Approaches in surgical treatment of fungal prosthetic joint infection

Hazem Mohammad Ishaq Alkhawashki; Carlo Luca Romanò; Heinz Winkler; Joseph Benevenia; Lorenzo Drago; Thami Benzakour; Guenter Lob

doi:10.71165/kva7-k6hf

Summary

Background: Fungal prosthetic joint infection (fPJI) is an infrequent but complex complication of arthroplasty, occurring in 0.6% to 2% of cases. Primarily caused by Candida species, these infections are characterized by insidious clinical presentations and the formation of resilient biofilms on prosthetic surfaces. Diagnosis is often delayed due to non-specific inflammatory markers and the requirement for prolonged culture incubation.

Objective: This review synthesizes current literature regarding the epidemiology, risk factors, diagnostic protocols, and surgical management strategies for fPJI to provide evidence-based clinical recommendations.

Key Points: Candida species account for 50% to 80% of cases, frequently involving polymicrobial biofilms with Staphylococcus species. Risk factors include immunosuppression, diabetes, and prior revision surgery. Diagnostic accuracy relies on standardized sampling, as systemic markers like C-reactive protein may remain normal. Surgical options include debridement, antibiotics, and implant retention (DAIR), which demonstrates low success rates (20-30%), and staged revision. Two-stage revision is the most utilized approach, with reported success rates between 47% and 100%. Emerging protocols suggest three-stage revisions or antifungal-loaded spacers containing amphotericin B or voriconazole. However, optimal antifungal duration and reimplantation timing remain controversial.

Conclusion: Management of fPJI requires aggressive surgical debridement combined with prolonged systemic antifungal therapy. While two-stage revision is the current preferred strategy, the lack of high-level evidence necessitates multicenter studies to standardize treatment algorithms and optimize local antifungal delivery methods.

Introduction

Among the many thousands of species of fungi, about a 100-cause infection in h umans [1] Kobayashi G S. (1990). Fungi. In: Davis B D, Dulbecco R, Eisen H N, Ginsberg H S, eds. Microbiology. Philadelphia: Lippincott, 737-65.. Fungal infections are not readily recognized and do not advertise their presence and are not easy to demonstrate [2], Marta L Cuellar, Luis H Silveira, Luis R Espinoza. (1992). Fungal Arthritis. Annals of Rheumatic Diseases, 51: 690-697.[3] Ehrlich G E. (1978). Fungal arthritis [editorial]. JAMA, 240:563.. Fungal arthritis has a worldwide distribution with prevalence ranging from 0.4% to 20%, is more in men and usually presents as oligoarthritic [2] Marta L Cuellar, Luis H Silveira, Luis R Espinoza. (1992). Fungal Arthritis. Annals of Rheumatic Diseases, 51: 690-697.. Fungal prosthetic joint infection (fPJI) ranges between 0.6-2% [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[5] Saconi ES, Carvalho VC, Oliveira PR, Lima AL. (2020). Prosthetic joint infection due to Candida species: case series and review of literature. Medicine, 99:15(e19735). Bone and joint fungal infection may result from direct inoculation, contiguous spread, or hematogenous seeding, which is the most common, and more commonly causes osteomyelitis than septic arthritis. [1], Kobayashi G S. (1990). Fungi. In: Davis B D, Dulbecco R, Eisen H N, Ginsberg H S, eds. Microbiology. Philadelphia: Lippincott, 737-65.[6], Bariteau JT, Waryasz GR, McDonnell M, Fischer SA, Hayda RA, Born CT. (2014). Fungal osteomyelitis and septic arthritis. J Am Acad Orthop Surg. Jun;22(6):390-401. doi: 10.5435/JAAOS-22-06-390. PMID: 24860135.[7] Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.. There are conflicting reports on the common age and commonest sex affected by fPJI, with a range between 52 and 85 years and some reports of male predominance and others of female predominance [5], Saconi ES, Carvalho VC, Oliveira PR, Lima AL. (2020). Prosthetic joint infection due to Candida species: case series and review of literature. Medicine, 99:15(e19735)[8], Ueng AWN, Lee C, Hu C, et al. (2013). What is the success of treatment of hip and knee candidal periprosthetic joint infection. Clin Orthop Relat Res, 471:3002–9.[9] Azzam K, Parvizi J, Jungkind D, et al. (2009). Microbiological, clinical, and surgical features of fungal prosthetic joint infections: a multi-institutional experience. J Bone Jt Surg Am, 91(Suppl 6):142–9..

Results

Fungal PJI is most commonly caused by the Candida Albicans and non -Albicans species (50-80%), followed by Aspergillus [19], E. Chisari, F. Lin, J. Fei et al. (2022). Fungal periprosthetic joint infection: Rare but challenging problem. Chinese Journal of Traumatology 25, 63-66.[20], Eric M. Ruderman, John P. Flaherty. (2016). Fungal infections of bone and joints. In Muskuloskeletal Key search engine, chapter 112,2015. [21], Theil C, Schmidt-Braekling T, Gosheger G, Idelevich EA, Moellenbeck B, Dieckmann R. (2019). Fungal prosthetic joint infection in total hip or knee arthroplasty: a retrospective single-centre study of 26 cases. Bone Joint J. May;101-B(5):589-595. doi: 10.1302/0301-620X.101B5.BJJ-2018-1227.R2. PMID: 31038988.[22] Talha Riaz, Aaron J. Tande, Lisa L. Steed, Harry A. Demos, Cassandra D. Salgado, Douglas R. Osmon, Camelia E. Marculescu. (2020). Risk Factors for Fungal Prosthetic Joint Infection. J. Bone Joint Infect. 5(2): 76-81. doi: 10.7150/jbji.40402..

