The Role of Beta Lactam Allergy in Antibiotic Stewardship...using a beta lactam use pathway in penicillin and cephalosporin allergic patients30 • Algorithm reduced broad-spectrum

The Role of Beta Lactam Allergy in Antibiotic Stewardship

Erin L. Reigh, MD, MSSection of Allergy and Clinical Immunology

Darthmouth-Hitchcock Medical CenterAssistant Professor of Medicine, Geisel School of Medicine

New Hampshire Antimicrobial Stewardship SymposiumMarch 20, 2019

Disclosures

• I have no disclosures.

Outline

• Discuss how beta lactam allergies lead to worse health outcomes

• Review beta-lactam allergy epidemiology and cross-reactivity

• Introduce a pathway for non-allergists to approach beta-lactam allergy

Would you feel comfortable giving…

• Amoxicillin to a 74 yo F with a history of childhood rash to penicillin?• How about cefepime?

• Ceftriaxone to a 56 yo M with a history of penicillin anaphylaxis?

• Cefpodoxime to a 62 yo F with a history of angioedema to cephalexin?

Beta Lactam Antibiotics

• Include penicillins (top) and cephalosporins (bottom), carbapenems, and monobactams

• Have a beta lactam ring structure in common, highlighted in red

• Our focus today is on penicillin and cephalosporin allergy

• Up to 10% of the general population and 15% of hospitalized patients list penicillin as an allergy1, 2

Beta Lactam Allergy:Not a Benign Diagnosis

Penicillin “Allergic” Patients are More Likely to…

• Receive fluoroquinolones, vancomycin, clindamycin3, 4

• Harbor drug resistant organisms such as MRSA (14-55%)3, 5 and VRE (30%)3

• Develop C. difficile colitis (23%-35% increase)3, 5

• Estimated mortality rate is 7%-35%6, 7


• Experience treatment failure (33% vs. 16%), infection recurrence (15% vs. 9%), and death (18% vs. 7%) from MSSA bacteremia8

• Experience treatment failure in gram negative bacteremia (38.7% vs 27.4%)2

• Experience a delay in empiric antibiotic treatment (Ave: 50 min)32

• Experience a surgical site infection (50% increased odds)31


• Develop new antibiotic “allergies” with alternative therapies3, 8

• Have an allergic reaction to vancomycin than cefazolin (3% vs. 2.4%)8

• Have side effects or toxicities from second-line therapies8

Economic Costs

• Penicillin-allergic patients have higher drug costs• $14-193 higher outpatient antibiotic cost

per patient9

• $300 more per patient per day of inpatient antibiotic therapy4

• $1253 more in length of stay costs per patient per admission3

• Penicillin-allergic patients have longer hospital stays• 10% longer hospital stays, estimated cost of

$21.5 million per year3

Penicillin Allergy:Not an Accurate Diagnosis

Most patients who list a penicillin allergy are not truly

allergic

• Less than 10% of these allergies are confirmed when tested1

• Two studies showed only 3% were truly allergic, and one of them was a very large study of 1300 patients3, 10

AAAAI Consensus Statement

“A misdiagnosis of allergy to beta lactams results in dramatically poorer clinical outcomes for patients and is

not acceptable any longer.”11

Penicillin Allergy:How Did We Get Here?

Why is Penicillin Allergy so Over Diagnosed?

• Childhood viral rashes are often misdiagnosed as drug rashes • Only 7-16% of kids with “drug allergy” during an

infection later test positive to the drug1

• Even if a patient is truly allergic, most people “outgrow” penicillin allergy• Over 50% of people with confirmed allergy to penicillin

lose their allergy after 5 years1

• Over 80% will lose it in 10 years1

Cephalosporin Trivia

• In a patient reporting a penicillin allergy, what is the overall likelihood of reacting to any cephalosporin?• A) <1%

• B) 2%

• C) 10%

• D) 15%


• In a patient reporting a penicillin allergy, what is the overall likelihood of reacting to any cephalosporin?

