Pharmacy News Capsule

Content Editor: Lynne M. Sylvia, PharmD Volume 16 Issue 1: January/February 2021

Update on Drug Allergy

the time since last exposure to the medication (i.e., weeks,
Issue Highlights:
months, years), the treatment of the reaction (i.e., no
In this issue, updates will be provided on the following
treatment, an oral antihistamine, hospitalization) and the
drug allergy-related issues:
tolerability of related medications (i.e., safe use of
 Graded challenge: What is it? How does it differ cephalexin or another cephalosporin in a patient reporting
from desensitization? What is the current status of amoxicillin allergy). After gathering these data, the patient’s
graded challenge at Tufts Medical Center?
reaction and allergy history may warrant reclassification. If
 Beta-lactam cross-reactivity: What are the risks of downgraded to remote, low severity and/or low risk of
cross-reactivity between penicillins and both reactivity, the patient may be deemed a candidate for test
cephalosporins and carbapenems, and between dosing, also known as graded challenge dosing, prior to
individual cephalosporins? subsequent drug exposure.
 Sulfa allergy: In a patient with suspected allergy to
furosemide, what is the risk of cross-reactivity to Unlike desensitization, graded challenge dosing does not
bumetanide? modify the immune response to a drug. Instead, it involves
the cautious introduction of a medication (or ‘test dosing’)
Drug allergy or hypersensitivity remains a clinical challenge. when the risk of reactivity is deemed low. In particular,
Contributing to this challenge is the high rate of mislabeling graded challenge is advised when the risk of a severe
of drug allergy and the unnecessary avoidance of ‘allergic’ reaction on drug re-exposure is low, alternative agents are
medications. True hypersensitivity requiring drug avoidance not equally effective, and a reliable skin testing method is
is relatively rare, manifesting as anaphylaxis, severe not available. At Tufts Medical Center, a Pilot Graded
cutaneous adverse reactions (SCARs), and other severe Challenge Clinical Guideline and Operating Procedure
systemic immune-mediated events temporally related to summarized below will be active as of February 16, 2021.
drug exposure. However, common adverse drug reactions
(e.g., nausea, headache) in addition to predictable Graded Challenge for Beta-lactam Allergy
pharmacologically-mediated effects (e.g., opiate-induced
itching) can be mislabeled as true allergic events, resulting Inclusion criteria as determined by Allergy/ID Consult are as
in unnecessary drug avoidance. In particular, only 10-15% follows:
o Patient with documented penicillin allergy in medical
of patients with self-reported penicillin allergies have been
record;
found to be allergic by skin testing. Use of alternative o Patient able to verbalize symptoms of allergic reaction, if
antibiotics in patients with mislabeled penicillin allergy has they occurred;
been associated with increased medical costs and an o Isolated reaction with questionable link to true allergy
increased frequency of infection with methicillin-resistant such as GI symptoms, headache, pruritus without rash,
Staphylococcus aureus and Clostridium difficile.1 nonspecific nonurticarial rash, remote reaction (> 10
years ago) without IgE features, family history of
Clarification of the drug allergy is the first step to addressing penicillin allergy
the potential for mislabeling. The clarification process Exclusion criteria:
involves a patient interview. Questions should be posed to 1) Moderate Risk Allergy
a. History of anaphylaxis
the patient and/or family in an attempt to identify the
b. Respiratory components (wheezing, shortness of
specific ‘allergic medication’ (i.e., amoxicillin, ampicillin), the
breath, throat or chest tightness)
type of reaction (i.e., isolated hives, shortness of breath, a c. Urticarial rash
maculopapular rash), the timing of the reaction (i.e., within d. Angioedema
hours of first dose administration or on day 5 of therapy),
Pharmacy NewsCapsule January/February 2021 Issue 1

