W1P3 Flashcards
Viruses
- type
- replication process
Viruses are obligate intracellular parasites
Viral replication depends primarily on synthetic processes of the host cell
Antiviral agents must ideally inhibit virus-specific events:
Block viral entry into the cell
Block viral exit from the cell
Be active inside the host cell
Exert some sort of immunomodulatory effect
What are the viral events that antivirals need to target
Antiviral agents must ideally inhibit virus-specific events:
Block viral entry into the cell
Block viral exit from the cell
Be active inside the host cell
Exert some sort of immunomodulatory effect
How is an antiviral’s therapeutic effect measured?
Since viruses are not “alive”, drugs cannot “kill” them
A therapeutic agent’s antiviral effect is measured by its ability to inhibit viral replication:
- 50% Inhibitory Concentration (IC50). should have half as many virally infected cells compared to when we started after giving antiviral
Steps of Viral Replication
- Attachment
- Entry
- Uncoating
- Synthesis
a. Early proteins
b. Nucleic acids
c. Late proteins - Assembly
- Release
Who are the people in Canada who are at high risk of influenza- related complications and thus should be vaccinated
Adults aged > 65 years; residents of nursing homes or long-term care facilities
All children aged <5 years, especially 6 to 23 months
children above 6 months should get vaccinated
Canada approved antivirals for Influenza
Oseltamivir (PO)
Zanamivir (inhalation)
Peramivir (IV) [Not marketed in Canada]
Baloxavir Marboxil (PO)
Oseltamivir (PO)
Oral capsule, liquid suspension
Aged >14 d
Generic version available
Antivirals for Influenza
Zanamivir (inhalation)
Powder for oral inhalation through a plastic device
Aged ≥7 y
Not recommended in patients with airway diseases (eg asthma, COPD)
Antivirals for Influenza
Peramivir (IV)
Given intravenously
Aged ≥2 y
appoved for use but Not marketed in Canada
Antivirals for Influenza
Baloxavir Marboxil (PO)
Oral tablets (1 dose) Aged ≥12 y (FDA approval pending for patients aged 1-11 y) - for non severe cases
Antivirals for Influenza
What are all circulaing influenze viruses RESISTANT to?
Adamantanes
Adamantanes
M2 ion inhibitors for influenza virus that has become useless because of resistance
Point mutation of the M2 protein lead to resistance
Resistance emerges rapidly during treatment
- 30% of adults and 80% of children treated with amantadine will excrete resistant virus
- Persistant or recurrent fever in children who develop amantadine-resistant strains on treatment
Viral replication, transmission and virulence are not impaired by these mutations
Neuraminidase Inhibitor
Neuroaminidase is a receptor/ active site*
NA^ inhibitors: Cleave the bond between HA (on virus) and sialic acid receptor on host epithelial cells which is otherwise used to attach the virus to host
Neuraminidase inhibitor = cleaves the bond stated above ^ = clumping of viral particles = shutting down replication
Resistance to oseltamivir does not necessarily confer resistance to zanamivir
Mutations in the receptor affect the conformational change of the oseltamivir = antibiotic resistance
But this doesn’t affect zanamivir: mutations that prevent this conformational change prevent binding of oseltamivir (Panel B). Zanamivir and sialic acid still bind to NA active site despite H274Y mutation
Polymerase Inhibitors: Mechanism of Action1
polymerase inhibitors: inhibit ENDONUCLEASE activity
Benefits of Oseltamivir therapy
REDUCTION of
- Duration of illness in adults and children
0. 5 to1.5 days or 25-32% - Viral shedding and viral load
- need for Antibiotics
- length of hospializations
- hospital mortality
- however you need to be treated EARLY. It peaks at day 2*
Who do you treat with Oseltamivir
- During periods of community circulation of influenza viruses
Prompt empiric treatment is recommended for persons with suspected or confirmed influenza and:
- Respiratory illness requiring hospitalization
- Outpatients with progressive, severe, or complicated illness
- Outpatients at higher risk for influenza complications (i.e. pneumonia)
- Outpatients without risk factors but presenting early (<48 h) on a case-by-case basis
Prophylaxis of influenza contacts?
Prophylaxis (HALF THE DOSE of oseltamivir/zanamivir) of household contacts
- Reduces transmission
- Previously recommended for high-risk contacts
Early treatment of contacts may now be preferred
- NOT GOOD if they are already infected, because then if you give them half dose; you’re exposing the virus to subtherapeutic environment which PROMOTES resistance
Take home points for Infuenza
- treatment
- Window to treat?
- Resistance characteristic in influenza?
Antivirals are beneficial in treatment of influenza
Early treatment (<48 hrs) increases benefits - Severe disease, immunocompromised may still benefit from late treatment (up to 5 days)
Influenza has the ability to change rapidly
Next year’s circulating strains and their resistance profiles will determine best treatment strategies
Physicians need to stay up to date
http://www.phac-aspc.gc.ca/fluwatch/index-eng.php
Herpes Simplex Virus
These are enveloped, double stranded DNA viruses
Uses the Lytic cycle to transcribe viral DNA by the host cell and form new viral proteins
They can also travel up sensory neurons to start the LATENT cycle
stay FOR LIFE.
