Pharmacy News Capsule
Content Editor: Lynne M. Sylvia, PharmD
Update on Drug Allergy
Issue Highlights:
In this issue, updates will be provided on the following
drug allergy-related issues:
 Graded challenge: What is it? How does it differ
from desensitization? What is the current status of
graded challenge at Tufts Medical Center?
 Beta-lactam cross-reactivity: What are the risks of
cross-reactivity between penicillins and both
cephalosporins and carbapenems, and between
individual cephalosporins?
 Sulfa allergy: In a patient with suspected allergy to
furosemide, what is the risk of cross-reactivity to
bumetanide?
Drug allergy or hypersensitivity remains a clinical challenge.
Contributing to this challenge is the high rate of mislabeling
of drug allergy and the unnecessary avoidance of ‘allergic’
medications. True hypersensitivity requiring drug avoidance
is relatively rare, manifesting as anaphylaxis, severe
cutaneous adverse reactions (SCARs), and other severe
systemic immune-mediated events temporally related to
drug exposure. However, common adverse drug reactions
(e.g., nausea, headache) in addition to predictable
pharmacologically-mediated effects (e.g., opiate-induced
itching) can be mislabeled as true allergic events, resulting
in unnecessary drug avoidance. In particular, only 10-15%
of patients with self-reported penicillin allergies have been
found to be allergic by skin testing. Use of alternative
antibiotics in patients with mislabeled penicillin allergy has
been associated with increased medical costs and an
increased frequency of infection with methicillin-resistant
Staphylococcus aureus and Clostridium difficile.1
Clarification of the drug allergy is the first step to addressing
the potential for mislabeling. The clarification process
involves a patient interview. Questions should be posed to
the patient and/or family in an attempt to identify the
specific ‘allergic medication’ (i.e., amoxicillin, ampicillin), the
type of reaction (i.e., isolated hives, shortness of breath, a
maculopapular rash), the timing of the reaction (i.e., within
hours of first dose administration or on day 5 of therapy),
Volume 16 Issue 1: January/February 2021
the time since last exposure to the medication (i.e., weeks,
months, years), the treatment of the reaction (i.e., no
treatment, an oral antihistamine, hospitalization) and the
tolerability of related medications (i.e., safe use of
cephalexin or another cephalosporin in a patient reporting
amoxicillin allergy). After gathering these data, the patient’s
reaction and allergy history may warrant reclassification. If
downgraded to remote, low severity and/or low risk of
reactivity, the patient may be deemed a candidate for test
dosing, also known as graded challenge dosing, prior to
subsequent drug exposure.
Unlike desensitization, graded challenge dosing does not
modify the immune response to a drug. Instead, it involves
the cautious introduction of a medication (or ‘test dosing’)
when the risk of reactivity is deemed low. In particular,
graded challenge is advised when the risk of a severe
reaction on drug re-exposure is low, alternative agents are
not equally effective, and a reliable skin testing method is
not available. At Tufts Medical Center, a Pilot Graded
Challenge Clinical Guideline and Operating Procedure
summarized below will be active as of February 16, 2021.
Graded Challenge for Beta-lactam Allergy
Inclusion criteria as determined by Allergy/ID Consult are as
follows:
o Patient with documented penicillin allergy in medical
record;
o Patient able to verbalize symptoms of allergic reaction, if
they occurred;
o Isolated reaction with questionable link to true allergy
such as GI symptoms, headache, pruritus without rash,
nonspecific nonurticarial rash, remote reaction (> 10
years ago) without IgE features, family history of
penicillin allergy
Exclusion criteria:
1) Moderate Risk Allergy
a. History of anaphylaxis
b. Respiratory components (wheezing, shortness of
breath, throat or chest tightness)
c. Urticarial rash
d. Angioedema
Pharmacy NewsCapsule
e. Cardiovascular components (arrhythmia, flushing,
syncope, hypotension)
f. Allergy associated with severe GI symptoms
2) High Risk Allergy
a. Stevens-Johnson Syndrome, toxic epidermal
necrolysis (TEN)
b. DRESS (drug rash with eosinophilia and systemic
symptoms)
c. Acute generalized exanthematous rash
d. Serum sickness
e. Erythema multiforme
f. Thrombocytopenia, anemia
3) Special populations
a. Pregnancy
b. Pediatrics
c. High dose corticosteroids (> 40 mg prednisone or
equivalent/day)
d. Recent allergic reaction to any medication (within 1
week)
4) Recent instability
a. Stable asthma with exacerbation within past 2 weeks
b. Hypotension requiring resuscitation within previous
72 hours
c. End stage heart failure or labile blood pressures
Five medications will be available for graded challenge:
o Oxacillin
o Ampicillin (can be used if planning to subsequently treat
with ampicillin/sulbactam)
o Piperacillin/tazobactam
o Cefazolin
o Ceftriaxone
Involved Patient Care Units:
o Med-Surg Floors = N4, N6, N7, N8, PG5N, PG7,
o ICUs = all adult
o NIMC
o Cardiomyopathy Unit (Pratt 8)
The Protocol:
Key aspects of the Clinical Guideline and Operating
Procedure are as follows:
1) Appropriateness for graded challenge will be determined
by ID Consult staff.
