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PEDIATRICS Vol. 104 No. 4 October 1999, p. e45
-Lactam Antibiotics in Children
From the Departments of Pediatric Pulmonology and Allergology, Sick Children Hospital, Paris V University, Paris, France
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Background. Skin tests with soluble
-lactams can be used to diagnose immediate and delayed
hypersensitivity (HS) reactions to -lactam antibiotics. Very few
studies have been performed with children with suspected -lactam
allergy. In these studies, immediate HS to -lactams was diagnosed by
skin tests in 4.9% to 40% of children. The diagnostic and predictive
values of immediate responses in skin tests are good, because very few
children with negative skin test results have positive oral challenge
(OC) test results. Delayed responses in skin tests (intradermal and
patch tests) have been reported in adult patients and children
suffering with urticaria, angioedema, and maculopapular rashes during
treatments with -lactam antibiotics. However, the diagnostic and
predictive values of late responses are unknown. Semi-late responses in
skin tests with -lactams have never been studied in adults or
children.
Objectives. The aims of this study were to confirm or rule
out the diagnosis of allergy to -lactams in children with histories
of adverse reactions to these antibiotics, to determine whether
allergic children were sensitized to one or several classes of
-lactams, and to evaluate the frequency and diagnostic value of
immediate, accelerated, and delayed responses in skin tests with
-lactam antibiotics in children.
Methods. We studied 325 children with suspected -lactam
allergy. Skin tests (prick and intradermal) were performed with soluble
forms of the suspected (or very similar) -lactams and with one or
several -lactams from other classes. The reaction was assessed after 20 minutes (immediate), 8 hours (accelerated), and 48 to 72 hours (delayed). OCs with the suspected -lactams were performed in patients with negative skin test results, except those with severe serum sickness-like reactions and potentially harmful toxidermias.
Results. Skin tests and OCs led to the diagnosis of
-lactam allergy in 24 (7.4%) and 15 (4.6%) of the children,
respectively. Thus, only 12% of the children were diagnosed as
allergic to -lactams by means of skin tests and OC. HS to
-lactams was suspected from clinical history in 30 (9.2%) children
reporting serum sickness-like reactions and potentially harmful
toxidermias. In a few children, we diagnosed food allergy and
intolerance to excipients or nonsteroidal antiinflammatory drugs. No
cause was found in the other children. Based on skin tests and OC, the prevalences of immunoglobulin
E-dependent and of semi-late or delayed sensitizations to -lactam assessed were similar (6.8% vs 5.2%, respectively). Most
immunoglobulin E-dependent sensitizations were diagnosed by means of
skin tests (86.4%). In contrast, most semi-late and delayed
sensitizations were diagnosed by OC (70.6%). The likelihood of
-lactam allergy was significantly higher for anaphylaxis (42.9% vs
8.3% in other reactions) and immediate reactions (25% vs 10% in
accelerated and delayed reactions).Of the children diagnosed as allergic to -lactam by means of skin
tests, OC, and clinical history, 11.7% were sensitized to several
classes of -lactams. The risk was significantly higher in children
with anaphylaxis (26.7% vs 7.5% of the children with other reactions)
and in children reporting immediate reactions (33.3% vs 8.5% of the
children with accelerated and delayed reactions). Finally, age, sex, personal history of atopy, number of reactions to
-lactams, and number of reactions to other drugs were not
significant risk factors for -lactam allergy.
Conclusion. The skin tests were safe, and the immediate
reaction to skin tests successfully diagnosed allergy to -lactam
antibiotics in children reporting reactions suggestive of immediate HS.
In contrast, most accelerated and delayed reactions were diagnosed by
OC. Thus, our results suggest that the diagnostic and predictive values
of skin tests for nonimmediate HS to -lactams in children are low.
They also strongly suggest that most reactions reported in children are
attributable to infectious diseases or interactions between drugs and
infectious agents rather than to -lactam HS. -lactams, allergy, skin tests, oral challenge, child.
