4/6/2016

Drug Allergy: Focus on Antibiotics

Jonathan Grey, Pharm.D. Clinical Coordinator/Antibiotic Stewardship Specialist Morton Plant Mease Healthcare April 9th, 2016

Disclosure Information

 I have no actual or potential conflict of interest in relation to this presentation

Objectives

 By the end of this presentation, you should be able to:  Classify the different types of drug hypersensitivity and explain the various strategies for drug avoidance based on these classifications  Describe the risk of cross sensitivity between the antibiotic classes, including the role of R1 side chains in determining β-lactam cross sensitivity  Delineate between the different roles of antibiotic desensitization, direct/graded challenges, and antibiotic skin testing in response to a patient with a reported allergy  Discuss the significance of some non- β-lactam drug allergies and their impact on patient care

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Predictable Drug Reactions

 Predictable  Dose dependent  Related to pharmacologic action  Occur in otherwise healthy individuals  i.e. Dizziness with BP meds, hypoglycemia with insulin

Unpredictable Drug Reactions Drug • Undesirable effect intolerance • Low doses • Normal metabolism, excretion, bioavailability • i.e. ASA tinnitis

Drug • Abnormal, unexpected idiosyncrasy • Underlying abnormality of metabolism, excretion bioavailability • i.e. Dapsone hemolytic anemia

Drug allergy • Immune mediated • Drug specific antibodies, T cells, or both • i.e. penicillin rash Pseudoallergy • Mimic anaphylaxis • No sensitization period, can occur with first dose • Not immune mediated • Occur due to direct release of mediators • i.e. Redman with vancomycin, Morphine histamine release

NEJM 2006;354:601-609

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Gell and Combs Classification

Type Classification Onset Clinical Features

I IgEmediated Immediate: 30-60 min Urticaria (Hives) immediate Angioedema Accelerated: 1-72 hrs Bronchospasm (T-cell mediated) Anaphylaxis

II Cytotoxic 5-12h/>72h Hemolytic anemia, Neutropenia, Thrombocytopenia

III Immune complex 3-8h/>72h Serum sickness

IV T-Cell mediated or 24-48h/>72h Contact dermatitis delayed Maculopapular/ morbilliform rash Interstitial nephritis SJS, TEN Other Unknown Variable DRESS, eosinophilic pneumonia, drug- induced lupusn

Treatment Alternatives for Allergies- Type II

 Avoid the offending agent  Cross sensitivity have been noted within the same class for some agents  Neutropenia with vancomycin and teicoplanin  β-lactams  Cephalosporin cross sensitivity- related to R1 and R2 side chain similarity  Carbapenems an option in patients with piperacillin/tazobactam induced hemolytic anemia?  Single case report of tolerance

J Clin Pathol. 1987 Jun;40(6):700-1. J Allergy Clin Immunol Pract. 2015 May-Jun;3(3):452-3.

Treatment Alternatives for Allergies- Type III

 Possibly agent specific (i.e. cefaclor)  Alternate metabolism results in reactive intermediate compounds  Limited data on cross sensitivity of other beta lactams  If β-lactam used, use alternate class with different R1/R2 side chains

http://www.aaaai.org/ask-the-expert/reactivity-β-lactams.aspx

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Treatment Alternatives for Allergies- Type IV/Delayed

 Contact dermatitis  Avoid same beta lactam/antibiotic class  Cephalosporin cross sensitivity with occupational contact dermatitis  SJS/TEN  Never take any remotely similar antibiotic  i.e. lifelong avoidance of all β-lactams

Dermatol Online J. 2011 May 15;17(5):13.

Treatment Alternatives for Allergies- Type IV/Delayed (continued)

 Maculopapular rash  May tolerate β-lactams with different side chains  Aminopenicillins  Childhood rash after exposure often linked to viral syndrome  True delayed type reactions can still occur  Can usually tolerate dissimilar cephalosporins, or even penicillin V

Treatment Alternatives for Allergies- Type IV/Delayed (continued)

 Interstitial nephritis  Only one documentd case of possible cross-reactivity  Piperacillin/tazobactam and Meropenem  Reasonable to try a different Beta-lactam class with different side chains

J Antimicrob Chemother. 2007 Jul;60(1):107-11.

