Pharmacology Consult

Penicillin skin testing: An underused approach to antibiotic de-escalation

Emir Kobic

The CDC estimates that nearly 50% of antibiotics prescribed in the United States are unnecessary. From 2006 to 2012, 55% of all hospitalized patients in the U.S. received at least one dose of antibiotics, with broad-spectrum antibiotic use (ie, carbapenems) increasing by nearly 37%. The inappropriate use and overuse of antibiotics remain some of the most crucial drivers of the development of antimicrobial resistance, and we are now in an era when “superbug infections” are emerging. Although congressional initiatives like the GAIN Act have provided incentives for the pharmaceutical industry to expand today’s antimicrobial arsenal, broader quality improvement projects aimed at preventive measures have been proposed by the 2015 White House Forum on Combating Antimicrobial Resistance. These projects are aimed to assist antimicrobial stewardship programs (ASPs), which serve as a mechanism to combat resistance; however, we need to evaluate further strategies to de-escalate and discontinue inappropriate antibiotic therapy. The 2016 antimicrobial stewardship guidelines set forth practical recommendations toward antibiotic de-escalation. One approach is for ASPs to promote allergy assessment and penicillin skin testing (PST) when appropriate.

Penicillin allergies are among the most common drug allergies reported by the general population; however, roughly 10% of these patients are truly allergic. Two different antibodies are known to mediate a true drug allergy: immunoglobulin E (IgE) and immunoglobulin G (IgG). Reactions that occur acutely (within minutes to 1-2 hours) leading to anaphylaxis with urticaria, wheezing, laryngeal edema and hypotension are considered IgE-mediated. On the other hand, IgG-mediated reactions are known to occur subacutely (1-2 days), activating the complement pathway and manifesting as fevers, urticaria and arthralgias. Unfortunately, 90% of documented penicillin allergies are not associated with either IgE or IgG reactions, leaving many patients to suffer from unintended consequences of broad-spectrum antibiotics. A retrospective matched cohort study of 51,582 hospitalized patients from 2010 through 2012 revealed that patients admitted with a history of penicillin allergy were more likely to be treated with alternative antibiotics such as vancomycin, fluoroquinolones and clindamycin (P < .0001). Furthermore, these patients had longer hospital stays (average, 0.59 more days) and increased rates of MRSA (14.1%), Clostridium difficile (23.4%) and vancomycin-resistant enterococci (30.1%) that may have been spurred by improper use of alternative antibiotics when penicillin would have been the preferred agent. Our ASP has observed similar prescribing trends in which providers are in the habit of selecting alternative antibiotics (primarily carbapenems) for patients with documented penicillin allergies. Despite evidence that penicillins are generally the safest and most effective class of antibiotics, providers are apprehensive when it comes to the topic of re-challenging due to fears of unintended drug reactions. Several methods, such as increased provider training and heightened pharmacist allergy assessments, can help curb inappropriate selection of alternative antibiotics in penicillin-allergic patients. PST serves as a tool to amend this practice and improve outcomes in patient care.

When PST is performed, patients can be safely tested for a true penicillin drug allergy by assessing local skin reactions to minute doses of major and minor penicillin determinants that elicit IgE-mediated reactions. The benzylpenicilloyl polylysine (Pre-Pen, AllerQuest) product received FDA approval in September 2009 and is the only commercially available skin testing product on the market. When used appropriately, PST has a negative predictive value of 97% to 99% for IgE-mediated reactions, putting the risk of anaphylaxis on par with the general population. Unfortunately, PST will not rule out the risk of IgG-mediated reactions such as Stevens-Johnson syndrome or interstitial nephritis, thus highlighting the importance of conducting a thorough allergy assessment with the patient. Lastly, performing a PST takes on average 2 hours to conduct and will therefore require personnel who can devote this time toward direct patient care.

Kimberly D. Boeser

Traditionally, institutions have relied on the use of an allergist to perform PST. However, for more than a decade, Geoffrey C. Wall, PharmD, and colleagues have run a pharmacist-managed PST service with a collaborative practice agreement under allergist supervision at Iowa Methodist Medical Center in Des Moines. Before its implementation, one question stood out in Wall’s mind: “We don’t require a pulmonologist to read a [tuberculin test], so why do you have to be an allergist to do penicillin skin test?” he was quoted as saying by the American Society of Health-System Pharmacists. This question addresses one of the main hurdles to providing PST, particularly in acute care settings where allergists generally do not practice. Despite this obstacle, ASPs have successfully implemented PST without institutional allergists on staff. Torney and colleagues implemented a pharmacist-managed PST service under the supervision of an ID physician at a community teaching hospital. In their study, 15 patients received PST, of whom 14 tested negative, none tested positive, and one was considered indeterminate, with 93% of patients transitioned to a preferred beta-lactam antibiotic.

