- Email: [email protected]
A Streamlined Approach to Optimize Perioperative Antibiotic Prophylaxis in the Setting of Penicillin Allergy Labels
Journal Pre-proof A streamlined approach to optimize perioperative antibiotic prophylaxis in the setting of penicillin allergy labels Merin Kuruvilla, MD, Mary Elizabeth Sexton, MD, MSc, Zanthia Wiley, MD, Terry Langfitt, MD, Grant C. Lynde, MD, MBA, Francis Wolf, MD PII:
S2213-2198(19)31050-5
DOI:
https://doi.org/10.1016/j.jaip.2019.12.016
Reference:
JAIP 2604
To appear in:
The Journal of Allergy and Clinical Immunology: In Practice
Received Date: 1 September 2019 Revised Date:
6 December 2019
Accepted Date: 10 December 2019
Please cite this article as: Kuruvilla M, Sexton ME, Wiley Z, Langfitt T, Lynde GC, Wolf F, A streamlined approach to optimize perioperative antibiotic prophylaxis in the setting of penicillin allergy labels, The Journal of Allergy and Clinical Immunology: In Practice (2020), doi: https://doi.org/10.1016/ j.jaip.2019.12.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology
1
Title: A streamlined approach to optimize perioperative antibiotic prophylaxis in the setting of
2
penicillin allergy labels
3
Authors: Merin Kuruvilla MD1, Mary Elizabeth Sexton MD, MSc 2, Zanthia Wiley MD 2, Terry Langfitt MD3,
4
Grant C Lynde MD, MBA 3, Francis Wolf MD 3
5
Affiliations:
6
1 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, 2 Division of Infectious Diseases,
7
3Department of Anesthesiology; Emory University School of Medicine, Atlanta, GA, USA
8
Corresponding author:
9
Merin Kuruvilla
10
1605 Chantilly Dr NE
11
Atlanta, GA-30324
12
Phone: 404-778-3261
13
Fax: 404-778-4431
14
Email: [email protected]
15
Funding: This research received no specific grant from any funding agency in the public, commercial, or
16
not-for-profit sectors. The authors’ academic departments generously supported the authors’ time in
17
producing this work.
18
Conflict of interests: The authors have no conflicts of interest to disclose.
19
20
Abstract (250 words):
21
Background: Patients with penicillin allergy labels often receive alternative antibiotics for peri-operative
22
prophylaxis, as opposed to first-line cephalosporins (cefazolin/cefuroxime). Provider misconceptions
23
about the risk of cross-reactivity likely drive this prescribing behavior, which is problematic because of
24
its association with increased risk of surgical site infections.
25
Objective: To develop, implement, and assess the safety of a streamlined approach to perioperative
26
antibiotic selection for surgical patients with a penicillin allergy label, in order to reduce the use of
27
second-line antibiotics.
28
Methods: A multidisciplinary task force developed an institutional algorithm for antibiotic selection in
29
penicillin-allergic surgical patients. The percentage of patients receiving a first-line cephalosporin was
30
compared before and after algorithm utilization. The safety of this approach was assessed via chart
31
review of all patients who received epinephrine or diphenhydramine in the operating room, or
32
diphenhydramine within twenty-four hours post-operatively, assessing for any adverse reactions to
33
cephalosporin administration.
34
Results: Between September 2016 and May 2019, 9.3% of surgical patients had documented penicillin
35
allergy (n=2296). At baseline, 22% of these patients received a cephalosporin, with an increase to >80%
36
following algorithm implementation (p<0.0001). Among 551 patients with penicillin allergy label who
37
received a cephalosporin following algorithm implementation, no immediate allergic reactions requiring
38
epinephrine were identified; one patient had a delayed rash that did not require cephalosporin
39
discontinuation. Three patients received diphenhydramine for "itching" without rash in the setting of
40
concomitant narcotic administration.
41
Conclusion: Using a streamlined algorithm, we were able to significantly reduce the use of second-line
42
antibiotics in penicillin-allergic surgical patients without severe adverse reactions.
43
Highlights:
44
1. What is already known about this topic? Use of second line antibiotics for peri-operative prophylaxis
45
is associated with increased risk of surgical site infections and other complications.
46
2. What does this article add to our knowledge? The use of second-line antibiotics for surgical
47
prophylaxis in patients with penicillin allergy labels can be reduced with a simplified approach.
48
3. How does this study impact current management guidelines? Current guidelines for perioperative
49
antibiotics in the United States continue to recommend alternative second line antimicrobial therapy in
50
the presence of type 1 hypersensitivity to penicillins – we report that most patients with a penicillin
51
allergy label can safely receive cefazolin and cefuroxime in this setting.
52
Key words: penicillin allergy, prophylactic antibiotics, cross-reactivity
53
Abbreviations: SSI – surgical site infection; SCAR – severe cutaneous adverse reaction; MRSA –
54
methicillin-resistant Staphylococcus aureus
55
Word count: 3625
56
Introduction
57
The timely administration of perioperative antibiotics plays an important role in reducing the risk of
58
surgical site infections (SSIs) 1. Clinical practice guidelines recommend cefazolin as the primary
59
prophylactic agent for most surgical cases 1 in the United States, with use of broader-spectrum
60
cephalosporins like cefuroxime potentially indicated in a smaller number of subspecialty cases 2.
61
However, due to concerns about cross-reactivity, these first-line agents for surgical prophylaxis may be
62
withheld in patients with a reported penicillin allergy, 3-5, and subsequent utilization of second-line
63
antibiotics has been shown to increase the risk of SSI 3,6-12.
64
This use of second-line antibiotics in patients with a documented penicillin allergy is often driven by
65
historical misconceptions concerning both the true incidence of penicillin allergies and the likelihood of
66
cross reactivity between penicillins and cephalosporins 13,14. While up to 15% of hospitalized patients
67
have a listed penicillin allergy 15, recent studies have found that only 1-10% of patients with self-
68
reported penicillin allergy are truly allergic 16-18. Furthermore, while the risk of cephalosporin allergy is
69
higher in the setting of a penicillin allergy label 14, the rate of clinically significant cross-reactivity is
70
significantly lower than previously thought and now estimated at 2-5% 19.
71
While the shared beta-lactam ring was previously assumed to be the mechanism for cross-reactivity
72
between penicillins and cephalosporins, it is now known that the allergenic determinants of
73
cephalosporins instead derive largely from the R1-group side chains, and to a lesser degree the R2 side
74
chains 13,20-22. This recognition has led to the recommendation that patients with a penicillin allergy may
75
receive a cephalosporin that lacks R1 side chain similarity even in the setting of confirmed penicillin-
76
induced anaphylaxis22. Avoidance of all beta-lactams is still recommended in patients with a history of
77
severe delayed reactions, including severe cutaneous adverse reactions (SCARs) and organ-specific
78
injuries such as hepatitis, nephritis, serum sickness, and hemolytic anemia, due to unpredictable cross-
79
reactivity in this setting 22,23. Cefazolin and cefuroxime, in particular, are recognized as having unique R1
80
and R2 side chains that are distinct from other cephalosporins and beta-lactam antibiotics 22. Based on
81
very limited data, there is no evidence of increased allergy risk with cefazolin in patients with
82
anaphylactic 24 or non-anaphylactic 25 penicillin allergy. Conversely, IgE-mediated cefazolin allergy
83
appears to be selective, with tolerance of other beta-lactams 24.
84
Despite this safety data, albeit limited, published antibiotic selection recommendations continue to
85
advise against utilizing beta-lactam antibiotics in surgical patients with moderate-to-severe penicillin
86
allergies without either graded provocation testing or referral to an allergy clinic for skin testing and
87
penicillin allergy de-labelling 22,23,26-30. However, these recommendations may be impractical in the
88
immediate perioperative period. Patients often present to the hospital on the day of surgery, with
89
allergy history often discussed immediately prior to administration of anesthesia and antibiotic
90
prophylaxis. As a result, both graded challenge administration and skin testing would likely produce
91
significant surgical case delays. We therefore developed a streamlined approach for evaluation of
92
penicillin allergy in preoperative patients, to allow for safe administration of prophylactic cephalosporins
93
without additional testing.
94 95 96 97 98 99 100
101 102
Methods
103
Human subjects: The Emory Institutional Review Board granted approval (IRB00095280) for this study as
104
part of a larger body of work to improve on-time perioperative antibiotic administration throughout the
105
healthcare system.
106
Setting: A working group of physicians from Anesthesiology, Surgery, Infectious Diseases, and
107
Allergy/Immunology as well as hospital pharmacists was established at a large academic medical center
108
in the southeastern United States to evaluate surgical prophylaxis selection in penicillin-allergic
109
perioperative patients. Perioperative antibiotic selection is guided by an institutional protocol, in which
110
cefazolin is recommended for the majority of cases where prophylaxis is indicated, and cefuroxime is
111
utilized in cardiothoracic surgical procedures with a mediastinal incision. Additional agents are added
112
for coverage of anaerobic and/or gram-negative organisms when indicated, and vancomycin is added in
113
patients at increased risk for methicillin-resistant Staphylococcus aureus (MRSA) infection. Prior to our
114
intervention, the protocol recommended using an alternative to cephalosporins (most commonly
115
vancomycin or clindamycin) in patients with the following reactions to penicillin: hives or rash,
116
angioedema, bronchospasm, or anaphylaxis, in addition to severe delayed hypersensitivity reactions.
117
Perioperative antibiotics were historically ordered by the surgical team; however, in an effort to
118
standardize practice, the primary anesthesia team assumed responsibility for ordering and administering
119
antibiotics in October 2017.
120
Protocol development: We undertook a literature review and subsequently constructed an algorithm to
121
guide the administration of perioperative prophylactic antibiotics in penicillin-allergic patients. We
122
focused on giving providers direction on when it is safe to prescribe the two most commonly-used
123
cephalosporins, cefazolin and cefuroxime. Given the safety data discussed above 22-25 and overall low
124
baseline likelihood of reactivity to penicillins and cephalosporins, the resultant algorithm recommended
125
administering cefazolin or cefuroxime as first-line agents in all patients with a history of allergy to
126
penicillin, except for those with a history of severe delayed hypersensitivity reactions (see Figure 1).
