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305 Cards in this Set

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Meningitis neurological after-effects
seizures
hearing loss
hydrocephalus
Meninges
membranes that surround the brain and spinal cord
Separate membranes of meninges
1. Dura mater
2. arachnoid
3. Pia mater
Dura mater
attached to skull
arachnoid
middle membrane of meninges
subarachnoid space
space between arachnoid and pia mater
pi mater
covers brain tissue
CSF
cerebrospinal gluid
fluid within the CNS that suspends brain and other CNS structures
Where is CSF produced?
In the choroids plexus
Normal contents of CSF
WBC < 5 cells/m
Portein < 50 mg/dL
Glucose 50-66% simultaneous serum value
Normal WBC in CSF
< 5 cells/m3
Normal protein in CSF
< 50 mg/dL
Normal glucose in CSF
50-66% simultaneous serum value
BBB
Blood-brain barrier
natural barrier
exchange of drugs and endogenous compounds among the blood, brain, and CSF
What is the BBB made of?
consists of tightly joined endothelial cells
Bacterial meningitis
bacteria is the cause of the meningitis
Aseptic Meningitis
meningeal inflammation without evidence of bacterial infection
Encephalitis
inflammation of brain tissue
Sequence of events for development of meningitis
1. colonization of host
2. bacteria invade bloodstream
3. bacteria invade CNS
Predisposing Risk Factors for Meningitis
Age > 50
immunosuppression
head trauma
neurosurgical patients
local infection
exposure to someone with meningitis
anatomical or functional asplenia
complement deficiency
recent travel to area with endemic meningococcal disease
Classic/Early signs and symptoms of meningitis
fever
nuchal rigidity
altered mental status
severe H/A
photophobia
Kernig sign +
Brudzinski sign +
Petechial rash (N. meningitidis only)
Kernig sign
laying down, can't raise leg to 90 degrees and keep leg straight
Brudzinski sign
life up head and knees bend while lying down
When is petechial rash a symptoms of meningitis?
Only if meningitis caused by N. meningitidis
Meningitis Triad symptoms
fever, nuchal rigidity, altered mental status
Late signs and symptoms of meningitis
irritability
drowsiness
seizures
coma
CSF Opening Pressure:
Normal
75-175 mm water
CSF Opening Pressure:
Bacterial
Elevated (>175)
CSF Opening Pressure:
Viral
Elevated (>175)
CSF WBC:
Normal
< 5
CSF WBC:
Bacterial
1000-5000
CSF WBC:
Viral
100-1000
CSF Differential:
Normal
>90 Monos
CSF Differential:
Bacterial
>80 PMNs
CSF Differential:
Viral
50 Lymphs
CSF Protein:
Normal
<50
CSF Protein:
Bacterial
100-500
CSF Protein:
Viral
30-100
CSF Glucose:
Normal
50-66% simultaneous serum value
CSF Glucose:
Bacterial
< 40
(<60% simultaneous serum value)
CSF Glucose:
Viral
<30-70
Meningitis Diagnosis Testing
History and PE
Lumbar Puncture
CSF Gram stain and culture
Latex agglutination
PCR
CT scan
Organisms causing meningitis:
< 1 month old
Strep agalactiae
E. coli
L. monocytogenes
Klebsiella
Organisms causing meningitis:
1-23 months old
S. pneumo
N. meningitidis
S. agalactiae
H. influenzae
E. coli
Organisms causing meningitis:
2-50 years old
N. meningitidis
S. pneumoniae
Organisms causing meningitis:
>50 years old
S. pneumo
N. meningitidis
L. monocytogenes
aerobic gram - bacilli
Persons at risk for N. meningitides
age group 5-29 years
close contacts
N. meningitides serotypes
A, B, C, Y W135
Most common symptoms of N. meningitides
petechiae
purpuric lesions
Post-infection immunologic reaction due to N. meningitides
10-14 days after onset of disease
fever, arthritis (large joints), pericarditis
Occurs even with successful treatment
Risk factors for S. pneumo caused meningitis
repeated episodes of otitis media
CSF leaks
fracture of sinuses
Common complications due to S. pneumo caused meningitis
coma seizures
(neuro complications)
Risk factors for H. influenzae caused meningitis
otitis media
paranasal sinus infections
CSF lead
Persons at risk for developing meningitis caused by gram - organisms
CNS trauma
Causes of Viral meningitis
enteroviruses
coxsackieviruses
cytomegalovirus (CMV)
herpes simplex virus (HSV)
Causes of Fungal meningitis
cryptococcus neoformans
Goals for bacterial meningitis treatment
eradicate invading organism
alleviate symptoms
prevent neurologic sequelae
When to give empiric antibiotics for suspected meningitis
Give for at least 48-72 hrs or until meningitis is ruled out
DO NOT delay initiation once meningitis is suspected
Higher doses used
Factors affecting penetration of antibiotics into the CSF
inflammation of the meninges
antibiotic characteristics
Which antibiotic is more likely to penetrate CSF?
