Download Allergic Cross-Reactivity

Allergic Cross-Reactivity
Among
-Lactam Antibiotics
(In patients with penicillin allergies)
TRACEY NGO
COH MEDICINE ROTATION
WESTERN UNIVERSITY OF HEALTH SCIENCES
COLLEGE OF PHARMACY
MAY 3, 2011
Overview
 Patient case
 Background
 Penicillin Allergies
 Structural differences among beta lactam antibiotics
 Historical data on allergic cross reactivity
 Current data on allergic cross reactivity rate:
cephalosporin, carbapenem, and monobactam
 IDSA guidelines for Febrile Neutropenia

Treatment for patients with penicillin allergies
 Conclusion
 Recommendation
Learning Objectives




Distinguish between IgE and non IgE mediated
allergic reactions
Describe factors that affect cross reactivity
List the cross reactivity rate among the beta
lactam antibiotics in patients with penicillin
allergies
Make recommendations for patients with
penicillin allergies
Patient Case
 YK is a 36 y/o Asian male with a hx of refractory non-Hodgkin’s lymphoma
(NHL) who is currently on cycle #1 of a clinical trial drug SGN 75.
 HPI:


Diagnosed with Hodgkin’s lymphoma stage 2A on Feb, 2010 which progressed to large Bcell NHL
Subjectives:


Objectives:



SOB, chest pain, significant cough, intermittent fever, and tingling & numbness in R arm to
hand
Weight 74 kg, height 168 cm
Physical Exam:
 Head and Neck: shows clear oropharynx. A large mass in the R cervical to supraclavicular
areas
 Lungs: coarse BS and occasional rhonchi. Diminished BS in the R, but air movement is
present
 EXTREMITIES: Shows 1+ ankle edema.
 I/O: 1860/925
Current Admission on 4/25/11 to COH for pain control
Patient Case (continue)
 PMH:
 Hypertriglyceridemia, sleep apnea
 SH:
 Smoked <1/2 pack per day x 20 yrs but quit in 2010
 Occasional drinker
 FH:
 Maternal family: multiple cancers including leukemia but no
lymphoma

Details unavailable
Patient Case (Pertinent Values)
 CBC:
 WBC: 10.3
 Hgb/Hct: 9.9/30.7
 Platelet: 65, 000
 Vital Signs:
 Temperature 37.2°C
 HR 119
 RR 16
 BP 108/73
 O2 sat 99%
 Pain Scale: 6-9/10
Patient Case (continue)
 Current Medications:




Ceftazidime 2g IV Q8H PRNtemp
Cefazolin 2g IV Q8H PRNtemp
Fentanyl (100mcg/hr) 1 patch Q72H
Fentanyl PCA
Basal: 25 mcg/hr
 Bolus: 25 mcg Q15 min





Xopenex 1 puff Q6H (COH TEAM)
Benzonatate 200mg PO Q8H for cough
Hycodan 5ml PO Q4HPRN for cough
Acetaminophen 650 mg PO Q4H PRN temp >38°C
 Allergies:

Penicillin G (hives and throat swelling)
PICO
 P: adult with a penicillin allergy
 I: beta lactam antibiotics
 C: n/a
 O: allergic cross reactivity rate
 Question: what is the allergic cross reactivity rate
among the beta lactam antibiotics in an adult with a
penicillin allergy?
Background
-Penicillin Allergy in
~10% of the population
-In a patient with
penicillin allergy,
historical data suggest
cross reactivity rate:
•
•
•
Cephalosporin: 5-15%
carbapenem: 50%
Aztreonam: 1-2%
Torres MJ, Blanca M (2010). The complex clinical picture of B-lactam hypersensitivity: penicillins, cephalosporins, monobactams,
carbapenems, and clavams. Med Clin N Am 94:805-820
Structural Similarities
Penicillin
Cephalosporin
http://en.wikipedia.org/wiki/Beta-lactam_antibiotic
Carbapenem
Monobactam
(Aztreonam)
Cross-Reactivity with Cephalosporin
Ceph
Penicillin
allergy
Non
penicillin
allergy
NNH
8.1%
1.9%
16
Based on the review by Petz in 1978, the cross reactivity rate of
cephalosporin in patients with penicillin allergies was estimated as 6.2%
Petz LD (1978) Immunologic cross-reactivity between penicillins and cephalosporins: a review. J Infect Dis 137: S74-S79
Cross-Reactivity with Cephalosporin
 Limitations of the study by Petz:




Allergy based on patient history-majority may be SE (N/V/D, nonspecific
rash, idiopathic rxn) and not true allergies
 Allergy was loosely defined
 Not all were IgE mediated hypersensitivity reaction (only true allergic
reactions)
Did not consider 3 fold increased risk of ADR to any unrelated drugs in PCN
allergic patients
Early 1st gen-cephalosporin was produced by Cephalosporium spp mold
contaminated with trace amounts of PCN (not seen with currently available
cephalosporin)
Did not perform statistical analysis
Petz LD (1978) Immunologic cross-reactivity between penicillins and cephalosporins: a review. J Infect Dis 137: S74-S79
Cross-Reactivity with Cephalosporin
 According to a review by
Pichichero, the cross
reactivity rate:

Based on the differences:



Cross-reactivity between
cephalosporin and penicillin
should be minimal


Chemical structure (S ring and
side chain(s))
Degradation process
Overall, the actual allergic
cross reactivity among
cephalosporin in penicillin
allergic patients is <1% which is
a lot lower than previously
thought
However, the data is not
statistically significant
Gen of
Ceph
Penicillin
allergy (%)
Non
penicillin
allergy (%)
NNH
First
1.9
1.4
200
Second
1.9
1.7
500
Third
0.6
1.4
No cross
reactivity
Pichichero ME (2005) A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin
antibiotics for penicillin-allergic patients. Pediatrics 115: 1048-1057
Pichichero ME (2007) Use of selected cephalosporins in penicillin-allergic patients: a paradigm shift. Diagnostic Microbiology
and Infectious Disease 57: 13S-18S
Pichichero ME (2007) Use of selected cephalosporins in penicillin-allergic patients: a paradigm shift. Diagnostic Microbiology
and Infectious Disease 57: 13S-18S
Cross-Reactivity with Cephalosporin
 Study Subjects: 534,810
 Record allergic reaction
within 30 days
 Allergic reaction defined
as:

Anaphylaxis, urticaria,
angioedema, erythema
multiforme, laryngeal
spasm, drug-induced
dermatitis, and toxic
epidermal necrolysis
Ceph
Penicillin
allergy
Non
penicillin
allergy
NNH
1.1%
0.11%
100
 Results: cross reactivity
is ~1%
Apter AJ, Kinman JL, Bilker WB, et al. Is there cross-reactivity between penicillins and cephalosporins? Am J Med. 2006;
119(4):354 e311-359
Cross-Reactivity with Carbapenem
Retrospective
Study
Crossreactivity
Rate
Statistical
Significant
Carbapenem
McConnell et al
(2000)
9.5%
N/A
IV
Imipenem/
cilastatin
Prescott et al
(2004)
8.3%
Yes
IV imipenem/
cilastatin or
meropenem
Sodhi et al
(2004)
5.3%
No
IV imipenem/
cilastatin or
meropenem
Study
PCN Allergy (%)
Non PCN Allergy (%)
NNH
McConnell
9.5
N/A
N/A
Prescott
11
2.7
12
Sodhi
9.2
3.9
18
Frumin J, Gallagher JC (2009). Allergic Cross Sensitivity Between Penicillin, Carbapenem, and Monobactam Antibiotics: What Are the Chances?
The Annals of Pharmacotherapy 43: 304-315
Cross-Reactivity with Carbapenem
 Limitations of retrospective studies:
 Broad definition of allergic rxn which included fever, rash,
hematologic abnormalities (leukopenia or
thrombocytopenia)not IgE mediated
 Rely on patient history
 No penicillin skin test80-90% of not true penicillin allergy
Frumin J, Gallagher JC (2009). Allergic Cross Sensitivity Between Penicillin, Carbapenem, and Monobactam Antibiotics: What Are the Chances?
The Annals of Pharmacotherapy 43: 304-315
Cross-Reactivity with Carbapenem
Prospective
Study
Crossreactivity
Rate
Statistical
Significant
Carbapenem
Saxon et al
(1988)
42.4%
Yes
Imipenemoylpolylysine or
imipenemoate
Romano et al
(2006)
0.9%
N/A
Imipenem/
cilastatin
Romano et al
(2007)
0.9%
Yes
Meropenem
AtanaskovicMarkovic (2008)
0.9%
N/A
Meropenem
Study
PCN Allergy (%)
Non PCN Allergy (%)
NNH
Saxon
47.4
5
2
Romano (2006)
0.9
N/A
N/A
Romano (2007)
0.9
N/A
N/A
Atanaskovic-Markovic
0.9
N/A
N/A
Frumin J, Gallagher JC (2009). Allergic Cross Sensitivity Between Penicillin, Carbapenem, and Monobactam Antibiotics: What Are the Chances? The
Annals of Pharmacotherapy 43: 304-315
Cross-Reactivity with Carbapenem
 Recent prospective studies:
 In penicillin allergic patients->negative carbapenem skin test

Indicates tolerabilityappears safe to use
 Currently, no studies on doripenem or ertapenem
cross reactivity
Frumin J, Gallagher JC (2009). Allergic Cross Sensitivity Between Penicillin, Carbapenem, and Monobactam Antibiotics: What Are the Chances?
The Annals of Pharmacotherapy 43: 304-315
Cross-Reactivity with Monobactam
Prospective
Study
Crossreactivity
Rate
Comment
 Clinically, no record of
hypersensitivity reaction when
receive IV aztreonam except in
cystic fibrosis population

Saxon et al (1984, 1985)
0%
0 had a positive skin
test
Jensen et al (1987, 1991)
0%
0 had a positive skin
test, 0 developed
hypersensitivity rxn
with IV aztreonam
Moss et al (1991)
5.3%
In cystic fibrosis
patient, 1/19 had a
positive skin test, 3
had hypersensitivity
rxn when treated
with IV aztreonam
Vega et al (1991)
3.4%
1/29 had a positive
skin test, but 0
developed
hypersensitivity rxn
when given IV
aztreonam
Martin et al (1992)
0%
Cannot be generalized to the
general population because CF
population is more prone to
developing hypersensitivity
reaction to medications.