An alternative approach that would avoid direct use of pharmacists and allergists was presented by Heil and colleagues, who conducted a prospective study of a PST service managed by ID fellows at a large academic medical center. Over 11 months, 90 patients were assessed for PST and 76 patients were tested. Results showed that 84% were negative, 4% tested positive and 12% were indeterminate. According to the researchers, 81% of patients had their therapy changed, with most patients switched to a penicillin (55%) or cephalosporin (40%).

PST has been successfully implemented without direct use of pharmacists, allergists or physicians. Jones and colleagues developed a pre-approved protocol for nurses to conduct PST. Eligible patients were identified by ID physicians or the ASP team. A total of 36 patients received PST, and all of them yielded a negative skin test. Twenty-seven of the 36 patients had their antimicrobial regimens de-escalated, and an average antimicrobial acquisition cost of $314 was saved due to therapy changes following a negative PST.

Several studies have demonstrated a positive impact of PST on antibiotic use and cost-effectiveness in the outpatient and inpatient setting. However, despite the encouraging evidence behind it, a recent survey of the Infectious Diseases Society of America’s Emerging Infections Network that was sent to 744 members (53% response rate) showed that only 60% had PST available, with the overwhelming majority performed by allergy and/or immunology physicians (90%). PST is an underused method and is no longer a service that needs to be performed under the sole guidance of an allergist. It is well-established that documented penicillin allergies are not a benign matter, and ASPs need to be creative in ways to restrain overuse of broad-spectrum antibiotics because pan-resistant microbes are emerging across the globe. PST is one method to have a collaborative team approach to antimicrobial stewardship with pharmacists, physicians and/or nurses. Further research and implementation of innovative PST practices are needed not only to enhance patient outcomes but also to attenuate antimicrobial resistance.

Disclosures: Boeser and Kobic report no relevant financial disclosures.

Emir Kobic

The CDC estimates that nearly 50% of antibiotics prescribed in the United States are unnecessary. From 2006 to 2012, 55% of all hospitalized patients in the U.S. received at least one dose of antibiotics, with broad-spectrum antibiotic use (ie, carbapenems) increasing by nearly 37%. The inappropriate use and overuse of antibiotics remain some of the most crucial drivers of the development of antimicrobial resistance, and we are now in an era when “superbug infections” are emerging. Although congressional initiatives like the GAIN Act have provided incentives for the pharmaceutical industry to expand today’s antimicrobial arsenal, broader quality improvement projects aimed at preventive measures have been proposed by the 2015 White House Forum on Combating Antimicrobial Resistance. These projects are aimed to assist antimicrobial stewardship programs (ASPs), which serve as a mechanism to combat resistance; however, we need to evaluate further strategies to de-escalate and discontinue inappropriate antibiotic therapy. The 2016 antimicrobial stewardship guidelines set forth practical recommendations toward antibiotic de-escalation. One approach is for ASPs to promote allergy assessment and penicillin skin testing (PST) when appropriate.

Penicillin allergies are among the most common drug allergies reported by the general population; however, roughly 10% of these patients are truly allergic. Two different antibodies are known to mediate a true drug allergy: immunoglobulin E (IgE) and immunoglobulin G (IgG). Reactions that occur acutely (within minutes to 1-2 hours) leading to anaphylaxis with urticaria, wheezing, laryngeal edema and hypotension are considered IgE-mediated. On the other hand, IgG-mediated reactions are known to occur subacutely (1-2 days), activating the complement pathway and manifesting as fevers, urticaria and arthralgias. Unfortunately, 90% of documented penicillin allergies are not associated with either IgE or IgG reactions, leaving many patients to suffer from unintended consequences of broad-spectrum antibiotics. A retrospective matched cohort study of 51,582 hospitalized patients from 2010 through 2012 revealed that patients admitted with a history of penicillin allergy were more likely to be treated with alternative antibiotics such as vancomycin, fluoroquinolones and clindamycin (P < .0001). Furthermore, these patients had longer hospital stays (average, 0.59 more days) and increased rates of MRSA (14.1%), Clostridium difficile (23.4%) and vancomycin-resistant enterococci (30.1%) that may have been spurred by improper use of alternative antibiotics when penicillin would have been the preferred agent. Our ASP has observed similar prescribing trends in which providers are in the habit of selecting alternative antibiotics (primarily carbapenems) for patients with documented penicillin allergies. Despite evidence that penicillins are generally the safest and most effective class of antibiotics, providers are apprehensive when it comes to the topic of re-challenging due to fears of unintended drug reactions. Several methods, such as increased provider training and heightened pharmacist allergy assessments, can help curb inappropriate selection of alternative antibiotics in penicillin-allergic patients. PST serves as a tool to amend this practice and improve outcomes in patient care.