A major factor of the virulence of Candida is its ability to form biofilms, attaching to biotic and abiotic substrates, and forming on synthetic polymers as prosthetic plastics, which are hard to eradicate and are resistant to conventional antifungal treatments [9], Azzam K, Parvizi J, Jungkind D, et al. (2009). Microbiological, clinical, and surgical features of fungal prosthetic joint infections: a multi-institutional experience. J Bone Jt Surg Am, 91(Suppl 6):142–9.[23] Ponde NO, Lortal L, Ramage G, Naglik JR, Richardson JP. (20210. Candida albicansbiofilms and polymicrobial interactions. Crit Rev Microbiol. 2021 Feb;47(1):91-111. doi: 10.1080/1040841X.2020.1843400. Epub, Jan 22. PMID: 33482069; PMCID: PMC7903066.. Candida Albicans produces larger and more complex biofilm than other Candida species [9] Azzam K, Parvizi J, Jungkind D, et al. (2009). Microbiological, clinical, and surgical features of fungal prosthetic joint infections: a multi-institutional experience. J Bone Jt Surg Am, 91(Suppl 6):142–9., hence it is recommended to remove the device affected, and the biofilm formation passes through 4 stages; i) adsorption and adhesion of C. albicans yeast cells to a substrate, ii) formation of microcolonies and production of extracellular matrix, iii) maturation and iv) dispersal of cells from the mature biofilm, (Fig. 1) [23] Ponde NO, Lortal L, Ramage G, Naglik JR, Richardson JP. (20210. Candida albicansbiofilms and polymicrobial interactions. Crit Rev Microbiol. 2021 Feb;47(1):91-111. doi: 10.1080/1040841X.2020.1843400. Epub, Jan 22. PMID: 33482069; PMCID: PMC7903066.. Once formed, the biofilm is highly tolerant to antifungal therapy and can serve as a reservoir for recurrent infection.

Figure 1: Stages of Candida albicans biofilm formation and development. Candida albicans biofilm formation is a multifactorial process that consists of four main stages. 1) Initial attachment of planktonic cells: C. albicans yeasts attach to a surface (e.g. epithelia, biomaterials or cellular aggregates) through adhesins. 2) Proliferation and filamentation: yeasts transition to hyphae and this process is regulated by many transcription factors 3) Biofilm maturation and extracellular matrix formation: the matrix forms around the C. albicans cells, positively regulated by the TF Rlm1p, providing structural support and protection against antifungals and the host immune system. Adhesion is maintained and amino acid metabolism is increased in the biofilm. 4) Biofilm dispersion: yeast cells disperse from the biofilm to colonise other parts of the body. These cells differ from initial planktonic cells as they are more virulent and more likely to form biofilms. Reprinted from open access reference (23)

It is a common occurrence to have a concomitant bacterial infection among cases of fPJI, ranging between 16%-66%, most commonly Staphylococcus species followed by streptococcus spp. [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[21], Theil C, Schmidt-Braekling T, Gosheger G, Idelevich EA, Moellenbeck B, Dieckmann R. (2019). Fungal prosthetic joint infection in total hip or knee arthroplasty: a retrospective single-centre study of 26 cases. Bone Joint J. May;101-B(5):589-595. doi: 10.1302/0301-620X.101B5.BJJ-2018-1227.R2. PMID: 31038988.[24] Kuiper JW, van den Bekerom MP, van der Stappen J, Nolte PA, Colen S. (2013). 2-stage revision recommended for treatment of fungal hip and knee prostheticjoint infections. Acta Orthop. Dec;84(6):517-23. doi: 10.3109/17453674.2013.859422. Epub 2013 Oct 31. PMID: 24171675; PMCID: PMC3851663.. This wide range of bacterial co-infection could be because the reported cases in literature included primary arthroplasty, re-explored knee joints, revision, and re-revision arthroplasty cases.

One other factor which may explain the high concomitant bacterial infection is the interactions of C. albicans with other microorganisms which can occur via co-aggregation and co-adhesion. C. albicans adhesins facilitate interaction with bacterial species such as Streptococcus gordonii and Staphylococcus aureus, (Fig. 2)[23] Ponde NO, Lortal L, Ramage G, Naglik JR, Richardson JP. (20210. Candida albicansbiofilms and polymicrobial interactions. Crit Rev Microbiol. 2021 Feb;47(1):91-111. doi: 10.1080/1040841X.2020.1843400. Epub, Jan 22. PMID: 33482069; PMCID: PMC7903066..

Figure 2: C. albicans interactions within a multispecies biofilm. Complex physical and chemical interactions govern the development of polymicrobial biofilms. A) Several factors influence C. albicans-bacterial adhesion. Staphylococcus aureus and Streptococcus gordonii can utilise C. albicans adhesins to directly bind to hyphae. In contrast, glycosyltransferases (Gtfs) secreted by Streptococcus mutans within the oral cavity can bind to C. albicans mannans, increasing the production of glucans and ECM production. Consequently, the glucan increases the ability of the bacterium to bind to C. albicans and forms a C. albicans-S. mutans biofilm on the tooth surface (dental plaque). B) Signalling molecules produced by C. albicans and bacterial species enable interkingdom communication within multispecies biofilms. For example, S. mutans and Pseudomonas aeruginosa can secrete quorum sensing molecules that influence the behaviour of C. albicans within the biofilm. Likewise, the C. albicans quorum sensing molecule farnesol, can influence the behaviour of interacting bacteria. Reprinted from open access reference (23)

