The perioperative setting presents a unique opportunity for anesthesiologists to play a role in improving the accuracy of allergy reporting by performing an allergy history assessment55 and, where necessary, considering allergy consultation and penicillin testing during the preoperative period, whether for the purpose of AMP administration or for the broader public health benefit. A proposed algorithm for the preoperative assessment of the penicillin-allergic patient and intraoperative decision making is presented in the Figure. In summary, cephalosporin cross-reactivity in penicillin-allergic patients is not necessarily a class effect, provided that cephalosporins with a side chain different from the penicillin responsible for the allergic reaction are used (Table).87 Anesthesiologists may be hesitant to administer cephalosporins to penicillin-allergic patients due to medicolegal concerns.107 While clinical judgment should be exercised and can be guided by a documented preoperative discussion with the patient regarding the rationale for cephalosporin administration,108 a review of legal outcomes in such cases found limited professional liability and identified precedence for clinicians prescribing cephalosporins to patients with a known penicillin allergy, with judges citing a lack of scientific evidence demonstrating that cephalosporins were contraindicated in patients with a penicillin allergy.107
1. Awad SS. Adherence to surgical care improvement project measures and post-operative surgical site infections. Surg Infect (Larchmt). 2012;13:234–237.
2. 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;66:329–336.
3. Berríos-Torres SI, Umscheid CA, Bratzler DW, et al.; Healthcare Infection Control Practices Advisory Committee. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017. JAMA Surg. 2017;152:784–791.
4. Allegranzi B, Bischoff P, de Jonge S, et al.; WHO Guidelines Development Group. New WHO recommendations on preoperative measures for surgical site infection prevention: an evidence-based global perspective. Lancet Infect Dis. 2016;16:e276–e287.
5. Bratzler DW, Dellinger EP, Olsen KM, et al.; American Society of Health-System Pharmacists; Infectious Disease Society of America; Surgical Infection Society; Society for Healthcare Epidemiology of America. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283.
6. Prokuski L. Prophylactic antibiotics in orthopaedic surgery. J Am Acad Orthop Surg. 2008;16:283–293.
7. van Schalkwyk J, Van Eyk N; Infectious Diseases Committee. Antibiotic prophylaxis in obstetric procedures. J Obstet Gynaecol Can. 2010;32:878–884.
8. Engelman R, Shahian D, Shemin R, et al.; Workforce on Evidence-Based Medicine, Society of Thoracic Surgeons. The Society of Thoracic Surgeons practice guideline series: antibiotic prophylaxis in cardiac surgery, part II: antibiotic choice. Ann Thorac Surg. 2007;83:1569–1576.
9. Anderson DJ, Podgorny K, Berríos-Torres SI, et al. Strategies to prevent surgical site infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35:605–627.
10. Marshall WF, Blair JE. The cephalosporins. Mayo Clin Proc. 1999;74:187–195.
11. David Warters R, Szmuk P, Pivalizza EG, Gebhard R, Ezri T. Preoperative antibiotic prophylaxis: the role of the anesthesiologist. Anesthesiology. 2003;99:515–516.
12. Hyder JA, Niconchuk J, Glance LG, et al. What can the national quality forum tell us about performance measurement in anesthesiology? Anesth Analg. 2015;120:440–448.
13. Warters RD, Szmuk P, Pivalizza EG, Gebhard RE, Katz J, Ezri T; American Association of Clinical Directors. The role of anesthesiologists in the selection and administration of perioperative antibiotics: a survey of the American Association of Clinical Directors. Anesth Analg. 2006;102:1177–1182.
14. Forbes SS, McLean RF. Review article: the anesthesiologist’s role in the prevention of surgical site infections. Can J Anaesth. 2013;60:176–183.
15. Jain V, Joshi N, Sidhu M, Kalicinsky C, Pun T. Penicillin allergies: referral and management practices of anesthesiologists. Allergy Asthma Clin Immunol. 2014;10:A20.
16. Kemp HI, Cook TM, Thomas M, Harper NJN. UK anaesthetists’ perspectives and experiences of severe perioperative anaphylaxis: NAP6 baseline survey. Br J Anaesth. 2017;119:132–139.
