Non-albicans Candida prosthetic joint infections: A systematic review of treatment

ARTICLE HIGHLIGHTS

Research background

Prosthetic joint infection (PJI) represents a severe complication of joint reconstruction surgery, causing total arthroplasty failure. Many pathogens have been identified in PJIs, such as Gram-positive and negative bacteria, while fungal microorganisms are considered rare causes, occurring in 1-2% of cases. Candida spp represent the most common fungal pathogens in these infections, with Candida albicans being the most prevalent species. However, the incidence of non-albicans Candida PJIs has increased over the last years. Hence, regarding non-albicans Candida PJIs, only case reports or small series have been reported so far. Optimal treatment is considered the two stage revision surgery in combination with an antifungal agent. However, no clear guidelines have yet been developed regarding the agent and treatment duration. Hence, a broad range of antifungal and surgical treatments has been reported so far. The present review article represents the first effort of evaluating the reported non-albicans Candida PJIs, aiming to clarify the treatment options of these infections and, possibly, to improve the medical and surgical care of such cases.

Research motivation

The absence of clear guidelines regarding fungal PJIs represents a primary issue in managing these infections in clinical practice. A broad range of antifungal and surgical treatments have been reported, while treatment duration remains unclear. Furthermore, due to the limited data regarding these infections, information about patient demographics, responsible non- albicans Candida species, time between initial arthroplasty and symptom onset, time between symptom onset and definite diagnosis (culture), and outcome of the infection has not been reported in a systematic way. Hence, it is of utmost importance in the future to report such cases in order to obtain a better understanding about this devastating arthroplasty complication.

Research objectives

The main objective of this study was to clarify, by systematically reviewing current published cases in the literature, the treatment options of non-albicans Candida PJIs and, possibly, to improve the medical and surgical care of such cases. During the process of reviewing the literature, it became apparent that information about patient demographics, fungal species, time between initial arthroplasty and symptom onset, time between symptom onset and definite diagnosis (culture), as well as outcome of the infection should also be reported, due to the absence of a systematic review regarding this topic.

Research methods

A meticulous electronic search of PubMed and MEDLINE databases was performed to identify all articles reporting the management of non-albicans Candida PJIs cases through April 2018 by two independent investigators. The citations in each article were reviewed to locate additional references that were not retrieved during the initial search. The evaluated parameters were patient demographics and comorbidities, affected joints, responsible non- albicans Candida species, duration and type of antifungal treatment, type of surgical treatment, time between initial arthroplasty and symptom onset, time between symptom onset and definite diagnosis (culture), and outcome of the infection. Data were recorded and analyzed using Microsoft Excel 2010 (Microsoft Corporation, Redmond, Washington). Two-sided Fisher’s exact tests were used to compare success rates between groups. Statistical analyses were carried out at the 5% level of significance.

Research results

A total of 83 non-albicans Candida PJIs were located, with a mean age of 66.3 years (SD = 10.2). The knee was the affected joint in 52 cases (62.6%), the hip in 29 (35%) and the shoulder in 2 (2.4%). The mean time from arthroplasty to symptoms onset was found to be 27.2 mo (SD = 43), while the mean time from symptoms onset to culture-confirmed diagnosis was 7.5 mo (SD = 12.5). The most commonly isolated non-albicans Candida species was C. parapsilosis, found in 45 cases (54.2%), followed by C. glabrata in 18 (21.7%), C. tropicalis in 10 (12%), C pelliculosa in 3 (3.6%) and C. lusitanae in 2 (2.4%), while C. famata, C. lipolytica, C. utilis, C. guilliermondii and C. freyschussii had caused one case each (1.2%). A two stage revision arthroplasty (TSRA) was performed in most cases (44 cases; 53%), followed by RA (18 cases; 22%), OSRA (8 cases; 9.6%), arthrodesis (5 cases; 6%), debridement (3 cases; 3.6%) and amputation (2 cases; 2.4%), while 3 cases (3.6%) received no surgical treatment. TSRA when compared to OSRA had a higher success rate (96% vs 73%; P-value = 0.023). Fluconazole was used in most cases as antifungal treatment [59; (71%), in 31 of them (52.5%) as monotherapy], followed by amphotericin B [41; (49.4%), in 4 (9.8%) as monotherapy], flucytosine [13; (15.7%), in 1 (7.7%) as monotherapy], caspofungin [7; (8.4%), in 1 (14.3%) as monotherapy], voriconazole [7; (8.4%), in 2 (28.6%) as monotherapy], ketoconazole [5; (6%), none as monotherapy], itraconazole [3; (3.6%), none as monotherapy] and anidulafungin [l; (1.2%), none as monotherapy]. The final outcome was successful in 74 cases (89.2%). The mean antifungal treatment duration was 12.8 wk (SD = 10.9), while the mean follow-up of these cases was 33.3 mo (SD = 19.6). The present review has shown that the optimal management of non-albicans Candida consists of a combination of the proper medical antifungal treatment and surgical intervention. Although there have been reports of the successful treatment of such cases with OSRA and debridement only, TSRA should be strongly recommended. The combination of TSRA and a prolonged period of antifungal therapy based on susceptibility testing is suggested on the basis of limited data. Additional issues, such as the duration of antifungal therapy after prosthesis implantation (second stage of the TSRA) and the role of antifungal-loaded cement spacers need to be addressed in order to determine an optimal treatment combination.

Research conclusions

The present study is an effort to review, in a systematic way, the non-albicans Candida PJI cases described in the literature. The study focuses on the preferred antifungal agent, the optimal surgical treatment, and the duration of therapy. C. parapsilosis was found to be the predominant pathogen causing PJIs, as compared to other non-albicans Candida species. For successful management of non-albicans Candida PJI, susceptibility testing to obtain accurate MIC values should always be performed following the Candida isolation, considering that different Candida species are characterized by intrinsic resistance to certain antifungal compounds. The mean duration of antifungal treatment in the present review was 12.8 wk, while it ranged from 1 to 53 wk. Although, guidelines for the treatment of osteoarticular infections from Candida spp are available, no clear recommendations exist for the treatment of such PJIs. Therefore, the treatment duration is mostly based upon clinical and laboratory findings. In most cases (44 cases; 53%) a TSRA was performed, followed by RA (18 cases; 22%), OSRA (8 cases; 9.6%), arthrodesis (5 cases; 6%), debridement (3 cases; 3.6%) and amputation (2 cases; 2.4%). Three cases did not receive surgical treatment (3.6%). RA, arthrodesis, amputation and debridement are usually considered alternative options to arthroplasty exchange. TSRA when compared to OSRA had a statistically significant higher success rate (96% vs 73%; P-value= 0.023). Therefore, it seems more proper that TSRA should be considered as the optimal surgical intervention. The present review has shown that the optimal management of non-albicans Candida PJIs consists of a combination of the proper medical antifungal treatment based on susceptibility testing and a surgical intervention, while TSRA should be strongly recommended. The combination of TSRA separated by 3–6 mo, in addition to a prolonged period of antifungal therapy, is suggested.

Research perspectives

Non-albicans Candida PJIs represent a dangerous reality. The combination of TSRA separated by 3–6 mo and a prolonged period of antifungal therapy is suggested on the basis of limited data. It is of paramount importance to report the treatment of such cases, even the failed ones, in order to obtain a better understanding of these infections and to determine the optimum treatment combination.