2) The ID consultant will discuss the rationale with the
patient and/or family.
3) The ID fellow or attending will contact the charge nurse
to plan the timing of the graded challenge. A 4-hour block
of time with a dedicated RN (1:1) is needed.
4) The graded challenge will be scheduled Mondays through
Fridays. Orders placed by the primary team must be
submitted to Pharmacy by 0800 with initiation of the
protocol prior to 1500 (3 PM). If unable to complete the
procedure in this time frame, the procedure will be
scheduled for the next business day.
5) Once the time frame has been established, the primary
team will place the orders via Soarian. There is a CPOE
January/February 2021 Issue 1
Order Set for Graded Challenge. The desired antibiotic
also needs to be ordered with the additional comment
“GRADED CHALLENGE PROTOCOL”.
Nursing Protocol involves the following key steps:
1) Assess for patient IV access.
2) Place patient on continuous ECG and O2 saturation
monitoring.
3) Obtain baseline vital signs.
4) Obtain Allergy Kit as ordered containing
diphenhydramine, epinephrine and famotidine from
Omnicell to be placed in patient room.
5) Obtain the patient-specific graded challenge antibiotic in
an infusion bag.
6) Use the GRADED CHALLENGE SETTING on the infusion
pump. Administer 10% of the dose (10 mL of a 100 mL
bag), then STOP THE INFUSION.
7) Observe vital signs every 15 minutes x 2.
8) If no allergic reaction is observed after the 30 minute
period, infuse the remaining 90% of the dose from the
same infusion bag.
9) Continuous observation (1:1) is required to assess for a
reaction. If signs or symptoms of a reaction are observed,
follow the guideline/order set in CPOE. The order set
provides specific instructions on actions to be taken in
the setting of observing subjective symptoms (e.g.,
scratchy throat, pruritus without rash), minor cutaneous
reaction (e.g., flushing, rash, hives) and possible systemic
reaction (e.g., anaphylaxis).
10) Obtain vital signs at completion of the infusion and every
30 minutes x 2.
The patient will be followed closely for the next 24 hours and
the results of the graded challenge procedure will be
documented in Soarian by the ID team. The allergy history
will also be updated to include the date of and the response
to the graded challenge. Anaphylaxis medications should be
discontinued at the end of the challenge.
Overall, the goal of the Graded Challenge Protocol is to
increase the number of patients receiving first-line antibiotic
therapy and to improve the accuracy of beta-lactam allergy
information in the patient’s medical record. The benefits
are improved clinical outcomes in patients treated with first-
line antibiotics, decreased cost and complications
associated with suboptimal therapies, and improved
reconciliation of allergy histories.
For any questions on the Graded Challenge Protocol, please
contact Maureen Campion, PharmD at X 6-3280 or pager #
0805.
1) Macy E, Contrarus R. Heath care use and serious infection
prevalence associated with penicillin allergy in
hospitalized patients. J Allergy Clin Immunol 2014; 133:
790-796.
Pharmacy NewsCapsule January/February 2021 Issue 1

the risk of cross-reactivity.

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

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
In terms of cross-reactivity to carbapenems, the second
analysis showed:
 a rate of 0.79% (95%CI 0.21-2.88) for imipenem
based on 9 studies involving a total of 917 penicillin-
allergic patients;
 a rate of 0.30% (95%CI 0.08-1.19) for meropenem
based on 5 studies;
 a rate of 0% (0 of 379 patients) for ertapenem;
 an overall risk of cross-reactivity to any carbapenem
of 0.87% (95%CI 0.32-2.32).
Based on these analyses, the risk of cross-reactivity between
an aminopenicillin and a cephalosporin is largely based on
R1 side chain similarity. All of the cephalosporins found to
have the highest risk of cross-sensitivity had identical R1 side
chains to an aminopenicillin. Cefazolin, cefuroxime and all
of the third and fourth generation agents included in the
analysis had low similarity scores and very low risk of cross-
reactivity (2.11%). So what about cephalosporins such as
ceftaroline that were not included in this analysis? Picard et
al1 conclude that ‘these findings can be extrapolated to
estimate the risk of cross-reactivity for cephalosporins for
which little or no data are available’.