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Tolerability of Cefazolin after Non-IgE Hypersensitivity Reactions to Nafcillin

 Blumenthal KG, et al. Antimicrob Agents Chemother. 2014 Jun;58(6):3137-43.  Observational study of 17 OPAT patients switched from nafcillin to cefazolin after non-IgE mediated allergies.  Maculopapular rash (n=10), immune mediated nephritis (n=3), isolated eosinophilia (n=2), immune mediated hepatitis (n=1)  16/17 completed course without further reaction  3 patients with maculopapular rash were switched to alternate agent first (daptomycin or vancomycin)  Observational washout period  Authors conclude that cefazolin is well tolerated in patients with non-Ige mediated hypersensitivity to nafcillin.

Question 1

Ivy Drugabusa is a 26 yo female admitted to Morton Plant Hospital with persistent fever, cough, and malaise.  PMH: hypothyroid SH: IVDA, “None in last year”.  Ht: 63” Wt 55.5 kg  VS: T 38.5, BP 105/60 HR 91 RR 16  BUN/SCR 14/0.9  WBC 15.9  Blood cultures reveal MSSA in 2/2 sets on admission, and again on repeat  TEE: Positive for vegetation in tricuspid valve  Patient was started on vancomycin in ER, and received this for two days until culture results returned. At thiat time they were switched to nafcillin and received this for several days. WBC normalized, and blood cultures are now negative.  On day 7 of admission, patient’s SCr increases to 2.4. Increased eosinophils in serum and urine  She is diagnosed by nephrology as having AIN

Question 1

Based on the risk of cross sensitivity of Non-IgE mediated reactions, which of the following is the best therapeutic plan? a) Change therapy to IV vancomycin, to complete a 6 week course. b) Change therapy to IV daptomycin, to complete a 6 week course. c) Continue IV nafcillin as it is the drug of choice. Refer to dialysis. d) Change therapy to IV cefazolin. Monitor carefully for persistent or worsening of renal function. Complete a 6 week course.

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IgE Type I Hypersensitivity Reactions

Urticaria  Anaphylaxis

IgE Sensitivity Reaction



Cutaneous Reactions

 Cutaneous drug eruptions of all types occur in 1-5% of population  PCN compounds are the most common cause  Highest incidence with ampicillin/amoxicillin

 Only small percentage are IgE mediated.

 urticaria versus morbilliform rash

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Urticaria versus Morbilliform Rash

Urticaria Morbilliform eruptions IgE mediated T-cell mediated

Immediate Delayed

Anaphylaxis

 Acute systemic allergic reaction  1-4 episodes/10,000 admissions  Affects multiple organs  Skin, Resp, GI, CV

 Symptoms  Urticaria  Swelling  Difficulty breathing  Abdominal cramps  Vomiting  Diarrhea  Circulatory collapse  Coma and Death

Penicillin Allergy

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PCN Allergy: Statistics

 9% of the US population report a history of penicillin “allergy”  Penicillins among most commonly reported “allergies”  Narcotics 13.9 %, NSAIDS 7.7%, ACEIs 2.9%, radiocontrast 2.3%  Most commonly reported antibiotic allergy  Sulfas 5.4%, cephalosporins 1.3%, macrolides 1.3%, tetracyclines 0.9%

Am J Med. 2009 Aug;122(8):778.e1-7.

PCN Allergy: correlation with skin testing results

 Number of patients with reported penicillin allergy and positive penicillin skin tests  Less than 5%  Skin test positive patients have been declining steadily over time  Previously ≥ 10%

Perm J. 2009 Spring;13(2):12-8.

Risk Factors for IgE Mediated PCN Allergy  Age 20-49  Route: topical > IV > oral  Frequency  Multiple drug allergy syndrome  Hereditary factors  Asthma  Risk of sensitivity not greater, but reactions more severe

Special Cases  HIV infection  Cystic Fibrosis

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What are the Penicillin Allergens?

