J Bone Joint Infect 2017; 2(2):114-121. doi:10.7150/jbji.17699

Review

Candida Prosthetic Joint Infection. A Review of Treatment Methods

Fernando Cobo1 Corresponding address, Javier Rodríguez-Granger1, Antonio Sampedro1, Luis Aliaga-Martínez2, José María Navarro-Marí1

1. Department of Microbiology, Hospital Virgen de las Nieves, Granada, Spain.
2. Department of Internal Medicine, Hospital Virgen de las Nieves, Granada, Spain.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Cobo F, Rodríguez-Granger J, Sampedro A, Aliaga-Martínez L, Navarro-Marí JM. Candida Prosthetic Joint Infection. A Review of Treatment Methods. J Bone Joint Infect 2017; 2(2):114-121. doi:10.7150/jbji.17699. Available from http://www.jbji.net/v02p0114.htm

Abstract

Fungal microorganisms are still a rare cause of bone and joint infections. We report a new case of knee prosthetic joint infection due to Candida albicans in a patient with a previous two-stage right knee arthroplasty for septic arthritis due to S. epidermidis occurred several months ago. Moreover, the treatment in 76 cases of Candida prosthetic joint infection has been discussed. Forty patients were female and mean age at diagnosis was 65.7 (± SD 18) yrs. No risk factors for candidal infection were found in 25 patients. Infection site was the knee in 38 patients and hip in 36; pain was present in 44 patients and swelling in 24. The most frequent species was C. albicans, followed by C. parapsilosis. Eleven patients were only treated with antifungal drugs being the outcome favourable in all of them. Two-stage exchange arthroplasty was performed in 30 patients, and resection arthroplasty in other 30; in three patients one-stage exchange arthroplasty was done. A favourable outcome was found in 58 patients after antifungal plus surgical treatment, in 11 after antifungal treatment alone and in one after surgery alone. The type of treatment is still not clearly defined and an algorithm for treatment in fungal PJI should be established, but various types of surgical procedures may be applied.

Keywords: Prosthetic joint infection, Candida albicans, arthroplasty, infection, antifungal drugs, surgical treatment

Introduction

Prosthetic joint infection (PJI) involves the joint prosthesis and contiguous tissue and is one of the main reasons for total arthroplasty failure [1, 2]. A wide range of microorganisms may cause PJI, most often Gram-positive bacteria, especially staphylococcal species, and Gram-negative pathogens [3]. However, other microorganisms can also be responsible for PJI, including fungi, particularly Candida species. PJI due to Candida is rare and represents a therapeutic challenge because no specific guidelines have been already established and published case reports vary widely in therapeutic approach [4]. Currently, the gold standard for treatment consists in a two-stage revision surgery [4, 5], although it is doubtful whether multiple procedures are able to provide any improvements and it is also unknown if other techniques such as one-stage exchange may be successful.

Here, we describe one patient seen at the Orthopaedics and Trauma Department of the Hospital Universitario Virgen de las Nieves (Granada, Spain) with PJI due to C. albicans which is being treated with antifungal drugs alone. Moreover, we have reviewed the medical literature searching case reports with Candida PJI discussing about the treatment methods applied.