Difficult to assess if the
hypersensitivity reaction is due
to:
 The cross sensitivity between
penicillin and aztreonam
 The high rate of generalized
immune responsiveness in CF
population
• Most likely since the reaction
was not immediate (not IgE
mediated)
0 developed
hypersensitivity rxn
Frumin J, Gallagher JC (2009). Allergic Cross Sensitivity Between Penicillin, Carbapenem, and Monobactam Antibiotics: What Are the
Chances? The Annals of Pharmacotherapy 43: 304-315
Cross-Reactivity with Monobactam
 Exception:
 Moss et al: cross reactivity rate in ceftazidime allergy patients and
aztreonam is 16.7%


Bronchospasm and angioedema
Aztreonam and ceftazidime have the same side chain

Potential for cross reactivity exist in patients with a specific allergy to
ceftazidime
 avoid using aztreonam in these patients
Aztreonam
Ceftazidime
Frumin J, Gallagher JC (2009). Allergic Cross Sensitivity Between Penicillin, Carbapenem, and Monobactam Antibiotics: What Are the
Chances? The Annals of Pharmacotherapy 43: 304-315
Cross-Reactivity with Monobactam
Aztreonam
http://en.wikipedia.org/wiki/Beta-lactam_antibiotic
Ceftazidime
Return to
Patient Case
Is cefazolin and
ceftazidime
appropriate for YK
given his penicillin
allergy?
Pichichero ME (2007) Use of selected cephalosporins in penicillin-allergic patients: a paradigm shift. Diagnostic Microbiology and Infectious
Disease 57: 13S-18S
IDSA Guidelines for Febrile Neutropenia
http://guidelinecentral.com/viewers/FeverNeutropenia.html
Conclusion
 In general, those with an immediate (IgE mediated)
hypersensitivity reaction to penicillin should not receive
any penicillin and its derivatives unless they undergo
desensitization
 Although recent studies stated that newer generations of
cephalosporin may be used in patients with immediate
hypersensitivity reaction to penicillin

However, this should be done cautiously since there is still a possible
risk of allergic cross reaction in these patients.
 According to IDSA guidelines cephalosporin should be
avoided in patients with an immediate hypersensitivity
reaction to penicillin.
Penicillin Desensitization
Solensky R. Hypersensitivity reactions to beta-lactam antibiotics. Clin Rev Allergy Immunol. Jun 2003;24(3):201-220
Penicillin Desensitization
Solensky R. Hypersensitivity reactions to beta-lactam antibiotics. Clin Rev Allergy Immunol. Jun 2003;24(3):201-220
Let’s Vote
Based on all the studies and data available, which
option would you have chosen for YK?
a. Ceftazidime and cefazolin
b. Aztreonam and vancomycin
c. Avoid all beta lactam antibiotics
Recommendation
 Even though the cross reactivity among
cephalosporin and penicillin allergy is low (~1%)

Looking at the severity of YK’s hypersensitivity reaction to
Penicillin G

Recommend against the use of cephalosporin
 Based on the information from the different studies
and IDSA guidelines for Febrile Neutropenia, I
would recommend:

Aztreonam and vancomycin
References









Apter AJ, Kinman JL, Bilker WB, et al. Is there cross-reactivity between penicillins and
cephalosporins? Am J Med. 2006; 119(4):354 e311-359
Frumin J, Gallagher JC (2009). Allergic Cross Sensitivity Between Penicillin, Carbapenem, and
Monobactam Antibiotics: What Are the Chances? The Annals of Pharmacotherapy 43: 304-315
http://en.wikipedia.org/wiki/Beta-lactam_antibiotic. Access April 30, 2011
IDSA 2011 guidelines pocketcard on Febrile Neutropenia in Cancer Patients.
http://guidelinecentral.com/viewers/FeverNeutropenia.html. Access April 20, 2011
Petz LD (1978) Immunologic cross-reactivity between penicillins and cephalosporins: a review.
J Infect Dis 137: S74-S79
Pichichero ME (2005) A review of evidence supporting the American Academy of Pediatrics
recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients.
Pediatrics 115: 1048-1057
Pichichero ME (2007) Use of selected cephalosporins in penicillin-allergic patients: a paradigm
shift. Diagnostic Microbiology and Infectious Disease 57: 13S-18S
Solensky R. Hypersensitivity reactions to beta-lactam antibiotics. Clin Rev Allergy Immunol.
Jun 2003;24(3):201-220
Torres MJ, Blanca M (2010). The complex clinical picture of B-lactam hypersensitivity:
penicillins, cephalosporins, monobactams, carbapenems, and clavams. Med Clin N Am 94:805820
Thank You