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Phase 2A > ICS (Part 4) > Flashcards

ICS (Part 4) Flashcards

1
Q

What are protozoa?

A

“One celled animals”

Single cell with nucleus
(Eukarytoic)

> 30,000 species

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2
Q

How is protozoa classified and what are the classifications?

A

Classified into 5 major groups based on motility:
1)Flagellates
- Trypanosoma spp
- Leishmania spp
- Trichomonas vaginalis
- Giardia lamblia

2)Amoeba
- Entamoeba histolytica

3)Sporozoa
- Toxoplasma gondii
- Cryptosporoidium spp
- Plasmodium spp

4)Cilliates
- Balantidium coli

5)Microsporidia

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3
Q

Talk about African Trypanosomiasis.

A
  • “Sleeping sickness”
  • endemic in Africa.
  • a) Trypanosoma brucei gambiense
  • b) Trypanosoma brucei rhodesiense
  • transmitted via the bite of an infected Tsetse fly
    Signs and Symptoms:
    - Chancre
    - Flu like symptoms
    - CNS involvement
    (sleepy, confusion, personality change)
    - Coma and death
    • Diagnosed on blood film or CSF
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4
Q

Talk about American Trypanosomiasis.

A
  • “Chagas Disease”
  • Trypanosoma cruzi
  • Spread by faeces of Triatomine Bug
  • Acute:
    >Flu like symptoms
  • Chronic:
    > Cardiomyopathy
    > Megaoesophagus
    > Megacolon

Classical Romana sign on the eye if you have a bite on the eyes, causes problems in luminal organs like the heart etc.

Diagnosed by visualising trypomastigotes seen on blood film, or amastigotes on biopsy (chronic).

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5
Q

Talk about Leishmaniasis.

A
  • Leishmania spp
  • Spread by the bite of the sandfly
  • 20 species affect humans
  • Three clinical pictures:
    > Cutaneous
    > Mucocutaneous
    > Visceral
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6
Q

Talk about Cutaneous Leishmaniasis.

A
  • Cutaneous leishmaniasis is the most common form of the disease
  • Incubation weeks to months
  • long lasting lesion, impressive scar , afghanistan

> Ulcers on the exposed parts of the body, eg face, arms and legs.
There may be a large number of lesions – sometimes up to 200 – which can cause serious disability.
When the ulcers heal, they invariably leave permanent scars, which are often the cause of serious social prejudice.

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7
Q

Talk about mucocutaneous leishmaniasis.

A
  • much more virulent, will generally affect structure around the nose and the pharynx and destructive

> partial or total destruction of the mucous membranes of the nose, mouth and throat cavities and surrounding tissues.
This disabling form of leishmaniasis can lead to the sufferer being rejected by the community.

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8
Q

Talk about diagnosis, treatment and possible complications.

A

Diagnosed through biopsy, serology or PCR

Treatment is available, but may have longstanding problems with scarring/destruction that isn’t reversible.

People particularly affected by mucocutanous leishmaniasis can have recurrent bacterial pneumonias and die from sepsis due to the destruction caused to their nose and palate.

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9
Q

Talk about visceral leishmaniasis.

A

Serious with high motility rate, lymph system and bone marrow system problems, anaemic,widely distributed, visceral is less distributed, mucocutaneous in south africa

Incubation days to years

Visceral leishmaniasis (ie affects the viscera - internal organs)

Also known as kala-azar (black fever)

Characterized by irregular bouts of fever, substantial weight loss, swelling of the spleen and liver, and secondary anaemia (which may be serious).

Diagnosed through biopsy, serology or PCR

High fatality if not treated.

Treatment is available

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10
Q

What are the signs and symptoms of Trichomonas vaginalis?

A
  • Sexually transmitted
  • Asymptomatic
  • Dysuria
  • Yellow frothy discharge
  • Treated with Metronidazole
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11
Q

Talk about Giardiasis.

A
  • caused by Giardia lamblia
  • Faeco-oral spread
  • Diarrhoea
  • Cramps, bloating, flatulence
  • Recent travel, childcare
  • Trophozoites/cysts seen in stool
  • Treated with metronidazole
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12
Q

Talk about amoebaiasis.

A
  • Amoebiasis - sanitation and handwashing, bloody diarrhea
  • Entaemoeba histolytica
  • Faeco-oral spread
    > Dysentry
    > Colitis
    > Liver and lung abscesses
  • Trophozoites/cysts seen in stool
  • Treated with metronidazole
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13
Q

Talk about sporozoa (Cryptosporidiosis).

A

Cryptosporidium spp

Waterborne

Diarrhoea (Watery, no blood)
Vomiting, fever, weight loss

Oocytes seen in stool (acid fast!)

Usually self limiting
Severe disease in immunocompromised

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14
Q

Talk about sporozoa (toxoplasmosis)

A

Toxoplasma gondii
- Ingestion of contaminated foodand water/feline faeces
- Can cause:
> Disseminated disease
>Toxoplasma Encephalitis
> Chorioretinitis

Acute maternal infection can be devastating in pregnancy

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15
Q

Case study, what can this patient have?

28F attends GP
Fit and well
Complaining of….
Fevers
Abdo discomfort
Myalgia
Tachycardic
Pyrexial (38.7C)
Generalised abdotenderness
Urine dip: blood and leucocytes
Went back to GP
Ongoing fevers
Dehydrated
Dark brown urine
Mild anaemia
Thrombocytopenia
Acute kidney injury
Derranged LFTs
Travelled to Ethiopia

A

UTI/
Viral disease ie malaria

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16
Q

Talk about the epidemiology and problems of malaria. `

A

Epidemiology of malaria
50% of world population at risk

Problems:
- Increasing resistance of parasite to antimalarials
- Increasing resistance of mosquito to insecticides
- Ecological and climate changes
- Increased travel to endemic areas

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17
Q

Malaria is transmitted by?

A

Transmitted by bite of female anopheles mosquito

5 species:
Plasmodium falciparum (most life threathening)
Plasmodium ovale
Plasmodium vivax
Plasmodium malariae
Plasmodium knowlesi

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18
Q

What test do we use to diagnose Malaria?

A
  1. Blood film
    - We diagnose malaria by using light microscopy
    - Three blood films are done on consecutive days, as this is the length of the lifecycle
    The first smear is probably positive in 95% of cases
  2. rapid diagnostic tests
    that work like pregnancy tests, and detect plasmodium antigens in the blood
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19
Q

What are the symptoms of malaria?

A

FEVER
- Chills
- Headache
- Myalgia
- Fatigue
- Diarrhoea
- Vomiting
- Abdo pain

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20
Q

What are the signs of malaria?

A

> Anaemia
Jaundice (look yellow)
Hepatosplenomegaly (big spleen and liver)
Black water fever occurs from haemolysis (haemoglobin then passes into the urine)

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21
Q

Talk about the life cycle of the protozoa plasmodium in Malaria.

A
  1. Sporogonic cycle
    - mosquito takes a blood meal
    - macrogametocyte
    - ookinete
    - oocyst
    - ruptured oocyst
  2. Human Liver stages
    - Liver cells
    - Infected liver cells
    - Schizont
    - Ruptured schizont
  3. Human blood stages
    - immature trophozoite
    - mature trophozoite
    - schizont
    - ruptured schizont
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22
Q

What happen to blood vessels during complicated malaria?

A

RBCs infected with p.falcip have proteinacious knobs on the surface that bind to endothelial cells in the vessels and other RBCs

This can cause small vessels to become obstructed by clumps of red blood cells causing hypoxia of the tissues, microinfarcts in brain and lung (will come on to later)

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23
Q

If there is obstruction of blood vessels in complicated malaria , what will this cause?

A
  1. Cerebral malaria
    > Vascular occlusion - drowsiness, increase ICP, Seizures, Coma, Death
    > Hypoglycemia
  2. Acute respiratory distress syndrome
    - Vascular occlusion, anaemia, lactic acidosis, increase vascular permeability
    > SOB, hypoxia, pulmonary oedema
  3. Renal failure
    - Vascular occlusion
    - Dehydration
    - Hypotension
    - Haemoglobinuria
    - Haemolysis
    > Proteinuria, Fatigue, Haematuria
  4. Bleeding
    - Thrombocytopenia, DIC(disseminated intravascular coagulation), Activation of coagulation cascade
    > Epistaxis
    > Abnormal bleeding
    > Worsening anaemia
  5. Shock
    - Pro-inflammatory cascade
    - Anaemia
    - Bleeding
    - Gram negative sepsis
    - Increase vascular permeability
    > Hypotension
    > Tachycardia
    > Drowsy
    > Pale
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24
Q

What is the treatment for Malaria?

A

Complicated
- IV artesunate
- (IV quinine + doxycycline)

Uncomplicated
- Lots of options!

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25
Q

What are the supportive measures to treat complicated malaria?

A

Cerebral: antiepileptics
ARDS: oxygen, diuretics, ventilation
Renal failure: fluids, dialysis
Sepsis: broad-spectrum antibiotics
Bleeding/Anaemia: blood products
Exchange transfusion if huge parasite burden

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26
Q

Which plasmodium will be more common in causing malaria relapse and why?

A

Vivax and ovale species can develop hypnozoites in the liver which can “reactivate”.

Primiquine to eliminate

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27
Q

What is inflammation?

A

A response to stimulation by invading pathogens or endogenous signals such as damaged cells that results in tissue repair or pathology.

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28
Q

What is host-pathogen interactions?

A

Describes how pathogens (microbes, viruses, etc) sustain themselves within host organisms.

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29
Q

Pathogens are micro-organisms capable of causing disease. What are the 3 key attributes?

A

> Infectivity, the ability to become established in host, can involve adherence and immune escape
Virulence, the ability to to cause disease once established
Invasiveness, the capacity to penetrate mucosal surfaces to reach normally sterile sites

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30
Q

What is virulence factor?

A

microbial factors that cause/modify disease

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31
Q

To cause disease, a pathogen must successfully achieve which four stages of pathogenesis?

