Transcript Penicillin allergy testing as an essential component of an

Penicillin Allergy Testing
and
Antibiotic Stewardship
7th DHM
Malaga, Espana
22 April, 2016
Eric Macy, MD MS FAAAAI
Kaiser Permanente Southern California
Penicillin Allergy Testing and Antibiotic Stewardship
 Disclosures for Eric Macy
 Partner
 Southern California Permanente Medical Group
 Research Grants
 ALK (the sellers of Pre-Pen®)
 Data and Safety Monitor Boards
 BioMarin
 UltraGenyx
 Consulting
 BioMarin
Penicillin Allergy Testing and Antibiotic Stewardship
 Why is it important to verify penicillin “allergy” as a part of
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an effective antibiotic stewardship program
Who can you safely test for penicillin allergy
How do you perform safe and effective penicillin allergy
testing
Current commercially available blood tests for penicillin
allergy are not useful
Resensitization or new sensitization after a negative
penicillin allergy test is very rare
Penicillin allergy testing significantly reduces costs
Cephalosporins are widely, safely, and appropriately
given to individuals with both confirmed penicillin allergy
and unconfirmed penicillin “allergy”
Penicillin Allergy Testing and Antibiotic Stewardship
Penicillin Allergy Testing and Antibiotic Stewardship
Don’t overuse non-beta lactam antibiotics in patients
with a history of penicillin allergy, without an
appropriate evaluation.
Macy E, Contreras R. Healthcare utilization and serious
infection prevalence associated with penicillin “allergy” in
hospitalized patients: a cohort study. J Allergy Clin Immunol
2014;133:790-6.
Solensky R. Penicillin allergy as a public health measure. J
Allergy Clin Immunol 2014;133:797-8.
Penicillin Allergy Testing and Antibiotic Stewardship
 It was possible to match 51,582 (99.6% of all possible
cases) unique penicillin ‘‘allergic’’ hospitalized
individuals to 2 unique control subjects each.
 Penicillin ‘‘allergic’’ cases averaged 0.59 (9.9%) [95%
CI, 0.47 to 0.71] more total hospital days during 20.1 ±
10.5 months of follow-up, compared to discharge
diagnosis category-, gender-, age-, and date of
admission-matched controls.
Macy E, Contreras R. Healthcare utilization and serious infection
prevalence associated with penicillin “allergy” in hospitalized patients: a
cohort study. J Allergy Clin Immunol 2014;133:790-6.
Penicillin Allergy Testing and Antibiotic Stewardship
 Cases were treated with significantly more
fluoroquinolones, clindamycin, and vancomycin, p <
0.0001, compared to controls.
 Cases had 23.4% [95% CI, 15.6% to 31.7%] more
Clostridium difficile, 14.1% [95% CI, 7.1% to 21.6%]
more MRSA, and 30.1% [95% CI, 12.5% to 50.4%]
more VRE infections than expected, compared to
controls.
Macy E, Contreras R. Healthcare utilization and serious infection
prevalence associated with penicillin “allergy” in hospitalized patients: a
cohort study. J Allergy Clin Immunol 2014;133:790-6.
Penicillin Allergy Testing and Antibiotic Stewardship
 Penicillin allergy testing is becoming recognized as an
important part of an effective antibiotic stewardship
program
 Implementing an Antibiotic Stewardship Program: Guidelines by the
IDSA and the SHEAhttp://cid.oxfordjournals.org/content/early/2016/04/11/cid.ciw118.full
 Canadian Pediatric society
http://www.cps.ca/documents/position/antimicrobial-stewardship
 New York Times
http://www.nytimes.com/2015/03/03/opinion/are-you-really-allergic-to-antibiotics.html
 Wall Street Journal
http://www.wsj.com/articles/SB10001424052702303779504579465563788334676
 Current Opinion in Infectious Diseases
https://www1.imperial.ac.uk/resources/CDF38D82-EC22-4068-BCF10E183C7E8FB3/tammaetalcurrentopinionininfectiousdiseases2014.pdf
Penicillin Allergy Testing and Antibiotic Stewardship
 Penicillin allergy testing is done to prevent the morbidity
associated with an active, but inaccurate, penicillin
“allergy” notation in the medical record.
 The gold standard test to determine penicillin tolerance is
an oral challenge with a therapeutic penicillin dose
 8% of the United States population carries a history of
penicillin allergy
 Penicillin allergy testing is easy and uses only
commercially available materials.
