Invasive candidiadis

INVASIVE
CANDIDIADIS
Presented by:
Nida Sehar Noman
MS (Pharmacology) & MBA Finance
nidasehar19@yahoo.com

CANDIDA
 Candida is the most common cause of fungal infection
worldwide and 4th most common cause of blood stream
infections in hospital setting.
 Associated with 47 % mortality rate.
 17 different species identified till yet.
 Most common among them are C. albicans, C.
glabrata, C. parapsilosis and C. tropicalis.

INVASIVE CANDIDIASIS
 Candida usually develops on mucous membranes (
mouth , genitals etc).
 Candida in blood stream it is known as candidemia.
 When it passes from blood stream to other body
parts(eyes, kidney, liver and brain etc) it is called
invasive candidiasis.

RISK FACTORS
o Patients immuno compromised due to
 Cancer chemotherpay
 Organ transplant
 HIV
o Diabetics
o Drugs (Broad spectrum antibiotics,
corticosteroids)
o Use of central venous catheter.

SIGNS AND SYMPTOMS
 Fever, chills
 Skin rash
 Generalized
weakness or fatigue
 Low blood pressure
 Muscle aches
 Vision changes
 Headaches and
neurological defects
 Abdominal pain

TREATMENT
 Three classes of drugs are most commonly
used
 Echinocandins (caspofungin, anidulafungin,
micafungin)
 Triazoles (fluconazole, itraconazole,
voriconazole, posaconazole)
 Polyenes (AmB deoxycholate, liposomal
AmB, AmB lipid complex, AmB colloidal
dispersion)

ECHINOCANDINS
 Echinocandins are inhibitors synthesis of glucan synthesis
in fungal cell wall , via noncompetitive inhibition of the
enzyme1,3-β glucan synthase.
 They have fungicidal activity against most Candida spp,
including strains that are fluconazole-resistant.
 They achieve therapeutic concentrations in all areas except
eye, CNS and urine.

ECHINOCANDINS
 The echinocandins have been shown to be efficacious for the
treatment of esophageal candidiasis, candidemia, and invasive
candidiasis.
 Micafungin is the only echinocandin approved for use as
prophylaxis against Candida infections in patients undergoing
HSCT.
 Resistance is still rare, are well tolerated, and have few drug-
drug interactions.
 The pooled analysis of recent trials suggest survival advantage
in therapy initiated with ecinocandin.

IDSA RECOMMENDATIONS
 An echinocandin (caspofungin: loading dose 70 mg, then50 mg daily;
micafungin: 100 mg daily; anidulafungin: loading dose 200 mg, then
100 mg daily) is recommended as initial therapy
 Neutropenic patients
 Non neutropenic patients (in ICU as well)

TRIAZOLES
 They inhibit 14α-lanosterol demethylase, a key enzyme in ergosterol
biosynthesis, resulting in depletion of ergosterol and accumulation of toxic
14α-methylated sterols in membranes of susceptible yeast species.
 All of the azoles have less activity against C. glabrata and C.krusei than
other species.
 Fluconazole is standard therapy for oropharngeal, esophageal and
vaginal candidiasis as well as UTIs.
 As greatest penteration in CSF and vitreous used in CNS and intraocular
candida infections.
 As urine concentration 10-20 times more than in serum it is preferred
option for symptomatic cystitis.

TRIAZOLES
 Itraconazole only available in oral formulation and reserved for
flucanazole resistant patients of mucosal candidiasis.
 Voriconazole is structurally similar to fluconazole and has
spectrum of activity like itraconazole.
 Effective for both mucosal and invasive candidiasis.
 Primarily used as step down therapy in C. krusei infections and
fluconazole resistant voricanzole susceptible C glabrata.
 CSF and vitreous concentrations are high so used on these
sites.

 Fluconazole, intravenous or oral, 800-mg (12 mg/kg) loading dose,
then 400 mg (6 mg/kg) daily is an acceptable alternative to an
echinocandin as initial therapy in
 Non neutropenic who are not critically ill and considered unlikely to
have a fluconazole-resistant Candida species
 As prophylaxis in in high-risk adult patients in ICUs with a high rate
(>5%) of invasive candidiasis.
o for infection due to C. glabrata, high dose fluconazole 800 mg daily or
voriconazole 200–300 Bid among patients with fluconazole or
voriconazole-susceptible isolates.

POLYENES
 It acts by binding with ergosterol in fungal cell membranes,
forming pores that cause rapid leakage of monovalent
ions (K+, Na+, H+ and Cl−and subsequent fungal cell death.
 Amphtericin B deoxycholate is associated with nephrotoxicity in
50% of patients and electrolyte wasting tubular acidosis in
majority.
 Lipid formulations have been developed which are more
expensive and less nephrotoxic.
 Can be used in all situations except UTIs as reduced renal
excretion.

