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Penicillin skin testing

Penicillin skin testing
Author:
Roland Solensky, MD
Section Editor:
Elizabeth J Phillips, MD, FRCPC, FRACP, FIDSA, FAAAAI
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2021. | This topic last updated: Apr 15, 2021.

INTRODUCTION — Penicillin skin testing is a tool used in the diagnosis of penicillin allergy. This topic will review the indications, safety, protocols, and interpretation of skin testing with penicillin and the aminopenicillins (amoxicillin and ampicillin).

An overview of allergy skin testing (for various types of allergens), a general discussion of the diagnosis of drug allergy, and the clinical manifestations of penicillin allergy, are discussed separately. (See "Overview of skin testing for allergic disease" and "An approach to the patient with drug allergy" and "Penicillin allergy: Immediate reactions".)

IMMEDIATE PENICILLIN REACTIONS — Penicillins include the following:

The natural penicillinsPenicillin V (oral), penicillin G (parenteral), benzathine penicillin (intramuscular), and procaine penicillin (intramuscular)

The antistaphylococcal penicillinsDicloxacillin, nafcillin, oxacillin, and cloxacillin

The aminopenicillinsAmoxicillin, amoxicillin-clavulanate, and ampicillin

The extended-spectrum penicillins – Carbenicillin, ticarcillin, and piperacillin

Allergic reactions to penicillins may be categorized based on the time of onset of symptoms. Reactions that begin within minutes to one hour of administration are classified as "immediate." Although there are exceptions, this definition captures the majority of type I, immunoglobulin E (IgE)-mediated reactions (table 1). Signs and symptoms of immediate reactions include flushing, pruritus, urticaria, angioedema, bronchospasm, laryngeal edema, gastrointestinal symptoms, and hypotension and shock. An array of symptoms may be seen (table 2). (See "Penicillin allergy: Immediate reactions", section on 'Definition'.)

MECHANISM OF SKIN TESTING — Skin testing is a bioassay performed on the skin, which detects the presence of allergen-specific IgE on a patient's mast cells. When allergen is introduced into the skin of a patient during skin testing, it comes into contact with cutaneous mast cells. Binding of the allergen occurs if the patient's mast cells are coated with IgE recognizing that specific allergen. If both IgE and allergen are present in sufficient quantities, then adjacent allergen-specific IgE molecules become cross-linked on the mast cell surface, and the cells are activated.

Mast cell activation results in a positive skin test, which is a transient "wheal-and-flare" reaction within 15 to 20 minutes from application of the allergen. Patients with detectable penicillin-specific IgE on their mast cells are said to be "sensitized" to penicillin and are at high risk for an immediate allergic reaction to the drug.

REFERRAL — Systematic skin testing of patients who have a history of penicillin allergy reveals that most patients have negative prick and intradermal skin testing and will go on to have negative oral challenge. This confirms that they currently do not have an immediate or IgE-mediated penicillin allergy, meaning that they were never actually allergic or have lost the allergy over time. Reintroducing penicillin as a treatment option can decrease antibiotic costs, optimize antibiotic choices, and reduce patient complications associated with broad-spectrum antibiotics, such as infections with vancomycin-resistant enterococcus and Clostridioides difficile, as discussed in more detail elsewhere. (See "Choice of antibiotics in penicillin-allergic hospitalized patients", section on 'Impact of penicillin allergy on care'.)

Penicillin skin testing should be performed only by specifically trained personnel, usually allergy specialists, because any procedure that involves the deliberate exposure of a patient to a substance to which he/she may be allergic should be undertaken by someone with expertise in that technique.

Indications — Skin testing is the most rapid, sensitive, and cost-effective testing modality for evaluating patients with immediate allergic reactions to penicillin and related drugs. It is recommended by the United States Centers for Disease Control and Prevention (CDC) to reduce the unnecessary use of broad-spectrum antibiotics. Penicillin skin testing is the best method for detecting patients at risk for penicillin-induced anaphylaxis, because it is more sensitive than in vitro tests for penicillin-specific IgE [1]. (See "Overview of skin testing for allergic disease".)

Although the results are most likely to be positive in patients with immediate reactions, skin testing is also useful in excluding immediate reactions in patients with unclear histories of past penicillin reactions, such as isolated urticaria, isolated angioedema, or unspecified rash. Skin testing has no role in the diagnosis of blistering skin reactions, such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), or in reactions that are caused by other known mechanisms (eg, hemolytic anemia, interstitial nephritis).

Skin testing is ideally performed when the patient is well and not in urgent or immediate need of antibiotic therapy. The indications for penicillin skin testing are evolving, with a trend for testing more patients even if they have alternatives to penicillin or beta-lactam therapy. Penicillin skin testing was traditionally reserved for patients who required penicillins because there was no other suitable antibiotic [2], a situation that has become increasingly uncommon. However, alternative antibiotics are often less effective, more toxic, and/or more expensive than available penicillins. In addition, it is important to avoid unnecessary use of broad-spectrum antibiotics.

Contraindications — Contraindications to penicillin skin testing are similar to those for other forms of skin testing, which are mentioned briefly here and discussed in more detail separately (see "Overview of skin testing for allergic disease", section on 'Contraindications'):

Certain skin conditions (chronic urticaria, dermatographism) in which the skin is over-reactive and false-positive results may occur if not properly controlled for.

The inability to temporarily discontinue medications that either interfere with skin test interpretation or inhibit the clinician's ability to treat anaphylaxis should it occur as a result of testing (which is rare). (See 'Patient preparation' below.)

Severe blistering past reactions to penicillin, such as TEN, in which exposure to even minute amounts of the drug could cause recurrent symptoms.

