Allergic Reactions to Penicillin: An Overview

Penicillin was the world's first antibiotic discovered, and it is still one of the most widely prescribed antibiotics nowadays. It has been used for a broad range of clinical indications and is effective against many different bacterial infections, including localized skin and soft tissue infections of the nose, throat, lower respiratory tract, and genitourinary tract. It is also commonly utilized for prophylaxis during gastrointestinal and/or genitourinary procedures (Miller, 2002). Despite being used to treat several infectious diseases, penicillin has been associated with some adverse effects. Allergic reactions to penicillin and its derivatives have been documented worldwide, with approximately 10% of the population reporting a history of allergic reaction. Because an allergic reaction to penicillin can be a life-threatening condition, it should be treated as a medical emergency (Miller, 2002).

Penicillin's Discovery, Mechanism of Action, and Risks Associated

In 1928, a chance event in a London laboratory changed the course of medicine. Alexander Fleming was a bacteriologist at St. Mary’s Hospital who returned from a vacation with his family and discovered something fascinating. Before Fleming went on vacation, he was working with a common bacteria named Staphylococcus aureus, a dangerous pathogen. Fleming left on his lab bench some bacteria in Petri dishes (a cylindrical glass-lidded dish containing a layer of a solid growing medium used to cultivate bacteria and fungi). After returning from his vacation, he noticed that the plate was contaminated with fungus. What intrigued him was that the bacteria were not able to grow in the area close to the fungus. There was a perfectly visible area surrounding the fungus –the zone of inhibition– that was completely free of bacteria. Therefore, Fleming discovered that a fungus (Penicillium notatum) was producing something that inhibited Staphylococcus aureus from growing. Fleming had just discovered an antibiotic, penicillin (Letek, 2020). Today, the penicillin family of antibiotics (also known as beta lactam antibiotics) includes penicillin derivatives of ampicillin and amoxicillin as well as cephalosporins, monobactams, carbapenems, and beta-lactamase inhibitors (Patterson & Stankewicz, 2023).

Figure 1: (A) Sir Alexander Fleming at his laboratory bench in London (1943). (B) Representation of the Petri dish where S. aureus was unable to grow in the area surrounding the colony of P. notatum (Letek, 2020).

Penicillin are bactericidal antibiotics, which act by inhibiting the activity of certain enzymes present in bacteria called penicillin-binding proteins (PBPs). The PBPs' activity is essential to the synthesis of the bacteria cell wall. In other words, in the presence of penicillin, bacteria are unable to produce the cell wall to protect themselves, so they eventually die (Lobanovska & Pilla, 2017). However, the use of penicillin and its derivatives comes with some concerns, and some factors may limit its use. For example, many bacteria can become resistant to penicillin either by producing enzymes that degrade these antibiotics (beta-lactamase) or by acquiring modified versions of the PBPs that do not bind to penicillin anymore. Antibiotic resistance has been attributed to the excessive and improper use of these drugs. Once the antibiotic resistance is confirmed during a patient's therapy, the current antibiotic should be discontinued and an alternative class of antibiotic should be employed (Lobanovska & Pilla, 2017). Furthermore, penicillin is one of the most frequently reported medications associated with hypersensitivity reactions (Patterson & Stankewicz, 2023), which is discussed further.

What is a Hypersensitivity Reaction?

Drug hypersensitivity reaction (DHR) is defined as a reaction clinically similar to an allergic reaction. Common signs and symptoms include nausea, vomiting, itching, rash and hives. These DHRs can be classified as immediate (occurring shortly after administration of the drug) and non-immediate (occurring after 1 hour to days after drug administration). Factors determining a patient's risk of an allergic response are not fully understood but include prior exposure, route of administration and dosage of the drug, genetic predisposition, age, and concomitant disease (Abrams & Khan, 2018).

