Protein Synthesis Inhibitors Flashcards
azithromycin
Protein Synthesis Inhibitor- Macrolide ATB (bacteriostatic)
-MOA:
++Bind reversibly to 50S subunit
++block tRNA/peptide movement from A to P site
++because of proximity of sites of action, macrolides competetively inhibit ribosome binding of streptogramins, clindamycin, chloramphenicol
-Narrow spectrum but greater then penicillins
-Accumulate to far greater extent in Gram+ bacteria
-more effective then erythromycin against anaerobes
-Resistance/cross-resistance can develop rapidly due to development of efflux pumps, methylase modification of bacterial ribosome so that in longer binds drug: MLS-type B resistance (macrolide, lincosamide, streptogramin), and hydrolysis of macrolides by esterases
-can be administered orally, stable in acid
-poor distribution to CNS, elimination unclear
-Clinical use as alt. to penicillins esp. with allergy (prophy. against endocarditis, oral facial infections)
-can cause GI issues and hepatotoxicity
clarithromycin
Protein Synthesis Inhibitor- Macrolide ATB (bacteriostatic)
-MOA:
++Bind reversibly to 50S subunit
++block tRNA/peptide movement from A to P site
++because of proximity of sites of action, macrolides competetively inhibit ribosome binding of streptogramins, clindamycin, chloramphenicol
-Narrow spectrum but greater then penicillins
-Accumulate to far greater extent in Gram+ bacteria
-MORE effective then erythromycin against anaerobes
-Resistance/cross-resistance can develop rapidly due to development of efflux pumps, methylase modification of bacterial ribosome so that in longer binds drug: MLS-type B resistance (macrolide, lincosamide, streptogramin), and hydrolysis of macrolides by esterases
-can be administered orally, stable in acid
-poor distribution to CNS, metabolized in liver, secreted by kidney
-Clinical use as alt. to penicillins esp. with allergy (prophy. against endocarditis, oral facial infections)
-can cause GI issues and hepatotoxicity
-inhibits CYP3A4 in the liver inc. other drug levels
erythromycin
Protein Synthesis Inhibitor- Macrolide ATB (bacteriostatic)
-MOA:
++Bind reversibly to 50S subunit
++block tRNA/peptide movement from A to P site
++because of proximity of sites of action, macrolides competetively inhibit ribosome binding of streptogramins, clindamycin, chloramphenicol
-Narrow spectrum but greater then penicillins
-Accumulate to far greater extent in Gram+ bacteria
-LESS effective against anaerobes
-Resistance/cross-resistance can develop rapidly due to development of efflux pumps, methylase modification of bacterial ribosome so that in longer binds drug: MLS-type B resistance (macrolide, lincosamide, streptogramin), and hydrolysis of macrolides by esterases
-can be administered orally, stable in acid
-poor distribution to CNS, but penetrates abscesses, excreted in bile
-Clinical use as alt. to penicillins esp. with allergy (prophy. against endocarditis, oral facial infections)
-can cause GI issues and hepatotoxicity
-inhibits CYP3A4 in the liver inc. other drug levels
telithromycin
Protein Synthesis Inhibitor- Macrolide ATB
- semi-synthetic derivative of erythromycin (1st member of new drug class)
- inc. acid stability, inc. affinity for 50S ribosome, and reduced induction of bacterial resistance
- MOA: binds 50S ribosome at two sites blocking protein synthesis; concentration-dependent bactericidal activity against susceptible S. pneumoniae
- oral admin, well absorbed, acid stable
- hepatic metabolism (50% by CYP3A4), hepatic and renal elimination
- Resistance: does not induce cross resistance via methylase expression; generally not subject to MLS-type B resistance
- clinical use reserved for highly resistant pathogens, esp. of resp. tract
quinupristin
Protein Synthesis Inhibitor- Streptogramin ATB
- MOA: binds 50S ribosomal subunit, same site as macrolides (enhanced synergistically by dalfopristin)
- individually BS, but BC when used in combo
- Uses: reserved for life-threatening and multidrug-resistant infections (combo therapy)
- S/Fx: pain, phlebitis at IV site; deregulation of drugs metabolized by CYPs
- Resistance (combo therapy): MLS-type B resistance; erm-encoded methylases (modify 50S ribosome)
dalfopristin
Protein Synthesis Inhibitor- Streptogramin ATB
- MOA: binds nearby ribosomal 50S subunit synergistically enhancing quinupristin binding
- individually BS, but BC when used in combo-Uses: reserved for life-threatening and multidrug-resistant infections (combo therapy)
- S/Fx: pain, phlebitis at IV site; deregulation of drugs metabolized by CYPs
- Resistance (combo therapy): MLS-type B resistance; erm-encoded methylases (modify 50S ribosome)
clindamycin
Protein Synthesis Inhibitors- Lincosamide ATB
- MOA: binds exclusively to 50S subunit fo bacterial ribosomes (can be BC in some bacteria)
- Spectrum: most gram+ are susceptible; better then macrolides against anaerobes
- resistance slow and step-wise; MLS-type B due to a ribosomal methylase that modifies the target
- clindamycin does not induce the methylase expression in microbes
- admin. oral or parenteral with wide dist. including bone; low CNS concen.
