Exam 1 lecture 6 Flashcards
How is clindamycin synthesized
From naturally occurring antibiotic lincomycin by treatment with chlorine and triphenylphosphine in acetonitrile.
Why is lindomycin not used
It wrks but has a lot of toxicity
MOA of clindamycin
MOA of clindamycin is similar to that of macrolides like erythromycin. It inhibits protein synthesis by binding to the bacterial 50S ribosome. Binds same site as erythromicin.
Antagonism and cross-resistance has been reported between clindamycin and erythromycin
With regard to clinical use, what is clindamycin most effective against
aerobic gram positive cocci- staphylococcus and streptococcus genre
anaerobic gram negative bacilli Bacteroides and fusobacter genre
What is clindamycin used for topically? systemically? When is it administered IV? What did it replace penicillin?
topically- Acne (vaginally- vaginosis)
Systemically- Bone infection with staph aureus
IV- administered with leucovorin to treat AIDS in pts with encephalitis caused by toxoplasma
replaced penicillin when- treatment for lung abscess and anaerobic lung and pleural space infections. Also used to treat MRSA
WHat limits use of clindamycin
DIarrhea and pseudomembraneous collitis
DOsage forms of clindamycin
Clindamycin preparations for oral administration include capsules and oral suspensions. Also available in IV form as clindamycin phosphate. also as topical forms
Metabolism of Clindamycin? PK of clindamycin? excreted?
Metabolism- clindamycin is extensively metabolized by cytochrome P450, metabolites are inactive
PK- approx 90% is absorbed from GI tract, penetrates and is absorbed in CNS enough to where it can be used as treatment for cerebral toxoplasmosis in HIV patients
Excreted- mainly in urine and bile
Adverse effects of clindamycin? Lethal condition associated with it?
diarrhea, pseudomembraneous collitis, N, V, abdominal cramps, rash
Pseudomembraneous collitis is a potentially lethal condition associated with it (growth of C diff which is resistant to clindamycin) treat with metronidazole or vancomycin
When did tetracyclines start getting used
In ancient egypt
What are chemical reactions that tetracyclines can go through? Describe them
Chelation- Tetracyclines form stable chelates with polyvalent metals like Ca, Al, Cu and Mg.
Epimerization- epitetracycline product forms and it is inactive.
Dehydration- Forms anhydrotetracycline (which is inactive) and can also form epianhydrotetracycline (which is inactive and toxic to the kidneys causing faconi syndorme
Cleavage in base- At PH 8.5 or above, they undergo inactivation`
Which tetracyclines do not turn into epihydrotetracycline
Minocycline
Doxycline
What type of food should be avoided with tetracyclines?
DO not consume foods rich in calcium due to the possibility that they form insoluble chelates, not getting absorbed in GI tract, no TUMS or multivalent metals
What should we do if concomitant therapy can not be avoided with therapy and metals
Administer metals 1 hour before or 2 hours after tetracycline
Why should tetracyclines never be administered to children? When to stop tetracycline during pregnancy
result in permanently brown or grey teeth during teeth formation.
Stop after 4th month of pregnancy
When is epimerization the most rapid? When does it happen?
PH 4 most rapid. Can occur at solid state aswell.
What is important to know about dehydration of tetracyclines
Forms anhydrotetracycline (which is inactive) and can also form epianhydrotetracycline (which is inactive and toxic to the kidneys causing faconi syndorme
Describe the MOA of tetracycline? most common use?
Inhibit the binding of the anticodon to the codon, so that inhibits protein synthesis
Most common use- acne, chylamydia
Therapeutics uses of tetracycline
Acne, chlamydia, (trachoma, salpingitis, lymphogranuloma)
Ricketsia (typhus, rocky mountain spotted fever)
Brucellosis
spirochetal infection
Anthrax and plague
What is tetracycline produced by? How does it affect absorption of food and milk?
Fermentation of streptomyces aureofaciens
lowers it by 50%
What are the different types of tetracyclines
Tetracycline
demeclocycline
minocycline
doxycycline
tigecycline
sarecycline
omadacycline
What is democloccycline produced by? How does it differ structurally from tetracycline? How does this change in structure affect it?
Genetically altered streptomyces aureofaciens
It has a secondary hydrocyl group instead of tertiary hydroxyl group, also has an added Cl group. so it dehydrates more slowly
also lowers food and milk absorption by 50%
Why is demeclocyclin more stable than tetracycline under dehydration
Demeclocycline forms an intermediate with higher energy and less stable cation, so we need a higher activation energy, so dehydration goes slower.
