Direct challenges recommended for most antibiotic allergy evaluations
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Key takeaways:
- Patients with mild cutaneous reactions more than 5 years previously may benefit from direct challenges.
- Patients with moderate to severe reactions less than 5 years previously should avoid direct challenges.
Physicians should perform graded direct challenges when patients at low risk for a reaction report an antibiotic allergy, according to a review published in Annals of Allergy, Asthma & Immunology.
In addition to improving clinical outcomes, these challenges often provide cost and time savings compared with skin testing, Allison C. Ramsey, MD, allergy and clinical immunology, Rochester Regional Health, and colleagues wrote in the review.
Penicillin allergies
Allergy labels for antibiotics adversely impact outcomes, the authors wrote, as they may preclude the use of appropriate first-line treatment. For example, risks from penicillin allergy labels include increases in resistant organisms, costlier care, adverse effects from second-line antibiotics and increased mortality.
“Many drug allergies that patients carry with them are either erroneous or have self-resolved,” Ramsey told Healio. “These can be removed from patient charts through direct challenges, which opens the door for patients to use these drugs going forward. In general, it allows for optimal use of antibiotics for specific infections.”
Historically, physicians have used penicillin skin testing (PST) with amoxicillin after a negative test to verify penicillin allergy. But the authors of the review noted that growing research indicates the use of direct challenges without prior PST for patients who have low-risk reaction histories.
These studies have included populations where 1.5% of patients experienced mild reactions with direct challenges, 2.6% who experienced allergic reactions and three of 79 with mild reactions.
One study found a rate of 0.06% of patients with direct challenges experiencing severe reactions during direct challenges. The overall 0.04% rate of anaphylaxis among new administrations of penicillin found by another study indicates the safety of these direct challenges, the authors wrote.
Compared with PST, the authors continued, direct challenges do not require specialized training and can be used in inpatient, primary care, ED and ICU settings, although the authors also cautioned that any settings that use direct testing should be equipped to handle anaphylaxis.
The authors also pointed to cost savings with direct challenges, including $340 per patient in one study. Net benefits included $3,122 for direct challenges and $2,849 for PST in outpatient settings in another study. Costs included $84 for direct challenges and $168 to $537 for PST in a third study.
Additionally, direct challenges took 66.7 minutes whereas PST took 72.7 minutes in another study, with further research finding 1 hour of turnaround time to complete consults with direct challenges compared with 7 hours for PST.
The Drug Allergy Practice Parameter Update does not recommend PST for pediatric patients who have a history of benign cutaneous reactions to penicillin, based on robust literature supporting the use of direct challenges instead, the authors said, although there was a lack of data on use of direct challenges among children in inpatient settings.
Still, the authors said, the advantages in time and cost savings found among adult patients as well as the lack of prick and intradermal testing would enormously increase the acceptability of direct challenges among pediatric populations.
Overall, the authors cautioned that these studies have a heterogenous definition for low-risk patients.
However, the authors also suggested that adult patients with histories of mild cutaneous reactions such as itching, rash or maculopapular eruptions more than 5 years before could sit for a graded challenge. Similarly, pediatric patients with reaction histories that only include cutaneous symptoms could benefit from graded challenges as well.
Adult patients with moderate to severe reactions including anaphylaxis, convincing angioedema, blistering, mucosal lesions, fever or joint pain within the previous 5 years, however, should not sit for a direct challenge, the authors said.
Other antibiotics
Cephalosporin allergies are less common than penicillin allergies, the authors continued, with direct challenges recommended for those patients with non-anaphylactic reactions and skin testing recommended for those with histories of anaphylactic reactions.
Sulfonamide antibiotics are the second most reported drug allergy in the United States, the authors continued. Growing evidence indicates safety and efficacy in single- or double-dose challenges to trimethoprim sulfamethoxazole, they added, although data for their use in pediatric populations are limited.
Hypersensitivity to fluoroquinolones has been increasing, the authors reported, but skin testing for these allergies has not been reliable. Direct challenges in appropriate cases may enable patients to use alternatives, they continued, adding that these challenges remain the gold standard for evaluating non-severe fluoroquinolone hypersensitivity.
Hypersensitivity to tetracycline is rarer than hypersensitivity to other antibiotic classes, the authors said, and skin testing for immediate hypersensitivity has not been validated. Also, cross-reactivity between tetracyclines has not been established.
Noting that true hypersensitivity to macrolides is uncommon, the authors said that clinical history alone is insufficient for confirming allergy. Skin testing remains controversial and unvalidated, the authors said, and direct challenges remain the gold standard.
