Protein synthesis inhibitors Flashcards
Which protein synthesis inhibitors can be used in pregnancy?
Macrolides (erythromycin, azithromycin), Clindamycin
Which protein synthesis inhibitors have good CSF penetration?
Linezolid (good)
Doxy/Minocyclines (moderate)
All protein synthesis inhibitors are bacteriostatic except ____.
Aminoglycoside - bactericidal
=> because cationic, cause fissures in cell membrane
How do aminoglycosides enter the bacteria cell?
Diffuse through aqueous porin channels in the outer membrane of gram-negative bacteria, then transported across inner membrane via active transport
Aminoglycoside requires active transport.
What conditions may inhibit this energy-dependent active transport into the bacteria cell?
- Anaerobic condition (e.g., abscess, infected bone)
- Drop in pH (more acidic)
- Hyperosmolarity
Tetracyclines and Tigecyclines do not cover _____ and _____
Pseudomonas and proteus (but covers H. influenzae, Yersinia pestis)
Also does not cover streptococcus and enterococcus (but covers MRSA, Strep pneumoniae) => except tige can cover MDR-strep, VRE
Covers atypicals, spirochete (treponema)
How are tetracyclines cleared?
Tetracycline - renal
Doxycyline - excreted unchanged in bile and urine
Minocycline - liver
Tetracyclines bind to tissues undergoing calcified tissues. What are the effects?
Primary dentition - grey discoloration, hypoplasia of teeth
Bones - stunt growth (*myasthenia gravis)
*Can cross placenta barrier to concentrate in fetal bones and dentitions
Tigecycline is structurally related to ______
However, it has expanded spectrum of activity + decreased susceptibility to development of resistance compared to tetracyclines
Minocycline
Why is Tigecycline a poor option for bloodstream infections?
It is given IV, penetrates well into tissues, but has low plasma concentration.
Tigecycline requires dose adjustment in _______
Severe hepatic dysfunction
*No dose adjustment in renal impairment
*Eliminated via bile and feces
What drugs cause photosensitivity?
Tetracyclines, Tigecyclines
Fluoroquinolones
Cotrimoxazole
Pyrazinamide
What are tetra/tigecycline adverse effects?
- Gastric discomfort, epigastric distress, esophageal irritation and ulceration
- Deposition and accumulation in bone and primary dentition
- Phototoxicity
- Hepatotoxicity
- Vestibular dysfunction (mino)
- Renal side effects due to accumulation of tetracyclines (tetra - renally cleared)
- Superinfection (CDAD >2months post antibiotic tx)
Name the drugs that can cover atypicals
Tetra/Tigecyclines
Macrolides
Fluoroquinolones (Levo and Moxi)
Describe the PK of Aminoglycosides?
Conc. dependent killing with PAE
Aminoglycoside has gram-positive coverage against staphylococcus and enterococcus only when used in combi. Name the combinations.
Gentamicin + Ampicillin => Enterococcus Endocarditis
Gentamicin + Ceftriaxone => Staphylococcus Endocarditis
*No activity against streptococcus
Aminoglycosides are commonly used as ______ therapy
Empiric
*Covers many aerobic gram-negative organisms
Which two aminoglycosides are active against mycobacterium tuberculosis?
Streptomycin
Amikacin
Neomycin is not used parenterally because?
Nephrotoxic
Aminoglycoside is dosed based on ______. Why?
Lean body mass (use AdjBW, not TBW if TBW >130%
Because aminoglycoside is hydrophilic and does not distribute to fat tissues
Aminoglycoside causes nephrotoxicity, what should be monitored?
Renal function test
- urea
- creatinine
- electrolytes
What are the 4 mechanisms of resistance to aminoglycosides?
- Increased efflux pump
- Aminoglycoside modification (e.g., acetylation due to aminoglycoside inactivating enzymes produced by the bacteria) => decrease binding affinity
- alter 30S subunit
- inhibition of aminoglycoside uptake by the bacteria
Which protein synthesis inhibitors cover enterococcus?
