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

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

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0.2

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0.6

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Year

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10

0,0

00

Po

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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

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Rat

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* 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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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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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

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Days after transplantDays after transplant

Gra

nu

locy

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Gra

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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)