= toxic dose (TD)/effective dose (ED)

drugs with low may require therapeutic drug monitoring (TDM) 

-- aminoglycosides and vancomycin

1+1=10

more than added

1+1 = 0.5

does not add; less

1. mycobacterium tuberculosis

2. S. aureus (fluroquinonlone, rifampin)

immediate treatment  prior to identification

- prior to growth, identification, or susceptibility reports

- based on epidemiology (most probable etiologies)

- severity of disease and local rates of disease

inability to kill or inhibit organism with clinically achievable drug concentrations

- may be innate (mutation) or acquired (acquisition of foreign DNA)

 - transglycosylases: transver of nascent peptidoglycan to growing backbone

- carboxypeptidases/transpeptidases: similar function as above, cleave the terminal D-ala from pentapeptide; ratio determines extent of cross-linking (influences cell shape)

-vancomycin/teicoplanim

-gram positive agents

bind to terminal D-ala of nascent cell wall peptides and prevents cross-linking of these peptides to form mature peptidoglycan

1. production of B-lactamase (most common)

2. altered penicillin binding proteins (s. pneumoniae)

3. novel penicillin binding proteins (MRSA)

4. altered permeability

- primary concern = enterococcus/S. aureus

- altered target, bacteria substitutes D-lac for D-ala; vancomycin can no longer bind

- clavulanate (w/ amoxicillin or ticarcillin)

- tazobactam (w/ piperacillin)

• S aureus
• H influenza
• Neisseria sp
• Bacteriodes fragilis
• E coli and Klebsiella
• not better for psudomonas or enterobacter

-macrolids, lincosamides, streptogramins (MLS), tetracyclines, aminoglycosides, linezolid

-binding may be reversable or irreversable

1. erythromycin

2. clarithromycin

3. azithromycin

4. telithromycin (ketolide)

exert antibacterial effect by inhibiting protein synthsis

- bind to 50s subunit of bacteria ribosomes

1. block growth of nascent peptide chain by stimulating dissociation of peptidyl-tRNA from ribosome

2. inhibit assembly of new large ribosomal subunits (depletion of functional ribosomal subunits in cell)

1. Efflux pump mef(A)

2. Target Site Modification erm(B)

S. pneumoniae

Where should you use macrolides? (1st and 2nd choice)

First Choice: 

    - community acquired pneumonia

    - pertussis

    - chlamydia trachomatis infections

    - mycoplasma infections

Second Choice:

    - pyogenic streptococcal infections

    - C. jejuni gastroenteritis

concentration-dependent and highly bactericidal

1st: nalidixic acid

2nd: ciprofloxacin - broader spectrum, anti-pseudomonal

3rd: moxifloxacin - enhanced gram (+), +/- anaerobic activity

Inhibit DNA Gyrase (gyrA)

Topoisomerase IV (parC)

   - spontaneous mutation in gyrA and parC 

   - efflux pumps (pump it out)

   - down regulation of porin channels (don't let it in)

- natural/semi-synthetic antibiotics (streptomycin - 1944)

- excellent gram (-) activity (pseudomonas)

- good gram (+) activity

- bactericidal/concentration dependent

ex. Gentamicin, Tobramicin, Amikacin

gain entry through inner membrane via energy dependent transport (dependent on electron transport)

-- this step is rate limiting and blocked by divalent cations and anaerobiosis

CANNOT work in anaerobic environments (abscess)

they irreversibly bind to 30S ribosomal subunit through energy dependent process; perturbs elongation of nascent polypeptides by impairing proofreading process; aberrant/truncated proteins

--can interfere with mammalian protein synthesis at high concentrations

1. altered ribosome binding sites (streptomycin only!)

2. reduced uptake or decreased cell permeability

3. enzymatic modification - most common form (>70 ezymes); different substrate specificities and plasmid mediated

• Trimethoprim/sulfamethoxazole (Septra, TMP/SMX)   ----- good gram (-), some gram (+)
• block folic acid synthesis at 2 points (TMP and SMX act synergistically)

PABA --> Dihydofolic Acid (by sulfonamides)

Dihydofolic Acid --> Tetrahydrofolic Acid (Trimethoprim)

- commonly used as 1st line antibioitc in uncomplicated UTIs

- gastro-intestinal infections

- management of penicillin resistant protein pneumonia

- very active anti-Staphylococcal agent (CA-MRSA)

• mechanism of action: short lived toxic intermediates or free radicals; damage to DNA (or other macromolecules)
• >90% bioavailablility
• long half life (BID dosing)
• Side effects: GI intolerance, antabuse effect, peripheral neuropathy
• cheap
• resistance is slow to develop

• anaerobic infections
• C. difficile colitis
• giardiasis
• Trichmonas vaginitis and BC
• H. pylori (in combination)
• Perianal disease in IBD