Antifungal treatment / Department / Indications / Antifungal
Prophylaxis / Paediatric / Neutropenia >10days
+ Candida colonization* / MIC 1mg/kg/d
Adult / Induction chemotherapy of AML,
GVHD treated by corticosteroids / POS**
Gastrointestinal GVHD / MIC 50mg/d or
CAS 70mg/d followed by 50mg/d
Empiric / Paediatric / Persistence of fever 48 to 96h
after initiation of antibacterial therapy / L-AMB 3mg/kg/d or
CAS 70mg/m2 day 1 followed by 50mg/m2/day
Adult / L-AMB 3mg/kg/d or
CAS 70mg/d day 1 followed by 50mg/day

Table S1: Standard procedures of care in paediatric and adult departments. L-AMB: Liposomal Amphotericin B, MIC: Micafungin, POS: Posaconazole, CAS: Caspofungin, AML: Acute Myeloid Leukemia, GVHD: Graft Versus Host Disease

*defined as 2 Candida positive stool cultures, ** posaconazole were administered either in oral suspension (before June 2015: 600 mg/day) or delayed-release tablet (after June 2015: 600 mg/day followed by 300 mg/day)

Case / Age
(years)/
sex / Underlying
disease / BMT / Underlying
disease status / ATF therapy prior
diagnosis / Catheter
colonization / Date of serum
sample/
diagnosis
(Days) / BDG at
diagnosis
(+/-3d)* / Mannan at
diagnosis
(+/-3d) / Causative
species / ATF therapy
(duration) / Outcome
1 / 67/F / RAEB / HSCT
(-6 mo) / CR / No / Yes / D0 / N / N / C. albicans / CAS (14 d) / Survival
2 / 49/F / AML / HSCT
(-6 mo) / Hepatic GVHD / No / No / D+1 / N / P / C. tropicalis / L-AMB (7d) / Death 7d
3 / 68/F / RAEB / No / Aplasia / CS 47d / No / D-3 / P / N / C. kefyr / L-AMB (3 d) then FLU (3 d) / Death 6d
4 / 39/H / T cell lymphoma / No / Refractory / No / No / D+2 / N / ND / C. tropicalis / L-AMB 4d
followed by
CAS 10d / Survival
5 / 46/H / Myeloma / ASCT
(-8 d) / Aplasia / No / No / D-3 / N / ND / C. parapsilosis / CAS 14d / Survival
6 / 76/F / Multiple
Myeloma / Relapse / Aplasia / No / Yes / D-2 / N / ND / C. albicans / CAS 14d / Survival
7 / 67/F / Myeloma / ASCT
(-15d) / Aplasia / No / Yes / D0 / N / N / C. albicans / FLU 14d / Survival
8 / 12/F / AML / No / Aplasia / AB 4d / No / D-2 / P / N / C. albicans / CAS 14d / Survival
9 / 47/M / Plasmablastic
lymphoma / ASCT
(-1.5 mo) / Aplasia / No / No / D1 / P / P / C. tropicalis / CAS 2d / Death 3d
10 / 9/M / AML / No / Aplasia / MC 8d / No / D+2 / N / N / C. kefyr / L-AMB 8d
followed by
CAS 7d / Survival
11 / 2/F / ALL / No / Aplasia / No / No / D-2 / P / P / C. parapsilosis / CAS 14d
followed by
FLU / Persistent
positive
blood-cultures
Survival
12 / 36/M / AML / 2nd ASCT / CR / CS 3d / No / D+3 / P / ND / C. parapsilosis / CAS 21d / Survival
13 / 1.3/M / ALL / No / Aplasia / No / No / D0 / E / ND / C. kefyr / CAS 24d / Survival
13 bis / 1.6/M / ALL / No / CR / No / No / D1 / P / ND / C. kefyr / CAS 13d / Survival
14 / 5/F / ALL / No / Aplasia / No / Yes / D+3 / N / ND / C. tropicalis / L-AMB 8d / Survival
15 / 6/M / AML / No / Aplasia / No / Yes / D+2 / N / N / C. parapsilosis / CAS 13d / Survival
16 / 60/F / Hodgkin
lymphoma / HSCT (-1mo) / Refractory / CS 20d / No / D-17 / P / P / C. albicans / MIC 2mo / CDC,
Death 2mo
17 / 48/F / Myelofibrosis / HSCT
(-14d) / Digestive
GVHD / No / No / D-2 / N / P / C. dubliniensis / CAS 3.5mo / Survival
18 / 11/F / AML / No / Aplasia / No / No / D0 / P / P / C. tropicalis / MIC 1.5mo
followed
by L-AMB / CDC;
Survival
19** / 63/M / ALL / No / Relapse aplasia / CS
1mo = No / No / D-15 / P / P / C. tropicalis / L-AMB 33d / CDC;
Death 33d
20 / 12/F / AML / No / Aplasia / No / No / D0 / E / ND / C. lusitaniae / CAS 11d
followed by
FLU 2y / CDC;
Survival
21 / 9/M / ALL / No / Aplasia / No / No / NA / N / ND / C. albicans / CAS 22d
followed by
FLU 6mo / CDC;
Survival
22 / 58/F / Hodgkin
lymphoma / HSCT
(-3 d) / Aplasia / No / No / D0 / P / P / C. albicans / CAS 4d
followed by
FLU 14d / Death 14d

