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A survey of inpatient practitioner knowledge of penicillin allergy at 2 community teaching hospitals
Ann Allergy Asthma Immunol xxx (2017) 1e6
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A survey of inpatient practitioner knowledge of penicillin allergy at 2 community teaching hospitals Mary L. Staicu, PharmD *; Dipekka Soni, MD *; Kelly M. Conn, PhD, MPH y; Allison Ramsey, MD * * Pharmacy y
Department, Rochester General Hospital, Rochester, New York St. John Fisher College, Wegmans School of Pharmacy, Rochester, New York
A R T I C L E
I N F O
Article history: Received for publication March 9, 2017. Received in revised form April 13, 2017. Accepted for publication April 16, 2017.
A B S T R A C T
Background: The negative effect of the penicillin allergy label on antibiotic use and patient outcomes has brought to light the need for thorough penicillin allergy assessments and heightened practitioner education. Objective: To evaluate practitioner knowledge of penicillin allergy and the clinical approach to the patients with penicillin allergy. Methods: An electronic survey was distributed to attending physicians, residents, pharmacists, nurse practitioners, and physician assistants practicing adult inpatient medicine at 2 community-based teaching hospitals from February to April 2016. Results: A total of 276 (39%) of 716 practitioners completed surveys were analyzed. Most respondents were attending physicians (45%) with more than 10 years of experience (53%). Approximately half of the respondents indicated that they were unfamiliar with the rate of cross-reactivity between penicillin and cephalosporin (46%), carbapenem (42%), and monobactam (48%) antibiotics. When evaluating the role of penicillin skin testing and temporary induction of drug tolerance in the case vignettes, only 41% and 19% of respondents appropriately considered these options as the leading antibiotic management plan, respectively. Despite acknowledging the need for allergy/immunology consultation in clinical scenarios, 86% of respondents indicated that they never consult an allergist or immunologist or do so only once per year. Overall, pharmacists had a better understanding of the natural history of penicillin allergy and antibiotic cross-reactivity (P < .05). Conclusion: There is an overall limited understanding of the management of patients with a history of penicillin allergy in the hospital setting, where collaborative efforts between allergy and nonallergy health care practitioners are sparse. The expansion of a multidisciplinary approach may optimize antimicrobial prescribing in this subset of patients. Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction The approach to the treatment and management of infectious diseases in patients with a penicillin allergy remains a significant clinical conundrum. The complexity of drug hypersensitivity reactions paired with the increasing prevalence of multidrugresistant bacteria make it challenging for health care practitioners to determine proper therapeutic strategies in such clinical settings. Second- and third-line antibiotic therapy used in patients diagnosed with a penicillin allergy predisposes them to the development of infections caused by Clostridium difficile, Reprints: Mary L. Staicu, PharmD, Pharmacy Department, Rochester General Hospital, 1425 Portland Ave, Rochester, NY 14621; E-mail: mary.staicu@ rochesterregional.org. Disclosures: Authors have nothing to disclose. Previous Presentation: Presented as an oral abstract at the American College of Allergy, Asthma, and Immunology; November 14, 2016; San Francisco, California.
methicillin-resistant Staphylococcus aureus, and vancomycinresistant Enterococcus.1,2 In addition, the presence of penicillin allergy increases health care facility exposure by prolonging the duration of hospitalization and increasing the rate of hospital readmissions.2,3 The negative effect of the penicillin allergy label on antibiotic use, patient outcomes, and overall health care costs has brought to light the need for thorough penicillin allergy assessments and, if indicated, penicillin skin testing.4e7 Despite the increasing body of literature on the natural history of penicillin allergy, the minimal penicillin allergic cross-reactivity rate with cephalosporin and carbapenems, and the substantial implications of a penicillin allergy label, significant drug allergy knowledge deficits remain among various strata of health care professionals.1,4,8e11 Previous studies evaluating inpatient practitioner drug allergy knowledge have reported that 42% of physicians have never received prior drug allergy education, have low awareness of penicillin skin testing, and lack general knowledge of
http://dx.doi.org/10.1016/j.anai.2017.04.023 1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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penicillin allergy.9 In addition, a recent survey of allergist and nonallergist physicians found that allergists were more likely to confirm penicillin allergy with skin testing, more likely to avoid penicillin antibiotics in patients with a history of Stevens-Johnson syndrome, and less concerned about the cross-reactivity between cephalosporin and penicillin antibiotics compared with nonallergists.12 The current inpatient health care environment includes a multidisciplinary team of physicians, advanced practice practitioners (APPs), residents, and clinical pharmacists. Previous surveys have had limited assessment of the knowledge of APPs (ie, physician assistants and nurse practitioners) and pharmacists regarding penicillin allergy. Given the increasing interest in the effect of penicillin allergy and penicillin skin testing among national organizations from various subspecialties, we sought to evaluate the clinical approach to the penicillin-allergic patient in a diverse group of health care professionals at 2 community teaching hospitals. Methods Study Design and Setting An electronic questionnaire was distributed to inpatient practitioners practicing adult medicine at 287- and 528-bed tertiary community-based teaching hospitals in February 2016. Both institutions included in the analysis have available allergy/immunology consultative services. Attending physicians, residents, APPs, and pharmacists practicing in internal medicine (general and subspecialty), surgery (general and subspecialty), and obstetrics and gynecology were considered for inclusion. Practitioners exclusively practicing in the outpatient setting or in the pediatric population were excluded. Eligible candidates had 60 days to voluntarily complete the questionnaire and were asked to refrain from the use of external resources to aid in their responses. The research protocol was agreed on by the investigators and approved by the Rochester General Hospital Clinical Investigations Committee. Questionnaire The questionnaire (Table 1) was constructed with the combined efforts of an allergist, infectious diseases pharmacist, and internal medicine resident. SurveyMonkey (Palo Alto, CA) was used to electronically develop the questionnaire, which contained a total of 15 questions that critically assessed respondent demographic characteristics (4 questions), general penicillin allergy knowledge (6 questions), and self-reported practice patterns through clinical vignettes (5 questions). Temporary induction of drug tolerance was referred to as desensitization in the clinical vignettes because most nonallergist practitioners within our health care system were familiar with this term. Results of the questionnaire were anonymous and were therefore not stratified by institution. Outcome Measures and Statistical Analysis The primary objectives were to describe health care practitioner clinical practice patterns and identify potential knowledge gaps pertinent to the management of the penicillin-allergic patient. Descriptive statistics were used to describe the population and their knowledge and practices. c2 test (Fisher exact test, 2-tailed) was used to compare survey responses among medical professionals. Pharmacist, APP, and physician responses were compared separately for each question. Results that were statistically significant were further broken down to better understand which practitioner group was integral in generating differences. Results A total of 276 (39%) of 716 eligible health care practitioners completed some or all of the questionnaire. Most respondents were attending physicians (125 [45%] of 276) practicing general internal
medicine (118 [43%] of 276) for more than 10 years (147 [53%] of 276). Additional demographic characteristics are presented in Table 2. When clinically evaluating a penicillin allergy history, nearly all respondents indicated that they always ask the name of the medication allergy (260 [95%] of 275) and what specific symptoms were experienced (236 [86%] of 274). Approximately half (145 [53%] of 274) of the respondents indicated that they always ask how long ago the allergic reaction occurred, with pharmacists asking more frequently than other professions (73% vs 50%, P ¼ .02); however, only 71 (26%) of 275 respondents indicated they always ask at what point during the antibiotic course the symptoms were experienced. Most health care practitioners (197 [72%] of 274) indicated that they spend less than 2 minutes to assess an allergy history, followed by 64 (23%) and 13 (5%) respondents that indicated they spend 2 to 5 minutes or more than 5 minutes to evaluate, respectively. All but 5 (268 [98%] of 273) respondents disagreed with the avoidance of penicillin in patients with a family history of penicillin allergy who reported no personal history of penicillin allergy. When asked whether an allergy to penicillin could resolve with time, 158 (58%) of 273 respondents agreed, yet only 82 (30%) of 274 knew that 9 of 10 penicillin-allergic patients will tolerate a penicillin antibiotic. Further electronic medical record review of administered antibiotics in penicillin-allergic patients was reported in 219 (80%) of 275 respondents. Pharmacists were more aware that penicillin allergy can resolve with time (78% vs 55%, P ¼ .01), knew that 90% of penicillin-allergic patients will tolerate a penicillin antibiotic (64% vs 25%, P < .001), and were more likely to review historical electronic medical record antibiotic administrations (100% vs 78%, P ¼ .002) compared with the other respondents. Clinician knowledge of penicillin antibiotic cross-reactivity among cephalosporin, carbapenem, and monobactam antibiotics is indicated in Figure 1. Responses were approximately split between 10% to 20% cross-reactivity (119 [43%] of 274) and less than 5% cross-reactivity (147 [54%] of 274) with cephalosporins and less than 5% cross-reactivity (108 [40%] of 271) and no cross-reactivity (141 [52%] of 271) with monobactams. Of note, there was a wide variation in responses when asked about the cross-reactivity rate with carbapenem antibiotics. A total of 156 [58%] of 271 respondents selected less than 5% cross-reactivity, with the remainder of the cohort divided among the other 3 options. The clinical vignettes were designed to evaluate the management approach to an array of clinical scenarios in patients with a reported penicillin allergy. Question 1 assessed penicillin antibiotic use in a patient with an allergy history suggestive of StevensJohnson syndrome. Approximately half of respondents (129 [48%] of 269) indicated they would appropriately avoid penicillin antibiotics, whereas 24 (9%) indicated they would directly administer penicillin antibiotics. Significantly more APPs chose to directly administer penicillin antibiotics compared with pharmacists and physicians (15% vs 6%, P ¼ .02). Question 2 sought to evaluate the respondents’ stance on the use of penicillin skin testing in the event of b-lactam antibiotic clinical superiority. Only 110 (41%) of 271 considered penicillin skin testing as their leading antibiotic management plan. Question 3 aimed to determine the participant’s threshold in rechallenging penicillin in a patient with a history of penicillin intolerance. Physician respondents expressed that they were less likely to initiate use of a penicillin antibiotic with a penicillin allergy listed as nausea or vomiting compared with other professions (84% vs 95%, P ¼ .002). Additional practitioner responses are summarized in Table 3 and Table 4. Despite acknowledging the need for allergy/immunology consultation and the role of penicillin skin testing in numerous clinical scenarios, most health care practitioners (237 [86%] of 275) indicated that they either never consult an allergist or immunologist
M.L. Staicu et al. / Ann Allergy Asthma Immunol xxx (2017) 1e6
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Table 1 (continued )