SAFETY

Overall — Penicillin skin testing performed in the described manner rarely leads to systemic allergic reactions, although all allergy skin testing should take place in a setting prepared to treat possible allergic reactions, including anaphylaxis. Systemic allergic reactions are more likely with intradermal testing because more allergen is introduced into the skin. Fatal anaphylaxis in response to testing has not been reported since modern skin testing methods have been in use [3-7].

Special populations

Pregnancy — Skin testing can be safely performed in pregnant patients [8,9]. Historically, testing has been reserved for situations in which a penicillin is considered essential, such as the treatment of syphilis. (See "Syphilis in pregnancy", section on 'Patients with immediate type allergic reactions to penicillin'.)

However, the label of penicillin allergy can complicate prophylaxis for group B streptococcus (GBS) and antibiotic choice during peripartum surgeries and is associated with increased morbidity and hospital utilization [10]. As a result, there is interest in the safety of routine "delabeling" of pregnant patients with a history of penicillin reactions, particularly those classified as "low risk." In the largest study, 222 pregnant patients were referred by obstetricians for evaluation in an allergy clinic if they had penicillin reactions that occurred more than five years before, and either had features of IgE-mediated allergy or could not be characterized [9]. All patients underwent skin testing, and those with negative skin test results were challenged with 500 mg of oral amoxicillin. Overall, 94 percent had the label of penicillin allergic removed from their charts. The electronic medical record was retrospectively reviewed to determine how subsequent care of these patients differed from 141 similarly referred patients who did not follow up for allergy evaluation. Delabeled patients were more likely to receive penicillin (adjusted odds ratio [aOR] 18.0, 95% CI 6.3-51.2) and less likely to receive broad-spectrum alternatives (eg, vancomycin, clindamycin, and gentamicin) (aOR 0.29, 95% CI 0.17-0.50). Use of first-line prophylaxis for GBS (penicillin) and C-section (cefazolin) was also higher in patients who had been delabeled. These findings support the inclusion of referral and penicillin skin testing as an option for management of women with reported penicillin allergy in the American College of Obstetrics and Gynecology 2020 guidelines for prevention of GBS early-onset disease in newborns [11,12]. (See "Early-onset neonatal group B streptococcal disease: Prevention", section on 'Antibiotic regimen' and "Society guideline links: Group B streptococcal infection in pregnant women and neonates", section on 'United States'.)

Critical illness and immunosuppression — Penicillin skin testing can also be performed safely and with accuracy in critically ill patients [13-15] and immunocompromised patients with cancer [16-18]. Antihistamines (H1 and H2) must be stopped for several days prior to skin testing, but glucocorticoids and most other immunosuppressant drugs do not generally interfere with immediate skin testing results. However, when performing skin testing in critically ill patients, it is important to ensure that the patient's skin is normally reactive to the positive histamine control. In a case control study, care in an intensive care unit during skin testing was associated with a high odds ratio for a negative histamine response [19]. The mechanism was not clear but it could be that critical illness itself and the psychotropic and neuromuscular blocking drugs used in this setting may dampen mast cells, making a negative histamine response more likely. (See "Overview of skin testing for allergic disease", section on 'Factors affecting results'.)

PROCEDURE — Penicillin skin testing results are obtained in less than one hour with minimal patient discomfort. Skin testing is valid in both adults and children [20]. The standard skin testing procedure involves two steps. Epicutaneous (prick-puncture) skin testing should be performed first and if negative, followed by intradermal (or intracutaneous) testing. In a study of 642 patients with delayed or unclear reaction histories, only intradermal penicillin skin testing (without prior prick testing) was performed, and no systemic reactions were observed. However, omission of prick testing warrants further research before becoming a standard of care [21].

Patient preparation — The following factors should be considered when planning penicillin skin testing:

Skin testing should not be performed in the weeks immediately following an episode of anaphylaxis, because during this type of severe allergic reaction, there is massive activation of mast cells, and the cells may then be hyporeactive for a period of time, leading to possible false-negative results. It is customary to allow a period of at least four weeks to elapse after anaphylaxis before any skin testing is performed. (See "Overview of skin testing for allergic disease".)

The patient's medications should be reviewed.

Any medications that could interfere with the results of skin testing (eg, antihistamines) should be temporarily discontinued, if possible. The duration that various medications should be withheld is reviewed separately. (See "Overview of skin testing for allergic disease", section on 'Medications that should be discontinued'.)

Any medications that could interfere with the ability to treat anaphylaxis should be noted (eg, beta-blockers, angiotensin-converting enzyme [ACE] inhibitors). If possible, these medications may be held temporarily (particularly in patients with extremely severe reaction histories) or this may not be necessary since most patients are very unlikely to develop anaphylaxis as a result of skin testing. (See "Overview of skin testing for allergic disease", section on 'Beta blockers and ACE inhibitors'.)

Skin testing reagents and concentrations — Most penicillin-allergic patients are not allergic to the intact penicillin molecule. The majority of patients are allergic to degradation products of penicillin covalently linked to self-proteins. Thus, skin testing with a simple solution of the drug as it is normally administered is not adequate to identify allergy in most patients. Insight into the immunochemistry of penicillin allowed for the development of skin testing reagents to detect penicillin-specific IgE antibodies (figure 1).

Penicillin skin testing is usually performed with the following reagents (table 3):

The major determinant

Penicilloyl-polylysine (PPL) (Pre-Pen) (6 x 10-5 M)

The minor determinants:

Penicillin G (10,000 units/mL)

Penicilloate (if available) (0.01 M)

Penilloate (if available) (0.01 M)

Ampicillin and or amoxicillin (3 to 25 mg/mL) if relevant to the patient's care

The minimal reagents required are positive and negative controls, the major determinant (PPL) and the minor determinant penicillin G. The minor determinant mixture (MDM) is included, if available, and the aminopenicillins are included if the patient reacted to these drugs or may need them in the future.

