FUNGAL INFECTIONS IN ICU

DR GC KHILNNANI
DR BHUMIKA
CLASSIFICATION
FUNGI CAUSING INFECTONS IN ICU
• Candida
• Aspergillois
• Mucormycosis
• Histoplasmois
• Cryptococcus
• Pneumocystsis carinii
• Blastomycosis
• Fusarium, Scedosporium, Trichosporon, Hansenula, Rhodotorula
and Malassezia (rare and intrinsically reistant to Echhinicandins)
 EPIDEMIOLOGY
• The global mortality rate of IFIs is 10-49%.
• Approximately 3 million people - chronic invasive
fungal infections
• 1.9 million people –acute severe IF
• 1.6 million –deaths per year
• Patients were included based on the confirmed diagnosis
of IFI and excluded based on lack of a microbiologically
and histologically proven diagnosis of IFI. Of the 1477
patients recruited in this study, confirmed cases of
fungal infection were 490 (169 proven; 321 cases
probable). Among the fungi recovered, Candida species
had the highest frequency 337 (68.8%) followed by
Aspergillus species 108 (22.1%), Zygomycetes species 21
(4.3%), non-Candida yeast 9 (1.8%). Others were black
fungi 5 (1%), mycetoma agents 5 (1%), Fusarium 4
(0.8%), and Trichoderma (0.2%).
 Invasive
Fungal and
Fungal-like
Infections
Years in which available antimycotics were licensed for treating invasive
fungal infections
Candida spp. -4 th leading cause of blood stream
infections
Rates of non-albicans species are increasing in North
America; C. glabrata is the second most common
pathogen isolated, followed by C. parapsilosis, which
is commonly seen in patients with chronic catheter
placement (e.g., total parenteral nutrition). The rates
of C. tropicalis, C. krusei, and C. lusitaniae remain
stable, and these are still considered important
pathogens. This
 1. Direct microscopic examination of
clinical samples including
histopathology
APPROACH 2. Culture of the organism-The
TOWARDS sensitivity of the culture varies with
diseases (e.g. blood culture may
DIAGNOSING miss ≥50% of patients of
A FUNGAL disseminated candidiasis, recovery
of Histoplasma capsulatum from
INFECTION sputum of patients with active
pulmonary histoplasmosis is only 10-
15%)
3. Antigen detection tests
4. Serologic tests
5. Molecular diagnostics (DNA probe
tests)
 DIRECT MICROSCOPIC
EXAMINATION
Method Primary Use Advantages Disadvantages

Detects Nocardia and some isolates Tissue homogenates are difficult to

Detection of mycobacteria and observe because of background
Acid fast stain an Nocardia, respectively of B.dermatitidis
d partial acid fast staining
stain
Can be mixed with KOH: detects
Calcofluor white Detection of fungi fungi rapidly because of bright Requires use of fluorescence
microscope
fluorescence
Will detect most fungi if present in Some fungi stain weakly
Gram stain Detection of bacteria
that specimen (e.g. Cryptococcus spp)

Detection of  Positive in less than 50% of cases of

If present, is diagnostic of
India Ink cryptococcal meningitis meningitis, not sensitive in non-HIV
Cryptococcus neoformans in CSF meningitis

Clearing of some specimen make

Clearing of specimen to make fungi Rapid detection of fungal elements take hours, experience required
Potassium hydrox more readily visible since background artifacts are
ide (KOH) mount
often confusing

Methenamine Detection of fungi in histologic Requires a specialized staining

Best stain to detect fungal elements
silver stain section method

Stain fungal elements well; hyphae

Periodic acid-Schiff Detection of fungi of molds and yeasts can be readily
(PAS) stain distinguished

Examination of bone marrow or Detects H.capsulatum and C.

Wright stain peripheral blood sample  
neoformans
 Antigen detection tests
• Galactomanan- acell wall polysaccharide specific
to
aspergillus,penicillium,paecilimyces,hisytoplasma
• An exoantigen-Serum,BAL,CSF
• IN some patients,can be detected in serum even
before clinical symptoms/even inabsence of
positive cultures
• US FDA considers
 ANTIGEN DETECTION
• Berta d glucan-candida
• (glucuronoxylomannan) of Cryptococcus neformans in
the spinal fluid can be detected.
•  In invasive aspergillosis (galactomannan  
• Detection of polysaccharide antigen of Histoplasma
capsulatum in body fluids, especially urine, has been
useful in presumptive diagnosis of histoplasmosis in
patients with disseminated disease.
• Immunoassays have also been developed for detection
of galactomannan from B. dermatitidis and C. immitis in
urine and other body fluids.
 SEROLOGICAL TESTS
•  immunodiffusion (ID), complement
fixation (CF), and enzyme immunoassay
(EIA)-coccidioidomycosis,
histoplasmosis, and blastomycosis.
• Advantages-results may be positive
when cultures are difficult to obtain
• Disadvantages-false negatives
• Lack sensitivity and specificity
 MOLECULAR DIAGNSOTICS
1.Non-Culture-Based Molecular Diagnostic Methods—
MALTI TOF
2.Culture-Based Molecular Diagnostic Methods
•  FilmArray Blood Culture Identification (BioFire
Diagnostics, Inc.), which is a PCR-based reaction
performed on positive blood cultures and detects
mainly Candida spp is a FDA approved fungal
identification method.
• ests involving DNA probes can identify colonies
growing in culture at an earlier stage of growth than
can tests based on visual detection of colonies. 
Proteomics Profiling/Fingerprinting

• Matrix-Assisted Laser
Desorption/Ionization Time-of-Flight
(MALDI-TOF) is the most popular and
fastest growing non-nucleic acid
sequence based molecular diagnostic
assay for fungi.
• The T2Candida system is the only FDA-cleared PCR assay
for Candida to date.It detects the five most common species
of Candida (C. albicans, C. glabrata, C. parapsilosis, C.
tropicalis and C. krusei), has a detection limit of 1 cfu/mL and results
in a >10-fold decrease in time to result (compared with blood
cultures), and is devised to not amplify freely circulating, non-cell-
associated DNA.9,
•  the Aspergillus-specific lateral-flow device (LFD) is an
immunochromatographic test that uses the JF5 monoclonal antibody
to detect an extracellular glycoprotein (mannoprotein) antigen
secreted by actively growing Aspergillus species.25
• The CrAg lateral flow assay (LFA) has been validated in serum and
CSF, with 99.3% sensitivity and >99.1% specificity in CSF
 Summary of new non-culture
laboratory diagnostic tests for systemic
fungal diseases

Disease Test Comments

Candidaemia/deep-seated T2 Candida panel.  Detects Candida DNA directly in
candidaemia  whole blood. Detection limit of 1 
cfu/mL. Greater than 10-fold decrease
in reporting time. 

Pulmonary aspergillosis  Immunochromatographic technology POC or near-POC test for detecting

– lateral flow devices/dip sticks.  cell wall components in serum, BAL
and urine. Impact of antifungal
prophylaxis on sensitivity not
known. 

  Aspergillus proximity ligation assay.  Detects cell wall mannoprotein. 

Cryptococcosis  Various lateral flow formats.  Designed to detect cryptococcal
polysaccharide antigen in CSF,
whole blood and saliva. Adopted by
WHO on their Essential Diagnostics
List. 
Histoplasmosis  Various ELISA platforms, lateral flow Rapid, lateral flow devices are
devices, and a loop-mediated suitable for POC testing, urine is the
isothermal amplification assay.  preferred clinical sample. 
Method Primary Use Advantages Disadvantages

Detection of mycobacteria and Detects Nocardia and some isolates Tissue homogenates are difficult to
Acid fast stain and pa Nocardia, respectively observe because of background
rtial acid fast stain of B.dermatitidis staining

Can be mixed with KOH: detects

Calcofluor white Detection of fungi fungi rapidly because of bright Requires use of fluorescence
microscope
fluorescence

Will detect most fungi if present in Some fungi stain weakly

Gram stain Detection of bacteria
that specimen (e.g. Cryptococcus spp)

Detection of  If present, is diagnostic of Positive in less than 50% of cases of

India Ink cryptococcal meningitis meningitis, not sensitive in non-HIV
Cryptococcus neoformans in CSF meningitis

Clearing of some specimen make take

Clearing of specimen to make fungi Rapid detection of fungal elements hours, experience required since
Potassium hydroxide more readily visible background artifacts are often
(KOH) mount
confusing

Methenamine silver Detection of fungi in histologic Best stain to detect fungal elements Requires a specialized staining
stain section method

Periodic acid-Schiff Stain fungal elements well; hyphae

Detection of fungi of molds and yeasts can be readily
(PAS) stain
distinguished

Examination of bone marrow or Detects H.capsulatum and C.

