Rapid intravenous cephalosporin desensitization

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To the Editor:

On review of the literature, 2 protocols for intravenous cephalosporin desensitization were found requiring either a 2-day¹ or 14-day² period of time. Although cephalosporins are commonly prescribed in numerous nonemergency clinical settings, situations arise in which urgent cephalosporin therapy is the best or only treatment option available. One such setting is in the patient with cystic fibrosis who requires either an intravenous third- or fourth-generation cephalosporin for the treatment of Pseudomonas aeruginosa–induced pneumonia. It would thus be desirable to have a rapid protocol for cephalosporin desensitization, as is currently available for penicillin. Here we report rapid intravenous cephalosporin desensitization protocols that have been used successfully at the University of Iowa Hospitals and Clinics (UIHC) and Barnes-Jewish Hospital (BJH) over the past several years.

After institutional review board approval at both institutions, a retrospective chart review was performed. There were 49 patients who were seen between July 1997 and June 2002 at UIHC and 44 patients who were seen between January 1999 and January 2004 at BJH in whom penicillin and cephalosporin skin testing was performed. The 8 individuals, 2 from UICH and 6 from BJH, included in this retrospective study were those who had positive skin test results and eventually underwent rapid intravenous desensitization to a cephalosporin (Table I). At both UICH and BJH, it is our practice not to give cephalosporins to patients with penicillin allergy without prior penicillin and cephalosporin skin testing. Patients who had uniquely positive skin test results to penicillin determinants (negative skin test results to cephalosporins) were not desensitized to cephalosporin before receiving cephalosporin therapy. The remainder of the 93 subjects had negative skin test results and received a β-lactam antibiotic without adverse events. Given that this is a retrospective study, we were unable to reliably determine the time between index adverse antibiotic reaction and skin testing. Skin testing and desensitization were always accomplished on the same day. In every case, the risks and benefits of skin testing and rapid intravenous cephalosporin desensitization were discussed with the patient in detail, and written consent was obtained. At UIHC, desensitizations were performed in either a medical or surgical intensive care unit, and at BJH, they were performed on either standard inpatient floors or intensive care units, depending on the patients' location. Rapid intravenous desensitizations at both locations were supervised by a clinical fellow of allergy and immunology, an attending physician in allergy and immunology, or both.

Table I. Subjects undergoing rapid intravenous cephalosporin desensitization

PCN, Penicillin; ST+, positive skin test result (intradermal); CS, cephalosporin; UIHC, University of Iowa Hospitals and Clinics; CF, cystic fibrosis; PNA, pneumonia; U, urticarial rash; MaD, major determinant; MiD, minor determinant; BJH, Barnes-Jewish Hospital; AML, acute myelogenous leukemia; NF, neutropenic fever; Ana, anaphylaxis.

At both institutions, skin testing was performed according to standard percutaneous and intradermal skin testing methods.³ Patients were tested either on the volar aspect of the forearm or the posterior aspect of the upper arm, with normal saline as the negative control, histamine as the positive control, penicillin major (benzylpenicilloyl polylysine-Pre-pen; Hollister-Stier, Spokane, Wash), and minor determinants (benzylpenilloate, benzylpenicilloate, Pen A,⁴ and Pen G) and cephalosporins. Cephalosporins were diluted to 6.0 mg/mL at UIHC and 3.33 mg/mL at BJH.⁵ Prior negative skin test results to these penicillin and cephalosporin preparations in patients at UIHC and BJH showed that these concentrations have no irritant effect on normal human skin. There was a 15-minute period between the time that skin tests were placed and when they were read. A skin prick test result was considered positive if the wheal was greater than or equal to 5 mm in diameter. Negative epicutaneous skin prick test results were followed by intradermal testing with diluent-negative, histamine-positive controls and 0.02 mL of the drug (6.0 mg/mL at UIHC=0.12 mg and 3.33 mg/mL at BJH=0.07 mg). An intradermal test result was considered positive if the wheal was at least 3 mm greater than that elicited by the negative control.

Desensitization to cefepime (fourth generation) and ceftriaxone (third generation) at UIHC was performed by using a protocol requiring 8.5 hours and 7 hours, respectively. Protocols were initiated at 0.5- to 1-mg doses (similar dose exposure to the intradermal skin test dose of 0.12 mg) and increased at a rate that approximately doubled the dose every 30 minutes. Once higher doses and volumes were reached, time between doses was increased accordingly.