There are several risk factors reported in literature. Fungal PJI occurs most commonly in immune compromised patients, those with previous surgeries and revision cases of joint replacement. Riaz et al. [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[22] Talha Riaz, Aaron J. Tande, Lisa L. Steed, Harry A. Demos, Cassandra D. Salgado, Douglas R. Osmon, Camelia E. Marculescu. (2020). Risk Factors for Fungal Prosthetic Joint Infection. J. Bone Joint Infect. 5(2): 76-81. doi: 10.7150/jbji.40402. reported that antimicrobial therapy within three months before the diagnosis of PJI and the presence of wound drainage lasting longer than five days prior to the diagnosis of PJI are independent risk factors and significantly associated with increased odds of fPJI when compared with bacterial PJI. Other risk factors of fPJI include diabetes, prolonged use of antibiotics, previous PJI and immunosuppression (chemotherapy, cancer patients, HIV, those on corticosteroids, and organ transplant patients), those on indwelling catheter, parenteral nutrition and the illicit IV drug users [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[19], E. Chisari, F. Lin, J. Fei et al. (2022). Fungal periprosthetic joint infection: Rare but challenging problem. Chinese Journal of Traumatology 25, 63-66.[25], Maria N Gamaletsou, Thomas J Walsh, Nikolaos V Sipsas. (2014). Epidemiology of Fungal Osteomyelitis. Current Fungal Infection Reports, Dec 8 (4): 262-270. [26], Koutserimpas, C.; Chamakioti, I.; Zervakis, S.; Raptis, K.; Alpantaki, K.; Kofteridis, D.P.; Vrioni, G.; Samonis, G. (2021). Non-Candida Fungal Prosthetic Joint Infections. Diagnostics, 11, 1410. [CrossRef][27], Koutserimpas, C.; Zervakis, S.G.; Maraki, S.; Alpantaki, K.; Ioannidis, A.; Kofteridis, D.P.; Samonis, G. (2019). Non-albicans Candida prosthetic joint infections: A systematic review of treatment. World J. Clin. Cases, 7, 1430–1443. [CrossRef] [PubMed][28] Koutserimpas, C.; Samonis, G.; Velivassakis, E.; Iliopoulou-Kosmadaki, S.; Kontakis, G.; Kofteridis, D.P. (2018). Candida glabrata prosthetic joint infection, successfully treated with anidulafungin: A case report and review of the literature. Mycoses, 61,266–269[CrossRef] [PubMed]..

To diagnose fPJI the surgeon should have a high suspension index, especially in high-risk patients. It is not routine to do all diagnostic tests, except in the most uncertain cases. We recommend following the WAIOT 10 golden rules of sampling for diagnosis of PJI, (Fig. 3) [29] Drago L, Clerici P, Morelli I, Ashok J, Benzakour T, Bozhkova S, Alizadeh C, Del Sel H, Sharma HK, Peel T, Mattina R, Romanò CL. (2019). The World Association against Infection in Orthopaedics and Trauma (WAIOT) procedures for Microbiological Sampling and Processing for Periprosthetic Joint Infections (PJIs) and other Implant-Related Infections. J Clin Med., Jun 28;8(7):933. doi: 10.3390/jcm8070933. PMID: 31261744; PMCID: PMC6678965. and using the WAIOT definition of high and low grade PJI, Table 1 [30] Romanò CL, Khawashki HA, Benzakour T, Bozhkova S, Del Sel H, Hafez M, Johari A, Lob G, Sharma HK, Tsuchiya H, Drago L; (2019). World Association against Infection in Orthopedics and Trauma (W.A.I.O.T.) Study Group on Bone and Joint Infection Definitions. The W.A.I.O.T. Definition of High-Grade and Low-Grade Peri-Prosthetic Joint Infection. J Clin Med., May 10;8(5):650. doi: 10.3390/jcm8050650. PMID: 31083439; PMCID: PMC6571975..

Figure 3: Microbiology best practice for the diagnosis of peri-prosthetic joint infections and implant-related infections in ortho-trauma. The 10 WAIOT golden rules. Reprinted with permission of Publisher. Open access reference [29]

Table 1: WAIOT proposed definition of peri-prosthetic joint infection (PJI)

A diagnostic arthrocentesis is performed, unless there is a sinus tract or exposed metal, and surgical debridement is a must [7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[13], Osmon DR, Berbari EF, Berendt AR, et al. (2013). Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis, 56: e1–25.[35] Beam, E.; Osmon, D. (2018). Prosthetic Joint Infection Update. Infect. Dis. Clin. N. Am., 32, 843–859. [CrossRef]. Aspirate is analysed for low sugar, high protein, and cell count (more than 3000), although they may be of limited value [19] E. Chisari, F. Lin, J. Fei et al. (2022). Fungal periprosthetic joint infection: Rare but challenging problem. Chinese Journal of Traumatology 25, 63-66.. The aspirate is sent for both bacterial and fungal cultures, the latter will take up to 4 weeks or longer [19] E. Chisari, F. Lin, J. Fei et al. (2022). Fungal periprosthetic joint infection: Rare but challenging problem. Chinese Journal of Traumatology 25, 63-66.. Intraoperative samples are taken in accordance with WAIOT 10 rules and sent for cultures and histopathology [29] Drago L, Clerici P, Morelli I, Ashok J, Benzakour T, Bozhkova S, Alizadeh C, Del Sel H, Sharma HK, Peel T, Mattina R, Romanò CL. (2019). The World Association against Infection in Orthopaedics and Trauma (WAIOT) procedures for Microbiological Sampling and Processing for Periprosthetic Joint Infections (PJIs) and other Implant-Related Infections. J Clin Med., Jun 28;8(7):933. doi: 10.3390/jcm8070933. PMID: 31261744; PMCID: PMC6678965..