In the rare patient with a history of exquisite penicillin sensitivity (eg, a nurse who reacts to airborne penicillin), initial skin testing reagents may be diluted beyond the standard concentrations.

Penicillin intradermal skin testing involves raising a 2 to 3 mm bleb in the skin with each of the test solutions. (See "Overview of skin testing for allergic disease", section on 'Intradermal method'.)

Each test solution may be applied in duplicate (as stated in the Pre-Pen package insert) or singly. The recommendation to test in duplicate comes from a single large study in which 7 percent of duplicate tests were discordant [4]. If a single intradermal test result is equivocal, it should be repeated in duplicate.

The package insert for penicillin G potassium states that after reconstitution of the vial from the powder form, the full-strength solution (eg, 1 million units/mL) can be stored and used for one week if refrigerated. Published data about the impact of longer-term storage on penicillin solutions for use in skin testing are not available, and this practice is discouraged.

Controls — Both a positive control of histamine (10 mg/mL as histamine dichloride; 6.6 mg/mL as histamine base, for epicutaneous use) and a negative intradermal control of diluent identical to that of the allergen extracts (usually glycerinated saline) should always be applied in order to verify that the patient's skin is normally responsive.

Major determinant — The majority of penicillin antigens arise from degradation to the penicilloyl determinant following administration. Penicilloyl is the major determinant, and when complexed to polylysine, it constitutes a multivalent skin test reagent known as PPL. PPL is important for reliable skin testing, as up to 75 percent of penicillin skin test-positive patients react only to PPL, depending on the population studied [4,22,23]. Hence, skin testing without PPL may fail to identify many penicillin-allergic individuals and is not recommended.

Of note, the percentage of patients reacting only to PPL appears to be lower in European populations compared with North American patients [24]. One potential explanation for this is the higher prevalence of patients selectively allergic to amoxicillin/ampicillin in Europe. Despite geographic and perhaps temporal differences in the prevalence of unique PPL sensitivity, use of PPL in penicillin skin testing is essential to maximize clinical sensitivity.

PPL is commercially available as Pre-Pen. This product was not available in the United States for approximately five years, but its production was resumed in late 2009. Other products may be available in different countries [25]. Pre-Pen contains PPL at a single concentration of penicilloyl and is applied to the skin undiluted for both prick and intradermal testing. Diluted solutions may be used initially for the rare patient whose history suggests exquisite sensitivity.

Minor determinants — The minor penicillin antigenic determinants are benzylpenicillin (penicillin G), benzylpenicilloate, and benzylpenilloate. Of these, only penicillin G is available commercially.

Standard intravenous preparations of benzylpenicillin (penicillin G) may be used for skin testing at a concentration of 10,000 units/mL (table 3).

Benzylpenicilloate and benzylpenilloate (also known as MDM) are not commercially available (except for a product available in Spain and South America), but the importance of these reagents is controversial. In large scale studies, about 10 percent of penicillin skin test-positive patients are positive only to penicilloate and/or penilloate [4,22,23,25-30]. One small study suggested that patients who tested positive only to the MDMs were at higher risk for severe allergic reactions. However, larger studies found that the negative predictive value of skin testing with PPL plus MDM was similar to that of PPL plus benzylpenicillin alone [5,13,31-33]. Stated differently, although patients exist who only test positive to MDM, challenges of patients skin test-negative to PPL and benzylpenicillin had similar reaction rates compared with patients skin test-negative to the full set of major and minor penicillin determinants [4,27,34]. However, these studies had insufficient power to detect a small difference in rates. Thus, the presumed clinical value of the MDM as a skin testing reagent compared with benzylpenicillin alone is based on the observation that a few more patients with positive skin tests will be detected using the full skin test battery (table 3).

Although the recommended approach is to include PPL in skin testing of all patients, one study retrospectively evaluated the utility of testing with only the minor determinant penicillin G during a three-year period when PPL was not commercially available [35]. The study population consisted of children with past allergic reactions (immediate or nonsevere-delayed) to any penicillin drug (including amoxicillin and ampicillin), of whom 89 percent had reacted to amoxicillin. They were tested with benzylpenicillin (penicillin G), and if negative, challenged with a three-step protocol using the penicillin that caused the original reaction (ie, amoxicillin in most cases). Positive skin test results were obtained in 33 percent, which is much higher than in most studies, and those children were not challenged. Of the 378 children with negative skin test results, all but three were challenged, and 18 reacted (4.8 percent), yielding a negative predictive value for testing with penicillin G alone of 95 percent in that population (95% CI, 93-97 percent). However, these findings are different from those of many previous studies and require confirmation in other populations before the importance of PPL is questioned.

Aminopenicillins — Aminopenicillins, such as amoxicillin and ampicillin, should be included in the skin testing panel for any patient who reports an immediate systemic reaction to these drugs. Patients who are selectively allergic to the aminopenicillins form IgE antibodies which recognize, at least in part, the side R-group side chain rather than the core penicilloyl determinant [34,36-39]. These individuals react only to amoxicillin or ampicillin on skin testing and are negative to PPL, benzylpenicillin, and MDM. The importance of the MDM in diagnosing selective allergy to the aminopenicillins is not clear for the reasons discussed previously.

Concentrations ranging from 3 to 25 mg/mL of aminopenicillins have been reported to be nonirritating and may be used for skin testing (table 3) [22,37,40-42]. In the author's clinic, the following are used:

Amoxicillin – 3 mg/mL (prepared via a compounding pharmacy from bulk amoxicillin available as sodium salt of the pure acid) [43].

In Europe, higher concentrations of amoxicillin have been used, and these require that the sodium salt is used and also require a higher pH in order to maintain solubility [44].