• A) <1%• B) 2%

• C) 10%

• D) 15%


• In a patient with confirmed penicillin allergy, what is the overall likelihood of reacting to anycephalosporin?• A) <1%

• B) 2%

• C) 10%

• D) 15%


• In a patient with confirmed penicillin allergy, what is the overall likelihood of reacting to anycephalosporin?• A) <1%

• B) 2%• C) 10%

• D) 15%

Cephalosporin Cross-Reactivity with Penicillin

• Overall cross-reactivity based on multiple studies is actually very low:• In a reported (but unconfirmed) penicillin allergy: 0.1%1

• In a confirmed penicillin allergy: 2%1

• New cases of cephalosporin allergy (with no prior penicillin allergy) occur at a rate 0.5-1% in the US3

• These numbers exclude patients

with penicillin anaphylaxis

Where Did 10% Come From?

• Drug preparations have changed. Early on these drugs were created from mold cultures; now they are synthetic

• The available cephalosporins have changed.

Throwing the Beta Lactams out with the Bath Water

• Despite more reassuring statistics, the 10% myth is still quoted by clinicians, and there is still reluctance to use cephalosporins in patients with penicillin allergy

• Result: more broad spectrum antibiotic use

Penicillin Skin Testing

• Limited resource: scarcity of allergists

• Time consuming (takes about 1 hour)

• Reagents expensive (~$100)

• If negative: <2% risk of allergy1

• If positive: 50% risk of allergy1

• Must be followed by a drug challenge to confirm

http://www.chp.edu/our-services/allergy-immunology/skin-allergy-testing

PredictingCross-Reactivity:

Beta Lactam Allergy is not a Class Effect


• Research indicates cross-reactivity is due almost entirely to the R1 side chain, not the beta lactam ring


• Research indicates cross-reactivity is due almost entirely to the R1 side chain, not the beta lactam ring

Example of Cross-Reactivity Chart


• A meta-analysis found an average rate of cross-reactivity between 1-10% for first generation cephalosporins and NO significant cross-reactivity for 2nd generation and higher cephalosporins12

• Most cross-reactive side chains are in 1st and 2nd generation cephalosporins1, 12, 13, 14, 15, 16

• AAP has advocated giving 2nd gen and up cephalosporins to patients with non-anaphylactic reactions to penicillin for over 10 years now


• Highest cross-reactivity for confirmed penicillin allergy observed in cefadroxil (27%)10

• Risk for cephalexin reaction in confirmed penicillin allergy is 7-10% vs. 1% for penicillin non-allergic12, 13

• Cefazolin is low risk. There were NO reactions in a retrospective cohort of 299 penicillin allergic patients who got cefazolin for orthopedic surgery17

Cephalosporin Anaphylaxisin Penicillin “Allergy”

• Study of 820,000 patients found that, out of nearly 70,000 patients with a PCN allergy label who got cephalosporins, only 3 had anaphylaxis over a period of 2 years (0.00005%)3

• Even if your patient was truly allergic to penicillin, they are still more likely than not to tolerate a first generation cephalosporin.

Cephalosporin/Cephalosporin Cross-Reactivity

NOT a class effect

• Based on the side chains (R1 and R2)

• Retrospective study of 820,000 patients: 3,313 patients with cephalosporin allergy label who received 6,404 courses of cephalosporins –no cases of anaphylaxis3

Cephalosporin/Cephalosporin Cross-Reactivity

• Patients with one cephalosporin allergy may safely receive other cephalosporins via test dose

• Choose a cephalosporin that doesn’t share a side chain

Penicillin and Cephalosporin Allergies:

Applying the Data

Blumenthal 2015

• 2014 MGH study looked at the safety and efficacy of using a beta lactam use pathway in penicillin and cephalosporin allergic patients30

• Algorithm reduced broad-spectrum antibiotic use by 5-30%

• No increase in adverse drug reactions.