Case Report

A 66-year-old man had a right knee arthroplasty due to osteoarthritis suffered for several years. In January 2015, the patient underwent a two-stage right knee arthroplasty for septic arthritis due to S. epidermidis, as well as treatment with vancomycin + gentamycin. He was immunocompromised due to a splenectomy performed several years ago. In July 2016, the patient was attended at the Emergency Department of our Hospital due to pain, inflammation and joint leak for two weeks. The physical examination revealed inflammatory signs and swelling on the knee. The complete blood count, chemical profile and urinalysis were normal, except for a C-reactive protein (CRP) of 100 mg/L. A joint fluid (JF) was drawn by puncture from the affected knee and sent to the microbiology laboratory. The sample was inoculated after centrifugation in aerobic and anaerobic blood agar (BD Columbia Agar 5% Sheepblood®, Becton Dickinson), chocolate agar (BD Choco Agar, Becton Dickinson) and thioglycollate broth (BDTM Fluid Thioglycollate Medium), all incubated at 37º C. Previously, 1 mL of the JF was inoculated into an aerobic blood culture bottle (BACTEC, 9240 BD, Becton Dickinson, Franklin Lakes, NJ, USA), being positive after 24 hours of incubation. Pathogen growth was observed on aerobic blood agar and chocolate agar. Identification of C. albicans and susceptibility to this strain were then tested using the Vitek system (BioMérieux, Mercy L'Etoile, France) as well as mass spectrometry (Bruker Biotyper, Billerica, MA, USA). The isolate was susceptible to anidulafungin (0.015 µg/ml), micafungin (<0.008 µg/ml) caspofungin (0.06 µg/ml), voriconazole (<0.008 µg/ml), itraconazole (0,03 µg/ml) fluconazole (0,125 µg/ml), and amphotericin B (1 µg/ml). Breakpoints from CLSI were used for the majority of antifungal drugs, but only from EUCAST for amphotericin B [6, 7]. No blood cultures were taken at this stage. The patient rejected a prosthesis exchange, so a surgical procedure was then done with local debridement of the lesion, and five intraoperative periprosthetic tissue samples were taken from different locations, following recommendations of Kamme and Lindberg [8]. In the laboratory, each sample (1 cm2) was placed in 3 ml of sterile saline solution and vortexed for 30 seconds. Then, the sample was inoculated in aerobic and anaerobic blood agar (BD Columbia Agar 5% Sheepblood®, Becton Dickinson), chocolate agar (BD Choco Agar, Becton Dickinson) and thioglycolate broth (BDTM Fluid Thioglycollate Medium, Becton Dickinson), all incubated at 37º C., and chromogenic candida agar (CandiSelect TM, Bio-Rad, Redmond, WA, USA) incubated at 30º C. After 18 hours of incubation, microorganism growth was again observed and further identified as C. albicans.

Treatment with caspofungin (50 mg/day) was administered for 14 days, and the patient was then discharged under oral suppressive treatment with fluconazole (200 mg/12 h.) for 6 months. At 2 months of follow-up, the patient remained clinically stable, and laboratory findings were normal. At the moment, the patient has rejected prosthesis reimplantation and is currently waiting for a 6 months of antifungal treatment.

Literature Review

We describe one patient recently seen at the Orthopaedics and Trauma Department of the Hospital Universitario Virgen de las Nieves (Granada, Spain) with PJI due to C. albicans.

Using the key words “fungal prosthetic joint infection” and “candida prosthetic joint infection” we searched MEDLINE (National Library of Medicine, Bethesda, MD), Web of Science, CINAHL, and Cochrane systematic review databases for case reports of this condition. We also checked the references cited in the papers for additional case reports published before 1966.

We traced 75 cases caused by Candida species and described in sufficient detail. These cases, along with our patient, are the basis of the present report. Among others, data on treatment, outcome and follow-up were recorded. A patient was considered to have Candida infection and was then included when a positive preoperative aspiration culture and/or a positive intraoperative culture were obtained. We did not include cases with Candida infection accompanied by another pathogen or cases with insufficient details for comparisons (clinical and laboratory data).

The basis for this review was recently published [9], but we have added three new cases of Candida PJI. Table 1 summarizes the treatment, outcome and follow-up of all cases here reviewed.

General Characteristics

There were 40 (52.6%) women, while the sex was not reported in two patients. The mean age of patients was 65.7 (± SD 18) yrs (range 35-93 yrs). Thirty-five cases were from the USA [10-33], 10 from Taiwan [34-36], six from the United Kingdom [37-41], six from Germany [42], four from France [43-45], three from Italy [46-48], two each from Japan [49, 50] and Spain [9, and present report], and one each from China [51], India [52], Slovenia [53], Belgium [54], Turkey [55], Canada [56], Malaysia [57] and Sweden [58]. No risk factors for candidal infection were found in 25 patients (32.8%). The joint involved was the knee in 38 (50%), the hip in 36 (47.3%) and the shoulder in two cases. Pain was reported by 44 (57.8%) patients, and the second most frequent symptom was swelling in 24 (31.5%) patients. Symptoms were not reported for 18 (23.6%) patients.

The most frequently isolated Candida species was C. albicans, found in 36 (47.3%), followed by C. parapsilosis in 17 (22.3%), C. glabrata in 12 (15.7%) and C. tropicalis in 8 (10.5%), with infection by both C. albicans and C. glabrata in one patient [40]. Candida species were diagnosed by culture of joint fluid (JF) aspirate in 33 cases (43.4%), culture of intraoperative sample (IoS) in 18 (23.6%) and culture of both JF and IoS samples in 19 (25%). Blood cultures were taken only in eight (10.5%) patients, and were positive for Candida in four of these (50%).

 Table 1 

Treatment, outcome and follow-up of 76 patients with Candida species PJI.

