Penicillin Allergy: Symptoms, Risks, and Alternatives

May 6, 2025

Penicillin allergy is an immune-mediated reaction that occurs when the body identifies penicillin or its breakdown products as harmful, triggering an allergic response. Although penicillin is a widely used and highly effective antibiotic, originally discovered by Alexander Fleming in 1928 and first used extensively during World War II, it remains one of the most commonly reported drug allergies.

In individuals with penicillin allergy, the immune system overreacts to the drug, leading to symptoms that can range from mild skin rashes and hives to severe, potentially life-threatening anaphylaxis. While many people report a history of penicillin allergy, true allergic reactions are confirmed in only a small proportion of cases, often through skin testing or other diagnostic measures.¹

Why does Penicillin Allergy occur?

Penicillin allergy occurs when the immune system mistakenly identifies penicillin or its breakdown products as harmful. These compounds can bind to proteins in the body, forming antigenic complexes that trigger an immune response in susceptible individuals. This response often involves the release of IgE antibodies and other inflammatory mediators, which can result in symptoms ranging from mild rashes to severe complications like anaphylaxis.² Because of this hypersensitivity reaction, individuals with a penicillin allergy must avoid the drug, and doctors usually recommend alternative antibiotics.³

How do I know if I am allergic To Penicillin?

If you experience an allergic reaction after taking a penicillin antibiotic, such as the appearance of a skin rash, hives (urticaria), swelling, or difficulty breathing, it may indicate that you are allergic to penicillin. In some cases, more severe reactions may occur, requiring immediate medical attention.

Symptoms of Penicillin Allergy

Generally speaking, it is often reported that individuals with a history of asthma, eczema, and fever are typically more inclined towards developing penicillin allergy. However, it cannot be applied to each individual. Individuals often present to the doctor with different concerns; their intensity and allergic symptoms vary. Most patient comes with the complaint of the following symptoms:⁴

Woman with Facial swelling and redness from penicillin allergy. — Swelling and redness of the face in penicillin allergy

Common allergic symptoms: Hives, itching or rash, swelling of the face, swelling of the feet, hands, and face (angioedema).
Severe symptoms: Swelling of the throat and tongue, trouble breathing, low blood pressure (potential anaphylaxis).
Other symptoms: Nausea, abdominal pain, diarrhea, vomiting (side effects, not true allergic reactions).

A patient experiencing hives (urticaria) after taking penicillin

Types of Hypersensitivity Reactions to Penicillin

Penicillin allergy reactions are classified into different types based on the underlying immunologic response. These hypersensitivity reactions can also be categorized based on the timing of symptoms, which helps clinicians determine the nature of the allergic response.

Type	Immune Mechanism	Timing	Symptoms
Type I	IgE-mediated (Immediate)	Typically within 1 hour, but up to 6 hours	Anaphylaxis, hives, difficulty breathing, swelling
Type II	Cytotoxic (IgG- or IgM-mediated)	Hours to days after administration	Hemolytic anemia, thrombocytopenia, and blood cell destruction
Type III	Immune complex (IgG/IgM-mediated)	Occurs days after administration	Serum sickness: fever, rash, joint pain, lymph node swelling
Type IV	T-cell-mediated (Delayed)	More than 1 hour, often days later	Hemolytic anemia, thrombocytopenia, and blood cell destruction

Based on the Timing of Symptoms

Types of penicillin allergic reactions can also be categorized based on the timing of the immune response.

Immediate Reactions

These reactions occur within 1 hour after administration and are usually IgE-mediated (Type I). Symptoms may include anaphylaxis, hives, or angioedema.

Nonimmediate (Delayed) Reactions

These reactions happen more than 1 hour after administration, often several hours to days later. They are typically T-cell-mediated reactions (Types II, III, or IV) and can involve rashes, organ damage, or other systemic effects. The two main types of delayed cutaneous reactions reported with penicillins are maculopapular (Morbilliform) eruptions and urticarial eruptions.

Penicillin Allergy: A common issue?

Penicillin allergy is one of the most commonly reported drug allergies, but true allergic reactions are much less common than people believe. It is estimated that around 10% of the U.S. population reports a penicillin allergy, but over 90% of these individuals are not truly allergic upon further testing. This discrepancy often results from childhood reactions that were never reevaluated, or from symptoms that were not caused by allergy in the first place.

Many people mistakenly associate gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, with an allergy when, in fact, these are side effects, not immune-mediated responses.