Penicillin Allergy Testing and Antibiotic Stewardship
 OK to test for penicillin allergy (almost everyone)
 Anaphylaxis
 Hives
 Other benign rashes
 GI symptoms
 Headaches
 Other benign symptoms
 Unknown reactions
 Do not test for penicillin allergy, just avoid (all these are extremely rare)
 Any serious cutaneous adverse reaction (SCAR)
 Drug reaction with eosinophilia and systemic symptoms (DRESS)
 Toxic epidermal necrolysis (TEN)
 Stevens Johnson syndrome (SJS)
 Serious hepatitis
 Hemolytic anemia
 Interstitial nephritis
Penicillin Allergy Testing and Antibiotic Stewardship
 The major determinant, penicilloyl-poly-lysine (Pre-Pen®)
accounts for the majority of positive penicillin skin test
results
 It is critical to use at least 5 mm of wheal, with flare
greater than wheal, as the criteria for a positive penicillin
intradermal test result
 Only one minor determinant is needed, native penicillin G
at 0.01 M.
 Puncture followed by intradermal testing using both
reagents is recommended.
Macy E, Ngor EW. Safely diagnosing clinically significant penicillin
allergy using only penicilloyl-poly-lysine, penicillin, and oral
amoxicillin. JACI In Practice 2013;1:258-63
Penicillin Allergy Testing and Antibiotic Stewardship
 An oral amoxicillin 250 mg challenge, with one hour of
observation, is given to all skin test negative individuals.
 This dose can be adjusted down for children under age 5.
Macy E, Ngor EW. Safely diagnosing clinically significant penicillin
allergy using only penicilloyl-poly-lysine, penicillin, and oral
amoxicillin. JACI In Practice 2013;1:258-63
Penicillin Allergy Testing and Antibiotic Stewardship
Penicillin skin testing and oral amoxicillin challenge
Data collection sheet
Test performed by: _________________ Test ordered by: ________________
Last Name: ________________________ First Name: ________________________
Medical Record Number: ________________
Date of test: __/__/____
Date of birth: __/__/____
Gender: (M / F)
Date of index penicillin-associated adverse reaction: __/__/____
Route of administration: (oral / parenteral)
Time to onset: (< 1 hour / 1-24 hours / 25 – 72 hours / > 73 hours)
Type of index reaction: (anaphylaxis / shortness of breath / hives / angioedema / non-hive rash / GI / other)
Treatment of index reaction: (stopped penicillin only / antihistamine / epinephrine / systemic steroid / other)
Puncture
Time placed:______ Time read:______
1) Penicilloyl-poly-lysine
____/____
2) Penicillin G (0.01M)
____/____
3) Saline Control
____/____
4) Histamine
____/____
Intradermal
Time placed:______ Time read:______
5) Penicilloyl-poly-lysine
____/____
6) Penicillin G (0.01M)
____/____
7) Saline Buffer Control
____/____
8) Histamine
____/____
(Report results as mm wheal / mm flare, a positive result is ≥ 5 mm wheal with flare > wheal)
Skin test reaction:
Treatment given:
(None / hives / hypotension)
(None / antihistamine / epinephrine)
Oral amoxicillin 250 mg challenge time given: ____________
Objective acute oral challenge reaction: (None / hives / hypotension / other)
Time of onset: _______
Acute challenge reaction treatment given: (None / antihistamine / epinephrine)
Delayed challenge reaction reported: (None / rash / other)
Time to delayed onset reaction: _________
Delayed challenge reaction treatment given: (None / antihistamine / systemic steroids)
Penicillin Allergy Testing and Antibiotic Stewardship
 Penicillin allergy skin testing is essentially done to reduce
the number of clinically significant positive oral amoxicillin
challenges.
 Penicillin allergy skin testing using inappropriately lax
criteria (specifically < 5 mm wheal) for a positive result
produces many more false positives, particularly in
women
 Improperly performed penicillin allergy testing causes
more patient morbidity, because individuals are still
mistakenly treated as if they truly were penicillin allergic
Solensky R, Macy E. Minor determinants are essential for optimal
penicillin allergy testing: a pro/con debate. J Allergy Clin Immunol Pract.
2015 Jul 8. pii: S2213-2198(15)00311-6. doi: 10.1016/j.jaip.2015.05.033.
[Epub ahead of print]
Penicillin Allergy Testing and Antibiotic Stewardship
 The rate of positive penicillin allergy evaluations has been
falling over the past 20 years.
