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In patients with a history of an allergic reaction to penicillin or other p -lactam antibiotics, penicillin skin testing should be done electively. Only 20% of adults and 10% of children with this diagnosis turn out to be actually allergic based on allergy skin testing (the positive penicillin allergy skin test rate is higher in the first year after labeled allergic to penicillin).

  1. In many cases, the original reaction, usually a rash, is a result of an infection (usually viral) rather than the antibiotic used to treat that infection.
  2. In cases of true penicillin allergy, the reaction rate dissipates about 10%/yr.
  3. In children, toxic (nonallergic) maculopapular rash to ampicillin/amoxicillin and to some cephalosporins like Ceclor are common (5% of antibiotic therapies).

In most cases it is advisable to refer the suspected penicillin-allergic patient to an allergist-immunologist specialist for evaluation of the condition. Table 6 lists the peni-

Penicillin Allergy Skin Tests

  • p-lactams are the only type of antimicrobial agents in which a suspected reaction (allergic) can be verified by skin tests.
  • Of those patients with a history of a prior reaction, only 20% of adults and 10% of children have been found to be skin test positive.
  • Positive skin test to penicolloyl-polylysine (Pre-Pen) correlates best with rash(usually urticarial reactions); positive skin test to penicillin "minor determinant mix" correlates with anaphylaxis.
  • Skin testing with penicillin G metabolites is usually a measure of potential clinical reactions to the p-lactam ring in amoxicillin and cephalosporins.

Table 6

Penicillin Skin Testing


Type of test


Penicilloyl-polylsine (Pre-Pen)a


1 drop

test strength


0.02 mL

Penicillin G, 10,000 U/mLb


1 drop


0.02 mL

Penicillin—minor determinant mixture Not commercially available in the US

"Schwartz Pharma, Kremers Urban Co., Milwaukee, WI.

^Serial dilutions (10, 100, 1000 U/mL) advisable in very sensitive individuals.

"Schwartz Pharma, Kremers Urban Co., Milwaukee, WI.

^Serial dilutions (10, 100, 1000 U/mL) advisable in very sensitive individuals.

cillin skin tests bases on commonly available agents. Penicolloyl polylysine (PPL) is an example of the major breakdown product of penicillin drug metabolism coupled to a carrier protein. This test reagent is responsible for positive skin tests in patients with an isolated skin rash (especially urticaria, or urticaria and angioedema). Penicillin G (Pen G) is the parent drug. A positive skin test to Pen G correlates with all types of allergic reactions. A positive minor determinant mixture (MDM) skin test (minor or secondary penicillin metabolites) (see Fig. 2) correlates best with more serious life-threatening, systemic anaphylaxis penicillin reactions. Unfortunately, this latter skin test reagent is not available commercially, but is available in some academic centers and large clinics.

In addition, in 2000-2001 and again in 2004-2005, PPL commercial manufacture was suspended. Because of the uncertainty of future supplies, allergists may have to consider preparation of p -lactum antibiotics allergy skin test reagents in their own local laboratories (see Suggested Readings, Macy et al. and Verumi et al.).

In studies of penicillin allergic individuals, skin testing with PPL, Pen G, and MDM is safe, can be done electively, and is predictive of the risk of subsequent challenge with penicillin. If all tests are negative, there is only a small risk of a minor skin rash upon challenge. The positive predictive value of skin testing to assess the future risk for allergic reactions to p-lactam antibiotics using only Pre-Pen and Pen G is unclear but has been estimated to be 70-97% reliable (see Suggested Reading).

Penicillin skin testing also tests to reactions directed to the p-lactam ring in cephalosporins and other penicillins. In some cases, individuals may develop sensitivity to the side chain (R in Fig. 1) rather than to the p-lactam ring. Usually this occurs in reaction to either ampicillin/amoxicillin or a specific cephalosporin. Fortunately, this is uncommon in p -lactam-allergic individuals in North America. Allergy skin testing can be done to other penicillins and cephalosporins and if positive, may be helpful information. However, these types of skin tests have not been validated in controlled studies.

In cases in which the skin test results are equivocal or the history of the prior reaction is severe but the skin tests are negative, a graded challenge with a single usual oral dose of the p-lactam antibiotic in question under controlled conditions (see Graded Drug Challenge Test Dosing). In most situations, when MDM skin testing reagent is not available, an oral p -lactam challenge is advised following negative PPL and Pen G allergy skin testing.

In cases in which the individual is found to be allergic (positive history of reaction, confirmed by skin test and/or challenge), all p-lactam antibiotics should be avoided. Usually substitute medications are used to treat subsequent infections.

The overall cross-reactivity rate between penicillin allergy and cephalosporin allergy is estimated to be 4% or less (third and fourth generation) to 10% or more (first generation). Some authorities have recommended the use of third- or fourth-generation cephalosporin in suspected penicillin-allergic individuals. However, most experts feel that all p-lactam antibiotics should be avoided in proven penicillin-allergic individuals.

In select cases, in which individuals who are proven p-lactam antibiotic-allergic and need a p-lactam antibiotic (life-threatening or other serious infections without suitable substitutes available), then penicillin or the appropriate p-lactam antibiotic desensitiza-tion may be indicated. In these cases it is advisable to consult an allergist-immunologist specialist.

Table 7 shows an example of an oral penicillin desensitization protocol that can be used as a protocol for desensitization with penicillin and other p -lactam antibiotics. This procedure should be done only in the hospital under controlled conditions, such as an intensive care unit with a doctor present during the entire procedure. Each individual case is different, and published protocols are only guides to the procedure.

The oral route is felt to be safest, but the iv route may be preferable in some cases. Studies have shown that reactions during the procedure should be expected approx 30% of the time. When these occur, the patient should be treated appropriately and stabilized before restarting the desensitization procedure. The next desensitizing dose should be less than the one producing the reaction.

Once the procedure is complete, the patient is usually maintained at a full treatment dose of the medication until the therapy is complete. Once the drug has been stopped for 12-24 h, the patient should be considered to have reverted to his or her previous sensitized (allergic) state.

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