• Patients received beta lactams 2 days faster than before the pathway was introduced

• We have customized these MGH guidelines for use at DHMC

Risk Stratification by Allergic Response

• Treatment options are based upon the allergy history and the type of allergic reaction

• Broken into 3 categories:• Mild, Delayed (Type IV)

• Immediate (Type I)

• Severe (Type II-IV)

Mild Type IV

- Slow onset – usually days into treatment course

- Itchy, mostly flat, red, blanching rash (when confluent can look like a sunburn)

- Uncomfortable but not life-threatening

- T-cell mediated

www.uptodate.com

Immediate, Type I

• RAPID onset, usually within minutes of exposure

Time to Cardiovascular Collapse in Patients with Fatal Anaphylaxis18

Foods: 30 min

Insect Sting: 15 min

Drugs: 5 min

Immediate, Type I

• RAPID onset, usually within minutes of exposure

• Activation of pre-formed IgE antibodies – prior exposure required

Immediate, Type I

• Hives most common (raised welts like mosquito bites or coalesced into larger plaques)

• May also get angioedema (dramatic swelling), wheezing, dizziness, hypotension…

• Treatable with epinephrine and antihistamines, resolution usually within 24h

Immediate, Type I

• Hives most common (raised welts like mosquito bites or coalesced into larger plaques)

• May also get angioedema (dramatic swelling), wheezing, dizziness, hypotension…

• Treatable with epinephrine and antihistamines, resolution usually within 24h

www.uptodate.com

Severe Reactions: Type II-IV

• Mechanisms include antibody complex deposits and T-cell responses

• Examples: Stevens-Johnson syndrome, hemolytic anemia, serum sickness, drug rash eosinophilia and systemic symptoms (DRESS), acute interstitial nephritis (AIN)

• Look for: cytopenias, easy bruising, jaundice, joint pains, fevers, abnormal liver/kidney function, blistering rashes, mucous membrane involvement

Severe Reactions: Type II-IV

• Mechanisms include antibody complex deposits and T-cell responses

• Examples: Stevens-Johnson syndrome, hemolytic anemia, serum sickness, drug rash eosinophilia and systemic symptoms (DRESS), acute interstitial nephritis (AIN)

• Look for: cytopenias, easy bruising, jaundice, joint pains, fevers, abnormal liver/kidney function, blistering rashes, mucous membrane involvement

www.uptodate.com

Test Doses

Test Dose

• Small percentage of the total dose (usually 10%)

• Monitor for symptoms

• If none occur, full dose can be given

• Once tolerated, patient does not need test dose in the future for that drug

Test Dose

• Recommended when we do not believe the patient will have a reaction! Done out of caution.

• Only rule out Immediate (Type I) reactions

• Delayed-type reactions can still occur after a test dose, but these are not life-threatening

Communication: Patients

• WHAT NOT TO SAY: “We don’t really think you are allergic and we are going to give you this drug anyway.”

• WHAT TO SAY: “A lot of studies show people outgrow allergies. Your chances of reacting to this drug are less than 2%. If you react, it will mostly likely be a mild rash which we can treat. A different drug may not be as effective and may cause life-threatening side effects like C. diff and MRSA. Would you like to receive the drug while we monitor you closely?”

Communication: Team

• Nursing staff should be involved early on to arrange the necessary care at the bedside• We incorporate a life safety nurse consult who can

arrange back-up nursing or facilitate transfer to ICU

• Order set in EMR and pharmacy preparation of test dose helps avoid errors and move process along more efficiently

FAQs

Drug Challenges without Testing

“You want me to give penicillin… to someone with a penicillin allergy… without testing?”

Yes!


AAAAI Consensus Statements11:

• “Direct oral drug provocation tests are safe and effective in confirming or excluding drug hypersensitivity reactions to beta lactams in low risk patients with delayed-onset benign rashes.”

• “Regarding T-cell mediated non immediate reactions, skin prick testing is not mandatory.”

AAAAI Practice Parameters 2010 (most recent update)1:

• “Patients with a vague and/or distant history of penicillin allergy may be candidates to receive penicillins via graded challenge.”

