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Primary Pharmacology > Infectious Disease Pharmacology > Flashcards

Infectious Disease Pharmacology Flashcards

1
Q

Give and example and describe the coverage of each of the following divisions of penicillins
- Narrow spectrum
- Narrow spectrum resistant to staph beta lactamase
- moderate spectrum
- broad spectrum resistant to staph beta lactamase
- antipseudomonal

A

Petkov blue

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2
Q

Give an example of each of 4 generations of cephalosporins

A

petkov blue

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3
Q

Give an example of each of the 4 beta lactam classes

A

Petkov blue

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4
Q

What class does Vancomycin belong to?

A

Glycopeptides
Petkov blue

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5
Q

What is the coverage of the class glycopeptides? Give an example of one

A

Gram + inc. MRSA
Vancomycin

Petkov blue

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6
Q

Macrolides coverage and example?

A

Gram + cocci, gram negative cocci and anaerobes
Erythromycin/clarithromycin

Petkov blue

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7
Q

Lincosamides have what coverage?

A

Gram positive aerobics, most anaerobes,MRSA

petkov blue

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8
Q

Lincosamides examples

A

CLindamycin, lincomycin

Petkov blue

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9
Q

Aminoglycoside coverage and example?

A

Gram - aerobes
Gentamicin

Petkov blue

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10
Q

Tetracycline coverage and example

A

Doxycycline
Gram +and gram -

Petkov blue

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11
Q

Quinolones cover what bacteria? Example?

A

Ciprofloxacin
Mostly gram -

Petkov blue

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12
Q

Metronidazole belongs to what class? Coverage (2)

A

Nitroimidazoles
Anaerobes and protozoa

petkov blue

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13
Q

Trimethoprim class

A

Pyramiding derivities

Petkov blue

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14
Q

Rifampicin coverage?

A

Gram + and mycobacteria

Petkov blue

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15
Q

Fusidic acid coverage?

A

Narrow spectrum Staph Aureus

Petkov blue

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16
Q

Mechanism of beta lactams?

A

Petkov blue

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17
Q

Vancomycin MOA

A

Glycopeptides inhibit glycol-peptide synthase
Prevents peptidoglycan-glycan formation in the bacterial cell wall

Petkov blue

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18
Q

Which antibiotics act by preventing protein synthesis?

A

Petkov blue

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19
Q

Chloramphenicol MOA

A

Petkov blue

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20
Q

Lincomycin MOA

A

Petkov blue

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21
Q

Which antibiotics act via 50s ribosomal subunit? How does this affect bacteria

A

Petkov blue

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22
Q

How do aminoglycosides work

A

Petkov blue

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23
Q

How do tetracyclines work

A

Petkov blue

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24
Q

WHich antibiotics act via 30s ribosomal subunit? How does this impact bacteria?

A

Petkov blue

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25
Q

How do quinolones work?

A

Inhibition of alpha subunit of DNA gyrase causing inhibition of nucleic acid synthesis

Petkov blue

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26
Q

How does ciprofloxacin work

A

Inhibition of alpha subunit of DNA gyrase causing inhibition of nucleic acid synthesis

Petkov blue

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27
Q

Which antibiotics act via inhibition of nucleic acid synthesis directly?

A

Quinolones, nitroimidazoles

Petkov blue

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28
Q

How does metronidazole work

A

Inhibition of alpha subunit of DNA gyrase causing inhibition of nucleic acid synthesis

Petkov blue

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29
Q

Which 2 classes act via inhibition of folic acid synthesis

A

Sulphonamides
Trimethoprim

Petkov blue

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30
Q

How do sulphonamides work?

A

Mimic folic acid by acting as false substrates

Petkov blue

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31
Q

How does trimethoprim work

A

Competitive inhibition of bacterial Di-hydro-folate reductase - inhibiting folic acid synthesis

Petkov blue

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32
Q

Name 3 bacteriocidal antibiotics

A

Petkov blue

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33
Q

Bacteriostatic antibiotics (4)

A

Lincosamides
Tetracycline
Sulphonamides
Macrolides at low plasma concentrationsPetkov blue

Petkov blue

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34
Q

How are fungi different from bacteria?

A

Bacteria have cell walls, membranes and are prokaryotes that rapidly replicate, asexually with DNA arranged in single circular chromosme in the cytoplasm. Bacterial ribosomes are structurally different from mammaliana nd non membran eassociated

Fungi are eukaryoytes ith nuclear material enclosed in a membrane, replicate slowlyt and have intracelular organelles . Most antifungals therefore target fungal cell membrane where erogsterol replaces cholesterol

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35
Q

What are the 4 classes of beta lactams?

A

Pencillins
Cephalosporins
Carbapenams
Monobactams

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36
Q

What two main classes of antibiotics attack the cell wall

A

Beta lactams
Glycopeptides

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37
Q

What differentiates pencillins and cephalosporins structurally

A

Both have acyl side chains connecting to a beta lactam ring, however the side chain may have different offshoots, and pencillins have a thiazolidine ring whereas cephalosporins have a dihydrothiazine ring

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38
Q

What is the significance of the acyl side chain in pencillins and cephalosporins?

A

Suscepatability to acid degredation in the stomach
Spectrum of acitivty

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39
Q

Which pencillins are produced naturally

A

Pencillin V and pencillin G

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40
Q

MOA of penicillins

A

Bacteriocidal, inhibit celll wall synthesis by prevenitng peptidoglycan cross linkage weakening cell walls - the beta lactam ring resembles the natural substrate D-ala-D-ala on the side chain of peptidoglycan where cross linkage occurs. Penicillins bind to several pencillin binding proteins in the cel wall that act as transpeptidase enzymes responsible for forming the cross links. Binding is irreversible due to acelyation of active serine site after cleavage of the beta lactam ring. Growth continues in the baceria but with reduced cross linkage of peptidoglycan until the cell wall weakens to the point at which it lyses

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41
Q

How do beta lactamases work?

A

hydrlyses the beta lactam ring

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42
Q

Which species have intrinsic resistance to beta lactams?

A

Gram negative are encoded in bacterial chromosomes and plasmids which may be disseminated leading to acquired resistance

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43
Q

Are beta lactams bacteriocidal?

A

Yes
However rarely does complete eradication occur, a significant number of beta lactam sesntiive cells known as persistors remain dormant until the antibiotic is removed.
Complete erradication required addition of synthergistic antibiotic e.g. gentamicin
Synergistic antibiotics have increased potency when cell wall damage has occured giving better intracellular access

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44
Q

How does a gram negative bacteria experience beta lactam induced peptidoglycan cross linkage effects?

A

The peptidoglycan layer to start with is thin, and although if weakened it weakens the cell wall the thicker lipopolysaccharide outer layer remains intact such that the cell doesn’t lyse generally. Internal hydrostatic pressure forces the bacteria to become spherical, in cells with high intracellular osmolality the pressure may be sufficient to lyse.

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45
Q

What is pencillin V

A

Phenoxymethypenicillin

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46
Q

What is pencillin G

A

Benzylpenicillin

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47
Q

How is flucloxacillin different to benzylpenicillin

A

reistsance to beta lactamase in staph

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48
Q

What is an extended spectrum aminopencillin?

A

Ampicillin, amoxicillin

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49
Q

What does pencillin intestinal absorption depend on?

A

whether it is susceptible to acid induced degradation in the stomach (hydrolysis) - if it is then it has reduced oral absorption

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50
Q

Amoxicillin vs ampicillin oral absorption? Why?

A

Amoxicllin has better oral absorption as it is less susceptable to acid induced degredation

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51
Q

Plasma half life of benzylpenicillin

A

30 minutes

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52
Q

Ampicillin plasma half lfie

A

2 hours

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53
Q

Tissue penetration in penicillins

A

Generally good, inflammation necessary for pencillins to pass into bone and through the BBB.

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54
Q

Pencillin excretion

A

Kidneys unchanged 60-90%
Mainly by renal tubular secretion
Bile 10%
20% metabolised

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55
Q

What agent blocks pencillin renal tubular secretion

A

Probenicid

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56
Q

Give an example of beta lactamase inhibitor

A

Tazobactam clavulinic acid

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57
Q

Do beta lactamases have intrinsic antimicrobial activity?

