What type of hypersensitivity is a penicillin allergy

  1. Most patients who own a history of penicillin allergy are not allergic when the allergy is formally evaluated.
  2. Unverified penicillin allergy leads to increased treatment failures and delay to first antibiotic dose in sepsis patients.
  3. Even patients with true, IgE-mediated penicillin allergy can safely get most cephalosporins, and every carbapenems and monobactams.
  4. Other harms of unverified penicillin allergy labels include increased risk of adverse events, Clostridium difficile infection, surgical site infection, and colonization with antibiotic resistant organisms.
  5. Systemwide approaches to hospitalized patients with beta-lactam allergies are needed to improve the quality and safety of care.

Kimberly G.

Blumenthal, MD, MSc
Assistant Professor of Medicine
Quality and Safety Officer for Allergy
Professor of Radiology and Neuroradiology



AUG 15, | LINDSAY COURTNEY, PHARMD, AND MEGHAN JEFFRES, PHARMD, BCIDP*

The first-generation intravenous cephalo­sporin, cefazolin, is a workhorse in most hospitals. It is the preferred choice for a majority of procedures in the surgical prophylaxis guidelines endorsed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Surgical Infection Society, and the Society for Healthcare Epidemiology of America.1 Additionally, cefazolin has become a first-line choice for the treatment of methicillin-sensitive Staphylococcus aureus infections.

The results of several studies show that patients treated with cefazolin own lower mortality rates, fewer adverse events, and less allergic reactions compared with the antistaphylococcal penicillins, nafcillin and oxacillin. Unfortunately, cefazolin is often avoided in patients with penicillin allergies due to the concern for cross-reactivity between penicillins and cephalosporins.

It is our belief that avoidance of cefazolin due to concerns about cross-reactivity results in measurable patient harm and is not supported by published evidence.

There are clear patient care consequences of avoiding cefazolin, especially as surgical prophy­laxis. A study of over surgeries found that the odds of getting a surgical site infection were higher in patients who were not given cefazolin due to concerns about a penicillin allergy.5 In the multi­variable logistic regression model adjusting for age, sex, race, surgery type, American Society of Anesthesiologists risk class, procedure duration, and wound class, a reported penicillin allergy was associated with increased odds of surgical site infection (adjusted odds ratio, ; 95% CI, ).

Based on the results from the multi­variable model, the authors concluded that the increased surgical site infection risk was mediated by the patients’ receipt of an alternative perioperative antibiotic. Patients labeled as penicillin allergic were far less likely to get cefazolin than nonallergic patients (12% vs 92%), and they received significantly more clindamycin, vancomycin, and gentamicin. Almost 98% of patients who received vancomycin prophylaxis received it 24 minutes prior to incision instead of the recommended 60 to minutes.1

A HABIT OF AVOIDANCE
The habit of avoiding cephalosporins in patients with a penicillin allergy is pervasive.

Clinicians are inundated with best-practice and safety alerts in electronic medical records proclaiming that the use of cephalosporins is contraindicated in patients with a penicillin allergy. To ister a cephalosporin, clinicians must override these alerts, but that is often not done due to fear of litigation and a misunderstanding of the pathophysiology of cross-reactivity among β-lactams.

For years, clinicians and students own been taught there is 10% cross-reactivity between penicillins and cephalosporins.

The origin of this 10% cross-reactivity dogma is largely based on data published in the s and s.6,7 The original authors assumed cross-reactivity was due to the β-lactam structure, but we now know that their findings were most likely due to contamination of ancient drug preparations. Modern investigations by Romano et al8,9 established that cross-reactivity between penicil­lins and cephalosporins is primarily based on the R1 side chain, not the shared β-lactam ring structure (Table 1).10

The first study included patients with confirmed delayed (Type IV) hypersensitivity to penicillins.8 Investigators used patch and/or skin testing to assess for cross-reactivity to several cephalosporins and aztreonam.

None of the participants experienced reactions to dissim­ilar side chain β-lactams (cefuroxime, ceftriaxone, aztre­onam), while 40 (19%) had reactions to similar side chain β-lactams (cephalexin, cefaclor, cefadroxil).

The second study included patients with confirmed immediate allergy (Type I) to penicillins. Investigators used skin and/or radioallergosorbent tests to assess for cross-reactivity to several cephalosporins.9 They found that 95 patients (38%) reacted to similar side chain cephalospo­rins and 4 (%) reacted to dissimilar side chain cepha­losporins.

These data protest a 20% cross-reactivity rate between similar side chain β-lactams for patients with Type IV reactions and 40% cross-reactivity rate for Type I reactions. Only 1% of patients will own an allergy to both a penicillin and a cephalosporin with a dissimilar side chain. Since cefazolin has a unique side chain not shared by any other penicillin or cephalosporin, we can predict that approximately 1% of patients with a penicillin allergy will also experience hypersensitivity to cefazolin. Several recent reviews own created side-chain charts to aid clini­cians in selecting β-lactams with dissimilar side chains to the suspect allergen (Table 2).

In addition to these specific allergy evaluations, there are 4 retrospective clinical studies that own investigated how often cefazolin is tolerated in patients with self-reported penicillin allergies (Table 3).

The first study included patients labeled as penicillin allergic, of whom received a cephalosporin during the surgical procedure.14 Most patients received cefazolin, and 1 received ceftazidime.

One of the patients received diphenhydramine and hydrocortisone after the cephalo­sporin was istered and was assumed by authors to own experienced an allergic reaction. Although cefazolin was istered in of of those cases, it was not stated if cefazolin was the culprit cephalosporin in this case. The second study included surgical interventions in pediatric patients labeled as penicillin allergic.15 Cefazolin was ­istered in surgical interventions. One patient (%) experienced hives and erythema and was successfully treated with diphen­hydramine. The majority of patients received clindamycin, and % experienced allergic reactions, almost 3 times the reaction rate among patients treated with cefazolin.

