Invasive Fungal Infections in
Critically Ill Patients
Abhay Dhand M.D.
Director, Transplant Infectious Diseases
Westchester Medical Center, Valhalla NY
Invasive Fungal Infections in
Critically Ill Patients
Objectives:
1. To understand the epidemiology and risk factors for
invasive fungal infections in critically ill patients.
2. To familiarize with various investigative modalities for
diagnosis of invasive fungal infections.
3. To understand the available anti-fungal therapies and
their optimal use in patients in ICU setting.
4. To learn important drug interactions between anti-fungal
therapies and commonly used drugs in ICU setting.
Incidence of Fatal Invasive
Mycoses in USA
Rate per 100,000 Population
0.6
Candidiasis
0.4
0.2
Aspergillosis
0.0
1981
1986
1991
Year
Mc Neil et al 2001 Clin Infect Dis 33;641
1996
Focus on Candidiasis
• Invasive Candida infections:
– 4th most common nosocomial bloodstream
infection in the USA with mortality
approaching 40% in line related candidemia*
Pathogen
Coagulase-negative staphylococci
Staphylococcus aureus
Enterococci
Candida species
No. of Isolates
Incidence (%)
3908
1928
1354
934
31.9
15.7
11.1
7.6
*In a 3-year (1995–1998) surveillance study of 49 hospitals in the United States.
Adapted from Edmond MB et al Clin Infect Dis 1999;29:239–244; Andriole VT J Antimicrob Chemother 1999;44:151–162;
Uzun O, Anaissie EJ Ann Oncol 2000;11:1517–1521.
Species of Candida Most Commonly
Isolated in Bloodstream Infections
In an international surveillance study 1997-1998:
C. tropicalis
8%
C. krusei
2%
other Candida spp
5%
C. albicans
54%
C. parapsilosis
15%
C. glabrata
16%
Adapted from Pfaller MA et al and The SENTRY
Participant Group Antimicrob Agents Chemother
2000;44:747–751.
Since then increase in Candida spp. with higher incidence of fluconazole
resistance.
Snydman DR. 2003. Chest 123(Suppl 5):500S-503S). Garbino J. et al. 2002. Medicine;81:425-433.
Invasive Candidiasis in the ICU
Common in the ICU
(9.8/1000 admissions)
With high morbidity
(increased LOS ~22 days)
& mortality (~ 30-40%)
• Difficult to diagnose (cultures positive in only ~ 50%).
• We can define ICU risk factors for candidiasis and
target the population at highest risk with empiric Rx.
• Recent increase in Candida spp. resistant to
fluconazole.
Eur J Clin Microbiol Infect Dis. 2004:23; 739-744.
Risk for Invasive Mycosis
•Non-Neutropenic patients: related to barrier breakdown,
change in colonization.
–
–
–
–
–
–
–
–
Acute renal failure (RR 4.2)
Parenteral nutrition with intralipid (RR 3.6)
Prior surgery specially GI (RR 7.3)
Indwelling central line ? Triple lumen (RR 5.4)
Broad spectrum antibiotics
Diabetes
Burns
Mechanical Ventilation
Adapted from Blumberg HM et al, and the NEMIS Study Group Clin Infect Dis 2001;33:177–186; Garber G Drugs 2001;
61(suppl 1):1–12.
Risk for Invasive Mycosis
• Neutropenic patients:
risks related to non- neutropenic patients
plus
immune cell suppression and underlying
malignancy.
– Steroids
• Severe immunosuppression: BMT or SOT
Adapted from Blumberg HM et al, and the NEMIS Study Group Clin Infect Dis 2001;33:177–186; Garber G Drugs 2001;
61(suppl 1):1–12.
Major Risk Factors: Candidiasis
Prior antibiotic use,
Central venous catheters,
Total parenteral nutrition,
Major surgery (abdominal) within one week,
Steroids, Immunosuppression.
Intensive care unit length of stay: the rate of
infections rising rapidly after 7-10 days
Dimopoulos G, et al. Candidemia in immunocompromised and immunocompetent critically ill patients: a
prospective comparative study. Eur J Clin Microbiol Infect Dis. 2007
Candidemia in Non-neutropenic ICU Patients
Risk Factors for Non-albicans Candida Spp.
Nationwide Australian prospective cohort study.
Patients with ICU-acquired candidemia over 3 yr.
C albicans 62%, C glabrata 18%, C parasilopsis 8%, C
tropicalis 6%, C krusei 4%, Other Candida spp. 2%
Independent risk factors for non-albicans candida or
potentially fluconazole-resistant species:
Age (OR 1.3),
Recent GI surgery (OR 2.9),
Prior exposure to systemic antifungal agents (OR 4.6)
especially fluconazole (OR 5.7).
.
EG Playford et al. Crit. Care Med. 2008; 36(7): 2034-2039
Risk Factor Selection
Malignancy, Diabetes, Renal disease,
Steroids, TPN, Burns
Fever
Antibiotics
Selection of Candida and Colonization
Skin or mucosal
damage
Instrumention
CVC
GI surgery
Infection: Invasive Candidiasis
Pathogens Responsible for Invasive
Fungal Infections in HSCT and SOT
Recipients*
Based on data on 886 invasive fungal infections;
71% of infections were caused by Candida or Aspergillus spp
29%
42%
Candida spp
Aspergillus spp
Other fungi
29%
*Pooled data from infections in HSCT and SOT recipients.
