Penicillin Allergy

Pregnant women can safely tolerate testing for reported penicillin allergy

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Pregnant women who report a penicillin allergy can safely undergo penicillin skin testing and incremental drug challenges without adverse effects in their pregnancy, according to a study published in Annals of Allergy, Asthma & Immunology.

The need for delabeling

Beta-lactam antibiotics are first-line treatment for preterm pre-labor rupture of membranes (PROM), chorioamnionitis and prophylaxis for cesarean deliveries among other conditions in pregnancy, according to the researchers. Although approximately 10% of the population report a penicillin allergy, the researchers continued, more than 90% of patients with reported penicillin allergy can safely tolerate it after a complete evaluation.

“There are two reasons for this,” Jumy (Olajumoke) Fadugba, MD, FAAAAI, study author, chief of section of allergy and immunology at Penn Medicine, and associate professor of clinical medicine and fellowship program director of allergy and immunology at the University of Pennsylvania Perelman School of Medicine, told Healio.

Jumy (Olajumoke) Fadugba

“One is that some people’s original rash/hives may have been due to the illness itself, especially viral illness in children,” she said. “The other reason is that even people who had a true allergic to a penicillin antibiotic in their youth often ‘outgrow’ it. The further out you are from the original reaction, the less likely you are to still be allergic to it.”

People with a penicillin allergy label have significantly worse clinical outcomes than those who don’t have one, Fadugba continued. Additionally, patients who use more broad-spectrum antibiotics have more microbial antibiotic resistance, which is a rising public health problem, and gut infection such as Clostridium difficile, she said.

Allergists should then try and test patients for penicillin allergy, Fadugba said. If the test is negative, allergists should then remove the label so these patients can receive appropriate antibiotics for their condition.

“Pregnant women are a particularly important population to try and delabel because during the course of pregnancy, delivery and right after delivery, there are many reasons why a pregnant woman may need a penicillin or related beta-lactam antibiotic,” Fadugba said.

Approximately one-third of pregnant women eventually need penicillin or a related antibiotic, Fadugba said, adding that penicillin allergy during pregnancy is associated with increased rates of cesarean delivery, post-cesarean wound complications and increased hospital stays.

Even though the American College of Obstetricians and Gynecologists recommends that women with penicillin allergy be evaluated before delivery, penicillin allergy testing during pregnancy was infrequent when this study was initiated, with persistent hesitancy to test or refer pregnant women, Fadugba said.

“There are reports that some doctors are concerned about the safety of testing pregnant women and may worry about an adverse effect on the woman or baby,” she said.

The study’s results

Noting previous studies showing that pregnant women could undergo penicillin testing successfully, the researchers set out to demonstrate that the skin test for penicillin and the oral challenge for amoxicillin do not result in worse outcomes for mother and child.

The single-center, retrospective electronic chart review involved 136 pregnant women (mean age, 32.5 years; standard deviation, 4.2; 78% white) referred to an outpatient allergy and immunology clinic for penicillin allergy evaluation, where they were risk-assessed via a screening questionnaire through the electronic medical record about their allergy history.

According to the study, 112 women said a penicillin antibiotic was the index drug, and four women reported that cephalosporin caused their drug reaction. These reactions occurred more than 5 years before in 91% of the cases and more than 10 years before in 85% of the cases.

These reported reactions included unspecified rash (44%), hives (39%), angioedema or facial swelling (4%), shortness of breath (4%), throat symptoms (1%), prolonged gastrointestinal symptoms (< 1%) and dizziness (< 1%).

Providers at the clinic then performed skin prick and intradermal testing per standard protocol on 133 of the women. Penicillin skin testing (PST) was negative for 129 (97%) of them. Three (2%) of the participants had suboptimal intradermal histamine. Avoidance was recommended for the one patient with a positive PST.

Next, 133 of the participants took a two-step or three-step oral incremental drug challenge (IDC) to amoxicillin or oral penicillin V during the same visit. All participants passed the IDC, and their penicillin label was removed.

