Conservative treatment with antibiotics in early infections
Antibiotic treatment is commonly initiated in cases of fever, chills, persistent inflammation, or wound drainage following joint arthroplasty surgery. It is difficult to differentiate superficial wound infection from early post-operative prosthetic joint infection, and wound issues are a risk factor for PJI [51, 52]. Long-term antibiotic therapy with the intent of limiting inflammation and improving clinical symptoms without prior revision surgery has not been found to eradicate infection. As stated above, delayed surgery compromises the likelihood of success of treatment. Prompt surgery followed by antibiotic therapy is the cornerstone of successful treatment of PJI. Suppressive antibiotic therapy has limited clinical efficacy and is associated with a substantial risk of adverse effects and should be reserved for patients in whom further surgical treatment is unadvisable (i.e., extreme frailty, comorbidities) .
Antibiotic treatment prior to microbiological diagnosis
Corollary of the aforementioned point, the diagnostic accuracy of synovial fluid culture results is compromised if synovial fluid aspiration is performed after initiating antibiotic therapy, increasing the risk of false-negative results. The same is true for peri-operative tissue cultures, and preoperative antibiotic therapy is the most important cause of culture-negative PJI . If diagnostic measures are planned in a patient currently being under antimicrobial treatment, antibiotics should be withheld for two weeks prior to microbiological sampling. Nevertheless, culture of sonicate fluid could improve the diagnostic accuracy of patients under antimicrobial treatment [47, 54].
Failure to individualize treatment
Treatment of an infected prosthesis should be tailored to the type of infection (early/acute or late/chronic infection), the causative micro-organism, the quality of the soft tissue envelope, stability of the implant, surgeon experience, and ultimately host factors (comorbidities and functional status) and patient preferences [55, 56]. In acute PJI, the duration of symptoms is less than three weeks (haematogenous or contiguous infections) or four weeks (early post-operative infections); all other infections with longer duration of symptoms are defined as chronic PJI (Table 1) . Implant retention using the DAIR strategy can be used in acute PJI; all mobile parts should, however, be exchanged, as patients in whom all modular components have been exchanged are shown to have higher treatment success rates [16, 57, 58]. Other requisites for success with DAIR are sufficient debridement, infection due microorganisms sensitive to biofilm-active antibiotics, a stable arthroplasty, and good soft tissue envelope. Chronic PJI presents with a mature biofilm; thus, the prosthesis must be exchanged. This can be performed in one or two stages, depending on the causative micro-organisms, soft tissue condition, and surgeon and patient preference. While two-stage exchange of an infected prosthesis is considered the gold standard and is the dominant option in the USA, single-stage exchange is favoured in some European countries. One-stage exchange may not be an option in patients with signs of systemic sepsis, extensive comorbidities, infection with resistant organisms, culture-negative infections, and poor soft tissue coverage [59,60,61]. With proper selection of surgery, success rates of PJI treatment can exceed 80–90% .
In patients too frail or too sick for surgery that have low functional demand or who reject surgical treatment, improvement of the patient’s quality of life should be the goal of treatment, with or without the use of antibiotics. The success rate of suppressive antimicrobial therapy has been reported to be between 23 and 83% [53, 62]. In a series of six patients in stable condition and with well-fixed prostheses treated expectantly withholding antibiotic therapy, Giacometti Ceroni et al.  reported that 83.3% of patients were pain-free and without systemic symptoms after a mean follow-up of 6.7 years (range 2–10 years).
Arthroscopic lavage for treatment of PJI
Arthroscopic lavage of an infected prosthetic joint does not allow access to all parts of the joint, particularly the posterior part of the knee joint and the polyethylene liner backside in knee as well as other joints. In addition, it does not allow for exchange of mobile parts, reflecting insufficient debridement as mentioned above (error 12). In prosthetic hip joints, debridement is insufficient without dislocation of the femoral head, which is difficult to perform without arthrotomy. Byren et al.  observed four times higher failure rate following arthroscopic lavage than standard DAIR surgery. Hyman et al.  described favorable results in a series of eight patients with late acute hip PJIs—all patients were, however, managed with chronic antibiotic suppression in addition to arthroscopic lavage. Arthroscopy has a limited role in the diagnostic workup of a painful prosthesis, allowing for inspection of the components in search of instability and wear, exclusion of non-infectious causes, visualization of the synovium, and retrieval of samples for microbiology and histology in selected cases [14, 66,67,68]. Importantly, arthroscopy is an invasive intervention, which is associated with a small risk of infection; therefore, the indication for diagnostic arthroscopy should be considered carefully.
Insufficient debridement or incomplete exchange of implants
A common reason for treatment failure is inadequate debridement. All diseased or devitalized tissue and bone should be removed during surgery. This includes old scar tissue, sinus tracts, osteolytic regions, sequestra, and any devitalized tissue until bleeding margins are obtained. In infections with mature biofilm, all foreign material including cerclages and bone cement should be rigorously removed. Although some series have documented partial exchange of implants with acceptable results, particularly in cases in which a prosthetic component is so well-fixed that its removal could result in significant bone loss and compromise of fixation at the time of the later prosthesis reimplantation and the causative organisms are not multidrug-resistant, in immunocompetent patients without sinus tracts, this option should be the exception rather than the norm [15, 66, 69, 70], and surgeons should be aware that this could compromise treatment success.
High-pressure pulse lavage during surgery
Pulse lavage is commonly used in PJI surgery. In the clinical setting, the success rate in treating orthopaedic implant–related infections is similar when using high-pressure and low-pressure pulsatile lavages (81.6% vs. 84.4%, respectively; p = 1.00) . Several in vitro studies have shown, however, that pulse lavage may not be suitable for PJI surgery, especially in cases of DAIR. Not only is pulse lavage ineffective in removing biofilms from the implant surface , it can also potentially increase soft tissue damage and propagate bacteria deeper into soft tissue, leading to increased bacterial retention .