HSCT indicates hematopoietic stem cell transplant;
SOT, solid organ transplant.
Pappas PG, et al. In: Program and Abstracts of the
42nd Annual Meeting of the Infectious Diseases
Society of America. 2004. Abstract 671.
Candidiasis in SOT Recipients
Analysis of data from 19,237 HSCT and SOT recipients from
25 centers in the United States from 2001 to 2003
SOT recipients
Incidence of invasive candidiasis, %
2.6
• Based on pooled data for both patient populations, the
investigator-determined mortality attributable to invasive
candidiasis was 24% ( overall mortality of 40%)
HSCT indicates hematopoietic stem cell transplant;
SOT, solid organ transplant.
Andes D, et al. ICAAC 2004. Abstract M-1014.
Invasive Candida Infections
Reported in Various Transplant
Types*
60
Prevalence, %
50
42
38
40
30
17
20
12
8
10
0
Liver
Kidney
Pancreas
*Numbers reflect data collected by TRANSNET from 2001 to 2004.
Lung
Heart
Andes D, et al. ICAAC 2004. Abstract M-1014.
Invasive Mycosis
MICU or SICU
Oncology
Candidiasis
Loss of
Barrier
immunity
SOT or BMT
Aspergillosis
Decreasing immunity
Loss of barrier
plus
cellular immunity
Aspergillosis in SOT Recipients
Analysis of interim data from 4110 SOT procedures from 19
centers in the United States from March 2001 to December 2002
Incidence*
Mortality†
Heart
3 (0.8)
2 (66.7)
Kidney
3 (0.1)
2 (66.7)
Liver
3 (0.3)
1 (33.3)
Lung
10 (3.5)
2 (20.0)
Other
1 (0.4)
0
Transplant type, n (%)
*Weighted aggregate incidence after 12 months.
†Three months after diagnosis of aspergillosis.
SOT indicates solid organ transplant.
Morgan J, et al. Med Mycol. 2005;43(suppl 1):S49-S58.
Case-fatality Rate, %*
Aspergillosis Is Associated With
a High Rate of Mortality in Many
Patient Populations
100
80
60
40
20
0
Leukemia/
Bone
Lymphoma Marrow/
HSCT
Kidney Lung/Lung
Liver
Transplant and Heart Transplant
Transplant
AIDS/
HIV
*Determined from 1941 patients from 50 studies published between 1995 and 1999.
Lin SJ, et al. Clin Infect Dis. 2001;32:358-366.
HSCT indicates hematopoietic stem cell transplant.
Zygomycosis
• Vulnerable populations
– Malignancy
– Bone marrow transplantation
– Solid organ transplantation
•
•
•
•
•
Corticosteroid exposure
GvHD
CMV reactivity
Neutropenia
Uncontrolled Diabetes mellitus
– Initial presentation with sinusitis
– Occurrence as breakthrough prior
Voriconazole prophylaxis
• 56% mortality
others…
Fusarium sp.
Penicillium sp.
Trichosporon sp.
Marr, CID 2002
Steinbach, J Infect 2004
Roden, et al. Clin Inf Dis 2005;41:634-53.
Kontoyiannis et al. JID, 2005; 191:1350-60.
Siwek et al. CID 2004; 39:584-87.
Laboratory Diagnosis: Candida
• Microbiology methods:
– Recovery of Candida species from sterile sites (ex. blood,
peritoneal fluid) is diagnostic of IC and recovery from
multiple non-sterile sites is highly suggestive of IC in the atrisk patient.
– Blood culture is positive in less than 50% of patients with
autopsy proven IC.
• Molecular methods:
– early identification ex PNA FISH
• Serological methods:
– early diagnosis ex. 1,3 beta D glucan assay.
• Histopatholgic methods.
Clinical Diagnosis: Candida
The clinical manifestations of IC are nonspecific, but may include:
• Fever and progressive sepsis with multi-organ failure despite
antibiotics.
• Invasive candidiasis (IC) related cutaneous lesions.
– Macronodular rash frequently confused with drug allergies.
A biopsy of the deeper layers of skin particularly the
vascularized areas and the dermis is important.
• Ophthalmic lesions (Candida endophthalmitis).
– A fundoscopic evaluation for the presence of Candida
endophthalmitis should be performed in patients with
candidemia.
Serological Methods ? early aid in empiric
therapy decision making
• Plasma beta-D-glucan, a cell wall constituent of fungi, was
measured before starting antifungal therapy empirically on
postoperative patients, colonized with candida & having risk
factors for candida infection.
• 47% of those with positive test responded to Rx but 9% of
those negative responded (p<.01) (OR= 13).
• Number of sites colonized with candida also predicted
response. Colonization at ≥ 3 sites vs. 1 site (p=0.03)
(OR=7.57).