Fungi are notoriously difficult to isolate [19] E. Chisari, F. Lin, J. Fei et al. (2022). Fungal periprosthetic joint infection: Rare but challenging problem. Chinese Journal of Traumatology 25, 63-66., and although Candida is readily recovered using blood culture bottles (BCB) [36] Tai DBG, Wengenack NL, Patel R, Berbari EF, Abdel MP, Tande AJ. (2022). Fungal and mycobacterial cultures should not be routinely obtained for diagnostic work-up of patients with suspected periprosthetic joint infections. Bone Joint J., 104-B (1):53-58. doi: 10.1302/0301-620X.104B1.BJJ-2021-0876.R1, but Sabouraud dextrose brain heart infusion (BHI) or plain BHI are universal media for most fungi, and other special media are required for other types of fungi [37], Bosshard PP. (2011). Incubation of fungal cultures: how long is long enough? Mycoses., 54:539e545. https://doi.org/10.1111/j.1439-0507.2010.01977.x.[38] Williamson MA, Snyder LM, Wallach JB. (2011). Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis. Philadelphia, PA: Wolters.

More sophisticated serology and molecular tests are not readily available, and their clinical use is still under investigation and include organism-specific antigens, serum beta-glucan, enzyme immunoassays, DNA based tests and mass spectrometry [20], Eric M. Ruderman, John P. Flaherty. (2016). Fungal infections of bone and joints. In Muskuloskeletal Key search engine, chapter 112,2015. [39] Benoit Pilmis, et.al. (2017). In Infectious Diseases, 439-470 (4th edition), Elsevier Limited.. In some culture -negative cases, uncultivable organisms should be considered, and other identification techniques are performed, such as polymerase chain reaction (PCR) and next generation sequencing (NGS) [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[40] Nace, J.; Siddiqi, A.; Talmo, C.T.; Chen, A.F. (2019). Diagnosis and Management of Fungal Periprosthetic Joint Infections. J. Am. Acad. Orthop. Surg., 27, e804–e818. [CrossRef].

Radiological assessment and diagnoses are beyond the scope of this review, but in fPJI all what may be needed is a plain x-ray. Although radionucleotide scans, MRI and CT are used in other fungal infections, their use in diagnosing and managing PJI is questionable [7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[41], Carol A. Kemper, Stanley C. Deresinski. (2009). In clinical Mycology, 525-546 (2nd edition), Churchill Livingstone/Elsevier [42], Elizabeth G. Demicco, et.al. (2018). In Diagnostic Pathology of Infectious Disease, 404-428 (2nd edition), Elsevier [43] Prasanna G. Vibhute, et.al. (2009). In Clinical Mycology 109-159 (2nd edition), Churchill Livingstone/Elsevier.

Discussion

The literature lacks both evidence and clear algorithm regarding the best treatment approach in treating fPJI, but there has been preference toward certain surgical approaches and recommendations regarding both medical and surgical managements [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[5], Saconi ES, Carvalho VC, Oliveira PR, Lima AL. (2020). Prosthetic joint infection due to Candida species: case series and review of literature. Medicine, 99:15(e19735)[7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[19], E. Chisari, F. Lin, J. Fei et al. (2022). Fungal periprosthetic joint infection: Rare but challenging problem. Chinese Journal of Traumatology 25, 63-66.[44] Cobo F, Rodríguez-Granger J, Sampedro A, Aliaga-Martínez L, Navarro-Marí JM. Candida Prosthetic Joint Infection. (2017). A Review of Treatment Methods. J Bone Jt Infect. Feb 5;2(2):114-121. doi: 10.7150/jbji.17699. PMID: 28540147; PMCID: PMC5441142..

Regarding medical treatment, the Infectious Disease Society of America (IDSA) guidelines for the duration of treatment with antifungal agents in the treatment of joint arthritis are 6 to 12 months [12] Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Reboli AC, Schuster MG, Vazquez JA, Walsh TJ, Zaoutis TE, Sobel JD. (2016). Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. Feb 15;62(4):e1-50. doi: 10.1093/cid/civ933. Epub 2015 Dec 16. PMID: 26679628; PMCID: PMC4725385.. For Candida PJI, the European Society for Clinical Microbiology and Infectious Disease recommends implant removal with at least 14 days of parenteral antifungals followed by a subsequent minimum of 4 to 6 weeks of oral agents [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[45], Izakovicova, P.; Borens, O.; Trampuz, A. (2019). Periprosthetic joint infection: Current concepts and outlook. EFORT Open Rev., 4,482–494. [CrossRef][46] Ullmann, A.J.; Aguado, J.M.; Arikan-Akdagli, S.; Denning, D.W.; Groll, A.H.; Lagrou, K.; Lass-Flörl, C.; Lewis, R.E.; Munoz, P.; Verweij, P.E.; et al. (2018). Diagnosis and management of Aspergillus diseases: Executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin. Microbiol. Infect., 24 (Suppl. S1), e1–e38.. In the case of two-stage exchange, the International Consensus Meeting (ICM) recommends a minimum of 6 weeks antifungal treatment after prosthesis removal [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[47] Parvizi, J.; Gehrke, T.; Chen, A.F. (2013). Proceedings of the International Consensus on Periprosthetic Joint Infection. Bone Jt. J., 95, 1450–1452. [CrossRef]. A meta-analysis by Ueng et al. [8] Ueng AWN, Lee C, Hu C, et al. (2013). What is the success of treatment of hip and knee candidal periprosthetic joint infection. Clin Orthop Relat Res, 471:3002–9. identified an improved eradication of infection with prolonged systemic therapy from 3-6 months.