Table 1 Penicillin Allergy Questionnaire Question
Possible Selection
1. What is your level of training?
Attending physician First-year resident Second-year resident Third-year resident Fourth-year resident Fifth-year resident Advanced practice practitioner Pharmacist
2. What is your specialty?
General internal medicine Internal medicine subspecialty Obstetrics/gynecology Surgery Pharmacy
3. How many years have you been practicing?
<1 year 1e5 years 5e10 years >10 years
4. How many years have you been practicing at the current institution?
<1 year 1e5 years 5e10 years >10 years
5. How much time do you generally take to assess medication allergies?
No time <2 minutes 2e5 minutes >5 minutes
6. In patients with antibiotic allergies, do you review previously administered antibiotics in the electronic medical record?
Yes No
7. How often do you consult allergy/ immunology for antibiotic allergies and/or evaluation of skin testing?
Never 1 time per year 2e5 times per year >5 times per year
8. What is the approximate rate of crossreactivity between penicillin and carbapenem antibiotics?
No cross-reactivity <5% 10%e20% 30%e50%
9. What is the approximate rate of crossreactivity between penicillin antibiotics and aztreonam?
No cross-reactivity <5% 10%e20% 30%e50%
10. What is the approximate rate of crossreactivity between penicillin and cephalosporin antibiotics?
No cross-reactivity <5% 10%e20% 30%e50%
11. Should patients with a family history of penicillin allergy but no personal history of a penicillin allergy avoid penicillin’s?
Yes No
12. What percentage of patients with a reported penicillin allergy will tolerate penicillin antibiotics?
0%e10% 20% 50% 90%
13. Can an allergy to penicillin resolve over time?
Yes No
Question
Possible Selection
14. How often do you ask patients the following questions to assess a drug allergy history? a. What is the name of the medication? b. How long ago did the reaction occur? c. Which organ systems were involved in the reaction and/or what specific symptoms were experienced? d. When during the course did the reaction occur?
Always ask Sometimes ask Never ask
15. Clinical Vignettes a. 55-year-old man with methicillin-susceptible Staphylococcus aureus endocarditis with a history of oral sores and skin blisters to amoxicillin at the age of 45 years. What is the best mode of antibiotic management? b. 70-year-old woman with sepsis secondary to Enterococcus faecalis, susceptible to ampicillin, with a history of hives to penicillin 30 years ago. What is the best mode of antibiotic management? c. 75-year-old man with methicillin-susceptible Staphylococcus aureus nonhealing wound with a history of nausea and vomiting with penicillin. What is the best mode of antibiotic management? d. 45-year-old woman readmitted to the hospital with methicillin-susceptible Staphylococcus aureus endocarditis with a history of anaphylaxis to nafcillin 2 weeks ago. What is the best mode of antibiotic management?
Avoid penicillin antibiotics Consult allergy/immunology for penicillin skin testing Consult allergy/immunology for desensitization or temporary induction of drug tolerance Rechallenge with penicillin antibiotics
Table 2 Demographic Characteristics of Survey Respondents Characteristic Level of training Attending physician First-year resident Second-year resident Third-year resident Fourth-year resident Fifth-year resident Advanced practice practitioner Pharmacist Specialty General internal medicine Internal medicine subspecialty Obstetrics/gynecology Surgery Pharmacy Total years in practice <1 year 1e5 years 5e10 years >10 years Total years at current institution <1 year 1e5 years 5e10 years >10 years
No. (%) of Respondents (n ¼ 276)
125 (45) 7 (3) 10 (4) 8 (3) 1 (0.4) 0 (0) 92 (33) 33 (12) 118 55 20 50 33
(43) (20) (7) (18) (12)
16 68 45 147
(6) (25) (16) (53)
21 92 44 119
(8) (33) (16) (43)
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M.L. Staicu et al. / Ann Allergy Asthma Immunol xxx (2017) 1e6
allergic reaction and what symptoms were experienced (95% and 86%, respectively). Only 53% and 26% of respondents report always asking how long ago the allergic reaction occurred and when during the antibiotic course the symptoms were experience, respectively. Appropriately categorizing medication drug reactions is an opportunity to identify patients for whom penicillin antibiotics may be rechallenged safely (ie, family history of penicillin allergy or an intolerance), skin testing would be beneficial (ie, IgE-mediated reactions), and penicillin antibiotic reintroduction is contraindicated (ie, Stevens-Johnson syndrome). These basic yet important details of a drug allergy assessment are simple to incorporate into practice and have the potential to cause tremendous clinical benefit. A potential solution to overcome this knowledge gap may include standardization of the drug allergy history in the electronic medical record. Allergic cross-reactivity between penicillin and other antibiotic classes, such as cephalosporins and carbapenems, is a topic of interest given the wide array of disparate observations. Before 1980, penicillin-allergic patients who were given cephalosporin antibiotics had a reported cross-reactivity rate of approximately 10% to 20%.14,15 More recent prospective studies, however, suggest that the overall true risk for cross-reactivity is 2%, with even lower rates in patients without a history of a severe reaction (0.1%).16e20 The former rate of 10% to 20% is partly attributed to the use of cephalosporin antibiotics that were contaminated with trace amounts of penicillin.21 In our questionnaire, 54% of participants selected a penicillin and cephalosporin cross-reactivity rate of less than 5%, with the remainder of respondents selecting more than 10%. Considering health care practitioner demographic data in participants of our questionnaire, we surmise that this finding may be a reflection of practices learned before the availability of more robust b-lactam cross-reactivity studies. Similar to cephalosporin antibiotics, carbapenem antibiotics were once thought to have penicillin cross-reactivity rates as high as 50%,21 yet more recent data suggest the extent of cross-reactivity is less than 1%.21e27 When evaluating participants’ knowledge of these data, the responses we observed were quite varied. Most participants (58%) selected a less than 5% cross-reactivity rate, whereas the remaining participants were split among the other 3 options. A surprising finding was that 14% of participants selected no cross-reactivity between the 2 antibiotic classes. We postulate that a targeted educational initiative and prescribing guidelines at our institution for practitioners could overcome the outdated teaching surrounding penicillin cross-reactivity with other antibiotics, as has been previously reported.28 The monobactam antibiotic aztreonam is less immunogenic compared with other b-lactam antibiotics.29 Numerous studies,
70 60
Respondents, %
50 40 Cephalosporins 30
Carbapenems Monobactams
20 10 0 No Cross-reacƟvity
<5%
10%-20%
30%-50%
AnƟbioƟc Cross-ReacƟvity Rates with Penicillins
Figure 1. Responses to approximate rate of cross-reactivity between penicillin and other antibiotics.
