Antifungals in icu

Dr. M. V. K. KIRAN
Clinical Associate
Critical Care Medicine

 Well documented complication – procedures & conditions –
immunosuppression – transplantation, HIV infection, treatment of
malignancy
 Opportunistic fungi – severe nosocomial threat
 About one half of all candidemias occur in ICUs – death rates
almost double
 Attributable mortality – 20 – 40%
 Aspergillosis – Increasingly common in transplant (hematopoietic
stem cell) , hematologic malignancy
 Left untreated, mortality with invasive aspergillosis – 100%

 Invasive fungal disease – substantial financial burden
 Longer ICU care
 Expensive Antiungal pharmacotherapy
 Greater overall use of hospital resources
 Numerous advances – changed invasive fungal disease management
 Availability of new drugs & new drug classes
 New therapies in ICU
 Improved Outcomes
 Preventive role
 Advances – Fungal diagnostics & Antifungal Susceptibility
 Who needs Antifungal
 Drug selection

Epidemiology
Invasive Fungal Infection
ICU

Candida spp.
 Host of diseases – mild mucocutaneous to serious deep seated –
meningitis , endocarditis , intra abdominal infections
 4th most common bloodstream infection in hospitals , attack rates
higher in ICU ( > 10times), Mortality 40% in untreated cases
 Speciation – important
 Local epidemiology of Candida spp. is important for appropriate
empiric & pre-emptive therapy
 Institution as well as unit level

Candida sp. - Speciation
Candida albicans
•Most commonly isolated
•Invasive candidiasis –
40 – 50 %
Candida nonalbicans
Candida glabrata
Candida tropicalis
20 – 30% of disease cases
Candida parapsilosis
10 – 20 %
Candida krusei
Candida lusitaniae
< 15 %
susceptibility to azoles esp.
fluconazole
Highest mortality than other
Candida sp.
Widely susceptible to available
antifungals
More important in Indian
scenario
More common in nosocomial
candidiasis
Associated with use of plastic
devices – IV catheters, TPN use
Less Virulent
Intrinsic resistance to
Fluconazole
Intrinsic resistance to
Amphotericin B

Mold Pathogen
 Invasive Mold infection – Invasive Aspergillosis – primarily
immunosuppressed as transplant recipients(hematopoeitic stem
cell), hematological malignancies, associated severe
neutropenia(prolonged)
 Rare but can occur in ICU in non immunosuppressed patients –
chronic lung disease, severe liver failure
 Unfortunately most data is from isolates from autopsy

Mold Pathogen
 Other Mold Pathogens – Zygomycetes, Fusarium sp., Scedosporium sp.
– each poses therapeutic challenges & poor outcome
 Nosocomial outbreaks – aerosolization of spores in setting of
construction, contaminated medical product including equipments,hand
lotion.
 Commonest – lungs & sinus infection
 Also affect – Skin & CNS
 Rare – Bloodstream infection

Advances
in
Diagnosis
of
Fungal Infection

Traditional Methods
 Challenging aspect – proper identification
 Traditional methods –
 Clinical evaluation
 Direct Demonstration
 Culture
 Radiographic evidence
 Histopathology
 Difficulties in detecting the pathogens & host factors in at risk patients

Traditional Methods – Limitations
 Direct demonstration –
 Low sensitivity
 Culture –
 Reliable in detecting fungemia – commonest invasive fungal ds in ICU
 Delay – prolong time to appropriate antifungal treatment
 Histopathology–
 Less sensitive and specific diagnosis not possible
 Radiograpic findings –
 Depends on host immunity

Newer Methods – The Galactomannan Assay
 Much anticipated – Highly sensitive and specific for Aspergillus in BAL and serum
 Approved for prospective screening – invasive aspergillosis – hematopoeitic stem cell
transplantation (HSCT) recipients
 Common strategy –
 High risk – routine screening – upto 2/week
 Upto 1 week prior to clinical symptoms of invasive aspergillosis
 Highest specificity & sensitivity in BAL
 Other samples –CSF, urine, other body fluids
 False positive – Concomitant use of  - lactams – use higher cut off value
 False Negative –
 Prior antifungal use – difficult in people on antifungal propphylaxis
 Non neutropenic patients

Newer Methods – The Beta – Glucan Test
 Non specific, highly sensitive pan-fungal marker
 Can detect all fungi including Candida, Aspergillus, not Cryptococcus or Zygomycetes
 Prospective monitoring programme – earlier initiation of antifungals – before clinical
symptoms appear
 It has high negative predictive value
 Other environmental sources of  - glucan, Specificity greatly  if > 1 samples are tested
 ICU – monitoring – 1 – 2/weekly – identify who needs further diagnostic work up
 False Positive – common with single test, patients on hemodialysis
 Persistent elevation over time – identifies true invasive Fungal Infections

