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pr3151 > protein cell wall inhibitors - 30s and 50s > Flashcards

protein cell wall inhibitors - 30s and 50s Flashcards

1
Q

where does protein synthesis takes place

A

in ribosomes

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2
Q

what are the components and features of the bacterial ribosome

A

50s and 30s subunits and has three binding sites for tRNA (A,P,E sites)

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3
Q

which abx target 30s subunits

A

aminoglycosides and tetracyclines

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4
Q

which abx target 50s subunits

A

macrolides, clindamycin, linezolid

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5
Q

what is the moa of tetracyclines

A

enter susceptible organisms via passive diffusion and energy dependent transport protein mechanism -> concentrate intracellularly in susceptible organism -> bind irreversibly to 30s subunit of bacterial ribosome -> prevent binding of tRNA to A site of mRNA-ribosome complex -> inhibit bacterial protein synthesis

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6
Q

what is the type of activity of tetracyclines

A

bacteriostatic

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7
Q

what is the spectrum of activity for tetracyclines

A

broad coverage for gram pos, gram neg, atypical and spirochete

inadequate activity for pseudomonas and proteus

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8
Q

is tetracycline suitable for pregnancy and lactation and why

A

no it is category D as it crosses placenta barrier

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9
Q

what is the absorption for tetracyclines

A

adequately absorbed after oral ingestion, best on empty stomach

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10
Q

what is the important counselling points for tetracyclines

A

take on empty stomach

avoid dairy products as it contains Ca or any other substances that contains divalent or trivalent cations (Mg, Fe, Al) as it can cause formation of non absorbable chelates which decreases absorption

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11
Q

what is the distribution of tetracyclines

A

well distributed in bile, kidney, liver, gingival fluid, skin

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12
Q

where kind of tissue does tetracyclines bind to

A

binds to tissues undergoing calcification like bones and teeth or tumors with high Ca content

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13
Q

what are the drugs that are tetracyclines

A

tetracyclines, doxycycline, minocycline

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14
Q

route, indication and excretion of tetracycline

A

PO

chlamydia, mycoplasma pneumoniae, vibrio chloerae, plague due to yersinia pestis

kidney

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15
Q

route, indication and excretion of doxycycline

A

PO, IV

chlamydia, mycoplasma pneumoniae, vibrio chloerae, plague due to yersinia pestis, rickettsial, acne, CAP, strep pneumoniae, influenzae, skin and tissue infections by MRSA

kidney, unchanged in bile and urine

completely absorbed from GIT

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16
Q

route, indication and excretion of doxycycline

A

PO, IV

chlamydia, mycoplasma pneumoniae, vibrio chloerae, plague due to yersinia pestis, rickettsial, acne, CAP, strep pneumoniae, influenzae, skin and tissue infections by MRSA

kidney, unchanged in bile and urine

completely absorbed from GIT

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17
Q

route, indication and excretion of minocycline

A

PO

chlamydia, mycoplasma pneumoniae, vibrio choloerae, plague due to yersinia pestis, severe acne, influenzae, klebsiella

kidney, extensively metabolised in liver before excretion

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18
Q

what are the mechanisms of resistance to tetracyclines

A
  1. efflux pumps
  2. ribosomal protection through synthesis of Tet(O) and Tet(M) proteins which dislodges tetracycline from 30S subunit
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19
Q

what are the adverse effects of tetracyclines

A
  1. gastric discomfort (take on empty stomach, drink plenty of fluids, do not take right before bed)
  2. effects on calcified tissues (discolouration of teeth, temporary stunting of growth)
  3. hepatotoxicity
  4. phototoxicity
  5. vestibular dysfunction (dizziness, vertigo, tinnitus esp with minocycline)
  6. renal (less renal toxicity with doxycycline)
  7. superinfection due to prolonged use (like CDAD, pseudomembranous colitis)
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20
Q

what are the c/i for tetracyclines

A

not for pregnant or breastfeeding or children <8, extra caution for patient with myasthenia gravis

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21
Q

what is myasthenia gravis

A

chronic autoimmune neuromuscular disease

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22
Q

what are the ddi for tetracyclines

A

enhances effects of sulfonylureas which can cause hypoglycemia

enhances effects of digoxin, lithium and theophylline which have narrow therapeutic index

decrease effectiveness of oral contraceptives

enhances effect of oral anticoagulant warfarin

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23
Q

which class is tigecycline derived from and what structure is it similar to

A

derived from tetracycline, structure similar to minocycline

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24
Q

how is tigecycline’s activity affected due to molecular alterations from minocycline