Table S2: Characteristics of 22 with haematological malignancy who developed candidemia. D0 corresponding to the candidemia diagnosis, ie date of first positive blood culture sample.

F: Female, M: male, BMT: Bone Marrow Transplantation, ATF: antifungal, RAEB: Refractory anemia with excess blasts; AML: Acute Myeloid Leukaemia; ALL: Acute Lymphoblastic Leukemia; HSCT: heterogeneic stem cell transplantation; ASCT: Autologous stem cell transplantation; CR: complete remission, BMT: Bone marrow transplantation, GVHD: Graft versus Host Disease, PR: Partial response; N: negative; P: Positive; E: equivoqual;

CAS: Caspofungin; FLU: Fluconazole; VOR: Voriconazole; MIC: Micafungin; L-AMB: Liposomal Amphotericin B; CDC: Chronic disseminated Candidiasis; NA: not available; ND: Not done. D: day, mo: month, y: year

KT: catheter. Catheter colonization corresponding to bloodcultures positive only when sampled through the catheter and recovery of the episode after catheter removal.

* Values lower than 8 pg/ml and higher than 523 pg/ml were considered as being 8 and 523 pg/ml. Manufacturer’s recommendations are to consider values lower than 60 pg/ml as negative, higher than 80 pg/ml as positive and equivocal between 60 and 80 pg/ml.

** Patient previously treated with caspofungin who developed a candidemia due to C. tropicalis, with a strain resistant to echinocandins

Case / Age (years)/ sex / Underlying disease / BMT / Underlying disease status / ATF prior diagnosis / Candidemia species*** / Colonization / Date first of serum sample/ diagnosis (days) sample / BDG at diagnosis (+/-3d)* / Mannan at diagnosis (+/-3d) / ATF therapy (duration) / BDG normalisation / CT-Scan recovery / Outcome
16 / 60/F / Hodgkin lymphoma / HSCT (-1mo) / Refractory / CAS 20d and MC 4d / C. albicans (D-4) / C. albicans / D-21 / P / P / MIC 2mo / NA / NA / Death 2mo
18 / 11/F / AML / No / CR / MIC 18d / C. tropicalis (D-16) / C. tropicalis / D-16 / P / P / MIC 30d, followed by L-AMB / 3mo decrease / NA / Survival
19** / 63/M / ALL / No / Relapse / CAS 1mo followed by L-AMB 4d / C. tropicalis
(D-6) / C. tropicalis / D-20 / P / P / L-AMB 29d / NA / NA / Death 29d
20 / 12/F / AML / No / CR / CAS 11d followed by FLU 17d / C. lusitaniae (D-28) / C. lusitaniae / D-21 / P / ND / FLU 2y / 6mo / 2y / Survival
21 / 9/M / ALL / No / Aplasia / CAS 20d / C. albicans (D-20) / C. albicans / D-23 / P / ND / CAS 2d followed by FLU 6mo / 6mo / 14 mo still pos / Survival
23 / 63/M / AML / HSCT (-30d) / CR
Aplasia / CAS 4d / No / C. albicans and C. dubliniensis / J-22 / P / N / CAS 3.5mo / 3mo / 5mo / Survival
24 / 45/M / Hodgkin lymphoma / HSCT (-40d) / PR / No / No / C. albicans / D-6 / P / P / CAS 2mo followed by FLU 5mo / 5mo / 7mo / Survival
25 / 9/F / ALL / No / CR / L-AMB 16d / No / C. albicans / D+3 / N / P / L-AMB 10d followed by FLU 7.5mo / NA / Stabilization of lesions 7mo / Survival
26 / 12/F / ALL / No / Relapse aplasia / L-AMB 8d / No / C. albicans / D+7 / N / N / L-AMB 14d, CAS 14d, FLU 4mo / 57d / Stability of lesions 4mo / Survival
27 / 61/F / ALL / No / CR / L-AMB 2d / No / C. albicans / D-1 / P / N / L-AMB 13d followed by VOR 7d CAS 3mo / 2mo / 5mo / Survival
28 / 12/M / ALL / No / CR / No / No / C. albicans / D-14 / N / P / CAS 4.5mo / NA / 4.5mo persistence few lesions / Survival

