The classical case of PA develops within a few minutes after administration of penicillin and is a IgE-mediated type I hypersensitivity reaction. Histamine, prostaglandins, leukotrienes and platelet activating factors are released and cause systemic symptoms of different severity.

Histamine increases vascular permeability and this effect provokes angioedema, flushing, urticaria and edema of the mucous membranes, particularly visible in lips, oral cavity and the upper respiratory tract. Blood pressure decreases significantly.

Stimulation of sensory nerve endings by histamine causes pruritus of skin and mucous membranes. Patients often claim their eyes and oral mucosa to itch. Mucous membrane swelling in the respiratory tract is further complicated by spasms of smooth muscles. Wheezing may be a sign of life-threatening bronchospasm. Smooth muscle spasms also lead to abdominal cramps. Gastric acid secretion is stimulated. Consequently, patients report nausea and vomiting.

Light-headedness and headaches have been observed.

Severe hypotension and respiratory distress are signs of advanced anaphylaxis and may trigger a fatal anaphylactic shock.

In rare cases, symptoms similar to acute PA are observed within several hours or even a few days after administration of penicillin. Here, dermatological symptoms, mucous membrane alterations and respiratory problems similar to these described above may be observed, but hypotension is usually not an issue.

The above mentioned IgG-mediated form of PA is associated with urticaria, fever, arthralgias and arthritis and may manifest up to one week after penicillin application.

• Swelling

  For more serious problems such as swelling, she might give you a medicine called a corticosteroid. With anaphylaxis, she may give you a drug called epinephrine right away. [webmd.com]

  Nephritis or swelling of the kidneys, which can lead to uremia, concussion, fever and general swelling Drug reaction with eosinophilia and systemic symptoms (DRESS), which causes high white blood cell counts, rashes, general swelling and recurrence of [news-medical.net]

  If your mast cells carry IgE antibodies to penicillin on their surface, then you react to the reagents introduced by forming a local swelling, redness, and itching. [trinityallergy.com]

  The most common allergic reactions were rash (37%), unknown/undocumented (20.2%), hives (18.9%), swelling/angioedema (11.8%), and anaphylaxis (6.8%). [ncbi.nlm.nih.gov]

• Pain

  Low Back Pain, Disabling Low Back Pain, Lumbar Spinal Stenosis Lumbar Puncture Malaria Malnourishment, Adult Medical Decision-Making Capacity Melanoma Meningitis, Adult Menopause Migraine Mononucleosis Murmur, Diastolic Murmur, Systolic Myasthenia Gravis [jamaevidence.mhmedical.com]

  Is skin testing painful and what are the risks? A skin prick test, also called a scratch test, checks for immediate allergy and is the first step in skin testing. Skin prick testing is usually not painful. [aaaai.org]

  I would have to be force fed antibiotics because every time I would take an antibiotic, like penicillin, it would make me vomit, give me uncomfortable rashes, cause horrible stomach pains, fevers and so forth. [americanmedical-id.com]

  The computerized system used a series of questions about the patient's past allergic reactions to penicillin, such as whether the patient experienced a rash, fever, or joint pain. [invisiverse.wonderhowto.com]

  Side effects of antibiotics that affect the digestive system include: vomiting nausea (feeling like you may vomit) diarrhoea bloating and indigestion abdominal pain loss of appetite These side effects are usually mild and should pass once you finish your [nhs.uk]

• Anemia

  They include nonpruritic maculopapular eruptions, hemolytic anemia, serum sickness, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, acute interstitial nephritis, and toxic epidermal necrolysis. 9 Ask about previous and current [mdedge.com]

  Procaine penicillin G is a parenteral preparation that gives extended action for up to 24 hours and benzathine penicillin G is a very slow-release, parenteral preparation that maintains blood levels for several days. penicillin-induced hemolytic anemia [medical-dictionary.thefreedictionary.com]

  Examples of these reactions include the following: Drug-induced anemia, where the production of red blood cells is reduced leading to arrhythmia, fatigue, and difficulty breathing Serum sickness, which can cause rashes, fever, pain in the joints, nausea [news-medical.net]