 β-lactam ring

 Antimicrobial metabolite/s

 Chemical side chain

β-lactam Antibiotics

Metabolites

75% of PCN allergic patients react to the Major determinant

NEJM 2006;354:601-609

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Reaction to Side Chain

More common in Southern Europe

Penicillin Skin Testing

 Preferred method for the evaluation of possible IgE mediated PCN allergy  Performed in setting prepared to treat a possible allergic reaction.  Test for PCN major and minor determinants  Useful if want to use penicillin drug, but there is a questionable IgE mediated allergy  Not useful in ruling out allergies to other β- lactam classes

Penicillin Skin Test Reagents Major determinant  Penicilloyl-polylysine (Pre-Pen)  US: Up to 75% of PCN skin test + patients react Minor determinants  Penicillin G- Commercially available  Penicilloate  Penilloate  Ampicillin/amoxicillin

 Pencilloyl-polylysine/Pen G skin testing  Amoxicillin 250 mg oral challenge if negative  0.2% of patients will react, and not to Pencilloyl-polylysine/Pen G  Safely identifies patients with penicillin allergies  NPV > 95%

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Pencillin Skin Test Process at Morton Plant Mease

 Inclusion Criteria  Documented infection where PCN agent is drug of choice  Histamine antagonits held for 24 hours  Amenable skin surface (usually right and left forearms)  Exclusion  Non IgE mediated reaction  Adverse effect, not allergy  Anaphylaxis in last four weeks  Hemodynamic instability  Age < 18  Current part of protocol, but not a true exclusion for PST  Pregnancy  Current part of protocol, but PST is option in these patients if risk outweighs benefits

Pencillin Skin Test Process at Morton Plant Mease

It’s a TEAM effort!

Administration of Penicillin Skin Test

 Step 1: Scratch test  Place one drop of solution onto patient arm and use lancet to make shallow puncture  Histamine: positive control  Saline: negative control  Pre-Pen®: major determinant  Penicillin G: minor determinant  Wait 15 minutes and observe for wheal (> 5 mm) and erythema reaction

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Administration of Penicillin Skin Test

 Step 2: Intradermal test  Intradermally inject a small bleb of Positive each component on opposite arm Test  Saline: negative control (one bleb)  Pre-Pen®: major determinant (two blebs)  Penicillin G: minor determinant (two blebs)  Observe for 15 minutes and then read skin test Negative test: sites produce no wheal or wheal is < 3 mm larger than saline control (or < 5 mm total)

Remove PCN Allergy From Profile

Document Negative Penicillin Skin Test

Penicillin skin testing at Morton Plant Mease

o Protocol in place since end of 2014

o 12 patients received PCN skin testing  11 negative skin test  switched to a β-lactam antibiotics  PCN allergy removed from their profiles  1 patient who was anergic and not able to proceed with intradermal test

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Question 2

Alma Mycins is an 86 year old female admitted to Mease Countryside with altered mental status and dysuria.  Allergies: Penicillin (swelling as child), Keflex (swelling), Ciprofloxacin (dizziness), SULFA (unknown), doxycycline (N/V), Vancomycin (unknown), ALL MYCINS  PMH: overactive bladder, depression  Medications: Ditropan, Sertraline  UA: WBC TNTC, LE 3+  CBC, BMP: WNL  Patient is admitted with complicated UTI  Reflex Urine Cultures are positive for Vancomycin Resistant Enterococcus faecalis, sensitive to ampicillin  Currently on IV daptomycin (which she is amazingly able to tolerate despite her ALL MYCINS allergy)  She has improved after 3 days of therapy, and is no longer confused  Physician is looking for an oral option to facilitate discharge

Question 2

The physician asks if penicillin skin testing is an option for Alma. Which of the following is correct? a. Penicillin skin testing is not an option for this patient since she has a history of reported IgE mediated reaction. It is not worth the risk of anaphylaxis. b. There is no need for penicillin skin testing. Proceed with a graded challenge of amoxicillin. c. Given her history, penicillin skin testing may be of value. If negative, may skip the oral challenge if treatment will begin with amoxicillin d. This patient requires a full ampicillin desensitization. Immediately transfer to the ICU to begin the process.