 Lipid formulation amphotericin B (AmB) (3–5 mg/kg daily)is a
reasonable alternative but less attractive alternative due to
toxicity
 In non neutropenic patients if there is intolerance, limited
availability, or resistance to other antifungal agents
 Neutropenic patients

Condition Initial Treatment Step down
therapy
Follow up
Hepatosplenic
candidiasis
lipid formulation AmB
Or
Echinocandin
Oral fluconazole Continue therapy for
several months until
lesions resolve
Candida intravascular
infection
Lipid formulation
AmB, + /-
Flucytosine, ,Or
High-dose
Echinocandin
Fluconazole Valve replacement or
long term suppression
with fluconazole
Candida Osteoarticular
infections
Fluconazole or an
echinocandin
Echinocandin followed
up by fluconazole for
6-12 months
Surgical debridement
in selective cases

Condition Initial Treatment Step down
therapy
Follow up
Candida Edophthalmitis Fluconazole/Voricon-
azole or Liposomal
Amp B
- Therapy continued for
4-6 weeks until
resolution of lesions
CNS Candidiasis liposomal AmB, +/-oral
ﬂucytosine,
Fluconazole Therapy continue until
all signs and symptoms
and
CSF and radiological
abnormalities have
resolved
Symptomatic Candida
Cystitis
Oral fluconazole,C
krusei or floconazole
Resistant C glabrata
Amp B deoxycholate
Removal of indwelling
bladder catheter if
feasible

ETIOLOGY
 EBV also called human herpes virus 4.
 Two subtypes in human infection: EBV-1 and EBV-2. EBV-1 and
EBV-2 differ in the organization of the genes that code for the EBV
nuclear antigen (EBNA-2, EBNA-3a, EBNA-3b, and EBNA-3c)
 Best known cause of infectious mononucleosis.
 Infecting nearly 90% of population at some stage.
 It is spread primarily through saliva and genital secretions.
 Replication in B lymphocytes or in epithelial cells of pharynx and
parotid duct.
 First detected in Burkitt’s lymphoma cells they are the first viruses to
be associated with malignancies in humans.

VIRION STRUCTURE
 The viral glycoproteins
gp350, gHgL and gp42
are essential for binding
and fusion with CD 20
expressing B lymhocytes.
 Viral tegumens upregulate
transcription of genes involved in
replication.
 The viral RNAs protect virus from cytotoxic T cells and help in
transition from lytic to latent phase.

CLINICAL SYNDROMES
ASSOCIATED WITH EBV
o Primary Syndromes
 Infectious Mononucleosis
 Chronic active EBV infection
 X- linked lymphoproliferative syndrome
o EBV Associated Tumors
 Post transplant lymphoproliferative disorders (PTLD)
 Burkitts lymphoma
 Nasopharyngeal carcinoma
 T/NK lymphomas
 Angioblastic T cell lymphoma
o EBV Associated Post Transplant Diseases
 Encephalitis
 Pneumonia
 Hepatitis

CHRONIC EBV (CAEBV)
 It starts with acute infection wth markedly elevated antibodies or EBV
DNA in blood.
 Evidence of organ infiltration.
 Detection of EBV protein in tissue.
 Signs and symptoms include fever, liver dysfunction, splenomegaly,
lymphadenopathy, thrombocytopenia, hypersensitivity to mosquito bites,
rash, hemophagocytic syndrome and coronary artery aneuryms.
 Also associated with hypersecretion of pro inflammatory cytokines, such
as IFN-γ, TNF-ά, IL-6, IL-10, and macrophage-colony-stimulating factor
 Presence of thrombocytopenia, onset at age 8 or older and infection with
T cells are poor prognostic markers.
 Death is due to liver failure, malignant lymphoma or opportunistic
infection.

POST TRANSPLANT LYMPHOPROLIFERATIVE
DISORDER (PTLD)
 They are heterogenous group of EBV diseases with
neoplastic lymphopoliferation, developing after
transplant and caused by iatrogenic suppression of T
cell function.
 Risk Factors
 Major: mismatch HSCT, T cell depletion, EBV serology
mismatch, cord blood HSCT
 Minor: Primary EBV infection, splenectomy

EBV ASSOCIATED
MALIGNANCIES
 .Affect both immune-competent hosts and immune-
compromized patients who have received an organ
transplant or who exhibit iatrogenic immune suppression.
 It is largely dependent on environmental factors and genetic susceptibility to viral infection.
 EBV PRODUCTS:
 EBNA-1: replication and maintenance of EBV genome.
 EBNA2: Up-regulate expression of viral and cellular
Genes e.gCD23 (a surface marker of activated B-cells),
c-myc (a cellular proto-oncogene).
 EBNA-LP: interacts with EBNA-2 to drive resting B
lymphocytes into the G1phase by binding and
inactivating cellular p53 and retinoblastoma protein
tumor suppressor gene products.
 LMP-1: mimics CD40 by associating with the same TNF
receptor-associated factors. Also cause an overexpression of
proteins BCL-2 and A20,which protects the infected cell from
p53-mediated apoptosis.

