Clinical Characteristics and Risk Factors for Complications of Candidaemia in Adults: Focus on Endophthalmitis, Endocarditis, and Osteoarticular Infections

Journal Pre-proof Clinical Characteristics and Risk Factors for Complications of Candidaemia in Adults: Focus on Endophthalmitis, Endocarditis, and Osteoarticular Infections Sung Un Shin, Yohan Yu, Soo Sung Kim, Tae Hoon Oh, Seong Eun Kim, Uh Jin Kim, Seung-Ji Kang, Hee-Chang Jang, Kyung-Hwa Park, Sook In Jung

PII:

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https://doi.org/10.1016/j.ijid.2020.01.049

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IJID 3940

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International Journal of Infectious Diseases

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Clinical Characteristics and Risk Factors for Complications of Candidaemia in Adults: Focus on Endophthalmitis, Endocarditis, and

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Osteoarticular Infections

Sung Un Shin, Yo han Yu, Soo Sung Kim, Tae Hoon Oh, Seong Eun Kim, Uh Jin Kim, Seung-Ji Kang, Hee-Chang Jang, Kyung-Hwa Park, Sook In Jung

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Department of internal medicine, Chonnam National University Medical School,

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Gwangju, South Korea

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Patients with Candidaemia

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Running title: Endophthalmitis, Endocarditis, and Osteoarticular Infections in Adult

Address for correspondence:

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Sook In Jung, M.D. PhD.

Department of Infectious Disease, Chonnam National University Medical School 42, Jebong Ro, Donggu, Gwangju61469, Korea Tel: +82.62.220-6502, Fax: +82.62.225-8578 E-mail: [email protected] 1

Highlights  Complications occurred in 4.4% of adults with candidaemia  C. albicans was an independent risk factor for complicated candidaemia in adults.  Complications of candidaemia might need prolonged treatment and additional

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procedures or surgery.

Abstract

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Objectives: This study evaluated the incidence, risk factors, and clinical characteristics of complications of candidaemia in adults, with a focus on endophthalmitis,

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endocarditis, and osteoarticular infections.

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Methods: All patients ≥18 years old with candidaemia in two Korean tertiary hospitals from 2007 to 2016 were investigated. Complications of candidaemia were defined as

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the presence of endophthalmitis, endocarditis, or osteoarticular infections documented in patients with candidaemia. The clinical characteristics and risk factors for

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candidaemia with complications were analysed in the patients who underwent ophthalmological examinations.

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Results: Of 765 adult patients with candidaemia, 34 (4.4%) met the definition of complications, including endophthalmitis in 29 (3.8%), endocarditis in 4 (0.5%), and osteoarticular infections in 3 (0.4%). Of the 225 patients who underwent ophthalmological examinations, 29 (12.9%) had endophthalmitis. Candida albicans was an independent risk factor for complicated candidaemia (OR, 5.12; 95% CI, 2.17–12.09; P < 0.001). Although the mortality rate was no higher in complicated candidaemia, the 2

duration of antifungal therapy was longer (23.1 ± 17.6 vs. 16.4 ± 10.8 days, P = 0.042), and 13 patients (39.3%) underwent additional procedures or surgery. Conclusions: Complications of candidaemia occurred in 4.4% of adult patients. C. albicans was an independent risk factor for complicated candidaemia in adults. Complications of candidaemia might need prolonged treatment and additional procedures or surgery. Therefore, careful evaluation and active treatment of

Keywords: Candidaemia, Complication, Candida albicans

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Introduction

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candidaemia with complications should be encouraged.

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Candidaemia is a nosocomial bloodstream infection with a high mortality rate (Asmundsdottir et al., 2002; Bassetti et al., 2014). Candida species can disseminate to

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various organs, causing complications that not only are difficult to treat but also require surgical intervention and cause sequelae (Kauffman, 2015). Candida endophthalmitis is

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the most common complication of candidaemia and occurs in 2–16% of patients with candidaemia (Feman et al., 2002; Oude Lashof et al., 2011; Huynh et al., 2012;

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Geraymovych et al., 2015). Recent clinical practice guidelines for the management of candidiasis recommend a routine ophthalmological examination for all patients with

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candidaemia (Cornely et al., 2012; Pappas et al., 2016). However, American and European guidelines for managing candidiasis have different views on using transoesophageal echocardiography to detect endocarditis (Cornely et al., 2012; Pappas et al., 2016). In a recent study, infective endocarditis occurred in 8.3% of patients with candidaemia, most of whom had no well-established risk factors (Fernández-Cruz et al., 3

2010). Therefore, the European Society for Clinical Microbiology and Infectious Diseases recommends routine transoesophageal echocardiography to detect organ involvement (Cornely et al., 2012), whereas the Infectious Diseases Society of America (IDSA) recommends that endocarditis should be suspected when blood cultures are persistently positive; when a fever persists despite appropriate antifungal therapy; or when a new heart murmur, heart failure, or embolic phenomenon occurs comorbid with

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candidaemia (Pappas et al., 2016). Therefore, it is necessary to know the incidence of and risk factors for complications in patients with candidaemia to establish a strategy for their early diagnosis and appropriate management.

