A detailed discussion and description on fungal diseases and management. The focus is kept on those facts which frequently come across an intensivist but it is also important for the Internist.
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Fungal diseases intensivist should know
1. Fungal diseases
Intensivist should know
Abid Alwan
MD, JBIM, SF-CCM
Intensive Care Services
Prince Sultan Military Medical City
Muhammad Asim Rana
BSc, MBBS, MRCP, MRCPS, FCCP, EDIC, SF-CCM
Department of Critical Care Medicine
King Saud Medical City
4. Candida Species
• Albicans
Most common if patient not on azole prophylaxis
• Glabrata
Azole resistant strains selected out by azole prophylaxis
• Paraspillosis
Skin flora-most often seen in NICU
• Krusei
Inherently resistant to azole
5. Candida Species
• The clinical manifestations range from local
mucous membrane infections to widespread
dissemination with multisystem organ failure.
• In the neutropenic host or the severely ill
patients, widespread visceral dissemination
occurs when Candida species gain access to
the bloodstream…… Candidemia !!!
6. Disseminated candidiasis
• This is frequently associated with multiple
deep organ infections or may involve single
organ infection.
• Unfortunately, blood cultures are negative in
up to 40-60% of patients with disseminated
candidiasis.
7. Disseminated candidiasis
• The history of a patient with presumptive
disseminated candidiasis reveals a fever
unresponsive to broad-spectrum
antimicrobials and negative results from blood
culture.
• Physical examination reveals fever (may be the
only symptom) with an unknown source and
associated sepsis and septic shock.
8. Terminology
• Candidemia
– Presence of Candida species in the blood.
• Candida in a blood culture should never be
viewed as a contaminant and should always
prompt a search for the source of infection.
• Invasive Candidiasis
– hematogenous spread to multiple viscera
– (e.g. eye, kidney, heart valves, brain)
9. Clinical clues
To hematogenous spread of Candida
• Characteristic eye lesions
– chorioretinitis with or without vitritis
• Skin lesions
– appear suddenly as clusters of painless pustules
on an erythematous base
• muscle abscesses
10. EPIDEMIOLOGY
• Fourth most common cause of nosocomial
bloodstream infections, accounting for 9
percent of cases in a national survey of United
States hospitals from 1995 to 2002
• Most often part of the host's endogenous
flora
11. EPIDEMIOLOGY
• C. albicans is the most common cause of
candidemia.
• C. glabrata was responsible for 26 %.
• C. parapsilosis 16 percent.
• C. tropicalis 8 %
• C. krusei 3 %
Knowing the prevalence of the non- albicans
Candida species is important because
susceptibility to antifungal agents varies among
the species
13. Invasive Candidiasis in the ICU
• Common in the ICU (9.8/1000 admissions) with
high morbidity (increased LOS ~22 days) &
mortality (~ 30-40%) resulting in increased cost
(~ $44,000/ episode).
• Difficult to diagnose (cultures positive in only ~
50%).
14. Invasive Candidiasis in the ICU
• We can define ICU risk factors for candidiasis
and target the population at highest risk with
empiric Rx.
• Recent increase in Candida spp. resistant to
Diflucan.
• Advances in antifungal therapy have resulted in
agents, like
– echinocandins and triazoles, with high activity, a
broad spectrum, and low toxicity ideal for empiric
therapy and combination therapy options.
15. Risk factors
• Patients in the intensive care unit (ICU) and those
who are immunocompromised are most at Risk
• factors for nosocomial candidemia :
Hickman catheters (adjusted odds ratio OR 9.5).
gastric acid suppressants (adjusted OR 6.4).
ICU admission (adjusted OR 6.4).
nasogastric tube (adjusted OR 3.7).
administration of antibiotics (adjusted OR 1.5 per
antibiotic given).
16. PATHOGENESIS
Three major routes to the bloodstream:
• Through the gastrointestinal tract mucosal
barrier ( the most common mechanism)
• Via an intravascular catheter
• From a localized focus of infection, such as
pyelonephritis
17. Colonization
• It’s an independent predictor of candidemia.
