-
tetracycline, doxycycline, minocycline
- 30S inhibitor - tetracyclines
- action: reversible binding to 30S subunit on bacterial ribosome, block aminoacyl tRNA from entering ribosome
- spectrum: VERY broad: superinfections; generally more active against G+, bacteriostatic
- resistance: decreased intracellular levels (decrease influx, inc. efflux), enzymatic inactivation of drug, expression of proteins that protect ribosomes from drug
- pharmacokinetics: oral admin (30-100% absorption), decreased by divalent and trivalent cations (dairy products, antacids, iron supplements) w/ exceptions (doxy and mino can be given with dairy), decreased when gastric pH is elevated
- Wide distribution - liver, spleen, bone marrow, skin, tears, bone, dentine, enamel (in inactive form), good CNS penetration (doxy and mino for CSF), crosses placenta
- Excretion: through kidneys, some enterohepatic cycling, resorption in small intestines; exception - doxy eliminated as inactive chelate in feces w/ no impact on normal flora, mino passed in fecesuse: acne, drug of choice in treatment of Ricksettial diseases (chlamydia, myco pneumoniae, Y pestis, Borrelia
- Adverse effects: GI irritation and superinfections (including pseudomembranous colitis), photosensitivity, hepatotoxicity, renal toxicity, vestibular disturbances, discoloration of teeth - fetal and childhood risks (therefore, should not be givent to pregnant women or children under 8)
- drug interactions: MANY
- - antagonizes cidal antibiotics
(penicillins) - - increase other drug levels by altering hepatic / intestinal CYP3A4 metabolism (flibanserin, lomitapide)
- - digoxin - increase levels via changes in intestinal flora, reduced metabolism
- - tretinoin and acitretin - increase intracranial pressure, unclear how
-
Tigecycline
- minocycline derivative
- give IV
- mechanism: similar to tetracyclines, but binds with higher affinity to 30S ribosomeeffective against strains that are tet-resistant, some MRSA, treat skin, intra-abdominal infections
-
Gentamicin
- aminoglycoside - bind irreversibly to 30S ribosomal subunit and inhibit protein synthesis at several levels
- bactericidal
- concentration-dependent killing with significant PAE
spectrum: extended spectrum, primarily G- aerobic bacilli, combination therapy with penicillin or vancomycin acts synergistically on S auerus and S epidermidis - pharmacokinetics
- -absorption: highly polar; poor GI absorption - IM or IV admin
- -distribution: not well distributed to most cells, eye or CNS, high concentrations only in inner ear and renal cortex = toxicities
- adverse effects: ototoxicity (tinnitus and largely irreversible loss of hearing), vestibular toxicity, renal toxicity
- use: severe G- infections
-
spectinomycin
- structurally related to aminoglycosides - binds 30S subunit
- bacteriostatic
- Extended spectrum: Mostly G- but many G+
- use: antibiotic-resistant gonorrhea, MRSA, enterococci
- few adverse effects but resistance develops rapidly
-
azithromycin, clarithromycin, erythromycin
- macrolide - bind reversibly to 50S subunit
- competitively inhibit ribosome binding of streptogramins, clindamyin, and chloramphenicol = antagonism
- bacteriostatic (generally) - dosing and pH considerations
- narrow spectrum (broader than pens), greater accumulation in G+ bacteria, clarithro and azithro are more effective than erythro against anaerobes
- resistance: rapid and cross-resistant; efflux pump, methylase modifies the bacterial ribosome making drug unable to bind (MLS-type B resistance (macrolide, lincosamide, streptogramin)), hydrolysis by esterases in Enterobacteriaceae
- pharmacokinetics
- - administration: oral because acid stable (erythromycin not acid stable, given as salt)
- - distribution: poor penetration of CNS, WIDE erythromycin penetrates into abcesses
- adverse effects: GI disturbances, hepatotoxicity - allergic type of reversible cholestatic hepatitis with erytheomycin estolate
- Interactions - inhibit CYP3A4, potentiates other drugs (azithromycin is structurally unique, no interaction with CYP 450 system)
-
telithromycin
- ketolid
- structural derivative of erythromycin - inc. acid stability, inc affinity for bacterial 50S ribosome, reduced induction of bacterial resistance
- mechanism: binds 50S ribosome at 2 sites, bacteriostatic (cidal against susceptible S. pneumoniae)
- pharmacokinetics: oral, well absorbed with food
- use: community acquired RTI's (pneumonia), acute bacterial sinusitis, chronic bronchitis
- drug interaction: increase levels of other CYP3A4 substrates
-
chloramphenicol
- bacteriostatic
- binds reversibly to 50S ribosome - near binding of clindamycin and macrolidesBroad spectrum, inhibits most anaerobic bacteria, inhibits most G- bacilli
- resistance: huge problem, due to acetyltransferases, modify drug
- pharmacokinetics: oral, topical, or parenteral, wide distribution (CNS, crosses placenta), complete absorption, metabolized by liver
- use: few, restricted toxicity, severe infections unresonsive to tetracyclines or cephalosporins
- adverse effects: many, hematological (aplastic anemia), hypersensitivity, gray baby syndrome - can't metabolize drug; vomiting, cyanosis, ashen color, hypothermic, 40% death within 2 days
-
Synercid (Quinupristin/dalfopristin 30:70)
- streptogramin
- mechanism: binds to 50S ribosome at same site as macrolides; dalfopristin binds nearby, enhances quinupristin binding = synergism
- use: MRSA, serious / life-threatening vancomycin-resistant G+ infections (VREF, VRSA, S. pneumoniae
- adverse effects: pain, phlebitis at IV site, deregulation of levels of drugs that are metabolized by CYPs
- resistance:to quinupristin - erm-encoded methylases (50S rib), vgb-encoded lactonases (drug)
- - to dalfopristin - vat or sat-encoded acetyltransferases (drug), vga-vgb-encoded ATP binding efflux proteins to transport the drug out of the cell
-
Linezolid
- mechanism: binds novel site in 23S ribosomal RNA of the 50S ribosomal subunit
- characteristics: no cross-resistance with other protein synthesis inhibitors, bacteriostatic (cidal vs streptococci), oral admin (100% bioavailability),
- use: serious infections (MRSA, VREf, multidrug-resistant S. pneumoniae)
-
clindamycin
- lincosamide
- action: binds 50S subunit of bacterial ribosomes
- MLS-typeB resistance
- narrow spectrum - most G+ are susceptible, better than macrolides against anaerobes, NOT aerobic G-, STATIC
- resistance: slow / stepwise, due to ribosomal methylase that modifies target, clindamycin does not induce methylase expression in microbes
- pharmacokinetics: oral or parenteral, wide distribution (bone - active form), metabolized in liver
- use: drug of choice for RTI caused by anaerobes, abcesses, severe GroupA strep infections, MRSA, skin and soft tissue infections, osteomyelitis
- adverse effects: diarrhea, pseudomembranous colitis (C diff), skin rash, Stevens-Johnson syndrome, anaphylaxis
-
mupirocin
- topical use only, useful for treating impetigo caused by MRSA or Group A strep
- mechanism: inhibits isoleucyl tRNA synthetase
- rapid metabolized to inactive form
- resistance = rare
- static at [low], cidal at [high]
|
|