When PST is performed, patients can be safely tested for a true penicillin drug allergy by assessing local skin reactions to minute doses of major and minor penicillin determinants that elicit IgE-mediated reactions. The benzylpenicilloyl polylysine (Pre-Pen, AllerQuest) product received FDA approval in September 2009 and is the only commercially available skin testing product on the market. When used appropriately, PST has a negative predictive value of 97% to 99% for IgE-mediated reactions, putting the risk of anaphylaxis on par with the general population. Unfortunately, PST will not rule out the risk of IgG-mediated reactions such as Stevens-Johnson syndrome or interstitial nephritis, thus highlighting the importance of conducting a thorough allergy assessment with the patient. Lastly, performing a PST takes on average 2 hours to conduct and will therefore require personnel who can devote this time toward direct patient care.

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Kimberly D. Boeser

Traditionally, institutions have relied on the use of an allergist to perform PST. However, for more than a decade, Geoffrey C. Wall, PharmD, and colleagues have run a pharmacist-managed PST service with a collaborative practice agreement under allergist supervision at Iowa Methodist Medical Center in Des Moines. Before its implementation, one question stood out in Wall’s mind: “We don’t require a pulmonologist to read a [tuberculin test], so why do you have to be an allergist to do penicillin skin test?” he was quoted as saying by the American Society of Health-System Pharmacists. This question addresses one of the main hurdles to providing PST, particularly in acute care settings where allergists generally do not practice. Despite this obstacle, ASPs have successfully implemented PST without institutional allergists on staff. Torney and colleagues implemented a pharmacist-managed PST service under the supervision of an ID physician at a community teaching hospital. In their study, 15 patients received PST, of whom 14 tested negative, none tested positive, and one was considered indeterminate, with 93% of patients transitioned to a preferred beta-lactam antibiotic.

An alternative approach that would avoid direct use of pharmacists and allergists was presented by Heil and colleagues, who conducted a prospective study of a PST service managed by ID fellows at a large academic medical center. Over 11 months, 90 patients were assessed for PST and 76 patients were tested. Results showed that 84% were negative, 4% tested positive and 12% were indeterminate. According to the researchers, 81% of patients had their therapy changed, with most patients switched to a penicillin (55%) or cephalosporin (40%).

PST has been successfully implemented without direct use of pharmacists, allergists or physicians. Jones and colleagues developed a pre-approved protocol for nurses to conduct PST. Eligible patients were identified by ID physicians or the ASP team. A total of 36 patients received PST, and all of them yielded a negative skin test. Twenty-seven of the 36 patients had their antimicrobial regimens de-escalated, and an average antimicrobial acquisition cost of $314 was saved due to therapy changes following a negative PST.

Several studies have demonstrated a positive impact of PST on antibiotic use and cost-effectiveness in the outpatient and inpatient setting. However, despite the encouraging evidence behind it, a recent survey of the Infectious Diseases Society of America’s Emerging Infections Network that was sent to 744 members (53% response rate) showed that only 60% had PST available, with the overwhelming majority performed by allergy and/or immunology physicians (90%). PST is an underused method and is no longer a service that needs to be performed under the sole guidance of an allergist. It is well-established that documented penicillin allergies are not a benign matter, and ASPs need to be creative in ways to restrain overuse of broad-spectrum antibiotics because pan-resistant microbes are emerging across the globe. PST is one method to have a collaborative team approach to antimicrobial stewardship with pharmacists, physicians and/or nurses. Further research and implementation of innovative PST practices are needed not only to enhance patient outcomes but also to attenuate antimicrobial resistance.

Disclosures: Boeser and Kobic report no relevant financial disclosures.