Journal of Hospital Infection 87 (2014) 54e58 Available online at www.sciencedirect.com
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Short report
Nosocomial Candida parapsilosis candidaemia: risk factors, antifungal susceptibility and outcome Y. Hirai a, b, *, S. Asahata a, Y. Ainoda a, A. Goto c, T. Fujita a, K. Totsuka a a
Department of Infectious Diseases, Tokyo Women’s Medical University Hospital, Shinjuku-ku, Tokyo, Japan Department of Haematology, Tokyo Women’s Medical University Hospital, Shinjuku-ku, Tokyo, Japan c Laboratory of Microbiology, Tokyo Women’s Medical University Hospital, Shinjuku-ku, Tokyo, Japan b
A R T I C L E
I N F O
Article history: Received 24 October 2013 Accepted 10 February 2014 Available online 12 March 2014 Keywords: Candida parapsilosis Candidaemia Minimum inhibitory concentration Minimum fungicidal concentration Cardiovascular prosthetic materials
S U M M A R Y
A retrospective analysis was undertaken from 2000 to 2010 to show the risk factors associated with death within 30 days in patients with C. parapsilosis candidaemia (CPC). Fifty-one cases of nosocomial CPC were included in the analysis. All isolates from blood cultures were susceptible to micafungin and fluconazole. The overall mortality rate was 23.5%, and the most severe complications were endocarditis (5.9%) and endophthalmitis (5.9%). On multi-variate analysis, APACHE II score >25 (odds ratio 43.9) and retained cardiovascular prosthetic materials (RCPM) (prosthetic valve or graft) (odds ratio 14.6) were found to be risk factors associated with death. Prompt surgical removal should be considered in CPC patients with RCPM. ª 2014 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction Candida spp. remain a major cause of morbidity and mortality in healthcare settings. Candida parapsilosis is often the second or third most commonly isolated Candida spp. from blood cultures.1 Intravenous catheters and parenteral nutrition are well-known risk factors. C. parapsilosis demonstrates an * Corresponding author. Address: Department of Infectious Diseases, Tokyo Women’s Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan. Tel.: þ81 3 3353 8111. E-mail address: [email protected] (Y. Hirai).
increased in-vitro minimum inhibitory concentration (MIC) to echinocandins such as caspofungin.1 Recent studies have shown increasing incidence of C. parapsilosis candidaemia (CPC) of 7e24%.2 Although risk factors associated with death attributed to candidaemia have been documented in the literature, any specific risk factors associated with nosocomial CPC are not known. The primary outcome of this study was to establish the risk factors associated with death within 30 days by multivariate analysis. The secondary outcome was to determine antifungal MICs and minimum fungicidal concentrations (MFCs) for C. parapsilosis isolated from blood cultures.
0195-6701/$ e see front matter ª 2014 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jhin.2014.02.006
Y. Hirai et al. / Journal of Hospital Infection 87 (2014) 54e58
Patients and methods Study design
55
Spearman’s rank correlation coefficient was used to show correlation between antifungal MIC and MFC values. P < 0.05 and r > 0.5 were considered significant. Multi-variate analysis was used to determine the independent risk factors associated with mortality using forward stepwise logistic regression. All variables with P < 0.1 on univariate analysis were entered into the multi-variate model. Statistical analyses were performed using R Version 2.14.1 (http://www.r-project.org/) for Microsoft Windows 7.
A retrospective observational study was performed between 1 April 2000 and 31 March 2010. The setting was Tokyo Women’s Medical University (TWMU) Hospital in Japan, a 1423-bedded university hospital that includes the nation’s largest institute of cardiovascular disease. All cases of nosocomial CPC were included in the study. The study protocol was approved by the Ethics Committee at TWMU Hospital.
Results
Definitions
Clinical features
A case of candidaemia was defined as a patient with at least one positive blood culture yielding any Candida spp. Cases with positive blood cultures occurring 48 h after admission were defined as nosocomial candidaemia. Blood samples were drawn under sterile conditions and processed using BACTEC 9240 (Becton Dickinson Diagnostic Instrument Systems, Towson, MD, USA). C. parapsilosis was identified using the API 32C system (bioMe ´rieux, Marcy l’Etoile, France).
