Fungal Infections

Slides prepared by – Dr Pankaj Anand, Dr Bikram Gupta

Case Discussion 1
• 24 year old female
• Psoriasis with arthropathy
• Obesity (110kg)
• Admitted to ICU
• Methorexate 10mg weekly
1. COVID pneumonitis
2. ARDS
3. Pancytopenia
4. Severe sepsis
 Day 6
• Persistent sepsis
• Respiratory failure

• Treated with broad-spectrum antibiotics

• Identify - Candida glabrata from airways

• Is the Candida culture relevant?
What would you do next?
Would you treat?

• Candida in respiratory secretions alone - not significant

• Wait and watch
 When to give?

Proven IFD Lower levels of diagnostic certainty

• Culture from a sterile site obtained Based on three factors 1. Host factors 2. Clinical Criteria 3. Mycological tests
by a sterile procedure (Excluding BAL
fluid, a sinus specimen & Urine)
Or Probable IFD Possible IFD
• From a freshly placed (<24 h ago)
drain into a normally sterile site If all three are present If mycological test are not done or
showing the disease process negative
Or
• Blood culture for yeast or a mould
like fusarium
Or
• Cryptoccal Ag from CSF for
Cryptococcus
Or
• If from a non-sterile site, Culture (to
show the particular fungus) +
histology (for invasion & tissue
damage)
 High Risk Patients Lab. Confirmed Diagnosis
1. Critical illness with long term ICU Stay Conventional diagnosis
2. Abdominal surgery with anastomotic • Direct Microscopy
leakage/ repeat laparotomies • Histopathology
3. Acute necrotising pancreatitis • Culture
4. Hematologic malignant disease Non-conventional diagnosis
5. Solid organ transplantation Serodiagnosis
6. Solid organ tumors (Mannan-antimannan
7. Neonates, particularly those with LBW assay)
and preterm infants
8. Use of broad spectrum antibiotics When to Biomarker detection
Beta 1,3-Glucan assay
9. Presence of central venous catheters,
TPN give? Galactomannan assay
Lateral flow assay

<
10. Haemodialysis Molecular diagnosis
11. Glucocorticoid use or chemotherapy PNA FISH
for cancer T2 Candida Panel
12. Candida colonization, particularly if
multifocal (colonization index >0.5 or
corrected colonization index >0.4)
13. Suspected Cryptococcal
infection/Aspergillosis
 Day 7

• Identify Candida glabrata from urine

• Is two Candida cultures relevant?

What would you do next?
Would you treat (and if so with what)?
• Candida tropicalis in urine –
• Single site – only change foleys
• No anti fungal needed
 But will you initiate antifungals in this case?

• Several risk factors such as

• Immunocompromised
Initiate Antifungal
• 2 sites positive for candida
agents
• Sepsis +
• Receiving broad spectrum antibiotics
 Presence of high-grade fever with chills, nausea and vomiting with isolation of
Candida non albicans in the urine is indicative of complicated urinary tract
infection (UTI) or pyelonephritis.
 Start anti fungal pre-emptively
 Predictive scores
• Leon et al. 2006 • Ostrosky-Zeichner et al. 2007
• 1*(total parenteral nutrition) • Any systemic antibiotic (days 1–3)
• +1*(surgery) • OR CVC(days 1–3)
• +1*(multifocal Candida species • AND at least 2 of the following
colonization) • total parenteral nutrition (days 1–3)
• +2*(severe sepsis) • any dialysis (days 1–3)
• any major surgery (days −7–0)
• pancreatitis (days −7–0)
• Score >2.5 • any use of steroids (days −7–3)
• Sensitivity 81% • or use of other immunosuppressive
• Specificity 74% agents (days −7–0)
 Colonisation scores
• Pittet et al. 1994
• Colonization index
• No. of non-blood body sites colonised (heavy growth) by Candida
spp./total no. of sampled sites

• 100% sensitivity and specificity.

 Pre-emptive treatment
• Very few studies

• Piarroux et al. 2004

• Bases of colonisation index
• Reduced rates of invasive candidiasis (compared to historial controls)
• Fluconazole

Piarroux et al. 2004 CCM 32:2443–2449

 Risk Fever Biomar Fungus Diagno Therap
and/or ker isolate stic eutic
focal d certaint strateg
Treatment strategies Present
signs y y
Prophyl
actic
Present Present Probabl Pre-
e IFI if emptiv
fever e
&/or
focal
signs &
biomar
ker is
positiv
e
Present Present Non Possibl Empiric
sterile e IFI al
site
Regardl Regardl Regardl Sterile Proven Directe
ess ess ess site d/
Remote Probable Possible Proven Specific
 Non-albicans Candida species
• Increasingly reported as both colonisers and pathogens