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Studies of the complications of candidaemia have mainly examined the

incidence of and risk factors for Candida endophthalmitis (Donahue et al., 1994;

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Geraymovych et al., 2015; Kato et al., 2018). Risk factors for disseminated candidiasis

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have been evaluated in paediatric patients with candidaemia (Zaoutis et al., 2004). However, there are few studies on the incidence and clinical features of all complications of candidaemia in adults. Therefore, this study evaluated the incidence,

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risk factors, clinical characteristics, and outcome of complications of candidaemia in

Materials and Methods

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adults, with a focus on endophthalmitis, endocarditis, and osteoarticular infections.

Patients

All patients older than 18 years with candidaemia at two tertiary care hospitals in

South Korea (Chonnam National University Hospital [1,000 beds] in Gwangju, and Chonnam National University Hwasun Hospital [700 beds] in Hwasun) from 2007 to

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2016 were investigated. Patients with a recurrence of candidaemia during the study period were included only for the initial episode of candidaemia.

Definitions Candidaemia was defined as a case in which Candida was isolated from at least one blood culture in patients with signs and symptoms of infection (Pappas et al., 2016).

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Complications of candidaemia were defined as the presence of Candida endophthalmitis, Candida endocarditis, or Candida osteoarticular infections

documented (Kauffman, 2015). Candida endophthalmitis was defined as a case of

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candidaemia in which an ophthalmologist diagnosed Candida endophthalmitis after an

ophthalmological examination (Jampol et al., 1996; Khan et al., 2007; Geraymovych et

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al., 2015). Candida endocarditis was defined as meeting the modified Duke criteria

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(Durack et al., 1994; Li et al., 2000). Proven Candida arthritis was defined as a patient with a positive culture or histological evidence from synovial fluid analysis. Probable Candida arthritis was defined as a patient with a positive culture or histological

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evidence other than from a synovial fluid specimen, such as bone, cartilage, bone marrow, adjacent abscess, blood, central venous catheter, thrombus, tendon, disc, or

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operative samples, along with compatible clinical and radiological features (Kauffman,

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2015; Gamaletsou et al., 2016). Proven Candida osteomyelitis was defined as a patient with evidence of (1) compatible clinical characteristics; (2) consistent radiographic features; and (3) isolation of Candida in culture, or shown by histological analysis of samples of bone tissue or metal hardware obtained at open surgery, or via a percutaneous biopsy. Probable Candida osteomyelitis was defined as a patient with a culture positive for Candida or histological evidence other than from bone tissue or 5

metal hardware specimens, including disk, cartilage, adjacent abscess, blood, and synovial fluid with compatible clinical and radiological features (Gamaletsou et al., 2012; Kauffman, 2015). Persistent candidaemia was defined as the presence of Candida species in blood cultures more than 5 days after the start of antifungal therapy (Kang et al., 2017). Empirical antifungal therapy was considered to be appropriate when the isolated Candida showed in vitro susceptibility to an antifungal drug administered in an

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adequate dose (Zilberberg et al., 2010; Cuervo et al., 2015). Chronic kidney disease was defined as a glomerular filtration rate < 60 mL/min/1.73 m2 over 3 months (Levey & Coresh, 2012). Neutropenia was defined as an absolute neutrophil count < 500/mm3

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(Boxer, 2012). Severe sepsis was defined as one or more findings of organ failure with

sepsis. Septic shock was defined as a case of sepsis in which the systolic blood pressure

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was < 90 mmHg despite appropriate fluid replacement for more than 1 h, or when

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inotropics were needed to maintain the systolic blood pressure > 90 mmHg or the mean

Data collection

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arterial pressure > 70 mmHg (Dellinger et al., 2013).

