Mycopathologia (2014) 177:291–298 DOI 10.1007/s11046-014-9744-6
Recurrent Arthritis by Candida glabrata, a Diagnostic and Therapeutic Challenge Mahzad Erami • Hasan Afzali • Mansoureh Momen Heravi • Ali Rezaei-Matehkolaei • Mohammad Javad Najafzadeh • Maryam Moazeni • Somayeh Dolatabadi • Leila Hosseinpour
Received: 29 October 2013 / Accepted: 29 March 2014 / Published online: 22 April 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Infectious arthritis due to Candida glabrata is very rare. A 40-year-old Iranian man had developed a painful swelling on the left knee since a year ago. A surgery (meniscectomy) was performed on his knee. However, in follow-up visit after 2 months, the patient’s condition was deteriorated. Direct examination of synovial fluid with Gram and hematoxylin–eosin stains were negative for any bacterial or fungal infection or crystal elements; however, inoculation into BACTECTM Mycosis IC/F and Plus Aerobic/F culture bottles led to the isolation of a yeast strain. The macroscopic examination on CHROMagarTM Candida medium combined with microscopical examination on CMT80 agar made a
presumptive identification of the isolate to be considered as C. glabrata, and it was later on confirmed by ITS sequencing. Initial empirical treatment was started with intravenous amphotericin B for 4 weeks followed by oral itraconazole which was unsuccessful. Prescription of an oral 150-mg tablet of fluconazole was considered for a 2-month course. All symptoms completely declined, and no recurrence of infection was detected. Antifungal susceptibility testing (AFST) was performed for this isolate, and the result showed sensitivity to both amphotericin B and itraconazole and less susceptibility to fluconazole while clinical recovery was achieved by fluconazole. In any suspected clinical case caused by infectious agents, application of an effective fungal diagnostic
M. Erami Kashan Shahidbeheshti Hospital, Kashan University of Medical Sciences, Kashan, Iran
M. Moazeni Invasive Fungi Research Center, Department of Medical Mycology and Parasitology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
H. Afzali M. M. Heravi Department of Infectious Diseases, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran A. Rezaei-Matehkolaei (&) Department of Medical Mycology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, 6135715794 Ahvaz, Iran e-mail: [email protected]
S. Dolatabadi CBS-KNAW Fungal Biodiversity Centre, Utrecht, The Netherlands L. Hosseinpour Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
M. J. Najafzadeh Department of Parasitology and Mycology, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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test should be considered to avoid complications due to misdiagnosis. The correlation of AFST result with real in vivo therapeutic responses can be strain or patient dependent, and this should be considered for a successive treatment. Keywords Candida glabrata Arthritis AFST Fluconazole
Introduction The occurrence of infections caused by Candida species other than C. albicans has increased over the recent decades [1–3]. Among Candida species, C. glabrata is of special significance due to its upward trend in acquisitive antifungal resistance [3–6]. Candida species are common cause of candidiasis in Iran, but there has been no report of fungal arthritis caused by C. glabrata in the country so far [2]. Infectious arthritis due to fungal infections is not common, and it is even rarer to be caused by C. glabrata. However, due to increased predisposing factors such as chronic corticosteroid therapy, aging, diabetes, overuse of antibiotics, fungemia and arthroplasty, the risk of such infections have increased as well [5, 7–13]. Considering the emergence of azole resistant Candida strains, it is essential to perform in vitro antifungal susceptibility testing (AFST) for appropriate treatment of Candida infections, although AFST cannot guarantee or preclude the favorable clinical recovery by itself [4, 14]. In this paper, we describe a case of arthritis due to an unusual strain of C. glabrata. Despite clinical recovery by fluconazole prescription, the strain showed to be fluconazole resistant in in vitro AFST. In this study, we tried to cover current diagnostic and therapeutic strategies available for C. glabrata arthritis. In addition, we provide a brief, but comprehensive review of C. glabrata arthritis episodes from past up to now.
Case Report On October 2010, a 40-year-old miner was admitted to our clinic in Kashan Shahidbeheshti Hospital, Kashan, Iran, with a painful swelling in his left knee. He was originally from Mahallat, Markazi Province located in west–central Iran. At the time of admission, he was
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suffering from a progressive chronic pain in his knee joint for one year. Besides, he had complains about limited motion. Consequently, he underwent knee surgery (meniscectomy). After two months, in December 2010, he came back to the hospital with developed swelling and constant pain in his joint. Physical examination revealed localized warmth around the knee (Fig. 1a). Afterward, the patient was hospitalized in infectious ward. Knee arthrocentesis performed and yielded 10 ml of cloudy blood-tinged fluid containing 6 9 103/mm3 WBC with predominance of neutrophils (82 %) versus lymphocytes (18 %) and 46 9 103/mm3 RBC. Other biochemical and hematologic findings were as follows: erythrocyte sedimentation rate (ESR) is 41 mm/h and C-reactive protein (CRP) is 5 mg/dl. Serologic tests for human immunodeficiency virus (HIV), rheumatoid factor (RF), antinuclear antibodies (ANA) and Brucella infection were negative. A magnetic resonance imaging (MRI) of the knee showed a large joint effusion and enhanced synovium, indicating severe inflammation of the knee joint. The early diagnosis was likely to be a septic arthritis. Staining of synovial fluid with Gram and hematoxylin–eosin (H&E) stains demonstrated no bacterial or fungal infection or crystal elements. Additionally, direct microscopy and culture of urinary sediment on blood agar and Sabouraud dextrose agar (SDA; Difco, Detroit, MI, USA) were negative. A portion of the synovial fluid was inoculated into Mycosis IC/F and Plus Aerobic/F culture vials (BACTECTM; Becton–Dickinson Inc, Sparks, MD, USA) for fungal and bacterial detection and then incubated in BACTEC 9050 automatic system at 35 °C for 11 and 7 days, respectively. Next to synovial fluid, blood culture on mentioned vials was carried out. After 24 h of incubation, the synovial aspirate, but not blood specimen, was detected as positive. Since it was interpreted as contaminant, all samplings and cultures were repeated twice and monitored at 24-h intervals. Surprisingly, both new attempts yielded the same results. Subsequently, some contents of the positive bottles were inoculated into Blood Agar as well as SDA, and presence of a yeast strain in both media was confirmed. To determine the causative agent of infection, the colony was transferred to the differential CHROMagar Candida medium (CHROMagar, Paris, France), and Cornmeal Tween-80 agar (CMT80; Difco, Detroit, USA) and incubated at 37 and 25 °C, respectively, for 48 h.