There is no agreement on the optimal choice of antifungal medication or whether to use monotherapy or combined therapy and the choice should be driven by resistance patterns and patient factors as well as the chronicity of the case. Most reports favor fluconazole, variconazole and amphotericin B [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[5], Saconi ES, Carvalho VC, Oliveira PR, Lima AL. (2020). Prosthetic joint infection due to Candida species: case series and review of literature. Medicine, 99:15(e19735)[7] Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.. The liposomal compounds of amphotericin B have a better record in reducing nephrotoxicity [7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[48], Hamill, R.J. Amphotericin B formulations: (2013). A comparative review of efficacy and toxicity. Drugs, 73, 919–934. [CrossRef] [PubMed][49] Nett, J.E.; Andes, D.R. (2016). Antifungal Agents: Spectrum of Activity, Pharmacology, and Clinical Indications. Infect. Dis. Clin. N. Am., 30, 51–83. [CrossRef] [PubMed]. There are no existing guidelines for the use of prophylactic anti-fungal therapy in high-risk, immunocompromised patients going for total joint replacement [7] Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606..

There has not been adequate studies of the elution characteristics of antifungal agents from bone cement (PMMA) or calcium sulphates, although the commonly used amphotericin B was reported to have the longest elution properties of up to 100 days, but other agents including fluconazole and variconazole have been used also [7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[50] Henry MW, Miller AO, Walsh TJ, Brause BD. (2017). Fungal Musculoskeletal Infections. Infect Dis Clin North Am. Jun;31(2):353-368. doi10.1016/j.idc.2017.01.006. PMID: 28483045.. A few papers have reported both In-vitro and In-vivo result to know more of the elution properties of antifungal agents as well as finding the best vehicle to assure a higher concentrations and longer elution. Butcher MC et al. [51] Mark C. Butcher, Jason L. Brown, Donald Hansom, Rebecca Wilson-van Os,Craig Delury,Phillip A. Laycock,Gordon Ramagea. (2021). Assessing the Bioactive Profile of Antifungal-Loaded Calcium Sulfate against Fungal Biofilms. Antimicrob Agents Chemother., 05 18; 65(6) has reported on antifungal-loaded triple agents (fluconazole (FLZ), amphotericin B (AMB), and caspofungin (CSP), calcium sulfate beads, producing a sustained antimicrobial effect that inhibits and kills clinically relevant fungal species in vitro as planktonic and biofilm cells. Romera D et al. [52] David Romera , Beatriz Toirac, John-Jairo Aguilera-Correa, Amaya García-Casas, Aránzazu Mediero, Antonia Jiménez-Morales and Jaime Esteban.(2020). A Biodegradable Antifungal-Loaded Sol–Gel Coating for the Prevention and Local Treatment of Yeast Prosthetic-Joint Infections. Materials (Basel). Jul 15; 13(14). have reported a Novel hybrid organo-inorganic sol-gel coating of fluconazole or anidulafungin, with the highest concentration to prevent and locally treat yeast PJI. They have showed an excellent anti-biofilm behavior. Coatings loaded with fluconazole proved to be effective against both Candida species. The use of resorbable beads have been reported by Yung-Heng Hsu et al. [53] Yung-Heng Hsu, Huang-Yu Chen, Jin-Chung Chen, Yi-Hsun Yu. (2019). Resorbable Beads Provide Extended Release of Antifungal Medication: In Vitro and In Vivo Analyses. Pharmaceutics, October, 11(11):550 . They reported a high level of fluconazole (beyond the minimum therapeutic concentration [MTC]) release for more than 49 days, using biodegradable compression-molded PLGA (Poly(d,l-lactide-co-glycolide) /fluconazole beads.

Following surgical debridement, reports have had different approaches in dealing with fungal PJI. The numbers reported are small to draw firm conclusions, although recent meta-analysis and systematic reviews have shed more light into the best surgical approach in dealing with fPJI. The options at hand are DAIR (Debridement, Antibiotics, Implant Retention), one stage revision arthroplasty (Single-SRA), two stage revision arthroplasty (Two-SRA), three stage revision arthroplasty (Three-SRA), resection arthroplasty, arthrodesis, and amputation [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[5], Saconi ES, Carvalho VC, Oliveira PR, Lima AL. (2020). Prosthetic joint infection due to Candida species: case series and review of literature. Medicine, 99:15(e19735)[7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[19], E. Chisari, F. Lin, J. Fei et al. (2022). Fungal periprosthetic joint infection: Rare but challenging problem. Chinese Journal of Traumatology 25, 63-66.[21], Theil C, Schmidt-Braekling T, Gosheger G, Idelevich EA, Moellenbeck B, Dieckmann R. (2019). Fungal prosthetic joint infection in total hip or knee arthroplasty: a retrospective single-centre study of 26 cases. Bone Joint J. May;101-B(5):589-595. doi: 10.1302/0301-620X.101B5.BJJ-2018-1227.R2. PMID: 31038988.[24], Kuiper JW, van den Bekerom MP, van der Stappen J, Nolte PA, Colen S. (2013). 2-stage revision recommended for treatment of fungal hip and knee prostheticjoint infections. Acta Orthop. Dec;84(6):517-23. doi: 10.3109/17453674.2013.859422. Epub 2013 Oct 31. PMID: 24171675; PMCID: PMC3851663.[54] Baecker H, Frieler S, Geßmann J, Pauly S, Schildhauer TA, Hanusrichter Y. (2021). Three-stage revision arthroplasty for the treatment of fungal periprosthetic joint infection: outcome analysis of a novel treatment algorithm: a prospective study. Bone Jt Open., Aug;2(8):671-678. doi: 10.1302/2633-1462.28.BJO-2021-0002.R2. PMID: 34406077; PMCID: PMC8384437..

