General Details of Aminoglycosides:  Streptomycin, Kanamycin/Neomycin, Amikacin, Gentamicin/Tobramycin

Structure?

MOA?

Resistance?

PK?

Adverse Reactions?

- Developed in search to be effective against gram (-) bacteria

- Each compound has hexose nucleus

- Contain a lot of positively charged amino groups

- Degree of positive charge ~ Degree of toxicity

 - Cidal effect

- Penetrate outer membrane via porin channel; oxygen dependent transport across inner cytosol; anaerobic microbes therefore resistant

- Hyperosmolality decreases uptake into cels

- Acidic conditions decreases uptake into cells

- Bind 30S subunit on ribosome complex, also binds 50S but not as important.

- Prevents initiation of protein synthesis

- Interferes with completion of process

- misreading of mRNA, incorporation of wrong AA

- Turns polysome into monosome

Resistance stems from Alteration in transport, receptor protein, and increased phosphorylation/acetylation/adenylation to metabolize

- Give IM or IV (slowly)

- Not absorbed very well because of positive charge

- Poor CNS penetration due to positive charge

- Concentrated in proximal tubules, cleared by GF.

- Adverse reactions include nephrotoxicity because of positive charges and accumulation in tubules. 

- Ototoxicity is due to concentration of aminoglycosides here, either cochlear damage or vestibular damange.

- Treatment of tuberculosis (Resistant strains)

- Can be used in treatment of Tularemia (rabbit fever)

- Can be used in combination with penicillin if necessary to increase effects

- Least nephrotoxic of aminoglycosides

- Causes ototoxicity, particularly cells associated with vestibular function

- Kanamycin is not used so much these days

- Neomycin is the most nephrotoxic because of the many positive groups

- Also has ototoxic effects like loss of hearing

- Limited to topical use or oral administration for GI bacterial clearance

- Seen prior to GI tract surgery (possibility for super infection)

- Topical --> Neosporin cream

- Broad spectrum agent

- Derived from Kanamycin but it has less toxicity

- Resistant to enzymes that modify gentamost mycin or tobramycin

- Auditory toxicity is the most common

- Gentamycin is an aminoglycoside you may see more than the other ones

- Both are used in treatment of gram (-) bacterial infections (Severe)

- Tobramycin is used as an inhaled preparation in treatment of infections associated with cystic fibrosis Pseudonomas infections

- Both can be used in combination with Penicillin; however, gentamicin and penicillin must be administered separately or else they make some bullshit sugar molecule that is completely useless.

What are some examples of Tetracyclines?

General details of Tetracyclines:  Chlortetracycline, Oxytetracycline, Demeclocyclineli, Methacycline, Doxycycline, Minocycline

Structure?

MOA?

Resistance?

SOA?

PK?

Adverse reactions?

- Cl at C-7 will cause photosensitization

- Chlortetracycline and Oxytetracycline have Half-lives of 6-8 hours

- Demechlocycline and Methacycline have Half-lives of 12 hours

- Doxycycline and Minocycline tend to be given once a day, about 24 hour half-life

- when OH at C-6 is missing, the compounds tend to be more stable in acidic and basic conditions, increased T1/2.

- Doxycycline and Minocycline are the most lipid soluble, only given once a day, food has less effect on absorption, increased plasma protein binding. 

- Pass diffusion through porin in gram (-)

- Active transport across inner membrane in (+) and (-)

- Binds to 30S ribosomal subunit to block incoming amino-acyl tRNA molecule to A site.  Interferes with protein synthesis. 

- Resistance can take the form of altered transport, efflux system, ribosomal protection proteins, enzymatic inactivation; this is all done by plasmids. 

- SOA is broad spectrum, lipophilic has greatest spectrum of action

- Treats Pneuomonia, Rocky Mountain Fever, Lyme's disease

- Food will decrease absorption (Except doxy- and mino-), forms complex with divalent cations to retard bone growth and stain teeth brown, crosses placenta and into breast milk, Doxy- is handled by GF and biliary secretion, so good for pateitns with kidney failure.

- Dehydration can't occur in Doxy- or Mino-

- GI effects are common, hepatotoxicity, acs as chelation agent, photosensitivity. 

Details of Chloramphenicol

Structure?

MOA?

Resistance?

SOA?

PK?

Adverse reactions?

- Benzene ring makes it very soluble; Palmitate given orally, succinate is IV.  Ester bond hydrolyzed when injected. 

- MOA very similar to Macrolides

- Binding site is 50S subunit to inhibit peptide bond formation (peptidyl transferase)

- Same site as Erythromycin, which would inhibit it.