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Fig. 1 The clinical appearance of arthritis lesion on the left knee (a) and morphology of the C. glabrata isolate on CHROMagar Candida medium (b)
Light pink colonies grew on CHROMagar Candida medium. The centre of the colonies became dark mauve and the borders developed to be pale after 72 h of incubation (Fig. 1b). Microscopically, the colony on CMT80 agar appeared as small-sized yeast cells, mostly spherical rather than ellipsoidal with single buds. No pseudohyphae or hyphae were seen. Intravenous amphotericin B (0.7 mg/kg/day) was started immediately as empirical treatment. After 4 weeks, this regimen was shifted to oral itraconazole) 200 mg/days) for 2 weeks. Knee pain and swelling diminished gradually, so that the patient was able to move his knee. Six months later, he returned with a painful swelling in the same knee. Fungal examination of aspirated joint fluid was indicative of recurrent fungal synovitis caused by the same previous isolate. As an available medication, oral fluconazole (150 mg tablet) was prescribed. Interestingly, after 2-month course of therapy, microscopic examinations and culture of joint fluid were negative. In addition, the symptoms such as pain, swelling and limited motion were completely subsided, and no recurrence of infection was detected after one year of follow-up. In order to confirm the diagnosis and to assess the antifungal susceptibility test, the yeast isolate was sent to Centraalbureau voor Schimmelcultures collection (CBS) in Utrecht, the Netherlands. The strain was subjected to molecular identification and AFST. The entire ITS1-5.8S rDNA-ITS2 region was sequenced, and BLAST in NCBI revealed 99.87 % identity with C. glabrata strain Kw1154 (GenBank accession
number HE993757). The sequence was deposited in GenBank under accession number KJ009319. The Minimal inhibitory concentrations (MICs) of the isolate against six antifungal agents were determined according to the Clinical and Laboratory Standards Institute (CLSI) guidelines (M27-A3 document) [15]. Candida krusei (ATCC 6258), C. parapsilosis (ATCC 22019) and Paecilomyces variotii (ATCC 22319) were included for quality controls. The MICs of antifungal drugs were as follows: amphotericin B: 0.250 lg/ml, fluconazole: 32 lg/ml, itraconazole: 0.250 lg/ml, voriconazole: 0.125 lg/ml, isavuconazole: 0.063 lg/ml and posaconazole: 0.125 lg/ml.
Discussion The case studied here represented the long-standing challenge between microbiology laboratories and clinicians for rapid and precise diagnosis of a fungal infection. Considering that infectious arthritis is associated with potentially devastating complications, early detection and differentiation from other nonseptic inflammatory arthropathies are important for the effective treatment [11, 16]. It is known that current modalities for diagnosis of fungal arthritis, relying on the demonstration of the fungal elements in joint fluid by histological staining and culture are challenging [5, 12, 17]. From the mycological point of view, it is well known that despite the specificity due to low sensitivity, direct microscopy is an unreliable
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procedure to make an early diagnosis for mycotic arthritis [12, 17, 18], and we experienced this fact in our study. A multi-institutional study of fungal joint infections (thirty-one cases) indicated that Gram stain did not reveal the causative organisms in any of the patients [12]. Moreover, today in microbiology laboratories, a culture may immediately be considered as negative for fungal growth, whereas it should be at least incubated for 4 weeks [12]. On the other hand, a fungal positive culture is falsely narrated as contamination in many instances. Moreover, the rate of fungal isolation from systemic samples is not optimal due to the use of nonselective media [19]. In the present study, a misdiagnosis led to a wrong surgery (meniscectomy) and deteriorating patient’s condition, because mycologic investigation was neglected in the first patient’s visit. Additionally, the isolated strain was considered as a contaminant in the primary sampling. However, it subsequently was isolated in two different time intervals from BACTEC Mycosis IC/F vial which is a sensitive and effective selective fungal medium for detection of C. glabrata in terms of positivity rate [19, 20]. These issues signify that well-timed application of a fungal diagnostic test, and correct interpretation of its result is important not only from the standpoint of patient’s health but also from fungal infections epidemiology point of view. According to the literatures reviewed, C. albicans is the most common species causing fungal arthritis [11, 12, 17, 21]. Candida-related arthritis often resulted from blood dissemination or transient candidemia, rather than direct inoculation via injection, trauma or surgery [7, 8, 22, 23]. In the context of our case, there were no evidences of dissemination from blood or adjacent tissues. Most likely, the patient was primarily infected by inoculation of skin microflora but not via knee surgery or hematologic dissemination. C. glabrata was historically considered as a relatively nonpathogenic saprophyte and rarely causing infection in humans. However, with increased use of immunosuppressive drugs, broad-spectrum antibiotics and azole antifungals, it has emerged as a common cause of mucosal and systemic candidiasis [1, 2, 10]. Recent investigations showed that there are two new cryptic and closely related species within the C. glabrata clade; C. nivariensis [1] and C. bracaransis [24]. Similar to many Candida spp., two newly discovered species and some strains of C. glabrata sensu stricto produce white colony on CHROMagar Candida