 Even if truly present at one point in time, it may wane
over time in most (but not all) individuals.
Macy E, Schatz M, Lin C, Poon KWT. The falling rate of positive
penicillin skin tests from 1995 to 2007. Perm J, 2009;13:12-18.
Penicillin Allergy Testing and Antibiotic Stewardship
 We calculated that we have about 1 more positive oral
challenge reaction for every 3000 individuals tested for
penicillin allergy not using the other minor determinants,
penilloate, penicilloate, and amoxicillin, as skin test
reagents.
Macy E, Ngor EW. Safely diagnosing clinically significant penicillin
allergy using only penicilloyl-poly-lysine, penicillin, and oral
amoxicillin. JACI In Practice 2013;1:258-63
Penicillin Allergy Testing and Antibiotic Stewardship
Kaiser Permanente San Diego experience from 6-8-2010 through
3-31-2016
 2,033 total individuals tested for penicillin allergy
 No exclusions for SCARs, hepatitis, hemolytic anemia, or nephritis
 1,960 (96.4%) skin test-, acute oral challenge-, and delayed oral
challenge-negative
 36 (1.8%) skin test-positive
 23 (1.1%) acute objective oral challenge-positive.
 78 (3.8%) had acute subjective reactions to the oral challenge
 14 (0.7%) objective, delayed onset (> 24 hours), challenge
reactions
 10 (0.5%) presumed T-cell mediated rashes, 4 GI upset or nausea
Penicillin Allergy Testing and Antibiotic Stewardship
 Direct oral challenge
 Studied in both adults and children with mainly delayed onset
amoxicillin-associated rashes
 Most of these rashes occur in the setting of a viral infection,
mistreated with an antibiotic
 A single therapeutic amoxicillin dose is adequate with one
hour of observation
Goldberg A, Confino-Cohen R. Skin testing and oral challenge in patients with a history of
remote penicillin allergy. Ann Allergy Asthma Immunol 2008;100:37-43
Caubet JC, Kaiser L, Lemaitre B, Fellay B, Gervaix A, Eigenmann PA. The role of penicillin in
benign skin rashes in childhood; a prospective study based on drug rechallenge. J Allergy Clin
Immunol 2011;127:218-22
Murphy K, Scanlan B, Coghlan D. Does this child really have a penicillin allergy? Ir Med J
2015;108:103-6
Mill C, Primeau MH, Medoff E, et al. Assessing the diagnostic properties of a graded oral
provocative challenge for the diagnosis of immediate and nonimmediate reactions to amoxicillin
in children. JAMA Pediatr. doi:10.1001/jamapediatrics.2016.0033
Penicillin Allergy Testing and Antibiotic Stewardship
 Currently available in vitro tests for penicillin-specific IgE
are not useful because their results do not correlate to
oral challenge reactions.
Macy E, Goldberg B, Poon KWT. Use of commercial antipenicillin-IgE FEIAs to diagnose penicillin allergy. Ann
Allergy Asthma Immunol, 2010;105:136-141.
Penicillin Allergy Testing and Antibiotic Stewardship
 Penicillin allergy testing can be safely and effectively
performed in the hospital environment by Pharmacists,
Registered Nurses, or Physicians trained in skin testing.
 We penicillin allergy tested 141 (8.7%) of the 1627 (12.4%)
penicillin allergic individuals hospitalized at the San Diego
Medical center between 8-2002 and 2-2003 with one part time
nurse working on her own.
Macy E, Roppe L, Schatz M. Routine penicillin skin testing in
hospitalized patients with a history of penicillin allergy. Perm J,
2004;8:20-24.
Rimawi RH, Cook PP, Gooch M, Kabchi B, Ashraf MS, Rimawi BH,
Gebregziabher M, Siraj DS. The impact of penicillin skin testing on
clinical practice and antimicrobial stewardship. J Hosp Med
2013;8:341-5
Penicillin Allergy Testing and Antibiotic Stewardship
 Resensitization or new sensitization after a negative penicillin
allergy test is very rare.