A

clavulanic acid does
Tazobactam does not

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58
Q

Side effects of penicillins

A
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59
Q

Mechanisms of resistance to pencillins come from (3)

A

Inactivation by lactamases
Altered permeability of porins in gram negative bacterial outer membrane
Altered pencillin binding proteins

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60
Q

Cephalosporins differ in structure to penicillins how?

A

Beta lactam ring is fused with a dihydrothiazine ring to produce cephem nucleus

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61
Q

Cephalosporins are more or less sensitive to beta lactamses?

A

Less

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62
Q

As generations of cephalosporins progress describe the changes in antimicrobial coverage

A

Gram positive cover is maintained, gram negative cover improved

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63
Q

MOA of cephalosporins

A

Bactericidal
Disrupt peptidoglycan cell wall integrity
Modified beta alctam ring is more stable making them less susceptable to beta lactamases

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64
Q

Distribution of cephalosporins

A

Widely
Readily cross placenta
Third generation cephalosporins penetrated the CSF especially if meningeal inflammation occurs (10% penetration)

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65
Q

Cephalosporin half lives

A

1-1.5 hours with exception of ceftriaxone which has a half life of 5.5-11 hours (R+D) (8hrs Smith)

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66
Q

Which cephalosporins are excreted unchanged in the urine?

A

Cepradine, cefuroxime, ceftazidime

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67
Q

Cefotaxime is metabolsied how?

A

Liver - 10% acitvity of metabolites compared to parent drug (desacetyl cefotaxime)
50% unchanged in urine

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68
Q

How are cephalosporins generally excreted

A

Urine unchanged, except for ceftriaxone which is 50% metaboised iin the liver
Renal excretion both filtration and tubular secretion
Probenicid increases peak concentration and plasma half life but to a lesser extent than penicillin

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69
Q

Side effects of cephalosporins?

A

Hypersensitivity
GI - C diff, especially third generation
Transient positive coombs test
LFT abnormalities

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70
Q

First generation cepahlosporins - examples + spectrum

A

Cefalexin, cefaclor, cefradine
Gram positive cocci

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71
Q

Second generation cephalosporins e.g. and spectrum

A

Cefuroxime, cefaclor, cefoxitin
Gram positive cocci
Cefuoxime also covers H influenzae

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72
Q

Third generation cephalosporins e.g. and spectrum

A

Cefotaxime, ceftazidime, Ceftriaxone
Broader spectrum, enahanced resistance to beta lactamse
Less potent against gram +
Pseudomonas sensitvie
Cross BBB

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73
Q

4th generation cephalosporins e.g. and spectrum vs 3rd gen

A

Cefepime, cefpirome
Enterobacter and pseudomonas

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74
Q

5th generation cephalosporins e.g. and activity

A

Ceftaroline, ceftobipole
MRSA, VRSA

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75
Q

Amoxicillin chemically is?

A

Aminopenicllin derivitve of ampicillin
(Scarth and smith)

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76
Q

Amoxicillin is available in what preparations?

A

Vials, sachets, capsules, suspension and syrup

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77
Q

Amoxicillin spectrum of acitvity

A

Bactericidal
- Some strains of haemophilus influenzae
- Some strains of E Coli
- Proteus, bordatellla pertussis, neiseria, salmonella, shigella
- Strep and Clostridium (not difficile)

Ineffective against
- Pseudomonas, klebsiella and pencillinase producing organisms
- 90%of Staph are resistance

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78
Q

What effect does adding clavulinic acid have to amoxicillin?

A

Reduces the MIC againt staph aureus, E Coli, H influenza and Klebsiella

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79
Q

AMoxicillin side effects

A

Allergy
GI
Intersisital nephritis
haemopoietic disturbances
Cholestatic jaundice late with clavulanic acid use

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80
Q

Amoxicillin pharmacokinetics

A

Absorption - rapidly absobed, 70-90% bioavailability
Distribution 20% protein bound in plasma, to labumin
Vd 0.3 - 0.4L/kg
Metabolism - 30% by liver
Excretion 250-350 ml/min
Eliminiation half life 60 minutes
40% renal elimination (20-35% unchanged)
Removed by haemodialysis

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81
Q

Clavulinic acid pharmacokinetics

A

Clavulinic acid 60% bioavailability (marked variability)
Clavulinic acid 20% protein bound Vd 0.2L/kg
Clavulanic acid 50-70% hepatically metabolised
Excretion 250-350ml/min
Elimination half life 60 minutes
Removed by haemodialysis

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82
Q

What preparations are cephalosporins available in?

A

1st and 2nd generation - oral and IV
3rd generation IV only

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83
Q

Cefuroxime bioavailability?

A

35-50%

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84
Q

Distribution of cephalosporins - % protein bound
- Cefradine
- Cefotaxime
- Cefuroxime
- Ceftazidime
Widely or narrowly distributed

A

Cefradine - 8-17%
Cefuroxime/cefotaxime 35-50%
Ceftazidime <10%
Ceftriaxone 95%

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85
Q

What % of ceftriaxone is excreted in bile?

A

40%

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86
Q

Cephalosporins vs dialysis

A

They are haemodialysed

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87
Q

Flucloxacillin chemical

A

Semisynthetic isoxazolyl penicillin

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88
Q

Flucloxacillin is acid stable or not?

A

Yes because it has good oral bioavailability

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89
Q

What is fluclox effective against?

A

Staph auerues
Beta haemolytic strep
Pneumococci

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90
Q

Flucloxacillin toxicity and side effects

A

GIT
CNS
Rashes
Glossitis
Jaundice in the critically ill
Pseudomembranous colits

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91
Q

Pharmacokinetics of flucloxacillin

A

Absorption - 50-70% orally absorbed
Distribution - 95% protein bound, Vd 6.8-9.4 L
Metabolism - 8-13% metabolised to active form 5 hydroxy-methyl-flucoxacilin
4% hdyrolused in liver to penicilloic acid which is inactvie, the rest is excreted uncahnged
Excretion - filtration and secretion, 35-75% of dose appear in the urine
Clearance 3ml/min/kg
Elimination half life 45 minutes

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92
Q

Fluclox vs haemodialsyis

A

Not dialysed

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93
Q

Interaction with administration of flucloxacillin - what is it incompatabile with

A

aminoglycosides cause precipitation

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94
Q

Out of the below agents what is Phenoxymethylpenicillin active against?
- Streptpcoccus
- Staphylococcus
- Oral anaerobes
- Enterococcus
- Bacillus
- Clostridium
- Listeria
- Trepnoma palladium
- E Coli
- Pseudomonas
- Bacteriodes

A
  • Streptpcoccus - yes
  • Staphylococcus - variable
  • Oral anaerobes - yes
  • Enterococcus - no
  • Bacillus - yes
  • Clostridium - yes
  • Listeria - yes
  • Trepnoma palladium - yes
  • E Coli - variable
  • Pseudomonas - variable
  • Bacteriodes - variable
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95
Q

Give 2 penicllin binding proteins

A

Transpeptidase
Carboxypeptidase

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96
Q

Side effects of phenoxymethylpenicilin and BenPen

A

Hypernatraemia, hypokalaemia
Allergy
GIT
Haemolytic anaemia
Neuropathy/nephropathy

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97
Q

Phenoxymethylpenicillin and BenPen pharmacokinetics

A

A - 15-30% of oral dose of benpen , unstable under acid. 60% of oral phenoxymethylpenicillin
D - 60% protein bound, albumin. Vd 0.3 - 0.9 L/kg
Metbaolism - penicilloic acid which is inactive, further transformation
Excretion - 60-90% in urine, 25% unchanged, by active tubular secretion
Elimination half life 0.7 hours
Ben Pen is removed by haemodialysis

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98
Q

Piperacillin chemical preparation

A

semi synthetic penicillin

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99
Q

What spectrum does piperacillin cover

A

Gram negatives including - E coli, H influenzae, Klebsiella, neisseria, preoteus, shigella, serratia
Anaerobes including bacteriodes and clostridium
Gram postiive enterooccci stpah and streo
Pseudomonas
Indole positive proteus
Strep faecalis
Serratia

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100
Q

How does piperacillin sodium load and fluid load compare to other penicillins?

