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Respiratory > Antimicrobials 1 > Flashcards

Antimicrobials 1 Flashcards

1
Q

What is an antibiotic?

A

A natural substance produced by micro-organisms antagonistic to growth or life of others in high dilution
Loosely interchangeable with antimicrobial

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2
Q

What occurred during the 19th century?

A

Louis Pasteur and Robert Koch

Bacteria as causative agents and recognised need to control them

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3
Q

What did Paul Ehrlich achieve in the 20th century?

A

Chemotherapy and Magic Bullet (value of dyes)

Therapeutic Index= Toxic concentration/ effective concentration

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4
Q

What did Gerhard Domagk achieve?

A

Prontosil active against infection
Active component- Sulphanilamide
1st synthetic antibacterial in general clinical use

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5
Q

What did Alexander Fleming achieve?

A

Killing of staphylococci by fungal exudate
Unable to purify compound penicillin
Predominantly active against Gram positive bacteria

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6
Q

What did Selman Waksman achieve?

A

Gram-negatives and mycobacterium tuberculosis

Streptomycin

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7
Q

What is pharmacodynamics?

A

Bactericidal and bacteriostatic activity
Minimum Inhibitory Concentration
Minimum Bactericidal Concentration

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8
Q

How are antibiotics classified?

A
  • Effect on microorganism
  • Chemical structure
  • Target site
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9
Q

What are the effects on microorganisms?

A
  • Bacteriostatic= prevents the multiplying of bacteria without destroying them
  • Bactericidal (particularly preferred in serious infections)= kills bacteria
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10
Q

What are the different mechanisms of action/ target sites?

A
  • Cell wall
  • Cell membrane
  • Protein synthesis
  • Nucleic acid synthesis= tetrahydrofolate synthesis (folic acid), RNA synthesis, DNA synthesis
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11
Q

What are the general components of a bacterium?

A
  • Infolding of plasma membrane
  • Capsule
  • Cell wall
  • DNA coiled into nucleoid
  • Flagellum
  • Basal body (attaches to flagellum)
  • Ribosomes
  • Cytoplasm
  • Plasma membrane
  • Pili
  • Cytoplasmic inclusion
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12
Q

Describe cell wall synthesis inhibitors

A
  • Earliest known antibiotics
  • Still some of the safest antibiotics
  • Selectively toxic to bacteria because there is no cell-wall in mammalian cells
  • Removal of cell-wall destroys bacterial maintenance of osmotic pressure
  • Usually bactericidal in action
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13
Q

Examples of cell wall synthesis inhibitors

A

-Beta-lactams
-Glycopeptides=
Vancomycin/ Teicoplanin/ Fosfomycin/ Cycloserine/ Bacitracin

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14
Q

What is the action of Fosfomycin?

A

inhibitor of the MurA enzyme, UDP- N -acetylglucosamine-enolpyruvyltransferase, that catalyzes the first committed step in peptidoglycan synthesis, the reaction of UDP- N -acetylglucosamine (UDP-GlcNAc) with phosphoenolpyruvate (PEP) to form UDP-GlcNAc-enoylpyruvate plus inorganic phosphate

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15
Q

What is the action of Cycloserine?

A

alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl).[12] The first enzyme is a pyridoxal 5’-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form.[12] The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules

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16
Q

What are beta lactams?

A

All posses a beta lactam ring
Differ in the side chain attached to this nucleus
Target site is peptidoglycan which is present only in bacteria

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17
Q

Examples of beta lactams

A 
Penicillins
Cephalosporins
Monobactams
Carbapenems (meropenem)
Clavulanic acid
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18
Q

What is the mechanism of action of beta lactams?

A

Act in the final step of cell wall synthesis by binding to the enzymes (transpeptidases/ penicillin binding proteins) responsible for cross linking of the polysaccharide chains in the cell wall peptidoglycan

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19
Q

Describe the action of cell wall synthesis inhibitors

A

NAG-NAMA-pentapeptide-phospholipid and amino acids for interpeptide bridge into ell wall- blocked by Glycopeptides
Cell wall to cross-linking of peptidoglycan strands blocked by beta lactams

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20
Q

What does NAG-NAMA stand for?

