4.91 ppm. The
ratio of the sum of the areas of the lysine He peaks to the
area of the benzylic proton peak or the ratio of the lysine
peak areas to the aromatic proton peak can also be used to
estimate the degree of substitution. For benzylpenicillanyl,
the aromatic and benzyl protons gave the only clear signals.
There was a small doublet at 5.07 ppm with a coupling con-

stant at 4.5 Hz. Presence of the b-lactam ring was suggested

by the different chemical shift and small coupling constant.

Discussion and Conclusions

The allergenic recognition of side-chain groups on
penicillins and cephalosporins is well established [30
36,38,43,44]. When this is consideredtogether with the
number of individual penicillins and cephalosporins
prescribed, the heterogeneity of b-lactam allergenic
determinants, and the possible presence of more than one
population of b-lactamreactive antibodies [31,36]it is
clear that a much broader battery of test reagents is needed
for in vivo and in vitro diagnostic procedures. In addition
to covering the different members of the two families,
drug conjugates should include the major, or -oyl,
determinant and at least one, but preferably more,
minor determinants shown to be of value as diagnostic
agents. For the penicillins, a reasonably good start has
been made [29,3133,37,38,3942,4550], but for the
cephalosporins [36,38,51] progress remains slow. Results
presented here show that tests (skin or in vitro detection
of IgE) on only a single penicillin (eg, benzylpenicilloyl)
or cephalosporin conjugate may fail to detect sensitivities
to the many different possible b-lactam specificities.
Failure to detect such sensitivities by using inadequate or
too few test reagents may have serious consequences for
both patient and clinician.
The predominance of cephalosporin recognition by
serum IgE antibodies is surprising and appears to be at
odds with the prevailing beliefs on the incidence
of reactions to the two different families of b-lactam
antibiotics. However, the frequency of cephalosporin
use has been increasing. Further, the wide range of drug
specificities used in our studiesa relatively large number
of different penicillins and cephalosporins in both -oyl
and -anyl formspreviously has never been evaluated

30

Anaphylaxis and Drug Allergy

side by side in as large a group of subjects with clinical

histories suggesting allergy to b-lactam antibiotics. Also,
more cephalosporins than penicillins may be injected,
leading to a higher incidence of sensitization and
reactions. In addition, clinical diagnosis based on history
and symptoms in patients with cephalosporin sensitivities
may produce a more tightly diagnosed group of patients
compared with diagnosis of patients with penicillin
sensitivities that is based on rashes and other delayed
reactions, which may skew clinical evaluations.
When con sid erin g drug-r eact ive IgE-ant ibody
responses detected in vitro, it is important to remember
that detection of antibodies may prove sensitization but
not necessarily the existence of allergy as a clinical disease.
In addition to the need for a wide range of characterized
penicillin and cephalosporin conjugates for skin- and
laboratory-based tests, provocation tests remain essential
to establish in vivo the clinical relevance of serum IgEantibody results.
Application of suitable diagnostic tests for suspected
antibiotic allergies serves the obvious need of establishing
whether a patient has type I hypersensitivity to an antibiotic,
particularly a b-lactam antibiotic, and identifying the
individual drug or drugs responsible. The tests also may
have beneficial effects on antibiotic use, particularly use of
vancomycin. Any effect on vancomycin use has important
implications for the spread and acquisition of vancomycinresistant enterococci. Guidelines for the prudent use of this
last resort antibiotic have been issued together with the
recommendation to use b-lactam antibiotics, provided
allergy to these drugs is not present. A study by Harris et al.
[52] suggests that skin testing with some penicillin antigens
may be useful in the effort to control vancomycin use.

References and Recommended Reading

Papers of particular interest, published recently, have been
highlighted as:

Of importance
Of major importance
1.

2.

3.
4.
5.

6.
7.

8.

Johnson JA, Bootman JL: Drug-related morbidity and

mortality: a cost-of-illness model. Arch Intern Med
1995, 155:19491956.
Pilzer JD, Burke TG, Mutnick AH: Drug allergy assessment
at a university hospital and clinic. Am J Health Syst Pharm
1996, 53:29702975.
Arndt KA, Kick H: Rates of cutaneous reaction to drugs.
JAMA 1976, 235:918923.
Lin RY: A perspective on penicillin allergy. Arch Intern Med
1992, 152:930937.
Sullivan TJ: Allergic reactions to antimicrobial agents: a
review of reactions to drugs not in the beta lactam
antibiotic class. J Allergy Clin Immunol 1984, 74:594599.
Landsteiner K: The Specificity of Serological Reactions.
New York: Dover; 1962.
Baldo BA: Immunochemical perspectives of allergy: in
the steps of Karl Landsteiner. In Molecular Approaches to the
Study of Allergens. Edited by Baldo BA. Basel: Karger; 1990:110.
Braun W, Schutz R: Gentamycin allergy. Hautarzt
1969, 20:108112.

