Two Allergies or Cross-Reactive?
The story of penicillin and cefazolin.
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 have lower mortality rates, fewer adverse events, and less allergic reactions compared with the antistaphylococcal penicillins, nafcillin and oxacillin.2-4 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 9000 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, 1.51; 95% CI, 1.02-2.22). 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 receive cefazolin than nonallergic patients (12% vs 92%), and they received significantly more clindamycin, vancomycin, and gentamicin. Nearly 98% of patients who received vancomycin prophylaxis received it 24 minutes prior to incision instead of the recommended 60 to 120 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 administer 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 have 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 1960s and 1970s.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 old 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 214 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 252 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 (1.5%) reacted to dissimilar side chain cepha­losporins. These data demonstrate 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 have 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 have created side-chain charts to aid clini­cians in selecting β-lactams with dissimilar side chains to the suspect allergen (Table 2).10-13
In addition to these specific allergy evaluations, there are 4 retrospective clinical studies that have investigated how often cefazolin is tolerated in patients with self-reported penicillin allergies (Table 3).14-20
The first study included 413 patients labeled as penicillin allergic, 300 of whom received a cephalosporin during the surgical procedure.14 Most patients received cefazolin, and 1 received ceftazidime. One of the 300 patients received diphenhydramine and hydrocortisone after the cephalo­sporin was administered and was assumed by authors to have experienced an allergic reaction. Although cefazolin was administered in 299 of 300 of those cases, it was not stated if cefazolin was the culprit cephalosporin in this case. The second study included 624 surgical interventions in 513 pediatric patients labeled as penicillin allergic.15 Cefazolin was admin­istered in 127 surgical interventions. One patient (0.8%) experienced hives and erythema and was successfully treated with diphen­hydramine. The majority of patients received clindamycin, and 2.1% experienced allergic reactions, nearly 3 times the reaction rate among patients treated with cefazolin. The third study included 196 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 all 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 determined that more than 95% of patients labeled as having a penicillin allergy will have a negative penicillin skin test and do not have an IgE-mediated (Type I) allergy to penicillin.21 A penicillin skin test does not rule 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 All 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 have 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 0.5% (95% CI, 0%-1.5%) (Table 3). The reaction rate among patients who self-report an allergy to penicillin is 0.4% (95% CI, 0%-1.4%). The reaction rate among patients with a confirmed penicillin allergy is 1.4% (95% CI, 0%-8.4%). This is far lower than the 20% or 40% seen between penicillins and cephalosporins with similar side chains and similar to the 1.5% reaction rate seen in prior studies.8,9 Ultimately, a reaction rate of 1.4% is too low to call the relationship between cefazolin, penicillin, and amoxicillin cross-reactive and instead most likely represents patients who have 2 indepen­dent allergies. This reaction rate is also in line with data indicating that 1.2% 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 help 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 Center, 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. Find her on Twitter @ PharmerMeg. *She is an active member of the Society of Infectious Diseases Pharmacists.
1. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect (Larchmt). 2013 Feb;14(1):73-156. doi: 10.1089/sur.2013.9999
2. Eljaaly K, Alshehri S, Erstad BL. Systematic review and meta-analysis of the safety of antistaphylococcal penicillins compared to cefazolin. Antimicrob Agents Chemother. 2018 Mar 27;62(4). pii: e01816-17. doi: 10.1128/AAC.01816-17.
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. 2018 Feb;24(2):152-158. doi: 10.1016/j.cmi.2017.07.001.
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. 2014 Jun;58(6):3137-43. doi: 10.1128/AAC.02504-13.
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. 2018 Jan 18;66(3):329-336. doi: 10.1093/cid/cix794.
6. Petz LD, Fudenberg HH. Coombs-positive hemolytic anemia caused by penicillin administration. N Engl J Med. 1966 Jan 27;274(4):171-8. doi: 10.1056/NEJM196601272740401.
7. Dash CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother. 1975;1(3 Suppl):107-18. doi: 10.1093/jac/1.suppl_3.107.
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 T cell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2016 Jul;138(1):179-186. doi: 10.1016/j.jaci.2016.01.025.
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. 2018 Sep - Oct;6(5):1662-1672. doi: 10.1016/j.jaip.2018.01.020.
10. Trubiano JA, Stone CA, Grayson ML, et al. The 3 Cs of antibiotic allergy-classification, cross-reactivity, and collaboration. J Allergy Clin Immunol Pract. 2017 Nov - Dec;5(6):1532-1542. doi: 10.1016/j.jaip.2017.06.017.
11. 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. 2019 Jun 4. pii: S2213-2198(19)30495-7. doi: 10.1016/j.jaip.2019.05.038.
12. Zagursky RJ, Pichichero ME. Cross-reactivity in β-Lactam Allergy. J Allergy Clin Immunol Pract. 2018 Jan - Feb;6(1):72-81.e1. doi: 10.1016/j.jaip.2017.08.027.
13. DePestel DD, Benninger MS, Danziger L, et al. Cephalosporin use in treatment of patients with penicillin allergies. J Am Pharm Assoc (2003). 2008 Jul-Aug;48(4):530-40. doi: 10.1331/JAPhA.2008.07006.
14. 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. 2001 Dec;13(8):561-4.
15. 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 center. J Pediatr Surg. 2015 May;50(5):856-9. doi: 10.1016/j.jpedsurg.2014.10.048.
16. Haslam S, Yen D, Dvirnik N, Engen D. Cefazolin use in patients who report a non-IgE mediated penicillin allergy: a retrospective look at adverse reactions in arthroplasty. Iowa Orthop J. 2012;32:100-3.
17. Stone AH, Kelmer G, MacDonald JH, Clance MR, King PJ. The impact of patient-reported penicillin allergy on risk for surgical site infection in total joint arthroplasty. J Am Acad Orthop Surg. 2019 Feb 27. doi: 10.5435/JAAOS-D-18-00709.
18. Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp Allergy. 2001 Mar;31(3):438-43.
19. 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. 2011 Nov;41(11):1602-8. doi: 10.1111/j.1365-2222.2011.03846.x.
20. Uyttebroek AP, Decuyper II, Bridts CH, et al. Cefazolin hypersensitivity: toward optimized diagnosis. J Allergy Clin Immunol Pract. 2016 Nov - Dec;4(6):1232-1236. doi: 10.1016/j.jaip.2016.05.011.
21. Sacco KA, Bates A, Brigham TJ, Imam JS, Burton MC. Clinical outcomes following inpatient penicillin allergy testing: a systematic review and meta-analysis. Allergy. 2017 Sep;72(9):1288-1296. doi: 10.1111/all.13168.
22. 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. 2018 Oct;73(10):2012-2023. doi: 10.1111/all.13440.