Types of drug reactions

• Drug reactions, including antibiotics, are divided into 4 categories:
  • Non-allergic reactions: these are side effects rather than allergic reactions, symptoms like diarrhea, vomiting, feeling sick to my stomach, or sometimes vaginitis after an antibiotic use are all considered side effects rather than allergic reactions.
  • Immediate IgE-mediated allergic reactions: Urticaria, bronchospasm, anaphylaxis, angioedema, laryngeal edema, or hypotension are examples of this type.
  • Mild allergic reactions without the features of immediate allergic IgE-mediated reactions: these patients may develop a skin rash with or without itching, or sometimes they describe isolated sneezing or itching in the eyes, the risk of developing serious IgE-mediated reactions in these patients is minimal.
  • Delayed allergic reactions: these are serious reactions that develop days to weeks after taking the antibiotic, and include SJS Steven Johnson syndrome), TEN (toxic epidermal necrolysis), DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), serum sickness, Drug-induced cytopenia (thrombocytopenia, hemolytic anemia, Neutropenia & agranulocytosis), and Drug-induced organ damage which includes acute interstitial nephritis & drug-induced hepatitis.

Antibiotics allergy history

• Previous Use of Antibiotic
  • Ask if the patient has ever received the antibiotic before.
  • If yes, inquire about the most recent time they used it.
• Reaction Details
  • Ask what type of reaction the patient experienced.
• Allergy Symptom Assessment
  • Skin Rash
    • Differentiate between drug eruptions and urticaria:
      • Urticaria: Intensely pruritic, raised red plaques that appear and resolve within hours.
      • Drug Eruptions: Mild skin eruptions, which may be diffuse or localized, do not resolve quickly, and pruritus, if present, is less intense than urticaria.
  • Lips or Tongue Swelling
    • Indicates previous angioedema.
  • Breathing Issues
    • Breathing difficulty, wheezing, chest tightness, or repetitive dry cough might indicate a previous bronchospasm.
  • Throat Tightness or Voice Changes:
    • Might indicate laryngeal edema.
  • Severe Skin Reactions:
    • Ask if the patient has ever experienced a severe reaction that caused their skin to peel.
  • Joint Issues:
    • Inquire about any joint swelling or pain.
  • Organ and Blood Concerns:
    • Ask if they had any issues with their blood counts or kidney or liver function.
• Antibiotic allergies are not inherited, a family history of an allergy to a particular antibiotic is not a reason to avoid it.
• Some mild allergic reactions like isolated skin rash, sneezing, runny nose, or itchy eyes can resolve over 5-10 years. Therefore, an individual who experienced a penicillin allergy as a child may have outgrown that immune response. In such cases, a trial dose may be considered,

Miscellaneous Points

• If a patient develops a serious IgE-mediated or severe delayed-type allergic reaction to an antibiotic, that antibiotic and any related ones should be avoided.
• The cross-reactivity between penicillin and third-, fourth-, and fifth-generation cephalosporins is around 2-3%, while it can reach up to 10% with first-generation cephalosporins.
• In cases of serious penicillin allergies, cephalosporins and carbapenems should be avoided due to possible cross-reactivity. Aztreonam or other unrelated antibiotics are generally safe alternatives.
• For serious allergies to quinolones, all drugs in this class should be avoided. The same approach applies to macrolides, tetracyclines, and aminoglycosides.
• For sulfa drugs, cross-reactivity between antibiotic and non-antibiotic sulfa compounds is extremely low. An allergy to one type does not require avoiding the other. For example, if a patient has a serious allergy to trimethoprim/sulfamethoxazole, it is generally safe to use non-antibiotic sulfa drugs like furosemide or hydrochlorothiazide, and vice versa.

Clinical scenarios

(1) A 68 yo gentleman presented with LLQ abdominal pain, CT confirmed acute sigmoid diverticulitis with a contained perforation, IV piperacillin/tazobactam was ordered, and the electronic medical record give you a warning the patient is allergic to penicillins, what would you do?

There are two options here, first, go and find out more about this allergy as we explained earlier, and second which is the easiest option is to discontinue piperacillin/tazobactam and order an equally effective but unrelated antibiotic, In this case, we can discontinue piperacillin/tazobactam and start the patient on a combination of IV Levofloxacin and metronidazole instead, both antibiotics are unrelated to PCN.

