Infection

Question 1

Describe the principles of “an infection” and how an individual develops an infection

Answer 1

Infection - invasion of host’s tissue by microorganisms. Disease caused by replication of microorganism, toxins and host response.
How you get infected - contact, inhalation, ingestion, vertical transmission.

Question 2

How do microorganisms cause disease and some disease determinants

Answer 2

How do they cause symptoms:

Virulence factors Exotoxins(cytolytic, AB toxins, superantigens, enzymes) and
Endotoxins
Host cellular damage - direct or because of host immune response.

Disease determinants:
virulence factors
inoculum size
antimicrobial resistance
Site
Co-morbidities

Question 3

Describe the 4 exotoxins produced by gram positive bacteria

Answer 3

Exotoxins are secreted

Cytolytic - membrane damaging
AB toxins - 2 part - B binds to cell and delivers A to cytosol which is often an enzyme that interferes with cell function.

Super antigens - microbial proteins that bind both class II MHC molecules and T-cell receptors (causing activation of the T cell)
Enzymes - destroy tissue that bacteria is trying to invade

Question 4

What are endotoxins gram neg

Answer 4

lipopolysaccharide-protein complexes
components of cell wall of Gram Negative Bacteria
liberated only on cell lysis or death of bacteria.
Mildly toxic and do not bind to specific receptors.
Cause host cell damage either directly or as a result of the immune response e.g. cytokine determinants storms/SEPSIS.

Question 5

Describe how to identify that a patient has an infection including history, examination and investigations.

Answer 5

How to identify:
History - symptoms - focal or systemic, severity, duration, potential exposures
Examination - organ dysfunctions
Investigations - specific and supportive

Supportive:
Full blood count(eg neutrophilia means bacterial infection)
CRP(inflammation)
Liver and kidney function tests(to see if drugs can be given)
Imaging
Histopatholoy(look at sample under microscope)

Specific(to determine cause):

Bacteriology- Collect specimen(eg swab, fluids, tissues). Then microscopy, culture and sensitivity.
Use gram stain
Or can look at antigen detection, nuclei acid detection(PCR) or antibiotic susceptibility.

Virology - ELISA tests with antigens or antibodies in well or detecting viral nuclei acid (PCR).

Question 6

Microorganisms broad categorisation

Answer 6

bacteria - prokaryotic
viruses

parasites(eukaryotic) - Protozoa(single celled) and helminths (multi-cellular)

Fungi (eukaryotic) - yeasts (single-celled) and molds (multicellular)

Question 7

Key features of bacteria
Look at diagram on notion

Answer 7

All are prokaryotes- do not have nucleus

Gram positive or negative
Cocci or bacilli
Aerobes or anaerobes

Question 8

Gram stain

Answer 8

Treated with a solution of crystal violet, the bacterial cells will stain purple.
then treated with a solvent - alcohol
gram-positive organisms retain the stain, whereas gram-negative species lose the stain, becoming colourless.
Addition of the counterstain safranin stains gram-negative bacteria pink.

Question 9

Agar plates

Answer 9

Used for culture of bacteria
Resists digestion by bacterial enzymes
Enriched medium as the plate with the protein and blood provides nutrients for a number of common bacteria.

Question 10

bacterial structure
Look at notion

Question 11

Virus features

Answer 11

Consists of DNA or RNA

Surrounded by a protein coat

A virus may also have an envelope derived from the membrane of the host cell.

Viruses contain the genetic information necessary for replication but require the host’s cellular structures and enzymatic machinery to complete the process.

The fate of the host cell following viral infection ranges from rapid lysis and release of many progeny virions to gradual, prolonged release of viral particles.

Question 12

virus structure
Look at notion

Question 13

Gram positive and neg diff
Look at notion

Answer 13

thick, multi-layered, peptidoglycan cell wall
or
negative:
have cell wall with 2 membranes which are separated by the periplasmic layer containing peptidoglycan. This layer is thin and so more susceptible to damage. Outer membrane has LPS which has a lipid portion that is toxic(endotoxin). Antigenic so can identify species.

Question 14

Virulence factors - Factors that enhance pathogenicity

Answer 14

– Host entry (e.g. polysaccharide capsule to protect from enzymes and hostile environments)

– Adherence to host cells (e.g. pili to prevent from being washed away by mucus)

– Invasiveness (e.g. enzymes such as collagenase to degrade extracellular matrix and have easier access to host cell surfaces)

– Iron sequestration (siderophores - capture iron from host for growth)

Question 15

Ses 2

Question 16

Understand and describe a model of infection - see notion for flowchart

Answer 16

For any patient you are examining – think:
1) Patient – age, gender, social status, health status, time of year, home, recent
travel.

2)Pathogen – virus, bacteria, fungus, parasite.

3) Mechanism of infection - contiguous (direct) spread, inoculation, haematogenous, ingestion, inhalation, vector, vertical transmission.

4) Process of the infection – attachment, interaction with host defences, host.

5) Management of the patient – history, examination, investigations, treatment (specific and supportive).

6)Patient outcomes – cure, disability, chronic infection or death.

Question 17

To understand how to apply the model of infection to a specific illness

Answer 17

Example:
Cellulitis - severe inflammation of dermal and subcutaneous layers of the skin.

Patient - children, elderly and immunocompromised.
Pathogen - Group A streptococcus, Staphylococcus aureus and Haemophilus influenza type B
Mechanism -break in skin so pathogens invade subcutaneous layers
Management- antibiotics
Patient outcomes- cure or septic shock

Thrush
Patient - Most HIV-positive individuals oral candidiasis, which often spreads to the oesophagus(AIDS).
Pathogen - yeast Candida albicans - normal body flora of skin, mouth, vagina and intestines
Mechanism - competing bacterial flora eliminated so yeast over grows
Management - nystatin or clotrimazole.
Patient outcomes

Question 18

Identify microbes commonly found on the skin and other body sites

Answer 18

The skin
Staphylococcus aureus Staphylococcus epidermidis Streptococcus pyogenes Candida albicans

The mouth and nasopharynx
Streptococcus mutans Streptococcus pneumoniae Neisseria meningitidis Haemophilus influenza type B.

