antibiotics Perspective Candida Periprosthetic Joint Infection: Is It Curable? Laura Escolà-Vergé 1,2,3, * , Dolors Rodríguez-Pardo 1,2,3 , Pablo S. Corona 2,3,4 and Carles Pigrau 1,2,3 1 Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain; dolorodriguez@vhebron.net (D.R.-P.); cpigraus@gmail.com (C.P.) 2 Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003), Instituto de Salud Carlos III, 28029 Madrid, Spain; pcorona@vhebron.net 3 Study Group on Osteoarticular Infections of the Spanish Society of Clinical Microbiology and Infectious Diseases (GEIO-SEIMC), 28003 Madrid, Spain 4 Septic and Reconstructive Surgery Unit (UCSO), Orthopaedic Surgery Department, Vall d’Hebron University Hospital, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain * Correspondence: lauraescola@gmail.com; Tel.: +34-932-746-090; Fax: +34-934-894-091 Abstract: Candida periprosthetic joint infection (CPJI) is a rare and very difficult to treat infection, and high-quality evidence regarding the best management is scarce. Candida spp. adhere to medical devices and grow forming biofilms, which contribute to the persistence and relapse of this infection. Typically, CPJI presents as a chronic infection in a patient with multiple previous surgeries and long courses of antibiotic therapy. In a retrospective series of cases, the surgical approach with higher rates of success consists of a two-stage exchange surgery, but the best antifungal treatment and duration of antifungal treatment are still unclear, and the efficacy of using an antifungal agent-loaded cement spacer is still controversial. Until more evidence is available, focusing on prevention and identifying   patients at risk of CPJI seems more than reasonable. Citation: Escolà-Vergé, L.; Rodríguez-Pardo, D.; Corona, P.S.; Keywords: Candida spp.; periprosthetic joint infection; fungus; biofilm; antifungal-loaded cement Pigrau, C. Candida Periprosthetic spacer; two-stage exchange surgery Joint Infection: Is It Curable?. Antibiotics 2021, 10, 458. https:// doi.org/10.3390/antibiotics10040458 1. Introduction Academic Editor: Periprosthetic joint infection (PJI), which occurs in approximately 1–2% of all pro- Wolf-Rainer Abraham cedures, is one of the most feared complications after arthroplasty due to its associated comorbidities and the possible need for implant removal [1]. Candida periprosthetic joint Received: 15 March 2021 infection (CPJI) represents a rare etiology among all PJIs; sometimes it is very difficult Accepted: 13 April 2021 to diagnose, and it is especially difficult to treat when the prosthetic material cannot Published: 17 April 2021 be removed [2]. In addition, we have no clear guidelines regarding the best antifungal management in these cases [3–7], and evidence is based on small retrospective series. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 2. Epidemiology published maps and institutional affil- iations. There have been a few recent studies analyzing the prevalence of these infections, and most of them are retrospective in nature [8–11]. A Spanish retrospective multicenter study that analyzed the etiology of PJIs from 2003 to 2012 found that a fungal etiology represented 1.3% of all culture-positive PJIs (n = 2288), and Candida spp. were responsible for 90% of all fungal infections [9]. A smaller retrospective multicenter study performed Copyright: © 2021 by the authors. in Australia from 2006 to 2008 found that CPJI accounted for 0.7% (1/152) of all culture- Licensee MDPI, Basel, Switzerland. positive infections [10], and another study that compared the etiology of PJIs between two This article is an open access article referral centers in Europe and in the United States between 2000 and 2011 found that fungal distributed under the terms and conditions of the Creative Commons PJIs were responsible for 2.3% of 772 cases and 0.3% of 898 cases, respectively [11]. Attribution (CC BY) license (https:// The species of Candida depends on the local epidemiology of the geographical area. creativecommons.org/licenses/by/ In two multicenter studies in Spain [2,9] and one in the United States [12], C. albicans 4.0/). was the most frequently isolated fungus (55–65%), followed by C. parapsilosis (13–33%). Antibiotics 2021, 10, 458. https://doi.org/10.3390/antibiotics10040458 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, 458 2 of 10 Other species, such as C. glabrata and C. tropicalis, were more anecdotic (3–7% and 2–4%, respectively). Smaller series have found similar results [13,14], and in a recent review of the literature, C. albicans (47.3%) was the most frequent strain isolated, followed by C. parapsilosis (22.3%) [15], but epidemiology may still vary among regions. 