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CLINICAL RESEARCH

How Successful Is Antibiotic Treatment for Superficial Surgical Site Infections After Open Fracture? A Fluid Lavage of Open Wounds (FLOW) Cohort Secondary Analysis

Prada, Carlos MD, MHSc; Tanner, Stephanie L. MS; Marcano-Fernández, Francesc A. MD, PhD; Bzovsky, Sofia MSc; Schemitsch, Emil H. MD, FRCSC; Jeray, Kyle MD; Petrisor, Brad MD, MSc; Bhandari, Mohit MD, PhD, FRCSC; Sprague, Sheila PhD, on behalf of the FLOW Investigators

Author Information
Clinical Orthopaedics and Related Research: December 2020 - Volume 478 - Issue 12 - p 2846-2855
doi: 10.1097/CORR.0000000000001293

Abstract

Introduction

No clear guidelines exist regarding the best approach to treat superficial surgical site infections (SSIs) after an open fracture. Current strategies range from nonoperative management with antibiotics and dressing changes to immediate surgical irrigation and débridement. This variation in treatment practices is probably influenced by the controversies generated by (1) a lack of consensus on clear infection-definition guidelines; [20] (2) the orthopaedic community’s belief that the CDC SSI definition might not appropriately fit surgeons’ needs because of its proposed time frame and the need to differentiate between deep and organ/space infections, and (3) the surgeon’s inability to differentiate the different SSI subtypes that might be specifically challenging in some anatomical regions (such as, the ankle) [2, 18, 20]. Current guidelines have focused almost exclusively on periprosthetic infections and deep or organ/space infections [7, 15, 17], which have been extrapolated to fracture-related infections. This lack of consensus and low-quality evidence on prognostic factors and poor infection definition make it difficult to predict how successful nonoperative treatment will be once a superficial SSI has been diagnosed. Conversely to what happens when a deep or organ/space infection is diagnosed [10, 17]—where there is consensus—there is limited agreement on how to treat patients who are diagnosed with a superficial SSI after an open fracture.

Having a better understanding of how successfully antibiotic treatment resolves a superficial SSI after an open fracture and identifying the risk factors for persistent infection could provide clinicians and patients with better prognostic information and important insights about the appropriateness and results of treating a superficial SSI with antibiotics in patients with open fracture wounds. Research to address this current gap in the evidence may also help clinicians and patients make decisions about how to counsel participants who present with this condition during the follow-up period.

Therefore, using data from the Fluid Lavage of Open Wounds (FLOW) trial [8], we asked: (1) What proportion of patients with superficial SSIs after open fracture treatment developed persistent infection after nonoperative treatment (that is, treatment with antibiotics alone)? (2) What risk factors are associated with SSIs that do not resolve with nonoperative (antibiotic) treatment? Additionally, as a secondary objective, we planned to analyze the microbiological information about participants wound cultures, when these were available, and the proportion of positive cultures for patients whose SSIs were not resolved by antibiotics alone.

Patients and Methods

FLOW Trial

This is a secondary (retrospective) analysis of the dataset of FLOW trial, an international, blinded, randomized controlled trial that used a 2-by-3 factorial design to evaluate the effects of high- versus low- versus very-low- (gravity) flow irrigation pressures, and soap versus normal saline solutions on reoperation rates among patients with an open fracture [8]. This large cohort of open fracture patients (n = 2445) provided an ideal opportunity to address relevant clinical questions in this population.

Patients enrolled in the FLOW study were followed for 12 months after their index surgical procedures for an open fracture at 1, 2, 6 weeks as well as 3, 6, 9, and 12 months. The primary endpoint was reoperation, defined as surgery that occurred within 12 months after the initial procedure to treat an infection at the operative site or near it, manage a wound healing problem, or promote bone healing. Nonoperatively managed complications were considered as secondary endpoints. The FLOW study was approved by the ethics committees at the coordinating center, McMaster University (REB: 08-268), and at each participating center. All patients provided written informed consent before enrollment. The FLOW trial was registered at clinicaltrials.gov (Clinical Trials Identification Number: NCT00788398).

