Bacterial Protein Synthesis Inhibitors Flashcards
What is the MOA of tetracyclines?
Concentrate intracellularly in susceptible organisms
Drug binds reversibly to 30S subunit of bac ribosome -> prevents binding of tRNA to A site of mRNA-ribosome complex -> inhibit bac protein syn
What is the MOA of tigecycline?
Like minocycline, it binds to bac 30S ribosome, blocking entry of tRNA
What is the MOA of Aminoglycosides?
AGs bind to 30S sub, distorting subunit structure and causing misreading of mRNA
AGs transported across inner memb via active transport. Energy-dependent phase inhibited by anaerobic conditions, drop in pH and hyperosmolarity.
Absorption of Tetracyclines? Good or poor oral bioavailability?
Good oral F (adequately abs after oral ingestion)
Absorption of Tigecycline? Good or poor oral bioavailability?
IV, poor oral F
Absorption of AGs? Good or poor oral bioavailability?
Poor oral F; parenteral adm except neomycin (oral)
Elimination of Tetracycline
primarily eliminated by kidney
Elimination of Doxycycline
Doxycycline: bile and urine (hepatic)
Elimination of Minocycline
Minocycline: extensively metabolised by liver before excretion (hepatic)
Elimination of Tigecycline
- Not extensively metabolised
- Biliary/faecal
- No dosage adjustments are necessary for pts w renal impairment
- Dose reduction recommended in severe hepatic dysfn
Excretion of AGs
Renal clearance. Dose adjustment needed w renal impairment.
Pregnancy Category for Tetracyclines
Cat D
Pregnancy Category for Tigecycline
Cat D
Tetracycline is effective against which type of bacteria?
Activity against broad spectrum of Gram +ve/-ve, atypical bac and spirochete bacteria
Inadequate activity against Pseudomonas aeruginosa and Proteus
Tigecycline is effective against which type of bacteria?
Broad-spectrum activity:
MRSA
Multidrug-resistant (MDR) streptococci
Vancomycin-resistant enterococci (VRE)
useful against carbapenem resistant strains of Extended-spectrum β-lactamase (ESBL)–producing gram-negative bacteria
Not active against Pseudomonas species and Proteus
Glycylcycline designed to overcome what common mechanisms of tetracycline resistance? 2 of them
- efflux pumps
- Ribosomal protection
AGs is effective against which type of bacteria?
aerobic Gram-ve bac
Gram-ve infections; Enterobacteriaceae (Klebsiella, E.Coli), MDR microbes (Pseudomonas and Acinetobacter)
2nd-line defence for MDR TB
Empiric therapy for serious infection
Once causative microbe is identified, AGs discontinued
Why is AGs combined with cell wall synthesis inhibitors?
Expand empiric spectrum of activity of antimicrobial regimen to ensure presence of at least one drug active against a suspected pathogen
Provide synergistic bacterial killings
Prevent emergence of resistance to individual agents
Which tetracycline is used effectively against acne vulgaris and community-acquired pneumonia and skin and soft tissues caused by MRSA?
Doxycycline
Which AGs is the widest antimicrobial spectrum of AGs?
Amikacin
What is streptomycin primarily used for?
Primarily in combi w other antimicrobial agents in therapy of TB and other mycobacterial diseases.
Neomycin is given oral administration for ____
bowel prep for surgery
Why is neomycin not given parenterally?
severe nephrotoxicity
Adverse effects of Tetra and Tige?
- Gastric discomfort: (drink plenty of fluids and shouldn’t be taken immediately before going to bed) taken on EMPTY STOMACH
- Effects on calcified tissues: discolouration & hypoplasia of teeth; temp growth stunt
- Hepatotoxicity
- Phototoxicity: severe sunburn
- Vestibular dysfn: dizziness, vertigo, tinnitus
- Renal side effects (less w doxycycline, more for tetracycline)
- Superinfection: CDAD (observed >2 months post AB
Contraindications for Tetra and Tige; not compatible for which age groups?
- breast-feeding women;
- children <8yo
- Last half of pregnancy - affects primary teeth
What are the 6NOs + other adv effects of AGs
- No to Protein Synthesis (inhibition at 30S)
- Mainly aerobic Gram-Negative Organisms
- No to use during pregnancy; Cat D
- No to oral adm
- No to CSF penetration
- Nephro and Oto toxicities
- Neuromuscular paralysis (Myasthenia gravis): rapid inc conc or concurrent adm w neuromuscular blockers
- Hypersensitivity reactions: skin rashs (esp for topically applied neomycin)
Why must we monitor the use of AGs?
• Caution for renal impairment
- Myasthenia gravis
- Avoid usage w other nephrotoxic drugs (Amp B, Vanco, NSAIDs, neuromuscular blocking agents
Which factors predispose to Nephro and Ototoxicity for AGs?
Dose
Duration of treatment > 5 days
Concomitant use of nephrotoxic drugs
Age: elderly pts predisposed because of reduced renal fn
Genetic predisposition (oto occurs in pts w point mutations in mit DNA)
Why is there resistance of AGs?
- Inc efflux pumps red effective intracellular conc
- Gram -ve produce AG inactivating enzymes
- Some bac alter 30S, prevents AGs to interfere in protein syn
- Low level resistance may result from inhibition of AGs uptake by bacteria
What is the MOA of Macrolides?
