As mentioned, ensuring that patients meet the IDSA criteria for DAIR can increase the likelihood of treatment success. The rationale for these criteria is to select patients with acceptable local conditions at the joint prosthesis/bone interface, without a chronic infection or mature biofilm and with bacteria that may be treated with antibiotics with a good anti-biofilm profile. However, the specific cut-offs and definitions of some of these criteria are somewhat arbitrary, and some observational studies have shown that the violation of these rules does not lead unequivocally to treatment failure.

The definition of what constitutes an acute infection is controversial, because PJI may be considered acute according to two clinical criteria: (a) the duration of symptoms and signs (i.e. time from onset of symptoms to surgical debridement) and (b) the age of the prosthesis (i.e. time from the prosthesis placement to surgical debridement). The first may be difficult to establish because the onset of symptoms can be subtle, especially for postoperative cases when symptoms and signs may be masked by the expected pain and inflammation of the postoperative period. Duration of symptoms is therefore preferred for haematogenous PJI, where the onset is usually more evident.

To this end, a 21-day symptom limit was established, though it was not based on comparative studies. This cut-off was established on the maximal time that the patients included in Zimmerli’s pivotal trial were submitted to debridement [32]. However, it remains unclear whether patients could still have benefited from rifampin plus a fluoroquinolone if they had undergone surgery later. In fact, several studies have addressed this issue and suggested limits other than 21-day symptom duration. For instance, in a cohort of patients with staphylococcal PJI treated mainly with β-lactams , Brandt et al. observed that a debridement delay of more than 2 days was associated with a higher likelihood of failure [33]. However, this time could not be confirmed by later studies using rifampin and fluoroquinolones [27, 31]. Also, in a recent cohort of streptococcal PJI managed by DAIR, a long symptom duration was associated with a poor result, but the 21-day cut-off did not discriminate patients with a better prognosis [34]. Many other case series have also reported that, although a long symptom duration was associated with an unfavourable outcome, no precise and reproducible cut-offs could be provided [24, 35–40].

In this regard, it must be noted that symptom duration may be a surrogate marker of severity. Patients with sepsis, bacteraemia or purulent wound discharge may require surgery earlier than stable patients, yet a short time to debridement would paradoxically be associated with a worse prognosis because of the higher likelihood of failure in this setting [27, 31].

To conclude, no specific time limit has consistently defined a worse prognosis. In this regard, we are certain that candidates for DAIR should be submitted to debridement as early as possible, but we are unable to support the 21-day time limit unreservedly.

By contrast, the age of the prosthesis may be a more objective parameter for postoperative infections. Optimal candidates for DAIR are those with an early postoperative PJI, but again the specific definition is not without controversy. Indeed, the concept of early postoperative PJI has evolved over time in several landmark publications, ranging from 1 month [3, 8] to 2 or 3 months [2, 32]. While most physicians will agree that 3 months is a reasonable limit for PJI to be considered as chronic, thereby excluding patients from treatment by DAIR, the debate continues to focus on patients in the timeframe between the first and third month. According to the IDSA guidelines , patients with a prosthesis that is older than 1 month should not receive DAIR, yet a large observational cohort study of staphylococcal PJI showed conflicting results. In that study, the long-term prognosis of patients with a postoperative infection and prostheses aged 1–3 months was similar to that for prostheses aged 1 month or less, whereas patients with a prosthesis older than 3 months had significantly worse prognosis (Fig. 4.2) [27]. These observations were also reproduced in a large cohort of patients with streptococcal PJI [34]. Together, these findings challenge the conventional wisdom that the limit for considering DAIR for postoperative infection should be prosthesis age of 1 month.

In summary, while DAIR should certainly be considered for patients meeting the IDSA criteria, decisions should be made by a multidisciplinary team with expertise in PJI and therapy individualised to the complexities of each patient’s condition. On balance, decisions should focus on the stability of the prosthesis, the condition of the surrounding soft tissue and the clinical presentation as the most important criteria. In this regard, DAIR should be performed as early as possible and in cases of haematogenous or postoperative PJI with a prosthesis no older than 30–90 days.

The mechanical removal of macroscopic (and microscopic) infection is essential to the success of DAIR management. A suboptimal debridement will probably lead to treatment failure, regardless of the quality of antibiotic treatment and medical management. Therefore, it should be performed by specialist orthopaedic surgeons who are experienced with surgery for infectious complications.

Surgical debridement must be thorough, complete, early and aggressive. It should begin by reopening the previous wound and excising any scar tissue or permanent sutures. All necrotic material, purulent collections and debris must be removed, along with the synovial tissue. Fixation of the prosthesis should be confirmed, and all inert surfaces should be generously irrigated. After this lavage, some authors recommend replacing the surgical field and instruments before wound closure [41].