What about the cross-reactive risk BETWEEN
cephalosporins? Recent studies reinforce that
cephalosporin allergy is not a class effect. Again, similarity
in the R 1 side chain is a major determinant in evaluating the
risk of cross-reactivity between cephalosporins. Skin testing
and subsequent graded challenge dosing was conducted by
Romano et al2 in 102 patients with cephalosporin allergy.
The majority of these patients had history of allergy to
ceftriaxone (60%), followed by cefaclor (12%), then
ceftazidime (9%) and cefazolin (6%). Skin testing was
performed with 11 different cephalosporins including the
cephalosporin associated with prior reactivity. Based on the
skin testing results, patients were placed in 1 of 4 groups
being:
 Group A: positive response to 1 or more of
ceftriaxone, cefuroxime, cefotaxime, cefepime,
cefodizime, and ceftazidime (n=73);
 Group B: positive response to an aminocephalo-
sporin such as cefaclor and cephalexin (n=13);
 Group C: positive response to cephalosporins not
included in Groups A and B (n=7);
 Group D: positive response to cephalosporins
belonging in 2 different Groups (n=9).
Of note, 59 (58%) of the 102 patients were skin test positive
only to the cephalosporin associated with the original
allergic event (e.g., ceftriaxone, ceftazidime, cefazolin). In
the 73 patients in Group A, the largest subset of patients,
January/February 2021 Issue 1
the relative risk of cross-reacting to 1 other cephalosporin in
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
than A was 0.33 (95%CI 0.11-0.99; p< 0.05). All 326
challenges with alternative cephalosporins (ceftibuten in
101, cefazolin in 96, cefaclor in 82, cefuroxime axetil and
ceftriaxone in 22 patients) associated with skin test
negativity were well tolerated.
Overall, 91% of patients in Romano et al’s study exhibited
skin test sensitivity to cephalosporins with similar R1 side
chains. Group D, consisting of 9 patients, exhibited
sensitivity to cephalosporins categorized in 2 different
structure-designated groups. These data further support a
structure activity relationship with cross-sensitivity between
cephalosporins in the majority of patients. Evidence
suggests that the R2 side chain [see Figure 2] is disrupted by
opening of the beta lactam ring, leading to fragmented, ill-
defined allergenic determinants.3 Thus, the R1 side chain
appears to be the dominant allergenic side chain to be
considered when assessing the risk of cross-reactivity. In
addition, this study demonstrated that allergic reactions to
a single cephalosporin are not uncommon. In particular,
cefazolin has a relatively unique R1 side chain, possibly
accounting for ‘cefazolin’ only allergy.
References:
1) Picard M et al. Cross-reactivity to cephalosporins and
carbapenems in penicillin-allergic patients; two systematic
reviews and meta-analyses J Allergy Clin Immunol Prac
2019;7:2722-38.
2) Romano A et al. IgE-mediated hypersensitivity to
cephalosporins: cross-reactivity and tolerability of alternative
cephalosporins. J Allergy Clin Immunol 2015;136:685-9.
3) Khan DA et al. Cephalosporin allergy: current understanding
and future challenges. J Allergy Clin Immunol Pract
2019;7:2105-14.
Furosemide Allergy: Use of Bumetanide
Unlike the penicillins, the sulfa drug class has been poorly
studied in terms of cross-reactivity. Drugs with the sulfa
moiety (SO2NH2) include a wide variety of medications:
antibiotics, thiazide and loop diuretics, oral hypoglycemic
agents in the sulfonylurea class, carbonic anhydrase
inhibitors, tamsulosin, the antivirals amprenavir and
darunavir, triptans, and an anticonvulsant, zonisamide.
These agents can be further classified into aromatic sulfas
and nonaromatic sulfas based on their chemical structure.
The aromatic sulfas, such as sulfamethoxazole and
sulfadiazine, have been shown to have higher rates of
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
and is not readily available for use. At Tufts Medical Center,
at least 8 patients in the past year with self-reported allergy
to furosemide or observed cutaneous non-IgE mediated
reactions to furosemide have been successfully treated with
bumetanide. Prior to introducing bumetanide in a patient
with furosemide ‘allergy’, the severity of the allergy must be
considered. A causal relationship between furosemide and
either a severe IgE mediated reaction or a SCAR would
preclude the use of bumetanide or another sulfa diuretic. In
1) Strom BL et al. Absence of cross-reactivity between
sulfonamide antibiotics and sulfonamide
nonantibiotics. NEJM 2003;349:1678-35.
2) Bumetanide (Bumex®) product information;
Hospira Inc, Lake Forest IL, 11/20.
3) Gratadour P, Guillaume C, Bui-Xuan B et al. Absence
of cross-sensitivity between furosemide and
bumetanide. Press Med 1990;19:1504.
Pharmacy NewsCapsule January/February 2021 Issue 1