The authors called hypersensitivity reactions to metronidazole uncommon as well, although immediate and delayed reactions have been reported. The few studies examining skin testing for these patients found low sensitivity and unclear validity, the authors said, making direct challenges an essential tool in determining hypersensitivity.
Carbapenem allergy has an incidence rate of 0.3% to 3.7%, the authors wrote, with no anaphylaxis in multiple trials including two with 6,000 and 9,000 patients each. Robust literature indicates that direct challenges with carbapenem have been safe for patients with penicillin allergies.
Although aztreonam allergies are rarely reported, the authors said, most patients with an aztreonam or ceftazidime allergy tolerated challenges to aztreonam in a case series the authors examined.
Generally, the authors recommend graded challenges for these alternative antibiotics for appropriate patients with mild reaction histories that occurred more than 5 years prior to the testing.
Conclusions
The authors concluded that patients with antibiotic allergies and low-risk reaction histories should get direct challenges, with most data supporting the use of these challenges in allergy and immunology offices.
Advantages of direct challenges may include future generalizability outside of these clinics, cost and time savings and timely transfers to appropriate antibiotics as well as safety and efficacy compared with skin testing, the researchers wrote.
Ramsey advised doctors to be aware that the drug allergy field is fluid and should be revisited. Collaboration is key to success as well, she continued.
“MDs and other health care professionals should just be aware that allergists can help them with patients with antibiotic allergies,” Ramsey said.
Also, Ramsey emphasized the need for further studies.
“The most significant finding is that we have some more to learn regarding challenges and de-labeling in some antibiotic classes — for example, fluoroquinolones,” Ramsey said.
“Big data studies will be the most helpful in this area,” she continued. “Studies with larger numbers of patients will be helpful, especially for the lesser studied antibiotic classes.”
For more information:
Allison C. Ramsey, MD, can be reached at allison.ramsey@rochesterregional.org.
Perspective
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The article by Dr. Allison C. Ramsey and her collaborators is a well written and extremely well documented publication that summarizes the evidence regarding the use of direct oral challenges, whether as one single dose or two doses (1/10 and 9/10 of the therapeutic dose at intervals of 30 to 60 minutes) for de-labeling pediatric and adult patients with an antibiotic allergy label including penicillin, beta lactams and others.
There has been an increase in the need to de-label antibiotic allergic patients in the last 10 years supported by the strong personal, medical and social implications of carrying an antibiotic allergy label. Pediatric and adult patients labeled as antibiotic allergic have delays in treatment at the time of antibiotic needs whether for infections or protection at the time of procedures including surgery, use more expensive and less effective antibiotics with more side effects and spend more time in hospital, in addition to promoting antibiotic-resistant organisms.
De-labeling typically has required skin testing, followed by challenges for patients with negative skin tests. But recent questionnaires providing risk stratification allow for the direct safe challenge of patients at low risk.
The findings in this review are greatly surprising and highly significant, since most pediatric and adult patients at low risk based on mild reactions occurring more than 5 years at the time of evaluation did not present severe symptoms of either type 1 reaction including anaphylaxis or type IV severe reactions including Stevens-Johnson syndrome (SJS) when given a direct oral challenge, and they were able to be safely de-labeled.
The findings also are similar to my clinical experience. Now, the evidence has been provided in multiple and large studies encompassing hundreds of pediatric and adult patients, validating my personal experience.
One important caveat to these studies would be the group of patients who have presented SJS or other severe cutaneous adverse reactions more than 5 years before evaluation. Since these reactions are likely mediated by human leukocyte antigen genotypes, this population of patients cannot be de-labeled and remains at high risk when re-exposed, even if they experienced a reaction more than 5 years before the evaluation.
These findings will greatly improve the safe and efficient approach to patients with low risk since skin testing may no longer be necessary. A direct challenge also will save patients time and provider efforts, and they will lead to a substantial decrease in resources and costs as well.
While allergists with knowledge in risk stratification need to perform the direct challenges of patients with antibiotic allergy labels, large studies are needed to validate these results. Once larger studies are available, pediatricians, urgent and primary care providers, and other physicians will be able to use risk stratification to identify low-risk patients and promote direct antibiotic challenges.
This will allow for wide de-labeling efforts in patients at risk, such as pregnant women with penicillin allergy labels, patients undergoing bone marrow transplants and new gene or cell therapies, in addition to the general patient population in need of surgery, procedures or infections in need of urgent antibiotics.
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