1. enter cell via passive diffision and some through active transport into bacteria only
2. bacteria accumulate drug
3. bind reversiblly to 30S subunit of prok. ribosome
4. block binding of aminoacyl-tRNA to A site on mRNA-ribosome complex
5. prevent addition of AA's

• tetracycline
• doxycycline- increase lipid solubility, low renal clearance
  • allows for longer half life, wider activity
• minocycline- increase lipid solubility, low renal clearance
  • allows for longer half life, wider activity
• tigecycline (actually drug class called glycylcycline)

• absorption- via oral admin through small intestines
  • impaired by food and divalent metals
• binds 40-80% to serum proteins
• distribution- wide in body
  • NOT CSF
    • exception: minocycline reach CNS
  • cross placenta, present in breast milk
• elimination
  • mainly via bile and urine
  • all EXCEPT tetracycline eliminated via non oral mechanism, so safe for patients with impaired renal function

• pregnancy
• children under 8
• nursing mothers

• indications- very broad spectrum
  • intra-abdominal infection
  • skin infection
  • tetracyclin-R bacteria
• contraindications- UT infection
  • Proteus
  • Pseudomonas
• adverse effects- GI toxicity
• pharmacokinetics
  • excretion- biliary (no dose reduction in kidney failure)
  • metabolism- P450 enzymes DO NOT play major role

• plasmid mediated and confers cross resistance with other drugs like aminoglycosides, chlorqamphenicol
• decrease influx or increase efflux
  • Tet(AE) efflux pump expressed in gram negative: still tigecycline S
  • Tet(K) efflux pump expressed in Staph.: still sensitive to Tigecycline, Doxcycline, Minocycline
  • chromosomal multidrug transporter expressed in Pseudomonas and Proteus: resists ALL tetracyclines
• ribosome protection
  • Tet(M) protein expressed in gram positive: still sensitive to Tigecycline
• enzymatic inactivation by organism via acetylation

• nausea, vomit, GI irritation (hit GI microflora and cause irritation)
  • you could give with food, but it will impede absorption
• vestibular dysfunction (minocycline) (doxycycline at high doses)
• Fanconi syndrome (outdated drugs)- aminoaciduria, nausea, renal tubular acidosis
• superinfetion (Proteus, Pseudo, Staph)
• possibly interfere with oral contraception
• photosensitivity (exaggerated response to sunburn)
• chelation of divalent metals lead to:
  • tooth discoloration
  • impaired bone growth in fetus

• Streptomycin (first gen.)
• Gentamycin
• Neomycin
• Amikacin (semi-synthetic, so less resistance)

1. bind to 30 S subunit
2. leads to blocking protein syn. by:
   • disrupt initiation
   • misreading of mRNA
   • block movement of ribosome
3. truncated/aberrant proteins alter membrane function
4. cause increase permeability and leakage

Irreversible inhibitors that are synergistic with beta lactams or vancomycin

• bactericidal and exhibit strong post antibiotic effect (hrs)
• exhibit concentration dependent killing
• absorption- give IV or IM due to poor oral administration
  • EXCEPTION: GI disease, ulceration
  • due to low binding to serum proteins as well
• distribution
  • enter cells via passsive diffusion through porins (outer membrane)
  • oxygen dependent transport across cell mem. (coupled to proton pump driven by electrochemical gradient)
  • polar, cationic, so does not enter tissue readily
  • NOT CNS or eye
  • may enter CSF in condition of inflammation or intrathecal/ intraventricular injection
• excretion- urine (monitor dose if renal impairment)

• enzymatic inactivation (MAJOR) by attacking aminoglycosides amine or alcohol group (still sensitive to Amikacin)
  • acetylation
  • phosphorylation
  • adenylation
• impaired uptake
  • porin gene mutation
  • mutation of proteins needed for gradient
  • anaerobic conditions
• mutation of ribosomal protein
  • less common
  • usually specific to streptomycin (limits usage)

Mechanism of synergy between aminoglycosides and cell wall syn. inh. What kind of bacteria is this synergy affective against?

• cell wall synthesis inhibitors will increase the uptake of aminoglycosides
• allow for synergy against aerobic gram positive cocci

• bacteria resistant to aminoglycosides are difficult to treat because they are often resistant to penicillin and vancomycin as well (no more synergy)
• bacteria resistant to gentamicin also cross resistant to tobramycin, amikacin, kanamycin, netilmicin
  • still streptomycin sensitive

• irreversible ototoxicity
• reversible nephrotoxicity
• neuromuscular toxicity

• mechanism
  • accumulation of drug in inner ear/ cochlea
  • leads to heair cell death via binding of phospholipids, calcium, oxidative stress
• increased risk if renal impairment, prolonged use, or loop diuretics
• manifestation
  • vestibular damage (w/ streptomycin and gentamicin)- vertigo, ataxia/balance loss
  • auditory dammage- high freq. hearing loss, tinnitis

• lead to increase serum drug conc.
• esp. seen with amikacin, gentamicin, neomycin
• mechanism
  1. uptake into kidney cortex
  2. accum. in PCT
  3. bind to phospholipids
  4. leads to increase serum creatinine and decrease clearance

1. at high doses, you interfere with calcium signalling
2. this means you wont release ACh
3. leads to resp. depression (MG symptoms)

• QD dosing (repeated dosing will increase the time above the threshould of 2 microns/mL)

• broad spectrum
  • aerobic or anaerobic
  • gram positive and negative
  • ex: alternative treatment for beta lactam antibiotics for menigococceal meningitis in:
    • penicillin hypersensitive ind.
    • penicillin R pneumococci

• chlamydia
• infants

• oral administration
• absorption- rapid
• distribution- large volume of distribution
  • penetrates CNS and CSF
  • cross placenta, breast milk
• elimination- mainly urine, some bile
  • 10% active drug elim.
  • 90% inactive met. elim.
• met.- in liver, can inh. CYP2C and CYP3A P450 family (dose reduction in hepatic disease)

• gram pos. and neg. bacteria
• streptococci, enterococci (in combo with vancomycin)
• severe infection (sepsis, pneumonia)

• 2nd line TB
• enterococcal infection due to gentamicin R

1. bind to 50S subunit
2. inhibit peptidal transferase
   • does not interact with 80S euk. ribosomes
   • but it does interact with euk. mitochondrial ribosomes
     • inhibit aerobic met., leading to decreased ATP, leading to cell death

• hematological effects
• Gray baby syndrome
  • drug deactivated by glucoronidation
  • remember, babies dont have UGT
  • this means they cannot excrete the drug
• potential for drug interaction
  • inhibits P450 enzymes
  • increases half life of:
    • warfarin
    • phenytoin
    • antiretroviral protease inhibitors

• reversible bone marrow suppression
  • ex: anemia, leukopenia, thrombocytopenia
  • dose related
  • due to mit. toxicity
• irreversible aplastic anemia
  • idiosyncratic and not dose related
  • can lead to fatal pancytopenia
  • mechanism
    • inh. mit. protein synthesis, preventing iron incorperation into heme

• plasmid encoded chloramphenicol acetyltransferase (catP) (MAJOR)- the acetylated form cannot bind prok. ribosomes
• ribosomal mut.- minor