ORIGINAL ARTICLES
A study of allergy to penicillin antibiotics in 1995 in the Child Allergy Department of the Gregorio Marañón University Hospital
M. A. Mínguez, L. Zapatero, M. Caloto and M. I. Martínez-Molero
Child Allergy Department of Gregorio Marañón University Hospital. Madrid. España.
SUMMARY
We present 219 cases of adverse reactions to penicillin and related antibiotics during 1995 in the Child Allergy Department of Gregorio Marañón University Hospital. Amoxicillin was the most frequent cause of the reaction. The most common clinical symptom was urticaria followed by angio-edema and other characteristic exanthemas. A diagnosis of allergy to penicillin and related drugs was only made in 20 cases in which the predominant symptomatology was urticaria and the antibiotic most commonly involved was again amoxicillin. Diagnosis was confirmed by a skin test, specific IgE determination and controlled provocation. In 3 of the 20 cases diagnosis was made in the reassessment or second study, which was carried out in all cases in which more than one year had passed between the reaction and the initial allergological study.
Key words: Hypersensitivity. Penicillin and related antibiotics. Urticaria. Prick-test. Intradermic reaction. Controlled provocation.
Allergol et Immunopathol 1998;26:43-6.
INTRODUCTION
The group of antibiotics most used in our country are penicillin-related drugs due to their high efficacy and their low toxicity. This group includes the natural penicillins, semisynthetic penicillins and cephalosporins (table I).
| Table I |
| Penicillin and related antibiotics |
| 1. Natural Penicillins: Penicillin G. Penicillin V. |
| 2. Semisynthetic penicillins: |
| Ampicillin |
| Amoxicillin |
| Cloxacillin |
| Methycillin |
| Methampicillin |
| Carbenicillin |
| Pivampicillin |
| 3. Cephalosporins: |
| First generation: |
| Cephalexin |
| Cephradine |
| Cefadroxil |
| Cefaclor |
| Cephaloridine |
| Cephapirine |
| Cephazolin |
| Cephacetryl |
| Cephalothin |
| Second generation: |
| Cefoxitin |
| Cephamandole |
| Cefuroxim |
| Third generation: |
| Cefotaxim |
| Moxalactam |
Side effects from penicillin are unusual in children and of these 6-10% are mediated by the immune system and most are type I (1) according to Gell and Coombs classification although type II, III and IV reactions have also been described (2, 3).
A diagnosis of allergy to penicillin and related drugs is based on clinical background, studies on live subjects (skin tests and controlled provocation) and in vitro studies (determination of specific IgE and other techniques such as histamine release (4-6).
We present a review of adverse reactins to penicillin and related drugs in patients attending our clinic during 1995 previously diagnosed as possibly penicillin-sensitized.
MATERIAL AND METHODS
Patients
A total of 219 children with a clinical background suggestive of penicillin allergy of which 11 had been diagnosed in outpatient centres as being sensitized to these drugs. In four cases the mothers of the children could not remember which antibiotic the children were allergic to and these children were included in our protocol under the heading "unknown antibiotic" which includes the study of penicillin-related drugs.
Methods
The following were performed in all patients:
A. Initial examination
1. Detailed record of clinical background.
2. Determination of specific IgE by the CAP technique (Pharmacia).
3. Skin prick test and intradermic reaction with:
* PENICILLIN G (Unicilina® 10,000 U/ml).
* PPL (Prepen®) (Conjugated penicilloyl poly-lysine) at a concentration of 6 x 10 (-5) M.
* AMOXICILLIN at a concentration of 20 mg/ml with dilution of the parenteral solution of Clamoxyl® 500 mg with physiological saline.
* AMPICILLIN at a concentration of 20 mg/ml dilution of the parenteral solution of Britapen® with physiological saline.
* AMOXICILLIN-CLAVULANIC ACID at a concentration of 20 mg/ml diluting the parenteral solution of Augmentine® with physiological saline.
Saline solution was used as a negative control and histamine hydrochloride at 10 mg/ml and 0.1 mg/ml as positive controls for the skin prick test and intradermic reaction respectively. The amount injected for the IDR was 0.02 ml. The skin prick test was considered to give a positive result when the papule diameter was 3 mm larger than the negative control (7). The intradermic reaction was considered as positive when the papule diameter exceeded 10 mm with a clear pseudopodic deformation and erythema (8).
4. Oral and/or intramuscular provocation were performed (depending on the drugs involved and the mode of administration) starting with 1/8 of the therapeutic dose and increasing the dose until reaching the total dose according to the weight.
5. Sking tests or patch test were performed in patients with a background suggestive of hypersensitive reactions of late onset.
B. Diagnostic reassessment
A diagnostic reassessment was mode in both the skint tests and provocation 15 days after the first study if one year or more had passed since thes last reaction had taken place. The specific IgE determination was not repeated since this is more costly and less sensitive and specific than the other two tests (9).
RESULTS
Most of the 219 children studied presented a reaction with natural or semisynthetic penicillin followed in prevalence by a reaction to cephalosporins (table II).
| Table II | |
| Antibiotics involved in the reactions | |
| Amoxicillin | 89 |
| Clavulanic-amoxicillin | 48 |
| Penicillin G | 26 |
| Cefaclor | 20 |
| Other cephalosporins | 17 |
| Outpatients centres | 11 |
| Unknown antibiotic | 4 |
| Ampicillin | 3 |
| Cloxacillin | 1 |
| Total | 219 |
A diagnosis of penicillin allergy was made in 20 patients corresponding to 9.5% of the patients studied (table III).