 In penicillin allergy test negative individuals given therapeutic
penicillins, about 3% will note a new reaction per course, but
only about 1 in 33 will be repeat penicillin allergy test positive
Solensky R, Earl HS, Gruchalla RS. Lack of penicillin resensitization in
patients with a history of penicillin allergy after receiving repeated penicillin
courses. Arch Inter Med 2002;162:822-6
Macy E, Mangat R, Burchette RJ. 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;111:1111-5
Hetrshkovich J, Broides A, Kirjner L, Smith H, Gorodischer R. Beta lactam
allergy and resensitization in children with suspected beta lactam allergy. Clin
Exp Allergy 2009;39:726-30
Penicillin Allergy Testing and Antibiotic Stewardship
 Even in individuals with a history of verified
penicillin allergy, cephalosporins are tolerated with
adverse reactions rates not significantly different
from non-allergic individuals
Macy E, Ho NJ. Adverse reactions associated with therapeutic
antibiotic use after penicillin skin testing. Perm J, 2011;15:31-37.
Penicillin Allergy Testing and Antibiotic Stewardship
 Cephalosporins are currently the most common
class of antibiotics given to individuals in KP
Southern California with a history of penicillin
allergy
Macy E, Contreras R. Adverse reactions associated with oral
and parenteral cephalosporin use: a retrospective populationbased analysis. J Allergy Clin Immunol 2015;135:745-52.e5
Penicillin Allergy Testing and Antibiotic Stewardship
 There would be about 1 more new cephalosporin “allergy” noted for
every 135 individuals given a cephalosporin who have a penicillin
“allergy” compared to individuals with no drug “allergy”.
 There would be about 1 more new cephalosporin “allergy” noted for
every 159 individuals given a cephalosporin who have a penicillin
“allergy” compared to individuals with any non-beta-lactam “allergy”.
 There would be about 1 more new cephalosporin “allergy” noted for
every 233 individuals given a cephalosporin who have a penicillin
“allergy” compared to individuals with another cephalosporin “allergy”.
Macy E, Contreras R. Adverse reactions associated with oral and
parenteral cephalosporin use: a retrospective population-based analysis.
J Allergy Clin Immunol 2015;135:745-52.e5
Penicillin Allergy Testing and Antibiotic Stewardship
 The most frequent serious cephalosporin-associated adverse
drug reactions were Clostridium difficile within 90 days
(0.91%), nephropathy within 30 days (0.15%), and all cause
death within 1 day (0.10%). All were un-correlated to drug
“allergy” history.
 5917/10750 (55%) of all new Clostridium difficile cases in
Kaiser Permanente Southern California had a cephalosporin
exposure within 90 days and in 4301(40%) it was a 3rd or
higher generation.
Macy E, Contreras R. Adverse reactions associated with oral and
parenteral cephalosporin use: a retrospective population-based
analysis. J Allergy Clin Immunol 2015;135:745-52.e5
Penicillin Allergy Testing and Antibiotic Stewardship

It was possible to match 308 (73.2%) of penicillin allergy cases to 1251 unique penicillin
allergic controls, based on age, gender, Charlson comorbidity index, drug class allergies,
and outpatient visits, emergency room visits, hospital days, and antibiotic courses per
year.
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Matched cases had lower lead-in Charlson scores and fewer annual antibiotic courses,
outpatient visits, emergency room visits, and hospital days compared to average cases,
but higher lead-in Charlson scores and more annual antibiotic courses and outpatient
visits compared to average potential controls.
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During the follow-up period that ended on March 31, 2015, cases had 0.78 ± 4.63 fewer
outpatient visits (p = 0.0003), 0.07 ± 0.72 fewer emergency room visits (p = 0.0487), and
0.24 ± fewer hospital days (p < 0.0001) per year of follow-up compared to controls.
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During follow-up significantly more cases were exposed to penicillins (p < 0.0001) and 1st
generation cephalosporins (p < 0.0001) and fewer to clindamycin (p < 0.0001) and
macrolides (p = 0.0009).
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Penicillin allergy testing the 308 matched cases saved the health plan slightly over one
million dollars over 3.6 years.
Penicillin Allergy Testing and Antibiotic Stewardship
Unverified penicillin “allergy” is a significant public health problem and
all hospitalized patients with a penicillin “allergy” should have their
allergy confirmed or removed
Less than 5% of individuals with a history of penicillin “allergy” can be
confirmed to be allergic by properly performed penicillin skin testing,
followed by oral amoxicillin challenge, if skin test negative
Penicillin skin testing can be safely done at this time using only native
penicillin G, penicilloyl-poly-lysine (Pre-Pen®) when followed by an
oral 250 mg amoxicillin challenge, if skin test negative
Cephalosporins are safely used even in individuals with confirmed
penicillin allergy and are widely and appropriately used in individuals
with only a history of penicillin “allergy”