The return of penicillin

How to fight drug resistance without inducing allergic reactions


About 10% of patients in the United States report a penicillin allergy, but most of these patients are not currently allergic, meaning that they could safely take drugs in the beta-lactam class. “The vast majority of patients who think they have penicillin allergies actually don't when they undergo penicillin allergy skin testing,” said Emily Heil, PharmD, of the University of Maryland School of Pharmacy in Baltimore.

In fact, 96% of patients at one acute care facility who self-reported penicillin allergy had a negative skin test in a recent study by Dr. Heil and colleagues. Clinicians were able to switch about 80% of these patients to a more effective beta-lactam antibiotic, which also was usually narrower in spectrum and less costly, they reported in the July 2016 Open Forum Infectious Diseases.

Many of these reported reactions to beta-lactams occurred decades earlier and the patients were never worked up or re-challenged, according to experts. Ruling out penicillin allergies enables hospitalists to optimize therapy for susceptible infections, slow the emergence of multidrug-resistant pathogens, reduce harm to the microbiome, and save costs, they said.

Photo by Thinkstock
Photo by Thinkstock

But these opportunities are often missed. “If a patient reports a history of penicillin allergy, clinicians often jump right away to using a nonpenicillin medication without evaluating the patient for penicillin allergy,” said Leonard Bielory, MD, an allergist at Rutgers University New Jersey Medical School in Newark. “If the infection is sensitive to penicillin and the patient is actually not allergic, you have just wiped out a whole family of antibiotics that might have been the best choice.”

The pros of beta-lactams

Consider a stable inpatient with methicillin-sensitive Staphylococcus aureus infection (MSSA). The EHR notes a penicillin allergy, with no additional information. It might seem natural to prescribe an alternative antibiotic, but there are reasons not to, according to data and experts.

First, doing so can lead to suboptimal treatment, studies indicate. In a recent cohort analysis, patients with MSSA who reported penicillin allergy were 36% less likely to receive optimal therapy with nafcillin, oxacillin, cefazolin, or penicillin G than patients who did not report penicillin allergy. The difference was statistically significant even after controlling for other factors, Kimberly Blumenthal, MD, and colleagues reported in the July 2016 PLoS One.

Conversely, the study found that “allergic” patients who received an allergy consultation for possible skin testing were more than twice as likely to receive optimal therapy than patients who did not receive a consult, said Dr. Blumenthal, an allergist at Massachusetts General Hospital in Boston. “Patients whose infections should be treated with a beta-lactam antibiotic should receive a beta-lactam,” she said. “If they do not, there is an increased risk of adverse events, including complications like Clostridium difficile colitis.”

This is the second reason to treat beta-lactam sensitive infections with penicillin instead of broad-spectrum agents. “One of the side effects of antibiotics that we are only beginning to appreciate is the impact of the ancillary damage that they cause to our healthy bacteria,” said James Baggs, PhD, an epidemiologist at the CDC in Atlanta. “Broad-spectrum antibiotics disrupt the microbiome more than narrower-spectrum agents, and hence, a shift toward narrower-spectrum antibiotics could have important benefits by protecting our bacteria that promote health.”

In the United Kingdom, Clostridium difficile infections dropped significantly after clinicians began prescribing more penicillin and fewer fluoroquinolones and cephalosporins, Dr. Baggs noted. In the United States, the CDC projects that hospitals could cut C. difficile infections by 26% if they achieved a 30% reduction in the use of antibiotics that pose the highest risks for C. difficile, he added.

But that shift has not occurred, Dr. Baggs and co-investigators reported in the November 2016 JAMA Internal Medicine. Between 2006 and 2012, U.S. hospitals did not decrease their overall antibiotic use and significantly increased the use of several important broad-spectrum agents, according to an analysis of a national inpatient drug database. “Of particular concern was a 37% rise in the use of carbapenems,” Dr. Baggs said, noting that carbapenem-resistant Enterobacteriaceae (CRE) infections are difficult to treat and often fatal when invasive.

Using penicillin saves money, too. “In MSSA bacteremia, the cost of the skin testing evaluation is immediately offset by the lower rate of recurrence and metastatic disease in patients treated with beta-lactams over alternative drugs,” said Dr. Blumenthal. In patients with pneumococcal pneumonia, derivatives of aztreonam and vancomycin also are costlier than beta-lactams, Dr. Bielory said.

Drug allergy history

Penicillin's strengths do not negate the specter of anaphylactic reactions, however. “Where I trained at the National Institutes of Health, we had a patient die from anaphylaxis from a drug,” Dr. Bielory said. “Once you see one case like that, you respect anaphylaxis, and you're very careful about it.”