Wright stain peripheral blood sample  
neoformans
• The classical well-known CT findings in the
angio-invasive form of IPA consist of dense
and well-circumscribed lesions >1 cm, with
the presence of a halo of ground-glass
attenuation (halo sign) at early stages. 5
A macronodule with a halo sign at the level
of the middle lobe In IPA
C XRAY
• Histoplasmosis
• Epidemiology and clinical features
• It is the most common among endemic mycosis,
and is caused by a soil-dwelling dimorphic
fungus, Histoplasma capsulatum
• positive travel history to the endemic area, while
the demonstration of Histoplasma antigen in urine,
blood or bronchoalveolar lavage fluid of infected
patients is diagnostic and rapid. If disseminated
histoplasmosis is suspected, then a bone marrow
biopsy may be helpful.
• severe and disseminated disease involves
administration of amphotericin B; both the
conventional and the lipid formulations can be
used
•  Following initial stabilization, oral itraconazole
can be added twice daily for at least 12 months.
Chronic disseminated candidosis in a patient suffering from AML under salvage
chemotherapy (a and b). Lung involvement appearing as multiple
nodules is much better assessed by using the maximum intensity
projection (suppress CR) post-processing tool (b
Invasive sinonasal aspergillosis.
 usual clinical presentation - community-acquired
Blastomycosis pneumonia not responding to usual antibiotics. It is
Epidemiology less common in HIV-infected patients, but, if present,
and clinical produces widely disseminated disease often involving
the meninges.
features
• presumptive diagnosis is made by demonstration
of characteristic appearance of the fungus on 10%
KOH digest of the respiratory secretions or
bronchoalveolar lavage fluid.
• The treatment for the severe infection causing
respiratory distress is by Amphotericin B (both
conventional and liposomal), and followed by oral
itraconazole twice daily for 12 months after initial
stabilization. 
 Coccidioidomycosis
Epidemiology and clinical features
Click icon to add picture
• echinocandins are the treatment of choice in adult
patients. In a randomized study of the treatment of
candidemia, anidulafungin was at least equivalent to
fluconazole; a secondary analysis even found that it
was superior (response rate for fluconazole 60.2%, for
anidulafungin 75.6%, difference 15.4% [95%
confidence interval: 3.9; 27.0]). For this reason,
fluconazole should be used only in patients without
critical illness and at a high initial dosage (800 mg/d) (
12). Fluconazole is, however, still relevant for oral
treatment continuation after successful initial treatment
with an echinocandin. L-AmB constitutes an
alternative where resistance to other classes of
substances is confirmed. Furthermore, L-AmB is
important in treating chronically disseminated
candidosis/candidiasis, endocarditis due to Candida,
and in pediatric patients (12, 13). Voriconazole usually
does not provide any additional benefits over
fluconazole—with the exception of infection with C.
krusei or where additionally a mold infection is
suspected.
• Candidemia should be treated for at least two weeks
after the bloodstream infection has disappeared (28).
The exact treatment duration can be defined only after
follow-up blood cultures have been produced. In
continuing symptoms or granulocytopenia, the
treatment should be continued for longer. Chronically
disseminated candidosis should be treated for a
minimum of 8–12 weeks, and in some cases for several
months, until the lesions have resolved (12, 14, 17, 28
). Central venous catheters should be removed if at all
possible. If this is not possible then the patient should
be treated with an echinocandin or L-AmB, because of
their effectiveness against biofilms in vitr
Years in which available antimycotics were licensed for
treating invasive fungal infections
fungal co-infections in COVID-19 patients 
 EORTC/MSG 2019 DEFINITION
• The endemic mycoses are caused by environmental fungi
• Probable invasive fungal diseases
(IFD) requires the presence of at
least 1 host factor, a clinical feature
and mycologic evidence and is
proposed for immunocompromised
patients only, whereas
• proven IFD can apply to any patient,
regardless of whether the patient is
immunocompromised. Probable IFD
requires the presence of a host
factor, a clinical feature, and
mycologic evidence.
• Cases that meet the criteria for a
host factor and a clinical feature but
for which mycological evidence has
not been found are considered
possible IFD
that are usually restricted geographically and cause
disease in immunocompetent and immunocompromised
hosts. Causative agents include Histoplasma
capsulatum var. capsulatum and H.
capsulatum var. duboisii, Blastomyces species complex
(eg, B. dermatitidis, B. gilchristii, B. helicus, B. silverae,
and B. parvus), Coccidioides immitis/Coccidioides
posadasii, Paracoccidioides
brasiliensis/Paracoccidioides lutzii, Sporothrix species
complex (S. brasiliensis, S. schenckii sensu stricto, S.
globosa, and S.
luriei), Talaromyces (formerly Penicillium) marneffei,
and Emergomyces species (E. pasteurianus, E.
africanus, E. orientalis, E. canadensis, and E. europaeus)
[75–80]. Probable endemic mycoses are defined by
evidence of environmental exposure to the fungus, a
compatible clinical illness, and the presence of
either Histoplasma or Blastomyces antigen in any body
fluid or antibody to Coccidioides species in serum or
CSF as recovery by culture and histopathologic evidence
of infection is generally lacking. There are no approved
serologic tests for T. marneffei, S. schenckii species
complex, or P. brasiliensis. 
 Host factors 
 Recent history of neutropenia (<0.5 × 109 neutrophils/L [<500
neutrophils/mm3] for >10 days) temporally related to the onset of
invasive fungal disease 

 Hematologic malignancya 

Probable  Receipt of an allogeneic stem cell transplant 

 Receipt of a solid organ transplant 

Invasive  Prolonged use of corticosteroids (excluding among patients with

allergic bronchopulmonary aspergillosis) at a therapeutic dose of

Pulmonary
≥0.3 mg/kg corticosteroids for ≥3 weeks in the past 60 days 

Mold  Treatment with other recognized T-cell immunosuppressants,

such as calcineurin inhibitors, tumor necrosis factor-a blockers,
lymphocyte-specific monoclonal antibodies, immunosuppressive

Diseases nucleoside analogues during the past 90 days 

 Treatment with recognized B-cell immunosuppressants, such as

Bruton’s tyrosine kinase inhibitors, eg, ibrutinib 

 Inherited severe immunodeficiency (such as chronic

granulomatous disease, STAT 3 deficiency, or severe combined
immunodeficiency) 

 Acute graft-versus-host disease grade III or IV involving the gut,

lungs, or liver that is refractory to first-line treatment with steroids 
 Clinical features 

Pulmonary aspergillosis 
The presence of 1 of the following 4 patterns on CT: 
 Dense, well-circumscribed lesions(s) with or without a halo sign 

Probable  Air crescent sign 

 Cavity 

Invasive  Wedge-shaped and segmental or lobar consolidation 

Other pulmonary mold diseases 
Pulmonary As for pulmonary aspergillosis but also including a reverse halo sign 

Mold Tracheobronchitis 
 Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or
Diseases eschar seen on bronchoscopic analysis 

Sino-nasal diseases 
 Acute localized pain (including pain radiating to the eye) 
 Nasal ulcer with black eschar 
 Extension from the paranasal sinus across bony barriers, including into
the orbit 

Central nervous system infection 

1 of the following 2 signs: 
 Focal lesions on imaging 
 Mycological evidence 
 Any mold, for example, Aspergillus, Fusarium, Scedosporium species or
Mucorales recovered by culture from sputum, BAL, bronchial brush, or
aspirate 
 Microscopical detection of fungal elements in sputum, BAL, bronchial
brush, or aspirate indicating a mold 
Tracheobronchitis 
Probable  Aspergillus recovered by culture of BAL or bronchial brush 

Invasive  Microscopic detection of fungal elements in BAL or bronchial brush

indicating a mold 
Pulmonary Sino-nasal diseases 

Mold  Mold recovered by culture of sinus aspirate samples 

Diseases  Microscopic detection of fungal elements in sinus aspirate samples

indicating a mold 
Aspergillosis only 
Galactomannan antigen 
Antigen detected in plasma, serum, BAL, or CSF 
Any 1 of the following: 
 Single serum or plasma: ≥1.0 
 BAL fluid: ≥1.0 
 Single serum or plasma: ≥0.7 and BAL fluid ≥0.8 
 CSF: ≥1.0 
Aspergillus PCR 
Any 1 of the following: 
 Candidiasis 
Host factors 
 Recent history of neutropenia <0.5 × 109 neutrophils/L (<500 neutrophils/m
days) temporally related to the onset of invasive fungal disease 

 Hematologic malignancy 
 Receipt of an allogeneic stem cell transplant 
 Solid organ transplant recipient 

Other  Prolonged use of corticosteroids (excluding among patients with allergic

bronchopulmonary aspergillosis) at a therapeutic dose of ≥0.3 mg/kg corticoste
weeks in the past 60 days 

Probable  Treatment with other recognized T-cell immunosuppressants, such as calcine

inhibitors, tumor necrosis factor-a blockers, lymphocyte-specific monoclonal a
immunosuppressive nucleoside analogues during the past 90 days 

Invasive  Inherited severe immunodeficiency (such as chronic granulomatous disease,

deficiency, CARD9 deficiency, STAT-1 gain of function, or severe combined
immunodeficiency) 

