Secondary Logo

Journal Logo

Misconceptions Surrounding Penicillin Allergy: Implications for Anesthesiologists

Vorobeichik, Leon MD*; Weber, Elizabeth A. MD, FRCPC†,‡; Tarshis, Jordan MD, FRCPC*,§

doi: 10.1213/ANE.0000000000003419
Anesthetic Clinical Pharmacology

Administration of preoperative antimicrobial prophylaxis, often with a cephalosporin, is the mainstay of surgical site infection prevention guidelines. Unfortunately, due to prevalent misconceptions, patients labeled as having a penicillin allergy often receive alternate and less-effective antibiotics, placing them at risk of a variety of adverse effects including increased morbidity and higher risk of surgical site infection. The perioperative physician should ascertain the nature of previous reactions to aid in determining the probability of the prevalence of a true allergy. Penicillin allergy testing may be performed but may not be feasible in the perioperative setting. Current evidence on the structural determinants of penicillin and cephalosporin allergies refutes the misconception of cross-reactivity between penicillins and cefazolin, and there is no clear evidence of an increased risk of anaphylaxis in cefazolin-naive, penicillin-allergic patients. A clinical practice algorithm for the perioperative evaluation and management of patients reporting a history of penicillin allergy is presented, concluding that cephalosporins can be safely administered to a majority of such patients.

From the *Department of Anesthesia

Division of Clinical Immunology and Allergy, Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Drug Safety Clinic

§Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Published ahead of print May 10, 2018.

Accepted for publication March 30, 2018.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Leon Vorobeichik, MD, Department of Anesthesia, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Room M3-200, Toronto, ON M4N 3M5, Canada. Address e-mail to

Postoperative surgical site infection (SSI) is of concern to surgeons and anesthesiologists alike. The development of an SSI increases hospital length of stay by approximately 7–10 days, is associated with long-term disability, has a mortality rate of 3%, and is estimated to cost over $25,000 US dollars per SSI.1,2 There has been renewed focus on SSI prevention with the release of updated recommendations by a number of organizations, including the Centers for Disease Control and Prevention3 and World Health Organization.4 Administration of preoperative antimicrobial prophylaxis (AMP) is the mainstay of SSI prevention guidelines among all surgical specialties.5–9 The choice of a prophylactic antimicrobial agent is based on the principle of effecting a minimal impact on normal microbial flora while demonstrating potency against the skin organisms of concern, namely aerobic Gram-positive cocci (streptococcal species, Staphylococcus aureus, and coagulase-negative staphylococci).5 Cefazolin, a first-generation cephalosporin, is highly active against these organisms while demonstrating the least activity against Gram-negative species compared to later-generation cephalosporins10 and is thus typically indicated as the first-line agent, with alternatives, particularly clindamycin and vancomycin, recommended for patients with β-lactam allergies.5

The responsibility for the initial administration of preoperative AMP is often delegated to the anesthesiologist,11–13 as this ensures timely antimicrobial dosing and consequently, lower rates of SSI.14 Unfortunately, due to inaccurate penicillin allergy reporting and prevalent misconceptions surrounding cephalosporin cross-reactivity, patients reporting a history of penicillin allergy do not receive the indicated antibiotic agent,15 placing them at risk of a number of adverse effects and increased morbidity. A UK survey of the Sixth National Audit Project revealed that among perioperative antibiotics, penicillins were perceived to be the most likely agents to cause anaphylaxis, and are thus avoided most often.16 The survey concluded that “anesthetists exhibit avoidance behaviors, and such perceptions may not correlate with actual risk.”16

Anesthesiologists may be complacent about administering alternative AMP to patients inaccurately reporting a penicillin allergy.2,15 In part, this is attributable to inadequate training in antibiotic selection among the majority of anesthesiologists, despite holding the belief that such education is required.13 To bridge this gap in knowledge translation, we seek to highlight the evidence base for cephalosporin administration to patients reporting penicillin allergy to inform daily anesthesia practice.

