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PoM - Principles of Medicine Week 2 > Antimicrobial Therapies > Flashcards

Antimicrobial Therapies Flashcards

Antibiotic Resistance

1
Q

What are the 4 types of antibiotic drugs?

A
  1. Beta-Lactams - interfere with bacterial cell wall synthesis
  2. Sulfonamides - interfere with folic acid synthesis
  3. Aminoglycosides - target protein synthesis (30S ribosomal subunit), RNA proof-reading, damage cell membrane
  4. Macrolides - targets protein synthesis (50s ribosomal subunit)
  5. Quinolones - synthetic, targets cell replication
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2
Q

What was the first anti-bacterial drug (antibiotic)?

A

Prontosil

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3
Q

How does protonsil work?

A

It is bacteriostatic - it works by stopping the bacteria from growing, rather than directly killing it
Targets folate biosynthesis in bacteria

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4
Q

Is protonsil still used today and if so, for what?

A

Yes, variants of the drug is still used to treat UTIs
2 variants - Trimethroprim and sulfonamides
Both stop same reaction pathway at different points - synergistic activity, and so are best effective together

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5
Q

What are the 2 types of gram bacteria?

A

Gram positive and gram negative bacteria

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6
Q

What are some features of gram positive bacteria?

A

Single membrane

Thick cell wall

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7
Q

What are some features of gram negative bacteria?

A

Two membranes - inner membrane with phospholipids and outer membrane with phospholipids and lipopolysaccharides

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8
Q

Why does prontosil only work on gram positive drugs?

A

Outer layer on gram negative is difficult for drugs to penetrate and pass through

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9
Q

What properties should a drug typically have to work on gram negative bacteria?

A

A part that is hydrophillic to get thorugh the outer layer, and then a part that is hydrophobic to get through the inner layer
To find molecules with both those properties is difficult

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10
Q

What were the issues with early penicillin?

A

Short half life - rapidly left the body - was quickly excreted via the urine
Often urine was collected from these patients and purified to recollect the penicillin (massive shortage)

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11
Q

What category of antibiotics is penicillin an example of?

A

Beta-Lactams

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12
Q

How do Beta-Lactams work?

A 
All have the characteristic beta-lactam ring
The most commonly used antibiotic as they:
Interfere with the synthesis of the peptidoglycan component of the bacterial cell wall
Mimic molecules (precursors) involved in this process and bind to the enzymes, inactivating them - bacteria begin to grow, but soon after die
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13
Q

What is an antibiotic?

A

An antimicrobial agent produced by a microorganism that kills or inhibits other microorganisms
Strictly speaking, a ‘natural product’ (taken from microbes) - although today, many are (semi-)synthetic versions

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14
Q

What is an antimicrobial?

A

Chemical that selectively kills or inhibits certain microbes

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15
Q

What is bactericidal?

A

Kills bacteria

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16
Q

What is bacteriostatic?

A

Inhibits bacterial growth

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17
Q

What is antiseptic?

A

Chemical that kills or inhibits microbes, usually used topically to prevent infection

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18
Q

Define resistant bacteria?

A

Bacteria that are able to replicate in environments with high concentrations of the drug present (any concentration that is above what can be reasonably achieved therapeutically)

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19
Q

What is a breakpoint?

A

An estimate of what could theoretically be given to / achieved in a patient - i.e. the strength of a dose that could realistically be given to a patient

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20
Q

What can increase the speed of resistance arising towards a specific antibiotic and why?

A

Bacteria lie on a scale of sensitive to resistant towards the antibiotic
There are bacteria around the breakpoint that are neither susceptible, nor resistant
Hence over-prescription / or under-dosage can cause those bacteria to be able to survive the drug, and mutate to become more resistant

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21
Q

How does the usage of antibiotics impact antibiotic resistance?

A

Using antibiotics more frequently causes higher rates of resistance - applies selective pressure on bacteria i.e. selects for resistance
Susceptible drugs killed, resistant left behind, increasing their prevalence
Loss of efficacy in drugs

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22
Q

Why is it economically not profitable to invest in finding a new antibiotic?

