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ED Primary Exam > Week 9 Pharmacology - Antibiotics > Flashcards

Week 9 Pharmacology - Antibiotics Flashcards

1
Q

ADME of penicillins?

A

A: Dicloxacillin, ampicillin, amoxicillin are acid stable, well absorbed orally, but absorption impaired by presence of food, take 1-2 hours post
D: Equal to serum, but poor penetrance of eyes, CNS, prostate
M: Penicillin, t1/2 30min, Ampicillin T1/2 1 hr
E: 90% renal excretion

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2
Q

Adverse reactions of penicillins?

A

Anaphlaxis/allergy/rash, serum sickness, interstitial nephritis, seizures (in high doses)

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3
Q

What is the fundamental structure of a penicillin?

A

Thiazolidine ring attached to beta-lactam ring

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4
Q

What is the impact of beta-lactamase?

A

Hydrolysis of the beta lactic ring yields peniclloic acid, which lacks antibacterial activity

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5
Q

What are the 3 different classifications of penicillins?

A

Penicillins
Anti-staphylococcal penicillins
Extended spectrum penicillins

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6
Q

What are examples of (standard) penicillins?

A

Penicillin G, phenoxymethylpenicillin

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7
Q

What are the organisms that are covered by penicillins?

A

GRAM +VE organisms, including some gram negative cocci, non beta lactase anaerobes

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8
Q

What are examples of anti-staphylococcal penicillins and the organism/s they cover?

A

Flucloxacillin, dicloxacillin, nafcillin
Indicated for beta lactamase producing staphylococcal
Active against staph and strep, but not anaerobes, enterococci, gram -ve cocci/rods

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9
Q

What are examples of extended spectrum penicillins and the organism/s they cover?

A

Ampicillin, Amoxicillin, anti-pseudomonas penicillins
Coverage is the same as for penicillins, but improved activity against gram negative rods

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10
Q

What is the mechanism of action of penicillins?

A

Inhibit bacterial cell wall synthesis. “Penicillin binding protein” is part of bacteria’s cell wall synthetic process, which trims the terminal alanine and allows for cross linking of peptides. The beta-lactam component binds to the active site of PBP and inhibits this reaction, causing cell death

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11
Q

What are the mechanisms of resistance to penicillin antibiotics?

A
  1. Inactivation due to beta-lactamase
  2. Modification of Penicillin Binding Proteins (methicillin resistance)
  3. Impaired penetration of drug into bacteria (as in gram -ve species due to outer membrane of cell wall)
  4. Antibiotic efflux
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12
Q

What is extended spectrum beta-lactamase? (ESBL)

A

Having beta lactamase activity against most classes of antibiotics (i.e. Staph aureus, Haemophilus influenza both have narrow spectrum beta lactamase which prefers penicillins to cephalosporins) Whereas pseudomonas has extended spectrum activity against multiple agents.

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13
Q

Which are more stable to beta lactamase? Penicillins or cephalosporins?

A

Cephalosporins

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14
Q

What are examples of first generation cephalosporins? What organisms are they active against?

A

Cephazolin, cephalexin

Gram +ve cover (staph and strep), anaerobic cocci, E. coli, K. pneumonia, Proteus mirabilus

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15
Q

What do organisms do cephazolin and cephalexin have no coverage of?

A

Enterococcus, pseudomonas

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16
Q

What are common indications for cephalexin?

A

Staph and strep infections, UTI,l

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17
Q

What is the major route of elimination for cephalosporins and what is the most notable exception to this?

A

Largely renal excretion, except for Ceftriaxone, which is excreted largely from biliary tract

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18
Q

What are examples of second generation cephalosporins?

A

Cefaclor, cefuroxime, cefoxitin, cefprozil

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19
Q

What is the main additional cover provided by second generation cephalosporins?

A

Extended gram -ve cover, including klebsiella species.

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20
Q

What are examples of third generation cephalosporins?

A

Ceftriaxone, cefotaxime, ceftazidime

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21
Q

What additional cover/indications are provided by third generation cephalosporins?

A

Further gram -ve coverage
Does offer some ability cross BBB

**Ceftazidime only agent which offers some pseuodomonal activity

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22
Q

What is the main example of 4th Generation cephalosporins? What advantage does it offer?

A

Cefepime - more resistant to beta lactamases produced by enterobacter, very broad spectrum –> has activity against pseudomonas, enterobacteraceae, MRSA, good CNS penetration

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23
Q

What are common adverse effects of cephalosporins?

