Antibiotics Flashcards

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1
Q

Antibiotics are widely used and misused

A

Widely used and misused drugs – 20-50% questionable use

In hospitals - >10% of drug budget

25% of patients have received antibiotics within previous 24h

In ICU 50% of patients are on antibiotics

50 million prescriptions per year

80% of human use is in the community as a result of prescription of antibiotics

50% - respiratory infections

15% urinary tract infections

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2
Q

What are antibiotics natural products of?

What does chemical modification allow?

A

Natural products of fungi and bacteria - soil dwellers

  • Have natural antagonism and selective advantage over other organisms in the soil
  • Kills or inhibit the growth of other microorganisms

Most derived from natural products by fermentation, then modified chemically :

  • Increased pharmacological properties
  • Increased antimicrobial effect

so can be absorbed and survive inside bloodstream

some antibiotics synthetic e.g sulphonamides

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3
Q

Antibiotics have selective toxicity, what does this mean?

A

Due to differences in structure and metabolic pathways between host and pathogen

Harm microorganisms, not the host

Target in microbe, not host (if possible)

Difficult for viruses (intracellular), fungi and parasites

Variation between microbes

Effect on commensals – can be severe, needs to be considered when using antibiotics

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4
Q

Antibiotics must have therapeutic margin, what is this?

A

Difference between active dose that needs to be given to kill the organism, compared to the toxic dose that will cause a toxic effect in the host.

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5
Q

Antibiotics must have an active dose (MIC)

A

Active dose (MIC) vs toxic effect

Narrow for toxic drugs – e.g aminoglycosides, vancomycin, ototoxic, nephrotoxic

If you don’t get dose right it can have toxic effects

There is no safe drug, need to balance therapeutic imperative and host damage..

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6
Q

What antibiotics are involved in loss of flora?

Bacterial/pathogen overgrowth

A

E.g in colitis

Clindamycin, broad spectrum lactams, fluoroquinolones

Pseudomembranous colitis – caused if C. difficile overgrows

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7
Q

Overgrowth of clostridium difficile

What does overgrowth cause?

A

But can be part of normal flora of 3% of population

a spore forming condition which can contaminate environment, can get outbreaks

Causes:

Ulcerations – inflammation

Severe diarrhoea

Serious hospital cross infection risks

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8
Q

A combo of antibiotics and immunity causes bacterial clearance

What do immunosuppression patients need?

A

Immunosuppression patients e.g due to cancer chemotherapy, myeloma, HIV with low CD4, elderly, babies, diabetes, alcoholics

Treating these people requires different antibiotics, e.g different dosage, to ensure bacteria is cleared

Classified by:

Type of activity

Structure

Target site for activity

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9
Q

Antibiotics activity can be bactericidal or bacteriostatic

What is bactericidal antibiotics?

A

Kill bacteria

Used when the host defence mechanisms are impaired

Required in endocarditis, kidney infection

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10
Q

What are bacteriostatic antibiotics?

A

Inhibit bacteria

Used when the host defence mechanisms are intact

Used in many infectious diseases

Varies for drug, species and concentration of drug e.g normal concentration might be bactericidal but increasing its concentration might make it bacteriostatic.

Both work clinically very well.

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11
Q

What two spectrums can antibiotics be?

A

Broad spectrum antibiotics

  • Effective against many types e.g cefotaxime

Narrow spectrum antibiotics

  • Effective against very few types e.g Penicillin G
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12
Q

How has the activity of cephalosporins been refined?

A

First generation cephalosporins not very good at killing gram negatives but good at gram positives

Second generation even distribution

Third generation good for gram negatives but lost activity against some gram positives

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13
Q

What antibiotics are beta-lactams?

A

Penicillin’s

Basic penicillin’s e.g benzylpenicillin (PenG, penicillin V)

  • Active against streptococci, pneumococci, meningococci
  • Most strains of Staphylococcus aureus are resistant
  • Need a different type to kill off Staph Aureus

Anti-staphylococcal penicillin’s e.g flucloxacillin

  • Narrow spectrum, G+ves beta-lactamase resistant, less potent that PenG for some other organisms
  • Not MRSA
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14
Q

What are the other types of penicillin besides basic and anti-staphlococcal penicillin?

A

Broader spectrum penicillin’s e.g ampicillin

  • Spectrum of activity is similar to basic penicillin’s but also includes some gram negative organisms and also enterococci

Anti-pseudomonal penicillin’s e.g piperacillin

  • Extended spectrum beta-lactam antibiotic
  • Also G+ve, G-ve, anaerobes

Beta-lactam/beta-lactamase inhibitor combinations e.g co-amoxiclav (Augmentin)

  • Spectrum like amoxicillin plus activity against some gram-negatives and S.aureus
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15
Q

Many antibiotics target enzymes that make cell walls

If bacteria can’t make cell wall it dies

What antibiotics target cell wall synthesis?

A

Cyclocserine

Vancomycin

Penicillin’s

Monobactams

Carbapenems

Beta lactam antibiotics

Cephalosporins

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16
Q

What antibiotics inhibit protein synthesis?

A

50S inhibitor:

  • Erythromycin (Macrolides)
  • Clindamycin
  • Chloramphenicol – toxic, used topically e.g eyedrops
  • linezolid

30S inhibitors:

  • Tetracycline
  • Spectinomycin
  • streptomycin
  • Gentamicin, tobramycin (aminoglycosides)
  • Amikacin
  • Tigecyclin
  • Doxycycline

have little effect on protein synthesis of eukaryotes

17
Q

What antibiotics affect DNA and RNA processing?

A

Quinolones inhibit DNA gyrase, unique to bacteria when they wind and unwind their DNA in replication.

