Bacitracin for Injection Recall: Impact on Immediate Breast Implant Surgical Outcomes

Background Triple-antibiotic irrigation of breast implant pockets is a mainstay of infection prophylaxis in breast reconstruction and augmentation. The recall of bacitracin for injection due to risk of anaphylaxis and nephrotoxicity in January 2020, a staple component of the irrigation solution, has raised concern for worsened postoperative sequelae. This study aimed to investigate pre- and post-recall implant-based breast surgery to analyze the impact of bacitracin in irrigation solutions on infection rates. Methods All implant-based breast reconstruction or augmentation surgeries from January 2019 to February 2021 were retrospectively reviewed. In a regression discontinuity study design, patients were divided into pre- and post-recall groups. Patient demographics, surgical details, and outcomes including infection rates were collected. Differences in complication rates were compared between groups and with surgical and patient factors. Results 254 implants in 143 patients met inclusion criteria for this study, with 172 implants placed before recall and 82 placed after recall. Patients in each cohort did not differ in age, BMI, smoking status, or history of breast radiation or capsular contracture (p > 0.05). All breast pockets were irrigated with antibiotic solution, most commonly bacitracin, cefazolin, gentamycin, and povidone-iodine before recall (116,67.4%) and cefazolin, gentamycin, and povidone-iodine after recall (59,72.0%). There was no difference in incidence of infection (6.4% vs. 8.5%, p=0.551) or cellulitis (3.5% vs. 3.7%, p=0.959) before and after recall. Implant infection was associated with smoking history (p < 0.001) and increased surgical time (p=0.003). Conclusions Despite the recent recall of bacitracin from inclusion in breast pocket irrigation solutions, our study demonstrated no detrimental impact on immediate complication rates. This shift in irrigation protocols calls for additional investigations into optimizing antibiotic combinations in solution, as bacitracin is no longer a viable option, to improve surgical outcomes and long-term benefits.


Introduction
Irrigation of breast implant pockets is a cornerstone for preventing infectious sequelae during implant-based breast reconstruction and augmentation. Postoperative infections of breast implant cases range between 1% and 35% [1]. Infections require antibiotic therapy, lead to undesired reoperations, and yield unsatisfactory results. For patients undergoing breast reconstruction after oncologic resection, postoperative infection is associated with delays in oncologic treatment [2]. Biofilm formation from inflammation and infections within the prosthetic pocket and capsule can contribute to subsequent capsular contracture (CC), a painful and distorting complication of breast implant surgery [1,3].
Research has repeatedly demonstrated the benefits of antibiotic irrigation of breast pockets in reducing both bacterial load and rates of postoperative infection [4,5]. Adams et al. explored the clinical efficacy of antibiotic irrigations, and their recommendation of a triple-antibiotic solution comprised of a cephalosporin, bacitracin, and gentamycin became the gold standard for intraoperative infection prevention in breast implant cases [4]. Even so, a consensus on optimal antibiotics to include has not been reached, and a variety of combinations is used among plastic surgeons in the United States [6]. e off-label use of povidone-iodine, an antiseptic, in irrigation has also been inconsistent [6]. Prior to 2000, povidone-iodine was commonly implemented as an irrigation material for breast implants; however, a moratorium on its use in irrigation was enacted by the US Food and Drug Administration (FDA) over concerns about silicone implant degradation [7]. Since its return to the market in 2017, it has been reintroduced to irrigation solutions by many plastic surgeons [6,7].
On January 31, 2020, the FDA requested the withdrawal of bacitracin for injection after the Antimicrobial Drugs Advisory Committee deemed that its benefits were outweighed by its risks of nephrotoxicity and anaphylaxis [8,9]. ough it has been used regularly for intraoperative irrigation in many surgical fields to prevent infection, it is now only approved for use in infant pneumonia and empyema [10]. Since bacitracin previously served as a staple antibiotic in breast implant irrigation solutions, concerns for worse postoperative outcomes have risen as a result of this recall.
Despite the potential for unfavorable results after the removal of bacitracin from irrigation solutions, this recall has provided an opportunity to reassess antimicrobial breast implant irrigation through a regression discontinuity experiment [11]. erefore, the central aim of this study was to investigate outcomes after implant-based breast surgery before and after recall and analyze the impact bacitracin truly had on outcomes in the immediate postoperative period.