• Although colonization alone does not predict
which patients will develop fungemia,
candidemia is very uncommon in a patient
who is free of colonizing yeasts.
23. Question
A serum beta glucan test would be expected to
be negative for which of the following
• a) Candida albicans
• b) Candida glabrata
• c) Aspergillus niger
• d) Mucor
• e) Histoplasma capsulatum
24. Diagnosis of Candidemia
• Blood culture
Routine cultures in 24-72 hours , 50% sensitivity.
• Serology and Bronchoalveolar Lavage.
Beta glucan: sensitive(70-85%) but not specific for all
fungi EXCEPT MUCOR-not specific for
Candida
Galactomannan: ”Aspergillus Test”
• positive for molds, not yeast and NOT Mucor
• Physical exam
• Imaging
25. Significance of Candida
• Blood :
50% sensitivity
Always merits treatment
Catheters should always be replaced.
• Respiratory:
“Never” merits treatment.
• Urine:
Usually insignificant.
• Sterile fluids or tissue:
Obviously needs therapy.
26. Therapy of Invasive Candidiasis
in the ICU
• A definitive diagnosis of IC may be delayed when
the clinical and laboratory tools readily available
to clinicians are used to assess patients for
Candida infection.
• A delay in diagnosis will unfortunately result in a
delay in initiation of antifungal therapy, which is
associated with increased mortality*.
• Therefore, in the patient with suspected Candida
infection, treatment may need to be initiated on
the basis of individual patient factors before a
definitive diagnosis is made.
*Morrel M et al. 2005. Antimicrob Agents Chemother. 49(9): 3640-5.
*Garey K et al. 2006. Clin Infect Dis. 43: 25-31.
27. Can we wait for the blood culture
results in candidemia?
• Retrospective cohort analysis 1/2001-12/2004:
N=157 patients with candidemia.
• Delay in empiric Rx of candidemia till after
blood cultures turn positive resulted in higher
mortality.
• Start of anti-fungal Rx >12 hrs of drawing a
blood culture that turns positive had AOR=
2.09 for mortality, p=0.018.
Morrel M et al. 2005. Antimicrob Agents Chemother. 49(9):3640-5
28. Candida prophylaxis in the Surgical ICU
(patients with high risk for candidemia)
• Eggiman et al. 1999. CCM 27: 1066-1072.
– Fluconazole reduced Candida peritonitis and colonization in 43 patients
with complicated GI surgeries. High risk patients.
• Pelz et al. 2001. Ann Surg. 233: 542-548.
– Fluconazole reduced candida infection in critically ill surgical patients in
SICU > 3 days. No mortality benefit.
– Predictors included: APACHE II score, fungal colonization, TPN, days to first
dose of prophylactic drug.
• Paphitou et al. 2005. Med Mycol. 43(3):235-43.
– 327 patients in SICU > 3 days were reviewed to identify predictive factors.
– Combination of DM, HD, TPN, broad-spectrum antibiotics had an invasive
candidiasis rate of 16.6% versus a 5.1% rate for patients lacking these
characteristics (P = 0.001).
29. Candida Prophylaxis in MICU & SICU
(MV > 48h & expected LOS > 72h)
Incidence of IC=5.8%
Incidence of IC=16%
Garbino et al. Intensive Care
Med. 2002;28:1708-17
30. Summary (Candida Prophylaxis)
• Prophylaxis is effective in the highest risk
patients.
• Prophylaxis reduces the incidence of IC.
• A positive impact on mortality has not been
shown except in severely
immunocompromised hosts (neutropenia,
BMT, or solid organ transplantation).
• Distinction between prophylactic &
preemptive therapy needed specially in ICU.
Risk ? Dose?.
31. Azoles
• Floconazole
• approved (FDA) in 1990.
• The azoles work primarily by inhibiting the
cytochrome P450-dependent enzyme
lanosterol 14-alpha-demethylase.
• Some laboratories only screen C. glabrata
isolates for susceptibility to fluconazole
because this species has varying susceptibility.
32. Azoles
• Voriconazole superior to Floconazole
• However, cross-resistance between
fluconazole and voriconazole is seen
frequently, especially with C. glabrata.
