Penicillin Skin Testing

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Penicillin skin testing

Author: Roland Solensky, MD
Section Editor: Elizabeth J Phillips, MD, FRCPC, FRACP, FIDSA, FAAAAI
Deputy Editor: Anna M Feldweg, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2022. | This topic last updated: Sep 09, 2022.
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 penicillins – Penicillin V (oral), penicillin G (parenteral), benzathine penicillin (intramuscular), and procaine penicillin
(intramuscular)
● The antistaphylococcal penicillins – Dicloxacillin, nafcillin, oxacillin, and cloxacillin
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● The aminopenicillins – Amoxicillin, 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 "Prevention of early-onset group B
streptococcal disease in neonates", 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). Penicilloyl-polylysine is also known as benzylpenicilloyl-polylysine.
● 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
● Mechanism of skin testing – 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.)
● Safety and referral – 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.)
● Procedure – 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.)
● Positive and negative predictive values – 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.)
● Confirmatory challenge after negative skin testing – 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.)
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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.
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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 admi
nistration, and use in skin testing may require IRB approval at some centers. www.sigmaldrich.com (Accessed on October 10, 2011).
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skin tests to beta-lactams. J Allergy Clin Immunol Pract 2019; 7:2404.
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54. Mendelson LM, Ressler C, Rosen JP, Selcow JE. Routine elective penicillin allergy skin testing in children and adolescents: study of
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2003; 24:199.
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3:365.
61. Macy E. Elective penicillin skin testing and amoxicillin challenge: effect on outpatient antibiotic use, cost, and clinical outcomes. J
62. Solensky R, Earl HS, Gruchalla RS. Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving
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Topic 16503 Version 26.0
GRAPHICS
Gell and Coombs classification of immunologic drug reactions
Type Description Mechanism Clinical features
I IgE-mediated, immediate- Antigen exposure causes IgE-mediated activation of mast Anaphylaxis

type hypersensitivity cells and basophils, with release of vasoactive
Immediate reaction (within Angioedema
substances, such as histamine, prostaglandins, and
one hour)
leukotrienes. Bronchospasm
Urticaria (hives)
Hypotension
II Antibody-dependent An antigen or hapten that is intimately associated with a Hemolytic anemia

cytotoxicity cell binds to antibody, leading to cell or tissue injury.
Thrombocytopenia
Neutropenia
III Immune complex disease Damage is caused by formation or deposition of antigen- Serum sickness
antibody complexes in vessels or tissue. Deposition of
Arthus reaction
immune complexes causes complement activation and/or
recruitment of neutrophils by interaction of immune
complexes with Fc IgG receptors.
IV Cell-mediated or delayed Antigen exposure activates T cells, which then mediate Contact dermatitis
hypersensitivity tissue injury. Depending upon the type of T cell activation
Some morbilliform
and the other effector cells recruited, different subtypes
reactions
can be differentiated (ie, types IVa to IVd).
Severe exfoliative
dermatoses (eg, SJS/TEN)
AGEP
DRESS/DiHS
Interstitial nephritis
Drug-induced hepatitis
Other presentations
IgE: immunoglobulin E; Fc IgG: Fc portion of immunoglobulin G; SJS/TEN: Stevens-Johnson syndrome/toxic epidermal necrolysis; AGEP: acute
generalized exanthematous pustulosis; DRESS/DiHS: drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity
syndrome.
Adapted from: Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18:515.
Graphic 80466 Version 18.0
Immediate allergic reactions to drugs (IgE-mediated or non-IgE-mediated): Possible signs and symptoms
Skin
Itching*
Urticaria*
Angioedema*
Warmth
Flushing
Other exanthema
Eyes, ears, nose
Periorbital edema*
Rhinorrhea*
Nasal itching*
Nasal congestion*
Ocular itching
Tearing
Conjunctival injection and/or edema
Sneezing
Mouth
Itching or tingling of lips, tongue, oral mucosa*

