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Benzylpenicilloyl Polylysine


(BEN zil pen i SIL oyl pol i LIE seen)

Index Terms

  • Benzylpenicilloyl-polylysine
  • Penicilloyl-polylysine
  • PPL

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution:

Pre-Pen®: 6 x 10-5 M (0.25 mL)

Brand Names: U.S.

  • Pre-Pen

Pharmacologic Category

  • Diagnostic Agent


Benzylpenicilloyl polylysine, a conjugate of the benzylpenicilloyl structural group (hapten) and the poly-l-lysine carrier (protein), is an antigen which reacts with benzylpenicilloyl IgE antibodies to elicit the release of chemical mediators, thereby producing type I (immediate or accelerated) urticarial reactions in patients hypersensitive to penicillins.

Use: Labeled Indications

Adjunct in assessing the risk of administering penicillin (penicillin G or benzylpenicillin) in patients suspected of clinical penicillin hypersensitivity

Use: Unlabeled

Adjunct in assessment of hypersensitivity to other beta-lactam antibiotics (penicillins and cephalosporins) to determine the safety of penicillin administration in patients with a history of reaction to cephalosporins


Systemic or marked local reaction to a previous administration of benzylpenicilloyl polylysine skin test; patients with a known severe hypersensitivity to penicillin should not be tested

Dosing: Adult

Diagnostic aid for detection of penicillin allergy:

Note: Benzylpenicilloyl polylysine should always be applied first via the puncture technique. Do not administer intradermally to patients who have a positive reaction to the puncture test.

Puncture test: Apply a small drop of the skin test solution using a 22- to 28-gauge needle and make a single shallow puncture of the epidermis through the drop of solution. A positive reaction consists of a pale wheal surrounding the puncture site which develops within 10 minutes and ranges from 5-15 mm or more in diameter (wheal may be surrounded by erythema and variable degrees of itching). If a positive response is evident, the solution should be wiped off immediately. If the puncture test is negative or equivocal (<5 mm wheal, with little or no erythema and no itching) 15 minutes following the puncture test, an intradermal test may be performed.

Intradermal test: Using a 0.5-1 mL tuberculin syringe with a 3/8 to 5/8 inch, 26- to 30-gauge short bevel needle, inject a volume of skin test solution sufficient to raise a small intradermal bleb ~3 mm in diameter intradermally, in duplicate at least 2 cm apart. A control of 0.9% sodium chloride or allergen-diluting solution should be injected at least 5 cm from the antigen test site. Most skin responses to the intradermal test will develop within 5-15 minutes. A response to the skin test is read at 20 minutes.

Interpretation of intradermal test:

(-) Negative: No increase in size of original bleb or no greater reaction compared to the control site

(±) Ambiguous: Wheal only slightly larger than original bleb with or without erythematous flare and slightly larger than control site; OR discordance between duplicate test sites

(+) Positive: Itching and marked increase in size of original bleb to ≥5 mm. Wheal may exhibit pseudopods and be >20 mm in diameter.

Control site should be reactionless. If wheal >2-3 mm develops at control site, repeat the test. If same reaction occurs, consultation is necessary.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling.


Puncture test: Administer initially by puncture technique on the inner volar aspect of the forearm, followed by an intradermal injection only in patients with a negative reaction.

Intradermal: Do not administer intradermally to patients with a positive reaction (wheal of 5-15 mm or more in diameter). Administer the intradermal test on the upper, outer arm, below the deltoid muscle in the event a severe hypersensitivity reaction occurs and a tourniquet needs to be applied. During the skin test, immediate treatment with epinephrine should also be available.


Refrigerate at 2°C to 8°C (36°F to 46°F); discard if left at room temperature for longer than 1 day.

Drug Interactions

Alpha-/Beta-Agonists: May diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Consider use of a histamine skin test as a positive control to assess a patient's ability to mount a wheal and flare response. Exceptions: Dipivefrin; EPINEPHrine (Nasal); EPINEPHrine (Oral Inhalation); Isometheptene. Consider therapy modification

Alpha1-Agonists: May diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Consider use of a histamine skin test as a positive control to assess a patient's ability to mount a wheal and flare response. Exceptions: Naphazoline (Nasal); Naphazoline (Ophthalmic); Oxymetazoline (Nasal); Phenylephrine (Nasal); Phenylephrine (Ophthalmic); Phenylephrine (Topical); Propylhexedrine; Xylometazoline. Consider therapy modification

Antihistamines: May diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Suspend systemic H1 antagonists for benzylpenicilloyl-polylysine skin testing and delay testing until systemic antihistaminic effects have dissipated. A histamine skin test may be used to assess persistent antihistaminic effects. Consider therapy modification

Adverse Reactions

Frequency not defined.

Cardiovascular: Hypotension

Dermatologic: Erythema, pruritus, urticaria (including local reaction at skin test site)

Hypersensitivity: Angioedema, hypersensitivity reaction (including anaphylaxis; rare)

Local: Local inflammation (intense; at skin test site)

Respiratory: Dyspnea


Concerns related to adverse effects:

• Allergic reactions: Rare systemic allergic reactions, including anaphylaxis, have been associated with penicillin skin testing. Penicillin skin testing should only be performed by skilled medical personnel under direct supervision of a physician, and testing should be performed only in an appropriate healthcare setting prepared for the immediate treatment with epinephrine. To decrease the risk of a systemic allergic reaction, the manufacturer recommends puncture skin testing prior to intradermal testing.

Disease-related concerns:

• Severe penicillin allergy: Patients with a reliable history of a severe life-threatening penicillin allergy, including Stevens-Johnson syndrome or TEN, should NOT receive penicillin skin testing.

Concurrent drug therapy issues:

• Histamine H1 antagonists: Responses to skin testing may be attenuated by concurrent administration of antihistamines. Consider delaying testing until these medications can be withheld to allow time for their effects dissipate.

Other warnings/precautions:

• Accuracy: According to the manufacturer, a negative skin test is associated with an incidence of immediate allergic reactions of <5% after penicillin administration and a positive skin test may indicate >50% incidence of allergic reaction occurring after penicillin administration.

• Appropriate use: Adequate penicillin skin testing should ideally involve reagents of both the major antigenic determinant (penicilloyl-polylysine) and minor determinants (penicilloate or penilloate). Benzylpenicilloyl polylysine alone does not identify those patients who react to a minor antigenic determinant. The minor determinant mixture (MDM) is not commercially available in the U.S.; however, diluted penicillin G (concentration: 10,000 units/mL) has been used as a minor determinant for skin testing purposes (Bernstein, 2008). Penicillin skin testing does not predict the occurrence of late reactions (eg, type II, III, IV or idiopathic reactions).

Pregnancy Risk Factor


Pregnancy Considerations

Animal reproduction studies have not been conducted with benzylpenicilloyl polylysine. The Centers for Disease Control and Prevention (CDC) states that penicillin skin testing may be useful in assessing suspected penicillin hypersensitivity in pregnant women diagnosed with syphilis (of any stage) due to a lack of proven alternatives to the use of penicillin in this population (CDC, 2006).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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