Clindamycin and Tetracycline Antibiotics Flashcards
Clindamycin is synthesized from…
naturally occuring Lincomycin by treatment with Chlorine and Triphenylphosphine
Why isn’t Lincomycin used anymore?
Toxicity
Clindamycin mechanism of action
Inhibition of protein synthesis by binding the 23S RNA part of the 50S ribosomal subunit.
Reason to expect antagonism/cross-resistance between clindamycin and erythromycin?
It has the same binding site on the ribosome
Clindamycin is most effective against
Aerobic G+ Cocci
Anerobic G- bacilli
Most common uses for Clindamycin
S. aureus bone infection Topically for severe acne Cream for bacterial vaginosis. Lung abscess MRSA Toxoplasma gondii in AIDS patients
When Clindamycin is used to treat AIDS patients, what other drugs are added
Pyrimethamine and Leucovorin
What is an important limiter of Clindamycin use?
It increases the incidence of C Diff pseudomembranous colitis
Dosage form of Clindamycin
Oral administration
IV (Clindamycin phosphate)
Topical foams/solutions)
Clindamycin is metabolized extensively by…
Cytochrome P450 enzymes in liver
Breakdown products of Clindamycin?
Sulfoxide
N-Demethylated Derivative
Approx __% of Clindamycin is absorbed in the GI
What about Clindamycin’s PK makes it especially useful
90
Can get through the BBB
Adverse effects of Clindamycin
Diarrhea, pseudomembranous colitis, nausea, vomiting, cramps, rash
Possibly contact dermatitis
Effects of pseudomembranous Colitis?
Treatment?
Diarrhea, Colitis, Toxic Megacolon
Metronidazole or Vancomycin
Tetracycline is produced by
Streptomyces
What happens when tetracyclines are exposed to polyvalent ions? Examples of polyvalent ions?
Tetracyclines for stable chelates
Ca++, Al+++, Cu++, Mg++
Consequences of Tetracycline forming insoluble chelates?
Can’t be administered with high calcium foods, antacids with multivalent metals, hemainics containing irons.
Can’t give to kids or it will mess up their teeth
Preferred route of administration for Tetracycline
Oral
Why can’t little kids use Tetracycline?
Tetracyclines chelate Ca during formation of teeth, causing them to be permanently brown or gray.
Discoloration gets worse over time from photooxidation
Why does it hurt to inject Tetracyclines?
Formation of insoluble Calcium complexes
Minimize with EDTA to chelatate Ca and buffered to acidic pH
What happens as a result of the hydrogen on the amine-bearing Carbon of Tetracycline?
Enolization
Epimerization
In the epimerization reaction, Hydrogen coming in from above will generate _____ and below will generate ______
Tetracycline
Epitetracycline (Inactive)
Why should we care about the Tetracycline epimerization reaction?
This is how old Tetracycline products can lose approximately half of their potency.
When is epimerization of Tetracycline slow? fast?
Slow – Solid State
Fast – pH 4.0
What side group is especially set up to cause the dehydration reaction to occur?
The tertiary benzylic hydroxyl group at C6
End result of Tetracycline dehydration reactions
Anhydrotetracycline – Inactive
or
4-Epianhydrotetracycline – Inactive and Toxic
Whats so bad about 4-Epianhydrotetracycline?
Toxic to Kidneys
Produces Fanconi-like syndrome (Failure of reabsorption in PCT)
Perk of Tetracycline derivatives without a C6 group?
No risk of dehydration toxicity
What happens to Tetracycline in pH 8.5 or above?
Generates a lactone product that is inactive.
Tetracycline mechanism of action
Bind the 30S ribosomal subunit and inhibit bacterial protein synthesis. Block attachment to the A site.
Do Tetracycline and Erythromycin interact competitively?
No, their binding sites do not overlap with eachother
Why doesn’t Tetracycline trash the ribosomes of the host?
It can in super high doses, but usually won’t be dosed high enough to. Bacteris have an uptake mechanism that makes Tetracycline especially effective against them.
Name the ribosomal site Tetracycline primarily binds to
Tet1
Therapeutic use of Tetracyclines?
Broad Spectrum Antibiotics
Acne
Chlamydia, Rickettsia, Brucellosis, Spirochetal
Anthrax, Plague, Tularemia, Legionaire’s
Tetracycline is made by _______
Perks?
Cons?
Streptomyces aureofaciens
Generic, inexpensive
Food and Milk drop absorption by 50%
What is Dimeclocycline?
Tetracycline, but with a secondary hydroxyl at C6 instead of a tertiary hydroxyl.
Benefit of Dimeclocycline’s change to a secondary hydroxyl?
It dehydrates more slowly because the secondary cation intermediate formed is less stable than the tertiary cation intermediate
Con of Dimeclocycline?
Food and Milk lower absorption by about 50%
What is Minocycline?
Dimeclocycline modified to lost the c6 hydroxyl group
perks of Minocycline?
No C6-hydroxyl means no acid-catalyzed dehydration
No potential for 4epi…. toxicity
90-100% bioavailability
Cons of Minocycline?
Absorption down 20% when taken with food or milk Vestibular toxicities (vertigo, ataxia, nausea)
Oxytetracycline is made by
fermentation of Strep. rimosis
Important details for Oxytetracycline?
It fuckin sucks.
pretty much replaced now.
Most hydrophillic tetracycline.
Important structural details of Doxycycline?
It lacks a C-6 hydroxyl – no dehydration = no toxicity
Bioavailability of Doxycycline?
With food/milk?
90-100%
Absorption lowered by approx. 20% when taken with food/milk
Half life of Doxycycline?
18-22 hours
First antibiotic to be manufactured synthetically on a large scale?
Chloramphenicol
Why don’t people use Chloramphenicol so much anymore?
Toxicities
Still prevalent in the 3rd world because cheap
How does Chloramphenicol work?
It binds reversibly to the 50S ribosomal subunit near the erythromycin and clindamycin spot (competitive interactions occur). Specifically, it blocks peptide bond formation btw the P and A sites
Therapeutic use of Chloramphenicol?
Ointment/Eye drops
IV in severe disease states
Indications for IV Chloramphenicol
Bacterial Meningitis
Typhoid Fever
Rickettsial infections
Intraoccular infections
How does resistance to Chloramphenicol happen?
Reduced membrane permeability
50S Ribosome Mutation
Elaboration of Chloramphenicol acetyltransferase
What does Chloramphenicol acetyltransferase do?
Acetylates one/both ydroxyl groups to form metabolites that can’t bind 50S
Toxicity risks for Chloramphenicol?
Aplastic Anemia
Bone Marrow Suppression
Childhood Leukemia
Nausea, Vomiting, Diarrhea
Why does it take months after Chloramphenicol treatment to see Aplastic Anemia symptoms?
RBC life is 3-4 months
Takes time for the loss of new blood cells to be apparent
Highest risk way to use Chloramphenicol? Lowest?
Highest – Oral
Lowest – eye drops
How is Chloramphenicol metabolized?
Metabolized to glucuronide in the liver
Pharmacologically inactive and readily excreted
Mechanism for Chloramphenicol metabolism?
Nucleophilic attack of the less hindered primary alcohol of UDPGA, performed by glucuronyl transferase.
Can babies have Chloramphenicol?
No. Neonates can’t metabolize it.