Immediate Reactions

Hypersensitivity reactions can occur shortly after or within hours after penicillin administration (or beta lactam derivatives) and are usually mediated by immunoglobulin E (IgE) (Felix et al., 2021). IgE are antibodies produced by the immune system during allergic reactions. During an immediate hypersensitivity reaction, the patient can develop urticaria, which is characterized by hives (pruritic, transient, reddish papules disseminated throughout the body). In addition, cases of deep dermis edema may occur, which mainly affects the face (eyelids, lips, and ears) and genitalia and is accompanied by pain and heat (Felix et al., 2021). Ultimately, some patients develop anaphylaxis, a life-threatening condition that affects multiple body systems and results in wheezing, laryngeal oedema, and, ultimately, cardiovascular collapse. The patient may present symptoms such as pruritus in the palms of hands and soles of feet that become generalized, erythema, urticaria, dyspnea, hypotension, tachycardia, and loss of consciousness (Abrams & Khan, 2018).

Figure 2: Symptoms of penicillin allergy (Vincent, 2021).

Non-immediate Reactions

Non-immediate or late reactions occur within one hour to several days of the antibiotic administration and involve a wide spectrum of conditions. These reactions are not IgE-mediated but studies have suggested the involvement of T lymphocytes (Torres, Mayorga & Blanca, 2009). The most frequent type is the maculopapular rash, characterized by small, flat, and raised red spots on the skin, affecting mainly the chest, back, abdomen, and extremities. Another reaction is Stevens-Johnson syndrome, characterized by severe and painful bullous eruptions associated with fever that occur 4 to 28 days after administration of the drug (Felix et al., 2021). Another severe condition is the drug rash with eosinophilia and systemic symptoms (DRESS). DRESS is a severe reaction characterized by extensive skin rash, fever, and enlarged lymph nodes in association with visceral organ involvement (liver, kidneys, and lungs) (Abrams & Khan, 2018; Felix et al., 2021). Another example of a late hypersensitivity reaction is the serum sickness-like disease. Serum sickness manifestations include fever, swelling, joint pain, and rash. Symptoms can occur one to three weeks after first exposure to the drug (Abrams & Khan, 2018).

Diagnosis

A correct identification of allergy to penicilin is critical, as it has been demonstrated that 10% of patients report penicillin allergy but about 90% of people once considered allergic are ultimately able to tolerate penicillin (Har & Solensky, 2017). It is worth noting that many people are falsely labeled as being penicillin-allergic, as it can be associated with adverse reactions observed during childhood after a penicillin treatment and then carried on into adulthood. The wrong diagnosis can have an impact on treatment options for patients, due to fewer alternatives to effective antibiotics, prolonged hospitalizations and readmissions, increased treatment costs, and the development of multi-drug-resistant organisms (Har & Solensky, 2017). These are some examples of complications associated with misleading allergy diagnoses, but there are more. An important strategy is to develop educational programs for the lay public and healthcare professionals in order to improve recognition and diagnosis of hypersensitivity reactions to penicillin, thus reducing the negative impact on patient outcomes and healthcare systems and contributing to the overall effectiveness of antimicrobial treatments (Mabilat et al., 2022).

Figure 3: Accurate identification of penicillin allergy holds great significance in healthcare (JN Learning, n.d.).

All patients with suspected penicillin hypersensitivity should be evaluated, seeking the correct diagnosis. Allergy to penicillin should ideally be evaluated by a specialist healthcare professional when the patient is in good clinical condition. A thorough exam and appropriate diagnostic tests are essential for an accurate diagnosis. A physician will conduct a physical examination of the patient and ask questions about the symptoms and medical history. A patient may be referred to an allergy specialist (allergist) for the following tests:

