Penicillin allergy

Penicillin Allergy
Lalita Tearprasert; MD
1

Introduction
Prevalence
Impact of penicillin allergy
Chemical structure and classifications
Cross reactivity
Reactions to penicillin
Risk factors
Diagnosis : In vitro, In vivo
Natural evolution
Desensitization, Graded challenge
Resensitization
Scope
2

Introduction
Accidentally discovered Penicillin in 1928
Sir Alexander Fleming (Scottish biologist, pharmacologist and botanist)
Noticed antibacterial properties in a mold (Penicillium notatum)
growing on a bacterial culture plate
First called the substance “mould juice”
and then “penicillin”
3

Penicillin eventually came into use during World War II as the result
of the work of a team of scientists led by Howard Florey at the
University of Oxford
His coworker Ernst Chain, and Fleming shared the 1945 Nobel Prize
4

Prevalence
Penicillin is the most prevalent medication allergy
About 10% of patients reporting a history of penicillin allergy,
but up to 90% of these individuals are able to tolerate penicillins
- Penicillin specific IgE antibodies are known to rapidly
wane over time
- Some reactions, particularly cutaneous eruptions, were the
result of an underlying viral or bacterial infection
- Mislabel
Khan and Solensky. J Allergy Clin Immunol 2010;125:S126-37.
Practice parameter : Drug allergy 2010.
5

Prakongwong T. J Med Assoc Thai 2010; 93 (Suppl. 6): S106-S111.
6

Patients labeled as allergic are more likely to be treated with
broad spectrum antibiotics such as quinolones and vancomycin
leading to
- the development of bacterial resistances
- high medical cost
Solensky R.J Allergy Clin Immunol 2012. Volume 130, Number 6.
Impact of penicillin allergy
7

Chemical structure
Bicyclic structure composed of a 4-member beta-lactam ring
and a 5-member thiazolidine ring
8

Low molecular weight molecule
Native state: Inert
Spontaneous conversion under physiologic conditions to
a number of products that can covalently bind tissue and serum
proteins leading to formation of new hapten-protein structures
that may induce production of specific IgE responses
Middleton's Ed 8. Drug allergy. 1274-95.
Al-Ahmad M, et al. Asia Pac Allergy 2014;4:106-112.
9

10

11
Transformation products
- Major antigenic determinants (95% of the tissue-bound penicillin)
>> Penicilloyl group
- Minor antigenic determinants
>> Penicilloate and Penilloate

Khan and Solensky. J Allergy Clin Immunol 2010;125:S126-37.
Major
Minor
Minor determinant–specific IgE responses to β-lactams are
of major clinical importance because of their association with anaphylaxis,
whereas penicilloyl IgE responses may be more associated clinically with
urticarial reactions
12

Classifications
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
Substitution at the R1 side chains resulting in various antibiotics with
different chemical structures
Amoxycillin is the drug most frequently allergy
13

Cross-reactivity : bicyclic nucleus (beta-lactam ring) or side chain
Cross-reactivity is not equal among all BLs and that the immunologic
mechanism and the primary drug inducing the sensitization need to be
taken into account
Beta- lactams
15

Similar chemical configurations
Low molecular weight
Beta-lactam ring
Difference
Penicillin : 5-membered thiazolidine ring
Cephalosporin : 6-membered dihydrothiazine ring
Differences in degradation >> cross-reactivity minimal
- Penicillin forms a stable penicilloate ring, preservation of the
thiazolidine ring
- Cephalosporin undergo rapid fragmentation of the
beta-lactam and dihydrothiazine rings
Pichichero ME. Pediatrics Vol. 115 No. 4 April 2005.
Penicillin & Cephalosporin
16

Since 1980, studies show that approximately 2% of penicillin skin
test–positive patients react to treatment with cephalosporins,
but some of these reactions may be anaphylactic reactions. (C)
Patients with a history of allergy to penicillin are not skin tested
but given cephalosporins directly, the chance of a reaction is
probably less than 1%. However, some of these reactions were
fatal anaphylaxis
Cross-reactivity increases in cases where penicillins and cephalosporins
share the same side chain
First generation cephalosporins can cross-react with penicillins
more than second and third generation
17