The researchers then followed 135 of these women during their pregnancy, with 68 (50%) of them using at least one beta-lactam during delivery. Specifically, 47 (35%) used penicillin and 34 (25%) used cephalosporin. Of the 68 women, 67 (97%) tolerated treatment without reactions.

The patient with a reaction experienced immediate nausea and itching after receiving penicillin V with no documented changes in vital signs or observed rash or angioedema. After successful treatment with diphenhydramine and ondansetron, a penicillin label was added back to her chart.

During the postpartum period, 21 (15%) of the participants who were evaluated for penicillin allergy received antibiotics, and 14 of them (10%) used beta-lactams. There were no adverse drug reactions reported.

Compared with a control group of 1,349 women with a penicillin allergy label who were not evaluated for penicillin allergy, the participants (mean age, 32.5 years; standard deviation, 4.2; 78% white) who were evaluated saw no difference in gestational age at delivery (38.8 weeks in the evaluation group vs. 38.5 weeks in the control group).

Also, there were no differences in neonatal birth weight (3,185 g vs. 3,174 g) or risks for cesarean section (OR = 1.3; 95% CI, 0.88-1.96). The researchers further found no association between evaluation and preterm labor, gestational hypertension, preeclampsia, eclampsia, placental abruption or PROM, nor were there any differences in the risk for having a pregnancy complication between the groups (OR = 1.4; 95% CI, 0.84-2.36).

The researchers concluded that pregnant women could be evaluated for penicillin allergy safely via PST and oral IDC and potentially see their penicillin allergy label removed, enabling them to benefit from the use of these antibiotics without increased risk for adverse pregnancy outcomes.

“We found that penicillin testing in pregnant women was not associated with worse outcomes for the woman and baby,” Fadugba said. “The findings were not surprising, but rather confirmed what we expect.”

Next steps for care, research

When pregnant patients have a penicillin or amoxicillin allergy on their record, providers should discuss the importance of having this label addressed and should refer patients to a specialist — usually an allergist — who can perform testing with the required expertise in a safe environment where the patient can be monitored for a reaction, Fadugba said.

“Allergy specialists will hopefully use this data to support the idea that penicillin testing in low-risk pregnant patients does not result in worse outcomes for mother and child and may therefore perform testing more readily in appropriate patients,” she said.

However, Fadugba also noted that providers first need to take a good history of their patients to ensure they are at very low risk for having a severe hypersensitivity reaction before undergoing testing. She also said that there were disproportionately fewer nonwhite (African American and Hispanic) pregnant women who underwent evaluation during the study.

“An important future endeavor would be to identify potential barriers that patients may face to being evaluated for their allergy and to address these barriers in order to benefit a broader patient population,” she said.

For more information:

Jumy (Olajumoke) Fadugba, MD, FAAAAI, can be reached at olajumoke.fadugba@pennmedicine.upenn.edu.

PERSPECTIVE

 Allison C. Ramsey, MD, FACAAI, FAAAAI)

Allison C. Ramsey, MD

These results are in further support of the safety of PST in pregnancy. I think it is also helpful to see that disproving penicillin allergy in pregnancy can affect antibiotic choice postpartum as well.

My own experience is that PST in pregnancy is safe and well-tolerated. It also can lead to more appropriate use of antibiotics during pregnancy, peripartum and postpartum.

In our health system, we have set up a rapid referral system to evaluate pregnant women with penicillin allergy during pregnancy. This study and others show that penicillin evaluations in pregnancy should be standard of care.

Because the data on penicillin evaluations in pregnancy shows that it is safe and effective, I would be more worried about leaving a penicillin allergy label without an evaluation as we know the label is associated with many adverse outcomes.

Next, I think it would be interesting to see an analysis of a large dataset to determine if a mother’s penicillin status has an impact on immediate neonatal outcomes.

