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FM 2 > Protein & Nucleic Acid Synthesis Inhibitors > Flashcards

Protein & Nucleic Acid Synthesis Inhibitors Flashcards

1
Q

Aminoglycosides: MOA

A

• Inhibit elongation cycle by binding to 30S ribosome

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2
Q

Aminoglycosides: Types

A 
o	Natural (made by fungi): Gentamicin, Tobramycin, neomycin, streptomycin (TB)
o	Semisynthetic: Amikacin (Kanamycin + hydroxy butyric acid)
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3
Q

Aminoglycosides: Pharmacodynamics

A

o Concentration-dependent killing
o Prolonged post-antibiotic (persistent) effects
o High peak levels (8x MIC or higher) result in better efficacy
o Preferred: large once-daily doses (over multiple smaller doses)

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4
Q

Aminoglycosides: Pharmacology

A

o Water-soluble
o Poor oral absorption
o Distribution in ECF; reduced CNS penetration
o Primarily renal elimination

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5
Q

Aminoglycosides: Spectrum

A 
Aerobic Gram-negative bacilli:
•	Enterobacteriaceae:
•	E. coli
•	Klebsiella
•	Enterobacter
•	Serratia
•	Proteus
•	Staphylococci
•	NOT streptococci or enterococci
Tobramycin, Gentamicin, and Amikacin = active against Pseudomonas aeruginosa

When combined with beta-lactam antibiotic = synergistic killing of streptococci and enterococci
• Gentamicin = most active against Gram-positive cocci
o Streptomycin and Amikacin = most active against mycobacteria
o NO activity against anaerobic bacteria
• Drug depends on O2-dependent active transport system to get into cell

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6
Q

Tetracyclines: MOA

A

• Inhibit elongation cycle by binding to 30S ribosome

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7
Q

Tetracyclines: Types

A

o Natural tetracyclines
o Semisynthetic: Doxycycline
o Glycylcyclines: Tigecycline

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8
Q

Tetracyclines: Pharmacodynamics

A

o Bacteriostatics (binding to 30s ribosome is reversible)
o Bactericidal for some organisms (ex: pneumonococci)
o Time dependent killing
o Produces prolonged persistent effects

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9
Q

Tetracyclines: Pharmacology

A 
o	Good oral absorption (except for new glycylcyclines)
o	Extensive tissue distribution 
o	Good intracellular concentrations
o	Doxycycline (and minocycline) = eliminated in liver > urine
o	Tetracycline = eliminated in urine > liver
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10
Q

Tetracyclines: Spectrum

A

o Broad Spectrum: Gram-positive and Gram-negative bacteria
o Mycoplasma
o Chlamydia
o Rickettsia
o Spirochetes
o Malaria parasites
o Minocycline > doxycycline against staphylococci (including MRSA)
• Tigecycline also more active against MRSA
o Poor activity against enteroccoi and Pseudomonas

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11
Q

Chloramphenicol: MOA

A

• Inhibit the elongation cycle by binding 50S ribosome

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12
Q

Chloramphenicol: Pharmacodynamics

A

o Bacteriostatic agent (reversible binding)

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13
Q

Chloramphenicol: Pharmacology

A

o Excellent oral bioavailability
o High lipid solubility (not ionized at pH 7.4) → Extensive distribution
o Good intracellular concentrations
o Eliminated by metabolism (glucuronidation to make more soluble) in liver
o Metabolite excreted in urine

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14
Q

Chloramphenicol: Spectrum

A

o Broad spectrum

o Poor against Pseudomonas and Legionella

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15
Q

Macrolides: MOA

A

• Inhibit the elongation cycle by binding 50S ribosome

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16
Q

Macrolides: Types

A

o Natural: erythromycin, dirithromycin

o Semisynthetic: Clarithromycin, Azithromycin

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17
Q

Macrolides: Pharmacology

A

Modest oral absorption with erythromycin
• Acid labile
• Ionized in GI tract = not as lipid soluble
Better absorption with Azithromycin and Clarithromycin (more acid stable)
Modest serum concentrations
High intracellular levels
• High concentrations in epithelial lining fluid of lung
• Effective in treating pneumonia
Eliminated by liver (metabolized and biliary excretion)