127
Patients with a history of unknown reactions in childhood, rash, or episodes suggestive of IgE-mediated
128
hypersensitivity reactions (including anaphylaxis) to penicillin were recommended to receive cefazolin or
129
cefuroxime according to the algorithm. Beta-lactam agents were avoided in patients with a history of
130
severe cutaneous adverse reaction (SCAR) or organ-specific injury (e.g. hepatitis, nephritis) due to the
131
uncertain mechanism and severe nature of these reactions. Patient screening questions were
132
formulated to help providers in the perioperative anesthesia clinic assess patients for a history of severe
133
delayed hypersensitivity reactions (see Figure 2). Algorithm implementation was accompanied by a
134
series of educational interventions starting in August 2018, incorporation of the algorithm into written
135
perioperative protocols, and electronic distribution of the algorithm.
136
Data collection and analysis: We queried our institutional Clinical Data Warehouse to identify all
137
patients who had a surgical procedure from 9/1/2016-5/31/2019. Patients were excluded from analysis
138
if they had a surgical procedure for which perioperative antibiotics were not indicated or if a
139
cephalosporin was not the recommended first-line agent. For all remaining patients, the following
140
additional data were abstracted: antibiotics administered perioperatively; presence or absence of a
141
documented allergy to penicillin or its derivatives; any administration of epinephrine in the operating
142
room; and any administration of diphenhydramine either intraoperatively or in the twenty-four hours
143
postoperatively.
144
For patients with a documented penicillin allergy, chart review was performed to identify the allergy
145
type. Based on the comments entered in the electronic medical record allergy history, allergies were
146
classified as: (a) not documented (if the allergy was listed without any explanation); (b) unknown (e.g.
147
“patient does not recall” or “childhood reaction”); (c) side effect (e.g. headache, diarrhea); (d) rash
148
and/or itching; (e) type I hypersensitivity reaction (e.g. urticaria, angioedema, bronchospasm, or
149
anaphylaxis); or (f) severe delayed hypersensitivity reaction (e.g. organ dysfunction, drug fever, skin
150
blistering, mucosal involvement). We calculated the percentage of surgical patients with a penicillin
151
allergy, as well as the proportion of each allergy type present within the group of penicillin-allergic
152
patients. We then compared the percentage of penicillin-allergic patients who received a cephalosporin
153
before (9/1/2016-8/31/2018) and after (9/1/2018-5/31/2019) algorithm implementation.
154
Patients with a documented penicillin allergy who received a cephalosporin were then assessed for any
155
resultant allergic reactions, using epinephrine administration at the time of surgery as a surrogate for a
156
life-threatening acute reaction and diphenhydramine administration both during surgery and in the
157
twenty-four hours post-operatively as a potential marker for more delayed reactions. Chart reviews
158
were performed on all patients who received epinephrine or diphenhydramine to determine the reason
159
for medication administration. The medication order, the medication administration record, the
160
anesthesia record, the operative report, nursing notes, and daily progress notes were evaluated as
161
necessary to identify whether either epinephrine or diphenhydramine had been given in response to an
162
allergic reaction. Of note, using epinephrine administration as a marker of anaphylaxis may still miss
163
some reactions, as vasopressors other than epinephrine are often given, depending upon institutional
164
practice.
165
Statistical analysis: Statistical comparisons were performed using chi-square testing (p<0.05 significance
166
level) using OpenEpi: Open Source Epidemiologic Statistics for Public Health, Version 3.01.
167 168
169
Results
170 171
Penicillin allergy prevalence and documentation
172
The overall prevalence of documented penicillin allergy among surgical cases that required
173
perioperative antibiotics was 9.3% (2296/24,629). This included 1608 of 17,376 cases (9.3%) prior to
174
implementation of the algorithm, and 688 of 7253 cases (9.5%) post-algorithm. Of the 2296 cases
175
involving a patient with a penicillin allergy label, 880 (38.3%) did not have a penicillin reaction type
176
documented in the chart, 118 (5.1%) had an unknown reaction to penicillin, 168 (7.3%) had a side effect
177
rather than an allergy, 487 (21.2%) had rash and/or itching, 623 (27.1%) had a type I hypersensitivity
178
reaction, and 20 (0.9%) had a label consistent with a severe delayed hypersensitivity reaction (see Figure
179
3).
180 181 182
Cephalosporin utilization pre- and post-algorithm implementation
183
Prior to algorithm implementation, a perioperative cephalosporin was administered in 22.3% of cases
184
involving a penicillin-allergic patient. This included 43% of cases with documentation suggesting a side
185
effect rather than true allergy, 38% of cases suggestive of a severe delayed hypersensitivity reaction,
186
29% of cases with an unknown reaction, 24% of cases with rash/itching, 22% of cases where the allergy
187
was not documented, and 14% of cases with a type I hypersensitivity reaction (see Figure 4).
188
Following algorithm implementation, cephalosporin administration increased to 80.1% of cases involving
189
a patient with a penicillin allergy (p<0.0000001). Administration rose to >80% of cases with
190
undocumented reactions, unknown reactions, side effects, and rash/itching, and to 73% in cases with a
191
type I hypersensitivity reaction (see Figure 4); 43% of cases where the patient had documentation
192
suggestive of severe delayed hypersensitivity reaction history received a cephalosporin.
193 194 195
Adverse reactions
196
Following algorithm implementation, 21 penicillin-allergic patients received a cephalosporin and were
197
given epinephrine in the operating room. None of these epinephrine administrations was documented
198
as the result of an allergic reaction, nor was the administration of epinephrine temporally correlated
199
(within 60 minutes) with cefazolin use in 20 of 21 subjects. The last patient received epinephrine for
200
hemorrhagic shock 45 minutes following cefazolin administration. The majority (18 of 21 cases) involved
201
the use of epinephrine as one of multiple blood pressure support medications in patients who were
202
hemodynamically unstable as a result of underlying comorbidities or surgical factors. There were three
203
cases in which epinephrine was given in patients who appeared at risk for imminent cardiac arrest; two
204
of these were bradycardic responses to anesthesia that started prior to antibiotic administration and
205
one was determined to be the result of intravascular air.
206
Twenty-two penicillin-allergic patients who received a cephalosporin following algorithm
207
implementation also had diphenhydramine administered within twenty-four hours post-operatively.
208
The majority of these patients received diphenhydramine for nausea/vomiting or insomnia, or did not
209
have an indication documented and had no mention of allergic symptoms in the medical record. One
210
patient had a documented rash which resolved despite continuation of a cephalosporin (cefepime), and
211
four patients complained of itching without a rash; in these cases, there were alternative explanations
212
for pruritus including narcotic administration and a surgical tape reaction. Thus, of 551 penicillin-allergic
213
patients who received a cephalosporin following algorithm implementation, 0.18% developed a rash and
214
0.9% complained of either rash or itching not felt to be attributable to the cephalosporin. Another
215
patient noted facial and chest flushing over twenty-four hours after the last cephalosporin
216
administration (while also receiving vancomycin), and one patient noted wheezing that was attributed
217
to underlying asthma. An additional patient complained of post-operative shortness of breath,
218
experienced hypotension and bradycardia, and then had seizure-like activity. The symptoms developed
219
approximately five hours after cefazolin administration and resolved without administration of any
220
medications for a potential allergy.
221
Discussion:
222
We describe a streamlined approach to safely increase the use of cephalosporins for perioperative
223
antimicrobial prophylaxis in patients with penicillin allergy labels, including those with a history of
224
anaphylaxis. Risk stratification was based on the exclusion of patients with a history of severe delayed
225
hypersensitivity reactions to penicillin (or another beta-lactam) due to unknown risks with re-challenge.
226
Our allergy history-driven algorithm combined with recommended screening questions significantly
227
augmented cefazolin and cefuroxime administration. Over the course of nine months, use of second-line
228
antibiotics among surgical cases involving patients with a penicillin allergy decreased from 77.7% to
229
19.9%, with no reported immediate adverse reactions and one delayed rash (<0.2% of patients) in an
230
initial safety assessment of 551 patients with purported penicillin allergy who received a perioperative
231
cephalosporin.
232
Our findings regarding change in antibiotic selection align with previous studies of perioperative allergy
233
assessment programs, which have been shown to enhance beta-lactam uptake. For example, Vaisman et
234
al demonstrated that simply taking a structured penicillin allergy history increased safe perioperative
235
beta-lactam prescribing from 18% to 57%, despite the exclusion of those with IgE-mediated allergy 26. A
236
more thorough approach including application of preoperative penicillin skin testing was associated with
237
a 90% rate of perioperative beta-lactam use 18. Reilly and colleagues reported on outcomes with
238
incorporation of penicillin allergy testing into preoperative evaluation in a recent meta-analysis 31. This
239
measure was found to significantly decrease rates of non-beta-lactam antibiotic prescriptions without
240
adverse reactions. However, it is presently untenable to address comprehensive beta-lactam allergy de-
241
labeling preoperatively in most circumstances, due to the large numbers of patients affected and non-
242
availability of skin testing/oral challenge in many institutions.
243
The safety of our approach is well founded. While early reports suggested 10% cross-reactivity between
244
penicillins and cephalosporins, this data has subsequently been refuted, with current estimates of 2-5%
245
13,22
246
and R2 side chains 13,20-22. Both immediate and non-immediate reactions to cephalosporins appear to be
247
attributable to the side-chain structures of these drugs. The recognition of these cross-reactivity
248
mechanisms has led to the suggestion that patients with a penicillin allergy label may receive
249
cephalosporins that do not share R1 side chain similarity with penicillins, as long as they do not have a
250
history of a severe delayed reaction, including a SCAR 22,27. A recent meta-analysis quantified similarity
251
between R1 side chains of cephalosporins and penicillins based on physicochemical and structural
252
properties, and the authors confirmed a significant association between the R1 side chain similarity
253
score and risk of cross-reactivity in studies involving subjects with confirmed penicillin allergy. Both
254
cefazolin and cefuroxime have R1 side chains with low similarity scores and thus run a very low risk of
255
cross-reaction, regardless of whether PCN allergy is IgE or T cell mediated 32. Accumulating data supports
256
their tolerance in penicillin-allergic populations. However, this data derives mostly from retrospective
257
cohorts that are liable to selection bias. There was only one isolated adverse reaction to cefazolin in one
258
review of 300 penicillin-allergic patients 33, and none in another cohort of 54 subjects with benign rashes
259
documented as their penicillin allergy 34. Similarly, in a cohort of 513 penicillin-allergic surgical patients,
260
there were zero cases of anaphylaxis among those who received 153 courses of cefazolin or cefoxitin.
