Cushman 6 Flashcards
Clindamycin and Tetracycline Antibiotics - Synthesis.
___ is synthesized from the naturally occurring antibiotic lincomycin by treatment with chlorine and triphenylphosphine in acetonitrile.
- The reaction proceeds with inversion of configuration. Lincomycin has antibiotic activity but it is rarely used because of its
___
clindamycin
- toxicity
Clindamycin and Tetracycline Antibiotics
MOA: The mechanism of action of clindamycin is similar to that of the
___ antibiotics like erythromycin. It inhibits protein synthesis by binding to the bacterial ___ ribosome. It binds to the same site as erythromycin.
- Antagonism and cross- ___
between clindamycin and erythromycin have been reported
- macrolide
- 50S
- resistance
Clindamycin and Tetracycline Antibiotics - Clinical Use
Clindamycin is most effective against:
1) ___ Gram ( ___ ) cocci, including some members of the Staphylococcus and Streptococcus genera.
2) ___ Gram ( ___ ) bacilli, including some members of the Bacteroides and Fusobacterium genera.
Clindamycin may be used systemically to treat bone infections with ___ ___, or
topically to treat severe acne.
- available as a vaginal cream for treatment of bacterial vaginosis.
- has replaced ___ for treatment of lung abscesses and anaerobic lung and pleural space infections. It is also used to treat MRSA.
- administered ___ with pyrimethamine and leucovorin to treat ___ patients with
encephalitis caused by Toxoplasma gondii.
Note: The relatively high incidence of pseudomembranous ___ and ___ limit the use of clindamycin to infections in which it is clearly the superior agent
- aerobic, positive
- anaerobic, negative
- S. aureus
- IV, AIDs
- colitis, diarrhea
Clindamycin and Tetracycline Antibiotics
Dosage Forms. Clindamycin preparations for ___ administration include capsules and suspensions. It is also available for ___ injection as clindamycin phosphate. ___ foams or solutions contain either clindamycin hydrochloride or clindamycin phosphate
- oral
- IV
- topical
Clindamycin and Tetracycline Antibiotics: Metabolism
Clindamycin is extensively metabolized by ___ enzymes in the ___ to the sulfoxide and the N-demethylated derivative. The metabolites are pharmacologically inactive
CYP P450, liver
Clindamycin PK
Approximately ___ % of the administered dose is absorbed from the GI tract.
- penetrates the CNS in high enough concentrations to be useful in the
treatment of cerebral ___ in human immunodeficiency virus-infected patients
- Clindamycin and its metabolites are mainly excreted in the ___ and ___.
- half- life is 1.5-5 hours
- Accumulation of clindamycin can occur in patients with hepatic failure, and adjustment of the dosage may be required.
- 90%
- toxoplasmosis
- urine, bile
Clindamycin AE
Common: diarrhea, pseudomembranous colitis, N/V, abdominal cramps, and rash, contact dermatitis (topical)
- ___ ___ is a potentially lethal condition commonly associated with clindamycin. It may affect up to 2–10% of patients treated with clindamycin. Overgrowth of
___ ___, which is inherently resistant to clindamycin, results in the production of a toxin that causes a range of adverse effects ranging from diarrhea to colitis and ___ ___
- should be recognized and treated promptly with ___ or vancomycin
- Pseudomembranous colitis, C. difficile
- toxic megacolon
- metronidazole
Tetracyclines - History
Tetracycline is a broad-spectrum antibiotic produced by ___ bacteria
- fun fact: found in ___
- Streptomyces
- mummies
Tetracyclines - Chemical Properties
Chelation: Tetracyclines form stable chelates with polyvalent metal ions such as ___ , ___ , ___ , and ___
- Ca2+, Al2+, Cu2+, Mg2+
Tetracyclines - Chemical Properties: Consequences
The ability of tetracyclines to form ___ chelates has a number of consequences:
1) should not be administered with foods that are rich in ___ because the
insoluble calcium chelates are not absorbed from the GI tract. They should not be administered with ___ that contain multivalent metals (e.g. TUMS), or with hematinics containing ___
- if cannot be avoided metals should be administered __ hour before or __ hours after the tetracycline.