• Mortality – 30-60%

Risk factors (compared to C. albicans)

C. glabrata (Fluconazole prophylaxis), BMT, Surgery, Solid organ cancer
C. tropicalis BMT, Solid tumours, Intravascular device
C. krusei Neutropenia, Fluconazole prophylaxis, BMT
C. parapsilosis BMT, Neonates
C. krusei Fluconazole prophylaxis
C. lusitaniae Polyene use (inducible resistance)
JoHI (2002) 50:243-260
 Q
• What is your choice of antifungal agent ?
 High Least Reasonable
efficacy toxicity cost

What will be rational

antifungal agent ?
Least disruption
Preservation of of our microbial
the utility of ecology
antifungal agents
 Efficacy Safety

Is this drug is
Early initiation effective and
PK/PD Optimization safe ?
Fungicidally
Source control
Adequate duration
PK/PD of antifungal agents Side effects
Drug Characteristics
 Drug Characteristics
Site of Action

Flucytosine
 What is your therapeutic plan in this case?

• Removal of the indwelling catheter if possible

• Administering antifungal agents which achieve adequate

concentration in urine.
 Triazoles
Voriconazole Posaconazole
Fluconazole
Oral/IV Oral (40 mg/ml) & IV (300 mg)
Oral/IV
Mainly for Aspergillus Effective against :-
Fungistatic
Step down oral therapy for:- Invasive Aspergillosis
Enters CNS, vitreous body,
C. Krusei Candida
Urinary tract
C. glabrata Mucormycosis
Mainly for C. Albicans & C.
Neoformans Drug- drug interactions are
common with voriconazole Adverse reactions:-
Non-Albicans Candida species
more likely to exhibit primary Caution:- IV voriconazole is not Hepatotoxicity
resistance (Candida Krusei, recommended in patients with
a creatinine clearance <50 Prolonged QTc
Candida tropicalis)
ml/min b/o cyclodextrin Diarrhoea
accumulation.
 Echinocandins

• Caspofungin, Mikafungin, Anadulafungin

• Inhibit 1,3-β-D-Glucan synthase
• Only parenteral preparations
• Covers most of candida species
• Fungicidal
• Few adverse effects
• Minimal drug-drug interaction
• All administered IV once daily
• No dosage adjustments for renal insufficiency or dialysis
• Only Caspofungin – dosage reduction in patient for moderate to severe hepatic dysfunction
 IDSA Guidelines for invasive Candidiasis
Non Neutropenic Neutropenic Candida Parapsilosis Solid organ transplant
patients
Candida glabrata recipient (PX)
patients
First line treatment First line treatment First line treatment First line treatment First line treatment
1. Caspofungin 70 mg 1. Caspofungin 70 mg Echinocandin Fluconazole Fluconazole 200-400
loading f/by 50 mg IV loading f/by 50 mg IV mg/day IV/PO for 7-14
OD or OD or days
2. Mikafungin 100 2. Mikafungin 100
mg/day or mg/day or
3. Anadulafungin 200 mg 3. Anadulafungin 200
loading dose then 100 mg loading dose then
mg/day IV 100 mg/day IV
Alternative regimen(s)
Alternative regimen(s) Alternative regimen(s) Alternative regimen (S)
1. Fluconazole 800 mg Alternative regimen(s)
1. Fluconazole 800 mg Echinocandin, if already Liposomal amphotericin B
(12 mg/kg) IV loading Fluconazole or
(12 mg/kg) IV loading responding to therapy 1-2 mg/kg/day IV for 7-14
dose, then 400 Voriconazole with
dose, then 400 days
mg/day IV/PO susceptibility testing
mg/day IV/PO
2. Voriconazole if mold
coverage desired
Voriconazole 6 mg/kg
IV first two dose then
4 mg/kg bd IV or 200
mg bd
 In this case…

• For Fluconazole-susceptible species  Fluconazole is the drug of choice, given

intravenously in this case, as it is excreted in the urine in its active form thereby
achieving concentration above minimum inhibitory concentration (MICs) in urine.

• For Fluconazole-resistant C. glabrata  Amphotericin B (AmpB) deoxycholate for

1–7 days with or without oral flucytosine, is recommended.

