On January 31, 2020, the US Food and Drug Administration (FDA) issued a voluntary recall of bacitracin for injection due to efficacy and safety concerns, including nephrotoxicity, anaphylactic reactions, and the need for repeated intramuscular injections.1 The drug is active in vitro against most gram-positive organisms, including Staphylococcus aureus. Its only approved indication is for the treatment of infants with pneumonia and empyema caused by staphylococci shown to be susceptible to the drug, but off-label use of bacitracin for intraoperative irrigation of surgical wounds is widespread in hospitals across the United States.2 One survey showed that>50% of general and orthopedic surgeons, 30%–39% of neurosurgical and spinal surgeons, 26% of cardiothoracic surgeons, and 22%–23% of obstetrics-gynecology and plastic surgeons use antibiotic irrigation fluids, often containing bacitracin.Reference Edmiston, Spencer and Leaper3
High-quality evidence to support the use of intraoperative antimicrobial irrigations to prevent surgical site infections (SSIs) is lacking.Reference Edmiston, Leaper and Spencer4,Reference de Jonge, Boldingh and Solomkin5 Multiple guidelines on SSI prevention as well as the International Consensus Meeting on Orthopedic Infections statement either do not recommend the use of antibiotic irrigations or, due to insufficient evidence, make no recommendation (Table 1).Reference Blom, Cho and Fleischman6 Published literature on antibiotic irrigations for the prevention of SSIs mostly consists of retrospective, observational, single-center studies across a variety of surgery types including orthopedic, neurosurgical, cardiac, abdominal, vascular, and breast reconstruction procedures.Reference Edmiston, Leaper and Spencer4,Reference Blom, Cho and Fleischman6,Reference Norman, Atkinson and Smith11
Table 1.Summary Guideline Recommendations on Topical Antimicrobial or Antiseptic Therapy to Reduce Surgical Site Infections
Reviews and meta-analyses conducted in the last 60 years have repeatedly concluded that available studies have been flawed and of low quality, and that they are insufficient to support intraoperative topical antibiotics for SSI prevention.Reference Edmiston, Leaper and Spencer4 One recent meta-analysis of 21 randomized-controlled trials (RCTs) found no benefit of antibiotic irrigations compared to saline or no irrigation (OR, 1.16; 95% CI, 0.64–2.12; P = .63), but it found a decrease in SSIs with the use of intraoperative aqueous povidone-iodine solution compared to saline irrigation (OR, 0.31; 95% CI, 0.13–0.73; P = .007).Reference de Jonge, Boldingh and Solomkin5 A Cochrane analysis found that there may be a lower incidence of SSI in participants treated with antibacterial irrigation solutions compared with nonantibacterial (ie, saline) irrigants in patients undergoing abdominal, spine, orthopedic, gynecologic, vascular, thoracic, and general surgeries.Reference Norman, Atkinson and Smith11 This tentative conclusion was, however, based only on low-level evidence, which was downgraded because of a risk of publication bias as well as overall bias involving a variety of domains. Furthermore, the “antibacterial” group included individuals that received either antibiotics or antiseptics, making results difficult to interpret.
