Antibiotics That Target Bacterial Protein Synthesis

Front 1

Why is the prokaryotic 70S ribosomal complex a common antibiotic target?

Back 1

It is different enough from mammalian ribosomes to avoid most, but not all, cross-toxicity

Front 2

What are two subunits of a prokaryotic ribosome?

Back 2

30S (mRNA decoding)

50S (peptide synthesis)

Front 3

What are the two tRNA binding sites on a prokaryotic ribosome?

Back 3

P (peptidyl or donor) site

A (acceptor) site

Front 4

Steps in bacterial protein translation

Back 4

1) Initiation - assembly of the 70S complex

2) Early elongation - a new amino acid binds to the A site

3) Late elongation - a bond is formed between the existing peptide (at the P site) and the new amino acid (at the A site)

4) Translocation - the tRNA and peptide move from the A to the P site

Front 5

Is protein suppression usually bacteriostatic or bactericidal?

Back 5

Bacteriostatic

Front 6

How can bacteria potentially survive protein suppression?

Back 6

By going dormant

Front 7

Which classes of antibiotics target the 50S subunit?

Back 7

Macrolides

Chloramphenicol

Lincosamides

Streptogramins

Oxazolidinones

Front 8

Which classes of antibiotics target the 30S subunit?

Back 8

Aminoglycosides

Tetracyclines

Front 9

What are the three tetracycline subgroups?

Back 9

"Older" tetracyclines (more hydrophilic)

"Newer" tetracyclines (more hydrophobic)

Glycylcyclines

Front 10

What is the prototype "newer" tetracycline?

Back 10

Doxycycline

Front 11

What is the prototype glycylcycline?

Back 11

Tigecycline

Front 12

Tetracyclines inhibit which step in protein translation?

Back 12

Early elongation

Front 13

What is the mechanism of action of the tetracyclines?

Back 13

They bind to the 30S subunit, preventing the binding of aminoacyl tRNAs to the A site

Front 14

Are tetracyclines bacteriostatic or bactericidal?

Back 14

Bacteriostatic

Front 15

Are tetracyclines broad or narrow-spectrum?

Back 15

Broad-spectrum

Front 16

Why has use of tetracyclines decreased?

Back 16

Resistance

Front 17

What are two common mechanisms for high-level tetracycline resistance?

Back 17

Expression of efflux pumps

Ribosomal protection proteins (GTP-dependent displacement of tetracyclines from their binding site on the ribosome)

Front 18

How is tigecycline able to overcome tetracyline resistance?

Back 18

It is a poor pump substrate

It is not easily displaced from the ribosome

Front 19

What kinds of bacteria are covered by the tetracylines?

Back 19

Gram-postivie

Gram-negative

Intracellular

Spirochetes

Front 20

Why are tetracyclines used as alternative (and not primary) drugs for many infections?

Back 20

Resistance

Adverse effects

Front 21

Doxycycline is most useful for ____ and ____ pathogens

Back 21

Intracellular

Spirochete

Front 22

____ is most often a last-resort treatment for various multi-drug resistant pathogens

Back 22

Tigecycline

Front 23

Describe the pharmacokinetics of doxycycline

Back 23

Best oral bioavailability and least food interactions of the tetracyclines

Mixed renal and hepatic elimination

Good distribution, except CNS

Binds multivalent ions somewhat less than other tetracyclines

Front 24

Describe the pharmacokinetics of tigecycline

Back 24

Only available for injection

Mostly hepatic elimination (more lipophilic)

Very large Vd (volume of distribution) that can make it difficult to maintain desired blood levels

Tissue binding continually pulls drug out of blood, contributing to unexpected therapeutic failure and deaths during monotherapy

Front 25

Why should patients avoid ingesting dairy products, iron supplements, and some antacids two hours before and after taking a tetracycline?

Back 25

Tetracyclines bind multivalent ions

Front 26

Adverse effects of tetracyclines

Back 26

GI distress

Photosensitivity

Nephrotoxicity or hepatotoxicity (uncommon)

Discoloration of teeth (in children up to 8 years old)

Front 27

What is the prototypical aminoglycoside?