Study Design.
All breast reconstruction or augmentation surgeries that involved the placement or exchange of silicone breast implants from January 2019 to February 2021 were retrospectively reviewed. rough a regression discontinuity study design, patients were divided into two groups based on the date of bacitracin for injection recall (January 31, 2020). Patients were excluded from analysis if their surgery involved placement of tissue expanders or revisional surgeries without implant exchange. A minimum period of six months of postoperative follow-up was required for inclusion in this analysis to allow for adequate time after the index surgery. is study was approved by the Institution Review Board (MHRI 2018-173).

Antimicrobial Surgical
Technique. Surgical sites were prepared with 2% chlorhexidine gluconate in 70% isopropyl alcohol. All patients received standard systemic prophylaxis consisting of 2 grams of IV cefazolin unless an existing allergy required the use of an alternative antibiotic. Intraoperatively, all patients underwent antibiotic irrigation of the breast pocket(s). Gloves were changed prior to handling the breast implant, and an aseptic technique of implant placement was performed using a sterile surgical funnel. Implant manipulation after insertion into the breast pocket was minimized.

Data Collection.
Demographic and comorbidity information including age, race, body mass index (BMI), and smoking history was collected. Charlson comorbidity index (CCI) scores were calculated to determine comorbidity burdens. Preoperative risk factors including a history of breast radiation, capsular contracture, or prior non-autologous reconstruction with an implant or tissue expander (TE) were recorded.
Details of surgical procedures were collected, including type of surgery. In patients who underwent reconstruction after oncologic resection, type of primary surgery, such as mastectomy or lumpectomy, was recorded. Reconstructive surgeries were also defined as immediate reconstruction with an implant, delayed-immediate reconstruction in which a TE was placed initially with subsequent exchange to an implant, and delayed reconstruction. Other details collected included surgical time, implant volume, use of acellular dermal matrix (ADM), and implant surgical plane. Type of irrigation solution was noted. e type and number of antibiotic and antiseptic additives were recorded. Surgical complications were collected, including infection, cellulitis, seroma, hematoma, and delayed healing. A follow-up period for each patient was determined.

Statistical Analysis.
Continuous variables were described by means and standard deviations, and categorical variables were described by frequencies and percentages. Two-sample t-test was used to examine differences in the averages of continuous variables between groups when normality assumption was satisfied. Chi-squared test and Fisher's exact test compared differences in categorial frequencies between groups as appropriate. Bivariate analysis was performed to assess associations between complication rates and patient or surgical characteristics. Statistical analysis was performed using STATA v.15 (StataCorp, College Station, Texas) with significance defined as p ≤ 0.05.

Results
143 patients underwent breast augmentation or reconstruction surgery with 254 implants between January 2019 and February 2021. 172 implants were placed before recall in 97 patients, and 82 implants were placed after recall in 46 patients.