or they consult an allergist or immunologist only one time per year (Fig 2). Discussion Our study evaluated the clinical prescribing practices and knowledge of penicillin allergy in a multidisciplinary sample of health care practitioners at 2 community teaching hospitals. We found that there is an overall limited understanding of penicillin allergy and a wide variation in the clinical management of the penicillin-allergic patient. Although most participants were internal medicine attending physicians with greater than 10 years of experience, we identified several opportunities to improve clinical practices, including the evaluation of a drug allergy history, determination of the potential cross-reactivity with alternative antibiotics, and the management approach to the penicillin-allergic patient in clinical scenarios. A thorough medication allergy assessment is an essential component in the clinical evaluation and diagnosis of drug hypersensitivity.4 Most respondents to our survey reported spending 2 minutes or less reviewing a drug allergy history. Recent data suggest that a complete history can be obtained within this interval13; however, based on participant responses, we suspect that not all key elements of a penicillin allergy history are reviewed. Components of a drug allergy history that may assist with classification of drug hypersensitivity include how long ago the allergic reaction occurred, clinical manifestations experienced, and the temporal association with the onset of symptoms (immediate vs delayed reaction). Most respondents report that they always ask the name of the medication that caused the
Table 3 Responses to Clinical Scenarios Question
No. (%) of Respondents Avoid Penicillin Antibiotics
55-year-old man with MSSA endocarditis with a history of oral sores and skin blisters to amoxicillin at the age of 45 years (n ¼ 269) 70-year-old woman with sepsis secondary to Enterococcus faecalis, susceptible to ampicillin, with a history of hives to penicillin 30 years ago (n ¼ 271) 75-year-old man with MSSA nonhealing wound with a history of nausea and vomiting with penicillin (n ¼ 270) 45-year-old woman readmitted to the hospital with MSSA endocarditis with a history of anaphylaxis to nafcillin 2 weeks ago (n ¼ 267)
Consult Allergist for Penicillin Skin Testing
Consult Allergist for Penicillin Antibiotic Desensitization
Rechallenge With Penicillin Antibiotic
129 (48)
85 (32)
31 (12)
24 (9)
54 (20)
110 (41)
21 (8)
86 (32)
10 (4)
15 (6)
3 (1)
242 (90)
203 (76)
9 (3)
51 (19)
4 (2)
Abbreviations: MSSA, methicillin-susceptible Staphylococcus aureus.
M.L. Staicu et al. / Ann Allergy Asthma Immunol xxx (2017) 1e6 Table 4 Pharmacist Responses Compared With APPs and Physicians Survey Question
Answered Correctly, No./Total No. (%)
Antibiotic Cross-Reactivity What is the approximate rate of cross-reactivity between penicillins and imipenem? What is the approximate rate of cross-reactivity between penicillins and aztreonam? What is the approximate rate of cross-reactivity between penicillins and cephalosporins? Clinical Vignettes 55-year-old man with MSSA endocarditis with a history of oral sores and skin blisters to amoxicillin at the age of 45 years. 70-year-old woman with sepsis secondary to Enterococcus faecalis, susceptible to ampicillin, with a history of hives to penicillin 30 years ago. 75-year-old man with MSSA nonhealing wound with a history of nausea and vomiting with penicillin 45-year-old woman readmitted to the hospital with MSSA endocarditis with a history of anaphylaxis to nafcillin 2 weeks ago
P Value
Pharmacist
APP or Physician
23/33 (70)
133/238 (56)
.14
27/33 (82)
114/238 (48)
<.001
27/33 (82)
120/241 (50)
<.001
13/33 (39)
116/236 (49)
.35
19/33 (58)
91/238 (38)
.04
33/33 (100)
209/237 (88)
.06
11/33 (33)
40/234 (17)
.03
Abbreviations: APP, advanced practice practitioner; MSSA, methicillin-susceptible Staphylococcus aureus.
including in vitro analyses and clinical challenges, have consistently reported a lack of cross-reactivity between monobactams and b-lactam antibiotics.30e34 Similar to the chosen cross-reactivity rates for the other classes of antibiotics, only 52% of respondents selected no monobactam cross-reactivity in our questionnaire. Our findings regarding the knowledge of cross-reactivity between penicillin and alternative antibiotics are similar to previously published reports.1,8 The case vignettes highlighted in our questionnaire were designed to determine health care practitioner approaches to complex scenarios in penicillin-allergic adult patients with an infectious disease. When questioned about antibiotic management
60
Respondents, %
50 40 30 20 10 0 Never
1 Time
2-5 Times
>5 Times
Annual Allergy/Immunology ConsultaƟons
Figure 2. Frequency in which respondents consult allergists or immunologists for antibiotic allergy assessment and/or penicillin skin testing (n ¼ 275).
5
in a patient with a history of Stevens-Johnson syndrome, 43% of respondents chose to consult an allergist or immunologist for penicillin skin testing or desensitization, whereas 9% chose to rechallenge a penicillin antibiotic. This finding raises a significant patient safety concern because the reevaluation and readministration of a drug that caused a severe noneIgE-mediated reaction is generally contraindicated and should be avoided, with few exceptions.4 Our survey found the concerning finding that APPs were significantly more likely to introduce penicillin in a scenario where it is contraindicated. Health care practitioner unfamiliarity with drug hypersensitivity reactions in which reintroduction of the medication is contraindicated has been similarly described in numerous studies.9,12 In cases of suspected IgE-mediated reactions, such as a history of immediate hives, only 41% of participants selected penicillin skin testing as their management approach. Interestingly, more than 30% of participants chose the response to directly rechallenge the patient with a penicillin antibiotic. We suspect this may reflect suggestibility in the question rather than true clinical practice. In the event of a history of a recent severe IgE-mediated reaction, most respondents (76%) chose to avoid penicillin antibiotics rather than consider temporary induction of drug tolerance. These results suggest potential practice tendencies with important negative clinical implications because treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with a b-lactam antibiotic is associated with significantly lower relapse and mortality rates compared with therapy with vancomycin.35e37 The use of alternative antibiotics, including vancomycin, in patients with a severe penicillin reaction history is frequently described in the medical literature as the preferred option by most clinicians, although our survey illustrates that other options, such as temporary induction of drug tolerance and penicillin skin testing, may not be recognized.1,8e10 Particularly remarkable is that more than 85% of respondents indicated that they never consult an allergist or immunologist or do so only once per year, despite readily available consultative services at both institutions. We hypothesize that the underuse of consultation is attributed to the paucity of insight into the benefits of penicillin skin testing and allergy delabeling. In a survey ascertaining baseline drug allergy knowledge before the implementation of a clinical allergy guideline, Blumenthal et al9 illustrated that 2 of 5 inpatient practitioners reported no prior drug allergy education. When assessing provider knowledge of penicillin skin testing, only 36% of respondents knew it was a valid tool for determining penicillin allergy. Furthermore, Puchner et al10 found that less than 8% of respondents pursued penicillin skin testing in different clinical scenarios in a survey of community and academic internal medicine, pediatric, and allergy physicians. Practitioners were more likely to consult an infectious diseases specialist for further antibiotic management. Similar findings have also been reported by Abbo et al,38 who found that more than 1,400 adult and pediatric infectious diseases physicians reported frequent infectious diseases consultation, at least once per month, to assist with the management of patients with antibiotic allergies. The low incidence of allergy/immunology consultations for the management of penicillin allergy, compared with that of infectious diseases consultations, emphasizes the need for increased awareness and education across all levels of training in physician and nonphysician health care practitioners. Given the wide variation in drug allergy education, we sought to evaluate penicillin allergy knowledge between participating health care professionals. Overall, there was improved awareness of the natural history of penicillin allergy, antibiotic cross-reactivity, and clinical management strategies among pharmacists compared with APPs and physicians. This finding may be secondary to more extensive pharmacology education and active dissemination of