261
Ironically, there was a higher incidence of adverse events with the use of clindamycin or ciprofloxacin as
262
alternative agents 35. Cefuroxime shares a comparable safety profile 36,37. In our cohort, we similarly
263
observed no cases of anaphylaxis, one rash (0.18% of cases), and four complaints of itching with
264
potential alternate explanations (0.73% of cases), which adds support to the safety of this approach.
265
While recent guidelines have recommended to cephalosporin skin testing and incremental challenge in
266
patients with confirmed IgE-mediated penicillin allergy 29, the risk of cross-reactivity is highest with
, given the new understanding that the allergenic determinants of cephalosporins derive from the R1
267
aminocephalosporins. In a cohort of 128 subjects with immediate onset penicillin allergy, 14 (10.9%) had
268
positive skin tests to cephalosporins 38, mostly to cephalothin and cefamandole. When these ST positive
269
patients as well as the remainder of the cohort (n = 101) underwent challenges with cefuroxime and
270
ceftriaxone, there were no reactors. In a larger cohort of 252 subjects with a history of anaphylaxis from
271
penicillin with positive penicillin skin tests, 99 participants (39.3%) also had positive cephalosporin skin
272
tests. Of these positive tests, 95 were to aminocephalosporins, and only 4 to cephalosporins with
273
dissimilar side chains. These positive skin tests were attributed to concomitant sensitization as opposed
274
to true cross-reactivity. Further, they were not confirmed by oral challenge and have unclear clinical
275
relevance given the unproven predictive value of cephalosporin skin testing 21. Of note, cefazolin was
276
not used for skin testing or oral challenge in the study population. Similarly, among 213 adults with T-
277
cell mediated penicillin hypersensitivity 39, cross-reactivity defined by skin testing and challenges was
278
confined almost exclusively between aminopenicillins and aminocephalosporins. Again, in a cohort of
279
175 individuals with self-reported penicillin allergy who received cefepime, ceftriaxone, cephalexin, or
280
cefoxitin in a hospital setting, allergic reactions were observed only with cefepime and cefoxitin further
281
confirming the concept of side chain cross reactivity 40.
282
These studies even run the risk of overestimating cross reactivity since the positive predictive value of
283
cephalosporin ST could not be evaluated. The pitfalls of cephalosporin skin testing were highlighted in a
284
study of 1421 patients without known β-lactam allergy requiring perioperative cephalosporin
285
prophylaxis 41. Subjects were tested to five different cephalosporins, with a 5% sensitization rate to at
286
least one cephalosporin. However, only 0.3% of patients had an immediate hypersensitivity reaction and
287
none of these reactors had been skin test positive. Thus, cephalosporin skin testing demonstrated 0%
288
sensitivity in this cohort.
289
Despite accumulating safety data, guidelines for perioperative antibiotics in the United States continue
290
to recommend alternative second line antimicrobial therapy in the presence of type 1 hypersensitivity to
291
penicillins 1. This is reflected in the various algorithms that have been generated to optimize the
292
perioperative management of penicillin allergic patients, most of which continue to recommend skin
293
testing in patients with symptoms of IgE/mast cell sensitization including anaphylaxis 26-30. When skin
294
testing is not able to be performed -- which would be common in a perioperative setting secondary to
295
time constraints -- many of these algorithms call for the use of alternative agents, which have been
296
associated with increased rates of SSI 3,6-12.
297
Of note, we intended for our algorithm to avoid administration of cephalosporins in patients with a
298
history of severe delayed hypersensitivity reaction, and anesthesiologists were instructed to utilize the
299
patient questionnaire as a guide. However, the small number of patients with documentation
300
suggestive of severe delayed hypersensitivity to penicillin received a cephalosporin ~40% of the time
301
before and after the intervention. We suspect this may be secondary to poor allergy documentation in
302
the medical record, rather than to inappropriate cephalosporin administration. For example, any
303
reaction that documented “skin blistering” or “skin peeling” in the medical record was classified as a
304
SCAR, although many of these comments did not include sufficient detail to determine whether a SCAR
305
was truly present. It is possible that upon questioning by the anesthesiologist, it was evident that the
306
reaction did not meet SCAR criteria. The small number of patients with severe delayed hypersensitivity
307
reaction makes these results more difficult to interpret; however, ongoing education may be needed.
308
The major limitation of our study is that most of the penicillin allergy labels were likely erroneous. Our
309
study does not necessarily confirm the safety of cefazolin (or cefuroxime) in truly penicillin allergic
310
patients, but rather the low baseline likelihood of reactivity to cephalosporins in our cohort. Our study
311
does not endorse the broad administration of all cephalosporins in all comers with penicillin allergy, but
312
rather the selective administration of cefazolin/cefuroxime in subjects without severe reactions. We
313
attempted to document in the medical record that the patient had tolerated cefazolin but continue to
314
evaluate the best way to communicate the information to the patient so that there is not an assumption
315
by them or other providers that any cephalosporin is safe, since cefazolin’s structure is so unique.
316
Ongoing work is need to evaluate communication with the patient and non-allergy providers about what
317
is and is not safe following uneventful cefazolin administration.
318
Also, patients were more likely to receive cefazolin in the setting of unknown reaction/rash with
319
penicillin and 27% of those labelled as type I hypersensitivity reactions were not given a cephalosporin,
320
reflecting possible selection bias in those with a more suggestive history. Another limitation was that
321
our focus was limited to intraoperative cefazolin/cefuroxime use in patients with a listed penicillin
322
allergy. It did not address other beta-lactam allergies, and did not tackle the larger issue of erroneous
323
penicillin allergy de-labeling in the context of antimicrobial stewardship. Our objective was to increase
324
utilization of first-line perioperative antibiotics with associated potential for reduced rates of SSIs, and to
325
decrease rates of complications associated with common alternative antibiotic agents. However,
326
tolerance of cefazolin does not confer penicillin allergy resolution. Thus, outpatient allergy referral for
327
investigation of the primary penicillin allergy on discharge can still have utility. While comprehensive
328
penicillin allergy evaluation and de-listing could have additional benefits, our algorithm provides a
329
valuable practical strategy for the perioperative setting, in which a more extensive workup may not
330
feasible.
331
In addition, while cefazolin is the drug of choice for perioperative prophylaxis in the United States,
332
clinical practice varies around the world. Our algorithm was developed for healthcare facilities where
333
cefazolin is used as the first-line agent for surgical prophylaxis, and may not be suitable for institutions
334
that utilize a penicillin as first-line agent. ~3% of patients administered a third-generation or higher
335
cephalosporin develop Clostridium difficile in 90 days14. Thus, penicillins are first line agents in many
336
countries. In those cases, the algorithm would not help to evaluate safety of first-line antibiotic use in an
337
allergic patient, but does offer a way to evaluate a second-line alternative other than vancomycin.
338
Conclusion: We present a streamlined algorithm for the perioperative administration of antibiotics in
339
patients with a penicillin allergy label, based on a brief bedside assessment to assess for history of a
340
severe delayed hypersensitivity reaction to confirm appropriateness of cefazolin or cefuroxime. Our
341
initial results suggest that implementation of this algorithm can increase perioperative cephalosporin
342
utilization without significant risk of adverse reactions.
343
Acknowledgements:
344
The authors would like to thank Lisa Cogdill, Addison Jones, and Sun Choi for performing the Emory
345
Clinical Data Warehouse data search. We would also like to thank the Emory University School of
346
Medicine Department of Anesthesiology, Division of Allergy and Immunology, and Division of Infectious
347
Diseases for their support of the authors’ time in instituting the protocol.
348
References
349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391
1. 2.
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13. 14.
Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195-283. Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg. 2012;143(1):4-34. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The Impact of a Reported Penicillin Allergy on Surgical Site Infection Risk. Clin Infect Dis. 2018;66(3):329-336. Jain P, Fabbro M, 2nd. ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation: A Review of the 2017 Document for the Cardiac Anesthesiologist. J Cardiothorac Vasc Anesth. 2019;33(2):274-289. Pichichero ME. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics. 2005;115(4):1048-1057. Robertsson O, Thompson O, A WD, Sundberg M, Lidgren L, Stefansdottir A. Higher risk of revision for infection using systemic clindamycin prophylaxis than with cloxacillin. Acta Orthop. 2017;88(5):562-567. Kheir MM, Tan TL, Azboy I, Tan DD, Parvizi J. Vancomycin Prophylaxis for Total Joint Arthroplasty: Incorrectly Dosed and Has a Higher Rate of Periprosthetic Infection Than Cefazolin. Clin Orthop Relat Res. 2017;475(7):1767-1774. Ponce B, Raines BT, Reed RD, Vick C, Richman J, Hawn M. Surgical Site Infection After Arthroplasty: Comparative Effectiveness of Prophylactic Antibiotics: Do Surgical Care Improvement Project Guidelines Need to Be Updated? J Bone Joint Surg Am. 2014;96(12):970977. Bull AL, Worth LJ, Richards MJ. Impact of vancomycin surgical antibiotic prophylaxis on the development of methicillin-sensitive staphylococcus aureus surgical site infections: report from Australian Surveillance Data (VICNISS). Ann Surg. 2012;256(6):1089-1092. Murphy J, Isaiah A, Dyalram D, Lubek JE. Surgical Site Infections in Patients Receiving Osteomyocutaneous Free Flaps to the Head and Neck. Does Choice of Antibiotic Prophylaxis Matter? J Oral Maxillofac Surg. 2017;75(10):2223-2229. Uppal S, Harris J, Al-Niaimi A, Swenson CW, Pearlman MD, Reynolds RK, et al. Prophylactic Antibiotic Choice and Risk of Surgical Site Infection After Hysterectomy. Obstet Gynecol. 2016;127(2):321-329. Wyles CC, Hevesi M, Osmon DR, Park MA, Habermann EB, Lewallen DG, et al. 2019 John Charnley Award: Increased risk of prosthetic joint infection following primary total knee and hip arthroplasty with the use of alternative antibiotics to cefazolin: the value of allergy testing for antibiotic prophylaxis. Bone Joint J. 2019;101-B(6_Supple_B):9-15. Pichichero ME, Zagursky R. Penicillin and cephalosporin allergy. Ann Allergy Asthma Immunol. 2014;112(5):404-412. Macy E, Contreras R. Adverse reactions associated with oral and parenteral use of cephalosporins: A retrospective population-based analysis. J Allergy Clin Immunol. 2015;135(3):745-752 e745.