• Voriconazole has significantly greater in vitro
activity against C. krusei isolates compared
with fluconazole,
33. Azoles
• Posaconazole only as an oral.
• It is approved for use as a prophylactic agent
for fungal infections
– in allogeneic hematopoietic cell transplant
recipients with graft-versus-host disease
– in patients with prolonged neutropenia due to
chemotherapy for hematologic malignancies.
– for oropharyngeal candidiasis
– not for systemic candidiasis.
34. Azoles
• Itraconazol:
• is sometimes used for mucosal candidiasis,
but is not used for systemic infections
35. Azoles
Pfaller:
• 610 isolates of C. glabrata : Sensitivity (MIC ≤ 1 μg/ml)
– Posaconazole : 85. 4%
– Ravuconazole : 90. 7%
– Voriconazole : 92.8%
• 46 fluconazole – resistant isolates of C. glabrata
– Posaconazole : 4%
– Ravuconazole : 8.7%
– Voriconazole : 13%
• Voriconazole Rx : potential for the emergence of
voricanazole-resistant Candida glabrata
36. Echinocandins
• Caspofongin, Anidulafungin, and Micafungin
• It’s noncompetitive inhibitors of the synthesis
of 1,3-beta-D-glucan, which is an integral
component of the fungal cell.
• Excellent activity against most Candida
species.
• Favorable toxicity profiles.
37. Echinocandins
• Approved for the treatment of candidemia and
other forms of invasive candidiasis.
• Preferred over azoles for the initial treatment of
candidemia if C. glabrata or C. krusei is identified
or suspected.
• Adverse effects are generally mild and include
– fever
– thrombophlebitis
– Headache
– elevated aminotransferases.
38. Amphotericin B
• A polyene antifungal agent that disrupts
fungal cell wall synthesis because of its ability
to bind to sterols, primarily ergosterol, which
leads to the formation of pores that allow
leakage of cellular components.
• Amphotericin B deoxycholate, which was the
standard drug for decades, demonstrates
rapidly cidal in vitro activity against most
species of Candida.
39. Amphotericin B
• It is also associated with significant nephrotoxicity.
• This has led to the development of various lipid-based
derivatives, including
• Liposomal Amphotericin B
• Amphotericin B lipid complex (ABLC).
• Amphotericin B colloidal dispersion (ABCD) is
used infrequently, in part because it causes more
infusion-related reactions than Amphotericin B
deoxycholate.
• These lipid-based compounds have much less
toxicity than Amphotericin deoxycholate but are
significantly more expensive.
40.
41. Factors to be considered
• History of recent azole exposure
• Prevalence of different Candida species and current
antifungal susceptibility data in the clinical unit and
medical center
• Severity of illness
• Relevant comorbidities that increase the risk
of Floconazole -resistant Candida species (e.g.,
neutropenia )
• Evidence of involvement of the central nervous system,
cardiac valves, eyes, and/or visceral organs
• History of intolerance of to an antifungal agent
42. RECOMMENDATIOS
for treatment of candidemia
• Non-neutropenic patients :
If clinically stable, who have not been
exposed to recent azole therapy, and who are in
clinical units or medical centers in which C.
glabrata or C. krusei are uncommonly isolated
(<15 percent of all species causing candidemia),
the initial therapy with Fluconazole rather than
an Echinocandins.
43. RECOMMENDATIONS
for treatment of candidemia
• In non- neutropenic patients with moderately
severe or severe infections and/or who are at
increased risk of C. glabrata or C. krusei
infection, we favor an Echinocandins and we not
use Floconazole as initial therapy, prior to the
identification of the causative species.
• However, in patients who have documented C.
glabrata infection, who are already improving
clinically on fluconazole or Voriconazole, and
whose follow-up blood cultures are negative,
continuing with the azole is reasonable.
44. Aspergillosis
• The term "aspergillosis" refers to illness due to
allergy, airway or lung invasion, cutaneous
infection, or extrapulmonary dissemination
caused by species of Aspergillus, most
commonly A. fumigatus, A. flavus, and A.
terreus
45. RISK FACTORS
Underlying conditions that compromise pulmonary
and systemic immune responses to inhaled
Aspergillus.