The third study included patients labeled as penicillin allergic who received hip and knee arthroplasty surgeries.16 A subset of 54 patients reporting non–immunoglobulin E (IgE)- mediated penicillin allergies received and tolerated cefazolin. The fourth study included 55 patients who received cefazolin for surgical prophylaxis regardless of penicillin allergy history description.17 None experienced an allergic or adverse reaction.

SELF-REPORTED VS CONFIRMED ALLERGIES
Although the reaction rate to cefazolin was low in every 4 studies, the study samples consisted entirely of patients with self-reported penicillin allergies.

We now know that most self-reported penicillin allergies are incorrect. A meta-analysis of 24 studies sure that more than 95% of patients labeled as having a penicillin allergy will own a negative penicillin skin test and do not own an IgE-mediated (Type I) allergy to penicillin.21 A penicillin skin test does not law out other immune-mediated hypersensitivities, including Type II, III, and IV reactions.10

Not only does cefazolin appear to be safe to use in patients with a self-reported peni­cillin allergy, cefazolin tolerance has been studied in patients with a proven penicillin hypersensitivity.

A prospective study out of Spain evaluated tolerance to cefazolin in patients with immediate allergies to penicillin or amoxicillin.18 Every 41 patients underwent skin testing and/or an oral challenge with peni­cillin and amoxicillin to confirm their allergy history. They then underwent skin testing and an intramuscular challenge for cefazolin and other cephalosporins. None of these patients experienced an allergic reaction.

Two other prospective studies from France and Italy included patients with a history of perioperative hypersensitivity suspected to be due to cefazolin, which was subsequently confirmed by skin tests and/or challenge tests.

These patients then underwent skin testing to assess their tolerance to penicillins.19,20 In the first study, 1 of the 10 patients allergic to cefazolin had a positive skin test for amoxi­cillin and ampicillin.19 This patient was also skin test positive for cefuroxime and cefo­taxime, which own almost identical R1 side chains but are not similar to any penicil­lins. In the second study, 19 patients allergic to cefazolin were evaluated and none of them displayed a positive skin test to any of the penicillins.20

The overall reaction rate of these 7 studies is % (95% CI, 0%%) (Table 3).

The reaction rate among patients who self-report an allergy to penicillin is % (95% CI, 0%%). The reaction rate among patients with a confirmed penicillin allergy is % (95% CI, 0%%). This is far lower than the 20% or 40% seen between penicillins and cephalosporins with similar side chains and similar to the % reaction rate seen in prior studies.8,9 Ultimately, a reaction rate of % is too low to call the relationship between cefazolin, penicillin, and amoxicillin cross-reactive and instead most likely represents patients who own 2 indepen­dent allergies.

This reaction rate is also in line with data indicating that % of the popula­tion has multiple drug allergy syndrome.22
Research about and awareness of the risks associated with avoiding β-lactams in patients labeled as penicillin allergic has increased dramatically recently. However, more data and guidance are needed to assist clinicians distin­guish between cross-reactivity and multiple β-lactam allergies. In the meantime, distribu­tion of the existing data and education from infectious diseases and allergy champions will result in increased use of cefazolin in both patients labeled as penicillin allergic as well as those with proven penicillin allergies.

Courtney is completing her PGY1 pharmacy practice residency at the University of Pittsburgh Medical Middle, Shadyside, in Pennsylvania.

Jeffres delights in conducting contrarian clinical research at the University of Colorado Anschutz Medical Campus but is happiest when creating innovative educational material. Discover her on @ PharmerMeg. *She is an athletic member of the Society of Infectious Diseases Pharmacists.


References:

1. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect (Larchmt). Feb;14(1) doi: /sur
2. Eljaaly K, Alshehri S, Erstad BL. Systematic review and meta-analysis of the safety of antistaphylococcal penicillins compared to cefazolin. Antimicrob Agents Chemother.

Mar 27;62(4). pii: e doi: /AAC
3. Lee S, Song KH, Jung SI, et al. Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective multicentre cohort study in Korea. Clin Microbiol Infect. Feb;24(2) doi: /
4. 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. Jun;58(6) doi: /AAC
5. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. Jan 18;66(3) doi: /cid/cix.
6. Petz LD, Fudenberg HH. Coombs-positive hemolytic anemia caused by penicillin istration. N Engl J Med. Jan 27;(4) doi: /NEJM
7. Dash CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother. ;1(3 Suppl) doi: /jac/_
8.

Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Caruso C, Quaratino D. Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a Tcell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. Jul;(1) doi: /
9. Romano A, Valluzzi RL, Caruso C, Maggioletti M, Quaratino D, Gaeta F. Cross-reactivity and tolerability of cephalosporins in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol Pract. Sep — Oct;6(5) doi: /
Trubiano JA, Rock CA, Grayson ML, et al. The 3 Cs of antibiotic allergy-classification, cross-reactivity, and collaboration. J Allergy Clin Immunol Pract.

Nov — Dec;5(6) doi: /
Picard M, Robitaille G, Karam F, et al. Cross-reactivity to cephalosporins and carbapenems in penicillin-allergic patients: Two systematic reviews and meta-analyses. J Allergy Clin Immunol Pract. Jun 4. pii: S(19) doi: /
Zagursky RJ, Pichichero ME. Cross-reactivity in β-Lactam Allergy. J Allergy Clin Immunol Pract. Jan — Feb;6(1)e1. doi: /
DePestel DD, Benninger MS, Danziger L, et al. Cephalosporin use in treatment of patients with penicillin allergies.