9.

Hall FJ: Anaphylaxis after gentamycin [letter]. Lancet

1977, 2:455.
10. Abeck D, Kuvert C, Segnini-Torres M, et al.: Streptomycininduced anaphylactic reaction during in vitro
fertilization (IVF). Allergy 1994, 49:388389.
11. Knowles S, Shapiro L, Shear N: Serious adverse reactions
induced by minocycline: report of 13 patients and
review of the literature. Arch Dermatol 1996, 132:934939.
12. Steinbruegge JM, Judson FN: Type I allergic reaction to orally
administered tetracycline hydrochloride: a case report.
Sex Transm Dis 1980, 7:193194.
13. Shapiro LE, Knowles SR, Shear NH: Comparative safety of
tetracycline, minocycline, and doxycycline. Arch Dermatol
1997, 133:12241230.
14. Fawcett IW, Pepys J: Allergy to a tetracycline preparationa
case report. Clin Allergy 1976, 6:301303.
15. Pham NH, Baldo BA, Puy RM: Studies on the mechanism of
multiple drug allergies: structural basis of drug recognition.
J Immunoassay Immunochem 2000, in press.
This article contains immunochemical findings based on recognition
of structurally diverse drugs by subjects with multiple drug allergies,
including allergies to b-lactam antibiotics. It is the first study,
together with supporting data, to explain the structural basis
of multidrug allergic recognition.
16. Demoly P, Benahmed S, Valembois M, et al.: LAllergie aux
macrolides: revue de la littrature [in French]. Presse Med
2000, 29:321326.
This is a comprehensive and valuable review of the literature on
allergies to macrolide antibiotics in a field where little understanding
of the structural basis of allergenicity has been forthcoming.
17. Davies RJ, Pepys J: Asthma due to inhaled chemical agents:
the macrolide antibiotic spiramycin. Clin Allergy
1975, 1:99107.
18. Pascual C, Crespo JF, Quiralte J, et al.: In vitro detection of
specific IgE antibodies to erythromycin. J Allergy Clin Immunol
1995, 95:668671.
19. Mancuso G, Masara N: Contact urticaria and severe anaphylaxis from rifamycin SV. Contact Dermatitis 1992, 27:124125.
20. Cardot E, Tillie-Leblond I, Jeannin P, et al.: Anaphylactic
reaction to local administration of rifamycin SV.
J Allergy Clin Immunol 1995, 95:17.
21. Cnudde F, Leynadier F: The diagnosis of allergy to rifampicin
confirmed by skin test [letter]. Am J Med 1994, 97:403404.
22. Bassi L, Di Berardino L, Silvestri LG: IgE antibodies in
patients allergic to rifampicin. Int Arch Allergy Appl Immunol
1976, 51:390394.
23. Polk RE, Healy DP, Schwartz LB, et al.: Vancomycin and the
red-man syndrome: pharmacodynamics of histamine
release. J Infect Dis 1988, 157:502507.
24. Knudsen JD, Pedersen M: IgE-mediated reaction to vancomycin and teicoplanin after treatment with vancomycin.
Scand J Infect Dis 1992, 24:395396.
25. Schlemmer B, Falkman H, Boudjadja A, et al.: Teicoplanin
for patients allergic to vancomycin. N Engl J Med
1988, 318:11271128.
26. Palchick BA, Funk EA, McEntire JE, Hamory BH: Anaphylaxis
due to chloramphenicol. Am J Med Sci 1984, 288:4345.
27. Liphshitz I, Loewenstein A: Anaphylactic reaction following
application of chloramphenicol eye ointment [letter].
Br J Ophthalmol 1991, 75:64.
28. Orgel HA, Hamburger RN: Chloramphenicol antibody: V: a
method for the detection of antichloramphenicol antibody
in human serum. Immunology 1971, 20:233239.
29. de Weck AL: Penicillins and cephalosporins. In Allergic
Reactions to Drugs. Edited by de Weck AL, Bundgaard H.
Berlin: Pringer-Verlag; 1983:423482.
30. Blanca M, Vega JM, Garcia J, et al.: Allergy to penicillin with
good tolerance to other penicillins: study of the incidence
in subjects allergic to beta-lactams. Clin Exp Allergy
1990, 20:475481.

Structural Determinants of Antibiotic Allergy Baldo et al.

31.

