Protein synthesis inhibitors Flashcards
List of antibiotic classes that function as Protein Synthesis Inhibitors
7 listed
- Aminoglycosides
- Macrolides
- Tetracyclines
- Chloramphenicol
- Clindamycin
- Linezolid
- Streptogramins
Rifampin target
Bacterial RNA polymerase
Rifampin is used to treat?
Tuberculosis
Bacterial ribosomal subunits
- 50s subunit
- 30s subunit
Bacterial protein synthesis inhibitors that block the iniation phase of translation
- Aminoglycosides
- Linezolid
Bacterial protein synthesis inhibitors that block the adding of tRNAs phase of translation
Tetracycline
Bacterial protein synthesis inhibitors that block the adding of peptides in translation
- Chloramphenicol
- Macrolides
- Clindamycin
List of Aminoglycosides
- Gentamycin
- Neomycin
- Amikacin
- Tobramycin
- Streptomycin
Aminoglycosides MOA
- Require O2 for transport into cells (not effective against anaerobes)
- Also, not effective against intracellular organisms (Chlamydia, Rickettsia) because they are not transported into Eukaryotic cells
- once in the cell they block the initiation phase of protein synthesis primarily by binding the bacterial ribosomal 30S subunit causing misreading of the genetic code and some of the misread proteins will go to the cells surface resulting in cell death from increased permeability
- Bactericidal (most other bacterial protein synthesis inhibitors are bacteriostatic)
- They do not affect Eukaryotic cells because they have different ribosomes and they are not transported into Eukaryotic cells
Aminoglycosides bacterial effect
Bactericidal
Clinical uses of Aminoglycosides
- Rarely used alone to treat serious Gneg infections
- Streptomycin has been historically used for tuberculosis in combination with other drugs
- Neomycin is given prior to bowel surgery
- poorly absorbed so it stays in the gut
- often with Erythromycin (macrolide)
- Decreases colonic bacteria
- Often used in combination with Beta-lactams
- synergystic effects
- combination is more effective than the sum of effects expected
- synergystic effects
- Vancomycin/Gentamycin for endocarditis when the cause is unknown (Enterococcus endocarditis)
- Ampicillin/Gentamycin for newborn meningitis
- Pip/Tazo + Tobramycin for CF patients (Pseudomonas)
Resistance mechanisms for Aminoglycosides
- Most common is acquisition of “Aminoglycoside modifying enzymes”
- modify the structure reducing Aminoglycosides ability to bind ribosomes effectively usually by phosphorylation (aminoglycoside kinases) or adeylation/acetylation (transferases)
Aminoglycosides adverse effects
- Ototoxicity
- Toxic to 8th cranial nerve
- hearing loss, balance problems
- mechanism is unclear
- Nephrotoxicity
- acute tubular necrosis
- 5-10% drug taken up by proximal tubular cells
- Serum Cr will rise
- Rare: Neuromuscular blockade
- can block/limit release of ACh at neuromuscular junctions
- usually occurs at high concentrations or with pre-existing neuromuscular disease
- Pregnancy Class D
- reports of renal and ototoxicity in fetus
Aminoglycosides contraindications
Pregnancy (class D)
- Reports of ototoxicity and renal toxicity in fetus
Considerations when giving Aminoglycosides
- Contraindicated during pregnancy
- plasma level monitoring
- trough and peak levels
- Low peak = less effective therapy
- High trough = risk of toxicity
- trough and peak levels
List of Macrolides
3 listed
- Azithromycin
- Clarithromycin
- Erythromycin
Macrolides MOA
- Bind to the 50S ribosomal subunit and blocks the process of translocation by binding into the P site so that the tRNA cannot move to the P site
- Also promotes tRNA dissociation
- may also block peptidyl transferase
Macrolides coverage
covers
- Gpos cocci (especially strep)
- some Gneg
- Concentrated inside cells and macrophages making them effective against intracellular pathogens (Chlamydia (obligate), Legionella (facultative)) can cause -> ***Atypical pneumonia***
- these feautres make macrolides a good choid for pneumonia because they cover strep as well as Chlamydia and legionella which can cause atypical pneumonia
Clincial uses of macrolides: Azithromycin
- Community acquired pneumonia
- Azithromycin covers Strep, H. flu, atypicals
- ***good for penicillin allergic patients***
- Chlamydia infection
- Azithromycin (safe in pregnancy)
- often co-administered with Ceftriaxone to cover (N. gonorrhea)
Clinical uses of Macrolides: Erythromycin
GI motility disorders
- binds to motilin receptors in the GI tract which stimulates smooth muscle contraction
Clinical uses of Macrolides: Clarithromycin
Part of triple therapy for H. pylori
A standard triple therapy is amoxicillin, clarithromycin, and a proton pump inhibitor such as omeprazole, lansoprazole, pantoprazole, or esomeprazole.
Mechanisms of resistance to Macrolides
Alter the 23S rRNA = component of the 50S ribosome changing the location of macrolide binding (methylation of this site -> resistance)
Adverse effects of Macrolides
- NVD (motility)
- Erythromycin is the worst offender
- Prolonged QT on EKG
- Erythromycin also worst offender
- Acute Cholestatic hepatitis
- increased AST/ALT/Alk Phos is way eleveated/Bilirubin from case reports of patients on Azithromycin
- Contraindicated with history of cholestatic jaundice or hepatic dysfunction
- Rash
- P450 enzyme inhibitors (raise P450 drugs and things like Warfarin and Theophylline)
Macrolides contraindications
Hx of Cholestatic jaundice or hepatic dysfunction
List of Tetracyclines
4 listed
- Tetracycline
- Doxycycline
- Demeclocycline
- Minocycline
Tetracyclines MOA
transported into bacterial cells and binds the 30S ribosome preventing the attachment of tRNA
Demeclocycline is not used as an antibiotic but instead an ADH antagonist given in SIADH Causing nephrogenic DI to reverse SIADH
What is the most commonly used Tetracycline?