Between 1% and 10% of patients treated with Delayed responses to individual Other tests, such as radioallergosorbent test, have low specificity and
sensitivity.11,13,2227-31 Moreover, it has been shown
that >50% of patients with positive radioallergosorbent test results
have negative test results after 1 year.32-34
We studied immediate, accelerated, and delayed responses to skin tests
with soluble Patients
This study included 325 children (169 boys and 156 girls), 8 months to 17.8 years of age (mean: 5.25 years). Of the children, 146 (44.9%) had a personal history of atopy. The mean time between the
most recent reaction and the tests was 18.5 months (1 month to 15 years). Patients took no antihistamines or oral corticosteroids for 2 to 4 weeks before skin tests and OC.
Reactions to TABLE 1-lactam
antibiotics report reactions suggestive of allergy to these
drugs.1-4 Immediate responses to prick tests and
intradermal (ID) tests with benzyl-penicilloyl polylysine (PPL) and
minor determinant mixture (MDM) have good diagnostic and predictive
values in patients with reactions suggestive of immediate
hypersensitivity (HS) to penicillins.25-7 However, skin
tests with PPL and MDM may fail to detect specific sensitization to individual -lactams.8-12 In contrast, skin tests
using soluble -lactams diagnose a significant number of
immediate sensitizations to penicillins and
-lactams.512-18
-lactams in skin tests (ID and patch
tests) have been reported in adult patients and children with delayed
reactions to -lactam antibiotics, such as urticaria and
angioedema, maculopapular rash (MPR), and unidentified
rashes.19-26 Accelerated responses in skin tests with
-lactams have never been studied in patients with suspected
-lactam allergy.
-lactams and oral challenge (OC) in children reporting
reactions suggestive of allergy to -lactam antibiotics. Our goals
were to confirm or rule out allergy to -lactams and to determine
whether the children were sensitized to one or several classes of these
drugs. We also evaluated the frequency and diagnostic value of
accelerated and delayed responses to skin tests with -lactam
antibiotics in children.
METHODS
Top
Abstract
Methods
Results
Discussion
Conclusion
References
-lactams were classified as described by
Levine.35 A total of 469 reactions were reported, with 117 children (36%) reporting 
2 reactions to treatment with a particular -latam (n = 10; 3.1%) or several -lactams
(n = 107; 32.9%). Amoxicillin alone or associated with
clavulanic acid was most frequently reported to cause adverse reactions
(60%), followed by first generation cephalosporins (cephadroxil,
cefaclor, cephatrizine, and cephalexine: 29.6%). Other suspected
-lactams were cefixime, cefpodoxime, penicillins V and M,
cefuroxime, and ampicillin. Children reporting several reactions were
classified based on the most severe and/or most rapid reaction (Table
1). Of the children, 75 (23.1%) had
tolerated treatment with other classes of -lactams since his or her
most recent reaction.
Clinical Data for Children With Suspected -Lactam Allergy According
to Nature, Severity, and Time of Onset of Adverse Reactions*
Of the children, 138 (42.5%) also reported one or several reactions (primarily urticaria, angioedema, and unidentified rashes) to other drugs. Macrolides and sulfonamides were the primary drugs involved.
Skin Tests
Skin tests were performed with the soluble form of the suspected
(or very similar) -lactams and one or several -lactams from other
classes, at various concentrations (250-25 000 IU/mL for
benzylpenicillin and 0.25-25 mg/mL for other -lactams), as described by Vervloet and Pradal.36 The stock solution was
prepared by reconstituting the freeze-dried -lactam with 0.9% NaCl.
Solutions of the required concentrations were obtained by serial
dilutions of the stock solution with 0.9% NaCl. For children reporting
reactions to a combination of amoxicillin and clavulanic acid, skin
tests were performed with amoxicillin only.