Ampicillin – Vials containing 250 mg, 500 mg, 1 g, and 2 g ampicillin sterile powder for parenteral administration may be reconstituted with an appropriate volume of sterile water to provide a solution of appropriate concentration. The author's approach is to make a 250 mg/mL solution initially and then dilute it 20-fold to yield a concentration of 12.5 mg/mL for skin testing. If reconstituted under correct conditions and refrigerated, it will maintain potency and can be used for skin testing for up to 72 hours.

If a solution of amoxicillin is not readily available, the clinician could skin test to PPL, benzylpenicillin, and MDM (if available), as well as ampicillin at the concentrations discussed previously. This approach will detect the majority of patients who are allergic to amoxicillin. However, the clinician should be aware that it is possible to be selectively allergic to amoxicillin and not ampicillin (and vice versa), since the structures are similar but not identical. Therefore, if skin tests with ampicillin and other penicillin reagents are negative and the patient is to undergo graded challenge with amoxicillin to exclude immediate allergy, appropriate precautions should be taken if the patient's past reaction was more significant than urticaria/angioedema.

Clavulanate testing in patient reactive to amoxicillin-clavulanate — Patients who reacted to the combination of amoxicillin-clavulanate may be allergic to clavulanate, although this is uncommon [45,46]. Clavulanate allergy should be considered in a patient who reacted to the combination of amoxicillin-clavulanate but has negative skin tests to penicillin and amoxicillin reagents. Although skin testing to clavulanate alone (20 mg/mL) is more sensitive than testing with the combination of amoxicillin and clavulanate, obtaining clavulanate for testing is extremely difficult outside of certain areas, such as Europe, where clavulanate is commercially available as a testing reagent.

INTERPRETATION OF RESULTS — A positive reaction consists of a central area of superficial skin edema (wheal) surrounded by erythema (flare). The site is usually pruritic. This reaction represents the immediate phase of the allergic reaction. If the patient's cutaneous mast cells are not activated, then no edema or erythema develops, and the test is negative. Falsely-negative skin tests can result when patients have received medications, such as antihistamines, that block the skin effects of immediate mast cell mediators. (See 'Patient preparation' above.)

Prick-puncture skin testing results are read 15 minutes after application:

A positive response is a wheal that is 3 mm or greater in mean diameter than the negative control.

A negative response is no reaction at the prick site or erythema alone without a wheal.

Intradermal skin testing is read 15 to 20 minutes after application:

A positive response is a wheal that has increased in size from the original bleb and is 3 mm or greater in mean diameter than the negative control.

A negative response is no increase in the size of the original bleb and no wheal greater than the control site.

Positive predictive value — Data on the positive predictive value of penicillin skin testing are limited due to ethical concerns of challenging skin test-positive patients with penicillin. In addition, drug-specific IgE is believed to be a necessary but not always sufficient factor for a symptomatic drug reaction. A 2019 systematic review of the published literature found the positive predictive value of penicillin skin testing, in well-characterized patients, to be 83 percent [47]. If studies with imprecise methodology are included, the positive predictive value ranged from 10 to 100 percent, but most studies report a value over 50 percent. [5,21,27,28,34,48-52]. Even these lower rates are comparable with that observed in Hymenoptera allergy skin testing [53].

Patients who test positive to penicillin should avoid all penicillins (ie, including the aminopenicillins and newer semisynthetic penicillins). (See "Penicillin allergy: Immediate reactions", section on 'Options for future treatment'.)

Negative predictive value — The negative predictive value of penicillin skin testing when performed with the major determinant plus penicillin G (or a full MDM panel) is very high. Serious immediate reactions in patients challenged with penicillin following negative penicillin skin testing have not been reported. In large scale studies, 1 to 3 percent of penicillin skin test-negative patients (ie, when tested with the major determinant plus penicillin G [or a full MDM panel]) developed mild, usually self-limiting reactions upon being challenged with the drug [4,7,13,27,33,48,54-57].

The clinical importance of including the MDM in skin testing is controversial, since the negative predictive value of skin testing with only PPL and benzylpenicillin is comparable with testing with all the reagents [4,5,13,27,31-34]. The best available estimate is that at least another 10 percent of penicillin-sensitized patients can be identified by using the full panel of MDM reagents (ie, penicillin G, benzylpenicilloate, and benzylpenilloate). Skin testing with the minor determinant penicillin G alone is not the recommended approach. (See 'Minor determinants' above.)

Skin testing with the aminopenicillins is not as well-studied, and very few data are available on the predictive value. There is an impression from the Spanish experience that the negative predictive value is not as high as that of the benzylpenicillin determinants, but this has not been demonstrated conclusively.

CONFIRMATORY CHALLENGE AFTER NEGATIVE SKIN TESTING — In a patient with negative skin test results, the absence of allergy should be confirmed by administering an age-appropriate dose of the penicillin to which the patient initially reacted, followed by one to two hours of observation to ensure that an immediate reaction does not occur. Challenge is indicated because the negative predictive value for penicillin skin testing with the combination of PPL and penicillin G is very high, but not 100 percent. Also, confirming that the drug is tolerated will maximize the comfort of the patient and other clinicians with using penicillins in the future [58].

It is best to challenge the patient with the specific penicillin to which he/she reacted, when possible. The following examples are illustrative:

In a patient who reacted to amoxicillin, challenging with amoxicillin ensures that the patient is not selectively allergic to amoxicillin. The negative predictive value of penicillin skin testing in patients primarily allergic to aminopenicillins is not well-defined. Challenge with amoxicillin will detect allergy to amoxicillin or penicillin, whereas challenge with penicillin would only identify penicillin allergy.

In a patient who reacted to amoxicillin-clavulanate, challenge with the combination can help identify clavulanate allergy if both penicillin and amoxicillin skin tests were negative but clavulanate was not available for testing.