Irrigation with a triple antibiotic solution (commonly cefazolin, bacitracin, and gentamicin) is currently frequently used with the hope of reducing SSI and capsular contracture rates in breast implant surgery, despite conflicting evidence for efficacy.2 Drinane et al conducted a meta-analysis of 8 studies (2 case series and 6 retrospective studies) with 10,923 total patients and failed to detect a decreased incidence of capsular contracture in association with antimicrobial irrigation of implant pockets.2 No trials have directly compared antibiotic to antiseptic irrigations for the prevention of SSIs.Reference Edmiston, Leaper and Spencer4,Reference Norman, Atkinson and Smith11
The American Heart Association Scientific Statement on the management of cardiovascular implantable electronic device infections makes no recommendations on the use of antimicrobial irrigation of the pocket.2
Patient Safety, Regulatory and Hospital Oversight Issues
Intraoperative topical antibiotics pose patient safety issues. The US Food and Drug Administration found that the most commonly reported adverse events following the use of bacitracin containing irrigation solutions included allergic reactions (including anaphylaxis) and nephrotoxicity.2 It additionally revealed medication errors of inadvertent intravenous administration of irrigation solutions. However, adverse events are likely underreported. Most hospitals may not be able to track topical antibiotics easily because they are often available in drug carts or automated dispensing cabinets in the operating room suites, not ordered through the pharmacy. A recent survey of infection prevention practitioners revealed that although most facilities use intraoperative topical antibiotics, <17% of antibiotic irrigation solutions were monitored by their hospital’s antimicrobial stewardship team.Reference Edmiston, Leaper and Spencer4 Additionally, irrigation solutions mixed in the operating room may become contaminated or may be diluted inappropriately because they are not compounded by the pharmacy, which operates under strict federal and state regulations. Povidone-iodine, commercially available as a 10% solution (100 mg per 1 mL) is often diluted to a 0.35% solution for orthopedic procedures because this concentration results in the least chondrotoxicity on articular cartilage, an effect that is significantly magnified with increasing concentrations.Reference Edmiston, Leaper and Spencer4,Reference Norman, Atkinson and Smith11 To achieve this concentration, 7.5 mL sterile 10% povidone-iodine may be diluted with 500 mL sterile normal saline. Povidone-iodine in 1% and 5% formulations have also been described for other surgery types.Reference Norman, Atkinson and Smith11 Inappropriate dilutions may result in excessive and toxic concentrations in irrigation solutions.
Other concerns include insufficient contact time against the bacterial target, toxicity, and the potential for developing antibiotic resistance.Reference Edmiston, Leaper and Spencer4 The WHO guideline emphasizes the unnecessary risk of the emergence of antibiotic resistance with the use of antibiotic intraoperative wound irrigations.Reference Allegranzi, Zayed and Bischoff9
In summary, the removal of bacitracin injection from the market, 72 years after its introduction in 1948, should not be viewed as a loss but rather as a catalyst for critical reevaluation of an unregulated and non–evidence-based practice. Intraoperative antibiotic irrigations lack evidence of efficacy and pose serious risks. Various surgery groups may argue for the use of vancomycin as an alternative, especially in spine surgeries, but this, too, is mostly based on weak studies with limitations and shortcomings similar to those mentioned above.Reference Maria, Deyanira and Francesca12
Instead of squeezing the antibiotic balloon, shifting to antiseptic solutions is a more evidence-based approach. Chlorhexidine gluconate (CHG) is more rapidly lethal than povidone-iodine and has shown promise when used as a 0.05% irrigation solution in experimental laboratory and animal models, and 1 human study in hip and knee arthroplasty.Reference Edmiston, Spencer and Leaper3,Reference de Jonge, Boldingh and Solomkin5 CHG intraoperative irrigation warrants further clinical study for use in the prevention of SSIs. Dilute povidone-iodine has shown efficacy in orthopedic/spine, general, and cardiovascular surgeries.Reference de Jonge, Boldingh and Solomkin5,Reference Blom, Cho and Fleischman6,Reference Allegranzi, Zayed and Bischoff9 Use of dilute povidone-iodine solution prior to wound closure is supported by the World Health Organization and Centers for Disease Control and Prevention (CDC) guidelines on the prevention of SSIs and International Consensus Meeting on Orthopedic Infections.Reference Blom, Cho and Fleischman6,Reference Allegranzi, Zayed and Bischoff9,Reference Berrios-Torres, Umscheid and Bratzler10 Further study and high-quality evidence are needed on the role of topical antimicrobials in this setting.