17. Dellinger EP, Gross PA, Barrett TL, et al. Quality standard for antimicrobial prophylaxis in surgical procedures. Infectious Diseases Society of America. Clin Infect Dis. 1994;18:422–427.
18. Ponce B, Raines BT, Reed RD, Vick C, Richman J, Hawn M. Surgical site infection after arthroplasty: comparative effectiveness of prophylactic antibiotics: do surgical care improvement project guidelines need to be updated? J Bone Joint Surg Am. 2014;96:970–977.
19. 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;50:856–859.
20. 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;32:100–103.
21. MacPherson RD, Willcox C, Chow C, Wang A. Anaesthetist’s responses to patients’ self-reported drug allergies. Br J Anaesth. 2006;97:634–639.
22. Macy E. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Curr Allergy Asthma Rep. 2014;14:476.
23. Macy E. Penicillin allergy: optimizing diagnostic protocols, public health implications, and future research needs. Curr Opin Allergy Clin Immunol. 2015;15:308–313.
24. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: a cohort study. J Allergy Clin Immunol. 2014;133:790–796.
25. Knezevic B, Sprigg D, Seet J, et al. The revolving door: antibiotic allergy labelling in a tertiary care centre. Intern Med J. 2016;46:1276–1283.
26. 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. 2016;63:904–910.
27. Charneski L, Deshpande G, Smith SW. Impact of an antimicrobial allergy label in the medical record on clinical outcomes in hospitalized patients. Pharmacotherapy. 2011;31:742–747.
28. 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;72:1288–1296.
29. Leis JA, Palmay L, Ho G, et al. Point-of-care beta-lactam allergy skin testing by antimicrobial stewardship programs: a pragmatic multicenter prospective evaluation. Clin Infect Dis. 2017;65:1059–1065.
30. Kheir MM, Tan TL, Azboy I, Tan DD, Parvizi J. Vancomycin prophylaxis for total joint arthroplasty: incorrectly dosed and has a higher rate of periprosthetic infection than cefazolin. Clin Orthop Relat Res. 2017;475:1767–1774.
31. Wongworawat MD. Editor’s spotlight/take 5: vancomycin prophylaxis for total joint arthroplasty: incorrectly dosed and has a higher rate of periprosthetic infection than cefazolin. Clin Orthop. 2017;475:1762–1766.
32. Soriano A. CORR Insights®: vancomycin prophylaxis for total joint arthroplasty: incorrectly dosed and has a higher rate of periprosthetic infection than cefazolin. Clin Orthop Relat Res. 2017;475:1775–1778.
33. Alotaibi AF, Mekary RA, Zaidi HA, Smith TR, Pandya A. Safety and efficacy of antibacterial prophylaxis after craniotomy: a decision model analysis. World Neurosurg. 2017;105:906–912.e5.
34. Hawn MT, Richman JS, Vick CC, et al. Timing of surgical antibiotic prophylaxis and the risk of surgical site infection. JAMA Surg. 2013;148:649–657.
35. Robertsson O, Thompson O, W-Dahl A, Sundberg M, Lidgren L, Stefánsdóttir A. Higher risk of revision for infection using systemic clindamycin prophylaxis than with cloxacillin. Acta Orthop. 2017;88:562–567.
36. Pool C, Kass J, Spivack J, et al. Increased surgical site infection rates following clindamycin use in head and neck free tissue transfer. Otolaryngol Head Neck Surg. 2016;154:272–278.
37. Uppal S, Harris J, Al-Niaimi A, et al. Prophylactic antibiotic choice and risk of surgical site infection after hysterectomy. Obstet Gynecol. 2016;127:321–329.
38. Murphy J, Isaiah A, Dyalram D, Lubek JE. Surgical site infections in patients receiving osteomyocutaneous free flaps to the head and neck. Does choice of antibiotic prophylaxis matter? J Oral Maxillofac Surg. 2017;75:2223–2229.
39. Mitchell RM, Mendez E, Schmitt NC, Bhrany AD, Futran ND. Antibiotic prophylaxis in patients undergoing head and neck free flap reconstruction. JAMA Otolaryngol Head Neck Surg. 2015;141:1096–1103.
