The American Academy of Orthopaedic Surgeons’ (AAOS) clinical practice guidelines [4] defined obesity as a moderate-strength criteria for increased risk. It has been described that patients with a body mass index (BMI) of 35 or greater have a two- to six-fold increased risk of PJI [5,6]. Consensus opinion from the American Association of Hip and Knee Surgeons (AAHKS) suggests that consideration should be given to delaying total joint arthroplasty in a patient with a BMI > 40, especially when associated with other comorbidities, such as poorly controlled diabetes or malnutrition [7].

Since paradoxical malnutrition in patients having a high caloric but nutritionally poor diet is present in 42.9% of obese patients [8], malnutrition has been associated with a five to seven times greater risk of developing a major wound complication [9], ultimately leading to a PJI. Therefore, to cope with postoperative catabolic demands, nutritional supplementation has been strongly recommended to minimize PJI risk [10].

Diabetes is a well-known risk factor for complications following TJA [11]. Historically, patients with uncontrolled diabetes have been found to have a 2.8 times increased risk of infection after TJA [12,13]. More recently, the critical role of acute glycemic control in patients undergoing TJA has been determined since multiple studies have shown patients with peri-operative hyperglycemia, not simply diabetes alone, have a significantly higher risk for complications [14,15]. Blood glucose levels between 110 and 180 mg/dL, a non-fasting glucose value less than 200 mg/dL, and a hemoglobin A1c value less than 7.5–8% have all been reported as ideal for elective TKA [13,14,15].

Tobacco use and smoking are substantial risk factors for poor wound healing and infection. There is strong evidence that previous smokers had a similar risk profile to non-smokers: a few reports indicated that four weeks of cessation are required before elective surgery to attenuate the risk of surgical complications [16,17]. The normal value of serum cotinine assay has been reported as ≤ 10 ng/dl [18].

Recent studies suggest the use of preoperative chlorhexidine cloth skin decolonization to reduce PJI after TJA because of its superiority compared to regular soap for preoperative cleansing of the skin—this has been demonstrated particularly in reducing infections related to MRSA [19,20]. The use of octenidine-palmitate (OL 11) has also been shown to reduce SSIs [21].

Since S. aureus nasal colonization correlates with increased risk for surgical site infections (SSIs) [22] and a few reports showed that an institutional decolonization protocol helped to decrease overall infection rate [23], the AAOS workgroup [4] suggested preoperative nasal mupirocin decolonization in all patients who are MRSA carriers because of its minimal potential risk of nasal irritation and its relatively low cost.

Kowalski et al. [24] recommended that hair removal should be considered in all patients undergoing elective joint arthroplasty, and should be performed by clippers before arrival in the operating room.

Since the increasing number of MRSA and gram-negative PJIs [25], the classical single antibiotic prophylaxis prior to TJA has been recently challenged [26]. On the other side, Sewick et al. [27] demonstrated that the addition of vancomycin did not significantly reduce the rate of SSI when compared with cefazolin alone, but reduced the overall incidence of MRSA infections; because of this, it has been suggested by the same authors that only patients who are proven or potential carriers of MRSA, or those with a cephalosporin allergy, may benefit from vancomycin prophylaxis. This therapeutic strategy has also been shown to minimize the development of vancomycin-resistant Enterococcus [26,27].

Although the Centers for Disease Control and Prevention (CDC) guidelines recommend a single preoperative dose in the case of TJA, there is a surprisingly limited amount of literature to support this recommendation [28,29]. It has been shown that a single perioperative dose of antibiotics does not increase the SSI/PJI rates if compared to multiple doses [28]. Interestingly, Inabathula et al. [30] reported that extended postoperative antibiotic prophylaxis up to seven days led to a statistically significant and clinically meaningful reduction in the 90-day infection rate in a selected group of high-risk patients. Claret et al. [31] also demonstrated a reduction in PJI when a prolonged post-operative antibiotic treatment was applied to total joint arthroplasty revisions.

Chlorhexidine-gluconate (CHG) has been recommended as the most efficient intra-operative surgical site preparation agent [10]; dual skin preparation, before and after draping and adding alcohol in a secondary scrubbing phase, has also shown favorable outcomes [20,32] as a preventive PJI measure.