Cross-reactivity between penicillin and cephalosporins can
therefore be explained through similarity of the R1 side chain
18

Pichichero ME. Pediatrics Vol. 115 No. 4 April 2005.
R2 side chain
R1 side chain
Should avoid drug with identical R-group side chains or
or receive them via rapid induction of drug tolerance
19

Cephalosporin Administration to Patients
With a History of Penicillin Allergy
Skin testing to the cephalosporin followed by graded challenge
appears to be a safe method for administration of some
cephalosporins in penicillin allergic patients. (B)
Patients who have a history of a possible IgE-mediated reaction
to penicillin, regardless of the severity of the reaction, may receive
cephalosporins with minimal concern about an immediate reaction
if skin test results for penicillin major and minor determinants
are negative. (B)
20

Not a common consensus regarding the management
The following are options that may be considered
(1) substitute a non–beta-lactam antibiotic
(2) perform penicillin skin testing
(3) perform cephalosporin skin test and if the result is
negative perform a graded challenge
(4) treat with the cephalosporin (should be considered only
in the absence of a severe and/or recent penicillin allergy
reaction history)
21

22
If penicillin and cephalosporin skin testing is unavailable, depending on the reactio
or rapid induction of drug tolerance. (E)

Penicillin & Carbapenam
Limited data indicate lack of significant allergic cross-reactivity
between penicillin and carbapenems. (B)
No standardized skin test reagents are available, and skin testing
with nonirritating concentrations of the native antibiotic has
questionable predictive value
Biswas P et al. Int J Basic Clin Pharmacol. 2014 Aug;3(4):586-590.
23

Penicillin skin test–negative patients may safely receive carbapen
Penicillin skin test–positive patients and patients with
a history of penicillin allergy who do not undergo skin
testing should receive carbapenems via graded challenge
24

Penicillin & Monopenam
Monobactam class (prototype: aztreonam) is poorly immunogenic
and very weakly cross-reactive with other
β-lactams, possibly because of the absence of a second nuclear
ring structure
Aztreonam does not cross-react with other beta-lactams
except for ceftazidime, with which it shares an identical
R-group side chain (B)
Penicillin and cephalosporin allergic patients may safely
receive aztreonam, with the exception of patients who are
allergic to ceftazidime
25

Reactions to penicillin
Immediate < 1 hr.
Delayed
24-48 hr.
26

Risks of Anaphylaxis
Idsoe O, et al. Bull WHO. 1968;38:159–188.
0.004% to 0.015% , with a fatality rate of 0.002% to 0.0015%
Penicillin parenteral : 1-2 per 10,000 --> 0.01-0.02%
27

Risk factors
R. Mirakian et al. Clinical & Experimental Allergy, 2015 (45) : 300–327.
28

Ability of aminopenicillins (e.g., ampicillin, amoxicillin)
to polymerize may be a determinant of the high rate of
late-occurring exanthems especially when given to patients
- viral infection
- acute lymphocytic leukemia
- mononucleosis
- coadministered with allopurinol
The basis for these interactions is not known
29

Diagnosis
1.) History : Immediate VS Delayed
2.) Investigations
In vivo evaluations (Skin testing)
- Immediate reactions : SPT, ID
- Delayed reactions : Patch test, ID
In vitro evaluations
- Immediate reactions : IgE-antibody
- Delayed reactions : Lymphocyte activation test (LAT)
3.) Drug provocation test
30

History of allergy
Immediate-type penicillin allergy cannot be accurately
diagnosed by history alone
Reaction history is known to be a poor predictor of
skin test results, and therefore penicillin allergy cannot
be diagnosed accurately solely based on the history
Immediate VS Delayed, Dosage, Route, Previous exposure
31

Most reliable method for evaluating IgE-mediated penicillin
allergy (B)
Usually are applied first as a safety measure, and then intradermal
tests are recommended in case of negative puncture results
Performed electively
Positive test: a wheal of 3 mm or more in diameter with
surrounding flare greater than the wheal
Geng B. World Allergy Organization Journal 2015, 8(Suppl 1):A228.
Penicillin skin test
32