The gastrointestinal tract
E. Coli

Urogenital tract - Lactobacillus

Question 19

Describe how microbes, normally present as commensals (part of the microbiome) can cause disease / infections in certain situations and give
examples.

Answer 19

Normal flora is displaced from its normal location to sterile
location:
Breaching the skin integrity eg skin loss, surgery, IV lines
Fecal-oral route - Foodborne infection
Fecal-perineal-urethral route - Urinary tract infection (women)
Poor dental hygiene

Normal flora overgrows and becomes pathogenic
when host becomes immuno-compromised:
Diabetes o AIDS o Malignant diseases o Chemotherapy (mucositis)

When normal flora in mucosal surfaces is depleted by antibiotic therapy:
Intestine -> severe colitis (Clostridium difficile)
Vagina -> thrush (Candida albicans)

Question 20

Describe the different innate barriers to infection, including physical,
physiological, chemical and biological

Answer 20

1) Physical barriers – skin, mucous membranes(mouth, RT, GI tract, UT) and bronchial cilia

2) Physiological barriers – diarrhoea, vomiting(hepatitis, meningitis), coughing(pneumonia) and sneezing(sinusitis).

3) Chemical barriers – low pH and antimicrobial molecules eg IgA - tears, saliva, mucous
membrane
lysozyme - sebum, perspiration,
urine
mucus
β-defensins - epithelium
gastric acid

4) Biological barriers – normal flora in strategic locations - benefits:
synthesise vitamins (e.g. K, B12) immune maturation
Compete with pathogens for
attachment sites and ressources Produce antimicrobial chemicals

Question 21

Describe how these different barriers work together to maximise the response against microbes

Question 22

Recognize the different interventions that affect integrity of the innate
barriers

Answer 22

Normal flora is displaced from its normal location to sterile location
• Breaching the skin integrity - Skin loss (burns), Surgery, IV lines, Skin diseases, Injection drug users

• Fecal-oral route - Foodborne infection. Fecal-perineal-urethral route - Urinary tract infection esp women.

Poor dental hygiene - o Gingivitis

Normal flora overgrows and becomes pathogenic when host becomes immuno-compromised:
o Diabetes o AIDS o Malignant diseases o Chemotherapy (mucositis)

When normal flora in mucosal surfaces is depleted by antibiotic therapy:
o Intestine -> severe colitis (Clostridium difficile)
o Vagina -> thrush (Candida albicans)

Question 23

Understand the risk of infection associated with these interventions

Question 24

State name and function of the second line of defence, including the role of phagocytes and chemicals.
3 phagocytes
4 cells of innate IS
2 chemicals

Answer 24

1) Phagocytes - intracellular killing by O2 dependant pathway(mostly):
macrophages - Present in all organs, Ingest and destroy microbes (Phagocytosis), Present microbial antigens to T cells (adaptive immunity), Produce cytokines/chemokines

monocytes - In blood, Recruited at infection site and differentiate into macrophages

neutrophils - in blood, Increased during infection, Recruited by chemokines to the site of infection, Ingest and destroy pyogenic bacteria - Staph. aureus and Strep. pyogenes

2) Other key cells of the innate immune system
Basophils (mast cells) - Early actors of inflammation (vasomodulation), Important in allergic responses
Eosinophils - Defence against multi-cellular parasites (worms)
Natural killer cells - Kill all abnormal host cells
Dendritic cells - Present microbial antigens to T cells (acquired immunity)

3) Chemicals – complement system and cytokines

Question 25

Describe how pathogens are recognised by cells of the innate immune system

Answer 25

PAMPs – pathogen associated molecular patterns - and include carbohydrates, lipids, proteins and nucleic acids, e.g. peptidoglycan (a component of bacterial cell walls), lipopolysaccharide (a lipid/carbohydrate moiety found in bacterial cell membranes), ß-glucan (found in fungal cell walls) or dsRNA (some viruses). PRRs – pathogen recognition receptors – they are proteins that span the phagocyte membrane and they essentially bind Opsonisation of microbes enhances the interaction between the phagocyte and the microbe. Opsonins are proteins that bind to and coat the surface of the microbe. These are produced by various components of the immune system.

Question 26

Name and describe important opsonins

Answer 26

complement proteins - C3b, C4b. antibodies - IgG, IgM acute phase proteins - C-reactive protein (CRP), mannose-binding lectin (MBL).

Question 27

Describe how a clinical evaluation of the innate immune response helps to identify the presence of infection, and in particular that of acute inflammation and acute infection. As examples describe the role and evaluation of neutrophils and C-reactive protein.

Answer 27

Neutrophilia = bacterial infection Raised CRP - opsonise that inc phagocytosis - indicates inflammation

Question 28

Ses 3

Question 29

Sepsis definition

Answer 29

Sepsis is characterised by a life-threatening organ dysfunction due to a dysregulated host response to infection.

Question 30

Sepsis effect on organs in ABCDE

Answer 30

Airways - no specific effect Breathing/Respiratory: Raised respiratory rate (tachypnoea). Fluids and proteins leaking into interstitial tissues lead to lung oedema and decreased lung compliance. Circulation: Hypovalemia (due to vasodilation and increased capillary leakage) so low blood pressure. This would result in tachycardia. End-organ damage (kidneys, liver, and brain) Disability/CNS: As a result of reduced blood flow to the brain, patients can present with confusion, drowsiness, slurred speech, agitation, anxiety, and reduced level of consciousness. Exposure / Pyrexial (hypothalamic response to infection) BUT remember hypothermia for elderly. Renal: As a result of reduced blood transfusion to the kidneys, there is reduction in urine output.