Back to Top | Article Outline


We performed a literature search of MEDLINE (PubMed) on October 16, 2017, limited to the English language. Publication date was limited to the year 1994 onward to coincide with the publication of the first guideline on AMP in surgical procedures.17 See Supplemental Digital Content, Appendix 1,, for the search strategy relating to evidence on the safety of cephalosporin administration to penicillin-allergic patients. All article types were examined. Abstracts were manually reviewed for relevance, and full-text articles of relevant manuscripts were retrieved. Additional manuscripts were identified by manually reviewing references of relevant articles.

Back to Top | Article Outline


In response to the perceived risk of cephalosporin administration in penicillin-allergic patients, alternative antibiotics, often clindamycin and/or vancomycin, are used.2,18–21 Indeed, in a survey of anesthesiologists, all respondents indicated that they would choose an alternative antibiotic when presented with a history of penicillin allergy.15

Unverified penicillin allergy is said to be a significant and growing public health burden.22–24 The labeling of inpatients as penicillin allergic has been associated with longer hospital admissions, higher rates of readmission, treatment failure, and intensive care unit admission, and increased risk of exposure to significantly more antibiotics associated with Clostridium difficile, vancomycin-resistant Enterococcus, and methicillin-resistant S aureus (MRSA).24–27 Accordingly, inpatient penicillin allergy testing to delabel patients was demonstrated as a successful antimicrobial stewardship measure.28,29

In the perioperative setting, a retrospective cohort analysis of 8385 patients found that those reporting a penicillin allergy had 50% increased odds of SSI, attributed directly to the receipt of alternative antibiotics.2 Higher rates of SSI have been observed with vancomycin18,30–34 and clindamycin35–39 in orthopedic, gynecologic, otolaryngological, and neurosurgical procedures. Vancomycin is less effective than cefazolin against methicillin-susceptible S aureus.40,41 Mechanisms for these observations include vancomycin’s poor tissue penetration, reduced bactericidal rates, and the gradual reduction in susceptibility of S aureus to the drug.42,43 Vancomycin is thus best reserved either as primary or adjuvant AMP for patients colonized with MRSA or institutions with high prevalence of MRSA, although the evidence in this setting is conflicting.44 Furthermore, compared to cefazolin, vancomycin has a narrow spectrum of antibacterial coverage that does not include Gram-negative pathogens.44 Clindamycin similarly has poor coverage of aerobic Gram-negative bacteria.39,45 Because a variety of surgical procedures are associated with polymicrobial SSI, substitution of cefazolin with vancomycin alone may render the antimicrobial coverage incomplete5; familiarity with recommended AMP regimens for specific procedures is encouraged.

In addition, cefazolin has a favorable safety profile, while adverse effects of vancomycin include nephrotoxicity43,46,47 and of clindamycin are associated with C difficile colitis.24,48 Furthermore, slow infusion of vancomycin, necessary to prevent red man syndrome,43 may impact timely preoperative administration.49 Cefazolin is also the most cost-effective drug when compared to either clindamycin or vancomycin on a per-dose basis,20,50 while continued vancomycin treatment also requires further resources for monitoring drug levels.47

Back to Top | Article Outline


Penicillin allergy is the most commonly reported allergy in medical records, with a prevalence of 8%–12% among the patient population.51 However, most reported penicillin reactions are not associated with immunoglobulin-E (IgE)-mediated reactions after penicillin testing and rechallenge, with 95% of these patients having a negative penicillin skin test.28 This discrepancy can be attributed to highly variable and inadequate beta-lactam allergy documentation in the majority of cases,25,52,53 or due to the decrease of penicillin-specific antibodies over time.54 Unfortunately, due to various constraints, reported drug allergies are generally not challenged by anesthesiologists.21 One survey found that 89.5% of anesthesiologists have never referred patients for evaluation of drug allergy, although an equal number felt a referral would be helpful.15 However, 47.3% said that they have verbally communicated to their patients that they should speak to their family doctor for further evaluation.