  For patients with a history of severe non–IgE-mediated reaction, such as Stevens-Johnson syndrome or hemolytic anemia, use of an alternative antibiotic class should be advised. [pharmacytimes.com]

• Unconsciousness

  A medical ID bracelet or necklace can speak for you in emergencies when you may be unconscious or unable to. [americanmedical-id.com]

  […] rapid heartbeat increasing difficulty breathing caused by swelling and tightening of the neck a sudden intense feeling of apprehension and fear a sharp and sudden drop in your blood pressure, which can make you feel light-headed and confused falling unconsciousness [nhs.uk]

  “Regretfully, all of us will most likely end up in a situation where we need an antibiotic, and an unconscious patient can't provide a history. Testing for and ruling out penicillin allergy clears the way for a broader range of treatment options.” [acphospitalist.org]

• Fatigue

  Examples of these reactions include the following: Drug-induced anemia, where the production of red blood cells is reduced leading to arrhythmia, fatigue, and difficulty breathing Serum sickness, which can cause rashes, fever, pain in the joints, nausea [news-medical.net]

• Vomiting

  These low-risk symptoms included rash, itching, vomiting, diarrhea, runny nose, and cough. They also included children whose parents said they were allergic because of a family history of allergy. [health.harvard.edu]

  People with a more severe reaction may experience anaphylaxis which includes symptoms such as tightening of the throat and airways, drop in blood pressure, dizziness, lightheadedness, nausea, vomiting, diarrhea, rapid pulse and loss of consciousness. [requestatest.com]

  Consequently, patients report nausea and vomiting. Light-headedness and headaches have been observed. Severe hypotension and respiratory distress are signs of advanced anaphylaxis and may trigger a fatal anaphylactic shock. [symptoma.com]

  The researchers found that 302 of the children had previously experienced low-risk symptoms for penicillin allergy, including rash, vomiting, or diarrhea, according to parents. [clinicaladvisor.com]

  Side effects of antibiotics that affect the digestive system include: vomiting nausea (feeling like you may vomit) diarrhoea bloating and indigestion abdominal pain loss of appetite These side effects are usually mild and should pass once you finish your [nhs.uk]

• Nausea

  People with a more severe reaction may experience anaphylaxis which includes symptoms such as tightening of the throat and airways, drop in blood pressure, dizziness, lightheadedness, nausea, vomiting, diarrhea, rapid pulse and loss of consciousness. [requestatest.com]

  Consequently, patients report nausea and vomiting. Light-headedness and headaches have been observed. Severe hypotension and respiratory distress are signs of advanced anaphylaxis and may trigger a fatal anaphylactic shock. [symptoma.com]

  The signs and symptoms of this reaction include the following: Tightened airways causing difficulty breathing Stomach cramps Nausea and vomiting Diarrhea Rapid or weak pulse Dizziness Fall in blood pressure Seizure Loss of consciousness In some cases, [news-medical.net]

  Common side effects include fast, irregular or “pounding” heartbeat, sweating, nausea or vomiting, breathing problems, paleness, dizziness, weakness, shakiness, headache, feelings of over excitement, nervousness or anxiety. [epipen.com]

  Symptoms include difficulty breathing, hives, wheezing, dizziness, loss of consciousness, rapid or weak pulse, skin turning blue, diarrhea, nausea, and vomiting. [cigna.com]

• Abdominal Pain

  Side effects of antibiotics that affect the digestive system include: vomiting nausea (feeling like you may vomit) diarrhoea bloating and indigestion abdominal pain loss of appetite These side effects are usually mild and should pass once you finish your [nhs.uk]

  Myocardial Infarction Opiates and Abdominal Pain Osteoporosis Otitis Media, Child Paracentesis Parkinsonism Penicillin Allergy Peripheral Arterial Disease Pertussis, Adult or Adolescent Pleural Effusion Pleural Effusion, Thoracentesis Pneumonia, Adult [jamaevidence.mhmedical.com]

  Some of these reactions could be: Rash and itching Fever Nausea Abdominal pain, diarrhea, or vomiting Irregular heartbeat Tightness in the chest, difficulty breathing Swelling Unconsciousness Anaphylaxis Penicillin is the most common cause of anaphylaxis [americanmedical-id.com]