Classic risk factors include:
• Severe and prolonged neutropenia
• Receipt of high doses of glucocorticoids
• Chronic impaired cellular immune responses
– Immunosuppressives administered to treat autoimmune
diseases and to prevent organ rejection, and AIDS
46. CLINICAL FEATURES
Invasive aspergillosis most frequently occurs
in the lungs or sinuses after inhalation of
conidia, although, less commonly, disease can
spread from the gastrointestinal tract, or
result from direct inoculation into the skin.
47. CLINICAL FEATURES
PULMONARY
• Fever, chest pain, shortness of breath, cough,
and/or hemoptysis.
• The classic triad that has been described in
neutropenic patients with pulmonary
aspergillosis is
– fever
– pleuritic chest pain
– hemoptysis
48. CLINICAL FEATURES
PULMONARY
• Chest x-ray is insensitive for detecting the earliest
stages
• CT scans abnormality is variable, depending upon the
host and the type of disease:
– bronchopneumonia
– angioinvasive aspergillosis,
– Tracheobronchitis
– chronic necrotizing aspergillosis.
- small nodules (<1 cm) were most common (43 %).
- consolidation (26 %).
- large nodules (masses, 21 %).
- peribronchial infiltrates (9 %).
49. CLINICAL FEATURES
PULMONARY
In neutropenic patients, in
whom the initial findings
typically include nodules that
have surrounding ground glass
infiltrates (halo sign), reflecting
hemorrhage into the area
surrounding the fungus.
These nodules typically
enlarge, even during
appropriate therapy, and may
eventually cavitate, producing
the air-crescent sign
50. CLINICAL FEATURES
Tracheobronchitis
• Most often described in lung transplant
recipients and patients with AIDS.
• Affected patients typically present with
prominent dyspnea, cough, and wheezing;
they occasionally expectorate intraluminal
mucus plugs.
• Chest imaging may be normal or reveal areas
of airway thickening, patchy infiltrates,
consolidation, or centrilobular nodules.
51. CLINICAL FEATURES
Disseminated infection
• Disseminated infection — In the presence of
angioinvasive disease, Aspergillus spp can
disseminate beyond the respiratory tract to
multiple different organs, including the skin,
brain, eyes, liver, and kidneys.
• Disseminated infection is associated with a
very poor prognosis.
52. CLINICAL FEATURES
Rhinosinusitis
• In the paranasal sinuses, aspergillosis can present in an
identical fashion to mucormycosis. However,
rhinocerebral aspergillosis is usually seen in neutropenic
patients, whereas mucormycosis more often occurs in
those with diabetes mellitus.
• nasal congestion, fever, and pain in the face and around
the eye are common presenting features.
• If the orbit becomes involved, additional symptoms may
include blurred vision, proptosis, and chemosis. The
infection can also extend locally into the vasculature and
the brain, leading to cavernous sinus thrombosis and a
variety of central nervous system (CNS) manifestations.
53. CLINICAL FEATURES
Rhinosinusitis
• Imaging findings may be subtle and can
include focal soft tissue lesions, subtle focal
bony erosions, focal enhancement of the
sinus lining on magnetic resonance imaging or
focal hypodense areas on computed
tomography scan .
• Biopsy is necessary to establish the diagnosis;
multiple biopsies are sometimes necessary
54. CLINICAL FEATURES
Chronic necrotizing
chronic cavitatry pulmonary aspergillosis
• Patients who have underlying chronic lung
disease are at risk for indolent forms of
pulmonary aspergillosis, characterized by
cavities or infiltrates.
• Presumably, the slowly progressive nature of
this infection is a function of the host immune
response, which is enough to hold the
organism in check, but not to eliminate it.
55. CLINICAL FEATURES
Chronic necrotizing and chronic
cavitarty pulmonary aspergillosis
• Cough, weight loss, fatigue, and chest pain
are common, and the chest x-ray shows a
slowly progressive lesion, which can be better
defined by CT scanning. However,
interpretation of radiologic studies may be
complicated by the presence of concomitant
lung disease, since this is the setting in which
chronic invasive aspergillosis usually occurs.