Difference in structure between minocycline and doxycycline? What does this ensue?
Minocycline lacks C6 hydroxyl group, so does not undergo acid catalyzed dehydration, so has no possibility of 4-epianhydrotetracycline mediated toxicity
How is minocycline synthesized? How is the bioavailability? Unique toxicityies?
Synthesized from demecloicycline
90-100% oral bioavailability
has vestibular toxicities not shared with other tetracyclines
How is doxycycline synthesized? How does it differ structurally from tetracycoline? What does this ensue?
lacks C-6 hydroxy group, so does not undergo acid catalyzed dehydration, so no potential for epianhydritetracycline mediated toxicity
Why is doxyxyxline the antibiotic of choice for physicians over other tetracyclines
It has no potential for epianhydrotetracycline and it has half life that allows once daily dosing
What is Tigecycline active against? What is it produced from?
Active against gram-positive and gram negative bacteria.
Produce from glycycline antibiotic, a derivative of minocycline
How is tigecyclinr administered
Slow IV infusion
Does tigecycline have epianhydrotetracycline mediated toxicity? Why or why not?
No. This is because it lacks a C6 hydroxyl group so does not undergo acid catalyzed dehydration.
MOA of tigecycline? Resistance likelihood?
Inhibits protein translation in bacteria by binding to the 30S ribosomal unit and blocking entry of amino acyl tRNA molecules into the A site of ribosome. Prevents incorporation of amino acids into elongating peptide chains,
It is also protected from resistance development due to efflux pump induction and ribosomal protection proteins
What is the use of sarecycline? Dosage of sarecycline? Most common adverse rxn? Drug interaction? Effect on fetus?
used for moderate to severe acne
60 mg PO if 33-54 kg
100 mg PO if 55-84 kg
150 mg PO if 85-136 kg
Nausea most common adverse exn
Can cause feral harm
Do not administer with penicillin, decrease dose of anticoagulant
Omadacycline use? administration? effect on fetus? drug interactions?
used in skin infection and community acquired pneumonia
Administration- IV infusion for pneumonia or orally for skin infections
teratogenic
dosage reduction with anticoags
chloramphenicol MOA
Binds irriversibly to the 50S ribosomal unit at a site near erythromycin and clindamycin. It inhibits the peptidyl transferase activity of the ribosome, blocking peptide bond between P site and A site
Therapeutic use of chloramphenicol
Bacterial meningitis,
typhoid, rickettsial infection, intraocular infections
Resistance mechanism of chloramphenicol results from?
1) Reduced membrane permeability
2) Mutation of the 50S ribosomal subunit
3) Elaboration of chloramphenicol acetyltransferase, which acetylates one or both of the hydroxy groups to form metabolites that do not bind 50S ribosomal subunit
WHere is chloramphenicol metabolized? How is it excreted?
Metabolized in liver. The glucuronide s inactive. Excreted in kidneys. Reduce dose if hepatic dysfunction.
Toxicity of chloramphenicol
Most serious toxicity of chloramphenicol is aplastic anemia
Bone marrow suppression is common
Increased risk of childhood leukemia with increased length of treatment
drug interaction of chloramphenucol? Distribution?
P450 inhibiting drug
30-50% concentration achieved in brain and CSF when meninges not inflmaed, increased to 90% if meninges inflamed
The quinolone antimicrobial agents contain 4 core structure, name them and know structure
quinolone
Cinnolone
1, 8 Naphthyrodone
Pyridopyrimidone
Describe the activity of first gen quinolones? Name them
Developed due to activity against gram (-) bacteria. They have limited activity against gram + bacteria
Both drugs have been discontinued, oxolinic acid, nalidixic acid
Describe 2nd gen quinolones structure? Descirbe activity (what they act on) Name a drug
Have fluroines at C 6
Broader spectrum of bactericidal activity and are more potent.
Both gram positive and gram negative
Ciprofloxacin (most potent)
Describe the activity of 3rd and 4th gen quinolones. COmpare potency to cipro? Name the drugs?
3rd and 4th gen have improved activity against gram + organisms, particularly strep. Pneumoniae. None are as potent against gram negative than cipro.
Levofloxacin is 3rd gen
Moxifloxacin is 4th gen (last resort due to side effects)
WHat is the use of xepi? What is it? Precautions?