Patient Population

All patients identified with a superficial SSI by the treating surgeon and treated nonoperatively with antibiotics alone or with antibiotics and dressing changes at the time of diagnosis were included. As part of the FLOW trial, a central adjudication committee confirmed both the occurrence and the type of SSI according to the current CDC National Healthcare Safety Network’s reporting criteria (superficial, deep or organ/space [Table 1] [3]; however, the adjudication committee did not consider the time frame criteria when categorizing the SSIs [30-days for a superficial SSI; 90-days for a deep or organ space SSI]).

Table 1. - Adjudication committee criteria for all three types of surgical site infections (SSIs)
Type of infection Criteria
Superficial

An infection that involves only the skin or subcutaneous tissue AND at least one of the following:

  • Purulent drainage, with or without laboratory confirmation, from the superficial incision.

  • Organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial incision.

  • One of the following signs or symptoms: pain or tenderness, localized swelling, redness, or heat and superficial incision is deliberately opened by the surgeon, unless incision is culture-negative.

Deep

An infection that involves deep soft tissues (such as, fascial and muscle layers) AND at least one of the following:

  • Purulent drainage from the deep incision but not from the organ/space component of the surgical site.

  • A deep incision spontaneously dehisces or is deliberately opened by the surgeon when the patient has at least one of the following signs or symptoms: fever (> 38° C), localized pain, or tenderness, unless the site culture is negative.

  • An abscess or other evidence of infection involving the deep incision found on direct examination, during reoperation, or by histopathologic or radiologic examination.

Organ/Space

An infection that involves any part of the anatomy (such as, organs or spaces), other than the incision, which was opened or manipulated during an operation AND at least one of the following: 

  • Purulent drainage from a drain that is placed through a stab wound into the organ/space.

  • Organisms isolated from an aseptically obtained culture of fluid or tissue in the organ/space.

  • An abscess or other evidence of infection involving the organ/space that is found on direct examination, during reoperation, or by histopathologic or radiologic examination.

When interpreting these criteria, any infections that were superficial to the fascia were considered superficial SSI and any infections that were deep to the fascia were considered as either deep SSI or organ/space SSI.

Patient Characteristics

Of the 2445 eligible patients in the FLOW trial, 168 had a superficial SSI. In all, 83% (139 of 168) of patients with a superficial SSI were initially managed with either antibiotics alone or with antibiotics and dressing changes and were, therefore, included in this analysis (Fig. 1). Seventeen percent (29 of 168) of patients received another treatment (surgery, only dressings, or the information was missing) and were excluded from the analysis. The 139 patients included in the analysis were grouped into two categories: (1) 97 participants whose treatment with antibiotics alone resolved the superficial SSI and (2) 42 participants whose treatment with antibiotics alone did not resolve the SSI (defined as undergoing surgical management or the SSI being unresolved at latest follow-up [12-months post-fracture for the FLOW trial]). Of the participants whose treatment with antibiotics alone resolved the SSI, 92% (89 of 97) had complete follow-up, 6% (6 of 97) were lost to follow-up before 12 months, 1% (1 of 97) withdrew consent from the study before 12 months, and 1% (1 of 97) experienced mortality before 12 months. Of the participants whose treatment with antibiotics alone did not resolve the SSI, 90% (38 of 42) had complete follow-up, 7% (3 of 42) were lost to follow-up before 12 months, and 2% (1 of 42) withdrew consent from the study before 12 months. Most patients included in the analysis were males (71%), in their 40s, who sustained an open fracture because of a motor-vehicle collision (MVC) accident (53%) (Table 2).

