PRO synthesis inhibitors Flashcards
glycylglycine agents
MOA
tigecycline
- similar to tetracyclines, but binds with higher affinity; bacteriostatic agent against hershey isolate of MRSA
- effective against strains that are tetra resistant
aminoglycosides
MOA
-gentamicin, streptomycin
MOA: bind irreversibly to the 30S ribosomal subunit and inhibit PRO synthesis at several levels
-bactericidal
-concentration dependent killing with significant PAE
[-blocks initiation of PRO synth, terminates translation, misincorporation of AA –> generation of altered PRO]
aminioglycosides spectrum & resistance
- gentamicin, streptomycin
- primarily aerobic gram - rods, **combination therapy with PCN or vanco acts synergistically and extends coverage to gram + pathogens (cell wall disturbing agent allows better penetration of aminoglycosides)
resistance: mutatnt bacterial ribosome - decreased uptake or efflux
- enzymatic inactivation of drug**
aminoglycosides PK
- gentamicin, streptomycin
- absorption: highly polar, poorly absorbed from GI tract; given IV or IM
- not well distributed to most cells, eye or CNS
- high concentrations only in inner ear and renal cortex –> toxicity**
- renally cleared
aminoglycosides SE
- ototoxitiy: irreversible loss of hearing**
- vestibular toxicity (permenant)
- reversible renal toxicity
specifics to know re: streptomycin & use
- high resistance limiting use**
- mycobacterial infections (TB)
- pregnancy: deafness in newborns **
specifics to know and uses re: gentamicin
- resistance = poor drug uptake
- *main use severe gram - infections and for others with PCN/vanc
- topical for burns, wounds, skin lesions
- *ototoxicity, mainly vestibular and irreversible
macrolide antibiotics
azithromycin
clarithromycin
erythromycin
macrolide antibiotics MOA
**bind reversibly to 50S subunit
-block tRNA peptide movement from A to P site
-bc of the proximity to site of action, macrolides competitively inhibit ribosome binding of streptogramins, clindamycin, chloramphenicol **
bacteriostatic **
macrolide antibiotics spectrum
- narrow but somewhat broader than PCN
- accumulate to a far greater extent in gram + bacteria b/c of difficulty penetrating outer membrane of gram neg
- *clarithromycin and azithromycin are more effective than erythromycin against anaerobes
macrolides resistance
develops rapidly
-cross-resistance w/in class
3 mechanisms
-efflux pump
-methylase modifies the bacterial ribosome so unable to bind drug [MLS type B]
-hydrolysis of macrolides by esterases produced by enterobacteriacaea
macrolides PK
- erythromycine is unstable in acidic environement, salts and esters or EC tabs for use orally
- other macrolides are more acid stable
- poor penetration of CNS
- *erythromycin penetrates into abscesses
clinical use of macrolides
- *alternative to PCN esp for allergy
- *prophylaxis against bacterial endocarditis in PCN allergy
- *oral facial infections for periapical ascessis, azythromycin is as effective as amoxicillin/clavulanate
- resp infections from atypical microbes
- common bacterial infections but resistance develops rapidly
macrolides adverse effects
- *GI/motility disturbances
- *hepatotoxicity - cholestatic hepatitis, greater with erythromycin estolate; reversible
**erythromycin and clarithromycin inhibit CYP3A4 potentiates effects of (theophylline, warfarin, carbamazepine, astemizole, protease inhibitors)
ketolide
telithromycin
-1st member of new drug class
modified version of erithromycin w increased acid stability, affinity for bacterial 50S ribosome, and reduced induction of bacterial resistance [no MLS B]
telithromycin MOA
- *binds 50S ribosome at 2 sites, blocks PRO synthesis
* *concentration dependent bactericidal activity against susceptible S. PNA
telithromycin PK & resistance
- oral admin, well-absorbed and accid stable
- hepatic metabolism (CYP3A4)
- hepatic and renal elmin
- does not induce cross-reaction via methylase expression
- *not subject to MLS B resistance
telithromycin use
**reserved for highly resistant pathogens, esp resp tract
steptogramins
MOA
quinupristin/dalfopristin used together
MOA: **quinupristin binds the 50S ribosomal subunit, same site as macrolides; dalfopristin binds nearby, synergistically enhacing quinupristin binding
**individually: bacteriostatic, together: bactericidal
streptogramins uses
-reserved for serious/life-threatening and multidrug resistant infections
streptogramins SE
- pain and phlebitis at IV site
- deregulation of levels of drugs that are metabolized by CYPs
streptogramins resistance
**MLS B resistance; erm-encoded methylases modify 50S ribosome
lincosamides
MOA
clindamycin
- *binds exclusively to the 50S subunit of bacterial ribosomes
- can be bactericidal in some bacteria
lincosamides spectrum
- most gram +, better than macrolides against anaerobes ** esp B. fragilis (non-CNS)
- not aerobic gram -
lincosamides bacterial resistance
- slow and stepwise
- *MLS B, due to a ribosomal methylase that modifies target
- *clindamycin does not induce the methylase expression, but if already there, it is susceptible
lincosamides PK
-admin oral or IV
**wide distribution including bone
-low conc in CNS
elim
metabolized by liver, excreted in urine and bile
-impaired in pt with liver failure
lincosamides use
- DOC for resp tract infections caused by anaerobes
- *abscesses
- *prophylaxis against bacterial endocarditis in pt with PCN allergy
- severe group A strep infections
- *osteomyelitis
lincosamides SE
- *diarrhea and pseudomembranous colitis
- rash, stevens-johnson, anaphylaxis
mupirocin
- topical use only, useful to rx impetigo caused by MRSA or group A strep
- *MOA, inhibits isoleucyl tRNA sythetase
- rapidly metabolized to inactive form (why topical)
- resistance = rare