Increasing concentrations of the reagents were tested initially by the
prick method. If prick test results were negative, 0.02 mL of the
solutions were serially injected intradermally. A weal 3 mm (prick)
or 5 mm (ID) in diameter, present 15 to 20 minutes after the
application, was defined as an immediate positive response if
there was also a negative response to control solution (0.9%
saline) and a positive response to histamine (prick: 1 mg/mL; ID: 0.1 mg/mL). Accelerated and delayed responses to ID injections were
recorded after 8 hours (accelerated) and 48 to 72 hours (delayed) and
were classified as positive if weals 5 mm in diameter were present.
The soluble -lactams used were benzylpenicillin (Penicillin G;
Panpharma Laboratories, Fougeres, France), oxacillin (Bristopen; Bristol-Myers Squibb, New York, NY), amoxicillin (Clamoxyl;
Beecham, Philadelphia, PA), ampicillin (Totapen; Bristol-Myers
Squibb), ticarcillin (Ticarpen; Beecham), cephaloridin (Ceporine; Glaxo Wellcome, Greenford, UK), cephalotin (Keflin; Lilly,
Indianapolis, IN), cefazolin (Cefazolin; Panpharma, Fougènes,
France), cephamandole (Kefandol; Lilly), cefotaxime (Claforan;
Roussel, Frankfurt, Germany), ceftazidime (Fortum, Glaxo Wellcome), and
ceftriaxone (Rocephine; Roche, Burlington, NC).
OCs
OCs with the suspected -lactams were performed for children
with negative skin test results, except those reporting serum sickness-like reaction (SSLR) and potentially harmful toxidermias. Thus, 271 children underwent OC with the suspected -lactams, either
at the hospital for 24 to 48 hours (immediate and accelerated reactions; n = 96) or at home (delayed reactions;
n = 175). In the hospital, children received a first
dose of 0.5 mg of the drug. The dose was increased gradually until the
appropriate cumulative dose per day for age and weight was reached. At
home, daily therapeutic doses were prescribed for 5 to 7 days. Children
were advised to stop treatment and to take oral antihistamines and/or
corticosteroids if they experienced a reaction.
OCs also were performed with a -lactam from a class other than the
class suspected of causing the reaction in 39 children with positive
skin test results or OC for the suspected -lactams and negative test
results with -lactams from other classes and in children with SSLR
and potentially harmful toxidermias.
OCs were classified as positive if an adverse reaction of an allergic nature (eg, urticaria and/or angioedema, MPR, erythema multiforme [EM]) occurred during the treatment or within 24 to 48 hours of the end of the treatment.
Statistical Analysis
Differences were assessed by the 
2 test. A
P value < .05 was considered to be significant.
| |
RESULTS |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Skin Tests
Immediate assessments of prick tests were always negative, and
most immediate responses were recorded intradermally at concentrations of 2500 IU/mL for benzylpenicillin and of 2.5 mg/mL for the other -lactams. Accelerated and delayed responses with aminopenicillins and cephalosporins were observed intradermally at concentrations of 25 mg/mL. In 2 children with accelerated and delayed responses to ID
injections, prick tests (25 mg/mL) became positive at the 8th and the
48th to 72nd hours, respectively.
Skin test results were positive with one class or several classes of
-lactams in 22 children (6.8%), either immediately (19 cases:
5.9%) or at accelerated and delayed assessments (3 cases: 0.9%). Two
other children had negative skin test results, but reported the
development of an accelerated benign urticaria, probably attributable
to inadvertent subcutaneous injection of the reagent. These 2 children
were diagnosed as allergic to the suspected -lactams. Skin test
results were negative in all the children reporting MPR, SSLR, and
potentially harmful toxidermia. Thus, 24 children (7.4%) were
diagnosed as allergic to one -lactam or several -lactams by means
of skin tests (Table 2). There was no
significant difference between the children tested within 1 year of
their most recent reaction (16/178: 9%) and those tested later (8/147: 5.5%).
|
Oral Challenge
OC test results with the suspected -lactams were positive for
17 of 271 children (6.3%; Table 3; cases
25-41). Immediate or accelerated reactions were recorded in 7 hospitalized children. Delayed reactions were detected by a physician
in 10 children with OC performed at home. All the reactions were mild
and easily controlled with antihistamines and/or corticosteroids. The
frequency of positive OC was not significantly different between the
children tested within 1 year of their most recent reaction and the
children tested later.
|
OC test results with -lactams other than those suspected were
negative, except in 1 child with a severe SSLR to amoxicillin, associated with clavulanic acid, reporting delayed urticaria in response to OC with cefixime (case 42).