Harle DG, Baldo BA: Identification of Penicillin Allergenic

Determinants That Bind IgE Antibodies in the Sera of
Subjects With Penicillin Allergy. Mol Immunol
1990, 27:10631071.
32. Baldo BA, Pham NH: Structure-activity studies on
drug-induced anaphylactic reactions. Chem Res Toxicol
1994, 7:703721.
33. Baldo BA, Pham NH, Weiner J: Detection and side-chain
specificity of IgE antibodies to flucloxacillin in allergic
subjects. J Mol Recognit 1995, 8:171177.
34. Solley GO, Gleich GJ, Van Dellen RG: Penicillin allergy:
clinical experience with a battery of skin-test reagents.
J Allergy Clin Immunol 1982, 69:238244.
35. Moss RB, Babin S, Hsu YP, et al.: Allergy to semisynthetic
penicillins in cystic fibrosis. J Pediatr 1984, 104:460466.
36. Pham NH, Baldo BA: b-Lactam drug allergens: fine structural
recognition patterns of cephalosporin-reactive IgE
antibodies. J Mol Recognit 1996, 9:287296.
37. Zhao Z, Batley M, Dambrosio C, Baldo BA: In vitro reactivity
of penicilloyl and penicillanyl albumin and polylysine
conjugates with IgE-antibody. J Immunol Methods 2000, in press.
This is a useful reference study for the characterization of
penicillin antigen conjugates and comparison of the value of
penicilloyl (major) and penicillanyl (minor) determinant
conjugates for diagnosis.
38. Baldo BA: Structural and immunochemical considerations in
the diagnosis of allergy to penicillins and cephalosporins.
Allergy Clin Immunol Int 2000, in press.
39. Bondaruk J, Curcio-Vonlanthen V, Schneider CH: Basic aspects
related to penicillin-allergy skin testing: on the variability
of the hapten-paratope interaction. Allergy 1995, 50:671676.
40. Rolli H, Schneider CH: Penamaldate assay: improved
methodology for the quantitation of penicilloic acids,
penicilloyl amides and penicilloyl esters. Drug Res
1984, 34:12471249.
41. Caneva E, Di Gennaro P, Farina F, et al.: Synthesis and
characterization of a penicillin-poly(l-lysine) which
recognizes human IgE anti-penicillin antibodies.
Bioconjug Chem 1993, 4:309313.

42.

43.

44.

45.
46.

47.
48.

49.

50.

51.

52.

31

Bolzacchini E, Consonni V, Gramatica P, et al.: Toward an

in vitro test for the diagnosis of allergy to penicillins:
synthesis, characterization, and use of b-lactam and
b-lactam metabolite poly-l-lysine which recognize
human IgE antibodies. Bioconjug Chem 1999, 10:332337.
Silviu-Dan F, McPhillips S, Warrington RJ: The frequency of
skin test reactions to side-chain penicillin determinants.
J Allergy Clin Immunol 1993, 91:694701.
Audicana M, Bernaola G, Urrutia I, et al.: Allergic reactions
to beta lactams: studies in a group of patients allergic to
penicillin and evaluation of cross-reactivity with
cephalosporin. Allergy 1994, 49:108113.
Parker CW: Drug allergy. In Clinical Immunology. Edited by
Parker CW. Philadelphia: Saunders; 1980:12191260.
Levine BB: Immunochemical mechanisms of drug allergy.
In Textbook of Immunopathology, edn 2. Edited by Miescher PA,
Muller-Eberhard HJ. New York: Grune and Stratton; 1976:403420.
Dewdney JM: Immunology of the antibiotics. In The Antigens.
Edited by Sela M. New York: Academic Press; 1977:73228.
Edwards RG, Spackman DA, Dewdney JM: Development and
use of three new radioallergosorbent tests in the diagnosis
of penicillin allergy. Int Arch Allergy Appl Immunol
1982, 68:352357.
Blanca M, Mayorga C, Prez E, et al.: Determination of IgE
antibodies to the benzylpenicilloyl determinant: a
comparison between poly-l-lysine and human serum
albumin as carriers. J Immunol Methods 1992, 153:99105.
Daxun Z, Adriansson J, Martin AT, et al.: Diagnostic
capabilities of penicillin-based structures as tools in the
in vitro diagnosis of penicillin allergy. J Invest Allergol C
lin Immunol 1992, 2:240246.
Harle DG, Baldo BA: Drugs as allergens: an immunoassay
for detecting IgE antibodies to cephalosporins. Int Arch
Allergy Appl Immunol 1990, 92:439444.
Harris AD, Sauberman L, Kabbash L, et al.: Penicillin skin
testing: a way to optimize antibiotic utilization.
Am J Med 1999, 107:166168.