• Echinocandins and the lipid formulations of AmB are not able to achieve
adequate concentrations in urine and should not be used to treat UTIs.
Case Discussion 2
 CASE
• Mrs AB, 59 year old female
• Known SLE on steroids, Azathioprine
• Developed fever, dyspnea – since last 7 days , worsening since 3 days

• In ER, tachypneic, bronchospasm+

• Mild tachycardia, BP normal
• Given neb - responded
• CXR – hyper-expanded but clear lung fields
• Started on 3rd generation cephalosporin and
clarithromycin
 8 hours later
• Decompensation
• ICU – Intubated and put on MV
• Day 2 - persistent high grade fever (active cooling)
 Day 4
• Surveillance ET secretions
• Aspergillus fumigatus

• CXR
• widespread airspace infiltrates (ALI)
• Is the Aspergillus culture relevant?
What would you do next?
Would you treat?

• D/D – Invasive aspergillosis or coloniser

• Will do a BAL
Respiratory tract samples
• Colonisation or IPA?

• 172 patients, Belgium ICUs, 7 years

• 89 colonisation
• 83 IPA (EORTC/MSG criteria)
• Poor positive predicative value for IPA
 Day 5
• Bronchoscopy and BAL
• Culture positive for Aspergillus fumigatus.
• No evidence of bacteria growth or acid-fast bacilli.

• Serum Aspergillus PCR +ve.

• Blood cultures – No growth

• Fundus done – suggestive of endophthalmitis
• Is the Aspergillus culture/PCR relevant?
What would you do next?

Consider antifungal – possibility of IFI - aspergillus infection

- Immunocompromised state, Negative blood culture, necrotic retina
Q- How do we confirm the diagnosis ?
 Rapid diagnostic tests for invasive fungal infections
Test Species identified Sensitivity/ specificity Comments
BETA D GLUCAN CANDIDA SPP and 57-97% / 56-93% 1. High NPV
ASPERGILLUS
2. Controversial cut off
3. False positive in case of cellulose
containing dialysis membranes,
tubings, antibiotics such as
amoxicillin- clavulinic acid

MANNAN ANTIGEN/ ANTI- MANNAN Candida species only 83% / 86% when both 1. Unclear cut off values
ANTIBODY tests are used in
combination 2. Sensitivity varies depending on
species
NUCLEIC ACID PCR All species but Only available 96 % / 97% 1. Can detect deep seated infections
currently for Candida spp
( T2 CANDIDA/ SEPTIFAST) 2. Unavailable for many species

Aspergillus and some other Serum : 71% / 89% 1. False positives with plasmalye, beta
molds lactams
GALACTOMANNAN BAL : 76-88% / 87-
100%
 m
AJRCCM . 2008;177: 27-34.
• 110 ICU admission, IPA by EORTC/MSG criteria
c ta
• 1/3 hematological malignancy interpret with care
b a
z
• BAL GM probably useful; Serum GM probably not
a o
- t
il l in
a c
i p er
: P
a re
ew
B
 Imaging
• CT
• Frequently absent
• Halo sign, air crescent sign
and nodules much more
common in neutropenic
patients
• Difficult to interpret with
ARDS

Calliot et al. J Clin Oncol. 1997. 15:139-47

Q- What will be your DOC ?

Voriconazole – cidal for aspergillosis , good ocular penetration,

CNS penetration

Echinocandin – no ocular or CNS penetration.

Amphotericin B – inferior results to voriconazole

 IDSA guidelines for Invasive Aspergillosis

Alternative treatment
First line treatment • Lipid amphotericin B 3-5 mg/kg IV every
• Voriconazole 6 mg/kg IV first two dose 24 hourly or
then 4 mg/kg bd IV or 200 mg bd
• Caspofungin 70 mg loading f/by 50 mg IV
OD or

• Micafungin 100 - 150 mg/day

• Posaconazole 800 mg/day PO in 2-4

divided dose or

• Itraconazole dose depends on formulation

 Voriconazole
Q- Most patients with aspergillosis are
Oral/IV
on immuno- suppressants – how does
Mainly for Aspergillus
giving Voriconazole affect the same ?
Step down oral therapy for:-
- Increased concentrations of cyclosporine and C. Krusei
tacrolimus have been associated with C. glabrata

