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
Mc Neil et al 2001 Clin Infect Dis 33;641
0.0
0.2
0.4
0.6
1981 1986 1991 1996
Year
Ra
te p
er
10
0,0
00
Po
pu
lati
on
CandidiasisCandidiasis
AspergillosisAspergillosis
Focus on Candidiasis• Invasive Candida infections:
– 4th most common nosocomial bloodstream infection in the USA with mortality approaching 40% in line related candidemia*
*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.
Coagulase-negative staphylococci 3908 31.9Staphylococcus aureus 1928 15.7Enterococci 1354 11.1Candida species 934 7.6
Pathogen No. of Isolates Incidence (%)
C. glabrata 16%
C. albicans 54%
C. parapsilosis 15%
C. tropicalis 8%
C. krusei 2%
other Candida spp 5%
Adapted from Pfaller MA et al and The SENTRY Participant Group Antimicrob Agents Chemother 2000;44:747–751.
Species of Candida Most Commonly Isolated in Bloodstream Infections
In an international surveillance study 1997-1998:
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
• 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.
Common in the ICU (9.8/1000 admissions) With high morbidity
(increased LOS ~22 days) & mortality (~ 30-40%)
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•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
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.
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.
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%
Risk Factor Selection
Antibiotics
Selection of Candida and Colonization
Fever
Skin or mucosal damage
Infection: Invasive Candidiasis
Malignancy, Diabetes, Renal disease, Steroids, TPN, Burns
InstrumentionCVCGI surgery
Pathogens Responsible for Invasive Fungal Infections in HSCT and SOT Recipients*
Pappas PG, et al. In: Program and Abstracts of the 42nd Annual Meeting of the Infectious Diseases
Society of America. 2004. Abstract 671.
Based on data on 886 invasive fungal infections; 71% of infections were caused by Candida or Aspergillus
spp
29%29%
42%42%
29%29%
Aspergillus spp
Candida spp
Other fungi
*Pooled data from infections in HSCT and SOT recipients. HSCT indicates hematopoietic stem cell transplant;SOT, solid organ transplant.
Candidiasis in SOT RecipientsAnalysis of data from 19,237 HSCT and SOT recipients from
25 centers in the United States from 2001 to 2003
SOT recipientsSOT recipients
Incidence of invasive candidiasis, % 2.6
HSCT indicates hematopoietic stem cell transplant;SOT, solid organ transplant.
• Based on pooled data for both patient populations, the investigator-determined mortality attributable to invasive candidiasis was 24% ( overall mortality of 40%)
Andes D, et al. ICAAC 2004. Abstract M-1014.
Invasive Candida Infections Reported in Various Transplant
Types*
Pre
vale
nce
, %
Liver Kidney Pancreas Lung Heart
42
17
38
812
*Numbers reflect data collected by TRANSNET from 2001 to 2004. Andes D, et al. ICAAC 2004. Abstract M-1014.
0
10
20
30
40
50
60
Invasive Mycosis
Candidiasis Aspergillosis
Decreasing immunity
SOT or BMTMICU or SICU
Loss of Barrier immunity
Loss of barrier plus cellular immunity
Oncology
Aspergillosis in SOT Recipients
Transplant type, n (%)Transplant type, n (%) Incidence*Incidence* MortalityMortality††
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
Analysis of interim data from 4110 SOT procedures from 19 centers in the United States from March 2001 to December 2002
*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.
Aspergillosis Is Associated With a High Rate of Mortality in Many
Patient Populations
Lin SJ, et al. Clin Infect Dis. 2001;32:358-366.*Determined from 1941 patients from 50 studies published between 1995 and 1999.HSCT indicates hematopoietic stem cell transplant.
0
20
40
60
80
Leukemia/Lymphoma
BoneMarrow/HSCT
KidneyTransplant
Lung/Lung
and HeartTransplant
LiverTransplant
AIDS/HIV
Ca
se-f
ata
lity
Rat
e, %
* 100
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
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.
others…Fusarium sp.
Penicillium sp.Trichosporon sp.
Marr, CID 2002Steinbach, J Infect 2004
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 at-risk 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: CandidaThe 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.
“I don’t want you to make the wrong mistake” —Yogi Berra
TREATMENT
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
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Mo
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17%
Days
Variable Odds Ratio P Value
Time to start fluconazole
1.50 0.014
APACHE II 1.13 <0.001
Mortality vs. number of days toinitiate fluconazole after culture done
Multivariate model independentrisk factors for hospital mortality
Up to 70% patients did not receive antifungals within 24 hours + blood
Culture
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.
AspergillosisAspergillus 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
INHALATIONINHALATION
INFECTIONINFECTION
COLONIZATIONCOLONIZATION
DISSEMINATIONDISSEMINATION
Development of Aspergillosis
Pulse steroidOKT3/Antilymphocyte therapyAntibiotic useOrgan failureRe-transplantationThrombocytopenia
Environmental exposureConstruction
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
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Tem
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Tem
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Optimal antifungal management?Optimal antifungal management?
CultureCultureCultureCulture + TissueTissueTissueTissue +GalactomannanGalactomannanGalactomannanGalactomannan+
PCRPCRPCRPCR +
Treatment
Disease likelihood
-7-7 00 77 1414 2121 2828 3535 4242 4949 5656 6363-14-14
0.10.1
11
1010
Days after transplantDays after transplant
Gra
nu
locy
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Gra
nu
locy
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EmpiricalEmpirical
PossiblePossible
ProphylaxisProphylaxis
RemoteRemote
SpecificSpecific
ProvenProven
Pre-emptivePre-emptive
Probable diseaseProbable disease
Site of Action of Selected Anti-fungal Agents
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.
Cell membranePolyenes AmB
(sterols)
Azoles Fluconazole (CYP450)
Cell wall Echinocandins Caspofungin (Glucan synthesis inhibitors)