B&B Protein Synthesis Inhibitors Flashcards
Protein Synthesis Inhibitors
Aminoglycosides Macrolides Tetracyclines Chloramphenicol Clindamycin Linezolid Streptogramins
Bacterial Protein Synthesis
DNA inside cytoplasm which must be transcribed to RNA by RNA polymerase (target of Rifampin for tuberculosis)
To initiate protein synthesis
- Initiate Process: Ribosomal subunits have to bind mRNA
- 50s subunit and 30s subunit - Add tRNA
- Add peptides, translocate
Antibiotics that work on initiation process
Aminoglycosides/Linezolid
Antibiotics that block tRNA addition
Tetracyclines
Antibiotics that block addition of peptides and translocation
Chloramphenicol
Macrolides
Clindomycin
Aminoglycosides
Gentamicin Neomycin Amikacin Tobramycin Streptomycin
Aminoglycosides
Block protein synthesis initiation
Aminoglycoside MOA
Block initiation of protein synthesis
- Primarily bind 30S
- Misreading of genetic code
- Bacteria cannot divide, produce cellular proteins
- Cell death (bactericidal)
Aminoglycosides require what for transport into cells
O2
Not effective against anaerobes
Do aminoglycosides affect eukaryotic cells?
No (different ribosomes)
Are aminoglycosides transported into eukaryotic cells?
No. Therefore they are not effective against IC organisms like Rickettsia and Chlamydia
Aminoglycosides are usually used
in combination but can be used along for serious gram (-) infections
Streptomycin
Aminoglycoside used for tuberculosis in combo w/ other drugs
Neomycin
Given prior to bowel surgery
Poorly absorbed (stays in gut)
Often given with erythromycin
Decrease colonic bacteria
Aminoglyosides are often added to what drug
Beta-lactams
Synergistic effects: Combo effective than one drug alone
Endocarditis Tx
Vancomycin/Gentomycin
Newborn meningitis Tx due to Listeria
Ampicillin/Gentamycin
Pseudomonas Tx for CF patients
Pip/Tazo + tobramycin
Resistance to aminoglycosides
Bacteria acquire Aminoglycoside Modifying Enzymes
Bacteria acquired enzymes that modify drug structure
Modified structure binds poorly to ribosomes
Phosphorylation (mediated by aminoglycoside kinase)
Adenylation/acetylation (mediated by transferases)
Aminoglycosides: Adverse S/E
Ototoxicity: 8th CN -Hearing loss, balance problems Nephrotoxicity: -5-10% of drug taken up by proximal tubule cells -Serum creatinine will rise
Rare S/E of aminoglycosides
Neuromuscular blockade
- Can limit/block release of Ach at NMJ
- Usually occurs when levels are high or pre-existing neuromuscular disease
Can you give aminoglycosides to pregnant women?
No. Pregnancy Class D. Renal and Ototoxicity in fetus.
Aminoglycosides: plasma level monitoring
Trough level: just before next dose
Peak level: short time after dose
High aminoglycoside trough =
High risk for toxicity
Low aminoglycoside peak =
Less effective therapy
Macrolides
Azithromycin, Clarithromycin, Erythromycin
MOA Macrolides
Bind 50s ribosomal subunit and block process of translocation:
tRNA binds A site
Ribosome RNA catalyzes peptide bonds (peptidyl transferase)
Ribosome advances along mRNA
tRNA moves to P site
Block tRNA movement to P site (translocation)
Promote tRNA dissociation
May also block peptidyl transferase
Macrolides
Cover many gram (+) cocci, especially strep
Some gram (-) coverage
Concentrated inside macrophages, other cells
Effective against IC pathogens
-Chlamydia (obligate)
-Legionella (facultative)
Common uses of Macrolides
Community Acquired Pneumonia
-Azithromycin covers Strep, H. flu, Atypicals
-Good for penicillin allergic patients
Chlamydia Infections
-Azithromycin (safe in pregnancy)
-Often co-administered with Ceftriaxone (gonorrhea)
Erythromycin
Macrolide
Binds to motolin receptors in GI tract
Stimulates SM contraction
Can be used in GI motility disorders
Clarithromycin
Part of triple therapy for H. pylori
Macrolide Resistance
Bacteria methylate location of macrolide binding, which is 23S rRNA = component of 50S ribosome
Macrolides: Adverse Effects
Nausea, diarrhea, abdominal pain (motility)
-Erythromycin is worst offender
Prolonged Qt on EKG (prolonged K+ blocking)
-Erythromycin is also worst offender
Acute cholestatic hepatitis