50s
• Inhibit translocation step: nascent peptide chain residing at the A site fails to move to the peptidyl donor (P) site
What is the MOA of Clindamycin?
• Binds exclusively to 50S subunit of bac ribosome and inhibit peptide synthesis
What happens when clindamycin is taken with erythromycin?
antagonise each other’s action –> cross resistance w macrolides due to (erm) methylases can also occur
What is the MOA of Linezolid?
• Binds the bacterial 23S ribosomal RNA of the 50S subunit and prevents formation of functional 70S initiation complex (component of bacterial t/l process)
Absorption of Macrolides; Good or poor F?
good oral F, poor CNS penetration
oral/IV; oral = clarithromycin
Absorption of Clindamycin; Good or poor F?
Excellent oral F; Oral and IV
Available in topical soln, gel, lotion, vaginal cream
Effective topically/orally for acne vulgaris and bacterial vaginosis
Absorption of Linezolid; Good or poor F?
Excellent oral F; well abs after oral adm and may be adm w/o regard to food
Oral and IV
Elimination of Macrolides? Both metabolism and excretion
Erythro and Clarithro: Metabolised hepatically and excreted in bile and urine
Azithro: Largely eliminated unchanged in faeces via biliary excretion
Excretion of Clindamycin?
Mainly excreted as bioinactive metabolites
Excretion of Linezolid?
Approx 80% of dose in urine
No dose adjustments required for renal/hepatic dysfn
Why are there no dose adjustments required for renal/hepatic dysfn for Linezolid?
inactive metabolites - doesnt affect the dose
Pregnancy Category for Macrolides
Category B (Erythro,Azithro); Category C (Clarithro)
Pregnancy Category for Clindamycin
Category B
Pregnancy Category for Linezolid
Category C
Which 50S protein syn inhibitors are safe for pregnancy?
Macrolides, clindamycin save for pregnancy
Which bacterial protein syn inhibitors target atypical bacteria?
Macrolides and Tetracyclines
Which organisms does macrolides cover?
Atypical microbes MCL (Legionella pneumophilia, Mycoplasma, Chlamydia)
Resp tract infections (CAP), Chlamydial infections, Diphtheria, H. pylori (Clarithro/Azithro + ome + amox), Mycobacterial infections
Which organisms does Clindamycin cover?
Useful against Anaerobic infections
Gram +ve; MRSA and streptococcus, penicillin resistant anaerobic bacteria
Alternatives for pts w penicillin allergies
Toxic shock syndrome (anti-toxigenic effect)
For serious anaerobic infections
Anaerobic infections of skin and soft tissues – Bacteriodes, Clostridium perfringen
Good spectrum activity against oral pathogens
Almost all aerobic Gram -ve bac are resistant. (Use AGs)
Which organisms does Linezolid cover?
Gram +ve: Staph, Strep, Enterococci, Listeria monocytogenes
Not indicated for Gram-ve infections (resistant due to efflux pumps that force drug out of cell faster than it can accumulate)
Penicillin resistant strains of S. pneumoniae, Vancomycin-intermediate
MRSA , VRE (Vancomycin-resistant strains of enterococci), VRSA (Vancomycin-resistant strains of S. aureus)
Which bacterial protein synthesis inhibitors is used as an alternative for pts w penicillin allergies?
Macrolides, Clindamycin
Which drug is used for aerobic infections?
Aminoglycosides
Which drug is used for anaerobic infections?
Clindamycin
Which drugs only cover Gram +ve bacteria?
Linezolid, Vancomycin, Penicillinase Resistant Penicillin (Anti-staph)
Which bacterial protein syn inhibitors cover MRSA?
Linezolid and clindamycin
tetracyclines and tigecycline
Which macrolides is more active against resp infections, esp Community acquired pneumonia?
Azithromycin
Which macrolides is a preferred therapy for STD caused by Chlamydia trachomatis and Neisseria gonorrhoea?
Azithromycin
What does atypical bacteria consist of?
Mycoplasma, Chlamydia, Legionella
Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila are common causes of _________.
community-acquired pneumonia (CAP)
Why must we be aware of the risk of Torsades de Pointes for macrolides?
May prolong QT interval; caution in pts w pro-arrhythmic conditions
Which two drugs are required to drink a full glass of water and not to lie down immediately?
Clindamycin and tetracyclines
Which 2 drugs’ adverse effects is CDAD?
Tetracyclines and Tigecycline
Clindamycin
Why macrolides are contraindicated for pts w hepatic dysfn?
erythron and azithro accumulate in liver
Erythro and Clarithro: Metabolised hepatically and excreted in bile and urine
Azithro: Largely eliminated unchanged in faeces via biliary excretion
Which drug has an adverse effect for pseudomembranous colitis ?
Tetra and Tige
Which drug is contraindicated for pseudomembranous colitis ?
Clindamycin
Which drug is used as a choice of ABx in macrolide resistant strains (efflux pumps)
Clindamycin
Clindamycin not a substrate for macrolide efflux pumps making them a choice of ABx in such macrolide resistant strains
Number of days to cause BM suppression?
> 10 days of use
Number of days to cause Irreversible peripheral neuropathies and optic neuritis
> 28 days of use
in what ways can someone become resistant to clindamycin?
alter 50s or 23s