A

Hypersensitivity, interstitial nephritis, granulocytopaenia, haemolytic anaemia

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24
Q

What are the main categories of b-lactamase drugs?

A

Monobactams
B-lactamase inhibitors
Carbapenems

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25
Q

Example of monobactam, and uses?

A

Aztreonam, stable against most beta-lactamases
Narrow spectrum of activity, limited to aerobic gram -ve, with no gram +ve cover or anaerobes

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26
Q

Examples of B-lactamase inhibitors?

A

Clavulanic acid
Sulbactam
Tazobactam

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27
Q

What organisms are B-lactamase inhibitors effective against?

A

H. influenzae
N. gonorrhoea
Salmonella species
E. coli
K. pneumonia
Staphylococci
Pseudomonas

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28
Q

What are classes of b-lactams (produced by bacteria)

A

Ambler Class A (plasma encoded), B, C (chromosomal encoding, is Pseudomonas)

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29
Q

What are examples of carbapenems?

A

Meropenem
Imipenem
Ertapenem

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30
Q

What is the coverage of carbapenems?

A

Gram -ve rods (including pseudomonas)
Gram +ve
Anaerobes
Resistant to most b-lactamases

Mainly used where organisms proven resistant to other more narrow spectrum agents

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31
Q

What is the metabolism/excretion of carbapenems?

A

Generally renally excreted, with exception of Irtepenem, which is metabolised by di-peptidases in the renal tubules

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32
Q

What is the major consideration of giving carbapenems to patients with epilepsy?

A

Induces metabolism of valproate, decreased plasma levels by 90% –> risk of inducing seizures

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33
Q

How does Vancomycin exert its antibiotic effect?

A

Inhibits cell wall synthesis by binding to D-alanine –> D-alanine terminus of the peptidoglycan units, inhibits formation of glycosidic bonds (via transglycosylase) and prevents cross linking of peptidoglycans

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34
Q

What is the cover/spectrum of vancomycin?

A

Active against gram +ve only
C.difficile, enterococcus, staph, listeria, bacillus

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35
Q

What is the pharmacokinetics of vancomycin?

A

A: Poor oral absorption, T1/2 6-10 hours
D: High VD, including adipose and CSF
M: -
E: 90% Glomerular filtration

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36
Q

What are the indications for vancomycin?

A

Sepsis, Endocarditis (suspected/proven MRSA), c.diff colitis

37
Q

What are the important adverse reactions to vancomycin?

A

Ototoxicity
Nephrotoxicity
“Red man” syndrome

38
Q

What is the mechanism of action of fosfomycin?

A

Inhibits early stage of cell wall synthesis, good gram +ve and gram -ve cover

39
Q

What is the major indication for fosfomycin and why?

A

Good urine penetrance, therefore UTI treatment if known resistance to first line agents

40
Q

What is the mechanism of gentamicin? What is it’s spectrum of cover?

A

Bactericidal inhibitor of protein synthesis - interferes with ribosomal function of bacteria.

Binds to 30S subunit of ribosomal proteins –> misreading, breaks up polysomes, interferes with initiation complex

Primarily gram -ve aerobic, E. coli, Staphylococcus aureus, Enterobacter, Klebsiella, Serratia, Pseudomonas aeruginosa, and other gram negative bacteria, as well as S. aureus, but no activity against anaerobes

41
Q

What are the pharmacokinetics of gentamicin?

A

A: Poor GIT, t1/2 2-3 hours
D: Highly polar, doesn’t penetrate cells well, low in most tissues except renal cortex
M: exhibits concentration dependent killing, post-antibiotic effect
E: Renal excretion

42
Q

What organisms are gentamicin/aminoglycosides indicated for?

A

Gram -ve organisms: Pseudomonas, enterobacter, proteus, klebsiella

Treatment of sepsis, particularly urine source

43
Q

What is the prototype tetracycline, and what is its mechanism of action?

A

Doxycycline
Broad spectrum bacteriostatic agent that inhibits protein synthesis via binding to 30S subunit of Ribosomal subunit, prevents addition of amino acids to growing peptides

44
Q

Describe pharmacokinetics of doxycycline

A

A: 95-100% oral absorption, impaired by alkaline pH, t1/2 16-18 hours
D: Widely distributed, not to CSF
M: p450, shortened by co-administration with carbamazepine, phenytoin, barbiturates
E: Bile 50%, Urine 50% –> doesn’t accumulate in renal failure

45
Q

What are adverse effects of doxycycline?

