Introduction
Surgical site infection (SSI) is a challenging postoperative complication that negatively impacts patient recovery and increases the cost of care.1 Treatment of orthopedic SSI includes local decontamination of the affected site, administration of systemic antibiotics, and the removal of metallic implants after adequate healing of the surgical site.2,3 Successful clearance of orthopedic SSI with systemic antibiotics alone can be challenging due to several factors, including inability of the drug to penetrate the biofilm on metallic implants or bone and poor compliance.4,5 The presence of a multidrug-resistant pathogen complicates the management of an SSI and can require a prolonged treatment with systemic antimicrobials, increasing the risk of adverse drug events.6
Local antimicrobial administration is often considered an adjunct therapy, as it allows the sustained release of the antimicrobial at a high concentration with decreased systemic toxicity.7 Optimal vehicles for antimicrobial delivery should be sterile, biodegradable, and easy to administer; have a small volume; and provide controlled drug release.8,9 Calcium sulfate beads are commonly used in veterinary medicine for local antimicrobial delivery because they are bioresorbable and have osteoconductive properties.10–14 The use of a dextran polymer hydrogel vehicle for delivery of local antimicrobials has also been described for the management of dogs with infected tibial plateau leveling osteotomies (TPLO) and septic arthritis.9,15 Thirty percent poloxamer 407 (P407) hydrogel (Pluronic F-127 hydrogel) is a temperature-responsive poloxamer aqueous solution that is a versatile vehicle for local antimicrobial therapy and simple to administer, allowing delivery to infected sites with limited space or access.8 Antimicrobial elution using P407 hydrogel as a delivery vehicle has been reported for multiple drugs.16,17 Results for clindamycin, amikacin,16 and vancomycin17 showed local concentrations above minimal inhibitory concentrations against Staphylococcus for at least 4 to 8 days. Little is known about the outcome of orthopedic SSI treated with local antibiotic therapy using P407 hydrogel. The aims of the study were to report the outcomes of surgical implantation of antibiotic-impregnated P407 hydrogel in a population of client-owned dogs as part of the management of orthopedic SSI and to identify risk factors for treatment failure.
Materials and Methods
Study population
Medical records were searched to identify dogs that underwent intraoperative implantation of antibiotic-impregnated 30% P407 hydrogel at the authors’ institution between March 2018 and December 2020. The medical records were reviewed of dogs with a charge code indicating dispensation of P407 hydrogel during their hospitalization. Only dogs receiving P407 hydrogel for therapeutic purposes were included, and the eluted antimicrobial was recorded. Dogs were excluded if there was no evidence of a deep or organ space SSI based on CDC guidelines at the time of P407 hydrogel implantation18,19 or if the procedure was not an orthopedic procedure. Dogs that underwent total hip replacement (THR) were excluded if they were not diagnosed with a periprosthetic joint infection according to published guidelines.19 Open fractures that underwent surgical treatment within 24 hours of initial trauma or that lacked a positive bacterial culture at the time of surgery were also excluded.20,21 Dogs were also excluded if follow up duration after P407 hydrogel administration was shorter than 180 days or when owners were not available for long-term telephone follow-up.
Medical record data collection
Data collected from medical records included signalment, date of surgery, number and type of surgeries performed at the affected site before P407 hydrogel implantation, date when clinical signs of infection were noted, method of culture sample collection, bacterial culture and susceptibility results, duration of systemic antimicrobial therapy, P407 hydrogel preparation and implantation, antimicrobial eluted in the gel, dates, and findings of postprocedure evaluations. Clinical outcomes including complications, resolution of clinical signs, and radiographic findings were also recorded.
Definitions
Infections were defined as early infection when clinical signs of deep or organ space SSI were identified within 8 weeks of the original surgery and delayed infection when these signs were identified > 8 weeks after the initial orthopedic surgery.22,23 Infections were defined as complex if > 1 bacterial species was isolated from the surgical site. Infections were classified by pathogen, methicillin resistance, and the presence of a multidrug-resistant organism, defined as a bacterium resistant to > 1 class of antimicrobial agents.24 Initial surgeries were described as elective surgeries (TPLO, patellar luxation repair, THR, and arthrodesis for nontraumatic problems) or trauma surgeries (fracture repair and arthrodesis after trauma). The surgical procedure performed at the time of hydrogel implantation was described as implant retaining (retention or replacement) or implant removal. Anatomic location of the procedure was defined as upper extremity (involving the femur or humerus and proximal) or lower extremity (involving the tibia or radius/ulna or distal).