Graded Challenge and Desensitization

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Direct/Graded Challenge

 Appropriate when likelihood of being allergic is low  i.e. different β-lactam class with dissimilar side chains

 Does not desensitize patient

 Cautious way of administering drug

 Performed in setting prepared to treat a possible allergic reaction

 Does not require admission to ICU

Direct/Graded Challenge

 Dosing  1/100- 1/10 of the full dose  Increase 10 fold every 30-60 min until full therapeutic dose is reached  Example with Ceftriaxone  Ceftriaxone 1 mg over 15 minutes, observe 15 minutes  Ceftriaxone 10 mg over 15 minutes, observe 15 minutes  Ceftriaxone 889 mg over 30 minutes, observe for 30 minutes  Breath sounds and VS at baseline, then q30 minutes throughout procedure and 30 minutes after the last infusion  May want to wait longer between oral challenge doses to allow for absorption

 Patients who tolerate a graded challenge prove that they are not allergic

 Nursing education

Desensitization

 Alters the immune response to the antibody and results in TEMPORARY tolerance  Indication: known or strongly suspected IgE allergy and there are no acceptable alternatives  Contraindication: Non-IgE mediated reactions such as SJS or TEN  At MPM, performed in ICU  Patients need 1:1 nursing Do not give  Protocols •Glucocorticoids  Rapid versus Slow protocols •Antihistamines •Beta-Blockers  Oral and intravenous protocols

*MUST be repeated with each exposure*

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Desensitizations at Morton Plant Mease

 Established protocols for 12 different antibiotics  Order sets created for each desensitization protocol with antibiotics and rescue medications  For IV antibiotics, use continuous IV infusion, and double rate for each dose increase

Example-Ampicillin IV desensitization

Ampicillin Flow rate Cumulative Step Dose (mg) Bag (mg/mL) (mL/hour) dose (mg)

1 0.04 6 0.06 0.06 2 mg / 2 0.04 12 0.12 0.18 50 mL NS 3 0.04 24 0.24 0.42 4 0.4 5 0.50 0.92 5 0.4 10 1 1.92 6 0.4 20 2 3.92 400 mg / 100 7 0.4 40 4 7.92 mL NS 8 0.4 80 8 15.92 9 0.4 160 16 31.92 10 40 3 30 61.92 11 40 6 60 121.92 12 40 12 120 241.92 4,000 mg / 13 40 25 250 491.92 100 mL NS 14 40 50 500 991.92 15 40 100 1000 1991.92 16 40 200 2000 3991.92

Question 3

 Coughy McHackerson is a 58 year old male admitted with short of breath and fever for the last several days.  A chest X-ray in the ER reveals bilateral infiltrates. He is diagnosed with community acquired pneumonia.  Allergies: Penicillin (unknown reaction), Ciprofloxacin (hives), Shellfish  The physician starts the patient on aztreonam 2 g q8h and azithromycin 500 mg daily.

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Question 3

 Which of the following is true regarding treatment options for Mr. McHackerson? a. A graded challenge with ceftriaxone is a good option given the low rate of cross sensitivity between penicillin and dissimilar cephalosporins. b. A graded challenge with ceftriaxone requires an admission to the ICU, and may not be possible based on bed availability. c. Given the unknown reaction for penicillin, it is best to avoid cephalosporins at this time. Continue aztreonam. d. Penicillin “allergies” are rarely accurate. Initiate IV ampicillin/sulbactam.

Example-Ampicillin IV desensitization (order set)

In PCN allergy, can you safely administer structurally related antibiotics?

Cephalosporins Carbapenems Monobactams

If PCN allergy = No β-lactams  Significant Reduction in antibiotic options

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Cephalosporin Allergy Cephalosporin allergy  Reported in 1.3% of patients  Anaphylaxis is rare  1:1000 to 1:1,000,000  Cross-reactivity related to R1 and R2 side chains  Can be cephalosporin allergic and not PCN allergic  May be allergic to certain cephalosporins and still be able to tolerate others

J Allergy Clin Immunol 2015 Mar;135(3):745-52.e5.

Cephalosporin Potential for Cross Reactivity

 Source of cross reactivity  R-group side chain shared by specific drugs  β-lactam ring  Less important  Metabolites/haptens– Unknown #

 Cephalosporin skin testing is of limited value  Negative predictive value uncertain  Possibly could be considered for specific cephalosporins in emergency situations  2 mg/mL (0.005 M)  However, could also just perform a desensitization in these cases

Clin Rev Allergy Immunol. 2014 Aug;47(1):46-55.

