Enabling antibiotic allergy evaluations and reintroduction of first-line antibiotics for patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) often have a history of antibiotic adverse drug reactions (ADRs) that pose a barrier to receiving recommended first-line treatment. Targeted antibiotic allergy evaluations are increasingly recognized as an important strategy for optimization of antimicrobial stewardship. OBJECTIVE: To improve first-line antibiotic use in patients with CF with antibiotic ADRs by streamlining access to antibiotic allergy evaluations and standardizing documentation of plans for antibiotic reintroduction. METHODS: We incorporated allergy evaluations into a multidisciplinary CF clinic and used telemedicine when allergy evaluations could not be performed during CF clinic. Standard documentation of antibiotic allergy plans was used to enable safe reintroduction of first-line antibiotics by CF providers. RESULTS: Strategies used in this study allowed 81.3% (26 of 32) of patients with CF to receive allergy evaluations and antibiotic allergy plans for prioritized antibiotics (penicillin, cephalosporin, sulfonamide), with removal of 41.0% (16 of 39) of prioritized antibiotic ADRs. Only 5.1% (2 of 39) of prioritized antibiotic ADRs evaluated required strict avoidance after evaluation. There were 9 patients who received at least 1 prioritized antibiotic, with 66.6% (6 of 9) of these patients given the antibiotic after only 1 allergy evaluation visit. Furthermore, these strategies allowed allergy evaluations of 23 nonprioritized antibiotics to occur, with removal of the ADR in 39.1% (9 of 23) and use of 77.8% (7 of 9) of nonprioritized antibiotics after removal. CONCLUSION: Incorporating allergy evaluations into a multidisciplinary CF clinic can liberalize first-line antibiotic use in patients with CF. Standard documentation of antibiotic allergy plans allowed antibiotic reintroduction to occur even before complete removal of documented antibiotic ADRs.

Neo-antigens for the serological diagnosis of IgE-mediated drug allergic reactions to antibiotics cephalosporin, carbapenem and monobactam.

New antigens deriving from -lloyl and -llanyl, major and minor determinants, respectively, were produced for ß-lactam antibiotics cefuroxime, cefotaxime, ceftriaxone, meropenem and aztreonam. Twenty ß-lactam antigens were produced using human serum albumin and histone H1 as carrier proteins. Antigens were tested by multiplex in vitro immunoassays and evaluated based on the detection of specific IgG and IgE in the serum samples. Both major and minor determinants were appropriate antigens for detecting specific anti-ß-lactam IgG in immunised rabbit sera. In a cohort of 37 allergic patients, we observed that only the minor determinants (-llanyl antigens) were suitable for determining specific anti-ß-lactam IgE antibodies with high sensitivity (< 0.01 IU/mL; 24 ng/L) and specificity (100%). These findings reveal that not only the haptenisation of ß-lactam antibiotics renders improved molecular recognition events when the 4-member ß-lactam ring remains unmodified, but also may contribute to develop promising minor antigens suitable for detecting specific IgE-mediated allergic reactions. This will facilitate the development of sensitive and selective multiplexed in vitro tests for drug-allergy diagnoses to antibiotics cephalosporin, carbapenem and monobactam.

Hypersensitivity to antibiotics in drug reaction with eosinophilia and systemic symptoms (DRESS) from other culprits.

BACKGROUND: Antibiotics have been implicated in the reactivation of exanthema and systemic involvement in drug reaction with eosinophilia and systemic symptoms (DRESS); however, it is not clear whether these patients become sensitized to the antibiotic. OBJECTIVE: To evaluate if, after DRESS, patients become sensitized to antibiotics. METHODS: We retrospectively reviewed the patch test (PT) data and clinical files of DRESS patients who were administered antibiotics during DRESS from other culprits. RESULTS: Nine patients out of 17 (53%) were positive to antibiotics in PT: six to the penicillin group and three to cephalosporins (including one patient with additional positivity to vancomycin). Considering the eight patients who were negative to antibiotics in PT, seven were exposed to a fluoroquinolone. Four cases were patch tested again and three remained positive to antibiotics 2 to 5 years thereafter. Two patients with positive PT results had an accidental re-exposure to antibiotics and developed a maculopapular exanthema without systemic symptoms. CONCLUSION: Exposure to antibiotics during DRESS or its prodromal phase could enhance sensitization to antibiotics, as confirmed by a positive PT. Reproducibility of positive PTs to antibiotics after several years and reactivation after re-exposure support that T-cell-mediated hypersensitivity to antibiotics in the setting of DRESS is a specific reaction.