A

Already many antibiotics available that work effectively in most cases
Money/funding required
If a new antibiotic is found, it must be used sparingly, as greater usage is linked with greater loss in efficacy - cannot be distributed to many patients, lack of profit (little financial return to the companies / market)
Therefore almost total lack of investment

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23
Q

By which mechanism does antibiotic resistant resistance arise?

A

Evolution by natural selection

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24
Q

What were the major misconceptions of antibiotic resistance at the start of the era?

A
  1. Resistance to more than one class of antibiotics could occur in a single organism
  2. Bacteria can swap genetic information - horizontal gene transfer
  3. Resistant bacteria that would emerge would be significantly ‘less fit’ to survive (sometimes true, but often those with infections already have weakened immune systems so bacteria do not need to be aggressive)
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25
Q

When does resistance emerge against an antibiotic?

A

Soon after it is introduced into the wider population

26
Q

Why is resistance different in different countries, and why is it important to acknowledge that?

A

The frequency of the usage of that specific antibiotic in that area / country impacts resistance i.e. greater usage = greater selection = greater resistance
If a patient has been abroad, looking at statistics for that country can help determine which antibiotic is best to prescribe

27
Q

How does antibiotic resistance impact society / populations?

A

Greater mortality - greater morbidity - and so leads to more cost
Increased time for effective therapy - may need to come back for higher dosages / stronger antibiotics
Requirement for additional approaches – e.g. surgery (surgical drainage)
Use of expensive therapy (newer drugs)
Use of more toxic drugs e.g. vancomycin
Use of less effective ‘second choice’ antibiotics

28
Q

How are antibiotics given to patients? (i.e. following which diagnostic tool?)

A

Often, no diagnostic tool, given blindly on an educated guess

29
Q

Why are antibiotics often given blindly?

A

Because infection can take hold rapidly - by the time results from the diagnostic tool come back, it may be too late

30
Q

What are some examples of majorly resistant gram positive bacteria?

A 
Staphylococcus aureus (MRSA, VISA) - wound and skin infected, pneumonia, septicaemia, infective endocarditis
Streptococcus pneumoniae - pneumonia, septicaemia
Clostridium difficle - pseudomembranous colitis, antibiotic-associated diarrhoea
Enterococcus spp (VRE) - UTI, bacteraemia, infective endocarditis
Mycobacterium tuberculosis (MDRTB, XDRTB) - tuberculosis
31
Q

What are some examples of majorly resistant gram negative bacteria?

A

Pseudomonas aeruginosa - cystic fibrosis, burn wound infections, survives on abiotic surfaces.
E. Coli (ESBL) - GI infection, neonatal meningitis, septicaemia, UTI
Salmonella spp. (MDR) - GI infection , typhoid fever.
Acinetobacter baumannii (MDRAB) - opportunistic, wounds, UTI, pneumonia (VAP), survives on abiotic surfaces.
Neisseria gonorrhoeae - gonorrhoea

32
Q

Gentamycin and Streptomycin are examples of which type of antibiotics, and how do they work?

A

Aminoglycosides
Bactericidal - kill the bacteria
Target protein synthesis (30S ribosomal subunit), RNA proofreading and cause damage to cell membrane
Toxicity has limited use, but resistance to other antibiotics has led to increasing use

33
Q

What properties of Rifampicin may discourage patients to discontinue its use?

A

Bactericidal - targets RNA polymerase
Subject to spontaneous resistance frequently
Causes fluid secretions to turn orange / red e.g. tears, urine, faeces

34
Q

How does vancomycin work?

A

Bactericidal
Targets Lipid II component of cell wall biosynthesis
Toxicity has limited use, but resistance to other antibiotics has led to increasing use e.g. against MRSA

35
Q

How does linezolid work?

A

Bacteriostatic
Inhibits the initiation of by binding to the 50S rRNA subunit.
Only targets gram-positives

36
Q

How does dactomycin work?

A

Bactericidal
Targets bacterial cell membrane.
Only targets gram-positives
Toxicity limits dose

37
Q

Which major principle do antibiotics work on?