Question 31

Sepsis risk factors

Answer 31

• Very young (< 1 year old). • Elderly (>75 years) or very frail. • Pregnant, post partum (within last 6 weeks). • Patients with impaired immune system

Question 32

Sepsis screening

Answer 32

A patient should be screened for sepsis when: • a clinician or carer is worried • the NEWS2 score is 5 or more Scores to: Resp rate O2 sat Systolic BP Pulse rate Consciousness Temp • the patient is at risk of neutropenia • there's evidence of organ dysfunction e.g. lactate 2mmol/l or above

Question 33

Treatment for amber flag

Answer 33

Amber - (NEWS2 5 or 6 or 1-4 with one of lactate >2mmol, chemotherapy in last 6 weeks, organ failure, deteriorating): Send bloods Senior clinical review within 1 hr Antimicrobials and escalation plan in 3 hrs

Question 34

Red flag - sepsis 6

Answer 34

NEWS 2 more than 7 Sepsis 6 within the hour 1. Senior help 2. Give O2 to inc O2 sat 3. Send bloods - culture and FBC 4. IV antibiotics - consider likely organisms, penetration, patient factors. Source control - drain abscess. 5. Consider IV fluids - correct hypovalemia 6. Monitor - urine output, are they deteriorating Consider critical care if patient continues to deteriorate. Continue reviewing patients daily.

Question 35

Understand the mechanism by which micro-organisms trigger the inflammatory cascade

Answer 35

Micro-organisms trigger inflammatory responses via special methods in the following processes:  Gaining entry into the host (e.g. via respiratory, GI, urogenital, skin)  Adherence to host cells (e.g. via cell surface adhesion molecules, fimbriae/pili)  Invasive into host cells / mucosal surfaces (e.g. via enzymes such as collagenase and hyaluronidase)  This would then result in inflammation (either pyogenic or granulomatous)!

Question 36

Understand the relevance of HIV in a global and UK context

Answer 36

many millions of people living with HIV. Substantially fewer deaths due to HIV in the UK. Biggest burden of HIV infections in Africa.

Question 37

Describe the principles of HIV structure, replication notion for structure

Answer 37

HIV is a single stranded RNA retrovirus. Attachment to cells is accomplished via the gp120 portion of the envelope gene product on the HIV surface, which preferentially binds to the CD4 molecule. The virus infects helper T cells, lymphocytes, monocytes, and dendritic cells, which produce this glycoprotein on their surface. Replication - The ssRNA is converted to dsDNA and incorporated into the cell’s genome.

Question 38

Apply the infection model to a patient with HIV and acquired immunodeficiency syndrome (AIDS)

Question 39

Describe the principles of infection transmission and prevention with regard to HIV.

Answer 39

Transmission - Contact of infected bodily fluids with mucosal tissue / blood / broken skin eg sexual contact, blood transfusion, contaminated needles, vertical transmission to fetus during delivery. Affected by - viral load Prevention - Condom use, use of clean new needles, treatment during pregnancy, screening, Post-exposure prophylaxis (PEP), Pre-exposure prophylaxis (PrEP), Male circumcision

Question 40

Treatment notion

Answer 40

Anti-retroviral drugs (ARVs) ensure undetectable viral load and allowing CD4 count to recover. They work by: Targeting binding - CCR5 so entry inhibitor Target enzymes responsible for incorporation of viral DNA into host - integrase inhibitor. Target reverse transcriptase competitively or non - NNRTI or NRTI Prevent larger proteins breaking down into smaller proteins in viral life cycle - protease inhibitor Virus mutates frequently so multiple drugs to resist resistance.

Question 41

Who should be tested

Answer 41

Resp: bacterial pneumonia / TB • Neuro: meningitis/dementia • Derm: Severe psoriasis Gastro: Chronic diarrhoea Cancer

Question 42

HIV testing

Answer 42

Testing - a) serology – detects both antigens (viral proteins) and antibodies to HIV in the blood, b) PCR – detects the viral nucleic acid and c) rapid testing – usually picks up the antibodies to HIV in either blood or saliva.

Question 43

Ses 4

Question 44

Antimicrobial classes

Answer 44

Antibacterial, antifungal, antiviral & antiprotozoal agents

Question 45

Anti bacterial classes - 4 (not mechanism of action)

Answer 45

Bactericidal or bacteriostatic Spectrum – ‘broad’ v. ‘narrow’ Target site (mechanism of action) Chemical structure (antibacterial class)

Question 46

How to choose an antibiotic

Answer 46

Cause Active Site eg cross blood brain barrier Right formulation Half life - dosing Interaction with other drugs Toxicity - eg aminoglycosides are nephrotoxic Monitoring - therapeutic window

Question 47

different ways to measure antibiotic activity

Answer 47

Disc Sensitivity/Diffusion Testing – putting the organism on the agar plate and putting ‘paper discs’ containing antibiotics and reading the zone of clearance. Minimum Inhibitory Concentration (MIC) – The first concentration of antibiotic that inhibits the growth of bacteria. Done via: broth microdilution OR E-test strip.

Question 48

3 Types of antibiotic resistance:

Answer 48

Intrinsic - The antibiotic does not target the specific characteristics of the bacteria, therefore, unable to gain access to bacteria Acquired - via chromosomal gene mutation/horizontal gene transfer (via plasmids). 3 ways:  Enzymatic destruction of antibiotics  Enzymatic alteration or mutations of bacterial target sites  Overexpression of efflux pumps (multi drug resistance) Adapted: if there are a sub-therapeutic levels of antibiotics, this only causes a mild stress response to the bacteria – hence it will respond by becoming resistant to the antibiotic

Question 49

Classes of antibacterials and their mechanism of action

Answer 49

Cell wall synthesis Beta - lactams Protein synthesis Tetracycline, aminoglycosides, macrolides Cell membrane function Polymixins Nucleic acid synthesis Quinolones, Trimethoprim

Question 50

Beta lactams + glycopeptides

Answer 50

Penicillins eg penicillin(streptococci), amoxicillin(some gram -ve) Cephalosporins - broad spectrum but not anaerobes. Gives C.difficile infection. Eg Ceftriaxone (crosses blood-brain). Carbapenems - broad spectrum eg imipenem. Penicillin allergy. G -ve + G+ve + anaerobes. Glycopeptides Vancomycin - G +ve, C.difficile oral otherwise IV. Narrow therapeutic window.

