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Antibiotics Flashcards

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1
Q

Gram positive

A

Purple stain
Thick peptidoglycan wall
cell membrane

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2
Q

Gram Negative

A

cell membrane
thin peptidoglycan cell wall
periplasm
outer membrane

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3
Q

Antibiotic targets

A
  • Cell wall peptidoglycan
  • Metabolism
  • Ribosome (stops bacteria producing protein)
  • DNA (inhibit synthesis)
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4
Q

Bactericidal action

A
  • Achieve sterilisation of the infected site by directly killing bacteria
  • Lysis of bacteria can lead to release of toxins and inflammatory material
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5
Q

Bacteriostatic action

A
  • Suppresses growth but does not directly sterilise the infected site
  • Requires additional factors to clear bacteria – immune mediated killing
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6
Q

Antibiotic spectrum

A

range of bacterial species effectively treated by the antibiotic

Narrow

  • use when infection well defined +ve
  • limited range of bacteria -ve

Broad

  • wide range of bacteria +vr
  • colonisation “good bacteria” eliminated -vr
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7
Q

Gram positives

A
  • Streptococcus – mouth
  • Enterococcus – bowel
  • Staphylococcus – infections from skin
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8
Q

Gram negatives

A
  • Ecoli & other coliforms – urinary, biliary tract infecitons
  • Neisseria – meningitis, gonorrhoea
  • Haemophilus – respiratory tract
  • Pseudomonas – resistant organism that affects respiratory tract or urine
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9
Q

Anaerobes

A

Clostriduium
bacteriodes

Gram positive or negaive

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10
Q

Antibiotic use?

A

Guided therapy:
o Depends on identifying cause of infection and selecting agent based on sensitivity testing

Empirical therapy:
o Best (educated) guess therapy based on clinical/epidemiological acumen
o Used when therapy cannot wait for culture

Prophylactic therapy:
o Preventing infection before it begins

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11
Q

Antibiotic associated harm

A

Disruption of bacterial flora leads to:
o Overgrowth with yeasts – thrush
o Overgrowth of bowel – diarrhea

Antibiotic use associated with:
o development of C. difficile colitis
o future colonisation and infection with resistant organisms

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12
Q

Compromises for guided therap y and empirical therapy

A

Guided therapy:

Achieve clinical cure with as little impact on colonisation and resistance as possible

Empirical therapy

Accept that impact on colonisation and resistance may be greater

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13
Q

Types of B-lactam antibiotics

A

Penicillins

  • Benzylpenicillin,
  • flucloxacillin,
  • amoxicillin)

Cephalosporins
- ceftriazone)

Carbapenems
- (Meropenem)

Monobactams
- (aztreonam)

Combination antibiotics

  • Augmentin (co-amoxiclav): Amoxicillin/clavulanic acid
  • Tazocin : Piperacillin/tazobactam
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14
Q

Mechanism of action of B-lactams

A

Have B-lactam ring
Analgoye of branching structure of peptidoglycan
Binds to penicillin binding proteins/peptidoglycan polymerases
Inhibits cross linking of cell wall peptidogycan
Lysis of bacteria - bacteriostatic

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15
Q

Pharmacology of B-lactams

A 
Poorly absorbed from GI tract 
-	Must be given IV 
Some effective orally 
-	(amoxicillin, flucloxacillin most commonly used, vomiting limits dose) 
-usually excreted unchanged in urine
-half life varies enormously 
-reach site of infection
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16
Q

Adverse reactions of B-lactams

A 
-very well tolerated 
GI toxicity 
-	Nausea and vomiting 
-	Diarrhoea
-	Cholestasis 
Infection 
-	Candidiasis, oral vulvovaginal 
-	C diff 
-	Selection of resistant bacteria 
Hypersensitivity 
-	Type 1 urticaria, anaphylaziz 
-	Type 4- mild to severe dermatology 
-	Interstitial nephritis 
Miscellaneous rare reactions 
-	Seizure
-	Haemolysis 
-	Leukopaenia 
`
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17
Q

Penicillin examples

A

Benzylpenicillin
Amoxicillin
flucoxacillin

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18
Q

Fluxloxacillin cover and features

A

Staph a
Strep

NOT GN organsims

Nausea limits dose
Resists B-lactamase activity

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19
Q

Amoxciliin cover and features

A

Streps + haemophillus (chest)

