Large glycopeptide with attached vancosamine group.

Note: Polar molecule, so not absorbed from GI tract.

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Inhibition of cell wall biosynthesis.

Directly binds to pentapeptide on NAM, physically blocking transpeptidase from binding and cross-linking A to neighboring K.

Note: B-lactams also inhibit cell wall biosyntehsis, but mechanism is suicide inhibition of transpeptidase.

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Vancomycin intermediate-level resistance to S. aureus (VISA): overproduction of cell wall counteracts vancomycin.

Note: More generally known as GISA for glycopeptide intermediate-level resistance to S. aureus (remember, vancomycin is a glycopeptide antibiotic).

High-level resistance: acquisition of vanA gene, which changes last residue on cell wall pentapeptide from alanine to lactate, preventing vancomycin from binding.

Overview of vanA resistance: D-ala-D-ala peptide changed to D-ala-D-lac, which vancomycin can't bind to. 

Genes vanH, vanX, vanA acquired via vanA transposon:

-- vanH: encodes lactate

-- vanX: cleaves D-ala-D-ala

-- vanA: encodes enzyme that attaches lactate to alanine

Note: vanA transposon originally found in E. faecium

Note: high-level type of resistance responsible for VRSA; MIC>32ug/ml)

Note: not a simply mutation; high-level resistance took years to develop. VanA transposon encodes 9 polypeptides, at least 5 of which are required for vanA resistance.

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Production of thick peptidoglycan cell wall outpaces vancomycin.

Note: Cell wall thickness correlates to vancomycin resistance (but not B-lactam resistance)

-- Overproduction of peptidoglycan precursors

-- Overproduction of transpeptidases PBP and PBP2a

Note: PBP2a from mecA gene

Administered parenterally; polar molecule that will not be absorbed from GI tract.

Distributed widely to tissues/body fluids.

Minimally metabolized; moderate t_1/2 of 6hrs.

Excreted renally, unchanged.

1. "Red man" syndrome: flushing due to histamine release if vancomycin is infused too quickly.

2. Oto- and nephrotoxicity at high doses.

3. Hypersensitivity (uncommon)

Reserved for serious Gram+ infections that are not susceptible to other drugs.

-- MRSA

-- Pseudomembranous colitis caused by C. dificile

Large, cyclic lipopeptide (cubicin).

Note: Polar molecule, so not absorbed from GI tract.

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Bactericidal.

Bactericidal.

Fear of resistance (indeed, VRSA is emerging, VRE is out there).

Inserts into bacterial membranes and oligomerizes to form channels (Ca²⁺-dependent binding), producing depoarlization of membrane potential and K+ efflux. Depolarization is from concurrent efflux of negative ions?

Depolarization stops all molecular synthesis (protein, DNA, RNA).

There have only been isolated reports of resistance to daptomycin, but the mechanism is unknown (perhaps has to do with changing the charge on the membrane to inhibit binding).

1. Elevation of CPK: Evidences skeletal muscle breakdown (rhabdomyolysis)

-- Related to dosing interval, not peak concentration or total dose. Only dose once/day (or once every other day for patients with renal insufficiency due to renal excretion of daptomycin)

2. GI irritation

Administered by IV. Polar molecule will not be absorbed from GI tract.

Distributed to plasma and interstitial fluid; does not penetrate CSF

Note: Think about it mechanistically: drug gets "stuck" in cell membrane, can't cross BBB

Minimal metabolism; moderate t_1/2 of 8hrs

Excreted renally.

Note: Renal excretion means drug is concentrated in urine/kidney

Reserved for complicated skin and soft tissue infections, especially vancomycin-resistant infections.

Note: Targets Gram+ organisms, especially S. aureus

VISA, VRSA infections, (including S. aureus bacteremia, right-sided endocarditis).