Question 51

Protein synthesis

Answer 51

Tetracycline (30s ribosome subunit) & doxycycline - oral, g+ve, broad. Treats protozoa, chlamydia, atypical pneumonia. Not to children <12 years/pregnant women (causes staining of developing teeth). Aminoglycosides - gentamicin, g-ve, nephrotoxic Macrolides (50s) - erythromycin, g+ve

Question 52

Nucleic acid synthesis

Answer 52

Quinolones - ciprofloxacin, Inhibit DNA gyrase, Very active against Gram negs. Risk of tendinitis and rupture, aortic dissection, central nervous system effects and C.difficile infection. Trimethoprim & sulphonamides - Inhibitors of folic acid synthesis, treat UTI. Co-trimoxazole – Used to treat Pneumocystis jirovecii, Has activity against MRSA Rifampicin - inhibits RNA polymerase

Question 53

Antifungals

Answer 53

Azoles (active against yeasts, molds) • Inhibit cell-membrane synthesis • Fluconazole used to treat Candida Polyenes (nystatin and amphotericin) • Inhibit cell membrane function • Amphotericin for IV treatment of systemic + severe fungal infections (e.g. aspergillus) Nyastin for topical treatment of Candida

Question 54

Antivirals

Answer 54

Aciclovir • When phosphorylated inhibits viral DNA polymerase Herpes simplex – genital herpes, encephalitis Varicella zoster – chicken pox & shingles Oseltamivir (‘Tamiflu’) • Inhibits viral neuraminidase • Influenza A & B

Question 55

Metronidazole + Nitrofurantoin

Answer 55

anti-bacterial (anaerobes) and anti-protozoal Protozoal: 1. Amoebae (dysentery & systemic) 2. Giardia (diarrhoea) 3. Trichomonas (vaginitis) SHOULD NOT TAKE THIS WITH ALCOHOL - like disulfiram Nitrofurantoin - Mixed between preventing protein synthesis and DNA/RNA synthesis.

Question 56

Antimicrobial stewardship

Answer 56

Do not start antibiotics in absence of clinical evidence of bacterial infection

Question 57

antibiotic resistance.

Question 58

The global and local relevance of Hepatitis B & Hepatitis C

Answer 58

Greater numbers living with hepatitis than HIV worldwide – go on to develop end stage liver disease if left untreated. Far greater numbers of untested individuals since it is not on screening programmes where it is endemic.

Question 59

Hepatitis viruses - definitions

Answer 59

Hepatitis = inflammation of the liver Replication specifically in hepatocyte Destruction of hepatocytes

Question 60

How to remember

Answer 60

A = acute C = chronic B = bit of both D = double trouble - only with B E = like A

Question 61

Transmission

Answer 61

A + E= Faceo-oral B + C (only blood) + D = blood, sex, vertical B + C = chronic

Question 62

Liver function tests (LFTs)

Answer 62

Bilirubin Liver transaminase - hepatocyte damage Alkaline phosphatases - Biliary tract cell damage / cholestasis Lower Albumin - less function Coagulation - clotting factors made

Question 63

Three causes of ALT > 1000

Answer 63

Viral hepatitis Drugs/medication Blood clots

Question 64

B

Answer 64

Transmission - vertical but also sexual contact, intravenous drug use, close household contacts (low risk) where there is significant blood exposure and health care workers via needle stick injuries. Symptoms - jaundice (icteric sclera), fatigue, abdominal pain, anorexia/nausea/vomiting and arthralgia (joint pain). Replication - the virus integrates its genetic material into the host genome. Treatment - anti- viral, vaccine given to babies Testing - serology and HBV DNA PCR test. Incubation - 6wekks - 6 months Presentation- AST/ALT in 1000s Up to 50% - no/vague symptoms More likely to become chronic in infancy

Question 65

B serology

Answer 65

1) Surface antigen first 2) Followed by e-antigen - Highly infectious 3) Core antibody (IgM) - First antibody to appear 4) Followed by e-antibody - Heralds disappearance of e- antigen + infectivity 5) Surface antibody - Last antibody + Clearance of virus 6) Core antibody (IgG) - Persists for life

Question 66

Chronic Hep B infection Definition

Answer 66

Persistence of HBsAg after 6 months Leads to cirrhosis

Question 67

C

Answer 67

intravenous drug users Chronic Symptoms - vague - fatigue, anorexia, nausea, abdominal pain (RUQ)) and about 80% have no symptoms at all Testing - PCR, anti-Hep C antibody Treatment - anti-virals - can be cured No vaccine Disease progression - cirrhosis, carcinoma

Question 68

POST-EXPOSURE PROPHYLAXIS (PEP)

Answer 68

Risks of transmission via needle stick injury are as follow: HIV 1/300 (or even 0 if viral low undetectable) Hep C 1/30 Hep B 1/3 (or 0 if vaccinated). Bleed and wash wound Collect blood from patient and worker Give Hep B vaccine PEP for HIV and ARVs - earlier reduces replication. Monitor Use condoms

Question 69

Ses 5

Question 70

Describe features of Antigen Presenting Cells (APCs)

Answer 70

APC is a macrophage – then T-cells phagocytose the pathogen. If the APC is a B-cell then T-cells respond by stimulating the production of antibodies – the humoral response. Dendritic and langerhan cells present to naive T cells - not exposed to antigen - become effector cells. mucosal membranes, skin (i.e., Langerhans cells), blood (i.e., plasmacytoid cells), lymph nodes (i.e., follicular dendritic cells), and spleen. Capture by phagocytosis and Macropinocytosis