On January 31, 2020, the US Food and Drug Administration (FDA) issued a voluntary recall of bacitracin for injection due to efficacy and safety concerns, including nephrotoxicity, anaphylactic reactions, and the need for repeated intramuscular injections.1 The drug is active in vitro against most gram-positive organisms, including Staphylococcus aureus. Its only approved indication is for the treatment of infants with pneumonia and empyema caused by staphylococci shown to be susceptible to the drug, but off-label use of bacitracin for intraoperative irrigation of surgical wounds is widespread in hospitals across the United States.2 One survey showed that>50% of general and orthopedic surgeons, 30%–39% of neurosurgical and spinal surgeons, 26% of cardiothoracic surgeons, and 22%–23% of obstetrics-gynecology and plastic surgeons use antibiotic irrigation fluids, often containing bacitracin.Reference Edmiston, Spencer and Leaper3
High-quality evidence to support the use of intraoperative antimicrobial irrigations to prevent surgical site infections (SSIs) is lacking.Reference Edmiston, Leaper and Spencer4,Reference de Jonge, Boldingh and Solomkin5 Multiple guidelines on SSI prevention as well as the International Consensus Meeting on Orthopedic Infections statement either do not recommend the use of antibiotic irrigations or, due to insufficient evidence, make no recommendation (Table 1).Reference Blom, Cho and Fleischman6 Published literature on antibiotic irrigations for the prevention of SSIs mostly consists of retrospective, observational, single-center studies across a variety of surgery types including orthopedic, neurosurgical, cardiac, abdominal, vascular, and breast reconstruction procedures.Reference Edmiston, Leaper and Spencer4,Reference Blom, Cho and Fleischman6,Reference Norman, Atkinson and Smith11
Summary Guideline Recommendations on Topical Antimicrobial or Antiseptic Therapy to Reduce Surgical Site Infections
Abbreviations: ASHP: American Society of Health-System Pharmacists; IDSA: Infectious Diseases Society of America; SIS: Surgical Infection Society; SHEA: Society for Healthcare Epidemiology of America. ACS: American College of Surgeons; CDC: Centers for Disease Control; WHO: World Health Organization
Reviews and meta-analyses conducted in the last 60 years have repeatedly concluded that available studies have been flawed and of low quality, and that they are insufficient to support intraoperative topical antibiotics for SSI prevention.Reference Edmiston, Leaper and Spencer4 One recent meta-analysis of 21 randomized-controlled trials (RCTs) found no benefit of antibiotic irrigations compared to saline or no irrigation (OR, 1.16; 95% CI, 0.64–2.12; P = .63), but it found a decrease in SSIs with the use of intraoperative aqueous povidone-iodine solution compared to saline irrigation (OR, 0.31; 95% CI, 0.13–0.73; P = .007).Reference de Jonge, Boldingh and Solomkin5 A Cochrane analysis found that there may be a lower incidence of SSI in participants treated with antibacterial irrigation solutions compared with nonantibacterial (ie, saline) irrigants in patients undergoing abdominal, spine, orthopedic, gynecologic, vascular, thoracic, and general surgeries.Reference Norman, Atkinson and Smith11 This tentative conclusion was, however, based only on low-level evidence, which was downgraded because of a risk of publication bias as well as overall bias involving a variety of domains. Furthermore, the “antibacterial” group included individuals that received either antibiotics or antiseptics, making results difficult to interpret.