A

Selective toxicity - bacteria have many different characteristics unique to them (and not present in humans), and processes that occur with a sufficiently different mechanism to mammals, which are targeted by antibiotics e.g. cell replication cycle, bacterial cell wall synthesis, protein synthesis etc

38
Q

What are the 4 distinct mechanisms by which resistance occurs?

A
  1. Altered target site
  2. Inactivation of antibiotic
  3. Change metabolic profile
  4. Decreased drug accumulation (i.e. pump out the antibiotic)
39
Q

How does altering the target site work?

A

Can arise via acquisition of alternative gene or a gene that encodes a target-modifying enzyme e.g. MRSA encodes an alternative PBP (PBP2a) with low affinity for beta-lactams
Antibiotic can no longer bind to the specific protein structure it needs to, to inhibit / kill bacteria

40
Q

How is the antibiotic inactivated?

A 
Bacteria develop enzymes that digest molecules of the antibiotic
Particularly important for beta-lactams - target beta-lactam rings e,g, beta-lactamase or chloramphenicol acetyl-transferase (cat)
Renders huge class of antibiotics as ineffective
41
Q

How does altering the mechanism work?

A

By increasing the number of enzyme substrate / enzyme so it out-competes the effect of the antibiotic as an inhibitor
Or by switching the metabolic pathway to require less of the original enzyme substrate / enzyme
e.g. prontosil inhibited folate biosynthesis, but resistant bacteria developed the ability to acquire folate from surroundings

42
Q

How does decreased drug accumulation work?

A

Bacteria have selective pumps in their membranes that can recognise abd eject certain drugs / toxic chemicals
Or reduced penetration of antibiotic into bacterial cell (permeability)
Therefore the drug does not reach the concentration required to be effective

43
Q

How have bacteria, such as gonococcus (gram-negative), acquired resistance?

A
  1. Point mutations - single nucleotide is changed/deleted/added to the DNA or RNA typically causing a target site modification
  2. Plasmid transformation - take up pieces of DNA directly from the environment around the cell
  3. Plasmid conjugation - two bacteria can pair up and connect through structures in the cell membranes and then transfer DNA from one bacterial cell to another
  4. Transduction - viruses called bacteriophages can infect bacteria, these viruses sometimes bring along genes that they picked up during infection of another bacterium. These genes may then be incorporated into the DNA of the new bacterial host
44
Q

Erythromycin and azithromycin are examples of which type of antibiotic and how do they work?

A

Macrolides
Targets protein synthesis - 50s ribosomal subunit
Works on gram positive and some gram negative bacteria

45
Q

What is another type of antibiotic that is entirely synthetic and how do they work?

A

Quinolones
Entirely synthetic, broad spectrum, bactericidal
Target DNA replication cycle (specifically the winding / unwinding) by targeting DNA gyrase in gram positive and topoisomerase in gram negative bacteria

46
Q

What are the sources of antibiotic resistance genes in bacteria?

A
  1. Plasmids - extra, chromosomal, circular piece of DNA, often multiple copies, that frequently carry antibiotic resistance genes. Sometimes a single plasmids contains genes that confer resistance to multiple antibiotics. Applied selective pressure (e.g. the use of antibiotics) selects to keep that particular plasmid, as there is an energy cost to maintain the plasmid
  2. Transposons - molecular shuttles transfer genes from plasmid to chromosome or vice versa to enable transmission to daughter cells
  3. Naked DNA - dead bacteria release DNA into the environment
47
Q

What is an advantage of plasmids?

A

Can be swapped between bacteria via horizontal gene transfer (to those that are not their offspring)

48
Q

How can the selection of a single plasmid confer to multi-drug resistance?

A

A single plasmid may contain several genes of antibiotic resistance, but applying just one antibiotic, means at least one of those genes in the entire plasmid is useful / selected for, so the whole plasmid is retained within the bacterium, hence retaining the other antibiotic resistance genes

49
Q

What are the mechanisms for the transmission of plasmids?

A
  1. Transformation - uptake of naked DNA in the environment
  2. Conjugation - using a pillus, horizontal gene transfer
  3. Transduction - phages move DNA from organism to another
50
Q

What are some non-genetic factors that contribute to resistance?