In total, 307 cases of nosocomial candidaemia were identified. The incidence of nosocomial candidaemia was 0.074 cases per 1000 patient-admission-days during the study period. C. parapsilosis (N ¼ 89, 29%) was the second most common Candida spp. causing candidaemia after Candida albicans (43%). Fifty-one of the 89 cases of CPC with medical records met the inclusion criteria and were included in this study. The demographic and clinical characteristics of the 51 cases (39 survivors and 12 deaths) of CPC are shown in Table I. Eighteen of these 51 (35.3%) patients had digestive tract or hepatobiliary-pancreatic cancer. Seven cases had RCPM, consisting of prosthetic valves (N ¼ 5) and grafts (N ¼ 2). No significant differences were found between the survivors and the patients who died in terms of receipt of empirical or definitive antifungal treatment, serum C-reactive protein, BDG and white blood cell count. The crude 30-day mortality rate was 23.5% (12/51). APACHE II score >25 [odds ratio (OR) 43.9, 95% confidence interval (CI) 4.77e404; P ¼ 0.000839] and RCPM (OR 14.6, 95% CI 1.05e203; P ¼ 0.0459) were risk factors associated with death within 30 days on multi-variate analysis (Table I). The most severe complications identified in this study were endophthalmitis (N ¼ 3, 5.9%) and endocarditis (N ¼ 3, 5.9%). Two cases developed endophthalmitis during micafungin treatment and one case developed endophthalmitis during fluconazole treatment. Likewise, two cases developed endocarditis during micafungin treatment and one case developed endocarditis during fluconazole treatment.
Study population Patients were observed from the day of diagnosis of CPC until the end of follow-up at 30 days. The following data were obtained for all patients: age; sex; underlying disease; use of intravenous catheters; retained cardiovascular prosthetic materials (RCPM) (prosthetic valve or graft); empirical or definitive antifungal treatment; dose of antifungal agents; complications of candidaemia; Acute Physiology and Chronic Health Evaluation (APACHE) II scores at diagnosis of candidaemia; and crude mortality at 30 days. Hepato-biliary-pancreatic cancer was defined as including hepatocellular carcinoma, pancreatic cancer or bile duct cancer. Blood tests including white blood cell and neutrophil counts, serum C-reactive protein and 1,3-beta-D-glucan (BDG) assay using Fungitec G-test MK (Nissui, Tokyo, Japan; cut-off level 20 pg/mL) were performed within three days of a positive blood culture. Exclusion criteria were: age 25
22.39 5.62 16 (31.4%)
20.74 4.452 6 (15.4%)
27.75 5.879 10 (83.3%)
0.000056 0.000031
30 (58.8%) 371.4 112.5
23 (58.9%) 380 61.57
7 (58.3%) 366.66 81.64
1 0.2273
19 (37.2%) 100 18.89 2 (3.9%)
15 (38.4%) 103.3 22.88 1 (2.56%)
4 (33.3%) 100 1 (8.3%)
1 0.8029 0.96
Definitive antifungal treatment Fluconazole Micafungin Voriconazole Polyene (AMB or L-AMB)
30 (58.8%) 15 (29.1%) 2 (3.9%) 4 (7.8%)
24 (61.5%) 11 (28.2%) 2 (5.12%) 3 (7.69%)
6 4 0 1
0.518 0.7301 1 1
Treatment duration (days)
19.21 14.5
21 15.1 (7e84)
12.9 12.9 (2e29)
0.0863
0.125e0.5 0.5e128 0.25e1 1e8
0.267 0.49 0.383 0.546
8940 5.019 9.53 4.66 372.7 465.6 (N ¼ 12)
0.6496 0.1031 0.1104
Underlying diseases Digestive/hepato-biliarypancreatic cancer Non-digestive/hepatobiliary-pancreatic cancer IBD (ulcerative colitis and Crohn’s disease) Pancreatitis Retained cardiovascular prosthetic materials Diabetes mellitus CKD stage 5 or 5D
Empirical antifungal treatment Fluconazole Maintenance dose of fluconazole (mg/day) Micafungin Dose of micafungin (mg/day) Polyene (AMB or L-AMB)
Antifungal susceptibility against C. parapsilosis (mg/mL) Fluconazole MIC 0.125e1 0.125e1 Fluconazole MFC 0.5e128 0.5e128 Micafungin MIC 0.125e2 0.125e2 Micafungin MFC 0.5e8 0.5e8 Laboratory data White blood cell count (/mL) C-reactive protein (mg/dL) 1,3-beta-D-glucan (pg/mL) Complication Endophthalmitis due to C. parapsilosis Infective endocarditis due to C. parapsilosis Valve replacement during candidaemia
8352 5.060 6.96 6.24 780.1 1048.4
8171 5.124 6.17 6.50 948.6 1176.6 (N ¼ 29)
(50%) (33.3%) (0%) (8.3%)
3 (5.9%)
2 (5.12%)
1 (8.3%)
0.561
3 (5.9%)
1 (2.56%)
2 (16.6%)
0.134
1 (1.96%)
1 (2.56%)
0
1
Multi-variate analysis OR (95% CI), P-value
14.6 (1.05e203), 0.0459
43.9 (4.77e404), 0.000839
IBD, inflammatory bowel disease; CKD, chronic kidney disease; CLABSI, central-line-associated bloodstream infection; APACHE, Acute Physiology and Chronic Health Evaluation; AMB, amphotericin-B; L-AMB, liposomal amphotericin-B; MIC, minimum inhibitory concentration; MFC, minimum fungicidal concentration; SD, standard deviation; OR, odds ratio; CI, confidence interval.