Caubet 2011 88 children:delayed onset

rash to penicillins

skin or blood test

11 (12.5%)(+)

intradermal

2 (2.3%)(+)

blood

75 (85%)(-)

Challenge everyone regardless of result!

2 pos 73 neg2 neg0 pos4 pos 7 neg

• No challenge reactions were more severe than the index event

Allergy testing led to 9 false positives (10%) and 2 false negatives (2.3%)33

Mill 2016 818 childrenh/o amoxicillin

allergy

Challenge! (no skin testing)

17 (2.1%)Immediate

Reaction

31 (3.8%)Delayed

Rash

770 (94%)No reaction

Skin tested

1 (6%)pos

16 (94%)neg

• All reactions were limited to skin and resolved with antihistamines

• No severe reactions occurred• Skin testing would have

missed 94% of the immediate reactions19


• Tucker 2017: military recruits (ages 18-25) in San Diego with beta lactam allergy label (penicillin and cephalosporin)20. Initially, recruits had skin testing if they had a penicillin allergy, but…

“Because of time constraints and 74 consecutive negative skin test results (followed by negative

amoxicillin challenge), subsequent recruits bypassed skin testing and proceeded directly to amoxicillin

challenge.”


• Out of 328 recruits:

• 5 had a reaction to the challenge (1.5%)

• Combined with the first 74, the rate was only 1.2%.

• No cases of anaphylaxis

• All had cutaneous symptoms and 1 had a globussensation which resolved without transfer to higher level of care

Confino-Cohen 2017710 patientsBeta-lactam

allergy

68 immed.(<1h)

642 delayed reactions

62.3% Skin test neg

5.3% Skin test pos

32.4% equivocal

Challenge all!

9 (1.5%)immed. rxn

• Only one patient who reacted had a positive skin test• All reactions were mild rashes

24 (4%)delayed rxn


• Macy 2018: leader in drug allergy research at Kaiser San Diego. Standard protocol is to perform amoxicillin 250mg challenge without skin testing for benign rashes >12 mos. prior or unknown symptoms21

• 398 challenges over the course of 1 year:

• 1 (0.3%) acute reaction

• 5 (1.3%) delayed reactions

• None of the reactions were serious and all were managed in clinic

Iammatteo 2019 156 patientsNon-life-threateningPenicillin reaction

Placebo

80mgamoxicillin

500mgamoxicillin

16 “reactions”

120 (77%)No reaction

15 (10%)Non-allergic

reaction

4 (2.6%)Allergicreaction

• All allergic reactions were limited to the skin

• No life-threatening reactions

• Most reactions were delayed

• Skipping skin testing in low risk patients did not lead to more positive challenges (2.6% vs. 1.8%, p=0.59)

FAQs

Reaction Type

“Isn’t it possible my patient will have a worse reaction than the first one?”

Anything’s possible… but it is very, very unlikely.

Reaction Type

• 182 patients with positive beta lactam challenges

• Only risk factor for anaphylaxis was an initial reaction of anaphylaxis (>10 fold risk)25.• This has been seen in numerous other studies as well

• Patients who report anaphylaxis are 2-4x more likely to have a true allergy and have increased risk of cross-reactivity with other beta lactams25.

• Patients with no recall of their index reaction who have a positive challenge most often have only a benign rash25

FAQs

Legal Concerns

“It’s all fun and games until someone loses a lawsuit. Can you guarantee I won’t get sued?”

No, but it would be very unlikely!

2018 review: “Malpractice lawsuits based on prescribing or administering penicillin to a patient with a known

penicillin allergy is uncommon and rarely successful.”23

Legal Concerns

• For cephalosporins, judge ruled in favor clinicians for all cases that went to trial23

• Cited “lack of scientific evidence demonstrating that a cephalosporin or carbapenem was contraindicated”23

• For penicillin, 3 cases of liability23:• One in 1956 – very, very old…

• One in 1998 – drug not contributory but awarded money for ”pain and suffering” anyway

• One in 2007 – patient with a history of SJS

Legal Concerns

Legal Concerns

• “Patients seeing doctors who were sued in the past were significantly more likely to report that their doctor rushed them, did not explain reasons for tests or ignored them… communication was the most common complaint.”