- In spite of the chelation problem, the preferred route of administration is ___
- insoluble
- Ca, antacids
- 1, 2
- oral
Chemical Properties - tetracyclines: Consequences
2) Tetracyclines chelate calcium during formation of ___ , resulting in permanently brown or gray teeth.
- should not be administered to children when they are
forming their permanent teeth. The discoloration of the teeth becomes ___ with time as a result of a ___ reaction
3) Tetracyclines should be avoided after the ___ month of pregnancy in order to avoid undesirable effects on fetal bones and teeth.
- teeth
- worse
- photooxidation
- 4th
Chemical Properties - tetracyclines: Consequences
Epimerization. The hydrogen on the amine-bearing carbon atom is ___ , resulting in enolization and epimerization. The epitetracycline product is pharmacologically ___ .
- Old tetracycline preparations can lose approximately ___ of their potencies in this way
- Epimerization is slow in the solid state and most rapid in solution at pH 4
- acidic, inactive
- 1/2
Chemical Properties - tetracyclines: Consequences
Dehydration. The tertiary, benzylic hydroxyl group at C-6 has an antiperiplanar relationship with the proton at C-5a, so it is “set up” for ___
- Note that the C-12a hydroxyl group is ___ , but it is not next to an antiperiplanar hydrogen and is also deactivated by being next to a carbonyl
group, so it is ___
- elimination
- tertiary
- stable
Chemical Properties - tetracyclines: Consequences
Discolored, old tetracycline samples should be thrown out
- Not only is 4-epianhydrotetracycline
inactive as an antibiotic, it is also toxic to the ___ and can produce a ___ -like syndrome (failure of the reabsorption mechanism in the proximal convoluted tubules) that can be fatal
- tetracycline closely monitored for 4- epianhydrotetracycline.
- Some tetracyclines, such as ___ and ___ , lack a C-6 hydroxyl group and are therefore completely free of this potential for toxicity
- kidneys, fanconi
- minocycline, doxycycline
Chemical Properties - tetracyclines: Consequences
Cleavage in Bas: Tetracyclines undergo cleavage in base at pH values of ___ or above. The lactone product is ___
8.5
- inactive
Tetracyclines Mechanism
- bind to the ___ ribosomal subunit and inhibit bacterial protein synthesis by
blocking the attachment of the aminoacyl-tRNA to the __ site of the ribosome, resulting in ___ of peptide chain growth - inhibitors of the ___ - ___
interaction. The tetracycline binding sites do NOT overlap with the ___ binding site. - Tetracycline binds to the small ribosomal subunit in ___ different locations. The Tet1 site has
highest occupancy and is located near the site where the aminoacyl-t-RNA docks in the __ site of
the ribosome
- 30S, A, termination
- codon-anti-codon
- erythromycin
- 6, A
Tetracyclines: Therapeutic Use
- ___ -spectrum antibiotics
Common use:
- treatment of acne
- choice for infections caused by ___ (trachoma, psittacosis, salpingitis, urethritis, and lymphogranuloma venereum), Rickettsia (typhus, Rocky mountain spotted fever), brucellosis, and spirochetal infections (borreliosis/Lyme disease and syphilis).
- They are also used to treat ___ , plague, tularemia, and Legionnaires’
disease
- broad
- chlamydia
- anthrax
Tetracyclines: Specific Agents
Name: ___
1) classical antibiotic of the tetracycline class. It is produced by fermentation of Streptomyces ___ . It is generic and relatively inexpensive.
2) Food and milk ___ oral absorption by about 50%
Tetracycline
- aureofaciens
- lower
Tetracyclines: Specific Agents
Name: ___
1) produced by a genetically altered strain of Streptomyces ___
2) It has a ___ hydroxyl group at C-6 instead of the tertiary hydroxyl group.
3) dehydrates more ___ than tetracycline because the secondary cation intermediate formed from demeclocycline in the dehydration reaction is less stable) ( ___ energy) than the tertiary cation intermediate ( ___ energy) formed from tetracycline.
4) Food and milk ___ oral absorption by about 50%
Demeclocycline
1) aureofaciens
2) secondary
3) slowly, high, low,
4) lower
Tetracyclines: Specific Agents
Name: ___
1) lacks a C-6 ___ group and therefore does not undergo acid-catalyzed
___ (no potential for 4-epianhydrotetracycline-mediated ___ )
2) It is synthesized from ___
3) ___ - ___% oral bioavailability
4) The absorption of minocycline is lowered by about ___ % when taken with food or milk.