• Arthralgia

  The above mentioned IgG-mediated form of PA is associated with urticaria, fever, arthralgias and arthritis and may manifest up to one week after penicillin application. Symptoms associated with PA are little specific. [symptoma.com]

• Urticaria

  OBJECTIVES: To determine the prevalence of self-reported penicillin allergy in patients with chronic urticaria and the prevalence of chronic urticaria in patients with self-reported penicillin allergy. [ncbi.nlm.nih.gov]

  Urticaria, pruritus, transient erythema and angioedema are typical dermatological symptoms. Mucous membranes show hypersecretion. [symptoma.com]

• Angioedema

  Urticaria, pruritus, transient erythema and angioedema are typical dermatological symptoms. Mucous membranes show hypersecretion. [symptoma.com]

  The most common allergic reactions were rash (37%), unknown/undocumented (20.2%), hives (18.9%), swelling/angioedema (11.8%), and anaphylaxis (6.8%). [ncbi.nlm.nih.gov]

  Penicillin and Cephalosporin Cross-Reactivity and Risk for Allergic Reaction Summary : A Type I hypersensitivity reaction is IgE-mediated and often causes urticaria, angioedema, bronchospasm, pruritus, or anaphylaxis within minutes to hours of the medication [ebmconsult.com]

  The most common manifestations of sensitivity have been urticaria and angioedema. 1 2 3 Contact dermatitis among persons handling the drug has also been described, 4 5 6 7 and vesicular dermatitis is not rare. 8, 9 Reactions similar to the Arthus phenomenon [nejm.org]

• Skin Rash

  Common symptoms include skin rash, hives, itching, fever, shortness of breath, runny nose and itchy or watery eyes. [requestatest.com]

  During an allergic reaction, histamine and other chemicals can cause symptoms that include: Hives Skin rash Itchy skin or eyes Congestion Swelling in the mouth and throat Symptoms of more serious reactions include: Difficulty breathing Blueness of the [my.clevelandclinic.org]

  In most cases, the allergic reaction is mild to moderate and can take the form of: a raised, itchy skin rash (urticaria, or hives) coughing wheezing tightness of the throat, which can cause breathing difficulties These mild to moderate allergic reactions [nhs.uk]

  Hives that suggest true allergy are raised, intensely itchy spots that may appear and change within hours – but not all skin rashes are hives. Non-allergy-related rashes may be flat, blotchy, and spread over days rather than hours. [prnewswire.com]

  rashes, fever, swelling, difficulty breathing, runny nose and watery eyes. [news-medical.net]

• Pruritus

  Urticaria, pruritus, transient erythema and angioedema are typical dermatological symptoms. Mucous membranes show hypersecretion. [symptoma.com]

  The majority of patients experienced a rash with or without pruritus and fever. [ncbi.nlm.nih.gov]

  Penicillin and Cephalosporin Cross-Reactivity and Risk for Allergic Reaction Summary : A Type I hypersensitivity reaction is IgE-mediated and often causes urticaria, angioedema, bronchospasm, pruritus, or anaphylaxis within minutes to hours of the medication [ebmconsult.com]

  Symptoms consistent with IgE-mediated reactions include urticaria (most common), pruritus, angioedema, laryngeal edema, wheezing, shortness of breath, presyncope or syncope, hypotension, and cardiorespiratory collapse. [mdedge.com]

• Dizziness

  People with a more severe reaction may experience anaphylaxis which includes symptoms such as tightening of the throat and airways, drop in blood pressure, dizziness, lightheadedness, nausea, vomiting, diarrhea, rapid pulse and loss of consciousness. [requestatest.com]

  Fifteen persons (3.0%; 95% CI, 1.83%-4.98%) had subjective oral challenge reactions, either acute transient itching or dizziness. All were women and 11 (73.3%) had multiple drug intolerance syndrome. None had severe reactions or objective signs. [ncbi.nlm.nih.gov]

  If it is very severe, signs of anaphylaxis can occur, which are wheezing, dizziness and/or loss of consciousness. If there are signs of anaphylaxis, administration of epinephrine should occur immediately. [allergylosangeles.com]

