Ticarcillin

Penicillin (PCN) may cause a reaction in up to 10% of the population. No study has examined PCN skin testing longitudinally over a 20-year period. A total of 122 patients underwent PCN skin testing between September 1978 and May 1998. Patients were skin tested with the major determinant, penicilloyl polylysine, and three minor determinants, PCN, benzylpenilloate, and benzylpenicilloate. Ten of a total of 122 patients had positive skin test reactions. Nine reactions were to penicilloyl polylysine and one reaction was to the minor determinant benzylpenilloate. There was a total of four patients (3.6%) with false-negative results on skin testing. PCN skin testing with both the major and minor determinants should be performed when there is a history of PCN allergy, a serious illness, and no suitable alternatives. If either the major or minor determinants are positive without suitable alternative antibiotics, then the patient should undergo desensitization.

Introduction

Our study was designed to evaluate the utility and safety of penicillin (PCN) skin testing in PCN allergy. PCN skin testing with the major and minor determinants was available at our institution on an approved research protocol that started in September 1978 and continued until May 1998. From our data and a review of the literature, we present a stepwise approach to the evaluation of a patient with a history of PCN allergy.

PCN has been reported to cause a reaction in 0.7% to 10% of the general population.1 Immediate reactions, which usually occur within minutes after antibiotic administration, and accelerated reactions, which occur within 1 to 72 hours after antibiotic administration, are thought to be secondary to IgE mechanisms.2 These reactions can be severe, and PCN agents are responsible for most cases of drug-induced anaphylaxis.3 However, for the majority of patients, PCN reactions are not immediate or accelerated reactions and are secondary to non-IgEmediated events. In some instances, PCN therapy, which may be the drug of choice, is withheld from the patient.

PCN was first discovered in 1928 by Sir Alexander Fleming4 but did not have an established therapeutic use until the 1940 report published by Chain and Florey.5 The initial civilian use of PCN occurred in 1945 and 1 year later, in 1946, the first documented case of a fatality attributable to PCN was reported.6 PCN skin testing is performed with both the major and minor determinants. The major determinant, penicilloyl polylysine (PPL), is named the major determinant because 95% of protein-bound PCN metabolites consist of PPL. The minor determinants are not currently commercially available. Skin testing with PCN tests for an IgE-mediated response to these major and minor determinants.

Methods

One hundred twenty-two patients underwent PCN skin testing between September 1978 and May 1998. All patients had a history of an immediate-type reaction to a PCN agent within 48 hours after exposure. These reactions included generalized pruritus, cutaneous reactions, angioedema, respiratory distress, and/or anaphylactic shock. Patients were selected from both the inpatient and outpatient services. Skin testing was performed only if there were no suitable alternatives to administration of a PCN agent. This assessment was made with consultation from the Infectious Disease Service.

Skin test reagents consisted of the major determinant, PPL, and three minor determinants, PCN, benzylpenilloate (PO), and benzylpenicilloate (PC). PPL is commercially available as Prepen (Hollister Stier LLC, Spokane, Washington), used undiluted at a concentration of 6 × 10^sup -5^ M, and stored at 4°C; a final concentration of 10^sup -2^ M (5,000 U/mL) was used for testing. Lyophilized extracts of PO and PC were supplied by Dr. Andrew Saxon (Division of Clinical Immunology and Allergy, University of California, Los Angeles). Each extract was dissolved in Tris buffer, neutralized with 1.0 N NaOH to a pH of 7.4, and used at a final concentration of 10^sup -2^ M. These were kept stored at -70°C until the time of testing.

All patients were skin tested on the volar surface of the forearm with each of the four determinants. Tris buffer and diluent were used as negative controls, with histamine as a positive control. Percutaneous (prick) tests were performed first and read at 7 minutes (15 minutes for PPL). Intradermal tests using 0.02 mL of each determinant were conducted only if the prick tests were negative. Intradermal tests were read at 15 minutes and considered positive with wheals ≥5 mm larger than the negative controls, with surrounding erythema. Approval was received from the Veterans Affairs Greater Los Angeles Healthcare System institutional review board, and informed consent was obtained from all patients before testing.

