Macrolide Allergic Reactions

Macrolides are antimicrobial agents that can be used to treat a variety of infections. Allergic reactions to macrolides occur infrequently but can include minor to severe cutaneous reactions as well as systemic life-threatening reactions such as anaphylaxis. Most reports of allergic reactions occurred in patients without prior exposure to a macrolide. Cross-reactivity among macrolides may occur due to the similarities in their chemical structures; however, some published literature indicates that some patients can tolerate a different macrolide. Most published reports detailed an allergic reaction to erythromycin. Desensitization protocols to clarithromycin and azithromycin have been described in the literature. The purpose of this article is to summarize macrolide-associated allergic reactions reported in published literature. An extensive literature search was conducted to identify publications linking macrolides to hypersensitivity reactions.


Introduction
One of the most common causes of medication allergies among adults and children is antibiotics [1]. These allergic reactions can range from immediate to non-immediate (delayed) hypersensitivity reactions. Immediate reactions are typically IgE-mediated and can cause clinical manifestations that include urticaria, angioedema, and anaphylaxis [1,2]. Non-immediate reactions are frequently T-cell mediated and can lead to various degrees of cutaneous symptoms in patients [1,2]. Although many of the reported antibiotic allergies are from the beta-lactam class, cases of allergic reactions to macrolide antibiotics have been documented [1][2][3][4]. However, hypersensitivity reactions resulting from macrolide use occurs infrequently (0.4-3%) [4]. Since macrolide allergies are uncommon, there is a lack of recent data reviewing macrolide allergies and management of those allergies. This paper will review the medicinal chemistry, indications, reported allergic reactions, and desensitization protocols associated with macrolide antimicrobials.

Macrolide Structure
The structure of macrolides consists of a large lactone ring that varies in size from 12 to 18 atoms. Sugar molecules are attached to the lactone ring with glycosidic bonds. Macrolide antibiotics are

Place in Therapy
Macrolides are a well-established class of antibiotics. They exhibit bacteriostatic activity against a wide range of gram-positive, gram-negative, and atypical bacteria [9]. Erythromycin, the macrolide with the longest use in practice, has a few remaining indications as the drug of choice given the Pharmacy 2019, 7, 135 3 of 23 rise in antibiotic resistance and the availability of more effective and safer antibiotics. Azithromycin and clarithromycin have largely replaced erythromycin in clinical practice because of their broader spectrum of activity, better pharmacokinetics profile, and fewer gastrointestinal adverse effects [9]. In addition, azithromycin is associated with fewer drug-drug interactions than erythromycin and clarithromycin [9].
Macrolides are the drugs of choice for the treatment of various atypical bacteria [9]. Erythromycin is the drug of choice for the treatment of diphtheria caused by Corynebacterium diphtheriae, although antitoxin is the primary treatment. Erythromycin is also the drug of choice for the treatment of infants with pneumonia caused by Chlamydia trachomatis. Azithromycin is the drug of choice for the treatment of trachoma, urethritis, and cervicitis caused by Chlamydia trachomatis and chancroid caused by Haemophilus ducreyi. Azithromycin with or without rifampin is also one of the regimens of choice for the treatment of Legionella pneumophila, which can cause serious atypical pneumonia. Clarithromycin is the drug of choice for the treatment of Helicobacter pylori as part of a combination regimen with amoxicillin and omeprazole. Clarithromycin in addition to amikacin is the regimen of choice for the treatment of infections caused by Mycobacterium fortuitum and Mycobacterium chelonae. Erythromycin and azithromycin are the drugs of choice for the treatment of infections caused by Bartonella henselae (cat scratch fever), Bartonella quintana (trench fever), Campylobacter jejuni (diarrhea), Chlamydia trachomatis (conjunctivitis and urethritis), and Ureaplasma urealyticum (urethritis). Azithromycin and clarithromycin are the drugs of choice for the treatment of infections caused by Mycobacterium avium complex as part of a combination regimen with ethambutol and rifabutin or monotherapy for primary or secondary prophylaxis. Lastly, all three macrolides are the drugs of choice for the treatment of pertussis (whooping cough) caused by Bordetella pertussis and atypical pneumonia caused by Chlamydophila pneumonia and Mycoplasma pneumoniae.
Many clinical practice guidelines recommend the use of macrolides for the empiric treatment of respiratory tract infections although antibiotic resistance among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis is on the rise [10][11][12][13]. Current guidelines recommend the empiric use of macrolides as the drugs of choice for the treatment of atypical pneumonia in children and community-acquired pneumonia in adults as monotherapy in the outpatient setting and as combination therapy with a beta-lactam in the inpatient setting [10,11]. Current guidelines recommend the empiric use of macrolides as alternative choices for the treatment of acute otitis media and streptococcal pharyngitis [12,13].
Macrolides can also be used as alternative options for the treatment of various infections in patients who are not able to take the drugs of choice because of allergic reaction or intolerance [9]. For example, erythromycin can be used as an alternative to cephamycins as part of a combination regimen to prevent infections associated with colorectal surgeries or as an alternative to penicillins for the prevention of rheumatic fever. In rare circumstances, erythromycin can be used as an alternative to ciprofloxacin, doxycycline, and penicillins for the treatment of anthrax caused by Bacillus anthracis or as an alternative to tetracyclines for the treatment of infections caused by Lymphogranuloma venereum. More commonly, erythromycin can be used as an alternative to tetracyclines for the treatment of acne vulgaris. Azithromycin can be used as an alternative to ceftriaxone or fluoroquinolones for the treatment of typhoid fever caused by Salmonella typhi or as an alternative to fluoroquinolones for the treatment of diarrhea caused by Shigella dysenteriae. Azithromycin can also be used as an alternative to doxycycline and penicllins for the treatment of Lyme disease caused by Borrelia burgdorferi or as an alternative to clindamycin and quinine for the treatment of babesiois caused by Babesia microti. Azithromycin and clarithromycin can be used as an alternative to trimethoprim/sulfamethoxazole for the treatment of respiratory infections caused by Haemophilus influenzae. Lastly, all three macrolides can be used as an alternative to penicillins for the treatment of respiratory and skin and soft tissue infections caused by groups A, C, and G Streptococcus, Streptococcus pneumoniae, and Moraxella catarrhalis.
Fidaxomicin is a unique antibiotic, and represents the latest addition to the macrolides [14]. It exhibits bactericidal activity against Clostridoides difficile. Fidaxomicin is not systemically absorbed, is well tolerated, and is not associated with any known drug interactions. Clinical trials have shown that fidaxomicin is non-inferior to vancomycin for the treatment of Clostridioides difficile infection (CDI) and is associated with lower recurrence rates. Current CDI guidelines recommend the use of fidaxomicin for the treatment of initial severe, non-severe, and recurrent episodes [15].

