DR SUNIL NAGAR

MBBS : FCCM: DTCD

Invasive fungal infections have increased significantly in past decades due to

aging population with life sustaining therapies like renal dialysis

broad spectrum antimicrobial therapy and invasive medical devices

bone marrow transplantation and solid organ transplantation

chemotherapy for malignancies

HIV / AIDS

Require impairement of host immunity to cause serious infection

Yeasts

- candida spp. (albicans, tropicalis, parasilosis, krusei, glabrata, lusitaniae, etc.)

- Cryptococcus neoformans

Filamentous fungi

- Aspergillus spp. (fumigatus, niger, flavus)

- Zygomycetes (Rhizopus, Mucor, Rhizomucor, Absidia) - Fusarium spp.

- Penicillium spp. (marneffei)

- Pseudallescheria boydii (Scedosporium apiospermium)

Invasive Candida infections ; 4th most common nosocomial blood stream infection in developed countries with mortality approaching 40% in line related candidemia.

Species of candida isolated in blood stream infection

C. albicans 54%

C. glabrata 16%

C. parapsilosis 15%

C. tropicalis 8%

C. krusei 2% and other candida spp. 5%

Increasing incidence of candida non albicans

Candida parapsilosis is a/w central line and TPN

Candida krusei resistance to fluconazole and candida lusitaniaeresistant to amphotericin makes it important to identify the species.

Inspite of recent advances in antifungal medications the response rate remains suboptimal.

RISK FACTORS:

NON NEUTROPENIC : mainly related to barrier breakdown, change in colonization Acute renal failure

TPN

Prior surgery specially GI

Indwelling catheters

Broad spectrum antibiotics

Diabetes

Burns

Mechanical ventilation

Steriods

NEUTROPENIC – related to above plus immune cell suppression, Bone marrow transplant, solid organ transplant and underlying malignancy.

Microbiology methods

Recovery of fungal species from sterile sites (eg. Blood, peritoneal fluid) is diagnostic.

Recovery from multiple non sterile sites is highly s/o fungal infection in the at- risk patient.

But blood culture is positive in less than 50% of patients

Longer replication time cause longer time to interpret this results.

Unable to differentiate colonization from true infection.

May be negative for certain fungal specimen

May require invasive specimen.

Rapid diagnostic tools:

Galactomannan – identifies aspergillus only, false positive with B-lactum antibiotics, low sensitivity in solid organ transplants, no definitive cutoff value

Betaglucan – candida spp. and aspergillus only. False positive are common in patients on albumin , immunoglobulin, on dialysis, etc

PNA FISH – candida albicans and candida glabrata. Requires positive cultures.

Blood culture

Sens 50%, spec 100%

(13)-β-D-glucan

Sens 70%, spec 87%

PCR

Sens 90%, spec 100%

Fever >3 days and progressive sepsis with multi-organ failure despite broad-spectrum antibacterial therapy.

Invasive candidiasis related cutaneous lesions.macronodular rash frequently confused with drug allergies. A biopsy of deeper layers of skin particularly the vascularized areas and dermis is important.

Ophthalmic lesions (Candida endophthalmitis)a fundoscopic evaluation for the presence of Candida endophthalmitis should be performed in patients with candidemia.

• 110 ICU admission, IPA by EORTC/MSG criteria

• 1/3 hematological malignancy interpret with care

• BAL GM probably useful; Serum GM probably not

AJRCCM . 2008;177: 27-34.

36/1756 patients (2%)

20 IPA (defined as “pneumonia”)

14 colonised

Mortality Colonisation 50%

IPA 80%

127 of 1850 (6.9%) consecutive medical ICU admissions with IA or

colonisation (micro/histol).

89/127 (70%) did not have haematological malignancy

67/89 proven/probable IA

33 of 67 (50%) COPD

Mortality 80% (Predicted 48%)

AJRCCM. 2004;170: 621

Steroids (odds ratio = 4.5)

Prolonged corticosteroids treatment prior to ICU

Steroid treatment with a duration of 7 days

Immunosuppressive therapy

Chronic obstructive pulmonary disease (odds ratio = 2.9)

HIV

Severe burns

Prolonged stay in the ICU (>21 days)

Malnutrition

Post–cardiac surgery status

Liver cirrhosis

Solid-organ cancer

Compensatory anti-inflammatory response syndrome

Monocyte/macrophage deactivation

Neutrophil deactivation

HLA-DR antigen expression

Loss of antigen-presenting capacity

synthesis of pro-inflammatory cytokines

Pulmonary colonisation prior to ICU

Lobectomy, PM for unexpected cardiac death

30/74 (41%) patients with Aspergillus species

Environmental contamination

High concentration of air-bourne spores

Lass-Florl et al. BJH. 1999; 104:745-7

Colonisation or IPA?

