1. Antimicrobial agents & antibiotic resistance Flashcards by Eleanor Barnard

What is the difference between antibiotics and antimicrobial agents?

ANTIBIOTICS - natural chemical products of microbes that inhibit/kill other organisms
ANTIMICROBIAL AGENTS - synthetic/semi-synthetic compounds & antibiotics

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What is the difference between bacteriostatic and bactericidal?

BACTERIOSTATIC - Inhibits bacterial growth (protein synthesis)
BACTERICIDAL - kills bacteria (cell wall agents)

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What is the MIC, and what does it mean?

MINIMUM INHIBITORY CONCENTRATION

minimum concentration at which visible growth is inhibited
NB. smaller MIC = more active antibiotic

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What is synergism (antimicrobial interactions)?

The interaction of 2 antimicrobials to produce a combined effect greater than the sum of their activity given separately.

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Give an example of synergism that is used to treat endocarditis.

B-lactam & aminoglycoside

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What is antagonism?

One agent diminishes the activity of another.

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What are antibiotic targets in cells? (4)

Cell wall
Protein synthesis
DNA & RNA synthesis
Plasma membrane

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What is the main component of bacterial cell walls?

Peptidoglycan

- polymer of glucose derivatives (NAM &NAG)

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Why is the bacterial cell wall an ideal target for antibacterial agents?

Selective toxicity - no cell wall in animal cells

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Give 2 examples of synthesis inhibitors of bacterial cell walls.

B-lactams (ring structure)

Glycopeptides

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How does b-lactam act on bacterial cell walls?

Forms structural analogue of D-alanyl-D-alanine & interferes with function of penicillin binding protein.

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Give examples of B-lactams. (4)

Penicillins
Cephalosporins
Carbapenems
Monobactams (gram -ve only)

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How do glycopeptides act on bacterial cell walls?

They bind to terminal D-alanyl-D-alanine on NAM pentapeptides&raquo_space; inhibit cross-linking.

unable to penetrate gram -ve porins
eg. Vancomycin

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What happens during bacterial protein synthesis?

Translation of RNA&raquo_space; protein.

- 50S & 30S combine&raquo_space; 70S (initiation complex)

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What are the 5 main types of protein synthesis inhibitors?

Amino glycosides
Macrolides, lincosamides, streptogramins (MLS)
Tetracyclines
Oxazolidinones
Other (fusidic acid, mupirocin)

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How do aminoglycosides inhibit protein synthesis?

-Give an example.

Bind to 30S subunit

-gentamycin

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How do tetracyclines inhibit protein synthesis?

-Give an example.

Bind to 30S&raquo_space; inhibit RNA translation (tRNA&raquo_space; rRNA)

-DOxytetracycline

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How do oxazolidionones inhibit protein synthesis?

-Give an example.

Bind to 50S (&70S)&raquo_space; inhibit initiation of protein sysnthesis.
-Linezolid

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Name 4 types of DNA synthesis inhibitor.

Trimethoprim & sulfonamides (combine&raquo_space; CO-TRIMOXAZOLE), quinolones & fluoroquinolones

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How do trimethoprim & sulfonmides inhibit DNA synthesis?

Inhibit folate acid synthesis

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What is a side effect of co-trimoxazole?

Stevens-Johnson syndrome

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How do quinolones & fluoroquinolones inhibit DNA synthesis?

Inhibit DNA gyrase & topoisomerase IV (DNA remodelling)

- eg. nalidixic acid, ciprofloxacin

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Name an RNA synthesis inhibitor.

Rifampicin

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How does rifampicin inhibit RNA synthesis?

RNA polymerase inhibitor&raquo_space; prevents mRNA synthesis

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What is daptomycin and how does it act on bacteria?

Plasma membrane agent | -inserts lipophilic tail into cell membrane of gram +ve bacteria >> depolarisation

What are the side effects of aminoglycosides?

Renal impairment & ototoxicity (ear)

What are the side effects of linezolid?

Bone marrow depression

What are the side effects of B-lactams?

Allergic reactions (rash, anaphylaxis - rare)

What is used instead of B-lactams if a patient is allergic?

Non-specific penicillin allergy: CEPHALOSPORINS & CARBAPENEMS Any penicillin allergy: AZTREONAM

What is the most common cause of antibiotic-associated diarrhoea?

C. difficile | -Hypervirulent strain 027 = most severe

How does C. difficile cause diarrhoea, and what are common precipitating antibiotics associated with it?

Produces toxins A&B due to removal of normal colonisation resistance - cephalosporins & ciprofloxacin

What is the strategy for antibiotic use?

1. EMPIRIC THERAPY (know organ system, based on predicted susceptibility of likely pathogen) 2. TARGETED THERAPY (know infecting organism, based on predicted susceptibility) 3. SUSCEPTIBILITY-GUIDED THERAPY (based on antimicrobial susceptibility results)

What are the key antibiotic/bacteria combination for: - flucloxacillin? - benzylpenicillin? - cephalosporins? - metronidazole? - vancomycins? - meropenem?