  Common side effects include fast, irregular or “pounding” heartbeat, sweating, nausea or vomiting, breathing problems, paleness, dizziness, weakness, shakiness, headache, feelings of over excitement, nervousness or anxiety. [epipen.com]

  Symptoms include difficulty breathing, hives, wheezing, dizziness, loss of consciousness, rapid or weak pulse, skin turning blue, diarrhea, nausea, and vomiting. [cigna.com]

• Headache

  Common side effects include fast, irregular or “pounding” heartbeat, sweating, nausea or vomiting, breathing problems, paleness, dizziness, weakness, shakiness, headache, feelings of over excitement, nervousness or anxiety. [epipen.com]

  Light-headedness and headaches have been observed. Severe hypotension and respiratory distress are signs of advanced anaphylaxis and may trigger a fatal anaphylactic shock. [symptoma.com]

• Irritability

  Floaters and Flashes Fluid Responsiveness in Unstable Patients Generalized Anxiety or Panic Disorder Glaucoma Goiter Head Trauma Health Literacy Hearing Impairment Heart Failure Hepatomegaly Hypertension Hypovolemia, Adult Hypovolemia, Child Influenza Irritable [jamaevidence.mhmedical.com]

  […] include: Itching of skin Urticaria (hives) and/or angioedema Swollen lips and tongue, swollen face Tightening of throat Hoarseness Shortness of breath (trouble breathing), wheezing, asthma-like symptoms Runny or stuffy nose Watery eyes, redness, and irritation [dovemed.com]

• Vertigo

  Sleep Apnea Splenomegaly Streptococcal Pharyngitis Stroke Stroke, Hemorrhagic Temporal Arteritis Thoracic Aortic Dissection Upper Gastrointestinal Bleed Urinary Incontinence, Women Urinary Tract Infection, Child Urinary Tract Infection, Women Vaginitis Vertigo [jamaevidence.mhmedical.com]

Symptoms associated with PA are little specific. Indeed, a wide variety of allergens may trigger type I hypersensitivity reactions. The most certain indicator as to the trigger is a temporal link between drug application and symptom onset. This applies at least to the acute form of PA; it may be even harder to establish a connection between delayed allergic reactions and penicillin administration.

A skin test is recommended to proof the causative relation between the drug, histamine liberation, angioedema and urticaria. Here, penicillin G, its antigenic determinants, positive and negative controls should be applied. A positive reaction towards penicillin G, its major antigenic determinant or any of the minor determinants provides evidence that the individual possesses anti-penicillin IgE. Major and minor antigenic determinants are commercially available for skin testing. They account for 95 and 5% of PA cases, respectively.

Some experts also recommend to carry out an oral or graded challenge, but these carry considerable risks and should only be considered in cases of mild PA.

Of note, a positive skin test does not render a patient unfit to receive beta-lactam antibiotics for life. Many individuals that once tested positive yield negative results if the test is repeated after a few years. It has also been shown that the likelihood of a PA in patients with negative skin test findings is as high as the probability for this adverse event to occur in those that tested positive.

• Staphylococcus Aureus

  aureus infections and vancomycin-resistant enterococcus. [ncbi.nlm.nih.gov]

• Penicillium

  They are derived from Penicillium fungi. [en.wikipedia.org]

  […] danger of anaphylaxis, the patient may be desensitized with gradually increasing doses of penicillin. penicillin any of a large group of natural or semisynthetic antibacterial antibiotics derived directly or indirectly from strains of fungi of the genus Penicillium [medical-dictionary.thefreedictionary.com]

  Fungi penicillium were used for the production of the first penicillin antibiotic. Image Credit: Kateryna Kon / Shutterstock.com Penicillin allergy refers to situations when the immune system reacts abnormally to penicillin. [news-medical.net]

There are two principal therapeutic approaches to PA. On the one hand - and this is most frequently done - the current reaction against the drug is treated with anti-allergic compounds and if antibiotic therapy needs to be continued, another drug is given. Because of the high probability of cross-reactions, other beta-lactam antibiotics, particularly other penicillins, should not be administered either. On the other hand, a causative treatment in form of a desensitization may be realized. In any case, the current therapy with penicillin should be ceased.