Table S3: Characteristics of 11 with haematological malignancy who developed CDC. D0 corresponding to the CDC diagnosis, ie date of positive CT-scan lesions.

F: Female, M: male, BMT: Bone Marrow Transplantation, ATF: antifungal treatment, RAEB: Refractory anaemia with excess blasts; AML: Acute Myeloid Leukaemia; ALL: Acute Lymphoblastic Leukaemia; HSCT: heterogeneic stem cell transplantation; ASCT: Autologous stem cell transplantation; CR: complete remission, GVHD: Graft versus Host Disease, PR: Partial response; N: negative; P: Positive; CAS: Caspofungin; FLU: Fluconazole; VOR: Voriconazole; MIC: Micafungin; L-AMB: Liposomal Amphotericin B; CDC: Chronic disseminated Candidiasis; NA: not available; ND: Not done, d: day; mo: month; y: year

*Values lower than 8 pg/ml and higher than 523 pg/ml were considered as being 8 and 523 pg/ml. Manufacturer’s recommendations are to consider values lower than 60 pg/ml as negative, higher than 80 pg/ml as positive and equivocal between 60 and 80 pg/ml.

** Patient previously treated with caspofungin who developed a candidemia due to C. tropicalis, with a strain resistant to echinocandins

*** Candida species when candidemia occurred before CDC

Adult patients / Paediatric patients
Admissions / Candidemia (incidence %) / CDC
(incidence %) / Admissions / Candidemia (incidence %) / CDC
(incidence %)
2013 / 308 / 1 (0.32) / 0 (0.00) / 369 / 2 (0.54) / 2 (0.54)
2014 / 411 / 1 (0.24) / 1 (0.24) / 325 / 6 (1.85) / 2 (0.61)
2015 / 463 / 6 (1.29) / 1 (0.22) / 330 / 1 (0.30) / 1 (0.30)
2016 / 498 / 5 (1.00) / 3 (0.60) / 323 / 1 (0.31) / 1 (0.31)
Total / 1680 / 13 (0.77) / 5 (0.30) / 1347 / 10 (0.74) / 6 (0.44)

Table S4: Incidence of candidemia and CDC in adult and paediatric patients with haematological malignancy

CDC: chronic disseminated candidiasis

BDG positive / BDG negative / Sensitivity
Candida albicans
Candida non-albicans / 3
7 / 4
9 / P=0.67
Catheter as the source of positive blood culture
Yes
No / 0
10 / 5
8 / P= 0.087
Antifungal therapy > 6 days previous diagnosis
Yes
No / 2
8 / 1
12 / P=0.64
Outcome of the infection at D15
Survival
Persistence of infection/ CDC/ Death / 3
8 / 10
2 / P=0.022

Table S5: Potential factors for false negative BDG results during candidemia episodes

BDG: BD Glucan, CDC: Chronic Disseminated Candidiasis, D: Day post-infection

BDG
positive / BDG
negative / Sensitivity
Previous candidemia
Yes
No / 5
3 / 0
3 / p=0.24
CDC without candidemia: Antifungal therapy > 6 days previous diagnosis
Yes (liposomal amphotericin B)
No / 0
3 / 2
1 / p=0.38
Infection outcome 3mo
Survival
Death / 6
2 / 3
0 / p=0.93

Table S6: Potential factors for false negative BDG results during CDC episodes

BDG: BD Glucan, CDC: Chronic Disseminated Candidiasis, mo: months

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