Tetracyclins Flashcards
what are tetracyclins
derived from streptomyces bacteria or produced semi synthetic derivates of tetracycline (oxytetracycline)
- considered to have a braod spectrum of activity but mainly used to treat infections caused by atypical bacteria (neither gram pos or gram neg)
MOA tetracyclins
- bind 30S subunit of bacterial ribsomse (same as aminoglycosides) to inhibit proten synthesis
- do this by prevening the binding of aminoacyl-tRNA through allosterically binding to the ribosome
- binding is reversible (unlike aminoglycosides) and voerall effect is bacteriostatic not bacteriocidal
what are tetracyclins used to treat
- activity against gram pos and gram neg aerobes and anerobes but used to treat atypical like rickettsia, chamydia and mycoplasmab
^drug of choice in thsoe situations
- also have activity against some protozoa and effective but slow acting anti-malarial
what are examples of water soluble tetracyclins? what are exmaples of lipid solubel?
water soluble: chortetracycline, tetracycline and oxytetracyclne
lipid soluble: doxycycline and minocycline
how are ricketsia infections transmitted?
via ticks (including dog and deer ticks), fleas, lice and mice
- bacteria multiply inside mammalian cells esp capillary endothelial cells and cause diseases like rock mountain spotted fever in central and eastern canada
what type of infections does chlamydia cause
sexually transmitted infection causing respiratory, ocular and reproductive tract infections
what are mycoplasma ifnections
gram neg bacteria without a cell wall and can cause resp infections
routes of administration of tetracyclines
- oral, infectible and topics
- keep in mind with tetracyclins, divalent cations in food will inhibit absorption or oral tetracycline
- means that plasma concentrations of tetracyclins will be the highest on an empty stomach
describe distribution and elimination of tetracyclines
- depend on type of agent,
water soluble (chlortetracycline, tetracycline adn oxytetracycline)
- dsitribute to the extracellular fluid compartment
- half of the drug will be excreted unchanged in urien andahlf will be metbaolized in liver into bile
Lipid soluble (doxycycline, minocycline)
- can enter cells and entirely metabolized in the liver and secreted in the bile
- genreally most tetracyclines distribute poorly to CNS but enter most other tissues
resistance to tetracyclines
- resistnace is widespread
- two main acquired (plasmid encoded) emchanisms resp for this and include efflux pumps and ribosomal protective proteins
efflux pump: removes drug from bacterisl cell, pump can e overwhelemed by high drug concentrations - would explain the improved efficacy that is opserved with topical applications
ribosomal protective prteins: such as tetO inhibit the binding to tetracycline which can also contribute to resistance
*third but rare mech is enzymativ modification of tetracyline by tetracycline destructases
developemnt of tetracycline effux pump inhibitors
- complicated
- based on fact that several efflux pump sub families have been found to difficult to target
- efflux pmps and ribosomal protection mechanisms are present int he same bacterial isolates from clincial cases
tetracyclines for acne treatment
target propionibacteria
* also bee indicated for the plague, tularemia and brucellosis
what are the adverse effects of tetracyclines
- discoloration of teeth bc drug binds to calcium
minocylcine has the greatest effect on discoloration
- can also interfere with long bone growth due to binding of calcium, should be avoided in children and preg woman
- photosensitiation and renal damage may also occur
non antimicrobal effects of tetracyclines
- inhibition of matrix metalloproteinases MMPs
- scavening ROS
- anti inflammatory
describe tetracyclines for inhibition of matrix metalloproteinases
MMPS = family of zinc dependent proteases that are invoved in many physiological processes such as inflammation, tumor invasion and embryogenesis
- they reuqire zinc and calcium to operate
- doxycycline is most effective inhibitor of MMPs due to high affinity for zinc - it is also the only inhibitor in clincal use for treatment of periodontitis
tetracyclines in scavening ROS
ROS is produced in many pathological conditions including myocardial infraction, reperfusion injury and inflammator
the phenol rings on tetracyclines can interaect with free radical to generate phenolic radical that is relatively stbale and unreative
(minocycline and oxycycline are most effective
tetracyclines as antiinflammatory
- anti MMP and ROS scavening properties explain the anti inflammatory effect
- doxycyline tho can also inhibit phospholipase A2 - used to treat acne and rosacea with are both inflammatory skin conditions
what are glycylcylcines
new class of antibiotcs that are derived from tetracyclines
- Tigecycline is first made vaialble, its based on modification of minocycline that gives it a 5x greater affinity for ribosomal binding allowing it to overcome ribosomal protection
- has large side chain which may inhibit from permeating the efflux pump
when are glycylcylines used
- intially reccommended to eb reserved for multidrug resistance bacteria that are resistance to toher last resort drugs
- its bacteriostatic and has broad spectrum of action ncluding several Gram positive, Gram negative and anaerobic bacteria that are resistant to other drugs.
how is resistnace acquried to glycvylcylines
efflux pump resistnace
- initial therapy may succeed but then fail as pymp expression rises
- exposure of a tigecycline susceptible clinical strain to tigecycline caused a rapid rise in the MIC of tigecycline from 2 μg/mL to 24 μg/mL (indicating acquisition of high-level resistance), which was reversible with an efflux pump inhibitor. This is why tigecycline-resistant infections are becoming increasingly more common.
resistnace in acintebacteria
Acinetobacter, which has been shown to cause life threatening infections in immunocompromised patients
-Tigecycline-susceptible and non-susceptible isolates have been found to carry genes encoding various components of the pump.
Point mutations have been identified in some of these genes in tigecycline-resistant isolates.
Gene expression can be 40 to 50-fold higher in tigecycline-resistant isolates compared to tigecycline-susceptible isolates.