Over time, even patients who experienced a genuine IgE-mediated allergic reaction may lose their sensitivity. Studies have shown that about 80% of patients outgrow their penicillin allergy within 10 years, meaning they can safely take penicillin again after allergy testing.⁵

Understanding Penicillin Allergy and Cross-Reactivity

Penicillin is commonly prescribed to treat bacterial infections, especially those caused by staphylococcal and streptococcal bacteria. However, many people with a history of penicillin allergy are often confused about whether they can take related antibiotics safely.

The penicillin family includes several related antibiotics. All of them share a basic structure made up of a beta-lactam ring and a thiazolidine ring. This base structure is what helps kill bacteria, but it’s also what can trigger an allergic reaction in some people. These include natural penicillins (penicillin G, penicillin V, benzathine penicillin), antistaphylococcal penicillins (dicloxacillin, nafcillin, oxacillin), aminopenicillins (amoxicillin, ampicillin), and extended-spectrum penicillins (piperacillin-tazobactam).⁶

In addition to these, other antibiotics that contain the beta-lactam ring and may exhibit cross-reactivity in penicillin-allergic individuals include:

Cephalosporins (e.g., cefalexin, ceftriaxone)
Carbapenems (e.g., imipenem, meropenem)
Monobactams (e.g., aztreonam)

These antibiotics are related to penicillin and are known for their strong antibacterial properties. What makes them different from each other is the chain structure attached to the core ring. These slight changes in structure can affect how your body reacts to them.⁷

In some cases, people who are allergic to penicillin may also react to cephalosporins or other related antibiotics, especially if their chemical side chains are similar. But this isn’t always the case. For example, monobactams usually don’t cause allergic reactions in people with penicillin allergy unless they are allergic to a specific type, like ceftazidime, which has a similar side chain.

That’s why doctors are careful when prescribing antibiotics to anyone with a known penicillin allergy. They look at the exact type of reaction the person had in the past and choose the safest alternative.

How to diagnose Penicillin Allergy?

Generally, patients with penicillin allergy are referred to expert allergists and immunologists. They help diagnose the allergy and begin with the basic questions to understand the history, symptoms, and intensity of the symptoms. After a careful history and initial examination, patients with penicillin allergy are prescribed a skin test. For penicillin allergy, skin testing is a common and reliable method. While skin prick testing (SPT) is widely used for food allergies, penicillin allergy testing usually involves both a skin prick test and an intradermal test, using a standardized panel that includes the major and minor determinants of penicillin.

In the skin prick test, a small amount of the allergen is placed on the skin, usually on the forearm or back, and the skin is lightly pricked. If there is no reaction, an intradermal test follows, where a small amount of the allergen is injected just under the skin. The test sites are then monitored for signs of an allergic reaction, such as raised red bumps (wheals) or redness. A positive result suggests sensitivity to penicillin.

These tests are FDA-approved and should only be performed in a clinical setting under medical supervision due to the risk of allergic reactions.

A doctor is doing a skin prick test to diagnose penicillin allergy

Sometimes, after a negative skin test result, doctors administer a supervised oral dose of penicillin to confirm tolerance. Additionally, a blood test may be recommended to detect penicillin-specific IgE antibodies, which can help identify whether the patient has an IgE-mediated allergy to the antibiotic.⁸

Alternative Antibiotic Options for Penicillin-Allergic Patients

Penicillin is used to treat various infectious diseases that are caused by the following:

Gram-positive cocci
Gram-negative cocci
Most Anaerobes

Since penicillin is used as an antibiotic, it is prescribed to individuals affected by various infections, such as:

Strep Infections
Urinary tract infections (UTI)
Ear infections

When a penicillin allergy is confirmed, selecting an appropriate alternative depends on the infection being treated, its severity, and the patient’s individual allergy history. Cross-reactivity with other beta-lactams like cephalosporins and carbapenems must also be considered, although true cross-reactivity is relatively rare, especially with later-generation cephalosporins.
Here are recommended alternatives by infection type:

Urinary Tract Infections (UTIs):

In cases of urinary tract infections, alternatives differ by gender and infection type. Females with lower UTIs are typically treated with nitrofurantoin or trimethoprim, while upper UTIs in females are more often managed with co-trimoxazole or gentamicin. In males, trimethoprim or ciprofloxacin is generally prescribed to treat UTIs, considering both efficacy and tolerability.⁹

Intra-abdominal and Peritoneal Infections:

For intra-abdominal infections and peritonitis, especially in more severe presentations, physicians may recommend intravenous vancomycin combined with metronidazole and gentamicin. However, these regimens should be administered with caution and only under proper medical supervision due to their potential side effects and need for monitoring.