Broader spectum
Oral
Semis-synthetic

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20
Q

Benzylpenicillin cover and features

A

Streptococci and Neisseria

Narrow spectrum
IV

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21
Q

Examples of combination b-lactams/ B-lactam inhibitors

A

Co-administered with penicillin
Broadens spectrum of antibiotics
Gram negatives + staph A

Tazocin: Tazobactam + piperacillan - EVERYTHING

C0-amoxiclav: clavulanic acid + amoxicillin - not psudeomonas

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22
Q

Cephalosporins

A

Ceftriaxone

Good cover

  • not enterococcus + psuedomonas
  • Use meningitis

Problems:
Cause C.diff
Increased resistance

23
Q

Carbapenems

A

Broad spectrum GPs + -ves
NOT MRSA

Resistant to beta lactamases

24
Q

B-lactamases

A

Resistance
Enzymes that lyse and inactivate B-lactam drugs
Secreted by Gram -ves and staph aureus

25
Q

Vancomycin cover

A
  • Inhibits cell wall formation in Gram +ves only (no Gram –ve action) – big molecule
  • Not dependent on PBP binding so effective against resistant organisms
  • Resistance in clinical isolates is extremely rare

MRSA

26
Q

Vancomycin pharmacology

A
  • Not absorbed from GI tract so almost always given IV
  • Oral route only used for treatment of C. diff
  • Resistance occurs but is uncommon (esp. Staph)
  • Long half life so loading doses usually given
27
Q

Adverse reactions with vancomycin

A

Nephrotoxicity – more likely with higher doses

Red-man syndrome if injected too rapidly

  • Anaphylactoid reaction
  • Very rare now infusion rates slow

Ototoxicity - rare

Therapeutic drug monitoring undertaken

  • Narrow therapeutic range
  • Aim higher in severe illnesses

Main issue with vancomycin in clinical use is underdosing

28
Q

Antibiotics that target metabolism

A

Protein synthesis inhibitors

2 targets

  1. 50 s Ribosomal subunit
    a. Macrolides
    i. Erythromycin
    ii. Clarithromycin
    iii. Azithromycin
    b. Clindamycin
    c. Chloramphenicol
  2. 30s ribosomal subunit
    a. Aminoglycosides
    i. Gentamicin
    b. Tetracyclines
29
Q

Macrolides

  • examples
  • cover
  • Drug interactions
  • Adverse effects
  • resistance
A

Erthyromycin, clarithromycin, azithromycin

Gram positives+ respiratory gram negstives + atypicals (legionella, mycoplasma, chylamidia)

Drug interactions

  • stop simvistatin
  • warfarin
  • clarithromycin (>400 drug interactions)

Adverse effeects:

  • diarrhoea, vomitting, QT prolongaion
  • hearing loss

Restance:

  • typical (common)
  • atypical (rare)
30
Q

Clindimycin

  • cover
  • route
A

no action against gram negative + enterococcus + atypicals

excellent against aerobes (can cause C.diff)

Good oral absorption
Effective at stoping exotoxin release

31
Q

Chlorampenicol

  • cover
  • route
  • side effects
A

BACTERIAL MENIGINTIS WITH B-;ACTAM ALLERGY

-topical therapy to skin

side effects

  • Bone marrow suppression
  • Aplastic anaemia
  • Optic neuritis
32
Q

Anti-biotics that cause C.diff

A

4 Cs

  • clindamycin
  • co-amoxiclav
  • cephalosporins
  • ciprofloxacin
33
Q

Mechanism of how Abx cause C.diff

A
  • Antibiotics dramatically alter the colonic flora
  • C. difficile commonly colonises the human colon
  • Forms spores which can be difficult to eradiacate from hospitals
  • Has developed resistance to common antibiotic classes
  • Health individual with normal bowel
  • Antibiotics are given
  • Reduces gut microbial species
  • Carry or ingest from environment c diff
  • Spores able to rapidly grow
  • Development of c diff infection and psuedoemembranous colitis
34
Q

Amino glycosides ( 30s)