low MW vs. High MW
low molecular weight
Which antibiotic is more likely to penetrate CSF?
Non-ionized at physiologic pH vs. ionized
Non-ionized
Which antibiotic is more likely to penetrate CSF?
water soluble vs. lipid soluble
lipid soluble
Which antibiotic is more likely to penetrate CSF?
protein bound vs. non-protein bound
non-protein bound
Antibiotic therapy for meningitis in patients < 1 month old
Ampicillin PLUS cefotaxime
Antibiotic therapy for meningitis in patients 1-23 months old
3rd generation cephalosporin (ceftriaxone or cefotaxime) PLUS vancomycin
Antibiotic therapy for meningitis in patients 2-50 years old
3rd generation cephalosporin (ceftriaxone or cefotaxime) PLUS vancomycin
Antibiotic therapy for meningitis in patients > 50 years old
Ampicilling PLUS 3rd generation ceph. (ceftriaxone or cefotaxime) PLUS vancomycin
Duration of treatment for meningitis caused by:
N. meningitides
H. influenzae
7 days
Duration of treatment for meningitis caused by:
S. pneumo
10-14 days
Duration of treatment for meningitis caused by:
S. agalactiae
14-21 days
Duration of treatment for meningitis caused by:
aerobic gram - bacilli
21 days
Duration of treatment for meningitis caused by:
L. monocytogenes
>/= 21 days
When may Adjunctive dexamethasone therapy for meningitis help decrease neurologic sequelae?
infants/children with H. influenze type B meningitis
Adults with suspected S. pneumo meningitis
How much does adjunctive dexamthasone therapy for meningitis decrease time to eradication?
No significant difference in time to bacterial eradication
When should dexamethasone be given?
10-20 mnutes before or at same time as 1st dose of antibiotic
Duration of use for dexamethasone
2-4 days
Disadvantage of using dexamthasone for meningitis therapy
decreases inflammation )in meninges) --> decreased amount of drug that penetrates CNS
Prevention for N. meningitidis caused meningitis
Chemoprophylaxis
Vaccination
Chemoprophylaxis for N. meningitidis
Who gets it?
What drug is given?
Close contacts - persons with prolonged contact to infected person or secretions within 1 week before symptoms begin until 24 hrs after antibiotics are initiated
Rifampin 600 mg q12h x 4 doses
Vaccination for N. meningitidis
4 serotypes: A, C, Y, W135
Conjugated vaccine
Polysaccharide vaccine
What type of vaccine is preferred for N. meningitides
Conjugated vaccine
Which N. meningitides vaccine should be given to patients > 55?
Polysaccharide vaccine
Who is recommended to receive the N. meningitides vaccine?
all persons age 11-18
persons 9-23 months, 2-10 years, and 19-55 at increased risk
DOC for chemoprophylaxis for N. meningitidis
Rifampin 600 mg q12h x 4 doses
Prevention of S. pneumo caused meningitis
Vaccination
Types of vaccines for s. pneumo meningitis
pneumococcal polysaccaride vaccine (23-valent)
Pneumococcal conjugate vaccine (13-valent)
Who should receive the pneumococcal polysaccharide vaccine to prevent S. pneumo meningitis?
>/= 65 years old and 2-64 years old with increased risk factors
Who should receive the pneumococcal conjugate vaccine to prevent S. pneumo meningitis?