Question 71

Describe MHC molecules in relation to microbe presentation

Answer 71

APCs present pathogen antigenic peptide attached to major histocompatibility complexes. MHC II complexes are expressed on dendritic cells, B-cells and macrophages (APCs)and they present microbial peptides from extracellular microbes. MHC I complexes exist in all nucleated cells and present microbial peptides from intracellular microbes. Co-dominant expression of MHC class 1 and 2

Question 72

MHC presentation 3 features

Answer 72

Peptide binding cleft - has polymorphic residues Broad specificity - many peptides presented by same MHC Responsive T cells - CD4+ by class 2 and CD8+ by class 1

Question 73

Processing - Exogenous

Answer 73

Captured Degradation Peptide-rich vesicles fuse with vesicles containing MHC class II molecule Formation of complex Only APCs

Question 74

Processing - Endogenous

Answer 74

Viral protein in cytosol Marked for destruction by the proteasome Proteasome-generated viral peptide transported to ER by TAP proteins Complex formation

Question 75

Describe T cells and their role with regard to infections

Answer 75

Interact with APCs and/or nucleated cells to become activated. Then kill pathogens by cytotoxic pathway or activate B cells to produce antibodies.

Question 76

Describe how antigen presenting cells activate the right adaptive immune response

Answer 76

Present MHC2 to CD4+ Tcells to activate humoural immune response. Present MHC 1 to CD8+ T cells to activate cell mediated response.

Question 77

Clinical MHC

Answer 77

Major causes for organ transplant rejection o HLA molecules mismatch between donor and recipient (Allograft) o Graft-Versus-Host reaction (GVH) association with autoimmune disease Ankylosing spondylitis Insulin-dependent Diabetes Mellitus

Question 78

Antimicrobial Stewardship What is it? Why is antimicrobial stewardship important How does it work in practice

Answer 78

appropriate use of antimicrobials - limit the selection for antimicrobial resistant strains a) MDR (multi-drug resistant) - Non-susceptibility to at least one agent in 3 or more categories b) XDR (extensively drug resistant - Non-susceptibility to at least one agent in all but two categories c) PDR (pan-drug resistant) - Non-susceptibility to all agents in all antimicrobial categories 1. Does the patient need antibiotics? - Have they finished their course? 2. Can we switch this to oral from IV? - Can they swallow?, Are they improving? 3. Can we change broad to narrow-spectrum? sensitivity results 4. Do you need special authorisation from microbiology?

Question 79

Ses 6

Question 80

Why you get surface infections and how , example of natural + prosthetics

Answer 80

commensals carried on skin and mucosal surfaces. transfer to other sites can be harmful. Natural: Cellulitis Conjunctivitis Urinary tract infection Pneumonia Septic arthritis Osteomyelitis Endocarditis Prosthetic: Intravascular lines Cardiac valves Prosthetic joints catheters • Adherence to host cells or prosthetic surface • Biofilm formation • Invasion and multiplication

Question 81

Skin micro-organisms

Answer 81

Viruses • Papilloma • Herpes simplex Bacteria Gram positive • Staph aureus • Coagulase negative staphylococci Gram negative • Enterobacteriaceae Fungi • Dermatophytes Parasites • mites

Question 82

Other sites

Answer 82

Nasopharynx - Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae Mouth - Candida Stomach - Helicobacter Intestine - Clostridium Vagina - Lactobacilli, coagulase-negative staphylococci, mycoplasmas

Question 83

Explain a ‘biofilm’ and the implications for an infection on a surface

Answer 83

Biofilms comprise of microbial communities attached to surfaces and encased in an extracellular matrix of microbial origin. Colonise medical devices - staph aureus + epidermis. 2 types of staphylococcus: Coagulate +ve - acute Coagulate -ve - cause problems when in a biofilm - chronic Biofilms protect the bacteria by prevent bacterial phagocytosis, antibodies and complement recognition/binding of receptors. only solution to treat the infection is to remove the artificial surface on which the biofilm is growing.

Question 84

Describe the management of infected surfaces

Answer 84

sterilize tissue via antibacterial drugs, removing prosthetic material with surgery. The challenges are poor antibacterial penetration into biofilm, low metabolic activity of biofilm micro‐organisms and difficulties of surgical procedure.

Question 85

endocarditis mechanism

Answer 85

The endocardium is non sticky and normally resists bacterial seeding. Biofilm binds to valves. Aberrant flow = collection of fibrin + platelets Microorganisms that enter the blood stream from skin, mucosa or other site bind to bio-film Further fibrin deposition, platelet aggregation and bacterial invasion - cascade Staph aureus - fibronectin proteins so can bind to unifected endocardium.

Question 86

Hallmarks of endocarditis

Answer 86

1. constitutional symptoms which are cytokine mediated 2. local spread of infection causing destruction of myocardium 3. distal blood borne septic embolisation

Question 87

Clinical notion

Answer 87

Fever Heart murmur Other cardiac complications Embolic features: These are small bits of the biofilm) that become loose and travel to small capillaries where they can block or cause local infection: Janeway Lesions: These are haemorrhagic nodular lesions on palms and soles. They are related to micro-abscess formation and localised necrosis. Splinter Haemorrhages: capillary engorgements usually in distal third of the nail bed. Oslers nodes: These are painful, erythematous nodules on pads of fingers and toes.

Question 88

Prosthetic endocarditis microorganisms

Answer 88

With knee joints have to fuse bones Prosthetic valve - greater than 1 year = strep, enterococcus, candida, staph a Less than 1 = coagulase -ve strep Prosthetic joint - coagulase -ve staph Staph a Pacing wire - coagulase -ve staph Staph a

Question 89

Quorum sensing

Answer 89

all bacteria within the biofilm express certain genes which confer some advantage to the colony such as production of a multi drug resistant (MDR) efflux pump or antibiotic production to kill other bacteria so less competition.