Treatment with anti-histamines like clemastine, dimethindene or diphenhydramine is often sufficient in mild cases [5] [6]. These drugs provide relieve from angioedema, urticaria and pruritus. More severe symptoms like light-headedness, nausea, vomiting, hypotension and respiratory distress require application of corticosteroids. These patients should be monitored in order to guarantee early detection of first signs of anaphylaxis. The latter is the most serious form of PA, indicates immediate administration of adrenaline and constant control of blood pressure and respiratory function. If treatment of anaphylaxis is not initiated in a timely manner, it carries a high risk of death [7].

Penicillin desensitization should only be considered if there are little alternatives to penicillin therapy in order to treat the patient's primary disease [4]. A typical desensitization scheme starts with a dose that is at least six orders of magnitude below the therapeutic dose. After about half an hour, the following dose, 10-fold higher than the previous one, may be applicated. This scheme should be continued until a full dose has been administered [8].

Prognosis is excellent for the vast majority of PA patients. Most PA cases are mild allergic reactions that can be easily managed with anti-histamines and symptoms subside after a very short time.

With regards to the rare cases of penicillin-triggered anaphylaxis, immediate medical attention is required for a good prognosis. If left untreated, a fatal anaphylactic shock can develop [4].

Up to date, it is not possible to predict if a determined patient is or will be at one point in their lives allergic to penicillin. Epidemiologic changes in PA incidence rates have been observed over time and presumably result from a combination of internal and external stimuli that have undergone alterations, too.

Genetic factors have been proposed to influence susceptibility to PA, but the fact that some patients are perfectly fine with penicillin treatments before suddenly presenting an adverse reaction argues against genetics being the only trigger of this condition. Also, patients who were once found allergic to penicillin not necessarily stay allergic and may tolerate the drug if it is administered years later. Environmental factors seem to play another important role in provoking the type I hypersensitivity reaction behind PA.

Oral application of penicillins rarely triggers PA, it is usually provoked by parenteral administration of the drug.

Estimates regarding PA prevalence range between 3 and 10% [3]. Thereby, penicillin is considered to be the causative agent of the most common drug allergy. However, these values have to be interpreted with caution. As has been described in the previous paragraph, a significant share of patients that once presented with PA may lose this condition at later points in their lives. Their mast cells and basophil granulocytes become desensitized and do not any longer degranulate upon exposure to penicillin. This may be the case in as much of 90% of those patients who report to suffer from PA.

PA is less frequently observed in children and the elderly.

An allergic reaction towards penicillin may manifest in form of urticaria and pruritus, in form of anaphylaxis and any degree of severity in between those two extremes. Even though allergic reactions to penicillin are common, anaphylaxis is rare and occurs in less than 5 per 10,000 patients.

Of note, particularly high rates of incidence may be observed after administration of procaine penicillin. This drug combines allergenic penicillin G with allergenic procaine in order to provide relieve from pain associated with intramuscular injection of the former.

For a type I hypersensitivity reaction to occur, mast cells and basophil granulocytes of a patient need to be sensitized by prior exposure to the allergen, i.e., a patient presenting with PA has been treated with penicillin before. Due to as of yet unknown causes, this primary exposure to penicillin induces release of interleukin-4 by T cells and subsequent production of antibodies of type IgE by B lymphocytes. IgE then bind to mast cells and basophil granulocytes, leaving them in an "alarm state". No symptoms are experienced during the process of sensitization.

Repeated exposure to the antibiotic drug cross-links previously bound IgE and triggers degranulation of the aforementioned cells. Within a few minutes, sometimes even within seconds, histamine, prostaglandins, leukotrienes and platelet activating factors are released and trigger symptoms characteristic for an acute PA. On a systemic level, vasodilation and increased vascular permeability lead to hypotension and may induce an anaphylactic shock. It has been estimated that up to one third of the intravascular volume may shift to extravascular compartments during these rapid pathophysiological events. Urticaria, pruritus, transient erythema and angioedema are typical dermatological symptoms. Mucous membranes show hypersecretion. Most of these symptoms are closely related to augmented vascular permeability, but pruritus is provoked by stimulation of sensory nerve endings. Smooth muscles of respiratory and gastrointestinal tracts react spasms, in case of the former with asthma-like and potentially life-threatening bronchospasms.