  • example
  • cover
  • mechanism of action
  • toxicity
  • pharmacology
A

Gentamicin

  • Gram negative only
  • Two mechanism of actions
    a. Reversibly binds to 30 s into ribosome (bacteriostatic action, results in prolonged effect)
    b. poorly understood action on cell membrane (bactericidal action, prominent at high concentrations, resultsin rapid killing early in dosing interval)
toxicity 
-	Nephrotoxicity
-	Ototoxicity:	Irreversible!!
o	Hearing loss
o	Loss of balance
o	Oscillopsia
-	Neuromuscular blockade:
o	Usually only significant in myaesthenia gravis- Do not prescribe

Pharmacology

  • Give high initial dose to take advantage of rapid killing
  • Leave long dosing interval (24-48hrs) to minimise toxicity
  • Measure trough level to ensure drug not accumulating
  • Give for 3 days only
35
Q

Tetracyclines (30s)

  • example
  • cover
  • side efects
  • toxiciyt
A

DOXYCYCLINE

  • respiratory gram negatives, atypicals
  • avoid in pregnant women and children
  • relatively non-toxic
36
Q

Antibiotics that inhibit DNA repair & replications

A

Quinolones – DNA gyrase
o Ciprofloxacin
o Levofloxacin

Rifampicin – RNA polymerase

37
Q

Quinolones

  • examples
  • cover
  • Toxicity
A

Levofloxacin - gram negatives -respiratory tract

Ciprofloxacin - gram-ves - UTI, abdominal infection

Toxicity

  • GI
  • QT elongation
  • tendonitis
38
Q

Rifampicin

Uses
Interactions

A

RNA polymeraases

uses
o Tuberculosis (in combination therapy)
o In addition to another antibiotic in serious Gram positive infection (esp. Staph. aureus)

Interations
o Rifampicin is a potent CYP450 enzyme inducer
o Most drugs that undergo hepatic metabolism affected
o Important to look up interactions when starting

39
Q

Folate synthesis inhibitors

  • examples
  • mechanism of action
  • cover
  • toxicity
A

Inhibition of folate metabolism leadds to impaired nucleotide synthesis and impaired DNA replication

Trimethoprim

  • oral
  • resistance high
  • Gram +ves + -ves (Uncomplicated UTIS not)
  • Toxicity: increased K+, rash + GI disturbance

Co-trimoxazole

  • few advantages
  • trimpethoprim + sulphamethazozole
  • toxicity high- stephen johnsons, bone marrow suppression
40
Q

Metronidazole

A

enters by passive diffusion and produces free radicals
Do not use with alcohol
peripheral neuropathy
most anaerobes

41
Q

4 mechanisms of resistance

A

Production of enzymes to inactivate the drug (beta lactamases)

Synthesis of modified targets against which the drug has no effect (methylation of the 23s ribosomal subunti- resistance to erythromycin)

Decreased permeability to drug( porins which permit drug to pass into a cell can be down regulated)

Active drug export
(production of multi-drug resistance efflux pumps, bacteria such as Pseudomonas can produce these allowing them to become resistant to may drugs through a single mechanism. The drug is usually exchanged for protons.)

42
Q

Chromosomal resistance

A

Spontaneous mutations occur at a lower rate than acquisition of mobile pieces of DNA.

Mutation must occur in either the drug target or the transport system for uptake of the drug.

Treatment of some infections with two drugs acting in different ways is based on the principle that if a mutation occurs in one drug target the other drug will still kill the organism.

Less of a problem as frquence of crhomosoaml mutations is lower than that of plasmids

43
Q

Plasmids

A

Plasmids are pieces of circular double stranded DNA

Genetic information that can be carried on plasmids can include resistance to antibiotics, heavy metals, UV light. They can carry genes which encode pili and mediate adherence and they can encode toxins.

As well as carrying genes of
interest to the host cell they also carry genetic information to allow themselves to replicate and pass between cells.

44
Q

Plasmid mediated resistance

A

In some ways this is the more important mechanism

Plasmids have a high rate of transfer from one cell to another

Plasmids frequently carry resistance to multiple drugs

Plasmids can transfer between multiple species and this is most frequently seen in Gram negatives.

45
Q

Transposons

A

Transposons are pieces of DNA that are transferred within or between larger pieces of DNA such as a the bacterial chromosome and plasmids.

The gene for resistance is flanked by genes which mediate and inhibit excision and insertion of the DNA fragment

46
Q

Fitness cot

A

Genetic material acquired may affect more than just drug susceptibility.