For testing of inpatients with a current need for a particular penicillin product, the challenge procedure can be incorporated into the first parenteral dose by administering 1/10th of a normal dose, observing for one hour, then if there is no adverse reaction, administering the remaining 9/10th of the dose and observing for another hour. Patients who tolerate this type of challenge prove that they are not allergic and can receive additional doses normally.

UPDATING THE PATIENT'S RECORDS — For a patient with negative penicillin skin testing who has passed a confirmatory challenge, the final step is to update the patient's medical record and also make sure that the patient, the primary care provider (PCP), and the patient's pharmacy all understand that the label of penicillin allergy should be removed. The importance of these final steps was illustrated by a study in which 100 children who had tested negative for penicillin allergy after an initial reaction were followed up after an average of one year [59]. Phone surveys with the parent/caregiver and with the PCP revealed that 90 percent of parents understood the results of the previous testing, and 80 percent had informed their child's PCP as instructed. However, 84 percent of PCPs did not recall being notified, and 52 percent of the children's medical records from the PCP's office still listed the penicillin allergy as active. However, despite this imperfect communication, 36 children had been treated with penicillin or its derivatives, and just one child had developed a delayed exanthem. This study supports previous findings in adults, in which improving communication with the entire health care team enhanced the effectiveness of penicillin allergy label removal [60].

In addition to clearly explaining to the patient/caregiver that the patient can now safely take penicillins, the allergist should explain that negative skin testing (and single-dose challenge) does not mean that the patient will not get a delayed reaction, and it also does not exclude the possibility of future sensitization. However, the risk is comparable with that in the general population. Information for patients about this is provided. (See 'Information for patients' below.)

RESENSITIZATION — Based on available data, resensitization appears to occur in 0 to 3 percent of patients after a course of an oral penicillin and up to 20 percent after a course of a parenteral penicillin. However, resensitization does not predict clinical reactivity. The clinical implications of this must be weighed in the context of the severity of the patient's initial reaction.

Several studies have examined rates of resensitization, or the redevelopment of penicillin-specific IgE, in patients who had lost their sensitivity. Resensitization may be determined by the number of patients who convert their penicillin skin tests from negative (before the challenge) to positive (after the challenge). However, this method does not predict which patients will actually react, because sensitization does not predict actual allergy precisely. Another way to assess the risk of recurrence is to determine the number of patients with a history of penicillin allergy who tolerate two or more courses of penicillins, who can therefore be assumed to not have been resensitized by the initial course.

Following oral administration – Using the methods just described, most studies of penicillin resensitization after oral challenge or after a single course of an oral penicillin or amoxicillin showed resensitization rates between 0 and 3 percent [54,56,61-63], which are comparable with the rate of primary sensitization. Another study evaluated resensitization after repeated courses of oral penicillin in 53 adult patients [62]. Patients with a convincing history of penicillin allergy and initially negative penicillin skin tests were challenged with three consecutive penicillin V courses and underwent three repeat penicillin skin tests. None converted to a positive skin test during this process [62]. Based on these data, it is not routinely necessary to repeat skin testing in a patient with past penicillin reactions who has tolerated a subsequent course of oral penicillin. Similarly, if penicillin skin testing is not available and patients with a history of penicillin allergy are given and tolerate penicillin via graded challenge, no special precautions are required for future penicillin treatment courses.

Following intravenous or intramuscular administration – Early studies of resensitization following parenteral administration of penicillin reported that it may be more common (rates of 5 to 20 percent) [64,65]. However, more recent research has contradicted those data, finding rates of 0 percent [66]. Therefore, repeat skin testing (or cautious administration of penicillins if skin testing is not available) is not routinely necessary for patients with a history of penicillin allergy who have tolerated a parenteral course of penicillin. Consideration may be given to retesting individuals with recent or particularly severe previous reactions.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Significance of negative penicillin allergy skin testing (Beyond the Basics)" and "Patient education: Allergy to penicillin and related antibiotics (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Allergen skin testing is a bioassay that detects the presence of allergen-specific immunoglobulin (Ig)E on a patient's mast cells. Patients with detectable penicillin-specific IgE on their mast cells are said to be "sensitized" to penicillin and are at high risk for an immediate allergic reaction to the drug. Skin testing is the most rapid, sensitive, and cost-effective testing modality for identifying penicillin-sensitized patients. (See 'Immediate penicillin reactions' above and 'Mechanism of skin testing' above.)

Penicillin skin testing is a safe procedure, although it should be performed by allergy experts when possible, since they have the training to interpret the results accurately and the experience, staff, and equipment to treat possible (albeit rare) allergic reactions. (See 'Referral' above and 'Safety' above.)

Epicutaneous (prick-puncture) skin testing should be performed first, and if negative, intradermal tests should follow. The minimal reagents required are positive and negative controls, the major determinant (penicilloyl-polylysine [PPL]) and the minor determinant penicillin G (table 3). The minor determinant mixture (MDM) is included if available, and the aminopenicillins are included if the patient reacted to these drugs or may need them in the future. (See 'Procedure' above.)

The positive predictive value of penicillin skin testing performed in this manner is approximately 50 percent, which is similar to that of skin testing with many other allergens. The negative predictive value is very high (ie, 97 to 99 percent), although it may be lower for amoxicillin and ampicillin. (See 'Interpretation of results' above.)

Following negative skin test results, the absence of allergy should be confirmed with a drug challenge (usually oral). A dose of the penicillin to which the patient reacted in the past is administered, and the patient is observed for one to two hours to ensure that an immediate reaction does not occur. (See 'Confirmatory challenge after negative skin testing' above.)