Skin test: These tests can be performed on the volar surface of the forearm by percutaneously crossing the skin with a needle or a puncture device through a solution of the drug or by intracutaneous injection of the drug solution at the concentrations recommended for the test (Felix et al., 2021). Alternatively, adhesive strips containing the drug can be placed on the patient’s back or arm for 48 hours. Immediate reactions can be read within 20 minutes while late reactions can appear after 48 hours. A positive reaction to a test will cause a red, itchy, raised bump. A positive result indicates a high probability of a penicillin allergy, and a negative test result usually means the patient is not at high risk of developing an allergy to the antibiotic. However, a negative result can be challenging due to the possibility of a false-negative test, which is why some guidelines do recommend the inclusion of serum-specific IgE testing if skin testing is negative (Abrams & Khan, 2018). Skin tests are fast, easy to perform, low-cost, and safe. It is essential that these tests are performed by trained personnel in a setting with adequate support for reversing any anaphylactic reaction (e.g., a doctor’s office or a hospital). It is noteworthy that the incidence of adverse systemic reactions during penicillin tests is less than 1% (Felix et al., 2021).

Figure 4: Example of a positive penicillin skin test. PG penicillin G potassium, PRP pre-PEN benzylpenicilloyl, - normal saline negative control, + histamine positive control (Rimawi & Mazer, 2014).

Challenge test: If the diagnosis is uncertain, a graded drug challenge may be recommended. Challenge test is defined as the controlled administration of a medication to diagnose reactions to that drug. The main purpose of the challenge test is to confirm the negative test, in this case allowing the patient to be treated with penicillin. There are different protocols for the challenge test, but, in general, the patient receives up to five doses of the suspected penicillin, starting with a small dose and increasing to the desired dose. If the therapeutic dose (effective dose to treat the disease) is reached with no allergic reaction, then the doctor will conclude the patient isn't allergic to that type of penicillin. The patient will be able to take the drug as prescribed. If the patient is allergic to one type of penicillin, the doctor may recommend a graded challenge with a type of that is less likely to cause an allergic reaction. This procedure enables the doctor to identify an antibiotic that can be used safely (Har & Solensky, 2017).

Treatment Options

Treatment for a penicillin hypersensitivity reaction depends on the severity of the symptoms. When a reaction to penicillin is suspected, the first step is to interrupt exposure to the drug. Allergic processes are characterized by the release of large amounts of histamine, a molecule responsible for the symptoms of rash, itching, redness, and hives. During mild reactions, antihistamine can be given to the patient to neutralize histamine effects and relieve these symptoms. To help with other reactions such as swelling, a potent anti-inflammatory drug can be prescribed (e.g., corticosteroids). After the antibiotic treatment has been interrupted, antihistamines and corticosteroids can be prescribed for both immediate and non-immediate reactions (Green et al., 2023). In cases of anaphylactic shock, a severe reaction, epinephrine (the adrenaline hormone) needs to be injected immediately, in addition to the admission of the patient into a hospital in order to maintain blood pressure and support the patient’s breathing (Vaillant et al., 2023). Another treatment option is for patients that have a positive result on skin testing for penicillin allergy but still require treatment with it or a closely related antibiotic. In these cases, antibiotics are administered through a carefully observed desensitization process. Desensitization involves administering incremental doses of the drug in a monitored setting until the therapeutic dose is achieved. The purpose of desensitization is to induce tolerance to the drug without triggering adverse effects, and this is maintained only if the drug is administered continuously (Castellani et al., 2015).

Figure 5: Antibiotic allergy tests take place in a specialist allergy center (Cramp et al., 2018).

Case Study

During a routinary antenatal screening of a 25-year-old woman in her first trimester of pregnancy, positive results are obtained on serologic testing for syphilis. Standard treatment for syphilis in pregnancy consists of intramuscular injections of penicillin G benzathine, three times a week. However, the patient reports that she was told by her mother she suffered an allergic reaction to penicillin as a child, but the details of said allergic reaction neither the mother or the patient could actually recall (Castellani et al., 2015).

When a clear history cannot be elicited, skin testing is the method of choice for excluding an allergy to penicillin, and it can be safely performed during pregnancy. For safety reasons, a negative skin test result is typically followed by a graded challenge, which involves the administration of several incremental, subtherapeutic doses of penicillin. For patients who tolerate this graded challenge, penicillin can be prescribed. The patient was referred to an allergist for penicillin skin testing, the result of which was negative. This was followed by a graded challenge, which was tolerated. The patient was subsequently treated with intramuscular penicillin G benzathine for syphilis without adverse events. Her allergy history was updated in her clinic records to indicate that she did not have an allergy to penicillin (Castellani, Gold & MacFadden, 2015).