Published Allergic Reactions
To gather relevant information, a literature search was performed using the PubMed, EBSCOhost, and Google Scholar electronic databases for articles published up to 17 May 2019, with restrictions for English language and human subjects. Search terms used to identify the included articles were macrolides, azithromycin, clarithromycin, erythromycin, fidaxomicin, hypersensitivity, allergy, rash, toxic epidermal necrosis, Stevens Johnson Syndrome, fixed drug eruption, maculopapular rash, exanthema, and desensitization. Articles about macrolides used as immunosuppressants (e.g., tacrolimus, everolimus, pimecrolimus, and sirolimus) and uncommonly or commercially unavailable were excluded (e.g., kitasamycin, josamycine midecamycin, roxithromycin, spiramycin, telithromycin, and troleandomycin). References of publications for which the full text was retrieved were also reviewed for additional literature sources.
In general, allergic reactions to macrolides reported in the literature are rare. Macrolides are available in a variety of dosage forms, and of those, topical, oral, intravenous, and ophthalmic formulations have been reported to cause an allergic reaction. The initial search for articles regarding macrolide hypersensitivity yielded 1895 citations. Following completion of all search strategies and terms a total of 120 reports were included and summarized in this review. The types of reactions for erythromycin, clarithromycin, azithromycin, and fidaxomicin are summarized in Tables 1-4. The included reports were published between 1958 and 2018, with reports from 27 different countries. Reported reactions occurred in a variety of patient populations, such as pediatrics (n = 50), adults (n = 105), and unknown (n = 20). Many providers tested patients to confirm the hypersensitivity (n = 79). Several of the reactions involved patients who had received a prior macrolide (n = 43) and of those 23 patients with repeated reactions. Repeated occupational exposures led to 10 subjects with cutaneous adverse reactions to azithromycin [16][17][18].
The breakdown of studies included 88 case reports, 12 case series, 2 cross-sectional, 1 double-blind, placebo-controlled, 5 prospective, and 12 retrospective. There were 58 publications describing erythromycin-associated allergic reactions . There were 33 publications describing clarithromycin as a culprit for allergic reactions [72,73,75,. There were 31 published reports describing azithromycin associated allergic reactions [16][17][18]95,104,. Uniquely, the ophthalmic formulation of azithromycin was associated with contact dermatitis [119,123]. There was a single publication dedicated to a case series describing 12 patients who had hypersensitivity reactions to fidaxomicin [132]. Maculopapular exanthema eruptions developed in four subjects suffering from mononucleosis who were also on macrolide therapy [43,109,111,122]. Five cases involved the development of contact dermatitis with topical erythromycin [26,35,51,56,58]. Four cases resulted in a fatality secondary to the severe allergic reaction [19,33,88,91]. Fourteen patients were reported to have anaphylactic reactions to a macrolide [19,23,59,66,73,74,81,98,100,108,121,132]. Drug reaction with eosinophilia and systemic symptoms syndrome was reported in four patients who received azithromycin and one patient who received clarithromycin [105,118,120,124,129]. Erythromycin (n = 1), clarithromycin (n = 2), and azithromycin (n = 1) have been implicated in leukocytoclastic vasculitis [60,79,84,113]. Fourteen publications implicated a macrolide as the cause of an allergic reaction with subjects who received concomitant antimicrobials [25,41,[44][45][46]58,76,78,90,101,102,105,119,131]. The most common concomitant agents were an aminoglycoside (n = 3), a beta-lactam (n = 3), and a sulfa (n = 4) [41,[44][45][46]78,90,101,102,119,131]. It is possible that one of the concomitant antimicrobials could have elicited the allergic reaction. Two publications excluded a concomitant antimicrobial as the cause with allergy testing [45,58].       