3. Pathogenesis and Risk Factors Colonization by Candida spp. is regarded as the first step for subsequent infection [16], and Candida spp. are common commensals of the human skin and gut microbiota in healthy individuals [17–19]. Invasive disease, which encompasses both candidemia and deep- seated infections, usually results from an abnormal or increased number of fungi combined with alterations in the cutaneous and mucosal barriers due to weakening of host immu- nity [16,17], which permits the transition from Candida sp. commensalism to opportunism. Three possible routes of CPJI development have been described: (1) the hematogenous route from an infected catheter or a urinary or intraabdominal source; (2) direct inoculation during prosthesis implantation, revision surgery, or even after arthrocentesis, especially in colonized patients; and (3) extension into synovial fluid from contiguous infected tissues. Candida spp. have specific properties allowing them to adhere to surfaces and form biofilms, especially on prosthetic devices, which permits the development of persister cells, facilitating antifungal resistance, and explains treatment failure when the implant is not removed. In vitro experiments have shown that C. albicans biofilm formation begins with the adherence of yeast to a substrate and thereafter yeast cells proliferate across the surface and produce filamentous forms, including hyphae and pseudohyphae. As the biofilm matures, an extracellular matrix accumulates, facilitating antifungal resistance, notably to azoles and polyenes, through different mechanisms [20], which may explain the high failure rates in CPJI when the implant is not removed. Finally, non-adherent yeast cells are released from the biofilm into the surrounding medium (the dispersal step). C. albicans, the most frequent causative agent of CPJI, has been reported to form larger and more complex biofilms than other Candida species [21]. All parts of the immune system are involved in the response to this infection. For example, deficiencies in the T-helper 17 lymphocyte cell line impair the mucosal immune response to Candida spp. and facilitate Candida infections. Neutrophil dysfunction or leukopenia also predisposes patients to suffer invasive candidiasis, and complement or immunoglobulin deficiency or alteration is associated with complicated disease as well [17]. The regulatory pathways and mechanisms that govern Candida biofilm development are very complex [20]; gene expression of C. albicans is regulated by both a continuous host–pathogen interplay and by distinct genetic mechanisms [19], but this is not the scope of this review. However, there are other factors that are not only easier to identify than alterations in host immunity but also probably more prevalent in patients with CPJIs and may play a major role in the pathogenesis of invasive candidiasis. The most reported factors are as follows [17]: (1) the long-term or repeated use of broad-spectrum antibiotics, especially in the previous 3 months, which depletes commensal gut bacteria, enabling Candida sp. overgrowth. Many antibiotics are known to promote fungal growth and pathogenicity because they disrupt the microbiota and eliminate anaerobic bacteria in the gut which could have otherwise inhibited the fungi, and studies show that the introduction of small amounts of C. albicans to mice after antibiotic treatment caused significant changes in the gut microbiota, which may persist in the long term [22]. (2) Breach of the cutaneous and gastrointestinal barriers by chemotherapy, surgery, gastrointestinal perforation, or instrumentation, such as central venous catheters, which may facilitate Candida sp. translo- cation into the bloodstream. (3) Immunosuppression secondary to malignant diseases, immunodeficiencies, or immunosuppressive therapy. Other risk factors reported in pa- tients with CPJIs have been older age [18], diabetes, rheumatoid arthritis, malnutrition, and tuberculosis, which probably also reflect alterations in host immunity [2,12–14,23]. Other series have also identified that multiple previous surgeries at the site of the CPJI Antibiotics 2021, 10, 458 3 of 10 are also a risk factor [2,13,23,24]. A recent retrospective case–control study that compared fungal PJIs with bacterial PJIs found that recent antibiotic consumption (OR: 3.4; 95% CI: 1.2–9.3) and prolonged wound drainage (OR: 7.3; 95% CI: 2.02–26.95) were significantly associated with CPJI [13]. In our experience, patients treated with long courses of linezolid for multidrug-resistant chronic bacterial PJIs tend to present mucocutaneous candidiasis, and their colonization may persist for an unknown duration, which could also be another risk factor for hip CPJI. Although it has not been deeply studied, considering the pathogenesis of the disease, previous Candida spp. colonization in the urine or Candida intertrigo may also be risk factors in patients undergoing hip arthroplasty [2,13]. In a multicenter retrospective study of patients with CPJIs, we found 14% of patients with Candida intertrigo and 9% of patients with a previous urinary tract infection (three with positive blood cultures) caused by the same Candida spp. before the diagnosis of CPJI [2]. 