It has to be noted that amputation, arthrodesis, and resection arthroplasty (RA) may highly diminish the quality of life of the patients and the reported success rate of RA and arthrodesis from small series and heterogeneous reports is 80% and 67% respectively [7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[27] Koutserimpas, C.; Zervakis, S.G.; Maraki, S.; Alpantaki, K.; Ioannidis, A.; Kofteridis, D.P.; Samonis, G. (2019). Non-albicans Candida prosthetic joint infections: A systematic review of treatment. World J. Clin. Cases, 7, 1430–1443. [CrossRef] [PubMed], and that of amputation is 66% only [55] Enz, A.; Mueller, S.C.; Warnke, P.; Ellenrieder, M.; Mittelmeier, W.; Klinder, A. (2021). Periprosthetic Fungal Infections in Severe Endoprosthetic Infections of the Hip and Knee Joint-A Retrospective Analysis of a Certified Arthroplasty Centre of Excellence. J. Fungi, 7, 404. [CrossRef] [PubMed]. Therefore, they should be sought of as a salvage procedure in the most resistance cases or those with repeated uncontrollable infection despite multiple procedures and long anti-fungal treatment. The reported surgical treatment methods come from small case series, case reports and systematic reviews and are heterogeneous [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[5], Saconi ES, Carvalho VC, Oliveira PR, Lima AL. (2020). Prosthetic joint infection due to Candida species: case series and review of literature. Medicine, 99:15(e19735)[7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[12], Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Reboli AC, Schuster MG, Vazquez JA, Walsh TJ, Zaoutis TE, Sobel JD. (2016). Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. Feb 15;62(4):e1-50. doi: 10.1093/cid/civ933. Epub 2015 Dec 16. PMID: 26679628; PMCID: PMC4725385.[19], E. Chisari, F. Lin, J. Fei et al. (2022). Fungal periprosthetic joint infection: Rare but challenging problem. Chinese Journal of Traumatology 25, 63-66.[26], Koutserimpas, C.; Chamakioti, I.; Zervakis, S.; Raptis, K.; Alpantaki, K.; Kofteridis, D.P.; Vrioni, G.; Samonis, G. (2021). Non-Candida Fungal Prosthetic Joint Infections. Diagnostics, 11, 1410. [CrossRef][27], Koutserimpas, C.; Zervakis, S.G.; Maraki, S.; Alpantaki, K.; Ioannidis, A.; Kofteridis, D.P.; Samonis, G. (2019). Non-albicans Candida prosthetic joint infections: A systematic review of treatment. World J. Clin. Cases, 7, 1430–1443. [CrossRef] [PubMed][44], Cobo F, Rodríguez-Granger J, Sampedro A, Aliaga-Martínez L, Navarro-Marí JM. Candida Prosthetic Joint Infection. (2017). A Review of Treatment Methods. J Bone Jt Infect. Feb 5;2(2):114-121. doi: 10.7150/jbji.17699. PMID: 28540147; PMCID: PMC5441142.[56] Cobo F, Rodríguez-Granger J, López EM, Jiménez G, Sampedro A, Aliaga-Martínez L, Navarro-Marí JM. (2017). Candida-induced prosthetic joint infection. A literature review including 72 cases and a case report. Infect Dis (Lond). Feb;49(2):81-94. doi: 10.1080/23744235.2016.1219456. Epub 2016 Sep 1. PMID: 27586845..

Debridement, antibiotic, and implant retention (DAIR) have been used in small number of cases and mainly in cases reported within 4 weeks of the primary procedure and often resulting in persistent infection and 20-30% success rate only [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[5], Saconi ES, Carvalho VC, Oliveira PR, Lima AL. (2020). Prosthetic joint infection due to Candida species: case series and review of literature. Medicine, 99:15(e19735)[24], Kuiper JW, van den Bekerom MP, van der Stappen J, Nolte PA, Colen S. (2013). 2-stage revision recommended for treatment of fungal hip and knee prostheticjoint infections. Acta Orthop. Dec;84(6):517-23. doi: 10.3109/17453674.2013.859422. Epub 2013 Oct 31. PMID: 24171675; PMCID: PMC3851663.[31] Hwang BH, Yoon JY, Nam CH, et al. (2012). Fungal peri-prosthetic joint infection after primary total knee replacement. J Bone Joint Surg Br, 94:656–9.. For bacterial PJI, the consensus is that chronic infections should never be treated with DAIR, and the same has been suggested for fPJI, unless revision surgery is contraindicated or refused by the patient after adequate information [13], Osmon DR, Berbari EF, Berendt AR, et al. (2013). Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis, 56: e1–25.[24], Kuiper JW, van den Bekerom MP, van der Stappen J, Nolte PA, Colen S. (2013). 2-stage revision recommended for treatment of fungal hip and knee prostheticjoint infections. Acta Orthop. Dec;84(6):517-23. doi: 10.3109/17453674.2013.859422. Epub 2013 Oct 31. PMID: 24171675; PMCID: PMC3851663.[63] Crockarell JR, Hanssen AD, Osmon DR, Morrey BF. (1998). Treatment of infection with debridement and retention of the components following hip arthroplasty. J Bone Joint Surg (Am);80(9):1306–13. [PubMed] [Google Scholar].

