1. Module 3 (of 3): Allergy Review *
Welcome to Module 3 of the Antimicrobial Stewardship Training.
The Allergy Review that follows will focus on β-lactam allergy and the cross reactivity between the various classes of β-lactam antibiotics (penicillins, cephalosporins, carbapenems, etc).
This is final module of the three-part series comprising the Review of Basic Principles and Selected Antimicrobials. This training program has been developed to provide core background material to enhance inpatient pharmacists’ knowledge and expertise in providing antibiotic stewardship at Kaiser Permanente hospitals.
This program has been accredited by the California Accreditation for Pharmacy Education, a division of the Pharmacy Foundation of California, for two hours of continuing education (CE) credit for pharmacists. It is brought to you by the Inpatient Pharmacy Directors Subcommittee on Education, Kaiser Permanente Northern California Region.
To obtain continuing education (CE) credit for this program, you are required to complete study of the three modules: Microbiology Lab review, Antibiotic review and Allergy review, and to complete a 30-question post-test and program evaluation. A correct score of 70 percent is required for CE credit.
Please submit your completed post-test and evaluation to your inpatient director (IPD) or inpatient supervisor (IPS) who will score your test. Your IPD or IPS will then fax your graded post-test and evaluation form to Dan Dong for recordkeeping and issuance of your CE certificate. This will be ed to your Kaiser address within one week of submission. Please keep this certificate for your CE records.
Allergy to β-lactam Antibiotics
By Keith Teelucksingh, PharmD
Infectious Disease Pharmacist, Kaiser Permanente Vallejo
With contributions from Linh Van, PharmD
Infectious Disease Pharmacist, Kaiser Permanente Oakland
 See Notes

2. Goal
The goal of this presentation is to provide pharmacists with up-to-date information regarding penicillin allergy and the cross reactivity with related antibiotics.

3. Objectives
After completing this module, the participant will be able to:
Describe the different types of allergy (per Gell Coombs classification) as they relate to penicillin and the β-lactam-related antibiotics.
Be able to identify clinical situations where it is safe or unsafe to use β-lactam-related antibiotics given a patient’s allergy history.

4. Allergy to the β-lactam antibiotics
There are several classification schemes. They can be applied to other drug classes but are best characterized for the β-lactam antibiotics:
Gell and Coombs
Based on immunopathologic reactions (all of which have been seen w/β-lactam antibiotics).
Levine
Reactions specific to penicillin (PCN) according to time of onset.

5. Gell Coombs Classification
Type I: IgE mediation
Type II: Antibody mediation
Type III: Immune complex mediation
Type IV: Delayed hypersensitivity reaction

6. Type I: IgE mediation Serious and life threatening Mechanism
Can include erythema, pruritis, urticaria (hives), angioedema, bronchospasm, hypotension, arrhythmias.
Mechanism
Interaction of β-lactam antigens with preformed β-lactam specific IgE bound to mast cells  causes release of histamine, proteases, prostaglandins, leukotrienes.

7. Type I (cont’d) Time course Pearl:
Usually starts <15 min after drug administration, can also occur >1 hour after but less common.
Pearl:
If patient has type I hypersensitivity to PCN, unless patient has tolerated before, probably judicious to avoid cephalosporins. If unable to get specific history as to what type of rash occurred and in what timeframe, err on the side of caution.
If PCN use is absolutely indicated, consult allergy for skin testing (e.g., PCN for neurosyphilis).

8. Type II: Antibody Mediation
Reactions
Hemolysis, thrombocytopenia, neutropenia, interstitial nephritis
Mechanism
Result when β-lactam specific cytotoxic antibodies (usually IgG or IgM) become attached to circulating blood cells or renal interstitial cells that have β-lactam antigens bound to their cell surface. The antibody-antigen complex can activate complement system (resulting in cell lysis), neutrophil or macrophage attachment (leading to cell injury).

9. Type II (cont’d) Time course Pearl Usually longer term, > 7 days
Long term, high-dose β-lactam treatment predisposes to this reaction (nafcillin for endocarditis, high-dose Zosyn® for Pseudomonal infection).

10. Type III: Immune Complex Mediation
Serum-sickness like reaction
Mechanism
β-lactam specific IgG or IgM antibodies may form circulating complexes with β-lactam antigens. These complexes can fix complement and lodge in tissue sites, possibly causing serum sickness/drug fever.

11. Type III (cont’d) Time course: 6–21 days after exposure Pearl
Best example is classic serum-sickness like reaction seen with cefaclor.
Signs/symptoms: fever, arthralgia, lymphadenopathy, skin eruption

12. Type IV: Delayed Hypersensitivity
Delayed hypersensitivity reaction
Contact dermatitis, delayed non-urticarial rashes.
Mechanism
T-cell mediated release of cytokines causing tissue inflammation and injury.