Reference/
author
Treatment
Antifungal treatment Surgical treatment
OutcomeFollow-up (months)
51/Zhu YAmphotericin B
Voriconazole
NRCure3
52/Reddy KJFluconazole
Amphotericin B ICS
TEACure24
46/Artiaco SFluconazole
Miconazole
Drainage of abscessCure12
37/Lidder SAmphotericin BTEACure24
34/Ueng SWNFluconazole
Amphotericin B ICS
TEACureNR
34/Ueng SWNFluconazoleTEACureNR
34/Ueng SWNFluconazoleTEACureNR
34/Ueng SWNFluconazole
Amphotericin B ICS
TEACureNR
34/Ueng SWNFluconazole
Amphotericin B ICS
TEACureNR
34/Ueng SWNFluconazoleRANRNR
34/Ueng SWNFluconazoleRANRNR
34/Ueng SWNFluconazoleRADeadNR
42/Anagnostakos KCaspofunginTEACure28
42/Anagnostakos KFluconazoleTEACure22
42/Anagnostakos KFluconazoleTEACure70
42/Anagnostakos KFluconazoleTEACure15
42/Anagnostakos KFluconazoleTEACure36
42/Anagnostakos KFluconazoleTEACure47
47/Bartalesi FVoriconazole
Caspofungin + amphotericin B
Amphotericin B
TEACure48
35/Wu MHFluconazole
Amphotericin B ICS
RACure12
11/ Kelesidis TFluconazoleNRCure12
12/Graw BFluconazoleTEACure
Dead (UD)
240
13/Bland CMLiposomal amphotericin B + micafungin + fluconazoleRANRNR
43/Dumaine VCaspofungin + flucytosine
Fluconazole + flucytosine
RA
Arthrodesis
Cure15
53/Lejko-Zupanc TLiposomal amphotericin B + fluconazole
Caspofungin
RACure36
54/Fabry KVoriconazole (3 days)
Oral voriconazole (7 months)
NRCure
Dead (UD)
24
27 (/2004) Gaston GVoriconazole
Amphotericin B
Amphotericin B ICS
RAAmputation6
48/Lazzarini LAmphotericin BRACure48
15/Wyman JFluconazole
Amphotericin B
TEACure36
16/Phelan DMAmphotericin B
Ketoconazole
Fluconazole
TEACure73
16/Phelan DMNRTEACure51
16/Phelan DMAmphotericin B
Fluconazole
TEACure70
16/Phelan DMFluconazole
Fluconazole ICS
TEACure17
55/Açkgöz CZFluconazoleRA
Arthrodesis
Cure7.5
38/Bruce ASWFluconazole
Fluconazole IB
TEACure84
38/Bruce ASWFluconazole
Fluconazole IB
TEACure
Dead (UD)
48
56/Marra FFluconazole
Amphotericin B ICS
RA (twice)E. coli infection
NR final outcome
NR
44/Merrer JFluconazoleNRCure
Dead (UD)
11
36/Yang SHFluconazoleTEACure48
39/Ramamohan NAmphotericin B + 5-flucytosineTEACure24
57/Badrul BFluconazoleTEAMRSA infection
Cure
60
49/Wada MFluconazoleNRCure36
17/Brooks DHAmphotericin B
Fluconazole
NRCure24
40/Selmon GPFAmphotericin B
Itraconazole + fluconazole
OEACure48
18/Simonian PTKetoconazoleNRCure72
50/Fukasawa NFluconazoleNRP. aeruginosa
infection
Cure
24
19/Cushing RDFluconazoleNRCure12
58/Nayeri F5-flucytosine + amphotericin B
5-flucytosine + itraconazole
RACure22
20/Hennesy MJAmphotericin B
5-flucytosine
TEACure24
21/Cardinal EAmphotericin BRACure
Dead (UD)
NR
21/Cardinal EAmphotericin BRACure
Dead (UD)
12
21/Cardinal EFluconazoleRACure6
22/White AFluconazole
Amnphotericin B
Itraconazole
RACure24
23/Tunkel ARAmphotericin B
Ketoconazole
Fluconazole
RAAmputationNR
41/Paul JAmphotericin B + 5-fluorocytosine
Ketoconazole
RA
Arthrodesis
Cure24
24/Evans RPAmphotericin BTEACure24
24/Evans RPAmphotericin BTEAS. aureus infection
Cure
60
25/Darouiche ROAmphotericin BRACure8
25/Darouiche ROAmphotericin BRACure1.5
25/Darouiche ROAmphotericin B
Ketoconazole
RA
Arthrodesis
Cure36
25/Darouiche ROAmphotericin BRACure5
26/Lambertus MAmphotericin BRAS. epidermidis infection
Cure
24
26 /Lambertus MAmphotericin B
Ketoconazole
RA
Arthrodesis
Cure14
27/Levine MAmphotericin BRA
Arthrodesis
Cure24
28/Iskander MKAmphotericin B
Ketoconazole
RA
Arthrodesis
CureNR
29/Koch AEAmphotericin B
5-flucytosine
Ketoconazole
RA
Arthrodesis
Cure21
30/Lim EVAAmphotericin BRACure28
31/Younkin S5-fluocytosine + amphotericin BTEACure24
32/Lichtman EAAmphotericin B
Ketoconazole
RACure3
33/Goodman JSAmphotericin BRACureNR
33/Goodman JSAmphotericin BTEA
RA
Arthrodesis
Cure12
10/MacGregor RRAmphotericin B + 5-flucytosineRACure12
45/Jenny JYCaspofungine + 5-flucytosine
Voriconazole + 5-flucytosine
OEACure24
45/Jenny JYVoriconazole + 5-flucytosine
Fluconazole + 5-flucytosine
OEACure36
9/Cobo FCaspofungin
Fluconazole
No surgical treatmentCure6
PR/Cobo FCaspofungin 14 days
Fluconazole (expected 6 months)
No surgical treatmentNo relapse3