Linezolid
Aminoglycoside (in combi with penicillins for enteroccocus endocarditis)
Tigecycline (VRE)
Macrolide is a CYP450 ______
Which macrolide has reduced effect?
inhibitor
Azithromycin has reduced inhibitory effect on CYP450 enzyme
Clarithromycin and Azithromycin have structural modifications from Erythromycin that:
- improve acid stability (erythromycin destroyed by gastric acid)
- improve tissue penetration
- broaden spectrum of activity
What are macrolides effective against?
Atypicals
(Respi) Streptococcus Pneumoniae, H. influenzae, Moraxella catharrhalis
(STD) Neisseria gonorrhea, Chlamydia
Mycobacterial infections
H. pylori (part of triple therapy)
How are macrolides cleared?
Erythromycin and Clarithromycin - metabolized hepatically
Azithromycin - eliminated unchanged in feces and bile
Macrolide route of administration
Oral/IV
*Clarithromycin only oral
Azithromycin can be used with ______ against Neisseria gonorrhea
Ceftriaxone (IM)
Azithromycin also has activity against some common bacterial enteric pathogens such as:
Campylobacter, salmonella, shigella, vibrio cholerae
What are the adverse effects of macrolides?
- Gastric distress and motility
(Erythromycin is a motilin agonist with prokinetic effect, can reduce oral absorption of other drugs) - Hepatotoxicity (cholestatic jaundice)
(Treat pt with hepatic dysfunction cautiously) - Ototoxicity (Azithromycin highest risk)
- Prolong QT interval
What are the 2 mechanisms of macrolide resistance?
- Erm gene expressure => ribosomal methylation, reduce binding affinity
- Efflux pumps
Why might there be cross resistance of clindamycin to macrolides?
- Erm gene expression, ribosomal methylation of the 23s rRNA
- Alteration of 50S subunit by AA substitution
- Nucleotidylation of hydroxyl group of clindamycin
*Clindamycin is NOT a subtrate of the efflux pump
Which two drugs may antagonize each others action due to acting at sites of proximity?
Clindamycin and Erythromycin
Clindamycin coverage includes?
+ve: MRSA, MSSA, streptococcus (*NO activity against enterococcus)
*Toxic shock syndrome (caused by staphs or streps)
Anaerobes: Peptostreptococcus, Bacteroides, Clostridioides perfringen (*CAUSES C. diff)
Almost all ______ are resistant to clindamycin
Aerobic gram negatives
How is clindamycin cleared?
Hepatic oxidative metabolism into inactive metabolites which are excreted in bile and urine
*Dose adj required in hepatic impairment
What are clindamycin adverse effects?
- GI - diarrhea, vomitting
- Esophageal irritation
- Skin rash
- CDAD
Why can’t linezolid be used against gram-negatives?
Gram-negatives are intrinsically resistant to Linezolid due to efflux pumps that force linezolid out
What is linezolids coverage?
Gram positives (staph, strep, entero, listeria) LAME without A
as well as resistant strains (MRSA, VRE, VRSA)
*However not used first as it will hasten selection of resistant strains (it is reserved as alternative for MDR strains)
How is linezolid cleared?
Broken down by nonenzymatic oxidation to two inactive metabolites, appears in urine
*No dose adjustment for renal or hepatic dysfunction
What are linezolid adverse effects?
- Bone marrow suppression (>10 days)
- Serotonin syndrome (as it has nonselective monoamine oxidase inhibitory activity)
*do not use within 2weeks of MAOi
*avoid tyramine and histamine containing food - Peripheral neuropathy + optic neuritis (>28 days)
Others: GI effects, headache, rash
What are the mechanisms of resistance to linezolid?
- Mutations in 23S rRNA
- cfr rRNA methyltransferase modifies 23S rRNA
Linezolid is not approved for treatment of ______
intravascular catheter related bloodstream infections