What type of hypersensitivity is a penicillin allergy

J Am Pharm Assoc (). Jul-Aug;48(4) doi: /JAPhA
Goodman EJ, Morgan MJ, Johnson PA, Nichols BA, Denk N, Gold BB.

What type of hypersensitivity is a penicillin allergy

Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic response. J Clin Anesth. Dec;13(8)
Beltran RJ, Kako H, Chovanec T, Ramesh A, Bissonnette B, Tobias JD. Penicillin allergy and surgical prophylaxis: Cephalosporin cross-reactivity risk in a pediatric tertiary care middle. J Pediatr Surg. May;50(5) doi: /rg
Haslam S, Yen D, Dvirnik N, Engen D. Cefazolin use in patients who report a non-IgE mediated penicillin allergy: a retrospective glance at adverse reactions in arthroplasty.

Iowa Orthop J. ;
Rock AH, Kelmer G, MacDonald JH, Clance MR, King PJ. The impact of patient-reported penicillin allergy on risk for surgical site infection in entire joint arthroplasty. J Am Acad Orthop Surg. Feb doi: /JAAOS-D
Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp Allergy. Mar;31(3)
Pipet A, Veyrac G, Wessel F, et al. A statement on cefazolin immediate hypersensitivity: data from a large database, and focus on the cross-reactivities.

Clin Exp Allergy. Nov;41(11) doi: /jx.
Uyttebroek AP, Decuyper II, Bridts CH, et al. Cefazolin hypersensitivity: toward optimized diagnosis. J Allergy Clin Immunol Pract.

What type of hypersensitivity is a penicillin allergy

Nov — Dec;4(6) doi: /
Sacco KA, Bates A, Brigham TJ, Imam JS, Burton MC. Clinical outcomes following inpatient penicillin allergy testing: a systematic review and meta-analysis. Allergy. Sep;72(9) doi: /all
Blumenthal KG, Li Y, Acker WW, et al. Multiple drug intolerance syndrome and multiple drug allergy syndrome: epidemiology and associations with anxiety and depression. Allergy.

Oct;73(10) doi: /all

AUG 15, | LINDSAY COURTNEY, PHARMD, AND MEGHAN JEFFRES, PHARMD, BCIDP*

The first-generation intravenous cephalo­sporin, cefazolin, is a workhorse in most hospitals. It is the preferred choice for a majority of procedures in the surgical prophylaxis guidelines endorsed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Surgical Infection Society, and the Society for Healthcare Epidemiology of America.1 Additionally, cefazolin has become a first-line choice for the treatment of methicillin-sensitive Staphylococcus aureus infections.

The results of several studies show that patients treated with cefazolin own lower mortality rates, fewer adverse events, and less allergic reactions compared with the antistaphylococcal penicillins, nafcillin and oxacillin. Unfortunately, cefazolin is often avoided in patients with penicillin allergies due to the concern for cross-reactivity between penicillins and cephalosporins.

It is our belief that avoidance of cefazolin due to concerns about cross-reactivity results in measurable patient harm and is not supported by published evidence.

There are clear patient care consequences of avoiding cefazolin, especially as surgical prophy­laxis. A study of over surgeries found that the odds of getting a surgical site infection were higher in patients who were not given cefazolin due to concerns about a penicillin allergy.5 In the multi­variable logistic regression model adjusting for age, sex, race, surgery type, American Society of Anesthesiologists risk class, procedure duration, and wound class, a reported penicillin allergy was associated with increased odds of surgical site infection (adjusted odds ratio, ; 95% CI, ).

Based on the results from the multi­variable model, the authors concluded that the increased surgical site infection risk was mediated by the patients’ receipt of an alternative perioperative antibiotic. Patients labeled as penicillin allergic were far less likely to get cefazolin than nonallergic patients (12% vs 92%), and they received significantly more clindamycin, vancomycin, and gentamicin. Almost 98% of patients who received vancomycin prophylaxis received it 24 minutes prior to incision instead of the recommended 60 to minutes.1

A HABIT OF AVOIDANCE
The habit of avoiding cephalosporins in patients with a penicillin allergy is pervasive.

Clinicians are inundated with best-practice and safety alerts in electronic medical records proclaiming that the use of cephalosporins is contraindicated in patients with a penicillin allergy. To ister a cephalosporin, clinicians must override these alerts, but that is often not done due to fear of litigation and a misunderstanding of the pathophysiology of cross-reactivity among β-lactams.

For years, clinicians and students own been taught there is 10% cross-reactivity between penicillins and cephalosporins. The origin of this 10% cross-reactivity dogma is largely based on data published in the s and s.6,7 The original authors assumed cross-reactivity was due to the β-lactam structure, but we now know that their findings were most likely due to contamination of ancient drug preparations.

What type of hypersensitivity is a penicillin allergy

Modern investigations by Romano et al8,9 established that cross-reactivity between penicil­lins and cephalosporins is primarily based on the R1 side chain, not the shared β-lactam ring structure (Table 1).10

The first study included patients with confirmed delayed (Type IV) hypersensitivity to penicillins.8 Investigators used patch and/or skin testing to assess for cross-reactivity to several cephalosporins and aztreonam. None of the participants experienced reactions to dissim­ilar side chain β-lactams (cefuroxime, ceftriaxone, aztre­onam), while 40 (19%) had reactions to similar side chain β-lactams (cephalexin, cefaclor, cefadroxil).

The second study included patients with confirmed immediate allergy (Type I) to penicillins.

Investigators used skin and/or radioallergosorbent tests to assess for cross-reactivity to several cephalosporins.9 They found that 95 patients (38%) reacted to similar side chain cephalospo­rins and 4 (%) reacted to dissimilar side chain cepha­losporins. These data protest a 20% cross-reactivity rate between similar side chain β-lactams for patients with Type IV reactions and 40% cross-reactivity rate for Type I reactions. Only 1% of patients will own an allergy to both a penicillin and a cephalosporin with a dissimilar side chain.