A

exposure (contact),
adhesion (colonization),
invasion,
infection.

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32
Q

The agents that cause infectious disease fall into which five groups?

A

Viruses ( Microbiology)
Bacteria (Microbiology)
Fungi (Microbiology)

Protozoa (Parasitology)
Helminths (worms) (Parasitology)

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33
Q

Talk about commensal.

A

Commensal microorganisms are the resident flora and usually nonpathogenic, may cause disease in particular context e.g. prosthetic material

Normal flora can cause disease if overgrow or translocate

Asymptomatic carriage of potential pathogens

They can be primary pathogens that cause disease in a proportion of exposed individuals irrespective of immunological status

Opportunistic infections only arise if immune status altered

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34
Q

Talk about pathogen.

A

Elicits specific and non-specific mechanisms
Immune response patterns vary depending on the type of pathogen
> viruses
> bacteria
> protozoa
> helminths

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35
Q

Why viral infection need rapid cell entry?

A

> Need rapid cell entry
Free virus in blood stream easily neutralised
Infected cells destroyed

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36
Q

What are the different cells involved in humoral mediated immune response?

A
  1. Antibodies (IgG, IgM, IgA) - Block binding, block virus host cell fusion, Are involved in opsonisation
  2. IgM - agglutinate particles
  3. Complement - Opsonisation, lysis
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37
Q

Talk about the cell-mediated immune response in viral infections.

A
  • IFN from Th (CD4+) or Cytotoxic T lymphocytes (CTL)/Tc (CD8+) – has direct antiviral action
  • CTL can kill infected cells
  • NK cells and macrophages are involved in antibody-dependent cellular cytotoxicity(ADCC) killing
  • Interferon is released, infect bystander cells to induce antiviral proteins for subsequent infection
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38
Q

Talk about CTL activity in viral infection.

A
  • 3-4 days post-infection CTL activity increases
  • Peaks at 7-10 days then declines
  • 7-10 days virions eliminated
  • Parallels development of CTL
  • CTL eliminate virus-infected cells and so eliminates sources of new viral products
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39
Q

What are the different types of cell that involved in cell cytotoxicity during viral cell lysis.

A

Influenza/RSV virus - respiratory epithelium
Varicella Zoster virus - skin cells
Yellow Fever virus - liver cells
HIV – Th cells

Much of the damage to cells in viral infection is indirect and caused by innate or adaptive immune responses

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40
Q

What are the different types of viral evasion mechanism from the immune system (how they escape)?

A

> Influenza changes coat antigen
Rhinovirus, HIV, show antigenic variation
Mumps, measles, EBV, HIV, CMV cause immune suppression (lymphocytes or macrophages destroyed or altered)
Vaccinia protein inhibits classical complement pathway

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41
Q

What is influenza and what are the different types of influenza?

A

Influenza is a negative strand RNA virus
- Spherical particles surrounded by lipid bilayer acquired from infected host cell.
- Glycoprotein projections:
> haemagglutinin (HA) facilitates attachment (1000 per virion)
> neuraminidase (NA) facilitates viral budding.
- 3 virus types, A, B, C.
- Changes in HA and NA give coat variability.

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42
Q

What are the result from changes in coat antigens in influenza?

A

Antigenic Drift - spontaneous mutations, occur gradually giving minor changes in HA (haemagglutinin) and NA (neuraminidase). Epidemics.

Antigenic Shift - sudden emergence of new subtype different to that of preceding virus. Pandemics.

That’s why the flu vaccine changes each

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43
Q

Bacterial infection enter host via?

A

respiratory tract
gastrointestinal tract
genitourinary tract
skin/mucous membrane break

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44
Q

What are the 2 factors that determine defence mechanism employed in bacterial infection?

A
  1. Number of organism
  2. Their virulence
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45
Q

What does low and high number of virulence cause in bacterial infection?

A

> Low number or virulence – phagocytes active
High number or virulence – immune response

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46
Q

What does intracellular and extracellular bacteria cause?

A

Intracellular bacteria – cellular response
Extracellular bacteria – antibody response

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47
Q

How will bacteria compete with host cells and colonising flora

A

> sequestering nutrients,
using novel metabolic pathways
out-competing other micro-organisms

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48
Q

When sensing changes in competing bacteria, in cell density, in nutrient availability and other environmental factors, bacteria use ‘two component sensor-kinase’ systems to alter gene transcription regulating and this include which four factors?

A

> Virulence factors
Competence to exchange genetic material
Biofilm formation
Production of bacteriocins/toxins (to kill other bacteria)

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49
Q

How do we classify bacteria toxin?

A
  • tissue target
  • molecular action
  • biological effect
  • contribution to disease process
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50
Q

What does adhesin do in bacterial infection?

A

Help bacteria bind to mucosal surfaces

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51
Q

What are the different types of adhesins?

A

> Fimbriae and pili filamentous proteins e.g. - - Neisseria gonorrhoeae
Non fimbrial proteins e.g. Fibronectin
- binding protein of Treponema pallidum
Lipid e.g. lipid teichoic acid of Streptococcus pyogenes
Glycosaminoglycans of Chalmydia sp.

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52
Q

Bacteria can stick together on a surface by secreting an extracellular polymeric substance of protein, polysaccharides and DNA, what does this called?

A

Biofilms
- Seen in dental plaque, prosthetic materials and in otitis media
- S. aureus, Streptococcus mutans, and Pseudomonas aeruginosa

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53
Q

In bacterial infection, what do they do?
1. IgA
2. Ab C3b
3. Complement
4. antibody

A

IgA(s) - Block attachment to host cells

Ab C3b - Opsonisation, Prevents proliferation

Complement -Cell lysis, Prevents proliferation

Ab- Neutralise toxins

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54
Q

What happen in bacterial infection?

A

Sensitisation (1-2 weeks)
Th cell activation (DTH*)
Second contact – effector phase
T(DTH) cells secrete IFN, TNF, IL2
Macrophage recruitment

Delayed-type hypersensitivity - an immune response that occurs through direct action of sensitized Tcellswhen stimulated by contact with antigen

Activated macrophages engulf and kill infected cells by lytic enzyme release

Prolonged DTH
> continuous macrophage activation
> granuloma formation (macrophages adhere together - TB)
> lytic enzyme release
> tissue damage

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55
Q

State the different examples of how bacteria evade the immune system.

A

> Neisseria, HI - Secrete protease lyses IgA(s)
N.gonorrhoea - Pilli
- Antigenic variation
B.pertussis - Secrete adhesion molecules
S.pneumoniae - Polysaccharide capsule (84 serotypes) prevents phagocytosis
Staphylococci - Coagulase, forms fibrin coat round organism
Mycobacterium - Escape from phagolysosome and can live in cytoplasm

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56
Q

What are the 6 examples of protozoan infection?

A
  1. Malaria
  2. Sleeping sickness
  3. Amoebiasis
  4. Chagas disease
  5. Toxoplasmosis
  6. Leishmaniasis

Immune response and its effectiveness depends on location of parasite in host

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57
Q

What are the 2 stages of protozoan infection?

A

> Blood stage - Humoral immunity (antibody)
Tissue stage - Cell-mediated immunity (T cells/Macrophages)

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58
Q

Talk about protozoan infection in malaria.

A
  • triggers anIgE response. IgE elicits an immune response by binding to Fc receptors on mast cells, eosinophils, and basophils, causing degranulation and cytokine release
  • Excessive production of cytokines (TNF) may cause some of symptoms associated with malaria
  • Antibody produced against sporozoites – generates a poor response as sporozoites only present in blood for short time
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59
Q

In protozoan infection, what causes antigenic variation?

A

VSGswitching brings about antigenic variation. Combined with successive immune responses, this can generate a relapsing parasitaemia

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60
Q

Talk about Helminth (Worm) infections?

A
  • Do not multiply in humans (eggs formed and released)
  • Not intracellular
  • Few parasites carried
  • Poor immune response
  • Trigger anIgE response.
  • Immune response not sufficient to kill
  • IgE elicits an immune response by binding to - Fc receptors on mast cells, eosinophils, and basophils, causing degranulation and cytokine release
  • Eosinophil basic protein toxic to worms
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61
Q

Talk about worm evasion from immune system.

A

They can establish a hyporesponsiveness

Mediated by immunosuppressive T-cell subset, the regulatory T (Treg) cell

Decreased antigen expression by adult - shielding

Glycolipid/glycoprotein coat (host derived)
(ie. utilises host self antigens)

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62
Q

What is immunisation?

A

The process whereby people are protected against illness caused by infection with micro-organisms (formally called pathogens).

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63
Q

What are live attenuated vaccines and inactivated vaccines?

A

Anattenuated vaccine(or a liveattenuated vaccine) is avaccinecreated by reducing the virulence of a pathogen, but still keeping it viable (or “live”).

Aninactivated vaccine(or killedvaccine) is avaccineconsisting of virus particles, bacteria, or other pathogens that have been grown in culture and then lose disease producing capacity.

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64
Q

What are the other types of vaccines out there besides attenuated vaccine and inactivated vaccine?

A

> Recombinant antigen – hepatitis B
Recombinant vector - Oxford AZ - COVID
DNA/RNA vaccines - Pfizer/Moderna - COVID
Multivalent subunit - Influenza

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65
Q

Talk about the booster dose, stability, immunity and reversion of live attenuated vaccine.

A

Booster - single
Stability - less
Immunity - humoral, cell mediated
Reversion - may occur (polio)

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66
Q

Talk about the booster dose, stability, immunity and reversion of inactivated vaccine.

A

Booster - multiple
Stability - more
Immunity - humoral
Reversion - cannot occur

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67
Q

Can inflammation be non-infectious?

A

YES!
Immune cells (macrophages, platelets, mast cells) triggered by the inflammatory response, quickly react after an injury to protect and heal the injury.

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68
Q

Talk about inflammation.

