Cushman 4 Flashcards
Cephamycins
The cephamycins have a 7a- ___ group, and they are often classified as ___ generation cephalosporins.
- This group increases stability vs. ___
- methoxyl
- 2nd
- β-lactamases
Cephamycins
Name: ___
1) used ___ and has a ___ spectrum of activity
2) releases N-methylthiotetrazole, which can cause ___ , and can also cause a reaction to ethanol that is similar to ___
3) generally stable to ___
Cefotetan
1) parenterally, broad
2) hypoprothrombinemia, disulfuram
3) B-lactamases
Carbapenems
1) ___ is the N-formiminoyl derivative of thienamycin, a naturally occurring antibiotic isolated from ___ ___ . Thienamycin is too ___ to be used as a drug, since the primary amino group attacks the B-lactam intermolecularly. The N-formiminoyl group prevents this from happening.
2) The carbapenems are carbon analogs of the penicillins. The ___ that is present in the thiazolidine ring of the penicillins is replaced by a methylene group. This ___ reactivity because a methylene is smaller than a sulfur, so the ring strain is ___ in the carbapenems
3) Besides reacting with ___ , imipenem reacts with and inhibits ___
4) hydrolyzed by renal dehydropeptidase-1, but this can be overcome by co-administration of the dehydropeptidase-1 inhibitor ___
5) combo has ___ spectrum antibiotic activity. It is active against both Grams. Carbapenems referred to as “magic bullets” (restricted in order to avoid widespread bacterial ___ ). Imipenem is a good B-lactamase ___
6) The combination of imipenem with cilastatin is used to treat ___ infections of the gut, GI tract, bone, skin, and endocardium.
7) Imipenem-cilastatin sodium is administered ___
1) Imipenem, Streptomyces cattleya, reactive
2) S, increases, greater
3) PBPs, B-lactamases
4) cilastatin
5) broad, resistance, inducer
6) serious
7) parenterally
Monobactams
Name: ___
1) totally ___ but the design was inspired by monocyclic B-lactam natural products called monobactams.
2) The ___ acid group takes the place of the C-2 carboxyl group in the penicillins and cephalosporins.
3) The antibiotic spectrum focuses almost completely on Gram ___ bacteria. Used in severe infections (especially those by ___ - resistant organisms acquired in hospitals)
4) The ___ of the sulfamic acid activates the B-lactam ring toward chemical hydrolysis and to reaction with ___ .
5) Cross allergenicity with penicillins and cephalosporins has not been reported except for ___ , which has an identical oxime ether sidechain. Advantage: can be used in patients that have ___ allergy.
6) The ___ either makes it resistant to hydrolysis by β-lactamases
Aztreonam
1) synthetic
2) sulfamic
3) negative, PCN
4) electronegativity, PBPs
5) ceftazidime
6) oxime
Glycopeptide Antibiotics - Vancomycin
Production:
Vancomycin is a ___ glycopeptide antibiotic produced by fermentation of Nocardia ___ (note: this has been re-designated Streptomyces orientalis as well as Amycolatopsis orientalis).
About 200 glycopeptide antibiotics are known but only two (vancomycin and
teicoplanin) are in clinical use. Vancomycin is licensed for clinical use in the United States, while teicoplanin is not
- nonribosomal
- orientalis
Vancomycin MOA
- inhibitor of Gram ___ cell wall biosynthesis.
- The mechanism involves binding to the peptidyl side chain ___ - ___ terminus in the peptidoglycan precursor (before ___ ).
- The transpeptidase reaction that is required for cross-linking is inhibited by the high ___ binding of vancomycin to the substrate. This mechanism is similar to the ___ antibiotics in terms of the reaction that is inhibited, but the mechanisms of inhibition are different.
- Vancomycin also inhibits the ___ step in peptidoglycan synthesis.
- positive
- D-Ala-D-Ala, crosslinking
- affinity, B-lactam
- transglycosylation
Vancomycin - Spectrum of Activity
Vancomycin is primarily ___ and is active against Gram ____ bacteria.
- gram negative and mycobacteria not susceptible
A bacterium with an MIC __ μg/mL is considered a susceptible strain. ___ strains that are methicillin-resistant are usually inhibited with MIC values 1-5 μg/mL. ___ are also generally susceptible.
- bactericidal, positive
- 4
- Staphylococcus
- Streptococci
Vancomycin- resistance
- last line of defense in hospital-acquired multidrug-resistant ___ and ___ infections.
- Vancomycin-resistant enterococcal - VRE from giving livestock ___
- A limited number of vancomycin-resistant Staphylococcus ___ infections have been reported in the U.S.