Of note, PA may occur up to one week after penicillin administration and are then designated sub-acute allergies. They are mediated by immunglobulin G rather than IgE. This type of PA is less severe and is caused by activation of the complement system [2].

Penicillin has also been related to other adverse events such as type IV hypersensitivity reactions in form of contact dermatitis, Stevens-Johnson Syndrome and drug hypersensitivity syndrome.

Due to the high incidence of PA, patients should be asked if they experienced any adverse reaction during past treatments. Even if that is not the case, parenteral penicillin administration poses a certain risk. Individuals with a medical history of severe allergic reactions should be monitored for at least half an hour after receiving penicillin. Such people should be advised as to their condition and be prepared to react, possibly by carrying an emergency kit [9].

However, even a patient's clinical history does not guarantee or rule out an allergic reaction to penicillin. Skin tests may provide valuable hints, but patients with negative skin tests have been shown to present symptoms of PA. A positive skin test result obtained recently should prompt switching to another antibiotic drug, if possible.

Patients suffering from PA are also at higher risk of other drug allergies [10].

Penicillin is a beta-lactam antibiotic and thus pertains to the same class of antimicrobial drugs as amoxicillin, ampicillin, cephalosporins and carbapenems. Because a considerable share of these antibiotics is sensitive to beta-lactamase, inhibitors of this enzyme are also considered to be part of this drug class. Penicillin is very frequently used to treat bacterial infections, particularly those triggered by staphylococci, streptococci, bacilli, clostridia and leptospires.

Similar to other drugs, it may cause side effects and adverse events. One of the more serious, but luckily less frequent adverse reactions is a type I hypersensitivity reaction that is designated penicillin allergy (PA) [1] [2]. It is mediated by immunglobulin E (IgE). Upon contact with penicillin, IgE are produced by lymphocytes and bind to mast cells, thus rendering these cells sensitized towards the antibiotic drug. If penicillin comes into contact with these sensitized mast cells once more, i.e., if the patient is treated with penicillin again, they degranulate and release several mediators, notably histamine. Such an adverse reaction may be caused by any penicillin but is most often associated to parenteral administration of penicillin G. Cross reactions are common. PA does not necessarily manifest upon first application of penicillin but may also be presented by patients that have been treated with penicillin repeatedly before [1].

Penicillin allergy (PA) describes an adverse reaction towards treatment with this antibiotic or related drugs.

Causes

Penicillin and similar drugs may act as an allergen, similar to pollen, weeds or animal hair. In this context, penicillin may induce the production of antibodies that bind to mast cells and basophil granulocytes and leave them in an "alarm state". This process is called sensitization and does not necessarily occur upon first treatment with penicillin. If the patient receives another treatment with penicillin, these cells are activated and release a variety of mediators, e.g., histamine, prostaglandins and leukotrienes. These cause the symptoms of an allergic reaction.

The precise triggers of PA are not yet known.

Symptoms

• Urticaria, flushing, swelling and itching of the skin
• Hypersecretion of mucous membranes, e.g., of those pertaining to the upper respiratory tract
• Respiratory distress due to bronchospasms
• Abdominal cramps, nausea, vomiting
• Hypotension

Diagnosis

The acute form of PA manifests within minutes after administration of the drug and may be recognized based on its clinical presentation. It may be more challenging to associate less severe, delayed reactions with penicillin treatment. Skin tests may be of some help. However, while their results indicate the presence or absence of antibodies against penicillin, allergies change and a patient might react differently after some years have passed. In this line, patients are rarely diagnosed as life-long allergic to penicillin. They should nevertheless inform their physicians about any past adverse events experienced during drug therapy.

Treatment

Severe cases are potentially life-threatening because they may lead to an anaphylactic shock and need immediate medical attention. Adrenaline is administered in these rare cases. Most PA cases are mild to moderate and are managed with anti-histamines and corticosteroids.

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3. Kerr JR. Penicillin allergy: a study of incidence as reported by patients. Br J Clin Pract. 1994; 48(1):5-7.
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