A
  • Upregulation of adhesion molecules on monocytes, neutrophils and endothelial cells (IL-1, TNFa)
  • Chemotaxis (IL-8, C5a)
  • Degranulation (IL-8, C5a, IFN-g, LPS)
  • Vascular permeability (Prostaglandins and Leukotrienes)
  • Vasodilation (Prostaglandins and Leukotrienes, kinins)
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69
Q

Acute inflammation can cause tissue damage? What are the examples that will induce acute inflammation?

A

Trauma (surgical)
Necrosis (myocardial infarction)
Neoplasia
(Infection)

Damage mainly due to response rather than by injurious agent

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70
Q

Chronic inflammation has been linked to various steps involved in tumorgenesis, including:

A

Cellular transformation,
Promotion,
Survival,
Proliferation,
Invasion
Angiogenesis
Metastasis

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71
Q

The inflammatory microenvironment of tumours is characterized by what 2 factors?

A

presence of host leukocytes both in
a)the supporting stroma and
b) in tumour areas.

Tumour-infiltrating lymphocytes may contribute to cancer growth and spread and to the immunosuppression associated with malignant disease.

Tumour-associated macrophages (TAM) are a major component of the infiltrate of most cancers

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72
Q

What can Varicella Zoster Virus cause?

A

Varicella “chickenpox” – PRIMARY INFECTION
Herpes Zoster (HZ) “Shingles” – SECONDARY REACTIVATION

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73
Q

What are the structures on a virus?

A
  1. Glycoprotein spikes
  2. Lipid envelope
  3. Double-stranded DNA genome
  4. Nucleopasmid
  5. Tegument
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74
Q

How long is the incubation period for chickenpox?

A

1-3 weeks average

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75
Q

When is the person with chickenpox most infectious?

A

A person with chickenpox is most infectious from one to two days before the rash appears until all the blisters have crusted over.

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76
Q

Talk about 4 features of primary infection - chickenpox.

A
  1. Common in childhood
  2. Highly contagious,
  3. Usually benign but can be serious
    in certain groups e.g.
    > Immunocompromised and patients who
    have had transplants
    > Adults
    > Pregnant women
    > Smokers
    Infants
    >90% of adults raised in the UK
    have had chickenpox
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77
Q

Talk about the different stages of presentation of chickenpox.

A

Macule> Papule > Vesicle > Pustule > Crust

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78
Q

Talk about the distributions of lesions in chickenpox and smallpox diseases.

A

In chickenpox, it appear at warmer area of the body, thus the central part.

In smallpox, it appears at colder area of the body, thus the peripheral part.

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79
Q

Talk about the different period of time when lesion presents in chickenpox and smallpox.

A

Smallpox lesions all evolve at the same
time whereas with chickenpox and
measles, lesions at different stages of progression can appear on the body
concurrently

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80
Q

What factors should you consider when patients have chickenpox?

A

> Age of the patient
Onset of rash
Any contacts?
Immuno-suppressed?
Pregnant?

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81
Q

How do you diagnose chickepox?

A
  • Pop lesion with a sterile needle
    (Don’t wipe it with alcohol swab first)
  • Absorb vesicle contents onto swab
  • Replace swab in cassette and send for VZV/HSV PCR
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82
Q

What are the complications of chickepox?

A

Dehydration
Haemorrhagic change
Cerebellar ataxia (common)
Encephalitis
Varicella pneumonia
-Bacterial empyema
Skin and soft tissue infection typically with group A strep
-Bone and joint infections: deep sepsis-
osteomyelitis/pyomyositis
Congenital (foetal) varicella syndrome

> complications relatively rare in children but more in adult

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83
Q

Talk about chickenpox pneumonitis.

A
  • most common to adults
  • Chickenpox pneumonitis affects 15% of healthy adults
  • Risk doubles if underlying lung disease or if a smoker
  • 30% mortality untreated
  • Mortality 6% even with adequate treatment
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84
Q

Talk about Foetal Varicella Syndrome.

A
  1. Foetal infection occurs in 10-15% of cases of chickenpox in pregnancy
    > Usually transient and asymptomatic
    > If any manifestations – shingles in the first year of life
    > If maternal chickenpox occurs in the
    first half of pregnancy, about 2% of
    infants will develop FVS
  2. Potentially severe defects
    > Cicatricial skin scarring
    > Limb hypoplasia
    > Visceral and ocular lesions
    > Microcephaly and growth retardation
  3. FVS is very rare
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85
Q

During infection, which antibodies level should be observed for primary infection and secondary infection.

A

Primary infection - IgM
Secondary infection - IgG

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86
Q

Talk about an example of viral dormancy and reactivation.

A
  1. Primary infection - widespread chickenpox
  2. Viral dormancy in dorsal root or
    cerebral ganglion
  3. Localised reactivation – shingles
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87
Q

What is the overall term for Anti-bacterial, Anti-viral, Anti-fungal, Anti-protozoal
Anti-helminthic, and Anti-septic

A

Antimicrobial

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88
Q

What bacteria usually cause throat infection?

A

Streptococcus

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89
Q

What is antimicrobial?

A

Antibiotics are molecules that work by binding a target site on a bacteria

agents produced by micro-organisms that kill or inhibit the growth of other micro-organisms in high -dilution

Produced by micro-organism so gastric juice (acid), is not antibiotic.

Most agents currently used are semi-synthetic derivatives of antibiotics so more correctly termed ‘antimicrobials’.
Antimicrobials include :
antifungal, antibacterial, antihelminthic, antiprotozoal and antiviral agents
BUT, in practice
> antibiotic = antibacterial

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90
Q

What is the importance of antibiotic-binding site of bacteria?

A

the crucial binding site will vary with the antibiotic class

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91
Q

What are the 3 different types of antibiotics?

A
  1. Cell-well synthesis related
    a) Beta Lactams
    - Penicillin
    - Cephalosporin
    - Carbapenems
    - Monobactams
    b) Vancomycin
    c) Bacitracin
    d) Cell membrane
    - polymyxins
  2. Nucleic acid synthesis related
    a) DNA gyrase
    - quinolones
    b) RNA polymerase
    - rifampin
    c) Folate synthesis
    - sulfonamides
    - trimethoprim
  3. Protein synthesis
    a) 50s subunit
    - macrolides
    - clindamycin
    - linezolid
    - chloramphenicol
    - streptogramins

b) 30s subunit
- tetracyclines
- aminoglycosides > gentamycin

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92
Q

Beta lactams and glycopeptides are particularly useful in what type of bacteria?

A

Bacteria with thick cell walls - gram positive bacteria

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93
Q

Talk about the mechanism of beta-lactam antibiotics

A

disrupt peptidoglycan production
by binding covalently and irreversibly to the Penicillin Binding Proteins

cell wall is disrupted and lysis occurs

results in a hypo-osmotic or iso-osmotic environment

Active only against rapidly multiplying organisms

To bind to the PBPs, the β-lactam antibiotic must first diffuse through the bacterial cell wall.

Gram-negative organisms have an additional lipopolysaccharide layer that decreases antibiotic penetration.

*gram-positive usually more susceptible to β-lactams than gram-negative bacteria

  • Differences in the spectrum and activity of β-lactam antibiotics are due to their relative affinity for different PBPs.
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94
Q

Why are penicillin ineffective in the treatment of intracellular pathogens.

A

Because the penicillins poorly penetrate mammalian cells

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95
Q

Antibiotics related to cell wall synthesis?

A

a) Beta Lactams
- Penicillin
- Cephalosporin
- Carbapenems
- Monobactams

b) Vancomycin

c) Bacitracin

d) Cell membrane
- polymyxins

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96
Q

Antibiotics related to nucleic acid synthesis?

A

Rifampicin
**Metronidazole
Fluoroquinolones

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97
Q

Talk about antibiotics related to 50s ribosomes.

A

Macrolides - Clarithromycin
Chloramphenicol
Linezolid
Clindamycin
Streptogramins

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98
Q

Talk about antibiotics related to 30s ribosomes.

A

Aminoglycosides
- Gentamycin
Tetracycline
- Doxycycline

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99
Q

What are the antibiotics related to folate synthesis.

A

Sulphonamides
- Sulphamethoxazole
Trimethoprim
Co-trimoxazole

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100
Q

What is the “cholesterol” in the plasma membrane of fungi called?

A

Ergosterol

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101
Q

What are we trying to achieve with antibiotics?

A

Antibiotics give time and support for the immune system to deal with an infection.

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102
Q

What are the consequences of bacteria entry and infection?

A
  1. Direct Consequences - Destroy phagocytes or cells in which bacteria replicate
  2. Indirect - Inflammation - necrotic cells; immune pathology such as antibody
  3. Toxins (Protein Production) and Endotoxins (Gram-negative)
  4. Diarrhoea
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103
Q

Briefly state the 2 types of mechanism by which antibiotic works.

A
  1. Bactericidal
  2. Bacterialstatic
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104
Q

Talk about bactericidal antibiotics.

A
  • The agent kills the bacteria
  • Kill >99.9% in 18-24 hrs
  • Antibiotics that inhibit cell wall synthesis

> Sepsis
- the infection has become severe despite a functioning immune system and is so aggressive that the patient will die before a static antibiotic is able to help

> Meningitis and encephalitis
- the infection will cause death or irreversible brain damage before a static antibiotic will help

> Endocarditis
- the infection is in a site where the patient’s own immune system is unable to deal with the bacteria and therefore a static antibiotic won’t eliminate the bacteria as it is working alone (Bacteria within cardiac vegetations are at high concentration, and have lower rates of metabolism and cell division or are dormant, being surrounded by fibrin, platelets, and possibly calcified material. High levels of bactericidal agents are required for a prolonged period)

> Primary and secondary immunodeficiency
- the patient doesn’t have a properly functioning immune system to work with a static antibiotic e.g. febrile neutropaenia

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105
Q

Talk about bacteriostatic antibiotic.