- Mechanism: mutation of the peptidoglycan cell wall precursor from D-Ala-D-Ala to D-Ala-D- ___
- Vancomycin has 1000 times ___ affinity for the D-Ala-D-lactate precursor
- staphylococcal, streptococcal
- avoparcin
- aureus
- lactate
- less
Vancomycin - Pharmacokinetics and Distribution
- usually administered ___ (low levels in blood after oral administration)
- highly distributed and 90% eliminated by ___ ___ with a half-life of 4-11 hours.
- IV
- glomerular filtration
Vancomycin - Therapeutic Use
1) Vancomycin is given orally to treat ___ ___ pseudomembranous colitis (relapse or ___ treatment).
2) Vancomycin is used to treat methicillin-resistant ___ ___
1) Clostridium difficile, metronidazole
2) Staphylococcus aureus
Vancomycin - Toxicity and Side Effects
1) A ___ response that results in a red skin rash and potential ___ may occur with vancomycin.
2) ___ (0.1-1% of patients) and ___ (rare) are the most significant potential problems. These conditions are associated with high concentrations of circulating drugs and can be minimized by a careful dosing strategy
1) hypersensitive, anaphylaxis
2) Nephrotoxicity, ototoxicity
Lipoglycopeptide Antibiotics
Name: ___
- semisynthetic lipoglycopeptide antibiotic that inhibits ___ and ___
- disrupts the ___ of gram ___ bacteria
- It is active against a broad
spectrum including ___
Oritavancin
- transpeptidation, transglycosylation
- membrane, positive
- MRSA
Lipoglycopeptide Antibiotics
Name: ___
1) Mechanism: like vancomycin, it binds to the ___ - ___ terminus of the peptidoglycan in the growing cell wall. It inhibits ___ and ___
2) Therapeutic Use: ___ and
other gram ___ infections
Telavancin
1) D-Ala-D-Ala, transpeptidation, transglycosylation
2) MRSA, positive
Lipoglycopeptide Antibiotics
Name: ___
1) ___ generation lipoglycopeptide antibiotic
2) Mechanism: identical to ___ . It binds to the D-Ala-D-Ala residue on growing peptidoglycan chains and prevents transpeptidation and transglycosylation from occurring,
thus preventing peptidoglycan elongation and cell membrane formation.
3) It is active against a broad spectrum of gram ___ bacteria including ___ and __
Dalbavancin
1) 2nd
2) vancomycin
3) positive, MRSA, MRSE
Note the difference in half-lives:
Vancomycin half-life: 4-6 h
Telavancin half-life: 7-9 h
Dalbavancin half-life: ___ h
Oritavancin half-life: ___ h
204
245
latter 2 can be used in single dose regimens
Streptogramin Structure
Names: ___ and ___ (Synercid)
The streptogramins are a family of natural product derivatives that have been available for over 30 years.
- They are semisynthetic derivatives of a natural mixture of ___ I and II isolated from ___ ___ . Synercid is a mixture containing 30% ___ and 70% ___
quinupristin, dalfopristin
- pristinamycin
- Streptomyces pristinaespiralis
- quinupristin, dalfopristin
Streptogramin Structure
- The parent natural product mixture of pristinamycins lacks suitable ___ for reliable dosages.
- The derivatives ___ and ___ have amino side chains that allow salt formation and enhance the water ___
- Each of these compounds is ___ alone. Synercid is bacteriostatic against ___ ___ and bactericidal against strains of methicillin-susceptible and methicillin-resistant ___
- administered ___ , but there are other pristinamycin combinations under development that have useful oral activity
- solubility
- quinupristin, dalfopristin, solubility
- bacteriostatic, Enterococcus faecium, staphylococci
- parenterally
Dalfopristin Mechanism of Action
During peptide synthesis, when the second tRNA base pairs with the appropriate codon in the mRNA, ___ ___ (ribosomal RNA) catalyzes the formation of a ___ bond between the two amino acids present (while breaking the bond between met and its tRNA).
- Dalfopristin directly interferes with the ___ ___catalyzed step
- peptidyl transferase
- peptide
- peptidyl transferase
Quinupristin Mechanism of Action
Quinupristin binds in the ribosomal ___ and causes blockage of the tunnel.
- tunnel
Streptogramin Structure
T or F: dalfopristin and quinupristin create a ternary complex with the peptidoglycan
FALSE:
ribosome
Streptogramin Structure - Therapeutic Use
1) Vancomycin-resistant ___ ___ bacteremia(not faecalis) - Certain strains are resistant to all other antibiotics
2) skin infections caused by ___
3) Vancomycin-resistant Enteroccus faecium ___ ___ infections
1) Enterococcus faecium
2) MRSA
3) urinary tract
Streptogramin Structure - Resistance
1) most common resistance to quinupristin is due to adenine ___ of A2058 in the ___ rRNA as in the case of erythromycin and clindamycin. Dalfopristin is not affected by this rRNA modification, but renders synercid a ___ agent at the normal dose. Extension of the dosing to ___ is well tolerated and allows for more sustained tissue drug levels
2) Resistance can also be due to ___ and enzymatic inactivation (metabolism) by resistant bacteria
3) Streptogramin treatment of vancomycin-resistant ___ is currently resulting in a 70% cure rate. This drug will most likely be reserved for serious life-threatening infections caused
by Gram ( ___ ) organisms
4) The continued use of streptogramins ( ___ ) in animal feeds will continue to result in more resistant bacterial strains.