Commonly asymptomatic.
Symptoms include skin and mucous membrane lesions:
HSV1: Infections above the waist (mouth and tongue)
HSV2: infection below the waist (genitals)
* however there is a lot of cross over.
Herpes lesions in the mouth look like….
Cluster of small, painful, fluid-filled blisters
- They ooze and ulcerate
- Heal in a few weeks
Herpes has dormant stages and reactivation stages, it comes and goes.
reactivation is often asymptomatic BUT when it is,
you’ll see handful of blisters at the vermillion border (lip) on ONE side of the face
- these blisters a small and typically heal in a week
Acyclovir active against…
Active against:
HSV
VZV, varicella (lower affinity, thus requires higher doses)
Very poor activity against other herpesviruses
15-30% bioavailability p.o. (poor, need IV)
Acyclovir mechanism of action
Triphosphate form inhibits viral DNA synthesis by:
1) competing with dGTP for viral DNA polymerase
2) chain termination
Acyclovir - Resistance
in HSV and VZV
HSV Most often due to virus DEFICIENCY in TK [thymidine kinase, the target for this drug] Rarely due to altered TK or DNA pol Rare in immunocompetent 4-17% of isolates in immunocompromised
VZV
Mostly ALTERED TK (lower affinity for ACV)
Acylovir- clinical indications
- PO
- Topical
- IV
PO Genital herpes - Primary infection - Suppression of recurrences Oro-labial herpes - Primary - Recurrence Primary VZV
Topical
Keratoconjunctivitis
IV
- HSV encephalitis
- Neonatal HSV
- HSV in immunocompromised
- VZV (primary or reactivation) in immunocompromised
- Prophylaxis post bone marrow transplant
Acyclovir Side Effects
Well-tolerated
Neutropenia with prolonged courses
Nephrotoxicity when given IV
Neurotoxicity in renal failure
Valacyclovir
Pro-drug of acyclovir
Only p.o.
70% bioavailability** better bioavailability :)
Otherwise similar profile to acyclovir
Penciclovir / Famciclovir
Famciclovir is the prodrug of penciclovir and is available p.o. Guanosine analog 70% bioavailability Well-tolerated Same mechanism of action as acyclovir
Resistance:
- Able to overcome some resistance to acyclovir, but TK deficient mutants remain resistant
- Rare in immunocompetent
CMV- Cytomegalovirus
- which populations are at high risk of contracting this
usually you already have CMV and its just dormant
it gets activated in:
transplant patients who take immunosuppressants, creating an environment for CMV to reactivate
- so pts after allogenic HCT are at HIGH risk
in order of highest to least risk for allogenic HCT CMV R+ GVHD CMV R+ without GVHD CMV R- with GVHD CMV R- without GVHD
R+ means they’ve had CMV, R- i think means they haven’t prior too
AKA patient with GVHD are at higher risk
Define: Therapeutic Empirical Prophylactic Preemptive
Therapeutic: treat an established, clinical disease
Empirical: treat a possible disease, given signs or symptoms
Prophylactic: treat ALL members of a population to prevent the occurrence of clinical disease
Preemptive: treat individuals at high risk for clinical disease given laboratory markers
i.e. CMV and transplant patients* can’t be given prophylatically because of fatal side effects, they need to be MONITORED and carefully treated
Gancyclovir
Used to treat CMV
Guanosine analog
In vitro activity against all herpesviruses
100x more active against CMV than ACV
In CMV infected cells, the virally-encoded UL97 phosphotransferase performs first phosphorylation
After di and tri phoshorylation (cellular enzymes), GCV inhibits viral DNA pol
Should be given i.v., via central venous line
Gancyclovir RESISTANCE
CMV most often develops resistance by mutations in the UL97 gene (viral protein kinase) DNA pol (UL54) mutations are rare However, confer cross-resistance to cidofovir and foscarnet Double mutants (UL97 and UL54) are the most resistant ↑ duration of therapy ↑ chance of developing resistance
Gancyclovir clinical indications
CMV retinitis
- Treatment and suppression
- Can also be given intraocularly
CMV pneumonitis
- In combo with anti-CMV immunoglobulin
Prophylactic or pre-emptive
- Bone marrow transplant (Donnor-/Recipient+) -pre-emptive
- Solid organ transplant (D+/R-) ->prophylactically
Congenital CMV
Gancyclovir- Side Effects
Requires central line
Bone marrow toxicity
- Neutropenia (40%)
- Thrombocytopenia (15-20%)
Valgancyclovir
Oral pro-drug of gancyclovir
60% bioavailability
Indications:
- Treat & suppress CMV retinitis
- CMV prophylaxis in solid organ transplant
What you need to know about Cidofovir
- why is it second line and not first
Cytidine analog
In vitro activity against herpesviruses, papillomaviruses, polyomaviruses, adenoviruses
Does NOT depend on VIRAL ENZYMES for phosphorylation
good because resistance is RARE however it is SECOND line agent becuase it has DOSE dependant NEPHROTOXICITY
Cidofovir
- clinical indications
- Side effects
Clinical indications
CMV disease in
- immunosuppressed patients who do not tolerate GCV and foscarnet
- whose virus is suspected to be resistant to GCV and foscarnet
Side effects
- Dose-dependant nephrotoxicity
- Neutropenia
- Potentially carcinogenic and teratogenic
Foscarnet
- analog of?
