2. References are from –
• Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by
the Infectious Diseases Society of America.
• An Official American Thoracic Society Statement: Treatment of Fungal Infections
in Adult Pulmonary and Critical Care Patients :2010.
• Antifungal Therapy; 1st edition; Mahmoud A. Ghannoum, John R. Perfect.
• The Washington Manual Of Critical Care, 3rd edition.
• Fishman's Pulmonary Diseases And Disorders, 5th edition.
• Murray & Nadel's Textbook of Respiratory Medicine, 6th edition.
• ICM journal of ESICM.
4. Fungal microbiology
• Yeast : characterised by Budding cells, pseduhyphae.
• Mold : true filamentous hyphae.
• Dimorphic : features of both.
5.
6. Fungalinfections in Indian ICU
2014data:
INDIA
Sites of isolation:
Blood, Body fluids [ascitic fluid, pleural fluid, CSF], Respiratory samples, Urine, Pus, FNAC and Surgical drain fluid
In-vitro data. Kindly correlate clinically.
Singh T, Kashyap AK, Ahluwalia G, Chinna D, Sidhu SS. Epidemiology of fungal infections in critical care setting of a
tertiary care teaching hospital in North India: a prospective surveillance study. J Clin Sci Res 2014;3:14-25.
7.
8.
9. ICUCandidemiain India vsother countries
India Other countries
Incidence/1000
ICU
6.51 cases 0.24 – 6.9 casesforAustralia,France,
admission Germany
34.3 casesfor SpainandArgentina
Candidemia pts Younger(49.7 59.0 – 66.2 years
years )
ICU– acquired Earlier(8 days) 11-15 days
candidemia EarlieronsetinAustralia& France
APACHEII score lower mean Higherscorein Spain(20.1),Argentina
(17.2) (20.1) & USA(18.6)
C.tropicalis 41.6% Lesscommon(5.6 – 12.0%)in
developed
C.glabrata 7.1% C.albicans(45.0-74.0)
C.glabrata(16.7-22.6)
Crudemortality 44.7% 35-75%
10.
11. Definition: Invasive candidiasis is an infection caused by a yeast (a type of
fungus) called Candida. Unlike Candida infections in the mouth and throat (also
called “thrush”) or vaginal “yeast infections,” which are localized to one part of the
body, invasive candidiasis is a serious infection that can affect the blood, heart,
brain, eyes, bones, or other parts of the body. (CDC)
Candida is commensal of Skin,GI tract, GU tract, Respiratory tract.
Invasive Fungal InfectionDiagnosis
12. Blood Culture:
• Gold standard
• Only diagnosticapproach that allows subsequentsusceptibility testing.
• Sensitivity = 50%
• They may be negative in cases of extremely low-level candidemia,
intermittent candidemia, deep-seated candidiasis without candidemia.
• Slow turnaround times (median time to positivity of 2–3 days, ranging from
1 to ≥7 days).
14. • Themajor benefit isnegative predictive value.
• β-D-glucan detection can identify cases of invasive candidiasis days to weeks
prior to positive blood cultures.
• Antifungal agents may reduce diagnostic sensitivity , but decreasing β-D-glucan
levels may also correlate with responses to antifungal therapy.
• The role of β-D-glucan testing of samples other than serum in the diagnosis of
invasive candidiasis is not established.
• Normal level = <60 pg/ml.
17. Galactomannan assay:
• It's a cell wall component of Aspergillus spp., Fusarium, Zygomycetes.
• The diagnosis of invasive aspergillosis is difficult, but recent studies
suggest utility of diagnostic aides that detect Aspergillus galactomannan
antigen in serum, or even bronchoalveolar lavage (BAL) fluid.
• Recently, strategies of pre-emptive therapy based on the detection of
Aspergillus galactomannan antigen or polymerase chain reaction (PCR)
testing on serial blood samples of high-risk patients have been suggested.
• Monitoring of serum galactomannan levels can be useful to judge
response of therapy and outcome.
• false-positive results with antibiotics, such as amoxicillin-clavulanate and
piperacillin-tazobactam.
• Sensitivity= 71% (serum); 76-88% (BAL)
• Specificity= 89% (serum); 87-100% (BAL)
19. • "Candida score" is an interesting tool to differentiate among ICU patients
who exhibit hospital-acquired severe sepsis or septic shock those would
benefit from early antifungal treatment (score > 3) from those for whom
invasive candidiasis is highly improbable (score ≤ 3).