A
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25
Q

route, indication, csf, excretion

A

IV (poor oral F)

MRSA, MDR strep, VRE, ESBL (carbapenem resistant strains), complicated skin or skin structure infections, intra abdominal, CAP, not active against pseudomonas and proteus

10% in uninflamed meninges

not extensively metabolised, primarily cleared by biliary or fecal, no renal dose adjustments but yes hepatic adjustments

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26
Q

is tigecycline good for blood stream infections why

A

no it penetrates well into tissues but have low plasma conc

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27
Q

what is the moa of aminoglycosides

A

diffuse through aq porin channels in outer membrane of gram neg bacteria and is transported across the inner membrane by active transport which is energy dependent and requires aerobic conditions and can be enhanced by beta lactams -> distorts structure of ribosomes by binding to them and blocks formation of initiation complex -> causes misreading of codons as wrong amino acyls tRNAs can bind to A site without matching the codon of mRNA present at that site -> inhibit translocation

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28
Q

what is the activity of aminoglycosides

A

rapidly bactericidal and concentration dependent killing with PAE

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29
Q

why are aminoglycosides rapidly bactericidal

A

largely cationic which affects cell membrane by causing fissures in cell membrane to form

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30
Q

what is the type of activity of aminoglycosides

A

rapidly bactericidal and conc dependent killing with PAE, less effective in anaerobic environment

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31
Q

what is the spectrum of activity for aminoglycosides

A

broad spectrum against gram pos and gram neg

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32
Q

what are the indications for aminoglycosides

A

aerobic gram neg (enterobacter - klebsiella, ecoli; MDR pseudomonas and acinetobacter and TB), aerobic mycobacteria, aerobic gram pos with beta lactams

freq used for empiric therapy for serious infections (septicemia, complicated uti, nosocomial resp tract infections) -> usually discontinued once causative microbe identified

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33
Q

what is the rationale behind administering aminoglycosides with beta lactams

A
  1. to expand empiric spectrum of activity to ensure presence of at least one drug against a suspected pathogen
  2. for synergistic bacterial killing
  3. prevent emergence of resistance to individual agents
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34
Q

what is the distribution of aminoglycosides

A

penetration into most body fluids variable

low distribution into fatty tissue -> dosing based on lean body mass and not total body weight

csf conc low even in inflamed meninges

can cross placenta barrier and cause accumulation in fetal plasma and amniotic fluid

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35
Q

what are the drugs that are aminoglycosides

A

gentamicin, tobramycin, amikacin, streptomycin, neomycin

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36
Q

route, indication and excretion for gentamicin

A

IV, IM, IT, ophthalmic, topical

gram pos cocci (but not mono abx)
serious gram neg bacilli
gram neg enterobacteriaceae (klebsiella, pseudomonas, proteus) with penicillin/ ceftriaxone
gram pos enterococcal endocarditis

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37
Q

route, indication and excretion for gentamicin

A

IV, IM, IT, ophthalmic, topical

gram pos cocci (but not mono abx)
serious gram neg bacilli
gram neg enterobacteriaceae (klebsiella, pseudomonas, proteus) or MDR gram neg with penicillin/ ceftriaxone
gram pos enterococcal endocarditis with penicillin

renal, excreted unchanged in urine, renal dose adjustments required

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38
Q

route, indication and excretion for tobramycin

A

IV, IM, inhalation, ophthalmic, ointment, solution

pseudomonas (along with anti pseudomonal abx)
ineffective against mycobacteria
poor activity against enterococci with penicilin

renal excreted unchanged in urine, renal dose adjustments required

39
Q

route, indication and excretion for amikacin

A

IV, IM, IT

gram neg pseudomonas, proteus, gentamicin resistant ecoli and klebsiella
gram pos enterococci (but less effective than gentamicin)
mycobacterium TB

renal, excreted unchanged in urine, renal dose adjustments required

40
Q

route, indication and excretion for streptomycin

A

IM

enterococcal endocarditis with penicillin if resistant to gentamicin
with other abx for mycobacterial diseases
plague by yersinia pestis

renal, unchanged in urine, renal dose adjustments required

41
Q

route, indication and excretion for neomycin

A

PO, topical

klebsiella, e coli
staph aureus, enterococci faecalis
topical for skin infections, oral for bowel prep for surgery

97% unchanged in feces

42
Q

which aminoglycoside has the widest spectrum of activity

A

amikacin

43
Q

which aminoglycoside is the most toxic

A

neomycin

44
Q

what are the c/i for neomycin

A

hypersensitivity to neomycin or other aminoglycosides, intestinal obstruction, ulcerative GI disease

