Diagnosing Nonimmediate Reactions to Penicillins by in vivo Tests

Abstract

Background: Maculopapular and urticarial rashes are nonimmediate manifestations common during penicillin treatment; the former often represent cell-mediated hypersensitivity. Our objectives were to assess the incidence of allergy in adults reporting nonimmediate manifestations during penicillin therapy and to evaluate the diagnostic potential of patch tests, delayed-reading skin tests and challenges in such cases. Methods: We used prick and intradermal tests as well as patch tests with penicillin determinants, ampicillin, amoxicillin and any other suspect penicillins. We also performed challenges with the suspect antibiotics. Results: Such antibiotics were aminopenicillins in 93.1% of 259 patients, most of whom had suffered from maculopapular rashes followed by piperacillin (4.2%). Three subjects displayed immediate skin test positivity. Ninety-four subjects showed patch test and delayed intradermal test positivity to the culprit penicillin (90 to aminopenicillins and 4 to piperacillin) and were considered as having had delayed hypersensitivity reactions. Five of the 8 subjects who displayed delayed intradermal test positivity and patch test negativity to the suspect penicillin underwent challenges, 2 reacted positively to the responsible aminopenicillin. Among the remaining 154 with negative results in allergologic tests, 125 agreed to undergo challenges; only 3 reacted. In all, 98 patients – 93 of whom had experienced maculopapular rashes – displayed delayed hypersensitivity (94 to aminopenicillins and 4 to piperacillin). Conclusions: Both patch and intradermal tests are useful in evaluating nonimmediate reactions to penicillins, particularly maculopapular rashes. Patch test and delayed intradermal positivity together indicate delayed hypersensitivity. Intradermal testing appears to be slightly more sensitive than patch testing.

Diagnosis of nonimmediate reactions to β‐lactam antibiotics

“…However, considering only the 166 subjects with aminopenicillin-associated maculopapular exanthems, patch tests and delayed-reading intradermal tests with AM and AX were positive in 52.4 and 54.2%, respectively. Moreover, all but one of the 64 subjects who were negative to the allergologic tests tolerated provocation tests with the suspect aminopenicillin, indicating that most of the results were not falsely negative (42). Although patients with positive tests were not challenged in this study, it suggests that these tests can reduce the number of patients falsely labelled as Ôpenicillin allergicÕ.…”

“…de Haan et al (46) assessed 64 patients with late (beginning 24 h or more after the start of therapy) reactions to aminopenicillins, and patch testing with BP was positive in 9.3% of them, while that with AM and AX in 35.9%. In a more recent study, which evaluated 241 subjects with nonimmediate reactions to aminopenicillins, patch tests with BP were positive in 7.5% of them, while AM and AX elicited positive reactions in 37.3% (42). Delayedreading intradermal tests with penicillin determinants (MDM and BP) were positive in 12%, while that with AM and AX in 39%.…”

“…In delayed allergy to aminopenicillins, both the b-lactam core structure and the whole molecule (core structure and the amino-benzyl group of the side chain) are recognized by T cells (54,55). However, the amino-benzyl group plays a predominant role: more than 70% of patients with such hypersensitivity display negative responses to BP in intradermal and/or patch tests (32,33,37,42,46). This means that alterations of side chains affect recognition, but also that the same side chains presented by cephalosporin core structures are not recognized.…”

“…There are findings with b-lactams, particularly aminopenicillins, showing that delayed hypersensitivity may be a long-lasting condition, which does not appear to be influenced by the time interval between the last adverse reaction and allergologic testing (32,37,42). This differs from the immediate type, which tends to disappear with time if the culprit drug is avoided (58-61).…”

“…Only few studies have been carried out with large samples of subjects previously classified as nonimmediate reactors to b-lactams (37,42,46). de Haan et al (46) assessed 64 patients with late (beginning 24 h or more after the start of therapy) reactions to aminopenicillins, and patch testing with BP was positive in 9.3% of them, while that with AM and AX in 35.9%.…”