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medium [25]. All three species share many phenotypic traits and traditional chemotaxonomic and morphological criteria remain unreliable for species discrimination in C. glabrata clade [1, 25]. However, appropriate molecular analysis can help with this challenge [1, 24, 25]. Regarding the development of a distinct color on CHROMagar, our isolate was pure; thus, the possibility of any mixed colony was ruled out. The macroscopic profile on CHROMagar Candida together with micromorphological properties on CMT80 agar made a presumptive identification of our isolate as C. glabrata, and ITS sequencing confirmed it. The paucity of the reports on septic arthritis by C. glabrata made it difficult to take more epidemiological data. To the extent of our knowledge, thirteen incidents of arthritis by C. glabrata, including six cases in hip, one case in ankle and six knee joint infections, have been cited in the literatures [5–11, 13, 16, 17, 22, 23, 26]. Here, we presented the fourteenth case which was a primary joint infection. As shown in Table 1, in all available cases, the final diagnosis was made by a culture which accentuates the importance of primary screening based on mycological findings for prompt diagnosis and consequent favorable treatment of such infections. Furthermore, most episodes were secondary infections due to arthroplasty, candidemia or surgery rather than a primary infection. In most cases, the recovery was achieved by prolonged therapy with each of amphotericin B, itraconazole, voriconazole, caspofungin or flucytosine alone and/or in combination with together [6–8, 10, 17, 23, 26]. Along with medical therapy, surgical methods like exchange of the prosthesis and debridement or amputation of lesion also were noted to be helpful for treatment [11, 13, 23, 26]. From the clinical perspective, the major obstacle in the therapy of infections caused by C. glabrata is its increasing resistance to azoles like fluconazole [3–6]. Despite the fact that fluconazole may be applied as an effective and financially efficient treatment for C. glabrata infections, the susceptibility of this species to fluconazole or other azoles is not predictable and requires confirmation by ‘‘real-time’’ AFST [27]. Lejko-Zupanc et al. reported a case of hip joint infection by a strain of C. glabrata, susceptible-dose dependent (SDD) to fluconazole (MIC = 24 lg/ml) in which treatment with high dose of fluconazole failed, and the patient was successfully treated with caspofungin [5].
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Table 1 A brief on the clinical features of Candida glabrata arthritis in the literatures Patient no.
Age/ sex
Underlying conditions
Involved joint
Direct microscopy/ culture of joint fluid
Therapy
Clinical recovery
Reference
1
34/M
liver transplant, candidemia
Hip
NR/?a
High dose of amphotericin B
Recovered
[7]
2
NAb
No risk factor
Hip
NA
Intra-articular injection of amphotericin B, Prosthesis removal
Recovered
[26]
3
77/M
Colon cancer, diabetes, repeated intraarticular injection of steroids
knee
-/?
Radical debridement, together with a short period amphotericin B treatment.
Recovered
[13]
4
70/F
Total knee arthroplasty
Knee
-/?
Oral fluconazole (200 mg/days)
No recurrence in 30th week of follow-up
[17]
5
74/F
Total knee arthroplasty, catheter tip infected with C. glabrata
Knee
-/?
Catheter removal, IV voriconazole that converted into prolonged oral therapy
No reinfection after 2 years
[8]
6
40/M
COPD
Right ankle and left knee
NR/?
Intra-articular administration of amphotericin B, combined with oral itraconazole
Recovered
[22]
7
73/M
Diabetes, hip fracture, hip replacement
Hip
-/?
Prosthesis removal, A dose of 50 mg/days caspofungin for 3 weeks
[5]
8
62/F
Diabetes, hip prosthesis, previous candidemia and candiduria
Hip
?/?
Combine treatment with flucytosine and itraconazole for 6 weeks
Recovered. No recurrence of infection was observed after 3 years of follow-up Recovered. No recurrence 15 months after revision
9
65/F
No risk factor
Hip
NR/?
IV amphotericin B and 5-flucytosine for 7 weeks
Recovered. No complication after 2 years
[10]
10
72/NA
Diabetes, rheumatoid arthritis
Knee
?/?
IV caspofungin (50 mg/days) and flucytosine (5 g/d) for 4 months
Recovered. No recurrence after 15 months of follow-up
[6]
11
75/F
Total knee arthroplasty, abdominal surgery
Knee
-/?
One-stage exchange arthroplasty, Recovered. No systemic amphotericin B recurrence after (200 mg/days) for one week 4 years of and itraconazole (200 mg twice follow-up daily) for 2 weeks
[23]
12
42/F
Lupus, Total knee arthroplasty
Knee
-/?
Oral voriconazole and intraarticular amphotericin B failed. An above-knee amputation performed
[11]
Amputated site healed. No complication after 6 months of follow-up
[9]
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Table 1 continued Patient no.