45
Q

why is neomycin not given parenterally

A

severe nephrotoxicity

46
Q

what are the adverse effects of aminoglycosides

A

ototoxicity, nephrotoxicity, neuromuscular paralysis, hypersensitivity

47
Q

why can aminoglycosides cause ototoxicity and what are the risks between the different aminoglycosides

A

streptomycin: ++ for vestibular, + for cochlear
gentamicin: ++ for vestibular, + for cochlear
amikacin: + for vestibular, ++ for cochlear

abx can accumulate in endolymph and perilymph of inner ear, deafness may be irreversible

48
Q

why can aminoglycosides cause nephrotoxicity

A

retention of aminoglycosides by proximal tubular cells disrupts calcium mediated transport process thus leading to kidney damage

49
Q

why can aminoglycosides cause neuromuscular paralysis

A

rapid increase in conc or concurrent administration with neuromuscular blockers

50
Q

which aminoglycoside can cause hypersensitivity

A

topical neomycin can cause skin rash and contact dermatitis

51
Q

what should you monitor when using aminoglycoside

A

avoid/ limit use if renal impairment, hearing defects, myasthenia gravis

avoid/ limit use with other nephrotoxic drugs like amphotericin B, vancomycin, NSAIDs, neuromuscular blockers

TDM

renal function tests (urea, Cr, electrolytes)

52
Q

what are the factors predisposing to nephro and ototoxicity

A

dose, duration more than 5 days, other nephrotoxic drugs, age, genetic

53
Q

what are the mechanisms of resistance to aminoglycosides

A
  1. efflux pumps
  2. gram neg bacteria producing aminoglycosides inactivating enzymes
  3. alteration of 30S subunit by bacteria
  4. inhibition of aminoglycoside uptake by bacteria
54
Q

what is the moa of macrolides

A

inhibits protein synthesis by reversibly binding to the 50S ribosomal unit and inhibit translocation step as the nascent peptide chain at A site of the transferase reaction cannot move to peptidyl donor (P) site

55
Q

what are the drugs that are macrolides

A

erythromycin, clarithromycin, azithromycin

56
Q

what are the structural modifications of the macrolides and what is the benefit

A

clarithromycin is the methylated form of erythromycin

azithromycin has a 15C lactone ring with added methylated N group which reduces the inhibitory effect on cyp

structural modifications to clarithromycin and azithromycin from erythromycin improves acid stability, tissue penetration and broadens the spectrum of activity

57
Q

what are the indications for macrolides

A

alternative to penicillin if allergy to beta lactams, atypical microbes (legionella, mycoplasma, chlamydia), resp tract infections (CAP), diphtheria, h pylori, mycobacteria

58
Q

what are the implications of inhibitory effects on cyp

A

give rise to ddi

59
Q

what is the absorption of macrolides affected by

A

absorption of erythromycin and azithromycin affected by food (given with or after food)

60
Q

what is the distribution of macrolides like

A

distribute to most body tissues, poor cns penetration, azithromycin has higher distribution in phagocytes than plasma

61
Q

route, indication, distribution, excretion of erythromycin

A

IV, PO (destroyed by gastric acid, either enteric coated or esterified)

gram pos, gram neg, atypicals, strep pneumoniae

diffuse readily into intracellular fluids except csf, increased penetration wit inflammed meningitis

hepatic metabolism, excreted in bile

62
Q

limitation of erythromycin

A

no effect on fungi, yeast, virus

63
Q

route, indication, distribution, excretion of clarithromycin

A

PO

gram pos, gram neg, atypicals (legionella, pylori), mycobacteria

extensive tissue distribution, conc higher in tissues than in serum

hepatic metabolism, excreted in bile and urine

64
Q

benefits of clarithromycin

A

most active out of the three macrolides against gram pos, gram neg and mycobacterium

more effective against atypicals compared to erythromycin

wider spectrum than penicillin (all three are common substitutes)

better GI tolerance as stable in stomach acid and readily absorbed

65
Q

limitations of clarithromycin

A

no effect on fungi, yeast, virus

66
Q

route, indication, distribution, excretion of azithromycin

A

PO

atypicals, CAP due to influenzae and moraxella catarrhalis, STD due to chlamydia or gonorrhoea, common bacterial enteric pathogens (campylobacter, shigella, salmonella, vibrio cholerae)

extensively distributed in tissues, higher drug conc in tissue than plasma

excreted in bile, unchanged in feces

67
Q

benefits of azithromycin

A

more stable in stomach acid and more readily absorbed

wider spectrum than pencillin (all three are common substitute)