Since cefazolin has a unique side chain not shared by any other penicillin or cephalosporin, we can predict that approximately 1% of patients with a penicillin allergy will also experience hypersensitivity to cefazolin. Several recent reviews own created side-chain charts to aid clini­cians in selecting β-lactams with dissimilar side chains to the suspect allergen (Table 2).

In addition to these specific allergy evaluations, there are 4 retrospective clinical studies that own investigated how often cefazolin is tolerated in patients with self-reported penicillin allergies (Table 3).

The first study included patients labeled as penicillin allergic, of whom received a cephalosporin during the surgical procedure.14 Most patients received cefazolin, and 1 received ceftazidime.

One of the patients received diphenhydramine and hydrocortisone after the cephalo­sporin was istered and was assumed by authors to own experienced an allergic reaction. Although cefazolin was istered in of of those cases, it was not stated if cefazolin was the culprit cephalosporin in this case. The second study included surgical interventions in pediatric patients labeled as penicillin allergic.15 Cefazolin was ­istered in surgical interventions. One patient (%) experienced hives and erythema and was successfully treated with diphen­hydramine.

The majority of patients received clindamycin, and % experienced allergic reactions, almost 3 times the reaction rate among patients treated with cefazolin. The third study included patients labeled as penicillin allergic who received hip and knee arthroplasty surgeries.16 A subset of 54 patients reporting non–immunoglobulin E (IgE)- mediated penicillin allergies received and tolerated cefazolin. The fourth study included 55 patients who received cefazolin for surgical prophylaxis regardless of penicillin allergy history description.17 None experienced an allergic or adverse reaction.

SELF-REPORTED VS CONFIRMED ALLERGIES
Although the reaction rate to cefazolin was low in every 4 studies, the study samples consisted entirely of patients with self-reported penicillin allergies.

We now know that most self-reported penicillin allergies are incorrect.

What type of hypersensitivity is a penicillin allergy

A meta-analysis of 24 studies sure that more than 95% of patients labeled as having a penicillin allergy will own a negative penicillin skin test and do not own an IgE-mediated (Type I) allergy to penicillin.21 A penicillin skin test does not law out other immune-mediated hypersensitivities, including Type II, III, and IV reactions.10

Not only does cefazolin appear to be safe to use in patients with a self-reported peni­cillin allergy, cefazolin tolerance has been studied in patients with a proven penicillin hypersensitivity. A prospective study out of Spain evaluated tolerance to cefazolin in patients with immediate allergies to penicillin or amoxicillin.18 Every 41 patients underwent skin testing and/or an oral challenge with peni­cillin and amoxicillin to confirm their allergy history.

They then underwent skin testing and an intramuscular challenge for cefazolin and other cephalosporins. None of these patients experienced an allergic reaction.

Two other prospective studies from France and Italy included patients with a history of perioperative hypersensitivity suspected to be due to cefazolin, which was subsequently confirmed by skin tests and/or challenge tests. These patients then underwent skin testing to assess their tolerance to penicillins.19,20 In the first study, 1 of the 10 patients allergic to cefazolin had a positive skin test for amoxi­cillin and ampicillin.19 This patient was also skin test positive for cefuroxime and cefo­taxime, which own almost identical R1 side chains but are not similar to any penicil­lins.

In the second study, 19 patients allergic to cefazolin were evaluated and none of them displayed a positive skin test to any of the penicillins.20

The overall reaction rate of these 7 studies is % (95% CI, 0%%) (Table 3). The reaction rate among patients who self-report an allergy to penicillin is % (95% CI, 0%%). The reaction rate among patients with a confirmed penicillin allergy is % (95% CI, 0%%).

This is far lower than the 20% or 40% seen between penicillins and cephalosporins with similar side chains and similar to the % reaction rate seen in prior studies.8,9 Ultimately, a reaction rate of % is too low to call the relationship between cefazolin, penicillin, and amoxicillin cross-reactive and instead most likely represents patients who own 2 indepen­dent allergies. This reaction rate is also in line with data indicating that % of the popula­tion has multiple drug allergy syndrome.22
Research about and awareness of the risks associated with avoiding β-lactams in patients labeled as penicillin allergic has increased dramatically recently.

However, more data and guidance are needed to assist clinicians distin­guish between cross-reactivity and multiple β-lactam allergies. In the meantime, distribu­tion of the existing data and education from infectious diseases and allergy champions will result in increased use of cefazolin in both patients labeled as penicillin allergic as well as those with proven penicillin allergies.

Courtney is completing her PGY1 pharmacy practice residency at the University of Pittsburgh Medical Middle, Shadyside, in Pennsylvania.

Jeffres delights in conducting contrarian clinical research at the University of Colorado Anschutz Medical Campus but is happiest when creating innovative educational material. Discover her on @ PharmerMeg. *She is an athletic member of the Society of Infectious Diseases Pharmacists.


References:

1. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect (Larchmt). Feb;14(1) doi: /sur
2. Eljaaly K, Alshehri S, Erstad BL. Systematic review and meta-analysis of the safety of antistaphylococcal penicillins compared to cefazolin.

Antimicrob Agents Chemother. Mar 27;62(4). pii: e doi: /AAC
3. Lee S, Song KH, Jung SI, et al. Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective multicentre cohort study in Korea. Clin Microbiol Infect. Feb;24(2) doi: /
4. 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. Jun;58(6) doi: /AAC
5. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. Jan 18;66(3) doi: /cid/cix.
6. Petz LD, Fudenberg HH. Coombs-positive hemolytic anemia caused by penicillin istration. N Engl J Med. Jan 27;(4) doi: /NEJM
7. Dash CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother. ;1(3 Suppl) doi: /jac/_
8. Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Caruso C, Quaratino D.

Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a Tcell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. Jul;(1) doi: /
9. Romano A, Valluzzi RL, Caruso C, Maggioletti M, Quaratino D, Gaeta F. Cross-reactivity and tolerability of cephalosporins in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol Pract.

Sep — Oct;6(5) doi: /
Trubiano JA, Rock CA, Grayson ML, et al. The 3 Cs of antibiotic allergy-classification, cross-reactivity, and collaboration. J Allergy Clin Immunol Pract. Nov — Dec;5(6) doi: /
Picard M, Robitaille G, Karam F, et al. Cross-reactivity to cephalosporins and carbapenems in penicillin-allergic patients: Two systematic reviews and meta-analyses. J Allergy Clin Immunol Pract. Jun 4. pii: S(19) doi: /
Zagursky RJ, Pichichero ME. Cross-reactivity in β-Lactam Allergy. J Allergy Clin Immunol Pract.

Jan — Feb;6(1)e1. doi: /
DePestel DD, Benninger MS, Danziger L, et al. Cephalosporin use in treatment of patients with penicillin allergies. J Am Pharm Assoc (). Jul-Aug;48(4) doi: /JAPhA
Goodman EJ, Morgan MJ, Johnson PA, Nichols BA, Denk N, Gold BB. Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic response. J Clin Anesth. Dec;13(8)
Beltran RJ, Kako H, Chovanec T, Ramesh A, Bissonnette B, Tobias JD. Penicillin allergy and surgical prophylaxis: Cephalosporin cross-reactivity risk in a pediatric tertiary care middle. J Pediatr Surg. May;50(5) doi: /rg
Haslam S, Yen D, Dvirnik N, Engen D. Cefazolin use in patients who report a non-IgE mediated penicillin allergy: a retrospective glance at adverse reactions in arthroplasty.

Iowa Orthop J. ;
Rock AH, Kelmer G, MacDonald JH, Clance MR, King PJ. The impact of patient-reported penicillin allergy on risk for surgical site infection in entire joint arthroplasty. J Am Acad Orthop Surg. Feb doi: /JAAOS-D
Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp Allergy. Mar;31(3)
Pipet A, Veyrac G, Wessel F, et al.

A statement on cefazolin immediate hypersensitivity: data from a large database, and focus on the cross-reactivities. Clin Exp Allergy. Nov;41(11) doi: /jx.
Uyttebroek AP, Decuyper II, Bridts CH, et al. Cefazolin hypersensitivity: toward optimized diagnosis. J Allergy Clin Immunol Pract. Nov — Dec;4(6) doi: /
Sacco KA, Bates A, Brigham TJ, Imam JS, Burton MC. Clinical outcomes following inpatient penicillin allergy testing: a systematic review and meta-analysis. Allergy. Sep;72(9) doi: /all
Blumenthal KG, Li Y, Acker WW, et al.

Multiple drug intolerance syndrome and multiple drug allergy syndrome: epidemiology and associations with anxiety and depression. Allergy. Oct;73(10) doi: /all

References

1.Beeler, A., Engler, O., Gerber, B. O., Pichler, W. J. () Long-lasting reactivity and high frequency of drug-specific T cells after severe systemic drug hypersensitivity reactions. J. Allergy Clin. Immunol(2), – <>

2.Ben-Said, B., Arnaud-Butel, S., Rozières, A., Rodet, K., Bérard, F., Nicolas, J. F., Nosbaum, A. () Allergic delayed drug hypersensitivity is more frequently diagnosed in drug reaction, eosinophilia and systemic symptoms (DRESS) syndrome than in exanthema induced by beta-lactam antibiotics.

J. Dermatol. Sci(1), 71– <>

3.Blanca, M., Romano, A., Torres, M. J., Férnandez, J., Mayorga, C., Rodriguez, J., Demoly, P., Bousquet, P. J., Merk, H. F., Sanz, M. L., Ott, H., Atanaskovic-Markovic, M. () Update on the evaluation of hypersensitivity reactions to betalactams. Allergy64, – <>

4.Brockow, K., Garvey, L. H., Aberer, W., Atanaskovic-Markovic, M., Barbaud, A., Bilo, M. B., Bircher, A., Blanca, M., Bonadonna, B., Campi, P., Castro, E., Cernadas, J.

R., Chiriac, A. M., Demoly, P., Grosber, M., Gooi, J., Lombardo, C., Mertes, P. M., Mosbech, H., Nasser, S., Pagani, M., Ring, J., Romano, A., Scherer, K., Schnyder, B., Testi, S., Torres, M., Trautmann, A., Terreehorst, I.; ENDA/EAACI Drug Allergy Interest Group () Skin test concentrations for systemically istered drugs – an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy68(6), – <>

5.Demoly, P., Adkinson, N.

F., Brockow, K., Castells, M., Chiriac, A. M., Greenberger, P. A., Khan, D. A., Lang, D. M., Park, H. S., Pichler, W., Sanchez-Borges, M., Shiohara, T., Thong, B. Y. () International Consensus on drug allergy. Allergy69, – <>

6.Ebo, D. G., Leysen, J., Mayorga, C., Rozieres, A., Knol, E. F., Terreehorst, I. () The in vitro diagnosis of drug allergy: status and perspectives. Allergy66, – <>

7.El-Ghaiesh, S., Monshi, M. M., Whitaker, P., Jenkins, R., Meng, X., Farrell, J., Elsheikh, A., Peckham, D., French, N., Pirmohamed, M., Park, B. K., Naisbitt, D. J. () Characterization of the antigen specificity of T-cell clones from piperacillin-hypersensitive patients with cystic fibrosis.