We retrospectively reviewed electronic medical records to collect patients’

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demographic and clinical data. Comorbidities included diabetes mellitus, heart disease,

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chronic renal failure, solid tumours, and haematological malignancy. A history of neutropenia, surgery within the past 3 months, chemotherapy within the past month, steroids within the past month, urinary catheter, central venous catheter, antibiotic use within the past month, and total parenteral nutrition (TPN) were included as predisposing factors. Clinical data included the durations of candidaemia, hospitalisation, and antifungal therapy, and the clinical outcome. 6

4. Microbiological tests Blood cultures were performed with the BACTEC 9240 system (Becton Dickinson, Sparks, MD, USA), VITEK system (bioMérieux, Hazelwood, MO, USA), and BacT/ALERT system (bioMérieux). Candida species were identified using a VITEK2 YST card (BioMérieux, Marcy L’Étoile, France). Two commercial matrix-

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assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) systems—VITEK MS (BioMérieux), and Biotyper (Bruker Daltonics, Billerica, MA, USA)—were used together for species identification (since 2013). Antifungal

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susceptibility was tested with the VITEK2 fungal susceptibility card (BioMérieux)

(since 2010). CLSI species-specific clinical breakpoints were applied (Pappas et al.,

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2016). Candida spp. isolates with a minimum inhibitory concentration (MIC) ≤ 1 mg/L to amphotericin B were considered susceptible. For Candida spp. for which a CLSI

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breakpoint has not been established, Candida spp. isolates with a MIC ≥ 4 mg/L to fluconazole were considered non-susceptible to fluconazole. For echinocandin, Candida

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spp. isolates with a MIC ≥ 0.5 mg/L to echinocandin were considered non-susceptible

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(Cuervo et al., 2015).

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5. Statistical analyses

Continuous variables of the two independent groups were compared with

independent t-tests, and the data are shown as the mean and standard deviation (SD) or as the median and interquartile range (IQR). Categorical variables were compared with chi-square tests. P < 0.05 was defined as statistically significant. To analyse the clinical characteristics, outcomes, and risk factors of candidaemia with complications, subgroup 7

analysis was performed on the patients who underwent ophthalmological examinations. We performed multivariate logistic regression analyses of variables with P < 0.1 in univariate analyses. The odds ratio (OR) and 95% confidential interval (CI) were calculated. Statistical analyses were performed with SPSS ver. 25.0 (SPSS, Chicago, IL,

Results

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Incidence of complications in adults with candidaemia

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USA).

During the study period, 765 adults with candidaemia were enrolled, of whom

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225 (29.4%) underwent an ophthalmological examination and 112 (14.6%) underwent

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echocardiography. Transthoracic echocardiography was performed in 112 patients and 4 patients required additional transoesophageal echocardiography. Of the 765 patients, 34 (4.4%) met the definition of complicated candidaemia and 29 (3.8%) had Candida

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endophthalmitis. Of the 225 patients who underwent ophthalmological examinations, 12.9% had endophthalmitis. Candida endocarditis was diagnosed in four patients

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(0.5%) and Candida osteoarticular infections in three (0.4%). Of the 112 patients who

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underwent echocardiography, 3.6% had Candida endocarditis. Two patients had both Candida endophthalmitis and endocarditis (Table 1).

Clinical characteristics of the patients with Candida endophthalmitis The median age of the 29 patients with Candida endophthalmitis was 72 years (IQR: 66–75 years), and 16 of the patients (55.1%) were male (Table 2). C. albicans 8

(79.3%) was the most common pathogen of Candida endophthalmitis, followed by C. tropicalis (6.8%), C. parapsilosis (3.4%), and C. pelliculosa (3.4%). Only 10 patients (34.5%) complained of ocular symptoms before the fundus examination. Twenty-four patients (82.7%) had bilateral Candida endophthalmitis at the time of diagnosis. Extension into the vitreous was found in 14 patients (48.2%). Aqueous fluid cultures were performed in 9 patients, and no Candida species were identified in any fluid

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sample. Twelve patients (41.4%) underwent intravitreal injections (IVI) in addition to systemic antifungal therapy, two of whom (6.9%) underwent vitrectomy. The median

time taken to diagnose Candida endophthalmitis from the detection of candidaemia was

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7 days (IQR: 5–9 days). The median duration of antifungal therapy was 30 days (IQR: 19–44 days). Of the 20 patients who underwent ophthalmological follow-up, 14

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improved and 6 did not improve despite treatment.

Clinical characteristics of the patients with Candida endocarditis Four patients were diagnosed with infective endocarditis during the study period.

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One of these patients with Candida endocarditis had a prosthetic valve and the remaining three had native valves (Table 3). In one patient, both the mitral and aortic

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valves were involved. Candida species were identified within 48 h of hospitalisation in

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all four patients. Three patients with native valve endocarditis had been admitted to hospital within the previous 3 months or used antibiotics within 1 month. C. pelliculosa was isolated in the patient with prosthetic valve endocarditis, while among the patients with native valve endocarditis, two had C. albicans and one had C. tropicalis. Despite systemic antifungal therapy, two patients had persistent candidaemia, and three had complications, including cerebral infarction or endophthalmitis. The patient with 9

prosthetic valve endocarditis underwent redo mitral valve replacement with 6 weeks of antifungal therapy (case 2). The patient improved clinically, but died 1 year later due to recurrence. At the time of recurrence, C. pelliculosa was identified, which was the same Candida species seen in the first episode of candidaemia.