Ann Allergy Asthma Immunol. 2010 Oct;105(4):259-273.

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Cephalosporin Cross reactivity with Ampicillin/Amoxicillin

Amoxicillin Ampicillin Cefadroxil (Duricef) Cefaclor (Ceclor) Cefprozil (Cefzil) Cephalexin (Keflex) Cephradine (Velosef) Loracarbef (Lorabid)

Potential for Cephalosporin Cross- reactivity with Penicillins- Background

Cross reactivity with PCN  Older data suggested as high as 18%  Incidence confounded by non-immunologic ADRs  Up until 1985 the manufacturing process of PCN used a cephalosporin mold  Current Product labeling  "Cross hypersensitivity among the β-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with penicillin allergy.“  Based on retrospective, open studies  Lacked control group  PCN allergy not confirmed by skin testing

Cephalosporin Cross Reactivity: Literature Study Design Cross sensitivity DePestel, et al. • Metaanalysis of skin testing • 2.3%, mostly in 1st 2008 cross sensitivity studies, generation N=5420 cephalosporins

Apter, et al. 2006 • Large retrospective cohort • 43/3920 (1%) in using UK General Practice patients with prior Database reaction to penicillin. • N= 534,810 0.1% in patients • Determined “allergic type without prior reaction reaction” from diagnostic to penicillin (RR=10.0) codes for possible type I • RR for SULFA reaction reactions was similar (RR=7.2) • Not confirmed by skin testing

Park MA, et al. • Retrospective chart review. 85 • 2/85 (2%) in PCN PCN skin test positive patients skin test positive from 1991 to 2005. patient (both with 1st • 726 PCN skin test negative. generation cephalosporins). • 0.1% in PCN skin test negative patients. (p=0.0304)

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Cephalosporin Cross Reactivity: Literature Continued Study Design Cross sensitivity Macy E, et al. • Retrospective cohort. • PCN skin test positive: 2011 • 54 PCN skin test positive • 1/169 (0.6%) courses patients with 169 courses of of cephalosporins cephalosporins • 4/81 (4.9%) courses of • 819 PCN skin test negative SULFA patients with 2485 courses of • PCN skin test negative: cephalosporins 29/2485 (1.2%) courses of cephalosporins. • Concluded patients with PCN allergy can safely receive cephalsporins. Martinez Tadeo • Series of 22 PCN skin test • All tested negative to JA, et al. 2015 positive patients cephalosporins with dissimilar side chains via skin testing/oral challenge (Cefuroxime, cefixime). • Concluded cephalosporins with dissimilar side chains to penicillins may be used safely in patient with penicillin allergy.

Cephalosporin Cross Reactivity: Literature Continued Study Design Cross sensitivity Macy E, et • Large Retrospective • Physician documented cephalosporin al. 2015 cohort. associated anaphylaxis was 2.9-fold more • Total study likely in patients with history of penicillin population of allergy, but still very rare. 3,999,290 (1% of • 0.0024% if history penicillin allergy U.S) vs. 0.00082% if no history of • 65,915 patients penicillin allergy with penicillin • Again concluded that patients with history allergy who of PCN allergy may safely receive received 127,125 cephalosporins courses of cephalosporins

Romano, • 98 patients with IgE • Cross reactivity et al. 2010 mediated reactions • PCN-25%, 3.1% aztreonam, 2% to cephalosporins imipenem/cilastatin, 1% meropenem • Underwent skin • Critique- tests and serum IgE • IgE levels do not correlate with skin assays to other β- tests and oral challenge lactams • Threshold for reaction with scratch test was only 3 mm instead of 5 mm

Cephalosporin Cross Reactivity: Summary

 Rate of cross reactivity with PCN is only 1 to 2%  This is comparable to other agents (i.e. SULFA)  Cross reactivity rates are highest in first generation cephalosporins with similar side chains to penicillins  Even if patient does end up having cross reactivity, risk of anaphylaxis is very low (<1:10,000)  In patient with a history of “penicillin allergy”, graded challenges with a cephalosporin with dissimilar side chains are unlikely to cause a serious adverse event  Remember, <5% of penicillin “allergies” can be confirmed by skin testing

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Carbapenems Potential for Cross Reactivity

 Incidence of hypersensitivity  0.3-2.3% (rash, pruritus, urticaria)

 Structural similarity

 Agents  Imipenem (Primaxin®)  Meropenem (Merrem®)  Ertapenem (Invanz®)  Doripenem (Doribax®)

Ann Pharmacotherapy 2009;43:304

Why is this important?