Newer Methods
 MALDI – TOF – Matrix – Assisted Laser Desorption Ionization – Time of Flight
mass spectrometry
 Rapid identification method (30 min) from cultures
 Very useful for yeast
 Molds are difficult to identify
 PCR-based assays
 DNA sequencing: PNA FISH

Prophylactic, Preemptive &
Empiric Strategies

 Prophylactic therapy
• Preventive therapy given to everyone in a given class (ex. BMT patients who
are at very high risk for IC)
 Preemptive therapy
• Therapy given to deter or prevent anticipated infection; patients at risk are
monitored closely and therapy is initiated with early evidence suggesting
infection (ex. positive Candida cultures at non-sterile sites, clinical suspicion)
with the goal of preventing disease.

 Empirical therapy
• Therapy guided by practical experience and observation, but with nonspecific
evidence in a given patient (ex. therapy is started because a cancer patient has
remained febrile after several days of broad-spectrum antibiotics)
 Targeted Treatment
• is based on a clinical or laboratory finding indicating that an infection is present (ex.
positive blood culture for Candida species).

Antifungal Drugs Classification
Class Drugs
Polyenes
Amphotericin B
Nystatin
Pyrimidine Flucytosine
Azoles
Fluconazole
Itraconazole
Voriconazole
Posaconazole
Ketoconazole
Echinocandins
Caspofungin
Micafungin
Anidulafungin

The Pharmacological Basis of Therapeutics , 12TH ED, Goodman &
Gillman’s
Mechanism of Actions

Mechanism of Actions
Drug Class Mechanism of Action
Polyenes
Binds to ergosterol in cell membrane, formation of pores, cell
leakage
Pyrimidine Interferes with protein and DNA synthesis
Azoles
Inhibits CYP-dependent 14𝝰 demethylase, interferes with
sterol synthesis
Echinocandins
Inhibition of Fksp subunit of 𝝱1,3 glucan synthase,
increased cell wall permeability, cell lysis

Amphotericin B
 It is a natural polyene macrolide
 Broad spectrum antifungal, covers yeasts as well as moulds
 Use:
 Mucormycosis
 Aspergillosis
 Cryptococcosis
 Empiric antifungal therapy in ICU

Pharmacokinetics  Poorly absorbed orally , is effective for fungal infection of
gastrointestinal tract.
 For systemic infections given as slow I.V.I.
 Highly bound to plasma protein .
 Metabolized in liver
 Excreted slowly in urine over a period of several days.
 Half-life 15 days.

Adverse Effects
 Immediate reactions
(Infusion –related toxicity ).
 Fever,tachypnoea, muscle
spasm, vomiting ,headache,
hypotension.
 Can be avoided by :
 Slowing the infusion
 Decreasing the daily dose
 Premedication with
antipyretics, antihistamincs or
corticosteroids.
 A test dose.
 Late reactions
 Most serious is Nephrotoxicity
(nearly in all patients ).
 Hypokalemia
 Hypomagnesaemia
 Impaired liver functions
 Thrombocytopenia
 Anemia

Formulations
1. Amphotericin B (AmB) deoxycholate
2. Liposomal AmB
3. AmB lipid complex
4. AmB colloidal dispersion
 Last 3 are lipid conjugated, can be given at high doses due to
less incidence of nephrotoxicity

Fluconazole
 Completely absorbed from GIT
 Excellent bioavailability after oral administration
 Bioavailability is not affected by food or gastric PH
 Conc in plasma is same by oral or IV route
 Has the least effect on hepatic microsomal enzymes
 Use: Candida infections, Cryptococcal infections
 Spectrum: yeasts only
 A/E: Hepatotoxicity

Voriconazole
 A broad spectrum antifungal agent
 Given orally or IV
 High oral bioavailability
 Penetrates tissues well including CSF
 Inhibit P450
 Use: Treatment and prophylaxis of invasive aspergillosis
 A/E:
 Reversible visual disturbances
 Hepatotoxicity

Echinocandins
 Caspofungin, Anidulafungin and
Micafungin
 Given by IV route only
 Highly bound to plasma proteins
 Half-life 9-11 hours
 Slowly metabolized by hydrolysis &
N-acetylation
 Poor drug level in
 CNS
 Eye
 Lower urinary tract
 Spectrum: All fungi except Mucor
(less active than AmB)
 Use:
 Candidemia
 Empiric antifungal in ICU