Clinical characteristics of the patients with Candida osteoarticular infections

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One patient had proven Candida arthritis of the right knee joint and two had probable vertebral osteomyelitis of the lumbar spine (Table 4). None of the cases of osteoarticular infection occurring during the study had a history of surgery, such as

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artificial arthroplasty or vertebroplasty. Candida species were identified in blood

cultures more than 10 days after admission in all three cases. Total parenteral nutrition

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was administered in three cases and a central venous catheter in one. The causative

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organism was C. tropicalis in all three cases, although C. albicans was also identified in case 5. The patient with Candida arthritis (case 5) had persistent candidaemia despite systemic antifungal therapy before the diagnosis of arthritis. The patient with knee joint

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arthritis (case 5) underwent surgical drainage. All three patients with Candida

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osteoarticular infections improved without sequelae.

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Clinical characteristics and outcomes of patients with candidaemia in the complication and no-complication groups Of the 225 patients who underwent ophthalmological examinations, 33 (14.7%)

were in the complication group and the remaining 192 were in the no-complication group. One of four endocarditis patients (case 4) who did not undergo an ophthalmological examination was excluded from the subgroup analysis. Table 5 lists 10

the clinical characteristics and outcomes of the patients in each group. The complication group was older than the no-complication group (mean ± SD, 71.0 ± 7.8 vs. 65.2 ± 14.2 years, P = 0.001). Indwelling urinary catheters were more common in the nocomplication group (67.7% vs. 44.5%, P = 0.014). There were no significant differences in other underlying diseases or predisposing factors between the two groups. Candida albicans was more common in the complication group (72.7% vs. 30.2%, P < 0.001).

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The 30-day mortality rate did not differ between the groups (complication 18.2% vs. nocomplication 21.9%, P = 0.632). Follow-up blood cultures were performed in 223

(99.1%) patients. The interval from the positive blood culture collection to the first

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follow-up blood culture was 2.9 ± 2.6 days. There were no significant differences between groups in the duration of candidaemia (complication 6.2 ± 9.6 vs. no-

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complication 7.4 ± 9.7 days, P = 0.517) or frequency of persistent candidaemia

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(complication 27.3% vs. no-complication 34.4%, P = 0.687). Antifungal agents were administered to all patients in both groups. Fluconazole was the most commonly used antifungal agent in both the complication (78.8%) and no-complication group (84.9%).

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Of 210 Candida isolates tested for antifungal susceptibility, 16 (7.6%) and 5 (2.4%) were not susceptible to fluconazole and amphotericin-B, respectively. All 120 isolates

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tested were susceptible to micafungin and caspofungin. The appropriateness of

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empirical antifungal therapy did not differ between the complication (97%) and nocomplication (93.7%) groups (P = 0.474). The duration of antifungal therapy was longer in the complication group (mean ± SD, 23.1 ± 17.6 vs. 16.4 ± 10.8 days, P = 0.042). Thirteen patients (39.3%) in the complication group underwent additional procedures or surgery to treat complications: IVI only in nine patients, IVI and vitrectomy in two, redo MVR and IVI in one, and surgical drainage in one. 11

Risk factors for complicated candidaemia Multivariate analysis was performed to determine the risk factors for complicated candidaemia. Age, surgery within the past 3 months, indwelling urinary catheter, length of hospital day before candidaemia, diagnosis of candidaemia in the intensive care unit, and C. albicans infection were included in the analysis. In the

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multivariate analyses, C. albicans infection (OR, 5.12; 95% CI, 2.17–12.09; P < 0.001) was the only variable independently associated with complicated candidaemia (Table

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Discussion

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6).

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This study evaluated complications of candidaemia with a focus on endophthalmitis, endocarditis, and osteoarticular infections in adults with candidaemia. Candidaemia originating from a bowel source or an indwelling vascular catheter has the

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potential to spread to other organs, causing secondary infection. This study revealed that 4.4% of adult candidaemia patients had complications of candidaemia. The most

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common complication was Candida endophthalmitis (3.8%), whereas the incidences of

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endocarditis and osteoarticular infections were relatively low (0.5% and 0.4%, respectively).