Alternatives for Respiratory Tract Infections:

Respiratory tract infections require different choices based on whether the infection is in the upper or lower tract. Doxycycline is commonly used for infective exacerbations of chronic obstructive pulmonary disease (COPD) and as a first-line alternative for sinusitis and other upper respiratory infections. In more serious lower respiratory infections such as pneumonia, clinicians may prescribe a combination of antibiotics, including intravenous vancomycin, metronidazole, gentamicin, or levofloxacin, with the final decision depending on the suspected pathogen and disease severity.¹⁰

Alternatives for skin Infections:

For skin infections like cellulitis, doxycycline is frequently chosen as a safe and effective alternative. In cases involving animal bites, a combination of metronidazole and doxycycline is typically recommended to ensure coverage against both aerobic and anaerobic organisms.

Is Penicillin Allergy hereditary?

A common question among individuals is whether penicillin is a genetic disease. The answer is no; it is not a hereditary disease. Even if any of your family members have experienced adverse effects after taking penicillin and are allergic, that does not mean you or other family members will experience the same. Therefore, it is important to understand that you can take penicillin even if someone in your family is allergic and reports multiple symptoms or side effects.

Treatment of Penicillin Allergy

When experiencing an allergic reaction to penicillin, it’s important to stay calm and follow the correct steps to minimize harm. Immediate medical attention is crucial to prevent complications. Below are the key steps to take when managing penicillin allergies:

Discontinue the medication:

The first and most important step is to stop taking the medication immediately if symptoms of an allergic reaction are observed. Prompt action is essential to prevent the situation from worsening.

Seek medical attention

After discontinuing the medication, the patient must seek medical care as soon as possible. A healthcare provider will assess the severity of the reaction by measuring vital signs like blood pressure and oxygen saturation. A detailed history of the symptoms will help doctors determine the underlying cause of the allergic reaction.

Administration of anti-allergic medications

In most cases, doctors will prescribe antihistamines or steroids to mitigate the allergic response. These medications help to block the effects of histamine, the chemical responsible for triggering allergic reactions.

Treatment for severe reactions (Anaphylaxis)

In rare instances, penicillin allergies can trigger a severe reaction known as anaphylaxis. Symptoms may include shortness of breath, dizziness, or even loss of consciousness. In such cases, it is critical to transport the patient to an emergency facility immediately. Medical professionals may administer oxygen to improve oxygen saturation and epinephrine to counteract the severe allergic reaction.

Although not all individuals with penicillin allergies experience severe reactions, it’s important to understand that severe symptoms can occur unexpectedly. Therefore, prompt medical intervention is necessary to prevent any potential complications.

Conclusion

In conclusion, penicillin allergy is fairly common, and people with this allergy often need alternative medications. Recently, doctors have started prescribing other medications for bacterial infections that are safer for those with penicillin allergies. In severe cases, an epinephrine injection may be needed to prevent serious complications.

Penicillin allergies can cause serious symptoms, so if you experience any, it’s important to get a full medical check-up. Immediate medical care can help resolve the issue. If a doctor suggests an alternative medication, it’s important to follow their advice. Over time, some people may become less sensitive to penicillin, which could lead to a negative test result.

Refrences

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2
Idsoe O, Guthe T, Willcox RR, de Weck AL. Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull World Health Organ. 1968;38(2):159-88. PMID: 5302296; PMCID: PMC2554321.
3
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Sarfani, S., Stone, C. A., Jr, Murphy, G. A., & Richardson, D. R. (2022). Understanding Penicillin Allergy, Cross-reactivity, and Antibiotic Selection in the Preoperative Setting. The Journal of the American Academy of Orthopaedic Surgeons, 30(1), e1–e5. https://doi.org/10.5435/JAAOS-D-21-00422
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Sarfani, S., Stone, C. A., Jr., Murphy, G. A., & Richardson, D. R. (2022). Understanding penicillin allergy, cross-reactivity, and antibiotic selection in the preoperative setting. Journal of the American Academy of Orthopaedic Surgeons, 30(1), e1–e5. https://doi.org/10.5435/JAAOS-D-21-00422
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Shenoy, E. S., Macy, E., Rowe, T., & Blumenthal, K. G. (2019). Evaluation and Management of Penicillin Allergy: A Review. JAMA, 321(2), 188–199. https://doi.org/10.1001/jama.2018.19283
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Ramlakhan, S., Singh, V., Stone, J., & Ramtahal, A. (2014). Clinical options for the treatment of urinary tract infections in children. Clinical medicine insights. Pediatrics, 8, 31–37. https://doi.org/10.4137/CMPed.S8100
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