392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439
15.
16. 17. 18.
19. 20.
21.
22. 23. 24.
25.
26.
27. 28.
29.
30.
31.
32.
Lee CE, Zembower TR, Fotis MA, Postelnick MJ, Greenberger PA, Peterson LR, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med. 2000;160(18):2819-2822. Macy E, Ngor EW. Safely diagnosing clinically significant penicillin allergy using only penicilloylpoly-lysine, penicillin, and oral amoxicillin. J Allergy Clin Immunol Pract. 2013;1(3):258-263. Macy E. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Curr Allergy Asthma Rep. 2014;14(11):476. McDanel DL, Azar AE, Dowden AM, Murray-Bainer S, Noiseux NO, Willenborg M et al. Screening for Beta-Lactam Allergy in Joint Arthroplasty Patients to Improve Surgical Prophylaxis Practice. J Arthroplasty. 2017;32(9S):S101-S108. Macy E, Blumenthal KG. Are Cephalosporins Safe for Use in Penicillin Allergy without Prior Allergy Evaluation? J Allergy Clin Immunol Pract. 2018;6(1):82-89. Antunez C, Blanca-Lopez N, Torres MJ, Mayorga C, Perez-Inestrosa E, Montañez MI, et al. Immediate allergic reactions to cephalosporins: evaluation of cross-reactivity with a panel of penicillins and cephalosporins. J Allergy Clin Immunol. 2006;117(2):404-410. Romano A, Valluzzi RL, Caruso C, Maggioletti M, Quaratino D, Gaeta F. Cross-Reactivity and Tolerability of Cephalosporins in Patients with IgE-Mediated Hypersensitivity to Penicillins. J Allergy Clin Immunol Pract. 2018;6(5):1662-1672. Zagursky RJ, Pichichero ME. Cross-reactivity in beta-Lactam Allergy. J Allergy Clin Immunol Pract. 2018;6(1):72-81 e71. Macy E, Romano A, Khan D. Practical Management of Antibiotic Hypersensitivity in 2017. J Allergy Clin Immunol Pract. 2017;5(3):577-586. Uyttebroek AP, Decuyper, II, Bridts CH, Romano A, Hagendorens MM, Ebo DG, et al. Cefazolin Hypersensitivity: Toward Optimized Diagnosis. J Allergy Clin Immunol Pract. 2016;4(6):12321236. Blumenthal KG, Youngster I, Shenoy ES, Banerji A, Nelson SB. Tolerability of cefazolin after immune-mediated hypersensitivity reactions to nafcillin in the outpatient setting. Antimicrob Agents Chemother. 2014;58(6):3137-3143. Vaisman A, McCready J, Hicks S, Powis J. Optimizing preoperative prophylaxis in patients with reported beta-lactam allergy: a novel extension of antimicrobial stewardship. J Antimicrob Chemother. 2017;72(9):2657-2660. Vorobeichik L, Weber EA, Tarshis J. Misconceptions Surrounding Penicillin Allergy: Implications for Anesthesiologists. Anesth Analg. 2018;127(3):642-649. Moussa Y, Shuster J, Matte G, Sullivan A, Goldstein RH, Cunningham D, et al. De-labeling of betalactam allergy reduces intraoperative time and optimizes choice in antibiotic prophylaxis. Surgery. 2018. Savic LC, Khan DA, Kopac P, Clarke RC, Cooke PJ, Dewachter P, et al. Management of a surgical patient with a label of penicillin allergy: narrative review and consensus recommendations. Br J Anaesth. 2019;123(1):e82-e94. Hermanides J, Lemkes BA, Prins JM, Hollmann MW, Terreehorst I. Presumed beta-Lactam Allergy and Cross-reactivity in the Operating Theater: A Practical Approach. Anesthesiology. 2018;129(2):335-342. Reilly CA, Backer G, Basta D, Riblet NBV, Hofley PM, Gallagher MC. The effect of preoperative penicillin allergy testing on perioperative non-beta-lactam antibiotic use: A systematic review and meta-analysis. Allergy Asthma Proc. 2018;39(6):420-429. Picard M, Robitaille G, Karam F, Daigle JM, Bédard F, Biron É, et al. Cross-Reactivity to Cephalosporins and Carbapenems in Penicillin-Allergic Patients: Two Systematic Reviews and Meta-Analyses. J Allergy Clin Immunol Pract. 2019.
440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467
33.
34.
35.
36.
37. 38.
39.
40.
41.
Goodman EJ, Morgan MJ, Johnson PA, Nichols BA, Denk N, Gold BB. Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic response. J Clin Anesth. 2001;13(8):561-564. Haslam S, Yen D, Dvirnik N, Engen D. Cefazolin use in patients who report a non-IgE mediated penicillin allergy: a retrospective look at adverse reactions in arthroplasty. Iowa Orthop J. 2012;32:100-103. Beltran RJ, Kako H, Chovanec T, Ramesh A, Bissonnette B, Tobias JD. Penicillin allergy and surgical prophylaxis: Cephalosporin cross-reactivity risk in a pediatric tertiary care center. J Pediatr Surg. 2015;50(5):856-859. Caimmi S, Galera C, Bousquet-Rouanet L, Arnoux B, Demoly P, Bousquet PJ. Safety of cefuroxime as an alternative in patients with a proven hypersensitivity to penicillins: a DAHD cohort survey. Int Arch Allergy Immunol. 2010;153(1):53-60. Promelle V, Jany B, Drimbea A, Jezraoui P, Milazzo S. Tolerability of intracameral cefuroxime during cataract surgery in case of penicillin allergy. J Fr Ophtalmol. 2015;38(4):283-287. Romano A, Gueant-Rodriguez RM, Viola M, Pettinato R, Gueant JL. Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins. Ann Intern Med. 2004;141(1):16-22. Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Caruso C, Quaratino D. Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2016;138(1):179-186. Crotty DJ, Chen XJ, Scipione MR, Dubrovskaya Y, Louie E, Ladapo JA, et al. Allergic Reactions in Hospitalized Patients With a Self-Reported Penicillin Allergy Who Receive a Cephalosporin or Meropenem. J Pharm Pract. 2017;30(1):42-48. Yoon SY, Park SY, Kim S, Lee T, Lee YS, Kwon HS, et al. Validation of the cephalosporin intradermal skin test for predicting immediate hypersensitivity: a prospective study with drug challenge. Allergy. 2013;68(7):938-944.
468
Figures
469
Figure 1. Perioperative Penicillin Allergy Algorithm
470
Institutional algorithm for cefazolin/cefuroxime use in in patients with reported allergy to penicillin. In
471
the absence of a severe, delayed reaction, patients with a penicillin allergy can receive cefazolin and
472
cefuroxime.
473
Figure 2. Penicillin Allergy Evaluation Questionnaire
474
Suggested questions to assess for a history of a severe delayed hypersensitivity reaction to penicillin as
475
part an allergy evaluation. If the patient answers yes to any of the above items or there is
476
documentation of any of these reactions in the chart, all beta lactam antibiotics (including perioperative
477
cephalosporins) should be avoided. If none of the above are checked, cefazolin is expected to be safe in
478
the patient.
479
Figure 3. Penicillin Allergy Type Breakdown
480
Allergy types among surgical patients with a reported penicillin allergy. The percentage of surgical cases
481
with each type of reaction documented in the electronic medical record is shown.
482
Figure 4. Cephalosporin Utilization by Documented Allergy Type Pre- and Post-Intervention
483
The percentage of penicillin-allergic surgical cases receiving a cephalosporin before and after algorithm
484
implementation is shown, stratified by the type of allergic reaction documented in the patient’s medical
485
record.
1
Figure 1. Perioperative Penicillin Allergy Algorithm
2 3
.