- Mostly static effect

- Can inhibit eukaryotic protein synthesis to some extent

- Anemia involving bone marrow cells at higher concentrations

- Resistance is through plasmid acqusition of acetyl transferase, because acetylated chloramphenicol has poor binding. 

- Lipid soluble, so penetrates into celsl easily, wide SOA, lots of toxicity, restricted to cases of Bacterial meningitis, rocky mountain fever, Typhus, Anaerobic bacteria. 

- Given orally or IV

- Penetrates all tissues, including CNS, placenta, breast milk

- Secreted into bile

- Metabolized through conjugation with glucuronic acid

- 90% excreted as inactive conjugate through kidney, 10% excreted as active drug (parent compound), through kidneys

- Only worry about liver disease

- Adverse reactions include bone marrow toxicity (Leukopenia, Thrombocytopenia, Pancytopenia) by way of dose, idiosyncratic effect, could lead to neonatal toxicity. 

- Strong inhibitor of cytochrome P450.

Details of Macrolides: Erythromycin, Azithromycin, and Clindamycin (?)

Structure?

MOA?

Resistance?

SOA?

PK?

Adverse Reactions?

- Has a large lactone ring

- Nitrogen with two methyls makes weak bases

- Difference between molecules is at hydroxyl groups

- Erythromycin can form ketal to bother GI, this can only happen in molecules with an extra methyl (not Clarithromycin)

- Clarithromycin have increased acid stability, tissue penetration, SOA, and price.

- Bind to 50S ribosome; interfere with peptide bond formation, translocation.

- Produces mostly static effect

- Primarily gram (+), 100x more drug accumulates here

- Resistance occurs b/c of plasmid aquisition of a methylase that methylates the binding site on the ribosome, decreases binding, happened with S. Aureus. Plasmid mediated efflux pump as well.

- SOA includes gram (+)

- Erythromycin can substitute for penicillin, be used for whooping cough and Legionaire's.

- Clarithromycin can be for H. Pylori, and that with Azithromycin can be for mycobacterials as well

- Erythromycin inactivated by stomach acid, estolate derivative more stable in acid with increased absorption.  Won't penetrate CNS

- Food affects absorption of erythromycin and azithromycin. 

- Azithromycin has no effect on P450

- Clarithromycin has best absorption, and fewer GI problems. 

- All of these cross placenta and into breast milk

- GI cramping, jaundice, increased [ ] of other drugs because erythromycin and clarithromycin inhibit P450.

Details of Clindamycin

MOA?

Resistance?

PK?

Adverse reactions?

SOA?

- 50S subunit binding to interfere with translocation

- Decreases the formation of initiation complexes

- Resistance is through methylation or mutation of 50S ribosomal binding site.

- Cross resistance with other macrolides

- almost complete absorption from GI

- Widely distributed, doesn't penetrate CNS well

- Metabolized with N-desmethyl clindamcin and clindamycin sulfoxide

- Excreted in the bile and urine

- Only inactive metabolites excreted; only need to adjust with severe liver disease

- Adverse rxns include diarrhea from clostridium, skin rashes, block of neuromuscular transmission

- SOA is gram (+), some anaerobes, pneumonia (pneumosystic carinii)

Details of Quinupristin/Dalfopristin

Ratio?

MOA?

Resistance?

PK?

SOA?

Adverse reactions?

- Mixture is given as a single treatment

- 30:70 quinupristin/dalfopristin

- Synergistic effect

- Cidal effect when given as combo

- 50S binding, inhibits peptide bond formation, early termination.

- Resistance of quinupristin is methylation of binding site, production of lactonases which inhibit the compound

- Resistance of Dalfopristin is alteration of binding site by acetylation and an efflux pump

- Slow infusion; half-life of 8-12 hours

- Elimination primarily bile

- Inhibitors of P450

- SOA is gram positive organisms, treatment of vancomycin resistant enterobactor F., skin infections by MRSA. 

- Not first line, reserved for few cases that don't respond to other treatment. 

- Adverse reaction are pain at site of injection and join and muscle pain.

Details of Linezolid

MOA?

Resistance?

Interactions?

PK?

Adverse reactions?

SOA?

- Binding of 50S subunit

- Inhibits assembly of ribosome

- No cross-resistance

- Resistance is mutation of 50S binding site, metabolism of compound into inactive metabolites

- Not P450 mediated, so no interations

- Food doesn't affect absorption

- 80% renal excretion of linezolid/metabolites

- Adverse reactions include GI side effects, H/A, thrombocytopenia

- SOA is gram (+), reserved for serious cases, has static effect on MRSA, for Vancomycin resistant enterobacter f.