In 3 children, OC test results were positive for amoxicillin
associated with clavulanic acid, but negative with amoxicillin alone,
suggesting an allergy to clavulanic acid (cases 27, 31, and 40). Three
other children with positive OC test results for pediatric
suspensions of -lactams tolerated OC with tablets or capsules
of the same -lactams (cases 34, 35, and 41). These children are
probably intolerant to the excipients present in the pediatric suspension, because they also reported reactions to unrelated drugs
containing the same excipients. Thus, OC allowed the diagnosis of
-lactam allergy in 15 children (4.6%).
Clinical History
Based on clinical history, SSLR was diagnosed in 16 children; 6 reacted to amoxicillin only, 8 to cephalosporins only, and 2 to
amoxicillin and cephalosporins (including case 42). A total of 14 other
children were diagnosed as having severe EM, Stevens-Johnson syndrome
(SJS), generalized exanthematous pustulosis (GEP), or erythroderma associated with treatments with amoxicillin only (5 children), amoxicillin associated with clavulanic acid (6 children), or
other -lactams (3 children).
Final Diagnosis
Based on skin tests, OC, and clinical history, 68 (20.9%)
children (31 boys and 37 girls), from 4 months to 16 years of age (mean: 5.5 years), were diagnosed as allergic to one -lactam or
several -lactam antibiotics (Table 4).
A total of 57 (83.8%) reacted to penicillins or cephalosporins only, 3 (4.4%) to clavulanic acid, and 8 (11.8%) to both penicillins and
cephalosporins (Table 5). In 11 other
children, we diagnosed intolerance to excipients (3 cases) (Table 3),
food allergy (5 cases), and aspirin intolerance (3 cases; Table
6). The cause of the original reaction
was not identified for the other children.
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Potential Risk Factors for HS to -lactam Antibiotics
Based on skin tests and OC, HS to -lactams was diagnosed in 39 children (21 boys and 18 girls; mean age: 6.8 years). There was no
significant difference in the age and sex of children with positive and
negative skin and OC test results. Skin and OC test results were
positive in 18 of 146 (12.3%) children with a personal history of
atopy and in 21 of 179 (11.7%) children with no personal history of
atopy (P = not significant). Responses to skin
tests and OC were also similar for children reporting one reaction only and those reporting several reactions to -lactams, and there was no
significant difference between the children reporting reactions to
other drugs and those reporting reactions to -lactams only.
Based on the type of clinical reaction in children with positive skin
or OC test results, skin tests led to the diagnosis of HS to one or
several -lactams in 12 of 15 (80%) children reporting anaphylaxis
(cases 1-12), in 10 of 16 (62.5%) children with urticaria and
angioedema (cases 13-22), and in 2 of 7 (28.6%) children reporting unidentified rashes (cases 23-24). OC led to the diagnosis of HS to
-lactams in 3 (20%; cases 25-27), 6 (37.5%; cases 28-33), and 5 (71.4%; cases 36-40) of the allergic children reporting anaphylaxis,
urticaria and angioedema, and unidentified rashes, respectively. The OC
test result was also positive with a cephalosporin (cefixime) in 1 child reporting a severe SSLR to amoxicillin associated with clavulanic
acid (case 42). The differences between children reporting anaphylaxis,
urticaria, and angioedema, and those reporting other reactions were
highly significant (P < .001).