Xepi is a new quinolone
Used topically to treat impetigo in pts with staph aureus or strep pyogenes
Precaution- overgrowth with non susceptible bacteria and fungi
What kind of drug is baxdella? Use? Adverse effects
New quinolone
Treatment for skin infection
Adverse effects- tendonitis, tendon rupture, peripheral neuropathy, CNS effects, exacerbation of myasthenia gravis, N,V,D
WHat do topoisomerases and gyrases do?
During DNA replication, strand separation of the double helix causes DNA to twist, resulting in twisting and kinking of DNA. Topoisomerase and gyrase untangle DNA by cutting one (topo I) or 2 strands (topo II)
How do topoisomerase and gyrase cleave DNA?
by carrying out a neuclophilic attack on phosphodiesterase linkage so one strand becomes free and another becomes enzyme linked.
Describe themechanism of DNA transport in bacterial DNA gyrases and toposiomerase IV and mammalian toposiomerase II
1) G segment binds to high affinity site located on top of the CAP regions of the dimer
2) Two ATP molecules bind to the ATPase domains leading to N gate closure with a t segment trapped in the DNA capture domain
3) A gate opens in the G segment DNA
4) The T segment DNA is passed through the gate
Name some common features of bacterial gyrase, bacterial DNA, topoisomerase IV and mammalian topoisomerase II
1) dimeric enzyme binds duplex DNA and cleaves both opposing strands with 4 base dagger
2) Cleavage involves covalent attachment of each subunit of dimer through phosphotyrosine linkage to the 5’ end of the DNA (both 3’ hydroxyls leave areleaving groups)
3) The two DNA enda at the cleavage site are pulled apart by a conformational change of the enzyme to create an opening in the gated (G- segment) DNA. The transported DNA duplex (T-segment) is passed through opening (knotting or unknotting)
4) Transported DNA can be from same molecule or from different molecule (catenation and decatenation)
5) All of the type II enzymes can be distinguished by their relative abilities to relax DNA vs decatenate (or catenate)
6) ATP hydrolysis requires Mg
Describe DNA unwinding by the strand passage mechanism
1) binding of dsDNA that covers 140 bases and wraps around the two A subunits in the dimeric protein
2) Cleavage of a phosphodiester bond on each strand of DNA by the neucleophilic attack
3) The dsDNA is passed through the cleavage site and this is dependent upon the ATP hydrolysis in the B subunit to induce a conformational change
4) Phosphodiester backbone is rejoined (litigated) by neucleophilic displacement of the protein tyrosine residue
5) to repeat the cycle the ATP has to be hydrolyzed first
MOA of quinolone antibiotics
Quinolone antibiotics bind to the cleavage complex that exists after step 2.
The drug molecules are stacked between the base pairs at the cleavage site so that the cleavage complex is stabilized and religation reaction is inhibited. Leads to apoptosis
DNA religation is blocked by quinolones
What are some therapeutic uses of Quinolones
1) Urinary tract infections. Cipro is effective
2) Prostatitis. Cipro and ofloxacin
3) STD. Gonorrhoaea, haemophilus ducreyi- cipro (ceftriaxone now due to resistance)
chlamydia- levofloxacin
4) GI infections- Cipro works for Shigellosis
5) Respiratory tract infection. Many of the new fluoroquinolones (moxifloxacin) have excellent activity vs strep pneumoniae.
Cystic fibrosis have responded to fluoroquinolones
6) Bone joint and soft tissue infection- cipro has a sole therapy effective in 50% diabetic foot infection
What is fluoroquinolone resistance associated with
Resistence correlates use
Resistence mechanisms of quinolone
Increased efflux
Point mutations in enzyme
decreased permeability
How is the incidence of resistance compared to other antibacterial agents (other than fluoroquinalone)What is a common mutation seen in quinolone? Cross resistance? What not to do when dosing
Incidence of resistance is low
Point mutations in A subunit and B subunit
Cross resistance is present ( if resistant to one quinolone dont try another
Do not under dose to avoid resistant strain
How arequinolones absorbed? Distribution? Clearance? Relationship with heavy metals?
FLuoroquinolones are all readily absorbed
widely distributed
Renal and hepatic clearence
Insoluble chelates form if interacting w heavy metal so avoid
Major inactive metabolite of quinolone? How is it excreted?
Major inactive metabolite is the glucouronide at the 3 carboxyl position and excreted in urine
adverse effects of quinolones
N, V, D
Headache and dizziness
Hallucinations, delirium and seizures
Peripheral neuropathy
Damage growing cartilage ( so do not give to children under 18 unless they have cystic fibrosis)
Tendonitis in adults
Gatifloxacin adverse effects
hyperglycemia and hypoglycemia in diabetic patients