Various intraoperative irrigation solutions have been recently studied. The World Health Organization (WHO), CDC, and International Consensus Meeting Clinical Practice Guidelines advocate for the use of diluted povidone-iodine (PID) irrigation during surgical procedures [29,33,34]; interestingly, cytotoxicity studies have shown that the bactericidal effect occurs even before individual human cells are affected [35]. Multiple studies have been performed in order to determine the optimal PID dilution in normal saline [36,37,38] prior to irrigation. Cichos et al. [38] evaluated the minimal inhibitory concentration (MIC) and time to bacterial death for 1% PID, 0.05% CHG, and 5 μg/mL vancomycin against multiple bacteria: those authors reported that PID, with a MIC of 0.63%, killed all tested micro-organisms immediately after contact, concluding that PID-accurate intra-articular diffusion was more important than extended exposure time. A recent in vitro study by Schmidt et al. [39] suggested that chlorhexidine may be a more effective irrigation solution for S. epidermidis eradication in biofilm than other commonly used solutions, such as povidone-iodine, Dakin’s solution, and triple antibiotic solution.

Since postoperative hematoma represents a well-known risk factor for PJI and SSI, the use of tranexamic acid (TXA) was recently introduced in many multimodal TKA protocols, since its use was strongly associated with reduced blood loss and decreased transfusion rates without an increase in thromboembolic complications [40].

It has been reported that prolonged wound drainage (> 5 days) increases the risk of PJI by 13 times [41]: because of this, proper wound closing and postoperative wound monitoring represent key factors to avoid bacteria invading the joint space [41]. Recently, the use of a barbed monofilament suture was shown to provide a more watertight seal requiring no knots and allow for quick and cosmetic wound closure [42,43]. Interestingly, results from several meta-analysis studies showed that the incidence of SSI or wound infections decreased after using triclosan-coated sutures [44,45]. Since a moist environment protects the incision area from contamination, the use of silver-impregnated hydrofiber dressings have shown to decrease wound complications, the number of required re-dressings, and the rate of PJI by 4.6-fold [46,47]. In high-risk patients, wound checks and possible dressing changes should be performed on a daily basis—in the case of postoperative drainage, vacuum-assisted incisional dressing (iVAC) or negative-pressure wound therapy (NPWT) may play a role in reducing PJI risk [48].

Since bacterial adhesion to the implant surface represents a key step of biofilm formation, several studies have focused on the relationship between prosthetic biomaterials and the increased risk of PJI [49,50,51]. Material and surface engineering led to the development of bactericidal/bacteriostatic modification of implant surfaces, such as chemical immobilization of antimicrobials, coatings with a broad range of antibacterial compounds (Gentamycin polymer, DAC hydrogel, silver-coated and iodine-coated implants), micro-textured surfaces, or anti-adhesion topographies: nevertheless, no method seems ideal, different results are reported, and no consensus exists on the use of a specific bactericidal surface [28].

During an acute or chronic PJI, bacterial infiltration is mainly identified in the joint space which is poorly vascularized and more tolerant to bacteria proliferation before a local immune response can be stimulated. Because of this, a strategy to prevent bacterial colonization and biofilm formation may be needed to support a delayed and compromised immune response. Localized delivery of antibiotics is able to provide high concentrations of antibiotics that cannot be achieved systemically. Current evidence on the efficacy of Antibiotic-Impregnated Bone Cement (AIBC) in primary TKA is inconclusive [10,21,52]. Recently, calcium-sulphate antibiotic-added resorbable beads have received much attention, particularly due to their faster and longer elution compared to AIBC and poly-methyl-methacrylate (PMMA) beads. Unlike PMMA beads, calcium sulphate beads (CSB) do not need removal from the joint space and there is no risk of acting as a potential foreign body for bacterial colonization [53,54]. In vitro studies reported that calcium sulphate beads were capable of bacterial growth inhibition, preventing early bacterial colonization and biofilm formation by MRSA, S. epidermidis, and gram-negative bacteria by reaching localized antibiotic levels above the minimum inhibitory concentration (MIC) up to 39 days. However, various complications have been described when a higher volume of beads has been used—these include transient hypercalcemia, wound drainage, and heterotopic ossification [55,56].