F1
Fig. 1:
A flow diagram of the included participants in this secondary analysis cohort is shown here.
Table 2. - Participant characteristics
Patients with superficial SSI successfully treated with antibiotic (n = 97) Patients with superficial SSI with persistent infection despite antibiotic treatment (n = 42) Patients with superficial SSI treated initially nonoperatively (n = 139)
Age, mean (SD) 48 ± 18 47 ± 17 48 ± 17
Sex, % (n)
 Male 73 (71) 67 (28) 71 (99)
 Female 27 (26) 33 (14) 29 (40)
Current smokersa, % (n) 35 (34) 27 (11) 32 (54)
Diabetic, % (n) 7 (7) 10 (4) 8 (11)
Mechanism of injury, % (n)
 Motor-vehicle collision 53 (51) 52 (22) 53 (73)
 Falls (standing or height) 34 (33) 31 (13) 33 (46)
 Direct trauma (penetrating or blunt) 8 (8) 7 (3) 8 (11)
 Other mechanisms 5 (5) 10 (4) 7 (9)
Gustilo type, % (n)
 Type I 14 (14) 14 (6) 14 (20)
 Type II 46 (45) 41 (17) 45 (62)
 Type IIIA 29 (28) 29 (12) 29 (40)
 Type IIIB 10 (10) 17 (7) 12 (17)
Location of fracture, % (n)
 Upper extremity 10 (10) 7 (3) 9 (13)
 Lower extremity 90 (87) 93 (39) 91 (126)
 Hours to first incision from injury, median (IQR) 9 (6 to 15) 11 (7 to 14) 9 (6 to 15)
Fracture patterns, % (n)
 Simple patterns (spiral, oblique or transverse) 42 (41) 31 (13) 39 (54)
 Complex patterns (comminuted or segmental) 58 (56) 69 (29) 61 (85)
Surgeon expertise, % (n)
 Surgeon 53 (51) 57 (24) 54 (75)
 Resident 37 (36) 38 (16) 37 (52)
 Fellow 10 (10) 5 (2) 9 (12)
Time to superficial SSI diagnosis since initial injury (in days), median (IQR) 25 (13 to 44) 31 (13 to 69) 27 (13 to 48)
Wound area in cm2, median (IQR) 6 (1 to 20) 7 (2 to 40) 6 (1 to 23)
aOne participant from the group with persistent infection despite antibiotic treatment did not have information about his smoker status; SSI = surgical site infection; IQR = interquartile range.

Primary Outcome: Use of Antibiotics to Resolve Superficial SSIs

We determined the proportion of patients whose superficial SSI resolved with antibiotics. At each follow-up visit, the attending physician was asked to indicate on the study infection form what the outcome of the SSI was: (1) resolved, (2) resolved with subsequent impairment, (3) ongoing, or (4) fatal. The attending physician used their discretion to choose the final outcome. Also, we determined the proportion of patients who needed an operation or whose SSI was ongoing at 12 months.

Secondary Outcomes

Factors Associated with Antibiotics Not Resolving Superficial SSIs

We conducted a logistic binary regression analysis to identify potential risk factors for antibiotic therapy not resolving superficial SSIs. Based on biologic rationale and previous evidence, we identified potential factors a priori [12, 16, 23]. We theorized that persistent infection after superficial SSI antibiotic treatment would be associated with fracture grade (greater proportion of persistent infection for more severe fracture types), and other prognostic variables such as: age, fracture location, time from open fracture occurrence to initial surgery and to SSI diagnosis, the need to perform some degree of tissue débridement, presence of diabetes, and smoking status.

When selecting factors for each analysis, we ensured that there were at least five events for each factor to avoid having an overfitted or unstable model [26]. The number of factors included was based on the number of patients within this secondary analysis cohort who did not have their superficial SSI resolved with antibiotics. As 42 participants fulfilled the aforementioned criteria, eight pre-identified factors (corresponding to eight levels) were included in our final model. The prognostic variables included: age; time to superficial SSI diagnosis since initial injury (measured in weeks); fracture severity (measured by Gustilo-Anderson classification and grouped as less severe [Gustilo I and II] and more severe [Gustilo III A to III C]); smoking status (grouped as never smoked or quit smoking versus current smokers); time from injury to first operation (measured in hours); and need of skin, muscle, or bone débridement (grouped as no need for débridement versus any amount of débridement).

Of note, we were underpowered to detect any differences related to the participants’ diabetes status (nine patients in the superficial SSI cohort had diabetes) and fracture location (there were only 13 upper extremity fractures versus 126 lower extremity fractures in the conservatively treated superficial SSI cohort) so we conducted the logistic regression without including these variables that we had initially planned to assess.