In a recent systematic review, Sambri et al. [4] Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084. and Koutserimpas et al. [7] Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606. reported a predominance favoring of Two-SRA, (64.2%) and (54%) respectively. Other authors also reported a preference of Two-SRA among surgeons [9], Azzam K, Parvizi J, Jungkind D, et al. (2009). Microbiological, clinical, and surgical features of fungal prosthetic joint infections: a multi-institutional experience. J Bone Jt Surg Am, 91(Suppl 6):142–9.[11], Parvizi J, Gehrke T, Chen AF. (2013). Proceedings of the international consensus meeting on periprosthetic joint infection. Bone Joint J,95-B:1450–2.[19], E. Chisari, F. Lin, J. Fei et al. (2022). Fungal periprosthetic joint infection: Rare but challenging problem. Chinese Journal of Traumatology 25, 63-66.[24], Kuiper JW, van den Bekerom MP, van der Stappen J, Nolte PA, Colen S. (2013). 2-stage revision recommended for treatment of fungal hip and knee prostheticjoint infections. Acta Orthop. Dec;84(6):517-23. doi: 10.3109/17453674.2013.859422. Epub 2013 Oct 31. PMID: 24171675; PMCID: PMC3851663.[26], Koutserimpas, C.; Chamakioti, I.; Zervakis, S.; Raptis, K.; Alpantaki, K.; Kofteridis, D.P.; Vrioni, G.; Samonis, G. (2021). Non-Candida Fungal Prosthetic Joint Infections. Diagnostics, 11, 1410. [CrossRef][27], Koutserimpas, C.; Zervakis, S.G.; Maraki, S.; Alpantaki, K.; Ioannidis, A.; Kofteridis, D.P.; Samonis, G. (2019). Non-albicans Candida prosthetic joint infections: A systematic review of treatment. World J. Clin. Cases, 7, 1430–1443. [CrossRef] [PubMed][55] Enz, A.; Mueller, S.C.; Warnke, P.; Ellenrieder, M.; Mittelmeier, W.; Klinder, A. (2021). Periprosthetic Fungal Infections in Severe Endoprosthetic Infections of the Hip and Knee Joint-A Retrospective Analysis of a Certified Arthroplasty Centre of Excellence. J. Fungi, 7, 404. [CrossRef] [PubMed]. A success rate of over 92% has been reported for Two-SRA [7], Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.[57], Haleem, A.A.; Berry, D.J.; Hanssen, A.D. (2004). Mid-term to long-term followup of two-stage reimplantation for infected total knee arthroplasty. Clin. Orthop. Relat. Res., 35–39. [CrossRef][58] Anagnostakos, K.; Kelm, J.; Schmitt, E.; Jung, J. (2012). Fungal periprosthetic hip and knee joint infections clinical experience with a 2-stage treatment protocol. J. Arthroplast., 27, 293–298. [CrossRef] [PubMed], although there is wide variability of success rate. Anagnostakos et al. [58] Anagnostakos, K.; Kelm, J.; Schmitt, E.; Jung, J. (2012). Fungal periprosthetic hip and knee joint infections clinical experience with a 2-stage treatment protocol. J. Arthroplast., 27, 293–298. [CrossRef] [PubMed] reported a 100% success in a small series of 7 patients. Haleem et al reported infection eradication up to above 90% [4], Sambri, A.; Zunarelli, R.; Fiore, M.; Bortoli, M.; Paolucci, A.; Filippini, M.; Zamparini, E.; Tedeschi, S.; Viale, P.; De Paolis, M. (2023). Epidemiology of Fungal Periprosthetic Joint Infection: A Systematic Review of the Literature. Microorganisms, 11, 84 https://doi.org/10.3390/microorganisms11010084.[57] Haleem, A.A.; Berry, D.J.; Hanssen, A.D. (2004). Mid-term to long-term followup of two-stage reimplantation for infected total knee arthroplasty. Clin. Orthop. Relat. Res., 35–39. [CrossRef]. Kuiper et al [24] Kuiper JW, van den Bekerom MP, van der Stappen J, Nolte PA, Colen S. (2013). 2-stage revision recommended for treatment of fungal hip and knee prostheticjoint infections. Acta Orthop. Dec;84(6):517-23. doi: 10.3109/17453674.2013.859422. Epub 2013 Oct 31. PMID: 24171675; PMCID: PMC3851663. reported an 84.8% success rate, and Phelan et al [59] Phelan, D.M.; Osmon, D.R.; Keating, M.R.; Hanssen, A.D. (2002). Delayed reimplantation arthroplasty for candidal prosthetic joint infection: A report of 4 cases and review of the literature. Clin. Infect. Dis., 34, 930–938. [CrossRef] reported 80%. On the other hand, Azzam et al. [9] Azzam K, Parvizi J, Jungkind D, et al. (2009). Microbiological, clinical, and surgical features of fungal prosthetic joint infections: a multi-institutional experience. J Bone Jt Surg Am, 91(Suppl 6):142–9. reported a 47.4% success rate only. It is notable that the success rate diminishes in the case of bacterial co-infection [7] Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606..