Diseases Clinical features 

At least 1 of the following 2 entities after an episode of candidemia within the
weeks: 
 Small, target-like abscesses in liver or spleen (bull’s-eye lesions) or in the b
meningeal enhancement 
Mycological evidence 
 ß-D-glucan (Fungitell) ≥80 ng/L (pg/mL) detected in at least 2 consecutive
samples provided that other etiologies have been excluded 
 Positive T2Candidaa 
 osis 
b
 
mmunodeficiency virus infection 
an or stem cell transplant recipient 
gic malignancy 
deficiency (eg, common variable immunoglobulin deficiency) 
uppressive therapy (including monoclonal antibodies) 
e liver or renal disease 
c CD4 lymphocytopenia 
tures 
al inflammation 
cal lesion consistent with cryptococcal disease 
l evidence 
tosisc 
 
4 lymphocyte counts <200 cells/mm3 (200 × 106 cells/L) for any reason 
to medication (antineoplastic therapy, antiinflammatory, or immunosuppressive treatment) associated with T-cell dysfunction 
erapeutic doses of ≥0.3 mg/kg prednisone equivalent for ≥2 weeks in the past 60 days 
an transplant 
tures 
istent radiographic features particularly bilateral ground glass opacities, consolidations, small nodules or unilateral infiltrates lob
ltrate with or without cavitation, multifocal infiltrates, miliary pattern d 
ry symptoms with cough, dyspnea, and hypoxemia accompanying radiographic abnormalities including consolidations, small no
leural effusions, or cystic lesions on chest X-ray or computed tomography scan 
l evidence 
an (Fungitell) ≥80 ng/L (pg/mL) detection in ≥2 consecutive serum samples provided other etiologies have been excluded 
of Pneumocystis jirovecii DNA by quantitative real-time polymerase chain reaction in a respiratory tract specimen 
ycoses 
 
cable as these diseases affect both healthy and less healthy hosts 
 False • Treatment • Immunoglobulines
Albumin ,Coagulation
factors, Antibiotics
positives of (piperacillin –
tazobactam) Others?
beta d •
(chemotherapies …)
Hemodialysis with
glucan • Patient care
cellulose
membranes,Gauze or
other materials that
contain glucans, Tubes
handlin

• Gram negative
• Bacterial infection bacteria, Some
streptococc
 INCIDENCE
• Fungi are responsible for around 20% of microbiologically
documented infections in intensive care units (ICU).
• n the current severe acute respiratory syndrome-coronavirus-2
(SARS-CoV-2) pandemic, fungal co-infections among COVID-19
patients in intensive care units (ICUs) has been reported [3,4,5,6,7].
White et al. [7] reported an incidence of 14.1% and 12.6% for
aspergillosis and yeast infections, respectively, amongst critically ill
COVID-19 patients across multiple centers in Wales. Bartoletti et al.
[6] reported a higher incidence of 27.7% for invasive pulmonary
aspergillosis (IPA) (or COVID-19-associated pulmonary
aspergillosis, CAPA) amongst COVID-19 patients (of a 108 patient
cohort) requiring invasive mechanical ventilation between late
February and April 2020 in Italy
 management
• Pre-emptive treatment: It is considered in those patients who have a high risk of developing
candidiasis but lack a definitive diagnosis of infection. Fluconazole in a dose of 400 mg to 800
mg per day is usually used, and this therapy has shown to significantly reduce the incidence of
definitive candidiasis.[28] However, no improvement of outcome could be documented so far.
• Prophylactic treatment: The prophylactic use of fluconazole is recommended in patients
receiving chemotherapy for hematologic malignancies who are expected to be neutropenic, in
patients with solid organ transplantation and in patients undergoing bone marrow
transplantation. This prophylaxis can also be used in non-neutropenic at-risk intensive care
patients.[29] However, no benefit of such prophylaxis could be documented till now.[30]
• Definitive treatment: In patients with a definitive diagnosis of candidiasis, all catheters,
including the central venous catheter, should be removed and invasive candidiasis such as
endophthalmitis should be excluded.
• n clinically stable patients, fluconazole is used in a dose of 400 mg to a maximum of 1600 mg
per day for at least 2 weeks after the last positive blood culture unless azole resistance is
suspected. Echinocandins (caspofungin, micafungin, anidulafungin) should be preferred if
NAC such as C. glabrata or C. krusei are suspected
• In unstable and severely ill patients,
amphotericin B (conventional or liposomal)
alone or in combination with fluconazole,
echinocandins (caspofungin, micafungin,
anidulafungin), voriconazole or high-dose
fluconazole (800 mg per day) may be used.
 aspergillosis
• Primary therapy: Intravenous voriconazole in the dose of 6 mg/kg every 12 hourly followed 24
h later by 4 mg/kg every 12 hourly. This should be followed by oral voriconazole 200 mg
twice daily until clinical and radiological stabilization occurs. Alternatively, amphotericin B
(liposomal) can be used intravenously in a dose of 3-5 mg/kg/day followed by oral
voriconazole (200 mg twice daily) until clinical improvement.
• Salvage therapy: Echinocandins are utilized in this therapy when the primary therapy fails.
Intravenous Caspofungin in a dose of 70 mg on Day 1, followed by 50 mg per day thereafter is
usually used; however, intravenous micafungin can also be used. Recently, oral posaconazole
in a dose of 200 mg every 6 hourly, followed by 400 mg twice daily, has been found to be
equally effective.[35]
• Combination therapy: There has been interest in the combination of various antifungal agents
for the treatment of invasive aspergillosis and combination of liposomal amphotericin B and
itraconazole as well as combination of voriconazole with caspofungin has been studied and
found to be equally effective.[36] However, further studies are required for strongly
recommending any such therapies.
• The therapy is usually continued for 6-12 weeks. The galactomannan test can be used as a
marker of effectiveness of the therapy. The therapy is found to be more effective when the
 • This is an important opportunistic fungus that causes pneumonia in
immunocompromised patients, especially in patients with AIDS.
Pneumonia is caused by Pneumocystis jiroveci, which is commonly
present in the environment but is non-infectious in healthy individuals.[
40]
• The infection usually starts with fever and non-productive cough,
gradually progressing to shortness of breath and hypoxia.
Pneumothorax is a well known complication and should be suspected
in acute chest pain with breathlessness with unilateral reduced breath
sounds. It mainly involves the interstitial fibrous tissue of the lungs,
leading to thickening and impaired oxygenation.
• Diagnosis
• The diagnosis of P. jiroveci infection is usually made by characteristic
Pneumocystis appearance of widespread pulmonary infiltrates on chest radiograph in
an immunocompromised patient. The diagnosis is confirmed by
histological demonstration of organism in sputum or bronchoalveolar
lavage fluid, by staining showing characteristic cysts. PCR can also be
used to detect the DNA.
• Treatment
• Primary prophylaxis is indicated in patients with AIDS with CD4 cell
counts less than 200 cells/μl, patients on chronic steroid therapy,
patients with malignancy on cytotoxic drug therapy and patients with
organ transplantation. Co-trimoxazole is the first choice drug while
dapsone, atovaquone and aerosolized pentamidine may be used as
second-line drugs.[41]
• The treatment of established infection is by co-trimoxazole in divided
doses for at least 3 weeks. The other drugs that may be used as second
choice are dapsone, atovaquone, clindamycin, primaquine and
pentamidine. Adjunctive steroids are usually indicated in moderate to
severe disease to prevent inflammation and worsening of symptoms
due to the
 epidemiology
• Invasive candidiasis and invasive
aspergillosis
•  C. auris, the yeast behaving like bacteria,
has emerged as a potential threat to ICUs
• mycelial agents
like Mucorales, Paecilomyces spp., Fusariu
m spp., and Cladosporium spp., although
encountered infrequently, continue to be
reported as serious infections in ICU
 . Risk Factors for Invasive Fungal Infections
in the ICU
Broad-spectrum antimicrobials
Burns
Candida colonization
Central venous or urinary catheter
Chemotherapy
Corticosteroids
Diabetes mellitus
Graft-versus-host disease
Hematopoietic stem cell transplant
Hemodialysis
High severity of illness (APACHE II >20)
Immunosuppressing therapies Liver failure
Major surgery
Malignancy
Mucosal damage
Necrotizing pancreatitis
Neonates
Neutropenia
Prolonged duration of ICU stay Prolonged ventilation
Renal failure
Solid organ transplant
Structural lung disease T
otal parenteral nutritio
• Fungal diseases that affect people with weakened immune systems
• Weakened immune systems can’t fight off infections as well, due to conditions such as HIV, cancer, organ
transplants, or certain medications.
• Aspergillosis
• An infection caused by Aspergillus, a common mold that lives indoors and outdoors.
• Candida auris infection
• Emerging, often multidrug-resistant fungus found in healthcare settings that presents a serious global health threat.
• Invasive candidiasis
• A serious infection that can affect the blood, heart, brain, eyes, bones, and other parts of the body in hospitalized pa
tients.
• Pneumocystis pneumonia (PCP)
• A serious infection caused by the fungus Pneumocystis jirovecii.
• Candidiasis
• Candida
 normally lives inside the body and on the skin without causing any problems, but can cause infections if it grows ou
t of control or if it enters deep into the body.
• Cryptococcus neoformans infection
• Can infect the brain, causing meningitis, and is more likely to affect people with HIV/AIDS.
• Mucormycosis
• A rare but serious infection caused by a group of molds called mucormycetes.
• Talaromycosis
• Caused by Taloromyces, a fungus that lives in Southeast Asia, southern China, or eastern India.
 • DIRECT METHODS • INDIRECT METHODS
diagnosis • Cultures- • Biomarkers-
• sterile site, sensitivity • 1,3 beta d glucan
21-71%,long • Antimanan
incubation antibodies
period,negative in • galactomannan
deep seated
• PCR assays
infections,patient on
azoles(candida) • Radiological signs
• microscopy • NEWER METHODS
• y. Matrix-assisted laser
desorption ionization time of
flight mass spectrometry
(MALDITOF) is currently a
promising method for rapid
identification of bacterial and
fungal organism once they
have been isolated
• Matrix-assisted laser desorption ionization time of flight
mass spectrometry (MALDITOF) is currently a promising
method for rapid identification of bacterial and fungal
organism once they have been isolated (1) and works by
automatically analyzing the mass distribution of proteins
(29). Turnaround time is 10-15 minutes and the
diagnostic accuracy is at least 95 % (2) and 84-99 %
when compared to conventional methods
• Peptide nucleic acid-fluorescence in situ hybridization
(PNA-FISH) is a method that uses artificial PNA polymers
n. Galactomannan antigens in serum haven’t been proven useful in the ICU but measuring it in BAL
fluid (Bronchoalveolar Lavage) has shown a sensitivity of 50-88 % and specificity of 87 % and the
galactomannan index can be calculated based on the concentration found in the sample . If it is not
appropriate to obtain BAL, three sputum samples can be sent for microscopy and culture