A

GIT upset, oesophageal ulceration, liver toxicity, photosensitivity, cholestatic jaundice, growing bone + teeth effects (contraindicated in <8 years old)

46
Q

What is the “unique” thing about doxycycline?

A

It is active against human malaria parasites, and is standard chemoprophylaxis for it

47
Q

What are examples of macrolides?

A

Erythromycin (prototype drug)
Azithromycin
Clarithromycin

48
Q

What is the mechanism of macrolides?

A

Inhibition of bacterial protein synthesis by binding 50s ribosomal subunit. (Erythromycin also inhibits formation of the 50s subunit)

49
Q

What are mechanisms of bacterial resistance to macrolides?

A

Reduced permeability to drug in cell membrane
Enzymatic breakdown
Modification of ribosomal binding sites

50
Q

What are the pharmacokinetics of erythromycin?

A

A: food interferes with absorption, destroyed by stomach acid, requires enteric coating, t1/2 1.5 hrs
D: Widely, except brain/CSF, does cross placenta
E: 95% bile, 5% renal

51
Q

What are indications for erythromycin?

A

Chlamydial infections (resp, ocular, genital)
Corynebacterium (diphtheria)

52
Q

What is the common examples of sulfonamides?

A

Sulfamethoxazole, sulfasalazine

53
Q

What is the mechanism of Sulfamethoxazole?

A

Sulfonamides structurally similar to PABA, which is a protein that is essential for production of folate. Sulfonamides are synthetic bacteriostatic antibiotics that competitively inhibit conversion of p-aminobenzoic acid to dihydropteroate, which bacteria need for folate synthesis and ultimately purine and DNA synthesis.

54
Q

What is the mechanism of trimethoprim?

A

Selective inhibition of bacterial dihydrofolic acid reductase, step in folate synthesis –> purines –> DNA

55
Q

What are mechanisms of resistance to trimethoprim?

A

Reduced cell permeability
Overproduction of dihydrofolate reductase (outcompeted)
Coded trimethoprim resistant dihydrofolate reductase inhibitors

56
Q

What is the pharmacokinetics of trimethoprim?

A

A: Good oral bioavailability, 70% protein bound
D: Wide Vd, including CSF
E: Renal

57
Q

What are indications of trimethoprim?

A

UTI
Prostatitis
Pneumocystis Pneumonia
Shigella
Salmonella
Non tuberculous mycobacterial infections

58
Q

What are adverse reactions to trimethoprim?

A

Megaloblastic anaemia (folate effect)
Leukopaenia
Granulocytopaenia
GI upset
Cr + K+ elevation

59
Q

What are examples of fluoroquinolones?

A

Norfloxacin
Moxifloxacin
Ciprofloxacin

60
Q

What is the mechanism of fluoroquinolones?

A

Block DNA synthesis through inhibition of bacterial topoisomerase II (DNA Gyrase) + topoisomerase IV

**Effect is inability of tightly coiled bacterial genome to be ‘unwound’ for transcription and replication. TI IV inhibition impairs ability for separation of chromosomes to separate into daughter cells

61
Q

What organisms are fluoroquinolones commonly used for?

A

Generally gram -ve cocci and bacilli: enterobacter, pseudomonas, neisseria, haemophilus, campylobacter

62
Q

Does resistance to one type of fluoroquinolone mean that others also are likely resistant?

A

Yes

63
Q

What is the pharmacokinetics of fluoroquinolones?

A

A: good PO bioavailability, take 2 hrs before meals (impaired by di and trivalent cations)
D: widely
E: renal excretion (except moxifloxacin)

64
Q

What are adverse reactions to fluoroquinolones?

A

GI upset
Headache
LFT derangement
QTc prolongation
Cartilage damage/risk of tendon rupture, particularly <18 years and pregnancy

65
Q

What is concentration dependent killing?

A

Rate and extent of killing increases with increasing drug concentrations –> aminoglycosides and quinolones

66
Q

What is time dependent killing?

A

bactericidal activity continues as long as serum concentrations are greater than minimal bactericidal concentration –> b-lactams, vancomycin

67
Q

What are the 3 broad categories of bacterial resistance?

A
  1. Decreased cell wall/membrane permeability to drug OR increased efflux/pumping out of drug
  2. Alteration to target binding site, reducing efficacy/affinity of drug
  3. Enzymatic inactivation of antibiotic
68
Q

What are the first line agents for treatment of tuberculosis?