A

prevent growth of bacteria
> ‘inhibitory to growth’

In fact kill >90% in 18-24 hrs
defined as a ratio of Minimum Bactericidal

Concentration (MBC) to Minimum inhibitory Concentration (MIC) of > 4

Antibiotics that Inhibit protein synthesis, DNA replication or metabolism

Reduce toxin production and Endotoxin surge less likely*

Bactericidal antibiotics can lead to release of endotoxin (essentially bits of the cell wall) and the resulting increase in antigenic load causes an aggressive and dangerous inflammatory response – Gram-negative bacterial (GNB) sepsis secondary to lipopolysaccharide (LPS) and read about the Jarisch-Herxheimer (JH) reaction in Syphilis or leptospirosis.

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106
Q

How do we determine how much antibiotic do we need for getting rid of the bacteria?

A

Minimum inhibitory concentration

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107
Q

Does Minimum inhibitory concentration mean best antibiotic?

A

No!

108
Q

What are the the two major determinants of anti bacterial effects?

A

1)the concentration and
2) the time that the antibiotic
remains on these binding sites

  • drug must not only attach to its binding target but also must occupy an adequate number of binding sites, which is related to its concentration within the microorganism.
  • to work effectively, the antibiotic should remain at the binding site for a sufficient period of time in order for the metabolic processes of the bacteria to be sufficiently inhibited.

> penicillin works by time-dependent killing - give it regularly

> gentamycin - concentration dependent killing - one dose

109
Q

Talk about time-dependent killing of antibiotic.

A

Key parameter is the time that serum concentrations remain above the MIC during the dosing interval:
t>MIC

beta-lactams (penicillins, cephalosporins, carbapenems, monobactams),
clindamycin,
macrolides
oxazolidinones

110
Q

Talk about concentration-dependent killing of antibiotic.

A

Key parameter is how high the concentration is above MIC

peak concentration/MIC ratio

aminoglycosides
quinolones

111
Q

The antibiotic must reach and stay at the site of bacterial infection, this depends on ?

A

‘Pharmacokinetics’

The movement of a drug from its administration site to the place of its pharmacologic activity and then its elimination from the body

112
Q

What is the appropriate or available route of administration for antibiotics?

A

IV, tablet

113
Q

The pharmacokinetics of the antibiotics depends on ___?

A

Its release from the dosage form;

Its absorption from the site of administration into the bloodstream;

Its distribution to various parts of the body, including the site of action and

Its rate of elimination from the body via metabolism (LIVER) or excretion (KIDNEY) of unchanged drug.

114
Q

What are the 3 things we should consider when it comes to antibiotic distribution to site of infection?

A

Which antibiotics will penetrate that site?

What is the pH of the site?

Is the antibiotic lipid soluble?

115
Q

How do antibiotics work?

A

Target sites

Bacteriostatic and Bacteriocidal

Concentration and Time Dependency

Pharmacokinetics

116
Q

How do bacteria resist antibiotics?

A
  1. Change antibiotic target
  2. Destroy antibiotic
  3. Prevent antibiotic access
  4. Remove antibiotic from bacteria
117
Q

Talk about antibiotic resistance mechanism on the “Change antibiotic target”.

A

Bacteria change the molecular configuration of antibiotic binding site or masks it

118
Q

Talk about antibiotic resistance mechanism on the “Destroy antibiotic”.

A

Flucloxacillin (or methicillin) is no longer able to bind PBP of Staphylococci – MRSA*

Wall components change in enterococci and reduce vancomycin binding – VRE#

Rifampicin activity reduced by changes to RNA polymerase in MTB – MDR-TB$

119
Q

Talk about antibiotic resistance mechanism on the “Prevent antibiotic access”

A

The antibiotic is destroyed or inactivated e.g.

Beta lactam ring of Penicillins and cephalosproins hydrolysed by bacterial enzyme ‘Beta lactamase’ now unable to bind PBP

Beta lactam ring of Penicillins and cephalosproins hydrolysed by bacterial enzyme ‘Beta lactamase’ now unable to bind PBP

Staphylococci produce ‘penicillinase’ so penicillin but not flucloxacillin inactivated
Gram negative bacteria phosphorylate and acetylate aminoglycosides (gentamicin)

120
Q

Talk about antibiotic resistance mechanism on the “Prevent antibiotic access”.

A

modify the bacterial membrane porin channel size, numbers and selectivity
e.g.
Pseudomonas aeruginosa against imipenem,
Gram negative bacteria against aminoglycosides

Proteins in bacterial membranes act as an export or efflux pumps - so level of antibiotic is reduced

S. aureus or S. pneumoniae resistance to fluoroquinolones

Enterobacteriacae resistance to tetracylines

121
Q

Why do bacteria develop resistance?

A
  1. Intrinsic - naturally resistant
  2. Acquired
    a) spontaneous mutation
    b) horizontal gene transfer
    i) Conjugation
    ii) Transduction
    iii) Transformation
122
Q

Talk about the intrinsic resistance of antibacterial.

A

All subpopulations of a species will be equally resistant
examples

Aerobic bacteria are unable to reduce metronidazole to its active form

Anaerobic bacteria lack oxidative metabolism required to uptake aminoglycosides

Vancomycin cannot penetrate outer membrane of gram negative bacteria

The PBP in enterococci are not effectively bound by the cephalosporins

123
Q

In acquired resistance of antibiotic , talk about spontaneous gene mutation.

A

New nucleotide base pair change in amino acid sequence change to enzyme or cell structure reduced affinity or activity of antibiotic
eg Mycobacterium tuberculosis

124
Q

Talk about horizontal gene transfer in acquired resistance of antibiotic.

A
  1. Conjugation - sharing of extra chromosomal plasmid “bacteria sex”
    (New Delhi metallo-β-lactamase, ESβLs)
  2. Transduction of DNA by bacteriophages (mecA gene from MRSA)
  3. Picking up naked DNA
    (foreign DNA from S. mitis to S.pneumoniae, conferring penicillin resistance)
125
Q

Talk about important antibiotic resistance in Gram-positive bacteria.

A

MRSA
Methicillin resistant Staphylococcus aureus
Bacteriophage mediated acquisition of Staphylococcal cassette chromosome mec (SCCmec) contains resistance gene mecA
encodes penicillin-binding protein 2a (PBP2a)
confers resistance to all β-lactam antibiotics in addition to methicillin (= flucloxacillin)

VRE
vancomycin-resistant enterococci
Plasmid mediated acquisition of gene encoding altered amino acid on peptide chain preventing vancomycin binding
Promoted by cephalosporin use

126
Q

extended spectrum beta lactamase (ESBL) resistance strain remain sensitive to beta-lactamase inhibitors.

A

Amoxicillin + Clavulanate = Co-Amoxiclav
Pipericillin + Tazobactam = ‘Tazocin’

127
Q

Talk about important antibiotic resistance in Gram-negative bacteria.

A

ESBL
- Further mutation at active site extended range of antimicrobial resistance to form extended spectrum beta lactamase (ESBL) inhibition.
- These hydrolise oxyimino side chains of cephalosporins: cefotaxime,ceftriaxone, andceftazidime and monobactams: aztreonam
> TEM-1 in E. coli, H. influenzae and N. gonorrhoea
> SHV-1 in K. pneumoniae
> An even more extensive ESBL, this time plasmid mediated, is the CTX-M cephalosporinase in Enterobacteriacae

AmpC b-lactamase resistance
Broad spectrum penicillin, cephalosporin and monobactam resistance
encoded on the chromosome in bacteria such as Citrobacter spp., Serratia marcescens, Enterobacter spp.
b-lactamase inhibitor resistant!
inducible expression (gene only turned on by antibiotic)
… so they invented carabpenems

128
Q

Talk about carbapenems

A

ertapenem, imipenem, meropenem*

in contrast to other b-lactams, are highly resistant to degradation by b-lactamases or cephalosporinases.

often the antimicrobials of last resort to treat infections due to ESBL or AmpC -producing organisms of the Enterobacteriacae family*.

129
Q

Talk about carbapenemase-resistant Enterobacteriaceae.

A

Which produce ‘carbapenemases’
e.g.
metallo-β-lactamases
IMP or VIM – Pseudomonas aeruginosa, Acetinobacter spp.
NDM-1 - E. Coli, Klebsiella pneumoniae
OXA
(oxacillinases –Acetinobacter baumanii)
KPC
(Klebsiella pneumoniae)
Treatment options are very few
and very toxic

130
Q

What factors to consider when deciding if an antibiotic is safe to prescribe?

A

Intolerance, allergy and anaphylaxis
Side effects
Age
Renal and Liver function
Pregnancy and breastfeeding
Drug interactions
Risk of Clostridium difficile

131
Q

What is cephalosporin for?

A

They are a type of beta-lactam

Good for people with penicillin allergy
Work against some resistant bacteria
Get into different parts of the body e.g. meningitis

132
Q

When there is cellulitis or inflammation on the leg or foot, which bacteria involved and what antibiotic we use?

A

S. aureus and Group A, C, G strep

FLUCLOXACILLIN

133
Q

When there is tonsilitis, which bacteria involved and what antibiotic we use?

A

Group A, C, G strep

PO PENICILLIN V
IV BENZYLPENCILLIN

134
Q

When there is pneumonia, which bacteria involved and what antibiotic we use?

A

S. pneumoniae

PO AMOXICILLIN
IV BENZYLPENCILLIN

135
Q

What does MRSA stand for?

A

Methicillin*-resistant Staphylococcus aureus

136
Q

What are the 5 detailed mechanisms on which how antibiotic work?

A
  • Inhibitors of cell wall synthesis
  • Inhibitors of protein synthesis
  • Inhibitors of nucleic acid synthesis
  • Anti-metabolites
  • Inhibitors of membrane function
137
Q

For gram-positive bacteria, talk about macrolides that inhibit protein synthesis.