A

Lower sodium content
Serum potassium may decrease after administration

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101
Q

Toxicity and side effects of piperacllin

A

GIT
LFTs
Allergic reaction
Transient leucopenia
Transient neutorpenia

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102
Q

Piperacillin pharmacokinetics

A

Absorption - not acid stable, poor absorption, hydrolysed by acids
Distribution - 16% protein bound, Vd 0.32L/kg, hihg concentrations found in most tissues and body fluids
Metabolism - nil
Excretion - 20% in bile, remainder in urine by filtration and tubular secretion
Eliminatino half life 36 - 72 minutes

Dose reduction in renal impairement
30-50% removal by haemodialysis

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103
Q

Carbepenam spectrum of activity

A

Gram positive - not MRSA or enterococcus faecalis
Gram negative aerobic - not stenotrophomonas maltophilia
Anaerobic
ESBL

Do not cover MRSA or E faecalis
If used in isolation cause psuedomonas resisatnce

Imipenam - resistance to Beta lactamse, but only moderately effective against clostridium perfringens. Imipenam induces resisatnce to beta lactam agents in pseudomonas

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104
Q

How does imipenam compare to meropenam in preparation

A

IMipenam is metabolised by renal dehydropeptidsae I so is ocmbined with inhibitor cilastatin Meropenam is not metabolised in this way so not combined with cilastatin

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105
Q

MOA of carbopenams

A

Bind to penicillin binding proteins on the bacterial cytoplkasmic membrane blocking peptidoglycan synthesis and cell wall formation

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106
Q

Side effects and toxicity of carbopenams

A

Hypersiensitivity
Diarrhoea/vomiting
Pseudomomebranous colitis
positive coombs test
Can develop CNS side effects in those with pre-existing CNS disease

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107
Q

Pharmacokinetics of meropenam

A

Absorption - nil orally
Distribution - 12.5-20L
2% bound to plasma proteins
Metabolism - metabolised to inactive metabolite
Excretion - clearance equivalent to creatinine clearance, half life 60 minutes, 70% excreted unchanged in urine

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108
Q

Meropenam vs hepatic dysfunction?

A

Unaffected

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109
Q

Carbepenam effect on other drugs

A

Reduce sodium valproate levls

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110
Q

Which bacteria may have resistance to carbepenams?

A

Klebsiella pneumonia - CPE

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111
Q

What drug belongs to monobactams

A

aztreonam

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112
Q

What spectrum of acitivty does aztreonam have?

A

gram negative aeorbic e.g. enterobacter and speudomonas

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113
Q

Aztreonam methods of adminsitration?

A

nebulised

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114
Q

What are examples of glycopeptide antibiotics?

A

Vancomycin
Teicoplanin

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115
Q

Spectrum of acitivty of Glycopeptides

A

Aerobic and anaerobic gram positive - bacteriocidal (Staph, MRSA, enterococci, C difficile)
Bacteriostatic against enterococci and streptococci
All gram negatives are resistant

Due to large molecular weight and lack of penetratioun through gram negative cell membranes

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116
Q

MOA of glycopeptides

A

inhibit cell wall syntheiss
Large rigid structure binds to peptidoglycan precursers (peptidoglycan pentapeptide) hindering cross linkage and reduces cell wall rigidity - specifically binding to D-alanyl-D-alanine residues
no Competition between penicillins and glycopeptides for active activ peptide binding site

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117
Q

Vancomycin methods of administration

A

Oral
IV
Intrathecal

powder for reconstitution

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118
Q

Vancomycin pharmacokinetics

A

Absorption - no oral bioavailability
Distribution - 0.4-1L/kg, poor CNS penetration even with inflamed meninges, higher levels required for this. 50% protein bound. Widely distributed including in adpiose tissue. CSF level 7-30% of serum concentration in context of meningeal inflammation
Metabolism - very minimial hepatic metabolism
Excretion - 90% excreted unchanged in urine
Half life 6 hours

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119
Q

What factors into peak concentration vancomycin levels? What factors into trough levels?

A

Peak - dose
Trough - dose and interval

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120
Q

Teicoplanin vs vancomycin

A

similar acitvity
Longer duration of action
2-4x potency
Bone and CSF penetration more reliable (CNS penetration less reliable as per Smith)
Increased resistance to teicoplanin

Peck and Hill

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121
Q

Vancomycin side effects

A

Renal - nephrotoxicity 5-14%, usually seen with concurrent aminoglycosides, or with pre-existing renal impairmenet, usually resolves on withdrawal of vancomycin. Risk factors: dose >4g/day, trough levels >15, AUC >800/ 3% require dilaysis
Ototoxicity - discontinue if tinnitis occurs (1% and more seen with long duration and concurrent aminoglycosides
Phlebitis
Histamine release - if administered too rapidly, hypotension tachycardia and a widespread rash
Dose administration should not exceed 10mg/min
Haematological - neutropenia, thrombocytopenia 2% and reversible - more associated with prolonge duse

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122
Q

Teicoplanin side effects

A

Rash
Eosinophilia
Thrombocytopenia
Fever

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123
Q

What factor principally determines the level of bacteriocidal activity of teicoplanin if the bacteria is suceptable?

A

duration fo time where substance level is higher than the MIC

124
Q

Teicoplanin vs haemodialysis

A

not dialysed

125
Q

Teicoplanin toxicity

A

Cross hypersensitivtiy with vancomycin
Cutaneous reactions
LFTs increase
Infusion reactions
Cr increase

126
Q

Teicoplanin kinetics

A

Absorption - nil oral absorption, IM absorption 90%
Distribution - mostly serum albumin bound, 90%
Vd 0.7-1.4L/kg
Distributed mainly in lungs, myocardium, bone
Metabolism - minimal 2 metabolites formed from hydroxylation representating 2-3% of adminsitered dose
Excretion - unchanged in urine 80%, 3% to faeces
Elimintation half life 100-170 hours
Low clearance at 10-4ml/kg/hr

127
Q

Fluoroquinolones are notably actvie against?

A

Aerobic gram negative organisms - pseudomonas rapidly aquires resistance in monotherapy
legionella,. mycoplasma, ricketssia, chlamydia
Neisseria
Anaeorboes

Emerging resistance from E COli, shigella, neisseria gonorrhoea, acinetobacter and pseudomonas

128
Q

How do ciprofloxacin and moxifloxacin compare in spectrum of activity

A

Moxifloaxacin has greater pneumococcal activity

129
Q

MOA of fluoroquinolones?

A

Bactericidal
Block DNA replication by blocking topoisomerase enzymes and DNA gyrase essential for supercoiling, replication and separation of circular bacteria DNA

130
Q

Pharmacokinetics of ciprofloxacin

A

Absorption - readily absorbed 80%, with first pass metabolism occuring
Distribution - widely, protein binding 30-40%, 2-3L/kg Vd, high CSF and tissue penetration
Metabolism - limited hepatic metabolism
Excretion - urine and faeces in unchanged form, active tubular secretion of ciprofloaxicin 500ml/min excretion, half life 3-7 hours

131
Q

Side effects of fluoroquinolones

A

CNS - use with caution in epilepsy, especialy in coexistent use of NSAIDs; anxiety, insomnias and hallucinations
Tendon damage - rupture, especially with concurrent corticosteriods
CV - prolong QT
Haematological - haemolytic especially with G6PD
Photosensitivity
Allergy
Transient LFT elevations
Increased MRSA and C diff

132
Q

Origin of fluoroquinolones

A

nalidixic acid - fluorinated

133
Q

Preparations of ciprofloxacin

A

Oral - tablet and pwoder for suspension
IV
Eye drops
Eye ointment

134
Q

Ciprofloxacin vs haemodialysis

A

25-30% removed

135
Q

Ciprofloxacin vs haemodialysis

A

25-30% removed

136
Q

Rifampicin is active against?

