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Microbiology and immunology > Antibiotic resistance > Flashcards

Antibiotic resistance Flashcards

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1
Q

Why is antibiotic resistance a concern?

A

Increases mortality

Challenges control of infectious diseases

Threatens return to pre-antibiotic era

Increases cost of health care

Jeopardises health care gains to society

Drug resistant bacteria are NOT MORE pathogenic, we just have fewer antibiotic options for treatment.

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2
Q

History of methicillin resistant Staphylococcus aureus

A

When penicillin was used more widely, there was an increase in resistance.

Staphylococcus acquired gene that encodes for beta lactamase enzyme, stops antibiotics from working – resistance.

By using antibiotics not intelligently you drive selection of antibiotic resistance in S.aureus, until we got to MRSA infections in 1978.

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3
Q

Superbugs

What happens if you put MRSA organism in the same location as others that are resistant?

A

Enterococci, gram positive, live in gut, naturally resistant to vancomycin.

Acinetobacter, gram negative, in the gut, multiply resistant. Multiple mechanisms for resistance, can cause wound infections and is hospital acquired infection

MRSA, gram positive, causes gut and wound infections.

If these three organisms co-exist together in the gut, what would happen?

Because bacteria undergo genetic exchange readily, organisms start to exchange bits of DNA and genes by different mechanisms

If MRSA acquires genes that encode for vancomycin resistance

End up with vancomycin resistant MRSA

Occurring in some parts of the world , few options to treat

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4
Q

Mechanisms of antibiotic resistance

Drug inactivation

A

e.g beta lactamase.

Some bacteria acquire gene that encodes for beta lactamase, it will secrete this enzyme and destroy beta lactase ring in antibiotics and becomes resistant to them

Inactivating drug so organism becomes resistant

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5
Q

Mechanisms of antibiotic resistance

Altered target for antibiotic or acquire a new target

A

Ribosome

Porin – mutation in porin genes of gram negative bacteria, you can become resistant to multiple drugs, whole range of antibiotics can’t go across transporter porin

PBPs – certain bacteria acquire new enzymes through gene exchange, have new penicillin binding protein that no longer binds penicillin, becoming resistant

DNA gyrase – prevents quinolones from inhibiting DNA gyrase as mutation alters the conformation of enzyme so drug can’t bind

RNA polymerase

Mcr1 and colistin

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6
Q

Mechanisms of antibiotic resistance

Efflux pump

A

If antibiotic gets in through porin, bacteria can acquire genes that encode for efflux pump, increases their ability to pump out drugs

Although drug is getting into bacteria, they are pumped out faster, antibiotic concentration needed to inhibit bacteria is never achieved

Never achieve MIC

Resistance

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7
Q

Mechanisms of antibiotic resistance

Overproduction of target

A

Trimethoprim involved in folic acid synthesis

Bacteria overproduces precursors needed, leading to overproduction of targets (enzymes), there isn’t enough drug concentration to inhibit the targets

Overcomes inhibition from antibiotics

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8
Q

Mechanisms of antibiotic resistance

intrinsic permeability

A

Antibiotics can’t go across cell membrane

No new acquisitions, just intrinsically resistant to antibiotics

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9
Q

Mechanisms of antibiotic resistance

metabolic by-pass

A

New metabolic pathway that bypasses the part where vancomycin inhibits

No terminal D-ala D-ala, instead is D-ala-Dlac so vancomycin can’t bind

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10
Q

What are the different paths to resistance?

A

Directed at antibiotic itself

  • Degrading the drug
  • Modifying the drug

New or altered target

  • Antibiotic no longer binds e.g PBPs – PBP2a in MRSA

Altered transport

  • Actively pumping drug out – efflux pump
  • Porins no longer influx drugs

Metabolic by pass

  • Metabolic change D-ala-D-lac and vancomycin
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11
Q

What are the different types of mechaisms of resistance ?

A

Natural resistance

Genetic mechanisms – acquired

Non-genetic mechanisms (growth phases)

  • Tolerance, is reversible. Tolerate certain concentrations of drugs
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12
Q

What are some natural barriers?