5) There is a report of patients treated with a 14 day course of synercid selecting resistant forms
of ___ , ___ , and ___ . To avoid this selection, a careful approach to dosage
regimen and combination therapy will be required.
1) methylation, 23S, bacteriostatic, TID
2) efflux
3) E. faecium, positive
4) virginiamycin
5) E. faecialis, E. faecium, S. aureus
Streptogramin - Side Effects
T or F: There is no known significant toxicity presented by synercid
T
Several mild side effects have been reported and include inflammation and pain at the site of injection, nausea, diarrhea, muscle weakness and rash
Streptogramin - Pharmacokinetics
1) ___ because of the different elimination rates for each component and their metabolites.
2) The average t1/2 is 1.5 hours in serum with a ___ relationship between the dose and the AUC.
3) Most tissues of importance to Gram ( ___ ) infections achieve up to 85% of the serum concentrations of Synercid. The BBB or placental barriers are not penetrated. Macrophages concentrate the drug up to ___ x the extracellular fluid concentration.
4) Clearance is 75% through ___ excretion (fecal matter) and the remainder appears in the urine
1) complicated
2) linear
3) positive, 50x
4) biliary
Drug Interactions
Streptogramins inhibit ___
CYP 3A4
Oxazolidinones
Name: ___
MOA: Potent interaction with ___ ribosomal subunit. This interaction prevents the formation of the ___ initiation complex. Linezolid interacts specifically with ___
Linezolid
- 50S
-70S
- 23 rRNA
T or F: linezolid has affinity for the 30S ribosomal subunit
FALSE
50S and 23S rRNA
Oxazolidinones - Therapeutic Use
1) Vancomycin-resistant ___ ___
2) Nosocomial ___ caused by methacillin-–resistant strains of ___
3) ___ infections caused by methicillin–resistant strains of ___
To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid, it should be used only to treat/prevent infections that are proven or strongly suspected to be
caused by multiple drug-resistant Gram ( ___ ) bacteria, or when patients are ___ to otherwise effective alternatives
1) E. faecium
2) pneumonia, S. aureus
3) Skin, S. aureus
positive, allergic
T or F: Linezolid has excellent oral bioavailability, and it is also available for IV administration
T
Oxazolidinones - Resistance
___ site modification is virtually the only mechanism of resistance that has thus far been proven
- Resistance mutations identified in various species are associated with G to U substitution in the ___ ___center of 23S rRNA at position 2576 and result in reduced affinity of linezolid for the ___ subunit.
target
- peptidyl transferase
- 50
Oxazolidinones- Side Effects
Common
- (10%) were GI: N/V/D
Other adverse
- headache
- ___ discoloration
- oral Candidiasis ( ___ )
More Serious SE
- ___
- GI bleeding
- anemia
Long-term treatment resulted in fully
reversible ___ . CBC should be monitored ___ in patients receiving linezolid. Linezolid-induced ___ was also reported among patients receiving linezolid for more than 6 months.
- tongue
- thrush
- thrombocytopenia
- myelosuppression
- weekly
- neuropathy
Oxazolidinones - metabolism
Linezolid is metabolized via ___ ring oxidation. In humans, approximately 30% of a linezolid dose is excreted in the ___ as the parent drug.
- The two major metabolites do not appear to have significant toxicity or antimicrobial activity
- morpholine
- urine
Oxazolidinones - Drug Interactions
- Linezolid is a moderately potent, reversible, nonselective inhibitor of ___ ___. Therefore, it has the potential for interaction with adrenergic and ___ agent
- A reversible potentiation of pressor response to ___ has been observed when linezolid is administered to normotensive subjects. (use in caution in HTN patients)
- should not consume large quantities of foods or beverages that are rich in ___
- monoamine oxidase, serotonergic
- pseudoephedrine
- tyramine
Oxazolidinones
1) ___ phosphate (FDA approved June 20, 2014) is a ___ generation oxazolidinone used for treatment of acute bacterial ___ infections.
2) It is more potent than linezolid vs. ___
3) The mechanism of action is the same as ___
4) Administration can be ___ or ___
5) Tedizolid phosphate is a ___ of tedizolid that is activated by plasma ___
1) Tedizolid, 2nd, skin
2) MRSA
3) linezolid
4) oral, IV
5) prodrug, phosphatases