e. Cardiovascular components (arrhythmia, flushing, Order Set for Graded Challenge. The desired antibiotic
syncope, hypotension) also needs to be ordered with the additional comment
f. Allergy associated with severe GI symptoms “GRADED CHALLENGE PROTOCOL”.
2) High Risk Allergy
a. Stevens-Johnson Syndrome, toxic epidermal Nursing Protocol involves the following key steps:
necrolysis (TEN) 1) Assess for patient IV access.
b. DRESS (drug rash with eosinophilia and systemic 2) Place patient on continuous ECG and O2 saturation
symptoms) monitoring.
c. Acute generalized exanthematous rash 3) Obtain baseline vital signs.
d. Serum sickness 4) Obtain Allergy Kit as ordered containing
e. Erythema multiforme diphenhydramine, epinephrine and famotidine from
f. Thrombocytopenia, anemia Omnicell to be placed in patient room.
3) Special populations 5) Obtain the patient-specific graded challenge antibiotic in
a. Pregnancy an infusion bag.
b. Pediatrics 6) Use the GRADED CHALLENGE SETTING on the infusion
c. High dose corticosteroids (> 40 mg prednisone or pump. Administer 10% of the dose (10 mL of a 100 mL
equivalent/day) bag), then STOP THE INFUSION.
d. Recent allergic reaction to any medication (within 1 7) Observe vital signs every 15 minutes x 2.
week) 8) If no allergic reaction is observed after the 30 minute
4) Recent instability period, infuse the remaining 90% of the dose from the
a. Stable asthma with exacerbation within past 2 weeks same infusion bag.
b. Hypotension requiring resuscitation within previous 9) Continuous observation (1:1) is required to assess for a
72 hours reaction. If signs or symptoms of a reaction are observed,
c. End stage heart failure or labile blood pressures follow the guideline/order set in CPOE. The order set
provides specific instructions on actions to be taken in
Five medications will be available for graded challenge: the setting of observing subjective symptoms (e.g.,
o Oxacillin scratchy throat, pruritus without rash), minor cutaneous
o Ampicillin (can be used if planning to subsequently treat reaction (e.g., flushing, rash, hives) and possible systemic
with ampicillin/sulbactam) reaction (e.g., anaphylaxis).
o Piperacillin/tazobactam 10) Obtain vital signs at completion of the infusion and every
o Cefazolin 30 minutes x 2.
o Ceftriaxone
The patient will be followed closely for the next 24 hours and
Involved Patient Care Units: the results of the graded challenge procedure will be
o Med-Surg Floors = N4, N6, N7, N8, PG5N, PG7, documented in Soarian by the ID team. The allergy history
o ICUs = all adult will also be updated to include the date of and the response
o NIMC to the graded challenge. Anaphylaxis medications should be
o Cardiomyopathy Unit (Pratt 8)
discontinued at the end of the challenge.
The Protocol:
Overall, the goal of the Graded Challenge Protocol is to
Key aspects of the Clinical Guideline and Operating
increase the number of patients receiving first-line antibiotic
Procedure are as follows:
therapy and to improve the accuracy of beta-lactam allergy
1) Appropriateness for graded challenge will be determined
information in the patient’s medical record. The benefits
by ID Consult staff. are improved clinical outcomes in patients treated with first-
2) The ID consultant will discuss the rationale with the line antibiotics, decreased cost and complications
patient and/or family. associated with suboptimal therapies, and improved
3) The ID fellow or attending will contact the charge nurse reconciliation of allergy histories.
to plan the timing of the graded challenge. A 4-hour block
of time with a dedicated RN (1:1) is needed. For any questions on the Graded Challenge Protocol, please
4) The graded challenge will be scheduled Mondays through contact Maureen Campion, PharmD at X 6-3280 or pager #
Fridays. Orders placed by the primary team must be 0805.
submitted to Pharmacy by 0800 with initiation of the
protocol prior to 1500 (3 PM). If unable to complete the
1) Macy E, Contrarus R. Heath care use and serious infection
procedure in this time frame, the procedure will be
prevalence associated with penicillin allergy in
scheduled for the next business day.
hospitalized patients. J Allergy Clin Immunol 2014; 133:
5) Once the time frame has been established, the primary
790-796.
team will place the orders via Soarian. There is a CPOE
Pharmacy NewsCapsule January/February 2021 Issue 1

the risk of cross-reactivity.