The replacement of removable components is strongly recommended. This allows not only for the biofilm burden to be reduced but also for greater access to all areas of the joint space. It also facilitates lavage of most component’s surfaces. For instance, debridement of the surface of the tibial component of a knee prosthesis cannot be done unless the polyethylene liner is removed, as is valid for the posterior knee compartment (Fig. 4.3). In hip prostheses, it is also recommended that the polyethylene liner and the femoral head be exchanged. Several studies have outlined the benefits of exchanging the removable components of the prosthesis during debridement [41, 42].

Bearing these factors in mind, most authors recommend debridement to be performed by open arthrotomy rather than arthroscopy. An open wound permits a wider surgical window, an access to remote joint spaces, the exchange of removable components, the excision of infected scar tissues and the repair of damaged tissues. Supporting this approach, a large observational study of more than 100 patients with PJI managed by DAIR showed that debridement by arthroscopy was independently associated with failure (HR 4.2, 95% confidence interval [CI] 1.4–12.5) [26]. Some expert groups have published conflicting data, with good experience in selected patients with infected knee prostheses [43, 44]. In our opinion, the efficacy of arthroscopy for managing PJI needs further evidence before its use can be advocated.

Logically, the recommended antibiotic for a given PJI depends mainly on the microorganisms responsible for the infection and, therefore, on the need for a reliable microbiological diagnosis. The general regimens recommended by the aetiology of the infection may be found in Table 4.1. Before offering further insight into these particular recommendations, we should first consider some generic questions regarding the metabolic status of the bacteria involved in acute PJI and also regarding the total length of therapy.

However, acute PJIs, which are usually suitable for DAIR, may also present with a significant component of planktonic bacteria. These infections would be characterised by the presence of bacteraemia, fever, purulent wound discharge, inflammation, high CRP levels and high leukocyte counts. In several large series of PJI with different aetiologies that were managed by DAIR, these parameters were independently associated with the treatment failure, especially in the first weeks after debridement [27–29, 31, 34].

Also of importance, the possible emergence of antibiotic resistance must be considered. In the setting of acute PJI, this is more likely in the presence of high bacterial inoculum in a high replicative state of growth, such as the days before debridement or just thereafter, when the surgical drains are still present. The risk is also higher for some antibiotic classes such as the fluoroquinolones and rifampin [45].

Thus, in addition to surgical debridement, which is key to reducing the inoculum and fighting the planktonic component of the infection, the initial antimicrobial therapy should include antibiotics with good activity against bacteria in a planktonic state of growth and with a low risk of producing early resistance. In this regard, β-lactams are probably ideal. The likelihood of resistance developing is low, and their ability to clear bacteraemia and replicating bacteria is excellent. Once this initial phase is over, a specific antibiotic regimen may be prescribed that has activity against biofilm-embedded bacteria.

The only clinical trial assessing the comparative efficacy of short and long antibiotic treatment has been recently performed by our multicenter group (REIPI). In this study, 63 patients with acute staphylococcal PJI were managed by DAIR and were randomised to receive levofloxacin plus rifampin during for either 8 weeks (short schedule) or 3–6 months (long schedule). Unfortunately, the study was underpowered, and the non-inferiority hypothesis could only be confirmed in the intention-to-treat analysis, with cure rates of 58% and 73% for the long and short schedules, respectively. There was only a trend toward similarity in the per-protocol analysis (cure rate 95% and 91.7%, respectively) [50].

Overall, we believe that most patients with acute PJI managed by DAIR may be safely treated for 8 weeks with the use of an appropriate anti-biofilm therapy (rifampin-fluoroquinolones for staphylococci and fluoroquinolones for Gram-negative bacilli). Cases with suboptimal debridement or poor resolution of inflammation should be addressed separately.

Staphylococcus aureus is the most common pathogen associated with acute PJI and so has been the focus of many clinical and experimental studies. According to published case series, the success rate for DAIR management of PJI caused by S. aureus ranges from 13% to 90% [6, 25–27, 31, 33, 35, 38]. Our group previously reported a success rate of 55% (95% CI, 50–61%) in a large observational study of 345 patients. Acute infection caused by coagulase-negative staphylococci (CNS) is less frequent, but clinical management appears to be similar [51].

The model is considered as a reliable tool to mimic these infections, and it has been widely used to test the activity of antibiotics against biofilm -embedded bacteria [55, 56], providing relevant information for the clinical practice. Indeed, there are other models of device-related infections that have produced very interesting information, such as osteosynthesis-associated osteomyelitis [57] or actual periprosthetic joint infection [58]. However, the tissue cage model has been validated and used by different research groups for more than 30 years, and it has been proven as a reliable easy method that is relatively less expensive.