0.1697
13 3 11
6
1
2
1
4
5
1
5
5
3
2
3
5
2 8
7 4 2 10
3
4
3 9
6
9 4 17 22
14
7
1 6 2
20 3 5
14
10
3
6
2
3 4 1 18 10 24
26 2 3 8 25 5 12 2
39 1 49 5 VRCZ
ITCZ
FLCZ
AMB
MIC MFCa MIC MFCa MIC MFCa MIC MFCa MIC MFCa MCFG
MCFG, micafungin; AMB, amphotericin-B; FLCZ, fluconazole; ITCZ, itraconazole; VRCZ, voriconazole; MIC, minimum inhibitory concentration; MFC, minimum fungicidal concentration; r, Spearman’s rank correlation coefficient (1 & r & 1); shaded zone, MIC breakpoint of resistance according to EUCAST (AMB) or from susceptible dose dependent to resistant according to Clinical and Laboratory Standards Institute (MCFG, FLCZ, ITCZ, VRCZ). a MFC breakpoint not established.
0.2245
0.0078
0.2702
0.3619
0.0504
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Short report
Nosocomial Candida parapsilosis candidaemia: risk factors, antifungal susceptibility and outcome Y. Hirai a, b, *, S. Asahata a, Y. Ainoda a, A. Goto c, T. Fujita a, K. Totsuka a a
Department of Infectious Diseases, Tokyo Women’s Medical University Hospital, Shinjuku-ku, Tokyo, Japan Department of Haematology, Tokyo Women’s Medical University Hospital, Shinjuku-ku, Tokyo, Japan c Laboratory of Microbiology, Tokyo Women’s Medical University Hospital, Shinjuku-ku, Tokyo, Japan b
A R T I C L E
I N F O
Article history: Received 24 October 2013 Accepted 10 February 2014 Available online 12 March 2014 Keywords: Candida parapsilosis Candidaemia Minimum inhibitory concentration Minimum fungicidal concentration Cardiovascular prosthetic materials
S U M M A R Y
A retrospective analysis was undertaken from 2000 to 2010 to show the risk factors associated with death within 30 days in patients with C. parapsilosis candidaemia (CPC). Fifty-one cases of nosocomial CPC were included in the analysis. All isolates from blood cultures were susceptible to micafungin and fluconazole. The overall mortality rate was 23.5%, and the most severe complications were endocarditis (5.9%) and endophthalmitis (5.9%). On multi-variate analysis, APACHE II score >25 (odds ratio 43.9) and retained cardiovascular prosthetic materials (RCPM) (prosthetic valve or graft) (odds ratio 14.6) were found to be risk factors associated with death. Prompt surgical removal should be considered in CPC patients with RCPM. ª 2014 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction Candida spp. remain a major cause of morbidity and mortality in healthcare settings. Candida parapsilosis is often the second or third most commonly isolated Candida spp. from blood cultures.1 Intravenous catheters and parenteral nutrition are well-known risk factors. C. parapsilosis demonstrates an * Corresponding author. Address: Department of Infectious Diseases, Tokyo Women’s Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan. Tel.: þ81 3 3353 8111. E-mail address: [email protected] (Y. Hirai).
increased in-vitro minimum inhibitory concentration (MIC) to echinocandins such as caspofungin.1 Recent studies have shown increasing incidence of C. parapsilosis candidaemia (CPC) of 7e24%.2 Although risk factors associated with death attributed to candidaemia have been documented in the literature, any specific risk factors associated with nosocomial CPC are not known. The primary outcome of this study was to establish the risk factors associated with death within 30 days by multivariate analysis. The secondary outcome was to determine antifungal MICs and minimum fungicidal concentrations (MFCs) for C. parapsilosis isolated from blood cultures.