Humans use topoisomerase 4 instead of DNA gyrase, so selective toxicity against bacterial GYRASE and not against human Topoisomerase enzyme

Rifampicin key in TB medication, blocks bacteria’s ability to produce mRNA.

Inhibits bacterial RNA polymerase, bacteria dies

18
Q

What antibiotics affect folic acid metabolism?

A

Trimethoprim

Sulfonamides

Inhibits enzymes in folic acid metabolism pathway

19
Q

Gram-positive bacteria, antibiotics can diffuse through cell wall and inhibit enzymes that make cell wall

Why can’t antibiotics get through the membrane of gram negative bacteria?

A

Outer membranes full of lipopolysaccharides – impermeability barrier

Antibiotics have to get through the membrane, can only do this by going through certain pores. Not many can get through these pores – PenG wouldn’t work well here

Peptidoglycan in the periplasmic space, drug needs to get here before it can inhibit enzymes making peptidoglycan - so many antibiotics you can’t use here

Many antibiotics you can’t use on gram –ve bacteria, this is why you can’t use the same antibiotics as in gram positive bacteria, and the targets are different

20
Q

How is peptidoglycan synthesised in the cell wall?

A

Polymer of two saccharides cross linked with penta-peptide amino acids

Generates rigid network giving bacterial cell wall support.

Enzymes that synthesise them are different, therefore antibiotic that blocks cross linking for E.coli won’t inhibit enzymes in gram positive.

21
Q

Site of action of inhibitors of bacterial cell wall synthesis

A

Monomers have 5 amino chains and ends in terminal with two D-ala-D-ala

These are attached to lipid molecules and transported across lipid membrane, dimerised and cross linked, during this process

Add on poly-pentaglycine chains

Polymerised by enzymes, cleaves off terminal D-ala and cross link it, in red circle

Enzymes that make crosslink and make peptidoglycan structure called trans peptidases and carboxy-peptidases or known as penicillin binding proteins because they enzymes are inhibited by beta-lactam type antibiotics

  • Enzymes can’t work if they’re bound by penicillin and beta lactam antibiotics, therefore bacteria can’t cross link its peptidoglycans and dies

Vancomycin, treats MRSA, binds to the terminal D-ala-D-ala

Blocks availability of the active site for the enzyme that normally polymerases the polysaccharides, acts as antibiotic, preventing cell wall synthesis in a different way than beta lactam antibiotics does

Blocks access of antibiotics

22
Q

How do beta lactams work on pencillin binding proteins in gram negative bacteria?

A

normally bacteria builds up subunits using PBP enzyme for cross linking, peptidoglycan exists in periplasmic space.

Beta-lactam antibiotic comes , gets through porin of a gram negative bacteria

binds to PBP (enzymes that cross link peptidoglycan) blocks enzymes from working. Bacteria induces autolytic enzyme response

causes bacterial cell to die because it can’t make peptidoglycan structures.

23
Q

What bacteria doesn’t have peptidoglycans?

How can you treat them if they don’t have peptidoglycan?

A

Group of organisms, mycoplasma.

Mycoplasma pneumonia causes community acquired pneumonia.

Can’t treat with beta lactam antibiotic as they don’t have peptidoglycan.

Switch over and use protein synthesis inhibitor like erythromycin

24
Q

Why is folic acid needed in bacteria?

What enzymes do bacteria contain that are involved in folic acid pathway?

A

Tetrahydro folic acid is needed as a key component for many metabolic enzymes, without it metabolism doesn’t function

Bacteria has two enzymes, dihydropteroate synthetase and dihydrofolate reductase which are inhibited by sulfonamides or trimethoprim

Enzymes unique to bacteria, so antibiotics only work against these enzymes, good selective toxicity

25
Q

What do the enzymes dihydrofolic acid and dihydrofolate reductase do?

What drugs work to inhibt enzymes involved in folic acid metabolism pathway?

A

Humans need to get vitamin B9 from our diet, dihydrofolic acid, take it in and reduce it with dihydrofolate reductase to tetrahydrofolic acid

Trimethoprim works better against bacterial dihydrofolate reductase than human dihydrofolate reductase – potent selective toxicity

Using two drugs together, sulfonamides and trimethoprim, gives better antibacterial effects than either given on their own

Dapsone, another drug used to treat leprosy, inhibits dihydropteroate synthetase

26
Q

How do protein synthesis inhibitors work?

Examples of them

A

Antibiotics bind to ribosomes involved in protein synthesis

Blocks it from undergoing protein synthesis

antibiotics work at different stages of protein synthesis

30S ribosome:

  • Streptomycin
  • gentamicin
  • tetracyline

50S ribosome:

  • chlorampheicol
  • erhtyromycin
  • fusidic acid
27
Q

What are the routes of administration of antibiotics?

A

Community infections often treated orally by GP

Serious infections – hospitalisation – systemic treatment

  • E.G IV rapid delivery, high blood concentration to achieve MIC as fast you can so you use IV.

Unable to take orally for some conditions– due to vomiting or unconscious, poor gut absorption due to trauma , won’t absorb drug well from the gut.

Topical – conjunctivitis, superficial skin infections, burns, antiseptic creams, heavy metal ointments

  • Like chloramphenicol
28
Q

What is minimum inhibiton concentration?

A

The conc. you need to achieve in body to get clearance of infection / for the antibiotic to have an effect

Depend on age, weight, renal and liver function of the patient and the severity of infection

On the susceptibility of the organism to the antibiotic you’ve chosen, MIC level varies for different antibiotics

And upon properties of the antibiotic ie enough to give a concentration higher than the MIC

Have to achieve MIC at the site of infection, MIC must be good enough to treat infection– depends on the dose we give

second dose need to be given near first dose so conc. doesn’t drop below MIC