Positive immediate responses to skin tests were recorded in 11 of 35 (31.4%) children reporting anaphylaxis (cases 1-11), 6 of 175 (3.4%)
children with mild to moderate urticaria or angioedema (cases 13-17
and 22), and 2 of 75 (2.7%) children reporting unidentified rashes
(cases 23-24). OC led to the diagnosis of immediate HS in 3 (8.6%) of
the children with anaphylactic reactions (cases 25-27). Thus, based on
skin and OC tests, immediate HS to -lactam antibiotics was diagnosed
in 22 (56.4%) allergic children, including 14 of 15 (93.3%), 6 of 16 (37.5%), and 2 of 7 (28.6%) children with anaphylaxis, urticaria and
angioedema, and other reactions, respectively. The differences between
children reporting anaphylaxis and those reporting other reactions were
significant (P 
.01).
Accelerated and delayed responses to skin tests were recorded in 1 (2.8%) of the children with anaphylaxis (case 12) and in 4 (2.2%) of
the children with mild to moderate urticaria and angioedema (cases
18-21). OC led to the diagnosis of semi-late and delayed HS in 6 (3.4%) of the children with mild to moderate urticaria and angioedema
(cases 28-33) and 6 (6.6%) of the children with SSLR and unidentified
rashes (cases 36-40 and 42). Thus, based on skin and OC tests,
semi-late and delayed HS to -lactams was detected in 17 (43.6%)
children allergic to -lactams, including 1 (6.7%), 10 (62.2%), and
6 (75%) of the children reporting anaphylaxis, urticaria and
angioedema, and other reactions, respectively. The differences between
children reporting anaphylaxis and those reporting other reactions were
highly significant (P < .001).
Of the 15 (26.7%) allergic children reporting anaphylaxis, 4 were sensitized to both penicillins and cephalosporins, versus 4 of the 53 (7.5%) allergic children who reported other reactions (P < .001) (Table 5).
Based on the chronology of the clinical reactions in children with
positive skin or OC test results, skin tests led to the diagnosis of HS
to one or several -lactams in 8 of 9 (88.9%) children reporting
immediate reactions (cases 1-8), in 8 of 17 (47%) children with
accelerated reactions (cases 13-20), and in 8 of 12 (66.7%) children
with delayed reactions (cases 9-12 and 21-24). OC test results were
positive in 1 (11.1%; case 25), 9 (52.9%; cases 26-28, 31, 32, 36, 38-40) and 4 (33.3%; cases 29, 30, 33, 37) of the allergic children
reporting immediate, accelerated, and delayed reactions, respectively.
The differences between children reporting immediate reactions and
those reporting accelerated and delayed reactions were highly
significant (P < .001).
Positive immediate responses to skin tests were recorded in 8 of 36 (22.2%; cases 1-8), 5 of 128 (3.9%; cases 13-17), and 6 of 161 (3.7%; cases 9-11 and 22-24) children reporting immediate, accelerated, and delayed reactions, respectively. OC led to the diagnosis of immediate HS in 1 (2.8%) of the children with immediate reactions (case 25) and in 2 (1.6%) of the children reporting accelerated reactions (cases 26-27). Thus, based on skin and OC test
results, immediate HS to -lactams was diagnosed in 9 of 9 (100%), 7 of 17 (41.2%), and 6 of 13 (46.1%) allergic children with immediate,
accelerated, and delayed reactions, respectively. The differences
between children who reported immediate reactions and those who
reported accelerated and delayed reactions were significant
(P .01).
Accelerated and delayed responses in skin tests were recorded in 3 (2.4%; cases 18-20) and 2 (1.2%; cases 12 and 21) of the children
reporting accelerated and delayed reactions, respectively. OC led to
the diagnosis of semi-late and delayed HS in 7 (5.5%) of the children
with accelerated reactions (cases 28, 31, 32, 36, and 38-40) and 5 (3.1%) of the children with delayed reactions (cases 29, 30, 33, 37, and 42). Thus, based on skin and OC test results, semi-late and delayed
HS to -lactams was detected in 0, 10 (58.8%), and 7 (53.8%)
allergic children with immediate, accelerated, and delayed reactions,
respectively. The difference between the children reporting immediate
reactions and those reporting accelerated and delayed reactions was
highly significant (P < .001).