A
  1. Can grow in biofilms - growth or increase by the gradual accumulation of additional layers (accretions)
  2. Intra-cellular locations - hide within cells
  3. Grow slowly - antibiotics target biosynthetic prcoesses, which in slow-growing bacteria are used less frequently
  4. Spores - e.g. C. difficile
  5. Persisters - bacteria that do not replicate
51
Q

What are some non-genetic factors that contribute to treatment failure?

A
  1. Inappropriate choice for organism - not all antibiotics kill all bacteria
  2. Poor penetration of antibiotic into target site - penetrate different areas in varying amounts e.g. penetrate liver better than lungs
  3. Inappropriate dose / poor half life so the antibiotic is excreted too quickly before it can work
  4. Inappropriate administration (oral vs IV)
  5. Presence of antibiotic resistance within commensal flora , so the commensal microbiota in the gut e.g. via the secretion of beta-lactamase
52
Q

How or why do hospital acquired infections have greater antibiotic resistance?

A
  1. Crowded
  2. Many immuno-compromised - old, young, chemotherapy, transplants etc
  3. Many wounds / broken skin - from surgery, catheterisation etc.
  4. Indwelling devices - e.g. intubation
  5. Transmission by staff
    Therefore majority patients on several different antibiotics - environment with high selective pressure for resistant bacteria
    Many bacteria strongly linked to drug resistance and hospital acquired infections
53
Q

How can antibiotic therapy impair commensal microbiota (i.e. on guts and skin)?

A

Antibiotics can also kill good bacteria on our guts and skin
Those ‘good’ bacteria are an important defence against pathogenic bacteria, so when they die, selects for resistant bacteria and less competition for resistant bacteria to grow

54
Q

With which infection is gut microbiota important and how does the infection work?

A

C. difficile - lives in the gut amongst resident microbiota, completely harmless as it is kept in check by resident microbiota
If a patient undergoes antibiotic therapy that kills the resident microbiota, only C. difficile is left behind
Reduced competiton and increased space allows for C. difficile to grow and produce toxins, causing infection and harm
Causes diarrhoea, produces spores (which are hard to kill)

55
Q

How to address resistance?

A

Use new and existing drugs sparingly
Better diagnostics so antibiotics are prescribed less blindly
Prescribing strategies – tighter controls, temporary withdrawal of certain classes. Restriction of antibiotics for certain serious infections
Reduce use of broad-spectrum antibiotics
Quicker identification of infections caused by resistant strains
Combination therapy
Knowledge of local strains/resistance patterns

56
Q

How to overcome resistance?

A

Modify existing drugs - enhance efficacy
Use combinations of antibiotics and inhibitors e.g. beta-lactams with inhibitors of beta-lactamase
Infection control - works well with some infections e.g. MRSA (though others are endogenous - e.g. bloodstream infections from E. coli come from gut)

57
Q

What are fungi?

A

Eukaryotic organisms that digest their food outside of the cell by secreting hydrolytic enzymes - break down biopolymers to be absorbed for nutrition

58
Q

What are the 3 ways fungi affect humans (medically)?

A
  1. Allergy – allergic reactions to fungal products e.g. allergic bronchopulmonary aspergillosis (ABPA)
  2. Mycotoxicoses – ingestion of fungi and their toxic products e. g. aflatoxin
  3. Mycoses – superficial, subcutaneous or systemic colonisation, invasion and destruction of human tissue
59
Q

How are mycoses classified?

A

By the level of tissue affected:
Superficial - skin
Cutaneous - deeper into the skin
Subcutaneous - deeper, e.g. roots of hair
Systemic - deep, organs i.e. brain, lungs, kidney, spleen etc.

60
Q

What do anti-fungal therapies target?

A
  1. Cell membrane - fungi primarily use ergosterol instead of cholesterol
  2. DNA synthesis - some compounds may be selectively activated by fungi, therefore stopping synthesis
  3. Cell wall - unlike mammalian cells, fungi have cell walls

PoM - Principles of Medicine Week 2 (12 decks)

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