1. bind to L-15 protein (MLS binding site) on 50S ribosomal subunit
2. inhibits translocation of peptidyl tRNA from the A site to the P site
3. leads to premature release of polypeptides by preventing exit of nascent polypeptide chain

• gram positive cocci and bacilli (accum. 100 X more than gram negative)
  • inactive against most aerobic gram negative bacilli

• MAJOR- methylate 23S rRNA to disrupt drug binding, creates MLS_A phenotype
  • can be via:
    • inducible production (R to macrolides only)
    • constituitive production (leads to cross resistance)
  • modify target and decrease drug binding
  • cross R btw macrolides, clindamycin, type B streptogramins
• efflux pump
• metabolism of drug into inactive product
• mutate binding site

• administer oral or parenteral
  • gastric acid could destroy it, so we give it an enteric coat
  • food interfere with absorption
  • best absorbed form: erythromycin estolate
• distribution- concentrated in the liver, but widely distributed
  • NOT to CNS
  • will reach featus
• excretion- biliary
• half life- 1.5 hrs
• metabolism
  • metabolites inhibit P450 enzymes, leading to drug interaction

• drug interactions (SEE DIFFERENT CARD)
• anorexia, nausea, vomit, diarrhea
• GI effects
  • GI intolerance (decreased with estolate salt) due to direct stimulation of motilin, leading to gut motility,
    • promoting peristalsis post op
    • most frequent reason for discontinuation
• liver toxicity (increased with estolate salt)
  • reversible acute cholestatic hepatitis
    • probably a hypersensitivity rxn
    • fever, jaundice, impaired func.
    • most recover, but it will reoccur if readministered
• hypersensitivity
• reversible ototoxicity (hearing loss) at high doses given IV
• QT prolongation with vent. tachycardia (esp. in combo with quinidine)

• it is an inhibitor of CYP3A4, leading to potentiated effects
• ex: warfarin, carbamazepine, cyclosporin, theophylline, terfenadine, astemizole

• oral, more stable to acid
• absorption- well absorbed
• metabolism- liver as active metabolite
  • reduce dose in severe hepatic disease
• elimination- kidney
  • reduce dose in renal disease

• GI intolerance (lower freq. than erythromycin)
• reversible ototoxicity (hearing loss) at high doses (like erythromycin)
• teratogenic (CI: pregnancy)
• drug drug interactions (like erythromycin)

Azithromycin

Clarithromycin

Erythromycin

• SAME MECHANISM as erythromycin, resulting in cross resistance
• SAME CHEMICAL STRUCTURE as erytrhomycin
• SIMILAR spectrum
  • more active against Mycobacterium avium

• well tolerated orally
• food decrease bioavailability
• absorption- well absorbed
  • delayed by food
• free of drug drug interaction because it does NOT inhibit cyc. P450
• distribution- penetrates tissue very well (except CNS)
  • tissue conc. much greater than plasma
  • drug slowly released from plasma
  • half life of 3 days
  • clinical app.- properties allow for QD dosing and shorter duration of treatment

• class- ketolide (derived from erythromycin)
• methoxy and ketone substitutions of the macrolide ring
  • substitutions make it more active in some erythromycin resistant organisms

• rapidly absorbed
• half life- 10 hrs
• metabolism- liver
  • half by CYP3A4 and half by CYP independent metabolic process
  • leads to some drug interaction

• GI disturbance
• visual disturbance
  • slow accomadation abaility, leading to blurred vision and difficulty focusing
  • highest incident in woman over 40
• exaccerbation of MG (CI: myasthenia gravis)
• cross allergenicity to erythromycine
• reversible hepatic dysfunction (rare cases of hepatic necrosis
• QT prolongation (increased risk of ventricular arrhythmia in predisposed patients)

• mechanism- SAME AS erythromycin
• spectrum of activity- similar to erythromycin
  • gram positive aerobes
  • gram positive and negative anaerobes
• chemical structure- lincosamides, the L in MLS (derived from lincomycin)
• indications
  • serious infections of anaerobic Bacteroides
  • mixed infections of anaerobes
• contraindication- enterococci and gram negative aerobic organisms

• similar to erythromycin but.
  • only constitutive methylase producing strains are resistant (no inducible form of methylase)
  • NOT substrate for macrolide efflux pump
• confers cross R to otehr macrolides

Gram negative aerobes are intrinsically resistant because of their poor permeability of outer membrane.