It is advised that the perioperative physician ascertain the nature of previous allergic reactions on preoperative assessment to differentiate true IgE-mediated allergies from other hypersensitivity and nonspecific reactions. Clinical history strongly suggestive of a non-IgE–mediated adverse reaction (ie, maculopapular or morbilliform rash, gastrointestinal side effects, isolated pruritis or dizziness, headache)55–57 can exclude true penicillin allergy and obviate the need for further testing,55,56 although a vague history has less discriminatory value.58,59 Immediate hypersensitivities, classified as type I reactions, are IgE mediated, occur within 1 hour of exposure, and are characterized by urticaria, laryngeal edema, bronchospasm, angioedema, and anaphylaxis.55,60,61 Such reactions can be supported by elevated serum tryptase levels.61,62 The time elapsed since the penicillin reaction should also be ascertained, as approximately 50% of patients with IgE-mediated penicillin allergy lose their sensitivity after 5 years, further increasing to approximately 80% by 10 years.61 Subsequently, in patients with a high index of suspicion of true allergy and lacking a formal diagnosis, preoperative allergy testing can be considered. Preoperative allergy consultation and penicillin skin testing have been shown to reduce vancomycin use.63–66

Back to Top | Article Outline

Penicillin Allergy Testing

A clinically significant IgE-mediated penicillin allergy can be safely refuted or confirmed using skin testing and, if the skin test is negative, an oral penicillin VK or amoxicillin challenge (drug provocation test [DPT]).61 Tolerance of an oral penicillin-class antibiotic is the gold standard test for an absence of IgE-mediated penicillin allergy.61,67,68 However, per the 2010 Joint Task Force (American Academy of Allergy, Asthma and Immunology; the American College of Allergy, Asthma and Immunology; and the Joint Council of Allergy, Asthma and Immunology) practice guidelines, a negative skin test is sufficient for cephalosporin administration without further testing if the underlying concern was the presence of a penicillin allergy.61 There are few contraindications to performing a DPT after a negative skin test, namely history of severe, life-threatening cutaneous non-IgE–mediated type IV hypersensitivity reactions such as erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms syndrome that have been rarely associated with β-lactams.67,69

In practice, routine allergy consultation referral by anesthesiologists is fraught with challenges, including time constraints, the feeling that this is the responsibility of another physician, and the availability of alternative antimicrobials.15 Additionally, operational constraints may hinder preoperative outpatient allergy testing, including cost, estimated to be $220–$540 US dollars per patient70 (although, with 1 case of SSI prevented for every 112–124 patients who undergo testing for reported penicillin allergy,2 the financial burden of allergy testing can potentially be mitigated by the prevention of costly SSIs). Alternatively, an emerging testing method is point-of-care β-lactam allergy skin testing, which can be conducted with minimal resources in a timely fashion by a pharmacist trained in allergy testing and anaphylaxis treatment.29,51 A prospective multicenter trial performed skin prick and intradermal testing, which were read at 15 and 30 minutes, respectively.29 All negative skin tests were followed by an oral challenge followed by a 4-hour observation period by the patient’s nurse. The study reported 4.5-fold greater odds of patients receiving preferred β-lactam therapy. However, such trials were conducted in an inpatient setting, and adapting this process on an ambulatory basis would be logistically challenging. The potential for systemic reaction requires supervision for 1 hour after skin testing while DPT requires up to 6 hours,71 thereby requiring a specialized setting to administer allergy tests.

There are further limitations to performing skin testing. Given the high prevalence of penicillin allergy reporting, it is not feasible to test all patients preoperatively, particularly in a timely manner. Allergy testing may thus be best reserved for patients with vague or strong history suggestive of penicillin allergy undergoing elective surgery and who have risk factors for developing SSI (those at extremes of age and with poor nutritional status, obesity, diabetes mellitus, tobacco use, corticosteroid therapy, and an immunocompromised state), as these patients would benefit most from cephalosporin AMP.5

