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Personalised Medicine > Infectious Diseases > Flashcards

Infectious Diseases Flashcards

1
Q

What is tuberculosis

A

A contagious, debilitating (consuming) bacterial disease spread by airborne droplets

Coughing, speaking, sneezing
Left untreated, one person with tuberculosis will infect 10-15 people (R0)

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2
Q

What bacterium causes tuberculosis

A

Mycobacterium tuberculosis

Slow growing, difficult to kill, waxy coat

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3
Q

What imaging test can detect TB

A

X-ray showing multiple cavities, also lungs can undergo necrosis

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4
Q

What is a TB granuloma

A

Chronic granulomatous inflammatory responses

In the centre it is necrotic and liquified leading to cavities

Bacteria can grow in these cavities which may be released into the bronchus, coughed and spread

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5
Q

How many people with TB present with symptoms

A

Exposure - only 30% get infection - of this 5% progress to active disease while 90% have latent TB

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6
Q

How can you detect latent TB

A

A mantoux test (injection of TB Abs) shows reaction in latent infection

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7
Q

When is TB latency problematic

A

When the person is immunosuppressed

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8
Q

Why can TB become quickly resistant

A

High bacterial load in TB (unique) = many organisms, that can eventually gain resistance

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9
Q

How do you treat TB

A

Antibiotics - firstly streptomycin, however TB rapidly became resistant to this

4 drug combination trial - standard short course of 4 drugs for 6 months

Overcomes mutation rates, 95% effective with relapse rate 3-4%
Treatment must contain multiple drugs to which organisms are susceptible

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10
Q

What is the phases and drugs used in treatment of TB

A

Intensive phase - RHZE for 2 months

Continuous phase - RH for 4 months

Can last longer e.g. when infection of meninges

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11
Q

What drugs are used to treat TB

A

Isoniazid (INH/H) Rifampicin (RIF/R)
Pyrazinamide (PZA/Z)
Ethambutol (EMB/E)

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12
Q

What is the mechanism of action for isoniazid

A

Isoniazid (INH/H) – inhibits synthesis of mycolic acid, required for mycobacterial cell wall

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13
Q

What is the mechanism of action for rifampicin

A

It inhibits bacterial RNA polymerase

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14
Q

What is the mechanism of action for pyrazinamide

A

It binds to the ribosomal protein S1 (RpsA) and inhibits translation + other possible mechanisms

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15
Q

What is the mechanism of action for ethambutol

A

It inhibits arabinosyl transferases involved in cell wall biosynthesis of arabinogalactans

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16
Q

What is the molecular mode of action of isoniazid

A

Analogue of nicotinic acid

It’s a prodrug that is activated by catalase peroxidase inside the bacteria produced by KatG

This then adducts with Iso-NADH, binding the lipid synthetase preventing mycolic acid synthesis
These enzymes are coded by Inh A

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17
Q

What is the molecular mode of action of isoniazid

A

PZA is also a prodrug, activated inside the bacteria by pyrazinamidase , coded by PncA gene forming pyrazinoic acid

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18
Q

Why does it take so long to treat TB

A

TB therapy takes 6 months to treat as it grows rapidly forming biofilms inside granulomas

Initial rapid kill curve by sterilising effect of INH

There is a second persistent population who no longer are turning over their cell walls and their metabolic pathways are slowed down thus the prodrugs aren’t activated - thus becoming drug tolerant

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19
Q

What factors impact response to treatment

A

Due to many host factors

Disease type and extent meningeal, bone lung TB
Immuno-competence

Bacterial strain
Genotype-phenotype
Antibiotic resistance

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20
Q

What increases the chance of a patient having drug resistant TB

A

Patient has spent time with someone with active drug-resistant TB disease

Patient does not take their medicine regularly or does not take all of their medicine

Patient develops active TB disease after having taken TB medicine in the past

Patient comes from area of the world where drug-resistant TB is common

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21
Q

What is MDR and XDR

A

Moderately and extremely drug resistant

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22
Q

What is the difference between MDR-TB and XDR TB

A

MDR-TB = resistant to INH and RIF (RH)

XDR-TB is MDR-TB resistant to any fluroquinolone (levofloxacin, moxifloxacin and ofloxacin) and at least one of three injectable second-line drugs (capreomycin, kanamycin and amikacin)

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23
Q

What are TB drug resistance mechanisms

A

Barrier mechanisms - decreased permeability and efflux pump

Degrading or inactivating enzymes - e.g. β- lactamases

Modification of pathways involved in drug activation or drug metabolism
E.g. katG and isoniazid resistance