- active against?
- Resistance
- how is it administered?
- dose must be adjusted in patients with?
Pyrophosphate analog
Active against all herpesviruses
[Does not require any phosphorylation
Directly inhibits DNA pol]
Active against CMV resistant to GCV (UL97) and TK deficient HSV / VZV
CMV resistance is rare
DNA pol mutation, after prolonged or repeated exposure
Must be given i.v.
Adjust in renal failure
First line for CMV vs second line treatments
First line:
Gancyclovir
Valgancyclovir
second line:
cidofovir
Foscarnet
Letermovir
- when it is administered? (therapeutic, prophylaxis, preemptive, empirically)
We don’t prophylaxis CMV with gancyclovir (cause its marrow toxic) but we do for letermovir (different mech of action and doenst have same toxicitiy)
Approved for prophylaxis of CMV infection in adult CMV-seropositive allogeneic HSCT
DOUBT you need to know the mechanism but here it is:
CMV replication involves cleaving of concatemeric genomic DNA and packaging of each genome into preformed virus capsids
The CMV terminase complex (UL51, UL56, UL89) performs these sequential events, a viral process not present in uninfected human cells
Letermovir inhibits the terminase complex by binding to UL56, UL51
Anti Hepatitis agents
Interferon- (HBV & HCV)
Ribavirin (HCV)
Nucleoside / nucleotide analogues (HBV)
Interferon a
- what is it
- how does it work
- how it is administered (po? iv? im?)
Large glycoproteins
Cytokines that possess antiviral, immunomodulatory and antiproliferative effects
No direct antiviral effect, but antiviral activity occurs via activation of host cells to produce a series of antiviral proteins
Intramuscular or subcutaneous injection
Attachment of large, inert polyethylene glycol (PEG) molecules enables once-weekly dosing
Interferon a
- side effects
- clinical indications
Side-effects: Flu-like syndrome Myelosuppression Neurotoxicity Autoimmune disorders (thyroiditis) Cardiovascular effects
Clinical indications
Chronic HBV
Acute and chronic HCV
Refractory codylomata accuminata (intralesional)
* NOT USED REALLY… Don’t focus too much on this
Ribavirin
Purine nucleoside analog, inhibits wide range of RNA and DNA viruses (broad spectrum— however really only works well for HEPATITIS)
Resistance very rare
HEPATITIS treatments
Interferon A
Ribavirin
Nucleoside / nucleotide inhibitors in chronic hepatitis B infection
Treatment of Hep C
Direct acting antiviral therapy available
TAKE HOME points on Antivirals
Antiviral agents have unique mechanisms of activity
- Can only inhibit replication- only NEW ones, so those that have already replicated and triggered proinflammatory response are out of reach
Resistance tends to emerge in the context of active replication in the face of antiviral treatment (subtherapeutic)*
What are some diagnostic methods you learned about?
Microscopy Culture Bacterial identification - biochemical tests, - identification systems Susceptibility testing Serology Nucleic acid-based detection
Acid- fast stain
- What does it work on
- why is it used vs gram stain?
Stain with carbolfuschin (red) and heat
Decolorize with acid alcohol
Counterstain with methylene blue
Used for Mycobacteria sp. Some bacteria (Nocardia sp., Actinomyces sp.) are “partially acid-fast” (when a lower concentration of acid is used)
Cell wall lipids/waxy layer do not allow these organisms to stain well on gram stain.
The cell wall lipids of the Mycobacterium do not dissolve when the acid alcohol is applied so the red stain doesn’t wash off
Which bacteria cannot be gram stained?
Intracellular organisms (chlamydia),
those that lack a cell wall (mycoplasma),
those that have a lot of cell wall lipids (mycobacteria), those that are too small to be seen on light microscopy (spirochetes)
What are the 5 types of Cultures?