Conclusion

Hypersensitivity to penicillin can cause serious health conditions. This adverse effect is inherent in the use of this substance and deserves investigation. Around 10% of patients report penicillin allergy, but studies have shown that most individuals that report penicillin alergy can actually tolerate this medication. These patients are often in need of alternative medicines, which can lead to ineffective treatment, as shifting to alternative antibiotics carries its own set of risks, including the emergence of antimicrobial resistance, prolonged hospital stays, as well as increased readmission rates and treatment costs. A veridic penicillin allergy can be serious and warrant investigation, which is why reliable testing is mandatory. Therefore, it is necessary that tests to detect allergy to penicillin and its derivatives are carried out by trained professionals and in suitable facilities for this purpose.

Figure 6: It is recommended that individuals suspected of being allergic to penicillin undergo hypersensitivity testing (SLMA, n.d.).

Meanwhile, researchers have been working to develop new strategies to improve the investigation of hypersensitivity reactions to penicillin, in addition to more efficient antimicrobial therapies. Furthermore, is of paramount importance the development of educational programs, both for the lay public and for non-specialist healthcare professionals, in order to improve recognition, diagnosis, and treatment of hypersensitivity reactions to penicillin and its derivatives. It is of utmost importance that individuals suspected of being allergic to penicillin or its derivatives undergo hypersensitivity testing. This practice may lead patients to more appropriate treatment, thus improving antibiotic interventions.

Bibliographical References

Abrams, E. M., & Khan, D. A. (2018). Diagnosing and managing drug allergy. CMAJ, 190(17), E532-E538. https://doi.org/10.1503/cmaj.171315

Castellani, L. R., Gold, W. L., & MacFadden, D. R. (2015). A 25-year-old woman reporting an allergy to penicillin. CMAJ, 187(14), 1065-1066. https://doi.org/10.1503/cmaj.141123

Felix, M. M. R., Aun, M. V., Menezes, U. P., Queiroz, G., Rodrigues, A. T., D'Onofrio-Silva, A. C., . . . Malaman, M. F. (2021). Allergy to penicillin and betalactam antibiotics. Einstein (Sao Paulo), 19, eMD5703. https://doi.org/10.31744/einstein_journal/2021MD5703

Green, E. A., Fogarty, K., & Ishmael, F. T. (2023). Penicillin Allergy: Mechanisms, Diagnosis, and Management. Prim Care, 50(2), 221-235. https://doi.org/10.1016/j.pop.2022.11.002

Har, D., & Solensky, R. (2017). Penicillin and Beta-Lactam Hypersensitivity. Immunol Allergy Clin North Am, 37(4), 643-662. https://doi.org/10.1016/j.iac.2017.07.001

Justiz Vaillant, A. A., Vashisht, R., & Zito, P. M. (2023). Immediate Hypersensitivity Reactions. In StatPearls. StatPearls Publishing.

Lobanovska, M., & Pilla, G. (2017). Penicillin's Discovery and Antibiotic Resistance: Lessons for the Future?. The Yale journal of biology and medicine, 90(1), 135–145.

Mabilat, C., Gros, M. F., Van Belkum, A., Trubiano, J. A., Blumenthal, K. G., Romano, A., & Timbrook, T. T. (2022). Improving antimicrobial stewardship with penicillin allergy testing: a review of current practices and unmet needs. JAC Antimicrob Resist, 4(6), dlac116. https://doi.org/10.1093/jacamr/dlac116

Miller, E. L. (2002). The penicillins: a review and update. J Midwifery Womens Health, 47(6), 426-434. https://doi.org/10.1016/s1526-9523(02)00330-6

Patterson, R. A., & Stankewicz, H. A. (2023). Penicillin Allergy. In StatPearls. StatPearls Publishing.

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