4. Clinical Manifestations and Diagnosis CPJIs are usually chronic infections characterized by pain, swelling, and sinus tracts. Implant loosening may be observed on radiography in nearly 50% of cases, as previously reported in some studies [2,25]. In fact, the median duration from the index surgery and the diagnosis of CPJI averaged 17–25 months [12,13]. Blood tests could show no leukocytosis, and the C-reactive protein (CRP) level and erythrocyte sedimentation rate are usually normal or mildly elevated [2,12]. The same recently published study comparing patients with CPJIs with those with bacterial PJIs showed that patients with CPJIs had lower median CRP values (2.95 mg/dL vs. 5.99 mg/dL) and lower synovial fluid leukocyte levels (13,953 cells/mm3 vs. 33,198 cell/mm3 ) [13]. The criteria to diagnose CPJI are not well established, and the same criteria used in diagnosing bacterial PJIs may not be reliable in some cases. The Infectious Diseases Society of America (IDSA) guidelines [3], a previous International Consensus on PJIs [6], and a recent European Bone and Joint Infection Society (EBJIS) consensus [26] consider two or more intraoperative cultures or the combination of preoperative aspiration and intraop- erative cultures yielding the same organism definitive evidence of a PJI [3]. However, when reviewing published series of CPJI cases, the microbiological criteria changed from one study to another. Some authors consider that one positive preoperative aspiration culture and/or a positive intraoperative culture is sufficient [9], while others require two positive cultures [2,13] or one positive culture with additional criteria for PJIs [2,24]. In our opinion, when Candida spp. are found in only one intraoperative culture, the case should be evaluated carefully, and treating the Candida etiology should be considered, especially in patients with other risk factors for CPJI such as previous antibiotic therapy or multiple previous surgeries (Figure 1). In fact, even if another microorganism is isolated in two or more cultures, polymicrobial infection is not infrequent, particularly in the hip location, being found in 16% to 26% of cases, depending on the series [2,12], and this should not be a criterion for discarding the value of one positive culture for Candida spp. Antibiotics 2021, 10, x458 FOR PEER REVIEW 4 of 10 Figure 1. Figure Diagnosis of 1. Diagnosis of Candida Candida periprosthetic periprosthetic joint joint infection. infection. 5. Medical and Surgical Treatment 5. Medical and Surgical Treatment International guidelines on candidiasis and PJIs [5,7] recommend, with limited ev- International guidelines on candidiasis and PJIs [5,7] recommend, with limited evi- idence, the combination of prosthesis removal and reimplantation in two stages. They dence, the combination of prosthesis removal and reimplantation in two stages. They rec- recommend a prolonged period of antifungal therapy for at least 12 weeks after resection ommend a prolonged period of antifungal therapy for at least 12 weeks after resection arthroplasty and at least 6 weeks after prosthesis implantation, without specifying the best arthroplasty and at least 6 weeks after prosthesis implantation, without specifying the best antifungal option [5]. They state that the use of antifungal agent-loaded cement spacers antifungal option [5]. They state that the use of antifungal agent-loaded cement spacers is is controversial. controversial. The fact that Candida spp. grow and form biofilms on medical devices makes these The fact that Candida spp. grow and form biofilms on medical devices makes these microorganisms highly resistant to antifungal agents and the host immune system [27–30]. microorganisms highly resistant to antifungal agents and the host immune system [27– Therefore, the best surgical approach is to remove the prosthetic material to avoid the 30]. Therefore, problem the best surgical of antifungals penetratingapproach is to within and acting removethe thebiofilm. prosthetic material In this sense,to avoid the a two-stage problem of antifungals penetrating and acting within the biofilm. exchange arthroplasty strategy is probably the best option when feasible to eradicate In this sense, a two- the stage exchange arthroplasty strategy is probably the best option when infection and to preserve joint function [15], with variable success rates from 14% to almost feasible to eradicate the 100% infection depending and toonpreserve the series joint andfunction [15], with variable on the definition of success success rates from 14% to [2,12,14,23–25,31–35]. In almost 100% depending on the series and on the definition patients with reduced mobility, particularly old patients with multiple previous of success [2,12,14,23–25,31– surgeries 35]. in theIn same patients with reduced location, mobility, a resection particularly arthroplasty may be oldthe patients with multiple best alternative. Thereprevious is less surgeries evidence of success with a one-stage exchange arthroplasty strategy, which hasThere in the same location, a resection arthroplasty may be the best alternative. been is less evidence reported in onlyof success a few caseswith a one-stage [15,36,37]. exchange In a recent review