Cephalosporin Allergy: Current Understanding and Future Challenges.

Cephalosporins are commonly used antibiotics both in hospitalized patients and in outpatients. Hypersensitivity reactions to cephalosporins are becoming increasingly common with a wide range of immunopathologic mechanisms. Cephalosporins are one of the leading causes for perioperative anaphylaxis and severe cutaneous adverse reactions. Patients allergic to cephalosporins tend to tolerate cephalosporins with disparate R1 side chains but may react to other beta-lactams with common R1 side chains. Skin testing for cephalosporins has not been well validated but appears to have a good negative predictive value for cephalosporins with disparate R1 side chains. In vitro tests including basophil activation tests have lower sensitivity when compared with skin testing. Rapid drug desensitization procedures are safe and effective and have been used successfully for immediate and some nonimmediate cephalosporin reactions. Many gaps in knowledge still exist regarding cephalosporin hypersensitivity.

Misconceptions Surrounding Penicillin Allergy: Implications for Anesthesiologists.

Administration of preoperative antimicrobial prophylaxis, often with a cephalosporin, is the mainstay of surgical site infection prevention guidelines. Unfortunately, due to prevalent misconceptions, patients labeled as having a penicillin allergy often receive alternate and less-effective antibiotics, placing them at risk of a variety of adverse effects including increased morbidity and higher risk of surgical site infection. The perioperative physician should ascertain the nature of previous reactions to aid in determining the probability of the prevalence of a true allergy. Penicillin allergy testing may be performed but may not be feasible in the perioperative setting. Current evidence on the structural determinants of penicillin and cephalosporin allergies refutes the misconception of cross-reactivity between penicillins and cefazolin, and there is no clear evidence of an increased risk of anaphylaxis in cefazolin-naive, penicillin-allergic patients. A clinical practice algorithm for the perioperative evaluation and management of patients reporting a history of penicillin allergy is presented, concluding that cephalosporins can be safely administered to a majority of such patients.

Cross-Reactivity and Tolerability of Cephalosporins in Patients with IgE-Mediated Hypersensitivity to Penicillins.

BACKGROUND: Studies performed since 1990 on samples of at least 30 subjects with a documented IgE-mediated hypersensitivity to penicillins have found a rate of positive responses to allergy tests with cephalosporins ranging from 0% to 27%. OBJECTIVE: We sought to assess the cross-reactivity with cephalosporins and evaluate the possibility of using cephalosporins in penicillin-allergic subjects. METHODS: We conducted a prospective study of 252 consecutive subjects who had suffered 319 immediate reactions (mostly anaphylaxis) to penicillins and had positive skin tests to at least 1 penicillin reagent. All patients underwent serum specific IgE assays for cefaclor, as well as skin tests with 3 aminocephalosporins (cephalexin, cefaclor, and cefadroxil), cefamandole, cefuroxime, ceftazidime, ceftriaxone, cefotaxime, and cefepime. Patients with negative results for the last 5 cephalosporins were challenged with cefuroxime axetil and ceftriaxone; those with negative results for aminocephalosporins were also challenged with cefaclor and cefadroxil. RESULTS: Ninety-nine participants (39.3%) had positive allergy tests for cephalosporins. Specifically, 95 (37.7%) were positive to aminocephalosporins and/or cefamandole, which share similar or identical side chains with penicillins. All 244 subjects who underwent challenges with cefuroxime axetil and ceftriaxone tolerated them. Of the 170 patients who underwent aminocephalosporin challenges, 3 reacted to cefaclor and 4 to cefadroxil. CONCLUSIONS: Cross-reactivity between penicillins and cephalosporins seems to be mainly related to side chain similarity or identity. Subjects with an IgE-mediated hypersensitivity to penicillins could be treated with cephalosporins such as cefuroxime and ceftriaxone that have side-chain determinants different from those of penicillins and are negative in pretreatment skin testing.