- metabolized in liver and excreted in urine and bile (impaired in patients with hepatic failure)
- Uses: drug of choice for resp. tract infections caused by anaerobes, abscesses, prophy for bacterial endocarditis, osteomylitis
- S/Fx: diarrhea, pseudomembranous colitis, skin rash, Stevens-Johnson Syndrome
linezolid
Protein Synthesis Inhibitors- Oxazolidinone ATB
- MOA: binds to interface of 30S and 50S subunits of ribosomes to block translation initiation
- bacteriostatic, oral drug with 100% bioavailability
- reserve for tx of resistant infections
- no cross resistance with other protein synthesis inhibitors
mupirocin
Protein Synthesis Inhibitor
- topical use only for Tx of impetigo caused by MRSA or group A strep
- MOA: inhibits isoleucyl tRNA synthetase
- Rapidly metabolized to inactive form
- Resistance is rare
tetracycline
- reversible binding of the 30S subunit of the bacterial ribosome
- blocks aminoacyl tRNAs from entering the A site of ribosome
- selective toxicity: affects 70S subunit mitochondrial ribosomes, not cytoplasmic ribosomes
- VERY BROAD spectrum, superinfection
- generally more active against gram +
- bacteriostatic
- drug resistance: decreased intracellular levels (decreased influx, increased efflux), expression of proteins that protect ribosome from drug, enzymatic inactivation of drug, widespread resistance has limited clinical use
- oral administration yields variable absorption
- decreased absorption by divalent and trivalent cations (dairy, antacids, iron supplements)
- decreased absorption when gastric pH is elevated
- wide distribution, accumulation in liver, spleen, bone marrow, bone, dentine, enamel of unreupted teeth
- good CNS penetration
- cross the placenta
- renal excretion
- clinical uses: acne, treatment of rickettsial disease (Typhus, RMSF), Periodontitis (limited benefit/efficacy)
- side effects: GI irritation, superinfections (c. diff) photosensitivity, hepatotoxicity, renal toxicity, discoloration of teeth– do not give to pregnant women or children
doxycycline
tetracycline
- reversible binding of the 30S subunit of the bacterial ribosome
- blocks aminoacyl tRNAs from entering the A site of ribosome
- selective toxicity: affects 70S subunit mitochondrial ribosomes, not cytoplasmic ribosomes
- VERY BROAD spectrum, superinfection
- generally more active against gram +
- bacteriostatic
- drug resistance: decreased intracellular levels (decreased influx, increased efflux), expression of proteins that protect ribosome from drug, enzymatic inactivation of drug, widespread resistance has limited clinical use
- oral administration yields variable absorption
- decreased absorption by divalent and trivalent cations (dairy, antacids, iron supplements)
- decreased absorption when gastric pH is elevated
- wide distribution, accumulation in liver, spleen, bone marrow, bone, dentine, enamel of unreupted teeth
- good CNS penetration
- cross the placenta
- eliminated by inactive chelate or conjugate in feces (reduced GI complications, lesser impact on normal flora)
- clinical uses: acne, treatment of rickettsial disease (Typhus, RMSF), Periodontitis (limited benefit/efficacy)
- side effects: GI irritation, superinfections (c. diff) photosensitivity, hepatotoxicity, renal toxicity, discoloration of teeth– do not give to pregnant women or children
minocycline
tetracycline
- reversible binding of the 30S subunit of the bacterial ribosome
- blocks aminoacyl tRNAs from entering the A site of ribosome
- selective toxicity: affects 70S subunit mitochondrial ribosomes, not cytoplasmic ribosomes
- VERY BROAD spectrum, superinfection
- generally more active against gram +
- bacteriostatic
- drug resistance: decreased intracellular levels (decreased influx, increased efflux), expression of proteins that protect ribosome from drug, enzymatic inactivation of drug, widespread resistance has limited clinical use
- oral administration yields variable absorption
- decreased absorption by divalent and trivalent cations (dairy, antacids, iron supplements)
- decreased absorption when gastric pH is elevated
- wide distribution, accumulation in liver, spleen, bone marrow, bone, dentine, enamel of unreupted teeth
- good CNS penetration
- cross the placenta
- metabolized by liver, passed in feces
- clinical uses: acne, treatment of rickettsial disease (Typhus, RMSF), Periodontitis (limited benefit/efficacy)
- side effects: GI irritation, superinfections (c. diff) photosensitivity, hepatotoxicity, renal toxicity, discoloration of teeth– do not give to pregnant women or children
gentamicin
aminoglycoside
- binds irreversibly to 30S subunit & inhibit protein synthesis at several levels
- bactericidal
- concentration-dependent killing with significant PAE
- primarily aerobic gram - rods
- combination therapy with penicillin or vancomycin acts synergistically & extends coverage to gram+
- main use: SEVERE gram- infections
- drug resistance: decreased uptake
- highly polar and poorly absorbed from GI
- IM or IV administration
- topical for burns, wounds, skin lesions
- not well distributed to most cells, eye or CNS
- high concentration only in inner ear & renal cortex
- renal clearance
- adverse effects: ototoxicity (irreversible hearing loss) vertigo, reversible renal toxicity
tigecycline
glycylglycine
tetracycline analogue
-bind with higher affinity than tetracycyline
-bacteriostatic against Hershey isolate of MRSA
-effective against strains that are tetracycline resistant
streptomycin
aminoglycoside
- binds irreversibly to 30S subunit & inhibit protein synthesis at several levels
- bactericidal
- concentration-dependent killing with significant PAE
- primarily aerobic gram - rods
- combination therapy with penicillin or vancomycin acts synergistically & extends coverage to gram+
- mycobacterial infections (TB)
- drug resistance: decreased uptake, mutant bacterial ribosome, enzymatic inactivation of drug (high resistance limiting use)
- highly polar and poorly absorbed from GI
- IM or IV administration
- not well distributed to most cells, eye or CNS
- high concentration only in inner ear & renal cortex
- renal clearance
- adverse effects: ototoxicity (irreversible hearing loss) vertigo, reversible renal toxicity
- Pregnancy: deafness in newborns