Microbiological Profile

Information regarding the growth of identified pathogens and the proportion of positive cultures was described for patients whose SSIs were resolved with antibiotics and for patients who SSIs were not resolved by antibiotics alone. Superficial wound swabs were done in some patients who underwent antibiotic treatment. For the patients who underwent a reoperation because of antibiotics not resolving the infection, results for intraoperative cultures were reported when available. Twenty-six percent (25 of 97) of patients who had their SSIs resolved with antibiotic treatment underwent wound culture.

Statistical Analysis

Patients were the unit of analysis. Variables were tested for normal distribution using the Shapiro-Wilk test. For normally distributed continuous variables, we used means as the central tendency measure and SDs as the measure of spread. For skewed data, we used medians as the central tendency measure and interquartile ranges (IQRs) as the measure of spread. We tested for statistical significance using either nonparametric tests when data were not normally distributed or parametric tests when data were normally distributed. We considered p values less than 0.05 as significant.

Logistic regression analysis was conducted using the previously described prognostic variables and each independent regression coefficient was tested for multicollinearity by computing the variance inflation factor (VIF). Values of VIF exceeding 5 were considered evidence of collinearity [11]. All variables had a value of VIF well below 5, indicating no collinearity. Results from the regression analysis were reported as odds ratios, 95% confidence intervals, and associated p values. All tests were two-tailed with alpha = 0.05.

The data analyses were conducted using SPSS software (version 25, IBM Corp, Armonk, NY, USA) and R (version 3.6.1, R Foundation for Statistical Computing, Vienna, Austria).

Results

Use of Antibiotics to Resolve Superficial SSIs

The antibiotic treatment resolved the superficial SSI in 70% (97 of 139) of patients and did not resolve the SSI in 30% (42 of 139) of patients. Of the 42 patients in whom antibiotic treatment did not resolve the SSI, 90% (38) underwent reoperation for infection and 12% (five) had unresolved infections at final follow-up. Of the patients who underwent reoperation, the most common procedures were irrigation and débridement (68%; 26 of 38) followed by wound coverage procedures for infected or necrotic wounds (26%; 10 of 38), and reoperations for hardware failure, implant exchange or bone graft (45%; 17 of 38). To note, since some patients had more than one procedure performed, the sum of these percentages exceeds 100%.

Factors Associated with Antibiotics Not Resolving Superficial SSIs

After controlling for potential confounding variables such as age, fracture severity, and time from injury to initial surgical irrigation and débridement, superficial SSIs that were diagnosed later in follow-up were associated with antibiotics not resolving the SSI (OR 1.05 [95% CI 1.002 to 1.01] for every week of follow-up; p = 0.04). For those participants who developed a superficial SSI within 30 days of their open fracture wound, 72% (55 of 76) had their infection resolved with antibiotics. When the SSI occurred between 31 to 90 days, 71% (35 of 49) had their infection resolved with antibiotics. Conversely, when analyzing the 14 participants whose SSI were diagnosed 90 days after their open fracture wound, just 50% (seven) were resolved with antibiotic treatment. Age, fracture severity, smoker status, need of skin, muscle or bone débridement, and time from injury to initial surgical irrigation and débridement were not associated with antibiotics not resolving superficial SSIs (Table 3).

Table 3. - Factors associated with antibiotics not resolving superficial SSIs (n =139, 42 events)
Independent variable Odds ratio (95% CI) p value
Age (change per year) 0.99 (0.97 to 1.01) 0.34
Gustilo Grade 1.23 (0.54 to 2.80) 0.63
 Type IIIA-IIIB vs. Type I-II
Smoker status 1.85 (0.78 to 4.42) 0.16
 Current smokers vs. non-smokers/previous smokers
Skin débridement 0.67 (0.26 to 1.68) 0.39
 Any amount of débridement vs. none
Muscle débridement 1.15 (0.49 to 2.67) 0.75
Any amount of débridement vs. none
Bone débridement 0.71 (0.32 to 1.59) 0.40
 Any amount of débridement vs. none
Time to surgery (change per minute) 1.00 (0.999 to 1.001) 0.87
Time to SSI diagnosis (change per week) 1.05 (1.002 to 1.095) 0.04

