Protein Synthesis Inhibitors Flashcards
1
Q
Protein Synthesis Inhibitors
A
Bind to bacterial ribosomes to block protein translation
2
Q
Bind to 30s Ribosome
A
- Aminoglycosides
- Tetracyclines
3
Q
Bind to 50s Ribosome
A
- Macrolides
- Lincosamides
- Streptogramins
- Oxazolidinones
4
Q
Aminoglycoside MoA
A
Block initiation complex formation, proofreading, and ribosomal translocation
5
Q
Aminoglycoside Examples
A
- Streptomycin
- Kanamycin
- Gentamimcin
- Tobramycin
- Amikacin
- Neomycin
6
Q
Tetracyclines MoA
A
Prevents binding of incoming tRNA
7
Q
Tetracycline Examples
A
- Tetracycline
- Doxycycline (Vibramycin/Doryx)
- Minocycline (Minocin)
8
Q
Macrolide MoA
A
Blocks polypeptide exit tunnel
9
Q
Macrolide Examples
A
- Erythromycin
- Clarithromycin (Biaxin)
- Azithromycin (Z-PAK, Zithromax)
10
Q
Lincosamides MoA
A
Binding site overlaps with macrolides
11
Q
Lincosamides Example
A
Clindamycin (Cleocin)
12
Q
Streptogramins MoA
A
-Binding site overlaps with macrolides
13
Q
Streptogramins Examples
A
-Quinupristin/Dalfopristin (Synercid)
14
Q
Oxazolidinones MoA
A
Binds 23s rRNA, prevents ribosome assembly
15
Q
Oxazolidinones Examples
A
- Linezolid (Zyvox)
- Tedizolid (Sivextro)
16
Q
Aminoglycosides
A
- Pass Gram “-“ outer membrane via porins
- Pass inner membrane by oxygen/energy dependent transport (no activity against anaerobes)
- Irreverisble
- Bactericidal
- Used with B-lactams in serious aerobic, Gram “-“ bacteria OR gentamicin with vanco/B-lactam for Gram “+” endocarditis
17
Q
Aminoglycosides PK
A
- Efficacy: concentration dependent
- Synergy with cell wall synthesis inhibitors
- IV administration
- Dosing goal: [plasma] = >= 10-12x the MIC
18
Q
Aminoglycoside Resistance
A
- Ribosome mutations that prevent binding
- Aminoglycoside modifying enzymes (AME) - acetylation, phosphorylation
- Impaired entry: porin deletion/mutation, loss of active transport
- Efflux pumps
19
Q
Aminoglycoside AE
A
- Reversible nephrotoxicity in 10-20% of patients on treatment >5 days (monitor SCr)
- Irreversible ototoxicity from destruction of hair cells in cochlea (~10%)
- NMJ blockage at high doses
20
Q
Aminoglycoside Nephrotoxic Mechanism
A
- Bind to cytoplasmic membrane of proximal tubular cells, are internalized, and trapped in lysosomes
- Lysosomes also accumulate myeloid bodies and lead to leaky, damaged membranes
21
Q
Aminoglycoside Monitoring
A
- Renal function
- 8th nerve function
- Peak/trough [serum]
- Urine specific gravity/protein
- Serum BUN, creatinine, and CrCl
- Serial audiograms
22
Q
Garamycin
A
- Gentamicin
- Isolated from micomonospora sp.
23
Q
Tobramycin
A
-Slightly more active against P. aeruginosa
24
Q
Amikin
A
- Amikacin
- Used to treat severe, HA-infections with MDR Gram “-“ bacteria
- Highly resistance against enzyme inactivation
- Combined with gentamicin against resistant bugs and is administered IV, IM, or nebulized
25
Neomycin
-Topical
26
Streptomycin
- Isolated from streptomyces sp.
