Effect of a Single Preoperative Dose of Oral Antibiotic to Reduce the Incidence of Surgical Site Infection Following Below-Knee Dermatological Flap and Graft Repair

Background Surgical site infection (SSI) rates for below-knee dermatological surgery are unacceptably high, particularly following complex flap and graft closures. The role of antibiotic prophylaxis for these surgical cases is uncertain. Objective To determine whether SSI following complex dermatological closures on the leg could be reduced by antibiotic prophylaxis administered as a single oral preoperative dose. Methods A total of 115 participants were randomized to 2 g of oral cephalexin or placebo 40–60 minutes prior to surgical incision in a prospective, randomized, double-blind, placebo-controlled trial at a primary care skin cancer clinic in North Queensland, Australia. Results Overall 17/55 (30.9%) controls and 14/55 (25.5%) intervention participants developed infection (P = 0.525). There was no difference between the study groups in adverse symptoms that could be attributed to high-dose antibiotic administration (P = 1). Conclusion A single oral 2-g dose of cephalexin given before complex below-knee dermatological closure did not reduce SSI.

Despite the importance of this topic, few randomized controlled trials (RCTs) have been published on the use of oral antibiotic prophylaxis in dermatological surgery [17]. The aim of our randomized, double-blind, placebo-controlled trial was to ascertain the effect of a single preoperative oral prophylactic antibiotic dose on SSI following complex below-knee dermatological surgery. lower limb have ranged from 14.75% to 18.18% [13,16]. Below-knee surgery has been shown to have an even higher infection rate [13,16,17]. The reasons for this are unclear, but reduced perfusion pressure in the distal limbs [18], higher tension closures [19], as well as the frequent necessity for complex graft/ flap surgery are postulated reasons.

Methods
More complex skin closures, such as flap and graft procedures, are known also to be independently associated with significantly higher risk of SSI [20].
Large observational prospective studies have shown that flap repair increases the likelihood of infection by 2 to 15 times compared with simple elliptical closure [3,18,20,21]. Graft repair has also been linked to much higher infection rates [3,18,20,21].
Established SSI may require multiple medical visits, can result in poorer cosmetic outcome and significant bacteremic complications [8,17], and also requires several days of treatment with antibiotics. Antibiotic treatment may be associated with unpleasant side effects, allergy, and the development of antibiotic resistance [8]. As a result of indiscriminate antibiotic prescribing, antibiotic resistance is increasing at a dramatic rate, causing significant morbidity and mortality globally [22,23]. A single, high-dose preoperative oral prophylactic antibiotic has been proposed for anatomical sites and dermatological procedures at high risk of SSI [8]. It is suggested that administration of such a single prophylactic dose may be less likely to result in antibiotic resistance than a longer-term course prescribed for established infection, with a resulting reduction in the quantity of antibiotics prescribed overall [17,19,24].
If antibiotic prophylaxis is to be effective, antibiotics should optimally be in the bloodstream and at the operative site at the time of incision [25,26].
The administration of antibiotics within 2 hours prior to incision is associated with the lowest risk of SSI [26].   All data were analyzed using intention-to-treat analysis. Incidence of SSI was compared between intervention and control groups using chi-square test. The difference in infection rate was calculated and presented with 95% confidence interval (95% CI). The number needed to treat for benefit was calculated with 95% CI [29].

Statistical Analysis and Presentation
Statistical analysis and result preparation followed the CONSORT guidelines [28]. Numerical data were described using mean and standard deviation when symmetrically distributed and median and interquartile range when skewed. Categorical data were presented using absolute and relative frequencies.
Eligible nonparticipants were compared with participants using unpaired If SSI was suspected, a swab was taken for microscopy, culture, and sensitivity and a 5-day course of cephalexin (500 mg 4 times a day) was prescribed pending swab results. Each participant was phoned by the study nurse 1 month after surgery to ensure no SSI was inadvertently missed.

Randomization and Blinding
The randomization sequence was gen-  during the study follow-up period. Three participants (2 controls, 1 intervention) were lost to follow-up despite repeated attempts at phone contact. There were no demonstrable differences between the characteristics of the 5 participants who did not complete the study and the 110 who did.