56. CLINICAL FEATURES
Central nervous system
• (CNS) aspergillosis may occur in the setting of
disseminated infection, as well as from local
extension from the paranasal sinuses. Patients
with CNS involvement with Aspergillus spp may
present with seizures or focal neurological signs.
• * very poor prognosis.
57. CLINICAL FEATURES
Central nervous system
• In a study of the computed tomography
and/or magnetic resonance imaging findings
associated with CNS aspergillosis, three
patterns were observed :
• A- Ring-enhancing lesions consistent with
brain abscesses .
• B- Cerebral cortical and subcortical infarction,
with or without superimposed hematomas .
• C- Mucosal thickening of a paranasal sinus
with secondary intracranial dural
enhancement consistent with direct extension
from the sinuses .
58.
59.
60.
61. CLINICAL FEATURES
Endophthalmitis
• Involvement of the deep structures of the eye results
not only from hematogenous spread. In other
patients, corneal infection or direct inoculation
following trauma is the genesis of infection . Patients
present with eye pain and visual changes .
• Progressive infection is characterized by destruction
of multiple components of the eye. The outcome is
usually poor with loss of useful vision in the affected
eye, and a requirement for enucleation in some
cases.
62. CLINICAL FEATURES
Endocarditis
• Aspergillus spp are second only to Candida spp
as a cause of fungal endocarditis .
• This infection occurs primarily in patients with
prosthetic heart valves. In many patients,
infection occurs at the time of surgery, with the
fungus contaminating the surgical site. Patients
may present at any time postoperatively.
• Other patients at risk for the development of
Aspergillus endocarditis include patients with
indwelling central venous catheters and
intravenous drug users.
63. CLINICAL FEATURES
Endocarditis
• Patients typically present with fever and
embolic phenomena. Blood cultures are rarely
positive, even when a fungal isolator system is
used. Microscopic examination of an embolus
will reveal the typical hyphae suggestive of
aspergillosis, but definitive microbiologic
diagnosis depends upon culture of the
organism.
• The prognosis of Aspergillus endocarditis is
poor. Even with combined medical and
surgical therapy, the mortality rate has
approached 100 percent
64. CLINICAL FEATURES
Cutaneous Aspergillosis
• A healthy hosts can develop cutaneous disease in
surgical wounds. While burn victims, neonates, and
solid organ transplant recipients tend to develop
primary cutaneous disease in the presence of
prolonged local skin injury, patients with hematologic
malignancies and hematopoietic cell transplant
recipients more frequently develop disease due to
contiguous or blood-borne invasion.
• Diagnosis can only be verified by skin biopsy,
which should be taken from the center of the lesion
and reach the subcutaneous fat.
65. CLINICAL FEATURES
Gastrointestinal aspergillosis
• Aspergillosis can involve the (GI) tract,
causing focal invasion as a primary site of
inoculation and presenting as typhlitis, colonic
ulcers, abdominal pain, and/or GI bleeding .
Direct inoculation from the GI tract is likely,
with risk factors including neutropenia, receipt
of glucocorticoids, and mucosal breakdown
(mucositis).
66. Diagnosis of invasive aspergillosis
• It is based upon both isolating the organism
(or markers of the organism) and the
probability that it is the cause of disease.
• Culture in combination with evidence of
tissue invasion on histopathology, or culture
from a normally sterile site, provides the most
certain evidence of invasive aspergillosis
67. Diagnosis of invasive aspergillosis
• Direct examination of respiratory specimens:
• Gomori methenamine silver can be used to stain
cytology preparations. Organisms can be
observed as narrow (3 to 6 microns wide),
septated hyaline hyphae with acute angle (45°)
branching .
• However, several filamentous fungi, including
Scedosporium spp and Fusarium spp, have similar
appearances to Aspergillus spp on direct
microscopy.
68. Diagnosis of invasive aspergillosis
• CULTURE:
• Often visible in culture within one to three
days of incubation.
