Drug Cross Reaction.

beta-lactam sulfonamides quinolones salicylate NSAIDs

beta-lactam Penicillins Penicillin Aminopenicillin e.g. amoxicillin, ampicillin Oxacillin e.g. cloxacillin, dicloxacillin

Cephalosporins

Carbapenem e.g. imipenem, meropenem

Formation of penicillin metabolites in vivoCNSOCH3CH3OHONHROCNSOCH3CH3OHONHRONHProteinCHNSOCH3CH3OHONHROOHHNSCH3CH3OHONHROPenicilloyl(major determinant)Penicilloate Penilloate(minor determinant)> 90%

penicillin CephalosporinRR1R2

-S-RONRC OOHCarbapenemsCOOHOOR - C - NHNPenicillins penicillin CarbapenemBeta-lactam ringBeta-lactam ringModified thiazolidine ring

beta-lactam IgE Ab MP rash antigenic determinant beta-lactam

anaphylaxis, angioedema, urticaria IgE Ab antigenic determinant beta-lactam ---- > alternative

-

-

H2NArylamineS NHNOCH3ONNHSOONH2SulfamethoxazoleHypersensitivity reactionSevere skin reactionOOSulfonamideFive-member ring with a N adjacent to the point of attachment and a methyl group attached to 2nd C atom (Beta-position) from the sulfonamide substituent SulfonamidesHydroxylamine metaboliteAntigenic determinant for IgE

sulfonamides e.g. sulfamethoxazole, sulfadiazine carbonic anhydrase inhibitors e.g. acetazolamide sulfonylurea e.g. glyburide, glipizide e.g. hydrochlorothiazide, furosemide e.g. probenecid inflammatory bowel disease e.g. sulfasalazine selective serotonin-1receptor agonists e.g. sumatriptan specific COX-2 inhibitor e.g. celecoxib

precautioncontraindication

SulfadiazineChlorpropamideCelecoxibSulfamethoxazoleGlimepirideValdecoxibSulfisoxazoleGlipizideBumetanideSulfapyridineGlibenclamideFurosemideAmprenavirTolbutamideTorsemideFosamprenavirTolazamideProbenecidAcetazolamideChlorothiazideSulfasalazineBrinzolamideChlorthalidoneTamsulosinDorzolamideHCTZTipranavirMethazolamideIndapamideNaratriptanIbutilideSotalolSumatriptanTopiramateZonisamide

Fluoroquinolones Cross reaction

Quinolones

generationdrugFristNon-fluorinated drug; nalidixic acidSecondNorfloxacin, Ofloxacin, CiprofloxacinThirdLevofloxacinFourthMoxifloxacin

Fluoroquinolones structure1678

StructureQuinolonesFloroquinolonesNalidixic acidR side chain = covalent bond of protein to Adduct carboxylic group = Drug Interaction position7618

Fluoroquinolones StructureR = piperazineciprofloxacinnorfloxacinlevofloxacinofloxacinCH3

New fluoroquinolones Moxifloxacin

Immediate hypersensitivity to quinolones: moxifloxacin cross-reactivity. Gonzales, I, et al. J Invest Allergol Clin Immunol 2005; Vol.15(2):146-149

Patient YearsSex Clinic Culprit drug139femaleurticariaciprofloxacin250femaleurticariamoxifloxacin329femaleurticariaofloxacinciprofloxacin442femaleurticariaciprofloxacin563femaleanaphylaxismoxifloxacin653maleurticariamoxifloxacin

High degree of cross-reactivity between different groups of quinolonesWT=well tolerate, NT=not test, + = positiveAVOID !!!

PtciprofloxacinnorfloxacinlevofloxacinofloxacinmoxifloxacinSkin testOral challenge testSkin testOral challenge testSkin testOral challenge testSkin testOral challenge testSkin testOral challenge test1ciprofloxacin+NT-NT+NT-NT++2moxifloxacin++-NT-NT++++3ofloxacinciprofloxacin-WT-NT++-NT++4ciprofloxacin-+-NT+WT+NT++5moxifloxacin-WT-NT-WT+NT++6moxifloxacin+WT-NT-NT-NT-+

Immediate reactions of fluoroquinolones pathomechanism 7 quinolone molecule covalent binding IgE-molecule Some immediate-type reactions to fluoroquinolone may also be attributed to a nonspecific histamine release from mast cells and basophilsNonallergic histamine release may induce an anaphylactoid reactionCurrent allergy and Asthma Reports 2005, 5:15-21

Most patients are sensitized to more than on fluoroquinolone, suggesting an extensive cross-reactivity between the different moleculesThis is probably due to the high structural similarity among fluoroquinolones, which all share a common core structure Immediate reactions of fluoroquinolones Current allergy and Asthma Reports 2005, 5:15-21

Photosensitivity Formation of quinolone-photoadducts is thought to be the initial step for sensitizationCross-reactivity in the photoallergic response are differences in the potency to evoke photoallergic reactions for different molecules

Substituent at position 8 of the structureProtein-photobinding site seems to be the piperazinyl ring at position 7, photodegraded by UVA light.dose-dependent phenomenon that requires exposure to direct or indirect ultraviolet A (UVA) light [Can J Infect Dis. 2002 JanFeb; 13(1): 5461.]

Fluoroquinolones Photosensitivityciprofloxacinnorfloxacinlevofloxacinofloxacinsparfloxacinnorfloxacin, ciprofloxacin, levofloxacin < ofloxacin < sparfloxacin

PhotosensitivityTwo types of photosensitivity reactions have been associated with fluoroquinolone therapy: photoallergic reactions and phototoxic responses. Photoallergic reactions are rare and require previous exposure to a drug in the class. In contrast, phototoxic responses are more common and can develop without previous exposure to a fluoroquinolone if the dose of the photo-labile drug and exposure to UVA light (around 350 to 360 nm) are sufficiently high, as demonstrated with the use of some fluoroquinolones in a murine model (Table III).[33,34] Halogenation at position C8 is responsible for many of the photosensitivity reactions occurring during fluoroquinolone treatment.[22] Some of the fluoroquinolones induce mild photosensitivity reactions, such as erythema of sun-exposed skin, with varying frequency; however, drugs such as lomefloxacin and sparfloxacin, with a C8-fluorine substituent, and clinafloxacin, with a C8-chlorine substituent, exhibit a greater incidence of phototoxic reactions than drugs without this substituent.Safety of the Fluoroquinolone Antibiotics: Categorized Adverse Effects. http://www.medscape.com/viewarticle/410202_4

Salicylates NSAIDs True allergy Angioedema Urticaria Anaphylaxis Pseudo allergy aspirin-exacerbated respiratory distress (AERD) chronic idiopathic urticaria (CIU) anaphylactoid

NSAIDs Cross Reactivity

/ CIU NSAIDs 1 NSAIDs > 1 Cross Reactivity--/

Anticonvulsant Hypersensitivity Syndrome (AHS) --- > SJS, TEN eosinophilia onset 1-12 1/1000 1/10000 aromatic ring 10%

Aromatic Anti-Convulsant Drug metabolized CYP450 arene oxide metabolized epoxide hydrolase non-toxic substance arene oxide AHS cross reactivity aromatic anticulvulsant ~ 75% phenytoin carbamazepine phenobarbitone lamotrigine

Preventable ADR : ADR Schumock-Thornton 7 ADR ADR 1 : 2 : 3 : Lab

Preventable ADR () 4 : ADR 5 : drug interaction 6 : Lab 7 :

A : B : C : D : E : F : G : H : I :

The National Coordinating Council For Medication Error Reporting and Prevention

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