23. Amphotericin B
• A polyene
• Insoluble in water
• Solubilized by sodium deoxycholate
• Most broadspectrumantifungal
• Once“gold standard”
• Pharmacokinetics
• Extensively tissue bound-
• Highest concentrations in liver, spleen, bone marrow with lessin kidneys
and lung.
• Half-life-
• Tissue ~15 days, Plasma ~5 days.
27. Preparation :
AmphoB should be prepared in 5%D only.
Dose:
• 0.5-0.7 mg/kg/d of AmB-d (preceded by a test dose of 1mg over 30min.)
• 3-5 mg/kg/d of liposomal AmB
Cost:
Aprox Rs. 17000/ day for liposomal form
29. Spectrum:
• Candida albicans
• Cryptococcus
• Coccidioidomycosis
• Less active - non-albicans candida
• C. krusei is intrinsically fluconazole resistant while C. glabrata has higher
minimum inhibitory concentration (MICs) and the ability to develop
resistance to all azoles as well as echinocandins, especially after
exposure.
Cost:
Rs. 200 / day aprox.
30. Voriconazole
Secondgeneration synthetic derivative offluconazole.
Spectrum-
• Candida
• Aspergillus
Dose -
400 mg BD for 1 day, then 200 mg BD.
Because of cyclodextrin accumulation in renal failure patient, IV voriconazole is contraindicated
in CrCL< 50 ml/min.
Oral voriconazole doesn't require dose adjustment in renal failure. But requires in hepatic failure.
Cost - Rs 1800/ day
31. Posaconazole
• Second generation.
• Treatment of oropharyngeal candidiasis.
• Prophylaxis of invasive Aspergillus, Candidiasis.
• No dose adjustment needed in renal, heparic failure.
• Contraindicated with drugs prolonging QTc.
• Dose : for oropharyngeal candidiasis - 100 mg BD for 1 day then 100 mg
OD for 13 days.
for prophylaxis - 200 mg TDS.
• Cost - Rs. 3000/ day.
32. Isavuconazole
• Treatment of invasive aspergillosis and mucor (Mucorales,
Rhoizopus, Mucormycetes).
• Dose - 372 mg TDS for 6 doses, then 372 mg OD.
• No dose adjustment needed in renal, heparic failure.
• Contraindicated with CYP450 substrates.
33. Echinocandin
• Includes Caspofungin, Micafgin, Anidulafungin.
• These are fungicidal.
• Minimal side effects and drug interaction.
• All echinocandins are given IV once daily.
• No echinocandin requires dose adjustment in renal failure.
• Caspofungin requires dose adjustment in hepatic failure.
• Spectrum : All Candida and Aspergillus spp.
• Dose : Caspofungin 70 mg loading then 50 mg OD.
Micafungin 100 mg OD.
Anidulafungin 200 mg loading then 100 mg OD.
• Cost : Caspofungin = Rs. 13000/d; Micafungin = 12000/d, Anidulafungin
= 20000/d.
34.
35.
36.
37.
38. Guideline for the Management of Candidiasis: 2016 Update
IDSANON NEUTROPENIC NEUTROPENIC
1st Choice ECHINOCANDIN (strong
recommendation; high-quality
evidence)
ECHINOCANDIN
Alternative FLUCONAZOLE (oral/IV) (800
mg loading then 400 mg OD)
who are not critically ill and who
are considered unlikely to have a
fluconazole-resistant Candida
species (strong recommendation;
high-quality evidence).
LIPOSOMAL AmB (3-5 mg/kg/d)
intolerance, limited
availability, or resistance to other
antifungal agents (strong
recommendation; high-quality
evidence).
LIPOSOMAL AmB (strong
recommendation; moderate-
quality evidence) /
FLUCONAZOLE (weak
recommendation; low-quality
evidence)
39. NON NEUTROPENIC NEUTROPENIC
Drug sensitivity testing Azole susceptibility for all
bloodstream and other clinically
relevant Candida isolates.
Echinocandin susceptibility test in
patients who have had prior
treatment with an echinocandin and
among those who have infection
with C. glabrata or C. parapsilosis
Transition from an echinocandin/
AmB to fluconazole
clinically stable, have isolates that
are susceptible to fluconazole (eg,
C. albicans), and have negative
repeat blood cultures following
initiation of antifungal therapy
(strong recommendation; moderate-
quality evidence).
Same
Role of Voriconazole Voriconazole is recommended as
step-down oral therapy for selected
cases of candidemia due to C.
krusei.
First line in C. krusei.
step down therapy.