A

RIPE:
- Rifampicin
- Ioniazid
- Pyrazinamide
- Ethambutol

69
Q

What is the mechanism of rifampicin?

A

Binds to the beta subunit of RNA polymerase, causing inhibition of RNA synthesis (bactericidal) - it is a prodrug activated by a mycobacterial enzyme, katG.

70
Q

What is the mechanism of ioniazid?

A

Inhibits synthesis of mycolic acids, which are component of mycobacterial cell wall (bactericidal)

71
Q

What is the mechanism of pyrazinamide?

A

Taken up into macrophages, acts against intracellular mycobacterium, which is converted to pyrazinoic acid by mycobacterial enzyme and this then disrupts cell membrane metabolism and transport - needs a pH of 5.5 to be active (works in lysosomes)

72
Q

What is the common, and what is a unique toxicity for each anti-tuberculosis drug?

A

All cause hepatotoxicity

Pyrazanamide = hyperuricaemia (think pyramids of renal medulla)

Ethambutol = retrobulbar neuritis –> E = eye

Rifampicin = orange urine/sweat/tears

Ioniazid = peripheral neuropathy

73
Q

What is the mechanism of aciclovir?

A

It acts as a defective guanosine purine which gets incorporated into the viral DNA –> disrupts DNA replication/synthesis.

Requires activation by virus specific enzyme, thymidine kinase (which is how this doesn’t cause DNA damage in uninfected cells)

74
Q

What is the pharmacokinetics of acyclovir?

A

A: 15-20% oral bioavailability (2-4x more with valaciclovir)
D: Wide, CSF 20-50% that of serum levels
M: Within host cells, dependent on viral enzymes
E: Renal excretion

75
Q

What are the indications for acyclovir?

A

HSV encephalitis, neonatal HSV infection, early shingles, active/recurrent genital herpes

76
Q

What is the main adverse effect of acyclovir?

A

Reversible renal toxicity, induces crystal deposition, can cause interstitial nephritis

77
Q

What is anti-sepsis?

A

Application of agent to living tissue to prevent infection

78
Q

What is decontamination?

A

Process that produces marked reduction in in number or activity of micoorganisms

79
Q

What is disinfection?

A

Chemical or physical treatment that that destroys vegetative microbes and viruses on inanimate surface

80
Q

What is sanitisation?

A

Reduction of microbial load on inanimate surface to a level considered acceptable for public health purposes

81
Q

What is sterilisation?

A

process intended to kill all microorganisms, including spores, and viruses, with acceptably low probability of survival

82
Q

What is pasteurisation?

A

Process that kills non-sporulating microorganisms by hot water or steam at 65-100 degrees Celsius.

83
Q

What is chlorhexidine? What is it active against?

A

Cationic biguanide, low water solubility. Active against vegetative bacteria and mycobacteria, fungi and viruses. Strongly absorbs to cell membranes, causing disruption/cell death

84
Q

What are common gram positive pathogens?

A

Staph
Strep
Enterococcus
Gram +ve rods: diphtheria, listeriosis, nocardiosis

85
Q

What are common gram negative pathogens?

A

E. coli
Klebsiella
Enterobacter
Pseudomonas
Bacteroides
Legionella
Proteus

86
Q

What is the difference between bactericidal and bacteriostatic mechanisms?

A

Bactericidal – cell wall active (aminoglycosides, lactams, isoniazid, metronidazole, quinolones, rifampin, vancomycin)
- either conc-dependent killing (aminos, quinolones) or time dependent killing (beta lactams, vanc)
- better if host defences impaired – use for endocarditis, endovascular infections, meningitis, neutropenia
Bacteriostatic – inihibit protein synthesis (chloramphen, clinda, macrolides, nitro, tetra, trimeth)

87
Q

What is the mechanism of metronidazole?

A

Reductive bioactivation of their nitro group by ferredoxin (present in anaerobic parasites) to form reactive cyto- toxic products that interfere with nucleic acid synthesis.

88
Q

How do Nucleoside Reverse Transcriptase Inhibitors (NRTIs) work to treat HIV?

A

competitively inhibit binding of natural nucleotides to the Deoxyribonucleotide triphosphate (dNTP)- binding site of reverse transcriptase but also act as chain termi- nators via their insertion into the growing DNA chain.

ED Primary Exam (46 decks)

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