Long-term follow-up
Long-term follow-up was conducted by telephone calls to owners by a single researcher (JS) to determine whether additional therapy was ongoing, limb use was satisfactory, and clinical signs of persistent infection such as wound drainage, swelling, or pain were present. A standard list of questions was used while conducting telephone calls (Appendix). Complications related to antibiotic-impregnated P407 hydrogel implantation were defined as minor, major, or catastrophic.25 Outcomes were deemed successful when the animal was no longer receiving antimicrobial therapy and had no clinical signs of surgical site infection, no radiographic evidence of infection, and no macroscopic suppuration at the time of long-term follow-up or > 180 days from P407 hydrogel administration. Clinical signs providing evidence of persistent infection included discharge from the surgical site, wound dehiscence, macroscopic or microscopic suppuration, or a positive bacterial culture obtained from a tissue or implant sample. Radiographic criteria for suspected persistent infection included periosteal reaction, bone lysis, implant loosening without a mechanical cause, and impaired fracture healing without an identifiable cause.
Statistical analysis
Data from each dog’s medical record were managed in Excel (Microsoft Corp) and transferred to JMP Pro predictive analytics software (version 16.0.0; SAS Institute Inc) for further analysis. Descriptive statistics were performed to assess data distribution, and continuous data were reported as median (range). Data normality was assessed on visual inspection of histograms and confirmed by Shapiro-Wilk tests. Nominal or binomial data were tested for association using Pearson χ2 tests, and ordinal and continuous data were tested with Wilcoxon rank sum tests. Multivariable analysis was performed to assess confounders using a multivariable logistic regression analysis model. Factors with a P < .20 in univariable model were included and further refined using backward stepwise model selection. Likelihood ratio tests were performed to construct the final model, retaining all factors with P < .10. Odds ratios and 95% CIs were reported for variables significantly associated with the outcome. Significance was set at P < .05 for all tests.
Results
Eighty-four implantations of antibiotic-impregnated P407 hydrogel were identified in 76 dogs. Forty-two dogs were excluded from the study because of the absence of SSI (n = 34), wound care associated with soft tissue trauma (2), a soft tissue procedure (1), or loss of follow-up (5). Thirty-four dogs (34 procedures) were included in the analyses.
Signalment
The median age of the 34 dogs at presentation was 59 months (range, 4 to 171 months). There were 16 castrated males, 12 spayed females, 5 sexually intact males, and 1 sexually intact female. The breeds included 12 mixed-breed dogs, 8 German Shepherd Dogs, 2 Labrador Retrievers, 2 Australian Shepherds, 2 Chihuahuas, 2 Saint Bernards, and of 1 each of the following breeds: Border Collie, German Wirehaired Pointer, Greyhound, Great Dane, Mastiff, Newfoundland, Pitbull Terrier, and Rottweiler. The median weight was 32.2 kg (range, 2 to 83 kg). Twenty-six dogs had an optimal or overweight body condition score (4 to 6).26 Eight dogs had a body condition score ≥ 7, and 2 dogs had a body condition score ≤ 3.
Surgical history and clinical presentation
The median number of surgeries performed on the affected site before P407 hydrogel implantation was 2 (1 to 5). Nineteen initial procedures performed before P407 hydrogel implantation were elective (9 TPLO, 4 THR, 3 medial patellar luxation, 2 carpal arthrodesis, and 1 femoral head ostectomy), and 15 initial procedures were performed after trauma (11 fractures, 2 tarsal arthrodeses, and 2 carpal arthrodeses). Twenty-one procedures were lower extremity procedures (12 stifles, 4 carpi, 2 radii/ulnas, 2 tarsi, and 1 tibia), 11 were upper extremity procedures (4 femurs, 5 hips, and 2 humeri), and 2 involved the axial skeleton (1 ilium and 1 lumbar vertebra). Twenty-seven dogs had 2 or more of the following clinical signs: fever, swelling, heat, drainage, joint effusion, or limited joint range of motion with no other recognized cause. Four dogs had joint fluid analysis performed, and 3 dogs had an increased neutrophil count (> 104/dL). Positive cultures were obtained from bone or joints in 31 dogs. Early onset of infection was documented in 12 dogs, while 22 dogs presented with delayed onset of infection.