Age/ sex
Underlying conditions
Involved joint
Direct microscopy/ culture of joint fluid
Therapy
Clinical recovery
Reference
13
60/F
Hip arthroplasty
Hip
NR/?
Prosthetic hip resection plus combination therapy by caspofungin and amphotericin B
Joint sterilization after 6 weeks therapy
[16]
a
NR not reported
b
NA not available
Bartalesi et al. [16] described a case of hip joint infection by C. glabrata strain which was susceptible to caspofungin (MIC, 0.125 lg/ml) and amphotericin B (MIC, 0.25 lg/ml), and SDD to voriconazole (MIC, 1 lg/ml) and fluconazole (MIC, 32 lg/ml). The treatment failed with oral voriconazole (200 mg, twice daily) and accomplished with combination therapy by caspofungin plus liposomal amphotericin B, but no effort for fluconazole therapy was mentioned by the authors. There are many available in vitro antifungal data for clinical isolates of Candida spp.; nevertheless, a limited number of attempts have been directed to correlate the in vitro activity of antifungal agents with in vivo efficacy. While susceptibility testing against yeasts has shown a relationship between fluconazole resistance and therapeutic failure [28], conversely such a resistance in our isolate was associated with clinical improvement. The isolated strain was sensitive to both amphotericin B and itraconazole in vitro and less susceptible to fluconazole, while the antifungal therapy failed with amphotericin B and itraconazole and achieved by fluconazole. These evidences contradict this concept that in vitro ‘‘resistance’’ of an infecting agent is linked to clinical failure. In clinical practices, such lack of correlation was observed between in vitro susceptibility of Aspergillus fumigatus and Cryptococcus neoformans to some antifungal agents and clinical recovery from related infections [29, 30]. Rex et al. isolated two C. glabrata strains for which fluconazole MICs were C32 lg/ml during the antifungal susceptibility evaluation of clinical Candida isolates from patients who responded to initial therapy by this drug [4]. Tunkel et al. reported a case of prosthetic knee infection by C. parapsilosis in which antifungal therapy with amphotericin B followed by ketoconazole failed; however, clinical recovery was obtained by fluconazole.
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They stated that fluconazole may be useful as follow-up therapy after a course of amphotericin B regimen [21]. The converse can also happen, meaning that an effective treatment does not necessarily equate with susceptibility testing results. Rex et al. observed that several isolates of C. albicans and C. tropicalis had unstable response patterns when tested against fluconazole by NCCLS M27-A method [14]. Based on interpretive criteria for fluconazole and Candida spp. (MIC B 8 lg/ml = susceptible; MIC of 8–32 lg/ml = susceptible-dose dependent (SDD); MIC C 64 lg/ml = resistant) [31, 32], our strain was in the category of SDD strains which can be treated by increasing doses of fluconazole. However, the patient was treated with constant oral dose of 150 mg/days which is a subtherapeutic dosage of fluconazole for C. glabrata infections [32]. Based on in vivo observation, our isolate was a fluconazole sensitive strain. Likewise, according to the in vitro activities of amphotericin B and itraconazole (MICs B 0.125 lg/ml), it was susceptible to these agents, while on the contrary it appeared resistant to these drugs in real-time AFST. It was also noted that C. glabrata has variable susceptibility patterns to the newer azoles, and a likely explanation for such observation is that yeast cells in a pure C. glabrata colony are disparate in their susceptibility to azoles [10]. Another stated commentary for in vitro/ in vivo discordance is that yeast isolates with various genotypes and fluconazole susceptibility can coexist in the same clinical lesion [33, 34]. This heterogeneity in the same clinical lesion can occur at two levels: In some specimens, a mixed culture of two distinct species (like C. albicans and non-albicans Candida) is encountered, and in a number of samples, different strains of one species with various antifungal susceptibilities are recovered. Given that a single culture-grown colony is
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included in the current antimicrobial sensitivity procedures, the MIC patterns achieved in these ways may not be representative of the heterogeneous Candida population in clinical lesion [33]. To date, no investigations have verified the concept of routine susceptibility testing as a predictor of antifungal therapy outcome, because there are majority of in vivo confounding factors e.g., patients native ability, host immunologic status, in vivo stability of an antifungal agent, site-dependent bioavailability and dosage-dependent efficacy of antifungal drugs that independently influence the therapy outcomes, but are not taken into consideration in the in vitro interaction [4, 14, 21, 28, 31]. The self-improvement in patients infected by highly resistant organisms supports this concept [31]. As evidenced in Table 1, there is no concurrence on the optimum treatment for Candida joint infection, and in most occasions, the surgical removal followed by antifungal therapy is prescribed [5, 6, 8, 11]. Recently, attentions have been directed toward the combination therapy by caspofungin and another antifungal, as an alternative to monotherapy. This echinocandin was shown to have great in vitro activity against Candida biofilms and was also effective in C. glabrata-infected animal models [5, 6]. Reports regarding its therapeutic effect on clinical infections due to C. glabrata are, however, lacking [5]. In conclusion, any case clinically suspected to be caused by fungi should be confirmed by mycological tests. In addition, application of reliable DNA-based methods like sequencing is recommended for species delineation in the C. glabrata clade and for clarifying the epidemiological aspects of infection by two recently defined species; C. nivariensis and C. bracaransis. Here, the particular behavior of the presented case in the in vitro AFST reemphasized that the reliability of such tests, to produce results correlating with in vivo therapeutic responses, can be strain or patient (case) dependent. To ensure the success of treatment or recurrence of a Candida-related systemic infection, a constantly long-term monitoring is recommended.