• “Primary care physicians sued less often are those more likely to spend time educating patients about their care, more likely to use humor and laugh with their patients and more likely to try to get their patients to talk and express their opinions.”


• Amoxicillin to a 74 yo F with a history of childhood rash to penicillin?• How about cefepime?

• Ceftriaxone to a 56 yo M with a history of penicillin anaphylaxis?



• Amoxicillin to a 74 yo F with a history of childhood rash to penicillin? OK with a test dose• How about cefepime? OK with a full dose

• Ceftriaxone to a 56 yo M with a history of penicillin anaphylaxis? OK with a test dose



• Amoxicillin to a 74 yo F with a history of childhood rash to penicillin? OK with a test dose• How about cefepime? OK with a full dose

• Ceftriaxone to a 56 yo M with a history of penicillin anaphylaxis? OK with a test dose

• Cefpodoxime to a 62 yo F with a history of angioedema to cephalexin? OK with a test dose

Balancing Risk

We Need To Think About Risk Differently

• Risk of life-threatening reaction to beta lactams in those with reported allergies is exceedingly low if patients are screened for mild reactions and the drug is chosen carefully

• Conversely, the risk of a life-threatening infection is much, much higher when alternative agents are used, and use of these agents is a growing public health issue• C. difficile colitis kills 29,000 people a year (CDC.gov)

• Anaphylaxis from all causes kills <225 people a year24

Resources are Finite

• Allergy specialists cannot meet the population demands of penicillin allergy. Pathways created by allergists that empower non-allergists to address penicillin allergy are necessary25

• Up to one third of patients continue to erroneously report a penicillin allergy after delabeling, further burdening the system25

Other Creative Solutions

• Telemedicine allergy consults have been used to aid in skin testing programs26

• Pharmacists, nurses, ID fellows, and other healthcare professionals have been trained to perform skin testing on selected inpatients with penicillin allergy labels and reduced length of stay and broad spectrum antibiotic use27, 28, 29

• Pre-operative skin testing programs allow the use of beta-lactams in the OR

Summary

• Penicillin allergy is not a benign diagnosis and leads to poor health outcomes

• Most patients with a penicillin allergy label are not truly allergic

• Beta lactam cross-reactivity is not as extensive as once thought

• Clinical guidelines at an institutional level can help clinicians feel more comfortable reintroducing beta lactam antibiotics

[email protected]

References1. Solensky, Khan, ed. “Drug Allergy: An Updated Practice Parameter.” Annals of Allergy, Asthma, and Immunology. Volume 105, Oct. 2010.

2. Jeffres, M. et al. “Consequences of avoiding beta lactams in patients with beta lactam allergies.” JACI 2016; 137: 1148-53.

3. Macy E. et al. “Health care use and serious infection prevalence associated with penicillin ‘‘allergy’’ in hospitalized patients: A cohort Study” J Allergy Clin Immunol Vol 133, No. 3, 2014

4. Sastre, J. et al. “Medical and economic impact of misdiagnosis of drug hypersensitivity in hospitalized patients.” JACI 2012; Vol. 129: 566.

5. Blumenthal, K. et al. “Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study.” BMJ 2018;361:k2400 doi: 10.1136/bmj.k2400 (Published 27 June 2018)

6. Kelly, C.; LaMont, T. “Clostridium difficile — More Difficult Than Ever.” N Engl J Med 2008; 359:1932-1940.

7. Hota, S.; Achonu, C.; Crowcroft, N.: et al. “Determining Mortality Rates Attributable to Clostridium difficileInfection.” Dispatch. Volume 18, Number 2—February 2012

8. Blumenthal, K. et al. “Improving Clinical outcomes in patients with methicillin-sensitive Staphylococcus aureusbacteremia and reported penicillin allergy.” Clin Infect Dis. 2015 Sep 1; 61(5): 741–749

9. Mattingly, TJ. Et al. “The Cost of Self-Reported Penicillin Allergy: A Systematic Review” J Allergy Clin ImmunolPract 2018;6:1649-54.