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. Torres, ? We accept pre-submission inquiries ? Our selector tool helps you to discover the most relevant journal ? We provide circular the clock customer support ? Convenient online submission ? Thorough peer review ? Inclusion in PubMed and every major indexing services ?

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The Case

A year-old man with a past medical history of hemorrhagic stroke, coronary artery disease, and severe aplastic anemia required immunosuppressive therapy (antithymocyte globulin, cyclosporine, and prednisone) and regular blood and platelet transfusions.

On the day of presentation, the patient arrived at the infusion middle for a scheduled platelet transfusion. Prior to starting the infusion, he became unresponsive and hypotensive (59/26 mm Hg). The patient was immediately transported to the emergency department (ED) where, after resuscitation, he described a 1-day history of lethargy, abdominal discomfort, diaphoresis, and bloody bowel movements. Additionally, the patient had an allergy to penicillin, with a reaction of hives documented in the electronic health record.

However, it was unclear when this reaction had occurred or whether it had been witnessed by a health care provider.

In the ED, the patient’s vital signs were initially stable: temperature °C, blood pressure /60 mm Hg, heart rate 57 beats per minute, respiratory rate 18 breaths per minute, and SpO2 94%. Physical examination was notable for a tired-appearing man with slight abdominal distention without significant tenderness or peritoneal findings. A finish blood count was notable for platelets of /µL, white blood cell count of /µL, and absolute neutrophil count of /µL. Chemistry panel and liver function tests were within normal limits, and urinalysis was unremarkable.

Soon after the initial evaluation (during which he appeared hemodynamically stable), the patient developed hypothermia (°C), hypotension (70/40 mm Hg), and worsening mental status.

The patient promptly received 3 L of intravenous fluid. Given continued instability and concern for septic shock, vancomycin was istered. However, neither gram-negative nor anaerobic coverage were ordered due to concern for the penicillin allergy and unknown infection source.

The patient remained hypotensive, and a lactate level returned at mg/dL. A CT scan of the abdomen/pelvis with contrast suggested colitis as a possible source of infection. The absence of gram-negative coverage went unrecognized until the primary admitting team took over 4 hours after the patient’s initial presentation, at which point they ordered aztreonam.

However, the aztreonam was not istered for another 2 hours. As the aztreonam was being given, anaerobic coverage with metronidazole was also ordered but not istered for another 9 hours. Thus, despite the patient’s immunocompromised state (neutropenia and on athletic immunosuppressive therapy) and sepsis from a likely intraabdominal source, ordering and istration of antibiotics with gram-negative and anaerobic coverage was significantly delayed.

Following the patient’s prolonged ED course, he was admitted to the intensive care unit where his sepsis worsened.

Antimicrobial therapy was broadened to meropenem, caspofungin, azithromycin, and vancomycin. The patient developed anuric renal failure necessitating continuous renal replacement therapy. Ultimately, he was transitioned to comfort care and died. Autopsy revealed the likely cause of death to be septic shock due to neutropenic enterocolitis.

The cause of the patient’s death was deemed to be multifactorial (i.e., high medical complexity, delayed sepsis recognition, unfamiliarity with antibiotic coverage, prolonged ED boarding time, and multiple involved services). However, given the data on relationship between time to antibiotic istration and sepsis mortality, the delayed antibiotic istration likely contributed to the death.

Furthermore, the documented penicillin allergy may own contributed to this delay by preventing reflexive istration of empiric gram-negative antibiotic treatment with piperacillin-tazobactam or cefepime. Moreover, the lack of familiarity with the limited efficacy of aztreonam in anaerobic coverage led to a delay in the addition of appropriate anaerobic treatment.

by Kimberly G. Blumenthal, MD, MSc

Sepsis affects more than 1 million Americans per year and is a leading cause of death in the United States.(1) Sepsis requires swift recognition and management of infection, with beta-lactam antibiotics (often piperacillin-tazobactam or cefepime) indicated as empiric therapy.

Additional coverage of resistant gram-positive bacteria may be required with vancomycin, and as in this case, anaerobe coverage may be needed for enteric organisms.

Mortality in sepsis increases even with extremely short delays in antimicrobial istration.(2) The patient in this case did not own gram-negative coverage for 6 hours, and the penicillin allergy history likely contributed to the delay to first dose of antibiotic. Among patients presenting to the ED with pneumonia, urinary tract infection, bacteremia, and sepsis, patients with a penicillin allergy had a longer mean time to first antibiotic dose than patients without a penicillin allergy history ( minutes vs minutes, p=).(3) The antibiotic ultimately istered in this case was aztreonam, which is considered inferior to piperacillin-tazobactam and cefepime, especially for Pseudomonas species.

Similarly, one prior study found patients with beta-lactam allergy histories experienced higher clinical failure for gram-negative bloodstream infections compared to patients without (39% vs 27%, p=).(4)

Patients who own a history of penicillin allergy comprise approximately 10% of the US population.(5) However, numerous penicillin allergic patients actually are not allergic to the drug, yet the allergy label prevents them from being treated with beta-lactams. In fact, patients with historical penicillin reactions own their allergy disproved more than 95% of the time after undergoing formal testing.(5) Additionally, drugs on a patient’s allergy list often include adverse effects and intolerances.

These nonimmunologic reactions may be considered allergies by patients, but often do not warrant penicillin avoidance.(6) A history of «hives» or «rash» are among the most commonly reported reactions, but may own been from a childhood viral exanthem rather than a drug allergy. Even if there were an immunoglobulin E (IgE)-mediated penicillin reaction, penicillin allergy wanes over time. This means that years later, patients are unlikely to be allergic.(5)

Shared chemical structures between penicillins and cephalosporins can be the source for clinical cross-reactivity, including the beta-lactam ring and side chains (e.g., ampicillin shares a side chain with the cephalosporins cefaclor and cephalexin).

