Roberto Luzzati

SC Malattie Infettive,

Ospedale Maggiore, Trieste

Le Infezioni Fungine in Medicina Interna

Strollo S & NIH, E.I.D. 2017

Strollo S, E I D 2017

Strollo S, E I D 2017

Age-adjusted annual rates decreasing during 2002-12 (-4.5%^ per year)

Hospitalization (median lenght) = from 21 days (2002) to 17 days (2012)

Median unadjusted associated cost (inpatient care) = 46,684 US

Overall mortality rate = 22% (average decrease of 3.7% / year)

Italy: PPS data (49 hospitals) period 2011-2012

Most frequently isolated microorganisms in HAIs (bloodstream

infections) in acute care hospitals in Italy (n=178 microorganisms)

Country/

City

Period MWs Surgical

wards

ICUs Hematology

wards

References

Italy/

Verona1992-1997 6.3% 24.8% 68.7% --

Luzzati R. et al Nosocomial candidemia in non-neutropenic patients

at an Italian tertiary care hospital. EJCMID 2000; 19(8): 602-7.

France/

Lyon1998-2001 32% 23% 23% 22%

Martin D. et al. Candida species distribution in bloodstream cultures

in Lyon, France, 1998-2001. EJCMID. 2005; 24(5): 329-33

USA2004-2008 66% -- -- --

Horn DL et al. Epidemiology and outcomes of candidemia in 2019

patients: data from the prospective antifungal therapy alliance

registry. CID 2009; 48(12): 1695-703.

Italy Rome/Turin

EOC2004-2008 51.3% 21.3% 27.3% --

De Rosa FG. et al. Mortality in patients with early- or late-onset

candidaemia. JAC. 2013; 68(4): 927-35.

Italy Rome/Turin

LOC2004-2008 41.7% 35.0% 23.1% -- IDEM

Italy/

Genua2008-2010 39.7% 32.1 19.7% 8.4%

Bassetti M. et al. Candidaemia in internal medicine departments: the

burden of a rising problem. CMI. 2013; 19(6): E281-4.5

Italy/

Spain2008-2010 49.7% 24.6% 19.6% 6.1%

Bassetti et al. Epidemiology, species distribution,antifungal

susceptibility, and outcome of candidemia across five sites in Italy

and Spain. JCM 2013; 51(12): 4167

Italy/

Udine2008-2010 57% 17% 16% 10% IDEM

Italy/

Trieste2008-2010 67% 16% 15% 0% IDEM

Spain/

Barcelona2008-2010 32% 27% 32% 8% IDEM

Spain/

Seville2008-2010 28% 17% 43% 10% IDEM

Tascini C , CMI 2015

Pathogenesis of Invasive Candidiasis.

Kullberg BJ, Arendrup MC. N Engl J Med 2015;373:1445-1456

Risk Factors for Invasive Candidiasis.

Kullberg BJ, Arendrup MC. N Engl J Med 2015;373:1445-1456

EJIM 2017

EJIM 2017

EJIM 2017

EJIM 2017

EJIM 2017

Int J Clin Pract 2018

Int J Clin Pract 2018

+ 1

+ 1

+ 5

+ 2

+ 1

SCORE > 7

(sensitivity 79.2%, specificity 82.6%)

RR 29.8; CI 95% 10.6-93.3

P< 0.001

SCORE

Int J Clin Pract 2018

Infection 2018

Infection 2018

Infection 2018

Diagn Microb Infect Dis 2019

Diagn Microb Infect Dis 2019

Risk Factors for Candidemia

in patients admitted to Internal Medicine wards

Risk factor Falcone 2017 Sozio 2018 Ruiz-R. 2018 Atamna 2019

Severe sepsis/Septic shock X

Recent C. difficile infect. X

Diabetes mellitus X

CVC/PICC X (PICC) X (PICC) X (CVC)

TPN X X X

COPD X

Antibiotic therapy X (glycop) X X X (cephal)

