pharmacy Review Aminoglycoside Allergic Reactions Lindsey M. Childs-Kean 1,* , Kristy M. Shaeer 2, Sheeba Varghese Gupta 3 and Jonathan C. Cho 4 1 Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL 32610, USA 2 Department of Pharmacotherapeutics and Clinical Research, University of South Florida College of Pharmacy, Tampa, FL 33612, USA 3 Department of Pharmaceutical Sciences, University of South Florida College of Pharmacy, Tampa, FL 33612, USA 4 Department of Clinical Sciences, Ben and Maytee Fisch College of Pharmacy, The University of Texas at Tyler, Tyler, TX 75799, USA * Correspondence: [email protected]fl.edu Received: 13 July 2019; Accepted: 25 August 2019; Published: 29 August 2019 Abstract: Aminoglycosides are antimicrobial agents that are primarily used for infections caused by Gram-negative pathogens. The purpose of this article is to review the allergic reactions reported in the published literature to aminoglycoside antibiotics. A thorough PubMed search was conducted and excluded non-allergic adverse reactions to aminoglycosides. Allergic reactions to aminoglycosides occur infrequently, but can include cutaneous reactions as well as systemic reactions, including anaphylaxis. Of the evaluated aminoglycosides, gentamicin had the most reported allergic reactions, including the most reports of anaphylaxis, followed by tobramycin, and then amikacin. Most reports of allergic reactions occurred in patients who had a prior exposure to some dosage form of an aminoglycoside. Cross-reactivity among aminoglycosides is common and occurs due to the similarities in their chemical structures. Desensitization protocols to tobramycin have been described in the literature. Keywords: aminoglycosides; allergy; hypersensitivity; gentamicin; tobramycin; amikacin 1. Introduction Antibiotics are one of the most common causes of life-threatening medication allergies [1]. These allergic reactions can be broadly categorized into immediate (IgE-mediated) or non-immediate reactions (T cell-mediated). Patients with immediate allergic reactions can present clinical manifestations that include urticaria, angioedema, and anaphylaxis, whereas those with non-immediate reactions can present symptoms ranging from contact dermatitis to a maculopapular rash [1]. A vast number of hypersensitivity reactions have been reported from the beta-lactam class (up to 15% of patients), but allergic reactions from aminoglycosides are less frequently reported (<2%) [1,2]. Similar to beta-lactam antibiotics, non-immediate reactions to aminoglycosides are more commonly seen [2]. Contact dermatitis from topical aminoglycoside use is the most frequently reported reaction with aminoglycosides, even when compared with other topical medications [3,4]. Due to the infrequent nature of aminoglycoside allergies, a review of the current literature on aminoglycoside hypersensitivity reactions and associated management is lacking. This paper will review the medicinal chemistry, indications, reported allergic reactions, and desensitization protocols associated with aminoglycoside utilization. Pharmacy 2019, 7, 124; doi:10.3390/pharmacy7030124 www.mdpi.com/journal/pharmacy Pharmacy 2019, 7, 124 2 of 12 Pharmacy 2019, 7, x FOR PEER REVIEW 2 of 12 2. Medicinal Medicinal Chemistry Chemistry 2.1. Aminoglycoside Aminoglycoside Structure The structure of aminoglycosides consists of a hexose ring, to which various amino sugars are attached via glycosidic linkages. Aminoglycosides Aminoglycosides can can be be classified classified into two main structural classes based on the aminocylitol nucleus: streptidine (s (streptomycin)treptomycin) and deoxystrepatamine (gentamicin, tobramycin, amikacin,amikacin, kanamycin, kanamycin, neomycin, neomycin, and and plazomicin) plazomicin) (Figure (Figure1). Irrespective 1). Irrespective of their structural of their structuraldifferences, differences, all aminoglycosides all aminoglycosides exhibit concentration-dependent exhibit concentration-dependent bactericidal activity bactericidal through inhibition activity throughof protein inhibition synthesis. of The protein structural synthe disis.fference The structural seems to play difference an important seems roleto play inescaping an important the bacterial role in escapingresistance the mechanisms, bacterial resistance especially mechanisms, by offering structuralespecially robustnessby offering against structural metabolizing robustness enzymes, against metabolizingsuch as Aminoglycoside enzymes, such Modifying as Aminoglycoside Enzymes (AMEs),Modifying and Enzymes target-modifying (AMEs), and 16S target-modifying rRNA methyl 16Stransferases rRNA methyl (16S-RMTases), transferases produced (16S-RMTases), by the bacteria produced [5]. Amikacinby the bacteria and plazomicin [5]. Amikacin have beenand plazomicinshown to have have increased been shown stability to have against increased AMEs stab comparedility against to gentamicin AMEs compared [5]. All currently to gentamicin marketed [5]. Allaminoglycosides currently marketed are affected aminoglycosides by 16S-RMTases, are rendering affected themby 16S-RMTases, inactive against rendering the organisms them producing inactive againstthe enzyme the organisms [5]. producing the enzyme [5]. FigureFigure 1. ChemicalChemical structures structures of of aminoglycosides, aminoglycosides, with with structural differences differences highlighted in blue [[5].5]. 