REFERENCES

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  8. Macy E. Penicillin skin testing in pregnant women with a history of penicillin allergy and group B streptococcus colonization. Ann Allergy Asthma Immunol 2006; 97:164.
  9. Wolfson AR, Mancini CM, Banerji A, et al. Penicillin Allergy Assessment in Pregnancy: Safety and Impact on Antibiotic Use. J Allergy Clin Immunol Pract 2021; 9:1338.
  10. Desai SH, Kaplan MS, Chen Q, Macy EM. Morbidity in Pregnant Women Associated with Unverified Penicillin Allergies, Antibiotic Use, and Group B Streptococcus Infections. Perm J 2017; 21:16.
  11. Prevention of Group B Streptococcal Early-Onset Disease in Newborns: ACOG Committee Opinion, Number 797. Obstet Gynecol 2020; 135:e51.
  12. Committee Opinion No. 797: Prevention of Group B Streptococcal Early-Onset Disease in Newborns: Correction. Obstet Gynecol 2020; 135:978.
  13. del Real GA, Rose ME, Ramirez-Atamoros MT, et al. Penicillin skin testing in patients with a history of beta-lactam allergy. Ann Allergy Asthma Immunol 2007; 98:355.
  14. Arroliga ME, Radojicic C, Gordon SM, et al. A prospective observational study of the effect of penicillin skin testing on antibiotic use in the intensive care unit. Infect Control Hosp Epidemiol 2003; 24:347.
  15. Rimawi RH, Mazer MA. Expanding the pool of healthcare providers to perform penicillin skin testing in the ICU. Intensive Care Med 2014; 40:462.
  16. Taremi M, Artau A, Foolad F, et al. Safety, Efficacy, and Clinical Impact of Penicillin Skin Testing in Immunocompromised Cancer Patients. J Allergy Clin Immunol Pract 2019; 7:2185.
  17. Trubiano JA, Thursky KA, Stewardson AJ, et al. Impact of an Integrated Antibiotic Allergy Testing Program on Antimicrobial Stewardship: A Multicenter Evaluation. Clin Infect Dis 2017; 65:166.
  18. Trubiano JA, Grayson ML, Phillips EJ, et al. Antibiotic allergy testing improves antibiotic appropriateness in patients with cancer. J Antimicrob Chemother 2018; 73:3209.
  19. Geng B, Thakor A, Clayton E, et al. Factors associated with negative histamine control for penicillin allergy skin testing in the inpatient setting. Ann Allergy Asthma Immunol 2015; 115:33.
  20. Fox SJ, Park MA. Penicillin skin testing is a safe and effective tool for evaluating penicillin allergy in the pediatric population. J Allergy Clin Immunol Pract 2014; 2:439.
  21. Confino-Cohen R, Rosman Y, Meir-Shafrir K, et al. Oral Challenge without Skin Testing Safely Excludes Clinically Significant Delayed-Onset Penicillin Hypersensitivity. J Allergy Clin Immunol Pract 2017; 5:669.
  22. Macy E, Richter PK, Falkoff R, Zeiger R. Skin testing with penicilloate and penilloate prepared by an improved method: amoxicillin oral challenge in patients with negative skin test responses to penicillin reagents. J Allergy Clin Immunol 1997; 100:586.
  23. Bousquet PJ, Co-Minh HB, Arnoux B, et al. Importance of mixture of minor determinants and benzylpenicilloyl poly-L-lysine skin testing in the diagnosis of beta-lactam allergy. J Allergy Clin Immunol 2005; 115:1314.
  24. Bousquet PJ, Pipet A, Bousquet-Rouanet L, Demoly P. Oral challenges are needed in the diagnosis of beta-lactam hypersensitivity. Clin Exp Allergy 2008; 38:185.
  25. Matheu V, Pérez E, González R, et al. Assessment of a new brand of determinants for skin testing in a large group of patients with suspected beta-lactam allergy. J Investig Allergol Clin Immunol 2007; 17:257.
  26. Adkinson NF, personal communication.
  27. Sogn DD, Evans R 3rd, Shepherd GM, et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med 1992; 152:1025.
  28. Macy E, Burchette RJ. Oral antibiotic adverse reactions after penicillin skin testing: multi-year follow-up. Allergy 2002; 57:1151.
  29. Jost BC, Wedner HJ, Bloomberg GR. Elective penicillin skin testing in a pediatric outpatient setting. Ann Allergy Asthma Immunol 2006; 97:807.
  30. Park MA, Matesic D, Markus PJ, Li JT. Female sex as a risk factor for penicillin allergy. Ann Allergy Asthma Immunol 2007; 99:54.
  31. BROWN BC, PRICE EV, MOORE MB Jr. PENICILLOYL-POLYLYSINE AS AN INTRADERMAL TEST OF PENICILLIN SENSITIVITY. JAMA 1964; 189:599.
  32. Shepherd G. Clinical experience using only PrePen and penicillin G to detect penicillin allergy in hospitalized patients. J Allergy Clin Immunol 1997; 99:S134 (Abstract).
  33. Macy E, Ngor EW. Safely diagnosing clinically significant penicillin allergy using only penicilloyl-poly-lysine, penicillin, and oral amoxicillin. J Allergy Clin Immunol Pract 2013; 1:258.
  34. Solley GO, Gleich GJ, Van Dellen RG. Penicillin allergy: clinical experience with a battery of skin-test reagents. J Allergy Clin Immunol 1982; 69:238.
  35. Picard M, Paradis L, Bégin P, et al. Skin testing only with penicillin G in children with a history of penicillin allergy. Ann Allergy Asthma Immunol 2014; 113:75.
  36. Moss RB. Drug allergy in cystic fibrosis. Clin Rev Allergy 1991; 9:211.
  37. Blanca M, Vega JM, Garcia J, et al. Allergy to penicillin with good tolerance to other penicillins; study of the incidence in subjects allergic to beta-lactams. Clin Exp Allergy 1990; 20:475.