There is also a lack of consensus on how to proceed when patients test positive for a penicillin allergy,72 as it is unclear as to what information can be gleaned regarding potential cephalosporin allergy. Logically, the next step would involve cephalosporin allergy testing.54 However, while European allergy guidelines describe skin testing methodology for specific cephalosporin agents, US guidelines recommend against cephalosporin testing due to the unknown negative predictive value of such testing and lack of validation.71–73 An alternative strategy is a graded cephalosporin challenge. A sample protocol describes the administration of one-tenth of the dose followed by a half-hour observation, then followed by administration of the remainder of the dose with another observation period; this is similarly not strongly evidence based, requires monitoring, and is unlikely to be feasible on the day of surgery.72

Back to Top | Article Outline


The often-quoted cross-reactivity between penicillins and cephalosporins of 10%–15% is not supported by current literature. The misunderstanding of such cross-reactivity is primarily historical in nature. Early studies in the 1960s and 1970s reported an 8%–18% cross-reactivity between penicillin and cephalothin, the first marketed cephalosporin,74 in a small group of patients.75–77 These findings have since been propagated and have broadly shaped the paradigm of cephalosporin administration in penicillin-allergic patients,74 despite alternative early evidence of minimal cross-reactivity between penicillin and cefazolin.78 Older studies may have, in part, overestimated the degree of cross-reactivity between penicillins and cephalosporins because, before the development of purification techniques in the 1980s, early cephalosporin antibiotics were derived from Acremonium (formerly Cephalosporium) mold and thus contaminated with penicillins.74,79–81

Likewise, a review of anaphylaxis during anesthesia concluded that first-generation cephalosporins should be avoided in patients with a history of penicillin allergy.82 This recommendation was based on a meta-analysis whereby cefazolin was represented by only 1 trial from 1978.83 This conclusion may be erroneous, in part, because of the manufacturing process during that time. Additionally, there is a common misconception that the classification scheme of cephalosporins by generation is based on structural characteristics of the respective molecules. In fact, cephalosporins are grouped into generations according to the spectrum of activity against Gram-negative bacteria.10 Cefazolin, while classified as first generation, is structurally different from all other cephalosporins, accounting for its different immunogenicity profile.81

Penicillins and cephalosporins both have a backbone structure consisting of a β-lactam ring joined to a second ring structure, a thiazolidine ring for penicillins and a dihydrothiazine ring for cephalosporins.84 Contrary to popular belief, cephalosporin allergy is not mediated by reaction to the β-lactam ring. Under physiological conditions, the dihydrothiazine and β-lactam rings of cephalosporins undergo rapid degradation into products that do not function as haptens.54,74 Rather, the potential cross-reactivity of penicillins and cephalosporins is derived from structural similarities of their R1 side chains that are attached to the β-lactam ring at the 7-position on cephalosporins, corresponding to the 6-position on penicillins.54,60,74,85 Cephalothin shares a similar side chain with penicillin G (along with cefoxitin), thereby accounting for the cross-reactivity seen in the aforementioned early studies, along with modern ones.86 Likewise, amoxicillin, ampicillin, and cephalexin, to name a few, share similar side chains and thus may cross-react. Cefazolin has a unique R1 side chain (structure similar only to ceftezole,74 a cephalosporin derivative not currently in clinical use) and does not cross-react with penicillins. An additional source of immunogenicity unique to cephalosporins is the R2 side chain at the 3-position of their dihydrothiazine ring; cefazolin once again has a unique structure. A matrix table of penicillin and cephalosporin drugs is available to physicians looking to assess for allergic cross-reactivity based side chain structures.87

Of note, in contrast to IgE-mediated reactions, severe T cell–mediated delayed hypersensitivity reactions such as Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug-induced vasculitis are excluded from this discussion. In these exceedingly rare88 reactions, T cells can recognize the whole β-lactam molecule or the core structure and possibly part of the side chain, and thus, cross-reactivity between penicillins and cephalosporins is hard to predict.69 Expert consultation is advised regarding appropriate antibiotics in patients with a history of such reactions.

