Nonimmediate Reactions: Clinical Features and Management

Type of ReactionTimingCutaneous SymptomsSystemic SymptomsPossible Laboratories in Acute SettingDifferential DiagnosisCommonly Involved AntibioticsTestingManagement
Delayed drug reaction7–14 dMaculopapular exanthemaLow-grade feverEosinophilia (mild)Viral exanthemAminopenicillinsDelayed intradermal testingAvoidance drugs and/or cross-reactive drugs
UrticariaPruritusIgE-mediated drug allergySulfonamidesDrug provocation testing
Early DRESS syndrome or SJS and/or TENClindamycin
SJS and/or TEN4–28 dPainful erythematous macules with purpuric or dusky centersProdromeAnemiaEMSulfonamidesLTT and/or ELISPOTAvoidance drug and/or drug class
Superficial sloughingHigh feverLymphopeniaBullous pemphigoidMinocycline (used for acne)HLA screening
Mucositis in ≥2 surfacesMalaiseStaphylococcal scalded skin syndromeβ-lactams
Pneumonitis (occasionally)FDE
DRESS syndrome
DRESS syndrome2–8 wkMorbilliform eruption >50% BSAFeverEosinophiliaViral or drug exanthemVancomycinPatch testingAvoidance of drugs and/or cross-reacting drugs
Nonerosive mucositisLymphadenopathyAtypical lymphocytesEarly SJS and/or TENβ-lactamsLTT and/or ELISPOT
≥2 facial edema, infiltrated lesions, scaling, and purpuraHepatitisSevere eczema or psoriasisTetracyclinesHLA screening
Renal impairmentRifampin
Antituberculosis drugs
Sulfonamides and/or sulfonesa,91
FDE1–14 db1 or more well-demarcated, round, dusky-to-violaceous macules or plaquesNoneNoneEMSulfonamidesPatch testingDrug provocation testingc
Blistering may occurBullous pemphigoidTetracyclinesAvoidance of drug and/or cross-reactive drug
Mucosal predilection but limited mucositisSJS and/or TENβ lactams
Postinflammatory hyperpigmentationQuinolones
Acute generalized exanthematous pustulosis24–48 hDozens to hundreds of pustules on erythematous backgroundHigh feverNeutrophiliaPustular psoriasisAminopenicillinsPatch testingAvoidance of drugs and/or cross-reactive drugs
Flexural accentuationEdemaEosinophiliaBullous impetigoClindamycin
Subcorneal pustular dermatosisSulfonamides
DRESS syndromeQuinolones
Serum-sicknesslike reaction1–2 wkPruritic urticarial or serpiginous plaques (usually at injection site)High feverNeutropeniaVasculitisβ lactams (especially cefaclor)NoneAvoidance of specific drugd
MalaiseMild eosinophiliaRheumatic feverMacrolides
Polyarthralgia or polyarthritisMild proteinuriaOther drug reactionsSulfonamides
  • BSA, Body Surface Area; EM, erythema multiforme; FDE, fixed drug eruption; HLA, human leukocyte antigen.

  • a Sulfonamides include trimethoprim-sulfamethazole and sulfones include dapsone. There is no cross reactivity between sulfa antimicrobials and non-antibiotic sulfonamides (such as acetazolamide, bumetanide, celecoxib, chlorothiazide, diazoxide, dorzolamide, furosemide, glyburide, hydrochlorothiazide, indapamide, metolazone, sumatriptan, torsemide and zonisamide).

  • b Rapid recurrence on drug re-exposure.

  • c Contraindicated in generalized FDE.

  • d Controversial. Some sources recommend avoiding drug and drug class while others (ie cefaclor) just recommend avoiding culprit drug.