1 2
Figure 2. Penicillin Allergy Evaluation Questionnaire Penicillin Allergy Assessment Did you have a severe skin reaction involving blisters on your skin and shedding or detachment of your skin? (SJS/TEN) • Were you told you had Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN)? • Did you have liver injury or hepatitis caused by the medication? • Did you have kidney injury, nephritis or acute renal failure caused by the medication (acute interstitial nephritis)? • Were you told you had hemolytic anemia caused by the medication? (Low hemoglobin or hematocrit or "blood counts" counts caused by penicillin) • Did you have painful swollen joints caused by the medication (serum sickness)? • Were you diagnosed with "drug fever"? (A fever caused by the antibiotic that developed about a week after starting the medication and then went away when you stopped the antibiotic?) • Did you have a severe reaction involving the inside of your mouth, eye, or genital ulcers? •
3 4
Figure 3. Penicillin Allergy Type Breakdown
Figure 3. Penicillin Allergy Type Breakdown
1% 27% 39%
21%
5% 7%
Not Documented
Unknown
Side Effect
Rash/Itching
Type I Hypersensitivity Reaction
Severe Delayed Hypersensitivity Reaction
1 2
Figure 4
Percentage of Cases Receiving a Cephalosporin
Figure 4. Cephalosporin Utilization by Documented Allergy Type Pre- and Post-Intervention 100 90 80 70 60 50 40 30 20 10 0 Reaction Not Documented
Unknown Reaction
Side Effect
Rash/Itching
Documented Allergy Type Pre-Intervention
3 4 5
Post-Intervention
Type I Hypersensitivity Reaction
Severe Delayed Hypersensitivity Reaction
S2213-2198(19)31050-5
DOI:
https://doi.org/10.1016/j.jaip.2019.12.016
Reference:
JAIP 2604
To appear in:
The Journal of Allergy and Clinical Immunology: In Practice
Received Date: 1 September 2019 Revised Date:
6 December 2019
Accepted Date: 10 December 2019
Please cite this article as: Kuruvilla M, Sexton ME, Wiley Z, Langfitt T, Lynde GC, Wolf F, A streamlined approach to optimize perioperative antibiotic prophylaxis in the setting of penicillin allergy labels, The Journal of Allergy and Clinical Immunology: In Practice (2020), doi: https://doi.org/10.1016/ j.jaip.2019.12.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology
1
Title: A streamlined approach to optimize perioperative antibiotic prophylaxis in the setting of
2
penicillin allergy labels
3
Authors: Merin Kuruvilla MD1, Mary Elizabeth Sexton MD, MSc 2, Zanthia Wiley MD 2, Terry Langfitt MD3,
4
Grant C Lynde MD, MBA 3, Francis Wolf MD 3
5
Affiliations:
6
1 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, 2 Division of Infectious Diseases,
7
3Department of Anesthesiology; Emory University School of Medicine, Atlanta, GA, USA
8
Corresponding author:
9
Merin Kuruvilla
10
1605 Chantilly Dr NE
11
Atlanta, GA-30324
12
Phone: 404-778-3261
13
Fax: 404-778-4431
14
Email: [email protected]
15
Funding: This research received no specific grant from any funding agency in the public, commercial, or
16
not-for-profit sectors. The authors’ academic departments generously supported the authors’ time in
17
producing this work.
18
Conflict of interests: The authors have no conflicts of interest to disclose.
19
20
Abstract (250 words):
21
Background: Patients with penicillin allergy labels often receive alternative antibiotics for peri-operative
22
prophylaxis, as opposed to first-line cephalosporins (cefazolin/cefuroxime). Provider misconceptions
23
about the risk of cross-reactivity likely drive this prescribing behavior, which is problematic because of
24
its association with increased risk of surgical site infections.
25
Objective: To develop, implement, and assess the safety of a streamlined approach to perioperative
26
antibiotic selection for surgical patients with a penicillin allergy label, in order to reduce the use of
27
second-line antibiotics.
28
Methods: A multidisciplinary task force developed an institutional algorithm for antibiotic selection in
29
penicillin-allergic surgical patients. The percentage of patients receiving a first-line cephalosporin was
30
compared before and after algorithm utilization. The safety of this approach was assessed via chart
31
review of all patients who received epinephrine or diphenhydramine in the operating room, or
32
diphenhydramine within twenty-four hours post-operatively, assessing for any adverse reactions to
33
cephalosporin administration.
34
Results: Between September 2016 and May 2019, 9.3% of surgical patients had documented penicillin
35
allergy (n=2296). At baseline, 22% of these patients received a cephalosporin, with an increase to >80%
36
following algorithm implementation (p<0.0001). Among 551 patients with penicillin allergy label who
37
received a cephalosporin following algorithm implementation, no immediate allergic reactions requiring
38
epinephrine were identified; one patient had a delayed rash that did not require cephalosporin
39
discontinuation. Three patients received diphenhydramine for "itching" without rash in the setting of
40
concomitant narcotic administration.
41
Conclusion: Using a streamlined algorithm, we were able to significantly reduce the use of second-line
42
antibiotics in penicillin-allergic surgical patients without severe adverse reactions.
43
Highlights:
44
1. What is already known about this topic? Use of second line antibiotics for peri-operative prophylaxis
45
is associated with increased risk of surgical site infections and other complications.
46
2. What does this article add to our knowledge? The use of second-line antibiotics for surgical
47
prophylaxis in patients with penicillin allergy labels can be reduced with a simplified approach.
48
3. How does this study impact current management guidelines? Current guidelines for perioperative
49
antibiotics in the United States continue to recommend alternative second line antimicrobial therapy in
50
the presence of type 1 hypersensitivity to penicillins – we report that most patients with a penicillin
51
allergy label can safely receive cefazolin and cefuroxime in this setting.
52
Key words: penicillin allergy, prophylactic antibiotics, cross-reactivity
53
Abbreviations: SSI – surgical site infection; SCAR – severe cutaneous adverse reaction; MRSA –
54
methicillin-resistant Staphylococcus aureus
55
Word count: 3625
56
Introduction
57
The timely administration of perioperative antibiotics plays an important role in reducing the risk of
58
surgical site infections (SSIs) 1. Clinical practice guidelines recommend cefazolin as the primary
59
prophylactic agent for most surgical cases 1 in the United States, with use of broader-spectrum
60
cephalosporins like cefuroxime potentially indicated in a smaller number of subspecialty cases 2.
61
However, due to concerns about cross-reactivity, these first-line agents for surgical prophylaxis may be
62
withheld in patients with a reported penicillin allergy, 3-5, and subsequent utilization of second-line
63
antibiotics has been shown to increase the risk of SSI 3,6-12.
64
This use of second-line antibiotics in patients with a documented penicillin allergy is often driven by
65
historical misconceptions concerning both the true incidence of penicillin allergies and the likelihood of
66
cross reactivity between penicillins and cephalosporins 13,14. While up to 15% of hospitalized patients
67
have a listed penicillin allergy 15, recent studies have found that only 1-10% of patients with self-
68
reported penicillin allergy are truly allergic 16-18. Furthermore, while the risk of cephalosporin allergy is
69
higher in the setting of a penicillin allergy label 14, the rate of clinically significant cross-reactivity is
70
significantly lower than previously thought and now estimated at 2-5% 19.
71
While the shared beta-lactam ring was previously assumed to be the mechanism for cross-reactivity
72
between penicillins and cephalosporins, it is now known that the allergenic determinants of
73
cephalosporins instead derive largely from the R1-group side chains, and to a lesser degree the R2 side
74
chains 13,20-22. This recognition has led to the recommendation that patients with a penicillin allergy may
75
receive a cephalosporin that lacks R1 side chain similarity even in the setting of confirmed penicillin-
76
induced anaphylaxis22. Avoidance of all beta-lactams is still recommended in patients with a history of
77
severe delayed reactions, including severe cutaneous adverse reactions (SCARs) and organ-specific
78
injuries such as hepatitis, nephritis, serum sickness, and hemolytic anemia, due to unpredictable cross-
79
reactivity in this setting 22,23. Cefazolin and cefuroxime, in particular, are recognized as having unique R1
80
and R2 side chains that are distinct from other cephalosporins and beta-lactam antibiotics 22. Based on
81
very limited data, there is no evidence of increased allergy risk with cefazolin in patients with
82
anaphylactic 24 or non-anaphylactic 25 penicillin allergy. Conversely, IgE-mediated cefazolin allergy
83
appears to be selective, with tolerance of other beta-lactams 24.
84
Despite this safety data, albeit limited, published antibiotic selection recommendations continue to
85
advise against utilizing beta-lactam antibiotics in surgical patients with moderate-to-severe penicillin
86
allergies without either graded provocation testing or referral to an allergy clinic for skin testing and
87
penicillin allergy de-labelling 22,23,26-30. However, these recommendations may be impractical in the
88
immediate perioperative period. Patients often present to the hospital on the day of surgery, with
89
allergy history often discussed immediately prior to administration of anesthesia and antibiotic
90
prophylaxis. As a result, both graded challenge administration and skin testing would likely produce
91
significant surgical case delays. We therefore developed a streamlined approach for evaluation of
92
penicillin allergy in preoperative patients, to allow for safe administration of prophylactic cephalosporins
93
without additional testing.
94 95 96 97 98 99 100
101 102
Methods
103
Human subjects: The Emory Institutional Review Board granted approval (IRB00095280) for this study as
104
part of a larger body of work to improve on-time perioperative antibiotic administration throughout the
105
healthcare system.
106
Setting: A working group of physicians from Anesthesiology, Surgery, Infectious Diseases, and
107
Allergy/Immunology as well as hospital pharmacists was established at a large academic medical center
108
in the southeastern United States to evaluate surgical prophylaxis selection in penicillin-allergic
109
perioperative patients. Perioperative antibiotic selection is guided by an institutional protocol, in which
110
cefazolin is recommended for the majority of cases where prophylaxis is indicated, and cefuroxime is
111
utilized in cardiothoracic surgical procedures with a mediastinal incision. Additional agents are added
112
for coverage of anaerobic and/or gram-negative organisms when indicated, and vancomycin is added in
113
patients at increased risk for methicillin-resistant Staphylococcus aureus (MRSA) infection. Prior to our
114
intervention, the protocol recommended using an alternative to cephalosporins (most commonly
115
vancomycin or clindamycin) in patients with the following reactions to penicillin: hives or rash,
116
angioedema, bronchospasm, or anaphylaxis, in addition to severe delayed hypersensitivity reactions.
117
Perioperative antibiotics were historically ordered by the surgical team; however, in an effort to
118
standardize practice, the primary anesthesia team assumed responsibility for ordering and administering
119
antibiotics in October 2017.
120
Protocol development: We undertook a literature review and subsequently constructed an algorithm to
121
guide the administration of perioperative prophylactic antibiotics in penicillin-allergic patients. We
122
focused on giving providers direction on when it is safe to prescribe the two most commonly-used
123
cephalosporins, cefazolin and cefuroxime. Given the safety data discussed above 22-25 and overall low
124
baseline likelihood of reactivity to penicillins and cephalosporins, the resultant algorithm recommended
125
administering cefazolin or cefuroxime as first-line agents in all patients with a history of allergy to
126
penicillin, except for those with a history of severe delayed hypersensitivity reactions (see Figure 1).