Angioedema of lips, tongue, or uvula*
Metallic taste
Throat
Itching*
Sense of constriction or swelling in throat*
Change in voice quality*
Difficulty swallowing*
Stridor*
Hoarseness
Drooling
Lungs
Shortness of breath*
Chest tightness*
Repetitive cough*
Wheezing*
Drop in oxygen saturation, cyanosis
Cardiovascular
Lightheadedness/faintness/dizziness*
Tachycardia or occasionally, bradycardia*
Hypotension*
Syncope/loss of consciousness
Palpitations
Tunnel vision
Difficulty hearing
Urinary or fecal incontinence
Cardiac arrest
Gastrointestinal
Nausea
Vomiting
Abdominal cramping or pain
Diarrhea
Gynecologic
Vaginal itching
Uterine cramping or bleeding
Neurologic
Anxiety
Sense of impending doom
Altered mental status/confusion
Seizures
Immediate reactions to drugs often present with combinations of the signs and symptoms listed in the table. Those bolded and marked with an
asterisk (*) are more consistent and representative than the others, and one or more of these should be present to consider the reaction
immediate.
IgE: immunoglobulin E.
Penicillin: Major and minor determinants
Penicillin-allergic patients may form IgE molecules against the beta-

lactam core or against the R groups (shown in red).
IgE: immunoglobulin E.
Penicillin skin test reagents
Reagent Concentration used for skin testing
Penicilloyl-polylysine (Pre-Pen) 6 x 10-5 M
Penicillin G 10,000 units/mL
Penicilloate 0.01 M
Penilloate 0.01 M
Ampicillin/amoxicillin 3 to 25 mg/mL
Commonly used penicillin skin test reagents.
Contributor Disclosures
Roland Solensky, MD Grant/Research/Clinical Trial Support: ALK [Allergic rhinitis]; GSK [Asthma].
All of the relevant financial relationships listed have
been mitigated. Elizabeth J Phillips, MD, FRCPC, FRACP, FIDSA, FAAAAI Equity Ownership/Stock Options: IIID Pty Ltd [HLA-B*5701 testing for abacavir
hypersensitivity].
Patent Holder: IIID Pty Ltd[(Pending) Detection of HLA-A*3201 in connection with determining DRESS and methods of treating
bacterial infection in vancomycin-induced DRESS];IIID Pty Ltd [(Pending) HLA-B*5701 testing for abacavir hypersensitivity].
Grant/Research/Clinical Trial
Support: National Health and Medical Research Council of Australia[Allergy/Immunology];National Institutes of Health [Drug hypersensitivity].
Consultant/Advisory Boards: AstraZeneca[Allergy/Immunology];BioCryst [Hereditary angioedema];Janssen [Drug toxicity];Regeneron [COVID-19
monoclonal antibodies];Vertex [Cystic fibrosis post-marketing studies];Verve[Allergy/Immunology].
All of the relevant financial relationships listed have
been mitigated. Anna M Feldweg, MD No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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IMMEDIATE PENICILLIN REACTIONS

Penicillins include the following:

● The aminopenicillins – Amoxicillin, amoxicillin-clavulanate, and ampicillin

MECHANISM OF SKIN TESTING

● The patient's medications should be reviewed.

● The major determinant:

• Penicilloyl-polylysine (PPL) (Pre-Pen) (6 x 10-5 M). Penicilloyl-polylysine is also known as benzylpenicilloyl-polylysine.

● 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

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

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

CONFIRMATORY CHALLENGE AFTER NEGATIVE SKIN TESTING

UPDATING THE PATIENT'S RECORDS

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Terms of Use.

26. Adkinson NF, personal communication.

Gell and Coombs classification of immunologic drug reactions

Type Description Mechanism Clinical features

I IgE-mediated, immediate- Antigen exposure causes IgE-mediated activation of mast Anaphylaxis

II Antibody-dependent An antigen or hapten that is intimately associated with a Hemolytic anemia

Graphic 80466 Version 18.0

Eyes, ears, nose

Itching or tingling of lips, tongue, oral mucosa*

Graphic 100732 Version 5.0

Penicillin: Major and minor determinants

Penicillin-allergic patients may form IgE molecules against the beta-

Graphic 67647 Version 3.0

Penicillin skin test reagents

Reagent Concentration used for skin testing

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

Penicillin G 10,000 units/mL

Commonly used penicillin skin test reagents.

Graphic 58347 Version 5.0

Conflict of interest policy

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