All children < 23 months and children 24-59 months with chronic illness
PCP
Pneumocystis jirovecci pneumonia (previously known as pneumocystis carinii pneumonia)
What is PCP?
organism with protozoal and fungal properties
How is PCP classified?
as a fungus
T/F.
PCP is part of normal colonization in the lungs.
True
Who is at risk for PCP?
Only those immunocompromised
PCP:
signs and symptoms
Slow onset (days-weeks)
fever, fatigue, dyspnea, tachypnea, nonproductive cough
Most common form of PCP
pneumonia
Common PCP coinfection
thrush
How is PCP diagnosed?
CXR: crushed glass appearance all over lungs
arterial blood glass (ABG)
sputum culture
What does a CXR of PCP look like?
crushed glass appearance all over lungs
1st line treatment for PCP pneumonia
TMP/SMX 15-50 mg/kg/day IV in 3-4 divided doses
x 21 days
TMP: SMX
Dosing based on...
5:1 (TMP:SMX)
Dosing based on TMP
Most efficacious and cost-effective treatment for PCP pneumonia
TMP/SMX
What two enzymatic steps are inhibited by TMP/SMX?
DHFR and dihydroptenroate synthas
TMP/SMX:
ADRs
photosensitivity
rash
bone marrow suppression (esp. neutropenia)
When should adjuvant steroids be given with PCP pneumonia?
Patients with severe PCP and PaO2 < 70 mmHg
When should adjuvant steroid therapy begin with PCP pneumonia?
within 72 hours of treatment
(for qualifying patients only)
When should steroid regimens begin with PCP pneumonia treatment?
within 72 hours of treatment
Steroid regimen for PCP pneumonia
Days 1-5: Prednisone 40 mg BID
Days 6-10: Prednisone 40 mg QD
Days 11-21: Prednisone 20 mg QD
What steroid regimen should be used for patients with PCP pneumonia who are unable to take PO?
IV methylprednisolone (75% of PO prednisone dose)
What is the advantage to using adjuvant steroids in patients with PCP pneumonia?
Mortality rates and rates of respiratory failure reduced
Candidates for PCP pneumonia prophylaxis
CD4+ < 200 cells/micoL or history of oropharyngeal candidiasis
PCP Pneumonia:
Primary Prophylaxis
TMP/SMX double strength 1 tab PO QD
OR
TMP/SMX DS 1 tab TIW
OR
TMP/SMX SS 1 tab PO QD
What can TMP/SMX double strength be used as a prophylaxis regimen for?
PCP pneumonia
toxoplasmosis
some respiratory bacterial pathogens
When should PCP pneumonia primary prophylaxis be discontinued?
Patients who have responded to HAART with an increase in CD4 count to > 200 for at least 3 months
PCP pneumonia:
Secondary prophylaxis
Same as primary prophylaxis using TMP/SMX
When should PCP pneumonia secondary prophylaxis be discontinued?
Same as with primary prophylaxis

Patients who have responded to HAART with an increase in CD4 count to > 200 for at least 3 months
What organism causes Toxoplasmic encephalitis?
Toxoplasma gondii
What is toxoplasma gondii?
intracellular parasite
passed to humans from raw/undercooked meat and by contact with feces from infected cats
How is toxoplasma gondii classified?
protozoa
Counseling to prevent exposure to toxoplasma gondii
Do not eat raw/undercooked meat
Wash hands after handling raw meat, after gardening/contact with soil
Wash fruits/veggies before eating raw
Change cat litter box daily (by HIV neg., non-pregnant)
Wash hands thoroughly after changing litter box
Keep cats inside; do not adopt/handle stray cats
Only feed cats canned/dried commerical food or well-cooked table food (no raw/undercooked meat)
Toxoplasmic encephalitis:
Signs and symptoms
CNS infection
typically associated with fever, seizures, focal neurological deficits, other symptoms associated with encephalitis
Diagnosis of Toxoplasmic encephalitis
serological testing for Toxoplasma IgG
neuroradiological scans (CT/MRI)
brain biopsy (reserved for patients refractory to empiric therapy)
Toxoplasmic encephalitis:
1st line treatment
Sulfadiazine PLUS pyrimethamine PLUS leucovorin
x at least 6 weeks
Toxoplasmic encephalitis
Duration of treatment
at least 6 weeks
Most active sulfonamide against T. gondii
Sulfadiazine
Which other sulfa drugs can be substituted for sulfadiazine for toxoplamic encephalitis treatment?