- General purpose: capable of detecting most aerobic and facultatively anaerobic organisms
- Sheep’s blood agar - Enriched: supplemented with nutrients to promote the growth of more fastidious organisms
- Chocolate agar
3. Selective: supports growth of one type or group of microbes while inhibiting the growth of others MacConkey agar (for enterobacteriacea)
- Differential: allows grouping of microbes based on different characteristics demonstrated on the medium
- Sheep’s Blood Agar, MacConkey agar - Specialized: developed with additives for the purpose of isolating a specific pathogen
Sheeps Agar
Type of DIFFERENTIAL culture
Sheeps blood: the ability of the bacteria to hemolyze RBC helps you differentiate them
Alpha= partial hemolysis- so a greenish colour
Beta = complete hemolysis- clears the red, so it’s yellow area that is clear
Gamma = nothing hemolyzed – faint, mostly red
What are the different environments that need to be included in a culture
- Provide an example of which organism each environment is well suited for
After plating of specimen onto selected agars, these must be incubated
a. Aerobic environment
b. Microaerophilic environment – Campylobacter sp
c. CO2 rich environment – Streptococcus sp.
d. Anaerobic environment – Clostridium sp.
Blood culture
- difference in the two bottles
- what do the bottles contain
-
One bottle for aerobic recovery and another for anaerobic recovery
Bottle contains:
- Liquid media that is nutritionally enriched
- Antibiotic removal device or resin
- Anticoagulant
It is incubated at 35C for 5 days in a continuous-monitoring blood culture system
How do we detect growth in blood cultures
Growth is detected based on how much CO2 is produced
Continuous-monitoring systems
- Microbial growth and metabolism causes release of CO2
This can be detected in several ways:
- Using a pH sensitive membrane at the bottom of the bottle that changes color as CO2 is produced – alters the amount of light reflected
- Using a gas-permeable sensor at the bottom of the bottle that increases fluorescence output as CO2 is produced.
Catalase tests
- what is it used to differentiate
If bacteria produces catalase enzyme, it will break down H2O2 and bubble will appear
i.e. Staph are catalase positive
Strep are catalase NEG that’s how we differentiate between these two GRAM POSITIVE bacteria :)
Oxidase
- used on which type of bacteria
often used for gram neg. to see if it produces cytochrome oxidase, if it DOES it’ll turn purple/blue
Which test helps to differentiate between staph aureus and staph epidermis?
These are both Gram POSITIVE bacteria
use Coagulase test
aureus: coagulase positive
epidermis: coagulase neg
Motility Medium
- What is a type of bacteria this can help differentiate
You grow the bacteria in a line
if you only get a single dark line then you know the bacteria is NOT motile vs if the whole tube turns red, then you know the bacteria IS motile
Motility via flagella is common in the gram negative bacilli (enterobacteriaceae) – growth is indicated by the presence of red color
Triple Sugar Iron Agar
Used for gram Neg
Has three different types of sugars in it
Colour changes dictate what sugars ur bacteria is fermenting to help identify them
API vs automated system
API = many different wells
Suspension of bacterial into each well
Each well has a different solution / test
Can see which wells have a reaction or not
Determine which tests are positives and negative,
You input the data onto computer
It will identify the bacteria (i.e fingerprinting the bacteria)
Automated systesm:
Computer will analyze and tell u the name of organism
Sinus Lavage
Nasal irrigation is a personal hygiene practice in which the nasal cavity is washed to flush out mucus and debris from the nose and sinuses, in order to enhance nasal breathing.
If patient comes in with headache and you see gram negative diplocci in CSF
- what bacteria should you be suspicious of
- what illness should you be suspicious of?
with Neisseria meningitidis
if you do further testing: Blood agar plate from CSF sample would
show grey, moist, glistening colonies if it is compatible with Neisseria meningitidis
be highly suspicious of MENINGITIS and treat appropriately ASAP
Purpose of E test
on the strip, the concentration of AB decreases and you see until which point down the strip bacterial growth starts
purpose: to figure out the Minimum Inhibitory Concentration of AB to inhibit the growth of bacteria
MIC
- how is it measured
MIC: minimal inhibitory concentration = lowest concentration of a drug that will inhibit visible growth of a microorganism
Can be measured directly by - E-test and automated systems
- Can be inferred by disk diffusion (larger zone = smaller MIC)
Susceptibility results
The bacterial isolate is tested against several antimicrobial agents.
For each drug, the isolate is deemed to be Susceptible (S), Intermediate (I) or Resistant (R)
Standards for S/I/R established according to:
- Therapeutic success
- Levels achievable at site of infection with usual dose
you can give a patient something with S but NOT I or R because that = too much resistance = not effective
Meaning of S on susceptibility results
Susceptible (S): Bacterial isolates inhibited by the usually achievable concentration of drug when the dosage recommended to treat the site of infection is used.
Meaning of R on susceptibility results
Resistant (R) : Bacterial isolates are NOT inhibited by the usually achievable concentration of the drug when the recommended dosage used OR the MIC falls in range where specific resistance mechanisms are likely and clinical efficacy is not reliably shown in treatment studies
Meaning of I on susceptibility results
Intermediate (I): Bacterial isolates with antimicrobial MICs that approach usually attainable blood and tissue levels, but for which response rates may be lower than for S isolates.
There may be clinical efficacy at body sites where the drug is usually concentrated (e.g. fluoroquinolones in urine) or when a higher than normal dosage can be used (e.g. -B lactams).