(2) A 45-year-old lady was admitted with pyelonephritis, her previous urine culture grew klebsiella PNA sensitive to ceftriaxone but resistant to quinolones, the patient reported PCN allergy, what would you do?

The easy way is to use an equally effective but unrelated antibiotic, Aztreonam would be a perfect choice, despite belonging to the beta-lactam it has no cross-reactivity with penicillins, and it has a pure excellent gram-negative coverage.

In this case, we wanted to give her IV ceftriaxone, the cross-reactivity between PCN and 3rd, 4th, and 5th generation cephalosporins is around 2-3% so it’s really low but still exists so we asked the patient about her PCN allergy, in this case, the patient didn’t remember but was told she had the reaction as a child more, this likely indicates it was likely a mild reaction if anything, we decided to proceed with IV ceftriaxone with close clinical monitoring when giving the first dose, she tolerated it very well without any reaction.

Mild reactions like isolated skin rash, itchy eyes, or sneezing without any associated serious reactions IgE-mediated reactions (specifically talking any associated Urticaria, angioedema, bronchospasm, laryngeal edema, anaphylaxis, or hypotension) carry a very small risk of serious IgE-mediated reaction, in these patients, it’s safe to give 3rd, 4th, and 5th generation cephalosporins.

A couple of days later her culture was finalized as ESBL-producing klebsiella PNA which was resistant to ceftriaxone, Carbapenems are the drug of choice for such infection, if it is safe to give cephalosporins then it’s safe to give a carbapenem, the patient received meropenem without any complications.

(3) A 35 yo gentleman presented to the ED with right leg erythema, he was diagnosed with right leg cellulitis, the ER physician wanted to discharge the patient on cephalexin, but he has a PCN allergy described in the chart as a skin rash, would you give cephalexin or not?

I will not give Cephalexin without more information about the skin rash, cephalexin is a first-generation cephalosporin, and cross-reactivity with PCN can reach up to 10%, upon further questioning the patient reported that he received Amoxycillin a few months earlier where he developed intensely pruritic skin lesions, he visited local urgent care where he was given some treatment, those lesions disappeared later that evening! He clearly described urticaria which is an IgE-mediated reaction, these patients have a higher risk of developing a more serious IgE-mediated reaction if exposed to PCN or related antibiotics again.

So cephalexin or other first or second-generation cephalosporins,  the risk is less with 3rd, 4th, and 5th generations cephalosporins but still there, and the same applies to carbapenems.

Is there an equally effective unrelated oral antibiotic to treat the patient’s cellulitis? Clindamycin, trimethoprim/sulfamethoxazole, doxycycline, and linezolid, all these antibiotics can be used. This patient was discharged on oral clindamycin.

With IgE-mediated reactions, avoid all related antibiotics regardless of how low the cross-reactivity, if PCN or related antibiotic is required, a consult to infectious disease, and allergist is required. Inpatient Allergists consultations are only available in big centers, test dosing and desensitization may be performed then.

(4) A 60 yo lady presented with extreme fatigue one week after she was discharged on oral levofloxacin and metronidazole for acute diverticulitis treatment, the patient has a PCN allergy documented in her chart, the patient was diagnosed with UTI and admitted for IVF and antibiotic, her blood work showed leukopenia with WBC at 1.3 compared to 12 upon discharge, what empiric antibiotic would you pick for UTI?

Is levofloxacin or ciprofloxacin still a valid option given her penicillin allergy? The patient developed leukopenia following her discharge a week ago, which could potentially be a delayed allergic reaction to levofloxacin. However, in clinical practice, it’s challenging to definitively confirm or rule out this possibility at this time. We decided against using quinolones and documented quinolones allergy in her chart.

The best next step is to ask the patient about her PCN allergy, unfortunately, she didn’t know much about it, she grew up with PCN listed as one of her allergies! This likely indicates she doesn’t have any serious IgE-mediated reaction and we felt comfortable to start IV ceftriaxone.

Aztreonam is a good choice, as well, especially if we don’t have the time or energy to gather more info about her penicillin allergy.