The optimal time interval for reimplantation is unknown. A minimum of six weeks is usually recommended [19], E. Chisari, F. Lin, J. Fei et al. (2022). Fungal periprosthetic joint infection: Rare but challenging problem. Chinese Journal of Traumatology 25, 63-66.[24] Kuiper JW, van den Bekerom MP, van der Stappen J, Nolte PA, Colen S. (2013). 2-stage revision recommended for treatment of fungal hip and knee prostheticjoint infections. Acta Orthop. Dec;84(6):517-23. doi: 10.3109/17453674.2013.859422. Epub 2013 Oct 31. PMID: 24171675; PMCID: PMC3851663., although this is extended to 3-6 months in revision and re-revision cases [7] Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.. In all cases reimplantation is performed when the clinical picture and blood markers have come to normal [24] Kuiper JW, van den Bekerom MP, van der Stappen J, Nolte PA, Colen S. (2013). 2-stage revision recommended for treatment of fungal hip and knee prostheticjoint infections. Acta Orthop. Dec;84(6):517-23. doi: 10.3109/17453674.2013.859422. Epub 2013 Oct 31. PMID: 24171675; PMCID: PMC3851663.. There is no conclusive evidence to support the use of an antimicrobial holiday period prior to reimplantation in case of fungal PJI treated with staged revision [21] Theil C, Schmidt-Braekling T, Gosheger G, Idelevich EA, Moellenbeck B, Dieckmann R. (2019). Fungal prosthetic joint infection in total hip or knee arthroplasty: a retrospective single-centre study of 26 cases. Bone Joint J. May;101-B(5):589-595. doi: 10.1302/0301-620X.101B5.BJJ-2018-1227.R2. PMID: 31038988..

The Single-SRA has been used and reported with discordant results. A success rate of 90% has been reported by Klatte et al (60) in a small series of 10 patients. On the other hand, Ji et al [61] Ji, B.; Zhang, X.; Xu, B.; Guo, W.; Mu, W.; Cao, L. (2017). Single-Stage Revision for Chronic Fungal Periprosthetic Joint Infection: An Average of 5 Years of Follow-Up. J. Arthroplast., 32, 2523–2530. [CrossRef] reported a recurrence rate of 36%. Others have reported a 75% success rate [7] Koutserimpas, C.; Naoum, S.; Alpantaki, K.; Raptis, K.; Dretakis, K.; Vrioni, G.; Samonis, G. (2022). Fungal Prosthetic Joint Infection in Revised Knee Arthroplasty: An Orthopaedic Surgeon’s Nightmare. Diagnostics, 12, 1606. https://doi.org/ 10.3390/diagnostics12071606.. A Single-SRA might be considered in patients with unfit medical situation or those who may not tolerate multiple procedures, along with prolonged anti-fungal therapy.

The gold standard of bacterial PJI has been the Two-SRA, although Gregor Dersch and Heinz Winkler [62] Dersch, G.; Winkler, H. Periprosthetic Joint Infection (PJI)—Results of One-Stage Revision with Antibiotic-Impregnated Cancellous Allograft Bone—A Retrospective Cohort Study. Antibiotics 2022, 11, 310. https://doi.org/10.3390/antibiotics11030310 have reported favorable and encouraging results of Single-SRA by using Antibiotic-Impregnated Cancellous Allograft Bone, on 70 cases. Whether their technique could be adopted for fPJI is for future research to decide.

Recently, a three-SRA for fungal PJI was reported and claimed 88.8% success [54] Baecker H, Frieler S, Geßmann J, Pauly S, Schildhauer TA, Hanusrichter Y. (2021). Three-stage revision arthroplasty for the treatment of fungal periprosthetic joint infection: outcome analysis of a novel treatment algorithm: a prospective study. Bone Jt Open., Aug;2(8):671-678. doi: 10.1302/2633-1462.28.BJO-2021-0002.R2. PMID: 34406077; PMCID: PMC8384437.. This technique is in accordance with the recommendations of PRO-IMPLANT Foundation for difficult to treat (DDT) microorganisms [64] Izakovicova P, Borens O, Trampuz A. (2019). Periprosthetic joint infection: current concepts and outlook. EFORT Open Rev.;4(7):482–494 . The principles of this algorithm include, but are not limited to, the following key points:

First stage; debridement, removal of implant (sonication & culture). A custom-made cement spacer loaded with 0.4 g liposomal amphotericin B and voriconazole 0.4 g combined with 1 g gentamicin and 2 vancomycin per 40 g cement powder is used. If fungi not diagnosed preoperatively 1 g Gentamycine and 2 g Vancomycine spacer is used only.

Second stage; 3 weeks revision, debridement, and exchange of spacer. The same custom-made cement spacer with amphotericin B and voriconazole is used again to ensure continuously high local antimycotic therapy. The residual AB therapy will be adapted according to sonication.

Third stage; 3 weeks reimplantation. Again, debridement and final implantation of revision implant with custom made cement including amphotericin B 0.2 g and Voriconazol 0.2 g combined with 0.5 g Gentamicin and 2 g vancomycin is performed. This is followed by six months systemic anti-fungal treatment which is switched to oral after uneventful postoperative period and wound healing.

While Two-SRA appears as the most adopted surgical approach, there are no comparative studies, showing its superiority over Single-SRA, while the overall results of a 3-stage revision surgery do not seem to provide a substantial benefit, compared to 2-stage. In this regard, it should be noted that staged procedures are inevitably associated with additional operative risks, prolonged duration of the treatment and higher costs and an increase of the number of several subsequent procedures should be well balanced in each patient, weighing the potential benefits and risks.

Recommendations and conclusion

According to the presented data and review of literature, we believe that we can recommend the following generally agreed approach in treating fungal PJI, even if the specific treatment for each patient must be decided by the surgical team after open discussion with the patient and based on the general and local conditions, the clinical history and the expectations of the patient:

We believe that fPJI management lacks proper evidence and high volume, multi-center studies to draw sound conclusions regarding anti-fungal therapy agents, duration, combination treatment and success, as well as the best surgical options. In addition, more studies on the elution of antifungal agents, the minimum time interval between the two stages as well as establishing potent antibiofilm, antimicrobial agents and the possibility of using antifungal medications impregnation in bone graft in Single-SRA. These questions cannot be answered without the collaboration between multiple centers worldwide.

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