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18
Q

Macrolides: Spectrum

A 
Good against:
•	Gram-positive bacteria (primarily Streptococci and pneumonia)
•	Legionella
•	Mycoplasma
•	Chlamydia
•	Helicobacter pylori
•	Some atypical mycobacteria

Weak against:
• Hemophilus influenzae with clarithromycin and azithromycin (because hemophilus has efflux pump for macrolides)

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19
Q

Clindamycin: MOA

A

• Inhibit the elongation cycle by binding 50S ribosome

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20
Q

Clindamycin: Pharmacology

A

o Good oral bioavailability
o Good extra- and intra-cellular distribution
o Eliminated by liver (metabolized and biliary excretion)

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21
Q

Clindamycin: Spectrum

A

Good against:
• Staphylococci
• Streptococci
• Anaerobic bacteria (including Bacteroides fragilis)

Modest activity against:
• Toxoplasma
• Pneumocystis jiroveci

Fair/poor against:
• Mycoplasma
• Chlamydia
• Legionella

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22
Q

Oxazolidinones (Linezolid): MOA

A

• Inhibit 70S initiation complex

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23
Q

Oxazolidinones (Linezolid): Pharmacodynamics

A

o Considered bacteriostatic, but does kill bacteria slowly

24
Q

Oxazolidinones (Linezolid): Pharmacology

A

o Excellent oral bioavailability
o Good intracellular and extracellular levels (especially in respiratory tract)
o Excellent CSF penetration
o Eliminated by BOTH liver and kidney

25
Q

Oxazolidinones (Linezolid): Spectrum

A 
Gram-positive bacteria
•	Staphylococci (including MRSA)
•	Streptococci
•	Pneumococci
•	Enterococci (both E. faecium and E. faecalis including vancomycin resistant strains)
26
Q

Streptogramins: MOA

A

• Inhibit the elongation cycle by binding 50S ribosome

27
Q

Streptogramins: Pharmacodynamics

A

o Used alone: bacteriostatic

o Used together: bactericidal

28
Q

Streptogramins: Pharmacology

A

o Not orally absorbed (must be given IV)
o Modest serum and tissue levels
o Metabolized in serum and tissues
o Eliminated by biliary excretion

29
Q

Streptogramins: Spectrum

A

o Staphylococcu (including MRSA)
o Streptococci
o Enterococcus faecium (including vancomycin resistant strains)
o NOT active against Enterococcus faecalis

30
Q

Nitrofurantoin: MOA

A

o Nitrofuan reductase produces reduced derivatives → bind to various proteins involved in protein synthesis

31
Q

Nitrofurantoin: Properties

A

o Urinary agent

32
Q

Nitrofurantoin: Pharmacology

A

o Good oral absorption

o Rapid enzyme degradation → only get adequate concentrations in urine

33
Q

Nitrofurantoin: Spectrum

A

o E. coli
o Enterococci
o Group B streptococci
o Only 20-50% of enterobacter and Klebsiella species

34
Q

Aminoglycosides: Resistance

A

Chromosomal mutation
o At or near ribosomal binding site → lowers drug affinity
o Uncommon cause of resistance (expect with Streptomycin and TB)

Enhanced efflux:
o Gram-negative bacilli (especially Pseudomonas aeruginosa)
o Efflux pumps pump drug out of cell

Inactivating enzymes:
o Determined by transposable genes usually transported by plasmids
o Enzymes act by adenylating, acetylating, or phosphorylating various amino or hydroxy groups
o More organisms are obtaining genes for multiple enzymes
o Semisynthetics = created to block the binding of these enzymes (via steric hindrance)

35
Q

Tetracyclines: Resistance

A

• Enhanced drug efflux
• Ribosomal protection (inability to accumulate adequate amounts of drug within cell at ribosome)
• Ribosomal mutation (uncommon cause)
• Extensive cross-resistance among tetracyclines
o Can test one tetracycline = reflects susceptibility to all
• New glycylcyclines = active against bacteria with major tetracycline-resistance mechanisms (ex: MRSA)