Back 27

Gentamicin

Front 28

What is the mechanism of action of gentamicin?

Back 28

It binds to and changes the conformation of the 30S subunit

Front 29

What translation defects are induced by gentamicin?

Back 29

1) Stops ribosomal movement at the start codon

2) Altered 30S conformation allows incorrect aminoacyl-tRNAs to bind, resulting in abnormal or truncated proteins

3) Forces premature termination

Front 30

Are aminoglycosides (gentamicin) bactericidal or bacteriostatic?

Back 30

Bactericidal

Front 31

Why are aminoglycosides (gentamicin) bactericidal?

Back 31

They result in aberrant proteins that can insert into cell membranes, causing lethal damage

Front 32

What are two important characteristics of aminoglycosides (gentamicin) that should be kept in mind when selecting a dosing protocol?

Back 32

Concentration-dependent killing

Long post-antibiotic effect

Front 33

Why is once daily dosing with aminoglycocides (gentamicin) just as effecting as traditional dosing (every 8 hours)?

Back 33

Higher peak concentrations are very effective due to concentration-dependent killing

Bacterial growth does not resume when the drug concentration falls below the MIC because of the post-antibiotic effect

Front 34

What mechanism is responsible for bacterial resistance to aminoglycosides (gentamicin)?

Back 34

Enzymatic inactivation (e.g. acetylation at amine sites)

Front 35

What kinds of bacteria are covered by aminoglycosides?

Back 35

Gram-positive

Gram-negative

Front 36

Why aren't anaerobic bacteria killed by aminoglycosides (gentamicin)?

Back 36

Aminoglycoside transport is facilitated by a high membrane potential, and anaerobic bacteria are too depolarized

Front 37

Describe the pharmacokinetics of the aminoglycosides (gentamicin)

Back 37

Not absorbed orally

Mainly renal elimination with short T1/2 (1-3 hrs)

Poor distribution (including CNS)

Front 38

What is the main use of aminoglycosides (gentamicin)?

Back 38

In the hospital setting for serious infections (e.g. systemic infections by Gram-negative rods)

Front 39

Aminoglycosides (gentamicin) are often combined with ____ for a synergistic bactericidal effect

Back 39

β-lactams

Front 40

Adverse effects of aminoglycosides (gentamicin)

Back 40

Nephrotoxicity (reversible unless severe)

Ototoxicity (resulting in tinnitus or high-frequency hearing loss; only partially reversible)

Vestibular toxicity (resulting in vertigo; only partially reversible)

Neuromuscular junction block (contraindicated with myasthenia gravis)

Front 41

Why is therapeutic drug monitoring required for the aminoglycosides (gentamicin)?

Back 41

Renal toxicity

Front 42

How do the aminoglycosides (gentamicin) accumulate in renal tubular epithelial cells?

Back 42

By binding to megalin (a membrane receptor) and undergoing clathrin-dependent endocytosis

Front 43

How can the renal toxicity of the aminoglycosides (gentamicin) be minimized?

Back 43

By keeping "trough" concentrations low

Avoiding use of other nephrotoxic drugs

Front 44

How does once daily dosing of the aminoglycosides (gentamicin) decrease renal toxicity?

Back 44

High concentrations of aminoglycosides saturate megalin-mediated drug uptake, leading to a net decrease in intracellular drug accumulation

Front 45

Chloramphenicol inhibits which step in bacterial protein translation?

Back 45

Late elongation

Front 46

What is the mechanism of action of chloramphenicol?

Back 46

It binds to the 50S subunit, preventing the transfer of the polypeptide chain to the waiting tRNA at the A site and preventing peptide bond formation

Front 47

What drugs bind the 50S subunit adjacent to chloramphenicol? Why is this important?

Back 47

Clindamycin

Macrolides

They could interfere with each other if used together

Front 48

What mechanism is responsible for bacterial resistance to chloramphenicol?

Back 48

Enzymatic inactivation (acetylation by chloramphenicol acetyl transferase)

Front 49

Is chloramphenicol broad or narrow-spectrum?

Back 49

Broad-spectrum

Front 50

Is chloramphenicol bactericidal or bacteriostatic?