  38. Vega JM, Blanca M, García JJ, et al. Immediate allergic reactions to amoxicillin. Allergy 1994; 49:317.
  39. Blanca M, Perez E, Garcia J, et al. Anaphylaxis to amoxycillin but good tolerance for benzyl penicillin. In vivo and in vitro studies of specific IgE antibodies. Allergy 1988; 43:508.
  40. Miranda A, Blanca M, Vega JM, et al. Cross-reactivity between a penicillin and a cephalosporin with the same side chain. J Allergy Clin Immunol 1996; 98:671.
  41. Marcos Bravo C, Luna Ortiz I, González Vázquez R. Hypersensitivity to cefuroxime with good tolerance to other betalactams. Allergy 1995; 50:359.
  42. Sastre J, Quijano LD, Novalbos A, et al. Clinical cross-reactivity between amoxicillin and cephadroxil in patients allergic to amoxicillin and with good tolerance of penicillin. Allergy 1996; 51:383.
  43. Amoxicillin is available from Sigma-Aldrich, St Louis, MO (product number A 8523). This preparation is not intended for human administration, and use in skin testing may require IRB approval at some centers. www.sigmaldrich.com (Accessed on October 10, 2011).
  44. Montañez MI, Torres MJ, Perez-Inestrosa E, Blanca M. Clarification concerning amoxicillin skin testing. J Allergy Clin Immunol 2011; 128:685; author reply 686.
  45. Fernandez-Rivas M, Perez Carral C, Cuevas M, et al. Selective allergic reactions to clavulanic acid. J Allergy Clin Immunol 1995; 95:748.
  46. Torres MJ, Ariza A, Mayorga C, et al. Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for immediate hypersensitivity reactions. J Allergy Clin Immunol 2010; 125:502.
  47. Chiriac AM, Vasconcelos MJ, Izquierdo L, et al. To challenge or not to challenge: Literature data on the positive predictive value of skin tests to beta-lactams. J Allergy Clin Immunol Pract 2019; 7:2404.
  48. Caubet JC, Kaiser L, Lemaître B, et al. The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. J Allergy Clin Immunol 2011; 127:218.
  49. Adkinson NF Jr, Thompson WL, Maddrey WC, Lichtenstein LM. Routine use of penicillin skin testing on an inpatient service. N Engl J Med 1971; 285:22.
  50. Chandra RK, Joglekar SA, Tomas E. Penicillin allergy: anti-penicillin IgE antibodies and immediate hypersensitivity skin reactions employing major and minor determinants of penicillin. Arch Dis Child 1980; 55:857.
  51. Levine BB, Zolov DM. Prediction of penicillin allergy by immunological tests. J Allergy 1969; 43:231.
  52. Goldberg A, Confino-Cohen R. Skin testing and oral penicillin challenge in patients with a history of remote penicillin allergy. Ann Allergy Asthma Immunol 2008; 100:37.
  53. Hunt KJ, Valentine MD, Sobotka AK, et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978; 299:157.
  54. Mendelson LM, Ressler C, Rosen JP, Selcow JE. Routine elective penicillin allergy skin testing in children and adolescents: study of sensitization. J Allergy Clin Immunol 1984; 73:76.
  55. Kamboj S, Yousef E, McGeady S, Hossain J. The prevalence of antibiotic skin test reactivity in a pediatric population. Allergy Asthma Proc 2011; 32:99.
  56. Macy E, Mangat R, Burchette RJ. Penicillin skin testing in advance of need: multiyear follow-up in 568 test result-negative subjects exposed to oral penicillins. J Allergy Clin Immunol 2003; 111:1111.
  57. Solensky R, Jacobs J, Lester M, et al. Penicillin Allergy Evaluation: A Prospective, Multicenter, Open-Label Evaluation of a Comprehensive Penicillin Skin Test Kit. J Allergy Clin Immunol Pract 2019; 7:1876.
  58. Warrington RJ, Burton R, Tsai E. The value of routine penicillin allergy skin testing in an outpatient population. Allergy Asthma Proc 2003; 24:199.
  59. Vyles D, Chiu A, Routes J, et al. Antibiotic Use After Removal of Penicillin Allergy Label. Pediatrics 2018; 141.
  60. Bourke J, Pavlos R, James I, Phillips E. Improving the Effectiveness of Penicillin Allergy De-labeling. J Allergy Clin Immunol Pract 2015; 3:365.
  61. Macy E. Elective penicillin skin testing and amoxicillin challenge: effect on outpatient antibiotic use, cost, and clinical outcomes. J Allergy Clin Immunol 1998; 102:281.
  62. Solensky R, Earl HS, Gruchalla RS. Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses. Arch Intern Med 2002; 162:822.
  63. Hershkovich J, Broides A, Kirjner L, et al. Beta lactam allergy and resensitization in children with suspected beta lactam allergy. Clin Exp Allergy 2009; 39:726.
  64. Parker PJ, Parrinello JT, Condemi JJ, Rosenfeld SI. Penicillin resensitization among hospitalized patients. J Allergy Clin Immunol 1991; 88:213.
  65. Lopez-Serrano MC, Caballero MT, Barranco P, Martinez-Alzamora F. Booster responses in the study of allergic reactions to beta-lactam antibiotics. J Investig Allergol Clin Immunol 1996; 6:30.
  66. Dorman SM, Seth S, Khan DA. Risk of Allergic Reactions to Recurrent Intravenous Penicillin Administration in Penicillin Skin Test Negative Patients. J Allergy Clin Immunol Pract 2018; 6:196.
Topic 16503 Version 23.0