| Table III | |
| Drugs involved in the cases of confirmed allergy to penicillin-related antibiotics | |
| Amoxicillin | 8 |
| Cefaclor | 4 |
| Penicillin G | 3 |
| Ampicillin | 2 |
| Clavulanic-amoxicillin | 1 |
| Benzylpenicillin G | 1 |
| Cefuroxim | 1 |
| Total | 20 |
The most frequent symptomatology presenting in most of the positive cases is recorded in table IV although the most common symptom by far was urticaria (table IV).
| Table IV | |
| Clinical symptomatology recorded in positive cases | |
| Urticaria | 10 |
| Micropapular exanthemas | 1 |
| Angioedema | 4 |
| Respiratory difficulty | 2 |
| Multiform exudative exanthema1 | 2 |
| Purpuric exanthema | 1 |
| Anaphylaxis2 | 3 |
| Total3 | 23 |
| 1. Both of them with cefaclor. | |
| 2. Two with amoxicilin and another one with clavulanic-amoxicillin. | |
| 3. Anafilaxis cases had some of the referred sinthoms. | |
A diagnosis was confirmed by the skin prick test in 11 of the 20 cases, in 1 case by specific IgE and in 2 cases by provocation/tolerance. In the remaining 6 cases in spite of negative in vivo and in vitro studies provocation and tolerance test were not performed because these patients had presented critical reactions probably due to these drugs (anaphylaxis on two occasions in one patient after ingestion of antibiotic, one extensive purpuric exanthema, two cases of multiform exudative erythema, a severe urticaria reaction with angio-edema and one case of positive autoprovocation by the patient after a first episode highly suggestive of allergic reaction).
Three of the 20 patients, i.e. 1.3% of the total studied and 15% of those with a positive diagnosis of penicillin allergy, were diagnosed in the reassessment. The diagnosis was made in two of these using the oral provocation test (the first presented symptoms of urticaria, 30 min after administration of 62.5 mg of amoxicillin and the second patient symptoms of urticaria, labial angio-edema and respiratory difficulty 45 min after administration of 62.5 mg of clavulanic-amoxicillin); the third was diagnosed by the skin prick test and presented and intradermic reaction 2 mm larger than that obtained in the control with histamine (table V).
| Table V |
| Results of the diagnostic reassessment |
| Patient 1: positive IDR with amoxicillin. |
| Patient 2: positive oral prov. with clavulanic-amoxicillin* |
| Patient 3: oral prov. with positive amoxicillin** |
| * With a dose of 62.5 mg. |
| ** With a dose of 62.5 mg. |
None of the cases referred from the outpatients centre or those included in the unknown antibiotic protocol were positive for penicillin allergy in the initial study or reassessment.
The skint tests or patch tests performed on patients with reactions not suggestive of immediate reaction (one case of micropapular exanthema, one case of purpuric exanthema and two cases of multiform exudative exanthema) all gave negative results.
The diagnosis of anaphylaxis in three cases was made as follows: the first on the basis of a positive skin prick test with amoxicillin, the second patient had a history of two anaphylactic episodes each following ingestion of amoxicillin (this was one of the patients diagnosed as being allergic to penicillin without conducting either in vitro or in vivo studies), the third was diagnosed in the reassessment as presenting symptoms of urticaria, labial angio-edema and respiratory difficulty 45 min after administration of 62.5 mg of clavulanic-amoxicillin.
DISCUSSION
Penicillin and penicillin-related drugs are the most commonly used in the treatment of infections, especially in the case of infections in children.
In our study the most used antibiotic, amoxicillin, was the most common cause of hypersensitivity, followed by Cefaclor. This could simply reflect the tendency to use an increasing amount of semisynthetic penicillins and cephalosporins instead of the natural penicillins.
The most common symptomatology of the patients attending our clinic was urticaria, followed by angio-edema and other kinds of exanthema. These clinical pictures also coincied in frequency with those presented by patients with a positive diagnosis, as found in other studies (8).
Of all the reassessments carried out (82 of 219), a positive diagnosis was only made in 3 cases. Although this initially seems to be rather a small proportion it should, however, be taken ver seriously if we consider the danger that can ensue from not correctly diagnosing a person with penicillin allergy.
Therefore, in our experience, also corroborated by other authors (8), the allergological study should be repeated when more than one year has passed between the reaction which motivated the initial study and the allergological study. The fact that skin tests give negative results after a certain time period and that the second carried out in the second phase gives a positive result could result from the same phenomenon such as the natural reduction in specific IgE antibodies probably due to a lack of contact with the antigen responsible (10, 11). In accordance with other authors (8) this could also be explained by the fact that the patients could be made sensitive with the provocation regime.
RESUMEN
Presentamos 219 casos de reacciones adversas a la penicilina y antibióticos relacionados con ella durante 1995 en el Departamento de Alergia Infantil del Hospital Universitario Gregorio Marañón. La causa más frecuente de tal reacción fue la amoxicilina. El síntoma clínico más común fue la urticaria, seguida del angioedema, así como otros exantemas característicos. Se realizó un diagnóstico de alergia a la penicilina y medicamentos relacionados con ella en 20 casos en los que la sintomatología predominante fue la urticaria y el antibiótico más comúnmente implicado fue de nuevo la amoxicilina. El diagnóstico se confirmó mediante pruebas epidérmicas, determinación específica de IgE y provocación controlada. Entre tres de 20 casos se realizó el diagnóstico en la re-evaluación o un segundo estudio, que se llevó a cabo en todos los casos en los que había transcurrido más de un año entre la reacción y el estudio alergológico inicial.
Palabras clave: Hipersensibilidad. Penicilina y antibióticos. Urticaria. Prick-test. Reacción intratérmica. Provocación controlada.
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| Correspondence address: Dra. M. I. Martínez Molero Sección de Alergia Infantil Hospital General Universitario Gregorio Marañón C/. Dr. Castelo, 49 28007 Madrid |