Of the 9 allergic children reporting immediate reactions, 3 (33.3%) were sensitized to both penicillins and cephalosporins, versus 5 of the 59 (8.5%) allergic children who reported other reactions (P < .001).
| |
DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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In this article, we report the largest series of children with
suspected -lactam allergy. Our results are similar to those of
Mendelson et al37 but conflict with those of Pichichero et
al,17 who reported positive skin or OC test results in
23.5% of children. These differences in results probably stem from
differences in the selection of children.
-lactam allergy may not have been diagnosed in some children in our
study. Previous results show that 9% of children with negative skin
and OC test results relapse during subsequent treatment with the
suspected -lactams.17,27,37 The allergic immune
response in some patients with negative skin test results is also
boosted by OC or inadvertent contact with -lactams.17,38 However, preliminary results from an
ongoing prospective unpublished study have shown that only a few
children with negative skin and OC test results relapse during
subsequent treatment with the suspected -lactams.
Skin Tests
Skin tests were performed with soluble -lactams at
concentrations 25 000 IU/mL for benzylpenicillin and 25 mg/mL for
other -lactams. Some reports have suggested that -lactams at
concentrations >1 mg/mL are irritant.39 However, most
children in our study had negative skin test results, including those
with positive OC test results. Thus, concentrations of 2.5 mg/mL and 25 mg/mL gave no false-positive responses in the skin tests.
Only 0.6% of the children in our study reported mild accelerated
urticaria induced by skin tests, consistent with previous studies
showing that skin tests with penicillin derivatives and soluble
-lactams are well tolerated.27,28 However, anaphylactic
reactions have been reported in some adult patients7 but
not in children.
Immediate responses to skin tests were recorded in 5.9% of children,
consistent with previous studies showing a positive immediate response
in skin tests with penicillin derivatives and soluble -lactams in
3% to 40% of patients.6,8,17,23,27,28,40,41 The
frequency of positive immediate responses in skin tests was significantly higher in children reporting severe anaphylaxis and
immediate reactions than in children reporting other reactions, consistent with the results of previous studies performed with adults7,8,13,42 and children.27,28
Delayed responses in skin tests have been reported in 0.6% to 17% of
patients with suspected -lactam allergy, especially in patients with
MPR and accelerated or delayed urticaria or angioedema during treatment
with ampicillin or amoxicillin.1921-26 In these
patients, immunohistological skin test studies showed a typical
delayed-type hypersensitivity (DTH) reaction.43-45 We
found positive accelerated and delayed responses in skin tests in 0.9%
of children, consistent with previous works suggesting that DTH
reactions to -lactams are rare.21
Discordance Between Skin and OC Tests
OC allowed the diagnosis of -lactam allergy in 4.6% of the
children in our study. Our results are consistent with previous studies
showing that 17% of patients with negative skin test results have
positive OC test results.17,27,28,41 There may be several
reasons for differences in skin and OC test results.
First, we did not perform skin tests with PPL and MDM. Previous studies
have shown that most patients who have positive skin test results with
PPL and/or MDM also have immediate responses in skin tests with soluble
penicillins and that a few allergic patients have immediate responses
to PPL and/or MDM only,11,13 especially
children.17,23 Only 2 children with negative skin test
results and immediate responses in OC with amoxicillin (cases 25 and
26) could have been diagnosed as having immediate HS to penicillins by
skin tests with PPL and MDM. Our results are very similar to those of
Pichichero and Pichichero,17 who diagnosed immediate HS to
-lactams based on OC in 8.6% of allergic children skin-tested
with PPL, MDM, and soluble -lactams.
Second, patch tests were not performed, because most patients with
positive patch tests also have delayed responses in ID tests, and ID
tests identify DTH to -lactams in more patients than do patch
tests.22,24 Thus, very few of the children with negative
skin test results and positive OC test results could have been
diagnosed as allergic by patch tests.