EORTC/MSG consensus group, the diagnosis of aspergillosis can be based on three criteria; 1) risk and
host factors, 2) clinical and radiological signs and symptoms, and 3) laboratory testing that indirectly
or directly proves the existence of Aspergillus.

If an invasive fungal infection is suspected in a patient with suggestive lesions on a CT-scan together
with a negative Aspergillus galactomannan serum test and negative BAL; an invasive mucormycosis
infection should be suspected. In selected patients (hematologic malignancy, recipients of stem cell
transplants) imaging with CT can show the “reverse halo sign” which can help differentiate
mucormycosis from aspergilloma. The “reverse halo sign” is a ring of consolidation with a center of
ground glass opacity

Considering the Cryptococcus spp, the capsule antigen of C. neoformans and C. gattii can be tested
for in serum and CSF. Testing for β-D-glucan is not appropriate for the Cryptococcus and Mucorales
spp. since they don’t produce it
Amphotericin B
CONVENTIONAL amphotericin B
 • test dose: 1 mg in 20 mL dextrose,
slow IV over 20 to 30 minutes,
with monitoring for 2 to 4 hours
afterward.
Initial dose (patients with good
cardio-renal function and well
tolerated test dose): 0.25 mg/kg
slow IV daily
Dose of Initial dose (severe and rapidly
progressive infection): 0.3 mg/kg
amphotericin B slow IV daily
Initial dose (patients with impaired
cardio-renal function OR severe
reaction to test dose): use smaller
doses (e.g. 5 to 10 mg)
-Gradually increase dose by 5 to 10
mg/day to a final daily dose of 0.5
to 0.7 mg/kg IV once a day
depending on cardio-renal status.
 Duration of therapy
• Invasive aspergillosis-11 months
• Patients undergoing urologic procedures: 0.3 to 0.6 mg/kg IV once a day for several days
before and after the procedure

Fluconazole-resistant candida glabrata: 0.3 to 0.6 mg/kg IV once a day for 1 to 7 days

Symptomatic ascending candida pyelonephritis from fluconazole-resistant candida

glabrata: 0.3 to 0.6 mg/kg IV once a day for 1 to 7 days
-Use with or without flucytosine

Symptomatic ascending candida pyelonephritis from fluconazole-resistant candida kryseu:

0.3 to 0.6 mg/kg IV once a day for 1 to 7 days
• Central nervous system candidiasis in patients in whom a ventricular device cannot be
removed: 0.01 to 0.5 mg in 2 mL of 5% dextrose administered THROUGH THE DEVICE
into the ventricle

Medically reviewed by Drugs.com. Last updated on Mar 1, 2021.

• Amphotericin B lipid complex-5mg/kg OD
• Amphotericin B colloidal suspension-3-4mg/kg day
• Amphotericin B liposomal-3-6 mg/kg
• Conventional amphotericin B
• Test dose-1mg infused over 20-30 minutes I/V(many do not recommend)
• I/V adults:0.3-1.5 mg/kg/day over 4-6 hrs
• Folllowed by 1-1.5mg/kg every other day can be given once therapy is established
• Renal dysfunction-50% dose reduction or alternate day therapy
• Duration of therapy: 10 to 14 days
Maximum dose: 1.5 mg/kg total daily dose - UNDER NO CIRCUMSTANCES
SHOULD THIS DOSE BE EXCEEDED
• Administer by slow IV infusion, over approximately 2 to 6 hours, depending on
dose.
-The recommended concentration for infusion is 0.1 mg/mL.
 Azoles

FLUCONAZOLE-Candida but
ITRACONAZOLE-broad VORICONAZOLE-Invasive
less against glabrata and none
spectrum-endemic fungi and aspergillosis,fusarium,superior
against krusei.,Endemic
molds activity for glabrata and krusei
fungi(histo,coccidio,blasto)

POSOCONAZOLE AND
Broad spectrum of activity
ISAVUCONAZOLE-
FLUCONAZOLE
itraconazole
 • DOSE
• INTRAVENOUS
• LOADING-6 mg/kg every 12 hours for two doses
• MAINTENACE-3-4 MG/KG every 12hours
• ORAL-
• LOADING-400 mg 12 hourtly for 2 doses
• MAINTENACE -200 mg every 12 hourly
• I/V dose should be avoided in renal insufficiency
due to accumulation of cyclo dextrin vehicle

voriconazole
 • Vision changes- Photopsia,
photophobia, colour changes
• Periostitis
• Cardiac- QT prolongation, torsades de
ADVERSE pontes,sudden cardiac death
REACTIONS • Neurogical- Hallucinations(visual and
auditory), confusion, agitation,
OF myoclonic movements, peripheral
demylenating polyneuropathty specially
VORICONA in transplant patients on tacrolimus
• Skin- Stevens-johnson syndrome and
ZOLE long term use can cause skin cancers
• Drug interactions-
Warfarin,cyclosporin,tacrolimus,sulphon
ureas,statins,benzodiazepines,rifampicin
 POSOCONAZOLE
INDICATIONS

prophylaxis of invasive fungal infections in patients of hematological malignancies on

prolonged chemotherapy induced neutropenia, hemotopoetic stem cell tansplant
Step down or salvage therapy in mucormycosisn and other invasive fungal infections

DOSAGE

ORAL SUSPENSION-200MG 3 times dailuy to 400mg two times daily

DELAYED RELEASE TYABLETS AND I/V –

Loading dose-300mg every 12 hours on day 1, f/b 300mg daily

Suggested not to use I/V formulations in patients of modrarte to severe renal

impairment( creatinine clearance <50)
ADVERSE EFFECTS OF POSOCONAZOLE

• Metabolic-
Hypokalemia(30%),hypomagnesmia,hypocalcemia,hypergly
cemia,rarely vitamin k deficiency
• Hematologic- Thrombocytopenia (up to 29%), anemia (up to
25%), neutropenia (up to 23%), febrile neutropenia (up to
20%),rarely HUS and TTP
• Respiratory- epistaxis (up to 17%), pneumonia (up to 12.5%), 
pharyngitis (up to 12%) and rarely PE
• Cardiovascular-Hypertension (up to 18%), tachycardia (up to
12%), Long QT syndrome,TORSADES PONTES
• Hepatic-transient rise in enzymes
• MusculoskeletalMusculoskeletal pain (up to 16%)
 DOSE
ISAVUCONAZOLE
LOADING-200 MG every 8 hrly for six doses(48
hrs) via oral or I/V formulation

MAINTENCE-200 mg once daily

ADRS

Nausea,vomiting,daihrrhoea

Hypokalemia,hepatotoxicity,transfusion
reactions
ECHINOCANDIN
 ]