Briefly, the tissue cage model involves subcutaneously implanting 2–4 perforated polytetrafluoroethylene (Teflon) tissue cages containing two polymethylmethacrylate coverslips. Once the wounds heal (usually 3 weeks later), a standard inoculum is introduced percutaneously (usually 1 × 10⁴ to 8 × 10⁵ colony-forming units). After a variable period (24 h to 3 weeks), which determines the chronicity of the infection, antimicrobial regimens are given during several days (usually 4–14 days). The inflammatory liquid in the tissue cages may then be sampled percutaneously, and viable bacteria measured quantitatively, allowing antibiotic activity to be tested and compared. Thereafter, tissue cages and coverslips may be recovered to perform quantitative counts of any biofilm-embedded bacteria [18, 59, 60]. Table 4.2 summarises the most important studies using this model for staphylococcal foreign body infection [18, 52, 59–81].

After this initial period, a targeted anti-biofilm treatment may be started, which is determined by the addition of rifampin .

In the context of this background, Zimmerli et al. published a landmark double-blind randomised clinical trial in 1998, comparing ciprofloxacin alone with ciprofloxacin plus rifampin for orthopaedic hardware-associated acute infection caused by MSSA managed by implant retention. The per-protocol analysis showed a significantly higher success rate for the combined therapy (100% (12/12) vs. 58% (7/12), P = 0.02). This pivotal study forms the clinical basis for using rifampin in staphylococcal PJI managed by DAIR [32].

Later observational studies have confirmed the benefits of rifampin. In a large study of staphylococcal PJI, Senneville et al. observed that fluoroquinolone plus rifampin was independently associated with a lower likelihood of failure (odds ratio 0.40, 95%CI 0.17–0.97) [6]. The benefits of rifampin also seem to apply to MRSA, as shown in experimental models [19, 59, 62, 74, 75]. Case series of staphylococcal PJI where the use of rifampin-based combination therapy was widespread have shown a similar prognosis for MRSA and MSSA episodes [27, 51].

The recommended dose of rifampin is another matter of controversy. In the landmark trial by Zimmerli et al., the dose was 450 mg twice daily [32]; by contrast, the IDSA guidelines use a wider dose range of 300–450 mg twice daily [8]. Other groups have also reported their experience with a dose of 600 mg once daily, similar to the regimen used for tuberculosis. In this regard, the area under the curve (AUC) in relation to the MIC seems to be the best pharmacokinetic/pharmacodynamic parameter for predicting efficacy [86]. It must be noted that the transport of rifampin in the liver is saturable, producing non-linear increases in the AUC for single doses exceeding 300–450 mg. Given this, it is likely that a single fasting dose of 600 mg causes AUCs similar to those seen for 450 mg twice daily [87, 88]. In addition, rifampin dose higher than 600 mg has not been associated with any improvements in outcome [89].

As mentioned, resistance to rifampin develops rapidly and predictably when administered alone, therefore necessitating the use of combination therapy. Beyond this, there is interest in evaluating the relative activities of specific combinations. In this regard, fluoroquinolones have a good anti-staphylococcal activity, bone diffusion and bioavailability [14, 90]. Clinical comparison of fluoroquinolone-rifampin regimens with other rifampin-based combinations is scarce, mainly because of the inherent limitations of retrospective studies. Still, there is some indirect clinical data suggesting that fluoroquinolone-rifampin combination therapy may be superior to other regimens. In our large study of staphylococcal PJI managed by DAIR, treatment with fluoroquinolones plus rifampin delayed the moment of failure until the antibiotics were stopped, whereas patients treated with other rifampin-based antimicrobial regimens did fail despite continued treatment [27].

Regarding the specific fluoroquinolone choice, there is wide consensus that newer fluoroquinolones such as levofloxacin or moxifloxacin are preferable to ciprofloxacin because of their higher anti-staphylococcal activity and the lower likelihood of resistance developing during treatment [90, 91]. On the basis of several clinical experiences, expert recommendations and our own opinion, the combination of levofloxacin plus rifampin is currently the best choice in this setting [2, 8]. Moxifloxacin has lower MIC values [90, 92], but the experimental animal model has failed to provide evidence of superiority over levofloxacin [72]. Also, the antimicrobial spectrum of moxifloxacin is unnecessarily wide for treating staphylococcal infection (i.e. it also includes anaerobic microorganisms). Finally, there is evidence that moxifloxacin levels may decrease when combined with rifampin [93].