40. Finkelstein R, Rabino G, Mashiah T, et al. Vancomycin versus cefazolin prophylaxis for cardiac surgery in the setting of a high prevalence of methicillin-resistant staphylococcal infections. J Thorac Cardiovasc Surg. 2002;123:326–332.
41. Bull AL, Worth LJ, Richards MJ. Impact of vancomycin surgical antibiotic prophylaxis on the development of methicillin-sensitive Staphylococcus aureus
surgical site infections: report from Australian surveillance data (VICNISS). Ann Surg. 2012;256:1089–1092.
42. Deresinski S. Counterpoint: vancomycin and Staphylococcus aureus
–an antibiotic enters obsolescence. Clin Infect Dis. 2007;44:1543–1548.
43. Kollef MH. Limitations of vancomycin in the management of resistant staphylococcal infections. Clin Infect Dis. 2007;45(suppl 3):S191–S195.
44. Crawford T, Rodvold KA, Solomkin JS. Vancomycin for surgical prophylaxis? Clin Infect Dis. 2012;54:1474–1479.
45. Smieja M. Current indications for the use of clindamycin: a critical review. Can J Infect Dis. 1998;9:22–28.
46. Courtney PM, Melnic CM, Zimmer Z, Anari J, Lee GC. Addition of vancomycin to cefazolin prophylaxis is associated with acute kidney injury after primary joint arthroplasty. Clin Orthop Relat Res. 2015;473:2197–2203.
47. Jeffres MN. The whole price of vancomycin: toxicities, troughs, and time. Drugs. 2017;77:1143–1154.
48. Yam FK, Smith KM. “Collateral damage”: antibiotics and the risk of Clostridium difficile
infection. Orthopedics. 2005;28:275–279.
49. Cotogni P, Barbero C, Passera R, Fossati L, Olivero G, Rinaldi M. Violation of prophylactic vancomycin administration timing is a potential risk factor for rate of surgical site infections in cardiac surgery patients: a prospective cohort study. BMC Cardiovasc Disord. 2017;17:73.
50. Mukhtar RA, Throckmorton AD, Alvarado MD, et al. Bacteriologic features of surgical site infections following breast surgery. Am J Surg. 2009;198:529–531.
51. Chen JR, Tarver SA, Alvarez KS, Tran T, Khan DA. A proactive approach to penicillin allergy testing in hospitalized patients. J Allergy Clin Immunol Pract. 2017;5:686–693.
52. Inglis JM, Caughey GE, Smith W, Shakib S. Documentation of penicillin adverse drug reactions in electronic health records: inconsistent use of allergy and intolerance labels. Intern Med J. 2017;47:1292–1297.
53. Shah NS, Ridgway JP, Pettit N. Documenting penicillin allergy: the impact of inconsistency. PloS One. 2016;11:e0150514.
54. Kim MH, Lee JM. Diagnosis and management of immediate hypersensitivity reactions to cephalosporins. Allergy Asthma Immunol Res. 2014;6:485–495.
55. Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. JAMA. 2001;285:2498–2505.
56. Sigona NS, Steele JM, Miller CD. Impact of a pharmacist-driven beta-lactam allergy interview on inpatient antimicrobial therapy: a pilot project. J Am Pharm Assoc (2003). 2016;56:665–669.
57. Macy E, Ho NJ. Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management. Ann Allergy Asthma Immunol. 2012;108:88–93.
58. Stember RH. Prevalence of skin test reactivity in patients with convincing, vague, and unacceptable histories of penicillin allergy. Allergy Asthma Proc. 2005;26:59–64.
59. Krishna MT, Huissoon AP, Li M, et al. Enhancing antibiotic stewardship by tackling “spurious” penicillin allergy. Clin Exp Allergy. 2017;47:1362–1373.
60. Lagacé-Wiens P, Rubinstein E. Adverse reactions to β-lactam antimicrobials. Expert Opin Drug Saf. 2012;11:381–399.
61. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105:259–273.
62. Krishna MT, York M, Chin T, et al. Multi-centre retrospective analysis of anaphylaxis during general anaesthesia in the United Kingdom: aetiology and diagnostic performance of acute serum tryptase. Clin Exp Immunol. 2014;178:399–404.