A

Gram positive bacteria
Limited gram negative - legionella, neisseria, H influenza

137
Q

MOA of rifampicin

A

Bactercidal
Binds ot the beta subunit of DNA dependent RNA polymerase preventing DNA transcription into RNA

138
Q

Antibiotics antagonised by rifampicin?

A

ciprofloxacin

139
Q

Rifampicin kintetics

A

Absorption -
Distribution - very lipid soluble, penetrates CNS, abscesses and heart valves
Metabolism - liver mirosomes
Excretion - bile, active transport into bile can become saturated, additional drug then excreted uncahined in the urine imparting red colour

140
Q

Rifampicin interactions primarily via?

A

CYP450 reducing plasma concentrations of anticonvulsants, OCP and warfarin

141
Q

Metronidazole range of activity

A

obligate anaerobes and protozoe e.g. trichomaonas, clostridia, abcteriodes, trepnoma pallidum, campylobacter
Resisatnce in streptococci, lactobacilli

142
Q

Metronidazole MOA

A

passive diffusion entry into cells
Metronidazole is reduced by pyruvate:ferridoxin oxidoreductase system in obligate anaeroboes and the nitro group of reduce metronidazole acts as an electron sink capturing electrons that would usually be transferred to hydrogen ions in the metabolic cycle as a result cytotoxic intermediates accumulate with free radicals inducing DNA strand breakage and cell death

Acts via a reactive intermediate which reacts with bacteria DNA so the resultant DNA complex can no longer function as an effective primer for DNA and RNA polymerases so all nucleic acid synthesis si thus blocked

143
Q

Metronidazole pharmacokinetics

A

Absorption - almost 80-100% bioavailability orally, 75% rectally
Distribution - Widely distributed, CSF, cerebreal absecesses, prostate and pleural fluid
half life 8 hours
10% rpotein bound
Vd 0.75L/kg
Metabolism - completely in liver with active hydroxy metabolite eliminated slowl form the plasma (oxidation and glucuronidation)
Excretion - through kidney - 60% unchanged, does not accumulate in renal failure. Clearance is 1.22 ml/kg/min
Elimination half life is 6-10 hours

144
Q

Metronidazole side effects

A

Nausea
Metallic taste
Not be consumed with alcohol as severe disulfiram like reaction
Prolonged use - peripheral neuropathy, leucopenia

145
Q

What are the 3 sites involved in the formation of an elongating protein chain?

A

Aminoacyl site (A)
Peptidyl (P)
Exit (E)

146
Q

Macrolide antibiotic spectrum of activity

A

Gram positive, some gram negative (esp azithro)
Anaerobes gram positive and negative
Obligate intracellular parasites -mycoplasma and legionella sensitive

147
Q

Which is the parent macrolide

A

erythromycin

148
Q

How is clarithromycin different to erythromycin in its pharmacodynamics

A

Less GI upset

Better coverage for streptococci, listeria and legionella

149
Q

How is azithromycin different in its pharmacodynamics and kinetics to other members of its class

A

Better gram negative cover
e.g. moraxela catarrhalis, neisseria, H influenzae

Improved bioavailabiliy and longer half life than erythromycin

150
Q

Macrolides are bacteriocidal or bacteriostatic?

A

Depends on plasma concentration

151
Q

Macrolide MOA

A

Halt bacterial protein synthesis by binding to 50S ribosomal subunit after formation of the initiation complex - subsequent prevention of peptidyltransferase activity and or movement of tRNA from A to the P site prevents elongation of the peptide chain

152
Q

Macrolide kinetics

A

Absorption - Orally or parenterally; erythromycin 10-60% absorption, clarithromycin 50%, azithromycin 37%
Distribution - CSF penetration poor, sputum and lung penetration good. Vd for erythromycin 0.34 - 1.22L/kg
Azithromycin 0.44 L/kg
12-50% azithromycinbound to plasma proteins
Metabolised - liver - erythromycin –> demethylation, clarithromycin –> 14-hydroxyclarithromycin, azithromycin via hepatic N and O demethylation to inactive metaboliutes
Excretion - Erythromycin and clarithromycin renally, erythromycin half life 1.6 hours, 2-15% unchanged in urine. CLarithromycin non linear, half life 5-6 hours, 33% excreted unchanged
Azithromycin - clearance 10ml/kg/min, 68 hour half life, 12% excreted uncahnged in urine but predominantly excreted in bile

153
Q

Macrolide interactions

A

erythromycin and clarithromycin strong inhibitors of hepatic cytochrome CYP3A4 and p glycoprotein (the transport portein responsible for limiting enteral uptake of many drugs)

Simvastatin, warfarin, methylprednisone, phenytoin, ciclosporin, theophulline, sodium valproate, tacrolimus, midazolam, digoxin and carbamazepine levels are increased

154
Q

macrolide side effecgts

A

GIT - common, prokinetic, avoid erythromycin in porphyria
CV - prolonged QT associated with erythromycin and clarithromycin
Ototoxicity has been reported
Heptic dysfunction
Allergy rare

155
Q

Chemical structure of macrolides

A

Macrocyclic lactone ring to which deoxy sugars are attached

156
Q

Does azithromycin dosing need to be adjusted in dialysis

A

No

157
Q

In what patients should erythromycin not be given

A

prolonged QT
Porphyria
Digoxin toxicity

Caution if on warfarin, antiepileptics. immunosuppressants

158
Q

Metronidazole chemically

A

synthetic imidazole derivitive

159
Q

Metronidazole interactions

A

Increased anticoagulant effect of warfarin
Disulfuram reaction whe alcohol is consumed
Prolongs vecuronium

160
Q

Metronidazole vs dialysis

A

removed by dialysis

161
Q

Aminoglycoside coverage

A

Gram negative aerobes - E Coli, speudomonas, enterobacter, proteus, klebsiella, serratia
Staphylococcus
Strep limited
No anaerobic activity

162
Q

What combination are aminoglycosides sometimes used in

A

With Vanc or Beta lactams it will be synergistic

163
Q

Amikacin vs Gentamicin spectrum of activity

A

Amikacin has less resistance to enzyme inactivation

164
Q

MOA of aminoglycosides

A

bactericidal - concentration dependent killing, post antibiotic effect
Block protein synthesis by irreversibly binding to bacterial 30S ribosome subunit - interfering with tRNA attachment and mRNA is either not transcribed or misread
Large polar molecules need active transport to gain entry into bacterial cells - passive diffusion into cell via porin channels, then oxygen dependent active transport into cytoplasm. Active transport enhanced by cell wall active drugs. Low pH and anaerobic conditions inhibit transport by reducing gradient.
Transport is inhibited by divalent cations calcium, magnesium, acidosis and low oxygen tension

165
Q

What factors interfere with aminoglycoside penetration into a cell

A

Large polar molecules need active transport to gain entry into bacterial cells
Transport is inhibited by divalent cations calcium, magnesium, acidosis and low oxygen tension

166
Q

Pharmacokinetics of Gentamicin

A

Absorption - No significantly absorbed when administrered orally as not lipid soluble, given parenterally only. NOT Inactivated in the GIT
Distribution - Low protein binding for other aminoglycosides (amikacin 20%), but 70-85% for gentamicin, distribute in extracellular fluid and penetrate cells, CSF and sputum poorly. Vd 0.14-0.7 L/kg for gentamicin. Hihg concentrations in the renal cortex
Metabolism - Not metabolised
Excretion - Excreted unchanged in urine by filtration, gentamicin clearance 1.18 - 1.32 ml/kg/min
Half life 2-3 hours with normal renal fucntion, 24-48 hours with severe renal impairment

167
Q

Aminoglycoside side effects

A

Ototoxicity - vestibular and rarely auditory dysfunction occurs when significant amount accumulates in the inner ear perilymph - 1-5% receiving for >5 days. Effects permanent. Risk is increased in renal failure and with simultaneous furosemide use
Nephrotoxcity - 37% of ICU patients, reversible on discontinuing treatment. ATN as accumulates in renal cortex, manifests within a week of Tx, synergistic toxicity with cephalosporins

