Carmine hypersensitivity ("red pill") masquerading as azithromycin hypersensitivity

Macrolide hypersensitivity is a rarely reported event. Carmine dye has become increasingly important as a provocative agent for allergic reactions.

Carmine, also called Crimson Lake, Cochineal, Natural Red 4, C.I. 75470, or E120, is a pigment of a bright red color obtained from the carminic acid produced by some scale insects ("beetle juice"), such as the cochineal and the Polish cochineal, and is used as a general term for a particularly deep red color.
href="http://upload.wikimedia.org/wikipedia/commons/thumb/f/f9/Carminic_acid_structure.png/233px-Carminic_acid_structure.png">
Carminic acid. Image source: Wikipedia, public domain.

This is a case report of a woman with documented carmine hypersensitivity, who reported anaphylaxis 90 minutes after ingestion of a generic azithromycin. She had not problems with the brand name Zithromax taken on previous occasions.

The cause of anaphylaxis was an allergy to the carmine dye in the tablet's coating rather than to the antibiotic (azithromycin).


Azithromycin. Image source: Wikipedia, public domain.

Seven extracts were prepared including carmine dye, crushed dried female cochineal insects, crushed tablets of Zithromax (Pfizer Inc.) and generic azithromycin (Teva Pharmaceuticals), and the crushed colored coatings from both tablets. The exctracs were dissolved in normal saline, and then applied as a skin-prick test and read at 30 minutes.

The skin-prick skin test results were 4+ to histamine and carmine dye, but negative to cochineal insect extract, Pfizer crushed tablets, and negative control. The patient was 1+ to the Teva crushed tablet, but was 4+ to the Teva brand coating and negative to the Pfizer brand coating, which did not contain carmine.

The patient subsequently ingested Pfizer Zithromax without any sequelae.

According to the authors, this is the first reported case of carmine anaphylaxis attributed to carmine-containing medication.

References:


Carmine hypersensitivity masquerading as azithromycin hypersensitivity. Greenhawt, Matthew1; McMorris, Marc; Baldwin, James. Allergy and Asthma Proceedings, Volume 30, Number 1, January/February 2009 , pp. 95-101(7).
Testing for red coloring agents added to foods - AAAAI Ask the Expert, 2011.
The data suggests an extremely rare occurrence of azithromycin allergy http://goo.gl/6fZHL
Q&A: How can I find out which ingredients are in a medication?  http://goo.gl/UQWQf
Carmine, from Wikipedia, the free encyclopedia. The best price for azithromycin is at Costco: 18 tablets for $18. Drug provocation tests remain the key to diagnosing macrolide allergy http://goo.gl/WM5rj
"Starbucks admits Strawberry Frappuccino contains crushed bugs" - carmine is natural alternative to artificial dyes http://goo.gl/XXIhW
The Fascinating Story of How Tropical Insects Were the Best Choice to Color Your Starbucks Coffee (cochineal red) http://goo.gl/ecZmL
Image source: Variations on a common tablet design, which can be told apart by both color and shape. Wikipedia, Ragesoss, Creative Commons Attribution ShareAlike 3.0 License.

Twitter comments:

 @AllergyNet: For me, x2/25 yrs, x1 in sausage x1 in chocolate RT @Allergy: Carmine allergy masquerading as azithromycin allergy http://goo.gl/gST6h

@AllergyNet: Macrolide antibiotic allergy: Which tests are really useful? http://j.mp/jAr3zV Bottom line: NONE (except challenge) Full PDF

Dr. Ellis @DrAnneElli: Have seen this as well - great summary and work up plan for Carmine Allergy.

David Fischer, MD @IgECPD4: Once saw a pt with reaction to strawberry yogurt. Negative to strawberry and milk but +ve to carmine dye

From Phil Lieberman, M.D.:

There are a number of published protocols for azithromycin skin testing. Copied below are abstracts of these articles. I would use the intravenous preparation. The article by Brockow, et al., in Allergy 2013 is available to you free of charge online and gives skin testing concentrations and protocols not only for azithromycin but also for a number of other drugs.

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.
Source
Department of Allergy and Immunology, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
Abstract
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.
Source
Allergy Division, Hospital Universitario de S Joao, Immunology Department, Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4200 - 319 Porto, Portugal.
Abstract
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.
Source
INSERM U454-IFR3, Hôpital Amaud de Villeneuve, CHU de Montpellier.
Abstract
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.

References:
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.

Allergy. 2013 Jun;68(6):702-12. doi: 10.1111/all.12142. Epub 2013 Apr 25.s skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper.
Brockow K1, Garvey LH, Aberer W, Atanaskovic-Markovic M, Barbaud A, Bilo MB, Bircher A, Blanca M, Bonadonna B, Campi P, Castro E, Cernadas JR, Chiriac AM, Demoly P, Grosber M, Gooi J, Lombardo C, Mertes PM, Mosbech H, Nasser S, Pagani M, Ring J, Romano A, Scherer K, Schnyder B, Testi S, Torres M, Trautmann A, Terreehorst I; ENDA/EAACI Drug Allergy Interest Group.
Abstract
Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable indicator of true hypersensitivity. To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group.We recommend drug concentration for skin testing aiming to achieve a specificity of at least 95%. It has been possible to recommend specific drug concentration for betalactam antibiotics, perioperative drugs, heparins, platinum salts and radiocontrast media. For many other drugs, there is insufficient evidence to recommend appropriate drug concentration. There is urgent need for multicentre studies designed to establish and validate drug skin test concentration using standard protocols. For most drugs, sensitivity of skin testing is higher in immediate hypersensitivity compared to nonimmediate hypersensitivity.