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Recurrent Arthritis by Candida glabrata, a Diagnostic and Therapeutic Challenge Mahzad Erami • Hasan Afzali • Mansoureh Momen Heravi • Ali Rezaei-Matehkolaei • Mohammad Javad Najafzadeh • Maryam Moazeni • Somayeh Dolatabadi • Leila Hosseinpour
Received: 29 October 2013 / Accepted: 29 March 2014 / Published online: 22 April 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Infectious arthritis due to Candida glabrata is very rare. A 40-year-old Iranian man had developed a painful swelling on the left knee since a year ago. A surgery (meniscectomy) was performed on his knee. However, in follow-up visit after 2 months, the patient’s condition was deteriorated. Direct examination of synovial fluid with Gram and hematoxylin–eosin stains were negative for any bacterial or fungal infection or crystal elements; however, inoculation into BACTECTM Mycosis IC/F and Plus Aerobic/F culture bottles led to the isolation of a yeast strain. The macroscopic examination on CHROMagarTM Candida medium combined with microscopical examination on CMT80 agar made a
presumptive identification of the isolate to be considered as C. glabrata, and it was later on confirmed by ITS sequencing. Initial empirical treatment was started with intravenous amphotericin B for 4 weeks followed by oral itraconazole which was unsuccessful. Prescription of an oral 150-mg tablet of fluconazole was considered for a 2-month course. All symptoms completely declined, and no recurrence of infection was detected. Antifungal susceptibility testing (AFST) was performed for this isolate, and the result showed sensitivity to both amphotericin B and itraconazole and less susceptibility to fluconazole while clinical recovery was achieved by fluconazole. In any suspected clinical case caused by infectious agents, application of an effective fungal diagnostic
M. Erami Kashan Shahidbeheshti Hospital, Kashan University of Medical Sciences, Kashan, Iran
M. Moazeni Invasive Fungi Research Center, Department of Medical Mycology and Parasitology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
H. Afzali M. M. Heravi Department of Infectious Diseases, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran A. Rezaei-Matehkolaei (&) Department of Medical Mycology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, 6135715794 Ahvaz, Iran e-mail: [email protected]
S. Dolatabadi CBS-KNAW Fungal Biodiversity Centre, Utrecht, The Netherlands L. Hosseinpour Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
M. J. Najafzadeh Department of Parasitology and Mycology, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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test should be considered to avoid complications due to misdiagnosis. The correlation of AFST result with real in vivo therapeutic responses can be strain or patient dependent, and this should be considered for a successive treatment. Keywords Candida glabrata Arthritis AFST Fluconazole
Introduction The occurrence of infections caused by Candida species other than C. albicans has increased over the recent decades [1–3]. Among Candida species, C. glabrata is of special significance due to its upward trend in acquisitive antifungal resistance [3–6]. Candida species are common cause of candidiasis in Iran, but there has been no report of fungal arthritis caused by C. glabrata in the country so far [2]. Infectious arthritis due to fungal infections is not common, and it is even rarer to be caused by C. glabrata. However, due to increased predisposing factors such as chronic corticosteroid therapy, aging, diabetes, overuse of antibiotics, fungemia and arthroplasty, the risk of such infections have increased as well [5, 7–13]. Considering the emergence of azole resistant Candida strains, it is essential to perform in vitro antifungal susceptibility testing (AFST) for appropriate treatment of Candida infections, although AFST cannot guarantee or preclude the favorable clinical recovery by itself [4, 14]. In this paper, we describe a case of arthritis due to an unusual strain of C. glabrata. Despite clinical recovery by fluconazole prescription, the strain showed to be fluconazole resistant in in vitro AFST. In this study, we tried to cover current diagnostic and therapeutic strategies available for C. glabrata arthritis. In addition, we provide a brief, but comprehensive review of C. glabrata arthritis episodes from past up to now.
Case Report On October 2010, a 40-year-old miner was admitted to our clinic in Kashan Shahidbeheshti Hospital, Kashan, Iran, with a painful swelling in his left knee. He was originally from Mahallat, Markazi Province located in west–central Iran. At the time of admission, he was
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suffering from a progressive chronic pain in his knee joint for one year. Besides, he had complains about limited motion. Consequently, he underwent knee surgery (meniscectomy). After two months, in December 2010, he came back to the hospital with developed swelling and constant pain in his joint. Physical examination revealed localized warmth around the knee (Fig. 1a). Afterward, the patient was hospitalized in infectious ward. Knee arthrocentesis performed and yielded 10 ml of cloudy blood-tinged fluid containing 6 9 103/mm3 WBC with predominance of neutrophils (82 %) versus lymphocytes (18 %) and 46 9 103/mm3 RBC. Other biochemical and hematologic findings were as follows: erythrocyte sedimentation rate (ESR) is 41 mm/h and C-reactive protein (CRP) is 5 mg/dl. Serologic tests for human immunodeficiency virus (HIV), rheumatoid factor (RF), antinuclear antibodies (ANA) and Brucella infection were negative. A magnetic resonance imaging (MRI) of the knee showed a large joint effusion and enhanced synovium, indicating severe inflammation of the knee joint. The early diagnosis was likely to be a septic arthritis. Staining of synovial fluid with Gram and hematoxylin–eosin (H&E) stains demonstrated no bacterial or fungal infection or crystal elements. Additionally, direct microscopy and culture of urinary sediment on blood agar and Sabouraud dextrose agar (SDA; Difco, Detroit, MI, USA) were negative. A portion of the synovial fluid was inoculated into Mycosis IC/F and Plus Aerobic/F culture vials (BACTECTM; Becton–Dickinson Inc, Sparks, MD, USA) for fungal and bacterial detection and then incubated in BACTEC 9050 automatic system at 35 °C for 11 and 7 days, respectively. Next to synovial fluid, blood culture on mentioned vials was carried out. After 24 h of incubation, the synovial aspirate, but not blood specimen, was detected as positive. Since it was interpreted as contaminant, all samplings and cultures were repeated twice and monitored at 24-h intervals. Surprisingly, both new attempts yielded the same results. Subsequently, some contents of the positive bottles were inoculated into Blood Agar as well as SDA, and presence of a yeast strain in both media was confirmed. To determine the causative agent of infection, the colony was transferred to the differential CHROMagar Candida medium (CHROMagar, Paris, France), and Cornmeal Tween-80 agar (CMT80; Difco, Detroit, USA) and incubated at 37 and 25 °C, respectively, for 48 h.