Question 90

Describe the antigen receptor present on T cells

Answer 90

T: o T cell receptor (TCR): a and b chains o CD3 complex o Accessory molecules (CD4 or CD8) Antigen recognised determined by what peptides on MHC

Question 91

Understand the mechanisms leading to T cells activation notion

Answer 91

Signals on APCS - costimulation Signal 1: MHC class 1 or 2 B7 Cytokines - Il1, Il6, TNF alpha Extracellular = CD4+ - effector is T helper cells Intracellular = CD4+ and CD8+ - effector is cytotoxic T cells

Question 92

Describe the antigen receptor present on B cells

Answer 92

B Cell Receptor or BCR: Membrane bound antibodies - Unique specificity for each cell Recognises Macromolecules + small chemicals

Question 93

Understand the mechanisms leading to B cells activation notion for exam diagram

Answer 93

1st signal: BCR engagement Signal transduction Antigen processing and presentation Increased B7 costimulators 2nd signal: TCR engagement Antigen specific Role of B7 costimulators 3rd signal Cytokines CD40 activation Effect = Proliferation and differentiation Antibody production (IgM production is T helper independent. IgG, IgA, IgE production is T helper dependent (isotype switch)) Heavy chain class switching Affinity maturation in antibody response - Prolonged or repeated exposure Memory B cells - Upon re-challenge can give a faster, stronger and longer antibody response

Question 94

Describe the effector mechanisms of cell-mediated immunity and humoral immunity Notion

Question 95

Effector functions of Antibodies

Answer 95

IgG Fc-dependent phagocytosis Complement activation Neonatal Immunity Toxin/virus neutralization IgA Mucosal Immunity IgE Immunity against helminths Mast cell degranulation (allergies) IgM Complement activation

Question 96

Ses 7

Question 97

Hospital-acquired Infections

Answer 97

infections acquired in hospitals 48 hours after admission.

Question 98

pathogens, patients, practice, place

Answer 98

Viruses: blood borne viruses (hepatitis B, C, HIV), norovirus, influenza, chickenpox, COVID-19 Bacteria - staph aureus including MRSA, Clostridioides difficile, Escherichia coli, Mycobacterium Fungi: Candida albicans, Aspergillus species Parasites: Malaria Patient - extremes of age, immunosuppression, surgical patient, emergency admission. Self infection Intervention- stop smoking, controlled diabetes, antimicrobial prophylaxis, hand hygiene. Patient to patient - isolation of infected Worker to patient- vaccinated, hand hygiene, PPE, Good clinical techniques (e.g. sterile non-touch) Practice factors - Policies, engagement, leadership. Place factors - eg no of beds in a bay. Environment to patient transmission intervention - Cleaning (Disinfectants), Single use equipment, Sterilisation.

Question 99

I fived

Answer 99

Identify: Abroad Blood borne Colonised Diarrhoea Expectorating Funny rash Initiate Inform

Question 100

Ses 8

Question 101

Describe common global and imported tropical infections and their pathogenesis, including malaria,

Answer 101

Plasmodium falciparum - most severe form - resistance emerging Plasmodium vivax - usually less severe & relapsing Plasmodium ovale - usually less severe & relapsing Plasmodium malariae - relatively mild Plasmodium knowlesi - macaque monkeys – zoonotic transfer Vector - female Anopheles mosquito. Incubation Period: Minimum 6 days. However, P. falciparum - 4 weeks, P. vivax/ovale - 1 year! A Symptoms and Signs: Fever, chills, headache, confusion, seizures, jaundice haemoglobinuria. Investigation:  Blood film (thick and thin smears)  Blood test: FBC, U&E, LFT  CXR  CT-Head Management  Removal of the vector (mosquito): bed nets, sanitation facilities.  Drugs: artesunate, quinine (IV/PO), doxycycline. Don’t use chloroquine (unless for P.vivax). Primaquine is given for liver-related malaria. (However, you don’t give this for G6PD patients – inc oxidative damage - MEH).

Question 102

enteric fever (typhoid when secondary to )

Answer 102

Mechanism of infection – faecal-oral from contaminated food/water Salmonella typhi or Salmonella parathyphi - gram neg bacilli factors: Only needs small dose to be infectious Survives gastric acid Fimbriae adhere to epithelium over ileal lymphoid tissue (Peyer’s patches) - get into blood/reticuloendothelial system Reside within macrophages so affect spleen + liver Susceptible patients: Usually children. Travellers from Asian countries (also African and South America). Incubation Period: 7-14 days Symptoms and Signs: fever, headache, abdominal discomfort, dry cough, bradycardia. Complications - intestinal haemorrhage & perforation, seeding. chronic carrier. Prevention - vaccination, good food and water hygiene. Diagnostic investigations: blood culture Treatment options: IV ceftriaxone, Azithromycin, Ciprofloxacin (but there is increasing resistance to this antibiotic)

Question 103

and dengue fever

Question 104

Understand and describe the life cycle of malaria.

Answer 104

Sporozoytes liver cells Merozoites Infect RBCs Reproduce and rupture Infect other cells Gametocytes remain in blood and taken up by mosquito when they are bitten again.