10. Campagna, J. et al. “The use of cephalosporins in penicillin-allergic patients: A literature review.” The Journal of Emergency Medicine, Vol. 42, No. 5, pp. 612–620, 2012

References11. Torres, MJ, et al. “Controversies in Drug Allergy: Beta Lactam Hypersensitivity Testing.” JACI:IP 2019; 7:40-45.

12. Pichichero, M.; Casey, J. “Safe use of selected cephalosporins in penicillin-allergic patients: A meta-analysis.”Otolaryngology–Head and Neck Surgery (2007) 136, 340-347.

13. Pichichero, M. “A Review of Evidence Supporting the American Academy of Pediatrics Recommendation for Prescribing Cephalosporin Antibiotics for Penicillin-Allergic Patients” Pediatrics. Vol 115, No. 4, April 2005.

14. Atanaskovic´-Markovic´ M. et al. “Immediate allergic reactions to cephalosporins and penicillins and their cross-reactivity in children” Pediatr Allergy Immunol 2005: 16: 341–347

15. Somech, et al. Evaluation of Immediate Allergic Reactions to Cephalosporins in Non-Penicillin-Allergic Patients” Int Arch Allergy Immunol 2009;150:205–209

16. Novalbos, et al. “Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins” Clinical and Experimental Allergy, 2000, Volume 31, pages 438±443

17. Goodman, EJ, et al. “Cephalosporins can be given to penicillin allergy patients who do not exhibit an anaphylactic response.” Journal of Clinical Anesthesia 2001; 13: 561-564.

18. Campbell, R. et al. “Emergency department diagnosis and treatment of anaphylaxis: a practice parameter.” Ann Allergy Asthma Immunol 113 (2014) 599e608

19. Mill, C. et al. “Assessing the Diagnostic Properties of a Graded Oral Provocation Challenge for the Diagnosis of Immediate and Nonimmediate Reactions to Amoxicillin in Children.” JAMA Pediatr. 2016 Jun 6;170(6).

20. Tucker, M. et al. “Amoxicillin challenge without penicillin skin testing in evaluation of penicillin allergy in a cohort of Marine recruits.” JACIIP 2017; Vol5, issue3: 813-815

https://www.ncbi.nlm.nih.gov/pubmed/27043788

References

21. Macy, E. Et al. „Controversies in Allergy: Is Skin Testing Required Prior to Drug Challenges?” JACI:IP 2018; 7, 412-

417

22. Iammatteo, M. et al. “Safety and Outcomes of Oral Graded Challenges to Amoxicillin without Prior Skin Testing” J

Allergy Clin Immunol Pract 2019;7:236-43

23. Jeffres, M. et al. “Systematic review of professional liability when prescribingβ-lactams for patients with a known

penicillin allergy.” Ann Allergy Asthma Immunol 121 (2018) 530–536

24. Jerschow, E. et al. “Fatal anaphylaxis in the United States, 1999-2010: Temporal patterns and demographic

associations.” J Allergy Clin Immunol 2014;134:1318-28

25. Chiriac AM, et al. “Controversies in Drug Allergy: Drug Allergy Pathways.” JACI:IP 2019; 7: 46-60.

26. Staicu ML, et al. “The use of telemedicine for penicillin allergy skin testing JACI:IP 2018;2198. 30315-5.

27. Chen, J. et al. “A Proactive Approach to Penicillin Allergy Testing in Hospitalized Patients” J Allergy Clin Immunol

Pract 2017;5:686-93

28. Sacco, K. et al. “Clinical outcomes following inpatient penicillin allergy testing: A systematic review and meta-

analysis” Allergy. 2017;72:1288–1296.

29. Heil EL, et al. “Implementation of an infectious disease fellow-managed penicillin allergy skin testing service. Open

Forum Infect Dis 2016; 3:ofw155.

30. Blumenthal, K. et al. “Impact of a clinical guideline for prescribing antibiotics to inpatients reporting penicillin or cephalosporin allergy.” Ann Allergy Asthma Immunol 115 (2015): 294-300.