Surgical Site Infection
The main analysis based on available cases at follow-up (Table 3)      rate of 12.5% in the intervention group, although this study was underpowered to produce statistical significance [17].
Our study differed in that we included only below-knee excisions, which are at higher risk than the entire lower limb, and flap and graft surgery, which are at higher infection risk than ellipse excisions.
Other studies examining antibiotic prophylaxis for surgical sites elsewhere have also demonstrated the effectiveness of antibiotic prophylaxis, in contrast with our study. Two RCTs-one involving flap and graft repairs in a dermatological surgery setting [31] and the other involving ear and nose only [32]-confirmed that single-dose oral antibiotic prophylaxis prevented SSI. Although a further RCT involving graft repairs on the nose was underpowered to show a reduction in SSI, graft survival was better for those randomized to antibiotic prophylaxis [33]. A recent meta-analysis of 12 RCTs studying antibiotic prophylaxis in dermatological surgery demonstrated that preoperative antibiotic prophylaxis was effective in preventing SSI and furthermore that single antibiotic use is of adequate efficacy and safety for preventing SSI [34]. It should be noted, however, that only 2 of these RCTs investigated oral antibiotic prophylaxis, with intravenous antibiotics investigated in the remaining 10 studies [34].
In 4 participants with SSI, the infection did not respond to cephalexin. Swabs in 2 cases (1 intervention, 1 control) isolated organisms not sensitive to cephalexin (Pseudomonas aeruginosa in one case, Enterobacter cloacae in the other).
In a further 2 participants (1 control, 1 intervention), 2 organisms were isolated on microscopy and culture: the S aureus found in each case was sensitive to cephalexin but the second organism isolated (P aeruginosa in one case and Streptococcus C in the other) was not sensitive to cephalexin.
Ciprofloxacin was introduced for each SSI not responding to cephalexin, in accordance with swab sensitivity results.

Discussion
The results of this trial did not show any clinically or statistically significant reduction in the rate of SSI from a single dose of cephalexin administered 40-60 minutes before skin incision. There was no increase in adverse outcomes related to antibiotic administration in the intervention group.
These results contrast to the only previously identified study examining the effect of antibiotic prophylaxis in lower limb ellipse skin excisions, which showed a reduction in the incidence of SSI from a similar baseline rate of 35.7% to a

Conclusions
Despite confirmation that the majority of complex belowknee closure SSIs responded effectively to oral cephalexin postoperatively, we were unable to demonstrate that a single preoperative 2-g dose of cephalexin could prevent SSI from occurring.
Infection rates for below-knee surgery are unacceptably high, even in temperate climates. As antibiotic prophylaxis has been shown to be helpful for other dermatological highrisk areas, further research experimenting with different antibiotic prophylactic regimens is worthwhile.
The recruited cases for this study were at particularly high infection risks, and we postulate that this was the reason for the failure of antibiotic prophylaxis in our study. First, the anatomical site studied was below the knee, which has been shown to have higher risk of infection than other anatomical sites [13,16]. Second, only flap and graft surgery was included, which is known to be of higher SSI risk than simpler surgical techniques [20]. Third, the study was conducted in a tropical setting, where infection rates have previously been shown to be increased (8.6% and 11.7% in studies in the Mackay region) [35,36]. The reason for this remains unclear, but might be related to tropical humidity. We hypothesize that a single-dose antibiotic prophylaxis was simply insufficient in dose and duration to prevent SSI in these circumstances.
Minimizing antibiotic dose and duration is an increasingly important focus of research [37]. Given the advantages of prophylactic antibiotics in reducing morbidity, and potentially reducing the total amount of antibiotic prescribed [17], we would recommend that future research investigate other prophylactic regimens, such as larger or multiple pre-or perioperative doses of antibiotic or antibiotic mixed with local anesthetic and injected directly into the wound site preoperatively [38,39].
The strengths of our study were a blind, randomized design with placebo control, a standardized protocol for excision and follow-up, as well as the collection of a large amount of demographic, medical, and excision-related data for comparison of groups.
We must, however, acknowledge some limitations to our study. Infection may have been underreported, with participants presenting to doctors outside the study practice after surgery. Various characteristics influence SSI, and although information on as many variables as possible was recorded, it is difficult to ensure that all possible variables are comparable at baseline. Despite the intention to take swabs for microscopy culture and sensitivity for all cases of clinical SSI, only 21 swabs were taken in 31 suspected SSI cases.
There may also be limitations to generalizing our findings. This study included complex procedures only, and we do not know the effect of this regimen for elliptical excisions albeit that few nasal and aural skin cancers can be effectively excised with an ellipse. The climate in North Queensland is hot and humid, with a mean daily maximum temperature ranging between 24.2°C and 30°C during the summer months and a relative humidity of 75%-79%. The results may not necessarily be generalizable to a temperate climate with a lower baseline infection rate.
The diagnosis of infection, even when guidelines are used, is subjective, and interobserver and intraobserver variation may occur [40]. However, the definition we used is the most widely implemented standard definition of wound infection [27].