Radiographic findings
Radiographs acquired before P407 hydrogel implantation were available for 32 dogs. Two dogs did not have radiographs performed. Twenty-two of 32 dogs had radiographic evidence of osteomyelitis, including periosteal proliferation, osteolysis, implant loosening/failure, and soft tissue swelling, and 10 dogs had no radiographic signs of osteomyelitis. Two of these dogs had the following radiographic changes consistent with an inflammatory process: joint effusion and soft tissue swelling. Two dogs only had radiographic evidence of implant loosening (n = 1) or failure (1). The remaining 6 dogs had no radiographic abnormalities.
Bacterial culture and sensitivity
Culture samples were collected prior to surgery and intraoperatively at the time of P407 hydrogel implantation in all dogs and included samples of purulent material associated with the infected site, tissue sampled from the infected site or implants removed from the infected site. Thirty-one dogs had a positive culture with 1 or more bacterial species. Twenty-seven dogs cultured a single bacterial species, as follows: 18 isolates of Staphylococcus pseudintermedius, 3 isolates of coagulase-negative Staphylococcus spp, and 1 isolate each of Pseudomonas aeruginosa, Enterococcus spp, Pasteurella spp, Staphylococcus schleiferi, Staphylococcus aureus, and Actinomyces spp. Four dogs had complex infections, which included 2 dogs that underwent open reduction internal fixation of fractures. In 1 open reduction internal fixation, P aeruginosa and Escherichia coli were isolated, and S pseudintermedius with Streptococcus viridians were isolated from the second fracture. Other bacteria isolated included the following: Staphylococcus spp and Enterococcus faecalis after an infected partial tarsal arthrodesis, Proteus mirabilis, E faecalis, and S pseudintermedius after cemented THR. Twelve isolates of S pseudintermedius and 2 isolates of coagulase-negative Staphylococcus spp were methicillin and multidrug resistant. Three dogs had no growth on the sample collected, despite evidence of clinical signs associated with bacterial infection (n = 3), radiographic osteomyelitis (3), or gross osteomyelitis documented in the surgical report (2).
Surgical procedures
Metallic implants were present in 34 dogs before P407 hydrogel implantation. Surgical implants were removed at the time of P407 hydrogel implantation in 20 dogs, replaced in 12, or retained in 2. Gross osteomyelitis was documented in the surgery report in 19 dogs.
Antimicrobial-impregnated poloxamer 407 hydrogel solution implantation
Vancomycin was the antimicrobial eluted in the P407 hydrogel solution for all dogs included in the study. The antimicrobial choice was based on the results of culture and sensitivity report and the antibiogram at the authors’ institution. A final concentration of 20 mg/mL of vancomycin hydrochloride in P407 hydrogel was administered in all dogs.
One gram of vancomycin hydrochloride that was FDA approved for IV administration was reconstituted to a concentration of 200 mg/mL by adding 5 mL of sterile water (Hospira). The antimicrobial-impregnated P407 hydrogel solution was then compounded by mixing 2.5 mL of the 200 mg/mL vancomycin hydrochloride solution with cool (4 °C) liquid form of 22.5 mL of 30% P407 hydrogel solution (Medisca) that was FDA approved for use as a drug excipient. This volume ratio was selected to maintain a final concentration of P407 hydrogel ranging between 20% to 35% to maintain ideal gelation temperatures in the perioperative period as previously reported.27 The suspension was gently mixed using two 60-mL syringes connected by a 3-way stopcock until a semiopaque, homogenous solution was achieved. The P407 hydrogel was prepared the morning of surgery and refrigerated at a standard temperature of 4 °C until implantation.