IDSA
(Infectious Disease Society of America)
Treatment Guidelines for
Invasive Candidiasis

Candidemia/ Invasive Candidiasis
 Candidemia:
 Defined as a single positive blood culture for Candida spp
 Invasive candidasis:
 Encompasses 3 entitles
 Candidemia without deep-seated candidiasis
 Candidemia with deep-seated candidiasis
 Deep-seated candidiasis without candidemia
Pappas et al, Clin Infect Dis. 2016 Feb 15;62(4):409-17

Candidemia/ Invasive Candidiasis
 More than 90% of invasive disease is caused by the 5 most
common pathogens
 Candida albicans
 Candida glabrata
 Candida tropicalis
 Candida parapsilosis
 Candida krusei
 More than 50% are due to non-albicans species in the western
world; it is 80-90% in India
 Indian data: Incidence of ICU acquired candidemia in Indian ICUs is
6.5/1000 ICU admissions in a multicentric study conducted in 27
Indian ICUs
Chakraborti et al, Intensive Care Med. 2015 Feb;41(2):285-95

Antifungal options we have
Drugs Uses
Echinocandins
Drug of choice for candidemia and
invasive cadidiasis
Fluconazole
Can be used in resource limited
settings
Liposomal Amphotericin B (AmB)
Used when broad spectrum
coverage is desired
Voriconazole C. krusei infections
• IDSA guideline recommends to start with parenteral/oral therapy (Initial therapy) for 1 week
• Step-down therapy is oral, started after the initial regimen

Why speciation is important
Species Susceptibility pattern
Candia albicans Most susceptible species
Candida
tropicalis
Increasing resistance to fluconazole
C. krusei Inherently resistant to fluconazole
C. parapsilosis
High MICs for echinocandins in the western
data
C. glabrata
Large data on echinocandin and azole
resistance
C. lusitaniae Inherent resistance to Amphotericin B

Candidemia: Non-Neutropenic Patients Candidemia: Neutropenic Patients
Echinocandins:
• Caspofungin 70mg stat, then
50mg OD, or
• Micafungin 100mg OD, or
• Anidulafungin 200mg stat and 100
mg OD
Echinocandins:
• Caspofungin 70mg stat, then
50mg OD, or
• Micafungin 100mg OD, or
• Anidulafungin 200mg stat and 100
mg OD
Fluconazole: 800mg stat and 400mg OD
IV or oral, is an alternative for
• Not critically ill
• Unlikely to have fluconazole
resistant Candida spp
Amphotericin B lipid formulations:
3–5 mg/kg
• Effective alternative
• Restricted use due to toxicity
Amphotericin B lipid formulations:
3-5mg/Kg
• Suspected azole or echinocandin
resistant Candida spp
• Intolerance or limited availability
of other drugs
Fluconazole: 800mg (12mg/Kg) stat and
400mg (6mg/Kg) OD IV or oral, is an
acceptable alternative for
• Not critically ill
• No h/o azole exposure
Voriconazole:
• Not preferred as initial therapy,
can be used
Voriconazole:
• Not preferred as initial therapy, can
be used for mould coverage
InitialTherapy

Candidemia: Non-Neutropenic
Patients
Candidemia: Neutropenic Patients
Transition to Fluconazole:
• After 5-7 days of initial therapy
• Clinically stable patient
• Fluconazole susceptible
isolates
• Negative blood cultures
following initial therapy
Transition to Fluconazole:
• Clinically stable patient with
persistent neutropenia
• Fluconazole susceptible
isolates
• Negative blood cultures
following initial therapy
Transition to Voriconazole:
• For candidemia due to
Candida krusei
Transition to Voriconazole:
• Voriconazole susceptible
isolates
Step-downtherapy

Source Control:
• Central venous catheters (CVCs) to
be removed as early as possible when it
is the presumed source
Source Control:
• Removal of CVCs is not routinely
recommended
Follow-up Blood Cultures:
• Daily or on alternate days
Follow-up Blood Cultures:
• Daily or on alternate days
Duration of Therapy:
• 2 weeks after documented
bloodstream clearance of Candida spp
AND
• Resolution of symptoms
• No obvious metastatic complications
Duration of Therapy:
• 2 weeks after documented
bloodstream clearance of Candida spp
AND
• Resolution of symptoms and
neutropenia
• No obvious metastatic complications
OtherRecommendations

OtherRecommendations
Dilated Ophthalmological Examination:
• Within first week of diagnosis
Dilated Ophthalmological Examination:
• Within the first week after recovery
from neutropenia
G-CSF mobilised granulocyte transfusions
considered in persistent candidemia with
protracted neutropenia
G-CSF, granulocyte-colony stimulating
factor