• Pneumocandins (cyclic hexapeptides linked

to a long-chain fatty acid)
• Echinocandin B not clinically used, risk of
hemolysis
• Cilofungin withdrawn from trials due to
solvent toxicity
• Caspofungin (trade name Cancidas, by
Merck)
• Micafungin (FK463) (trade name Mycamine,
List of by Astellas Pharma.)
• Anidulafungin (VER-002, V-echinocandin,
echinocandins LY303366) (trade name Eraxis, by Pfizer)
• Rezafungin formerly CD101 IV, Rezafungin
is considered to be safest echinocandins
which also acts longest (weekly single
dose). It is developed by Cidara
Therapeutics. The STRIVE Trial (phase 2)
showed weekly treatment with Rezafungin
was safe and efficacious in the treatment of
candidemia and/or invasive candidiasis. 
ADVANTAGES
 DOSE ADJUSTMENT/ DOSE
CASPOFUNGIN
• Has hepatic metabolism
• Not an inhibitor of CYP 3A4
• Requires dose to be
adjusted to 35 mg OD for
moderate hepatic
insufficiency(CPT 7-9)
• DOSE -70 mg stat f/b 50mg
once daily
MICA AND ANIDULAFUNGIN
• Micafungin has hepatic
metabolism
• No dose adjustment
required
• MICAFUNGIN-100 mg stat
and once daily
• ANIDULAFUNGIN-200 mg
loading f/b 100mg once
daily
 • Broad range (especially against all Candida),
thus can be given empirically in febrile
neutropenia and stem cell transplant
• Can be used in case of azole-
resistant Candida or use as a second-line
agent for refractory aspergillosis
• Long half-life (polyphasic elimination: alpha
phase 1–2 hours + beta phase 9–11 hours +
gamma phase 40–50 hours)
• Low toxicity: only histamine release (3%),
fever (2.9%), nausea and vomiting (2.9%),
and phlebitis at the injection site (2.9%), very
ADVANTAGES OF rarely allergy and anaphylaxis
• Not an inhibitor, inducer, or substrate of the
ECCHINOCANDINS cytochrome P450 system, or P-glycoprotein,
thus minimal drug interactions
• Lack of interference from kidney failure and
hemodialysis
• No dose adjustment is necessary based on
age, gender, race
• Better (or no less effective) than amphotericin
B and fluconazole against yeast
(mainly Candida, NOT yeast form of
dimorphic) infections
• FUNGISTATIC against Aspergilosis and
Pneumocystis jerovecii
• Caspofungin (70 mg loading dose, then 50 mg
daily) Fluconazole (800 mg loading, then 400
mg daily) Micafungin (100 mg daily) Lipid-
formulation Amphotericin B (3-5 mg/kg/day)
Anidulafungin (200 mg loading, then 100 mg
daily
 • Echinocandin resistance is rare
among Candida spp. However, case studies have
shown some resistance in C. albicans, C.
glabrata, C. lusitaniae, C. tropicalis, and C.
parapsilosis. Resistance patterns include alterations
in the glucan synthase (Fks1-Fks2 complex),
overexpression of efflux pumps, strengthening of cell
wall by increased chitin production, upregulation of
stress-response pathways,[and dysregulation of
mismatch repair pathways.
• In addition a few species and strains of Candida spp.
DISADVANTAGES and Aspergillus spp. show a "paradoxic effect", i.e.,
they are susceptible to low concentrations but
resistant to high concentrations in broth microdilution
studies.
• Several non-candidal yeasts,
e.g., Cryptococcus, Trichosporon, Rhodotorula and B
lastoschizomyces and filamentous fungi
like Fusarium, zygomycetes and Scedosporium are
often resistant to echinocandins.[ Echinocandins
have weak in vitro activity (a high minimum inhibitory
concentration) and very little clinical efficacy
against Histoplasma, Blastomyces,
and Coccidioides, especially their yeast forms.
 Normally a commensal of sKin,mouth,throat and
genitourinary system
Can cause

Mucositis,

Eosophagiitis

CANDIDA
Candidemia

UTI

Infections of lung,heart ,kidney brain

peritonitis

Vulvovaginitis
 • Use of broad spectrum antibiotics-92%
• Presence of central venous catheter-74%
• Use of immunosuppressive drugs,
. Risk factors glucocorticoids, chemotherapy-18%
• Major trauma Recent surgery (particularly
associated abdominal surgery with anastomotic leakage &
with Candida ≥1 surgery)-15%
• Pneumonia-32.9%
spp. • ARDS-18%
infections in • COPD-15%
the ICU • Neutropenia
• Solid organ transplantation
• Hematologic malignant disease-12%
• Hemodialysis -23%
• Pancreatitis
• Total parenteral nutrition-13%
• Diabetes mellitus
• Multifocal colonization (colonization index
≥0,4)
 • total parenteral nutrition (1 point)
• multifocal colonisation sites (1 point),
• severe sepsis (2 points)
Candida • and surgery (1 point).
score/Candida • Accordingly, a “Candida Score” was calculated
and a score of ≥3 predicted invasive candidial
colonization disease with a sensitivity of 81% and a specificity
index of 74%.
• Candida Colonization Index (CI) is the ratio of the
culture positive sites over the total number of
sites cultured for candida. a CI ≥ 0,4 could be
used as the cutoff-value for introducing
preemptive treatment
 OSTROSKY-ZEICHNER RULE
• Icu stay for 4 days+antibiotic
use+cvc
• Plus any 2 of the following-
• Surgery
• TPN
• Hemodilaysis
• Pancreatitis
• Steroids
• Immunosuppression
 Candida tropicalis-41.60%

Candida albicans-20.90%

Candida parapsilosis-10.90%

Candida glabrata-7.10%-fluconazole resistance high

SPECIES
DISTRIBUTION Candida auris-5.70%
OF CANDIDA
Candida rugosa-3.15%

Candida guillimondi-3.15%

Candida krusei-3.15%-inherently resistant to

fluconazole but sensitive to voriconazole
 Diagnostic Tests for CANDIDA
TEST sensitivity and specificity
• 75 and 80%
. β-D-glucan

Mannan antigen/ Anti-mannan • 83/75%

antibody

Nucleic-acid PCR 80-90 and70-90%

Blood culture 50 and 100%

T2 candida
• 91 and 99%
 CANDIDA AURIS
Multidrug resistasnt yeast
Cutaneous and invasive forms
High mortality
Thermotolerant and salt tolerant
Biofilm formation
Resistance patterns-
Fluconazole>90%
Voriconazole>50%
Amphoterticin B>30%
Echinocandins_7-10%
 • Remains astandard of therapy for
selected patients who have proven
or probable IC
• No previous azole exposure
• Mild to moderate illness
• Not at high risk for
c.glabrata(elderly,dibetics
• DOC for suspected genitourinary
FLUCONAZOLE candidiasis as it has excellrnt
urinary concentration
• Step down therapy from
echinocandin/amphotericin B
 VORICONAZOLE AND POSACONAZOLE

• Effective alternative for a week followed by

fluconazole
• Effective against krusei and most glabrata
 • For candidemia without
persistent fungemia or
metastatic
complications-2 weeks
after documented
DURATION OF clearance of candida
TREATMENT from the blood-
stream,resolution of
symptoms attributable
to candedimia, and
resolution of
neutropenia
 Transition from an echinocandin to
fluconazole(within 5-7 days by IDSA and 10 days by
ESCMID) is recommended for patients who are

Clinically stable

Have isolates which are susceptible to

fluconazole(c.albicans)

DESCALATION Have negative blood cultures following initiation of

antifungal therapy

C.glabrata-transition to higher dose fluconazole 800

mg(12mg/kg)daily or voriconazole 200-300(3-4)
mg/kg twice daily in fluconazole/vpriconazole
susceptible isolates
C krusei-voriconazole
 • Infections caused
by C. parapsilosis are a significant
problem among neonates, transplant
recipients and patients receiving
parenteral nutrition
certain C. parapsilosis isolates have
been found to be increasingly resistant to
azoles
• Rates of fluconazole resistance
in C. parapsilosis isolates were found
to be five times higher than those

CANDIDA
in C. albicans 

• When it comes to echinocandin

PARAPSILOSIS resistance, C. parapsilosis has a
unique intrinsic resistance to these
drugs, with MIC values, according to
CLSI, for echinocandins being naturally
higher than other
common Candida species (2 mg/L vs
0.25 mg/L
for C. parapsilosis and C. albicans,
respectively

• Unlike
other Candida species, C. tropicalis sh
ows low resistance to echinocandins
 • A discussion on the current epidemiology of candidaemia wo
incomplete without mention of Candida auris. First discovere
in 2009
• It is a colonizer of the skin, unlike most Candida spp., which a
predominantly in the gastrointestinal tract, it can heavily con
the hospital environment and it has been responsible for num
ongoing outbreaks. In addition, C. auris is frequently resistant
antifungals and some isolates are multidrug resistant. e only
that has isolates shown to be resistant to all four cla
human antifungal drugs is C. auris 
It has been found that almost half of C. auris isolates are
Candida resistant, showing resistance to two or more classes of drug
low number (about 4%) show resistance to all classes of an
auris • Although clinical breakpoints have yet to be defined
for C. auris, newer azoles such as posaconazole (rang
mg/L) and isavuconazole (range <0.015 to 0.5 mg/L) s
excellent in vitro activity against C. auris 
• As for treatment of C. auris infections in patients, the CD
recommends initial therapy with an echinocandin
If the patient is clinically unresponsive to this treatment o
persistent fungaemia for >5 days, then switching to a liposo
amphotericin B (5 mg/kg daily) is recommended

•  Disinfectants with sporicidal activity and hydrogen

based products to clean surfaces and healthcare facilitie
Summary of IDSA Recommendations
for the Treatment of Candidiasis