Desensitization to cefepime (fourth generation), ceftriaxone (third generation), and cefazolin (first generation) at BJH was performed in 2.25 hours, as shown in Table II. Protocols were initiated according to the goal therapeutic intravenous dose, either 1 or 2 g. In both examples, the initiating dose is 0.1 mg (similar dose exposure to the intradermal skin test dose of 0.7 mg). Dosing was calculated in a retrospective fashion so that the cumulative dose administered over the course of rapid desensitization equaled the goal therapeutic dose (1-2 g intravenously depending on the circumstance). Doses were rounded to make accurate preparations and administration feasible. Dose escalation was done by half-log₁₀ (approximately 3.162278) increments, and dosing intervals were set at 15 minutes.

Table II. Rapid intravenous cephalosporin desensitization protocol: Goal dose, 1 g and 2 g intravenously

Protocol for intravenous desensitization to all cephalosporins with a goal dose of 1 g and 2 g (Barnes-Jewish Hospital).

IV, Intravenous.

The patients who underwent rapid intravenous cephalosporin desensitization are detailed in Table I. All patients included in this analysis had positive skin test results to cephalosporins, and 6 of these 8 subjects also had positive skin test results to penicillin determinants. In 3 subjects (subjects 4-6) the patient underwent skin testing to cefazolin, ceftazidime (third generation), or both but later underwent intravenous desensitization to cefepime. Outside of the β-lactam ring, there are no shared side chains (R1 or R2) between the cefazolin and ceftazidime.⁶ Cefepime and ceftazidime have similar R1 chains; however, it is not clear whether the structural similarity is solely responsible for this potential cross-reactivity. Romano et al⁷ showed that 5 of 14 patients had positive skin test results to at least 1 cephalosporin, which have side-chain structures different from those of penicillins. These results demonstrate that the increased risk for cross-reactivity is not solely a result of structural similarities. The specific haptens involved in hypersensitivity to cephalosporins have not been identified. Given this, we presumed the potential for cross-reactivity and desensitized. The time for desensitization varied from 2.25 hours (BJH) to 8.5 hours (UIHC), depending on the protocol used. All 8 subjects underwent rapid intravenous cephalosporin desensitization without adverse events.

Intravenous cephalosporin desensitization procedures requiring 2-day¹ or 14-day² periods have been documented in the literature. In these studies no problems or major systemic reactions were observed.¹, ² Our examples demonstrate intravenous desensitization protocols that were well tolerated in a much shorter time frame. The 8 aforementioned patients illustrate the feasibility and safety of acute intravenous desensitization to selected cephalosporins over a 2.25- to 8.5-hour period. Although the time frames among the protocols presented vary, we believe that with the proper precautions, including close patient observation and very small initial dosing, intravenous cephalosporin desensitization can be successfully accomplished in 1 day. Because all 8 rapid desensitizations were without adverse event, we suggest using the shorter BJH protocol encompassing a 2.25-hour time span, as outlined in Table II.

The literature remains controversial as to the necessity of penicillin skin testing for a history of penicillin allergy when a cephalosporin is the drug of choice. Per practice parameters, the recommendation remains that these patients be skin tested to penicillin major and minor determinants to determine whether the patient has specific IgE antibodies. If skin test results are negative, the patient can receive a cephalosporin at no greater risk than that of the general population.⁸ Anne and Reisman⁹ reported that if patients with a history of allergy to penicillin are not skin tested but given a second- or third-generation cephalosporin directly, the overall incidence of adverse reactions from cephalosporins ranges from 1% to 10%, with rare anaphylaxis (<0.02%). From this, Anne and Reisman proposed that penicillin skin tests do not predict the likelihood of allergic reactions to cephalosporins in patients with histories of penicillin allergy because 1 (1%) reaction occurred in 98 patients with positive penicillin skin test results, and 6 (2%) reactions occurred in 310 patients with negative test results. They concluded that it is safe to administer cephalosporin antibiotics to patients with penicillin allergy. However, Pumphrey and Davis¹⁰ reported from their data analysis of fatal anaphylaxis in the United Kingdom between 1992 and 1997 that 6 of the 12 anaphylactic reactions to antibiotics occurred with the first dose of cephalosporin. Three patients had a history of allergy to amoxicillin and one to penicillin, but none had been skin tested. Furthermore, a recent study by Romano et al⁷ showed that 10 (71.4%) of 14 subjects with positive skin test results to cephalosporins also reacted to the penicillin minor determinant mixture. Our study is in agreement with the latter because 6 (75%) of our 8 subjects who had positive skin test results to cephalosporins also had positive skin test results to penicillin determinants.

According to current practice guidelines,⁵ there is a continued need for cephalosporin desensitization in patients who have had severe IgE-mediated allergic reactions to penicillin. This retrospective study documents rapid intravenous desensitization to a first-, a third-, and a fourth-generation cephalosporin in less than 1 day. Furthermore, the BJH protocol can be accomplished safely and effectively in 2.25 hours.

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