13. Type IV (cont’d) Time course: not well defined Pearl/example
Penicillin was available topically in the past, but high rate of dermatitis led to its discontinuation as a marketed product.

14. Idiopathic Reactions
Not included in Gell Coombs classification since pathogenesis is not well defined.
Examples
Maculopapular reactions (rash, etc.)
Occurs in 2 percent to 3 percent of penicillin courses, usually late in treatment.
Eosinophilia
Stevens-Johnson syndrome
Exfoliative dermatitis

15. Choosing an Antibiotic
Always note the REACTION to a given drug
Nausea, vomiting, GI upset are NOT allergic reactions.
Rash reactions:
Need to either clarify type of rash and onset or err on side of caution and use alternative agents with low chance of cross reactivity.

16. Cross-Reactivity If patient is allergic to: Can this be used?
1. Penicillin
Penicillin-class drug
(amoxicillin, ampicillin, etc.)
2. Penicillin
Cephalosporin
3. Cephalosporin
Penicillin
4. Penicillin
Carbapenem

17. Penicillin – Penicillin Class
If patient has IgE mediated reaction to penicillin, likely to have similar reaction to ampicillin, amoxicillin, dicloxacillin and piperacillin.
Patients with allergy to penicillin may be prone to allergic reactions to drugs in general.
Aztreonam seems to be safe to use even in patients with Type I reactions. Use caution in patients with ceftazidime allergy, since these drugs have the same side chain. Reactions still can occur but tend to be very rare.

18. Penicillin – Cephalosporin
Incidence may have been higher with earlier preparations of cephalosporins .
In general, patients with documented Type I reactions to penicillin should not be challenged with a cephalosporin unless there is documentation that patient has tolerated cephalosporins in the past.
No good answer at this time.

19. Cephalosporin - Penicillin
Allergic reactions to cephalosporins in the general population tend to be rare.
Chance of cross-reactivity between patients with cephalosporin allergy being exposed to penicillin may be higher (50 percent) with first-generation cephalosporins than that with second or third generation (~10 percent).
For example, if a patient is allergic to cefazolin and exposed to a penicillin-class drug, s/he may be more likely to have an allergic reaction. If the patient is allergic to either cefuroxime or ceftriaxone, s/he may be less likely to have an allergic reaction to a penicillin-class drug.

20. Penicillin – Carbapenem
Incidence was thought to be close to 50 percent.
Emerging data suggests that carbapenems may be safe to use in patients with Type I penicillin allergy.
Some data to suggest that patients with type IV reactions to penicillins will have a ~5 percent chance of cross-reaction with carbapenems (imipenem).

21. References Chen, S. Serum sickness. http://emedicine.com
Weiss, M., Adkinson, N. Chapter 24: β-lactam Allergy. Mandell, Bennett & Dolin. Principles and Practice of Infectious Disease. 7th ed
Robinson, et al. Practical aspects of choosing an antibiotic for patients with a reported allergy to an antibiotic. Clin Infect Dis Jul 1;35(1):26-31.
Patriarca, et al. Tolerability of aztreonam in patients with IgE-mediated hypersensitivity to beta-lactams. Int J Immunopathol Pharmacol Apr-Jun;21(2):375-9.
Schiavino, et al.Cross-reactivity and tolerability of imipenem in patients with delayed-type, cell-mediated hypersensitivity to beta-lactams. Allergy 2009 Apr 14.
Romano, et al. Brief communication: tolerability of meropenem in patients with IgE-mediated hypersensitivity to penicillin. Ann Intern Med Feb 20;146(4):266-9
Prescott, et al. Incidence of carbapenem-associated allergic-type reactions among patients with versus patients without a reported penicillin allergy. Clin Infect Dis Apr 15;38(8):1102-7

22. Acknowledgments
Thank you to the following individuals for their support of and/or assistance with this program:
Dan Dong, Pharm D, Area Pharmacy Director Kaiser Permanente East Bay Service Area
Kathleen Hiroshima, Pharm D, Drug Information Services Kaiser Permanente California Regions
Matangi Venkateswaran, Pharm D, Inpatient Quality-Clinical Supervisor, Kaiser Permanente Central Valley Service Area
Sam S Lee, Pharm D, Inpatient Pharmacy Supervisor Kaiser Permanente Santa Rosa

23. Conclusion *
This concludes Module 3 of the Review of Basic Principles and Selected Antimicrobials.
Upon completion of Modules 1, 2 and 3, you may proceed to the post-test and evaluation.
Thank you for participating in this continuing education program.
Please submit your completed post-test and evaluation to your inpatient director (IPD) or inpatient supervisor (IPS) who will score your test. Your IPD or IPS will then fax your graded post-test and evaluation form to Dan Dong for recordkeeping and issuance of your CE certificate. This will be ed to your Kaiser address within one week of submission. Please keep this certificate for your CE records.
 See Notes