 Carbapenems are broad spectrum, β- lactamase stable agents

 Often used for the treatment of infections caused by multi-drug resistant pathogens:  Extended Spectrum β-lactamase producing organisms (ESBLs)  Acinetobacter species  Pseudomonas aeruginosa

Carbapenems Potential for Cross Reactivity

 Cross Sensitivity Studies  range from 0.9% to 47.4%  Early prospective studies  Saxon et al. – 47.4% cross reactivity by imipenem skin testing in patients with + PCN skin test

Ann Pharmacotherapy 2009;43:304

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Carbapenem Cross Sensitivity Prospective Studies Author PCN skin test Carbapenem Result of Cross reactivity positive verification between PCN and carbapenem (N) Skin Test

Romano 112 Imipenem skin test, • 1/112 (0.9%), to imipenem skin (2006) then IM challenge test No skin test neg patients reacted to Carbapenem challenge

Romano 104 Meropenem skin test, • 1/104 (1%), to meropenem test (2007) then IV challenge • No skin test neg patients reacted to Carbapenem challenge

Atanaskovi 108 Meropenem skin test, • 1/108 (0.9%), to meropenem c-Markovic Children then IV challenge test (2008) 3-14YO • No skin test neg patients reacted to Carbapenem

Romano 212 Skin test and IV • No patients reacted to skin test (2015) challenge to aztreonam, to any agent, or subsequent IV imipenem-cilastatin, challenge meropenem, ertapenem

Ann Pharmacotherapy 2009;43:304 J Allergy Clin Immunol. 2015 Apr;135(4):972-6

Carbapenem and Cross Sensitivity Recommendations

 Clinical cross reactivity between PCN and carbapenems appears to be lower than would be expected  Carbapenems are a reasonable option in patients with a history of IgE mediated PCN allergy  Should still proceed with caution- i.e., graded challenge  Based on the fact that <5% of individuals with a history of PCN allergy will be skin test positive, and of those over 99% are able to tolerate carbapenems

Clin Infect Dis. 2014 Oct 15;59(8):1113-22.

Monobactam Cross Reactivity Aztreonam  Weakly immunogenic  Allergic reaction directed to the side chain  No cross reactivity with PCN or Cephalosporins  except ceftazidime- share similar side chain

 Indication: Treatment of infection caused by Gram negative aerobic organisms in patients with an IgE mediated allergy to PCN compounds

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Cross-reactivity: Ceftazidime and Aztreonam

Aztreonam Ceftazidime

Similar spectrum of activity- aerobic gram negative bacilli

Allergy Assessment

Allergy Validation Allergies are poorly reported in the medical record!!!!

 68% of allergies lack information about the nature and severity  Allergic patients- 2 X more likely to receive Vancomycin and 3 X more likely to receive FQ  416 reported allergic reactions, only 36.3% had a description of allergic reaction in the medical records  The cost of antimicrobials increased 63% for inpatients and 38% for discharged patients with penicillin allergies compared with non-allergic patients  History of β-lactam allergy is a barrier to the effective delivery of preoperative prophylaxis

Arch Int Med. 2000;160:2819, Pharmacotherapy. 2008;28:1348, Clin Exp Allergy. 2003;33:501, Infec Control Hosp Epidemiol 2005;26:478-85

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Allergy Assessment

Antibiotic allergies influences antibiotic selection

Use of expensive alternative agents Use of ineffective agents Affect institutional resistant patterns Adversely affect the patient Increase in health care cost

Allergy Assessment

 Name of the agent/s  Nature of the event, symptoms and severity  How long ago did reaction occur?  Timing, onset of reaction  Course of the reaction  Any prior exposure to agents in the same class and presence or absence of any reactions  Previous ADRs and outcomes

Allergy History

Very important question to answer

 When did the reaction occur?  Gradual loss of penicillin IgE over time  50% lost sensitivity after 5 years  80% lost the sensitivity after 10 years