However, the later generation cephalosporins, such as cefepime, are tolerated in the overwhelming majority of cases, even in patients who own anaphylactic penicillin allergy histories.(7) In patients with a history of nonsevere penicillin allergy, treatment with cephalosporins without preceding penicillin skin testing leads to a reaction rate lower than the expected new rate of reactions to cephalosporins.(7) Even in patients with proven penicillin allergy, only about 2% react to treatment with cephalosporins.(7) Higher reaction rates might be observed in acutely ill patients—one study found % reactions to cefepime and % reactions to ceftazidime in patients with IgE-mediated penicillin allergy histories not confirmed with testing.(8) Carbapenem use in patients with penicillin allergy histories is also safe; even among 56 acutely infected hospitalized patients with IgE-mediated penicillin allergy histories, none reacted to carbapenems.(8)

The choice to not give a penicillin, or beta-lactam antibiotic, due to a penicillin allergy history may own other immediate and longer term consequences.

Use of non–beta-lactam alternatives in patients reporting penicillin allergies leads to more treatment failures in methicillin-sensitive Staphylococcus aureus bacteremia and more surgical site infections.(9,10) Infected hospitalized patients not treated with a beta-lactam had a threefold increased odds of adverse events that included drug toxicities and Clostridium difficile colitis.(11) Penicillin allergy reporters also had a 26% increased risk of Clostridium difficile and a 69% increased incidence of methicillin-resistant Staphylococcus aureus colonization or infection over a mean follow-up time of 6 years.(12)

To make better antibiotic choices, it is crucial to do a systematic evaluation of the history of penicillin response, beginning with a thorough allergy history.

Numerous patients report symptoms that were highly unlikely to be a true allergy, such as family history or gastrointestinal intolerance. Patients whose allergy history is an adverse effect or intolerance should own the «allergy» deleted or the «reaction type» changed to indicate there was no genuine allergy. When time and resources permit, penicillin allergies that may be IgE-mediated (such as hives, angioedema, shortness of breath, anaphylaxis) can be evaluated with a penicillin skin test. While historically performed by allergy specialists, penicillin allergy testing in hospital-based patients has been performed by nurses, pharmacists, and physicians from other specialties (medicine, infectious diseases).

Penicillin skin testing takes about 1 hour to act out. If tests are negative, one full dose of a penicillin (usually amoxicillin) is given under observation. If there is no reaction, then the penicillin allergy is deleted from the record. When penicillin skin testing is not possible (or not necessary because of low risk), drug challenges or test doses can be considered, either with amoxicillin to disprove the underlying penicillin allergy or with the indicated therapeutic beta-lactam. One example test dose protocol gives 1/10th drug dose followed by % dose 1 hour later under observation.

Decision support around penicillin allergies can be incorporated into antibiotic prescribing and sepsis bundles to ensure the quick and safe istration of a beta-lactam antibiotic.

Decision support might indicate which patients can own piperacillin-tazobactam and cefepime. For patients with higher risk beta-lactam allergy histories, decision support can still indicate that full dose carbapenems and the monobactam aztreonam are safe for use. At Massachusetts General Hospital and other academic and community Partners Healthcare System hospitals in the greater Boston area, we use test dose challenges in the ED and inpatient areas to optimize beta-lactam antibiotic use in patients with penicillin and cephalosporin allergy histories.(13) Our data indicate that inpatient penicillin and cephalosporin use increased approximately twofold; moreover, among more than test doses analyzed, fewer than 4% of patients had reactions (three patients needed intramuscular epinephrine).(8,14) Our penicillin allergy algorithm modified based on our most recent data is shown in the Figure.

Clinical decision support tools to urge standardized approaches to penicillin allergy in inpatients might include alerts, order sets, or web-based tools.(13) Alternative approaches to skin testing and test dose methods include implementation of allergy consultations (even virtually with telehealth [15]) and/or drug desensitization protocols to facilitate safe drug istration in patients who are truly allergic (e.g., recurrent IgE-mediated reactions or skin test positive), or too acutely ill to discover out (i.e., the patient would be unlikely to recover from anaphylaxis).

Allergy documentation in health records is often inaccurate and incomplete.

Although every allergy entries warrant attention to improve quality and safety, penicillin allergy documentation is a priority.(6) Large-scale efforts to improve the characterization of penicillin allergies include a recent professional society–endorsed review (5) and Centers for Disease Control and Prevention support in proclaiming a National Penicillin Allergy Day (September 28).(16)


Figure

Figure. Partners HealthCare System Penicillin Allergy Pathway. Reprinted from (17) with permission from Copyright Clearance Middle.

Test dose procedures use 1/10th of the dose for parenteral beta-lactams and 25% dose for oral beta-lactams followed by 30–60 minutes of observation.

If there is no reaction, % of the dose is istered with 60 minutes of observation. If there is no reaction, the next dose of the beta-lactam antibiotic is given per its usual therapeutic schedule. Unlike desensitization procedures, which typically require intensive care unit monitoring, test dose procedures can be performed on the medical floors. Common cephalosporins by generation: 1st cephalexin/cefazolin; 2nd cefoxitin/cefuroxime; 3rd ceftriaxone/cefixime/cefotaxime/cefpodoxime/ceftazidime*; 4th cefepime; 5th ceftaroline* Abbreviations: HSR, hypersensitivity reaction; PCN, penicillin * Antibiotics restricted by Partners antimicrobial stewardship committees.

§ Alternative agents by microbial coverage: Gram positive coverage: Vancomycin, linezolid*, daptomycin*, clindamycin, doxycycline, trimethoprim/sulfamethoxazole Gram negative coverage: Quinolones, sulfamethoxazole/trimethoprim, aminoglycosides, aztreonam*

A year-old man presents with fever, chills, and facial pain. He had an upper respiratory infection 3 weeks ago and has had persistent sinus drainage since. He has tried nasal irrigation and nasal steroids without improvement.