5) has vestibular toxicities ( ___ , ___ , nausea) not shared with other tetracyclines
Minocycline
1) OH, dehydration, toxicity
2) demeclocycline
3) 90-100%
4) 20%
5) ataxia, vertigo
Tetracyclines: Specific Agents
Name: ___
1) synthesized from ___
2) It lacks a C-6 ___ group and therefore does not undergo acid-catalyzed ___. No potential for 4-epianhydrotetracycline mediated ___
3) produces fewer ___ symptoms, it is considered to be the tetracycline of choice by many physicians.
4) It has __ - ___ % oral bioavailability.
5) The absorption of doxycycline is lowered by about ___ % when taken with food or milk.
6) It has a half-life (18-22 hours) that permits ___ a day dosing
Doxycycline
1) oxytetracycline
2) OH, dehydration toxicity
3) GI
4) 90-100%
5) 20%
6) once
Tetracyclines: Specific Agents
Name: ___
1) glycylcycline antibiotic derivative of ___
2) Active against a variety of gram ___ and gram ___ bacteria
3) ___ , administered by slow IV infusion, no oral form is available.
4) lacks a C-6 ___ group and therefore does not undergo acid-catalyzed ___ . No potential for 4-epianhydrotetracycline-mediated ___
5) ___ (rare), ___ , and anaphylactoid reactions may occur.
6) Inhibits protein translation in bacteria by binding to the ___ ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the ___ site of the ribosome.
7) Prevents incorporation of amino acid residues into ___ peptide chains.
6) protected from resistance development due to ___ pump induction and also due to ___ protection proteins.
Tigecycline
1) minocycline
2) positive, negative
3) parenteral
4) hydroxyl, dehydration, toxicity
5) hepatotoxicity, pancreatitis
6) 30S, A, enlongating
7) efflux, ribosomal
Tetracyclines: Specific Agents
Name: ___ (Seysara)
1) treatment of moderate to severe ___
2) The recommended dosage of sarecycline is ___ per day with or without -__
3) The most common adverse reaction is ___
4) It can cause ___ harm when administered to a pregnant woman and is not recommended during ___
5) Drug Interactions: It should not be co-administered with oral ___ (both can cause increased ICP), ___ , and ___ preparations
6) It may interfere with antibacterial action of ___ because tetracyclines are ___ and penicillins work on ___ bacteria
7) ) Dosage reduction is recommended with ___ (both may depress prothrombin activity) and P-glycoprotein substrates (e.g ___ )
Sarecycline
1) ACNE
2) ONCE
3) N
4) fetal, breastfeeding
5) retinoids, antacids, iron
6) PCNs, bacteriostatic, dividing
7) anticoagulants, digoxin
Tetracyclines: Specific Agents
Name: ___
1) treatment of ___ infections and community-acquired bacterial ___
2) It is recommended for treatment of pneumonia caused by: Streptococcus ___ , Staphylococcus ___ ( ___ -susceptible isolates), Haemophilus ___ , Haemophilus ___ , ___ pneumoniae, ___ pneumophila, ___ pneumoniae, and ___ pneumoniae.
3) It is recommended for treatment of skin infections caused by Staphylococcus ___ ( ___ -susceptible and -resistant isolates), Staphylococcus ___ , Streptococcus ___ , Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Enterococcus ___ , Enterobacter
___ , and ___ pneumoniae.
4) It is administered by ___ infusion for treatment of pneumonia or skin infections, or ___ for treatment of skin infections
5) The most common adverse reactions are ___ / ___ / ___ , as well as
___ , headache, and insomnia.
6) Omadacycline is ___ : Breast feeding is not recommended while taking this drug.
7) Drug Interactions: Dosage reduction is recommended with ___ (both may depress prothrombin activity). Oral absorption is ___ by heavy metals.
Omadacycline
1) skin, pneumonia
2) Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae
3) Staphylococcus lugdunensis, Streptococcus pyogenes, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Enterococcus faecalis, Enterobacter cloacae, and Klebsiella pneumoniae
4) IV, oral
5) N/V/D, HTN
6) teratogenic
7) anticoagulants, reduced