Serology
- what does it measure
- when is it often used
Traditional definition: measure of a patient’s antibody response to an infection/antigen
Techniques can also be used to detect antigen in patient samples
Often used for the identification of infection with organisms for which culture is difficult (i.e. viruses) or requires prolonged incubation
Enzyme immunoassays (EIA) vs ELISA
- what are they used to test for?
Use of Ab or Ag conjugated with an enzyme which forms a measurable reaction product upon reacting with its substrate
- Often color reaction
When Ab or Ag is absorbed to a solid phase, the assay is referred to as an ELISA (enzyme-linked immunosorbent assay)
Use: HIV test, E.coli enterotoxin, rotavirus, hepatitis B markers,
indirect vs sandwich ELISA
Indirect: antigen coated well- testing if blood has antibodies
Sandwich: monoclonal antibody coated well: testing if blood is infected/has antigens
Immunochromatographic assay (Lateral flow assay)
Detects the presence of a target substance in a liquid sample by migration on a solid support by capillary flow.
The identification and detection procedures are based on the antigen–antibody immune reaction
i.e. the covid rapids we’ve done
Immunofluorescence assays: IFA
Indirect fluorescent antibody test (IFA)
Used to detect specific antibody in patient sample
you need a specific microscope to see it
Immunofluorescence assays: DFA
- What can it be used to detect
Direct fluorescent antibody test (DFA)
Directly tests for an antigen and allows detection of infectious agents inside infected cells
Labeled Ab is applied to the fixed specimen
Herpes Simplex Virus, Varicella Zoster Virus Influenza Virus Respiratory Syncytial virus Pneumocystis jiroveci T. pallidum
Nucleic acid-based identification
e.g. PCR
Diagnosis of infection (often difficult to culture organisms)
Ex: Mycobacterium tuberculosis, respiratory viruses
Identification of colonization
Ex: MRSA
Outbreak investigation (PFGE)
Genotyping – MRSA, C.difficile
And so much more in the next years
PCR
Polymerase Chain
Reaction (PCR)
Reverse Transcription PCR (RT-PCR) is used when starting material is RNA. Through reverse transcription, complimentary DNA (cDNA) is created, which is then amplified.
The tube has primers for agent of choice, if the dna matches it’ll be amplified
What is Tropical Medicine?
Geography: Many infections are geographically restricted more ecological “microniches” in tropics biodiversity gradients towards equator complex ecological relationships
- PARASITIC infections also occur outside the tropics
HOWEVER, ALSO:
Poverty:
Both infectious and non-infectious
Huge intersection btw poverty & health - “bottom billion”
Examples of Protozoa
Intestine: Entamoeba histolytica Giardia Isospora Cryptosporidium Cyclospora
Systemic: malaria Babesia Toxoplasma Leishmania Trypanosoma
Helminths
Nematodes
- Strongyloides
- Ascaris
- Trichuris
- hookworm
Cestodes
- tapeworms
Trematodes
- intestinal flukes
- Schistosoma
Define Protozoa
eukaryote”..has genetic material encased in
a nuclear membrane (unlike bacteria and
viruses)
classified traditionally by morphology
(eg. organelles of locomotion), life
cycle and mechanisms of
reproduction etc.
Trophozoite
any stage in a protozoan’s life cycle which can ingest food- it is in it’s activated stage. In practice also refers to the motile form.
Cyst
the non motile form which is protected by a distinct membrane or cyst wall. This is an infective stage of the parasite, waiting to find another host.
Excystation
the process of emergence of the trophozoite from the cyst (vs. encystation) just a transitional stage
Entamoeba histolytica
(amoebiasis)
3rd leading parasitic cause of death in the world
Dysentery (BLOODY DIARRHEA) important cause of diseases throughout history
Dysentery
is an infection of the intestines that causes diarrhoea containing blood or mucus.
Ameobiasis generally presents with:
1) asymptomatic carrier state
2) acute amoebic dysentry***
3) amoebic liver abscess
4) amoeboma
Amoebic Dysentery
Presentation
Bloody, mucousy diarrhea (colitis)
Fever
Abdominal pain
Diagnosis
Microscopy:
- Amoebic (hematophagous trophozoites) in stool
Mixed WBCs in stool
Patchy inflammation seen on colonoscopy (biopsy)
Stool PCR or antigen capture (where available)
AMOEBIC LIVER ABSCESS
Presentation
- persisting fever
- RUQ or epigastric pain and/or shoulder pain
- rarely diarrhea
Diagnosis
- ultrasound 2. raised WBC
- serology
- aspirate microscopy, PCR
- response to metronidazole 750 t.i.d.
Laboratory problems with diagnosing AMOEBIC infection
LOW sensitivity and specificity
What are the two types of Entamoeba that look similar
- which one is more common
Entamoeba Dispar - 90%, this is a non invasive one
Entamoeba Histolytica - 10%
Entamoeba histolytica
- what vector do they spread through
- transmission route
Humans the only source (not a zoonosis)
Fecal-oral transmission
Our understanding is still in transition because of misidentified cases.