Although no report has dealt primarily with complications in adults with

candidaemia, recent data suggest that about 16% of patients with candidaemia have some ocular involvement (Pappas et al., 2016), and in rare cases endocarditis and osteoarticular infections are involved (Antinori et al., 2016). Although the overall 12

incidence of endophthalmitis (3.8%) was relatively low in this series, 12.9% of the patients who underwent ophthalmological examinations had Candida endophthalmitis, similar to a previous study. However, the true incidence of complications in candidaemia might be higher if patients cannot be examined because of high early mortality or if patients cannot complain of their symptoms because they are very ill or in intensive care. In this study, compared with the 225 patients who underwent

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ophthalmological examinations, the 540 patients who did not undergo ophthalmological examinations had a higher 30-day mortality rate (51.5% vs. 21.3%, P < 0.001) and

shorter time from candidaemia to death (9.3 ± 13.2 vs. 22.7 ± 25.6 days, P < 0.001)

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(data not shown). Recent guidelines for the management of Candida infections

recommend fundus examinations for all patients with candidaemia (Pappas et al., 2016).

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Only 29% of the adults with candidaemia in this study underwent fundus examinations

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during the study period. Although the rate of annual fundus examination during the study period had increased in recent years based on recent guidelines (r = 0.830, P = 0.003, data not shown), a significant number of patients with candidaemia did not

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undergo fundus examinations. Furthermore, the 30-day mortality rate and hospitalisation period after candidaemia did not differ between the complication and no-

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complication groups. However, the duration of antibiotic treatment was longer in the

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complication group and additional procedures or surgery were performed in 38.2% of the patients in that group. The patients with Candida endocarditis had poor prognoses. Therefore, early active screening and treatment of complications of candidaemia is needed. Several risk factors for complications in candidaemia have been identified. Independent risk factors for disseminated candidiasis with candidaemia are persistent 13

blood cultures positive for Candida for > 3 days with a central venous catheter in place and immunosuppression in children (Zaoutis et al., 2004). In another study, having had recent gastrointestinal surgery and having 3 positive blood cultures were also significant risk factors for intraocular infection in patients with candidaemia (Geraymovych et al., 2015). In the current study, persistent candidaemia, recent gastrointestinal surgery, and removal of a central vascular catheter did not differ in the

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two groups. However, C. albicans was more common in the complication group compared to the no-complication group, which is consistent with a report that patients with Candida endophthalmitis were mostly infected with C. albicans (Oude Lashof et

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al., 2011). C. albicans is the most common causative organism of candidaemia and has several virulence factors (Canela & Cardoso, 2017). C. albicans secretes extracellular

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hydrolytic enzymes, such as phospholipase and proteinase, to facilitate attachment and

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avoid the host immune system, resulting in tissue damage (Chin et al., 2013; Mattei et al., 2013). It also facilitates seeding by secreting hemolysin (Chin et al., 2013). The C. albicans virulence factors may contribute to the development of complications, which

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need to be carefully evaluated in patients with bloodstream C. albicans infections. In this study, only 35% of those with Candida endophthalmitis complained of

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ocular symptoms before the fundus examination. A previous study revealed that

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reliance on visual symptoms alone as a predictor of Candida endophthalmitis had low sensitivity (28.6%) and a low positive predictive value (26.7%) (Ghodasra et al., 2014). We also found that most Candida endophthalmitis (87%) invaded both eyes simultaneously, which is consistent with previous studies (Oude Lashof et al., 2011; Geraymovych et al., 2015). Despite treatment, only 48.3% of patients showed improvement. Therefore, an ophthalmological examination should be performed in 14

asymptomatic patients with candidaemia following the American and European guidelines (Cornely et al., 2012; Pappas et al., 2016). A recent review reported Candida endocarditis in 0%–1.3% of patients with candidaemia (Antinori et al., 2016). However, a prospective cohort study assessing the incidence of endocarditis in adults with candidaemia diagnosed Candida endocarditis in 5.6% of the population based on echocardiography (Fernández-Cruz et al., 2015). We

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diagnosed endocarditis in 0.5% of the 765 patients with candidaemia and 3.6% of those who underwent echocardiography. The most common risk factors for Candida

endocarditis were a prosthetic valve (33%–55%) and intravenous drug use (30%)

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(Baddley et al., 2008; Lefort et al., 2012; Kauffman, 2015). However, in this study, only one patient had a prosthetic valve; the remaining three had native valve

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endocarditis with factors associated with health care, including recent hospitalisation

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and antibiotic use. Several reports have shown that despite active antifungal therapy and surgery, the mortality rate reaches 80% (Baddley et al., 2008). Three patients had complicating cerebral infarction or endophthalmitis. Given the relatively high incidence

be considered.