Update on Beta-Lactam Allergy
The results of the analyses support our prior observations
that the R1 side chain of the beta-lactam matters in terms
In previous issues of this newsletter, the risk of cross- of assessing the risk of cross-reactivity. [See Figure below of
reactions between the various beta-lactam antibiotics has cephalosporin chemical structure] In terms of cross-
been summarized in detail. As an update, recently reactivity with an aminopenicillin (amoxicillin, ampicillin),
published literature further supports that application of the analysis showed:
both medicinal chemistry and immunology principles is
needed for clinical decision-making in this area of practice.  The highest risk of cross-reactivity of 16.45% (95%CI
How often do you examine the chemical structure of a drug 11.07-23.75) for cephalosporins with similarity
with attention to its core molecule and side chains? To score 1 and identical R1 side chain (cefadroxil,
assess the risk of cross-reactivity among the beta-lactam cephalexin, cefprozil, cefaclor);
antibiotic class, you will need to go back to the basics.  A lower risk of 5.6% (95%CI 3.46-8.95) for a few
cephalosporins (cephalothin, cefamandole,
In 2019, Picard and co-workers1 were the first to publish two cephaloridine) with an intermediate similarity score
systematic reviews and meta-analyses examining the risks (0.56-0.714);
of cross-reactivity to both cephalosporins and carbapenems  The lowest risk of 2.11% (95%CI 0.98-4.46) for
in penicillin-allergic patients. These reviews/analyses had cephalosporins with low similarity scores (< 0.4)
numerous strengths including the inclusion of studies regardless of cephalosporin generation. These
published from January 1980 through March 2019. Studies agents included cefazolin, cefuroxime, cefixime,
published prior to 1980 were excluded based on the risk of cefotaxime, ceftriaxone, ceftazidime, cefpodoxime,
cephalosporin contamination with penicillins before 1980. ceftibuten, and cefepime.
Studies were identified via MEDLINE, EMBASE, Cochrane
Library, Google Scholar in addition to the web sites of Figure: Cephalosporin Chemical Structure with Side
national agencies. To be eligible, the study had to include at Chains
least 10 penicillin-allergic patients whose allergies were
confirmed by a positive skin or drug provocation test. Cross-
reactivity had to be assessed in the study to at least 1
cephalosporin or a carbapenem. A total of 21 observational
studies involving 1269 penicillin-allergic patients were
included in the analysis of cephalosporin cross-reactivity. A
total of 11 observational studies involving 1127 penicillin-
allergic patients were analyzed to assess for cross-reactivity
to a carbapenem.

Of note, almost all of the reactions to penicillin in the

involved patients were to aminopenicillins (amoxicillin,
ampicillin, bacampicillin, pivampicillin). In this regard, the
cross-reactive risks observed in these analyses are best
applied to patients with aminopenicillin allergy, not to those
with allergies to a non-aminopenicillin such as piperacillin,
ticarcillin, cloxacillin or penicillin V or G. The allergies were
IgE mediated in 57% of patients, T cell mediated in 39% of
patients, and not clearly defined in 4% of patients.

The risk of cross-reactivity to a cephalosporin was reported

using similarity scores. These scores reflected the similarity
between the R1 side chain of the aminopenicillin and the
cephalosporin. For example, a similarity score of 1 was used
for the aminocephalosporins that have an identical R1 side
chain with an aminopenicillin. A secondary objective was to
assess the correlation between R1 side chain similarity and
Pharmacy NewsCapsule January/February 2021 Issue 1