Which finding doesn’t fit E. histolytica amoebiasis
- High White count
- Enteritis
- Colitis
- Blood in stool
- WBCs in stool
- Right shoulder pain
3 and 4 and 5 go together so they all must be correct
the one that DOESN’T fit is 2. Enteritis
Giardia Lamblia
- characteristic microscopic feature
- route of transmission
- prevalence, common in which populations
- what vectors does it transmit through
owl’s eyes
fecal oral spread
- prevalence 3-5% of acute diarrhea in Canada; increased in travellers, backpackers, institutions, daycare centres
- zoonosis - found in most mammals; esp. beaver (“beaver fever”), cattle, cats, dogs, etc.
Symptoms vs Signs of Giardiasis
Symptoms: diarrhea flatulence abdominal cramps decreased appetite \+ /- loss \+/- nausea NO FEVER
- Emphasize importance of upper GI symptoms (70% sens) for making “colitis” very unlikely in dDx*
Signs:
mild abdominal
tenderness
Laboratory Findings of Giardiasis
no leukocytes in stool
no mucous in stool
giardia cysts/trophs intermittent in stool
giardia cysts/trophs in duodenal aspirate
Giardia Treatment
*Metronidazole 250-750 mg tid x 7-10 days
Resistance an increasing problem
others, don't stress about them: [Tinidazole, Albendazole Nitazoxanide Paromomycin Quinacrine Furazolidone]
Giardia causes which?
- Gas
- Fever
- Dysentery
- WBCs in the stool
- Colitis
- Beaver constipation
- GAS
think upper GI problems
and they emphasized Giardia has NO FEVER*
Cryptosporidium parvum
Cryptosporidium hominis
- What pandemic made this more prevalent
- now recognized as an important cause of _____
Large numbers seen with HIV pandemic
Now recognised as an important cause of self-limited foodborne diarrhea worldwide
CRYPTOSPORIDIUM
- reservoir
- transmission route
- where does it live
Epidemiology:
- bovine reservoir (zoonosis) here
- person-person in tropics - epidemic contamination of municipal water (fecal-oral)
Biology:
- lives in small intestine epithelial cell membrane
- Apicomplexa life cycle
Cryptosporidium
- clinical presentation
- which stain
Clinical:
- diarrhea 2-3 weeks (chronic in AIDS, other immune compromise)
- cholecystitis, respiratory
need Acid Fast stain
Cyclospora cayetanensis
- which population
- transmission route
- where does it live
- clinical symptom
- treatment
Epidemiology: in travellers to tropics (Nepal, Americas)
transmission otherwise : imported food-> raspberries, basil from Guatemala, Mexico
Biology: lives in small intestine epithelial cells
Clinical: prolonged diarrhea (2-6 wks)
Treatment: Trimethoprim-sulfa
Trichomonas vaginalis
- their reservoir
- transmission routes
- what does it cause/symptoms
- treatment
same family as Giardia
Not a GI tract problem…. TV is its own category
Its an STI
Epidemiology: reservoir is human
urogenital tract, sexual transmission
Biology: causes inflammation of
vaginal and urethral epithelium
Clinical: spectrum from asympt., foul PV d/c, dyspareunia, abdo cramps, to pre-term birth
Treatment: metronidazole
Concepts to remeber about zoonosis and commensalism
Commensalism (shared dinner table)- human only parasites are more adapted to us, mutally beneficial for us to survive VS
Zoonosis - more virulent and pathogenic.
Malaria
- What type of microbe
- intestinal or systemic effects?
Protozoa
Systemic, Blood
The problem with Malaria
One of the oldest infections of humans
500 million febrile episodes per year
Millions of deaths per year
Extremely widespread until 20th C
Exceptions include Sub-Saharan Africa
- Resurgent disease since 1980-1990s, recent decreases
- Multifactorial causes
- Emergent drug resistance
- Few affordable alternatives, inefficient vaccines
- Failed mosquito control
Key malaria GENUS that are the issue
- their reservoir
Plasmodium spp. protozoan
Anopheles mosquito vector
Humans are only reservoir (4/5 species)
Where in the world does Malaria continue to be an endemic problem?
Haiti Dominican Republic
Which 4/5 species cause malaria in humans
Plasmodium falciparum
vivax
ovale
malariae
the one that doesn't = knowlesi (zoonotic, so very bad if you do get it)The life cycle of Malaria
Mosquito carries the vector and injects you with the sporozoite
The sporozoite goes to the liver, liver releases the shits in the blood
It multiplies in the RBC-> RBC bursts infecting new cells -> cycle continues
Some of them turn into male and female gametes and mosquito can pick them up if it bites you, and will reproduce in mosquito -> cycle continues
Which protozoa is not a zoonosis?