Penicillin skin test
reagents
Late 1960 : Development of skin test reagents for penicillin
The combination of penicillin : first-line reagent for the penicillin skin test
- Major determinant (benzylpenicilloyl-polylysine [PPL])
- Minor determinant mixture (MDM)
recommended by both the American Practice Parameters on
Drug Allergy and the European Guidelines on the Diagnosis of
Immediate Allergic Reactions to Beta-lactams
Solensky and Macy. J Allergy Clin Immunol Pract 2015;3:883-7.
Levine B. et al. Ann NY Acad Sci 1967;145:298-309.
Allergy Asthma Proc 33:152–159, 2012.
33

Should be performed with both major and minor determinants (B)
- NPV for immediate reactions 100%
- PPV for immediate reactions 40-100%
Recommended for skin testing
- Penicilloyl polylysine (PPL) (PRE-PEN)
- MDM (BP and benzylpenilloic acid)
However, in countries where AX is the most important drug
involved in sensitization, this determinant is also required
for diagnosis
34

35
Torres MJ. et al.Clinical & Experimental Allergy, 2016 (46) 264–274.
USA, canada
Europe

Allergy Asthma Proc 33:152–159, 2012.
36
The accessibility of reagents is somewhat limited
Spain manufactures the Kit DAP-penicillin (Diater Laboratorios,
Madrid, Spain), which is comprised of separated vials of PPL and MDM
and mainly used in allergy centers in Europe

www.Pre-pen.com
Pre-Pen : commercially available since 1974 (except for 2004-2009)
Approved by FDA
37

75% of penicillin skin test–positive patients showed positive
responses to only penicilloylpolylysine (NPV of penicillin skin testing
without penicilloylpolylysine is poor)
Penicillin skin testing without the major determinant is not
recommended because this would fail to identify many patients (B)
38
Importance of major determinants in penicillin skin testing

Importance of minor determinants in penicillin skin testing
In large-scale studies about 10% of patients with positive skin test
responses have positive results to penicilloate, penilloate, or both
(and negative results to PPL and penicillin G)
39

Penicillin challenges of individuals skin test negative to
penicilloyl-polylysine and penicillin G have similar reaction
rates compared with individuals skin test negative to the full set
of major and minor penicillin determinants
Skin testing with only PPL and penicillin G (without other minor determina
Skin testing with PPL and penicillin G appears to have adequate
in the evaluation of penicillin allergy
40
When MDM are not available, Penicillin G has been used as an
alternative, with PPL

Evaluation of penicillin allergy is based on the reaction history and likelihoo
The time elapsed since the reaction is useful because penicillin
specific IgE antibodies wane over time
Patients with IgE-mediated penicillin allergy
5 years after reacting --> 50% lose their sensitivity
10 years after reacting --> 80% lose their sensitivity
Unavailable penicillin skin testing
41

1.) Vague and/or distant history of penicillin allergy
>> graded challenge
2.) Recent or convincing reaction histories
>> rapid induction of drug tolerance (Desensitization)
42

Contraindication for penicillin skin
test,
DPT, Desensitization
Histories of severe non–IgE-mediated reactions
- Stevens-Johnson syndrome
- DRESS
- Toxic epidermal necrolysis
- Interstitial nephritis
- Hemolytic anemia
are not candidates for skin testing, challenge or desensitization
penicillins should avoid indefinitely
Macy E. Curr Allergy Asthma Rep (2014) 14:476.
43

IgE antibodies directed at the R-group side chain
(rather than the core penicillin determinants)
Able to tolerate other penicillin class compounds
Skin test results that are positive to a nonirritating concentration of either
amoxicillin or ampicillin but test negative to penicillin major
and minor determinants
IgE-mediated
Parker CW, et al. J Exp Med 1962;115:803-19.
More common in some parts of Europe, compared with North America
Selective Amoxycillin allergy
44

non IgE-
mediated
Approximately 5% to 10%
Delayed maculopapular rash
Risk - concurrent viral illness esp. EBV (nonpruritic rash)
- allopurinol
- chronic lymphocytic leukemia
Most patients will tolerate future administration of penicillin other
than ampicillin and amoxicillin
Histories are known to be a poor predictor of skin test results.
be considered even in patients with a history suggestive of amoxicillin/ampicillin-assoc
before a future course of penicillin is given
45

