Pharmacology - Protein Synthesis Inhibitors Flashcards
What are the categories of protein synthesis inhibitors?
- Tetracyclines (+ tigecycline)
- Aminoglycosides
- Macrolides (+ clindamycin)
- Linezolid
Which categories of protein synthesis inhibitors are 30S inhibitors and 50S inhibitors respectively?
30S: Tetracyclines, tigecycline, aminoglycosides
50S: Macrolides
Linezolid binds to 23S bacterial ribosomal RNA of 50S subunit
What is the mechanism of action of the tetracyclines and tigecycline?
Inhibits protein synthesis by binding reversibly to 30S subunit of bacterial ribosome - prevents binding of tRNA to A site of mRNA-ribosome complex, to provide bacteriostatic effect
How are the tetracyclines administered?
(exclude tigecycline)
PO
(doxycycline can be given IV, rarely)
How is tigecycline administered?
IV (poor PO F)
What is the spectrum of action of doxycycline?
- Acne vulgaris
- Anthrax (Bacillus anthracis)
- Streptococcus pneumoniae
- Haemophilus influenzae
- MRSA SSTI
- Rickettsia (Rocky Mountain spotted fever), Chlamydia, Mycoplasma pneumoniae, Vibrio cholerae, Yersinia pestis plague
How is doxycycline eliminated?
Excreted unchanged in bile and urine
What is the spectrum of action of tigecycline?
Active against MRSA, multidrug resistant streptococci, vancomycin resistant enterococci, Extended Spectrum B Lactamase Producing Gram Negative bacteria (esp useful against carbapenem resistant strains)
Not active against Proteus & Pseudomonas
How is tigecycline eliminated?
Not extensively metabolised, mainly by biliary/fecal
What are the adverse reactions associated with the tetracyclines and tigecycline?
- GI Discomfort - irritation of gastric mucosa, drink plenty of water to avoid, do not take immediately before going to bed
- Effects on calcified tissues - deposition in bone and primary dentition during calcification, may cause hypoplasia of teeth and temporary stunting of growth - contraindicated in children and pregnant women
- Hepatotoxicity
- Phototoxicity
- Vestibular dysfunction - dizziness, vertigo, tinnitus (esp minocycline)
- Renal SE - less w doxycycline
- Superinfection - CDAD and/or Pseudomembranous colitis, may be observed >2/12 post Abx Tx
How should the tetracyclines be taken?
Take on an empty stomach, but drink plenty of water to avoid stomach discomfort
Do not take immediately before lying down/going to bed
Avoid dairy products and other substances with divalent/trivalent cations eg antacids - forms non-absorbable chelates, decreasing absorption
Stay away from the sun and wear sunblock if you need to go out - this medicine may increase your risk of sunburn temporarily
What are the contraindications for the tetracyclines and tigecycline?
CONTRAINDICATION W PREGNANCY (D) AND YOUNG AGE - bind to tissues undergoing calcification, interferes w growth, statins teeth irreversibly
How does tigecycline differ from the tetracyclines?
Molecule is altered from minocycline to expand spectrum of activity & dec resistance from efflux pumps and ribosomal protection in bacteria
Can tigecycline be used for bloodstream infection?
No
The use of tetracyclines and tigecycline is contraindicated in which populations of patients?
- Pregnant women,
- Breastfeeding women
- Children less than 8 years of age
What is the mechanism of action of the aminoglycosides?
Distorts ribosomal structure to
- block formation of initiation complex of ribosome
- cause misreading of codons as wrong amino acyl tRNAs are able to bind to A site to put the wrong amino acid in that position
- inhibit translocation
Diffuse through aq porin channels of outer membrane of Gram negative bacteria and transport across inner membrane by active transport - process may be inhibited by anaerobic conditions, pH, hyperosmolarity
List out the 5 aminoglycosides.
- Gentamicin
- Tobramycin
- Amikacin
- Streptomycin
- Neomycin
How is gentamicin administered?
IV/IM/Intrathecal/Opthalmic/Topical
What is the spectrum of activity of gentamicin?
For serious Gram negative infections - E.coli, Klebsiella spp, Proteus mirabilis, ESBL producing E.coli and Klebsiella spp, Amp-C producing GNR
**should not use for Pseudomonas aeruginosa anymore, following CLSI breakpoints (amikacin instead)
Not effective as monoTx for Gram positive, better when used synergistically w cell wall active antibiotics
Can be combined w a penicillin/ceftriaxone to treat Enterobacteriacae eg Proteus, Klebsiella and other MDR Gram negatives as empiric Tx and to avoid resistance
Combined w penicillin for enterococcal endocarditis
What is the spectrum of activity of amikacin?
Active against Proteus, P. aeruginosa, Mycobacterium tuberculosis, and gentamicin resistant Klebsiella, Enterobacter and E. coli
Less active than gentamicin against Enterococci, ineffective against most Gram positive anaerobic strains
How is amikacin administered?
IM/IV/Intrathecal
How is streptomycin administered?
IM
What is the spectrum of activity of streptomycin
Primarily used in combination w other antimicrobials against TB and other mycobacterial diseases
How is Tobramycin administered?
IM/IV/INH/
Opthalmic ointments & solutions
Can the aminoglycosides penetrate the CSF?
Poorly
How are the aminoglycosides excreted?