• In multicenter surveillance studies only 25 to
50 percent of hematopoietic cell transplant
recipients who met criteria for invasive
aspergillosis based upon galactomannan
antigen results had positive cultures
69. Diagnosis of invasive aspergillosis
• Galactomannan antigen detection:
• galactomannan antigen can be detected in the
serum before the presence of clinical signs or
symptoms
• False positive serum results have been
demonstrated in patients who are receiving
certain beta-lactam antibiotics, especially
PIP/TAZO.
• False positive results may be seen with infections
caused by organisms that share cross-reacting
antigens, (eg, Fusarium species , Histoplasma
capsulatum ).
70. Diagnosis of invasive aspergillosis
• Galactomannan antigen detection
• A meta-analysis that included 27 studies with
a total of 4000 patients (mainly with
hematologic malignancies), reported that
overall sensitivity and specificity of the
galactomannan antigen assay for proven
invasive aspergillosis were 71 percent (95% CI
68-74 percent) and 89 percent (95% CI 88-90
percent), respectively
71. Diagnosis of invasive aspergillosis
• Bronchoalveolar lavage fluid:
• A retrospective study was performed in which
251 patients who were at risk for invasive
aspergillosis and who presented with
unexplained nodular lesions or consolidation on
lung imaging underwent galactomannan antigen
testing of BAL fluid [8].
• the sensitivity of galactomannan antigen testing
of BAL fluid for diagnosing proven or probable
invasive aspergillosis was 86 percent and the
specificity was 91 percent.
72. Diagnosis of invasive aspergillosis
• Beta-D- glucan assay:
• In a 2011 meta-analysis that included 16
studies evaluating beta-D- glucan assays for
the diagnosis of invasive fungal infections, the
pooled sensitivity was 77 % ,and the pooled
specificity was 85%
73. Diagnosis of invasive aspergillosis
• Polymerase chain reaction:
• A meta-analysis suggested that sensitivity and
specificity of PCR to detect invasive
aspergillosis was 88 and 75%
75. Treatment of invasive aspergillosis
• Voriconazole rather than a formulation of
Ampho B (Grade 1, B).
• Echinocandins such as Caspo may also be
effective therapy, but have not been
adequately studied.
• Surgical debridement is usually required for
the treatment of Aspergillus rhinosinusitis,
76. Mucormycosis
• Mucormycosis is manifested by a variety of
syndromes in humans, particularly in
immunocompromised patients and those
with diabetes mellitus. Devastating rhino-orbital-
cerebral and pulmonary infections are
the major syndromes caused by these fungi
77. Mucormycosis
• A review of 929 cases of mucormycosis that
were reported between 1940 and 2003 noted
that diabetes was the most common risk
factor, found in 36 percent of cases, followed
by hematologic malignancies (17%), and solid
organ or hematopoietic cell transplantation
(12 %).
78. Mucormycosis
• PATHOGENESIS :
• Rhizopus organisms have an enzyme, ketone
reductase, which allows them to thrive in high
glucose, acidic conditions.
79. Mucormycosis
• Mucormycosis is characterized by infarction
and necrosis of host tissues that results from
invasion of the vasculature by hyphae. The
most common clinical presentation of
mucormycosis is rhino-orbital-cerebral
infection, which is presumed to start with
inhalation of spores into the paranasal sinuses
of a susceptible host.
80. Mucormycosis
• Pulmonary mucormycosis is a rapidly
progressive infection that occurs after
inhalation of spores into the bronchioles and
alveoli. Pneumonia with infarction and
necrosis results, and the infection can spread
to contiguous structures such as the
mediastinum and heart or disseminate
hematogenously to other organs.
81. Mucormycosis
• DIAGNOSIS:
• Histopathology with culture confirmation.
However, culture often yields no growth, and
histopathologic identification of an organism
with a structure typical of Mucorales may
provide the only evidence of infection.
• PCR-based technique used in this study
appears promising.
82. Mucormycosis
• TREATMENT:
• Ampho B (lipid formulation) is the drug of
choice. Oral Posaconazole is used as step-down
therapy for patients who have
responded to Amphotericin B and rarely as
salvage therapy for patients who don't
respond to or cannot tolerate Amphotericin B
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