Drugs Most Frequently Implicated in Anaphylaxis
Penicillin is the most common cause of drug-induced anaphylaxis, followed by aspirin/NSAIDs as the second most common cause, with neuromuscular blocking agents being the leading cause specifically during anesthesia. 1
Primary Culprits by Clinical Setting
General/Ambulatory Setting
Antibiotics are responsible for approximately 49.6% of severe drug-induced anaphylaxis cases, with penicillins being the single most common offender 1, 2:
- Penicillins (most common overall): Amoxicillin accounts for the majority of cases, with penicillins causing anaphylaxis at a rate of 45.9 per 10,000 patients 1, 3, 4
- Cephalosporins: Responsible for approximately 70% of antibiotic-induced anaphylaxis when combined with penicillins due to the shared β-lactam ring structure 1
- Sulfonamide antibiotics: Second most common antibiotic class at 15.1 per 10,000 patients 4
- Quinolones and pristinamycin: Less common but documented causes 2
NSAIDs and Aspirin represent the second most common cause of drug-induced anaphylactic reactions overall (10.2-13.0 per 10,000 patients), though these reactions appear to be medication-specific and do not cross-react with structurally unrelated NSAIDs 1, 4.
Anesthesia-Related Setting
The hierarchy differs significantly during anesthesia 1:
Neuromuscular blocking agents (NMBAs): Account for approximately 60-80% of anesthesia-related anaphylaxis cases 1, 5
Latex: Second most common cause in anesthesia settings, accounting for up to 20% of cases, though incidence appears to be declining 1
Antibiotics: Approximately 15% of anesthesia-related anaphylaxis, with this proportion increasing in recent years 1
Additional Important Drug Classes
Acetaminophen: Accounts for 3.9% of severe anaphylaxis cases 2
Contrast media: Iodinated or MRI contrast media cause 4.2% of severe reactions 2
Chemotherapy agents: Platinum-based agents (particularly carboplatin) have a 16% hypersensitivity rate, with risk increasing with number of exposures 7
Opioids: Uncommon cause of true anaphylaxis; morphine, pethidine, and codeine cause non-specific histamine release that mimics but is not true IgE-mediated anaphylaxis 1
Local anesthetics: Very uncommon cause of true anaphylaxis; esters more likely than amides to cause reactions, often due to preservatives like methyl-paraben or metabisulphites 1
Critical Clinical Considerations
Cross-Reactivity Patterns
- Penicillin-cephalosporin cross-reactivity: Appears low overall, but first-generation cephalosporins and cefamandole share similar side chains with penicillin/amoxicillin, increasing cross-reaction risk 1
- Aztreonam: Does not cross-react with other β-lactams except ceftazidime (shared R-group side chain) 1
- Carbapenems: Should be considered cross-reactive with penicillin 1
- NMBA cross-reactivity: Approximately 10% of the general population exhibits skin reactivity to NMBAs due to shared quaternary ammonium epitopes 5, 8
High-Risk Patient Populations
Patients at increased risk for severe or fatal anaphylaxis include 7, 8, 4:
- Females (particularly for NMBA reactions)
- White race (OR 2.38 for drug-induced anaphylaxis)
- Patients with asthma (OR 1.50)
- Patients with systemic mastocytosis (OR 4.60)
- Patients with Sjögren's syndrome (OR 1.94)
- Patients taking β-blocking drugs (may have refractory reactions)
Common Pitfalls
Over 90% of patients labeled with medication "allergies" don't have true allergies, leading to unnecessary use of less effective alternatives 7. The negative predictive value of penicillin skin testing is 97-99%, meaning approximately 90% of patients with a history of penicillin allergy have negative skin tests and can safely receive penicillins 1.
Less than 50% of patients allergic to NMBAs have documented prior exposure, indicating sensitization can occur through environmental quaternary ammonium compounds in products like cough medicines (particularly pholcodine), toothpastes, and detergents 1, 5, 8.