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information regarding penicillin allergy by antimicrobial stewardship pharmacists at one institution. A multidisciplinary approach to antibiotic selection in inpatients with penicillin allergy could potentially lead to more appropriate first-line antibiotic selection. There are numerous limitations to our analysis. Survey distribution to inpatient practitioners at 2 community hospitals where participant responses may not represent actual clinical practices limits the generalizability of our findings. It is also possible that the survey responses may not truly reflect practitioner knowledge and management of penicillin allergy on a large scale. However, our candidate participation rate is similar to other published studies,1,9 and our survey represents a diverse sampling of health care practitioners. A robust comparison between internal medicine subspecialities was not conducted given the small number of participants. Antibiotics are prescribed in more than 50% of hospitalized patients, where up to 1 in 5 patients will report a penicillin allergy.39,40 The relatively high frequency with which none b-lactam antibiotics are prescribed in penicillin-allergic inpatients highlights the need for improved quality efforts to raise awareness and educate front-line practitioners on the natural history of penicillin allergy, antibiotic cross-reactivity, and the value of penicillin skin testing in the appropriate clinical setting. Our study determines important inpatient practitioner knowledge gaps at 2 community teaching hospitals. We found that there is an overall poor understanding of the management of the penicillin-allergic patient where collaborative efforts between allergy and nonallergy health care practitioners are sparse. The expansion of a multidisciplinary approach to include allergists and pharmacists in the management of patients with infections may optimize antimicrobial prescribing in this subset of patients by facilitating the use of first-line b-lactam antibiotics. References [1] Solensky R, Ear H, Gruchalla R. Clinical approach to penicillin-allergic patients: a survey. Ann Allergy Asthma Immunol. 2000;84:329e333. [2] Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: a cohort study. J Allergy Clin Immunol. 2014;133:790e796. [3] MacFadden R, LaDelfa A, Leen J, et al. Impact of reported beta-lactam allergy on inpatient outcomes: a multicenter prospective cohort study. Clin Infect Dis. 2016;63:904e910. [4] Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010; 10:259e273. [5] Unger N, Gauthier T, Cheung L. Penicillin skin testing: potential implications for antimicrobial stewardship. Pharmacotherapy. 2013;33:856e863. [6] Rimawi R, Cook P, Gooch M, et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med. 2013;8:341e345. [7] Bourke J, Pavlos R, James I, Phillips E. Improving the effectiveness of penicillin allergy de-labeling. J Allergy Clin Immunol Pract. 2015;3:365e334. [8] Prematta T, Shah S, Ishmael F. Physician approaches to beta-lactam use in patients with penicillin hypersensitivity. Allergy Asthma Proc. 2012; 33:145e151. [9] Blumenthal K, Shenoy E, Hurwitz S, Varughese C, Hooper D, Banerji A. Survey of inpatient clinical providers’ antibiotic prescribing knowledge. J Allergy Clin Immunol Pract. 2014;2:407e413. [10] Puchner T, Zacharisen M. A survey of antibiotic prescribing and knowledge of penicillin allergy. Ann Allergy Asthma Immunol. 2002;88:24e29. [11] Trubiano J, Phillips E. Antimicrobial stewardship’s new weapon? A review of antibiotic allergy and pathways to ‘de-labeling’. Curr Opin Infect Dis. 2013;26: 526e537. [12] Suetrong N, Klaewongstram J. The differences and similarities between allergists and non-allergists for penicillin allergy management. J Allergy. 2014; 2014:214183.
[13] Staicu M, Ramsey A, Plakosh M. Evaluation of a penicillin allergy history algorithm in characterizing penicillin allergy. Poster presented at: ID Week; October 29, 2016; New Orleans, Louisiana. [14] Girard J. Common antigenic determinants of penicillin G, ampicillin and the cephalosporins demonstrated in men. Int Arch Allergy. 1968;33:428e438. [15] Assem E, Vickers M. Tests for penicillin allergy in man, II: the immunological cross-reaction between penicillin and cephalosporins. Immunology. 1964;27: 255e269. [16] Macy E, Mangat R, Burchette R. Penicillin skin testing in advance of need: multiyear follow-up in 568 test result-negative subjects exposed to oral penicillins. J Allergy Clin Immunol. 2003;111:1111e1115. [17] Saxon A, Beall G, Rohr A, Adelman D. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med. 1987;107:204e215. [18] Pichichero M, Pichichero D. Diagnosis of penicillin, amoxicillin and cephalosporin allergy: reliability of examination by skin testing and oral challenge. J Pediatr. 1998;132:137e143. [19] Romano A, Gueant-Rodriguez R, Viola M, Pettinato R, Gueant J. Crossreactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins. Ann Intern Med. 2004;141:16e22. [20] Pederson-Bjergaard J. Cephalothin in the treatment of penicillin sensitive patients. Acta Allergol. 1967;22:299e306. [21] Saxon A, Adelman D, Patel A, Hajdu R, Calandra G. Imipenem cross-reactivity with penicillin in humans. J Allergy Clin Immunol. 1988;82:213e217. [22] Sodhi M, Axtell S, Callahan J, Shekar R. Is it safe to use carbapenems in patients with a history of allergy to penicillin? J Antimicrob Chemother. 2004; 54:1155e1157. [23] Prescott W, DePestel D, Ellis J, Regal R. Incidence of carbapenem-associated allergic-type reactions among patients with versus patients without a reported penicillin allergy. Clin Infect Dis. 2004;38:1102e1107. [24] McConnell S, Penzak S, Warmack T, Anaissie E, Gubbins P. Incidence of imipenem hypersensitivity reactions in febrile neutropenic bone marrow transplant patients with a history of penicillin allergy. Clin Infect Dis. 2000;31: 1512e1514. [25] Gaeta F, Valluzzi RL, Alonzi C, Maggioletti M, Caruso C, Romano A. Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2015;135:972e976. [26] Atanaskovic-Markovic M, Gaeta F, Medjo B, Viola M, Nestorovic B, Romano A. Tolerability of meropenem in children with IgE-mediated hypersensitivity to penicillins. Allergy. 2008;63:237e240. [27] Atanaskowvic-Markovic M, Gaeta F, Gavrovic-Jankulovic M, Velickovic TC, Valluzzi RL, Romano A. Tolerability of imipenem in children with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2009;124:167e169. [28] Blumenthal KG, Shenoy ES, Varughese CA, Hurwitz S, Hooper DC, Banerji A. Impact of a clinical prescribing guideline for prescribing antibiotics to inpatients reporting penicillin or cephalosporin allergy. Ann Allergy Asthma Immunol. 2015;115:294e300. [29] Adkinson N, Saxon A, Spence M, Swabb E. Cross-allergenicity and immunogenicity of aztreonam. Rev Infect Dis. 1985;(suppl 4):S613eS621. [30] Adkinson N. Immunogenicity and cross-allergenicity of aztreonam. Am J Med. 1990;88(suppl 3C):S3eS14. [31] Saxon A, Hassner A, Swabb E, Wheeler B, Adkinson N. Lack of cross-reactivity between aztreonam, a monobactam antibiotic, and penicillin in penicillinallergic subjects. J Infect Dis. 1984;149:16e22. [32] Saxon A, Swabb E, Adkinson N. Investigation into the immunologic crossreactivity of aztreonam with other beta-lactam antibiotics. Am J Med. 1985; 78:19e26. [33] Vega J, Blanca M, Garcia J, et al. Tolerance to aztreonam in patients allergic to beta lactam antibiotics. Allergy. 1991;46:196e202. [34] Moss R. Sensitization to aztreonam and cross-reactivity with other betalactam antibiotics in high-risk patients with cystic fibrosis. J Allergy Clin Immunol. 1991;87:78e88. [35] Chang F, Peacock J, Musher D, et al. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine. 2003;82:333e339. [36] Gonzalez C, Rubio M, Romero-Vivas J, Gonzalez M, Picazo J. Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms. Clin Infect Dis. 1999;29:1171e1177. [37] Fowler V, Kong L, Corey R, et al. Recurrent Staphylococcus aureus bacteremia: pulsed-field gel electrophoresis findings in 29 patients. J Infect Dis. 1999;179: 1157e1161. [38] Abbo L, Beekmann S, Hooton T, Johannsson B, Polgreen P. Management of antimicrobial allergies by infectious diseases physicians. JAMA. 2013;173: 1376e1378. [39] Lee C, Zembower T, Fotis M, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med. 2000;160:2819e2822. [40] Fridkin S, Baggs J, Fagan R, et al. Vital signs: improving antibiotic use among hospitalized patients. MMWR Morb Mortal Wkly Rep. 2014;63:194e200.