- Widespread resistance
- Use limited to susceptible tuberculosis, plague, tularemia
27
Tetracyclines
- Generally bacteriostatic
| - Can inhibit protein synthesis in mammalian cells partially, but active efflux mechanism prevents accumulation
28
Tetracycline Cell Entry
- Enter Gram "+" by energy-dependent transport protein-carrier mechanism
- Enter Gram "-" bacteria by passive diffusion, porins in outer membrane, then energy-dependent tranport at cytoplasmic membrane
29
Tetracycline Resistance
- Active efflux system
- Acquiring genes that encode for ribosomal protection proteins that block tetracycline binding
- Antibiotic modification (enzymatic inactivation)
30
Tetracycline PK
- Absorption: oral, avoid dairy products, antacids, iron/zinc preparation, and bismuth subsalicylate or kaolin-pectin
- Distribution: liver, kidney, spleen, skin. Binds to tissues undergoing calcification (teeth and bones) and crosses the placenta
- Metabolism/Excretion: don't use if renally impaired, doxycycline: biles/feces mainly, alternative if there are renal problems
31
Tetracycline AE
- Gastric discomfort, take with nondairy foods
- Deposition in bone and teeth during growth in children (stunt growth/teeth discoloration)
- Possible hepatic toxicity with IV use
- Phototoxicity: more frequent with tetracycline and doxycycline
- Vestibular problems: dizziness, N/V, most common with minocycline (sometime doxy too)
- Superinfection by overgrowth of other bacteria like candidiasis, resistant staph in the intestine, or C. diff
32
Macrolides
- Generally bacteriostatic
| - Cover mainly atypicals
33
Macrolides PK
- Oral absorption (food interferes)
- Clarithromycin: short half-life, intra/extracellular
- Azithromycin: LONG half-life, purely intracellular
- Erythromycin: used at low-doses to stimulate GI motility in ICU patients
34
Macrolide Resistance
1. Inability to take up antibiotic
2. Efflux pump
3. Plasmid-associated eryhtromycin esterase
4. Decreased affinity of the 50s ribosome due to methylation of the adenine in the 23s bacterial ribosomal RNA (bacterial methylase) => confers macrolide inducible resistance to clindamycin)
5. Clarithromycin and azithromycin show cross-resistance with eryhtromycin
35
S. Pneumoniae Resistance
- High or low level macrolide resistance
- High: mutation in ribosome binding site
- Low: efflux pumps
36
Macrolide AE
- Epigastric distress
- Ototoxicity at high doses
- Liver toxicity probably from an allergic reaction
- Prolongs QT interval
37
Macrolide Interactions
- Inhibits metabolism of many P450s from extensive liver metabolism (Eryth>Clarith)
- Azithromycin DOESN'T interact with P450s
- Eliminates intestinal flora that inactivates digoxin, therefore greater absorption/toxicity likelihood with digoxin
38
Difficid
- Fidaxomicin
- Macrolide for relapsing/recurring C. difficile
- MoA: inhibits RNA polymerase sigma subunit, inhibits transcription and therefore protein synthesis
- PO administration, minimal systemic absorption
- Confined to GI tract largely
- Metabolism: intestinal hydrolysis to less active metabolite
- Mostly eliminated in feces
39
Cleocin
- Clindamycin
- Lincosamide
- Structurally different from macrolides but mechanistically similar
- Active against Gram "+" and anaerobes besides C. Diff
- Used in severe anaerobic infections
- Also used to treat SSTI from strept and staph and is active against MRSA
- Toxicity: hepatotoxicity and occasional neutropenia, also causes fever, rash, N/V, and diarrhea
- Boxed warning: C. diff associated diarrhea/colitis (~6%)
- DOESN'T penetrate into CNS or intracellular
40
Synercid
- Quinupristin and Dalfopristin (30:70)
- Two structurally distinct streptogramins that bind to separate sites on 50s ribosome unit
- Quinupristin: uses same site as macrolides/lincosamides and early inhibits polypeptide elongation and termination of protein synthesis
- Dalfopristin binds to nearby site and causes a conformational change in 50s unit that enhances the binding of quinupristin and directly interferes with polypeptide-chain formation
- Synergistically act to inhibits protein synthesis (bactericidal)
- Used for E. faecium (VRE) and MRSA complication skin infections
41
Synercid Interactions
- Inhibits CYP3A4
| - Don't give with CYP3A4 metabolized drugs that prolong QTc (cyclosporine)
42
Synercid AE
- Phlebitis with IV administration
- Severe arthralgias/myalgias
- Hyperbilirubinemia
43
Zyvox
- Linezolid
- Oxazolidinone
- MoA: Binds reversibly to 23S rRNA of 50s subunit to prevent ribosome assembly
- Bacteriostatic
- Active against Gram "+" including MRSA and E. faecium
- 100% oral bioavailability
- No cross resistance since its MoA is distinct
44
Zyvox Toxicities
- Duration dependent: bone marrow suppression/thrombocytopenia/anemia/neutropenia (reversible)
- Neuropathy
- Optic neuritis
45
Zyvox Drug Interactions
-MAOI: serotonin syndrome may occur when taken with other serotonergic agents (SSRIs)
46
Sivextro
- Tedizolid
- 2nd generation Oxazolidinone
- Used for ABSSSI
- Daily dosing for 6 days vs BID x 10-14 days with Linezolid
47
Bactroban
- Mupirocin
- Isoleucyl tRNA synthetase inhibitor
- MoA: Inhibits protein synthesis due to loss of critical amino acid (isoleucine)
- Active against Gram "+" cocci
- Used for topical treatment of skin infections like impetigo
- Also used for intranasal S. aureus
- Half-life: 17-36 minutes
- Excreted in urine