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in recent reports and high mortality rate, active echocardiographic surveillance should

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The number of reported cases of Candida osteomyelitis has doubled over the

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past 40 years according to a systematic literature review (Gamaletsou et al., 2012). In that study, Candida osteomyelitis was the first proven Candida site involvement in 48% of patients, and only 28% initially had candidaemia. Vertebrae were the most commonly involved bone sites in adults, whereas the femur was most common in paediatric patients (Gamaletsou et al., 2012). A study of Candida osteomyelitis and arthritis showed that C. albicans (65%) was the most commonly identified pathogen, 15

followed by C. tropicalis (16%) (Gamaletsou et al., 2012; Kauffman, 2015). In our study, two of three osteoarticular infections had vertebral osteomyelitis, and C. tropicalis was the predominant pathogen in osteoarticular infection in adults. The difference in the distribution of Candida species may be due to the study population, which was confined to patients with candidaemia in our study. The distribution of species in candidaemia complicated with osteoarticular infection needs to be studied

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further. This study had several limitations. Firstly, it was a retrospective study and not all patients underwent the same protocol. Secondly, the analysis of clinical characteristics

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and risk factors for complications of candidaemia was limited to the patients who

underwent ophthalmological examinations. Thus, there could have been a selection bias.

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However, we believe that this subgroup analysis was relatively objective, because

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minimal evaluation of the complications was performed to ensure that patients with complications were not classified into the no-complication group. Thirdly, we tested only for endophthalmitis, endocarditis, and osteoarticular infections as complications of

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candidaemia. Depending on the site of infection, it is not clear whether it is a cause or complication of candidaemia. Despite these limitations, this study included a relatively

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large population of adults with candidaemia and simultaneously evaluated the

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incidence, clinical characteristics, and risk factors for complications of candidaemia therein. Our results may help physicians to better understand the complications of candidaemia in adults. In conclusion, complications occurred in 4.4% of adults with candidaemia. C. albicans was an independent risk factor for complicated candidaemia in adults. Once a complication of candidaemia occurs, it may progress to a serious infection that not only 16

is difficult to treat but also may require additional procedures or surgery and lead to other complications. Therefore, careful evaluation and active treatment of candidaemia with complications should be encouraged.

Funding This study was supported by the Basic Science Research Program through the National

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Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF2013R1A1A3010554).

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Ethical approval

This study was approved by the institutional review board (IRB) of Chonnam National

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University Hospital. The need for consent was waived given the retrospective nature of

Declarations of interest

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None

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the study.

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f Total patients ( 18 years old)

Patients who underwent echocardiography

Pr

Patients with complications of candidaemia

e-

Patients who underwent ophthalmological examinations

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Table 1. Incidence of complications among adults with candidaemia.

Endophthalmitis*

No (%) 765 225 (29.4) 112 (14.6) 34

29/765 (3.8)

Patients with endophthalmitis/patients who underwent ophthalmological examinations

29/225 (12.9)

Infective endocarditis*

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Patients with endophthalmitis/total patients

4/765 (0.5)

Patients with infective endocarditis/patients who underwent echocardiography

4/112 (3.6)

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Patients with infective endocarditis/total patients

Osteoarticular infections

Patients with osteoarticular infections/total patients

3/765 (0.4)

* Two patients had both endophthalmitis and infective endocarditis

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Table 2. Clinical characteristics of 29 patients with Candida endophthalmitis. Characteristics

No (%)

Age, years, median (IQR)

72 (66-75)

Male

16 (55.1)

Visual symptoms Present

10 (34.5)

Absent

14 (48.2)

Unevaluable

5 (17.2)

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Infected eye Both

24 (82.7)

Left

3 (10.3)

Right

2 (6.8)

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Extension into the vitreous Candida species

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C. albicans C. tropicalis

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C. parapsilosis C. glabrata

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C. pelliculosa More than 2 species

14 (48.2)

23 (79.3) 2 (6.8) 1 (3.4) 0 (0) 1 (3.4) 2 (6.8) 3 (2-6)

The interval from the collection of the first positive blood culture to the diagnosis of complications, d, median (IQR)

7 (5-9)

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Duration of candidaemia, d, median (IQR)

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Treatment

AFT only

17 (58.6)

AFT + IVI

10 (34.4)

AFT + IVI + vitrectomy

2 (6.9)

Initial antifungal therapy Fluconazole

24 (82.8)

Amphotericin B

3 (10.3) 25

Micafungin

2 (6.9)

Modification of antifungal agents

11 (37.9)

Duration of antifungal agents, d, median (IQR)

30 (19-44)

Intravitreal injection (IVI) regimen Amphotericin B

9/12 (75)

Voriconazole

1/12 (8.3)

Amphotericin B + Voriconazole

2/12 (16.7)

Prognosis 14 (48.3)

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Improvement No improvement

6 (20.7)

Not evaluable

9 (31.0)

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Data are shown as n (%) unless otherwise stated.