127
Patients with a history of unknown reactions in childhood, rash, or episodes suggestive of IgE-mediated
128
hypersensitivity reactions (including anaphylaxis) to penicillin were recommended to receive cefazolin or
129
cefuroxime according to the algorithm. Beta-lactam agents were avoided in patients with a history of
130
severe cutaneous adverse reaction (SCAR) or organ-specific injury (e.g. hepatitis, nephritis) due to the
131
uncertain mechanism and severe nature of these reactions. Patient screening questions were
132
formulated to help providers in the perioperative anesthesia clinic assess patients for a history of severe
133
delayed hypersensitivity reactions (see Figure 2). Algorithm implementation was accompanied by a
134
series of educational interventions starting in August 2018, incorporation of the algorithm into written
135
perioperative protocols, and electronic distribution of the algorithm.
136
Data collection and analysis: We queried our institutional Clinical Data Warehouse to identify all
137
patients who had a surgical procedure from 9/1/2016-5/31/2019. Patients were excluded from analysis
138
if they had a surgical procedure for which perioperative antibiotics were not indicated or if a
139
cephalosporin was not the recommended first-line agent. For all remaining patients, the following
140
additional data were abstracted: antibiotics administered perioperatively; presence or absence of a
141
documented allergy to penicillin or its derivatives; any administration of epinephrine in the operating
142
room; and any administration of diphenhydramine either intraoperatively or in the twenty-four hours
143
postoperatively.
144
For patients with a documented penicillin allergy, chart review was performed to identify the allergy
145
type. Based on the comments entered in the electronic medical record allergy history, allergies were
146
classified as: (a) not documented (if the allergy was listed without any explanation); (b) unknown (e.g.
147
“patient does not recall” or “childhood reaction”); (c) side effect (e.g. headache, diarrhea); (d) rash
148
and/or itching; (e) type I hypersensitivity reaction (e.g. urticaria, angioedema, bronchospasm, or
149
anaphylaxis); or (f) severe delayed hypersensitivity reaction (e.g. organ dysfunction, drug fever, skin
150
blistering, mucosal involvement). We calculated the percentage of surgical patients with a penicillin
151
allergy, as well as the proportion of each allergy type present within the group of penicillin-allergic
152
patients. We then compared the percentage of penicillin-allergic patients who received a cephalosporin
153
before (9/1/2016-8/31/2018) and after (9/1/2018-5/31/2019) algorithm implementation.
154
Patients with a documented penicillin allergy who received a cephalosporin were then assessed for any
155
resultant allergic reactions, using epinephrine administration at the time of surgery as a surrogate for a
156
life-threatening acute reaction and diphenhydramine administration both during surgery and in the
157
twenty-four hours post-operatively as a potential marker for more delayed reactions. Chart reviews
158
were performed on all patients who received epinephrine or diphenhydramine to determine the reason
159
for medication administration. The medication order, the medication administration record, the
160
anesthesia record, the operative report, nursing notes, and daily progress notes were evaluated as
161
necessary to identify whether either epinephrine or diphenhydramine had been given in response to an
162
allergic reaction. Of note, using epinephrine administration as a marker of anaphylaxis may still miss
163
some reactions, as vasopressors other than epinephrine are often given, depending upon institutional
164
practice.
165
Statistical analysis: Statistical comparisons were performed using chi-square testing (p<0.05 significance
166
level) using OpenEpi: Open Source Epidemiologic Statistics for Public Health, Version 3.01.
167 168
169
Results
170 171
Penicillin allergy prevalence and documentation
172
The overall prevalence of documented penicillin allergy among surgical cases that required
173
perioperative antibiotics was 9.3% (2296/24,629). This included 1608 of 17,376 cases (9.3%) prior to
174
implementation of the algorithm, and 688 of 7253 cases (9.5%) post-algorithm. Of the 2296 cases
175
involving a patient with a penicillin allergy label, 880 (38.3%) did not have a penicillin reaction type
176
documented in the chart, 118 (5.1%) had an unknown reaction to penicillin, 168 (7.3%) had a side effect
177
rather than an allergy, 487 (21.2%) had rash and/or itching, 623 (27.1%) had a type I hypersensitivity
178
reaction, and 20 (0.9%) had a label consistent with a severe delayed hypersensitivity reaction (see Figure
179
3).
180 181 182
Cephalosporin utilization pre- and post-algorithm implementation
183
Prior to algorithm implementation, a perioperative cephalosporin was administered in 22.3% of cases
184
involving a penicillin-allergic patient. This included 43% of cases with documentation suggesting a side
185
effect rather than true allergy, 38% of cases suggestive of a severe delayed hypersensitivity reaction,
186
29% of cases with an unknown reaction, 24% of cases with rash/itching, 22% of cases where the allergy
187
was not documented, and 14% of cases with a type I hypersensitivity reaction (see Figure 4).
188
Following algorithm implementation, cephalosporin administration increased to 80.1% of cases involving
189
a patient with a penicillin allergy (p<0.0000001). Administration rose to >80% of cases with
190
undocumented reactions, unknown reactions, side effects, and rash/itching, and to 73% in cases with a
191
type I hypersensitivity reaction (see Figure 4); 43% of cases where the patient had documentation
192
suggestive of severe delayed hypersensitivity reaction history received a cephalosporin.
193 194 195
Adverse reactions
196
Following algorithm implementation, 21 penicillin-allergic patients received a cephalosporin and were
197
given epinephrine in the operating room. None of these epinephrine administrations was documented
198
as the result of an allergic reaction, nor was the administration of epinephrine temporally correlated
199
(within 60 minutes) with cefazolin use in 20 of 21 subjects. The last patient received epinephrine for
200
hemorrhagic shock 45 minutes following cefazolin administration. The majority (18 of 21 cases) involved
201
the use of epinephrine as one of multiple blood pressure support medications in patients who were
202
hemodynamically unstable as a result of underlying comorbidities or surgical factors. There were three
203
cases in which epinephrine was given in patients who appeared at risk for imminent cardiac arrest; two
204
of these were bradycardic responses to anesthesia that started prior to antibiotic administration and
205
one was determined to be the result of intravascular air.
206
Twenty-two penicillin-allergic patients who received a cephalosporin following algorithm
207
implementation also had diphenhydramine administered within twenty-four hours post-operatively.
208
The majority of these patients received diphenhydramine for nausea/vomiting or insomnia, or did not
209
have an indication documented and had no mention of allergic symptoms in the medical record. One
210
patient had a documented rash which resolved despite continuation of a cephalosporin (cefepime), and
211
four patients complained of itching without a rash; in these cases, there were alternative explanations
212
for pruritus including narcotic administration and a surgical tape reaction. Thus, of 551 penicillin-allergic
213
patients who received a cephalosporin following algorithm implementation, 0.18% developed a rash and
214
0.9% complained of either rash or itching not felt to be attributable to the cephalosporin. Another
215
patient noted facial and chest flushing over twenty-four hours after the last cephalosporin
216
administration (while also receiving vancomycin), and one patient noted wheezing that was attributed
217
to underlying asthma. An additional patient complained of post-operative shortness of breath,
218
experienced hypotension and bradycardia, and then had seizure-like activity. The symptoms developed
219
approximately five hours after cefazolin administration and resolved without administration of any
220
medications for a potential allergy.
221
Discussion:
222
We describe a streamlined approach to safely increase the use of cephalosporins for perioperative
223
antimicrobial prophylaxis in patients with penicillin allergy labels, including those with a history of
224
anaphylaxis. Risk stratification was based on the exclusion of patients with a history of severe delayed
225
hypersensitivity reactions to penicillin (or another beta-lactam) due to unknown risks with re-challenge.
226
Our allergy history-driven algorithm combined with recommended screening questions significantly
227
augmented cefazolin and cefuroxime administration. Over the course of nine months, use of second-line
228
antibiotics among surgical cases involving patients with a penicillin allergy decreased from 77.7% to
229
19.9%, with no reported immediate adverse reactions and one delayed rash (<0.2% of patients) in an
230
initial safety assessment of 551 patients with purported penicillin allergy who received a perioperative
231
cephalosporin.
232
Our findings regarding change in antibiotic selection align with previous studies of perioperative allergy
233
assessment programs, which have been shown to enhance beta-lactam uptake. For example, Vaisman et
234
al demonstrated that simply taking a structured penicillin allergy history increased safe perioperative
235
beta-lactam prescribing from 18% to 57%, despite the exclusion of those with IgE-mediated allergy 26. A
236
more thorough approach including application of preoperative penicillin skin testing was associated with
237
a 90% rate of perioperative beta-lactam use 18. Reilly and colleagues reported on outcomes with
238
incorporation of penicillin allergy testing into preoperative evaluation in a recent meta-analysis 31. This
239
measure was found to significantly decrease rates of non-beta-lactam antibiotic prescriptions without
240
adverse reactions. However, it is presently untenable to address comprehensive beta-lactam allergy de-
241
labeling preoperatively in most circumstances, due to the large numbers of patients affected and non-
242
availability of skin testing/oral challenge in many institutions.
243
The safety of our approach is well founded. While early reports suggested 10% cross-reactivity between
244
penicillins and cephalosporins, this data has subsequently been refuted, with current estimates of 2-5%
245
13,22
246
and R2 side chains 13,20-22. Both immediate and non-immediate reactions to cephalosporins appear to be
247
attributable to the side-chain structures of these drugs. The recognition of these cross-reactivity
248
mechanisms has led to the suggestion that patients with a penicillin allergy label may receive
249
cephalosporins that do not share R1 side chain similarity with penicillins, as long as they do not have a
250
history of a severe delayed reaction, including a SCAR 22,27. A recent meta-analysis quantified similarity
251
between R1 side chains of cephalosporins and penicillins based on physicochemical and structural
252
properties, and the authors confirmed a significant association between the R1 side chain similarity
253
score and risk of cross-reactivity in studies involving subjects with confirmed penicillin allergy. Both
254
cefazolin and cefuroxime have R1 side chains with low similarity scores and thus run a very low risk of
255
cross-reaction, regardless of whether PCN allergy is IgE or T cell mediated 32. Accumulating data supports
256
their tolerance in penicillin-allergic populations. However, this data derives mostly from retrospective
257
cohorts that are liable to selection bias. There was only one isolated adverse reaction to cefazolin in one
258
review of 300 penicillin-allergic patients 33, and none in another cohort of 54 subjects with benign rashes
259
documented as their penicillin allergy 34. Similarly, in a cohort of 513 penicillin-allergic surgical patients,
260
there were zero cases of anaphylaxis among those who received 153 courses of cefazolin or cefoxitin.