68
Q

limitations of azithromycin

A

no effect on fungi, yeast, virus

69
Q

what are the adverse effects of macrolides

A
  1. GI distress and motility (less with azithromycin and clarithromycin due to structural modifications)
  2. hepatotoxicity
  3. ototoxicity (transient deafness assoc with erythromycin, irreversible sensorineural hearing loss with azithromycin)
  4. QT prolongation
70
Q

what is the c/i for macrolides

A

hepatic dysfunction as erythromycin and azithromycin can accumulate in liver

71
Q

can macrolides be used in pregnancy

A

yes

erythromycin and azithromycin category B, clarithromycin category C

used for chlamydia, gonorrhea, gram pos urti, premature rupture of membranes, cases of beta lactamase allergy

72
Q

what are the ddi of macrolides

A

interfere with cyp and inhibit hepatic metabolism which can result in toxic accumulation (warfarin, digoxin, corticosteroids)

73
Q

what are the mechanisms of resistance to macrolides

A
  1. increased efflux pumps (pump out after abx enters cell but protein synthesis unaffected)
  2. acquisition of erm gene which results in ribosomal methylation which alters 50S subunit
74
Q

what is clindamycin ineffective against

A

gram neg aerobes

75
Q

what are the indications for clindamycin

A

gram pos (MRSA, streptococcus, penicillin resistant anaerobes), alternative to penicillin, anaerobic infections of skin and soft tissues (bacteriodes, clostridiodes), acne vulgaris, bacterial vaginosis

76
Q

what is the moa of clindamycin

A

bind exclusively to 50S ribosomal subunit

77
Q

what happens if clindamycin given with macrolides like erythromycin

A

binding of clindamycin occurs close proximity to erythromycin which means can antagonise each others actions and cross resistance due to erm methylases can also occur

78
Q

route, distribution, excretion of clindamycin

A

IV, PO with very good F, topical solution/gel/lotion, vaginal cream

distributes well into all bodily fluids including bones, poor csf penetration, excellent bond and salivary gland penetration

hepatic metabolism, excreted as bioinactive metabolites

79
Q

what are the c/i of clindamycin

A

UC, pseudomembranous colitis

80
Q

what bacteria is always resistant to clindamycin

A

clostridiodes difficile

81
Q

what are the adverse effects of clindamycin

A

esophageal irritation, GI effects (D/V), skin rash, CDAD

82
Q

how to manage esophageal irritation caused by clindamycin

A

take with a full glass of water, avoid taking before bed

83
Q

what are the mechanisms of resistance to clindamycin

A
  1. alteration of 50S subunit by AA substitution
  2. alteration in 23S ribosomal RNA unit by methylation of erm gene
84
Q

what is the difference between clindamycin and macrolides in terms of efflux pumps

A

clindamycin is not a substrate for efflux pumps

85
Q

what is linezolid mostly used for

A

treatment of MDR strains

86
Q

can linezolid be used for gram neg and why

A

no because the gram neg bacteria are intrinsically resistant to linezolid as the efflux pumps will remove them faster than it can accumulate

87
Q

what are the indications for linezolid

A

gram pos (staphylococcus, streptococcus, enterococcus, listeria monocytogenes), strains that are resistant to other agents like MRSA, VRE, VRSA, penicillin resistant, MDR gram pos cns infections

88
Q

route, distribution and excretion of linezolid

A

IV, PO with good F (well absorbed after oral administration can take without regard to food)

widely distributed throughout body, good csf penetration

metabolised via nonenzymatic oxidation into two inactive metabolites, 80% of dose in urine, no renal or hepatic dose adjustments

89
Q

what are the adverse effects of linezolid

A
  1. GI effects (N,D, headache, rash)
  2. bone marrow suppression (>10d use can cause thrombocytopenia, monitor blood counts)
  3. serotonin syndrome
  4. irreversible peripheral neuropathies and optic neuritis (>28d use)
90
Q

what are the c/i of linezolid

A

not for treatment of catheter site infections or blood stream infections, not within two weeks of MAOIs, avoid tyramine rich food and serotonergi drugs

91
Q

what are the mechanisms of resistance to linezolid

A

mutations in 23S RNA unit

92
Q

why does linezolid cause serotonin syndrome and what can be done

A

linezolid possess nonselective monoamine oxidase inhibitory activity and this will occur if given concomitantly with selective serotonin reuptake inhibitors or MAOi, condition is reversible if discontinue drug and avoid tyramine and histamine rich food as can affect adrenergic pathways

93
Q

what are examples of tyramine rich foods

A

aged cheese, cured/ smoked meats, draft beers, fava beans, soy products

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