arthroplasty strategy, of the literature of 76which has episodes been of CPJI,reported in only one-stage a few cases exchange [15,36,37].was arthroplasty In aperformed recent review onlyofinthe literature three patientsof 76 withepi-a sodes favorableof CPJI, one-stage outcome [15],exchange arthroplasty but in another series wasof 11performed only init three CPJI episodes, patients with was performed in afour favorable with success in two [14]. However, due to the publication bias, the small amount in outcome [15], but in another series of 11 CPJI episodes, it was performed of four with success experience and the indifficulty two [14]. of However, curing thisduetypeto the publication of infection, bias, with the small a high rate ofamount relapses,of experience in our opinion, and thethisdifficulty procedure ofshould curing be thisused typeonly of infection, with a high in very selected cases. rate of relapses, Irrigation and in our opinion, debridement thisprosthesis with procedure should usually retention be usedfailsonlytoincurevery theselected infectioncases. (cureIrrigation rates fromand 0% debridement to 20%), especiallywith prosthesis retention in cases of chronic usually[2,12,23,32,35]. infection fails to cure the infection Table (cure rates 1 summarizes thefrom type 0% to 20%), especially of treatment, the duration in cases of chronicand of follow-up infection [2,12,23,32,35]. the outcome Table of the larger case1 summarizes series (number the type of treatment, of patients ≥ 10) of CPJI. the duration of follow-up and the outcome of the larger case series (number of patients ≥ 10) of CPJI. Antibiotics 2021, 10, 458 5 of 10 Table 1. Treatment, follow-up, and outcome of the largest series (number of patients ≥ 10) of Candida periprosthetic joint infection. Antifungal-Loaded Study (Year) Number of Patients (n) Surgical Treatment (n) Antifungal Treatment (n) Follow-Up Outcome (n) Cement Spacers (n) Remission 5 Resection arthroplasty 6 Fluconazol 6 No Range 5.6–74 months Lost to follow-up 1 Fluconazol 2 Remission 2 Saconi et al. (2020) [14] 11 One-stage exchange 4 Itraconazol 1 No Range 2.1–84 months Failure 1 Micafungin 1 Lost to follow-up 1 Two-stage exchange 1 Voriconazol, itraconazol 1 No 48 months Remission 1 Azoles 13 Remission 13 Prosthesis removal 20 Antibiofilm-containing regimen * 6 Amphotericin B 3 24 months Escolà-Vergé et al. Failure 7 35 No antifungal 1 (2018) [2] Debridement with Azoles 10 Remission 4 No 24 months prosthesis retention 15 Antibiofilm-containing regimen * 5 Failure 11 Remission 5 Two-stage exchange 11 Amphotericin B 10 Failure 6 Debridement with No Failure 5 prosthesis retention 5 Not reported Remission 2 Brown et al. (2018) [24] 25 Resection arthroplasty 5 Fluconazol 25 No Failure 3 Prosthesis retention and No Remission 3 suppressive therapy 3 One-stage exchange 1 No Remission 1 Fluconazol 11 Caspofungin, fluconazol 1 Amphotericin B 3 Mean 65.1 months Remission 10 Gao et al. (2018) [35] 14 Two-stage exchange 14 Vorinconazol 1 Voriconazol 2 Range 25–129 months Failure 4 Amphotericin B, caspofungin, Fluconazol 2 fluconazol, voriconazol 1 Remission 8 Two-stage exchange 9 Fluconazol 9 Amphotericin B 5 Mean 41 months Failure 1 Ueng et al. (2013) [31] 16 Range 28–90 months Remission 4 Resection arthroplasty 7 Fluconazol 7 Amphotericin B 1 Failure 3 Antibiotics 2021, 10, 458 6 of 10 Table 1. Cont. Antifungal-Loaded Study (Year) Number of Patients (n) Surgical Treatment (n) Antifungal Treatment (n) Follow-Up Outcome (n) Cement Spacers (n) Mean 4.3 years Remission 22 Two-stage exchange 24 No Amphotericin B 21 Range 2.6–6.1 years Failure 2 Hwang et al. (2012) [32] 28 Amphotericin B, fluconazol 3 Debridement with Fluconazol 4 No Failure 4 prosthesis retention 4 Fluconazol 5 Two-stage exchange 7 Anidulafungin, fluconazol 1 No Failure 7 García-Oltra et al. Caspofungin, fluconazol 1 Mean 31 months 10 Range 2–67 months (2011) [23] Debridement with Fluconazol 3 No Failure 3 prosthesis retention 3 Remission 9 Two-stage exchange 19 Failure 10 Resection arthroplasty 10 (5 Fluconazol 23 Amphotericin B 5 Mean 45 months Azzam et al. (2009) [12] 31 Caspofungin, fluconazol 3 Range from 24 months to 11 Remission 6 with previous debridement Amphotericin B 5 years Failure 4 failure) Debridement with No Failure 7 prosthesis retention 7 * Antibiofilm-containing regimen: amphotericin B or an echinocandin. Antibiotics 2021, 10, x FOR PEER REVIEW 7 of 10 Antibiotics 2021, 10, 458 7 of 10 Fluconazole Fluconazole isis active active against against most most CPJI CPJI isolates, isolates, and and itit shows shows good good penetration penetration into into synovial synovial fluid and less toxicity than amphotericin B, but its activity against Candida sp. fluid and less toxicity than amphotericin B, but its activity against Candida sp. biofilms biofilms isis limited. limited.However, However, thethe antifungals antifungals that that have have demonstrated demonstrated better activity better activity against against biofilmsbiofilms are echinocandins are echinocandins and liposomal and liposomal