Irrigation with a triple antibiotic solution (commonly cefazolin, bacitracin, and gentamicin) is currently frequently used with the hope of reducing SSI and capsular contracture rates in breast implant surgery, despite conflicting evidence for efficacy.2 Drinane et al conducted a meta-analysis of 8 studies (2 case series and 6 retrospective studies) with 10,923 total patients and failed to detect a decreased incidence of capsular contracture in association with antimicrobial irrigation of implant pockets.2 No trials have directly compared antibiotic to antiseptic irrigations for the prevention of SSIs.Reference Edmiston, Leaper and Spencer4,Reference Norman, Atkinson and Smith11
The American Heart Association Scientific Statement on the management of cardiovascular implantable electronic device infections makes no recommendations on the use of antimicrobial irrigation of the pocket.2
Patient Safety, Regulatory and Hospital Oversight Issues
Intraoperative topical antibiotics pose patient safety issues. The US Food and Drug Administration found that the most commonly reported adverse events following the use of bacitracin containing irrigation solutions included allergic reactions (including anaphylaxis) and nephrotoxicity.2 It additionally revealed medication errors of inadvertent intravenous administration of irrigation solutions. However, adverse events are likely underreported. Most hospitals may not be able to track topical antibiotics easily because they are often available in drug carts or automated dispensing cabinets in the operating room suites, not ordered through the pharmacy. A recent survey of infection prevention practitioners revealed that although most facilities use intraoperative topical antibiotics, <17% of antibiotic irrigation solutions were monitored by their hospital’s antimicrobial stewardship team.Reference Edmiston, Leaper and Spencer4 Additionally, irrigation solutions mixed in the operating room may become contaminated or may be diluted inappropriately because they are not compounded by the pharmacy, which operates under strict federal and state regulations. Povidone-iodine, commercially available as a 10% solution (100 mg per 1 mL) is often diluted to a 0.35% solution for orthopedic procedures because this concentration results in the least chondrotoxicity on articular cartilage, an effect that is significantly magnified with increasing concentrations.Reference Edmiston, Leaper and Spencer4,Reference Norman, Atkinson and Smith11 To achieve this concentration, 7.5 mL sterile 10% povidone-iodine may be diluted with 500 mL sterile normal saline. Povidone-iodine in 1% and 5% formulations have also been described for other surgery types.Reference Norman, Atkinson and Smith11 Inappropriate dilutions may result in excessive and toxic concentrations in irrigation solutions.
Other concerns include insufficient contact time against the bacterial target, toxicity, and the potential for developing antibiotic resistance.Reference Edmiston, Leaper and Spencer4 The WHO guideline emphasizes the unnecessary risk of the emergence of antibiotic resistance with the use of antibiotic intraoperative wound irrigations.Reference Allegranzi, Zayed and Bischoff9
In summary, the removal of bacitracin injection from the market, 72 years after its introduction in 1948, should not be viewed as a loss but rather as a catalyst for critical reevaluation of an unregulated and non–evidence-based practice. Intraoperative antibiotic irrigations lack evidence of efficacy and pose serious risks. Various surgery groups may argue for the use of vancomycin as an alternative, especially in spine surgeries, but this, too, is mostly based on weak studies with limitations and shortcomings similar to those mentioned above.Reference Maria, Deyanira and Francesca12
Instead of squeezing the antibiotic balloon, shifting to antiseptic solutions is a more evidence-based approach. Chlorhexidine gluconate (CHG) is more rapidly lethal than povidone-iodine and has shown promise when used as a 0.05% irrigation solution in experimental laboratory and animal models, and 1 human study in hip and knee arthroplasty.Reference Edmiston, Spencer and Leaper3,Reference de Jonge, Boldingh and Solomkin5 CHG intraoperative irrigation warrants further clinical study for use in the prevention of SSIs. Dilute povidone-iodine has shown efficacy in orthopedic/spine, general, and cardiovascular surgeries.Reference de Jonge, Boldingh and Solomkin5,Reference Blom, Cho and Fleischman6,Reference Allegranzi, Zayed and Bischoff9 Use of dilute povidone-iodine solution prior to wound closure is supported by the World Health Organization and Centers for Disease Control and Prevention (CDC) guidelines on the prevention of SSIs and International Consensus Meeting on Orthopedic Infections.Reference Blom, Cho and Fleischman6,Reference Allegranzi, Zayed and Bischoff9,Reference Berrios-Torres, Umscheid and Bratzler10 Further study and high-quality evidence are needed on the role of topical antimicrobials in this setting.
Acknowledgments
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Conflicts of interest
All authors report no conflicts of interest relevant to this article.