Third, the interval between the most recent reaction and skin testing may be long. In most studies, the frequency of positive immediate responses in skin tests decreases as this interval increases with a negativation rate of 10% to 15% per year.2146-48 However, we found that the frequency of positive skin test results was similar for children tested within 1 year of their most recent reaction and children tested later, consistent with previous studies in children, showing no significant time-dependent decrease in the frequency of positive skin test results.17,37
Fourth, negative skin test results with positive OC test results may
result from antigenic differences in the reagents used for skin tests
and the drugs responsible for the reaction. This may account for
negative skin test results in patients reacting to oral -lactams
with no corresponding soluble form, such as cefaclor, cefatrizine, and
cefixime, as reported herein for some children. This notion is
supported by recent results showing in vitro reactivity with cefaclor
in children with severe allergy to this -lactam, but negative in
vitro and OC test results with a very closely related
-lactam.49
Fifth, accelerated and delayed reactions may be attributable to an
allergy to metabolites of -lactams rather than to the native drugs
themselves, as shown with SSLR to cefaclor and sulfonamide-induced or
anticonvulsive drug-induced toxidermias.50-52 This may
explain why most children with negative skin test results and positive
OC test results reported accelerated or delayed urticaria, angioedema,
and unidentified rashes in response to treatment with -lactams.
Sixth, negative skin test results with positive OC test results also
may result from allergy or intolerance to substances not used in skin
tests such as clavulanic acid and excipients. In 3 children, allergy to
clavulanic acid was suggested strongly by positive OC test results with
amoxicillin associated with clavulanic acid and negative OC test
results with amoxicillin alone. In 3 other children, we diagnosed
intolerance to excipients, although the parents did not agree to
double-blind, placebo-controlled OC. These children reacted with
pediatric suspensions of the suspected -lactams but tolerated OC
with tablets or capsules of the same -lactams. They also reported
reactions to other drugs containing the same excipients and tolerated
these drugs if the suspected excipients were absent. Previous reports
have shown that few patients have immediate53 or delayed
HS20 to clavulanic acid and that some patients who report
reactions to -lactams are actually intolerant to excipients rather
than to -lactams.27,28
Etiology in Children With Negative Test Results
Skin and OC test results were negative in most children in this
study, suggesting that most of the reactions reported were not
attributable to immediate, semi-late, and tuberculin-type DTH to
-lactam antibiotics.
SSLR and potentially harmful types of toxidermia may result from
lymphocyte-mediated cytotoxicity rather than from tuberculin-type DTH.5054-57 Lymphocyte-mediated cytotoxicity cannot be
assessed by ID or patch tests. Thus, our results are consistent with
those reporting negative responses in ID and patch tests in children
with bullous or pustular eruptions caused by
-lactams.22,58 We did not perform OC with the suspected
-lactams in children reporting SSLR and potentially harmful types of
toxidermia to avoid triggering a severe reaction. All the children
reporting severe SSLR, EM, SJS, GEP, or erythroderma were considered to
be allergic to the suspected -lactams. However, negative skin and OC
test results with -lactams have been reported for 10 children with
mild to moderately severe SSLR and EM.17 Thus, a
significant number of cases of SSLR and potentially harmful types of
toxidermia in our study may result from infectious diseases rather than
from allergy to -lactam antibiotics (see below).
Most of the reactions reported probably were caused by infectious diseases. Acute urticaria and angioedema are caused primarily by infections (especially benign viral illnesses) independent of treatment.59 Various infectious agents, such as mycoplasmas and viruses, cause urticaria morbilliform and unidentified rashes in children,60 and MPR, SJS, and toxic epidermal necrolysis may result from the destruction of infected epidermal cells by cytotoxic T lymphocytes.61 Skin reactions also may result from interactions between infectious agents and antibiotics, as described in Epstein-Barr virus, influenza virus, and human immunodeficiency virus infections.62,63 Subjects generally tolerate subsequent exposure to the drugs concerned,64 consistent with our observations that OC test results were seldom positive in children with negative skin test results.