When additional mold coverage
needed.
40. NON NEUTROPENIC NEUTROPENIC
Duration of antifungal 2 weeks after documented
clearance of Candida species from
the bloodstream and resolution of
symptoms attributable to
candidemia
2 weeks after documented
clearance of Candida from the
bloodstream,
provided neutropenia and
symptoms attributable to
candidemia have resolved.
Follow up Blood culture every day or every other day to
establish the time point at which
candidemia has been cleared
(strong recommendation; low
quality evidence).
Dilated Ophthalmologic exam.
All patient within 1 week of
diagnosis.
should be performed within the first
week after recovery from
neutropenia
CVC removal should be removed as early as
possible
Catheter removal should be
considered on an individual basis
because non catheter sources
predominte.
41. Empiric Treatment for Suspected Invasive Candidiasis in
Nonneutropenic Patients
• Should be based on presence of risk factors + persistent unexplained
fever + biomarkers positive with/without culture data from nonsterile site.
• should be started as soon as possible in patients who have risk factors
and who have clinical signs of septic shock .
• 1st choice : Echinocandin.
• alternative : Fluconazole (no recent azole exposure and are not colonized
with azole-resistant Candida species), Liposomal AmB (intolerance to
other antifungal agents).
• Duration is same as documented candidemia.
42. • For patients who have no clinical response to empiric antifungal therapy
at 4–5 days and who do not have subsequent evidence of invasive
candidiasis after the start of empiric therapy or have a negative non-
culture-based diagnostic assay with a high negative predictive value,
consideration should be given to stopping antifungal therapy.
43. Should Prophylaxis Be Used to Prevent Invasive Candidiasis
in the ICU
(Only risk factors are present)
• Fluconazole, 800-mg loading dose, then 400 mg daily, could be used in
high-risk patients in adult ICUs with a high rate (>5%) of invasive
candidiasis (weak recommendation; moderate-quality evidence).
• Alternative : Echinocandin (weak recommendation; low-quality evidence).
• Daily bathing of ICU patients with chlorhexidine is recommended.
44. Treatment for Intra-abdominal Candidiasis
• Empiric antifungal therapy in recent abdominal surgery, anastomotic
leaks, or necrotizing pancreatitis (strong recommendation; moderate-
quality evidence).
• Treatment of intra-abdominal candidiasis should include source control,
with appropriate drainage and/or debridement.
• 1st choice : Echinocandin.
• Alternative : Fluconazole/ Liposomal AmB
• Duration is determined by adequacy of source control and clinical
response.
45. Does the Isolation of Candida Species From the Respiratory
Tract
Require Antifungal Therapy?
Rarely needed (strong recommendation; moderate-quality evidence).
46. Treatment for Central Nervous System Candidiasis
• Start with liposomal AmB, 5 mg/kg daily, with or without oral flucytosine,
25 mg/kg 4 times daily.
• Switch to fluconazole (400–800 mg/d) after the patient has responded to
initial treatment.
• Therapy should continue until all signs and symptoms and CSF and
radiological abnormalities have resolved.
• Infected CNS devices should be removed.
47. Treatment for Urinary Tract Infections Due to Candida
Asymptomatic
Candiduria
Symptomatic Candida
Cystitis
Symptomatic Ascending
Candida Pyelonephritis
Foley's Catheter removal YES YES YES
Fluconazole sensitive
Candida
NO antifungal except -
• in neutropenia (same
as candidemia) and,
• patients who will
undergo urologic
manipulation (Oral
Fluconazole/ AmB
before and after
procedure).
oral fluconazole, 200 mg
daily for 2 weeks is
recommended
oral fluconazole, 200–400
mg daily for 2 weeks
C. glabrata AmB deoxycholate, 0.3–0.6
mg/kg daily for 1–7 days
AmB deoxycholate, 0.3–0.6
mg/kg daily for 1–7 days
C.krusei AmB deoxycholate, 0.3–0.6
mg/kg daily, for 1–7 days
AmB deoxycholate, 0.3–0.6
mg/kg daily for 1–7 days
Other management AmB deoxycholate bladder
irrigation, 50 mg/L sterile
water daily for 5 days
nephrostomy tubes or
stents replacement
48.
49. Invasive Pulmonary Aspergillosis
• Aspergillus spp. are the most commonly isolated invasive molds.
• Important spp. in ICU are A. fumigatus, A. flavus, and A. niger. A. terreus.
• In tissues, aspergilli may be seen as septate hyphae.