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Fig. 1 The clinical appearance of arthritis lesion on the left knee (a) and morphology of the C. glabrata isolate on CHROMagar Candida medium (b)
Light pink colonies grew on CHROMagar Candida medium. The centre of the colonies became dark mauve and the borders developed to be pale after 72 h of incubation (Fig. 1b). Microscopically, the colony on CMT80 agar appeared as small-sized yeast cells, mostly spherical rather than ellipsoidal with single buds. No pseudohyphae or hyphae were seen. Intravenous amphotericin B (0.7 mg/kg/day) was started immediately as empirical treatment. After 4 weeks, this regimen was shifted to oral itraconazole) 200 mg/days) for 2 weeks. Knee pain and swelling diminished gradually, so that the patient was able to move his knee. Six months later, he returned with a painful swelling in the same knee. Fungal examination of aspirated joint fluid was indicative of recurrent fungal synovitis caused by the same previous isolate. As an available medication, oral fluconazole (150 mg tablet) was prescribed. Interestingly, after 2-month course of therapy, microscopic examinations and culture of joint fluid were negative. In addition, the symptoms such as pain, swelling and limited motion were completely subsided, and no recurrence of infection was detected after one year of follow-up. In order to confirm the diagnosis and to assess the antifungal susceptibility test, the yeast isolate was sent to Centraalbureau voor Schimmelcultures collection (CBS) in Utrecht, the Netherlands. The strain was subjected to molecular identification and AFST. The entire ITS1-5.8S rDNA-ITS2 region was sequenced, and BLAST in NCBI revealed 99.87 % identity with C. glabrata strain Kw1154 (GenBank accession
number HE993757). The sequence was deposited in GenBank under accession number KJ009319. The Minimal inhibitory concentrations (MICs) of the isolate against six antifungal agents were determined according to the Clinical and Laboratory Standards Institute (CLSI) guidelines (M27-A3 document) [15]. Candida krusei (ATCC 6258), C. parapsilosis (ATCC 22019) and Paecilomyces variotii (ATCC 22319) were included for quality controls. The MICs of antifungal drugs were as follows: amphotericin B: 0.250 lg/ml, fluconazole: 32 lg/ml, itraconazole: 0.250 lg/ml, voriconazole: 0.125 lg/ml, isavuconazole: 0.063 lg/ml and posaconazole: 0.125 lg/ml.
Discussion The case studied here represented the long-standing challenge between microbiology laboratories and clinicians for rapid and precise diagnosis of a fungal infection. Considering that infectious arthritis is associated with potentially devastating complications, early detection and differentiation from other nonseptic inflammatory arthropathies are important for the effective treatment [11, 16]. It is known that current modalities for diagnosis of fungal arthritis, relying on the demonstration of the fungal elements in joint fluid by histological staining and culture are challenging [5, 12, 17]. From the mycological point of view, it is well known that despite the specificity due to low sensitivity, direct microscopy is an unreliable
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procedure to make an early diagnosis for mycotic arthritis [12, 17, 18], and we experienced this fact in our study. A multi-institutional study of fungal joint infections (thirty-one cases) indicated that Gram stain did not reveal the causative organisms in any of the patients [12]. Moreover, today in microbiology laboratories, a culture may immediately be considered as negative for fungal growth, whereas it should be at least incubated for 4 weeks [12]. On the other hand, a fungal positive culture is falsely narrated as contamination in many instances. Moreover, the rate of fungal isolation from systemic samples is not optimal due to the use of nonselective media [19]. In the present study, a misdiagnosis led to a wrong surgery (meniscectomy) and deteriorating patient’s condition, because mycologic investigation was neglected in the first patient’s visit. Additionally, the isolated strain was considered as a contaminant in the primary sampling. However, it subsequently was isolated in two different time intervals from BACTEC Mycosis IC/F vial which is a sensitive and effective selective fungal medium for detection of C. glabrata in terms of positivity rate [19, 20]. These issues signify that well-timed application of a fungal diagnostic test, and correct interpretation of its result is important not only from the standpoint of patient’s health but also from fungal infections epidemiology point of view. According to the literatures reviewed, C. albicans is the most common species causing fungal arthritis [11, 12, 17, 21]. Candida-related arthritis often resulted from blood dissemination or transient candidemia, rather than direct inoculation via injection, trauma or surgery [7, 8, 22, 23]. In the context of our case, there were no evidences of dissemination from blood or adjacent tissues. Most likely, the patient was primarily infected by inoculation of skin microflora but not via knee surgery or hematologic dissemination. C. glabrata was historically considered as a relatively nonpathogenic saprophyte and rarely causing infection in humans. However, with increased use of immunosuppressive drugs, broad-spectrum antibiotics and azole antifungals, it has emerged as a common cause of mucosal and systemic candidiasis [1, 2, 10]. Recent investigations showed that there are two new cryptic and closely related species within the C. glabrata clade; C. nivariensis [1] and C. bracaransis [24]. Similar to many Candida spp., two newly discovered species and some strains of C. glabrata sensu stricto produce white colony on CHROMagar Candida