If the puncture tests are negative, intradermal testing follows
Using the same test materials, 0.02 ml is administered
intradermally through individual 27 gauge tuberculin syringes
Positive test: a wheal of 3 mm or more in diameter with
surrounding flare greater than the wheal
Hx Immediate reaction : Read and recorded after 15 min
Hx Delayed reaction : Readings are taken at 48 and 72 hours
Rare systemic reactions
Penicillin Intradermal test
46

Specific IgE Antibodies
2 main methods
1.) Detection of antibodies in serum by solid-phase
immunoassays
- CAP/ RAST
2.) Detection on the basis of basophil activation on contact
with the hapten
- BAT
Commercially available serologic tests used to diagnose
penicillin allergy are not clinically useful at this time
Blanca et al. Allergy 2009: 64: 183–193.
47

CAP System
FEIA
Fluorescense immunoassay method
Phadia AB, Uppsala, Sweden
Sensitivity from 12.5% to 45%
Specificity ranges from 83.3% to 100%
48

Diagnostic sensitivity for penicilloyl-IgE
- 65% to 85% compared with penicilloyl-polylysine skin tests
- 32% to 50% compared with a combination of skin testing
and provocative challenge
Minor determinant penicillin IgE antibodies are not reliably
detected by available allergosorbent-type immunoassays
Skin testing remains the diagnostic procedure
of choice for IgE-dependent penicillin allergy
49

Basophil activation test
(BAT)
Flow cytometry assessment of drug-induced
basophil activation by means of increased surface markers
such as CD63 and CD203c
BAT for diagnoses of beta-lactam allergies
- Sensitivities : ranged from 28.6% to 55%
(approximately 50%, in patients with positive clinical
history and skin tests)
- Specificity was more than 90%
Song WJ, et al. Asia Pac Allergy 2013;3:266-280.
50

Song WJ, et al. Asia Pac Allergy 2013;3:266-280.
51

Sensitivity of in vitro tests for penicillin specific IgE was
as low as 45% compared with skin testing
Negative in vitro test result does not rule out an
IgE-mediated allergy
In vitro tests for IgE directed against penicilloylpolylysine,
penicillin G, penicillin V, amoxicillin, and ampicillin are
commercially available, but they are not suitable
alternatives to skin testing because these assays have
unknown predictive value, which limits their usefulness
52

Patch tests
Can be done with BP, AM, AX, and the culprit BL, using a concent
Readings 15 minutes after removal of the strips and
again 48 and 72 hours later
Intradermal and/or patch tests with a late reading
at 48 to 72 hours have usually been recommended for the
diagnosis of nonimmediate reactions to BL
53

Lymphocyte transformation tests (LAT)
Measures the proliferation of T cells to a drug in vitro,
from which one concludes a previous in vivo reaction
due to a sensitization
Often strongly positive in drug-allergic subjects,
but the response usually was not distinguishable from
patients receiving equally intense and recent therapy
but without reactions
54

Drug provocation test
Gold standard test
Used to confirm a clinically significant IgE-mediated penicillin allergy
Oral challenge with a typical therapeutic dose followed by 1 h
of observation
<1 % will have a delayed onset : typically diffuse macular papular
rash after 2–5 days
Used for evaluation of delayed onset beta-lactam associated rashes
in children, most of whom also have evidence for viral infections at
the time of their beta-lactam-associated ADRs
55

The methodology is not yet standardized
Giving increasing doses up to a maximum amount of
one-fifth of the therapeutic dose
If good tolerance exists in this first step, then at least 48 hours
later, increasing doses are usually given up to a full therapeutic
dose (mostly on an outpatient basis in milder reactions)
A full therapeutic dose should be given for a number of days
similar to a therapeutic regimen, because delayed appearing
reactions highly depend on the cumulative dose
56

Reagents & Conc.
for SPT, ID & DPT
57

DPT should not be performed if
- an acute reaction occurred within the last 4 to 6 weeks
- antihistamines or oral steroids are being used
- active signs of underlying disease such urticaria, uncontrolled
asthma (i.e., forced expiratory volume in 1 second [FEV1]
value less than 70% of predicted), or uncontrolled cardiac,
renal, or hepatic disease or current upper airway infection
Relatively contraindicated in patients with histories of TEN, SJS,
DRESS, DiHS, AGEP , or severe organ-specific involvements
58