Anaphylaxis is caused by immediate (IgE-mediated) hypersensitivity reactions. Therefore, hospitalists should take a careful drug allergy history to begin assessing whether a previous penicillin reaction may have been IgE-mediated, said John Kelso, MD, of the Scripps Clinic division of allergy, asthma, and immunology in San Diego.

Symptoms of IgE-mediated reactions are related to systemic mast-cell degranulation. These include urticaria (hives), rhinitis, upper airway edema, shortness of breath, gastrointestinal symptoms, and hypotension, Dr. Kelso noted. “Such symptoms would typically respond promptly to discontinuation of penicillin and treatment with epinephrine and antihistamines, although urticaria can persist for some time afterwards,” he said.

In contrast, delayed-type hypersensitivity reactions are associated with late-onset, non-urticarial rashes that are often benign and may or may not recur with subsequent penicillin exposure. Patients with histories of these benign maculopapular rashes often can often tolerate the same culprit drug again, Dr. Blumenthal said.

Two other rare but potentially life-threatening late-onset skin reactions deserve mention: Stevens-Johnson syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS). These “constitute a near absolute contraindication to subsequent administration of penicillin,” said Dr. Kelso.

Skin testing

If a patient's history suggests an IgE-mediated penicillin allergy, the standard of care is to perform immediate-type allergy skin tests with both penicillin and its major metabolic determinant, penicilloyl, Dr. Kelso said.

The evaluation starts with prick tests with positive and negative controls. If these are negative, the patient undergoes intradermal tests with positive and negative controls. If intradermal tests are negative, patients typically receive a dose of amoxicillin and are observed for one hour.

“The purpose of the amoxicillin challenge is to identify the tiny minority of patients who are sensitized to minor penicillin determinants or to the amoxicillin side chain,” Dr. Kelso said. “The small percentage of patients with negative penicillin skin tests who react to the amoxicillin challenge typically have only hives, but rarely such reactions have required treatment with epinephrine.”

The risk of anaphylaxis makes skin testing essential. Even when patients have had a prior IgE-mediated penicillin allergy, they will be negative on skin testing a majority of the time, Dr. Blumenthal noted. “The likelihood of true allergy decreases with time,” she said. “After a period of 10 years, 80% of patients with allergy who were skin test-positive [at the time of the initial episode] are no longer allergic.”

Payers cover both inpatient and outpatient penicillin skin testing, she added. However, the procedure code should be tied to the original drug reaction, such as urticaria, angioedema, or rash, not to the Z codes for history of penicillin allergy, she said.

Low-risk patients

Because the vast majority of penicillin skin tests and amoxicillin challenges are negative, some experts recommend eliminating skin testing and proceeding directly to what is called a dosing challenge, said Dr. Kelso. However, he and Dr. Blumenthal recommended reserving this approach for “low-risk” patients who report a temporally distant, mild reaction such as minor nonurticarial rash, maculopapular rash, or itching without rash, all of which indicate a low probability of a current IgE-mediated penicillin allergy.

For these patients and those who are suspected of having an inaccurate report of allergy in the EHR, Dr. Blumenthal and her colleagues at Massachusetts General Hospital ask clinicians to perform a two-step dose challenge, she said. The ideal inpatient for such a challenge is a medically stable individual with available culture results, such as a patient with MSSA bacteremia, she added.

For the challenge, the patient first receives one-tenth of the beta-lactam drug dose and is observed for 60 minutes. “Nursing is not at the bedside but takes vital signs 30 minutes after the test dose,” Dr. Blumenthal said. If all goes well, the patient receives an entire treatment dose, followed by another 60 minutes of observation, with vital signs at 30 minutes. The EHR order set for the test doses includes instructions to administer epinephrine and an antihistamine as needed.

“We perform these challenge doses on regular inpatient floors,” Dr. Blumenthal said. “We ask that nursing arrange to be one-to-one for those two hours in case of reactions, but reactions are rare, and we have done almost 1,000 of these [challenges] in our hospitals.” Ascertaining the allergy history takes “a small amount of effort, but these patients' infectious disease treatment will benefit.”

When inpatients cannot reasonably be evaluated for penicillin allergy, hospitalists should refer them for an outpatient allergy consultation so that their allergic status can be clarified and the medical record updated, Dr. Bielory emphasized.

“I always say, ‘Test patients for drug allergies while they are vertical, not horizontal,’” he added. “Regretfully, all of us will most likely end up in a situation where we need an antibiotic, and an unconscious patient can't provide a history. Testing for and ruling out penicillin allergy clears the way for a broader range of treatment options.”