63. Frigas E, Park MA, Narr BJ, et al. Preoperative evaluation of patients with history of allergy to penicillin: comparison of 2 models of practice. Mayo Clin Proc. 2008;83:651–662.
64. Park M, Markus P, Matesic D, Li JT. Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy Asthma Immunol. 2006;97:681–687.
65. Cook DJ, Barbara DW, Singh KE, Dearani JA. Penicillin skin testing in cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1931–1935.
66. McDanel DL, Azar AE, Dowden AM, et al. Screening for betalactam allergy in joint arthroplasty patients to improve surgical prophylaxis practice. J Arthroplasty. 2017;32:S101–S108.
67. Demoly P, Adkinson NF, Brockow K, et al. International consensus on drug allergy. Allergy. 2014;69:420–437.
68. Bernstein IL, Li JT, Bernstein DI, et al.; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol. 2008;100:S1–S148.
69. Rodilla EM, González ID, Yges EL, Bellido FJ, Bara MT, Toledano FL. Immunological aspects of nonimmediate reactions to beta-lactam antibiotics. Expert Rev Clin Immunol. 2010;6:789–800.
70. Blumenthal KG, Li Y, Banerji A, Yun BJ, Long AA, Walensky RP. The cost of penicillin allergy evaluation. J Allergy Clin Immunol Pract. 2017 September 22 [Epub ahead of print].
71. Torres MJ, Romano A, Celik G, et al. Approach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America. Clin Transl Allergy. 2017;7:7.
73. Mirakian R, Leech SC, Krishna MT, et al.; Standards of Care Committee of the British Society for Allergy and Clinical Immunology. Management of allergy to penicillins and other beta-lactams. Clin Exp Allergy. 2015;45:300–327.
74. Pichichero ME, Zagursky R. Penicillin and cephalosporin allergy. Ann Allergy Asthma Immunol. 2014;112:404–412.
75. Brandriss MW, Smith JW, Steinman HG. Common antigenic determinants of penicillin G, cephalothin and 6-aminopenicillanic acid in rabbits. J Immunol. 1965;94:696–704.
76. Batchelor FR, Dewdney JM, Weston RD, Wheeler AW. The immunogenicity of cephalosporin derivatives and their cross-reaction with penicillin. Immunology. 1966;10:21–33.
77. Petz LD. Immunologic reactions of humans to cephalosporins. Postgrad Med J. 1971;47:Suppl:64–9.
78. Mine Y, Nishida M, Goto S, Kuwahara S. Cefazolin, a new semisynthetic cephalosporin antibiotic. IV. Antigenicity of cefazolin and its cross reactivity with benzylpenicillin, ampicillin and cephaloridine. J Antibiot (Tokyo). 1970;23:195–203.
79. Saxon A, Beall GN, Rohr AS, Adelman DC. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med. 1987;107:204–215.
80. Annè S, Reisman RE. Risk of administering cephalosporin antibiotics to patients with histories of penicillin allergy. Ann Allergy Asthma Immunol. 1995;74:167–170.
81. Pichichero ME. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics. 2005;115:1048–1057.
82. Harper NJ, Dixon T, Dugué P, et al.; Working Party of the Association of Anaesthetists of Great Britain and Ireland. Suspected anaphylactic reactions associated with anaesthesia. Anaesthesia. 2009;64:199–211.
83. Pichichero ME, Casey JR. Safe use of selected cephalosporins in penicillin-allergic patients: a meta-analysis. Otolaryngol Head Neck Surg. 2007;136:340–347.
84. Baldo BA, Pham NH, Zhao Z. Chemistry of drug allergenicity. Curr Opin Allergy Clin Immunol. 2001;1:327–335.
85. Romano A, Gaeta F, Arribas Poves MF, Valluzzi RL. Cross-reactivity among beta-lactams. Curr Allergy Asthma Rep. 2016;16:24.
86. Romano A, Guéant-Rodriguez RM, Viola M, Pettinato R, Guéant JL. Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins. Ann Intern Med. 2004;141:16–22.