Both above are associated with high TROUGH concentrations

Muscle weakness - decrease prejunctional release of acetylcholine, reduce post junctional sensitivty to acetylcholine and increase non depolarisng muscle relaxant potency. i.e. avoid in myasthenia gravis

168
Q

Chemical structure of aminoglycosides

A

aminocyclitol ring derivative bound to amino sugars

169
Q

Gentamicin preparations

A

Liquid form for topical use
IV form
IM
Suitable for intrathecal or Intraventricular administrtion

170
Q

Resistance to gentamicin acquired from - mechanisms of resistance

A

plasmid translocation

Transferase enzyme inactviating drug
Impaired entry into cell
Alteration or delation of 30S ribosomal subunit receptor protein

171
Q

Aminoglycoside monitoring - what is the timing of a trough and a peak level

A

Trough - immediately prior
Peak -1 hour post

172
Q

What effect does haemodialysis have on gentamicin and amikacin

A

Both removed - in both haemofiltration and dialysis

173
Q

Effect of aminoglycosides on muscle paralysis

A

Proong non depolarising muscle relaxants by inhibiting pre synaptic acetylcholine release and stabilising the post synaptic membrane at the neuromuscular junction

Can be partially reversed by IV calcium

174
Q

What is an example of a lincosamide

A

clindamycin

175
Q

What is the antimicrobial coverage of clindamycin

A

Gram positive
Anaerobic
very little gram negative aerobic cover

176
Q

Clindamycin MOA

A

inhibits bacterial protein synthesis through disruption of 50s ribosomal subunit
Bacteriostatic or bactercidial depending on concentration and organism
Resistance is inducible in gram postivie organisms - imparts resisatnce to macrolides also

177
Q

Clindamycin side effects

A

Pseudomoembranous colitis and diarrhoea common
Fever
Rash
Eosinophilia

178
Q

Give two examples of tetracyclines

A

,minoclycine, doxycycline

179
Q

Tetracycline MOA

A

INhibiting attachment of tRNA amino acid complex to ribosome inhibiting codon-anticodon interaction

Binds to bacteria 30S ribosome preventing acces to amminoacyl transfer RNA (tRNA) to the mRNA-ribosome complex preventing elongation of polypeptide chain

180
Q

Tetracyclines interactions

A

Chelated by milk, calcium and magnesium

181
Q

Tetracycline contraindications

A

Avoid in renal and hepatic failure
Raised ICP
Increase muscle weakness in myasthenia gravis
Exacerbate SLE - photosensitivty
Deposited in growing teeth and bones so dont use in children
Prengant and lactating women should not receive

182
Q

Fusidic acid active against

A

Staph auerues
MRSA
Staph epidermitis
Strep and pneumococci resistant
Some gram negatives are sensitive but most resistant

183
Q

MOA of fusidic acid

A

Forms a complex with elongation factor and GTP blocking protein translocation and incorporation of amino acid residuals prevenitng protein syntheiss –> cell death

184
Q

Fusidic acid kinetics

A

Well distirbuted, penetrates abscesses well
No active in CSF
Bone penetration si good
Excreted uncahnged in bile, but little active durg in faeces
Minimal renal excretion

185
Q

Fusidic acid side effects

A

GIT
Otherwise well tolerated

186
Q

Tetracycline chemical structure

A

napthacenecarboxamide deriviative

187
Q

tetratcyline preparations

A

tablets
Syrup for IM injection
IV injection with ascorbic acid
Ointment

188
Q

tetracycline spectrum of acitvity

A

Bacteriosttic

Active against gram positive and gram negative
- Clostridium
- Streptococcus
- Neisseria
- Brucella
- Vibrio
- H influenzae
- Yersinia pestis
- Ricketsiae
- Mycoplasma
- Chlamydia
- Leptospira
- Treponoma

189
Q

Tetracycline pharmacokinetics

A

Absorption - incompletely absorbed, chelates with iron, calcium and aluminium. Theoretical bioavailability 77%
Distribution - widely, good tissue penetration,. 65% protein bound, Vd 0.75-1.37 L/kg
Metbaolism - 5% is metabolised to epitetracycline ootherwise unchanged
Excretion - 95% unchanined, 60% in urine via filtration and remainder inf aeces. Clearance 1.5 ml/min/kg
Half life 10-16 hours

190
Q

Tetracyclines in ICU - beware

A

Raised ICP
Increased duration fo action of non depolarising muscle relaxants
Incompatible with many drugs pharmaceutically

191
Q

What antimicrobial agents require no dose adjustment for renal replacement therapy?

A

Ciprofloxacin
Metronidazole
Azole antifungals
Penicillins apart from benzypenicillin (reduced by 30%)
Azithromycin

less commmon
- Rifampicin
Fusidic acid

192
Q

What antimicrobial agents requrie dose decrease for renal replacement therapy?

A

aztreonam, acyclovir,zidovudine

193
Q

What antimicorbial agents require more prolonged dosing intervals in the context of renal replacement therapy?

A

Cephalosporins, teicoplanin, macrolides erythromycin and clarithromycin

194
Q

Both dose and dosing interval require altering for antimicrobial agents in the context of RRT?

A

Meropenam

195
Q

Linezolid is what type of antibiotic and what chemical structure

A

Oxazolidinone

196
Q

Linezolid spectrum of activity

A

Gram postiive organisms - enterococcus, streptococcus, staph, gram postiive anaerobes inclduign clostridium perfingens

197
Q

Linezolid MOA

A

Inhibits bacterial protein synthesis by bidning to 50S binding subunit preventing initiation complex formation

198
Q

Linezolid toxicity and side effects

A

Headache
LFTs
taste alteration
GIT
Fertility reversibly affected
Skina nd bleeding disorders
Phelbitis
pancreatitis

199
Q

Linezolid Pharmacokinetics

A

Absorption - rapidly absorbed after oral administration and has oral bioavailabiltuy close to 100%
Distribution - drug is 31% protein bound, Vd 0.64L/kg
Metabolism - oxidised in liver to inactive carboxylic acid metbaolites
Excretion - 30% unchanged in urine, metabolites in urine and faeces
Eliminationhalf life 5 hours
Clearance 120ml/min

200
Q

Linezolid interactions

A

Reversible non selective MAOI

201
Q

Trimoprim sulfamethoxazole class

A

antifolate antibiotic

202
Q

Bactrim pharmacodyanmics

A

Synergistic combinatino of folate antagonists blocking purine production and nucleaic acid synthesis

Trimethoprim in combination wit sulphonamides becomes bactercidal due to blockade of sequential steps in folate synthesis - sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid, trimtheoprim blocks production of tetrahydrofolic acid

203
Q

Bactrim pharmacokinetics

A

Absorption - PO or IV
5:1 sulphamethoxazole:trimethoprime
Half life 8 hours
Renal clearance - 30-50% sulphonamide and 50-60% of trimethoprim excreted in urine within 24 hours

204
Q

Bactrim spectrum of acitivty

A

Staph aureus
Haemophilus
Moraxella
Klebsiella
Pneumocytstis pneumonia

205
Q

Bactrim side effects

A

GI
Fever, skin rashes - photosensivitiy, rarely SJS
Urinary tract disturbances - can precipitate
haematological - haemolytic or asplatic anaemia, thrombocytopenia (with diuretics)
Warfarin increases INR
CNS effects

206
Q

Bactrim contraindications

A

Hypersensitivty
Blood dyscrasia
Marked renal or hepatic impairment
Megaloblastic bone marrow

207
Q

What does this graph mean?

A

Concentration time curve describiong the relationship between antibiotic concentration and their killing power

Anitbiotic which kill over time are those which kill according to time spent over MIC

Antibiotics which kill be concentration kill according to the highest peak

208
Q

What does this graph mean?

A

Concentration time curve describiong the relationship between antibiotic concentration and their killing power

Anitbiotic which kill over time are those which kill according to time spent over MIC

Antibiotics which kill be concentration kill according to the highest peak

Some kill by both

209
Q

What are time or MIC dependent killing antibiotics?