NONE
Most potent folic acid antagonist
pyrimethamine
Why is leucovorin used for Toxoplasmic encephalitis treatment?
AKA folinic acid
mandatory to prevent bone marrow suppression
Toxoplasmic encephalitis:
Primary Prophylaxis Candidates
CD4 < 100 and Toxoplasma IgG + (= previous exposure)
What does + toxoplasma IgG mean?
previous exposure to bug
Toxoplasmic encephalitis:
Primary prophylaxis
TMP/SMX DS QD
Toxoplasmic encephalitis:
Discontinuation of primary prophylaxis
after response to HAART and CD4 > 200 for at least 3 months
Toxoplasmic encephalitis:
Secondary prophylaxis (chronic suppression)
Sulfadiazine PLUS pyrimethamine PLUS leucovorin
(also protective against PCP)
Toxoplasmic encephalitis:
Discontinuation of secondary prophylaxis (chronic suppression)
after completion of initial therapy and CD4>200 on HAART for at least 6 months
Toxoplasmic encephalitis:
Restarting secondary prophylaxis
when CD4 count decreases to < 200
Organism causing cryptococcal meningitis
cryptococcus neoformans
What is cryptococcus neoformans?
encapsulated yeast
What is the most common life-threatening fungal infection in AIDS patients?
cryptococcus neoformans (cryptococcal meningitis)
How is cryptococcus neoformans transferred?
grows in pigeon droppings and nesting areas
acquired by direct inhalation
disseminates from lungs to meninges in setting of compromised T-lymphocytes function
Cryptococcal meningtis:
Signs and symptoms
progressive development of frever and/or H/A, neck stiffness, photophobia, CNS changes
disseminated disease (skin, pulmonary)
Cryptococcal meningtis:
Diagnosis
brain imaging
lumbar puncture
cryptococcal CSF antigen
Gram stain and culture
Cryptococcal meningtis:
1st line treatment
Induction: ampho. B deoxycholate PLUS flucytosine (5-FC0 x at least 2 weeks
Maintenence: fluconazole 400mg/day x 8 more weeks
Chronic suppression: fluconazole 200 mg/day until CD4 increases
Cryptococcal meningtis:
Duration of treatment
Induction: at least 2 weeks
Maintenance: 8 more weeks
Chronic suppression: until CD4 counts increase
CNS penetration of ampho. B
very good penetration
Ampho. B ADEs
high risk of renal failure
infusion reactions
alter electrolytes
Ampho. B formulations
ampho. B deoxycholate: 0.7 mg/kg/day
Lipid formulation: liposomal ampho. B (ABLC): 5mg/kg/day
What other meds are recommended for use with ampho. B?
Saline bolus 500 mL pre and post ampho infusion
Diphenhydramine and APAP 30 min pre-ampho
Meperidine to treat/prevent rigors and/or add hydrocortisone IV to ampho bag
Cryptococcal meningtis:
Primary prophylaxis
Not recommended
Cryptococcal meningtis:
Secondary Prophylaxis (chronic suppression)
Fluconazole 200 mg QD
Cryptococcal meningtis:
Discontinuation of secondary prophylaxis
after completion of initial therapy, patients must be asymptomatic and have sustained increase in CD4>200 after HAART for at least 6 months
Cryptococcal meningtis:
Restarting secondary prophylaxis
when CD4 decrease to < 200
MAC
Mycobacterium avium complex/infection (MAI)
What is organims is MAC comprised of?
mycobacterium avium and mycobacterium intracellulare
Where is MAC found?
ubiquitous in nature
commonly inhabiting soil and water
MAC process of colonization in body
begins with colonization of intestinal or respiratory tracts after organism ingestion or inhalation
subsequent development of localized infection and sometimes seeding of blood
MAC:
signs and symptoms
typically a multiporgan system (disseminated) disease in AIDS patients
fever, night sweats, anorexia, weight loss occurs in most
D, abdominal pain, increased LFTs, anemia, neutropenia, thrombocytopenia
hepatomegaly, splenomegaly, lymphadenopathy
MAC:
Diagnosis
Gold standard: culture
some patient with - blood culture have + liver, bone, marrow, or lymph node biopsies which confirm diagnosis
T/F.