Question 105

Describe common travel related respiratory infections, including emerging infections

Question 106

Understand the importance of a travel history

Answer 106

many travel related infections can have deadly consequences on patients ➢ Specific to certain areas (place) or activities so ask where have you come from? Sexual, tick bites, insect bites, animal bites? When did the symptoms develop? - calc incubation period ➢ Different strains of pathogen (antigen/resistance) - have you taken vaccinations? ➢ Infection prevention (ward/lab)

Question 107

Apply the infection model to a patient presenting with an infection linked to travel

Question 108

Expand the description of pathogen/person/practice/place as it applies to travel related infections

Question 109

Form a differential diagnosis based on region of travel, incubation period and clinical presentation

Answer 109

Short - less than 10 days - bacteria = shigella Medium - 10-21 days - protozoa- malaria Long - more than 21 days- virus - HIV Animal bite - rabies Rodents - leptospirosis Insect bite - malaria or dengue Tick bite - Rickettsia Undercooked meat - salmonella

Question 110

Ses 9

Question 111

Apply the infection model to a patient who is immunocompromised

Question 112

Describe the main reasons for a patient to be immunocompromised - primary

Answer 112

Primary = congenital causes - intrinsic gene defect. Antibody defects Defect in B cell development- X-linked agammaglobulinaemia Defect in antibody production - Common Variable Immunodeficiency, Selective IgA deficiency (asymptomatic) T cell defects - Di George syndrome Combined B and T cell defects - Severe combined immunodeficiency (SCID) Phagocytic detect - defect in resp burst - Chronic granulomatous disease (CGD) - normally presents with skin abscess, pulmonary aspergillosis (Halo sign on HRCT)

Question 113

secondary

Answer 113

Decreased production of immune components: malnutrition infection (eg HIV) liver diseases therapeutic treatment (eg corticosteroids) splenectomy. Increased loss of immune components: due to protein-losing conditions or burns. Increased susceptibility to infections: chemotherapy

Question 114

Understand the links between the innate and adaptive immune system and situations and illnesses where a patient is immunocompromised

Question 115

To consider primary immune deficiencies linked to patterns of infection.

Question 116

Describe the warning signs that suggest a primary immunodeficiency disease - SPUR + 3 more

Answer 116

Family history Failure to thrive Diagnosis of sepsis Severe - life-threatening Persistent Unusual - site eg deep and nature of organisms eg opportunistic - candida Recurrent Is the component there? Are they functional?

Question 117

Describe the most common primary immunodeficiency diseases

Answer 117

CVID

Question 118

Use of the clinical presentation to understand the immune defects

Answer 118

Onset: Less than 6 months = Tcell or phagocyte defect More than 6 months and less than 5 yrs = B cell, antibody or phagocyte defect. More than 5 yrs = B-cell/antibody or 2nd Disease: Bacterial - complement deficiency Bacterial + fungal = phagocytic defects Bacterial, viral, protozoal - antibody deficiency All 4 - T cell defects

Question 119

management of primary immunodeficiency diseases

Answer 119

Lab investigations for antibodies, T cells, neutrophils, complements Supportive treatment: Infection prevention (eg prophylactic antimicrobials) Passive immunization -avoid live attenuated vaccines in patients with severe PIDs (SCID) Nutritional support (Vitamins A-D) Specific: Immunoglobulin replacement therapy Hematopoietic Stem Cell therapy

Question 120

Ses 10

Question 121

Describe E. coli including the identification + serology + agar plate notion

Answer 121

Gram-negative rods - pink stain. lactose-fermenting - use MacConkey agar as it contains lactose (which will grow into pink/red colonies if the pH becomes acidic – when lactose is broken down into lactic acid). contain the O,H,K,F antigens K - capsule On- LPS F - fimbriae H- flagella

Question 122

Describe the role of E. coli in health and disease

Answer 122

Part of bowel microbiota Causes UTI and diarrhoea. EPEC and EIEC are most common among young children in the developing world. Can protect against salmonella

Question 123

E. coli as a cause of diarrhoea pathogenesis, role of toxins and clinical features of ETEC and STEC.

Answer 123

 Enterotoxigenic E. coli (ETEC) - causes ‘traveller’s diarrhoea’ through the production of 2 toxins (heat stable and heat labile) to cause watery diarrhoea - stimulate lining of intestine so secrete excess fluid. Cramping, fever, nausea.  Enteropathogenic E. coli (EPEC) - creates a translocation tube to access and anchor into the enterocyte.  Shiga toxin-producing E. coli (STEC) - Shiga toxin (A & B subunits) inhibits protein synthesis within the cell and this causes cell death. Haemorrhagic colitis, haemolytic uraemic syndrome (HUS - triad of acute renal failure, haemolytic anemia, and thrombocytopenia).

Question 124

Describe E. coli as a cause of urinary tract infections with virulence factors and clinical features

Answer 124

Uropathogenic E coli (UPEC) Virulence factors: Adhesins- Type 1 fimbriae- adhesive tips that bind to α-D-mannosylated proteins on uroepithelium, cause invasion of uroepithelium and the formation of intracellular bacterial communities (IBCs) . Toxins - LPS, alpha haemolysins ( HlyA - pore forming toxin that is cytotoxic to epithelial cells), siderophores (acquire iron from UT). Clinical features: Cystitis - Uropathogenic E coli transfer from the rectum to the urethra and then migrate to the bladder. Frequent and urgent urination, suprapubic pain, haematuria, malaise. Can go up to kidneys and cause pyelonephritis- back pain, fever, vomiting.

Question 125

Describe E. coli as a cause of blood stream infections and sepsis

Answer 125

commonest cause of bacterial bloodstream infection. Causes - UTIs, older than 75, urinary catheters, GI infections.

Question 126

Describe the management of E. coli infections

Answer 126

Diarrhoea - related Prevent - avoid raw / undercooked food and untreated water. Treatment- should recover within few days, clear liquids, oral rehydration solutions, avoid antibiotics UTI Antibiotics - trimethoprim or nitrofurantoin.

Question 127

Describe the structure of both the influenza virus and understand their replication.

Answer 127

Influenza structure: negative strand RNA genome Encodes RNA-dependent RNA transcriptase that synthesises viral mRNAs using the template. haemagglutinin (H) - binds to cell and neuraminidase (N) - releases the virus. a) The flu virus is constantly replicating b) Life cycle of approximately 6 hours c) Viral RNA polymerases have a high error rate

Question 128

the SARS-CoV-2 virus - structure and replication

Answer 128

large, enveloped, spikes on surfaces +ve single stranded RNA used as mRNA for replication of viral particles converted to –negative stranded RNA so template for new + strand RNA for new particles. major antigen is spike protein used to gain entry 10hrs RNA-dependent RNA polymerase

Question 129

Define the concept of an animal reservoir for both viruses and their major surface antigens.