Results

Positive Skin Test Reactions

A total of 122 patients underwent PCN skin testing and 10 patients had positive skin test reactions. Nine reactions were to PPL and one reaction was to the minor determinant PO. Of these 10 patients with positive reactions, 4 were desensitized to the PCN of choice without incident. The other six patients were given alternative antibiotics.

Negative Skin Test Reactions

Of the remaining 112 patients, 110 patients had a negative skin test and 2 had an indeterminate skin test. There was a total of four patients (3.6%) with false-negative results on skin testing. One patient developed generalized pruritus minutes after parenteral administration of ampicillin. Another patient had a reaction of dyspnea several minutes after parenteral PCN administration. A third patient developed generalized pruritus 30 minutes after parenteral oxacillin administration. A fourth patient developed urticaria 30 hours into his course of piperacillin. None of these reactions was life-threatening. The reactions were controlled with appropriate therapy. An alternative antibiotic was chosen except in the case of the fourth patient, who was able to continue the course of piperacillin.

One patient was tested only with PPL and PCN because the other two minor determinants were not available at the time of testing. With negative results on skin testing for PPL and PCN, this patient was then given parenteral ticarcillin-clavulanate. Within 30 minutes after antibiotic administration, the patient developed anaphylaxis and required immediate treatment with epinephrine, antihistamines, and corticosteroids, which was lifesaving.7

Discussion

PCN and other β-lactam antibiotics are the drugs of choice in many clinical situations. However, up to 10% of patients give a history of PCN allergy. As a result, these antibiotics are often withheld from the patient. Evaluation of PCN allergy through skin testing can allow 90% of these patients to receive a PCN agent after negative skin testing. Our 20-year longitudinal study supports the utility of PCN skin testing using both major and minor determinants.

PCN skin testing is an extremely safe procedure. Reactions can range from pruritus to more severe reactions such as anaphylaxis. Our data showed that no patients had a significant reaction upon PCN skin testing. Valyasevi and Van Dellen8 PCN skin tested 1,710 patients and had a systemic reaction rate of only 0.12%, with no fatalities. In our literature search, only one fatality was reported in 1966 after PCN testing.9

PCN skin testing is a reliable test. Of the 110 skin testnegative patients, there were 4 false-negative results (3.6%). Our false-negative rate was consistent with the literature, which reports a false-negative rate of 1.2% to 4.1%.10-12 The minor determinants are thought to be predictive of a more serious reaction than the major determinant PPL.13 During the study period, a single patient was tested only with PPL and PCN, because the other minor determinants were not available. A major immediate reaction occurred in this patient when PCN was given intravenously. This illustrates that testing with PPL and PCN alone may be inadequate for predicting systemic reactions. We did not determine the false-positive rate, because this would have required PCN skin testing of patients without a history of PCN allergy.

One controversial aspect of PCN skin testing relates to the type of previous reaction to PCN. In the second phase of this study,14 we suggested that everyone with a history of PCN allergy, whether strong or weak, be skin tested if PCN was indicated and no alternative agent was available. In contrast, another study, using a decision-analysis model, identified certain types of PCN allergy history for which skin testing was required.15 A recent report using meta-analysis supported our view and concluded that patients with vague PCN allergy histories should undergo PCN skin testing before administration of PCN.16

There are additional complexities in PCN skin testing, including resensitization and testing in advance of need. Resensitization is a result of inducing IgE antibodies to PCN after PCN skin testing. This is a theoretical risk of sensitization from previous exposure to the reagents of PCN skin testing. However, studies have shown that the risk of resensitization is minimal.17,18 PCN skin testing performed in advance of need was recently evaluated. Macy et al.19 found that the majority of patients with negative PCN skin testing performed in advance of need tolerated PCN at a later date without any adverse reaction.

Our data confirm previous reports that the majority of patients with a history of PCN allergy are skin test negative.20-22 Negative results with skin testing allow these patients to use a PCN agent. This permits the treating physician not to be restricted to alternative antibiotics, which could be more expensive, less efficacious, and potentially more toxic to the patient.