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Take Home Message

Allergy verification and documentation is critical

<5% OF REPORTED PCN ALLERGIES ARE IgE MEDIATED

β-lactam ANTIBIOTICS ARE DRUGS OF FIRST CHOICE FOR SEVERAL INFECTIONS

Sulfonamide Allergy

Sulfonamide Allergy (S02NH2)

 Second most common antibiotic associated allergy  Many patients labeled with a sulfonamide allergy may receive a sulfonamide antimicrobial

“SULFA” Allergy

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Sulfonamide Allergy

 Immunologic and non-immunologic  Detailed allergy history is critical  No useful in-vitro or in-vivo test for allergy  Desensitization protocols available

Hypersensitivity  Delayed onset  Fever & pruritic, maculopapular or morbilliform rash  Organ involvement  Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

SJS and TEN

Sulfonamide Allergy Facts

Cross reactivity between sulfonamide antimicrobials and non-antimicrobials sulfonamides is not seen (furosemide, bumetanide, HCTZ, acetazolamide, diazoxide, sumatriptan, glyburide, celecoxib)

Sulfonamide ≠ Sulfone ≠ Sulfyl ≠ Sulfate ≠ Sulfite      Sulfamethoxazole Dapsone Captopril, albuterol Foods Sulfisoxazole Omeprazole beverages Sulfadiazine Ranitidine Sulfamerazine Sulfamethizole Sulfapyridine Sulfamoxaole Sulfamethazine

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“Sulfa” Allergy Label

 TMP/SMX (Bactrim, Septra) is the drug of choice for infections caused by the following pathogens:  Stenotrophomonas maltophilia  Burkholderia cepacia (formerly Pseudomonas cepacia)  Nocardia spp.  Pneumocystis jiroveci (PCP)

VERY FEW THERAPEUTIC ALTERNATIVES

Summary

 MANY PATIENTS LABELED WITH ALLERGY TO ANTIBIOTICS ARE NOT ALLERGIC  <5% OF REPORTED PCN ALLERGIES ARE IgE MEDIATED  1-2% CROSS REACTIVITY TO CEPHALOSPORINS  1% CROSS REACTIVITY TO CARBAPENEMS  CHOICE OF ANTIMICROBIAL IS BASED ON:  IF KNOWN IgE MEDIATED  SKIN TEST RESULTS  SEVERITY OF REACTION

Summary

 THERE IS LESS DATA FOR NON-IgE MEDIATED ANTIBIOTIC HYPERSENSITIVITY  CAUTIOUS USE OF DIFFERENT β-LACTAM CLASS WITH DISSIMILAR SIDE CHAINS MAY BE APPROPRIATE  SJS, TEN- NEVER USE β-LACTAMS AGAIN  MOST IMPORTANT  OBTAIN A DETAILED ALLERGY HISTORY  DOCUMENT REACTION IN THE MEDICAL RECORDS  PATIENT EDUCATION

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Questions ?