A

Beta lactams
Carbepenams
Monobactams
Linezolid
Clindamycin
Macrolides

210
Q

Concentration dependent killing antibiotics include?

A

Aminoglycosides
Metronidazole
Daptomycin
Fluoroquinolones

211
Q

Combination of AUC and MIC dependent killing antibiotics are

A

Fluoroquinolones, azithromycin, tetracyclines, vancomycin, tigecycline, linezolid

212
Q

Time dependent killing -pathophysiological mechanism for having this characteristic

A
  • Those which kill bacteria most effectively at some specific event e.g. when about to divide
  • Those which do not have much post antibiotic effect i.e. the kill characteristic only occurs when the drug concentration remains high
213
Q

For what proportion of the duration of treatment does concentration need to be above MIC for drugs with concentration dependent kill characteristics to be functional?

A

Cephalosporins even with 40-50% of dosing interval above MIC killing efficacy close to maximal and cephalosporins have the hgihest requirement for time above MIC - beta lactams the next most frequency and carbepenams less (30% with early kill characterstics)

214
Q

When might the proportion of the duration of treatment above MIC be greater than conventionally required?

A

Areas of poor penetration e.g osteomyelitis, CNS ifnection

215
Q

Concentration dependent killing mechanism

A

Is a property of antibiotics which disable some sort of crucial steps in bacterial metabolism or protein synthesis - the higher the concentration reach the more synthetic enzyme molecules are inhibited e.g. aminoglycosides, metronidazole, daptomycin

216
Q

What level above MIC does gentamicin need to reach to have ~90% of potential effect?

A

8-10x MIC at peak levels

217
Q

AMinoglycoside killing is somewhat unique - describe why

A

Initially related to passive ionic binding of the drug to the bacterial lipopolysaccharide coat but later becomes more reliant on active uptake into the bacterial cell. Being exposed to aminoglycosides causes bacteria to downregulate this uptake and thus the first exposure to the drug increases subsequent MIC. The forst dose better be the bigger one as it will carry out the bulk of the killing. Once daily dosing allows enough time for this effect to dissapate somewhat between doses

218
Q

Which drug mechanisms exaplin time and concentration dependent killing both being a factor?

A

Inhibits steps in DNA synthesis or replication, or components crucial for cellular division

Time is important because inhibited enzymes are most active durnig division and therefore time immersed in the drug is necessary to catch a large portion of the bacteria attempting this

Concentrationsi important to disable more of target cell components

219
Q

Organisms intrinsically resistant to meropenam

A

Stenotrophomonas maltophila
Pseudomonas cepacia
Enterococcus faecium
MRSA

220
Q

List of organisms intrinsiically resistant to glycopeptides

A

Lactobacillis casei
Pediococcus pentosaceus
Leuconostoc mesenteriods

221
Q

What is the post antibiotic effect?

A

Persistent of effect long after serum concentration has fallen below MIC

222
Q

Which antibiotics are seen to have a post antibiotic effect?

A

Inhibit some life sustaining enzyme or bind tightly to cell wall components

Usually concentration dependent kill characteristics

223
Q

What drugs have a strong post antibiotic effect?

A

Aminoglycosides
Clindamycin
Macrolide antibiotics
Tetracyclines
Rifampicin
Quinupristin/dalfopristin

224
Q

Examples of moderate post antibiotic effect

A

Carbapenems
Fluoroquinolones
Glycopeptides
Linezolid

225
Q

Pharmacokinetics in critical illness are effected how

A

Factors which decrease the antibiotic peak dose:
- Poor gut absorption
- Increased volume of distribution - fluid overloaded
- Poor penetration to the site of action - ischaemic gut, oedamatous lung, poor tissue perfusion

Factors which increase the antibiotic peak dose:
- Decreased protein binding - increased fraction unbound
- Diminished clearance mechanisms
- Improved penetration into inflamed tissues (eg. meningitis)

Factors which increase the antibiotic half-life
- Decreased renal clearance
- Decreased hepatic clearance - blood flow diminished in shock and synthetic function may be poor if liver injury
- Decreased overall metabolism (eg. hypothermia)

Factors which decrease the antibiotic half-life
- Renal replacement therapy - e.g. fluconazole it totally removes
-Increased hepatic clearance, eg. enzymes induced by drug interactions; hyperdynamic circulation
- Increased glomerular filtration if hyperdynamic
- Hypermetabolic state

226
Q

Factors in critical illness decreasing antibiotic peak dose

A

Factors which decrease the antibiotic peak dose:
- Poor gut absorption
- Increased volume of distribution - fluid overloaded
- Poor penetration to the site of action - ischaemic gut, oedamatous lung, poor tissue perfusion

227
Q

Factors in critical illness increasing antibiotic peak dose

A

Factors which increase the antibiotic peak dose:
- Decreased protein binding - increased fraction unbound
- Diminished clearance mechanisms
- Improved penetration into inflamed tissues (eg. meningitis)

228
Q

Factors in critical illness prolonging half life

A
  • Decreased renal clearance
  • Decreased hepatic clearance - blood flow diminished in shock and synthetic function may be poor if liver injury
  • Decreased overall metabolism (eg. hypothermia)
229
Q

Factors which decrease half life in critical illness

A

Factors which decrease the antibiotic half-life
- Renal replacement therapy - e.g. fluconazole it totally removes
-Increased hepatic clearance, eg. enzymes induced by drug interactions; hyperdynamic circulation
- Increased glomerular filtration if hyperdynamic
- Hypermetabolic state

230
Q

How does pharmacodynamics differ inc ritical illness

A

Enhanced organ toxicity
Antibiotic toxicity will increase not only because clearance might be impaired, but because the organs themselves are likely damaged, and are therefore relatively defenceless. Toxicity may develop at drug levels which might otherwise be viewed as safe. Examples of this may include:

Increased nephrotoxicity from aminoglycosides, if the renal function is already impaired
Increased cardiotoxicity from bleomycin and vancomycin
Increased risk of QT prolongation and arrhythmia with fluoroquinolones in the context of cardiac ischaemia, profound hypothermia, or extreme electrolyte derangement
Increased bone marrow toxicity from linezolid, cotrimoxazole, gancyclovir, chloramphenicol, beta-lactams of all sorts…
With a disrupted blood-brain barrier, an increased risk of seizures from high-dose beta-lactams, due to enhanced penetration.
Worsening shock due to dapsone-induced methaemoglobinaemia and thus diminished oxygen-carrying capacity.

231
Q

What is MIC

A

MIC is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation.

The results are usually reported as µg/mL.

232
Q

WHy is MIC a good measure of antimicrobial susceptability

A

Easily performed
Frequently, an automated method is available
Simplicity and automation of the test enhances reproducibility
Rapid return of results

233
Q

Why si MIC not an optimal measure of antimicrobial susceptability

A

Minor variations in methodology can result in large variations of the MIC.
For example, extended incubation will make the MIC appear higher
Lower inoculum concentrations will make the MIC appear lower
Interlaboratory variation in technique makes comparison problematic
MIC is inhibition of visible growth: the microorganisms weren’t necessarily killed!
MIC may not be related to in vivo efficacy, which is a complex parameter determined by numerous factors among which the MIC is only one. An antibiotic with a low MIC may have no effect if it does not penetrate into the infected tissue. An antibiotic with a high MIC will still be effective if it happens to be concentrated in the infected tissue (eg. gentamicin in urine).

234
Q

Which aminoglycoside has the least antibiotic resisatnce?

A

Tobramycin is marginally more active than gentamicin against P. aeruginosa, but not against other aerobic Gram-negative bacteria. It is inactivated by a similar range of bacterial enzymes as gentamicin.

Amikacin is more resistant to bacterial enzymatic inactivation than gentamicin or tobramycin, so it should generally be reserved for treating infections resistant to other aminoglycosides.

Kanamycin, along with amikacin, has largely replaced streptomycin in the treatment of resistant mycobacterial infections, because of higher rates of susceptibility and better availability. However, kanamycin is inferior to other aminoglycosides against aerobic Gram-negative bacteria. Capreomycin has also been used for multidrug-resistant tuberculosis.