Errors using antibiotic-loaded cement spacers
The use of antibiotic-loaded bone cement (ALBC) spacers in two-stage revisions has two goals: first, it provides local delivery of high doses of antibiotics, above the minimal inhibitory concentration (MIC) normally attainable locally with systemic treatment without adverse effects. Second, it serves as a filler of dead space, limiting the presence of void-filling haematoma, avoiding joint contractures, and increasing joint stability and even mobility . The drug chosen for the mixture has to meet the following requirements: (1) it needs to be thermostable enough to still be effective after the exothermic reaction of polymethyl methacrylate (PMMA) polymerization, (2) it should not interfere with the polymerization process (i.e., impede hardening of PMMA), (3) it has to be able to elute from the bone cement after hardening, (4) it has to be hydrosoluble to diffuse into the surrounding tissues, and (5) it has to be available in powder form, as adding liquid antibiotics to the cement mixture significantly decreases its mechanical strength. Many premixed ALBC mixtures are commercially available; most, however, have relatively low doses of antibiotics and are primarily intended for fixation use in reimplantation surgery in two-stage exchanges or for primary arthroplasties in high-risk patients. Furthermore, hand-mixed ALBC allows for individual tailoring of the spacer to the causative micro-organism (Table 2). Common pitfalls are using antibiotics inadequate for mixing with bone cement or that are not effective for the type of micro-organism treated (e.g., vancomycin for gram-negative bacteria). Antibiotics elute from ALBC in a negatively exponential fashion, with high doses in the first post-operative days and a loss of therapeutic levels after days to weeks, depending on the type and dose of antibiotic and cement used. Thus, the risk of the spacer acting as a foreign body at risk for biofilm formation increases as time passes. Tan et al.  found that the risk of reinfection increased as the spacer was left implanted for longer periods, with a clear inflection above 100 days.
“Antibiotic holiday” and joint aspiration before re-implantation in two-stage exchange surgery
Currently, there is insufficient evidence to support ceasing antibiotic treatment before reimplantation to confirm eradication of infection (Fig. 4). The duration of an antibiotic holiday seems to be less related with reinfection than the time the antibiotic cement spacer is implanted . Joint aspiration before reimplantation is not recommended, as synovial markers do not correlate with reinfection rates, and the diagnostic accuracy is very low (sensitivity of 4.6% and 25.0% and specificity of 94.3% and 96.9% for synovial fluid and cell count, respectively) [75,76,77]. To date, there is no reliable marker to prove the eradication of infection at the time of reimplantation. In a recent study, the outcome of PJI treatment remained high despite omission of the antibiotic-free interval before re-implantation .
Errors in the selection of antibiotic treatment
Antibiotic treatment should be based on the type of microorganism, drug susceptibility, and the type of surgery performed (Table 3). Not all antibiotics are equally active against sessile bacteria embedded in biofilm (examples of biofilm active antibiotics are rifampicin for several gram-positive pathogens (e.g., Staphylococcus species, Cutibacterium species) and ciprofloxacin for gram-negative rods), and these should be reserved for the period after implantation of the definitive implant (Fig. 4). In two-stage exchanges, we do not recommend using the antibiotics in the prosthesis-free interval but rather initiate them once the prosthesis has been re-implanted. In one-stage exchanges and infections treated with DAIR, biofilm-active therapy should be initiated post-operatively as soon as the wounds are dry and drains removed . Another error is prescribing oral antibiotics with bad bone penetration and poor oral bioavailability, resulting in insufficient local concentrations at the site of infection (e.g., beta-lactam antibiotics). Furthermore, single-drug regimens such as rifampin monotherapy should be avoided in order to minimize the risk of selecting drug-resistant micro-organisms .
Inadequate management of soft tissues
Occasionally, there are difficulties for adequate closure of the soft tissue envelope surrounding a joint arthroplasty. A plastic surgeon should be consulted promptly, because any exposed prosthesis will quickly be colonized with micro-organisms and covered in biofilm. Wound revision, with revision of the prosthesis if necessary, is always indicated, as it is the only way to guarantee a favourable course, both from the infectious and from the functional point of view. Negative pressure wound therapy should not be used, as it can lead to superinfection with gram-negative or multiresistant micro-organisms ; if inevitable, its use should be limited in time, only as a short bridging therapy of a few days before the plastic surgeon can perform definite coverage with local or free flaps [14, 15, 55].
Lack of specialized multidisciplinary teamwork
The diagnosis and treatment of PJI involves multiple steps, including but not limited to the evaluation of the patient, particularly the affected joint, the interpretation of synovial fluid analysis and bacterial culture results, the development and execution of the surgical plan, and the choice of antibiotic treatment. This involves at least microbiologists, infectious disease specialists, and orthopaedic and plastic surgeons. The orthopedic surgeon should not choose the antibiotic cocktail alone, as choosing the right regimen is difficult. It is essential that the surgeon works very closely with an infectious disease specialist experienced in the treatment of implant infections. Conversely, the infectious disease specialist should not propose surgical treatments without understanding their impact and their importance to the patient and without knowing the different techniques employed by the surgeon. A microbiologist can assist in both the correct retrieval of samples and the processing of these in order to provide an exact diagnosis. Though, to our knowledge, no study has evaluated multidisciplinary interventions in a randomized manner , several authors have shown that a multidisciplinary protocol provides excellent results, with a lower length of in-hospital stay, number of surgeries, and number of antibiotics required [14, 31, 55, 81,82,83,84].