50. • patients without the traditional risk factors for Aspergillus infection,
particularly in ICU populations, are being increasingly encountered. e.g.-
COPD, post-influenza, cirrhosis, alcoholism.
51.
52. Diagnosis
Clinical features:
• fever (unless the patient is receiving corticosteroids),
• nonproductive cough
• Pleuritic chest pain and progression to pneumonia occur within 1 to 2
days
• Cavitation tends to occur in patients if immunosuppression is decreased (
clinical pearl - CAVITATION NEEDS IMMUNITY),
• massive hemoptysis
• Extrapulmonary sites may be involved including the highly vascular
organs such as the kidneys, liver, spleen, and central nervous system
53. Serum/ BAL fluid galactomannan:
• The galactomannan assay is relatively specific for invasive aspergillosis,
in the right clinical context.
• false-positive results have been described in patients receiving β-lactam
antibiotics, particularly piperacillin–tazobactam, as well as in those
ingesting certain cereals, pastas, nutritional supplements, and soy sauce,
blood transfusion.
• BAL GM has improved sensitivity compared to serum GM in high-risk
patients with IPA.
54. Culture/HP exam of tissue:
• Culture of Aspergillus spp in combination with the histopathologic
demonstration of tissue invasion by hyphae provides definitive evidence
of invasive aspergillosis
• However, sample collection specially biopsy is often not feasible due to
higher risk factors for the procedure.
• Takes more time.
55. • A rational first step to establishing the diagnosis of invasive aspergillosis
involves the use of noninvasive modalities- serum biomarkers
(galactomannan and beta-D-glucan), and obtaining sputum and/or BAL
specimens for fungal staining and culture. When BAL is performed, a
sample should be sent for galactomannan antigen testing.
• Patients with clinical and radiographic findings that are suggestive of an
invasive fungal infection but in whom both the serum galactomannan
assay and fungal stain and culture of the sputum are negative (or are not
able to be obtained) should ideally undergo bronchoscopy with BAL.
• Lung biopsy should be performed if feasible.
56. Aspergillus lateral-flow-device (LFD) test
• A new point-of-care test for IPA diagnosis developed at the University of
Exeter, United Kingdom.
• This single-sample test, based on the detection of Aspergillus antigen by
the monoclonal antibody (MAb) JF5, can be performed easily in every
laboratory using BAL fluid or serum specimens, and it has a time to
results of approximately 15 min.
• Recent studies have shown the immense potential of this test with human
BAL fluid and serum samples
58. Radiology:
• CXR are not sensitive in detecting early forms of bronchopulmonary IPA,
and up to 10% of patients with proven IPA have “normal” chest
radiographs.
• High-resolution CT is the inv. of choice---- HALO sign.
• This halo sign correlates with haemorrhage and oedema surrounding an
infarct caused by thrombosis and is highly suggestive of acute IPA.
• CT must be performed within 5 days of the onset of infection, because
more than 75% of initial halo signs disappear within a week.
• Late radiological feature -----AIR CRESCENT sign.
61. Treatment
Prophylaxis in High-Risk Patient:
• HEPA face mask
• Posaconazole - 200 mg oral suspension (5ml) TDS till recovery from
neutropenia/ immunosuppression.
• Voriconazole
62.
63.
64. Immunomodulatory therapy:
• Reversal of immunosuppression, such as withdrawal of corticosteroids,
results in better outcomes in allogeneic stem cell transplant patients, but
is often not feasible.
• Immunotherapy, such as with granulocyte colony-stimulating factor (G-
CSF) or granulocyte/macrophage colony-stimulating factor (GM-CSF) is
often used.
• However, exuberant immune responses during the course of cytokine
therapy may lead to tissue damage and potential worsening of disease.
65. Duration:
• Therapy is often prolonged, lasting several months to more than a year,
with duration individualized to an individual patient’s clinical response.
• Prerequisites for discontinuing treatment include clinical and radiographic
resolution, microbiologic clearance, and reversal of immunosuppression.
66. Pneumocystis Pneumonia
HISTORY AND BACKGROUND:
• The cyst form of Pneumocystis was first described in 1909 by the famous
parasitologist, Chagas and in 1910 by Carinii.
• Initially it was thought to be a parasite.
• By the mid-1990s genetic diversity among isolates of Pneumocystis from
different host species had been described suggesting that the organism
was a fungus.
• In humans and animals, three forms of the organism have been identified:
trophozoite, cyst, and sporozoite (or intracystic bodies).
67.