In terms of cross-reactivity to carbapenems, the second the relative risk of cross-reacting to 1 other cephalosporin in
analysis showed: the same group was 21 (95%CI 1.34-328.95; p <0.05) and the
risk of cross-reacting to a cephalosporin in a group other
 a rate of 0.79% (95%CI 0.21-2.88) for imipenem than A was 0.33 (95%CI 0.11-0.99; p< 0.05). All 326
based on 9 studies involving a total of 917 penicillin- challenges with alternative cephalosporins (ceftibuten in
allergic patients; 101, cefazolin in 96, cefaclor in 82, cefuroxime axetil and
 a rate of 0.30% (95%CI 0.08-1.19) for meropenem ceftriaxone in 22 patients) associated with skin test
based on 5 studies; negativity were well tolerated.
 a rate of 0% (0 of 379 patients) for ertapenem;
 an overall risk of cross-reactivity to any carbapenem Overall, 91% of patients in Romano et al’s study exhibited
of 0.87% (95%CI 0.32-2.32). skin test sensitivity to cephalosporins with similar R1 side
chains. Group D, consisting of 9 patients, exhibited
Based on these analyses, the risk of cross-reactivity between sensitivity to cephalosporins categorized in 2 different
an aminopenicillin and a cephalosporin is largely based on structure-designated groups. These data further support a
R1 side chain similarity. All of the cephalosporins found to structure activity relationship with cross-sensitivity between
have the highest risk of cross-sensitivity had identical R1 side cephalosporins in the majority of patients. Evidence
chains to an aminopenicillin. Cefazolin, cefuroxime and all suggests that the R2 side chain [see Figure 2] is disrupted by
of the third and fourth generation agents included in the opening of the beta lactam ring, leading to fragmented, ill-
analysis had low similarity scores and very low risk of cross- defined allergenic determinants.3 Thus, the R1 side chain
reactivity (2.11%). So what about cephalosporins such as appears to be the dominant allergenic side chain to be
ceftaroline that were not included in this analysis? Picard et considered when assessing the risk of cross-reactivity. In
al1 conclude that ‘these findings can be extrapolated to addition, this study demonstrated that allergic reactions to
estimate the risk of cross-reactivity for cephalosporins for a single cephalosporin are not uncommon. In particular,
which little or no data are available’. cefazolin has a relatively unique R1 side chain, possibly
accounting for ‘cefazolin’ only allergy.
What about the cross-reactive risk BETWEEN
cephalosporins? Recent studies reinforce that References:
cephalosporin allergy is not a class effect. Again, similarity 1) Picard M et al. Cross-reactivity to cephalosporins and
in the R 1 side chain is a major determinant in evaluating the carbapenems in penicillin-allergic patients; two systematic
reviews and meta-analyses J Allergy Clin Immunol Prac
risk of cross-reactivity between cephalosporins. Skin testing
2019;7:2722-38.
and subsequent graded challenge dosing was conducted by 2) Romano A et al. IgE-mediated hypersensitivity to
Romano et al2 in 102 patients with cephalosporin allergy. cephalosporins: cross-reactivity and tolerability of alternative
The majority of these patients had history of allergy to cephalosporins. J Allergy Clin Immunol 2015;136:685-9.
ceftriaxone (60%), followed by cefaclor (12%), then 3) Khan DA et al. Cephalosporin allergy: current understanding
ceftazidime (9%) and cefazolin (6%). Skin testing was and future challenges. J Allergy Clin Immunol Pract
performed with 11 different cephalosporins including the 2019;7:2105-14.
cephalosporin associated with prior reactivity. Based on the
skin testing results, patients were placed in 1 of 4 groups
being: Furosemide Allergy: Use of Bumetanide
 Group A: positive response to 1 or more of
ceftriaxone, cefuroxime, cefotaxime, cefepime,
cefodizime, and ceftazidime (n=73); Unlike the penicillins, the sulfa drug class has been poorly
 Group B: positive response to an aminocephalo- studied in terms of cross-reactivity. Drugs with the sulfa
sporin such as cefaclor and cephalexin (n=13); moiety (SO2NH2) include a wide variety of medications:
 Group C: positive response to cephalosporins not antibiotics, thiazide and loop diuretics, oral hypoglycemic
included in Groups A and B (n=7); agents in the sulfonylurea class, carbonic anhydrase
 Group D: positive response to cephalosporins inhibitors, tamsulosin, the antivirals amprenavir and
belonging in 2 different Groups (n=9). darunavir, triptans, and an anticonvulsant, zonisamide.
These agents can be further classified into aromatic sulfas
Of note, 59 (58%) of the 102 patients were skin test positive and nonaromatic sulfas based on their chemical structure.
only to the cephalosporin associated with the original The aromatic sulfas, such as sulfamethoxazole and
allergic event (e.g., ceftriaxone, ceftazidime, cefazolin). In sulfadiazine, have been shown to have higher rates of
the 73 patients in Group A, the largest subset of patients, allergenicity compared to the nonaromatic sulfas.
Pharmacy NewsCapsule January/February 2021 Issue 1