Cross-reactivity in ß-Lactam Allergy.

ß-Lactam drugs (penicillins, amoxicillin, and cephalosporins) account for 42.6% of all severe drug-induced anaphylaxis. In this review, we focus on clinically significant immunologic cross-reactivity in patients with confirmed penicillin allergy to cephalosporins, and the structural involvement of the R1 and R2 chemical side chains of the cephalosporins causing IgE-mediated cross-reactivity with penicillin and other cephalosporins. Skin tests predict IgE-mediated reactions and showed cross-reactivity between penicillins and early generation cephalosporins that shared side chains, but confirmatory challenge data are lacking. Later-generation cephalosporins, which have distinct side chains, do not have any skin test cross-reactivity with penicillin/amoxicillin. There is debate as to the involvement of R2 side chains as the antigenic determinants that cause IgE-mediated hypersensitivity with various cephalosporins. Avoidance of cephalosporins, when they are the drug of choice in a penicillin-allergic individual, results in significant morbidity that outweighs the low risk of anaphylaxis. We conclude that there is ample evidence to allow the safe use of cephalosporins in patients with isolated confirmed penicillin or amoxicillin allergy.

Drug allergy evaluation for betalactam hypersensitivity: Cross-reactivity with cephalosporines, carbapenems and negative predictive value.

BACKGROUND: There are no studies on cross-reactivity of betalactams among patients allergic to penicillin, or on the negative predictive value (NPV) of penicillin allergy evaluation from Arabian Gulf countries. OBJECTIVE: We aimed to assess the role and NPV of drug provocation test (DPT) for betalactam hypersensitivity reactions in patients referred for allergy evaluation in Kuwait. METHODS: Skin test (ST) was performed for all patients with a history of betalactam hypersensitivity, other than anaphylaxis. Patients with a negative ST were challenged with a DPT containing phenoxymethyl penicillin or the culprit drug. Patients with anaphylaxis or who tested positive to betalactams were then challenged with a DPT containing cefuroxime, meropenem or ceftriaxone. Patients who tested negative were contacted by phone to evaluate subsequent betalactam intake. RESULTS: A total of 214 patients were tested for betalactam hypersensitivity. We had 91(42.5%) positive cases. Among positives, there were 78 (85.7%) patients with an initial reaction to penicillin and 13 (14.3%) who reacted to cephalosporin. DPT with alternative betalactam was performed in fifty who tested positive for betalactam hypersensitivity and 45 (90%) tolerated alternative antibiotics. Phone calls to 113 (59.8%) patients with negative betalactam testing showed that among 40(35.4%) patients who were successfully contacted; 17 (15%) took betalactams and 23 (20%) did not. Among the 17 patients who took betalactams, our calculated NPV for penicillin testing range from 88.2 to 100%, as the 2 patients who reported a reaction refused confirmatory retesting. CONCLUSION: Carbapenems and cephalosporines can be safely given to penicillin allergic patients by means of skin testing and if negative, proceeding with a graded challenge. Our calculated NPV for penicillin testing is similar to other studies.

Penicillin and Beta-Lactam Hypersensitivity.

Ten percent of patients report penicillin allergy, but more than 90% of these individuals can tolerate penicillins. Skin testing remains the optimal method for evaluation of possible IgE-mediated penicillin allergy and is recommended by professional societies, as the harms for alternative antibiotics include antimicrobial resistance, prolonged hospitalizations, readmissions, and increased costs. Removal of penicillin allergy leads to decreased utilization of broad-spectrum antibiotics, such as fluoroquinolones and vancomycin. There is minimal allergic cross-reactivity between penicillins and cephalosporins. IgE-mediated allergy to cephalosporins is usually side-chain specific and may warrant graded challenge with cephalosporins containing dissimilar R1 or R2 group side chains.

Potential Cross-Reactivity Between Penicillin Derivatives and Cephalosporins.

Allergic reactions to both penicillins and cephalosporins are relatively common. Patients who have had a previous allergic reaction to a penicillin derivative may also be prone to a further reaction if treated with cephalosporins. This case illustrates several important points about potential cross-reactivity between penicillin derivatives and cephalosporins, as well as the benefits of an extended-hours pharmacy service in a longterm care facility.