235
Q

Wide spread use of carbepenams is linked to icnreasing prevalence of which infections?

A

However, widespread use of carbapenems is linked to an increasing prevalence of infections caused by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multidrug-resistant Gram-negative bacteria and Clostridioides difficile (formerly known as Clostridium difficile). Furthermore, carbapenem resistance is emerging worldwide

236
Q

Is meropenam active against extended spectrum beta lactamase enzymes?

A

Yes

237
Q

Carbopenams vs enterocccus?

A

Imipenem has activity against Enterococcus faecalis, which meropenem lacks.

238
Q

Imipenam is inactivated if given without an additional agent - what is it

A

Imipenem is formulated in combination with the renal dipeptidase enzyme inhibitor, cilastatin, to prevent inactivation.

239
Q

Meropenam vs CNS pentration? side effect of same?

A

High-dose meropenem achieves adequate concentrations in the cerebrospinal fluid and has a lower incidence of seizures than imipenem.

240
Q

Carbepenam spectrum of acitvity

A

Imipenem and meropenem have broad activity against Enterobacteriaceae (enteric Gram-negative bacilli), including isolates that produce extended-spectrum beta-lactamase enzymes (ESBLs), and Pseudomonas aeruginosa; this activity is comparable to that of aminoglycosides. They also have excellent activity against anaerobic Gram-negative bacteria (including Bacteroides fragilis), and many Gram-positive bacteria (including Nocardia species). Imipenem has activity against Enterococcus faecalis, which meropenem lacks.

241
Q

What are carbepenams not active against?

A

Carbapenems are inactive against MRSA, VRE, Enterococcus faecium, Mycoplasma species, Chlamydia species and Stenotrophomonas maltophilia.

242
Q

Narrow spectrum cephalosporin spectrum of acitivty

A

In terms of Gram-positive activity, they are active against streptococci and staphylococci, including beta-lactamase–producing (penicillin-resistant) staphylococci, but inactive against methicillin-resistant Staphylococcus aureus (MRSA), enterococci and Listeria monocytogenes. They are active against a narrow range of aerobic Gram-negative bacteria, including wild-type Escherichia coli and some Klebsiella species, but have no activity against anaerobic Gram-negative bacteria, including Bacteroides fragilis.

243
Q

Why is cefuroxime used for respiratory infections and not cephalexin?

A

For oral treatment of respiratory tract infections, cefuroxime is preferred to cefalexin because of its superior activity against S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis.

244
Q

What is an enterobacteriaceae

A

Enteric gram negative bacilli

245
Q

How do ceftriaxone and cefotaxime compare in their spectrum of acitvity to cephalexin

A

Activity against majority of community associated enterobacteriaceae
No active against pseudonomas
Less active against staphyloccci than cefazolin
Inactive against MRSA
Cefotax > ceftriaxone for staph but for both is dose depednent
Nil enteroccocus acitvity
Serratia, citrobacter and enterobacter have chromosomal resiatnce and ESBL inactive them

246
Q

Why is ceftriaxone bad in neonates

A

Highly protein bound
Kicks bilirubin off albumin increasing the risk of kernicterus

247
Q

What does ceftriaxone precipitate with

A

calcium

248
Q

How is ceftazidime different to ceftriaxone

A

Extended spectrum including pseudomonal activity
Both inactivated by ESBL

249
Q

How is cefepime different to ceftriaxone?

A

Extended spectrum including pseudomonal activity
Both inactivated by ESBL
Cefepime is bettyer for gram positive than ceftazidime

250
Q

Ceftaroline is special why?

A

Acts against MRSA

251
Q

Phenoxymethypenicillin absorption is blocked by?

A

Food

252
Q

Phenoxymethypenicillin vs benpen

A

Less intrinsically active
Same spectrum

253
Q

Absorption of flucloxacillin characteristics

A

Food impairs the absorption of of dicloxacillin and flucloxacillin. Ideally, they should be dosed at 6-hourly intervals, but for practical purposes (eg in children) four-times-daily dosing, evenly spaced during waking hours, is often used.

254
Q

FLucloxacillin side effect

A

Cholestatic jaundice, more likely if old or polonged use . Can occur as long as 6 weeks after

255
Q

Dicloxacillin side effects vs flucloxacillin

A

Less cholestatic jaundice - less irreversible hepatotoxicity
More interstitial nephriits

256
Q

Why is amoxicillin used instead of Phenoxymethylpenicillin for strep pneumonia infections and respiratory infections

A

Orally - Longer half life so longer time above MIC and reduced faily dosing

257
Q

Amoxicillin vs ampicillin

A

Same spectrum of acitivty, same pharmacodynamics

Orally has a better absorption, less affected by food

IV they are equivalent

258
Q

Which organisms primarily contain the beta lactamase that tazobactam and clavulinic acid impair?

A

Staphylococcus aureus, Bacteroides fragilis and Haemophilus influenzae, and some of the beta-lactamase enzymes produced by Escherichia coli and Klebsiella species.

259
Q

If treating pseudonomas with tazosin what specifically must be done?

A

6 hourly dosing

260
Q

Daptomycin spectrum of acitivity

A

Daptomycin is only active against Gram-positive bacteria, including most strains of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). It has a similar spectrum of activity to the glycopeptides.

261
Q

Which organ system does daptomycin have poor penentration into?

A

Lungs - inactvativated by pulmonary surfactant

262
Q

Side effect daptomycin

A

Myopathy is an adverse effect of daptomycin. In patients treated with daptomycin, measure plasma creatine kinase concentration at least once weekly, or more frequently if the patient has renal impairment (creatinine clearance less than 30 mL/minute) or is receiving concomitant drugs associated with myopathy (eg statins).

263
Q

Why is trimethoprim not used in neonates?

A

Avoid trimethoprim+sulfamethoxazole in neonates (up to 1 month old) because of the risk of kernicterus (precipitated by the displacement of bilirubin from albumin by sulfonamides).

264
Q

How does trimethoprim affect the kidneys

A

Trimethoprim inhibits tubular secretion of creatinine, which can elevate serum creatinine without any true decrease in glomerular filtration rate. Trimethoprim also inhibits tubular excretion of potassium and can cause hyperkalaemia. Monitor serum potassium after 3 days of treatment with trimethoprim in patients at increased risk of hyperkalaemia (eg patients with renal impairment, patients who are taking a high dose of trimethoprim or other drugs that can cause hyperkalaemia).

265
Q

Vancomycin vs C difficile

A

Oral vancomycin is used to treat Clostridioides difficile infection. In patients with severe disease, particularly in the presence of ileus, vancomycin can be given as a retention enema in addition to oral therapy. Intravenous vancomycin is not effective against C. difficile infection because of inadequate penetration of the drug into the lumen of the colon.

266
Q

Linezolid spectrum of acitivty

A

Linezolid is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci, vancomycin-resistant enterococci (VRE), and penicillin-resistant strains of Streptococcus pneumoniae

267
Q

Side effect linezolid

A

Bone marrow suppression and peripheral neuropathy can occur in patients taking linezolid for longer than 14 days, so haematological and neurological monitoring is required. A protocol for monitoring patients for linezolid toxicity has been proposed [Note 2].

Linezolid is a weak monoamine oxidase inhibitor, so it significantly interacts with some foods and drugs. Consult an appropriate resource on drug interactions if starting or stopping linezolid in patients taking other drugs.

268
Q

Macrolide spectrum of acitivity

A

The macrolides, azithromycin, clarithromycin, erythromycin and roxithromycin, have a broad spectrum of activity, including activity against Gram-positive cocci, Corynebacterium species, Gram-negative cocci, and Legionella, Mycoplasma and Chlamydia species, as well as some Gram-positive and Gram-negative anaerobic bacteria. Erythromycin, azithromycin and clarithromycin are also active against Bordetella pertussis.

269
Q

What is different about the spectrum of acitivty of clarithromycin to its other macrolides

A

Unlike other macrolides, clarithromycin has a microbiologically active metabolite. Clarithromycin is active against nontuberculous mycobacteria, including Mycobacterium avium complex (MAC), and is used in combination with other drugs for this indication. It is also used in combination with other drugs for eradication of Helicobacter pylori.