A 
NAG= N-acetylglucosamine
NAMA= N-acetylmuramic acid
ala= alanine
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21
Q

Overview of Penicillins

A
  • First antibiotic to be discovered
  • Natural and semi synthetic products available
  • Narrow spectrum (Penicillin G- Group A strep, meningococci) OR Broad spectrum (carbapenems)
22
Q

What are the side effects of Penicillins?

A
  • Relatively safe
  • Hypersensitivity rash
  • Avoid amoxicillin in patients with infectious mononucleosis- ‘glandular fever’- EBV
  • Anaphylaxis rare (0.004%) but can be fatal
  • Excreted by the kidneys: reduce dose in renal failure
  • Diarrhoea- not uncommon
23
Q

Describe Cefalosporins

A
  • More than 30 agents available
  • Grouped into “generations” or “classes”
  • Cefalexin, cefuroxime, cefotaxime
  • Exhibit broader spectrum cover than Penicillins
  • Lack activity against enterococci
24
Q

What are the clinical uses of Cefalosporins?

A
  • Mostly stable to staphylococcal beta lactamase
  • Much less than 10% cross allergy with Penicillins
  • So diverse- defy rigid classification
  • Oral cefalexin= UTI
  • IV cefuroxime/ ceftriaxone/ cefotaxime= sepsis, meningitis
  • IV ceftazidime= pseudomonas
  • Improved beta lactamase stability- cefalexin
25
Q

Name beta lactam antibiotic ‘allergy’ responses

A

Minor rash

Anaphylaxis

26
Q

Describe minor rash response to beta lactam antibiotic allergy

A
  • Localised, non itchy, >72hr after exposure to penicillin
  • Acceptable to use Cefalosporins, monobactams instead provided spectrum of cover appropriate
  • Consider penicillin use for severe infection
27
Q

Describe anaphylaxis response to beta lactam antibiotic allergy

A
  • Treated patient= wheezing, collapse, itchy rapid onset urticarial rash
  • Use no beta lactam= should consider alternative classes (Glycopeptides, quinolones, metronidazole)
28
Q

Describe Glycopeptides

A
  • Inhibit cell wall synthesis by binding to terminal D-ala-D-ala of the peptide chain and prevents incorporation of new sub units to the growing cell wall
  • vancomycin, teicoplanin
  • For Gram positives not Gram negatives= important in MRSA infection
  • Some nephro and ototoxicity= check spectrum levels
  • IV for systemic infection (but oral for C. difficile infection- no absorbed)
29
Q

Describe inhibitors of cell membrane function

A

Bacterial cell membrane is different from mammalian cell membrane
Bacitracin acts at Gram positive cell membrane

30
Q

Examples of Protein synthesis inhibitors

A
  • Aminoglycoside (gentamicin)
  • Tetracyclines
  • Macrolides (erythromycin, clarithromycin)
  • Chloramphenicol (rarely used in UK)
  • Lincosamides
  • Oxazolidones
  • Fusidic acid
31
Q

What is the action of protein synthesis inhibitors?

A

Aminoglycosides inhibit binding of 30S subunit to mRNA- do not bind 40S mammalian ribosomes so bactericidal
-Tetracyclines inhibit binding of tRNA- do not penetrate mammalian cells- bacteriostatic

32
Q

Describe Aminoglycosides

A
  • Low therapeutic Index
  • Very good vs Gram negative (E coli, pseudomonas aeruginosa and mycobacteria)
  • Anti-staphylococci activity
  • Not active against anaerobes
  • Not absorbed orally
  • Ototoxic and nephrotoxic
  • Monitor serum levels during therapy
33
Q

Describe tetracyclines

A
  • Bacteriostatic
  • Broad spectrum
  • Intracellular bacteria (chlamydia)
  • May cause diarrhoea, nausea
  • Teeth discolouration, avoid in children, pregnant and lactating women
34
Q

Describe Macrolides

A

-Erythromycin, clarithromycin, azithromycin
-Usually bacteriostatic, bactericidal in high concentrations
-Mainly narrow spectrum (mainly Gram positives- Aureus, Group A streptococci)
-Suitable for penicillin allergic patients
-Intracellular bacteria (legionella sp, chlamydia)
Erythromycin cheap

35
Q

What are the side effects of Macrolides?