Microbiological Profile

Of the 26% (25 of 97) participants with a superficial SSI that was solved by antibiotics and who had their wounds cultured, 64% (16 of 25) had a microorganism(s) identified. Single pathogen infections by Staphylococcus spp. were found in 56% (nine of 16) participants, which was the leading causative agent. On the other hand, 90% (38 of 42) of the participants in which antibiotics did not resolve the superficial SSI had their wounds cultured. From this group, 50% (19 of 38) had an infection pathogen identified. Polymicrobial infections, present in 37% of patients (seven out of 19), were the leading cause of infection, followed by infection by a single organism (S. aureus) as the second most common bacteriological cause in 26% of patients (five of 19) (Table 4).

Table 4. - Culture and microbiologic details by superficial surgical site infection (SSI) by antibiotic treatment results
Superficial SSI treatment group % with cultures taken (n) % of cultures taken identifying pathogen (n) Main pathogen(s) identified % (n)
Most common Second most common
Successfully treated (n = 97) 26 (25) 64 (16 of 25) 56 (9 of 16) Staphylococcus species 25 (4 of 16) polymicrobial
Unsuccessfully treated (n = 42) 90 (38) 50 (19 of 38) 37 (7 of 19) polymicrobial 26 (5 of 19) S. aureus
Total (n = 139) 45 (63) 56 (35 of 63) 46 (16 of 35) 26 (9 of 35)

Discussion

Many studies report the incidence and prevalence of SSIs after open fractures; however, there is limited information on the best treatment methods and subsequent outcomes of superficial SSIs in patients with open fractures, as well as on factors associated with persistent infection following nonoperative treatment with antibiotics. Having a better understanding of how successfully antibiotic treatment resolves a superficial SSI after an open fracture and identifying the risk factors for persistent infection could provide clinicians and patients with better prognostic information and important insights on how to treat a superficial SSI in patients with open fracture wounds. The FLOW trial was conducted to analyze the primary endpoint of reoperation within 12-months after the index surgery for the promotion of wound or bone healing or the treatment of a wound infection. The secondary analysis was primarily intended to obtain information about antibiotic treatment results when treating superficial SSIs and to identify potential risk factors that might result in antibiotics not resolving superficial SSIs.

Limitations

One of the limitations in this secondary analysis is that there were only 42 participants whose superficial SSI was not resolved with antibiotic treatment and only 38 of those underwent surgery. For this reason, we were underpowered to perform subgroup analyses and include more factors in our logistic regression. To have performed subgroup analyses by grouping variables as the time to superficial SSI diagnosis from initial surgery in different timeframes (for example, < 30 days, 30-90 days, > 90 days) would not have been possible. Additionally, some important factors that have been previously associated with an increased risk of developing SSI after an open fracture, such as being diabetic or having a lower extremity open fracture [12, 22], could not be evaluated for the same reason. Moreover, the follow-up period length was only 12 months, which in the context of SSIs in orthopaedics may not be sufficient because it is possible that the infections considered resolved may have recurred with a longer follow-up period. However, as most infections were deemed resolved and participants completed 12-months follow-up in more than 90% of times, we believe that our findings, although they should be considered with caution, are useful and probably are a good reflection of local infection control.

Lastly, only 26% (25 of 97) of patients who had their SSIs resolved with antibiotic treatment had their wounds cultured. This probably reflects the low reliability that superficial wound cultures have shown when taken from the superficial wound [4] so this microbiologic profile must be interpreted with caution.