UD: unrelated disease; NR: not reported; PR: present report; TEA: two-stage exchange arthroplasty; RA: Resection arthroplasty; OEA: one-stage exchange arthroplasty

ICS: impregnated cement spacer; IB: impregnated beads

Antifungal treatment

Seventy-five (98.6%) patients underwent antifungal treatment, with a single drug in 46 cases (60.5%), with two drugs in 16 cases (21%) and more than two in 13 (17.1%). Twenty-nine of the patients with monotherapy (63%) were treated with fluconazole and 14 (30.4%) with amphotericin B. One patient treated with amphotericin B alone suffered recurrence of the infection [33], while another patient treated with fluconazole alone died as a consequence of the infection [34].

Application of antifungal spacer cement was applied in ten (13.1%) patients (seven with amphotericin B and three with fluconazole).

Surgical treatment

Surgery was performed in 65 (85.5%) patients, 30 of whom (39.4%) underwent two-stage exchange arthroplasty; resection of arthroplasty without reimplantation was undertaken in other 30 (39.4%). One-stage exchange arthroplasty was undergone in 3 (3.9%) patients, and other procedures in two patients. Surgical treatment was not reported in 11 (14.4%) patients.

Outcome

The final outcome was not reported in four patients. A favourable outcome was found in 58 (76.3%) patients after antifungal plus surgical treatment, in 11 (14.4%) after antifungal treatment alone and in one after surgery alone. A patient experienced recurrence of infection with fluconazole therapy, but his outcome was positive with miconazole plus drainage of fluid abscess [46].

Regarding to the type of surgery, all patients who underwent a two-stage exchange arthroplasty cured, although two of them suffered a bacterial infection [24, 57]. From the patients treated with resection arthroplasty, one dead after fluconazole treatment [34], two suffered amputation [14, 23] and two were found to have a bacterial infection [26, 56]. All three patients treated with one-stage exchange arthroplasty cured [40, 45]. Our two patients are currently well with antifungal treatment only, and no relapse of disease has been observed in the short follow-up.

Discussion

PJI caused by Candida species is still a rare disease. However, the incidence is expected to rise because of the increasing number of patients implanted worldwide with joint arthroplasties [59, 60].

Risk factors for candidal infection, including immunosuppression, systemic disease and/or long-term antibiotics use, may play an essential role in the development of invasive candidal infections although other factors could be involved in triggering the infection, specially the presence of biofilm on bioprosthetic surfaces. Biofilm formation is considered the most prevalent growth form of microorganisms [61] and plays a key role in the development of clinical infections [62]. The majority of C. albicans infections are associated with biofilm formation on the host or on the surfaces of medical devices or prostheses [63]. Other factors, such as the adherence of C. albicans and their hydrolytic enzyme secretion may also have a strong influence on the development of PJI [64], and their modification may serve as possible targets for antifungal drugs against these infections.