2.2. Structural Structural Aspects Aspects behind Cross-Reactivity Neomycin has antigenic properties possessing diamino sugars sugars called called neosamines neosamines in in its its structure. structure. Similar diaminodiamino sugarssugars with with minor minor modifications modifications are are present present in kanamycin in kanamycin and tobramycin.and tobramycin. As a resultAs a resultof the structuralof the structural similarity similarity between between tobramycin tobramycin and neomycin, and neomycin, up to 65% ofup patients to 65% allergicof patients to neomycin allergic toare neomycin shown to haveare shown a cross-allergic to have reaction a cross-allergic to tobramycin reaction [6]. Figureto tobramycin2 shows the [6]. structural Figure 2 constituents shows the structuralof neomycin constituents B. Kanamycin of neomycin has also beenB. Kanamycin shown to has have also cross-sensitivity been shown to with have neomycin, cross-sensitivity owing to with the neomycin,presence of owing neosamine-like to the presence groups of in neosamine-like its structure [7]. gr Gentamicinoups in its has structure also shown [7]. Gentamicin cross-reactivity has withalso shownneomycin. cross-reactivity In the case ofwith gentamicin, neomycin. the In antigenicity the case of isgentamicin, contributed the by antigenicity the deoxystreptamine is contributed group by thein its deoxystreptamine structure, which isgroup also presentin its structure, in neomycin which [8]. is Generally also present speaking, in neomycin cross-reactivity [8]. Generally among speaking,aminoglycosides cross-reactivity with the among deoxystreptamine aminoglycosides group with (gentamicin, the deoxystreptamine tobramycin, amikacin, group (gentamicin, kanamycin, tobramycin,neomycin, and amikacin, plazomicin) kanamycin, is at leastneomycin, 50% [ 9and]. For plazomi this reason,cin) is at all least deoxystreptamine-containing 50% [9]. For this reason, all deoxystreptamine-containingaminoglycosides carry a contraindication aminoglycosides against carry use a contraindication if a patient has aagainst known use hypersensitivity if a patient has to a knownanother hypersensitivity deoxystreptamine-containing to another deoxystr aminoglycosideeptamine-containing [10–13]. aminoglycoside [10–13]. As mentionedmentioned above, above, cross-reactivity cross-reactivity is due is todue specific to specific functional functional groups presentgroups inpresent these antibiotics. in these antibiotics.Cross-reactivity Cross-reactivity between the deoxystreptamine-containing between the deoxystreptamine-containing aminoglycosides and aminoglycosides streptidine-containing and streptidine-containingstreptomycin has not beenstreptomycin observed. Streptidinehas not been in streptomycin observed. isStreptidine responsible in for streptomycin its antigenicity; is responsibletherefore, deoxystreptamine-sensitive for its antigenicity; therefore, individuals deoxystr areeptamine-sensitive less likely to develop individuals allergic cross-reactionsare less likely to developstreptomycin allergic therapy cross-reactions [14]. to streptomycin therapy [14]. Pharmacy 2019, 7, 124 3 of 12 Pharmacy 2019, 7, x FOR PEER REVIEW 3 of 12 Figure 2. StructuralStructural constituents constituents of Neomycin B [5]. [5]. 3. Medical Medical Conditions Conditions for for Which Which Aminoglycosides Aminoglycosides Are Used Aminoglycosides are are useful in the treatment of a wide variety of diseases, primarily infections caused by Gram-negative aerobic aerobic ba bacilli,cilli, typically in combination with another antimicrobial or as monotherapy for urinary tract infections (Table 1 1))[ [10–12,15–17].10–12,15–17]. Aminoglycoside monotherapy has been associated with a significantl significantlyy higher rate of bacteriological fa failureilure at at the end of therapy in the treatmenttreatment of nonurinary sources (e.g., pneumonia, abscess, central nervousnervous system,system, etc.)etc.) [[18,19].18,19]. Gentamicin hashas activityactivity against against many many Gram-negative Gram-negative organisms organisms