Allergic Cross-Reactivity

-Lactam Antibiotics (In patients with penicillin allergies)

Among

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-Hodgkins lymphoma

(NHL) who is currently on cycle #1 of a clinical trial drug SGN 75.

HPI:

Diagnosed with Hodgkins lymphoma stage 2A on Feb, 2010 which progressed to large Bcell NHL Subjectives:

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

Objectives:

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 37.2C 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 >38C Penicillin G (hives and throat swelling)

Allergies:

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

Carbapenem

Monobactam (Aztreonam)

http://en.wikipedia.org/wiki/Beta-lactam_antibiotic

Cross-Reactivity with Cephalosporin

Penicillin allergy Ceph 8.1%

Non penicillin allergy 1.9%

NNH

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:

Chemical structure (S ring and side chain(s)) Degradation process

Cross-reactivity between cephalosporin and penicillin should be minimal

Overall, the actual allergic cross reactivity among cephalosporin in penicillin allergic patients is <1% which is a lot lower than previously thought

Gen of Ceph First Second Third

Penicillin allergy (%) 1.9 1.9 0.6

Non penicillin allergy (%) 1.4 1.7 1.4

NNH

200 500 No cross reactivity

However, the data is not statistically significant

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

Penicillin allergy Ceph 1.1%

Non penicillin allergy 0.11%

NNH

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) Prescott et al (2004) Sodhi et al (2004)

9.5%

N/A

IV Imipenem/ cilastatin IV imipenem/ cilastatin or meropenem IV imipenem/ cilastatin or meropenem

8.3%

Yes

5.3%

No

Study McConnell Prescott Sodhi

PCN Allergy (%) 9.5 11 9.2

Non PCN Allergy (%) N/A 2.7 3.9

NNH N/A 12 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 test80-90% 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) Romano et al (2006) Romano et al (2007) AtanaskovicMarkovic (2008)

42.4%

Yes

Imipenemoylpolylysine or imipenemoate

0.9% 0.9% 0.9%

N/A Yes N/A

Imipenem/ cilastatin Meropenem Meropenem

Study Saxon Romano (2006) Romano (2007) Atanaskovic-Markovic

PCN Allergy (%) 47.4 0.9 0.9 0.9

Non PCN Allergy (%) 5 N/A N/A N/A

NNH 2 N/A 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 tolerabilityappears 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) Jensen et al (1987, 1991)

0% 0%

0 had a positive skin test 0 had a positive skin test, 0 developed hypersensitivity rxn with IV aztreonam In cystic fibrosis patient, 1/19 had a positive skin test, 3 had hypersensitivity rxn when treated with IV aztreonam 1/29 had a positive skin test, but 0 developed hypersensitivity rxn when given IV aztreonam 0 developed hypersensitivity rxn

Cannot be generalized to the general population because CF population is more prone to developing hypersensitivity reaction to medications.

Moss et al (1991)

5.3%

Vega et al (1991)

3.4%

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)

Martin et al (1992)

0%

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 Potential for cross reactivity exist in patients with a specific allergy to ceftazidime avoid using aztreonam in these patients

Aztreonam and ceftazidime have the same side chain

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

Ceftazidime

http://en.wikipedia.org/wiki/Beta-lactam_antibiotic

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

Lets 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 YKs 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