formulations formulations of amphotericin of amphotericin B [27–29,38].BIn[27– the 29,38]. absenceInofthe absence clear of clear recommendations recommendations for systemic for systemic antifungal antifungal treatment, treatment, the most the frequently used antifungals most frequently used have antifungals been fluconazolehave followed by amphotericin been fluconazole followed B in byolder series andB[15] amphotericin in by echinocandins older series and [15] in recent series [2], with by echinocandins different in recent outcomes, series [2], withespecially different in relation to outcomes, the espe- type of cially insurgical relation approach to the type (Table 1). However, of surgical approachdue(Table to the1). rarity of this infection, However, due to thethere raritywill of probably this not be infection, randomized there clinical will probably nottrials regarding the be randomized best trials clinical antifungal treatment. regarding In an- the best our retrospective tifungal multicenter treatment. In ourstudy, we foundmulticenter retrospective better results whenwe study, amphotericin found betterB results or echinocan- when dins rather than amphotericin fluconazole B or echinocandinswere combined rather thanwith implant removal fluconazole [2], with remission were combined rates with implant higher than removal [2], 80% withvs. 62%, similar remission ratesto valuesthan higher reported 80% vs.in previous 62%, similarstudies [32,39].reported to values Therefore, in we would recommend the use of an antifungal with antibiofilm activity, previous studies [32,39]. Therefore, we would recommend the use of an antifungal with amphotericin B or an echinocandin, after resection arthroplasty and after prosthesis implantation, antibiofilm activity, amphotericin B or an echinocandin, after resection arthroplasty and following our proposed after prosthesisdiagram of treatment implantation, in Figure following 2. our proposed diagram of treatment in Figure 2. Figure 2. Our proposal for optimal treatment of Candida periprosthetic joint infection. Figure 2. Our proposal for optimal treatment of Candida periprosthetic joint infection. On the other hand, few studies have evaluated the efficacy of using an antifungal On the other hand, few studies have evaluated the efficacy of using an antifungal agent-loaded cement spacer in staged exchange arthroplasty for CPJI, so the indication agent-loaded to use it remains cement spacer in staged controversial. exchange Moreover, therearthroplasty for CPJI, is no consensus onsowhich the indication antifungal to use it remains controversial. Moreover, there is no consensus agent should be used and at what dose to achieve the optimal balance between cement on which antifungal agent should stability beand used andelution. drug at what There dose tohave achieve beenthesomeoptimal casesbalance in which between cement Bstability amphotericin deoxy- and drugorelution. cholate an azole There (mainlyhavefluconazole been some or cases in which amphotericin voriconazole) was mixed with B deoxycholate the cement or in an theazole spacer (mainly fluconazole [2,15,35,40–42], withordifferent voriconazole) was mixed outcomes. In our with thepractice, clinical cement amphotericin in the spacer [2,15,35,40–42], with different B (200 mg of amphotericin outcomes. In our B deoxycholate clinical40practice, for every g of boneamphotericin cement) is often B (200usedmg of amphotericin B deoxycholate for every 40 g of bone cement) is often because of its broad antifungal spectrum and antibiofilm activity, its heat stability, and used because of its broad antifungal its availability inspectrum powder form.and antibiofilm However,activity, amphotericin its heatB stability, has beenand its availability proven to behave in powder form. differently However, amphotericin than water-soluble antibacterial B agents has been proven [43,44], andtoit behave is not cleardifferently whetherthan the water-soluble antibacterial agents [43,44], and it is not clear whether local dose is sufficiently high to elute from cement spacers [27,39,42–44] or whether it is the local dose is suf- ficiently high to elute toxic to osteoblasts from [45]. Ancement in vitrospacers [27,39,42–44] study found that the or whether elution of 800it is mgtoxic to osteo- of liposomal blasts [45]. An in vitro study found that the elution of 800 mg amphotericin B was higher than that of the same dose of deoxycholate amphotericin B of liposomal amphotericin Bwhen was higher mixed thanwith that of the acrylic same bone dose although cement, of deoxycholate amphotericin it was associated with B when a loss mixed with of compres- acrylic bone cement, sive strength [46]. Inalthough addition,it some was associated authors and with a loss ofhave ourselves compressive concernsstrength about using[46]. In addition, only antifungalsomeagents authors in and ourselves cement spacers,have andconcerns we prefer about using only to combine antifungal agents amphotericin B with in cement spacers, vancomycin and we prefer plus gentamycin