In all dogs, the P407 hydrogel was placed in the surgical site immediately before closure. The total volume of P407 hydrogel implanted varied on the basis of available anatomic space. All incisions were closed in a routine fashion.
Systemic antimicrobials
The median duration of antimicrobial administration was 40 days (10 to 138 days). For dogs in which implants were present after P407 hydrogel implantation, the median duration was 46 days (10 to 138 days). Systemic antimicrobial choice was guided by the results of bacterial culture susceptibility results.
Outcome
The median duration for follow-up was 363 days (15 to 1,339 days). No complications directly related to P407 hydrogel placement were identified. At final follow-up, infections were cleared in 26 of 34 (77%) dogs. These dogs had no clinical, cytologic, or radiographic evidence of osteomyelitis and reported satisfactory limb use during normal activity on phone interviews. Eight dogs had unsuccessful outcomes. One dog underwent implant explantation 16 weeks after revision surgery, refractured the affected limb 2 days later, experienced severe vasculitis leading to amputation, and was euthanized 1 week later after it was presented for the following progressive neurologic signs: obtundation, disorientation, and nonambulatory tetraparesis with cervical pain. One dog underwent explantation after recurrence of SSI 20 weeks after P407 hydrogel implantation. One dog had recurrence of SSI and was euthanized. One dog reportedly had poor limb function at home and persistent drainage from the surgical site and was euthanized 1 month after gel administration. One dog underwent explantation of an implant 4 months after revision surgery, developed severe multilobar aspiration pneumonia, and was euthanized 1 month after explant surgery. One dog underwent forelimb amputation secondary to nonunion, implant failure, and fracture 4 months after revision surgery. One dog was persistently lame with pain associated with a nonunion of the radius. One dog had persistent low-grade osteomyelitis and lameness of the operated limb, despite long-term systemic antimicrobial administration.
Analysis of risk factors for unsuccessful infection treatment
Demographics, perioperative variables, diagnostic findings, number of clinical signs, duration of clinical signs, duration of systemic therapy, and treatment outcomes were evaluated using univariable analysis (Table 1). Number of surgeries performed before P407 hydrogel implantation and multidrug or methicillin resistance were retained in the final model for multivariate logistic regression analysis. The number of surgeries performed before P407 hydrogel implantation (P = .005; unit OR, 0.25; 95% CI, 0.08 to 0.81) and presence of a multidrug- or methicillin-resistant infection (P = .042; OR, 0.13; 95% CI, 0.01 to 1.14) were found to be significantly associated with an increased risk of treatment failure.
Results of univariable analysis of case demographics and variables possibly associated with treatment outcome after vancomycin-impregnated poloxamer 407 gel implantation.
| Variable | Infection cleared (n = 26) | Recurrent infection (n = 8) | P value |
|---|---|---|---|
| Body condition score (1–9) | 5 (3–9) | 5 (4–7) | .419 |
| Thin (1–3) | 2 | 0 | — |
| Ideal (4–5) | 17 | 7 | — |
| Overweight or obese (6–9) | 7 | 1 | — |
| Body weight (kg) | 30 (2–83) | 31 (23–57) | .542 |
| Number of surgeries before gel administration | 1 (1–4) | 3 (1–5) | .005* |
| Duration of clinical signs before gel administration (d) | 37.5 (0–581) | 81 (0–422) | .183 |
| Days from the first surgery to gel administration | 212 (8–1465) | 273 (11–714) | .814 |
| Age at gel administration (mo) | 59.5 (4–158) | 57 (24–171) | .919 |
| Duration of systemic antibiotic therapy (d) | 34.5 (10–91) | 46 (21–138) | .086 |
| Breed | — | — | .593 |
| Surgery after trauma | 11 | 4 | .702 |
| Type of procedure performed | — | — | .367 |
| Onset of infection | — | — | .319 |
| Acute | 8 | 4 | |
| Delayed | 18 | 4 | |
| Gross osteomyelitis | 17 | 2 | .044* |
| ≥ 2 clinical signs | 19 | 7 | .400 |
| Radiographic osteomyelitis | 15 | 7 | .123 |
| Gender | .756 | ||
| Male | 4 | 1 | |
| Female | 1 | 0 | |
| Male castrated | 11 | 5 | |
| Female spayed | 10 | 2 | |
| Surgical location | .434 | ||
| Upper extremity | 9 | 4 | |
| Lower extremity | 17 | 4 | |
| Positive bacterial culture | 26 | 7 | .629 |
| Multidrug or methicillin resistance | 9 | 6 | .044* |
| Complex infection | 3 | 1 | .942 |
| Implant present | 8 | 6 | .027* |
| Infection susceptible to vancomycin | 20 | 6 | .281 |
Median values are reported as median with range.