87. Zagursky RJ, Pichichero ME. Cross-reactivity in β-lactam allergy. J Allergy Clin Immunol Pract. 2018;6:72–81.e1.
88. Macy E, Contreras R. Adverse reactions associated with oral and parenteral use of cephalosporins: a retrospective population-based analysis. J Allergy Clin Immunol. 2015;135:745–752.e5.
89. 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 Anaesth. 2001;13:561–564.
90. Epstein RH, Jacques PS, Wanderer JP, Bombulie MR, Agarwalla N. Prophylactic antibiotic management of surgical patients noted as “allergic” to penicillin at two academic hospitals. A A Case Rep. 2016;6:263–267.
91. Phillips E, Louie M, Knowles SR, Simor AE, Oh PI. Cost-effectiveness analysis of six strategies for cardiovascular surgery prophylaxis in patients labeled penicillin allergic. Am J Health Syst Pharm. 2000;57:339–345.
92. Gurrieri C, Weingarten TN, Martin DP, et al. Allergic reactions during anesthesia at a large United States referral center. Anesth Analg. 2011;113:1202–1212.
93. Baumgart KW, Baldo BA. Cephalosporin allergy. N Engl J Med. 2002;346:380–381.
94. Iammatteo M, Keskin T, Jerschow E. Evaluation of periprocedural hypersensitivity reactions. Ann Allergy Asthma Immunol. 2017;119:349–355.e2.
95. Kuhlen JL Jr, Camargo CA Jr, Balekian DS, et al. Antibiotics are the most commonly identified cause of perioperative hypersensitivity reactions. J Allergy Clin Immunol Pract. 2016;4:697–704.
96. 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;41:1602–1608.
97. Uyttebroek AP, Decuyper II, Bridts CH, et al. Cefazolin hypersensitivity: toward optimized diagnosis. J Allergy Clin Immunol Pract. 2016;4:1232–1236.
98. Kolawole H, Marshall SD, Crilly H, Kerridge R, Roessler P. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151–158.
99. Kroigaard M, Garvey LH, Gillberg L, et al. Scandinavian clinical practice guidelines on the diagnosis, management and follow-up of anaphylaxis during anaesthesia. Acta Anaesthesiol Scand. 2007;51:655–670.
100. Blumenthal KG, Shenoy ES, Hurwitz S, Varughese CA, Hooper DC, Banerji A. Effect of a drug allergy educational program and antibiotic prescribing guideline on inpatient clinical providers’ antibiotic prescribing knowledge. J Allergy Clin Immunol Pract. 2014;2:407–413.
101. Prematta T, Shah S, Ishmael FT. Physician approaches to beta-lactam use in patients with penicillin hypersensitivity. Allergy Asthma Proc. 2012;33:145–151.
102. Staicu ML, Soni D, Conn KM, Ramsey A. A survey of inpatient practitioner knowledge of penicillin allergy at 2 community teaching hospitals. Ann Allergy Asthma Immunol. 2017;119:42–47.
103. Persky MJ, Roof SA, Fang Y, Jethanamest D, April MM. Cephalosporin use in penicillin-allergic patients: a survey of otolaryngologists and literature review. Laryngoscope. 2015;125:1822–1826.
104. Blumenthal KG, Wickner PG, Hurwitz S, et al. Tackling inpatient penicillin allergies: assessing tools for antimicrobial stewardship. J Allergy Clin Immunol. 2017;140:154–161.e6.
105. Chen JR, Khan DA. Evaluation of penicillin allergy in the hospitalized patient: opportunities for antimicrobial stewardship. Curr Allergy Asthma Rep. 2017;17:40.
106. Trubiano J, Phillips E. Antimicrobial stewardship’s new weapon? A review of antibiotic allergy and pathways to ‘de-labeling.’ Curr Opin Infect Dis. 2013;26:526–537.
107. Jeffres MN, Hall-Lipsy EA, King ST, Cleary JD. Systematic review of professional liability when prescribing beta-lactams for patients with a known penicillin allergy. Ann Allergy Asthma Immunol. 2018 March 15 [Epub ahead of print].
108. Poetker DM, Smith TL. What rhinologists and allergists should know about the medico-legal implications of antibiotic use: a review of the literature. Int Forum Allergy Rhinol. 2015;5:104–110.