Delayed reaction to oral amoxicillin

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

A 12-year-old female is at the allergy clinic for evaluation of suspected drug allergy to amoxicillin. Two years ago, she was treated with Augmentin for acute sinusitis. After 7 days of taking the antibiotic, she developed hives. No angioedema or systemic symptoms. No allergy to other antibiotics or medications.

What is the most likely diagnosis?

One episode of acute urticaria with differential diagnosis including:

- idiopathic urticaria
- viral-induced urticaria
- delayed reaction to amoxicillin

What tests would you recommend?

Percutaneous skin testing with negative and positive control, and amoxicillin 1:1, 125 mg/5 ml. The test was negative for amoxicillin.

ImmunoCAP sIgE for PCN and amoxicillin was ordered and it was reported as negative 10 days later.

What would be the next step in management?

Regarding Delayed reaction to oral amoxicillin/clavulanic acid, skin test with amoxicillin and sIgE were negative. The risk for IgE-mediated reaction is low.

There are 2 diagnostic options:

1. Perform skin and intradermal test with Pre-Pen and penicillin G, followed by graded dose oral challenge with amoxicillin.

2. Perform graded dose oral challenge with amoxicillin.

Considering her history of delayed reaction and low risk, option 2 was recommended, a graded dose oral challenge with amoxicillin in the allergy clinic with observation for anaphylaxis.

Dosing protocol for Amoxicillin graded dose challenge:

Step 1: 0.1% of the dose of 500 mg (1/100th)
20 min later

Step 2: 10% of the dose
20 min later

Step 3: 30% of the dose
20 min later

Step 4: The remaining 60% of the dose.
Observe for 1 hour after the last dose.

What happened next?

The challenge was negative. The patient does not have an IgE-mediated allergy to amoxicillin.

For delayed or nonimmediate types of reactions, challenge procedures are less standardized. In general, the time between doses should be long enough that delayed symptoms have time to develop before the next higher dose is administered. Some protocols take 7-14 days. An example of a challenge procedure for delayed reactions would involve administering doses at weekly intervals, starting with 1/100 of a usual dose on day 0, 1/10 of a dose on day 7, and a standard dose on day 14. However, other studies have documented that some delayed reactions only develop after several days at a full therapeutic dose, or in the presence of a concomitant viral infection. Thus, there may be certain drug reactions that cannot be easily elicited with any challenge protocol.


Although allergy to antibiotics is commonly claimed, true allergy to these drugs is often absent

Adverse drug reactions affect up to 10% of people. When drug reactions resembling allergy happen, they are called drug hypersensitivity reactions (DHRs). Drug hypersensitivity reactions may be allergic or nonallergic. Drug allergies are drug hypersensitivity reactions caused by the immune system.

Clinical presentation in hypersensitivity reactions to beta-lactams is remembered by the mnemonic MAUS:

Maculopapular exanthema, 19.1%
Anaphylaxis without shock, 19.1%
Urticaria, 36.7%
Shock, anaphylactic shock, 17.6%

Anaphylactic shock and anaphylaxis occurs within 1 hour of beta-lactam administration. Exanthema occurs after 24 hours. Urticaria can occur at any time.

Hypersensitivity reactions to beta-lactam antibiotics: MAUS mnemonic 20-20-40-20%. Click here to enlarge the image.

Drug allergy management in 5 steps (click to enlarge the image).

Gell and Goombs classification of hypersensitivity reactions: ACID

Anaphylaxis, angioedema, asthma, type I
Cytotoxic, antibody-mediated, type II, e.g AIHA, ITP, Graves'
Immune complex disease (CIC), type III, e.g. GN, serum sickness, drug fever
Delayed, cell-mediated, type IV, e.g. contact dermatitis

Type I, IgE-mediated drug reactions may involve anaphylaxis or urticaria. Type I reactions occur early or late in a course of therapy and can persist for weeks or months after drug withdrawal.

Type II cytolytic reactions are to rapidly haptenating drugs such as penicillin.

Type III, drug-specific immune complexes result from high-dose, prolonged therapy. They produce drug fever, serum sickness, and cutaneous vasculitis.

Type IV, contact dermatitis occurs with topically applied drugs. Highly sensitizing drugs such as penicillins are no longer provided in a topical form.

What is serum sickness?

From a historical perspective, the term serum sickness means a self-limited immune complex disease caused by exposure to foreign animal proteins or haptens.

Some proteins and large polypeptide drugs (e.g. insulin) can directly stimulate antibody production. However, most drugs act as haptens, binding to proteins, and then stimulating an allergic reaction.

Gell and Coombs classification of drug hypersensitivity was established before T cell subsets were known.

T cell-meditated immunopathology has been subclassified as types IVa-IVd reactions

This subclassification considers the cytokine production and type of cells:

- monocytes (type IVa)
- eosinophils (type IVb)
- cytotoxic activity of both CD4 and CD8 T cells (type IVc)
- neutrophils (type IVd)

Type IVa (Th1)

Th1 cells activate macrophages by secreting large amounts of interferon-gamma. Th1 cells drive the production of complement-fixing antibodies involved in type II and III reactions (IgG1, IgG3).

TH1 are co-stimulatory for TNF, IL-12 and CD8 T cell responses. In vivo correlate is monocyte activation - in PPD or granuloma formation in sarcoidosis. Th1 cells activate CD8 cells, which might explain the common combination of IVa and IVc reactions (e.g., in contact dermatitis).

Type IVb (Th2)

Th2 cells secrete IL-4, IL13, and IL-5, which promote B cell production of IgE and IgG4, mast cells and eosinophils. There is a link to type I reactions, as Th2 cells boost IgE production by IL-4/IL-13 secretion.

Type IVc

T cells can act as cytotoxic cells. They emigrate to the tissue and kill tissue cells like hepatocytes or keratinocytes in a perforin/granzyme B and Fas ligand dependent manner.

Cytotoxic T cells play an important role in:

- maculopapular and bullous skin diseases
- neutrophilic inflammations (acute generalized exanthematous pustulosis, AGEP)
- contact dermatitis

Type IVc reactions are important in bullous skin reactions like Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), where activated CD8 T cells kill keratinocytes.

Type IVd

T cells coordinate sterile neutrophilic inflammation of the skin, in particular AGEP. In this drug-induced disease, T cells recruit neutrophils via CXCL8 release and prevent their apoptosis via GM-CSF. Such T cell reactions are also found in Behçet disease and pustular psoriasis.


T cell-meditated drug hypersensitivity subclassified as types IVa-IVd:

IVa - 1 = Th1
IVb - 2 = Th2
IVc = cytotoxic CD8 T cells


Clinical presentation and time course in hypersensitivity reactions to β-lactams. P. J. Bousquet, V. Kvedariene, H.-B. Co-Minh, P. Martins, M. Rongier, B. Arnoux, P. Demoly (2007). Allergy 62 (8), 872–876.

Drug Allergy. Middleton's Allergy: Principles and Practice, Mosby; 7 edition (November 19, 2008).
Clinical review: ABC of allergies. Adverse reactions to drugs. BMJ 1998;316:1511-1514.
Severe Cutaneous Adverse Reactions to Drugs. Current Opinion in Allergy and Clinical Immunology. Faith L. Chia; Khai Pang Leong. Published on Medscape, 08/2007.

References: 04-12-2013
Updated: 05-12-2104

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