261
Ironically, there was a higher incidence of adverse events with the use of clindamycin or ciprofloxacin as
262
alternative agents 35. Cefuroxime shares a comparable safety profile 36,37. In our cohort, we similarly
263
observed no cases of anaphylaxis, one rash (0.18% of cases), and four complaints of itching with
264
potential alternate explanations (0.73% of cases), which adds support to the safety of this approach.
265
While recent guidelines have recommended to cephalosporin skin testing and incremental challenge in
266
patients with confirmed IgE-mediated penicillin allergy 29, the risk of cross-reactivity is highest with
, given the new understanding that the allergenic determinants of cephalosporins derive from the R1
267
aminocephalosporins. In a cohort of 128 subjects with immediate onset penicillin allergy, 14 (10.9%) had
268
positive skin tests to cephalosporins 38, mostly to cephalothin and cefamandole. When these ST positive
269
patients as well as the remainder of the cohort (n = 101) underwent challenges with cefuroxime and
270
ceftriaxone, there were no reactors. In a larger cohort of 252 subjects with a history of anaphylaxis from
271
penicillin with positive penicillin skin tests, 99 participants (39.3%) also had positive cephalosporin skin
272
tests. Of these positive tests, 95 were to aminocephalosporins, and only 4 to cephalosporins with
273
dissimilar side chains. These positive skin tests were attributed to concomitant sensitization as opposed
274
to true cross-reactivity. Further, they were not confirmed by oral challenge and have unclear clinical
275
relevance given the unproven predictive value of cephalosporin skin testing 21. Of note, cefazolin was
276
not used for skin testing or oral challenge in the study population. Similarly, among 213 adults with T-
277
cell mediated penicillin hypersensitivity 39, cross-reactivity defined by skin testing and challenges was
278
confined almost exclusively between aminopenicillins and aminocephalosporins. Again, in a cohort of
279
175 individuals with self-reported penicillin allergy who received cefepime, ceftriaxone, cephalexin, or
280
cefoxitin in a hospital setting, allergic reactions were observed only with cefepime and cefoxitin further
281
confirming the concept of side chain cross reactivity 40.
282
These studies even run the risk of overestimating cross reactivity since the positive predictive value of
283
cephalosporin ST could not be evaluated. The pitfalls of cephalosporin skin testing were highlighted in a
284
study of 1421 patients without known β-lactam allergy requiring perioperative cephalosporin
285
prophylaxis 41. Subjects were tested to five different cephalosporins, with a 5% sensitization rate to at
286
least one cephalosporin. However, only 0.3% of patients had an immediate hypersensitivity reaction and
287
none of these reactors had been skin test positive. Thus, cephalosporin skin testing demonstrated 0%
288
sensitivity in this cohort.
289
Despite accumulating safety data, guidelines for perioperative antibiotics in the United States continue
290
to recommend alternative second line antimicrobial therapy in the presence of type 1 hypersensitivity to
291
penicillins 1. This is reflected in the various algorithms that have been generated to optimize the
292
perioperative management of penicillin allergic patients, most of which continue to recommend skin
293
testing in patients with symptoms of IgE/mast cell sensitization including anaphylaxis 26-30. When skin
294
testing is not able to be performed -- which would be common in a perioperative setting secondary to
295
time constraints -- many of these algorithms call for the use of alternative agents, which have been
296
associated with increased rates of SSI 3,6-12.
297
Of note, we intended for our algorithm to avoid administration of cephalosporins in patients with a
298
history of severe delayed hypersensitivity reaction, and anesthesiologists were instructed to utilize the
299
patient questionnaire as a guide. However, the small number of patients with documentation
300
suggestive of severe delayed hypersensitivity to penicillin received a cephalosporin ~40% of the time
301
before and after the intervention. We suspect this may be secondary to poor allergy documentation in
302
the medical record, rather than to inappropriate cephalosporin administration. For example, any
303
reaction that documented “skin blistering” or “skin peeling” in the medical record was classified as a
304
SCAR, although many of these comments did not include sufficient detail to determine whether a SCAR
305
was truly present. It is possible that upon questioning by the anesthesiologist, it was evident that the
306
reaction did not meet SCAR criteria. The small number of patients with severe delayed hypersensitivity
307
reaction makes these results more difficult to interpret; however, ongoing education may be needed.
308
The major limitation of our study is that most of the penicillin allergy labels were likely erroneous. Our
309
study does not necessarily confirm the safety of cefazolin (or cefuroxime) in truly penicillin allergic
310
patients, but rather the low baseline likelihood of reactivity to cephalosporins in our cohort. Our study
311
does not endorse the broad administration of all cephalosporins in all comers with penicillin allergy, but
312
rather the selective administration of cefazolin/cefuroxime in subjects without severe reactions. We
313
attempted to document in the medical record that the patient had tolerated cefazolin but continue to
314
evaluate the best way to communicate the information to the patient so that there is not an assumption
315
by them or other providers that any cephalosporin is safe, since cefazolin’s structure is so unique.
316
Ongoing work is need to evaluate communication with the patient and non-allergy providers about what
317
is and is not safe following uneventful cefazolin administration.
318
Also, patients were more likely to receive cefazolin in the setting of unknown reaction/rash with
319
penicillin and 27% of those labelled as type I hypersensitivity reactions were not given a cephalosporin,
320
reflecting possible selection bias in those with a more suggestive history. Another limitation was that
321
our focus was limited to intraoperative cefazolin/cefuroxime use in patients with a listed penicillin
322
allergy. It did not address other beta-lactam allergies, and did not tackle the larger issue of erroneous
323
penicillin allergy de-labeling in the context of antimicrobial stewardship. Our objective was to increase
324
utilization of first-line perioperative antibiotics with associated potential for reduced rates of SSIs, and to
325
decrease rates of complications associated with common alternative antibiotic agents. However,
326
tolerance of cefazolin does not confer penicillin allergy resolution. Thus, outpatient allergy referral for
327
investigation of the primary penicillin allergy on discharge can still have utility. While comprehensive
328
penicillin allergy evaluation and de-listing could have additional benefits, our algorithm provides a
329
valuable practical strategy for the perioperative setting, in which a more extensive workup may not
330
feasible.
331
In addition, while cefazolin is the drug of choice for perioperative prophylaxis in the United States,
332
clinical practice varies around the world. Our algorithm was developed for healthcare facilities where
333
cefazolin is used as the first-line agent for surgical prophylaxis, and may not be suitable for institutions
334
that utilize a penicillin as first-line agent. ~3% of patients administered a third-generation or higher
335
cephalosporin develop Clostridium difficile in 90 days14. Thus, penicillins are first line agents in many
336
countries. In those cases, the algorithm would not help to evaluate safety of first-line antibiotic use in an
337
allergic patient, but does offer a way to evaluate a second-line alternative other than vancomycin.
338
Conclusion: We present a streamlined algorithm for the perioperative administration of antibiotics in
339
patients with a penicillin allergy label, based on a brief bedside assessment to assess for history of a
340
severe delayed hypersensitivity reaction to confirm appropriateness of cefazolin or cefuroxime. Our
341
initial results suggest that implementation of this algorithm can increase perioperative cephalosporin
342
utilization without significant risk of adverse reactions.
343
Acknowledgements:
344
The authors would like to thank Lisa Cogdill, Addison Jones, and Sun Choi for performing the Emory
345
Clinical Data Warehouse data search. We would also like to thank the Emory University School of
346
Medicine Department of Anesthesiology, Division of Allergy and Immunology, and Division of Infectious
347
Diseases for their support of the authors’ time in instituting the protocol.
348
References
349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391
1. 2.
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13. 14.
Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195-283. Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg. 2012;143(1):4-34. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The Impact of a Reported Penicillin Allergy on Surgical Site Infection Risk. Clin Infect Dis. 2018;66(3):329-336. Jain P, Fabbro M, 2nd. ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation: A Review of the 2017 Document for the Cardiac Anesthesiologist. J Cardiothorac Vasc Anesth. 2019;33(2):274-289. Pichichero ME. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics. 2005;115(4):1048-1057. Robertsson O, Thompson O, A WD, Sundberg M, Lidgren L, Stefansdottir A. Higher risk of revision for infection using systemic clindamycin prophylaxis than with cloxacillin. Acta Orthop. 2017;88(5):562-567. Kheir MM, Tan TL, Azboy I, Tan DD, Parvizi J. Vancomycin Prophylaxis for Total Joint Arthroplasty: Incorrectly Dosed and Has a Higher Rate of Periprosthetic Infection Than Cefazolin. Clin Orthop Relat Res. 2017;475(7):1767-1774. Ponce B, Raines BT, Reed RD, Vick C, Richman J, Hawn M. Surgical Site Infection After Arthroplasty: Comparative Effectiveness of Prophylactic Antibiotics: Do Surgical Care Improvement Project Guidelines Need to Be Updated? J Bone Joint Surg Am. 2014;96(12):970977. Bull AL, Worth LJ, Richards MJ. Impact of vancomycin surgical antibiotic prophylaxis on the development of methicillin-sensitive staphylococcus aureus surgical site infections: report from Australian Surveillance Data (VICNISS). Ann Surg. 2012;256(6):1089-1092. Murphy J, Isaiah A, Dyalram D, Lubek JE. Surgical Site Infections in Patients Receiving Osteomyocutaneous Free Flaps to the Head and Neck. Does Choice of Antibiotic Prophylaxis Matter? J Oral Maxillofac Surg. 2017;75(10):2223-2229. Uppal S, Harris J, Al-Niaimi A, Swenson CW, Pearlman MD, Reynolds RK, et al. Prophylactic Antibiotic Choice and Risk of Surgical Site Infection After Hysterectomy. Obstet Gynecol. 2016;127(2):321-329. Wyles CC, Hevesi M, Osmon DR, Park MA, Habermann EB, Lewallen DG, et al. 2019 John Charnley Award: Increased risk of prosthetic joint infection following primary total knee and hip arthroplasty with the use of alternative antibiotics to cefazolin: the value of allergy testing for antibiotic prophylaxis. Bone Joint J. 2019;101-B(6_Supple_B):9-15. Pichichero ME, Zagursky R. Penicillin and cephalosporin allergy. Ann Allergy Asthma Immunol. 2014;112(5):404-412. Macy E, Contreras R. Adverse reactions associated with oral and parenteral use of cephalosporins: A retrospective population-based analysis. J Allergy Clin Immunol. 2015;135(3):745-752 e745.