A

Clarithromycin and erythromycin – oral (& IV)
Activity:
Gram positives (S. aureus, β haemolytic strep) and atypical pneumonia pathogens
Use: penicillin allergy
Use: severe pneumonia

138
Q

For gram-positive bacteria, talk about Lincosamides that inhibit protein synthesis

A

Clindamycin = oral (& IV)
Activity:
Gram positives eg S. aureus, β haemolytic strep , anaerobes
Use: cellulitis (if pen allergy)
Use: necrotising fasciitis (remember Elizabeth…)

TURNS OFF NASTY TOXINS MADE BY Gram positive bugs

139
Q

For gram-positive bacteria, talk about tetracycline that inhibit protein synthesis

A

Doxycycline = oral
Activity : Broad spectrum but mainly Gram positive (S. aureus and streps)
Use: cellulitis (if penicillin allergy)
Use: pneumonia

140
Q

For gram negative bacteria, talk about aminoglycoside that inhibit protein synthesis,

A

Gentamicin – IV only

Activity : Gram negatives and staphs (use synergistically to treat streps)
Use: urinary tract infections (UTIs)
Use: infective endocarditis (synergistically)

141
Q

For gram-negative bacteria, talk about quinolone that inhibit DNA synthesis.

A

Ciprofloxacin = oral (& IV)

Activity : Gram negative» Gram positive
Use: penicillin allergy
Use: UTIs
Use: intra-abdominal infections

142
Q

State the 2 drugs usually used for UTI?

A

> Trimethoprim – anti-metabolite (folate antagonist)
Activity: Broad spectrum but mainly used for Gram negatives
Use: UTIs

> Nitrofurantoin
Activity: Gram negatives and gram positives
Use: Lower UTIs

143
Q

If pt has aspiration pneumonia, severe CAP, more resistant urinary organisms, what do we use?

A

Co-amoxiclav (Augmentin)oral and IV

144
Q

If patient has:
HA-pneumonia, systemic Pseudomonas infections, >65s abdominal infection, immunocompromised

what do we use?

A

Piperacillin/tazobactam (Tazocin) - IV

145
Q

If patient has:
some surgical prophylaxis, <65s intra-abdominal infections, non-severe penicillin allergy
what do we use?

A

Cefuroxime - IV

146
Q

If patient has:
HAI (sickest, most at risk), resistant gram negatives, immunocompromised

what do we use?

A

Meropenem - IV

147
Q

If patient has:
Urinary tract infection (lower)
Bacteria: gram negatives (E. coli, proteus, klebsiella)
And gram positives (staph saprophyticus)

What do we use?

A

Management
Self care + back-up antibiotics
Immediate antibiotic treatment
Nitrofurantoin for 3 days

148
Q

If patient has:
66 year old woman
3 day history of fevers and nausea
Leg = hot, red, swollen

Likely diagnosis:
Cellulitis usually lower limbs - unilateral
Red, hot, painful, tender skin
Spreading
Systemic symptoms
Bacteria: S. aureus and β haemolytic strep (Group A, C & G)

What do we use?

A

Management:
- Assess severity

  • Samples
    > Bacterial swab for culture
    > Blood cultures

Antibiotics
PO or IV flucloxacillin
Penicillin allergy: clarithromycin or clindamycin
Duration ~ 7 days

149
Q

Which laws and regulation stated that Infection control is every health care workers responsibility

The possibility of health care related infections should be considered in all aspects of patient management?

A

The health act 2006

150
Q

What kind of infection we are worried about ?

A
  1. Bacteria
    > Methicillin resistant S.aureus
    > Clostridium difficile
    > Multi-drug resistant gram negatives
    > Glycopeptide resistant enterococci
    > Group A streptococcus
    > Mycobacterium tuberculosis
  2. Virus
    > Influenza
    > Norovirus
    > SARS-CoV-2
    > HIV
    > Hep B
    > Hep C
    > Varicella Zoster Virus
    > Viral haemorrhagic fevers

Others:
> Candida Auris
> Creutzfeldt–Jakob disease (rare, chronic neurological conditions)

151
Q

How do we prevent and control infection?

A

> Identify risks
- Patients/Staff
- Environment

> Ensure that staff (and students!) areaware of the risks and what to do!

> Develop strategies to reduce those risks

> Policy Development

> Audit

152
Q

Talk about the Principles of Infection Prevention & Control.

A
  • Identification of risks
    >Routes and modes of transmission
    >Virulence of organisms
    • Ease of spread
    • Likelihood of causing infection
    • Consequences of infection if it occurs
      > Minimisation of risks
153
Q

Talk about identification of risk in infection control.

A

Risk factors
e.g. recent return from Sierra Leone with fever

Screening
e.g. MRSA admission screening

Clinical diagnosis
e.g. cough and cavity on chest x-ray

Lab diagnosis
Carbapenemase Producing Enterobacteriaceae in urine

154
Q

What are the routes of transmission during infection in the healthcare setting?

A
  1. Patient > patient
  2. Patient > Environment > Patient
  3. Patient > Staff > Patient
155
Q

What are the examples of infection cases and outbreaks that are common?

A
  1. CPEs (Carbapenemase producing Enterobacteriaceae)
  2. MRSA
  3. Norovirus
  4. Clostridiumdifficile
  5. Endogenous infections
156
Q

What are CPEs?

A

Carbapenemase producing Enterobacteriaceae (CPE)

> Include E. coli, Klebsiella, Proteus, Serratia, Enterobacter
Colonisers of large bowel, skin below waist and moist sites
Most common causes of UTI, intra-abdominal infection
Historically, the vast majority of these germs were susceptible to the antibiotics that we currently use with Gram negative infection

157
Q

What are carbapenemase?

A

Enzyme which inactivates carbapenem antibiotics

Carbapenems are one of the broadest spectrum antibiotics available

Previously used as the antibiotic of last resort, now commonly used

158
Q

Enterobacter cloacae in blood cultures are sensitive to which 2 bacteria?

A

Gentamycin and Colistin

159
Q

Talk about MRSA.

A

Staph aureus is a common skin and nasal commensal

Most strains are susceptible to flucloxacillin (and other beta-lactam antibiotics)

MRSA was first described in 1971
Huge increase in numbers of cases in 1990s and 2000s

160
Q

Talk about norovirus.

A
  • usually happen in places with a lot of kids like nurseries, cruises, oyster and healthcare setting.
  • High attack rates amongst close contacts
    Low infecting dose
    Uncontained vomiting and diarrhoea
  • Short-lived immunity only
    Staff and patients at risk
  • Able to persist in the environment
  • Relatively resistant to conventional cleaning
161
Q

Talk about clostridium difficile.

A

C. difficile, diruption in their intestine microbial, spores , antibiotics will kill it usually but once antibiotics is gone, lots of C. difficile will grow, lots of toxin - clinical symptoms, can lead to several week of chronic diarhhoea, can cause complete inflamed large bowel, might need to have your colon excised

Clostridium difficile (C. diff) is a type of bacteria that can cause diarrhoea. It often affects people who have been taking antibiotics.

> Bacterial spores
Prolonged hospital stays
Toxic megacolon

162
Q

Talk about endogenous infections.

A

Infections caused by patients own bacterial flora.

Important in hospitalised patients, especially those with invasive devices or surgical patients.

Endogenous infection, not a type but a group, cause by commensal bacteria, biofilm, crawl out immune system and crawl down the cannula or plastic tube etc, cannula/catheter related infections

163
Q

How to prevent endogenous healthcare infection (HCAI)?

A

> Good nutrition and hydration
Antisepsis/skin prep where indicated
Good theatre practice
Remove lines and catheters as soon as clinically possible
Change from IV to oral treatment whenever appropriate

164
Q

Simple things that should be done to protect patient.

A
  • Hand hygiene (single most effective method)
  • Personal protective equipment
  • Disposal of sharps
165
Q

What are fungi?

A

Eukaryotic
Chitinous cell wall
Heterotrophic
“Move” by means of growth or through the generation of spores (conidia), which are carried through air or water

166
Q

What are the 2 types of fungi out there?

A
  • Yeast and Mould
  • Yeasts are small single celled organisms that divide by budding
  • Account for <1% of fungal species but include several highly medically relevant ones
    Moulds form multicellular hyphae and spores
  • Some fungi exist as both yeasts and moulds switching between the two when conditions suit – dimorphic fungi
167
Q

How do fungi affect humans?

A
  • 5 million species of fungi described
  • Only a few hundred have been reported as causing human infection

Why?
- Inability to grow at 37 degrees
- Innate and adaptive immune response
- The vast majority of human mycoses are caused by very few genera
1. Ascomycota – Aspergillus, Pneumocystis, Candida, Fusarium, Scedosporium
2. Basidiomycota- Cryptococcus, Trichosporon
3. Mucormycota – aka zygomycetes

168
Q

What is the difference between superficial fungal infection and invasive fungal infection.

A

Superficial fungal infection is very commonInvasive fungal infection is rare but easily missed

169
Q

Signs and symptoms of fungi infection?

A
  • Nappy rash and Vulvovaginal candidiasis
  • Tinea pedis (athlete’s foot)
  • Onychomycosis (fungal nail infections)
  • Otitis externa
  • Fungal asthma
  • Huge disease burden worldwide from tinea capitis and fungal keratitis
  • BUT Life-threatening fungal infection is rare in healthy hosts
170
Q

Talk about Invasive/life threatening fungal disease.

A
  1. Immunocompromised hosts
    > Candida line infections
    > Invasive aspergillosis
    > Pneumocystis
    > Cryptococcosis
    > Mucormycosis
    > Post-surgical patients
    > Intra-abdominal infection
  2. Healthy hosts
    > Fungal asthma
  3. Travel associated fungal infections
    > Dimorphic fungi
    > Post-influen
    za aspergillosis
171
Q

How much does NHS spend on fungal infection each year?

A

> £150m/year
Much of this cost is prophylaxis or empirical treatment of possible invasive fungal disease due to poor diagnostics.

172
Q

Talk about fungal diagnostics and relate to different fungi.

A
  1. Radiology
    Aspergillus and zygomycetes
  2. Microscopy
    Zygomycete vs Ascomycete
    Yeasts
  3. Culture
    Subsequent microscopy to ID - tease mounts/selotape
  4. Molecular
    PCR
    Antigen tests
    Cryptococcal Ag
    Galactomannan
    1,3 Beta-D-glucan
173
Q

Talk about fungal diagnostics and relate to different fungi.