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medium [25]. All three species share many phenotypic traits and traditional chemotaxonomic and morphological criteria remain unreliable for species discrimination in C. glabrata clade [1, 25]. However, appropriate molecular analysis can help with this challenge [1, 24, 25]. Regarding the development of a distinct color on CHROMagar, our isolate was pure; thus, the possibility of any mixed colony was ruled out. The macroscopic profile on CHROMagar Candida together with micromorphological properties on CMT80 agar made a presumptive identification of our isolate as C. glabrata, and ITS sequencing confirmed it. The paucity of the reports on septic arthritis by C. glabrata made it difficult to take more epidemiological data. To the extent of our knowledge, thirteen incidents of arthritis by C. glabrata, including six cases in hip, one case in ankle and six knee joint infections, have been cited in the literatures [5–11, 13, 16, 17, 22, 23, 26]. Here, we presented the fourteenth case which was a primary joint infection. As shown in Table 1, in all available cases, the final diagnosis was made by a culture which accentuates the importance of primary screening based on mycological findings for prompt diagnosis and consequent favorable treatment of such infections. Furthermore, most episodes were secondary infections due to arthroplasty, candidemia or surgery rather than a primary infection. In most cases, the recovery was achieved by prolonged therapy with each of amphotericin B, itraconazole, voriconazole, caspofungin or flucytosine alone and/or in combination with together [6–8, 10, 17, 23, 26]. Along with medical therapy, surgical methods like exchange of the prosthesis and debridement or amputation of lesion also were noted to be helpful for treatment [11, 13, 23, 26]. From the clinical perspective, the major obstacle in the therapy of infections caused by C. glabrata is its increasing resistance to azoles like fluconazole [3–6]. Despite the fact that fluconazole may be applied as an effective and financially efficient treatment for C. glabrata infections, the susceptibility of this species to fluconazole or other azoles is not predictable and requires confirmation by ‘‘real-time’’ AFST [27]. Lejko-Zupanc et al. reported a case of hip joint infection by a strain of C. glabrata, susceptible-dose dependent (SDD) to fluconazole (MIC = 24 lg/ml) in which treatment with high dose of fluconazole failed, and the patient was successfully treated with caspofungin [5].
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Table 1 A brief on the clinical features of Candida glabrata arthritis in the literatures Patient no.
Age/ sex
Underlying conditions
Involved joint
Direct microscopy/ culture of joint fluid
Therapy
Clinical recovery
Reference
1
34/M
liver transplant, candidemia
Hip
NR/?a
High dose of amphotericin B
Recovered
[7]
2
NAb
No risk factor
Hip
NA
Intra-articular injection of amphotericin B, Prosthesis removal
Recovered
[26]
3
77/M
Colon cancer, diabetes, repeated intraarticular injection of steroids
knee
-/?
Radical debridement, together with a short period amphotericin B treatment.
Recovered
[13]
4
70/F
Total knee arthroplasty
Knee
-/?
Oral fluconazole (200 mg/days)
No recurrence in 30th week of follow-up
[17]
5
74/F
Total knee arthroplasty, catheter tip infected with C. glabrata
Knee
-/?
Catheter removal, IV voriconazole that converted into prolonged oral therapy
No reinfection after 2 years
[8]
6
40/M
COPD
Right ankle and left knee
NR/?
Intra-articular administration of amphotericin B, combined with oral itraconazole
Recovered
[22]
7
73/M
Diabetes, hip fracture, hip replacement
Hip
-/?
Prosthesis removal, A dose of 50 mg/days caspofungin for 3 weeks
[5]
8
62/F
Diabetes, hip prosthesis, previous candidemia and candiduria
Hip
?/?
Combine treatment with flucytosine and itraconazole for 6 weeks
Recovered. No recurrence of infection was observed after 3 years of follow-up Recovered. No recurrence 15 months after revision
9
65/F
No risk factor
Hip
NR/?
IV amphotericin B and 5-flucytosine for 7 weeks
Recovered. No complication after 2 years
[10]
10
72/NA
Diabetes, rheumatoid arthritis
Knee
?/?
IV caspofungin (50 mg/days) and flucytosine (5 g/d) for 4 months
Recovered. No recurrence after 15 months of follow-up
[6]
11
75/F
Total knee arthroplasty, abdominal surgery
Knee
-/?
One-stage exchange arthroplasty, Recovered. No systemic amphotericin B recurrence after (200 mg/days) for one week 4 years of and itraconazole (200 mg twice follow-up daily) for 2 weeks
[23]
12
42/F
Lupus, Total knee arthroplasty
Knee
-/?
Oral voriconazole and intraarticular amphotericin B failed. An above-knee amputation performed
[11]
Amputated site healed. No complication after 6 months of follow-up
[9]
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Table 1 continued Patient no.