to combine to avoid bacterialamphotericin superinfections B with vancomycin [15]. Until moreplus gen- evidence tamycin to avoid bacterial superinfections [15]. Until more evidence is available, we believe that using antifungal agent-loaded cement spacers (preferably with is available, we be- lieve that usingB antifungal amphotericin and combined agent-loaded cement spacers with antibacterial agents)(preferably with amphotericin in staged exchange arthroplasty B and seems combined reasonable withtoantibacterial avoid relapsesagents) in staged secondary exchange to fungi that arthroplasty may remain seems adhered reasona- to the ble boneto and avoid relapses cement secondary to fungi that may remain adhered to the bone and cement spacer. spacer. Another unsolved issue is the duration of antifungal treatment. Although short antifungal Another courses unsolved(6 weeks) issue iswere successful the duration in a small treatment. of antifungal series when using a short Although staged ex- anti- change procedure [33], the median duration of antifungal treatment fungal courses (6 weeks) were successful in a small series when using a staged exchange in larger studies was 3 months [2,12,25,34], procedure [33], the medianconsistent with IDSA duration guideline recommendations of antifungal treatment in larger [5]. studies In our opinion, was 3 7 Antibiotics 2021, 10, 458 8 of 10 at least 3 months of antifungal treatment are necessary, especially with a drug with an- tibiofilm activity (an echinocandin or amphotericin B) and combined with implant removal whenever possible, preferably in the form of a two-stage exchange procedure to maintain joint functionality (Figure 2). In patients with high surgical risk for whom prostheses cannot be removed, suppressive therapy with azoles may be an alternative treatment to maintain joint functionality [2]. 6. Prognosis and Prevention The prognosis of patients with CPJIs varies depending on the medical and surgical ap- proach. Often, aggressive surgical treatment is dismissed due to the patient’s comorbidities, and resection arthroplasty or amputation is performed, resulting in poor patient functional- ity, but at least curing the infection. On the other hand, even if performing the best strategy (a two-stage exchange), some patients may persist with the infection or relapse. A recent study found that the main risk factors for two-stage exchange failure are hemodialysis, obesity, multiple previous procedures, diabetes, corticosteroid therapy, hypoalbuminemia, immunosuppression, rheumatological diseases, coagulation disorders, and infection due to multidrug-resistant bacteria or fungal species [47]. Therefore, if some of these risk factors coexist in a patient with CPJI, a resection arthroplasty, agreed with the patient, may be the best alternative to cure the infection even if it implies loosing functionality. Unfortunately, we have no score of risk that helps us in making the best decision. In addition, due to the formation of biofilms by Candida spp., CPJIs, when treated, may take several months or even years to relapse. Patient follow-up varies among some studies, and this makes it difficult to establish when CPJI can be considered cured. In our personal experience, due to the chronic nature of CPJI, follow-up periods shorter than 2 years may not be able to detect some relapses. As histories of previous antibiotic therapy or surgery are not modifiable, we believe that searching for and treating Candida intertrigo in patients with risk factors for CPJI would be a reasonable, cost-effective measure [2,13]. Therefore, although there is no strong evidence to support this hypothesis, we believe that patients with previous Candida infection or clinical Candida colonization may benefit from the addition of fluconazole to standard prophylaxis before hip arthroplasty. Another more debatable measure would be including fluconazole in surgical prophylaxis for patients with an advanced age, diabetes, a long course of antibiotic therapy in the previous months (especially if it was with linezolid) and multiple previous orthopedic surgeries. As these factors may be difficult to evaluate retrospectively, prospective multicenter studies are needed. Given the poor prognosis of this type of infection, until more evidence is available regarding the best antifungal treatment, the duration of treatment, and the efficacy of using antifungal agent-loaded cement spacers, focusing on CPJI prevention remains essential. Author Contributions: L.E.-V. and C.P. contributed to the conception, methodology, writing of the original draft, and writing of the review and editing with the assistance of a medical writer. D.R.-P. and P.S.C. contributed to the review and editing of the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of Interest: The authors declare no conflict of interest. Abbreviations PJI periprosthetic joint infection CPJI Candida periprosthetic joint infection Antibiotics 2021, 10, 458 9 of 10 References 1. Tande, A.J.; Patel, R. Prosthetic Joint Infection. Clin. Microbiol. Rev. 2014, 27, 302–345. [CrossRef] [PubMed] 2. Escolà-Vergé, L.; Rodríguez-Pardo, D.; Lora-Tamayo, J.; Morata, L.; Murillo, O.; Vilchez, H.; Sorli, L.; Carrión, L.G.; Barbero, J.M.; Palomino-Nicás, J.; et al. Candida Periprosthetic Joint Infection: A Rare and Difficult-to-Treat Infection. J. Infect. 