Drug target modification - e.g. rpoB and rifampicin resistance

Target amplification - e.g. inhA and isoniazid resistance
Too much enzyme that IZH cannot fully target

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24
Q

How can you detect drug resistance

A

Standard methods - culture and phenotypic drug susceptibility testing (DST) - weeks to months

Delays during which patients receive sub-optimal therapy

Additional resistance and further spread of drug resistant TB

25
Q

What are the conventional phenotypic, and the genotypic methods of drug resistance

A

Conventional – Phenotypic
Using solid and liquid media
Absolute concentration, resistance ratio and proportion susceptibility testing
Time consuming - weeks

Genetic tests for mutations in target
Rapid, predictive only
Needs accurate databases of mutations

26
Q

What is geneXpert

A

PCR in a cartridge which quantitates amount of TB DNA and identified rpoB gene

Identifies if it is TB and if there is rpoB mutation resistance to rifampicin

There are 5 probes - if one probe fails to bind, it shows there’s resistance to RIF within the rpoB gene

27
Q

What drugs can we confidently predict resistance for

A

High confidence calls
INH - katG or inhA SNPs
RIF - rpoB SNPs - codons 507-533
Quinolone - gyrA SNPs

28
Q

What are the difficulties when determining the impact of mutations?

A

Cross resistance
No DST (drug susceptibility) data for new SNP’s
DST and MICs (minimum inhibitory concentration) for drugs unknown
Compensatory and secondary mutations

29
Q

How is WGS used for TB

A

Genome wide mutation screening

Public health monitoring - tracking strains

30
Q

Why is WGS beneficial for TB treatment and monitoring

A

Quick, unbiased, cost effective and can help improve databases
However requires bioinformatics, good databases and many studies - not sure if accurate

Gives evidence based advice, allowing faster and more effective treatment for better patient outcomes
Reduces onwards transmission and chance of further resistance

31
Q

What other factors influence TB treatment

A

Other risk factors/comorbidities e.g. HIV, genetic susceptibility to poor response to TB, latent TB etc.

32
Q

Why might you use a drug for a patient with TB resistant to that drug

A

It may be a weak resistance, with a low MIC falling within the therapeutic index

Thus you only need to increase the concentration

33
Q

Pyrazinamide is a drug used for most if not all cases of TB - when might it not be used

A

When the evidence shows the strain is 100% resistant, there is no point wasting resources if you are 100% sure it wont work

34
Q

How may drug dosage be influence by drug susceptibility tests

A

By finding out the MIC and prescribing drugs at higher concentrations than the MIC, if safe to do so

35
Q

What are some of the clinical considerations when choosing a treatment

A

Drug side effects

Injectables need long central line – risk of infection and venous thrombosis

HEPA filtered negative pressure isolation room until culture negative for 6 weeks
Unpleasant for patients, expensive and difficult to manage for hospital

Poor compliance

Longer you wait for testing = drug resistance thus use empirical treatment first

False +ve/negative
-ve = ineffective treatment
+ve = unnecessary side effect

36
Q

What is an example of a viral STI and its effects

A

Viral - trichomoniasis

This targets mainly women, causing vaginal discharge, preterm birth, increased incidence of HIV, miscarriage and other complication including bacterial vaginosis

37
Q

What is an example of bacterial STI’s and its effects

A

Bacterial - syphilis, gonorrhoea, chlamydia, mycoplasma genitalium

Syphilis behaviours like a virus which causes a systemic long term illness

Gonorrhoea and chlamydia infect primarily the lower tracts
They can infect mucosal surfaces e.g. in pharynx, rectum and cause inflammation
Can cause blocking of the fallopian tubes, infertility, preterm birth miscarriage

Mycoplasma genitalium- recently recognised STD

Gonorrhoea and mycoplasma genitalium have developed antimicrobial resistance

38
Q

What is the public health impact of gonorrhoea

A

It does not tend to cause mortality now

Caused severe pelvic inflammatory disease, ectopic pregnancies, infertility

Gonorrhoea in eyes of foetus after birth can cause blindness

Can cause endocarditis (affecting heart lining) via disseminated gonococcal infection

It can increase risk of HIV transmission and acquisition though taking ART can make it safer

Antimicrobial resistance needs to be monitored

39
Q

What is gonorrhoea

A

Samples taken from discharge, gram stained
Gram negative intracellular diplococcus - inside neutrophils
A lipid membrane inside and outside of the cell wall

40
Q

Where is gonorrhea found within a patient

A

Gonorrhoea can be in back of throat, cervix or rectum which cannot be detected easily