THERAPY
CONDITION PRIMARY ALTERNATIVE COMMENTS
Central LFAmB, 3 to 5 mg Fluconazole, 400 Treat until all
nervous per kg, with or to 800 mg (6 to signs and
system without 12 mg per kg) symptoms,
candidiasis flucytosine daily for patients cerebrospinal
(Ancobon), 25 who cannot fluid
mg per kg, four tolerate LFAmB abnormalities,
times daily for and radiologic
several weeks, abnormalities
followed by have resolved;
fluconazole, 400 removal of
to 800 mg (6 to intraventricular
12 mg per kg) devices is
daily (B-III) recommended.
 Candida infection of the
cardiovascular system
Endocarditis LFAmB, 3 to 5 mg per kg, Step-down therapy Valve replacement is strongly
with or without to fluconazole, 400 recommended; in patients who
flucytosine, 25 mg per to 800 mg (6 to 12 are unable to undergo surgical
kg, four times daily; or mg per kg) daily, removal of the valve, chronic
AmB-d, 0.6 to 1 mg per for susceptible suppression with fluconazole,
kg daily, with or without organism in stable 400 to 800 mg (6 to 12 mg per
flucytosine, 25 mg per kg patients with kg) daily, is recommended;
four times daily; or an negative blood lifelong suppressive therapy is
echinocandin† (B-III) cultures (B-III) recommended for prosthetic
valve endocarditis if valve
cannot be replaced.
 Candidemia
Neutropenic An echinocandin* or Fluconazole, 800-mg (12-mg An echinocandin or LFAmB is
patients LFAmB, 3 to 5 mg per per kg) loading dose, then 400 preferred for most patients;
kg daily (A-II) mg (6 mg per kg) daily; or fluconazole is recommended for
voriconazole, 400 mg (6 mg per patients without recent azole
kg) twice daily for two doses, exposure who are not critically ill;
then 200 mg (3 mg per kg) voriconazole is recommended when
twice daily (B-III) additional coverage for molds is
desired; intravascular catheter
removal is advised but
controversial.
Nonneutropenic Fluconazole, 800-mg LFAmB, 3 to 5 mg per kg daily; An echinocandin should be used in
patients (12-mg per kg) or AmB-d, 0.5 to 1 mg per kg patients with moderately severe to
loading dose, then daily; or voriconazole, 400 mg severe illness and in those with
400 mg (6 mg per kg) (6 mg per kg) twice daily for recent azole exposure; transition to
daily; or an two doses, then 200 mg (3 mg fluconazole after initial
echinocandin* (A-I) per kg) twice daily (A-I) echinocandin may be appropriate;
intravascular catheter removal is
recommended, if possible; treat for
14 days after first negative blood
culture and resolution of signs and
symptoms of candidemia;
ophthalmologic examination is
recommended.
Esophageal Fluconazole, 200 to Itraconazole solution, Oral fluconazole is preferred;
400 mg (3 to 6 mg per 200 mg daily; or an echinocandin or AmB-d is
kg) daily (A-I); an posaconazole, 400 mg appropriate for patients who
echinocandin*; or twice daily; or cannot tolerate an ral agent;
AmB-d, 0.3 to 0.7 mg voriconazole, 200 mg duration of therapy is two to
per kg daily (B-II) twice daily (A-III) three weeks; for patients with
refractory disease, the
alternative therapy, AmB-d, or
an echinocandin is
recommended.
Candida isolated Therapy not Lower
from respiratory recommended respiratory tract
secretions (A-III) infection
with Candida is
rare and
requires
histopathologic
evidence to
confirm
diagnosis.
 Fluconazole 800 mg loading f/b 400 mg in high
risk patients(weak recommendation,moderate-
quality evidence)

Prophylaxis Echinocandins(weak recommendation,low

quality evidence

for IC IN
ICU CVC catheter removal if positive(strong
recommendation, moderate quality evidence)

Daily bathing of ICU patients with

chlorhexidine(weak
recommendation,moderate quality evidence)
 Asymtomatic candiduria
• Elimination of indwelling catheter
Treatment with antifungals is not recommended
unless, neutropenia,VLBW,urologic procedures
• DRUGS-ampho B and fluconazole
DESCALATION
 • immunocompromised status
• with hematologic malignancy,
• neutropenia,
• stem cell and solid organ
transplant recipients (especially
lung) and steroid treatment
Risk factors for Corticosteroids have been recognized
as a major risk factor and a category of
invasive patients who have been noted to have
an increasing incidence are patients
aspergilossis with chronic obstructive pulmonary
disease who are treated with
corticosteroids .
• Other risk factors are prior
antibiotic treatment, AIDS, H1N1
infection, chronic granulomatous
disease, acute renal failure and
receiving treatment with TNF-α
inhibitors
 a lung cavity that is filled with air and has
a round radiopaque mass.
• The halo sign in chest imaging is a
feature seen on lung window settings, 
ground glass opacity surrounding a
pulmonary nodule or mass and
represents hemorrhage. It is typically
seen in angioinvasive aspergillosis.
 DIFFERENTIALS OF HALO SIGN

• Infectious disease
• fungi
• pulmonary aspergillosis
• pulmonary mucormycosis
• pulmonary coccidioidomycosis
• pulmonary cryptococcosis
• pulmonary candidiasis
• septic embolism
• mycobacterial 
• pulmonary tuberculosis
• pulmonary non-tuberculous mycobacterial infection
• pulmonary  Mycobacterium avium complex infection
• rickettsia - rickettsia pneumonia
• Coxiella burnetii - Q fever pneumonia
• viral: herpes simplex virus, varicella-zoster virus (chickenpox), cytomegalovirus, myxovirus
• Neoplasia
• primary tumors
• adenocarcinoma of the lung, adenocarcinoma in situ or minimally invasive (formerly bronchioalveolar carcinoma) - has been described as the most commonly
encountered with halo sign in immunocompetent patients 5
• squamous cell carcinoma of the lung
• Kaposi sarcoma
• pulmonary lymphoma
• lung metastases (especially - hemorrhagic pulmonary metastases):
• angiosarcoma
• choriocarcinoma
• osteosarcoma
• melanoma
• metastasis from gastrointestinal adenocarcinoma (<10%)
• Non-neoplastic, non-infectious, inflammatory diseases
• pulmonary infarction
• granulomatosis with polyangiitis
• eosinophilic lung disease
• pulmonary endometriosis
• organizing pneumonia
• hypersensitivity pneumonitis
• iatrogenic injury
• radiation pneumonitis 6
• pulmonary pseudoaneurysm
• Types of aspergillosis infection:
• IA – invasive aspergillosis
• CPA – chronic pulmonary aspergillosis
• FRS – fungal rhinosinusitis
• Ear, eye and nail infections caused by Aspergillus
• Types of Aspergillus allergy:
• ABPA – allergic bronchopulmonary aspergillosis
• SAFS – severe asthma with fungal sensitivity
Pulmonary aspergillosis can be subdivided into five categories:

(a) saprophytic aspergillosis (aspergilloma),

(b) hypersensitivity reaction (allergic bronchopulmonary aspergillosis),

(c) semi-invasive (chronic necrotizing)

(d) airway-invasive aspergillosis (acute tracheobronchitis, bronchiolitis,

bronchopneumonia, obstructing bronchopulmonary aspergillosis), and 
(e) angioinvasive aspergillosis.
• In ABPA however, the IgE level is extremely
high (more than
• 1000 ng/ ml or 417 IU/ml)
• TREATMENT-STEROIDS and antifungals
 • RHINOCEREBRAL
• Inhalation of spores onto paranasal sinuses
• Tissue necrosisof palate-palatal eschars-
destruction of turbinater-paransal swelling
and erythema and cyanosis of facial skin
overlying the involved sinuses and orbit
• PULMONARY
• Rapidly progressing-inhalation into
CLINICAL bronchioles and alveoli
• Pneumonia with infarction and necrosis
PRESENTATION • Can spread to heart,mediastinum or
hemotagenouly to other organs
• DISSEMINATED- immunocompromised
• OTHERS
• LOCALISED
• CUTANEOUS
• GASTROINTESTINAL
 • neutropenia,
• diabetes,
• hematopoietic stem cell
transplantation and
penetrating trauma
• Chronic corticosteroid
treatment
• Hemochromatosis
• AIDS
Risk factors for • COVID
mucormycosis • malignancy,
• deferoxamine treatment-
leading to increased serum
iron
• renal failure
• Combat associated-in US
soldiers who sustained blast
injuries
• Hospitals-ECG leads,adhesive
tapes,
 complications
• CNS
• Cranial nerve palsies,sinus thrombosis,carotid
artery involvement,CNS
hemorrhage,abscess,cerebritis,blindness
• GASTROINTESTINAL
• Bowel gangrene,septic shock,anemia
• Renal-50%mortality
• infarction,vasculitis,microabscess,granuloma
 Mucor mycosi
• Rhizopus, Mucor and Rhizomucor (1). Other
genera are Lichtheimia, Cunninghamella,
Apophysomyces, Saksenae and other species.
• y. Mortality depends on the underlying
conditions and ranges from 19-35 % without
any underlying condition and up to 66 % for
malignanc
Reverse halo sign
study population comprised 235 patients with
DRC-confirmed probable or definite IPA 
 DIAGNOSIS
• Clinical history,host factors
• Radiological evidence -CT scan of brain,sinuses ,chest( in
form reverse halo sign –a focal area of ground glass
attenuation surrounded a ring of consolidation
• Negative galactomannan and beta d glucan
• BIOPSY of tissue with positive culture
• Serological tests attempted-antibodies to zygomces can
be detected by ELISA-not rroutinely used
• PCR
• MALTI TOF
 direct examination of
BAL,TS,biopsy,autopsy