Answer 129

C - pig and others infect animals as well H and N proteins Covid - zoonotic transfer from bats.

Question 130

Explain how the viruses gain entry to the human host and their subsequent uptake and spread from person to person.

Answer 130

Influenza: transmitted from person to person via the respiratory route attaches to sialic acid residues on host cell glycoproteins (NANA) Entry by receptor-mediated endocytosis. N cleaves residue and releases. SARS - resp route or contact with infected surfaces. Attaches to Ace2 transmembrane protein

Question 131

Describe the clinical symptoms and complications of influenza infection and SARS-CoV-2 infection.

Answer 131

Influenza - fever, headache, sore throat, cough Complications- otitis media, croup, sinusitis, pneumonia Covid - fever, sore throat, sneezing, muscle/joint pain, extreme fatigue and loss of taste/smell. Hospitalisation and death

Question 132

Describe how you would diagnose flu and COVID-19 in a clinical setting

Answer 132

Flu - symptoms and clinical assessment but there are rapid antigen tests and PCR. Covid - nasopharyngeal swab which detects the viral RNA using reverse transcription polymerase chain reaction (RT-PCR). Lateral flow (antibody/antigen detection systems) tests.

Question 133

Briefly outline the management of influenza & COVID-19 including treatment options and prevention and how this is determined (for influenza) by WHO each year.

Answer 133

Flu - antivirals and neuraminidase inhibitors, vaccination against A and B. Quadrivalent - 2A and 2B Children - live nasal spray WHO monitors antigenic changes each year and determines the composition of the vaccines Covid - mRNA vaccines

Question 134

Define the concepts of antigenic shift and antigenic drift in the influenza virus.

Answer 134

antigenic shift - major changes in the genes of flu viruses Diff strains combine change in the viral subtype resulting in different H and N proteins. reassortment of different RNA segments from each species in a new capsid No previous immunity Antigenic drift - random mutations in viral RNA - minor changes

Question 135

Define the concepts of mutation rate and production of variants for SARS-CoV-2.

Answer 135

entire replication process is approximately 10 hours. This short replication period combined with the RNA-dependent RNA polymerase (which is error prone) - means that the virus has a high mutation rate and numerous variants

Question 136

Define the concepts of pandemics and epidemics (seasonality) and how these may arise in relation to influenza.

Answer 136

antigenic shift - new subtype - no previous immunity - pandemics Can respond with cytokine storm - T-cells attack and destroy the tissues in which the virus is replicating – in particular the lungs.

Question 137

Ses 11

Question 138

Review the microbiology and classification of streptococci

Answer 138

Classification by haemolysis ( ability to break down RBCs) Alpha haemolysis - strep pneumoniae - viridans Beta - pyogenes Gamma - non - haemolytic Or Lancefield group for beta haemolytic strep based on cell wall antigens S pyogenes = A

Question 139

Highlight a range of virulence factors found in Streptococcus pyogenes More?

Answer 139

Hyaluronic acid capsule - Inhibits phagocytosis by neutrophils and macrophages. Poor immunogen because of similarity to human connective tissue hyaluronate. M protein - Resistance to phagocytosis by inhibiting activation of alternative complement pathway on bacterial cell surface. > 150 antigenically different serotypes as a consequence of nucleotide variants of emm gene. Adhesins, including lipoteichoic acid, M protein, fibronectin binding proteins - Adherence is first step in colonisation/infection. Streptolysins O and S - Lysis of erythrocytes, neutrophils, platelets Dnases A, B, C and D - Degradation of DNA

Question 140

virulence factors with clinical aspects of infection - strep toxic shock syndrome what is ARF

Answer 140

Strep toxic shock syndrome: Entry of group A strep into deeper tissues and bloodstream Streptococcal pyrogenice exotoxins stimulate T-cells through binding to MHC class II APCs inducing cytokines (TNF-α, IL-1β, IL-6). M-protein fibrinogen complex formation

Question 141

Describe streptococcal pharyngitis including microbiological features, clinical presentation and complications

Answer 141

• Peak incidence 5-15 years • Droplet spread • Association with over- crowding • Untreated patients develop M protein specific antibody Clinical features Abrupt onset sore throat Malaise, fever, headache Lymphoid hyperplasia Tonsillopharyngeal exudates Complications: Scarlet fever - Due to infection with streptococcal pyrogenic exotoxin strain of S.pyogenes, Local or haematogenous spread, High fever, sepsis, arthritis, jaundice. Suppurative complications - Peritonsillar cellulitis/abscess • Retropharyngeal abscess, Mastoiditis, sinusitis, otitis media, Meningitis, brain abscess Disease caused by immune response not by bacteria. Happens due to antibody produced due to disease reacting with body proteins?: Acute rheumatic fever - Inflammation of heart, joints, CNS Acute post-streptococcal glomerulonephritis • Acute inflammation of renal glomerulus

Question 142

Describe other clinical infections caused by Streptococci

Answer 142

S mutans - endocarditis S agalactiae - commensal of vagina but can invade in pregnancy

Question 143

Streptococcus pyogenes skin infections

Answer 143

Impetigo – Childhood infection, 2-5 years – Initial skin colonisation, followed by intradermal innoculation – No ARF but impetigo is most common cause of glomeruonephritis • Erysipelas – Dermis infection with lymphatic involvement – Face, lower limbs – Facial lesions frequently preceded by pharyngitis – Lower limb infection usually secondary to invasion of skin via trauma, skin disease or local fungal infection • Cellulitis – Skin and subcutaneous tissue infection – Impaired lymphatic drainage and illicit injecting drug use important risk factors • Necrotising fasciitis – Infection of deeper subcutaneous tissues and fascia. – Rapid, extensive necrosis – Usually secondary to skin break – Severe pain, even before gross clinical changes – High fever, fulminant course, high mortality (20-70%)