Pain and swelling are the main symptoms of PJI due to Candida species, although the onset of symptoms can be insidious and development of the disease can be slow. Because symptoms are mild and there is frequently no diagnostic suspicion of PJI caused by Candida, the diagnosis can often be delayed. Another important problem is to elucidate whether the presence of Candida species in samples can be considered as a contaminant or not, because there is still no standard definition of PJI.

The treatment of choice for PJI caused by Candida species has not yet been established. The use of antifungal agents locally (mixed with cement) or systemically administered is a challenging issue. Locally, amphotericin B appears to be the ideal drug, but some studies have reported several problems [65, 66], while there is no report on the use of novel antifungal drugs. However, this option has not been usually used, because from 76 cases reviewed, antifungal spacers were applied in only 10 (the majority of them with amphotericin B). In all cases the outcome was positive, but curiously in two patients with resection arthroplasty plus amphotericin B impregnated cement spacer application, an amputation [14] and a bacterial infection [56] was observed.

For systemic administration, lipid formulations of amphotericin B and fluconazole are the drugs of choice for this type of infection, and echinocandins may be an option [67].

Various authors have analysed the activity of some antifungal drugs against Candida biofilms. Two reports described resistance to fluconazole in these structures [68, 69], while another study found that it interfered with the development of C. albicans biofilms [70]. On the other hand, lipid formulations of amphotericin B have shown activity against C. albicans biofilms [70]. Anidulafungin was more active than amphotericin B against C. albicans biofilms of 24-h maturation, but amphotericin B was more active than anidulafungin against C. albicans biofilms of 48-h maturation [71].

In this review, various types of antifungal drugs have been used for treatment, and the majority of them with a positive result. In table 1, it can see that eleven patients (14.4%) were treated only with antifungal drugs [9, 11, 17-19, 44, 49, 50, 51, 54, and present report]; all these patients obtained a positive outcome, although the follow-up range from 3 to 72 months. According to these results, a correct and long treatment with antifungal drugs may be a good option, but due to the heterogeneity of the studies further research is required on this important issue, although it is highly recommended that these patients should be treated with drugs selected after antifungal susceptibility tests. In addition, a longer follow-up of these patients should be performed.

A two-stage arthroplasty exchange is currently considered the best approach in terms of eradication of the infection and preservation of the joint function in PJI caused by Candida species [4, 5]. Furthermore, when infection is chronic, this type of surgery is generally also recommended [72]. However, the success rate of this technique is controversial. One study reported a success rate of 93% for short-term infection control with 6 months of oral antifungal drugs after reimplantation [73], while another found that two-thirds of patients with PJ resection for fungal infection underwent reimplantation and that the infection was abolished in less than half of them [4].

On the other hand, resection arthroplasty was performed in around half of patients here reviewed (n=30). From these patients, in five of them the outcome was not initially favourable, and in three of them the final outcome was not reported. These results indicate that this procedure should not be the initial approach, also due to the important joint functional loss.

Regarding the third surgical method, some years ago Selmon et al reported a case with a positive outcome after a one-stage exchange arthroplasty [40]. Moreover, some authors have recently reported favourable outcome after one-stage exchange in selected cases of fungal PJI [45, 74]. In these cases, the responsible microorganism was identified post-operatively, with delayed specific antifungal treatment. In spite of this fact, the scientific evidence about these cases suggests that this technique may be appropriate in terms of eradication of infection, although the number of cases is still scarce. Further research should be done in order to establish the possible indications of one-stage exchange arthroplasty in cases of Candida PJI.

In summary, PJIs caused by Candida species are rare but fastidious infections that require a high index of suspicion because of their mild symptoms and insidious evolution. The diagnosis must be confirmed microbiologically and antifungal susceptibility testing of Candida strains is also highly recommended. The treatment is still not clearly defined and, although the association of long-term antifungal use with two-stage exchange arthroplasty is currently the gold standard to eradicate the infection, the analysis of the data of this review suggests the possibility of using one-stage exchange arthroplasty or antifungal treatment alone in order to obtain a favourable outcome for these patients. The next challenge for the scientific community is to establish the adequate algorithm for treatment in fungal PJI.

Informed consent

The patient described in this case report gave her informed consent for the inclusion in this publication.

Competing Interests

The authors have declared that no competing interest exists.

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Author contact

Corresponding address Corresponding author: Dr. Fernando Cobo, MD, PhD. Department of Microbiology, Hospital Virgen de las Nieves, Avda Fuerzas Armadas, 2 18014 Granada, Spain. Phone: +34958020072; Fax: +34958241245; E-mail: fernando.cobo.sspaes


Published 2017-2-5