This reduced growth is called a fitness cost

In an environment without a selective pressure these slower growing mutants will be outgrown by their wildtype colleagues and will slowly die away.

The time this takes depends on the significance of the fitness cost associated with that mutation.

Sometimes other mutations may develop which compensate for the fitness cost allowing the mutated bacteria to compete with wild type colleagues.

47
Q

Gram positive resistance -MRSA

A

MRSA stands for methicillin resistant Staphylococcus but it really means that the strains are resistant to all Beta-lactams except some very new cephalosporins.

The gene which codes for this resistance is the MecA gene which is situated in the bacterial chromosome.

The encodes a variant of the normal penicillin binding protein with a lower affinity for methicillin.

Penicillin binding proteins mediate the cross linking in the peptidoglycan which makes up the bacterial cell wall. The decreased affinity allows the bacteria to continue to produce cell wall even in high concentrations of the drug.

The MecA gene is encoded as part of a larger cassette of genes which includes insertion sequences and often genes for resistance to other antibiotics.

Several versions of these cassettes exist as you can see in the slide, larger ones encoding more resistance genes which traditionally circulated in hospitals and smaller ones which are more commonly seen in the community.

This is an example of where fitness cost is so important, as were you have a lesser selective pressure for such as in the community a larger amount of genetic material cannot be sustained.

48
Q

Resistance in coliforms

A

Gut commensals, e.g. E. coli and Klebsiella

Cause of infections such as UTI, intra-abdominal sepsis and HAP

Antibiotics commonly used to treat these include penicillins such as amoxicillin, quinolones, cephalosporins and aminoglycosides

Resistance to penicillins such as amoxicillin in these bacteria is mediated by several families of enzymes with beta-lactamase activity, similar to the enzymes we discussed in Staphylococcus.

Extended spectrum beta-Lactamases:

  • Plasmid encoded
  • These are enzymes which are able to hydrolyse the beta-lactam ring of not only penicillins but also cephalosporins
  • Options for treatment include ciprofloxacin, temocillin, gentamicin and meropenem.
49
Q

Non genetic mechanisms of resistance

A

Protected environment
Resting stage
Presence of a foreign body

50
Q

Protected environment

A

When the body detects infection it can attempt to isolate it in one area, i.e. by forming an abscess. This inadvertently provides the bacteria with an environment protected from antibiotics. For this reason surgery in some situations is the best cure for an infection. For example imaging a patient with a nasty appendicitis, the omentum and the immune system together can sometimes wall off the infection into a complex inflammatory mass and despite apparently correct antibiotic therapy in terms of sensitivity patterns the patient may remain septic. In this situation removal of the pus and the focus of the infection with surgery would be the correct treatment and the antibiotics only serve to keep the rest of the body relatively free of bacteria until that can happen.

51
Q

Resting stage

A

Bacteria which are not dividing i.e. in a ‘resting state’ are less susceptible to cell wall inhibiting agents such as penicillins and cephalosporins than rapidly dividing organsisms. This is also a problem seen in the treatment of Tuberculosis and treatment of slow growing dormat tubercule bacilli is the reason why such long courses of anti-tuberculous drugs is required.

52
Q

Foreign body

A

Presence of a foreign body can lead to apparent resistance for several reasons.

The first is that the immune system is not as effective in the presence of a foreign body and removal of bacteria is often a team effort between antibiotics and the immune system.

The second reason is biofilm
Biofilm is only recently becoming better understood. It is sometimes called a slime layer and it is often talked about on the surfaces of prosthetic material such as indwelling lines and prosthetic joints however, far from being as simple as a slime later it is a highly organised and complex bacterial community with channels for diffusion of water, oxygen and nutrients. It’s the state in which bacteria prefer to live in ponds and in the environment and it turns out in humans too.

There are three important ways in which the presence of biofilm can lead to resistance.

  1. The close proximity of bacteria to each other facilitates gene exchange including exchange of resistance determinants.
  2. The channels for diffusion of nutrients are sometimes too small for antibiotics to penetrate well.
  3. Add the bottom of the biofilm nutrients penetrate in smaller amounts and so the bacteria replicate slower making them less susceptible to cell wall agents.
53
Q

Ways to prevent spread of resistance

A

Narrow spectrum where possible

Short courses

Infection control precautions to prevent spread of existing cases

Microbiology (21 decks)

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