A blood culture - for MAC definitively rules out MAC.
False
some patient with - blood culture have + liver, bone, marrow, or lymph node biopsies which confirm diagnosis
How long does it take for MAC to grow?
2-6 weeks
What helps confirm a presumptive MAC diagnosis?
clinical improvement on empiric therapy
MAC:
1st line treatment
Clarithromycin 500 mg BID PLUS ethambutol 15 mg/kg/day

May consider rifabutin (many ADEs)
T/F.
MAC treatment has a higher efficacy if rifabutin is added.
False.
Ethambutol:
common ADE
ocular nephritis
MAC:
Discontinuation of treatment therapy
Completion of at least 12 months treatment, remain asymptomatic and have CD4 cound > 100 for at least 6 months on HAART
negative cultures
MAC:
restarting therapy
CD4 < 100
MAC:
candidates for primary prophylaxis
CD4 < 50
MAC:
primary prophylaxis
Azithromycin 1200 mg Qweek
MAC:
discontinuation of primary prophylaxis
CD4 > 100 for at least 3 months
Cytomegalovirus Disease
enveloped double-stranded DNA virus
member of herpes virus family
Can CMV become latent within infected cells?
Yes
How is CMV trasmitted?
through infected body fluids (mainly congenital and sexual contact)
Most common form of CMV in AIDS patients
CMV retinitis
Where can CMV manifest?
various organ systems
esophagitis, colitis, neurologic CMV
What can happen if CMV retinitis is left untreated?
Will rapidly progress to retinal necrosis and permanent blindness
CMV:
Signs and symptoms
visual changes
flashes of light
blurred vision
blind spots (floaters)
CMV:
Diagnosis
clinical diagnosis
cluture and antigen detection most sensitive methods for detecting CMV
CMV treatment:
CMV retinitis (immediate sight-threatening lesions)
Ganiciclovir intraocular implant
PLUS
valganciclovir 900 mg PO BID x 14-21 days
THEN
valganciclovir 900 mg PO QD

1 dose of intravitreal ganciclovir may be given immediately after diagnosis until implant can be placed
CMV treatment:
CMV retinitis (small peripheral lesions)
Valganciclovir PO 900 mg BID x 14-21 days
THEN
Valganciclovir PO 900 mg QD
CMV Treatment:
CMV esophagitis or colitis
Ganciclovir IV OR foscarnet IV x 21-28 days or until resolution of sx
If PO adequate, use valganciclovir PO

Maintenence therapy usually not necessary, but should be considered after relapses
CMV treatment:
CMV neurological disease
PROMPT initiation of treatment

Combo of ganciclovir IV PLUS foscarnet IV to stabilize disease and max response
Continue until symptomatic improvement
Maintenance therapy: PO valganciclovir PLUS IV foscarnet continued lifelong unless evidence of immune recovery
CMV retinitis:
Suppression (secondary prophylaxis)
valganciclovir 900 mg QD
OR
ganciclovir implant (may be replaced q6-8months if CD4 reamins <100) PLUS valganciclovir 900 mg QD until immune recovery
CMV retinitis:
D/C secondary prophylaxis
CD4>100 for at least 3-6 months on HAART
CMV retinitis:
restarting secondary prophylaxis
when CD4 <100
CMV treatment:
duration of induction therapy
14-21 days
CMV:
primary prophylaxis
controversial (expensive, toxic, resistance)
considered for pts with CD4 <50 and CMV IgG +
Give PO ganciclovir or valganciclovir

Fundascopic exams by ophthalmologist
Candidiasis causing organism
Candida species
yeast, part of normal flora in immunocompetent and immunocompromised hosts
Where can candida be found?
skin
mucosal surfaces (mouth, pharynx, vagina)
Most candidiasis caused by which form of candida?