Immunosuppress. therapy X X (steroids)

Neurological disability X

Hospitalization< 3 months X

Urinary catheterisation X

Male sex X

Underweight X

Infection 2016

Distribution of candidemia episodes (# 686)

according to hospital wards

21%

25%54%

2011-2013: 686 adult patients (52% males); mean age 70 + 15 yrs

Severe sepsis and septic shock presentation, and

mortality, according to hospitalization area

variables Surgery/ICUs

(319 pt)

Medicine wards

(367 pt)OR (95%CI) P-value

Inadeguate antifungal

therapy30/266 (11.27) 83/333 (25) 2.61 (1.66-4.11) <0.001

No antifungal therapy 25/266 (9.3) 48/333 (14.4) 1.62 (0.97-2.71) 0.062

Adeguate therapy + CVC

removal147/212 (69.3) 97/208 (46) 0.39 (0.2 6-0.58) <0.001

Table 4. Comparison of treatment and outcome

according to ward admission

Surgery/ICUs, surgery and intensive care units; OR, odds ratio (misure quantitative OR per unit); CI, confidence interval; NA, not available

Infection, 2016

Infection 2016

0

50

100

150

200

<40 41-50 51-60 61-70 71-80 > 80

nu

me

ro p

azi

en

ti

Vivi Morti con candida Morti senza candida

Impatto dell’età avanzata sull’epidemiologia e l’outcome della

candidemia nosocomiale in 642 pazienti

(Candidemia Triveneto study group)

unpublished data, 2019

VARIABLES ADULT ≤75

(390 patients)

ELDERLY > 75

(293 patients)