Back to Top | Article Outline

Safety of Cefazolin Administration

There is no contemporary evidence of an increased risk of anaphylaxis to cefazolin in penicillin-allergic patients.87 Specific to the perioperative setting, 5 studies examining the administration of cephalosporin AMP to penicillin-allergic patients were identified;19,20,89–91 one of these studies was limited to patients with non-IgE–mediated reactions.20 Four of the studies reported no adverse events.19,20,89,90 One study91 evaluated 6 AMP strategies in patients reporting penicillin allergy, ranging from either direct cefazolin or vancomycin administration, obtaining an allergy history and administering vancomycin if suggestive of an IgE-mediated reaction, performing allergy skin testing, or combining the allergy history with testing to guide decision making. While this study reported anaphylaxis rates ranging from 0.0004% in the cefazolin-only group to 0.000134% in the most comprehensive allergy assessment group (vancomycin to patients with either positive skin tests or suggestive histories), the authors did not report sample sizes or statistical analyses on these incidence rates. Nonetheless, it is reassuring that the rates of anaphylaxis in this study were very low in patients directly receiving cefazolin.

Outside of the perioperative setting, a retrospective study of over 900,000 patients exposed to over 1.2 million courses of cephalosporins identified only 3 cephalosporin-associated cases of anaphylaxis in >65,000 patients with a history of penicillin allergy who received >127,000 courses of cephalosporin therapy.88 While the specific cephalosporin agents implicated in those cases of anaphylaxis were not described, thereby limiting the ability to examine side chain cross-reactivity, there was no statistical difference in anaphylaxis rates when compared to cephalosporin administration to nonpenicillin-allergic patients.

It is important to note that independent cephalosporin allergies, distinct from penicillin allergies, do exist.74,85,86,92 In fact, IgE antibodies against cephalosporins may be more common than those against penicillin due the widespread use of cephalosporins.93 Cefazolin has been implicated as a causative agent in postoperative allergy testing after intraoperative allergic reactions.94–96 Of note, studies examining patients with proven IgE-mediated reactions to cefazolin demonstrated a lack of cross-reactivity with penicillins and other cephalosporins, further supporting the notion that cefazolin hypersensitivity is selective.96,97 It is reassuring that anaphylaxis from cephalosporins is rare overall, with a prevalence of 0.1%–0.0001%.74,88 Anaphylactic reactions are inherent to the practice of anesthesia, and familiarity with anaphylaxis management guidelines is recommended.98,99

Back to Top | Article Outline


Physicians as a whole have knowledge deficits regarding the management of patients with a history of penicillin allergy.100–103 However, antimicrobial stewardship, education programs, and concerted efforts to delabel patients have been successfully implemented in various medical disciplines to address inappropriate antibiotic therapy.100,104–106

AMP guidelines recommend alternative antimicrobial therapy in the presence of type I hypersensitivity to β-lactams.5 However, a limitation of such guidelines is that recommendations are applied to cephalosporins as a whole or to specific cephalosporin generations without an examination of individual cephalosporin agents. Emerging understanding of immunogenic mechanisms underlying antimicrobial allergies enables wider administration of certain cephalosporins and facilitates the administration of first-line AMP for the prevention of SSI while avoiding the morbidity associated with second-line antimicrobials. This evidence base should be reflected in future iterations of SSI guidelines.





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

Back to Top | Article Outline


Name: Leon Vorobeichik, MD.

Contribution: This author helped write the manuscript, approve the final manuscript, and archive the manuscript files.

Name: Elizabeth A. Weber, MD, FRCPC.

Contribution: This author helped write the manuscript and approve the final manuscript.

Name: Jordan Tarshis, MD, FRCPC.

Contribution: This author helped write the manuscript and approve the final manuscript.

This manuscript was handled by: Ken B. Johnson, MD.

Back to Top | Article Outline


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.
72. American College of Allergy, Asthma, and Immunology 2015 Drug Allergy and Anaphylaxis Committee. Beta-lactam antibiotic skin testing and oral challenge. Available at:–16.pdf. Accessed December 2, 2017.
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.

Supplemental Digital Content

Back to Top | Article Outline
Copyright © 2018 International Anesthesia Research Society