Potential Risk Factors for -lactam Allergy
The frequency of positive skin and OC tests was significantly
higher in children reporting anaphylaxis and immediate reactions, consistent with previous reports showing that severe immediate and
accelerated reactions are often attributable to immunoglobulin E-dependent HS to -lactams.7
A total of 20.5% of children with positive responses in skin tests or
OC were sensitized to several -lactams from various classes. This
crossreactivity between the various classes of -lactam antibiotics
was first suspected from clinical histories and skin tests10,4665-67 and then confirmed by immunologic
studies performed in vitro.66,68 The frequency of positive
skin or OC test results to penicillins and cephalosporins was
significantly higher in children with -lactam-induced anaphylaxis
than in allergic children reporting other reactions, suggesting that
anaphylaxis is a major risk factor for sensitization to crossreactive
allergenic determinants of -lactam antibiotics.
Atopy may be a risk factor for -lactam allergy (particularly for
anaphylaxis) in adults5,69,70 and children.28
However, responses to skin and OC tests were similar for children with
and without a personal history of atopy in our study, as previously
reported in adults1,70,71 and children.17,27
Our results are also consistent with previous reports showing that age
and sex are not significant risk factors for allergy to -lactams in
children.17,27
The frequency of positive skin and OC test results was slightly higher
in children with several reactions to -lactam antibiotics than in
those children with only one reaction, but this difference was not
significant. Therefore, the number of reactions associated with
-lactam treatments is probably not a risk factor for -lactam allergy, consistent with the results of Pichichero and
Pichichero,17 who found no difference in the frequency of
previous -lactam treatments in skin test-positive versus skin
test-negative children.
Nearly half the children reported reactions to other drugs, a higher
proportion than in other studies.72-74 Of the children, 3 were probably intolerant to excipients, and 5 were allergic to foods.
Our results agree with those of previous studies suggesting that
recurrent reactions to several drugs may be attributable to
intolerance to excipients, coincident allergy, or pseudo-allergy to
foods.27 Finally, the frequency of positive skin and OC
test results with -lactams was similar for children reporting
reactions to unrelated drugs and children reacting to -lactams only.
This is consistent with previous results suggesting that penicillin
allergy and non--lactam allergy develop independently.73
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CONCLUSION |
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We have shown that only a few of the children reporting reactions
suggestive of allergy to -lactams were really allergic to these
antibiotics. We also showed that skin tests with -lactam antibiotics
are safe and have a high diagnostic value in children who report
reactions suggestive of immediate HS, especially those with
anaphylactic reactions. Anaphylaxis was a major risk factor for
sensitization to crossreactive antigenic determinants of various classes of -lactams. Accelerated and delayed responses in skin tests
were seldom positive, and most children with nonimmediate HS to
-lactams were diagnosed using OC tests. Finally, most of the
reactions reported by children were probably attributable to infectious
diseases or to interactions between drugs and infectious agents rather
than to HS to -lactams.
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ACKNOWLEDGMENTS |
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This work was supported by a grant from the Association Immuno-Allergologie Infantile (the Sick Children Hospital, Paris, France), and by a prize from the Société Française d'Allergologie et d'Immunologie Clinique.
We thank Julie Knight for her help in writing this article.
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FOOTNOTES |
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Received for publication Sep 14, 1998; accepted Mar 9, 1999.
Reprint requests to (C.P.) Service de Pneumologie & Allergologie Pédiatriques, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015, Paris, France. E-mail: pneumo.allergo{at}nck.ap-hop-pari.fr
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ABBREVIATIONS |
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ID, intradermal; PPL, benzyl-penicilloyl polylysine; MDM, minor determinant mixture; HS, hypersensitivity; MPR, maculopapular rash; OC, oral challenge; SSLR, serum sickness-like reaction; EM, erythema multiforme; SJS, Stevens-Johnson syndrome; GEP, generalized exanthematous pustulosis; DTH, delayed-type hypersensitivity.
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