Use of Antibiotics to Resolve Superficial SSIs

Within our group of participants who were diagnosed with a superficial SSI and whose infections the treating surgeons deemed should be treated with antibiotics, we found that treatment with antibiotics alone did not resolve the SSI in 42 participants. These patients might have been either incorrectly categorized as superficial SSIs, and so represent deep infections that needed a different treatment approach, or they depict superficial SSIs with a microorganism that was not appropriately treated or was resistant to current antibiotic schemes. Within our group of participants who were diagnosed with a superficial SSI and whose infections the treating surgeons deemed should be treated with antibiotics, our results showed that a high proportion of infections resolved. Within this population, we found that almost 70% of superficial SSIs after an open fracture resolved when treated with antibiotics. One study found that 54% of SSIs resolved when treated with antibiotics alone after open and closed tibial fractures [6]. However, those authors did not report on the proportion of infections resolved with antibiotics by SSI type. The lack of data pertaining to the proportion of infections resolved with antibiotic treatment by SSI type is probably influenced by the lack of agreement and definition within the orthopaedic community on orthopaedic SSI definitions and treatment options. Additionally, in our cohort of patients, 83% (139 of 168) of participants who were diagnosed with a superficial SSI were initially managed with antibiotics; however, 11% of participants (19 of 168) with superficial SSIs were initially managed operatively, which underscores the lack of a standardized approach among surgeons. Most of the available evidence on this issue has focused on bone infections that have been classified as fracture-related infections [19, 25], deep or organ/space infection [13], or osteomyelitis [1, 14, 27]. For these types of infections there is some agreement on how to manage them.

Factors Associated with Antibiotics Not Resolving Superficial SSIs

Time to superficial SSI diagnosis from the time of initial injury was the only factor associated with a higher odds of antibiotics not resolving the SSI. Other plausible prognostic factors that we expected to be associated with increased odds of persistent infection after antibiotic treatment, such as fracture severity and pattern, wound size, and need for débridement, were not found to be associated with persistent infection [12]. Our finding that increased time from initial injury to SSI diagnosis was associated with a higher odds of antibiotic treatment not resolving the SSI may be explained by the fact that some of the superficial SSIs that were diagnosed later were not truly superficial (even though they presented as such). There is a possibility that in such cases these SSIs may have progressed over time and may have actually been deep or organ/space in nature, but clinically expressed as a superficial SSI. Interestingly, the subgroup of patients who had what was classified as a superficial SSI after 90 days had a lower chance of infection resolution with antibiotics. This should make orthopaedic surgeons suspicious when facing what seems to be a late superficial SSI (after 3 months) during the follow-up. It is possible that even when clinical symptoms and signs suggest a superficial infection, an important group of these may in fact be deep or organ/space infections if there has been a long period since the open fracture wound occurred; in these patients antibiotic treatment would not be the best option.

Our findings suggest that when superficial SSIs are diagnosed after an open wound fracture, antibiotic treatment could be generally a good management alternative, especially when infections occur early in the follow-up. Further research on diagnostic tools to help differentiate between superficial and deep SSIs and cohorts with longer follow-up is needed.

Microbiological Profile

Regarding the microbiological profile, even though it is known that superficial wound swabs are somewhat inaccurate [5], the microbiological profile in this study was similar to what has been reported previously [21, 24], with Staphylococcus spp. being the leading organism identified on cultures followed by polymicrobial infections. Fifty percent of the individuals who underwent surgery for their SSI had a positive culture despite having received previous antibiotic treatment, which is consistent with previous evidence [9]. Infection progression and the opportunity to obtain different intraoperative bone and deep soft tissue samples may have allowed us to identify a high proportion of this organism.

Conclusions

Our secondary analysis of prospectively collected FLOW data suggests that antibiotics alone can be an appropriate treatment option when dealing with superficial SSIs after an open fracture wound, especially when these are promptly diagnosed. The later the SSI is diagnosed, the lower the chances are of achieving infection resolution with antibiotics alone. This is possibly because the infections are not truly superficial, so eradication of bacteria seems more unlikely without adding supplementary measures (such as, irrigation and débridement). Further research with a focus on the follow-up period in this population is needed to better identify the natural history of this complication and the effect of different treatment alternatives. Longer follow-up cohorts might help us to determine if these infections are resolved or if they lie dormant or remain subclinical. This study and further research on this topic might help clinicians during the treatment decision-making process when treating superficial SSIs after open wound fractures.

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