C. albicans

increasing frequency with C. topicalis, C. glabrata, C. parapsilosis, C. krusei
What causes candidiasis?
overgrowth of normal flora due to breakdown in local defenses
Candidiasis:
signs and symptoms
mouth pain, pain with swallowing, difficulty eating
white plaques on buccal surfaces, palate, and tongue
Esophageal cand. may ave more severe symptoms (dysphagia, odynophagia, esophageal ulceration, anorexia)
Candidiasis:
Diagnosis
surface scraping for Gram stain
Presence and extent of esophageal plaques identified through bronchoscopy
Are fungal cultures helpful when diagnosis candidiasis?
No
useful in determining species of candida in patients who fail therapy
Oral candidiasis treatment
fluconazole 100mg/day
OR
nystatin 500,000 U swish/swallow QID
OR
clotrimazole troches 10 mg 5x/day
Vaginal candidiasis treatment
fluconazole 150 mg x 1
OR
topical azoles x 3-7 days
Esophageal candidiasis treatment
Systemic therapy

fluconazole preferred, 100-200 mg/day
OR
posaconazole 400 mg BID
Can you use topical treatment with nystatin or clotrimazole for esophageal candidiasis?
No
Candidiasis prophylaxis (chronic maintenance)
increases risk of azole resistance
may consider in patients with documented history of esophageal candidiasis and multiple episodes

Fluconazole 100-200 mg/day
Candidiasis primary prophylaxis
not recommended
TMP/SMX ADEs
GI disturbances (eg, anorexia, nausea, vomiting) and allergic skin reactions (eg, rash, urticaria)
Sulfadiazine ADEs
H/A, depression, insomnia, pruritis, phostosensitivity, anorexia, N, V, D, tinnitus
Pyrimethamine ADEs
anorexia, V, thrombocyopenia, hypersensitivity
Amphotericin ADEs
CNS: Headache.
GI: Anorexia; nausea; vomiting; diarrhea; dyspepsia; cramping; epigastric pain.
Hematologic: Normochromic anemia; normocytic anemia.
Local: Pain at the injection site with or without phlebitis or thrombophlebitis.
Musculoskeletal: Generalized pain, including muscle and joint pains.
Pulmonary: Hypotension; tachypnea
Fluconazole ADEs
N, V, D, H/A, rash, abdominal pain
Clarithromycin ADEs
abnormal taste, N, D, H/A, abdominal pain, dyspepsia
Azithromycin ADEs
N, D, chest pain, dizziness, H/A, photosensitivity, rash
Ethambutol ADEs
optic neuritis
Ganciclovir/Valgancyclovir ADEs
anemia, diarrhea, graft rejection, nausea, neutropenia, pyrexia, thrombocytopenia, tremor, and vomiting
Flucytosine ADEs
confusion, photosensitivity, rash, renal failure, H/A, peripheral neuropathy, respiratory arrest
Basic forms of fungi
Yeast
Moulds
Yeast
solitary forms of fungi that reproduce by budding
How do yeast reproduce?
budding
What do yeast look like?
moist, shiny appearance
Moulds
multi-cellular fungi
consist of many branching hyphae
reproduce by translocation or existing hyphae to a new area or through spore formation and spread
How do moulds reproduce?
translocation or existing hyphae to a new area or through spore formation and spread
What do moulds look like?
fuzzy appearance
Dimorphic fungi
Can exist in either yeast or mould form
Dimorphic fungi at room temperature
mould-like
Dimorphic fungi at body temperature
yeast-like
What is another name for dimorphic fungi? Why are they sometimes called this?
endemic fungi
cause infections endemic to certain regions of the world
Yeast species
Candida
Cryptococcus
Mould species
Aspergillus
Zygomycetes
Fusarium
Scedosporium
Dimorphic fungi species
Coccidioides
Blastomyces
Histoplasma
Paracoccidiodes
T/F.
Fungi are a cross between bacterial and human cells
True
Do fungi have a cell wall?
Yes
What is fungi cell wall made of?
chitin (beta-(1,4)-linked N-acetylglucosamine residues)
Do fungi cell walls contain peptidoglycan?
No
Do fungi have a cell membrane inside of their cell wall?