Contents lists available at ScienceDirect
A survey of inpatient practitioner knowledge of penicillin allergy at 2 community teaching hospitals Mary L. Staicu, PharmD *; Dipekka Soni, MD *; Kelly M. Conn, PhD, MPH y; Allison Ramsey, MD * * Pharmacy y
Department, Rochester General Hospital, Rochester, New York St. John Fisher College, Wegmans School of Pharmacy, Rochester, New York
A R T I C L E
I N F O
Article history: Received for publication March 9, 2017. Received in revised form April 13, 2017. Accepted for publication April 16, 2017.
A B S T R A C T
Background: The negative effect of the penicillin allergy label on antibiotic use and patient outcomes has brought to light the need for thorough penicillin allergy assessments and heightened practitioner education. Objective: To evaluate practitioner knowledge of penicillin allergy and the clinical approach to the patients with penicillin allergy. Methods: An electronic survey was distributed to attending physicians, residents, pharmacists, nurse practitioners, and physician assistants practicing adult inpatient medicine at 2 community-based teaching hospitals from February to April 2016. Results: A total of 276 (39%) of 716 practitioners completed surveys were analyzed. Most respondents were attending physicians (45%) with more than 10 years of experience (53%). Approximately half of the respondents indicated that they were unfamiliar with the rate of cross-reactivity between penicillin and cephalosporin (46%), carbapenem (42%), and monobactam (48%) antibiotics. When evaluating the role of penicillin skin testing and temporary induction of drug tolerance in the case vignettes, only 41% and 19% of respondents appropriately considered these options as the leading antibiotic management plan, respectively. Despite acknowledging the need for allergy/immunology consultation in clinical scenarios, 86% of respondents indicated that they never consult an allergist or immunologist or do so only once per year. Overall, pharmacists had a better understanding of the natural history of penicillin allergy and antibiotic cross-reactivity (P < .05). Conclusion: There is an overall limited understanding of the management of patients with a history of penicillin allergy in the hospital setting, where collaborative efforts between allergy and nonallergy health care practitioners are sparse. The expansion of a multidisciplinary approach may optimize antimicrobial prescribing in this subset of patients. Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction The approach to the treatment and management of infectious diseases in patients with a penicillin allergy remains a significant clinical conundrum. The complexity of drug hypersensitivity reactions paired with the increasing prevalence of multidrugresistant bacteria make it challenging for health care practitioners to determine proper therapeutic strategies in such clinical settings. Second- and third-line antibiotic therapy used in patients diagnosed with a penicillin allergy predisposes them to the development of infections caused by Clostridium difficile, Reprints: Mary L. Staicu, PharmD, Pharmacy Department, Rochester General Hospital, 1425 Portland Ave, Rochester, NY 14621; E-mail: mary.staicu@ rochesterregional.org. Disclosures: Authors have nothing to disclose. Previous Presentation: Presented as an oral abstract at the American College of Allergy, Asthma, and Immunology; November 14, 2016; San Francisco, California.
methicillin-resistant Staphylococcus aureus, and vancomycinresistant Enterococcus.1,2 In addition, the presence of penicillin allergy increases health care facility exposure by prolonging the duration of hospitalization and increasing the rate of hospital readmissions.2,3 The negative effect of the penicillin allergy label on antibiotic use, patient outcomes, and overall health care costs has brought to light the need for thorough penicillin allergy assessments and, if indicated, penicillin skin testing.4e7 Despite the increasing body of literature on the natural history of penicillin allergy, the minimal penicillin allergic cross-reactivity rate with cephalosporin and carbapenems, and the substantial implications of a penicillin allergy label, significant drug allergy knowledge deficits remain among various strata of health care professionals.1,4,8e11 Previous studies evaluating inpatient practitioner drug allergy knowledge have reported that 42% of physicians have never received prior drug allergy education, have low awareness of penicillin skin testing, and lack general knowledge of
http://dx.doi.org/10.1016/j.anai.2017.04.023 1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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penicillin allergy.9 In addition, a recent survey of allergist and nonallergist physicians found that allergists were more likely to confirm penicillin allergy with skin testing, more likely to avoid penicillin antibiotics in patients with a history of Stevens-Johnson syndrome, and less concerned about the cross-reactivity between cephalosporin and penicillin antibiotics compared with nonallergists.12 The current inpatient health care environment includes a multidisciplinary team of physicians, advanced practice practitioners (APPs), residents, and clinical pharmacists. Previous surveys have had limited assessment of the knowledge of APPs (ie, physician assistants and nurse practitioners) and pharmacists regarding penicillin allergy. Given the increasing interest in the effect of penicillin allergy and penicillin skin testing among national organizations from various subspecialties, we sought to evaluate the clinical approach to the penicillin-allergic patient in a diverse group of health care professionals at 2 community teaching hospitals. Methods Study Design and Setting An electronic questionnaire was distributed to inpatient practitioners practicing adult medicine at 287- and 528-bed tertiary community-based teaching hospitals in February 2016. Both institutions included in the analysis have available allergy/immunology consultative services. Attending physicians, residents, APPs, and pharmacists practicing in internal medicine (general and subspecialty), surgery (general and subspecialty), and obstetrics and gynecology were considered for inclusion. Practitioners exclusively practicing in the outpatient setting or in the pediatric population were excluded. Eligible candidates had 60 days to voluntarily complete the questionnaire and were asked to refrain from the use of external resources to aid in their responses. The research protocol was agreed on by the investigators and approved by the Rochester General Hospital Clinical Investigations Committee. Questionnaire The questionnaire (Table 1) was constructed with the combined efforts of an allergist, infectious diseases pharmacist, and internal medicine resident. SurveyMonkey (Palo Alto, CA) was used to electronically develop the questionnaire, which contained a total of 15 questions that critically assessed respondent demographic characteristics (4 questions), general penicillin allergy knowledge (6 questions), and self-reported practice patterns through clinical vignettes (5 questions). Temporary induction of drug tolerance was referred to as desensitization in the clinical vignettes because most nonallergist practitioners within our health care system were familiar with this term. Results of the questionnaire were anonymous and were therefore not stratified by institution. Outcome Measures and Statistical Analysis The primary objectives were to describe health care practitioner clinical practice patterns and identify potential knowledge gaps pertinent to the management of the penicillin-allergic patient. Descriptive statistics were used to describe the population and their knowledge and practices. c2 test (Fisher exact test, 2-tailed) was used to compare survey responses among medical professionals. Pharmacist, APP, and physician responses were compared separately for each question. Results that were statistically significant were further broken down to better understand which practitioner group was integral in generating differences. Results A total of 276 (39%) of 716 eligible health care practitioners completed some or all of the questionnaire. Most respondents were attending physicians (125 [45%] of 276) practicing general internal
medicine (118 [43%] of 276) for more than 10 years (147 [53%] of 276). Additional demographic characteristics are presented in Table 2. When clinically evaluating a penicillin allergy history, nearly all respondents indicated that they always ask the name of the medication allergy (260 [95%] of 275) and what specific symptoms were experienced (236 [86%] of 274). Approximately half (145 [53%] of 274) of the respondents indicated that they always ask how long ago the allergic reaction occurred, with pharmacists asking more frequently than other professions (73% vs 50%, P ¼ .02); however, only 71 (26%) of 275 respondents indicated they always ask at what point during the antibiotic course the symptoms were experienced. Most health care practitioners (197 [72%] of 274) indicated that they spend less than 2 minutes to assess an allergy history, followed by 64 (23%) and 13 (5%) respondents that indicated they spend 2 to 5 minutes or more than 5 minutes to evaluate, respectively. All but 5 (268 [98%] of 273) respondents disagreed with the avoidance of penicillin in patients with a family history of penicillin allergy who reported no personal history of penicillin allergy. When asked whether an allergy to penicillin could resolve with time, 158 (58%) of 273 respondents agreed, yet only 82 (30%) of 274 knew that 9 of 10 penicillin-allergic patients will tolerate a penicillin antibiotic. Further electronic medical record review of administered antibiotics in penicillin-allergic patients was reported in 219 (80%) of 275 respondents. Pharmacists were more aware that penicillin allergy can resolve with time (78% vs 55%, P ¼ .01), knew that 90% of penicillin-allergic patients will tolerate a penicillin antibiotic (64% vs 25%, P < .001), and were more likely to review historical electronic medical record antibiotic administrations (100% vs 78%, P ¼ .002) compared with the other respondents. Clinician knowledge of penicillin antibiotic cross-reactivity among cephalosporin, carbapenem, and monobactam antibiotics is indicated in Figure 1. Responses were approximately split between 10% to 20% cross-reactivity (119 [43%] of 274) and less than 5% cross-reactivity (147 [54%] of 274) with cephalosporins and less than 5% cross-reactivity (108 [40%] of 271) and no cross-reactivity (141 [52%] of 271) with monobactams. Of note, there was a wide variation in responses when asked about the cross-reactivity rate with carbapenem antibiotics. A total of 156 [58%] of 271 respondents selected less than 5% cross-reactivity, with the remainder of the cohort divided among the other 3 options. The clinical vignettes were designed to evaluate the management approach to an array of clinical scenarios in patients with a reported penicillin allergy. Question 1 assessed penicillin antibiotic use in a patient with an allergy history suggestive of StevensJohnson syndrome. Approximately half of respondents (129 [48%] of 269) indicated they would appropriately avoid penicillin antibiotics, whereas 24 (9%) indicated they would directly administer penicillin antibiotics. Significantly more APPs chose to directly administer penicillin antibiotics compared with pharmacists and physicians (15% vs 6%, P ¼ .02). Question 2 sought to evaluate the respondents’ stance on the use of penicillin skin testing in the event of b-lactam antibiotic clinical superiority. Only 110 (41%) of 271 considered penicillin skin testing as their leading antibiotic management plan. Question 3 aimed to determine the participant’s threshold in rechallenging penicillin in a patient with a history of penicillin intolerance. Physician respondents expressed that they were less likely to initiate use of a penicillin antibiotic with a penicillin allergy listed as nausea or vomiting compared with other professions (84% vs 95%, P ¼ .002). Additional practitioner responses are summarized in Table 3 and Table 4. Despite acknowledging the need for allergy/immunology consultation and the role of penicillin skin testing in numerous clinical scenarios, most health care practitioners (237 [86%] of 275) indicated that they either never consult an allergist or immunologist
M.L. Staicu et al. / Ann Allergy Asthma Immunol xxx (2017) 1e6
3
Table 1 (continued )