A
  1. Radiology
    Aspergillus and zygomycetes
  2. Microscopy
    Zygomycete vs Ascomycete
    Yeasts
  3. Culture
    Subsequent microscopy to ID - tease mounts/selotape
  4. Molecular
    PCR
    Antigen tests
    Cryptococcal Ag
    Galactomannan
    1,3 Beta-D-glucan
174
Q

What are the criteria for fungal diagnostic test?

A

Non-invasive
Rapid and easy technically
Sensitive and reproducible
Specific – both in terms of pathogen, significance of positive result
Cheap

175
Q

Talk about the specificity and sensitivity for fungal diagnostic test.

A
  1. Radiology
    Insensitive in early stages
  2. Microscopy
    Usually insensitive
  3. Culture
    OK for yeasts, poor for moulds
  4. Molecular
    PCR – mixed results
    Antigen tests
    Cryptococcal Ag - excellent
    Galactomannan - insensitive
    1,3 Beta-D-glucan – poorly specific
176
Q

What is the aim of aim of antimicrobial drug therapy?

A

Aim of antimicrobial drug therapy is to achieve inhibitory levels of agent at the site of infection without host cell toxicity

177
Q

Talk about selective toxicity in treating fungal disease.

A

> Target does not exist in humans
Target is significantly different to human analogue
Drug is concentrated in organism cell with respect to humans
Increased permeability to compound
Modification of compound in organism or human cellular environment
Human cells are “rescued” from toxicity by alternative metabolic pathways

178
Q

Is the treatment more difficult for fungi or bacteria?

A

Generally much more difficult for fungi than bacteria because they are eukaryotic

179
Q

Talk about the 3 structures on fungi that we can target for treatmnet.

A

DNA/RNA synthesis/protein synthesis , cell wall, plasma membrane protein

180
Q

Talk about the drug targeting the DNA/RNA synthesis/protein synthesis in fungi

A

DNA/RNA synthesis,
> protein synthesis
> Similar to mammalian
> Flucytosine

181
Q

Talk about the drug targeting cell wall in fungi.

A

Cell wall
> mannoproteins
> Β1,3 glucan
> Β1,6 glucan
> chitin
> Doesn’t exist in humans
> Echinocandins

182
Q

Talk about drug targeting plasma membrane in fungi.

A

Plasma membrane
ergosterol
Human cell membrane contains cholesterol not ergosterol
Amphotericin
Azoles
Terbinafine

183
Q

Which type of fungi species is susceptible to all drugs without resistance?

A

Wild type Candida albicans

184
Q

What is the mainstay of antifungal therapy currently?

A

Azoles are the mainstay of antifungal therapy currently
- fluconazole
- itraconazole
- voriconazole
- posaconazole
- isavuconazole

185
Q

Is there any adverse events with the mainstay drug for fungi infection azole?

A

Relatively safe
All associated with transaminitis and GI SEs
Rare severe hepatitis
Alopecia with long term fluconazole
GI symptoms more pronounced with Itra
Nausea, abdominal pain, diarrhoea
Discontinuation of drug in 10%
Rare life threatening liver failure
Voriconazole associated with reversible visual disturbance in 30%
Photosensitivity in 1-2% of patients receiving voriconazole and recent reports of skin malignancy

186
Q

Any drug-drug interaction of azole, the mainstay drug for fungal infection.

A
  • Largely a result of cytochrome P450 isoforms
  • Variable depending on relative affinity of drugs for individual enzymes.
  • Fluconazole hydrophilic and principally excreted unchanged – less significant interactions
  • Warfarin, phenytoin, calcineurin inhibitors, anxiolytics
  • Itraconazole is a potent CYP3A4 inhibitor
  • As above + steroids, statins, rifamycins,PIs
  • Posaconazole is only a mild CYP3A4 inhibitor.
  • Voriconazole inhibits a number of CYP enzymes
    Affected drugs similar to itraconazole
187
Q

Talk about Onychomycosis.

A
  • Common +++
  • Caused by dermatophyte moulds
    grow best at about 30OC
    have evolved ability to hydrolyse keratinous debris in soil
  • Trichophyton rubrum is most common
  • Some non-dermatophytes can be implicated and can lead to treatment failure
  • Broad differential diagnosis
  • Microscopy is most specific test but 30% culture negative
  • Slightly depressing
  • Results of sampling can be confusing
  • Limited treatment options
  • Topical amorolfine
  • Systemic itraconazole or terbinafine
  • Treatment takes ages
  • High failure rate with all therapies
188
Q

Talk about Pneumocystis Pneumonia (PCP)

A
  • Infection/colonisation of healthy people frequent and occurs early in life
  • Disease develops only with moderate-severe immunocompromise esp. HIV, transplant, steroids
  • Frequent clinical presentation of unknown HIV
  • Think about Pneumocystis when a patient has hypoxia more severe than CXR would suggest especially if gradual onset illness or risk factors.
  • Co-trimoxazole (plus steroids if hypoxic) is first line treatment
189
Q

Talk about UNAIDS 90/90/90 goal to eliminate the HIV epidemic

A

global target of
-90% of people living with HIV being diagnosed
-90% diagnosed on ART (antiretroviral therapy)
-90% viral suppression for those on ART by 2020

190
Q

What is Fast Track Cities?

A

The Fast-Track Cities initiative is a global partnership between a network of over 90 high HIV burden cities, where political leaders, affected communities, city health officials, clinical and service providers, and other stakeholders work together to accelerate their local HIV responses.

191
Q

What are the HIV Transmission routes?

A
  • Sexual
  • Vertical
  • Blood
192
Q

Talk about HIV prevention.

A
  1. Voluntary Medical Male Circumcision
  2. Treatment of STIs
  3. Female condoms
  4. Male Condoms
  5. HIV counselling and testing
  6. Behavioural Change
  7. Treatment as prevention
  8. Post-exposure prophylaxis (PEP)
  9. Oral Pre-exposure prophylaxis (PreP)
  10. Microbicides for women and some gay men
193
Q

What is U=U?

A

Undetectable viral load = Untransmittable HIV

194
Q

Talk about pre-exposure prophylaxis.

A

Several RCTs have reported on PreP; providing evidence for the effectiveness of daily dosing and event-based dosing

Effectiveness has been demonstrated in MSM (men who have sex with men), heterosexual serodifferent couples, and injecting drug users

195
Q

Talk about PEP.

A

Post-exposure prophylaxis

PEP = 28 days Combination Antiretroviral Therapy –must be started within 72 hours

Not as effective as PreP

196
Q

What are the benefits of knowing HIV status (benefits of HIV screening)?

A
  • Access to appropriate treatment and care
  • Reduction in morbidity and mortality
  • Reduction of vertical transmission
  • Reduction of sexual transmission
  • Public health /partner notification
  • Cost-effective
197
Q

Testing in HIV

A
  • Clinician initiated diagnostic testing triggered by clinical indicators of immuno-suppression disease /seroconversion
  • Routine screening in high prevalence locations
  • Antenatal screening
  • Screening in high risk groups
  • Patient initiated requests for testing
198
Q

Why do some doctors not test for HIV?

A

They don’t think of HIV

Underestimate the risk of HIV in their patients

Failure to recognise HIV as a modifiable prognostic indicator

Misconception they need pre-test counselling

Misunderstanding of the implications for insurance, etc

Fear of offending the patient

199
Q

Examples that show suspicion to HIV?

A

Generalised lymphadenopathy
Acute generalised rash
Glandular fever/ flu-like illnesses
Think about seroconversion
Oral candida
Unexplained weight loss or night sweats
Persistent diarrhoea
Gradually increasing shortness of breath and dry cough
Recurrent bacterial infections including pneumococcal pneumonia

200
Q

What are the common examples that we should consider HIV if they have a medical condition that is recurrent or severe or unexplained?

A

Multi-dermatomal shingles

Unexplained lymphadenopathy

Unexplained wt loss or diarrhoea, night sweats, PUO

Oral/oesophageal candidiasis or hairy leukoplakia

Flu-like illness, rash, meningitis

Unexplained blood dyscrasias

201
Q

Who can offer testing for HIV?

A

ANY competent healthcare professional

“Normalise” the test

Document verbal consent

Determine how results will be given

Written consent unnecessary

Pre-test HIV counselling is not required

202
Q

Talk about the screening test for HIV.

A

Venous blood sample is preferred

4th generation HIV tests include p24 antigen
and will detect the vast majority of infections at 4 weeks (if negative, repeat at 7 weeks if high index of suspicion)

High sensitivity and specificity

203
Q

Talk about HIV Point of Care Test (POCT).

A

Point of Care tests
Finger prick blood
Immediate result
Lower sensitivity and specificity
False positive and negative results
Longer incubation period

204
Q

What are the advantages of Point of Care Test (POCT) for HIV?

A

Outreach into community settings/ non-specialist clinics

Increased patient choice

Increased access to testing and case detection

Earlier diagnosis in non-healthcare seeking individuals

205
Q

What is HIV?

A

HIV is a retrovirus, an RNA virus which uses reverse transcriptase (RT) to make a DNA copy that becomes integrated into the DNA of the infected cell

206
Q

Where did HIV come from?

A

Generally, monkeys that are naturally infected with their own strain of simian immunodeficiency virus (SIV) do not develop disease

HIV-1 is similar to SIV in chimps from central Africa, and probably arose there

HIV-2 closely resembles SIV isolated from West African sooty mangabey monkeys - thought to have been at least eight separate entries from monkeys into humans, dating from the 1940s

207
Q

The origin and spread of the HIV epidemic

A

First documented HIV-infected human case in DRC 1959

from Haiti to USA)

208
Q

What is a potential route of transmission of simian retroviruses?

A

Bushmeat markets
in West and central Africa

209
Q

Talk about HIV genome structure.