Over the past 5 days, he has had thicker postnasal drip, the development of facial pain, and today fevers as high as degrees. He has a history of giant cell arteritis, for which he takes 30 mg of prednisone daily; coronary artery disease; and hypertension.

He has a penicillin allergy (rash on chest, back, and arms 25 years ago). Exam reveals temperature of and tenderness over left maxillary sinus.

What treatment do you recommend?

A. Amoxicillin/clavulanate.

B. Cefpodoxime.

C. Levofloxacin.

D. Trimethoprim/sulfamethoxazole.

I ponder cefpodoxime is probably the best of these choices to treat sinusitis in this patient. Choosing amoxicillin /clavulanate is an option only if you could give the patient a test dose in a controlled setting. I ponder giving this patient levofloxacin poses greater risk than a penicillin rechallenge.

This patient is elderly and on prednisone, both of which increase his risk of tendon rupture if given a quinolone. Also, the Food and Drug istration released a warning recently regarding increased risk of aortic disease in patients with cardiovascular risk factors who get fluoroquinolones.1

Merin Kuruvilla, MD, and colleagues described oral amoxicillin challenge for patients with a history of low-risk penicillin allergy (described as benign rash, benign somatic symptoms, or unknown history with penicillin exposure more than 12 months prior).2 The study was done in a single allergy practice where 38 of 50 patients with penicillin allergy histories qualified for the study.

Of the 38 eligible patients, 20 consented to oral rechallenge in clinic, and none of them developed immediate or delayed hypersensitivity reactions.

Melissa Iammatteo, MD, et al. studied patients with a history of non–life-threatening penicillin reactions.3 Study participants received placebo followed by a two-step graded challenge to amoxicillin. No reaction occurred in 77% of patients, while 20% of patients had nonallergic reactions, which were equal between placebo and amoxicillin.

Only % had allergic reactions, every of which were classified as mild.

Reported penicillin allergy occurs in about 10% of community patients, but 90% of these patients can tolerate penicillins.4 Patients reporting a penicillin allergy own increased risk for drug resistance and prolonged hospital stays.5

The American Academy of Allergy, Asthma & Immunology recommended more widespread and routine performance of penicillin allergy testing in patients with a history of allergy to penicillin or other beta-lactam antibiotics.6 Patients who own penicillin allergy histories are more likely to get drugs, such as clindamycin or a fluoroquinolone, that may carry much greater risks than a beta-lactam antibiotic.

It also leads to more vancomycin use, which increases risk of vancomycin resistance.

Allergic reactions to cephalosporins are extremely infrequent in patients with a penicillin allergy. Eric Macy, MD, and colleagues studied every members of Kaiser Permanente Southern California health plan who had received cephalosporins over a 2-year period.7 More than , courses were given to patients with penicillin allergy, with only about 1% having an allergic reaction and only three cases of anaphylaxis.


References

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Howell MD, Davis AM. Management of sepsis and septic shock. JAMA. ; [go to PubMed]

2. Kim RY, Ng AM, Persaud AK, et al. Antibiotic timing and outcomes in sepsis. Am J Med Sci. ; [go to PubMed]

3. Conway EL, Lin K, Sellick JA, et al. Impact of penicillin allergy on time to first dose of antimicrobial therapy and clinical outcomes. Clin Ther. ; [go to PubMed]

4. Jeffres MN, Narayanan PP, Shuster JE, Schramm GE. Consequences of avoiding ß-lactams in patients with ß-lactam allergies. J Allergy Clin Immunol. ; [go to PubMed]

5. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. ; [go to PubMed]

6. Blumenthal KG, Park MA, Macy EM.

Redesigning the allergy module of the electronic health record. Ann Allergy Asthma Immunol. ; [go to PubMed]

7. Macy E, Blumenthal KG. Are cephalosporins safe for use in penicillin allergy without prior allergy evaluation? J Allergy Clin Immunol Pract. ; [go to PubMed]

8. Blumenthal KG, Li Y, Hsu JT, et al. Outcomes from an inpatient beta-lactam allergy guideline across a large US health system. Infect Control Hosp Epidemiol. ; [go to PubMed]

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Blumenthal KG, Parker RA, Shenoy ES, Walensky RP. Improving clinical outcomes in patients with methicillin-sensitive Staphylococcus aureus bacteremia and reported penicillin allergy. Clin Infect Dis. ; [go to PubMed]

Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. ; [go to PubMed]

MacFadden DR, LaDelfa A, Leen J, et al. Impact of reported beta-lactam allergy on inpatient outcomes: a multicenter prospective cohort study. Clin Infect Dis. ; [go to PubMed]

Blumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK.

Risk of methicillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. BMJ. ;k [go to PubMed]

Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing inpatient beta-lactam allergies: a multihospital implementation. J Allergy Clin Immunol Pract. ;e7. [go to PubMed]

Blumenthal KG, Wickner PG, Hurwitz S, et al.

Tackling inpatient penicillin allergies: assessing tools for antimicrobial stewardship. J Allergy Clin Immunol. ;e6. [go to PubMed]

Staicu ML, Holly AM, Conn KM, Ramsey A. The use of telemedicine for penicillin allergy skin testing. J Allergy Clin Immunol Pract. ; [go to PubMed]

National Penicillin Allergy Day. [Available at]

Wolfson AR, Huebner EM, Blumenthal KG. Acute care beta-lactam allergy pathways: approaches and outcomes. Ann Allergy Asthma Immunol. Apr 19; [Epub ahead of print]. [go to PubMed]


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