Yes
Ergosterol
embedded in fungal cell membranes
analogue to cholesterol found in human cell membranes
Polyenes
Ampho B
Lipid formulations of ampho B
topical nystatin
Main amphotericin toxicities
nephrotoxicity
infusion-related reactions
How can amphotericin B toxicities be avoided?
Use lipidd formulation
Ampho B lipid formulations
ampho B colloidal dispersion
Ampho B lipid complex
Liposomal ampho B
Polyenes MOA
bind to ergosterol in cell membrane of fungi
disrupt cell membrane
causes pore leading to leakage
Polyenes:
fungicidal or fungistatic
fungicidal
Polyenes Target
cell membrane
Azoles target
Cell membrane
Echinocandins target
cell wall
Antimetabolites target
DNA/RNA synthesis
Ampho B, Nystatin:
spectrum
most Candida
most Aspergillus
Cryptococcus neoformans
dimorphic fungi
many moulds
some Zygomycetes
What Candida species does ampho B and nystatin not work well against?
Candida lusitaniae
Ampho B, nystatin:
ADEs
nephrotoxicity
infusion-related reactions (fever, chills, rigors)
electrolyte disturbances (decrease Mg, K, Ca)
How does ampho B cause nephrotoxicity?
direct effects on distal tubule and indirect effects through vasoconstriction of afferent arteriols
leads to wasting of Mg and K
What can be done to prevent nephrotoxicity from ampho B?
make sure patient is hydrated
give pre and post infusion saline boluses
What should be done to minimize infusion-related reactions due to ampho B?
Give pre-meds (APAP, diphenhydramine)
Give meperidine if needed and/or hydrocortisone
ampho B formulations:
dosing
Ampho B deoxycholate: 0.5-1.5 mg/kg/day
Lipid formulations: 3-6 mg/kg/day
Why is meperidine sometimes given with ampho B?
To treat rigors associated with infusion
Why is nystatin only given topically?
poor tolerance when given systemically
Drug interactions with ampho B
increase nephrotoxicity with other nephrotoxic agents (aminoglycosides, cyclosporine)
Ampho B:
DOC for....
cryptococcal meningitis
serious forms of other fungal infections (dimorphic fungi, some mould infections)
Why has ampho B use with candidiasis and aspergillosis declined?
availability of newer, safer agents
Antimetabolites
Flucytosine (5-FC)
Primary role of flucytosine
combination with ampho B for cryptococcal disease
Antimetabolites (flucytosine): MOA
interferes with DNA synthesis
enters fungal cell, converts to fluoruracil, competes with uracil, interferes with fungal RNA and protein synthesis
Flucytosine Spectrum
in combo with ampho B: cryptococcus neoformans, most Candida species
Flucytosine:
ADEs
bone marrow suppression (esp. in high doses for long periods)
GI/CNS effects: H/A, confusion, ataxia, hallucinations
When should peak concentration of flucytosine be checked?
2 hours after dose given
What values are more important than drug levels when monitoring for toxicity with flucytosine?
hematologic values
Drug interactions with flucytosine
increased effect with ampho B = increased risk of flucytosine toxicity with ampho B
Does flucytosine need to be adjusted for renal failure?
Yes
When should flucytosine therapy be reconsidered?
If hematologic toxicity develops
change med if WBCs decrease
Azoles
itraconazole
fluconazole
voriconazole
posaconazole
Azoles: MOA
broad spectrum
inhibit fungal cytochrome P450, decreasing ergosterol production
Azoles:
fungicidal vs. fungistatic
fungistatic
Triazoles
voriconazole
posaconazole
Itraconazole Spectrum
C. albicans
C. tropicalis
C. parapsilosis
C. lusitaniae
Cryptococcus neoformans
Aspergillus sp.
many dimorphic fungi
Fluconazole Spectrum
C. albicans
C. tropicalis
C. parapsilosis
C. lusitaniae
Cryptococcus neoformans
Coccidioides immitis
Some C. glabrata
Voriconazole Spectrum
C. albicans
C. tropicalis
C. parapsilosis
C. lusitaniae
Aspergillus sp
many other moulds
Some C. glabrata, krusei, albicans that are fluconzole-resistant
Fusarium Sp
Posaconazole Spectrum
C. albicans
C. tropicalis
C. parapsilosis
C. lusitaniae
Aspergillus sp
Zygomycetes sp.
