Protein & Nucleic Acid Synthesis Inhibitors

Question 1

Aminoglycosides: MOA

Answer 1

• Inhibit elongation cycle by binding to 30S ribosome

Question 2

Aminoglycosides: Types

Answer 2

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

Question 3

Aminoglycosides: Pharmacodynamics

Answer 3

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)

Question 4

Aminoglycosides: Pharmacology

Answer 4

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

Question 5

Aminoglycosides: Spectrum

Answer 5

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

Question 6

Tetracyclines: MOA

Answer 6

• Inhibit elongation cycle by binding to 30S ribosome

Question 7

Tetracyclines: Types

Answer 7

o Natural tetracyclines
o Semisynthetic: Doxycycline
o Glycylcyclines: Tigecycline

Question 8

Tetracyclines: Pharmacodynamics

Answer 8

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

Question 9

Tetracyclines: Pharmacology

Answer 9

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

Question 10

Tetracyclines: Spectrum

Answer 10

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

Question 11

Chloramphenicol: MOA

Answer 11

• Inhibit the elongation cycle by binding 50S ribosome

Question 12

Chloramphenicol: Pharmacodynamics

Answer 12

o Bacteriostatic agent (reversible binding)

Question 13

Chloramphenicol: Pharmacology

Answer 13

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

Question 14

Chloramphenicol: Spectrum

Answer 14

o Broad spectrum

o Poor against Pseudomonas and Legionella

Question 15

Macrolides: MOA

Answer 15

• Inhibit the elongation cycle by binding 50S ribosome

Question 16

Macrolides: Types

Answer 16

o Natural: erythromycin, dirithromycin

o Semisynthetic: Clarithromycin, Azithromycin

Question 17

Macrolides: Pharmacology

Answer 17

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)

Question 18

Macrolides: Spectrum

Answer 18

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)

Question 19

Clindamycin: MOA

Answer 19

• Inhibit the elongation cycle by binding 50S ribosome

Question 20

Clindamycin: Pharmacology

Answer 20

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

Question 21

Clindamycin: Spectrum

Answer 21

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

Modest activity against:
• Toxoplasma
• Pneumocystis jiroveci

Fair/poor against:
• Mycoplasma
• Chlamydia
• Legionella

Question 22

Oxazolidinones (Linezolid): MOA

Answer 22

• Inhibit 70S initiation complex

Question 23

Oxazolidinones (Linezolid): Pharmacodynamics

Answer 23

o Considered bacteriostatic, but does kill bacteria slowly

Question 24

Oxazolidinones (Linezolid): Pharmacology

Answer 24

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

Question 25

Oxazolidinones (Linezolid): Spectrum

Answer 25

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

Question 26

Streptogramins: MOA

Answer 26

• Inhibit the elongation cycle by binding 50S ribosome

Question 27

Streptogramins: Pharmacodynamics

Answer 27

o Used alone: bacteriostatic | o Used together: bactericidal

Question 28

Streptogramins: Pharmacology

Answer 28

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

Question 29

Streptogramins: Spectrum

Answer 29

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

Question 30

Nitrofurantoin: MOA

Answer 30

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

Question 31

Nitrofurantoin: Properties

Answer 31

o Urinary agent

Question 32

Nitrofurantoin: Pharmacology

Answer 32

o Good oral absorption | o Rapid enzyme degradation → only get adequate concentrations in urine

Question 33

Nitrofurantoin: Spectrum

Answer 33

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

Question 34

Aminoglycosides: Resistance

Answer 34

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)

Question 35

Tetracyclines: Resistance

Answer 35

• 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)

Question 36

Chloramphenicol: Resistance

Answer 36

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

Question 37

Macrolides: Resistance

Answer 37

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%

Question 38

Clindamycin: Resistance

Answer 38

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)

Question 39

Oxazolidinones: Resistance

Answer 39

* Primarily in Enterococcus faecium; still rare in S. aureus but increasing * Due to mutations near binding site to ribosome

Question 40

Streptogramins: Resistance

Answer 40

* 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

Question 41

Nitrofurantoin: Resistance

Answer 41

* Uncommon | * Due to reduced nitrofuran reductase activity

Question 42

Aminoglycosides: uses

Answer 42

* 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

Question 43

Tetracylcine: Uses

Answer 43

• 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

Question 44

Chloramphenicol: uses

Answer 44

• 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)

Question 45

Macrolides: uses

Answer 45

``` 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

Question 46

Clindamycin: uses

Answer 46

• 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

Question 47

Oxazolidinones: uses

Answer 47

• 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)

Question 48

Streptogramins: uses

Answer 48

* Vancomycin resistant E. Faecium infections | * MRSA infections (alternative to vancomycin)

Question 49

Nitrofurantoin: uses

Answer 49

* Treatment and prophylaxis of UTIs | * Not effective in patients with < 50% of normal renal function

Question 50

Aminoglycosides: adverse reactions

Answer 50

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

Question 51

Tetracyclines: adverse reactions

Answer 51

• 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

Question 52

Chloramphenicol: adverse reactions

Answer 52

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

Question 53

Macrolides: adverse reactions

Answer 53

• 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)

Question 54

Clindamycin: adverse reactions

Answer 54

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

Question 55

Oxazolidinones: adverse reactions

Answer 55

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)

Question 56

Streptogramins: adverse reactions

Answer 56

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

Question 57

Nitrofurantoin: adverse reactions

Answer 57

* Gastrointestinal | * Pulmonary Hypersensitivity (rare)