Perioperative Antibiotic Prophylaxis, Beta-Lactam Allergies and Cross Reactivity

Introduction

• Perioperative antibiotic use accounts for an estimated 12–15% of all antibiotic use in US acute care hospitals1,2, endowing anesthesiologists with a unique role in antimicrobial stewardship.
• In 2013, the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America, the Surgical Infection Society, and the Society for Healthcare Epidemiology jointly released clinical practice guidelines for the safe and effective use of antimicrobial agents to prevent surgical-site infections (SSIs).³
  • There was only 59% adherence to these practice guidelines across half a million inpatient elective surgeries performed in 2019 and 2020 in the US.²
  • Nearly 1 in 10 patients are labeled as “penicillin allergic,” yet among patients with a reported penicillin allergy, only 5 – 8% of adults have a positive penicillin skin test.^4,5,6
• Allergy mislabeling is associated with a host of negative externalities, including adverse drug events, decreased clinical efficacy, and antimicrobial resistance.⁷ Thus, anesthesiologists play a crucial role in patient safety and antimicrobial stewardship when selecting and utilizing perioperative antimicrobial agents.
• Herein, we describe the role of perioperative antibiotic prophylaxis, the classification of antibiotic hypersensitivity, and the mechanism of antibiotic cross-reactivity. We conclude with a framework for rational and safe antibiotic selection in the setting of beta-lactam allergy.

Perioperative Antibiotic Prophylaxis

• SSIs remain a significant public health burden for healthcare systems worldwide despite modern surgical techniques and infection prevention practices.
• While low- and middle-income countries face higher overall rates of SSI due to infrastructure and resource limitations, in the United States, SSIs contribute to patients spending more than 400,000 extra days in the hospital at an additional cost of $900 million annually.⁸
• Skin flora, including Staphylococcus aureus and coagulase-negative staphylococci, are the most common surgical-site pathogens, with gram-negative organisms and enterococci also implicated in clean-contaminated procedures, including abdominal surgery and solid organ transplantation.³
• An antimicrobial agent warrants specific criteria to meet the needs of surgical prophylaxis:³
  • Activity against the pathogens most likely to contaminate the surgical site
  • Administration at the correct time and dose to achieve adequate tissue and serum concentrations during the period of potential contamination
  • Acceptable safety profile
  • Administration for the shortest effective duration to minimize adverse effects, the development of antimicrobial resistance, and cost
• The 2013 ASHP guidelines recommend cefazolin as the drug of choice for most surgical prophylaxis, given its reliable spectrum of activity against gram-positive and gram-negative organisms, reasonable safety profile, and relatively low cost.
• Clindamycin and vancomycin are the most frequently recommended alternative agents across all surgical indications in patients with beta-lactam allergy.³
• For most indications, the first dose of antimicrobial prophylaxis should be administered within 60 minutes before the surgical incision.³
  • Intravenous administration is preferred as it produces rapid, reliable, and pharmacokinetically predictable serum and tissue concentrations.
  • Vancomycin and fluoroquinolones should be administered 120 minutes before surgical incision due to their prolonged infusion times.
• Intraoperative redosing is required to maintain adequate serum and tissue concentrations when the procedure duration exceeds two half-lives of the antimicrobial, or when excessive blood loss is encountered (more than1500 mL).³
  • Redosing may not be required in patients with prolonged antimicrobial half-life, for example, those with renal failure or renal insufficiency.
• Postoperative antimicrobial prophylaxis is not recommended for most procedures or in situations when indwelling drains or catheters remain in situ postoperatively.³
  • The practice of 48-hour perioperative prophylaxis for select cardiothoracic surgery procedures remains an area of controversy, with clinical practice guided by expert opinion, rather than available data

Antibiotic Hypersensitivity Reactions

• While true allergic drug reactions can range from mild (pruritus, urticaria) to life-threatening (anaphylactic shock), the reality is that antibiotic allergies are often poorly documented and characterized within the electronic health record.⁹
  • Gastrointestinal intolerance, such as nausea or unpleasant taste, is often mislabeled as an antibiotic allergy.
  • Childhood reactions are often carried forth into adult medical records, despite the risk of repeat IgE-mediated hypersensitivity to similar drugs diminishing by about 80% over 10 years.⁴
• To streamline the heterogeneous nature of ADR, they are typically classified as follows:
  • Type A ADR (dose-dependent, pharmacologically predictable, nonimmune mediated)
  • Type B ADR (nondose-dependent, pharmacologically unpredictable, immune-mediated)
    • Type B ADRs are further mechanistically classified as types I – IV by the Gell and Coombs framework.⁷
    • Type B ADRs can occur anywhere from 30 minutes to more than 72 hours after drug exposure, as mediated by various arms of the adaptive immune system (Figure 2).

Antibiotic Cross-Reactivity

• The framework of allergic cross-reactivity traditionally implicates the shared beta-lactam ring conserved across different beta-lactam antibiotics; however, our modern understanding of beta-lactam cross-reactivity instead relies on the predictive power of similar R1 or R2 side chains to elicit an immune response.^4,7
• If a penicillin allergy (including to aminopenicillins and anti-staphylococcal penicillins) is used as a reference point, then allergic cross-reactivity can be predicted against cephalosporins at less than 2% (except among shared group aminopenicillins and aminocephalosporins), and allergic cross-reactivity can be predicted against carbapenems at less than 1% based on similar side chain structure.
• Cefazolin remains a unique outlier among its peers, as it shares no R1 or R2 side chain similarity with any other beta-lactam antibiotics.⁷
• In clinical practice, we recommend eliciting a comprehensive history whenever an antibiotic allergy is encountered.
  • Particular attention should be paid to determine the nature of the reaction and its timeline after administration of the antibiotic in question.
• Any beta-lactam allergy involving a severe cutaneous adverse reaction, interstitial nephritis, hepatitis, or hemolytic anemia should preclude re-challenging with any other beta-lactam antibiotic.
• Cephalosporins and carbapenems should be avoided as surgical prophylaxis among patients with documented or presumed IgE-mediated penicillin allergy.