*Statistically significant results.
Discussion
In the current study, the success rate of clearing an orthopedic surgical site infection was 77%. Two factors were associated with an increased risk of treatment failure: a higher number of surgical procedures before hydrogel administration and the presence of multidrug or methicillin resistance. The chance of treatment success decreased by approximately 25% with each additional surgery performed before P407 hydrogel implantation. This can be due to compromise of the biologic environment (devascularization and fibrosis) resulting from surgery. The importance of preserving vascular supply, soft tissue envelope, periosteum, and endosteum to optimize fracture healing has been emphasized in the scientific literature.28 A recent study29 suggested that a reoperated fracture site had lower periosteal and endosteal blood flow values compared to a nonoperated limb. Decreased blood flow could negatively impact both bone healing and the delivery of systemically administered antibiotics to the fracture site. Multiple procedures requiring the insertion of orthopedic implants may also predispose the operated site to an increased risk of introducing additional bacterial contaminants.30
The second risk factor associated with treatment failure was the presence of a multidrug- or methicillin-resistant infection. Treatment failure after vancomycin-impregnated P407 hydrogel administration was 7.69 times more likely when a multidrug- or methicillin-resistant organism was present. Several orthopedic SSI studies reported a higher risk of treatment failure in cases with multidrug-resistant infections compared to those infected with antimicrobial-sensitive bacteria.31,32 The treatment of multidrug-resistant infections often requires extended systemic antimicrobial therapy and results in increased morbidity, increased number of surgical procedures, greater financial burden, and prolonged hospitalization.31,32 This is especially difficult in cases infected by virulent strains of biofilm-producing bacteria such as methicillin-resistant S pseudintermedius for which monotherapy with systemic antimicrobials is often ineffective.33 Treatment of these infections requires a higher minimum concentration of antimicrobials (minimal biofilm eradication concentration) that are able to penetrate biofilm (such as vancomycin); however, residual biofilm can still be observed.33 In humans, the use of local antimicrobials appears to be advantageous by achieving higher concentrations of antimicrobials in the local environment.8 Studies including a control group of animals are required to elucidate whether the use of local antimicrobial delivery increases the likelihood of treatment success for multidrug-resistant infections.
Implant retention following P407 hydrogel implantation was significantly associated with failure of SSI clearance in univariable analysis, but it was not included in the final model because it did not meet the set P value after backward stepwise selection. This may have been due to implant retention confounding with other factors, such as increased number of surgeries. It is also possible that debridement, lavage, removal of the existing implants, and placement of new implants free of biofilm minimized the risk of persistent infection. A controlled study comparing a population of dogs undergoing implant retention procedures for management of osteomyelitis is required to specifically evaluate the potential beneficial effects of local antimicrobial therapy.