Table 1 Penicillin Allergy Questionnaire Question
Possible Selection
1. What is your level of training?
Attending physician First-year resident Second-year resident Third-year resident Fourth-year resident Fifth-year resident Advanced practice practitioner Pharmacist
2. What is your specialty?
General internal medicine Internal medicine subspecialty Obstetrics/gynecology Surgery Pharmacy
3. How many years have you been practicing?
<1 year 1e5 years 5e10 years >10 years
4. How many years have you been practicing at the current institution?
<1 year 1e5 years 5e10 years >10 years
5. How much time do you generally take to assess medication allergies?
No time <2 minutes 2e5 minutes >5 minutes
6. In patients with antibiotic allergies, do you review previously administered antibiotics in the electronic medical record?
Yes No
7. How often do you consult allergy/ immunology for antibiotic allergies and/or evaluation of skin testing?
Never 1 time per year 2e5 times per year >5 times per year
8. What is the approximate rate of crossreactivity between penicillin and carbapenem antibiotics?
No cross-reactivity <5% 10%e20% 30%e50%
9. What is the approximate rate of crossreactivity between penicillin antibiotics and aztreonam?
No cross-reactivity <5% 10%e20% 30%e50%
10. What is the approximate rate of crossreactivity between penicillin and cephalosporin antibiotics?
No cross-reactivity <5% 10%e20% 30%e50%
11. Should patients with a family history of penicillin allergy but no personal history of a penicillin allergy avoid penicillin’s?
Yes No
12. What percentage of patients with a reported penicillin allergy will tolerate penicillin antibiotics?
0%e10% 20% 50% 90%
13. Can an allergy to penicillin resolve over time?
Yes No
Question
Possible Selection
14. How often do you ask patients the following questions to assess a drug allergy history? a. What is the name of the medication? b. How long ago did the reaction occur? c. Which organ systems were involved in the reaction and/or what specific symptoms were experienced? d. When during the course did the reaction occur?
Always ask Sometimes ask Never ask
15. Clinical Vignettes a. 55-year-old man with methicillin-susceptible Staphylococcus aureus endocarditis with a history of oral sores and skin blisters to amoxicillin at the age of 45 years. What is the best mode of antibiotic management? b. 70-year-old woman with sepsis secondary to Enterococcus faecalis, susceptible to ampicillin, with a history of hives to penicillin 30 years ago. What is the best mode of antibiotic management? c. 75-year-old man with methicillin-susceptible Staphylococcus aureus nonhealing wound with a history of nausea and vomiting with penicillin. What is the best mode of antibiotic management? d. 45-year-old woman readmitted to the hospital with methicillin-susceptible Staphylococcus aureus endocarditis with a history of anaphylaxis to nafcillin 2 weeks ago. What is the best mode of antibiotic management?
Avoid penicillin antibiotics Consult allergy/immunology for penicillin skin testing Consult allergy/immunology for desensitization or temporary induction of drug tolerance Rechallenge with penicillin antibiotics
Table 2 Demographic Characteristics of Survey Respondents Characteristic Level of training Attending physician First-year resident Second-year resident Third-year resident Fourth-year resident Fifth-year resident Advanced practice practitioner Pharmacist Specialty General internal medicine Internal medicine subspecialty Obstetrics/gynecology Surgery Pharmacy Total years in practice <1 year 1e5 years 5e10 years >10 years Total years at current institution <1 year 1e5 years 5e10 years >10 years
No. (%) of Respondents (n ¼ 276)
125 (45) 7 (3) 10 (4) 8 (3) 1 (0.4) 0 (0) 92 (33) 33 (12) 118 55 20 50 33
(43) (20) (7) (18) (12)
16 68 45 147
(6) (25) (16) (53)
21 92 44 119
(8) (33) (16) (43)
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M.L. Staicu et al. / Ann Allergy Asthma Immunol xxx (2017) 1e6
allergic reaction and what symptoms were experienced (95% and 86%, respectively). Only 53% and 26% of respondents report always asking how long ago the allergic reaction occurred and when during the antibiotic course the symptoms were experience, respectively. Appropriately categorizing medication drug reactions is an opportunity to identify patients for whom penicillin antibiotics may be rechallenged safely (ie, family history of penicillin allergy or an intolerance), skin testing would be beneficial (ie, IgE-mediated reactions), and penicillin antibiotic reintroduction is contraindicated (ie, Stevens-Johnson syndrome). These basic yet important details of a drug allergy assessment are simple to incorporate into practice and have the potential to cause tremendous clinical benefit. A potential solution to overcome this knowledge gap may include standardization of the drug allergy history in the electronic medical record. Allergic cross-reactivity between penicillin and other antibiotic classes, such as cephalosporins and carbapenems, is a topic of interest given the wide array of disparate observations. Before 1980, penicillin-allergic patients who were given cephalosporin antibiotics had a reported cross-reactivity rate of approximately 10% to 20%.14,15 More recent prospective studies, however, suggest that the overall true risk for cross-reactivity is 2%, with even lower rates in patients without a history of a severe reaction (0.1%).16e20 The former rate of 10% to 20% is partly attributed to the use of cephalosporin antibiotics that were contaminated with trace amounts of penicillin.21 In our questionnaire, 54% of participants selected a penicillin and cephalosporin cross-reactivity rate of less than 5%, with the remainder of respondents selecting more than 10%. Considering health care practitioner demographic data in participants of our questionnaire, we surmise that this finding may be a reflection of practices learned before the availability of more robust b-lactam cross-reactivity studies. Similar to cephalosporin antibiotics, carbapenem antibiotics were once thought to have penicillin cross-reactivity rates as high as 50%,21 yet more recent data suggest the extent of cross-reactivity is less than 1%.21e27 When evaluating participants’ knowledge of these data, the responses we observed were quite varied. Most participants (58%) selected a less than 5% cross-reactivity rate, whereas the remaining participants were split among the other 3 options. A surprising finding was that 14% of participants selected no cross-reactivity between the 2 antibiotic classes. We postulate that a targeted educational initiative and prescribing guidelines at our institution for practitioners could overcome the outdated teaching surrounding penicillin cross-reactivity with other antibiotics, as has been previously reported.28 The monobactam antibiotic aztreonam is less immunogenic compared with other b-lactam antibiotics.29 Numerous studies,
70 60
Respondents, %
50 40 Cephalosporins 30
Carbapenems Monobactams
20 10 0 No Cross-reacƟvity
<5%
10%-20%
30%-50%
AnƟbioƟc Cross-ReacƟvity Rates with Penicillins
Figure 1. Responses to approximate rate of cross-reactivity between penicillin and other antibiotics.