Natural evolution
Current evidence indicates that patients with immediate
allergic reactions to penicillins may convert from skin test-
positive to -negative after a variable period of time and results
indicate that in penicillin allergy the rate of negativization
differs between patients with cross-reactivity and those with a
selective IgE response
59

Group B : selective response to amoxicillin
Group A : response to benzylpenicilloyl
or minor determinant mixture
Blanca M. et al. J Allergy Clin Immunol 1999;103:918-24.
After a 5-year follow-up, only 40% of those with positive skin tests results to BP
determinants tested negative, whereas 100% of those with a selective response to AX
tested negative.
60

Increasing age and increasing TSR were associated with a lower rate
of positive PenST results
Macy E. et al.The Permanente Journal/ Spring 2009/ Volume 13 No. 2.
61

Fernandez et al. Allergy 2009: 64: 242–248.
62

Fernandez et al. Allergy 2009: 64: 242–248.
63

The objective of a graded challenge is to cautiously introduce
a drug in patients who are unlikely to be allergic to it
Does not modify an individual's immune response to a given
drug
The number of steps in the procedure may be 2 or several
The intervals between doses are dependent on the type of
previous reaction, and the entire procedure may take hours
or days to complete
Graded challenge
64

More caution should be exercised for graded challenge
procedures that use a parenteral route of administration
because more likely to produce severe anaphylaxis
Contraindicated : a severe non–IgE-mediated reaction
(such as SJS, TEN, or exfoliative dermatitis)
If penicillin skin testing is performed with only penicilloyl-
polylysine and penicillin G, initial administration of penicillin may
need to be done via graded challenge (ie, 1/100 of the dose,
followed by the full dose)
65

Induction of drug tolerance
(Desensitization)
Useful especially in Type 1 allergy (immediate reactions)
Indicated when an offending drug cannot be replaced
or significant more effective or fewer side effects than
other alternatives
Before desensitization, an accurate diagnosis needs to
be done, and the benefits must outweigh the risks
66

Administering progressive doses of a drug every 15 to 30 minutes for
IgE-mediated reactions until a full therapeutic dose is clinically
tolerated (render effector cells less reactive)
Typically are done within hours, and the typical starting dose is
in the microgram range
Performed via oral, intravenous, or subcutaneous routes
(no comparative studies to compare the safety of different routes)
The resulting state is temporary, and its maintenance requires
continued administration of the offending drug
67

Classical protocols for oral and intravenous desensitization to penicillin
start at 1/10,000 to 1/100 of the target dose; doubled doses are
administered every 15–20 min over the course of several hours until the
therapeutic dose is reached
In patients with histories of severe anaphylaxis (e.g., hypotension with loss
of consciousness, severe bronchospasm), the initial dose should be
between 1/1,000,000 and 1/10,000 of the full therapeutic one
Most cases, can be accomplished within 4 to 12 hours
Risk of acute allergic reactions, which occur in mild form in
30% to 80% of penicillin-allergic patients undergoing desensitization
Cernadas et al. General considerations on rapid desensitization for drug hypersensitivitya consensus statement. 2010.
68

69

70

Resensitizaion
Redevelopment of penicillin allergy in patients with a history of
penicillin allergy who later demonstrate negative penicillin skin test
results
Resensitization after oral treatment with penicillin is rare in both
pediatric and adult patients (B)
Routine repeat penicillin skin testing is not indicated in patients with a
history of penicillin allergy who have tolerated 1 or more oral courses of
oral penicillin
71

Resensitization after high-dose parenteral treatment with
penicillin appears to be more likely --> Repeat penicillin skin
testing in this situation may be warranted (C)
Consideration may be given to retesting individuals with recent or
particularly severe previous reactions
Consider to repeat penicillin skin test
72

73

74

The Standards of Care Committee of the British Society
for Allergy and Clinical Immunology (BSACI)
75

77
Romano and Cuabet. J Allergy Clin Immunol Pract 2014;2:3-12.

78
Romano and Cuabet. J Allergy Clin Immunol Pract 2014;2:3-12.

Penicillin allergy

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