Lecture 16 Macrolides, Clindamycin, Tetracyclines Flashcards
What are the 3 main macrolides available
Azithromycin,clarithromycin, erythromycin
Mechanism of action of macrolides
Bind reversible to 50S ribosomal subunit
Inhibit RNA-dependent protein synthesis
Development of resistance macrolides
1) active efflux
- results in M genotype with cross resistance between all 14 and 15 members ring macrolides
-most frequent resistance phenotype
2) ribosomal methylation
- gene responsible for methylation of the 50S ribosomal subunit is transmitted through a plasmid or transposon
-methylation of 23S ribosomal RNA of the 50S ribosomal subunit
- cross resistance with other macrolides (M), lincosamides (L), and streptograminB (SB)
3) alteration of 50S ribosomal subunit
4) enzyme inactivation
5) lower permeability of cell wall
Spectrum of activity for macrolides ( Azithromycin, Clarithromycin)
Gram positive
Gram negative
Anaerobes
Gram + = S. Aureus, streptococci (Not reliable), No enterococci
Gram -
moraxella catarrhalis, H.pylori, B.pertussis, B.burgdorefi, mycobactrtium spp
Atypical = legionella pneumophila
Anaerobes = oral anaerobes, not bacteroides fragilis
Clarithromycin PK and AE
PK: absorbed well, may be taken with food, wide tissue distribution, metabolised mainly by liver (3A4), decrease dose if eGFR <30,
t1/2 4.5 hours, BID dosing,, AE: GI - N/D/V, ab pain, dyspepsia
Azithromycin PK and AE
PK: may be given with food, distributed extensively to tissues, conc inside macrophages and PMNs, blood levels low,
little metabolism by liver, excreted in bile and feces,
t1/2 68 hours, dosed QD F3-5D,, AE: N/D/V, ab pain, dyspepsia
What is the spectrum of activity for clindamycin (lincosamide)?
Gram positive
Anaerobes
Gram +: S. aureus (MRSA, MSSE), CoNS, S. pyogenes, S. pneumoniae, Actinomyces,
Anaerobes : B. fragilis, oral anaerobes, clostridia, gardnerella vaginalis
Clindamycin PK and AE
PK: excellent absorption orally, delayed with food BUT not reduced, good penetration into most tissues (not CSF), mostly metabolized by liver, t1/2 2.4 hours,
AE: nausea (450 mg Q6H better tolerated than 600 mg Q8H), diarrhea (up to 20%), pseudomembranous colitis, allergic rxn - rashes,
hepatoxicity - increases transaminases,
neutropenia, thrombocytopenia, agranulocytosis
Tetracyclines MOA
enters cell by passive diffusion, binds reversibly to 30S ribosomal subunit and blocks binding of aminoacyl tRNA to acceptor site on mRNA, interferes with protein synthesis preventing addition of new aas to growing chain, inhibits mitochondrial DNA in 70S ribosome in some eukaryotic parasites
What are ways bacteria can develop resistance to tetracyclines?
inhibits accumulation of tetracycline in cell by decreased influx or efflux
What is the general spectrum of activity for tetracyclines?
Gram +: S. aureus (MRSA, MSSA), S. pneumoniae, Actinomyces,
Gram -: H. influenzae, M. catarrhalis, S. maltophilia, Legionella, V. cholera, h.pylori, rickettsiae, B.burgdorferi, Atypicals -= legionella
Anaerobes : oral anaerobes, not B.fragilis
What are things which affect tetracycline absorption?
when taken with or near Al, Ca, Mg, Fe, Zn, Na bicarbonate, or food (forms insoluble chelates),
reduced 30-50% with food, 50-60% with milk,
minocycline and doxycycline can be taken with food
What are AEs of tetracyclines?
skin and allergic rxn - photosensitivity (red rash to exposed areas), pigmentation of skin, nail, gums or thyroid, hypersensitivity, anaphylaxis, urticaria, periorbital edema, oral/vaginal candidiasis, staph, diarrhea, black hairy tongue, vertigo,
if taken in pregnancy ⇒ yellow-brown discoloration of teeth, hypoplasia of tooth enamel, depression of skeletal growth in infants ⇒ recommended to avoid in pregnant women and children up to 8 years old
What are different toxicities/effects tetracyclines can have on different body systems?
Hepatotoxicity: rare and associated with long term use of minocycline,
Renal Toxicity: increased azotemia in pt with renal failure, Fanconi-like syndrome (proximal tubular damage and acidosis), nephrogenic diabetes insipidus,
GI: N/V/D, esophageal ulceration ⇒ take with glass of water in upright position and not just before bed or laying down, bedridden pt be propped up
How is minocycline associated with hepatotoxicity?
Acute Hepatitis-like syndrome - within 1-3 months of tx,
and Chronic hepatitis-like syndrome - with autoimmune features with long term tx,
both associated with serum enzyme elevations (3-20x), autoantibodies, immunological features
What is tigecycline (spectrum, indications)
5x greater affinity for ribosome, active against resistant strains carrying both efflux and ribosomal protection proteins,
Spectrum: improved MSSA, MRSA, MSSE, MRSE,
streptococci including PRSP, enterococci including VRE, many gram - ⇒ H. influenzae, E. coli, Klebsiella, Enterobacter, Acinetobacter,
B. fragilis, active against NDM-1 producing organisms,
poor against P. aeruginosa,
Indications: pt > 18, complicated SSTIs, complicated intra-abdominal infections, CA