A

Small RNA virus (~ 10KB): expresses just 10 genes

Member of retrovirus family (uses reverse transcriptase to make DNA copy of itself)

Lentivirus: characterized by long incubation period

210
Q

Talk about HIV and CT4 T cells

A

HIV fuses to CD4 receptor and passes its contents into the CD4+ cell

Reverse Transcriptase

Viral DNA integrated into nucleus

New HIV budding from CD4 cell

211
Q

Talk about HIV replication cycle. (primary receptor and co-receptor)

A

Primary receptor for HIV is CD4. Co-receptors are CCR5 and CXCR4 chemokine receptors. CCR5 is used by HIV-1 in early infection, may switch to use CXCR4 later in infection. Once viral integration has occurred, infection persists for life in a reservoir of latently infected cells.

212
Q

Talk about genetic resistance to HIV-1 infection.

A

1% of Caucasians are homozygous for a 32bp deletion in the CCR5 gene (CCR5D32) necessary for primary HIV-1 infection

People with only one copy of the mutant gene can be infected with HIV but show delayed disease progression

It has been hypothesised that the origin in Caucasians could be related to protection from the Plague

213
Q

Talk about why HIV-1 can mutate quickly.

A

HIV-1 can evolve rapidly, due to:
Error-prone replication (the enzyme reverse transcriptase makes at least 1 error in every replication cycle)

Rapid viral replication (generation time ~2.5 days)

Large population sizes (~1010 new virus particles produced each day)

HIV-1 clades/subtypes differ by >20% in amino acid sequence: recombination between different clades/subtypes in the same person significantly increases HIV-1 diversity

214
Q

Talk about acute HIV-1 and its symptoms

A

Detection of very high levels of virus in the blood
Symptoms of Acute Retroviral Syndrome
> “Glandular fever”-like illness
> Fever, lymphadenopathy
> Sore throat, oral ulcers
> Skin rash (upper trunk)
> May include neurological features

215
Q

What do Immune responses during AHI thought to determine?

A

Long-term viral control
Disease progression

216
Q

Early initiation of ART is beneficial for?

A

Reduced risk of transmission

Smaller reservoir, lower set-point, delayed progression

217
Q

Clinical features of untreated HIV-1 infection can be observed via what graph or what substances level?

A

CD4+ count level, 500 is the determine point
Above 500:
- Vaginal/oral candidiasis
- skin disease
- fatigue
- bacterial pneumonia
- herpes zoster
- oral hairy leukoplakia, thrush, fever, diarrhoea, weight loss

Below 500:
- Kaposi’s sarcoma, non-Hodgkin’s lymphoma
- Pneumocystis carinii pneumonia
- Toxoplasmosis, oesophageal candidiasis, cryptococcosis
- CNS lymphoma

TB can appear at any level!

218
Q

Talk about TB relation with HIV.

A

TB: risk is 10%/year in co-infected subjects compared to 10% lifetime risk without HIV infection

218
Q

Talk about TB relation with HIV.

A

TB: risk is 10%/year in co-infected subjects compared to 10% lifetime risk without HIV infection

219
Q

What are the key features of HIV pathogenesis.

A

HIV is integrated into the DNA of the infected CD4-expressing cells

HIV infects a range of CD4 + immune cells in addition to helper T-cells, (including regulatory T-cells, T follicular helper cells, dendritic cells, macrophages and thymocytes)

However, the number of HIV-infected CD4+ T-cells in the blood does not explain the extent of immune suppression

HIV can pass directly from cell to cell, and so it is relatively inaccessible to antibodies in the blood

The small HIV genome encodes a range of genes that enable the virus to evade human immune system responses

220
Q

Talk about Immune activation drives HIV pathogenesis.

A

Early studies showed that immune activation, with activated T-cells in the blood, correlated better with disease progression than viral load or CD4 count

Early in HIV infection, there is a dramatic loss of CD4+ T-cells in the lymphoid tissue in the gut: this makes the gut mucosa leaky, allowing passage of bacteria and products (like LPS), stimulating immune cells and setting up a cycle of chronic immune activation that ultimately exhausts the immune system

Immune activation is also driven directly by HIV, e.g. through a form of inflammatory cell death (pyroptosis), and co-infections, particularly with cytomegalovirus (CMV)

221
Q

Why does the immune response to HIV-1 fail to clear the virus?

A

The immune system generates a massive immune response to HIV infection, involving up to 20% of all circulating T and B lymphocytes

Antibodies develop against most viral proteins, but neutralising antibodies take months to develop and rarely neutralise the primary HIV strains that are transmitted from person to person

One of the key immune responses to HIV-1, from CD4+ T-helper cells, is lost from very early in infection, because these are the cells HIV infects first

There is a very vigorous response from cytotoxic CD8+ T-cells, which provides the major force controlling viral replication but ultimately fail when “immune exhaustion” sets in

222
Q

Why do most HIV-1-infected people fail to make an effective antibody response?

A

The surface of the virion is derived from the host cell membrane containing only a few (6 – 10) envelope spikes

The HIV-1 envelope spike is heavily glycosylated (with sugars resembling human types), which makes it difficult for antibodies to bind to the surface

The really critical parts of the viral envelope that are needed to enter CD4+ T-cells are either in deep pockets overhung by sugar molecules or only revealed when the virus docks onto the CD4 molecule

The envelope (gp120/41) proteins can change substantially without affecting virus function
Thus the virus can evolve very quickly to avoid antibody recognition (including by the addition of more sugar molecules)

In infected people the circulating neutralising antibodies rarely recognise their own prevailing viral envelope variants

223
Q

Talk about Virus-specific cytotoxic T-cells clear infected cells after viral infection.

A

CD8+ cytotoxic T-cells identify cells expressing foreign material (from pathogens or tumours), processed as small fragments of protein (8-11 amino acids in length), presented on the surface of the infected cell by HLA class I molecules

Different HLA class I molecules are able to present peptides with different characteristics: a set of three distinct HLA class I molecules (A, B & C) are inherited from each parent

These peptides can come from any part of a pathogen, so include more conserved structural and functional internal proteins (whereas antibody recognition is largely limited to surface proteins)

Recognition triggers the release of soluble anti-viral factors and the death of the infected cell

> Cytokines – soluble anti-viral factors
CC- chemokines
(compete with HIV for
the receptor CCR5)
Cytotoxic factors
– kill the cell

224
Q

How does HIV-1 evade the CTL response ?

A

HIV can evolve to escape T-cell recognition at several points on the antigen processing and presentation pathway

Mutant HIV variants that evade the T-cell response appear within weeks of primary HIV infection

Initially responses develop to the new variants but these are progressively undermined by the failure of CD4+ cell help and dendritic cell function

The HIV-1 nef protein reduces cell-surface expression of HLA class I molecules needed for CTL recognition, whilst at the same time upregulating the “death” molecule Fas that can kill virus-specific CTL before they can kill the virus-infected cell

HLA- A and B molecules are down-regulated to undermine CTL killing of infected cells but HLA-C expression is maintained to prevent NK cell killing

Ultimately CTLs develop functional “exhaustion”, associated with expression of inhibitory molecules such as PD-1: levels of expression correlate with viral load

225
Q

Talk about Delayed disease progression in HIV-1 infection.

A

Natural history of HIV-1 infection without ART shows a normal distribution, median time to AIDS around 10-11 years (regardless of ethnicity or clade)

Long-term non-progressors (LTNPs): defined as survivors with HIV-1 infection for >7-10 years, no therapy, no symptoms and stable CD4+ T-cell count > 500mm3; RARE - around < 1-5 % of cohorts

“Elite controllers”: defined as HIV-1 infected individuals with plasma VL <50 copies/ml for over one year without ART: VERY RARE - 0.35-0.8% of cohorts

General but not complete overlap: controllers may progress to AIDS even with low VL, LTNPs may have high VL: most eventually develop disease

Strongly associated with HLA class I alleles, but generally not distinguished by stronger or better immune responses (except preserved HIV-specific CD4+ IL-2+ responses)

226
Q

Summary of immune response to HIV
on 4 criteria.

A
  • vigorous immune response but no demonstratable protective immunity with rare exceptions
  • excessive immune activation which favours viral replication
  • immunological dysfunction with involvement of all elements of host defence
  • ongoing viral replication with progressive immunological impairment leading to clinical manifestations of immunodefeciency
227
Q

Why is life expectancy still reduced in HIV-infected people on cART?

A
  • Issues of adherence, side-effects, drug resistance
  • Increase in non-AIDS-defining illnesses (NADIs): lung, cardiovascular and renal disease
  • Incidence of NADIs is related to:
    > Size of latent HIV reservoir
    > Persistent immune activation
    > CMV co-infection
228
Q

Talk about Anti-retroviral therapy controls HIV replication but a viral reservoir persists.

A

Even with the most effective available ART, a poorly-defined reservoir of latently-infected cells persists for years, and HIV starts replicating again (to pre-treatment levels) within weeks of cessation of therapy

HIV is thought to persist as DNA integrated into “resting” transcriptionally-silent CD4+ T-cells and other cells such as tissue macrophages and T follicular helper cells

HIV may continue replicating in lymphoid tissue and other immune-privileged sites

Reservoir size correlates with persistent immune activation, largely driven by translocation of microbial products across the gut (damaged gut-associated lymphoid tissue and leaky gut since primary infection)

229
Q

What is the current HIV cure strategies?

A

‘Shock and Kill’

230
Q

Who are the Key populations
to HIV prevention strategies ?

A

(i.e.
sex workers and their clients, gay men and other MSM, people who inject drugs,
transgender people) - account for >70% new infections globally

231
Q

Which regions are seeing the most rapid rise in new HIV infections?

A

Eastern Europe and central
Asia

232
Q

What are the Socio-economic impact of HIV/AIDS in Africa?

A

> Significant impact on life expectancy
Loss of economically-productive adults (including health-care workers)

> Increased spending on healthcare (particularly as ART drug use becomes more widespread)

> Distortion of health-care spending

> Change in social structure: orphans cared for by elderly grandparents

> Stigma of HIV infection persists

233
Q

Who is most at risk of acquiring HIV?