References

31. Blumenthal, K. et al. “The impact of a reported penicillin allergy on surgical site infection risk.” Clin Infect Dis 2018;66:329-336.

32. Sakoulas, G. et al. “Is a Reported Penicillin Allergy Sufficient Grounds to Forgo the Multidimensional Antimicrobial Benefits ofβ-Lactam Antibiotics?” Clinical Infectious Diseases 2019;68(1):157–64

33. Caubet, J. et al. “The role of penicillin in benign skin rashes in childhood: A prospective study based on drug rechallenge” J Allergy Clin Immunol 2011;127:218-22.

34. Confino-Cohen, R. et al. “Oral Challenge without Skin Testing Safely Excludes Clinically significant delayed onset penicillin hypersensitivity.” J Allergy Clin Immunol Pract 2017;5:669-75

Additional References• Macy E. “Penicillin and Beta-Lactam Allergy: Epidemiology and Diagnosis.” Curr Allergy Asthma Rep (2014) 14:476.

• Dickson, et al. “Diagnosis and Management of Immediate Hypersensitivity Reactions to Cephalosporins.” Clinic Rev Allerg Immunol(2013) 45:131–142

• Yu-Hor Thong, B. “Update on the Management of Antibiotic Allergy.” Allergy Asthma Immunol Res. 2010 April;2(2):77-86.

• Wulf, et al. “Sulfonamide cross-reactivity: Is there evidence to support broad cross-allergenicity?” Am J Health-Syst Pharm—Vol 70 Sep 1, 2013

• Lessa et al. “Burden of Clostridium difficile Infection in the United States.” N Engl J Med 2015; 372:825-834

• Pichichero, M. et al. “Penicillin and Cephalosporin allergy.” Ann Allergy Asthma Immunol 112 (2014) 404e412

• Cunha, et al. “Ertapenem: Lack of allergic reactions in hospitalised adults reporting a history of penicillin allergy.” Letters to the editor/International Journal of Antimicrobial Agents 42 (2013) 584-588

• Strom, B. et al. “Absence of Cross-Reactivity between Sulfonamide Antibiotics and Sulfonamide Nonantibiotics” N Engl J Med 2003;349:1628-35.

• Brackette, C. et al. “Likelihood and Mechanisms of Cross-Allergenicity Between Sulfonamide Antibiotics and Other Drugs Containing a Sulfonamide Functional Group.” Pharmacotherapy. 2004;24(7) via Medscape

• Wall, G. et al. “Assessment of hypersensitivity reactions in patients receiving carbapenem antibiotics who report a history of penicillin allergy.” J Chemother 2014 Jun;26(3):150-3.

• Audicana, M et al. “Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin.” Allergy 1994 Feb;49(2):108-13.

• Romano et al. “Cross-Reactivity and Tolerability of Cephalosporins in Patients with Immediate Hypersensitivity to Penicillins” Ann Intern Med.2004;141:16-22.

• Chiriac AM, et al. “Designing predictive models for beta lactam allergy using the drug allergy and hypersensitivity database. JACI:IP2018; 6:139-148.e2.

• Macy, E. et al. “Are Cephalosporins Safe for Use in Penicillin Allergy without Prior Allergy Evaluation?” JACI:IP; 2017: 6, 82-89

http://www-ncbi-nlm-nih-gov.beckerproxy.wustl.edu/pubmed/24090971

PENICILLIN ALLERGY EVALUATION AT DARTMOUTH HITCHCOCK MEDICAL CENTER

M DesBiens, M.D.