Age/ sex
Underlying conditions
Involved joint
Direct microscopy/ culture of joint fluid
Therapy
Clinical recovery
Reference
13
60/F
Hip arthroplasty
Hip
NR/?
Prosthetic hip resection plus combination therapy by caspofungin and amphotericin B
Joint sterilization after 6 weeks therapy
[16]
a
NR not reported
b
NA not available
Bartalesi et al. [16] described a case of hip joint infection by C. glabrata strain which was susceptible to caspofungin (MIC, 0.125 lg/ml) and amphotericin B (MIC, 0.25 lg/ml), and SDD to voriconazole (MIC, 1 lg/ml) and fluconazole (MIC, 32 lg/ml). The treatment failed with oral voriconazole (200 mg, twice daily) and accomplished with combination therapy by caspofungin plus liposomal amphotericin B, but no effort for fluconazole therapy was mentioned by the authors. There are many available in vitro antifungal data for clinical isolates of Candida spp.; nevertheless, a limited number of attempts have been directed to correlate the in vitro activity of antifungal agents with in vivo efficacy. While susceptibility testing against yeasts has shown a relationship between fluconazole resistance and therapeutic failure [28], conversely such a resistance in our isolate was associated with clinical improvement. The isolated strain was sensitive to both amphotericin B and itraconazole in vitro and less susceptible to fluconazole, while the antifungal therapy failed with amphotericin B and itraconazole and achieved by fluconazole. These evidences contradict this concept that in vitro ‘‘resistance’’ of an infecting agent is linked to clinical failure. In clinical practices, such lack of correlation was observed between in vitro susceptibility of Aspergillus fumigatus and Cryptococcus neoformans to some antifungal agents and clinical recovery from related infections [29, 30]. Rex et al. isolated two C. glabrata strains for which fluconazole MICs were C32 lg/ml during the antifungal susceptibility evaluation of clinical Candida isolates from patients who responded to initial therapy by this drug [4]. Tunkel et al. reported a case of prosthetic knee infection by C. parapsilosis in which antifungal therapy with amphotericin B followed by ketoconazole failed; however, clinical recovery was obtained by fluconazole.
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They stated that fluconazole may be useful as follow-up therapy after a course of amphotericin B regimen [21]. The converse can also happen, meaning that an effective treatment does not necessarily equate with susceptibility testing results. Rex et al. observed that several isolates of C. albicans and C. tropicalis had unstable response patterns when tested against fluconazole by NCCLS M27-A method [14]. Based on interpretive criteria for fluconazole and Candida spp. (MIC B 8 lg/ml = susceptible; MIC of 8–32 lg/ml = susceptible-dose dependent (SDD); MIC C 64 lg/ml = resistant) [31, 32], our strain was in the category of SDD strains which can be treated by increasing doses of fluconazole. However, the patient was treated with constant oral dose of 150 mg/days which is a subtherapeutic dosage of fluconazole for C. glabrata infections [32]. Based on in vivo observation, our isolate was a fluconazole sensitive strain. Likewise, according to the in vitro activities of amphotericin B and itraconazole (MICs B 0.125 lg/ml), it was susceptible to these agents, while on the contrary it appeared resistant to these drugs in real-time AFST. It was also noted that C. glabrata has variable susceptibility patterns to the newer azoles, and a likely explanation for such observation is that yeast cells in a pure C. glabrata colony are disparate in their susceptibility to azoles [10]. Another stated commentary for in vitro/ in vivo discordance is that yeast isolates with various genotypes and fluconazole susceptibility can coexist in the same clinical lesion [33, 34]. This heterogeneity in the same clinical lesion can occur at two levels: In some specimens, a mixed culture of two distinct species (like C. albicans and non-albicans Candida) is encountered, and in a number of samples, different strains of one species with various antifungal susceptibilities are recovered. Given that a single culture-grown colony is
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included in the current antimicrobial sensitivity procedures, the MIC patterns achieved in these ways may not be representative of the heterogeneous Candida population in clinical lesion [33]. To date, no investigations have verified the concept of routine susceptibility testing as a predictor of antifungal therapy outcome, because there are majority of in vivo confounding factors e.g., patients native ability, host immunologic status, in vivo stability of an antifungal agent, site-dependent bioavailability and dosage-dependent efficacy of antifungal drugs that independently influence the therapy outcomes, but are not taken into consideration in the in vitro interaction [4, 14, 21, 28, 31]. The self-improvement in patients infected by highly resistant organisms supports this concept [31]. As evidenced in Table 1, there is no concurrence on the optimum treatment for Candida joint infection, and in most occasions, the surgical removal followed by antifungal therapy is prescribed [5, 6, 8, 11]. Recently, attentions have been directed toward the combination therapy by caspofungin and another antifungal, as an alternative to monotherapy. This echinocandin was shown to have great in vitro activity against Candida biofilms and was also effective in C. glabrata-infected animal models [5, 6]. Reports regarding its therapeutic effect on clinical infections due to C. glabrata are, however, lacking [5]. In conclusion, any case clinically suspected to be caused by fungi should be confirmed by mycological tests. In addition, application of reliable DNA-based methods like sequencing is recommended for species delineation in the C. glabrata clade and for clarifying the epidemiological aspects of infection by two recently defined species; C. nivariensis and C. bracaransis. Here, the particular behavior of the presented case in the in vitro AFST reemphasized that the reliability of such tests, to produce results correlating with in vivo therapeutic responses, can be strain or patient (case) dependent. To ensure the success of treatment or recurrence of a Candida-related systemic infection, a constantly long-term monitoring is recommended.
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