• In postoperative patients colonized with candida, & with fever
despite antibiotics a beta-D-glucan assay was useful for
deciding whether to start empiric therapy.
Takesue Y et al. World J Surg. 2004; 28(6): 625-30.
TREATMENT
“I don’t want you to make the wrong
mistake” —Yogi Berra
Candidemia: Who do we treat?
• Answer: Essentially everybody
– Even a single +BC can be relevant
– Concerned about hematogenous seeding
• Spread to the eye
– Can cause blindness
– Lesions are common!
– 26-29% rate
Catheter Exchange? Yes!
• Lots of consistent data
– Without catheter removal, 82% had persistent infection
• Lecciones, Clin Infect Dis 1992;14:875-883
– Shortened duration of fungemia from 5.6 to 2.6 days
• P < 0.001 (Rex, Clin Infect Dis 1995;21:994-996)
– Reduced mortality: 41% to 21%
• P < 0.001 (Nguyen, Arch Intern Med 1995;155:2429-2435)
• Especially true for C. parapsilosis
– Very strong link with catheters
• Kojic, Clin Microbiol Rev 2004;17:255-267
Candiduria
• Asymptomatic candiduria
– No treatment unless high-risk dissemination (AIII).
– Focus on elimination of predisposing factors. (BIII).
• High risk for dissemination
– Urologic manipulations (BIII)
• Use short course fluconazole or even amphotericin B
– Neutropenic patients and low birth weight infants
• Treat as for invasive candidiasis.
• Consider imaging kidneys/collecting system (BIII)
Can we wait for the blood culture
results in candidemia?
• Retrospective cohort analysis 1/2001-12/2004:
N=157 patients with candidemia.
• Delay in empiric Rx of candidemia till after
blood cultures turn positive resulted in higher
mortality.
• Start of anti-fungal Rx >12 hrs of drawing a
blood culture that turns positive had AOR=
2.09 for mortality, p=0.018.
Morrel M et al. 2005. Antimicrob Agents Chemother. 49(9):3640-5
27
Mortality vs. number of days to
initiate fluconazole after culture done
45
Variable
40
Mortality, %
35
30
25
20
15
Multivariate model independent
risk factors for hospital mortality
17%
Odds Ratio
P Value
Time to start
fluconazole
1.50
0.014
APACHE II
1.13
<0.001
Up to 70% patients did not receive
antifungals within 24 hours + blood
Culture
10
5
0
0
1
2
3+
Days
Garey KW et al. Clin Infect Dis. 2006;43:25.
Therapy of IC in the ICU
• A definitive diagnosis of IC may be delayed when the
clinical and laboratory tools readily available to
clinicians are used to assess patients for Candida
infection.
• A delay in diagnosis will unfortunately result in a
delay in initiation of antifungal therapy, which is
associated with increased mortality*.
• Therefore, in the patient with suspected Candida
infection, treatment may need to be initiated on the
basis of individual patient factors before a definitive
diagnosis is made.
*Morrel M et al. 2005. Antimicrob Agents Chemother. 49(9): 3640-5.
*Garey K et al. 2006. Clin Infect Dis. 43: 25-31.
Aspergillosis
Aspergillus species are found in :
–
–
–
–
–
–
–
–
Soil
Air; spores may be inhaled
Water / storage tanks in hospitals etc
Food
Compost and decaying vegetation
Fire proofing materials
Bedding, pillows
Ventilation and air conditioning
systems
– Computer fans
Aspergillus spores
Development of Aspergillosis
INHALATION
COLONIZATION
Pulse steroid
OKT3/Antilymphocyte
therapy
Antibiotic use
Organ failure
Re-transplantation
Thrombocytopenia
INFECTION
DISSEMINATION
Environmental
exposure
Construction
Invasive aspergillosis in solid-organ
transplantation: diagnosis
• Radiology: chest X-ray and CT: no halo sign
• Microbiology
– Respiratory secretions: BAL/biopsy
• Direct microscopy
• culture
– Serological surveillance
• ELISA for galactomannan
• PCR
Ergin et al. Transplant International 2003; 16: 280-286
Strategies for dealing with
systemic fungal infectious
disease
Optimal antifungal management?
Temperature (°C)
Treatment
4
1
40
Prophylaxis
Empirical
Pre-emptive
Specific
39
38
37
36
PCR +
Galactomannan+
Culture +
Tissue +
10
0
Granulocytes
Disease
likelihood
Remote
Possible
Probable disease Proven
1
0.1
-14
-7
0
7
14
21
28
35
Days after transplant
42
49
56
63
Site of Action of Selected Anti-fungal
Agents
Cell membrane
Polyenes AmB
(sterols)
Azoles Fluconazole
(CYP450)
Cell wall
Echinocandins
Caspofungin (Glucan
synthesis inhibitors)
Adapted from Andriole VT J Antimicrob Chemother 1999;44:151–162; Graybill JR et al Antimicrob
Agents Chemother 1997;41:1775–1777; Groll AH, Walsh TJ Expert Opin Invest Drugs 2001;10(8):1545–
1558.