A

Porins, export pumps in organism, so you can’t treat that organism with that particular antibiotic

Natural resistance is part of some species of bacteria but not all

Gram positive peptidoglycan – highly porus – no barrier to diffusion

Gram negative outer membrane – barrier – resistance advantage

A single mutation in porin gene can give you multiple resistance because many drugs can no longer get through porins.

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13
Q

Genetic mechanisms

Chromosome-mediated

A

Due to spontaneous mutation:

in the target molecule

Or in the drug uptake system

Mutants are selected, NOT induced

Green is sensitive bacteria, add antibiotic, and bacteria become resistant bacteria – THIS IS FALSE, what people used to think.

What is actually happening is that there is a population of bacteria, random mutation occurs.

Selection for these mutations due to antibiotics and kill off sensitive mutations, end up with clonal selection for resistant strains.

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14
Q

Genetic mechanisms

plasmid-mediated gene exchange

A

Plasmid-mediated gene exchange

Common in Gram-negative bacteria

Transferred via conjugation

Multidrug resistance

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15
Q

How are genes transferred in bacteria?

A

Mechanism for genetic heterogeneity and evolution

Rapid, cross species

Can transfer virulence genes (toxins), drug resistance, antigens (for immune evasion)

three steps, transformation, transduction, conjugation

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16
Q

What happens during transformation in gene transfer?

A

Organisms can take up DNA from environment or other organisms that have died around it

Incorporates DNA into its own genome e.g acquires gene for beta lactamase, now in its own genome

17
Q

What happens during transduction in gene transfer?

A

Transfer of genetic material through use of phage

Virus that infects on bacteria, incorporates into its phage head and own genome parts of the genome it just infected

When it infects new host, it injects its own genome and genes acquired from previous host by phage

Transduced recipient becomes resistant

Rapid

18
Q

What happens during conjugation in gene transfer?

A

Two organisms come together

Conjugational tube encoded for by plasmids in bacteria

Allows genetic exchange from donor bacteria to recipient bacteria

19
Q

What happens in gram positive and negative bacteria once they acquire resistance to beta lactams?

A

Gram positive bacteria

  • Acquires B-lactamase enzymes (Pencillinase), breaks down penicillin
  • Have alterations of transpeptidase enzyme (PBP)

Gram negative

  • Acquire B-lactamase
  • Alterations of porins, stops drugs from entering

B-lactamase destroys the active part of the penicillin molecule, the beta lactam ring.

20
Q

What is the drug augmentin/ co-amoxiclav a combo of?

What does it inactivate?

A

A combo of clavulanic acid and amoxicillin.

Binds to and inactivates beta-lactamases

No anti-bacterial activity of its own (clavulanic acid), it binds to beta-lactamase enzyme of bacteria to block it

allows amoxicillin to inhibit protein synthesis and gives broad spectrum activity

21
Q

Beta lactam resistance in gram negative bacteria

How does beta-lactam normally work?

A

Beta lactam goes across porin, binds to PBP, stops cross linking of peptidoglycan and bacteria can’t survive

22
Q

What happens to beta lactam in gram negative bacteria when there is porin mutations?

A

If porin mutations or a new porin type is acquired through gene exchange means beta lactam can’t cross through, organism get multi drug resistances

23
Q

What happens to beta lactam when PBP mutates in gram -ve bacteria?

A

PBP mutates or bacteria acquires a new PBP

(How MRSA became MRSA, by acquiring new PBP)

Drug can get through porin but can’t bind or inactivate enzymes involved in peptidoglycan synthesis

24
Q

What happens to beta lactam in gram-ve bacteria when bacteria acquires a beta-lactamase enzyme?