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IQR, interquartile range; d, day; AFT, antifungal treatment; IVI, intravitreal injection

26

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Case 2

Case 3

Case 4

83/F

72/F

72/M

43/M

MVR, CABG,

Old MI, CKD, HTN, DM,

AF, HTN, ICH

ASD closure

RLL lobectomy

ESRD

N

Y

Y

N

Y

N

MV

MV

AV, MV

TV

N

Y

N

N

C. albicans

C. pelliculosa

C. albicans

C. tropicalis

1

1

2

1

HD of diagnosis

1

7

13

1

The interval from the collection of the first positive blood culture to the diagnosis of complications, d

0

6

11

0

Duration of candidaemia, d

8

20

1

3

Persistent candidaemia

Y

Y

N

N

Age/Sex

HTN Comorbidities Cholangitis Y

Antibiotics within the past 30 d

Y

Pr

Admission within the past 3 m

Involved valve

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HD Candida isolated

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Prosthetic valve Candida species

pr

Case 1

e-

Characteristics

f

Table 3. Clinical characteristics of four patients with Candida endocarditis.

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Cerebral infarction

Endophthalmitis

-

FLU (400 mg/day, 10) → L-AMB ( 5mg /kg/day, 20)

FLU (400 mg/day, 3)

57

30

3

redo MVR

-

-

Improved but recurred

Not evaluable

Expired/t candidaemia-

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Complication

f

Cerebral infarction, Endophthalmitis

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Surgery

-

e-

Duration of antifungal agents, d

Expire d/t candidaemia-

Pr

Outcome

AMB (0.7 mg/kg/day, 10) → ANID (100 mg/day, 47)

pr

FLU (400 mg/day, 11) → AMB (1 mg/kg/day, 5)

AFT (dose, d)

related

after 1year

related

M, male; F, female; N, No; Y, Yes; HTN, hypertension; MVR, mitral valve replacement; CABG, coronary artery bypass graft; ASD, atrial septal defect; MI,

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myocardial infarction; CKD, chronic kidney disease; DM, diabetes mellitus; RLL, Right lower lobe of lung; AF, atrial fibrillation; ICH, intracerebral hemorrhage; ESRD, end stage renal disease; m, month; d, day; MV, mitral valve; AV, aortic valve; TV, tricuspid valve; HD, hospital day; AFT, antifungal

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therapy; FLU, fluconazole; AMB, amphotericin-B; L-AMB, liposomal amphotericin-B(ambisome); ANID, anidulafungin

28

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Characteristics

Case 5

Case 6

Case 7

76/M

85/F

Compression fracture,

Atrial fibrillation

SMV thrombosis

COPD

N

Y

Y

N

Y

Y

Y

N

N

Y

Right knee joint

Lumbar spine

Lumbar spine

Synovial fluid

MRI

MRI

Proven arthritis

Probable osteomyelitis

Probable osteomyelitis

C. albicans & C. tropicalis

C. tropicalis

C. tropicalis

72/F

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Age/Sex

Traumatic ICH, Pyelonephritis Y

Antibiotics within the past 30 d

Y

Pr

Admission within the past 3 m

TPN CVC

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Candida species

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Involved lesion

Final diagnosis

e-

Comorbidities

Diagnostic tool

f

Table 4. Clinical characteristics of three patients with Candida osteoarticular infections.

HD Candida isolated

16

10

10

HD of diagnosis

30

20

130

The interval from the collection of the first positive blood culture to the diagnosis of complications, d

14

10

120

Duration of candidaemia

26

3

3

29

Complication

-

Duration of antifungal agents

97

N

-

-

FLU (400 mg/day, 94)

FLU (400 mg/day, 57)

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FLU (400 mg/day, 11) → AMB (0.7 mg/kg/day, 11) → ANID (100 mg/day, 48) → FLU (400 mg/day, 27)

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AFT (dose, days)

N

f

Y

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Persistent candidaemia

94

57

Drainage

-

-

Outcome

Improve

Improve

Improve

Pr

Surgery

M, male; F, female; N, No; Y, Yes; ICH, intracerebral hemorrhage; SMV, superior mesenteric vein; COPD, chronic obstructive pulmonary disease; m,

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month; d, day; TPN, total parenteral nutrition; CVC, central venous catheter; MRI, magnetic resonance imaging; HD, hospital day; AFT, antifungal therapy;

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FLU, fluconazole; AMB, amphotericin-B; ANID, anidulafungin

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Table 5. Clinical characteristics of the patients with candidaemia with and without complications. Complication group (n = 33)