-Increased AST/ALT/Alk Phos (out of proportion)/Bilirubin
-Case reports with Azithromycin
-Contraindicated with h/o cholestatic jaundice or hepatic dysfunction
Rash
-Maculopapular allergic reaction
P450 enzyme inhibitors
Will raise serum levels of P450 metabolized drugs
Theophylline, Warfarin
Tetracyclines
Tetracycline, Doxycycline, Demeclocycline, Minocycline
Tetracyclines MOA
Transported into bacterial cells
Binds 30S ribosome
Prevents attachment of tRNA
Demeclocycline
Tetracycline Not used as an antibiotic ADH antagonist Given in SIADH Causes nephrogenic DI to reverse SIADH
Doxycycline
Most commonly used member of tetracycline family
Accumulates IC
Covers many unusual/atypical bacteria
-most zoonoses
-chlamydia
Acne Vulgaris Tx (also minocycline)
-Covers propionibacterium acnes in follicles
Tetracyclines
Absorption impaired by minerals and antacids Cations chelate drug -Calcium, magnesium (antacids) -Iron -Dairy
Tetracyclines resistance
Decreasing influx or increasing efflux from cells
Plasmid-encoded transport pumps
Different from many other antibiotics
-No alteration of drug by bacteria
Tetracycline Adverse Effects
GI distress (common)
-Epigastric pain, N/V, anorexia
Photosensitivity
-Red rash or blisters from sun
Tetracycline Adverse Effects
Discolors teeth of children
Inhibits bone growth in children due to calcium chelation
Can you use tetracyclines if you are pregnant?
No. They cross placenta and accumulate in fetus bones and teeth.
Chloramphenicol
Inhibits peptidyl transferase:
50s ribosomal subunit
-tRNA binds A site
-Ribosome RNA catalyzes peptide bonds (peptidyl transferase)
-Ribosome advances along mRNA
-moves tRNA to P site
Chloramphenical blocks peptidyl transferase
Chloramphenicol is rarely used due to
toxicity and resistance
Chloramphenical
Broad coverage of gram (+), gram (-) and atypicals
Can be used in pregnancy instead of doxycycline
-Rickettsia (RMSF), Ehrlichia
-Only in 1st/2nd trimester
-3rd trimester: gray baby syndrome
Chloramphenical
Used for meningitis
- Covers Neisseria
- less effective than alternative drugs
Chloramphenical Adverse Effects
Anemia: bone marrow suppression
Aplastic anemia: Idiosyncratic, Irreversible, fatal
Gray baby syndrome
Babies lack liver UDP-glucuroynyl transferase Required for drug metabolism/excretion Skin turns ashen, gray Hypotension Often fatal
Clindamycin
Binds 50s ribosome
- 23s rRNA component
- Prevents translocation
- Same as macrolides
Clindamycin Resistance
23s rRNA = component of 50s ribosome
- Location of macrolide binding
- methylation of this site causes resistance
- same as macrolides
Clindamycin
Covers some gram (+)
-Staph, viridans Strep, Strep pyogenes, S. pneumonia
Covers many anaerobes
-Clostridium perfringens
-Mouth anaerobes: Fusobacterium, Prevotella, Peptostreptococcus
Main use of Clindamycin
Main use is to cover anaerobes “above the diaphragm”
-Aspiration pneumonia
-Lung abscesses
-Oral infections (mouth anaerobes)
Lots of resistance to Clindamycin in B. fragilis
-Anaerobic infections “below the diaphragm”
-Metronidazole
Clindamycin Adverse Effects
Classic cause of c. difficile infection -Up to 10% of pts -Pseudomembranous colitis -C. difficile overgrowth -Massive, watery diarrhea Antibiotic-associated diarrhea -Milder than c. diff infection -Changes in GI flora -Less absorption of solutes causes osmotic diarrhea -Stops when drug discontinued
Linezolid
Binds to 50s ribosome
Blocks initiation
Main use: Vancomycin resistant enterococcus (VRE)
-Epidemics in hospitals
-Usually occurs in patients with prior antibiotic treatment
Linezolid S/E
Weak monoamine oxidase (MAO) inhibitor
Can cause serotonin syndrome
High risk when given SSRIs
Fever, confusion, agitation, hyperreflexia
Streptogramins
Quinupristin/Dalfopristin -Block protein synthesis 50s ribosome -Used together for sequential protein synthesis block -Synercid (quinupristin/dalfopristin) Used for Vancomycin resistant bacteria -VRSA -VRE
Which protein synthesis inhibitor is not bacteriostatic?
Aminoglycosides: Bacteriocidal
-Misread proteins travel to cell membrane and increase permeability