- Giardia lamblia
- Entamoeba histolytica
- Cryptosporidium
- Plasmodium knowlesi
- beaver fever, zoonosis
- humans are the only source**
- bovine so. zoonosis
- in monkeys so, zoonosis
Which type of Malaria leads to tertian and quatran fevers?
In P vivax and P ovale malaria, a brood of schizonts matures every 48 hr, so the periodicity of fever is tertian (“tertian malaria”),
whereas in P malariae disease, fever occurs every 72 hours (“quartan malaria”)
falciform, the most severe, DOES NOT follow this pattern
P Vivax
- receptor
- resistant population
The P. vivax used to bind onto the Duffy/fy fy antigen receptors to infect us. But due to natural selection west africans became Duffy Ag negative = … Vivax can’t infect them via this method anymore -> vivax evolved to infect us differently
P. Falciparum
has many receptors, hence so infectious
- 2 x106 sites per RBC
Common Malaria Symptoms
very non specific
MUST HAVE: FEVER
* if no fever, likely NOT malaria
other symptoms: chills rigors perspiration fatigue headache delirium confusion coma shortness of breath jaundice
Signs of Malaria
anemia
splenomegaly
Malaria incubation period
around 2 weeks, at least 10 days before you’ll see symptoms
so in a traveller you have to ask last 10 days
Pathogenesis of fatal malaria
cerebral malaria 50%***
ARDS 46%
renal failure 40%
around 10% or under: hematological shock sepsis ruptured spleen
can lead to death within a week*
and you rarely see people on day 1 so you gotta treat ASAP
Black Water Fever
Blackwater fever is a complication of malaria infection in which red blood cells burst in the bloodstream (hemolysis), releasing hemoglobin directly into the blood vessels and into the urine, frequently leading to kidney failure.
better now since we STOPPED using Quinone therapy
Cerebral Malaria
- pathophysiology
- The RBC fill with plasmodium Falciprum becomes deformed and RIGID so its not able to pass through the capillaries
- It gets stuck, causes adherance sticky RBC knobs
- high TNF levels - vascular endothelial adhesiveness
- direct CNS effects
poor deformability of infected RBCs
- increased endothelial permiability
High Transmission and its effect on clinical severity
- compare to low transmission
High transmission intensity = we more likely to die young
Lots of mortlaity in children from this, but those that survive have good immunity in adults = can be misleading cause this can be seen as malaria being only a pediatric disease when its really not- if an adult goes there, aren’t immune to it so they WILL get infected
You need re-exposure for immunity maintenance
If you grew up in west africa, survived high transmission then moved to canada and then came back to africa = you’ll be at risk cause you’d lose ur immunity since no exposure in canada
LOW TRANSMISSION:
Low transmission = children survive but we see severe malaria in older age
Sensitivity of Malaria Technology
thin vs thick smear and such can give you accuracy of up to 5-25 parasites per mm3
however the clinical threshold for which SYMPTOMS actually start to appear is at 20 parasites per mm3
- challenge is to catch them at early rates before they are symptomatic inorder to prevent spread
Is malaria infectious?
No. Malaria is not spread from person to person like a cold or the flu, and it cannot be sexually transmitted.
What is one VISIBLE thing you can measure on people in a community to get an estimate of the malaria rate in that community
you can measure their SPLEEN because splenomegaly is a common manifestation of malaria
Some clues in CBC that indicate malaria
Fever but a low WBC is weird, major clue for malaria
What drug is malaria known to be resistant to?
- what is the alternative treatment?
Chloroquine
malaria is resistant to it
alternative:
quinine
3 ways Malaria Prophylaxis drugs work
- Kill parasites in the liver
Causal prophylaxis - Kill asexual parasites in RBCs Suppressive prophylaxis
- Kill sexual parasites (gametocytes) in RBCs
Gametocytocidal prophylaxis
Wide spread treatment for malaria used everywhere
Artemisinin combination therapy
What common product can you find quinine in ?
TONIC that is used in Gin and Tonic
Toxoplasma Gondii
- it’s two forms
Systemic Protozoa
Cyst form (stability in environment) vs Trophozoites form (free and in macrophage)
Main pathway of transmission for Toxoplasma is?
- concept of definitive host
it is specifically pregant women who are most susceptiable at it is transmitted congenitally*
it is zoonosis, farm animals (cows)
once infected, it sits in the muscles
i.e. eating meat from an infected animal will transmit to us
cooking meat helps
Definitive host= cat. Cat is the vessel the bacteria uses to multiply in the cat’s gut and sheds in the cat poop
- cat only host with sexual stage – sheds from intestinal tract
- reservoir is cyst (bradyzoite) in many animals and birds
- mode of transmission : fecal oral from cat
oral (raw/undercooked meat)
transplacental during acute infection
Essentially: cat poop in gardens gets in food we eat, or animals eat the poop garden and we eat the animal muscle (which is were the bacteria resides) but it is mostly pregnant women at risk?