68. CLINICAL PRESENTATION:
• The hallmark of infection due to P. jiroveci is the presence of marked
hypoxemia, dyspnea, and cough out of proportion to physical or radiologic
findings.
• constitutional symptoms such as weight loss can be prominent.
• PCP is generally acute-to-subacute in development.
• In the organ transplant recipient, PCP most frequently occurs
approximately 2 to 4 months after the initiation of immune suppression or
during periods of increased immune suppression (pulsed corticosteroids,
antilymphocyte therapies,CMV infection).
69. EXTRAPULMONARY PNEUMOCYSTOSIS
• Metastatic infections have been most commonly observed in patients with
untreated AIDS.
• Incidence = <1%.
• It has been thought that susceptible AIDS patients might be more likely to
develop extrapulmonary disease while on inhaled pentamidine
prophylaxis since this modality of prevention is largely lung-specific and
does not achieve significant systemic drug levels like TMP-SMX.
70. • Sites - liver, spleen, eye, ear, lymph nodes, thymus, skin, mastoids,
ascites, gastrointestinal tract and omentum, pleura, kidney, bone marrow,
pancreas, and adrenal glands.
• The presentation of extrapulmonary infection is generally a mass lesion
inaffected organ with accompanying fever, sweats, and malaise.
• CT) scan, many nonenhancing, low-attenuation masses, often with
necrosis and/or hemorrhage, may be seen in the liver or spleen.
• Histopathology will demonstrate granulomas with giant cells, calcification,
or cavities.
71.
72. Radiology
The chest radiograph plays a central role in the diagnosis of PCP.
• diffuse interstitial opacity on chest radiograph.
• fine, bilateral, perihilar, diffuse infiltrates
• progress to an interstitial alveolar butterfly pattern;
• from the hilar region, the infiltrates often spread to the apices or bases.
• It is followed by progressive consolidation with air bronchogram.
• Pneumothorax
73.
74. CT scan thorax
• Ground glass opacity in perihilar distribution.
• reticular opacities or septal thickening may also be present; a crazy
paving pattern may, therefore, be seen .
• pneumatoceles
Patients on prophylaxis have upeer zone predilection compared to those not
on prophylaxis who have lower zone predilection (because lung apices are
poorly ventilated)
79. SPUTUM examination:
• The gold standard for the diagnosis of PCP remains the identification of
characteristic organisms on examination of pulmonary specimens.
• The organism cannot be routinely cultured in the clinical laboratory, and
thus direct visualization and correct identification are required.
81. Staining method:
• For Trophozoite & Sporozoite : Giemsa or Diff-Quik.
• For Cyst : Siver or Toluidine blue O
• cysts represent only 5% to 10% of the organism burden.
• direct immunofluorescent staining with monoclonal antibodies- method of
choice now.
Nested PCR:
• Detects areas of rRNA, MSG gene.
• High senstivity, low specificity....it can't differentiate colonisation with
disease.
82. Histopathology:
• In the adult, the disease is predominantly alveolar.
• The airspaces are filled with a foamy eosinophilic exudate and appear
honeycombed.
• alveolar interstitium is infiltrated by polymorphonuclear leukocytes and
lymphocytes.
• By light microscopy, trophozoites predominate numerically (in more than
90% of the organisms), but cysts are more readily identified.
83. Whom to start prophylaxis
• Patients with risk factors for PJP.
• For patients with HIV infection, CD4+ T cell counts< 200 cells/μL are an
indication to start prophylaxis.
• For patients with HIV infection who are not receiving HAART, oral
candidiasis or prior PCP also is an indication for chemoprophylaxis,
regardless of CD4+ T cell count. For such patients not receiving ART, any
prior episode of an AIDS-defining illness or pneumonia should encourage
the use of chemoprophylaxis.
84. Duration:
• AIDS (on HAART) - undetectable viral load and CD4 counts> 200
cells/mm3 for consecutive 3 months.
• Stable transplant patient - for atleast initial 6 months following transplant.
• Lung transplant/ GVHD- life long.
87. Duration:
• 14 - 21 days.
• Residual organisms persist after treatment for a number of months, but
the role of these organisms in recrudescent or persistent infection is not
clear and may just reflect nonviable microbes.
Adjunctive therapies-
• Aggressive supportive care, corticosteroid and, colony-stimulating factors
(CSFs), ECMO.
• The use of corticosteroids (prednisone, 40–60 mg three or four times a
day, orally or equivalent intravenously) in the first 72 hours after admission
may reduce pulmonary inflammation to a degree sufficient to avoid
intubation.