Renal, excreted unchanged in urine
(except neomycin: 97% unchanged in feces due to only being used by PO route)
What are the adverse reactions associated with aminoglycosides
- Ototoxicity - from high peak plasma lvl,possibly irreversible
- Nephrotoxicity (monitor urea, Cr, renal panel) - proximal tubular cell retention disrupts calcium mediated transport processes, can range from mild & reversible to severe & potentially irreversible
- Neuromuscular paralysis - associated w rapid inc in conc or concurrent administration w neuromuscular blockers
Aminoglycosides demonstrate synergism when combined with which class of antibiotics? Name one class.
Beta lactams
What are the contraindications for aminoglycosides?
- Pregnant women,
- Patients suffering from myasthenia gravis because of the risk of prolonged neuromuscular blockade
- Patients with severe renal Impairment
What are the 6 “NOs” in relation to aminoglycosides?
- No to protein synthesis
- Particularly active against aerobic Gram-Negative Organisms
- No to use during pregnancy
- No to oral administration
- No to CSF penetration
- Nephro- and Oto- toxicities
What are the predisposing factors to nephro/ototoxicity?
(eg in the use of aminoglycosides?)
- dose
- duration of Tx > 5 days
- concomitant use of other nephrotoxic drugs eg vancomycin
- older age: due to reduced renal fn
- genetic predisposition: ototoxicity occurs in patients w point mutations in mitochondrial DNA
Name the 3 macrolides.
Erythromycin, Clarithromycin, Azithromycin
How are the macrolides administered?
PO/IV
(Clarithromycin not administered IV)
What is the spectrum of activity of erythromycin?
Effective against Atypicals and Gram-negatives
(Haemophilus influenzae coverage not strong)
Can be used against staphs and streps as an alternative
What is the spectrum of activity of clarithromycin?
Effective against Atypicals and Gram-negatives
(mainly used against Haemophilus influenzae)
Can be used against staphs and streps as an alternative
Stronger coverage of atypicals than erythromycin
What is the spectrum of activity of azithromycin?
More active than erythromycin against H. influenzae and Moraxella catarrhalis
Active against atypicals - preferred Tx for Chlamydia, gonorrhea (w ceftriaxone IM)
Can be used against staphs and streps as an alternative
Can the macrolides penetrate the CSF?
Poorly
How are the macrolides excreted?
Erythromycin and clarithromycin are metabolised heptically, excreted in bile
Azithromycin is largely eliminated unchanged in faeces via biliary excretion
What are the adverse reactions associated with macrolides
- GI Distresss - Gastric upset most common (less w clarithro and azithro than erythromycin)
- Hepatotoxicity - caution w hepatic dysfunction
- Ototoxicity - transient deafness has been associated w high doses of erythromycin, irreversible sensorineural hearing loss with azithromycin
- May prolong QT interval, should use w caution in patients w pro-arrhythmic conditions (avoid as needed)
Can the macrolides be used in pregnancy?
Yes (esp if beta-lactam allergic)
Name 2 mechanisms via which bacteria may acquire macrolide resistance.
ERM gene expression, efflux pumps
How is clindamycin administered?
PO/IV/TOP
What is the spectrum of action of clindamycin?
Useful against anaerobic infections, incl penicillin resistant anaerobes, but also has some aerobic coverage
For Gram positives (albeit yellow) - MRSA/MSSA, Streptococcus
Good activity against oral pathogens
ALMOST ALL AEROBIC GRAM NEGATIVES ARE RESISTANT
Can clindamycin penetrate the CSF?
Poorly
How is clindamycin excreted?
Hepatic, metabolised to inactive products
What are the adverse reactions associated with clindamycin?
- GI Sx - V/D, esophageal irritation, CDAD
- Skin rashes
How should clindamycin be taken by oral route?
Take w a full glass of water to reduce esophageal irritation
When does clindamycin exhibit cross resistance with the macrolides?
When the microbes acquire resistance by expressing erm methylases
Is not a substrate for macrolide efflux pumps
What is the mechanism of action of linezolid?
Binds to bacterial 23S ribosomal RNA of 50S subunit to prevent formation of 70S initiation complex - inhibit peptide synthesis
How is linezolid administered?
PO/IV
What is the spectrum of action of linezolid?
Used against Gram positives - Listeria monocytogenes, staphylococci (incl penicillin resistant strains, MRSA, VRSA), streptococci (incl S. pneumoniae), enterococci (incl VRE)
**used sparingly since its newer and so powerful - try to slow down resistance formation
Not indicated for Gram negative
Can linezolid penetrate CSF well?
Yes
How is linezolid excreted?
Non-enzymatic oxidation to 2 inactive metabolites, 80% in urine
No need dose adjustments for renal and/or hepatic dysfunctions
What are the adverse reactions associated w linezolid?
- GI Sx - N/D
- Headache
- Rash
- Thrombocytopenia if used for >10 days (monitor CBC)
- Serotonin syndrome - do not give within 2 weeks of SSRIs or MAOIs, avoid tyramine & histamine rich food
- Irreversible peripheral neuropathies and optic neuritis if used >28days
What infections should linezolid not be used against regardless of microbe?
Catheter site or catheter-related bloodstream infections
Name at least 2 key adverse effects associated with prolonged use of linezolid
- Irreversible peripheral neuropathies
- Optic neuritis
- Bone marrow suppression
Which of the protein synthesis inhibitors are safe for use in pregnant women?
Macrolides and Clindamycin