• absorption- well absorbed oral and parenteral
• distribution- penetrates tissue EXCEPT the CNS
• metabolism- liver
• excretion- urine and bile
• half life- 2.5 hrs (can accumulate in patients with severe liver disease so decrease dosage)

• diarrhea, nausea
• skin rashes
• Pseudomembranous colitis

• often caused by Clostridium difficile, a bacteria resistant to clindamycin
  • selected out by antibiotic therapy
• mechanism- secrete necrotizing toxin
• tx- metronidazole, oral vancomycin (only time we give oral vancomycin cause it normally is not absorbed in the GI tract)

• anaerobic infections
• pseudomembranous colitis caused by C. difficile

1. contains a nitrate group on its chemical structure which is reduced by bacterial nitroreductase
2. this forms freee radicals
3. these free radicals disrupt DNA and other macromolecules by forming covalent bonds

• absorption- well absorbed
• distribution- well distributed, including CNS
• metabolism- liver
• excretion- urine

Dose reduction with renal or liver disease

• one of the metabolites it produces inhibits aldehyde dehydrogenase
• leads to accumulation of aldehyde
• cause disulfiram like reaxtion with ethanol is consumed (nausea, vomit)
• inhibits cyc P450 metabolism of other drugs

• nausea, headace
• dry mouth
• metallic taste
• reddish brown urine
• CNS effects- vertigo, paresthesias, dizziness
• rare effects- pancreatitis, ataxia, seizures, peripheral neuropathy

• inhibit peptidoglycan synthase, so it cannot add building blocks onto the membrane

• streptogramins- protein syn. inh.
• linezolid- protein syn. inh.
• daptomycin- membrane depolarizer

• quinupristin- type B streptogramin
• dalfopristin- type A streptogramin

• quinupristin- same site as macrolides (binding 50S, blocking translocation, releasing premature polypeptide)
• dalfopristin- binds to a nearby, but separate site
  • inhibit peptide bond formation
  • enhance quinupristin binding
• synergistic activity of two units causes bacteriocidal activity

• always seen against streptogramin type A
  • mediated by inactivation via acetyl transferase
  • expression of ATP binding efflux pump
• resistant to type B often seen
  • methylation of binding site MLS
  • production of lactonase which inactivate type B streptogramin

• not activity against gram negative
• not cidal for Enterococcus faecalis
• vancomycin R infection caused by:
  • C difficile
  • E. faecium

• pain
• phlebitis at infusion site
• arthralgia/myalgia syndrome
• inhibitor of CYP3A4

• chemical class- oxazolidinone
• spectrum (SHOULD BE AN AGENT OF LAST RESORT)
  • infections due to vancomycin R organisms
    • MRSA skin infection
    • penicillin sensitive Strep. pneumoniae
    • E faecium
    • pneumonia caused by S aureus
  • little activity against gram negative

1. bind to 23S rRNA of 50S subunit at unique binding site
2. preventing formation of functional 70S subunit complex
3. inhibits protein synthesis

• cross resistance rare
• caused by mutation of ribosomal binding site on 23S RNA (seen in enterococci)
• SHOULD BE AGENT OF LAST RESORT for infection tx caused by multidrug resistant strains.

• absorption- oral and parenteral administration and can be given with food
• metabolism- liver
• excretion- urine
• half life- 5 hrs

No dosage adjustment needed for renal dysfunction

• nausea, diarrhea, vomit
• myelosuppresion, including anemai, leukopenia, thrombocytopenia
  • thrombocytopenia related to duration of tx (monitor platelet counts)
• hepatic enzyme elevation
• in high doses, prolonged use, lead to reversible peripheral and optic neuropathy (stop drug, and its reversed)

• PKU (oral suspension contains Phe)

• mild MAOI
  • HTN with eating wine, cheese, or any other food rich in tyramine
  • limit foods rich in tyramine
• caution if taking pseudoepherdine, SSRI's
• no interaction wtih CYP3A4 or other P450s

• chemical structure- cyclic lipopeptide
• spectrum
  • gram positive bacteria
    • MRSA
    • Enterococcus faecium/faecalis

• skin and skin structure infections (usually caused by MRSA)
  • remember, MIC's for vancomycin R bacteria are much higher than for fully susceptible organisms

CANT be used in pneumonias

1. inserts itself into bacterial plasma membrane
2. forms a pore allowing the influx of sodium and efflux of potassium
3. this leads to a loss of ion balance and an inability to restore that balance
4. causes rapid cell death (concentration dependent cell death, generally more rapid than vancomycin, streptogramins, vancomycin)

• half life- 9 hrs
• excretion- urine
• must be given IV

• GI disorders
• injection site reactions
• fever, headache insomnia, diziness, rash
• at high doses, reversible inhibit creatine PK
  • muscle weakness
  • discomfort
  • tx: consider stopping statins or other agents that cause rhabdomyolysis