Many moulds
Dimorphic fungi
Some C. glabrata
Some Fusarium sp
Which azole does NOT have activity against Aspergillus?
Fluconazole
Which azole has activity against Zygomycetes?
Posaconazole
Itraconazole:
ADEs
hepatotoxicity
negative inotrope (CI with HF)
Strong inhibitor of 3A4
QTc prolongation possible
Fluconazole:
ADEs
hepatotoxicity, rash
lower propensity for drug interactions (strong inhibitor of 2C9, 2C19, moderate inhibitor of 3A4)
QTc prolongation possible
Voriconazole:
ADEs
hepatotoxicity, rash
visual effects (wavy lines)(go away with cont. use)
hallucinations
Interactions (moderate inhibitor of 2C9, 3A4)
Posaconazole:
ADEs
hepatotoxicity, rash
GI disturbances
QTc prolongation possible
Interactions (strong inhibitor of 3A4)
Itraconazole formulations
Capsules have lower F than solution, less preferred for systemic fungal infections
Itraconazole administration
Capsules: always take with full meal
Solution: take on empty stomach
Take with soda if also taking PPIs (PPIs may decrease absorption)
Itraconazole DOC for...
some dimorphic infections (histoplasmosis)
Does fluconazole need to be adjusted for renal function?
Yes
Fluconazole and C. glabrata
Poorly active against C. glabrata
If using for this, check susceptibilities and give 800 mg/day
Fluconazole bioavailability:
High or low
High
T/F.
All species of candida are fluconazole-susceptible.
False
Voriconazole:
formulations
IV: contains cyclodextrin vehicle that accumulates in renal dysfunction, may be nephrotoxic
When is IV voriconazole contraindicated?
CrCl < 50
Use oral formulation
How is voriconazole eliminated?
hepatically
Is voriconazole useful for treatment of candiduria?
no
Voriconazole DOC for...
invasive aspergillosis
Posaconazole:
formulation
only available as oral suspension
Posaconazole:
Administration
give with food to increase absorption
foods high in fat improve absorption
Posaconazole:
Utility
prophylaxis in high-risk patients
zygomycetes infections
Echinocandins
Caspofungin
Micafungin
Anidulafungin
Echinocandins:
Pros (vs. other antifungals)
very well tolerated
excellent activity against Candida
fewer drug interactions than azoles
safer than polyenes
great activity against fluconazole-resistant yeasts
Echinocandins: MOA
inhibit synthesis of beta-1,3-glucan component of cell wall

destroys stability of membrane
Echinocandins:
fungicidal vs. fungistatic
fungicidal: Candida
fungistatic: Aspergillis
Echinocandins Spectrum
C. albicans
C. tropicalis
C. lusitaniae
C. glabrata
C. krusei
Aspergillus
Some C. parapsilosis
Which antifungals have activity against C. krusei?
Echinocandins
Which antifungals have activity against Aspergillus?
Echinocandins
Voriconazole
Posaconazole
Itraconazole
Ampho B
Nystatin
Echinocandins:
ADEs
mild histamine-mediated infusion-related reactions (not common, just slow infusion rate)
Caspofungin:
ADEs
increase LFTs
GI disturbances
Micafungin:
ADEs
GI disturbances
increase LFTs
Anidulafungin:
ADEs
Diarrhea
hypokalemia
Echinocandins:
formulations
all only available IV
Difference between echinocandins
minor differences, mostly PK
How are echinocandins eliminated?
Caspofungin and micafungin: hepatic elimination by non-Cyp450 metabolism
Anidulafungin: degrades in plasma, avoids hepatic elimination
Echinocandins:
drug interactions
interactions minor
cautious when using caspofungin/micafungin with immunosuppressants
(cyclosporine with caspofungin)
(sirolimus with micafungin)
Echinocandins:
Uses
Becoming DOC for invasive candidiasis, esp. if pt. unstable
Treat invasive aspergillosis (not as much evidence yet as voriconazole/ampho B)
Echinocandin transition after empiric therapy
echinocandins very expensive so transition to fluconazole if strain of Candida susceptible