References

1 : Accuracy of penicillin allergy diagnostic tests: A systematic review and meta-analysis.

2 : Drug allergy: an updated practice parameter.

3 : Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy.

4 : Clinical experience with penicillin skin testing in a large inner-city STD clinic.

5 : Evaluation of penicillin hypersensitivity: value of clinical history and skin testing with penicilloyl-polylysine and penicillin G. A cooperative prospective study of the penicillin study group of the American Academy of Allergy.

6 : Frequency of systematic reactions to penicillin skin tests.

7 : Skin testing to detect penicillin allergy.

8 : Penicillin skin testing in pregnant women with a history of penicillin allergy and group B streptococcus colonization.

9 : Penicillin Allergy Assessment in Pregnancy: Safety and Impact on Antibiotic Use.

10 : Morbidity in Pregnant Women Associated with Unverified Penicillin Allergies, Antibiotic Use, and Group B Streptococcus Infections.

11 : Prevention of Group B Streptococcal Early-Onset Disease in Newborns: ACOG Committee Opinion, Number 797.

12 : Committee Opinion No. 797: Prevention of Group B Streptococcal Early-Onset Disease in Newborns: Correction.

13 : Penicillin skin testing in patients with a history of beta-lactam allergy.

14 : A prospective observational study of the effect of penicillin skin testing on antibiotic use in the intensive care unit.

15 : Expanding the pool of healthcare providers to perform penicillin skin testing in the ICU.

16 : Safety, Efficacy, and Clinical Impact of Penicillin Skin Testing in Immunocompromised Cancer Patients.

17 : Impact of an Integrated Antibiotic Allergy Testing Program on Antimicrobial Stewardship: A Multicenter Evaluation.

18 : Antibiotic allergy testing improves antibiotic appropriateness in patients with cancer.

19 : Factors associated with negative histamine control for penicillin allergy skin testing in the inpatient setting.

20 : Penicillin skin testing is a safe and effective tool for evaluating penicillin allergy in the pediatric population.

21 : Oral Challenge without Skin Testing Safely Excludes Clinically Significant Delayed-Onset Penicillin Hypersensitivity.

22 : Skin testing with penicilloate and penilloate prepared by an improved method: amoxicillin oral challenge in patients with negative skin test responses to penicillin reagents.

23 : Importance of mixture of minor determinants and benzylpenicilloyl poly-L-lysine skin testing in the diagnosis of beta-lactam allergy.

24 : Oral challenges are needed in the diagnosis of beta-lactam hypersensitivity.

25 : Assessment of a new brand of determinants for skin testing in a large group of patients with suspected beta-lactam allergy.

26 : Assessment of a new brand of determinants for skin testing in a large group of patients with suspected beta-lactam allergy.

27 : Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults.

28 : Oral antibiotic adverse reactions after penicillin skin testing: multi-year follow-up.

29 : Elective penicillin skin testing in a pediatric outpatient setting.

30 : Female sex as a risk factor for penicillin allergy.

31 : PENICILLOYL-POLYLYSINE AS AN INTRADERMAL TEST OF PENICILLIN SENSITIVITY.

32 : Clinical experience using only PrePen and penicillin G to detect penicillin allergy in hospitalized patients

33 : Safely diagnosing clinically significant penicillin allergy using only penicilloyl-poly-lysine, penicillin, and oral amoxicillin.

34 : Penicillin allergy: clinical experience with a battery of skin-test reagents.

35 : Skin testing only with penicillin G in children with a history of penicillin allergy.

36 : Drug allergy in cystic fibrosis.

37 : Allergy to penicillin with good tolerance to other penicillins; study of the incidence in subjects allergic to beta-lactams.

38 : Immediate allergic reactions to amoxicillin.

39 : Anaphylaxis to amoxycillin but good tolerance for benzyl penicillin. In vivo and in vitro studies of specific IgE antibodies.

40 : Cross-reactivity between a penicillin and a cephalosporin with the same side chain.

41 : Hypersensitivity to cefuroxime with good tolerance to other betalactams.

42 : Clinical cross-reactivity between amoxicillin and cephadroxil in patients allergic to amoxicillin and with good tolerance of penicillin.

43 : Clinical cross-reactivity between amoxicillin and cephadroxil in patients allergic to amoxicillin and with good tolerance of penicillin.

44 : Clarification concerning amoxicillin skin testing.

45 : Selective allergic reactions to clavulanic acid.

46 : Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for immediate hypersensitivity reactions.

47 : To challenge or not to challenge: Literature data on the positive predictive value of skin tests to beta-lactams.

48 : The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge.

49 : Routine use of penicillin skin testing on an inpatient service.

50 : Penicillin allergy: anti-penicillin IgE antibodies and immediate hypersensitivity skin reactions employing major and minor determinants of penicillin.

51 : Prediction of penicillin allergy by immunological tests.

52 : Skin testing and oral penicillin challenge in patients with a history of remote penicillin allergy.

53 : A controlled trial of immunotherapy in insect hypersensitivity.

54 : Routine elective penicillin allergy skin testing in children and adolescents: study of sensitization.

55 : The prevalence of antibiotic skin test reactivity in a pediatric population.

56 : Penicillin skin testing in advance of need: multiyear follow-up in 568 test result-negative subjects exposed to oral penicillins.

57 : Penicillin Allergy Evaluation: A Prospective, Multicenter, Open-Label Evaluation of a Comprehensive Penicillin Skin Test Kit.

58 : The value of routine penicillin allergy skin testing in an outpatient population.

59 : Antibiotic Use After Removal of Penicillin Allergy Label.

60 : Improving the Effectiveness of Penicillin Allergy De-labeling.

61 : Elective penicillin skin testing and amoxicillin challenge: effect on outpatient antibiotic use, cost, and clinical outcomes.

62 : Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses.

63 : Beta lactam allergy and resensitization in children with suspected beta lactam allergy.

64 : Penicillin resensitization among hospitalized patients.

65 : Booster responses in the study of allergic reactions to beta-lactam antibiotics.

66 : Risk of Allergic Reactions to Recurrent Intravenous Penicillin Administration in Penicillin Skin Test Negative Patients.