Clinical forms of Toxoplasmosis
- lymphadenopathic/acute
- ocular
- neonatal
- in immunocompromised host
Lympathadenopathic toxoplasmosis
- signs and symptoms
- Duration
- Source
SIGNS AND SYMPTOMS
fever
lymphadenopathy
fatigue
Duration:
1-4 weeks
Source:
raw meat, (outdoor) kitty poop
Occular Toxoplasmosis
- Signs and Symptoms
- Duration
- Source
Signs and Symptoms: decreased vision
retinal lesions on retinoscopy
scars
Duration: weeks
Source: intrauterine infection
raw meat, kitty
Neonatal Toxoplasmosis
- Signs and Symptoms
- Duration
- Source
Signs and Symptoms:
Mother- lymphadenopathic toxoplasmosis
(fever, nodes and/or fatigue)
Child: splenomegaly (90%) jaundice (80%) fever, anemia, hepatomegaly, intracranial calcifications
Duration: days to weeks
Source: raw meat, kitty
Vertical Transmission of Toxoplasmosis
% of fetus infected vs severity of sequelae
the % of infection is lower in earlier trimesters but WORSE severity of sequelae
Trimester
1: 15%, high severity
2: 30%, med severity
3: 60%, low severity
possibly 95% of III trimester will have sequelae before
age 10, which may be subtle
Toxoplasmosis in immunocompromised
Signs and Symptoms
Duration
Source
Signs and Symptoms:
in HIV patients : Confusion, headache, fever
Intracerebral space occupying lesion
in Transplant patients get reactivation: any organ, lungs, generalized
Duration : indefinite
Source :
raw meat, kitty
from mother in utero
(vertical transmission
What are the Haemoflagellates
- two examples
Type of protozoa Leishmania: has 3 different types of disease i. cutaneous ii. mucocutaneous iii. visceral
Trypanosoma: African sleeping sickness
South American Chagas disease
Leishmania and Trypansoma
- what diseases do they form
Type of protozoa, a Haemoflagellate
Leishmania: has 3 different types of disease
cutaneous [ulcers on your skin :( ]
mucocutaneous
visceral
Trypanosoma: African sleeping sickness
South American Chagas disease
Leishmania
- motile vs non motile form names
- mode of transmission
promastigotes: motile
amastigotes: immotile, active in macrophages
transmitted by a flee bite.
Hemoflagellates
- two examples
- type of species
- type of transmission
- basic morphologic stages
- distinguishing features
Trypansoma and Leishmania
- protozoa
- important pathogens of both man and livestock (zoonoses)
- basic morphologic stages are motile promastigote and trypomastigote and immotile amastigote
In Leishmania what is the
host
vector
reservoir
host : Human
vector : Sandfly
reservoir : Dog, gerbil
Sandfly phelobotomus
nets don’t work against them because they are TINY
but cute because they have hairy wings and don’t fly well
they transmit leishmania* they are the vector
Diagnosis of Leishmania
Biopsy….granuloma
….impression smear stain–amastigotes
Aspirate and stain… amastigotes
Aspirate culture…promastigotes (amplification)
Aspirate or biopsy….PCR (speciation)
Mucocutaneous leishmaniasis
- harmful. should be detected right away and treated so hard and soft palates aren’t destroyed**
- can destroy you nose **any mucosal lining/surface
Visceral leishmaniasis
- Incubation period
hepato AND splenomegaly
both at the same time is not normal so this is a clue*
Incubation period 4-10 mo (10 days to 8 yrs)
Common: fever Hepatomegaly Splenomegaly Cough Lymphadenopathy - inguinal - axillary - post cervical
Treatment of Cutaneous vs Visceral Leishmaniasis
Cutaneous:
Destructive (eg liquid nitrogen)
Topical
Visceral
Antimony IV daily x 3-4 weeks
(or intra-lesional)
Liposomal Ampho B 7-10 doses
African Sleeping Sickness
- Two types
- vector
- reservoir
Trypanosoma
CNS disease
Theres 2 forms: gambienese and rhodesienes
West African disease = human disease, human parasite - well adapted to humans so NOT that severe
East African = zoonosis, predominantly a cattle disease and it can contaminate us… much more severe
vector: TSETSE FLY
Reservoir: Bush Buck
African trypanosomiasis
- physical manifestation
- parasitemia related
- Organ Specific
Chancre: localized edema, tenderness, heat
Parasitemia related: Periodic fever, headache, joint and muscle pain,
Lymphadenopathy, weight loss, pruritis, anemia
Organ specific:
Edema: peripheral, ascites, pulmonary, pericardial Cardiac: EGG changes, CHF, cardiac distention GI: diarrhoea, anorexia Neurologic: focal neurologic defects, confusion, lethargy, coma
For the following parasites, which three things should you know?
Toxoplasma
Leishmania
African trypanosomiasis
Remember:
Mode of transmission
Clinical features
Prevention strategies
Herpes Viruses
HSV1 HSV2 VZV CMV EBV HHV6 HHV8