Broad,nonseptate,ribbon no hyphae
Like hyphae,90 angle

culture + culture++ culture+ culture-

zygomycosis zygomycosis ?
repeat diagnostic tests
• Prognosis remains poor, mortality ranging
from 32 to 70%, and is linked to underlying
diseases and 64 clinical forms [
 TREATMENT GOALS
• Early diagnosis
• Elemination of predisposing factors-correction
of hyperglycemia,neutropenia,metabolic
acidosis
• Initiation of antifungal therapy
• Surgical debridemen(if approachable)
 • I/V amphotericin B liposomal is initial therapy
• Posoconazole-300 mg every 12 hours on day 1
followed by300 mg 0D-salvage therapy if ampho
not tolerated
• isavuconazole-200 mg every 8 hrs for six doses
followed by 200 mg orally OD(used as step
down/salvage therapy
• Ampho B with Posaconazole/echinocandin
• No convicing data found
• Rhinocerebral mucormycosis-combination of
TREATMENT •
caspofungin and polyene works
DEBATABLE
• Desfirrox/hyperbaric oxygen
• Duration of therapy
• Until complete resolution of clinical /radiological
sign and symptoms
• Disesase monitored closely for resurgence
Associated with a high morbidity and mortality

NO survivor before 1955

Rhinocerebral form-mortality 30-70%
• GI infected- 50-70%
• With HIV-100%
 Liposomal ampho B
• The ECMM recommends 5-10 mg/kg and 10 mg/kg in the event of CNS
involvement . In a prospective pilot study (Ambizygo), high doses of L-
AmB were tested as first-line treatment of mucormycosis . Response rate
was 43% (12/28) in patients who received ≥ 7.5 mg/kg/day during the
first week compared with 0% (0/5) in patients who did not. A high dose
of L-AmB (10mg/kg), combined with surgery in 71% of cases, led to an
overall response rate of 36% at week 4 and 45% at week 12. Compared to
another study using L-AmB ≥ 5 mg/kg in mucormycosis treatment,
response was similar at week 4 (36% vs 40%) but was better at week 12
(45% vs 35%) . Mortality rates were equivalent at week 12 (38% vs 42%

• Breakthrough Mucorales infections in patients receiving ISZ have been

reported
• To facilitate treatment in stable disease, ISZ PO
or PSZ DR tablets are strongly recommended.
Time between induction phase with AmB and
introduction of azoles depends on clinical and
imaging responses. Some authors
recommend at least 3 weeks of induction with
parenteral AmB
• ISZ, a new azole, was approved in the United States and in Europe in 2015 for the
treatment of mucormycosis . ISZ is available in oral and IV formulations, and
presents some advantages:
• linear pharmacokinetics
• Vvv
• , few interactions with cytochrome P450 isoenzymes leading to few drug– drug
interactions, QT decrease
• , no nephrotoxic cyclodextrin in the IV formulation (different from posaconazole
IV form), no need for dose adjustment in kidney or liver failure and in obesity, and

• excellent oral bioavailability with no food requirements . Although ISZ has shown
higher minimal inhibitory concentrations (MIC) than posaconazole , it is
demonstrably as effective as AmB to decrease fungal burden and to improve
survival in a neutropenic mouse model of mucormycosis
 Newer antifungals

• e Rezafungin, SCY-078, 154 orolofim, and encochleated amphotericin B

• None is effective against Mucorales
• Enochleated amphotericicn b effective against cryptococoisis
• VT-1161 – for mucormycosis
• Among antibiotics, colistin has presented modest in vitro and in vivo
activity against Mucorale
• Most combinations are indifferent, except for AmB + caspofungin (CAS),
PSZ + CAS and ISZ + CAS which were synergistic .
• Iron chelators have shown high synergy with antifungal drugs in vitro and
in vivo but this has not been confirmed in patients
• Calcineurin inhibitors (cyclosporine A and tacrolimus), which have
immunosuppressive effects, have shown synergy with AmB, PSZ or ISZ in
vitro and in vivo
• Current recommendations
• The ECMM and the ECIL-6 strongly recommend surgery
and control of underlying disease including management
of ketoacidosis and hyperglycemia in diabetic patients,
modulation of corticosteroids and immunosuppressive
drugs, and reduction of neutropenia duration using
hematopoietic growth factor if possible (A II, AII) .
Granulocyte colony-stimulating 238 factor (G CSF) and
hyperbaric oxygen are moderately recommended in case
of neutropenia and in diabetic patients respectively (B II),
while iron chelators are strongly discouraged.
• The most common fungal disease in hospitalized patients in developed countries is invasive candidiasis
(IC), which is associated with mortality upward of 40%, even with treatment.1
•  Invasive aspergillosis is more common in patients with hematologic malignancies and is the most
common fungal infection in lung transplant recipients, with an estimated mortality up to > 80% in the ICU.
• Several associations have been identified between the development of invasive aspergillosis and genetic
variants related to innate and humoral immunity in hematopoietic stem cell and solid organ
transplantation recipients and patients receiving chemotherapy. These include variations in genes
encoding toll-like receptors, dectin-1, CXC chemokine ligand-10, mannose-binding lectin, pentraxin-
related protein, and interleukin-10.
• ,  
•  Genetic susceptibility to candidemia and other Candida infections has been associated with
polymorphisms in genes related to innate immunity, cytokine production, and mucosal integrity,
including TLR genes, CD58, LCE4A-Clorf68, TAGAP, and IL-4.

• Vaccines targeting Candida and Aspergillus species could be implemented in patients prior to the onset

of immunosuppression

• An ideal diagnostic test would be minimally invasive, have a rapid turnaround time to result, be both
sensitive and specific for the diagnosis of IFD, differentiate between colonization and invasive disease,
and yield speciation and susceptibility data
• Laboratory methods for the diagnosis of candidiasis include mannan/anti-
mannan testing, β-D-glucan (BDG), PCR, Candida albicans germ tube
antibody, and T2 magnetic resonance (T2MR)/T2Candida panel (T2
Biosystems). A combined mannan/anti-mannan antibody assay performs well
in C albicans, Candida glabrata, and Candida tropicalis infections and may be
used in neutropenic patients and patients with impaired cellular immunity. 23
• ,  25
•  The cell wall component BDG is present in multiple fungal species and is
therefore not specific for Candida species infection; false-positive test results
may occur in bacteremic, critically ill, and lung transplantation patients. 23
•  A recent development in the diagnosis of C albicans, C tropicalis, C glabrata,
Candida krusei, and Candida parapsilosis infections is the T2Candida panel
using T2MR technology, which enables the detection of specific molecular
targets using magnetic resonance.
• Diagnostic tests for aspergillosis include the
galactomannan enzyme immunoassay, BDG, PCR, and
lateral flow device.
• There are standardized recommendations for the use of
PCR in diagnosis of aspergillosis, and diagnostic accuracy
is high in both blood and BAL specimens.
•  Lateral flow devices are a point-of-care
immunochromatographic assay for an extracellular
mannoprotein specific to Aspergillus species, and they
perform particularly well when combined with
galactomannan or PCR for both serum and BAL samples. 
Trial Name Agent Mechanism Development Description

Evaluate F901318 Treatment of Invasive Fungal Infections in Patients Lacking Treatment Options F901318 (olorofim) Disruption of de novo pyrimidine biosynthesis Phase II Evaluation of study drug for treatment of invasive fungal infections in patients with limited treatment
(FORMULA-OLS) (NCT03583164)38 options

Open-Label Study to Evaluate Efficacy and Safety of SCY-078 in Patients with Refractory or Intolerant SCY-078 (ibrexafungerp) Inhibition of BDG synthesis Phase III Multicenter noncomparator study to evaluate study drug in adult patients with documented fungal
Fungal Diseases (FURI) (NCT03059992)39 infection intolerant or refractory to standard of care

Open-Label Study to Evaluate the Efficacy and Safety of SCY-078 in Patients with Candidiasis Caused by Phase III Multicenter noncomparator study to evaluate oral SCY-078 as an emergency use treatment for patients
Candida Auris (CARES) (NCT03363841)40 with Candida auris infection

Oral SCY-078 vs Standard-of-Care Following IV Echinocandin in the Treatment of Invasive Candidiasis ( Phase II Evaluation of study drug administered at differing doses compared with standard of care following IV
NCT02244606)41 echinocandin therapy for IC