0195-6701/$ e see front matter ª 2014 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jhin.2014.02.006
Y. Hirai et al. / Journal of Hospital Infection 87 (2014) 54e58
Patients and methods Study design
55
Spearman’s rank correlation coefficient was used to show correlation between antifungal MIC and MFC values. P < 0.05 and r > 0.5 were considered significant. Multi-variate analysis was used to determine the independent risk factors associated with mortality using forward stepwise logistic regression. All variables with P < 0.1 on univariate analysis were entered into the multi-variate model. Statistical analyses were performed using R Version 2.14.1 (http://www.r-project.org/) for Microsoft Windows 7.
A retrospective observational study was performed between 1 April 2000 and 31 March 2010. The setting was Tokyo Women’s Medical University (TWMU) Hospital in Japan, a 1423-bedded university hospital that includes the nation’s largest institute of cardiovascular disease. All cases of nosocomial CPC were included in the study. The study protocol was approved by the Ethics Committee at TWMU Hospital.
Results
Definitions
Clinical features
A case of candidaemia was defined as a patient with at least one positive blood culture yielding any Candida spp. Cases with positive blood cultures occurring 48 h after admission were defined as nosocomial candidaemia. Blood samples were drawn under sterile conditions and processed using BACTEC 9240 (Becton Dickinson Diagnostic Instrument Systems, Towson, MD, USA). C. parapsilosis was identified using the API 32C system (bioMe ´rieux, Marcy l’Etoile, France).
In total, 307 cases of nosocomial candidaemia were identified. The incidence of nosocomial candidaemia was 0.074 cases per 1000 patient-admission-days during the study period. C. parapsilosis (N ¼ 89, 29%) was the second most common Candida spp. causing candidaemia after Candida albicans (43%). Fifty-one of the 89 cases of CPC with medical records met the inclusion criteria and were included in this study. The demographic and clinical characteristics of the 51 cases (39 survivors and 12 deaths) of CPC are shown in Table I. Eighteen of these 51 (35.3%) patients had digestive tract or hepatobiliary-pancreatic cancer. Seven cases had RCPM, consisting of prosthetic valves (N ¼ 5) and grafts (N ¼ 2). No significant differences were found between the survivors and the patients who died in terms of receipt of empirical or definitive antifungal treatment, serum C-reactive protein, BDG and white blood cell count. The crude 30-day mortality rate was 23.5% (12/51). APACHE II score >25 [odds ratio (OR) 43.9, 95% confidence interval (CI) 4.77e404; P ¼ 0.000839] and RCPM (OR 14.6, 95% CI 1.05e203; P ¼ 0.0459) were risk factors associated with death within 30 days on multi-variate analysis (Table I). The most severe complications identified in this study were endophthalmitis (N ¼ 3, 5.9%) and endocarditis (N ¼ 3, 5.9%). Two cases developed endophthalmitis during micafungin treatment and one case developed endophthalmitis during fluconazole treatment. Likewise, two cases developed endocarditis during micafungin treatment and one case developed endocarditis during fluconazole treatment.