EBV ASSOCIATED
MALIGNANCIES
 BCRF1 and IL-10.
EBV BCRF1 protein shows 84% sequence homology to IL-10 and help establish
latent infection by suppression of immune system .
 BHRF1 and BCL-2.
BHRF1 (25%) sequence homology to BCL-2 proto-oncogene, and both have been
shown to protect human B lymphocytes from apoptosis BHRF1 may enhance cell
survival, allowing oncogenic mutations to accumulate.
 Oncogenic Features of EBV
 EBV infected B cells if they proceed unchecked or acquire oncogenic
mutations, can become neoplastic.
 . With immune suppression, latently infected cells in the peripheral blood or
persistently infected cells on the oropharynx increase in number.
 Virus finally achieves oncogenecity by activate intracellular signaling involved
in control of proliferation. This is achieved through diverse virally expressed
genes.

X LINKED LYMPHOPROLIFERATIVE
DISORDERS
 It is characterized by three major phenotypes: fatal or fulminant infectious
mononucleosis, B-cell lymphomas, and dysgammaglobulinemia.
 Lymphomas are extranodal. Death (which is virtually universal by age 40) is
generally because of hepatic necrosis and bone marrow failure secondary to an
uncontrolled cytotoxic T-cell response.
 Patients seronegative for EBV can exhibit the X-linked lymphoproliferative disorder.
 The gene responsible for this disorder has been mapped to the long arm of the X
chromosome . This gene is important in T/B-cell homeostasis after viral infection and
decreased ability to control immune responses to viruses, including EBV.

INFECTIOUS
MONONUCLEOSIS
TREATMENT
 Infectious mononucleosis is generally self-limiting, so only symptomatic treatments
are used.
 The need for rest or return to usual activities depend on personal energy levels.
 Hydration and adequate nutrition.
 Activity restriction
 NSAIDs or acetaminophen for fever and throat discomfort.
 Throat lozenges and sprays with prescription lidocaine 2% for sore throat.
 Acyclovir inhibitor of DNA polymerase showed a suppression in the shedding of EBV
in the saliva but was limited to therapy duration.
 Upper airway obstruction, severe thrombocytopenia and severe hemolytic anemia
are life threatening condition which can be treated with corticosteroids.
 Prednisone 60mg PO daily followed by 10 day taper.
 Prednisolone 0.7 mg/kg PO for 4 days followed by 10 day taper.

CAEBV TREATMENT
 Antiviral therapy (e.g acyclovir, ganciclovir not effective as viral DNA
polymerase not required for replication.
 Immunosuppressive agents such as corticosteroids and cyclosporine
can temporarily reduce symptom and treat hemophagocytic
syndrome but underlying disease needs to be treated.
 Transplant is an option but patients with this disease are associated
with higher rates of transplant related complications due to multi
organ failure.

PTLD TREATMENT
 Prophylaxis
 B cell depletion might reduce risk
 Anti virals not recommended.
o Preemptive therapy after HSCT
 Rituximab 375 mg/m2, 1-2 doses
 Reduction of immunosuppressive therapy if possible
 Donor EBV specific cytotoxic cell therapy.
o First Line treatment
 Rituximab 375 mg/m2, 1-2 doses
 Reduction of immunosuppressive therapy if possible
o Second line treatment
 Chemotherpy if other options fail
 Adoptive immunotherapy with invitro generated CTL if available.

TREATED OF EBV
ASSOCIATED MALIGNANCIES
 Anti Virals
 Acyclovir and ganciclovir (nucleoside analogs) are not drugs of choice as virus in
latent phaseand viral thymidine kinase responsible for conversion to toxic active
triphosphates not expressed.
 Arginine butyrate which can selectively activate EBV thymidine kinase can be
coadministered.
 Foscarnet inhibitor of viral DNA polymeraselinked to isolatedcases of complete
remission in EBV associated lymphoproliferations.
 Cidofovir (DNA polymerase inhibitor) along with Rituximab can produce complete
remission of CD 20expressing post transplant lymphoproliferative disorders.
 Zidovudine in combination with IFN alpha can induce apoptosis in EBV positive
lymphoma cells from AIDS patients.
 Monoclonal Antibodies:
 Rituximab has a success rate of 69 % (complete response) in transplant recipents.
 As these lymphomas use IL 6 anti IL 6 antibdies have also been used with success
rate of 67 %.

Invasive candidiadis

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