Most anaphylactic fatalities after PCN administration occur among patients without a history of PCN allergy.23 Careful attention should be given to all high-risk patients, such as elderly patients with severe underlying heart disease, before PCN therapy. We previously reported two fatalities with PCN therapy among elderly cardiac patients with no history of PCN allergy.24 Therefore, PCN skin testing for these high-risk patients who do not have a history of PCN allergy may be warranted. In addition, these patients may be taking medications such as β-receptor blockers, which may blunt the response to rescue therapy in anaphylaxis.

There are different approaches on how to treat a patient with a history of PCN allergy. From our data and a review of the literature, we present a stepwise approach for the evaluation and management of PCN allergy. We recommend that the patient undergo PCN skin testing when the patient has a history of a PCN reaction (excluding severe skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis), is suitable for skin testing (no recent use of antihistamines, availability of a skin test site, and appropriate reactions to negative and positive controls), and has a lifethreatening disease (Table I) requiring antibiotic treatment with a PCN agent, with no suitable alternatives. Selection of an alternative drug for PCN-allergic patients can be challenging because of possible cross-reactivity. There are substantial data supporting some cross-reactivity among PCN, cephalosporins, and imipenem, whereas aztreonam seems to have little to no cross-reactivity.25-31 Maculopapular rash with semisynthetic PCNs such as ampicillin (5-10% incidence of rash) does not seem to be a risk factor for a reaction after repeat administration of ampicillin or PCN.32

We recommend that patients be skin tested with both the major and minor determinants when available. We are aware that the minor determinants PO and PC are not commercially available. Therefore, skin testing may be limited to PPL and PCN. The latter approach would not detect all PCN-sensitive patients, as observed for one patient described in this study. Should the patient have a negative skin test reaction, then we recommend treatment with the PCN agent. Approximately 5% of patients have a reaction to a PCN agent after a negative skin test; however, these reactions tend to be mild and not life-threatening.33 Should the patient have a positive reaction to skin testing, then we recommend desensitization.

Desensitization is a high-risk procedure. Therefore, desensitization should be performed in a setting where the patient can be monitored and treated with a physician present. Oral desensitization is generally thought to be safer than parenteral desensitization. Several detailed desensitization protocols for PCNs have been described.34^37 After successful desensitization, PCN should be given at least every 12 hours; if therapy is interrupted for > 12 hours, then densensitization may need to be repeated.37

In this longitudinal study, we observed a stepwise decrease in the number of consultations for PCN skin testing (Fig. 1). One possible explanation is the national trend of decreasing use of PCN agents. McCaig and Hughes38 reported this trend in a study from 1980 to 1992. The following decade, Steinman et al.39 reported increased use of broad-spectrum antibiotics from 1991 to 1999, which was most pronounced with alternatives to the β-lactams. Azithromycin and clarithromycin use increased from 2% to 13% and quinolone use increased from 8% to 16%, although use of the broad-spectrum j3-lactam amoxicillin-clavulanate increased only from 4% to 6% and use of the second- and third-generation cephalosporins increased only from 11% to 12%.

In summary, PCN skin testing should be performed only when there is a history of PCN allergy, a serious illness, and no suitable alternatives. In addition, PCN skin testing should be considered for high-risk patients (elderly patients with underlying heart disease) even without a history of PCN allergy. Skin testing ideally should be performed with both the major and minor determinants. Skin testing with only the major determinant PPL and the minor determinant PCN is a second choice. If either the major or minor determinants are positive, then the patient should undergo desensitization.

References

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Guarantor: William B. Klaustermeyer, MD

Contributors: Vinay C. Gowda, MD; William B. Klaustermeyer, MD

Department of Medicine, Division of Allergy and Immunology,Veterans Affairs Greater Los Angeles Healthcare System, The David Geffen School of Medicine at UCU, Los Angeles, CA 90073.

Presented at the annual meeting of the American College of Allergy, Asthma, and Immunology, November 8, 2003, New Orleans. LA.

Reprints: William B. Klaustermeyer, MD, Division of Allergy and Immunology (111R), Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073.

This manuscript was received for review in March 2004. The revised manuscript was accepted for publication in July 2004.

Copyright Association of Military Surgeons of the United States Aug 2005
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