Study population Patients were observed from the day of diagnosis of CPC until the end of follow-up at 30 days. The following data were obtained for all patients: age; sex; underlying disease; use of intravenous catheters; retained cardiovascular prosthetic materials (RCPM) (prosthetic valve or graft); empirical or definitive antifungal treatment; dose of antifungal agents; complications of candidaemia; Acute Physiology and Chronic Health Evaluation (APACHE) II scores at diagnosis of candidaemia; and crude mortality at 30 days. Hepato-biliary-pancreatic cancer was defined as including hepatocellular carcinoma, pancreatic cancer or bile duct cancer. Blood tests including white blood cell and neutrophil counts, serum C-reactive protein and 1,3-beta-D-glucan (BDG) assay using Fungitec G-test MK (Nissui, Tokyo, Japan; cut-off level 20 pg/mL) were performed within three days of a positive blood culture. Exclusion criteria were: age 25
22.39 5.62 16 (31.4%)
20.74 4.452 6 (15.4%)
27.75 5.879 10 (83.3%)
0.000056 0.000031
30 (58.8%) 371.4 112.5
23 (58.9%) 380 61.57
7 (58.3%) 366.66 81.64
1 0.2273
19 (37.2%) 100 18.89 2 (3.9%)
15 (38.4%) 103.3 22.88 1 (2.56%)
4 (33.3%) 100 1 (8.3%)
1 0.8029 0.96
Definitive antifungal treatment Fluconazole Micafungin Voriconazole Polyene (AMB or L-AMB)
30 (58.8%) 15 (29.1%) 2 (3.9%) 4 (7.8%)
24 (61.5%) 11 (28.2%) 2 (5.12%) 3 (7.69%)
6 4 0 1
0.518 0.7301 1 1
Treatment duration (days)
19.21 14.5
21 15.1 (7e84)
12.9 12.9 (2e29)
0.0863
0.125e0.5 0.5e128 0.25e1 1e8
0.267 0.49 0.383 0.546
8940 5.019 9.53 4.66 372.7 465.6 (N ¼ 12)
0.6496 0.1031 0.1104
Underlying diseases Digestive/hepato-biliarypancreatic cancer Non-digestive/hepatobiliary-pancreatic cancer IBD (ulcerative colitis and Crohn’s disease) Pancreatitis Retained cardiovascular prosthetic materials Diabetes mellitus CKD stage 5 or 5D
Empirical antifungal treatment Fluconazole Maintenance dose of fluconazole (mg/day) Micafungin Dose of micafungin (mg/day) Polyene (AMB or L-AMB)
Antifungal susceptibility against C. parapsilosis (mg/mL) Fluconazole MIC 0.125e1 0.125e1 Fluconazole MFC 0.5e128 0.5e128 Micafungin MIC 0.125e2 0.125e2 Micafungin MFC 0.5e8 0.5e8 Laboratory data White blood cell count (/mL) C-reactive protein (mg/dL) 1,3-beta-D-glucan (pg/mL) Complication Endophthalmitis due to C. parapsilosis Infective endocarditis due to C. parapsilosis Valve replacement during candidaemia
8352 5.060 6.96 6.24 780.1 1048.4
8171 5.124 6.17 6.50 948.6 1176.6 (N ¼ 29)
(50%) (33.3%) (0%) (8.3%)
3 (5.9%)
2 (5.12%)
1 (8.3%)
0.561
3 (5.9%)
1 (2.56%)
2 (16.6%)
0.134
1 (1.96%)
1 (2.56%)
0
1
Multi-variate analysis OR (95% CI), P-value
14.6 (1.05e203), 0.0459
43.9 (4.77e404), 0.000839
IBD, inflammatory bowel disease; CKD, chronic kidney disease; CLABSI, central-line-associated bloodstream infection; APACHE, Acute Physiology and Chronic Health Evaluation; AMB, amphotericin-B; L-AMB, liposomal amphotericin-B; MIC, minimum inhibitory concentration; MFC, minimum fungicidal concentration; SD, standard deviation; OR, odds ratio; CI, confidence interval.
0.1697
13 3 11
6
1
2
1
4
5
1
5
5
3
2
3
5
2 8
7 4 2 10
3
4
3 9
6
9 4 17 22
14
7
1 6 2
20 3 5
14
10
3
6
2
3 4 1 18 10 24
26 2 3 8 25 5 12 2
39 1 49 5 VRCZ
ITCZ
FLCZ
AMB
MIC MFCa MIC MFCa MIC MFCa MIC MFCa MIC MFCa MCFG
MCFG, micafungin; AMB, amphotericin-B; FLCZ, fluconazole; ITCZ, itraconazole; VRCZ, voriconazole; MIC, minimum inhibitory concentration; MFC, minimum fungicidal concentration; r, Spearman’s rank correlation coefficient (1 & r & 1); shaded zone, MIC breakpoint of resistance according to EUCAST (AMB) or from susceptible dose dependent to resistant according to Clinical and Laboratory Standards Institute (MCFG, FLCZ, ITCZ, VRCZ). a MFC breakpoint not established.
0.2245
0.0078
0.2702
0.3619
0.0504