Back 50

Bacteriostatic

Front 51

What kinds of bacteria are covered by chloramphenicol?

Back 51

Some Gram-negatives

Anaerobes

Intracellular (e.g. rickettsias)

Front 52

Describe the pharmacokinetics of chloramphenicol

Back 52

Only available as injection

Excellent distribution, including CNS and intracellular compartments

Mainly eliminated by hepatic glucuronidation

Front 53

What is an adverse effect of chloramphenicol in neonates?

Back 53

Gray baby syndrome

Front 54

Why does chloramphenicol cause gray baby syndrome?

Back 54

Slow metabolism in neonates

Front 55

Symptoms of gray baby syndrome

Back 55

Skin discoloration

Flaccidity

Respiratory distress

Shock

Front 56

What is important to remember about chloramphenicol in terms of drug interactions?

Back 56

It is a CYP inhibitor (drug interactions with anticoagulants, anti-epileptics, etc.)

Front 57

Adverse effects of chloramphenicol

Back 57

Idiopathic aplastic anemia (includes all formed blood elements)

Dose-dependent bone marrow depression

Front 58

How is chloramphenicol typically used?

Back 58

Used for complicated infections (rickettsioses, anaerobic infections, etc.) where less toxic antibiotics are either ineffective or can't be tolerated by the patient

Front 59

What is the prototypical lincosamide?

Back 59

Clindamycin

Front 60

What are topical forms of clindamycin used for?

Back 60

Acne vulgaris

Front 61

What are vaginal dosage forms of clindamycin used for?

Back 61

Bacterial vaginosis

Front 62

Clindamycin inhibits which step in bacterial protein translation?

Back 62

Late elongation

Front 63

What is the mechanism of action of clindamycin?

Back 63

Binds to the 50S subunit, preventing movement of the peptide from the P site to the A site and preventing peptide bond formation

Front 64

What mechanism is responsible for bacterial resistance to clindamycin?

Back 64

Methylation of the ribosome target by an inducible enzyme

Front 65

Is clindamycin broad or narrow-spectrum?

Back 65

Broad

Front 66

Is clindamycin bactericidal or bacteriostatic?

Back 66

Bacteriostatic

Front 67

What kinds of bacteria are covered by clindamycin?

Back 67

Gram-postive

Anaerobes (especially)

Also covers some protozoa

Front 68

Describe the pharmacokinetics of clindamycin

Back 68

Very good oral bioavailability

Eliminated mainly by hepatic oxidation

Remains in feces for a prolonged time

Well-distributed (including bone), except for CNS

Front 69

Adverse effects of clindamycin

Back 69

High incidence of diarrhea

Thrombocytopenia or agranulocytosis

High doses can cause neuromuscular junction block

Clostridium difficile-mediated psuedomembranous colitis

Front 70

How is clindamycin typically used?

Back 70

β-lactam alternative (non-MRSA and MRSA)

Anaerobic infections

Front 71

What is the prototypical macrolide?

Back 71

Azithromycin

Front 72

Macrolides inhibit which step in bacterial protein translation?

Back 72

Translocation

Front 73

What is the mechanism of action of the macrolides (azithromycin)?

Back 73

Macrolides bind to the 50S subunit, blocking the "exit tunnel" by which peptides leave the ribosome and stalling translation with the peptide at the A site

Front 74

Are macrolides (azithromycin) broad or narrow-spectrum?

Back 74

Broad-spectrum

Front 75

What kinds of bacteria are covered by macrolides (azithromycin)?

Back 75

Some Gram-positive

Gram-negative

Intracellular

Many atypical microbes (e.g. mycoplasma)

Front 76

What mechanisms are responsible for bacterial resistance to macrolides (azithromycin)?

Back 76

Enzymatic methylation of the macrolide binding site on the 50S subunit, decreasing drug affinity

Efflux of macrolides out of bacteria

Front 77

What advantage do ketolides have over macrolides (azithromycin)?