nephrotoxicity, and so patients should be Drug- drug interactions are

common with voriconazole
monitored for the development Caution:- IV voriconazole is not
of abnormal renal function. recommended in patients with a
Empirical dose reductions are recommended creatinine clearance <50 ml/min
b/o cyclodextrin accumulation.
for both cyclosporine (reduce to one-half) and
tacrolimus (reduce to one-third) when
initiating treatment with voriconazole, and
concentrations of cyclosporine or tacrolimus
should be carefully monitored during and
after cessation of treatment.
 What are the risk factors for invasive
aspergillosis?
• 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)
• Liver cirrhosis
• Solid-organ cancer
• HIV
• Severe burns
• Prolonged stay in the ICU (>21 days)
• Malnutrition
• Post–cardiac surgery status
Meersseman et al. CID. 2007;45: 205–16
Case Discussion - 3
• Mr KK 65 year old man,
• Recent recovery from moderate COVID-19 disease, on steroids
• Sugars uncontrolled on HAI
• Comes with h/o right sided orbital pain, right facial pain since 3
days
• h/o diplopia since 1 day
• O/e- CNS- GCS 15/15, No obvious neurological deficit
• Tenderness over the face and right maxillary region. Diplopia on
eye examination – on lateral gaze.
• MRI brain with PNS was done – which shows Pansinusitis –
involving maxillary and sphenoid sinuses with hypertrophic
turbinates
• Patient underwent FESS. (functional endoscopic sinus surgery) –
which showed necrotic mucous membrane.
• Biopsy taken and sent
• What do you suspect ?
What would be your next line of Mx?

• Likely Mucor
• Rx- Empirical liposomal amphotericin B
Q- What are the predisposing factors for Mucormycosis?

Poorly controlled sugars

Leukemia / Lymphoma
HIV/AIDS
Long term steroid and immunosuppressive therapy
Severe malnourishment
Severe burns
Cytotoxic therapy
Renal failure/cirrhosis/ Deferoxamine/iron overload
 If patient manifest side
effects then what will be
your strategy?
 Side effects of
Conventional Amp B & Its
lipid derivative
 Infusion related thrombophlebitis

• The addition of hydrocortisone (usual adult dose 25 mg) or

heparin (usual final concentration 500 to 1000U/L) to the
infusion
• Infusion of the drug using a central line
• Use of alternating infusion sites
• Avoidance of final amphotericin B infusion concentrations
exceeding 0.1 mg/Ml
• Avoidance of infusion times of less than four hours
 Amphotericin B
deoxycholate –
Nephrotoxicity

Directly constricts the Directly toxic to distal

Prolonged therapy
afferent arterioles of kidney tubules of kidney

Development of
hypokalemia & Inhibitory effects on
Decreased blood flow & GFR
Hypomagnesaemia, Type I erythropoietin secretion
RTA & Nephrogenic DI

IV NS (0.5-1 litre) before &

after amphotericin B infusion Potassium & Magnesium recombinant erythropoietin
Avoid concomitant infusion if symptomatic anaemia
nephrotoxic drug
 Strategy if Nephrotoxicity developed

• The decline in GFR caused by amphotericin B, but not the

manifestations of tubular dysfunction, is ameliorated by volume
expansion with saline.
• The nephrotoxicity associated with amphotericin B is usually
reversible with discontinuation of therapy. However, recurrent
renal dysfunction can occur if treatment is reinstituted.
• Monitoring of renal function test including serum potassium &
magnesium.
• IV infusion once daily over 2-6 hours, at a concentration of 0.1
mg/dl, Prepare in 5% dextrose.
 Continuous vs. conventional infusion of Amphotericin
B Deoxycholate

Conclusion:-
Continuous infusions of amphotericin B reduce nephrotoxicity and
side effects related to infusion without increasing mortality.

Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised

controlled trial.
AU
Eriksson U, Seifert B, Schaffner A
SO
BMJ. 2001;322(7286):579.
• Adjunctive therapy for Mx of Mucor ?

• Surgery – complete debridement of necrotic tissue

• High mortality rate 70-90%
• What is the duration of Amphotericin B to be given?

• 4-6 months
• Till repeat imaging shows halt in progress of the disease
• Other options of Rx if amphotericin cant be given

Initial therapy – Amphotericin B
• Liposomal Amphotericin B or
Amphotericin B lipid complex @
5 mg/kg , increase up to 10
mg/kg
• Renal mucormycosis – Drug of
choice is Amphotericin B
Deoxycholate
• Note :- Lipid formulations of
Amphotericin B do not penetrate
the kidney or achieve measurable
concentration in Urine
T/t of Mucormycosis
Step down therapy
• Oral Posaconazole – delayed release
tablets (300 mg every 12 hours on
the first day then 300 mg once daily)
taken with food if possible or
• Isavuconazole – loading doses of 200
mg (i.e. two capsule) of oral
Isavuconazole should be given every
8 hourly for six doses, followed by
200 mg od
Salvage therapy
• For patients who do not respond to
or cannot tolerate amphotericin B
• IV Posaconazole - loading dose of
300 mg every 12 hours on the first
day, followed by a maintenance
dose of 300 mg every 24 hours
thereafter
• Isavuconazole should be given as a
loading dose of 200 mg IV or orally
every 8 hours for the first six doses
followed by 200 mg IV or orally
every 24 hours thereafter.
Thank you