Thus a antimicrobial culture result needs to come back before a molecular test

Treatment given to prevent spread, but it cannot be personalised thus resistance may develop

41
Q

What is GRASP

A

A UK system to collect samples from STI clinics and microbiology labs

These are then tested to see prevalence of resistance and the region form which it came
Finds the rates of resistance in England/wales to which drug - determining which drug to avoid

42
Q

What common drug resistances are seen in the UK

A

Ciprofloxacin resistance has increased rapidly

Ceftriaxone and spectinomycin resistance has so far remained low
However in other countries there are so

MIC cut off varies between drugs - 1.25 for ceftriaxone
And you don’t want more than 5% of population with that resistant strain

43
Q

What is the physical properties of mycoplasma genitalium

A

Atypical class of bacteria - a mollicute, related to gram positives

No cell wall, not susceptible to penicillin

Lost ability to synthesise essential amines for survival and become parasitic and dependant on hosts

44
Q

What are the genomic properties of mycoplasma genitalium

A

The genome size is small - 580kb, coding for <500 genes

Does not have the genes to synthesise various essential amines

45
Q

What conditions can mycoplasma genitalium cause

A

Cervicitis, pelvic inflammatory disease, preterm birth, spontaneous abortion and may cause infertility

46
Q

What three drug classes may be used to treat mycoplasma genitalium

A

Macrolides - bind 50S subunit targeting 23S rRNA

Quinolones - bind DNA gyrase and topoisomerase IV

Tetracyclines - bind 30S ribosomal subunit

47
Q

What bacterium can cause genital discharge and pus

A

Pus could indicate chlamydia or gonorrhoea, trichomonas, and mycoplasma genitalium

48
Q

How is genital discharge investigated

A

Microscopy - however this cannot inform resistance

49
Q

How can point of care testing be used in STI clinics

A

PoC testing can help discriminate between the different causes of genital discharge

Rapid tests can test within hours

Done at microfluidic level which makes it faster

50
Q

What is the rapid test paradox

A

Molecular testing in labs tend to be accurate
Sensitivity (true positives, ruling out false results) and specificity
Important in STI’s as it can cause emotional distress for false results

BUT certain populations may not return e.g. live far, not mobile
Then you may prioritise speed over sensitivity
You may also pretreat them before they come back

51
Q

What is GeneXpert in TB and STI usage

A

Random access platforms

They have individuals modules/shelves which runs samples independently within 90mins

Realtime PCR
Expensive
Can test for chlamydia, gonorrhoea, trichomonas and HPV

Sample first - samples taken first, then put into geneXpert, wait, consultation and hopefully by the end the result is available

52
Q

What is the Binx health IO system

A

Microfluidic cartridge test - chambers where the sample in inserted and flows through

53
Q

Describe the process within the binx health io system

A

The DNA is extracted and goes into two different PCR chambers which amplify the targeted genes, there’s are them split into two more chambers for detection

Can look for multiple different diagnoses - up to 24!

Looks for molecular resistance markers

54
Q

What factors need to be considered to reduce transmission of resistant pathogens/what factors determine the R0 value

A

Biology of pathogen

Sexual behaviour of patients e.g. partner change

Duration of infectiousness

55
Q

What are the

mechanisms of resistance in gonorrhoea

A

Cell wall alteration - penicillin and cephalosporins

Change in porin protein channels preventing antibiotics entering cells

Changes in gene control of transporters e.g. efflux pumps which normally pump toxins
actively pump out antibiotics

Penicillin resistance due to mobile genetic elements - plasmids which can produce beta-lactamase

Ribosomal disruptors - macrolides

Fluroquinolones can be passed by mutations in topoisomerases
Topoisomerases are needed for unwinding of DNA for replication

56
Q

Describe fluoroquinolone action

A

Fluroquinolones targets topoisomerases II/DNA gyrase A which prevents unwound DNA from twisting

Topoisomerase do this by cutting the DNA and reattaching it - thus inhibition = DNA twist = no replication

It also targets topoisomerase IV or ParC/E e.g. moxifloxacin
This is involved in the circular chromosome

57
Q

What codon change in topoisomerases in gonorrhoea can confer resistance

A

Codon 91 Ser to Phe and codon 95 Asp to = resistance

58
Q

How can you test for codon 91 and 95 changes in gonorrhoea topoisomerase

A

PCR

This can be used to identify those who are susceptible to fluoroquinolones

59
Q

Why might WGS be used

A

It can help predict strains accurately

It has fast turn around - but it does depend on the platform e.g. NGS Vs long-read

Personalised Medicine (9 decks)

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