ODDS RATIO 95% CI P-VALUE

Age, median (IQ) 63 (53-70) 83 (79-88) <0.0001

Gender (male) 231/390 (59.2) 127/293 (43.3) 1.9 1.4-2.58 <0.0001

Surgery/ICUs 226/390 (57.9) 91/293 (31.1) 3.06 2.22-4.21 <0.0001

Medicine wards 164/390 (42.1) 202/293 (68.9) 0.33 0.24-0.45

HOST-RELATED FACTORS

Charlson score 3 (1-6) 3 (2-5) 0.73

Solid cancer 132/385 (34.3) 73/293 (24.9) 1.57 1.12-2.21 0.0085

Diabetes mellitus 99/389 (25.4) 74/293 (25.2) 1.01 0.71-1.43 1

Chronic renal failure 50/389 (12.8) 55/293 (18.7) 0.64 0.42-0.97 0.034

Auto-immune diseases 26/385 (6.7) 23/293 (7.8) 0.85 0.47-1.52 0.58

Haematological cancer 18/386 (4.7) 8/293 (2.7) 1.74 0.75-4.06 0.19

Transplantation 15/386 (3.9) 0/293 (0) - - 0.0006

Burns 11/384 (2.9) 6/293 (2.1) 1.41 0.51-3.86 0.5

HIV 3/387 (0.8) 0/293 (0) - - 0.26

Albuminemia 2.6 (±0.6) 2.5 (±0.6) 0.17

Candida colonization 59/347 (17) 29/260 (11.1) 1.63 1.01-2.63 0.043

Concomitant bacteraemia 107/390 (27.4) 79/292 (27) 1.02 0.72-1.43 0.92

HEALTHCARE-RELATED FACTORS

Central venous catheter 302/389 (77.6) 187/290 (64.5) 1.91 1.36-2.68 0.0002

Urinary catheter 242/343 (70.5) 201/253 (79.4) 0.62 0.42-0.91 0.014

Dialysis 36/386 (9.3) 11/292 (3.8) 2.63 1.31-5.26 0.0048

Chemo-radiotherapy 34/381 (8.9) 8/287 (2.8) 3.42 1.56-7.5 0.0012

Immunosuppressive therapy 30/387 (7.7) 5/291 (1.7) 4.81 1.84-12.5 0.0004

Antibiotic therapy 307/326 (94.1) 244/256 (95.3) 0.79 0.38-1.67 0.54

Corticosteroid therapy 70/384 (18.3) 31/288 (10.8) 1.85 1.17-2.91 0.0074

Mechanical ventilation 137/389 (35.2) 53/292 (18.1) 2.45 1.71-3.52 <0.0001

Major surgery 161/387 (41.6) 86/292 (29.4) 1.71 1.24-2.36 0.0011

Peripheral parenteral nutrition 52/381 (13.6) 65/290 (22.4) 0.55 0.37-0.82 0.003

Total parenteral nutrition 212/370 (57.3) 150/281 (53.4) 1.17 0.86-1.6 0.32

TABLE 1. Epidemiologic characteristics of candidemia episodes according to patient age

VARIABLES ADULT ≤75

(390 patients)

ELDERLY > 75

(293 patients)

ODDS RATIO 95% CI P-VALUE

SEVERITY OF ILLNESSES

Charlson score 3 (1-6) 3 (2-5) 0.73

Severe sepsis and septic shock 229/338 (67.7) 160/258 (62) 1.29 0.92-1.81 0.15

SOURCE CONTROL

CVC removal 237/296 (80) 119/176 (67.6) 1.92 1.26-2.94 0.0024

Time to CVC removal 3 (1-6) 2 (1-5) 0.27

NO ANTIFUNGAL THERAPY 31/339 (9.1) 41/257 (15.9) 0.53 0.32-0.87 0.012

TREATED WITH

ANTIFUNGAL THERAPY

308/339 (90.9) 216/257 (84.1) 1.89 1.15-3.1 0.012

ANTIFUNGAL THERAPY 0.0048

Adequate therapy with azoles 145/308 (47.1) 110/216 (51) 0.86 0.61-1.21

Adequate therapy with

echinocandins

104/308 (33.8) 46/216 (21.3) 1.88 1.26-2.82

Adequate therapy with

amphotericin B

5/308 (1.6) 2/216 (0.8) 1.77 0.34-9.19

Inadequate antifungal therapy 54/308 (17.5) 58/216 (26.8) 0.58 0.38-0.88

ADEQUATE THERAPY + CVC

REMOVAL

180/279 (64.5) 79/166 (47.6) 2 1.35-2.96 0.0005

OUTCOMES AT 30 DAYS <0.0001

Survivor 261/373 (70) 121/270 (44.8) 2.87 2.07-3.98

Died with candidemia 88/373 (23.6) 129/270 (47.8) 0.34 0.24-0.47

Died without candidemia 24/373 (6.4) 20/270 (7.4) 0.86 0.46-1.59

TABLE 2. Clinical characteristics and management of candidemia episodes according to patient age.

5558

1512

15 13

10 12

6 5

0

10

20

30

40

50

60

70

80

90

100

Adult patients Elderly patients

Candida albicans Candida glabrata Candida parapsilosis Candida tropicalis Other candida non-albicans spp

FIGURE 1 The species distribution (including ratio and number) of candidemia

episodes among adult and elderly patients.

TABLE 3. Univariate analysis of risk factors for 30-days mortality in patients aged over 75 years.