Back 77

They are less affected by the main bacterial resistance mechanism for the macrolides

Front 78

Macrolides (azithromycin) and ketolides are often the drugs of choice for ____ and ____ infections

Back 78

Mycoplasma

Chlamydiae

Front 79

Describe the pharmacokinetics of the macrolides (azithromycin)

Back 79

Good bioavailability (except for erythromycin)

Good distribution, except CNS

Mainly hepatic elimination

Azithromycin has notably longer T1/2 than others

Front 80

All macrolides except azithromycin are ____ inhibitors, meaning they...

Back 80

CYP3A4

They can elevate blood levels of anticonvulsants, anticoagulants, and immunosuppresants

Front 81

Adverse effects of macrolides (azithromycin)

Back 81

Ventricular arrhythmia

Front 82

What are the prototypical streptogramins?

Back 82

Quinupristin

Dalfopristin

Front 83

(Quinupristin or Dalfopristin?) is a "Group B" streptogramin

Back 83

Quinupristin

Front 84

(Quinupristin or Dalfopristin?) is a "Group A" streptogramin

Back 84

Dalfopristin

Front 85

Why are Group A and Group B streptogramins given together?

Back 85

Group A streptogramins promote the binding of group B streptogramins (synergistic effect)

Front 86

Which steps of bacterial protein synthesis are inhibited by the streptogramins?

Back 86

Early elongation - dalfopristin inhbits the new amino acid from binding to site A

Late elongation - quinupristin may inhibit formation of the peptide bond

Translocation - dalfopristin inhibits transfer of the tRNA/peptide from site A to site P

Front 87

The streptogramins bind which RNA subunit?

Back 87

50S subunit

Front 88

Is bacterial resistance to streptogramins common?

Back 88

No

Front 89

What mechanism is responsible for bacterial resistance to streptogramins?

Back 89

Enzymatic inactivation of the drug by lactonases

Front 90

Are streptogramins broad or narrow-spectrum?

Back 90

Narrow-spectrum

Front 91

What kind of bacteria is covered by the streptogramins?

Back 91

Gram-positive

Front 92

Are the streptogramins bactericidal or bacteriostatic?

Back 92

Can be either, depending on the species

Front 93

Describe the pharmacokinetics of the streptogramins

Back 93

Only available as injection

Good blood, tissue, and intersitial fluid levels

No CNS distribution

Mostly hepatic and/or biliary excretion

Front 94

What is important to remember about the streptogramins in terms of drug interactions?

Back 94

The are CYP3A4 inhibitors

Front 95

Adverse effects of streptogramins

Back 95

Significant arthralgia or myalgia

Substantial injection site irritation and thrombophlebitis

Front 96

How are the streptogramins typically used?

Back 96

For treatment of drug resistant Gram-positive bacteria (e.g. Staphylococcus aureus and Enterococcus faecium)

Front 97

What is the prototypical oxazolidinone?

Back 97

Linezolid

Front 98

Which step of bacterial protein translation is inhibited by linezolid?

Back 98

Initiation

Front 99

What is the mechanism of action of linezolid?

Back 99

It binds to the P site of the 50S subunit and prevents formation of the 70S complex

Front 100

Is linezolid bactericidal or bacteriostatic?

Back 100

Can be either, depending on the organism

Front 101

Is bacterial resistance against linezolid common?

Back 101

No

Front 102

What mechanisms are responsible for bacterial resistance to linezolid?

Back 102

Binding site mutation or methylation

Front 103

Is linezolid broad or narrow-spectrum?

Back 103

Narrow-spectrum

Front 104

What kind of bacteria are covered by linezolid?

Back 104

Gram-positive cocci and bacilli

Front 105

How is linezolid typically used?

Back 105

As an alternative treatment for multi-drug resistant Gram-positive cocci (e.g. S. pneumoniae, S. aureus, Enterococcus)

Front 106

Adverse effects of linezolid

Back 106

Mild to moderate thrombocytopenia or neutropenia (reversible)

Peripheral neurotoxicity (uncommon, but sometimes irreversible)

Front 107

Which class of drugs should linezolid never be combined with? Why?

Back 107

Antidepressants, because linezolid can increase serotonergic neurotransmission

Front 108

Describe the pharmacokinetics of linezolid

Back 108

Excellent oral bioavailability

Well-distributed, including CNS

Mainly non-enzymatic hepatic elimination (some renal elimination)