A
  • Gastrointestinal upset common- less with newer agents
  • Thrombophlebitis when given intravenously
  • Newer macrolides have broader spectrum- clarithromycin and azithromycin
36
Q

Describe Lincosamides

A
  • clindamycin
  • Gram positives- Group A strep, anaerobes
  • Bacteriostatic, oral/IV
  • Cheap/ diarrhoea/ colitis
37
Q

Describe Streptogramins

A
  • Pristinamycin, ‘Synercid’
  • Gram positives
  • Bacteriostatic, oral/IV gram positives
  • Costly, GI upset
38
Q

Describe Oxazolidones

A
  • Linezolid
  • Bacteriostatic, gram positives only
  • VRE/ MRSA, may cause pancytopenia, neuritis and neuropathy, oral/IV, costly
39
Q

What are the actions of inhibitors of nucleic acid synthesis?

A

-Inhibit synthesis of tetrahydrofolic acid (THFA)
-Inhibit synthesis of RNA
Inhibit synthesis of DNA

40
Q

Describe THFA inhibitors

A

-Sulphonamides- structural analogues of PABA (para-aminobenzoic acid)
-Trimothoprim- ‘folate’ antagonist- binds dihydrofolate reductase- selectively toxic to bacteria
(humans do not make folic acid)

41
Q

What is the mechanism of THFA inhibitors?

A

PABA to DHFA via synthase (inhibited by sulphonamides)
DHFA to THFA via reductase (inhibited by Trimethoprim)
THFA to Purines to DNA

42
Q

What are the reasons for combining Trimethoprim and sulphonamides (cotrimoxazole)?

A
  • There is in vivo synergy between the two drugs- the combined effect is greater than the expected sum of their activities- used in pneumocystis pneumonia
  • Individually the drugs are bacteriostatic- combination bactericidal
  • Use of 2 drugs delay the mergence of resistance
43
Q

What is the con of cotrimoxazole?

A

Side effects greater- clinical evidence of greater efficacy weak
UK- trimethoprim used alone for UTA

44
Q

Describe inhibitors of RNA synthesis

A
  • Rifampicin
  • Inhibits RNA polymerase enzyme
  • Used as part of combination treatment for mycobacterium tuberculosis and M. leprae
  • Also for severe S. Aureus infections
  • Always in combination as resistance develops easily on monotherapy
  • Significant drug interaction (hepatic enzyme inducer), colour secretions- inactivates oral contraceptive pill
45
Q

Describe the action of Rifampicin

A
  • Binds to DNA-dependent RNA polymerase
  • Forms stable complex with beta-subunit (encoded by rpoB gene mutates readily)
  • Inhibits initiation- not elongation
  • Usually bactericidal
46
Q

Describe inhibitors of DNA synthesis

A
  • Quinolones
  • Useful- mainly: multi R GNB; UTI; typhoid
  • Synthetic, well absorbed. IV/ PO
  • Act by inhibiting DNA gyrase (Gram negatives) and topoisomerase IV (Gram positives)
  • Enzymes act together to ensure that DNA molecule has proper conformation for efficient replication and packaging within cell
  • Bactericidal
47
Q

Describe fluoroquinolones (Ciprofloxacin)

A
  • Broad spectrum
  • Low MICs
  • Rapidly bactericidal
  • Resistance can be slow to develop
48
Q

What are the side effects of Quinolones?

A
  • Neurotoxicity, confusion, fits
  • Cartilage defects. Not used in pregnant women and children
  • Photosensitivity
  • Association with C. difficile infection
  • 1st choice for meningococcal contacts prophylaxis
49
Q

What are the qualities of an ‘ideal’ antibiotic?

A
  • Desirable pharmacokinetic and pharmacodynamic properties
  • High therapeutic index= good safety margin
  • Low toxicity
  • Bactericidal
  • Cheap
  • Does not accumulate/ increase resistance
  • No interaction with other drugs
  • Does not cause diarrhoea or C. difficile infection
50
Q

What are the main routes of administration?

A
  • Parenteral (intravenous/ intra muscular)
  • Intraperitoneal
  • Oral
  • Rectal
  • Topical often discouraged
51
Q

What are the important issues when choosing an antibiotic?

A
  • Infection present? Is it bacterial?
  • Source control- drain abscess, remove foreign body
  • Ideally obtain cultures before commencing antibiotics
  • Complete laboratory request details properly
  • Empiric (best guess) therapy may be started if required
  • Cost, route, dose, monitoring, frequency and duration
  • Document indication and review/ stop date

Respiratory (41 decks)

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