References

1. Gruchalla RS, Pirmohamed M. Clinical practice. Antibiotic allergy. N Engl J Med. 2006 Feb 9;354(6):601-9. 2. Lown JA, Barr AL. Immune thrombocytopenia induced by cephalosporins specific for thiomethyltetrazole side chain. J Clin Pathol. 1987 Jun;40(6):700-1. 3. Prince BT, McMahon BJ, Jain M, Peters AT. Meropenem tolerance in a patient with probable fulminant piperacillin-induced immune hemolytic anemia. J Allergy Clin Immunol Pract. 2015 May-Jun;3(3):452-3. 4. Antunes J, Silva R, Pacheco D, Travassos R, Filipe P. Occupational contact allergy to cephalosporins. Dermatol Online J. 2011 May 15;17(5):13. 5. Trcka J, Seitz CS, Bröcker EB, Gross GE, Trautmann A. Aminopenicillin-induced exanthema allows treatment with certain cephalosporins or phenoxymethyl penicillin. J Antimicrob Chemother. 2007 Jul;60(1):107-11. 6. Blumenthal KG, Youngster I, Shenoy ES, Banerji A, Nelson SB. Tolerability of cefazolin after immune- mediated hypersensitivity reactions to nafcillin in the outpatient setting. Antimicrob Agents Chemother. 2014 Jun;58(6):3137-43. 7. Macy E, Poon K-Y T. Self-reported antibiotic allergy incidence and prevalence: age and sex effects. Am J Med. 2009 Aug;122(8):778.e1-7. 8. Macy E, Schatz M, Lin C, Poon KY. The falling rate of positive penicillin skin tests from 1995 to 2007. Perm J. 2009 Spring;13(2):12-8. 9. Gruchalla RS, Pirmohamed M. Clinical practice. Antibiotic allergy. N Engl J Med. 2006 Feb 9;354(6):601-9. 10. Macy E, Contreras R. Adverse reactions associated with oral and parenteral use of cephalosporins: A retrospective population-based analysis. J Allergy Clin Immunol. 2015 Mar;135(3):745-52.e5. 11. Macy E, Ngor E. Recommendations for the management of β-lactam intolerance. Clin Rev Allergy Immunol. 2014 Aug;47(1):46-55. 12. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010 Oct;105(4):259-273. 13. DePestel DD, Benninger MS, Danziger L, LaPlante KL, May C, Luskin A, Pichichero M, Hadley JA. Cephalosporin use in treatment of patients with penicillin allergies. J Am Pharm Assoc (2003). 2008 Jul- Aug;48(4):530-40.

References (Continued)

14. Apter AJ, Kinman JL, Bilker WB, Herlim M, Margolis DJ, Lautenbach E, Hennessy S, Strom BL. Is there cross-reactivity between penicillins and cephalosporins? Am J Med. 2006 Apr;119(4):354.e11-9. 15. Park MA, Koch CA, Klemawesch P, Joshi A, Li JT. Increased adverse drug reactions to cephalosporins in penicillin allergy patients with positive penicillin skin test. Int Arch Allergy Immunol. 2010;153(3):268-73. 16. Macy E, Ho NJ. Adverse reactions associated with therapeutic antibiotic use after penicillin skin testing. Perm J. 2011 Spring;15(2):31-7. 17. Martinez Tadeo JA, Perez Rodriguez E, Almeida Sanchez Z, Callero Viera A, Garcia Robaina JC. No Cross- Reactivity With Cephalosporins in Patients With Penicillin Allergy. J Investig Allergol Clin Immunol. 2015;25(3):216-7. 18. Romano A, Gaeta F, Valluzzi RL, Caruso C, Rumi G, Bousquet PJ. IgE-mediated hypersensitivity to cephalosporins: cross-reactivity and tolerability of penicillins, monobactams, and carbapenems. J Allergy Clin Immunol. 2010 Nov;126(5):994-9. 19. Frumin J, Gallagher JC. Allergic cross-sensitivity between penicillin, carbapenem, and monobactam antibiotics: what are the chances? Ann Pharmacother. 2009 Feb;43(2):304-15. 20. Macy E, Contreras R. Adverse reactions associated with oral and parenteral use of cephalosporins: A retrospective population-based analysis. J Allergy Clin Immunol. 2015 Mar;135(3):745-52.e5. 21. Kula B, Djordjevic G, Robinson JL. A systematic review: can one prescribe carbapenems to patients with IgE-mediated allergy to penicillins or cephalosporins? Clin Infect Dis. 2014 Oct 15;59(8):1113-22. 22. Lee CE, Zembower TR, Fotis MA, Postelnick MJ, Greenberger PA, Peterson LR, Noskin GA. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med. 2000 Oct 9;160(18):2819-22 23. Lutomski DM, Lafollette JA, Biaglow MA, Haglund LA. Antibiotic allergies in the medical record: effect on drug selection and assessment of validity. Pharmacotherapy. 2008 Nov;28(11):1348-53. 24. Sade K, Holtzer I, Levo Y, Kivity S. The economic burden of antibiotic treatment of penicillin-allergic patients in internal medicine wards of a general tertiary care hospital. Clin Exp Allergy. 2003 Apr;33(4):501-6. 25. Turnbull BR, Zoutman DE, Lam M. Evaluation of hospital and patient factors that influence the effective administration of surgical antimicrobial prophylaxis. Infect Control Hosp Epidemiol. 2005 May;26(5):478-85.

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