ACDR defined as allergic reaction, adverse drug reaction, pruritis, general swelling, local or general redness, erythema, rash, urticaria, or other skin disease. π Review was meant to include azithromycin, clarithromycin, erythromycin, and fidaxomicin; however, there is a chance these data include excluded macrolides since the type of macrolides reported were not fully specified   ACDR defined as allergic reaction, adverse drug reaction, pruritis, general swelling, local or general redness, erythema, rash, urticaria, or other skin disease. π Review was meant to include azithromycin, clarithromycin, erythromycin, and fidaxomicin; however, there is a chance these data include excluded macrolides since the type of macrolides reported were not fully specified  time when symptoms began to occur either during macrolide therapy or after completion of macrolide therapy . ACDR defined as allergic reaction, adverse drug reaction, pruritis, general swelling, local or general redness, erythema, rash, urticaria, or other skin disease. π Review was meant to include azithromycin, clarithromycin, erythromycin, and fidaxomicin; however, there is a chance these data include excluded macrolides since the type of macrolides reported were not fully specified. Macrolide allergies are rare and available desensitization protocols are restricted to case reports, which all demonstrated success [74,100,102]. Three cases involved successful desensitization with clarithromycin, and one of the patients also completed a desensitization for azithromycin desensitization. Four desensitization protocols were identified in the literature: two involving clarithromycin in an adult patient, one for clarithromycin in a pediatric patient, and one for azithromycin in a pediatric patient (Appendix A, Tables A1-A4) [74,100,102]. Holmes et al. reported a case of a 68-year-old female with a history of anaphylaxis with erythromycin and bronchospasms with roxithromycin who underwent oral clarithromycin desensitization for use in a 18 month treatment course for a skin infection caused by Mycobacterium chelonae (Appendix A, Table A1) [74]. Swamy et al. reported a case of a 68-year-old female with a history of anaphylaxis with azithromycin and urticaria and bronchospasms with clarithromycin who underwent oral clarithromycin desensitization for use in a 3 month treatment course for an infection caused by Mycobacterium intracellularae (Appendix A, Table A2) [100]. Repeated intradermal skin testing with azithromycin 1 h after desensitization demonstrated a similar reaction seen at baseline. Six weeks after desensitization, azithromycin and clarithromycin skin prick tests were negative and intradermal skin tests were equivocal to the reactions seen at baseline. Petitto et al. described a case of an 11-year-old female with a history of diffuse urticaria with clarithromycin who underwent successful macrolide desensitization for use in osteomyelitis caused by Mycobacterium fortuitum (Appendix A, Tables A3 and A4) [102]. Initially, this patient completed an azithromycin desensitization protocol without complication; however, 24 h later, she developed a generalized urticarial rash within 75 min of a treatment dose. One week later, this patient underwent oral clarithromycin desensitization and all subsequent treatment doses were tolerated.

Conclusions
Macrolides are infrequently reported to cause various types of allergic reactions, with cutaneous reactions being the most common. Macrolides are similar in chemical structure, and limited reports have demonstrated cross-reactivity. Strategies to overcome hypersensitivity reactions, such as desensitization, or allergy testing for cross-reactivity to another macrolide have been utilized with successful outcomes. Consequently, if a patient has a severe hypersensitivity reaction to a macrolide, then the benefit versus the risk must be evaluated for using an agent in this class. In clinical practice, it may be more convenient and safer to change to an alternative class of medications if the option is available. However, if a macrolide must be used in a patient with a confirmed history of a severe allergic reaction, then allergy testing should be employed to investigate if the patient reacts to other agents in the macrolide class. If so, a desensitization may be conducted while the patient is monitored closely for signs and symptoms of an allergic reaction.