- flucloxacillin & s. aureus - benzylpenicillin & s. pyogenes - cephalosporins & gram -ve bacteria - metronidazole & anaerobes - vancomycins & gram +ve bacteria - meropenem & most bacteria

What is the main bacteria flucloxacillin is used against?

S. aureus

What is the main bacteria benzylpenicillin is used against?

S. pyogenes

What type of bacteria is cephlosporins used against?

Gram -ve bacteria

What type of bacteria is metronidazole used against?

Anaerobes

What type of bacteria is vancomycins used against?

Gram +ve bacteria

What type of bacteria is meropenem used against?

Most bacteria

Which antibacterial agents have good availability in CSF?

B-lactams

Which antibacterial agents have poor availability in CSF?

Vancomycin & aminoglycosides

Which antibacterial agents have good availability in urine?

Trimethoprim & B-lactams

Which antibacterial agents have poor availability in urine?

MLS

What are the reasons for using combination therapies? (3)

Increase efficacy Provide broad spectrum (eg. sepsis) Decrease resistance

Give an example of 2 antimicrobial agent that have an increased efficacy when used together.

B-lactam/aminoglycosides | >> endocarditis

What is meant by the 'antibiotic era'?

Widespread availability of antibiotics (1940s)

What is meant by the 'post-antibiotic era'?

Gradual resistance >> decreased availability

Give some examples of problematic bacteria.

``` MRSA VRE ESBL (B-lactamase) CBE (carbapenamase) Multi-drug resistant TB ```

What problems does antibiotic resistance cause for empiric treatment?

Risk of under-treatment | Risk of using excessively broad spectrum

What problems does antibiotic resistance cause for targeted therapy?

Requires use of alternatives - EXPENSIVE (eg. linezolid for MRSA) - "LAST-LINE" (eg. meropenem for multi-resistant enterobacteriaceae) - TOXIC (eg. colistin for NDM-1 producers)

What is the process of sensitivity testing?

- culture microorganism in presence of anti-microbial agent - organism grow = RESISTANT, doesn't grow = SENSITIVE - determine whether MIC is above predetermined 'breakpoint'

What are the reasons for sensitivity testing? (4)

- Transition from empiric >> targeted treatment - Explains treatment failures - Provides alternative antibiotics (eg. adverse effects) - Transition from IV >> oral antibiotics

What type of media gives a more accurate MIC during sensitivity testing?

A liquid media | -lower MIC = more sensitive organism

What are the limitations of sensitivity testing?

- infection may be caused by another organism - correlation between antimicrobial sensitivity & clinical response is not absolute - some organisms appear to respond but are clinically resistant

What are the 6 mechanisms of antibiotic resistance?

1. No target >> no effect 2. Decrease permeability (drug can't get it) 3. Altered target 4. Over-expression of target (>>effect diluted) 5. Enzymatic degradation (drug destroyed) 6. Efflux pump (>>drug expelled)

Give an example when no target leads to antibiotic resistance.

Using antibiotics >> fungi/virus

Give 2 examples when decreased permeability leads to antibiotic resistance.

- VANCOMYCIN: cannot permeate gram -ve bacteria | - GENTAMICIN: cannot permeate anaerobes (uptake requires o2 dependent AT)

Give an example when an altered target leads to antibiotic resistance.

Flucloxacillin: MRSA | -Altered penicillin-binding protein does not bind β-lactams

Give an example when enzymatic degradation leads to antibiotic resistance.

Penicillins & cephalosporins degrade β-lactamases

Give an example where efflux pumps lead to antibiotic resistance.

Many antibiotics, particularly in Gram -ve bacteria | -Eg. Candida spp.

How do bacteria become resistant to antibiotics?

- single gene resistance - resistance encoded in plasmids - horizontal transfer - vertical transfer

How do single genes lead to antibiotic resistance?

- Antibiotic-modifying enzymes | - Altered antibiotic targets

Give 2 examples of antibiotic-modifying enzymes

- B-lactamases (penicillins, cephalosporins) | - Aminoglycoside-modifying enzymes (gentamycin)

Give an examples of an altered antibiotic target.

-Penicillin-binding protein 2 (MRSA)

How are plasmids normally transmitted within/between species?

Conjugation

What molecules enable horizontal transfer of resistance? (2)

Integrons | Transposons

What is horizontal transfer?

Transfer of DNA between different genomes | -from plasmid >> plasmid/chromosome

What is vertical transfer?

Transfer of genes from parent to offspring | -asexual/sexual

What are the consequences of antibiotic exposure? (2)

- Sensitive strains exposed to sub-lethal concentrations - Resistance enhances the chance of survival >> out-competes sensitive strains (subsequent infection more likely to be sure to resistant strain)