270
Q

How is azithromycin different in its activity to erythrmoycin

A

Azithromycin is less active than erythromycin against Gram-positive bacteria, but has a broader range of Gram-negative activity (eg Salmonella species). Azithromycin is also active against nontuberculous mycobacteria (including MAC), Rickettsia species and some parasites (eg Toxoplasma gondii).

271
Q

Metronidazole spectrum of acitvity

A

The nitroimidazoles, metronidazole and tinidazole [Note 3], have activity against almost all Gram-negative anaerobic bacteria (eg Bacteroides fragilis) and most Gram-positive anaerobic bacteria (eg Clostridium species, but not Cutibacterium acnes [formerly Propionibacterium acnes]). It is also active against protozoa, including Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Helicobacter pylori resistance to metronidazole is common in Australia (about 50% of H. pylori infections, reflecting high community exposure to nitroimidazole drugs).

272
Q

Which bugs are resistant to quinolones?

A

Resistance to quinolones is now widespread, particularly in Enterobacteriaceae (enteric Gram-negative bacilli), Pseudomonas aeruginosa, Campylobacter species and Neisseria gonorrhoeae.

273
Q

Ciprofloxacin spectrum of activity

A

Ciprofloxacin has a broad spectrum of activity, which includes activity against aerobic Gram-negative bacteria (including Haemophilus influenzae, Enterobacteriaceae [enteric Gram-negative bacilli], P. aeruginosa and Gram-negative cocci) and some aerobic Gram-positive cocci. It is also active against intracellular bacteria, including Legionella species and some mycobacteria. Ciprofloxacin has poor activity against anaerobic bacteria and streptococci.

274
Q

Moxifloxacin spectrum of activity

A

Moxifloxacin, an extended-spectrum quinolone, has increased activity against Gram-positive aerobic bacteria (including staphylococci and streptococci) compared to ciprofloxacin. Susceptibility among strains of methicillin-resistant Staphylococcus aureus (MRSA) is variable. Moxifloxacin is active against many Gram-negative aerobic bacteria, but has poor activity against P. aeruginosa. Moxifloxacin has good activity against anaerobic bacteria and most atypical bacteria that cause pneumonia. It is also used for the management of some mycobacterial infections.

275
Q

Norfloxacin spectrum indications

A

Multidrug resistant cystitis and acute ifnectious diarrhoea

276
Q

Why are fluoroquinolones not used in children

A

adverse ffect in cartilage development based on animal studies - if required can be used

277
Q

What is the theory behind using combination therapy in enndocarditis or enterococcal infections?

A

Synergistic action of cell wall active drugs and aminoglycosides
- Higher rates of cure
- Shorter duration

278
Q

What are the 3 groups of patients in whom aminoglycosdies are contraindicated?

A

Toxicity previously - vestibular or auditory
Hypersensitivty (rare)
Myasthenia gravis

279
Q

Why can aminoglycosides be used at dosing so much less frequent than their half life would suggest?

A

Post antibiotic effect

280
Q

Do aminoglycosides cause C diff?

A

No

281
Q

Which infections are aminoglycosides synergstic with cell wall active drugs?

A

Enterococcal
Streptococcal

282
Q

Is nephrotoxicity from aminoglycosids reversible?

A

Generally yes

283
Q

Over what duration can gentamicin be infused?

A

3-5 minutes slow IV injection safe

284
Q

What weight should be used for gentamicin?

A

The appropriate aminoglycoside dosage is determined by the patient’s weight and kidney function. Adjusted body weight is used for children who are obese and adults who are obese class I (BMI 30 to 34.9 kg/m2). Expert advice is required for adults who are obese class II or III (BMI 35 kg/m2 or more).

Generally lean body weight is ideal due to dosage being dependent on renal clearance and Vd

285
Q

Gentamicin dose for critically ill patients if their renal function is
- CrCl >60
- CrCl 40-60
- CrCl <40

A

> 60 = 7mg/kg 24 hourly
40-60 5mg/kg 36 hourly
<40 is 4mg/kg single dose

286
Q

Gentamicin dosing for a patient who is 6’8 and 110kg - what factors to consider

A

NB4: If actual body weight (for patients who are not obese) or adjusted body weight (for patients who are obese) is greater than 100 kg, use a weight of 100 kg to calculate the dose.

287
Q

In what situations is aminoglycoside plasma concentration monitoring required?

A

when treatment is expected to continue for >48 hours - if so commence from the first dose

288
Q

How often does gentamicin concentration monitoring need to be performed?

A

48 hourly

289
Q

How to monitor aminoglycoside drug concentrations

A

Once daily dosing - clinical efficiacy related to AUC< toxicity minimised by undetectable trough plasma concentration. MIC is required for AUC calculations

Timing of tetsing - 30 minutes after infusion completed, 6-8hrs after the dose

290
Q

Nephrotoxicity risk in aminoglycoside use is found in which dosing regimen?

A

ANything >1 dose per day increases the risk
Prolonged Tx >5 days

291
Q

WHat predicts aminoglycoside vestibular and auditory toxicity?

A

Not predicted by p;lasma concentration
Can occur early or weeks after

292
Q

What symptoms are most commonly seen in aminoglycoside vestibular toxicity

A

Gait ataxia/imbalance
Oscillopsia - bouncing vision
Blurring vision with ehad movement
Hearing loss

293
Q

Is there any benefit proven to 7mg/kg over 5mg/kg for gentamicin?

A

No
Pharmacologically it makes sense
7mg/kg may have benefit for pathogens with a high MIC e.g. pseudomonas
However there is no published study showing clinical advantage

294
Q

How fast can you infuse vancomycin?
How long might a 1g dose take?
1.5g?

A

10mg/min

1g dose takes 1 hour
1.5g 90minutes

295
Q

What type of reaction is red man syndrome?

A

Histmaine mediated non allergic reaction

296
Q

Loading dose physiology for vancomycin?

A

Loading dose achieves therapeutic concentration more quickly b 12 hours - no evidence it improves clinical or microbiological outcomes

297
Q

Vancomycin weight based dosing is based on which weight?

A

actual body weight

298
Q

AUC for vancomycin dosing has what advantages?

A

Similar rates of clincial success
Reduced nephrotoxicity
Lower daily doses
Lower trough concentrations

299
Q

Vancomycin nephrotoxicity is predicted by?

A

Higher daily doses realtive to kidney function
High trough concentration
Prolonged therapy
Co-committant nephrotoxins (Tazosin concurrent therapy 3-4x risk)
Vasopressors

300
Q

Cefepime Vd

A

0.2L/kg

301
Q

Cefepime clearance

A

85% renal unchanged

302
Q

Clindamycin pharmacokinetics

A

Rapid absorption
90% bioavailable
Food does not affect absorption
Does not penetrate CSF but widely distributed
Oxidised by CYP3A4 wtih 10% unchanged in urine, 5% in faeces and the rest as metabolites

303
Q

Bactrim pharmacokinetics

A

Absorption 100%- PO or IV

Vd 1.6L/kg + PPB 40% for trimethoprim, 0.3L/kg and 50% PPB for sulfamethoxazole.
Trimethorpim 30% metabolism in CYP450, some metabolites active. Sulfamethox 80% liver metabolism
Renal clearance - 30-50% sulphonamide and 50-60% of trimethoprim excreted in urine within 24 hours. Filtration + secretion

304
Q

MOA of atrazoenam

A

The bactericidal action of aztreonam results from the inhibition of bacterial cell wall synthesis due to its binding to Penicillin Binding Protein 3 (PBP3). Aztreonam is resistant to hydrolysis by many beta-lactamases (i.e. penicillinases and cephalosporinases) produced by gram-negative and gram-positive pathogens

305
Q

Aztreonam side effects

A

Generally well tolerated

306
Q

Aztreonam pharmacokinetics

A

Nil absorption
50% protein bound
Minimally metabolised

307
Q
A

Primary Pharmacology (11 decks)

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