or they consult an allergist or immunologist only one time per year (Fig 2). Discussion Our study evaluated the clinical prescribing practices and knowledge of penicillin allergy in a multidisciplinary sample of health care practitioners at 2 community teaching hospitals. We found that there is an overall limited understanding of penicillin allergy and a wide variation in the clinical management of the penicillin-allergic patient. Although most participants were internal medicine attending physicians with greater than 10 years of experience, we identified several opportunities to improve clinical practices, including the evaluation of a drug allergy history, determination of the potential cross-reactivity with alternative antibiotics, and the management approach to the penicillin-allergic patient in clinical scenarios. A thorough medication allergy assessment is an essential component in the clinical evaluation and diagnosis of drug hypersensitivity.4 Most respondents to our survey reported spending 2 minutes or less reviewing a drug allergy history. Recent data suggest that a complete history can be obtained within this interval13; however, based on participant responses, we suspect that not all key elements of a penicillin allergy history are reviewed. Components of a drug allergy history that may assist with classification of drug hypersensitivity include how long ago the allergic reaction occurred, clinical manifestations experienced, and the temporal association with the onset of symptoms (immediate vs delayed reaction). Most respondents report that they always ask the name of the medication that caused the
Table 3 Responses to Clinical Scenarios Question
No. (%) of Respondents Avoid Penicillin Antibiotics
55-year-old man with MSSA endocarditis with a history of oral sores and skin blisters to amoxicillin at the age of 45 years (n ¼ 269) 70-year-old woman with sepsis secondary to Enterococcus faecalis, susceptible to ampicillin, with a history of hives to penicillin 30 years ago (n ¼ 271) 75-year-old man with MSSA nonhealing wound with a history of nausea and vomiting with penicillin (n ¼ 270) 45-year-old woman readmitted to the hospital with MSSA endocarditis with a history of anaphylaxis to nafcillin 2 weeks ago (n ¼ 267)
Consult Allergist for Penicillin Skin Testing
Consult Allergist for Penicillin Antibiotic Desensitization
Rechallenge With Penicillin Antibiotic
129 (48)
85 (32)
31 (12)
24 (9)
54 (20)
110 (41)
21 (8)
86 (32)
10 (4)
15 (6)
3 (1)
242 (90)
203 (76)
9 (3)
51 (19)
4 (2)
Abbreviations: MSSA, methicillin-susceptible Staphylococcus aureus.
M.L. Staicu et al. / Ann Allergy Asthma Immunol xxx (2017) 1e6 Table 4 Pharmacist Responses Compared With APPs and Physicians Survey Question
Answered Correctly, No./Total No. (%)
Antibiotic Cross-Reactivity What is the approximate rate of cross-reactivity between penicillins and imipenem? What is the approximate rate of cross-reactivity between penicillins and aztreonam? What is the approximate rate of cross-reactivity between penicillins and cephalosporins? Clinical Vignettes 55-year-old man with MSSA endocarditis with a history of oral sores and skin blisters to amoxicillin at the age of 45 years. 70-year-old woman with sepsis secondary to Enterococcus faecalis, susceptible to ampicillin, with a history of hives to penicillin 30 years ago. 75-year-old man with MSSA nonhealing wound with a history of nausea and vomiting with penicillin 45-year-old woman readmitted to the hospital with MSSA endocarditis with a history of anaphylaxis to nafcillin 2 weeks ago
P Value
Pharmacist
APP or Physician
23/33 (70)
133/238 (56)
.14
27/33 (82)
114/238 (48)
<.001
27/33 (82)
120/241 (50)
<.001
13/33 (39)
116/236 (49)
.35
19/33 (58)
91/238 (38)
.04
33/33 (100)
209/237 (88)
.06
11/33 (33)
40/234 (17)
.03
Abbreviations: APP, advanced practice practitioner; MSSA, methicillin-susceptible Staphylococcus aureus.
including in vitro analyses and clinical challenges, have consistently reported a lack of cross-reactivity between monobactams and b-lactam antibiotics.30e34 Similar to the chosen cross-reactivity rates for the other classes of antibiotics, only 52% of respondents selected no monobactam cross-reactivity in our questionnaire. Our findings regarding the knowledge of cross-reactivity between penicillin and alternative antibiotics are similar to previously published reports.1,8 The case vignettes highlighted in our questionnaire were designed to determine health care practitioner approaches to complex scenarios in penicillin-allergic adult patients with an infectious disease. When questioned about antibiotic management
60
Respondents, %
50 40 30 20 10 0 Never
1 Time
2-5 Times
>5 Times
Annual Allergy/Immunology ConsultaƟons
Figure 2. Frequency in which respondents consult allergists or immunologists for antibiotic allergy assessment and/or penicillin skin testing (n ¼ 275).
5
in a patient with a history of Stevens-Johnson syndrome, 43% of respondents chose to consult an allergist or immunologist for penicillin skin testing or desensitization, whereas 9% chose to rechallenge a penicillin antibiotic. This finding raises a significant patient safety concern because the reevaluation and readministration of a drug that caused a severe noneIgE-mediated reaction is generally contraindicated and should be avoided, with few exceptions.4 Our survey found the concerning finding that APPs were significantly more likely to introduce penicillin in a scenario where it is contraindicated. Health care practitioner unfamiliarity with drug hypersensitivity reactions in which reintroduction of the medication is contraindicated has been similarly described in numerous studies.9,12 In cases of suspected IgE-mediated reactions, such as a history of immediate hives, only 41% of participants selected penicillin skin testing as their management approach. Interestingly, more than 30% of participants chose the response to directly rechallenge the patient with a penicillin antibiotic. We suspect this may reflect suggestibility in the question rather than true clinical practice. In the event of a history of a recent severe IgE-mediated reaction, most respondents (76%) chose to avoid penicillin antibiotics rather than consider temporary induction of drug tolerance. These results suggest potential practice tendencies with important negative clinical implications because treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with a b-lactam antibiotic is associated with significantly lower relapse and mortality rates compared with therapy with vancomycin.35e37 The use of alternative antibiotics, including vancomycin, in patients with a severe penicillin reaction history is frequently described in the medical literature as the preferred option by most clinicians, although our survey illustrates that other options, such as temporary induction of drug tolerance and penicillin skin testing, may not be recognized.1,8e10 Particularly remarkable is that more than 85% of respondents indicated that they never consult an allergist or immunologist or do so only once per year, despite readily available consultative services at both institutions. We hypothesize that the underuse of consultation is attributed to the paucity of insight into the benefits of penicillin skin testing and allergy delabeling. In a survey ascertaining baseline drug allergy knowledge before the implementation of a clinical allergy guideline, Blumenthal et al9 illustrated that 2 of 5 inpatient practitioners reported no prior drug allergy education. When assessing provider knowledge of penicillin skin testing, only 36% of respondents knew it was a valid tool for determining penicillin allergy. Furthermore, Puchner et al10 found that less than 8% of respondents pursued penicillin skin testing in different clinical scenarios in a survey of community and academic internal medicine, pediatric, and allergy physicians. Practitioners were more likely to consult an infectious diseases specialist for further antibiotic management. Similar findings have also been reported by Abbo et al,38 who found that more than 1,400 adult and pediatric infectious diseases physicians reported frequent infectious diseases consultation, at least once per month, to assist with the management of patients with antibiotic allergies. The low incidence of allergy/immunology consultations for the management of penicillin allergy, compared with that of infectious diseases consultations, emphasizes the need for increased awareness and education across all levels of training in physician and nonphysician health care practitioners. Given the wide variation in drug allergy education, we sought to evaluate penicillin allergy knowledge between participating health care professionals. Overall, there was improved awareness of the natural history of penicillin allergy, antibiotic cross-reactivity, and clinical management strategies among pharmacists compared with APPs and physicians. This finding may be secondary to more extensive pharmacology education and active dissemination of