36
Q

Chloramphenicol: Resistance

A

Production of chloramphenicol acetyl transferase (CAT)
o Plasma-mediated
o Acetylates nitro group → inactivates

37
Q

Macrolides: Resistance

A

Methylation of 23s ribosome RNA
o Plasmid or chromosomal mediated
o Can be inducible
o Main cause of pneumococcal resistance to macrolides in Europe (Erm genes)

Enhanced efflux pumps
o Well documented in pneumococci
o Main cause of pneumococcal resistance to macrolides in USA (Mef genes)

Chromosomal mutation of 50s ribosome

Drug inactivation
o Esterases present in some Gram-negative bacilli

NOTE: rates of resistance:
o In S. pneumonia: 20-30%
o In S. pyogenes: 5-7%

38
Q

Clindamycin: Resistance

A

Methylation of 23s ribosome RNA
o Plasmid or chromosomal mediated
o Can be inducible
o Main cause of pneumococcal resistance to macrolides in Europe (Erm genes)

Chromosomal mutation of 50s ribosome

Drug inactivation
o Esterases present in some Gram-negative bacilli

OVERALL: similar resistance to macrolides except not effluxed
o So if pneumococci is resistant to macrolides and clindamycin = suggests presence of Erm genes or (rare) chromosomal mutation
o If resistant to macrolides but susceptible to clindamycin = presence of Mef genes (efflux)

39
Q

Oxazolidinones: Resistance

A
  • Primarily in Enterococcus faecium; still rare in S. aureus but increasing
  • Due to mutations near binding site to ribosome
40
Q

Streptogramins: Resistance

A
  • Not substrates for efflux pumps
  • Ribosomal mutation = primary mechanism for dalfopristin mutation

• Mythylation of 23s ribosome = decreases quinupristin activity
o Makes combination bacteriostatic
o This type of resistance = “MLSB”
• Affects macrolides, lincosamine (clindamycin), and quinupristin

41
Q

Nitrofurantoin: Resistance

A
  • Uncommon

* Due to reduced nitrofuran reductase activity

42
Q

Aminoglycosides: uses

A
  • Major drug for plague and tularemia
  • Complicated UTIs due to Gram-negative bacilli

Combination with beta-lactams for synergistic activity:
o Serious Pseudomonas and other Gram-negative bacillary infections
o Serious Staphylococcal, Streptococcal, and enterococcal infections (ex: endocarditis)

• Surgical prophylaxis (oral bowel prep)
o Oral neomycin to reduce aerobic gram-negative bacilli in bowel

• Mycobacteria: 2nd line agent; always in combination with other drugs

43
Q

Tetracylcine: Uses

A

• STD’s: non-specific urethritis (Chlamydia), gonorrhea, syphilis
• Borrelia infections: Lyme disease
• Ehrlichia infections
• Alternative for community-acquired pneumonia
o Active against typical and atypical pathogens
o Especially mycoplasma
• Rickettsial infections (Rocky Mountain Spotted Fever)
• Plasmodium falciparum malaria
• Prophylaxis and treatment of Anthrax
• Skin and soft tissue infections (doxycycline and minocycline)
• Oral therapy in CA-MRSA infections = minocycline

44
Q

Chloramphenicol: uses

A

• Serious salmonella infections (typhoid fever)
o Still a major agent in developing countries
• Bacterial meningitis in beta-lactam allergic patients
• Anaerobic infections (especially in CNS)

45
Q

Macrolides: uses

A 
Respiratory infections
o	Sinusitis 
o	Otitis media
o	Pneumonia
o	Chronic bronchitis
o	DOC for outpatient community-acquired pneumonia (including atypical pathogens)
o	Bordetella pertussis

Streptococcal infections (pharyngitis and cellulitis) in penicillin allergic patients

Atypical mycobacteria
o Major drugs for prophylaxis (alone) and for treatment (in combination) of mycobacterium avian complex (MAC)