Doxycycline
Coverage of Doxycycline
Accumulates intracellularly and covers many unusual/atypical bacteria
- most zoonoses
- Chlamydia
- used to treat Acne Vulgaris (also minocycline)
- covers propionibacterium acnes within follicles
Tetracyclines considerations when taking the drug
Absorption is impaired by minerals and antacids because these substances are cations and chelate the drug reducing absorption
- Calcium, magnesium (antacids)
- Iron
- Dairy including milk
- Cannot be taken wiith antacids or milk
Mechanisms of resistance to Tetracyclines
Decreasing influx or increasing efflux from cells by plasmid-encoded transport pumps
Different from many other antibiotics as there is no alteration of the drug by bacteria
Adverse effects of Tetracyclines
GI distress (common)
- Epigastric pain
- NV
- anorexia
Photosensitivity
- red rash or blisters in sun exposed areas
Contraindicated in children and pregnancy
- Discoloration of teeth
- Inhibition of bone growth in children
- cross placenta and accumulate in fetal bone and teeth
Chloramphenicol MOA
Inhibits peptidyl transferase
so the tRNA would bind to the A site on the 50S ribosomal subunit and then the peptidyl transferase (ribosomal RNA) would catalyze the peptide bond, this is prevented by Chloramphenicol
Clinical uses of Chloramphenicol
- Rarely used in the developed world because it has a lot of toxicities and there is increasing resistance
- Used in the developing world due to low cost
Chloramphenicol coverage
Broad coverage
- Gpos
- Gneg
- Atypicals
Can be used in pregnancy in place of doxycycline (tetracyclines) but only in the 1st and 2nd trimester ***3rd trimester risk of gray baby synrome***
- Rickettsia (RMSF), Ehrlichia
Can be used for meningitis (developing world)
- covers Neisseria
- less effective than alternative drugs
Adverse effects of Chloramphenicol
- Anemia
- bone marrow suppression
- Aplastic anemia (lose all 3 cell lines)
- Idiosyncratic
- Irreversible -> often fatal
- Gray baby syndrome
- Babies lack liver UDP-glucuronyl transferase which is required for metabolism/excretion of the drug
- skin turns ashen gray
- hypotension
- Often fatal
Clindamycin MOA
Similar to macrolides
binds to the 23S rRNA component of the 50S ribosome preventing translocation
Mechanism of resistance to Clindamycin
23S rRNA = component of the 50S ribosome which is the location of Clindamycin and Macrolide binding which can be methylated leading to bacterial resistance
Clindamycin coverage
- Some Gpos
- Staph
- Strep viridans
- Strep pyogenes
- S. pneumoniae
- Covers many anaerobes
- Clostridium perfringens
- Mouth anaerobes
- Fusobacterium
- Prevotella
- Peptostreptococcus
Clinical uses of Clindamycin
- Main use is to cover anaerobes above the diaphragm
- aspiration pneumonia
- Lung abscesses
- Oral infections (mouth anaerobes)
- B. fragilis has lots of resistance to Clindamycin
- For Anaerobic infections “below the diaphragm” = Metronidazole
Drug for Anaerobic infections “below the diaphragm”
Metronidazole
Clindamycin Adverse effects
- classic cause of C. difficile infection
- up to 10% of patients
- Causes Pseudomembraneous colitis
- C. difficile overgrowth
- Massive, watery diarrhea
- Antibiotic associated diarrhea
- milder than C. diff
- Changes in GI flora
- Less absorption of solutes -> osmotic diarrhea
- Stops when drug is discontinued
Linezolid MOA
Binds to the 50S ribosome and blocks initiation of protein synthesis
Linezolid Clinical use
VRE (Vancomycin Resistant Enterococcus)
- has cause epidemics in hospitalls
- usually occurs in patients with prior antibiotic treatment
Linezolid adverse effects
- Linezolid is a weak MOAI
- because of this it can cause serotonin syndrome
- at high risk when given with SSRIs
- Fever
- confusion
- Agitation
- Hypperreflexia
List of Streptogramins
2 listed
- Quinupristin
- Dalfopristin
Streptogramins MOA
Block protein synthesis 50S ribosome
used together in Synercid (Quinupristin/Dalfopristin) for sequential block of protein synthesis
Streptogramins clinical uses
Vancomycin Resistant bacteria (VRSA and VRE) rare but deadly bugs! These are referred to as the antibiotics of last resort for these bugs!
Aminoglycosides bacterial effect
Bactericidal
Macrolides bacterial effect
Bacteriostatic
Tetracyclines bacterial effect
Bacteriostatic
Chloramphenicol bacterial effect
Bacteriostatic
Clindamycin bacterial effect
Bacteriostatic
Linezolid bacterial effect
Bacteriostatic (mostly)
Streptogramins bacterial effect
Variable
Protein synthesis inhibitors bacterial effect
Almost all of the protein synthesis inhibitors are bacteriostatic EXCEPT for Aminoglycosides and this is because Misread proteins travel to the bacterial membrane increasing permeability causing death