A

Bacteria acquires a beta-lactamase enzyme

Drug can get into periplasmic space, but beta lactamase binds to and degrades beta-lactase antibiotics

bacteria becomes resistance to antibiotics like penicillin

25
Q

Mechanisms by which bacteria become resistant to pencillin

A

Produce penicillinases / beta lactamases that cleave the beta lactam ring – penicillin is inactivated

Acquire alternative forms of / or mutations in penicillin binding proteins (PBPs) - penicillin can’t bind

Acquire alternative forms of/mutations in porins – penicillin cannot get into cell

Acquire alternative forms of/mutations in efflux pump – penicillin’s are pumped out faster

26
Q

Treatment of MRSA

What drug is used?

How does it work?

A

Only effective treatment is vancomycin, a 1.5kDA glycopeptide

Binds to terminal D-ala-D-ala residues, stops enzymes from binding and bacteria can’t make peptidoglycan

Blocks availability of active site of enzyme

Bacteria instead of synthesising terminal D-ala-Dala synthesises terminal D-ala lac, causing vancomycin resistance

27
Q

How can a bacteria become vancomycin resistant?

A

Acquisition of van operon by transposition - causes altered target, drug can no longer bind

Makes D-ala-D-lactate terminal instead– prevents vancomycin binding

Some hydrogen bonds are missing in D-ala-D-lac, so drug doesn’t bind and doesn’t inhibit

Bacteria becomes resistant

28
Q

Non-genetic mechanism of resistance

Inaccessibility to drugs

A

e.g abscess, TB lesion, it is hard to get drugs to the site of infection

So it doesn’t seem like person is responding to drugs because drugs aren’t getting to where they should be in high enough concentrations.

29
Q

Non-genetic mechanisms of resistance

Stationary phase/vegetations and biofilms

A

When bacteria grow in body they reach stationary phase e.g like biofilm growth you might get on heart valves, not growing and dividing anymore but cause signs and symptoms

Organisms create complex biofilms of organisms

Not susceptible to inhibitors like antibiotics inhibiting cell wall synthesis because they’re not turning over their cell walls

Have to use antibiotics that target other targets in bacteria that are still active

30
Q

How can you prevent or overcome antibiotic resistance?

A

Control use

  • Not in animal feeds
  • Complete course (DOTS for TB, need 6 months, if you stop after 2-3 months you’re selecting for pre-existing mutations for resistance)
  • Appropriate prescribing

New or modified drugs

  • Few in past 25 years – difficult to do

Combination therapy

  • Different targets, limits selection for pre-existing mutants
  • Overcome mutation rates

Infection control

  • Individual – ward – society

Re-establish susceptible flora?

31
Q

What is the issue of treating Neisseria gonorrhoea?

How is it treated now?

A

In 60’s/70s to treat you gave single I/M of PenG, high dose

Gradually increase in pencillin resistance to gonorrhoea 15%, can’t give PenG now because it could be resistant and would cause it to transmit to others

Switched to ciprofloxacin, inhibits DNA gyrase, high dose

Risk emergence of ciprofloxacin, now 30% resistant to ciprofloxacin

Now treatment is short therapy:

  • Single oral dose of cefixime
  • Then I/m ceftriaxone + 1g Azithromycin
  • 125 – 250 – 500mg increasing MIC
  • 2019 now 1g injection of ceftriaxone and no azithro due to resistance
32
Q

Carbapenems treat gram negative bacteria like E.coli and Klebsiella

A

E.coli and Klebsiella main cause for UTIs, now there is CR E.coli and Klebsiellas, making it difficult to treat.

New strains destroy antibiotics – resistance

  • Acquired new gene, nmd1
  • An extended spectrum beta lactamase – ESBLs
  • E.coli and Klebsiella’s have ESBLs which mean they’re very resistant to most beta lactam antibiotics, and to carbapenems
  • Final drug to use to treat these are colistin, targets bacterial cell membranes, very toxic as eukaryotic membranes are similar to prokaryotic membranes
33
Q

What is antibiotic stewardship?

A

Anyone involved in prescribing or using antibiotics needs to now be aware of antibiotic stewardship

about knowing how antibiotics work, drug resistance and antibiotic therapy combinations

Restrict use of antibiotics and how we use them

34
Q
A

Microbiology and immunology (15 decks)

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