Patient Demographics, Comorbidities, and Breast History.
Patient demographic and comorbidity characteristics are described in Table 1. e average patient age was 50.9 years (SD: 11.9) in the pre-recall group and 53.8 years (SD: 12.7) in the post-recall group (p � 0.079). ere was no difference between the two groups in CCI or patient-reported race (p > 0.05). Average patient BMI was 26.1 kg/m 2 (SD: 5.1) and 26.3 kg/m 2 (SD: 4.6) in the pre-and post-recall groups, 2 e Breast Journal respectively (p � 0.662). Over 70% of patients had no history of smoking in both groups, with no statistically significant difference between groups (p � 0.332).
Both groups had similar rates of implants in place prior to surgery (50.6% versus 54.9%; p � 0.029); however, more patients had tissue expanders in place before recall in comparison with after recall (31.4% versus 17.1%; p � 0.029) ( Table 2). 16.1% of breasts operated on had a history of radiation therapy, with 29 (16.9%) in the pre-recall group and 12 (14.6%) in the post-recall group (p � 0.652). A history of capsular contracture was present in 12.6% of breasts, with no difference between groups (p � 0.080).
In both groups, all incisions were either inframammary (IM) or transverse incisions. Additional surgical details are displayed in Table 3. All implants were silicone, and average implant volume did not differ before and after recall (452.4 mL versus 439.3 mL; p � 0.497). ere was no difference in implant plane between groups, with over 90% of implants placed in the pre-pectoral position (p � 0.788). Use of ADM during reconstruction was more prevalent after recall, with 63.41% of implants placed with ADM after recall and 51.74% of implants before recall, though this difference was not statistically significant (p � 0.08). Average surgical time was 122.7 minutes (SD: 66.6) before recall and 145.8 minutes (SD: 63.0) after recall (p � 0.009).

Antimicrobial Irrigation Components.
e most irrigation solution used was 0.9% normal saline (NS), with only two implants (1.2%) in the pre-recall group irrigated in lactated Ringer's solution (p � 0.327) ( Table 3). Before recall, most irrigation solutions were composed of triple-antibiotic solution (83.1%), while most post-recall solutions were double-antibiotic ones (82.9%) (p < 0.001). Antibiotics used before recall included bacitracin 50,000 units, cefazolin 1 gram, gentamycin sulfate 80 milligrams, vancomycin 1 gram, and polymyxin B 500,000 units in varying combinations according to patient allergies; the same antibiotics, except for bacitracin, were used after recall. Povidone-iodine 10% solution was used in solutions in 83.7% of pre-recall and 87.8% of post-recall surgeries. Table 5 describes the antibiotic and antiseptic combinations added to irrigation before and after recall. e most common pre-recall composition was a triple-antibiotic solution of bacitracin, cefazolin, and gentamycin with povidone-iodine in 67.4% of implants; the same triple-antibiotic solution without povidone-iodine was used in 14.0% of implants. After recall, 72.0% of implants were irrigated with a double-antibiotic solution of cefazolin and gentamycin with povidone-iodine. Table 6. e overall complication rate was 9.84%, with no difference between groups (9.88% versus 9.76%; p � 0.952). Average implant infection and cellulitis rates were 7.1% and 3.5%, respectively, with no significant difference before and after recall (p > 0.05). Other complications included seroma in 2.0% of patients, hematoma in 1.2% of patients, and delayed healing in 0.8% of patients, with no differences between groups (p � 0.329). Average follow-up period was 357.1 days (SD: 307.6) before recall and 168.5 days (SD: 119.0) after recall (p < 0.001). Table 7 reveals complication rates specific to cases that utilized the gold standard triple-antibiotic irrigation solution before recall (bacitracin, cefazolin, gentamycin + povidoneiodine) and double-antibiotic solution after recall (cefazolin, gentamycin + povidone-iodine). ere was no difference between pre-and post-recall cohorts in overall complication rate (16.38% versus 10.17%; p � 0267) or infection rates ere was a significant decrease in other complications, including seroma, hematoma, and delayed healing (11.21% versus 1.69%; p � 0.028) after the recall.

Surgical Complications. Complications are displayed in
Patient and surgical factors were analyzed for association with complications in Table 8. Patient history of smoking, breast radiation, and increased surgical time was associated with the development of "any complication" (p < 0.05).