Study to Evaluate the Safety and Efficacy of the Combination Therapy of Ibrexafungerp (SCY-078) with Evaluation of combination therapy with study drug plus voriconazole compared with voriconazole
Voriconazole in Patients with Invasive Pulmonary Aspergillosis (SCYNERGIA) (NCT03672292)42 Phase II monotherapy in patients with IPA

Evaluation of Rezafungin Compared to Caspofungin in Subjects with Candidemia and/or Invasive CD101 (Rezafungin) Inhibition of BDG synthesis Phase III Multicenter, double-blind, randomized trial comparing study drug vs caspofungin in patients with
Candidiasis (ReSTORE) (NCT03667690)43 candidemia/IC

CD101 Compared to Caspofungin Followed by Oral Step Down in Subjects with Candidemia and/or Phase II Evaluation of safety and efficacy of study drug later in disease course compared with caspofungin in
Invasive Candidiasis-Bridging Extension (STRIVE) (NCT02734862)44 patients with candidemia/IC
 NEWER TECHNIQUES
•  Compounds that augment antifungal activity act synergistically with antifungal
agents by decreasing the ability of fungi to respond to stress.
• heat shock protein 90 inhibitors,
• calcineurin and calmodulin inhibitors
• statins,
• selective serotonin reuptake inhibitors,
• nonsteroidal antiinflammatory drugs,
• iron homeostasis inhibitors.
• and calcium homeostasis inhibitors.
• Another promising therapeutic intervention for infections
with Aspergillus and Candida species is phage therapy. Phage therapy
involves the application of bacterial viruses to treat infection and has shown
benefit in bacterial infections. There is some evidence that a bacteriophage
found in Pseudomonas aeruginosa isolates can inhibit both Aspergillus
fumigatus biofilms and C albicans growth likely via iron sequestration.
•  Candida accounts for approximately 15% of all hospital-acquired infections, more than
72% of all nosocomial fungal infections, and 8% to 15% of all nosocomial BSIs [1,2];25%
to 50% of nosocomial candidemia occurs in critical care units. [3According to the
Extended Prevalence in Intensive Care (EPIC) II point prevalence study, Candida spp. are
the third most frequent cause of infection in ICUs worldwide, accounting for 17% of all
ICU infections in culture-positive infected patients
• ] he studies have demonstrated that amphotericin B at 0.5-0.6 mg/kg/day and fluconazole
at 400 mg/day are similarly effective therapies of candidemia in nonneutropenic patients.
• CAS as salvage therapy for mucosal and invasive candidiasis in patients who had already
failed or were intolerant of conventional antifungal therapy. This population of patients
experienced a > 85% response rate to CAS in 18 of 21 patients with oral or esophageal
candidiasis and a similar response rate in 13 of 15 patients with refractory invasive
candidiasis.
•  posaconazole and voriconazole are active in vitro against clinical isolates of
various Candida species, including . albicans, C glabrata, C parapsilosis, C tropicalis,
and C krusei.
• Clinical resistance is the failure to
eradicate a fungal infection from a patient
even though an antifungal drug
with in vitro activity against the fungus has
been administered. Mycological resistance
is the ability of fungus to grow in the
presence of antifungal drugs that would
otherwise kill them or limit their
growth in vitro.
• In the USA, the proportion of C. albicans has dropped significantly and it
now accounts for ,50% of Candida infections.25–27 The largest
proportional increase in the USA is in C. glabrata, which now accounts for
one-third or more of all candidaemia isolates.26,27 This is followed closely
by an increase in C. parapsilosis, which accounts for 15% of all isolates.8
• In India and Pakistan C. tropicalis is the most prevalent species, followed by
C. albicans.
• n the USA, C. albicans, C. tropicalis and C. parapsilosis have low incidences
of fluconazole resistance, at 2%, 5% and 4%, respectively.
• An exception is C. glabrata: population-based surveillance in the USA
indicates that 10% of C. glabrata are resistant to fluconazole and this rate is
also seen in Belgium and Australia.10,26,28 Furthermore, 9% of C. glabrata
that are resistant to fluconazole are also resistant to the echinocandins
ge Candida albicans Non-albicans Candida Total

Male Female Male Female

0-10 1 1 4 2 8

11-20 2 2 2 0 6

21-30 6 0 2 1 9

31-40 0 1 0 7 8

41-50 1 0 2 5 8

51-60 7 2 5 2 16

61-70 7 1 0 2 10

71-80 3 0 2 0 5

Total 27 7 17 19 70
 Species No. (%)
Candida albicans 34 (48.57%)
Candida tropicalis 17 (24.28%)
Table 1 6 (8.57%)
Candida haemulonii
Species
distribution Candida glabrata 4 (5.71%)
of Candida Candida pelliculosa 2 (2.86%)
Candida sake 3 (4.29%)
Candida rugosa 2 (2.86%)
Candida famata 2 (2.86%)
 MIC breakpoints (mg/L)
Candida species
S R

C. albicans ≤0.25 ≥1

C. glabrata ≤0.12 ≥0.5

C. parapsilosis ≤2 ≥8

C. tropicalis ≤0.25 ≥1

C. albicans ≤0.25 ≥1

C. glabrata ≤0.12 ≥0.5

C. parapsilosis ≤2 ≥8

C. tropicalis ≤0.25 ≥1

MIC breakpoints (mg/L)

Candida species
S R

C. albicans ≤0.25 ≥1

C. glabrata ≤0.12 ≥0.5

C. parapsilosis ≤2 ≥8

C. tropicalis ≤0.25 ≥1

C. albicans ≤0.25 ≥1
Antifungal class Genetic basis for resistance Functional basis for resistance

Up-regulation of CDR1/CDR2 and MDR1 by point

mutations in TAC1 and MRR1 transcription Up-regulation of drug transporters
factors

Decreased lanosterol 14-α-demethylase binding

Point mutations in ERG11
affinity for the drug

Azoles

Up-regulation of ERG11 by gene duplication and Increased concentration of lanosterol 14-α-

transcription factor regulation demethylase

Point mutations in ERG3 Inactivation of C5 sterol desaturase leading to

alterations in the ergosterol synthetic pathway

Decreased glucan synthase processing for the

Echinocandins Point mutations in FKS1 and FKS2
drug
 CANDIDIASIS IN COVID 19
ranging from 0.03 to 10% of patients

severe pulmonary disease (e.g. diabetes, immune suppression, or older

ag
The inappropriate use of broad-spectrum antibiotic drugs favors the selection of
pathogens unaffected by ongoing antimicrobial treatment, such as C. difficile and
Candida spp
reports suggested a possible association between the use of tocilizumab, an anti-IL-6-receptor
agent, and the development of candidiasis (Antinori et al., 2020; Kimmig et al., 2020), while
other small case series suggested an increased risk of candidemia in patients receiving
corticosteroids.

SARS-CoV-2 infection could be by itself associated with a heightened risk of candidiasis

through microbial translocation

a profound dysregulation of the immune system,response to commensal pathogens, such as

Candida spp, could be impaired, and invasive candidiasis could develop more frequently.
 ASPERGILLOSIS IN COVID 19
Several studies analyzed the occurrence of pulmonary aspergillosis associated with COVID-19
reporting an incidence ranging from 1.7% to 34.4% ). The largest case series has been
described by Zhu et al. with 23.3% (60/243) of COVID-19 patients ranging from asymptomatic
to critical showing Aspergillus superinfection
, IL-6 is a pleiotropic cytokine that can play a role in protective immunity against various
pathogens, including Aspergillus fumigatus
All that considered, early intervention with IL-6 blockade target antagonists such as
tocilizumab could prevent progression of COVID-19 but potentially expose to increased
susceptibility to Aspergillus infection and other superinfections

isavuconazole, when compared to voriconazole, shows a more favorable pharmacokinetic

profile and it is less prone to hepatotoxicity and neurotoxicity, and has a decreased risk of QT
prolongation, having an overall non-inferior antifungal activity (Maertens et al., 2016).
L
However, being metabolized via CYP3A4, isavuconazole could still be potentially problematic in
 narrow therapeutic window,

DRAWBACKS OF
being metabolized via CYP2C19, CYP2C9 and
CYP3A4 presents the most interactions, especially
in the ICU setting and with COVID-19 drugs such as
VORICONAZOLE remdesivir, which is also a substrate of CYP3A4

IN COVID 19
acute adverse events, including photosensitivity,
visual and auditory hallucinations, cardiac
arrhythmias, and liver toxicity, renal toxicity
alongside long-term toxicities such as skin
carcinogenesis and fluorosis, that can lead to
periostitis.
 MUCORMYCOSIS IN COVID 19
. Singh et al. identified 82/101 cases (81.2%) coming from India, reflecting
the local epidemiology (with a prevalence 80 times higher than the rest of
the World). Most of the reported cases involved sinus cavities (88.9%) and
the rhino-orbital region (56.7%), while pulmonary involvement was
reported in 7.9% of cases. Overall mortality was noted to be 30.7%, with
higher mortality (up to 90%) associated with rhino-orbital-cerebral
involvement

the high incidence of mucormycosis in COVID-19 patients in India is in line

with local epidemiology of diabetes, with India having the second largest
population with this condition, with a prevalence of up to 14%