Critically ill patients
Empiric Therapy Prophylactic Therapy
• In non-neutropenic patients with risk factors
for invasive candidiasis
• In high-risk patients in ICUs, with a high
incidence (>5%) of invasive disease
Echinocandins:
Caspofungin 70mg stat, then 50mg OD, or
Micafungin 100mg OD, or
Anidulafungin 200mg stat and 100 mg OD
Fluconazole: 800mg stat and 400mg OD IV
or oral, is an alternative
 No H/O azole exposure
 Not colonised with azole-resistant
Candida spp
Lipid formulation AmB:
 Intolerance to other antifungals
Fluconazole: 800mg stat and 400mg OD IV
or oral, is an alternative
 No H/O azole exposure
 Not colonised with azole-resistant
Candida spp
Echinocandins: Same dosage
• Daily bathing with chlorhexidine

Critically ill patients: Empiric Therapy
 Duration of Therapy: 2 weeks, according to clinical response
 Indications for discontinuation:
 No clinical response after 4-5 days
 No subsequent evidence of invasive candidiasis
 Negative non-culture based assay with high negative predictive value
(beta D glucan assay)

CNS Candidiasis
 Liposomal AmB with or without Flucytosine :
• Most preferred as initial therapy
 Fluconazole:
• Step-down therapy
 Source removal:
• Ventricular drains, shunts, stimulators etc
• If devices can not be removed, AmB deoxycholate should be injected into the ventricle
through the device
 Duration:
• Till the resolution of clinical signs and symptoms, CSF and radiological abnormalities

Intra-abdominal Infections
 Empiric antifungals are given in patients with risk factors
 Recent abdominal surgery
 Anastomotic leaks
 Necrotising pancreatitis
 Treatment is mainly surgical by drainage and debridement
 Antifungal regimen is the same with non-neutropenic
candidemia patients

Symptomatic Candida Cystitis/
Pyelonephritis
 Removal of urinary catheter
 Fluconazole susceptible isolate: Oral Fluconazole 200mg OD for 2 weeks
 Fluconazole resistant C. glabrata: AmB deoxycholate
 C. krusei: AmB deoxycholate
 AmB bladder irrigation for fluconazole resistant species like C. glabrata
and C. krusei
 Elimination of urinary tract obstruction, removal or replacement of
nephrostomy tubes is advised in Candida pyelonephritis

Candida Endophthalmitis
 Dilated ophthalmological investigation is advised in all cases
Candida chorioretinitis without
vitritis
Candida chorioretinitis with vitritis
Azole susceptible isolates:
Fluconazole or Voriconazole IV
Same antifungal regimen
PLUS
Intravitreal antifungals in all cases
Azole resistance:
Liposomal AmB and/ or oral
flucytosine
With macular involvement:
Intravitreal injection of AmB
deoxycholate or voriconazole
Duration: 4-6 weeks

IDSA Treatment Guidelines for
Invasive Aspergillosis

Invasive Aspergillosis (IA)
 Invasive pulmonary aspergillosis
 Invasive sinonasal aspergillosis
 Invasive Tracheobronchial aspergillosis
 Chronic necrotizing pulmonary aspergillosis
 Aspergillosis of the CNS
 Aspergillus endocarditis, pericarditis and myocarditis
 Aspergillus osteomyelitis
 Aspergillus infections of the eye
 Aspergillus peritonitis
 Renal aspergillosis

Susceptible patients
 Hospitalised allogenic hematopoietic stem cell
transplant (HSCT) recipients
 Patients receiving induction/re induction
regimens for acute leukemia
 On corticosteroids
 Solid organ transplant (SOT) patients
 Inherited or acquired immunodeficiencies
Patterson TF et al, Clin Infect Dis. 2016 Aug 15;63(4):433-42

Antifungal options we have
Drugs
Voriconazole
• Drug of choice for treatment and prophylaxis
for IA
• Therapeutic drug monitoring (TDM) is
recommended
Amphotericin B(AmB) • Used in resource limited settings
• Acts against other fungi too
Aerosolised AmB
• Prophylaxis against IPA in high-risk patients,
eg, prolonged neutropenia
Posaconazole • Prophylaxis in hematologic malignancies
Isavuconazole
• Better toxicity profile than voriconazole
• Limited studies
Echinocandins
• Not preferred as monotherapy
• Can be used in combinations

