I have a 50 year old male with a convincing history of an urticarial reaction to Zithromax: he reacted within 36 hours of his first dose (but has had the medication before) with generalized urticaria but nothing else. Is there a protocol for skin testing with zithromax? Or should I just tell him to stay away from this class of antibiotics?


Thank you for your inquiry.

There are published protocols for skin testing to azithromycin (see abstracts copied below and References 1 through 3). However, the validity of the skin test has been challenged, and therefore my perception after reviewing these articles is that to be sure that a negative skin test ruled out the possibility of a reaction, you would have to do an oral provocation test.

Thus, unless this particular antibiotic is needed and you felt comfortable doing an oral provocation test, I would suggest avoidance at this time. The question becomes whether or not this would apply to other macrolides, and unfortunately the answer to this question has not been definitively established.

In summary, although skin test protocols have been published, in my opinion, based upon a review of the literature, to be certain that your patient would not react to azithromycin, if skin tests were negative, you would need to perform an oral provocation test. The decision as to whether or not to proceed with this would be based upon the need for azithromycin or another macrolide in the future, and could only be determined by an analysis of risk/benefit ratio that you would need to make in conjunction with the patient.

Nonetheless, if you do wish to proceed with a challenge, the references cited and the abstracts copied below will give you protocols to employ.

Thank you again for your inquiry and we hope this response is helpful to you.

Allergy Asthma Proc. 2011 Mar;32(2):99-105.
The prevalence of antibiotic skin test reactivity in a pediatric population.
Kamboj S, Yousef E, McGeady S, Hossain J.
Department of Allergy and Immunology, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
Although adverse drug reactions (ADRs) are not uncommon, true allergic (i.e., immunologic) reactions are infrequent. Estimates are that only 10% of reported "penicillin (PCN)-allergic" patients have true allergic drug reactions. Most studies of PCN-related ADR have been conducted in adult populations and suggest that the majority of adult patients presenting with PCN allergy history can safely receive the drug. The goal of this study was to examine the outcome of provocative drug challenges to antibiotics in a pediatric population and correlate outcomes with predictive factors. Through chart review, we identified 96 pediatric patients with history of an ADR to antibiotics who underwent skin testing (ST) and/or graded challenges to PCN (n = 52), cephalosporins (n = 7), azithromycin (AZT; n = 24), or clindamycin (n = 4). Of these children with an ADR, 87 (90.6%) tolerated provocative drug challenges and 9 (9.4%) were instructed to continue drug avoidance because of positive ST or failed challenge. Eight of the nine patients continued drug avoidance due to positive PCN ST (n = 4) or ADR during drug PCN challenge (n = 4). All AZT and cephalosporin challenges had negative outcomes, and only one patient did not proceed with the clindamycin challenge after a positive ST. True "antibiotic allergy" denoted by positive ST or failed challenge in patients with a history of ADR occurred in <10% of children included in this study, suggesting that without such testing nearly 90% might be treated with alternative antibiotics unnecessarily.

Curr Pharm Des. 2008;14(27):2840-62.
Macrolides allergy.
Araújo L, Demoly P.
Allergy Division, Hospital Universitario de S Joao, Immunology Department, Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4200 - 319 Porto, Portugal.
Macrolides are characterised by their basic structure which is made up of a lactonic cycle with 2 osidic chains. They are classified according to the number of carbon atoms in the cycle : 14 membered macrolides (erythromicin, roxithromycin, dirithromycin, clarithromycin), 15 membered (azithromycin) and 16 membered (spiramycin, josamycin, midecamycin) macrolides. Epidemiological studies show that macrolides are amongst the safest antibiotics, but in these series, no drug allergy work up was performed. An immediate IgE dependent hypersensitivity has been shown with erythromycin in some cases. The mechanism is unknown and the skin tests are negative in most other cases. It would appear that the macrolide allergies are unlikely to be class allergies. Eviction is the treatment of choice. Desensitization has been successful in a few cases.

Presse Med. 2000 Feb 19;29(6):321-6.
[Allergy to macrolide antibiotics. Review of the literature].
[Article in French]
Demoly P, Benahmed S, Valembois M, Sahla H, Messaad D, Godard P, Michel FB, Bousquet J.
INSERM U454-IFR3, Hôpital Amaud de Villeneuve, CHU de Montpellier.
Macrolide Classes: Macrolides are characterized by their basic structure made up of a lactonic cycle with 2 osidic chains. They are classified according to the number of carbon atoms in the cycle: 14-membered macrolides (erythromycin, troleandomycin, roxithromycin, dirithromycin, clarithromycin), 15-membered macrolides (azithromycin) and 16-membered macrolides (spiramycin, josamycin, midecamycin).
Macrolide Allergy: Allergy to macrolides is extremely rare (0.4% to 3% of treatments). The little information available in the literature is insufficient to establish the usefulness of diagnostic tests. An immediate IgE-dependent hypersensitivity has been shown with erythromycin in some cases but the mechanism remains unknown and skin tests are quite often negative. Clinical manifestations are the same as those encountered with beta-lactams. It would appear that macrolide allergies are unlikely to be class allergies. This is important as eviction advice could be limited to the single causal macrolide.

Empedrad R, et al. Nonirritating intradermal skin test concentrations for commonly prescribed antibiotics. J Allergy Clin Immunol 2003; 112(3):629-630.
Luu N, et al. Drug provocation test (DPT) in patients with a history of macrolide allergy. J Allergy Clin Immunol 2006; 117(2):S224 (abstract).
Lammintausta K. The usefulness of skin tests to prove drug hypersensitivity. British Journal of Dermatology 2005 (May); 152(5):968-974.

Phil Lieberman, M.D.

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