No-complication group (n = 192)

p-value

Age, years, mean (SD)

71.0 (7.8)

65.2 (14.2)

0.001

Male

18 (54.5)

125 (65.1)

0.244

Diabetes mellitus

10 (30.3)

55 (28.6)

0.846

Cardiac disease

5 (15.2)

23 (12.0)

0.610

Chronic kidney disease

2 (6.1)

13 (6.8)

0.880

46 (24)

0.632

Characteristic

10 (30.3)

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Solid cancer

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Comorbidities

Haematological disease

1 (3.0)

9 (4.7)

0.670

1 (3.0)

14 (7.3)

0.365

7 (21.2)

74 (38.5)

0.055

3 (9.1)

29 (15.1)

0.361

Chemotherapy within the past 30 d

3 (9.1)

30 (15.6)

0.327

Corticosteroid within the past 30 d

5 (15.2)

33 (17.2)

0.773

Indwelling urinary catheter

15 (45.5)

130 (67.7)

0.014

30 (90.9)

173 (90.1)

0.886

Total parenteral nutrition

26 (78.8)

151 (78.6)

0.985

Central venous catheter

14 (42.4)

102 (53.1)

0.256

13.2 (19.6)

21.9 (27.6)

0.081

2 (6.1)

37 (19.3)

0.064

C. albicans

24 (72.7)

58 (30.2)

< 0.001

Non-albicans Candida species

6 (18.1)

122 (63.5)

Neutropenia

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Surgery within the past 3 m

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Predisposing factors

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- Gastrointestinal surgery

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d

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Exposure to antibiotics within the past 30

LOS before candidaemia, d, mean (SD) Diagnosis of candidaemia in the ICU Candida species

31

4 (12.1)

33 (17.2)

C. parapsilosis

1 (3.0)

59 (30.7)

0 (0)

19 (9.9)

1 (3.0)

11 (5.7)

3 (9.1)

12 (6.3)

0.546

Duration of candidaemia, d, mean (SD)

6.2 (9.6)

7.4 (9.7)

0.533

Persistent candidaemia

9 (27.3)

66 (34.4)

0.687

Severe sepsis

6 (18.2)

24 (12.5)

0.375

Septic shock

3 (9.1)

C. glabrata Othersa Two or more species

33.1 (21.5)

Removal of CVC

12/14 (85.7)

Neutropenia

0/0

Non-neutropenia

12/14

3.2 (6.4)

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Fluconazole

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The interval from the collection of the first positive blood culture to removal of CVC, d, mean (SD) Empiric antifungal therapy

25 (13.0)

0.528

34.7 (33.8)

0.790

97/102 (95.1)

0.167

9/9

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LOS after candidaemia, d, mean (SD)

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C. tropicalis

88/93

5.7 (6.2)

0.186 0.275

26 (78.8)

163 (84.9)

3 (9.1)

17 (8.9)

4 (12.1)

7 (3.6)

Anidulafungin

0 (0)

4 (2.1)

Caspofungin

0 (0)

1 (0.9)

31/32 (97.0)

162/173 (93.6)

0.474

16.4 (10.8)

0.042

42/192 (21.9)

0.632

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Micafungin

na

Amphotericin B

Initial appropriate antifungal therapy

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Duration of antifungal agents, d, mean (SD) 23.1 (17.6) 30-day mortality

6/33 (18.2)

Data are shown as n (%) unless otherwise stated. SD, standard deviation; m, month; d, day; LOS, length of hospital stay; ICU, intensive care unit; CVC, central venous catheter

32

a

Include C. guilliermondii (5 isolates), C. pelliculosa (1 isolate), C. krusei (1 isolate),

C. famata (1 isolate), C. intermedia (1 isolate), C. catenulata (1 isolate), and unidentified Candida species (2 isolates) Table 6. Risk factors for complications of candidaemia in adults. 95% CI

P

Age

1.03

0.99-1. 07

0.142

Surgery within past 3 m

0.56

0.21-1.49

0.241

Indwelling urinary catheter

0.56

LOS before candidaemia, d

0.99

Candidaemia onset in the ICU

0.39

Candida albicans (vs. NAC)

5.12

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Adjusted OR

0.183

0.97-1.01

0.366

0.08-1.92

0.248

2.17-12.09

< 0.001

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0.24-1.32

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Variable

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OR, odds ratio; CI, confidence interval; LOS, length of hospital stay; d, day; ICU, intensive care unit; NAC, non-albicans Candida spp. The English in this document has been checked by at least two professional editors, both

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native speakers of English. For a certificate, please see:

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http://www.textcheck.com/certificate/8yOIV1

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