A

50% of all new infections occurring world-wide are in 15-24 year olds

234
Q

Talk about Paediatric HIV-1 infection in Africa.

A

Transmission occurs via 3 routes:
In utero: transplacental, mostly during the third trimester

Intra partum: exposure to maternal blood and genital secretions during delivery

Breast milk: ingestion of large amounts of contaminated milk

In breast-feeding populations, risk of mother-to-child transmission (MTCT) is up to 45%

Transmission can largely be prevented by ART given to pregnant women and to the infant (MTCT)

If maternal pVL is undetectable, risk of transmission is <2%

235
Q

Why do we need to perform HIV screening in pregnancy?

A

Increased HIV susceptibility (3x) of pregnant
Women and during the first six months post partum (4x):

therefore, need for more regular HIV screening in pregnancy.

236
Q

Talk about HIV exposed uninfected (HEU) infants.

A

Increasingly numerous: account for up to 30% of births in parts of southern Africa

HEU infants have increased mortality (2-3-fold) compared to unexposed infants: peak mortality aged 3-6 months

Increased morbidity from infections (despite maternal ART)

Increased hospital admissions, particularly with respiratory infections (including PCP, TB), failure to respond to antibiotics

Increased surgical complications

More likely to have growth stunting

Poor motor development

237
Q

What happens to the 50% of HIV-infected children who survive beyond 2 years?

A

Very high early mortality of untreated HIV+ children led to assumption that few would survive into adolescence

HIV prevalence data are scarce for this age-group: children < 16 years are not included in national testing strategies in most African countries

It is now thought that 30% of HIV+ children are slow progressors

238
Q

Barriers to adolescent testing:

A

difficulties in obtaining consent for HIV testing of older children in clinics

Absent/ poorly defined/changing guardianship,

Diagnosis leads to automatic disclosure of parental HIV status

239
Q

What do adolescents with HIV infection
in Africa need?

A
  • HIV testing & counselling
  • Linkage to HIV care
  • Adherence support for
    HIV treatment
  • HIV prevention &
    Sexual Reproductive Health care
    -
240
Q

Talk about oral testing for HIV.

A

Rapid Testing of Oral Fluid for HIV Antibody

241
Q

Talk about the 8 factors for

A

Consistent condom use (80 – 90% effective)

Male circumcision (60% reduction in infection – no benefit to female partners)

Treating STIs (genital ulcers and HSV infection increase transmission risk)

Microbicide gel for women (30 – 40% reduction in transmission risk)

Needle and syringe exchange for IVDUs

Post-exposure prophylaxis (PeP)

Treatment as prevention (TasP) (96% reduction)

Pre-exposure prophylaxis (PreP)

242
Q

How does male circumcision work to prevent HIV infection?

A

By removing foreskin, circumcision reduces the ability of HIV to penetrate due to keratinization of the inner aspect of the remaining foreskin

The inner part of the foreskin contains many Langherhans cells (tissue DCs expressing CD4) which are prime targets for HIV

Ulcers, characteristic of some STI’s that can facilitate HIV transmission, often occur on the foreskin - by removing the foreskin, the likelihood of acquiring these infections is reduced

The foreskin may suffer abrasions or inflammation during sex that could facilitate the passage of HIV

243
Q

Talk about the barriers to HIV-1 vaccine development

A

The tried and tested vaccine strategies that we have used for other organisms (live attenuated or killed vaccines) are deemed too risky for HIV – even though these approaches have been effective in some animal models

HIV-1 is highly variable – an effective vaccine would need to provide protection against the multiple variants of HIV present in each
infected person, as well as against the distinct clades of HIV throughout the world (which differ by 10-30% from one another) – and HIV diversity is increasing over time

A successful vaccine would also need to provide protection against HIV acquisition by different routes

There is evidence of protective immunity in most infections for which we have a successful vaccine – but most people infected with HIV-1 eventually develop AIDS – so we don’t really know if it is possible to generate protective immunity against HIV infection – or what is needed to do so

244
Q

Because of the difficulties in achieving an antibody response, researchers turned to?

A

T-cell vaccines

245
Q

Talk about The future for HIV vaccine studies.

A

After three human efficacy trials, there is one vaccine regimen (which is not going to be taken to licensure) that shows 31% efficacy, protective mechanism unclear

There are promising data from monkey models that are yet to be tested in humans

The design of future HIV vaccine clinical trials will need to take into consideration the other prevention mechanisms that have recently been shown to be effective, which is likely to increase the trial numbers needed to show efficacy

The use of ART to treat breakthrough primary HIV-1 infection will also need to be considered, which would add considerably to the cost of efficacy studies

So, an HIV vaccine seems possible in theory, but it is still some way off

246
Q

Talk about 3 facts of HIV.

A
  • HIV is a lentivirus that uses reverse transcriptase to replicate (retrovirus)
  • HIV replicates within CD4 cells, and overtime decimates their population causing immunodeficiency
  • HIV viral load increases over time
247
Q

What are the 2 markers that are used to monitor HIV infection?

A
  1. CD4 cell count
  2. HIV viral load

Both are important in the prognosis

248
Q

Case study:
Patient has :
28M presents
Fever, sore throat, headache

On examination:
Throat normal
Mouth ulcers
Mild lymphadenopathy
He has a diffuse symmetrical maculopapular rash

Never injected drugs
1 tattoo
12 casual female partners in last year
Uses condoms “sometimes”

HIV test at this stage would be positive

What disease is this?

A

Acute HIV

249
Q

Talk about the signs and symptoms of acute HIV

A

Symptoms usually start within 2-4 weeks of infection

Similar to glandular fever/flu

Fever*
Sore throat*
Myalgia*
Rash*
Vomiting + diarrhoea
Headache
Lymphadenopathy
Weight loss

Patients can sometimes present with an aseptic meningitis (due to the direct effect of HIV on the CNS); and people can occasionally present with an “opportunistic infection”, which we will talk about later

250
Q

In a patient with fever, rash and non-specific symptoms, what are the 2 things we do?

A

Ask about sexual history
Think of HIV seroconversion

251
Q

What happen during clinical latency of HIV?

A

No symptoms!

May notice some enlarged lymph nodes  Persistent Generalised Lymphadenopathy

252
Q

Think about doing a HIV test when faced with which 3 common problems:

A

In an unexpected patient
That is recurring
That has no clear underlying cause

253
Q

AIDS defining illness happens when….?

A

CD4 <200

254
Q

What is the most common AIDS defining illness?

A

Fungal pneumonia (Pneumocystis jirovecii)

Fevers, SOB, dry cough, pleuritic chest pain,exertional drop in oxygen saturations

An ABG is important to assess for the severity of the PCP and will help determine the treatment.

To diagnose, get an induced sputum- patient inhales nebulised saline to acquire sputum (as usually a dry cough!). A normal sputum is not sufficient, it needs to be a “deep” sample.

Sent for polymerase chain reaction (PCR) for pneumocystis detection

255
Q

Which fungal disease is susceptible to antibiotics?

A

Pneumocystis Pneumonia (PCP)
- Co-trimoxazole
+/- prednisolone (steroids) if hypoxic

256
Q

Which disease is the most common opportunistic infection (AIDS-defining illnesses)

A

AIDS defining illnesses frequency:
PCP – 42.6%
Oesophageal candida – 15%
Wasting – 10.7%
Kaposi’s Sarcoma – 10.7%
Disseminated atypical mycobacterial infection – 4.8%
TB – 4.5%
Cytomegalovirus (CMV) – 3.7%
HIV dementia – 3.6%
Recurrent bacterial pneumonia – 3%
Toxoplasmosis – 2.6%
Immunoblastic lymphoma – 1.9%
Chronic cryptosporidiosis – 1.5%
Burkitt’s lymphoma – 1.5%
Chronic Herpes Simplex Virus infection – 0.5%

257
Q

What happened when theres late diagnosis of HIV?

A

Increased transmission
Increased morbidity
Increased mortality

258
Q

All patients with TB require what test?

A

HIV
TB in HIV at any CD4 count: AIDS defining
Atypical presentations with lower CD4 count

Sample for Acid Fast Bacilli staining

259
Q

What are the 3 most common TB CNS presentations?

A
  1. Tuberculoma
  2. Ocular TB
  3. TB meningitis
  4. CNS Lymphoma
    - Reactivation of latent EBV
  5. CNS Toxoplasmosis
    - Reactivation of latent toxo
  6. CMV retinitis
    - Reactivation of latent CMV
  7. Ocular Toxoplasmosis
    - Reactivation of latent toxoplasmosis
  8. Cryptococcal Meningitis
    > Gradual onset headache / fever
    > High opening pressure on lumbar puncture
    > India ink used on microscopy
260
Q

How is the lumbar puncture in patients with HIV and hedache?

A

low threshold

261
Q

HIV increases the risk of any cancer that is associated with a virus, such as?

A

Human Herpesvirus 8  Kaposi’s sarcoma
Epstein Barr Virus  Lymphomas
Human Papillomavirus  Cervical, anal, penile carcinoma
Hepatitis B/C  Hepatocellulcar carcinoma

262
Q

Talk about Kaposi’s Sarcoma.

A

Human Herpesvirus 8

Usually associated with HIV

Single or multiple lesionsUsually on the skin

Treated with HAART and chemo/radiotherapy

Other sites – mouth, GI tract  GI bleed, respiratory tract
Can cause bleeding

263
Q

So, what do we use to treat HIV once it has been diagnosed?

A

HAART (Highly Active Anti-Retroviral Therapy)

264
Q

Why is currently HIV infection is an entirely manageable condition with a good prognosis?

A

With current HAART regimes

265
Q

How does HIV develop drug resistance?

A
  1. Non-adherence
  2. Drug-drug interaction
    Examples of DECREASED drug levels
    a) Clopidogrel + Boosted PI = ↓ clopidrogel active metabolite
    b) Lansoprazole + Rilpivirine = reduced rilpivirine levels +/- resistance

Phase 2A (11 decks)

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