Infectious Disease and Preventive Medicine Fellow, DHMC

March 20, 2019

DHMC COHORTAll adult patients aged 18 years or older, with admission date between 1/01/2017 and 12/31/2018, who received at least one antibiotic during their hospitalization

20,519 encounters

16,507 unique patients

Table 1a: Patients reporting penicillin allergy compared to patients not reporting penicillin allergy, patient level data

Reporting PCN allergy

Not reporting PCN allergy

p

Receipt of any antibiotic, n patients (%) 2,654 (16%) 13,853 (84%) <0.001

Age in years, mean (range) 61 (18-101) 61 (18-100) 0.52

Female, n (%) 1,885 (71%) 6,799 (49%) <0.001

Presence of any other allergy, n (%) 2,053 (77%) 8,234 (59%) <0.001

Presence of any other antibiotic allergy, n (%) 1,007 (38%) 2,307 (17%) <0.001

Clostridioides difficile, OR (95% CI) 1.2 (0.9,1.6)

MRSA Blood Stream Infection, OR (95% CI) 1.5 (0.9, 2.6)

VRE infection, OR (95% CI) 1.9 (1.2, 2.9)

Table 1b: Patients reporting penicillin allergy compared to patients not reporting penicillin allergy, encounters level data

Reporting PCN allergy

Not reporting PCN allergy

p

Receipt of any antibiotic, n encounters (%) 3,338 (16%) 17,181 (84%) <0.001

Length of stay in days, average (95% CI) 7.2 (6.9, 7.6) 6.8 (6.6, 7.0) 0.039

Total antibiotic days, average (95% CI) 5.5 (5.26, 5.70) 5.0 (4.84, 5.12) 0.003

Encounters receiving a formulary restricted antibiotic, n (% within subgroup) 1,012 (30%) 2,304 (13%) <0.001

Encounters receiving vancomycin, meropenem, and/or a fluoroquinolone, n (% within subgroup) 1,779 (53%) 5,250 (31%) <0.001

16% PCN allp<0.001

22% PCN allp<0.001

30% PCN allp<0.001

45% PCN allp<0.001

45% PCN allp<0.001

DHMC PENICILLIN EVALUATION PROJECT

Test Dose Protocol Implementation• Order characteristics• Outcomes• Pertinent antibiotic use over time

61 test dose protocols completedFeb 1, 2018-March 1, 2019

97%95%

88%

p=0.001

PREDICTIVE MODELINGAntibiotic stewardship

C diff, MRSA, VRE

Antibiotic-related AKI

Drug Costs

Widespread PCN allergy evaluation can save, annually: 5 cases of Clostridoides difficile infection 3 cases of MRSA BSI 7 cases of VRE infection 4 AKIs (at least) Improved stewardship in 1,159 patients (priceless)

DHMC inpatient pharmacy, LexiComp online

Modeled from 2017 data: 242 encounters with pts reporting

PCN allergy 2,149 days of meropenem

9 days per encounter

ASSUMPTIONS: 90% without IgE (218 encounters) 97% tolerate TDP (212) 1,908 days

pip-tazo: $52,088.4meropenem: $151,113.60

DIFFERENCE: $99,025.20 per year

Summary• In a large sample of adults admitted to a northern New England

tertiary care referral center, 16% reported allergy to penicillin.

• Adults reporting penicillin allergy have longer lengths of stay, more antibiotic-days, more formulary restricted antibiotics, and are more likely to develop C diff infection, MRSA bacteremia, and VRE infections than those patients not reporting penicillin allergy.

• Penicillin allergy may be safely and effectively evaluated with review of allergy history, and monitored dose challenge in patients without concern for severe reaction.

• Clinical guidelines at an institutional level can help all providers become better antibiotic stewards!

Antibiotic Stewardship

Clinical Outcomes

PCN Allergy

Evaluation

Patient Safety

“A misdiagnosis of allergy to beta lactams results in dramatically poorer clinical outcomes for patients and is not acceptable any longer.” (Torres 2019)

Special thanks to my team:Erin Reigh, MDMichael Calderwood, MD, MPHCraig Worby, PharmDJohn Trummel, MD, MPHDiane Beaulieu, BSN, RNPriya Katari, MDSteve Houston, MS, BS

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The Role of Beta Lactam Allergy in Antibiotic Stewardship...using a beta lactam use pathway in penicillin and cephalosporin allergic patients30 • Algorithm reduced broad-spectrum

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