172 patients, Belgium ICUs, 7 years

89 colonisation

83 IPA (EORTC/MSG criteria)

Poor positive predicative value for IPA

CT

Frequently absent

Halo sign, air crescent sign and nodules much more common in neutropenic patients

Difficult to interpret with ARDS

PCR

Not evaluated in critically ill patients

Biopsy

Gold standard

Difficult!

THE PLATELIA™ ASPERGILLUS EIA IS AN IMMUNOENZYMATIC SANDWICH MICROPLATE ASSAY FOR THE DETECTION OF ASPERGILLUS GALACTOMANNAN ANTIGEN IN SERUM

Helpful in early detection of IPA

High risk patients

Pulmonary infiltrates and fever, not responding to appropriate antibacterial agents

± some concern that Aspergillus may be a diagnostic possibility

Recent unidentified case which died

Isolation of Aspergillus from respiratory tract

Choice of agents depends on

Patient on previous azole prophylaxis

Culture results and local fungal sensitivity

Colonization

Renal or liver disease

Presence of drug-drug interactions

Presence of immunosuppression

Site of disease eg. urine

IDSA recommendations but little evidence in critically ill

Voriconazole

Hepatotoxicity and nephrotoxicity

IV formulation – cyclodextran

Substrate and inhibitor CYP2C19, 2C9 and 3A4

bioavailabity with fat – requires empty stomach

Lipid preparations of Amphotericin B

Less nephrotoxic than deoxycholate

Eichinocandin

Salvage therapy

Combination

Early and appropriate

Mortality (after +ve blood culture)

Day 0 – 15%

Day 1 – 24%

Day 2 – 37%

Later – 41%

A delay in diagnosis will unfortunately result in a delay in initiation of antifungal therapy, which is a/w 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

Species Fluconazole Voriconazole Flucytosine Amphotericin B Echinocandins

C. albicans S S S S S

C. glabrata S – DD to R S – DD to R S S to I S

C. tropicalis S S S S S

C. parapsilosis S S S S S to R

C. krusei R S I to R S to I S

C. lusitaniae S S S S to R S

CID (2009) 48:503–35

Retrospective cohort analysis in patients with candidemia.

Delay in empiric Rx of candidemia till after blood cultures turn positive resulted in higher mortality.

SHOULD A CENTRAL VENOUS CATHETER BE REMOVED ONCE CANDIDEMIA IS CONFIRMED?

Practice guidelines indicate that all central venous catheters should be removed once candidemia is

confirmed .

Of note is that a recent randomized controlled trial and other studies

question the benefit of early removal of central venous catheters in the onset of candidemia for some selected

patients.

24 year old female

Psoriasis with arthropathy

Obesity (110kg)

Admitted to ICU

Methorexate 10mg weekly

1. H1N1 pneumonitis

2. ARDS

3. Pancytopenia

4. Severe sepsis

Persistent sepsis

Respiratory failure (consider for NIV)

Treated with broad-spectrum antibiotics

Identify Candida tropicalis from airways

Identify Candida tropicalis from urine

Day 7Fluconazole 400mg daily

Day 14Caspofungin 70mg then 50mg

Day 20 Ambisome 3mg/kg

Day 53RIP

27 year old female

Known asthmatic

increasing SOB, wheeze and cough

NoPMHx (no DM)

Ex-smoker

Bronchospasm and tachycopnea

Mild tachycardia and normotension

CXR Hyper-expanded but clear lung fields

Responded to nebs

Clarithromycin 500mg BD (penicillin allergy)

Prednisolone 40mg od

Decompensation

ICU - Intubation and MV

Resistant bronchospasm (sedation, muscle paralysis, ketamine and Sevoflurane)

Day 2 - persistent high grade fever

Broad spectrum antibiotics and active cooling

Surveillance

Aspergillus fumigatus

CXR

widespread airspace infiltrates (ALI)

Bronchoscopy and BAL

Culture positive for Aspergillus fumigatus.

No evidence of bacteria growth or acid-fast bacilli.

Serum Aspergillus PCR +ve.

Voriconazole (loaded then 4mg/Kg bd) then to PO

Continued for 6 months (Asp IgG 26)

with

Caspofungin 70mg then 50mg for 30 days

Retrospective Day 0 IgG + IgE to Asp –ve

Day 8 Aspergillus IgG 148 mgA (0-40)

Extubated on day 25

CT (day 31) widespread cavities, ground glass opacity and bronchiectasis

Environmental cultures –ve

No immune defect found

?Systemic antifungal therapy should be strongly

considered, especially in a patient who is at high risk for

disseminated fungal infection, if:

•Fever persists despite antibacterial agents and negative

blood cultures

•High-grade funguria occurs in the absence of a bladder

catheter

•Funguria persists after removal of a bladder catheter

•Fungus is cultured from at least two body sites

•Visceral fungal lesions are confirmed

Candida and Aspergillus increasingly recognised as ICU pathogens

Increased morbidity and mortality

High index of suspicion

Diagnostic strategy (clinical, radiology, lab)

Treatment is complicated

ADR, interactions

The earlier the administration of antifungal treatment the lower the

mortality