The frequency of PJIs is increasing, according to the Nordic Arthroplasty Register Association , and the treatment of PJIs should target gram-positive pathogens because such organisms cause the majority of PJIs, and especially those that became antibiotic resistant [9–12]. In Japan, the proportion of gram-positive PJIs is over 70%, while 42% of those are methicillin-resistant Staphylococcus aureus (MRSA) . In Europe and the United States, more than 50% of PJIs are typically caused by staphylococcal organisms; and this percentage value is expected to increase [11, 12]. The increased frequency of gram-positive infections and the rise in resistance to commonly used antibiotics have led to the need of novel antibiotic therapies, such as DAP, which has high antimicrobial penetration into biofilms with low bactericidal concentration . According to the European Registry, DAP was effective and safe in patients with osteomyelitis or those with orthopedic device infections; it was also a valuable treatment option for the management of gram-positive infections [3, 14]. However, in the treatment of PJIs by using DAP, there is no consensus whether the implant should be removed or not.
In the current study, the clinical success rates in the implant removal group were significantly higher than those in the implant retention group. However, the patients without chronic late infection and with a score higher than 7 points did not require implant removal. Tsukayama et al.  analyzed the relationship between clinical settings and outcomes in 106 patients with PHIs, and reported that all patients with early postoperative infections (success rates: 71%) or acute hematogenous infection (success rates: 50%) had only debridement, while all patients with late chronic infection (success rates: 85%) were subjected to revision arthroplasty. Therefore, patients with late chronic infections may not be approved for implant retention even if DAP is administered.
Past reports of DAP treatment of PJI are shown in Table 3, and even some authors recommended the use of high-dose of DAP for the treatment of PJI with implant retention [2, 15–21]. Furthermore, the European Registry demonstrated high clinical success with DAP therapy, including both implant retention (56%) and removal (44%). Additionally, patients receiving both DAP and RFP showed higher success rates than those who did not concomitantly receive RFP . Interestingly, in vitro experiments showed that DAP had the fastest eradication rate for MRSA embedded in a biofilm; therefore, the combination of DAP and RFP may be a promising treatment option for implant-associated MRSA infections [22, 23]. Moreover, the combination of high-dose DAP (equivalent to 8–10 mg/kg/day in humans) and RFP was highly effective for the treatment of foreign body-related MRSA infections [24, 25]. Lora-Tamayo et al.  also analyzed 18 staphylococcal PJIs in a multicenter study and concluded that high-dose DAP (10 mg/kg/day) plus RFP was a good initial treatment for PJIs with implant retention. In the current study, however, the mean daily dose of DAP for successful cases of implant retention was not always high, although RFP was administered whenever possible. Either way, RFP may be an important addition to consider when treating PJIs with DAP, with or without implant removal.
Some limitations of our study must be noted. First, the sample size was small, involving only 20 individuals, due to the difficulties of obtaining a larger patient sample from a single institution. Furthermore, the current study was not performed as a randomized controlled trial. Patients with refractory PHIs required treatment on a case-by-case basis; therefore, the optimal surgical intervention and daily DAP dose also differed. Second, some patients, who did not undergo implant removal after treatment, continued to take other antibiotics orally. As a consequence, because they did not undergo implant removal, they may have actually experienced recurrent infections. Third, we administered DAP when a PHI was suspected prior to the identification of the specific pathogen, because such organisms cause the majority of PHIs and DAP still works in presence of antibiotic resistance. However, such approach may lead to administration of excessive levels of antibiotics if treatments need to be switched to a more appropriate antibiotic after pathogen identification.