2018, 77, 151–157. [CrossRef] 3. Osmon, D.R.; Berbari, E.F.; Berendt, A.R.; Lew, D.; Zimmerli, W.; Steckelberg, J.M.; Rao, N.; Hanssen, A.; Wilson, W.R. Diagnosis and Management of Prosthetic Joint Infection: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin. Infect. Dis. 2013, 56, e1–e25. [CrossRef] [PubMed] 4. Ariza, J.; Cobo, J.; Baraia-Etxaburu, J.; Benito, N.; Bori, G.; Cabo, J.; Corona, P.; Esteban, J.; Horcajada, J.P.; Lora-Tamayo, J.; et al. Executive Summary of Management of Prosthetic Joint Infections. Clinical Practice Guidelines by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). Enferm. Infect. Microbiol. Clin. 2017, 35, 189–195. [CrossRef] 5. Pappas, P.G.; Kauffman, C.A.; Andes, D.R.; Clancy, C.J.; Marr, K.A.; Ostrosky-Zeichner, L.; Reboli, A.C.; Schuster, M.G.; Vazquez, J.A.; Walsh, T.J.; et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 2015, civ933. [CrossRef] 6. Parvizi, J.; Gehrke, T.; Chen, A.F. Proceedings of the International Consensus on Periprosthetic Joint Infection. Bone Jt. J. 2013, 95, 1450–1452. [CrossRef] 7. Belden, K.; Cao, L.; Chen, J.; Deng, T.; Fu, J.; Guan, H.; Jia, C.; Kong, X.; Kuo, F.-C.; Li, R.; et al. Hip and Knee Section, Fungal Periprosthetic Joint Infection, Diagnosis and Treatment: Proceedings of International Consensus on Orthopedic Infections. J. Arthroplast. 2019, 34, S387–S391. [CrossRef] 8. Benito, N.; Mur, I.; Ribera, A.; Soriano, A.; Rodríguez-Pardo, D.; Sorlí, L.; Cobo, J.; Fernández-Sampedro, M.; del Toro, M.; Guío, L.; et al. The Different Microbial Etiology of Prosthetic Joint Infections According to Route of Acquisition and Time after Prosthesis Implantation, Including the Role of Multidrug-Resistant Organisms. J. Clin. Med. 2019, 8, 673. [CrossRef] 9. Benito, N.; Franco, M.; Ribera, A.; Soriano, A.; Rodriguez-Pardo, D.; Sorlí, L.; Fresco, G.; Fernández-Sampedro, M.; Do- lores Del Toro, M.; Guío, L.; et al. Time Trends in the Aetiology of Prosthetic Joint Infections: A Multicentre Cohort Study. Clin. Microbiol. Infect. 2016, 22, 732.e1–732.e8. [CrossRef] 10. Peel, T.N.; Cheng, A.C.; Buising, K.L.; Choong, P.F.M. Microbiological Aetiology, Epidemiology, and Clinical Profile of Prosthetic Joint Infections: Are Current Antibiotic Prophylaxis Guidelines Effective? Antimicrob. Agents Chemother. 2012, 56, 2386–2391. [CrossRef] [PubMed] 11. Aggarwal, V.K.; Bakhshi, H.; Ecker, N.U.; Parvizi, J.; Gehrke, T.; Kendoff, D. Organism Profile in Periprosthetic Joint Infection: Pathogens Differ at Two Arthroplasty Infection Referral Centers in Europe and in the United States. J. Knee Surg. 2014, 27, 399–406. [CrossRef] 12. Azzam, K.; Parvizi, J.; Jungkind, D.; Hanssen, A.; Fehring, T.; Springer, B.; Bozic, K.; Della Valle, C.; Pulido, L.; Barrack, R. Microbiological, Clinical, and Surgical Features of Fungal Prosthetic Joint Infections: A Multi-Institutional Experience. J. Bone Jt. Surg. Am. Vol. 2009, 91, 142–149. [CrossRef] [PubMed] 13. Riaz, T.; Tande, A.J.; Steed, L.L.; Demos, H.A.; Salgado, C.D.; Osmon, D.R.; Marculescu, C.E. Risk Factors for Fungal Prosthetic Joint Infection. J. Bone Jt. Infect. 2020, 5, 76–81. [CrossRef] [PubMed] 14. Saconi, E.S.; de Carvalho, V.C. Prosthetic Joint Infection Due to Candida Species. Medicine 2020, 99, e19735. [CrossRef] [PubMed] 15. Cobo, F.; Rodríguez-Granger, J.; Sampedro, A.; Aliaga-Martínez, L.; Navarro-Marí, J.M. Candida Prosthetic Joint Infection. A Review of Treatment Methods. J. Bone Jt. Infect. 2017, 2, 114–121. [CrossRef] 16. Pappas, P.G.; Lionakis, M.S.; Arendrup, M.C.; Ostrosky-Zeichner, L.; Kullberg, B.J. Invasive Candidiasis. Nat. Rev. Dis. Primers 2018, 4, 18026. [CrossRef] [PubMed] 17. McCarty, T.P.; Pappas, P.G. Invasive Candidiasis. Infect. Dis. Clin. N. Am. 2016, 30, 103–124. [CrossRef] [PubMed] 18. Kullberg, B.J.; Arendrup, M.C. Invasive Candidiasis. N. Engl. J. Med. 2015, 373, 1445–1456. [CrossRef] 19. Hube, B. From Commensal to Pathogen: Stage- and Tissue-Specific Gene Expression of Candida albicans. Curr. Opin. Microbiol. 2004, 7, 336–341. [CrossRef] 20. Finkel, J.S.; Mitchell, A.P. Genetic Control of Candida albicans Biofilm Development. Nat. Rev. Microbiol. 2011, 9, 109–118. [CrossRef] 21. Kuhn, D.M. Comparison of Biofilms Formed by Candidaalbicans and Candidaparapsilosis on Bioprosthetic Surfaces. Infect. Immun. 2002, 70, 878–888. [CrossRef] [PubMed] 22. Sam, Q.; Chang, M.; Chai, L. The Fungal Mycobiome and Its Interaction with Gut Bacteria in the Host. Int. J. Mol. Sci. 2017, 18, 330. [CrossRef] [PubMed] 23. García-Oltra, E.; García-Ramiro, S.; Martínez, J.C.; Tibau, R.; Bori, G.; Bosch, J.; Mensa, J.; Soriano, A. Prosthetic joint infection by Candida spp. Rev. Esp. Quimioter. 