Allison C. Ramsey, MD

Chair, American Academy of Allergy, Asthma & Immunology Adverse Reactions to Drugs, Biologicals and Latex Committee

Allergy and clinical immunology, Rochester Regional Health

Clinical assistant professor of medicine, University of Rochester School of Medicine and Dentistry

AAAAI: Penicillin Allergy Label Linked to MRSA, C. difficile

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Increase attributable to use of alternative antibiotics

Patients with general practitioner-reported penicillin allergies had an increased risk for developing methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile (C. difficile) infections mediated by increased use of beta-lactam alternative antibiotics, researchers reported here.

Findings from the newly reported study suggest that addressing patient over-reporting of penicillin allergies could prove to be an effective strategy for reducing MRSA and C. difficile incidence, researchers say.

Kimberly Blumenthal, MD, of Massachusetts General Hospital in Boston, reported the study findings during a presentation at a joint meeting of the American Academy of Allergy, Asthma & Immunology (AAAAI) and the World Allergy Organization (WAO).

Blumenthal and colleagues used mediation analysis to estimate the impact of a new penicillin allergy documentation by a general physician on the use of alternative antibiotics and risk of MRSA and C. difficile over 6 years of patient follow-up.

“We found that over a quarter to half of the risk of new infection was attributable to the alternative antibiotics,” Blumenthal told MedPage Today, adding that the study is the first to show a link between new-onset use of antibiotics and a first documentation of MRSA or C. difficile.

Since the patients did not undergo formal testing to confirm their penicillin allergy, many may have needlessly been taking the alternative antibiotics, she said.

Asked for his perspective, David Lang, MD, chairman of the Department of Allergy and Clinical Immunology and director of the Allergy/Immunology Fellowship Training Program at the Cleveland Clinic, who was not involved with the study, told MedPage Today that there is growing evidence that patient over-reporting of penicillin allergy has very real clinical consequences.

While approximately one in 10 people self-report having a penicillin allergy, studies suggest that only perhaps one in 20 actually have a clinically confirmable intolerance to the drug, he said. “As many as 19 in 20 people avoiding penicillin are doing so needlessly. These people are given alternative antibiotics that are more costly, have more side effects, and predispose them to untoward outcomes.”

Lang said the newly reported research provides further evidence that a label of penicillin allergy is not clinically benign: “A large focus of the antibiotic stewardship initiative is to limit the use of these broad-spectrum antibiotics when we can. It is clear that the low-hanging fruit of antibiotic stewardship is de-labeling these people who believe they have penicillin allergy, but don’t.”

For the study, Blumenthal and colleagues used a general practice database in the United Kingdom with patient data spanning 1995 through 2015, and studied a matched cohort of adults without prior MRSA or C. difficile.

Patients with incident penicillin allergy, as reported in their medical records, were matched with up to five penicillin users without allergy by age, sex, and index date.

The researchers calculated relative risks (RRs) for the association of penicillin allergy with incident MRSA and C. difficile, adjusting for potential confounders, and also examined beta-lactam alternative antibiotic use to determine whether it was a mediator for MRSA/C. difficile incidence.

Over a mean follow-up of 6 years, among 64,141 penicillin allergy patients and 237,258 matched comparators, 1,345 developed MRSA and 1,688 developed C. difficile.

Among the main study findings:

  • The adjusted RRs among penicillin allergy patients were 1.62 (95% CI, 1.42-1.85) for MRSA and 1.27 (95% CI, 1.13-1.43) for C. difficile
  • The adjusted RRs for antibiotic use among penicillin allergy patients were 4.08 (95% CI, 4.05-4.10) for macrolides, 3.73 (95% CI, 3.51-3.97) for clindamycin, and 2.13 (95% CI, 2.10- 2.16) for fluoroquinolones
  • Increased beta-lactam alternative antibiotic use accounted for 53% of the increased MRSA risk and 25% of the increased C. difficile risk

“The message from this research and other research to general practitioners, medical specialists, and surgeons is that when they see a patient with a label of penicillin allergy, send them to us to confirm or disprove this label,” Lang said. “Nine out of 10 — or even 19 of 20 — times we will be able to reduce the patient’s risk for bad outcomes by removing this label.”