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information regarding penicillin allergy by antimicrobial stewardship pharmacists at one institution. A multidisciplinary approach to antibiotic selection in inpatients with penicillin allergy could potentially lead to more appropriate first-line antibiotic selection. There are numerous limitations to our analysis. Survey distribution to inpatient practitioners at 2 community hospitals where participant responses may not represent actual clinical practices limits the generalizability of our findings. It is also possible that the survey responses may not truly reflect practitioner knowledge and management of penicillin allergy on a large scale. However, our candidate participation rate is similar to other published studies,1,9 and our survey represents a diverse sampling of health care practitioners. A robust comparison between internal medicine subspecialities was not conducted given the small number of participants. Antibiotics are prescribed in more than 50% of hospitalized patients, where up to 1 in 5 patients will report a penicillin allergy.39,40 The relatively high frequency with which none b-lactam antibiotics are prescribed in penicillin-allergic inpatients highlights the need for improved quality efforts to raise awareness and educate front-line practitioners on the natural history of penicillin allergy, antibiotic cross-reactivity, and the value of penicillin skin testing in the appropriate clinical setting. Our study determines important inpatient practitioner knowledge gaps at 2 community teaching hospitals. We found that there is an overall poor understanding of the management of the penicillin-allergic patient where collaborative efforts between allergy and nonallergy health care practitioners are sparse. The expansion of a multidisciplinary approach to include allergists and pharmacists in the management of patients with infections may optimize antimicrobial prescribing in this subset of patients by facilitating the use of first-line b-lactam antibiotics. References [1] Solensky R, Ear H, Gruchalla R. Clinical approach to penicillin-allergic patients: a survey. Ann Allergy Asthma Immunol. 2000;84:329e333. [2] Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: a cohort study. J Allergy Clin Immunol. 2014;133:790e796. [3] MacFadden R, LaDelfa A, Leen J, et al. Impact of reported beta-lactam allergy on inpatient outcomes: a multicenter prospective cohort study. Clin Infect Dis. 2016;63:904e910. [4] Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010; 10:259e273. [5] Unger N, Gauthier T, Cheung L. Penicillin skin testing: potential implications for antimicrobial stewardship. Pharmacotherapy. 2013;33:856e863. [6] Rimawi R, Cook P, Gooch M, et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med. 2013;8:341e345. [7] Bourke J, Pavlos R, James I, Phillips E. Improving the effectiveness of penicillin allergy de-labeling. J Allergy Clin Immunol Pract. 2015;3:365e334. [8] Prematta T, Shah S, Ishmael F. Physician approaches to beta-lactam use in patients with penicillin hypersensitivity. Allergy Asthma Proc. 2012; 33:145e151. [9] Blumenthal K, Shenoy E, Hurwitz S, Varughese C, Hooper D, Banerji A. Survey of inpatient clinical providers’ antibiotic prescribing knowledge. J Allergy Clin Immunol Pract. 2014;2:407e413. [10] Puchner T, Zacharisen M. A survey of antibiotic prescribing and knowledge of penicillin allergy. Ann Allergy Asthma Immunol. 2002;88:24e29. [11] Trubiano J, Phillips E. Antimicrobial stewardship’s new weapon? A review of antibiotic allergy and pathways to ‘de-labeling’. Curr Opin Infect Dis. 2013;26: 526e537. [12] Suetrong N, Klaewongstram J. The differences and similarities between allergists and non-allergists for penicillin allergy management. J Allergy. 2014; 2014:214183.
[13] Staicu M, Ramsey A, Plakosh M. Evaluation of a penicillin allergy history algorithm in characterizing penicillin allergy. Poster presented at: ID Week; October 29, 2016; New Orleans, Louisiana. [14] Girard J. Common antigenic determinants of penicillin G, ampicillin and the cephalosporins demonstrated in men. Int Arch Allergy. 1968;33:428e438. [15] Assem E, Vickers M. Tests for penicillin allergy in man, II: the immunological cross-reaction between penicillin and cephalosporins. Immunology. 1964;27: 255e269. [16] Macy E, Mangat R, Burchette R. Penicillin skin testing in advance of need: multiyear follow-up in 568 test result-negative subjects exposed to oral penicillins. J Allergy Clin Immunol. 2003;111:1111e1115. [17] Saxon A, Beall G, Rohr A, Adelman D. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med. 1987;107:204e215. [18] Pichichero M, Pichichero D. Diagnosis of penicillin, amoxicillin and cephalosporin allergy: reliability of examination by skin testing and oral challenge. J Pediatr. 1998;132:137e143. [19] Romano A, Gueant-Rodriguez R, Viola M, Pettinato R, Gueant J. Crossreactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins. Ann Intern Med. 2004;141:16e22. [20] Pederson-Bjergaard J. Cephalothin in the treatment of penicillin sensitive patients. Acta Allergol. 1967;22:299e306. [21] Saxon A, Adelman D, Patel A, Hajdu R, Calandra G. Imipenem cross-reactivity with penicillin in humans. J Allergy Clin Immunol. 1988;82:213e217. [22] Sodhi M, Axtell S, Callahan J, Shekar R. Is it safe to use carbapenems in patients with a history of allergy to penicillin? J Antimicrob Chemother. 2004; 54:1155e1157. [23] Prescott W, DePestel D, Ellis J, Regal R. Incidence of carbapenem-associated allergic-type reactions among patients with versus patients without a reported penicillin allergy. Clin Infect Dis. 2004;38:1102e1107. [24] McConnell S, Penzak S, Warmack T, Anaissie E, Gubbins P. Incidence of imipenem hypersensitivity reactions in febrile neutropenic bone marrow transplant patients with a history of penicillin allergy. Clin Infect Dis. 2000;31: 1512e1514. [25] Gaeta F, Valluzzi RL, Alonzi C, Maggioletti M, Caruso C, Romano A. Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2015;135:972e976. [26] Atanaskovic-Markovic M, Gaeta F, Medjo B, Viola M, Nestorovic B, Romano A. Tolerability of meropenem in children with IgE-mediated hypersensitivity to penicillins. Allergy. 2008;63:237e240. [27] Atanaskowvic-Markovic M, Gaeta F, Gavrovic-Jankulovic M, Velickovic TC, Valluzzi RL, Romano A. Tolerability of imipenem in children with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2009;124:167e169. [28] Blumenthal KG, Shenoy ES, Varughese CA, Hurwitz S, Hooper DC, Banerji A. Impact of a clinical prescribing guideline for prescribing antibiotics to inpatients reporting penicillin or cephalosporin allergy. Ann Allergy Asthma Immunol. 2015;115:294e300. [29] Adkinson N, Saxon A, Spence M, Swabb E. Cross-allergenicity and immunogenicity of aztreonam. Rev Infect Dis. 1985;(suppl 4):S613eS621. [30] Adkinson N. Immunogenicity and cross-allergenicity of aztreonam. Am J Med. 1990;88(suppl 3C):S3eS14. [31] Saxon A, Hassner A, Swabb E, Wheeler B, Adkinson N. Lack of cross-reactivity between aztreonam, a monobactam antibiotic, and penicillin in penicillinallergic subjects. J Infect Dis. 1984;149:16e22. [32] Saxon A, Swabb E, Adkinson N. Investigation into the immunologic crossreactivity of aztreonam with other beta-lactam antibiotics. Am J Med. 1985; 78:19e26. [33] Vega J, Blanca M, Garcia J, et al. Tolerance to aztreonam in patients allergic to beta lactam antibiotics. Allergy. 1991;46:196e202. [34] Moss R. Sensitization to aztreonam and cross-reactivity with other betalactam antibiotics in high-risk patients with cystic fibrosis. J Allergy Clin Immunol. 1991;87:78e88. [35] Chang F, Peacock J, Musher D, et al. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine. 2003;82:333e339. [36] Gonzalez C, Rubio M, Romero-Vivas J, Gonzalez M, Picazo J. Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms. Clin Infect Dis. 1999;29:1171e1177. [37] Fowler V, Kong L, Corey R, et al. Recurrent Staphylococcus aureus bacteremia: pulsed-field gel electrophoresis findings in 29 patients. J Infect Dis. 1999;179: 1157e1161. [38] Abbo L, Beekmann S, Hooton T, Johannsson B, Polgreen P. Management of antimicrobial allergies by infectious diseases physicians. JAMA. 2013;173: 1376e1378. [39] Lee C, Zembower T, Fotis M, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med. 2000;160:2819e2822. [40] Fridkin S, Baggs J, Fagan R, et al. Vital signs: improving antibiotic use among hospitalized patients. MMWR Morb Mortal Wkly Rep. 2014;63:194e200.