All dogs reported in the current study received vancomycin using P407 hydrogel as a vehicle for local delivery. It is not a routine practice for vancomycin, a critically important antimicrobial, to be used for therapeutic purposes. Antimicrobial stewardship aims to minimize or eliminate mass administration of important antimicrobials in groups of animals, particularly livestock.34 Widespread administration for purposes such as growth promotion or prophylaxis is a key contributor to antimicrobial resistance (AMR).34,35 This is such a concern that use of several antimicrobials for growth promotion was banned in the European Union.36 More recently, antimicrobials, including vancomycin, were deemed critically important to human health and should be reserved for human use.37 There is potential concern for the use of vancomycin in dogs, as this may constitute poor antimicrobial stewardship. However, the contribution of therapeutic antimicrobial use for companion animals to developing AMR in human medicine is unclear and therapeutic use in individual animals has not been found to be a risk or contributor to AMR.34,35 While close contact may raise concern for transmission of resistance from dogs to humans, 1 study exploring the transmission of vancomycin-resistant Enterococcus in canines found phylogenetic linkage for AMR between dogs and humans to be limited.38
The One Health initiative describes optimal use of antimicrobials in both human and veterinary medicine as therapeutic in purpose, with better control of the types and amounts of antimicrobials in use, and a decrease in the numbers of resistant bacteria that are allowed to be placed into the environment.34 Most dogs described in this report were at an increased risk for treatment failure due to a compromised biologic environment and the presence of a multidrug-resistant infection. A large number of the multidrug-resistant infections the authors’ institution are due to methicillin-resistant Staphylococcus or Enterococcus spp with susceptibility limited to vancomycin, amikacin, and rifampin. The alternative to escalated therapy for these animals included continued prolonged systemic therapy accompanied with prolonged morbidity and variable outcomes, or amputation of the affected limb. Systemic antimicrobials have varying success in cases of orthopedic SSI in the presence of an implant, with reported rates at approximately 70%.39 In light of this, a single dose of a local antimicrobial may be an important option to explore to improve standard of care and promote antimicrobial stewardship.
No adverse drug events related to vancomycin-impregnated P407 hydrogel implantation were observed. This may support that P407 hydrogel is a safe vehicle for local drug administration in dogs as demonstrated in previous studies.40,41 However, the systemic and local effects of vancomycin concentrations were not investigated. In vitro studies demonstrated that high local antimicrobial concentrations of vancomycin were cytotoxic.42,43 This cytotoxic effect caused by the local administration of vancomycin has not been evaluated in vivo; thus, future studies focused on osteoclastic activity and time to radiographic osteosynthesis following vancomycin-impregnated P407 hydrogel implantation are needed. Nephrotoxicity and increased risk for acute kidney injury has been demonstrated in humans as a result of prolonged use and increased doses of vancomycin.44 A pharmacologic study evaluating the systemic absorption of vancomycin after local administration in small animals and its potential toxicity should be considered. Additionally, an FDA-approved vancomycin- or amikacin-impregnated gel for local antimicrobial therapy is not currently available for use in veterinary medicine, and the gels were compounded in the authors’ institution under sterile conditions. Veterinarians should adhere to compounding regulations and be aware that pharmacokinetic properties may differ between compounded and FDA-approved products. The current study had limitations. A small population of dogs was evaluated over a relatively short period. All dogs were evaluated at least 180 days following initial infection; however, a prospective study at 1 year after conclusion of all therapies in a larger population may yield different results. Owner compliance in administration of systemic antimicrobials was unknown, and thus inconsistent dosing that affected treatment outcomes is possible. This study did not include a control population of animals treated for orthopedic SSI without local antimicrobials.
Lastly, the volume of vancomycin-impregnated P407 hydrogel administered to each surgical site was not standardized. Varying doses between dogs may have resulted in concentrations of vancomycin that were lower than minimum eradication concentrations and influenced outcomes. A pharmacologic study to develop a standardized dosing to ensure adequate concentrations can be considered.
In conclusion, the local administration of vancomycin-impregnated P407 hydrogel had a high success rate with no gross adverse events in this population of animals. Outcomes were negatively impacted by the presence of multidrug or methicillin resistance and, to a lesser extent, by an increased number of surgeries before gel implantation.
Acknowledgments
The authors have nothing to declare.
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Appendix
Script for long-term telephone follow-up questionnaire:
Confirm patient’s identity, date of procedure to debride surgical site infection and administer poloxamer gel to treat the surgical site infection, and the affected anatomic site.
Did your pet develop any clinical signs associated with surgical site infection after last follow-up (pain, swelling, redness, or discharge)?
If so, when and what additional treatment was prescribed?
How would you describe your pet’s limb use during normal activity after last follow-up and currently (if patient still alive)?