Therapeutic Drug Monitoring (TDM) & Interactions
 TDM is recommended during azole therapy to prevent toxicity, drug
interactions, diagnosis of breakthrough infections
 Azoles are inhibitors of CYP dependent liver enzymes and p-gp
membrane transporter
 Causes of toxicity
 Unpredictable metabolism due to polymorphisms of CYP2C19
 Narrow therapeutic index, esp of voriconazole
 Drug interactions
Levels  by azoles  Azole level
Cacineurin inhibitors
(cyclosporine,tacrolimus),
Corticosteroids
Rifampicin
Vincristine, Cyclophosphamide Anti retroviral drugs
Macrolies, Quinolones

Invasive Pulmonary Aspergillosis (IPA)
Treatment
Voriconazole
• Drug of choice for primary treatment
Liposomal AmB
or
Isavuconazole
• Alternate therapies
Echinocandins PLUS Voriconazole
• May be used in documented IPA
Duration:
• 6-12 weeks
• Depends on the degree and duration of immunosuppression
Drug regimen is same in paediatric patients

Prophylaxis of IA
 Indication:
Prolonged neutropenia (>10 days) and with risk factors for IA
 Drugs:
 Posaconazole: Drug of choice
 Voriconazole and/ or micafungin: equally effective
 Caspofungin: may be used
 Drug interactions should be considered due to concurrent use of
other interacting drugs in this patient group

Extrapulmonary Aspergillosis
Conditions Management
CNS Aspergillosis Voriconazole or AmB Lipid formulation
Endophthalmitis
Voriconazole oral or IV, Natamycin eye drops
PLUS
Voriconazole or AmB deoxycholate, intravitreal
Invasive fungal sinusitis Surgery and Voriconazole or Lipid AmB
Endocarditis, Myocarditis,
Pericarditis
Early surgery – to prevent embolisation
Voriconazole or Liposomal AmB initially, lifelong antifungal
prophylaxis after surgery
Osteomyelitis, septic
arthritis Surgery plus Voriconazole
Peritonitis Removal of peritoneal dialysis catheter plus Voriconazole
GI and Hepatobilliary Surgery and Voriconazole or Liposomal AmB
IA of ear Prolonged Voriconazole with surgery

Empiric Therapy
 Indication:
 High-risk patients with prolonged neutropenia (>10 days),
persistently febrile with broad-spectrum antibiotics
 Use of biomarkers (serum and BAL GM) is advised to
screen patients
 Drugs:
 Lipid AmB formulations and caspofungin are equally
effective

Salvage Therapy
 For patients with refractory or progressive IA
 Combination therapy:
 Antifungals chosen from different classes other than initial regimen class
 Reversal of underlying immunosuppression
 Surgical resection of necrotic areas, if possible
 Agents for salvage therapy:
 AmB, micafungin, caspofungin, posaconazole, itraconazole
 Azole salvage therapy – drug resistance should be considered

Mucormycosis
 Risk Factors:
 Uncontrolled DM and DKA
 HSCT
 Hematological malignancies
 Immunosuppressive drugs
 Major trauma or surgery
 Deferoxamine therapy
 Breakthrough infection during
therapy with voriconazole
 Disease Spectrum:
 Acute rhino-cerebral
mucormycosis
 Pulmonary mucormycosis
 Disseminated mucormycosis
These diseases are rapidly progressive and highly fatal even with treatment

Treatment: Mucormycosis
 Early diagnosis is the key to successful recovery
 Diagnosis is made usually made by direct demonstration of broad aseptate
hyphae in tissue samples
 High dose Amphotericin B is the drug of choice along with surgical
debridement
 Dosage: IV Liposomal AmB 1.5mg/Kg/day
 Total dose: 2-4g
 Alternative: Posaconazole, good choice

Cryptococcal Infections
 Cryptococcus neoformans causes meningitis in AIDS and
other immunosuprressed patients
 Highly fatal without treatment
 Diagnosis:
 India ink stain
 Latex agglutination test
 Culture
 It can also cause Pulmonary, Disseminated, Bone & Joint
infections

Treatment: Cryptococcal meningitis
 Induction therapy:
 Amphotericin B + Flucytosine x 2 weeks
 Consolidation therapy:
 Fluconazole x 8 weeks
 Maintenance therapy:
 Fluconazole x 6-12 months ( Lifelong in AIDS )

Summary
 Choice of antifungal agents is crucial for successful treatment
 Species level diagnosis of fungi is essential for appropriate choice
of drugs
 Candidemia carries high mortality, should be treated empirically in
ICUs
 Biomarkers like galatomannan and beta D glucan help in diagnosis
and monitoring of treatment in Invasive Fungal Infections
 Early initiation of AmB therapy is the key to recovery in
mucormycosis

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