Structural differences influence the metabolic conversion of these instances, the Department of Allergy should be
the sulfa drug into reactive metabolites that mediate consulted.
hypersensitivity. For example, the aromatic sulfas have an
arylamine group in the N4 position or an N-containing ring
in the N-1 position, increasing the metabolism of the sulfa
into reactive metabolites that confer antigenicity.
Sulfamethoxazole, an aromatic sulfa contained in Bactrim®,
has the highest associated rate of allergy occurring in 6% of
treated patients. In the largest study to data of sulfa allergy,
only 10% of patients who were allergic to an antibiotic sulfa
(e.g., sulfamethoxazole) reacted to a non-antibiotic,
nonaromatic sulfa (e.g., loop diuretic, thiazide diuretic, Sulfamethoxazole: an Aromatic Sulfa
sulfonylurea, acetazolamide), and none of these cross-
reactions were immediate.1

Both furosemide and bumetanide are non-aromatic sulfas

thereby having relatively lower rates of reactivity. However,
allergic reactions to furosemide manifesting as
maculopapular rash or a mixed urticarial and maculopapular
rash have been reported. In these patients, particularly
those with heart failure and the need for aggressive diuresis,
a common question relates to assessment of the risk of
cross-reactivity between furosemide and other loop
diuretics. In particular, in patients requiring IV diuresis,
what is the risk of cross-reactivity between our two available Furosemide: A Nonaromatic sulfa
IV loop diuretics, furosemide and bumetanide?

Data are limited on the risk of cross-reactivity between

these 2 nonaromatic sulfas, furosemide and bumetanide. A
review of the product information of bumetanide (Bumex®)
reveals the following statement, “Successful treatment with
Bumex® following instances of allergic reactions to
furosemide suggest a lack of cross-reactivity”.2 The
structural differences between these two nonaromatic
sulfas may contribute to the lack of or low risk of cross-
reactivity [See Figures]. Others have stated that,’ because
cross-sensitivity with furosemide has rarely been observed,
bumetanide can be substituted for furosemide in patients
allergic to furosemide’.3 Bumetanide: A Nonaromatic Sulfa

Ethacrynic acid is a non-sulfa loop diuretic, thereby References:

presenting the least risk of cross-reactivity with furosemide.
However, ethacrynic acid has limited commercial availability 1) Strom BL et al. Absence of cross-reactivity between
and is not readily available for use. At Tufts Medical Center, sulfonamide antibiotics and sulfonamide
at least 8 patients in the past year with self-reported allergy nonantibiotics. NEJM 2003;349:1678-35.
to furosemide or observed cutaneous non-IgE mediated 2) Bumetanide (Bumex®) product information;
reactions to furosemide have been successfully treated with Hospira Inc, Lake Forest IL, 11/20.
bumetanide. Prior to introducing bumetanide in a patient 3) Gratadour P, Guillaume C, Bui-Xuan B et al. Absence
with furosemide ‘allergy’, the severity of the allergy must be of cross-sensitivity between furosemide and
considered. A causal relationship between furosemide and bumetanide. Press Med 1990;19:1504.
either a severe IgE mediated reaction or a SCAR would
preclude the use of bumetanide or another sulfa diuretic. In
Pharmacy NewsCapsule January/February 2021 Issue 1