2011, 24, 37–41. [PubMed] 24. Brown, T.S.; Petis, S.M.; Osmon, D.R.; Mabry, T.M.; Berry, D.J.; Hanssen, A.D.; Abdel, M.P. Periprosthetic Joint Infection With Fungal Pathogens. J. Arthroplast. 2018, 33, 2605–2612. [CrossRef] 25. Kuiper, J.W.; van den Bekerom, M.P.; van der Stappen, J.; Nolte, P.A.; Colen, S. 2-Stage Revision Recommended for Treatment of Fungal Hip and Knee Prosthetic Joint Infections: An Analysis of 164 Patients, 156 from the Literature and 8 Own Cases. Acta Orthop. 2013, 84, 517–523. [CrossRef] Antibiotics 2021, 10, 458 10 of 10 26. McNally, M.; Sousa, R.; Wouthuyzen-Bakker, M.; Chen, A.F.; Soriano, A.; Vogely, H.C.; Clauss, M.; Higuera, C.A.; Trebše, R. The EBJIS Definition of Periprosthetic Joint Infection: A Practical Guide for Clinicians. Bone Jt. J. 2021, 103, 18–25. [CrossRef] 27. Kuhn, D.M.; George, T.; Chandra, J.; Mukherjee, P.K.; Ghannoum, M.A. Antifungal Susceptibility of Candida Biofilms: Unique Efficacy of Amphotericin B Lipid Formulations and Echinocandins. Antimicrob. Agents Chemother. 2002, 46, 1773–1780. [CrossRef] 28. Nett, J.E. Future Directions for Anti-Biofilm Therapeutics Targeting Candida. Expert Rev. Anti Infect. Ther. 2014, 12, 375–382. [CrossRef] 29. Iñigo, M.; Pemán, J.; Del Pozo, J.L. Antifungal Activity against Candida Biofilms. Int. J. Artif. Organs 2012, 35, 780–791. [CrossRef] 30. Mukherjee, P.K.; Chandra, J. Candida Biofilms: Development, Architecture, and Resistance. Microbiol. Spectrum. 2015, 3. [CrossRef] 31. Ueng, S.W.N.; Lee, C.-Y.; Hu, C.; Hsieh, P.-H.; Chang, Y. What Is the Success of Treatment of Hip and Knee Candidal Periprosthetic Joint Infection? Clin. Orthop. Relat. Res. 2013, 471, 3002–3009. [CrossRef] 32. Hwang, B.H.; Yoon, J.Y.; Nam, C.H.; Jung, K.A.; Lee, S.C.; Han, C.D.; Moon, S.H. Fungal Peri-Prosthetic Joint Infection after Primary Total Knee Replacement. J. Bone Jt. Surg. Br. 2012, 94, 656–659. [CrossRef] [PubMed] 33. Anagnostakos, K.; Kelm, J.; Schmitt, E.; Jung, J. Fungal Periprosthetic Hip and Knee Joint Infections. J. Arthroplast. 2012, 27, 293–298. [CrossRef] [PubMed] 34. Phelan, D.M.; Osmon, D.R.; Keating, M.R.; Hanssen, A.D. Delayed Reimplantation Arthroplasty for Candidal Prosthetic Joint Infection: A Report of 4 Cases and Review of the Literature. Clin. Infect. Dis. 2002, 34, 930–938. [CrossRef] [PubMed] 35. Gao, Z.; Li, X.; Du, Y.; Peng, Y.; Wu, W.; Zhou, Y. Success Rate of Fungal Peri-Prosthetic Joint Infection Treated by 2-Stage Revision and Potential Risk Factors of Treatment Failure: A Retrospective Study. Med. Sci. Monit. 2018, 24, 5549–5557. [CrossRef] [PubMed] 36. Selmon, G.P.F.; Slater, R.N.S.; Shepperd, J.N.; Wright, E.P. Successful 1-Stage Exchange Total Knee Arthroplasty for Fungal Infection. J. Arthroplast. 1998, 13, 114–115. [CrossRef] 37. Klatte, T.O.; Kendoff, D.; Kamath, A.F.; Jonen, V.; Rueger, J.M.; Frommelt, L.; Gebauer, M.; Gehrke, T. Single-Stage Revision for Fungal Peri-Prosthetic Joint Infection: A Single-Centre Experience. Bone Jt. J. 2014, 96-B, 492–496. [CrossRef] 38. Katragkou, A.; Chatzimoschou, A.; Simitsopoulou, M.; Dalakiouridou, M.; Diza-Mataftsi, E.; Tsantali, C.; Roilides, E. Differential Activities of Newer Antifungal Agents against Candida Albicans and Candida Parapsilosis Biofilms. Antimicrob. Agents Chemother. 2008, 52, 357–360. [CrossRef] 39. Schoof, B.; Jakobs, O.; Schmidl, S.; Klatte, T.O.; Frommelt, L.; Gehrke, T.; Gebauer, M. Fungal Periprosthetic Joint Infection of the Hip: A Systematic Review. Orthop. Rev. 2015, 7. [CrossRef] 40. Bruce, A.S.W.; Kerry, R.M.; Norman, P.; Stockley, I. Fluconazole-Impregnated Beads in the Management of Fungal Infection of Prosthetic Joints. J. Bone Jt. Surg. Br. Vol. 2001, 83, 183–184. [CrossRef] 41. Deelstra, J.J.; Neut, D.; Jutte, P.C. Successful Treatment of Candida Albicans–Infected Total Hip Prosthesis with Staged Procedure Using an Antifungal-Loaded Cement Spacer. J. Arthroplast. 2013, 28, 374.e5–374.e8. [CrossRef] [PubMed] 42. Marra, F.; Robbins, G.M.; Masri, B.A.; Duncan, C.; Wasan, K.M.; Kwong, E.H.; Jewesson, P.J. Amphotericin B-Loaded Bone Cement to Treat Osteomyelitis Caused by Candida albicans. Can. J. Surg. 2001, 44, 383. 43. Goss, B.; Lutton, C.; Weinrauch, P.; Jabur, M.; Gillett, G.; Crawford, R. Elution and Mechanical Properties of Antifungal Bone Cement. J. Arthroplast. 2007, 22, 902–908. [CrossRef] [PubMed] 44. Kweon, C.; McLaren, A.C.; Leon, C.; McLemore, R. Amphotericin B Delivery From Bone Cement Increases With Porosity but Strength Decreases. Clin. Orthop. Relat. Res. 2011, 469, 3002–3007. [CrossRef] [PubMed] 45. Harmsen, S.; McLaren, A.C.; Pauken, C.; McLemore, R. Amphotericin B Is Cytotoxic at Locally Delivered Concentrations. Clin. Orthop. Relat. Res. 2011, 469, 3016–3021. [CrossRef] [PubMed] 46. Cunningham, B.; McLaren, A.C.; Pauken, C.; McLemore, R. Liposomal Formulation Increases Local Delivery of Amphotericin from Bone Cement: A Pilot Study. Clin. Orthop. Relat. Res. 2012, 470, 2671–2676. [CrossRef] 47. Fagotti, L.; Tatka, J.; Salles, M.J.C.; Queiroz, M.C. Risk Factors and Treatment Options for Failure of a Two-Stage Exchange. Curr. Rev. Musculoskelet. Med. 2018, 11, 420–427. [CrossRef] [PubMed]