Helicobacter pylori infections
o Used in combination with proton pump inhibitor and other antibiotics

Azithromycin = Pseudomonas pulmonary exacerbations in CF patients
o Reduces biofilms
o No direct effect on pseudomonas

46
Q

Clindamycin: uses

A

• Anaerobic infections above diaphragm (ex: lung abscess)

• Streptococcal infections
o Used in combination with penicillin for serious Group A Strep cellulitis to decrease toxin production

• Staphylococcal infections
o Better drug than macrolides for Staph
o Active against many of the community MRSA

• Alternative drug for toxoplasmosis and pneumocystis

47
Q

Oxazolidinones: uses

A

• VRE (vancomycin resistant enterococcal) infections
• MRSA infections
o May be better than vancomycin in ventilator-associated pneumonia
o DOC for MRSA pneumonia
• MRSE (methicillin-resistant Staphylococcus epidermitis) infections
• CNS infections due to MRSA or MRSE
• First oral agent for these infections but very expensive ($50-80/day)

48
Q

Streptogramins: uses

A
  • Vancomycin resistant E. Faecium infections

* MRSA infections (alternative to vancomycin)

49
Q

Nitrofurantoin: uses

A
  • Treatment and prophylaxis of UTIs

* Not effective in patients with < 50% of normal renal function

50
Q

Aminoglycosides: adverse reactions

A

Nephrotoxicity
o Drug accumulates in renal cortex → death of renal tubular cells
o Damage is usually reversible (renal tubular cells can regenerate)
o Drug enters cells from urine side of tubular cell via pinocytosis
• Drug must bind megalin (lipoprotein on brush border or renal cells)
• Limited number of binding sites = saturable kinetics (less drug taken up with large doses once daily than multiple doses given more frequently)

Ototoxicity
o Due to damage of sensory (hair) cells involved in hearing and balance
o Hearing loss and vestibular dysfunction usually NOT reversible (hair cells can’t regenerate)
o Mechanism:
• Drug binds to vestibular and cochlear membranes
• Enters endolymph of inner ear
o Once daily dosing also reduces toxicity

51
Q

Tetracyclines: adverse reactions

A

• Relatively safe

Discoloration of teeth and bones
o Avoid during pregnancy
o Avoid in children < 8 years

GI intolerance: nausea, vomiting, diarrhea
Super infections: oral and vaginal candidiasis

52
Q

Chloramphenicol: adverse reactions

A

Bone marrow suppression
o Due to inhibition of mammalian protein synthesis
o Seen when given in high enough doses for long periods of time
o Reversible if stop drug

Aplastic anemia
o	Rare (incidence 1 in 25,000-40,000)
o	Non-reversible
o	Not dose-related
o	Nitroso derivative of chloramphenicol (may form in GI) = toxic to bone marrow stem cells

Gray syndrome in newborns
o Failure to conjugate chloramphenicol to glucuronide → Vascular collapse

53
Q

Macrolides: adverse reactions

A

• Overall = well-tolerated
• GI intolerance: nausea, diarrhea
o Less with new semisynthetic derivatives
• Hepatitis in pregnant women
• Ototoxicity with high IV doses (reversible because doesn’t damage hair cells)

54
Q

Clindamycin: adverse reactions

A

• Diarrhea
• Pseudomembranous colitis
o Due to clindamycin-resistant Clostridiu difficile infections = produces enterotoxin and cytotoxin

55
Q

Oxazolidinones: adverse reactions

A

Thrombocytopenia and anemia
o Bone marrow depression but rarely neutropenia
o Usually not seen until after 2 weeks therapy

Peripheral neuropathy
o Associated with long term use (> 4 weeks)

56
Q

Streptogramins: adverse reactions

A
  • Phlebitis (usually administered by central venous catheter)
  • Myalgias/arthralgias = can be very severe and require narcotics for control
57
Q

Nitrofurantoin: adverse reactions

A
  • Gastrointestinal

* Pulmonary Hypersensitivity (rare)

FM 2 (7 decks)

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