VARIABLES DIED (128 pts) SURV (121 pts) OR 95% CI P-value

Age 85 (81-88) 83 (79-87) 0.14

Gender (male) 58/128 (45.3) 49/121 (40.5) 1.22 0.74-2.01 0.44

HOSPITALIZATION AREA 0.0023

Surgery/ICUs 28/128 (21.9) 48/121 (39.7) 0.43 0.24-0.74

Medicine wards 100/128 (78.9) 73/121 (60.3) 2.35 1.35-4.09

HOST-RELATED FACTORS

Solid cancer 34/128 (26.6) 31/121 (25.6) 1.05 0.6-1.85 0.86

Diabetes mellitus 29/128 (22.6) 39/121 (32.2) 0.62 0.35-1.08 0.09

Haematological cancer 3/128 (2.3) 3/121 (2.5) 0.94 0.19-4.77 1

Charlson score 3 (2-6) 2.5 (2-5) 0.035

Albuminemia 2.5 (± 0.6) 2.5 (± 0.6) 0.98

Concomitant bacteraemia 37/127 (29.1) 31/121 (25.6) 1.19 0.68-2.09 0.54

HEALTHCARE-RELATED FACTORS

Central venous catheter 79/128 (61.7) 80/119 (67.2) 0.79 0.47-1.33 0.37

Dialysis 6/128 (4.7) 5/121 (4.1) 0.88 0.26-2.95 0.82

Prior antibacterial exposure 105/110 (95.4) 102/109 (93.6) 1.44 0.44-4.69 0.54

Corticosteroid therapy 18/126 (14.3) 10/120 (8.3) 1.83 0.81-4.15 0.14

Mechanical ventilation 21/128 (16.4) 27 /121 (22.3) 0.68 0.36-1.29 0.24

Major surgery 31/128 (24.2) 45/121 (37.2) 0.54 0.31-0.93 0.026

Peripheral parenteral nutrition 33/128 (25.8) 19/120 (8.3) 1.85 0.98-3.47 0.054

Total parenteral nutrition 71/123 (57.7) 65/116 (56) 1.07 0.64-1.79 0.79

CVC removal 36/66 (54.5) 66/83 (79.5) 0.31 0.15-0.64 0.0011

Adequate antifungal therapy 57/108 (52.8) 71/111 (64) 0.63 0.37-1.08 0.093

TABLE 4. Univariate analysis of risk factors for 30-days mortality in patients aged over 75 years.

VARIABLES DIED

(128 patients)

SURVIVOR

(121 patients)

ODDS

RATIO

95% CI P-

VALUE

CANDIDA SPP DISTRIBUTION 0.04

Candida albicans 81/127 (63.8) 67/119 (56.3) 1.37 0.82-2.28

Candida glabrata 15/127 (11.8) 17/119 (14.3) 0.8 0.38-1.69

Candida parapsilosis 9/127 (7.1) 22/119 (18.5) 0.34 0.15-0.76

Candida tropicalis 13/127 (10.2) 10/119 (8.4) 1.24 0.52-2.95

Other candida non-albicans spp 9/127 (7.1) 3/119 (2.5) 2.95 0.78-11.2 0.097

ANTIFUNGAL THERAPY 0.065

No 25/108 (23.2) 15/111 (13.5) 1.93 0.95-3.9

Yes 83/108 (76.8) 96/111 (86.5) 0.52 0.26-1.05

ANTIFUNGAL THERAPY 0.21

Azoli 40/83 (48.2) 48/96 (50) 0.93 0.52-1.67

Echino 16/83 (19.3) 24/96 (25) 0.72 0.35-1.46

Anfo 1/83 (1.2) 1/96 (1) 1.16 0.07-18.8

ANTIFUNGAL THERAPY 0.27

Inadequate 26/83 (31.3) 23/96 (24) 1.45 0.75-2.8

Adequate 57/83 (68.7) 73/96 (76) 0.69 0.36-1.34

SEVERITY OF SEPSIS

Sepsis 37/113 (32.7) 49/108 (45.4) 0.59 0.34-1.02 0.054

Severe sepsis 42/113 (37.2) 48/108 (44.4) 0.74 0.43-1.27 0.27

Septic shock 34/113 (30.1) 11/108 (10.2) 3.8 1.81-7.97 0.0002

Variable OR ( 95% CI) P value

Medical Ward 4.13 (1.67 – 10.19) 0.0020

Septic Shock 3.21 (1.18 – 8.74) 0.0221

TABLE 5. Multivariate analysis of risk factors for 30-days mortality in patients aged

over 75 years.

§ AUC (area under the ROC curve) = 0.701 (95% CI 0.61-0.78)