Protein Synthesis Inhibitors Flashcards
Protein Synthesis Inhibitors
Bind to bacterial ribosomes to block protein translation
Bind to 30s Ribosome
- Aminoglycosides
- Tetracyclines
Bind to 50s Ribosome
- Macrolides
- Lincosamides
- Streptogramins
- Oxazolidinones
Aminoglycoside MoA
Block initiation complex formation, proofreading, and ribosomal translocation
Aminoglycoside Examples
- Streptomycin
- Kanamycin
- Gentamimcin
- Tobramycin
- Amikacin
- Neomycin
Tetracyclines MoA
Prevents binding of incoming tRNA
Tetracycline Examples
- Tetracycline
- Doxycycline (Vibramycin/Doryx)
- Minocycline (Minocin)
Macrolide MoA
Blocks polypeptide exit tunnel
Macrolide Examples
- Erythromycin
- Clarithromycin (Biaxin)
- Azithromycin (Z-PAK, Zithromax)
Lincosamides MoA
Binding site overlaps with macrolides
Lincosamides Example
Clindamycin (Cleocin)
Streptogramins MoA
-Binding site overlaps with macrolides
Streptogramins Examples
-Quinupristin/Dalfopristin (Synercid)
Oxazolidinones MoA
Binds 23s rRNA, prevents ribosome assembly
Oxazolidinones Examples
- Linezolid (Zyvox)
- Tedizolid (Sivextro)
Aminoglycosides
- 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
Aminoglycosides PK
- Efficacy: concentration dependent
- Synergy with cell wall synthesis inhibitors
- IV administration
- Dosing goal: [plasma] = >= 10-12x the MIC
Aminoglycoside Resistance
- Ribosome mutations that prevent binding
- Aminoglycoside modifying enzymes (AME) - acetylation, phosphorylation
- Impaired entry: porin deletion/mutation, loss of active transport
- Efflux pumps
Aminoglycoside AE
- 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
Aminoglycoside Nephrotoxic Mechanism
- 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
Aminoglycoside Monitoring
- Renal function
- 8th nerve function
- Peak/trough [serum]
- Urine specific gravity/protein
- Serum BUN, creatinine, and CrCl
- Serial audiograms
Garamycin
- Gentamicin
- Isolated from micomonospora sp.
Tobramycin
-Slightly more active against P. aeruginosa
Amikin
- 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
Neomycin
-Topical
Streptomycin
- Isolated from streptomyces sp.
- Widespread resistance
- Use limited to susceptible tuberculosis, plague, tularemia
Tetracyclines
- Generally bacteriostatic
- Can inhibit protein synthesis in mammalian cells partially, but active efflux mechanism prevents accumulation
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
Tetracycline Resistance
- Active efflux system
- Acquiring genes that encode for ribosomal protection proteins that block tetracycline binding
- Antibiotic modification (enzymatic inactivation)
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
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
Macrolides
- Generally bacteriostatic
- Cover mainly atypicals
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
Macrolide Resistance
- Inability to take up antibiotic
- Efflux pump
- Plasmid-associated eryhtromycin esterase
- 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)
- Clarithromycin and azithromycin show cross-resistance with eryhtromycin
S. Pneumoniae Resistance
- High or low level macrolide resistance
- High: mutation in ribosome binding site
- Low: efflux pumps
Macrolide AE
- Epigastric distress
- Ototoxicity at high doses
- Liver toxicity probably from an allergic reaction
- Prolongs QT interval
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
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
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
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
Synercid Interactions
- Inhibits CYP3A4
- Don’t give with CYP3A4 metabolized drugs that prolong QTc (cyclosporine)
Synercid AE
- Phlebitis with IV administration
- Severe arthralgias/myalgias
- Hyperbilirubinemia
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
Zyvox Toxicities
- Duration dependent: bone marrow suppression/thrombocytopenia/anemia/neutropenia (reversible)
- Neuropathy
- Optic neuritis
Zyvox Drug Interactions
-MAOI: serotonin syndrome may occur when taken with other serotonergic agents (SSRIs)
Sivextro
- Tedizolid
- 2nd generation Oxazolidinone
- Used for ABSSSI
- Daily dosing for 6 days vs BID x 10-14 days with Linezolid
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