392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439
15.
16. 17. 18.
19. 20.
21.
22. 23. 24.
25.
26.
27. 28.
29.
30.
31.
32.
Lee CE, Zembower TR, Fotis MA, Postelnick MJ, Greenberger PA, Peterson LR, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med. 2000;160(18):2819-2822. Macy E, Ngor EW. Safely diagnosing clinically significant penicillin allergy using only penicilloylpoly-lysine, penicillin, and oral amoxicillin. J Allergy Clin Immunol Pract. 2013;1(3):258-263. Macy E. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Curr Allergy Asthma Rep. 2014;14(11):476. McDanel DL, Azar AE, Dowden AM, Murray-Bainer S, Noiseux NO, Willenborg M et al. Screening for Beta-Lactam Allergy in Joint Arthroplasty Patients to Improve Surgical Prophylaxis Practice. J Arthroplasty. 2017;32(9S):S101-S108. Macy E, Blumenthal KG. Are Cephalosporins Safe for Use in Penicillin Allergy without Prior Allergy Evaluation? J Allergy Clin Immunol Pract. 2018;6(1):82-89. Antunez C, Blanca-Lopez N, Torres MJ, Mayorga C, Perez-Inestrosa E, Montañez MI, et al. Immediate allergic reactions to cephalosporins: evaluation of cross-reactivity with a panel of penicillins and cephalosporins. J Allergy Clin Immunol. 2006;117(2):404-410. Romano A, Valluzzi RL, Caruso C, Maggioletti M, Quaratino D, Gaeta F. Cross-Reactivity and Tolerability of Cephalosporins in Patients with IgE-Mediated Hypersensitivity to Penicillins. J Allergy Clin Immunol Pract. 2018;6(5):1662-1672. Zagursky RJ, Pichichero ME. Cross-reactivity in beta-Lactam Allergy. J Allergy Clin Immunol Pract. 2018;6(1):72-81 e71. Macy E, Romano A, Khan D. Practical Management of Antibiotic Hypersensitivity in 2017. J Allergy Clin Immunol Pract. 2017;5(3):577-586. Uyttebroek AP, Decuyper, II, Bridts CH, Romano A, Hagendorens MM, Ebo DG, et al. Cefazolin Hypersensitivity: Toward Optimized Diagnosis. J Allergy Clin Immunol Pract. 2016;4(6):12321236. Blumenthal KG, Youngster I, Shenoy ES, Banerji A, Nelson SB. Tolerability of cefazolin after immune-mediated hypersensitivity reactions to nafcillin in the outpatient setting. Antimicrob Agents Chemother. 2014;58(6):3137-3143. Vaisman A, McCready J, Hicks S, Powis J. Optimizing preoperative prophylaxis in patients with reported beta-lactam allergy: a novel extension of antimicrobial stewardship. J Antimicrob Chemother. 2017;72(9):2657-2660. Vorobeichik L, Weber EA, Tarshis J. Misconceptions Surrounding Penicillin Allergy: Implications for Anesthesiologists. Anesth Analg. 2018;127(3):642-649. Moussa Y, Shuster J, Matte G, Sullivan A, Goldstein RH, Cunningham D, et al. De-labeling of betalactam allergy reduces intraoperative time and optimizes choice in antibiotic prophylaxis. Surgery. 2018. Savic LC, Khan DA, Kopac P, Clarke RC, Cooke PJ, Dewachter P, et al. Management of a surgical patient with a label of penicillin allergy: narrative review and consensus recommendations. Br J Anaesth. 2019;123(1):e82-e94. Hermanides J, Lemkes BA, Prins JM, Hollmann MW, Terreehorst I. Presumed beta-Lactam Allergy and Cross-reactivity in the Operating Theater: A Practical Approach. Anesthesiology. 2018;129(2):335-342. Reilly CA, Backer G, Basta D, Riblet NBV, Hofley PM, Gallagher MC. The effect of preoperative penicillin allergy testing on perioperative non-beta-lactam antibiotic use: A systematic review and meta-analysis. Allergy Asthma Proc. 2018;39(6):420-429. Picard M, Robitaille G, Karam F, Daigle JM, Bédard F, Biron É, et al. Cross-Reactivity to Cephalosporins and Carbapenems in Penicillin-Allergic Patients: Two Systematic Reviews and Meta-Analyses. J Allergy Clin Immunol Pract. 2019.
440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467
33.
34.
35.
36.
37. 38.
39.
40.
41.
Goodman EJ, Morgan MJ, Johnson PA, Nichols BA, Denk N, Gold BB. Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic response. J Clin Anesth. 2001;13(8):561-564. Haslam S, Yen D, Dvirnik N, Engen D. Cefazolin use in patients who report a non-IgE mediated penicillin allergy: a retrospective look at adverse reactions in arthroplasty. Iowa Orthop J. 2012;32:100-103. Beltran RJ, Kako H, Chovanec T, Ramesh A, Bissonnette B, Tobias JD. Penicillin allergy and surgical prophylaxis: Cephalosporin cross-reactivity risk in a pediatric tertiary care center. J Pediatr Surg. 2015;50(5):856-859. Caimmi S, Galera C, Bousquet-Rouanet L, Arnoux B, Demoly P, Bousquet PJ. Safety of cefuroxime as an alternative in patients with a proven hypersensitivity to penicillins: a DAHD cohort survey. Int Arch Allergy Immunol. 2010;153(1):53-60. Promelle V, Jany B, Drimbea A, Jezraoui P, Milazzo S. Tolerability of intracameral cefuroxime during cataract surgery in case of penicillin allergy. J Fr Ophtalmol. 2015;38(4):283-287. Romano A, Gueant-Rodriguez RM, Viola M, Pettinato R, Gueant JL. Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins. Ann Intern Med. 2004;141(1):16-22. Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Caruso C, Quaratino D. Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2016;138(1):179-186. Crotty DJ, Chen XJ, Scipione MR, Dubrovskaya Y, Louie E, Ladapo JA, et al. Allergic Reactions in Hospitalized Patients With a Self-Reported Penicillin Allergy Who Receive a Cephalosporin or Meropenem. J Pharm Pract. 2017;30(1):42-48. Yoon SY, Park SY, Kim S, Lee T, Lee YS, Kwon HS, et al. Validation of the cephalosporin intradermal skin test for predicting immediate hypersensitivity: a prospective study with drug challenge. Allergy. 2013;68(7):938-944.
468
Figures
469
Figure 1. Perioperative Penicillin Allergy Algorithm
470
Institutional algorithm for cefazolin/cefuroxime use in in patients with reported allergy to penicillin. In
471
the absence of a severe, delayed reaction, patients with a penicillin allergy can receive cefazolin and
472
cefuroxime.
473
Figure 2. Penicillin Allergy Evaluation Questionnaire
474
Suggested questions to assess for a history of a severe delayed hypersensitivity reaction to penicillin as
475
part an allergy evaluation. If the patient answers yes to any of the above items or there is
476
documentation of any of these reactions in the chart, all beta lactam antibiotics (including perioperative
477
cephalosporins) should be avoided. If none of the above are checked, cefazolin is expected to be safe in
478
the patient.
479
Figure 3. Penicillin Allergy Type Breakdown
480
Allergy types among surgical patients with a reported penicillin allergy. The percentage of surgical cases
481
with each type of reaction documented in the electronic medical record is shown.
482
Figure 4. Cephalosporin Utilization by Documented Allergy Type Pre- and Post-Intervention
483
The percentage of penicillin-allergic surgical cases receiving a cephalosporin before and after algorithm
484
implementation is shown, stratified by the type of allergic reaction documented in the patient’s medical
485
record.
1
Figure 1. Perioperative Penicillin Allergy Algorithm
2 3
.
1 2
Figure 2. Penicillin Allergy Evaluation Questionnaire Penicillin Allergy Assessment Did you have a severe skin reaction involving blisters on your skin and shedding or detachment of your skin? (SJS/TEN) • Were you told you had Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN)? • Did you have liver injury or hepatitis caused by the medication? • Did you have kidney injury, nephritis or acute renal failure caused by the medication (acute interstitial nephritis)? • Were you told you had hemolytic anemia caused by the medication? (Low hemoglobin or hematocrit or "blood counts" counts caused by penicillin) • Did you have painful swollen joints caused by the medication (serum sickness)? • Were you diagnosed with "drug fever"? (A fever caused by the antibiotic that developed about a week after starting the medication and then went away when you stopped the antibiotic?) • Did you have a severe reaction involving the inside of your mouth, eye, or genital ulcers? •
3 4
Figure 3. Penicillin Allergy Type Breakdown
Figure 3. Penicillin Allergy Type Breakdown
1% 27% 39%
21%
5% 7%
Not Documented
Unknown
Side Effect
Rash/Itching
Type I Hypersensitivity Reaction
Severe Delayed Hypersensitivity Reaction
1 2
Figure 4
Percentage of Cases Receiving a Cephalosporin
Figure 4. Cephalosporin Utilization by Documented Allergy Type Pre- and Post-Intervention 100 90 80 70 60 50 40 30 20 10 0 Reaction Not Documented
Unknown Reaction
Side Effect
Rash/Itching
Documented Allergy Type Pre-Intervention
3 4 5
Post-Intervention
Type I Hypersensitivity Reaction
Severe Delayed Hypersensitivity Reaction