Discussion
e use of topical antibiotics intraoperatively during implant-based breast augmentation has transpired for decades [12]. However, the popularity of triple-antibiotic irrigation, particularly cefazolin, gentamycin, and bacitracin, has become a mainstream option after substantial research [4]. e    brings concern for worsening postoperative complications. is study assessed outcomes prior to and immediately after the bacitracin recall and demonstrated no detrimental impact on complication rates. Most implants placed at our institution prior to the recall were irrigated with tripleantibiotic solution in combination with povidone-iodine. Once bacitracin was removed from the irrigation protocol, there was no increase in overall complication, infection, cellulitis, or seroma rates. ese results persisted when analyzing outcomes of cases that used only the gold standard triple-antibiotic combination of bacitracin, cefazolin, and gentamycin with povidone-iodine, before and after recall, as well as when patient subpopulations based on variations in surgery type and timing were analyzed for complication rates. Our early findings suggest that the recall of bacitracin from irrigation does not have a significant impact on immediate surgical outcomes, and thus alternative antibiotic and antiseptic sequences may be sufficient to provide thorough infection prophylaxis.
In addition to finding analogous outcomes after the bacitracin recall, this study also identified patient and surgical risk factors that were associated with postoperative complications. Patient history of smoking was associated with higher rates of infection, a well-known risk factor for sequelae particularly in breast reconstruction [1]. Our data also revealed that lengthier surgical times were correlated with higher complication rates, including infection and cellulitis. While longer times increase exposure to pathogens, there was no difference between pre-and post-recall groups despite longer times after recall.
Irrigation with triple antibiotics has become the standard of care; however, a survey of American Society of Plastic Surgery (ASPS) surgeons in 2018 found a lack of consensus with over 30 irrigation solution combinations in use [6]. Triple-antibiotic solution without povidone-iodine was favored by over 40% of members, with an additional 17% using triple-antibiotic solution with povidone-iodine [6]. Other surgeons use differing numbers of antibiotics or singularly dilute povidone-iodine solution [6]. Antibiotic selection aims to cover a broad spectrum of organisms; more than 75% of implant infections are Gram-positive and typically involve Staphylococcus aureus and Staphylococcus epidermidis; however, many are Gram-negative consisting of Pseudomonas and Escherichia coli [13]. Bacitracin was commonly used due to its low cost, broad spectrum of activity, and high potency versus Gram-positive skin flora [13]. Gentamycin has Gram-negative coverage including Pseudomonas while cefazolin is broad spectrum with good Staphylococcus coverage; thus, organisms covered by bacitracin should also be covered by the remaining two antibiotics [13]. Additionally, in vitro studies have shown that the combination of 10% povidone-iodine, gentamycin, and cefazolin is completely effective at eradicating strains of S. aureus, S. epidermidis, Pseudomonas, and E. coli [14].
Prior studies of the use of these antibiotics in irrigation solution have shown major reductions in infection rates in comparison with normal saline solution [13]. Even single antibiotic solutions have protective benefits against postoperative infections and reduced rates of other complications such as seromas [15,16]. ree antibiotics, however, may reduce infection rates substantially more. Adams et al. found infection rates less than 1% with triple-antibiotic irrigation [4]. Whether or not to combine triple-antibiotic irrigation with antiseptics such as povidone-iodine has been inconclusive as to whether it results in superior infection rates [5]. In vitro studies revealed that it reduces bacterial load by a factor of 10 4 to 10 5 for all methicillin-sensitive and resistant S. aureus and S. epidermidis strains and vancomycin-resistant Enterococcus, more effectively than tripleantibiotic solution is able to [7,13]. Despite clinical data lacking comprehensive evidence for its combination with triple-antibiotic solution, povidone-iodine was used in more than 85% of implant cases in this study, which highlights its potential benefits in preventing infections. e Breast Journal Capsular contracture is an intricate complication potentiated by tissue trauma, bacteria, and other sources of local inflammation; breast pocket irrigation, with or without antibiotics, is universally practiced as prophylaxis [4]. Conflicting data exists regarding the true impact of antibiotic irrigation on capsular contracture. A study by Giordano et al. found that triple-antibiotic irrigation plus povidone-iodine resulted in a capsular contracture rate of 0.6% in comparison to 6.0% without irrigation [17]. Another study found the rate of grade III-IV capsular contracture to be only 1.8% with triple-antibiotic solution [4]. ese findings were opposed by a systematic review by Samargandi et al., which identified only one randomized controlled trial and a few non-randomized studies that provided weak evidence for antibiotic irrigation as contracture prevention [18]. Despite the limited evidence, it is outweighed by the benefits of infection prevention and therefore is used regularly in implant surgery [19]. Although this study did not have sufficient follow-up to perform a true analysis of capsular contracture rates and their relationship to operative antibiotic solutions, future studies should investigate this dynamic.
Strengths of this study lie in its design as a regression discontinuity quasi-experiment. Regression discontinuity design allows patients to be assigned to intervention versus control groups based on falling above or below an arbitrary cutoff, in this case the date of bacitracin for injection recall [11]. Data on each side of the discontinuation are otherwise similar; there is no crossover of treatments nor nonrandom attrition of patients, and behavioral phenomena occur equally on both sides [11]. Patient cohorts were similar before and after recall in terms of surgery types, comorbidities, reconstruction timing, history of radiation or capsular contracture, and even incisional approach, as inframammary and transverse incisions have lower rates of infection in general in comparison with periareolar incisions [3].
Despite these advantages, this study is limited overall by its sample size and follow-up period. ough all cases involved implant-based breast surgery, there were variations in reconstructive timing, use of ADM, and prior prosthetic device use that introduce confounding factors; our subanalyses of our patient population suggest consistent results before and after recall in these groups; however, larger studies of these individual cohorts will need to be pursued to fully understand the impact of the recall. ere was also a substantially shorter follow-up period after recall, being likely the result of the temporal change in bacitracin use in combination with environmental factors. Briefly after the bacitracin recall, the COVID-19 pandemic started in March 2020, which significantly altered patient care towards virtual visits; patients may have avoided returning for follow-up, and those that engaged in telemedicine may not have caught early findings of various complications [20]. Additionally, while the bacitracin recall was the only major change in surgical protocols, causal inference in regression discontinuity study designs may be impacted by nonrandom manipulation around the treatment cutoff, such the COVID-19 pandemic [11].
Optimizing outcomes after breast implant surgery will call for larger studies to assess different antibiotic and antiseptic combinations, as the gold standard recipe with bacitracin is no longer an option.
is also allows us to reevaluate antibiotic use, so that it is used judiciously without unnecessary additives, preventing the spread of drug resistance among pathogens [9]. Among the antibiotics used, Gram-positive and Gram-negative coverage must be achieved, as with cefazolin and gentamycin alone [13]. is study provides reassurance that bacitracin in triple-antibiotic solutions may not have been the keystone antibiotic required to quell most complications. Additional investigation of the long-term development of capsular contracture before and after recall, however, is necessary to fully elucidate the impact of the recall. Further, the consistent inclusion of povidone-iodine should be explored. After the 2000 moratorium on povidone-iodine by the FDA out of concern for silicone degradation, triple-antibiotic irrigation without antiseptics became the model [7]. After its return to irrigation in 2017, a large segment of surgeons still favored antibiotic solution without povidone-iodine [6,13]. Its use as a primary irrigation should be reexplored given the known prophylactic effects on infection rates.

Conclusions
e recall of bacitracin for injection from use in intraoperative irrigation in January 2020 did not lead to worsened immediate complication rates after implant-based breast reconstruction and augmentation. is major shift in antibiotic irrigation protocols calls for additional investigation into the gold standard of preventative pocket irrigation, as bacitracin is no longer a viable option. Continued advancements in antimicrobial stewardship, in combination with optimizing surgical techniques, will improve surgical outcomes, patient satisfaction, and long-term benefits after breast implant surgery.

Data Availability
e clinical data used to support the findings of this study can be obtained from the corresponding author upon request.

Ethical Approval
is study was approved by the Institution Review Board (MHRI 2018-173).

Disclosure
Dr. Song receives royalties from Elsevier for Plastic Surgery, 3rd and 4th Editions, and Biomet Microfixation for SternaLock.

Conflicts of Interest
e authors declare that they have no conflicts of interest.