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
What drug is this?
Chloramphenicol
Chloramphenicol
- originally obtained from Streptomyces ___ and introduced into clinical practice in 1949
- It was the first antibiotic to be manufactured synthetically on a large scale
- It was one of the first ___ -spectrum antibiotics on the market, but its use has waned considerably due to its ___ .
- use is more prevalent in third-world countries because it is inexpensive
- venezuelae
- broad, toxicities
Mechanism of Action: Chloramphenicol
- binds ___ to the ___ ribosomal subunit at a site that is near the site for ___ and ___ (competitive binding interactions occur among these drugs)
- It inhibits the peptidyl ___ activity of the ribosome and thus blocks ___ bond formation between the __ site and the __ site
- reversibly, 50S, clindamycin, erythromycin
- transferase, peptide, P, A
Chloramphenicol: Therapeutic Use
- Chloramphenicol sodium succinate is a ___ for IV or IM administration that is ___ to chloramphenicol in the liver
- Chloromycetin succinate is specifically indicated for bacterial ___, ___ fever, ___ infections, ___ infections and other serious infections where bacteriological evidence or clinical judgment indicates that chloramphenicol is an appropriate antibiotic
- Chloramphenicol is ___ soluble, and it remains relatively ___ to plasma proteins. It penetrates effectively into all tissues of the body, including the ___
- prodrug, hydrolyzed
- meningitis, typhoid, rickettsial, intraocular
- lipid, brain
Chloramphenicol: Resistance Mechanism
1) reduced membrane ___
2) mutation of the ___ ribosomal subunit
3) elaboration of chloramphenicol ___ , which acetylates one or both of the hydroxy groups to form metabolites that do not bind to the 50S ribosomal
subunit
1) permeability
2) 50S
3) acetyltransferase
Chloramphenicol Metabolism
- metabolized to its glucuronide in the ___ (inactive), readily excreted by the ___ - reaction involves nucleophilic attack of the less hindered primary ___ , catalyzed by glucuronyl transferase
- The dose of chloramphenicol must therefore be reduced if ___ function is impaired. (Dose should be adjusted according to measured plasma concentrations)
- ___ cannot metabolize and should never receive
- Chloramphenicol is also metabolized by reduction of the ___ group to an amino. The metabolite is less active than chloramphenicol
- liver, kidney, UDPGA
- hepatic
- neonates
- nitro
Chloramphenicol Toxicity
most serious toxicity
- ___ anemia
- rare and generally fatal
- becomes apparent ___ or ___ after treatment has been stopped.
- highest risk is with ___ chloramphenicol (affecting 1 in 24,000–40,000) and the lowest risk occurs with ___ (affecting less than 1 in 224,716 prescriptions)
- recommended that blood levels be monitored to keep chloramphenicol concentrations less than ___ μg/mL
Common:
- ___ ___ suppression due to impairment of mitochondrial function resulting from inhibition of protein synthesis (completely reversible once the drug is stopped)
- predictable once a cumulative dose of ___ g has been given
- increased risk of childhood ___ and the risk increases with length of treatment.
- Nausea, vomiting and diarrhea occur occasionally in adults and rarely in children
- aplastic
- weeks, months
- oral, eye drops
- 25
- bone marrow
- 20
- leukemia
Chloramphenicol - Drug Interactions
Chloramphenicol inhibits ___
- drug metaolized by the same enzyme are affected
CYP P450
Chloramphenicol Distribution
The concentration achieved in brain and CSF is about ___ - ___ % that of the plasma even when the meninges are not inflamed
- increases to as high as ___ % when the meninges are inflamed
- 30-50%
- 89%
Quinolone Antimicrobial Agents
Core Structures (4)
Quinolone Antimicrobial Agents - First Gen
Names: ___ and ___
- The first generation quinolones were developed because of their activity against Gram ___ bacteria
- limited activity vs. Gram ___ bacteria
- They do not achieve useful systemic concentrations and are only useful for treatment of lower ___ ___ infections
- Both have been discontinued
oxolinic acid, nalidixic acid
- negative
- positive
- urinary tract
Quinolone Antimicrobial Agents - 2nd Gen
Name: ____
- The second generation agents have a ___ substituent at C-6 and a heterocyclic ring (usually ___ ) at C-7
- They have a ___ spectrum of ___ activity and are more ___
- ___ is the most potent fluoroquinolone showing MIC = 0.01 to 1 μg/mL for Gram ___ organisms
- These drugs have extended activity against Gram ___ organisms and ___
Ciprofloxacin
- F, piperazine
- broader, bactericidal, potent
- Ciprofloxacin, negative
- postive, Mycoplasma
Quinolone Antimicrobial Agents - Third Gen
Names: ___ (LEVAQUIN) and ___ (AVELOX)
- The third and fourth generation quinolones have improved activity against Gram ___organisms (particularly ___ ___ , and none of them are as potent as ___ against Gram ___ organisms)
- ___ shows a 40-100 fold increase in potency over ___ against most Gram ___ species including ___ spp., with ranges of values for MIC = 0.06 to 4 μg/mL
- ___ is considered to be a “drug of last resort” because of its severe side effects
levofloxacin, moxifloxacin
- positive, Streptococcus pneumoniae, ciprofloxacin, negative
- levofloxacin, nalidixic acid, negative, Pseudomonas
- moxifloxacin
Quinolone Antimicrobial Agents - New
Name: ____ (Xepi)
- used topically to treat impetigo due to ___ ___ or___ ___ in adults and pediatric patients 2 months of age or older
- Precautions: ___ with nonsusceptible bacteria and fungi (Employ alternative therapy)
Ozenoxacin
- S. aureus, S. pyogenes
- overgrowth
Quinolone Antimicrobial Agents - New
Name: ___ (Baxdela)
Therapeutic Use:
- approved for oral or IV use for the treatment of ___ infections caused by a wide variety of Gram ___ and Gram ___ bacteria, including ___
- Adverse Effects: ___ , ___ rupture, peripheral ___ , ___ effects, exacerbation of myasthenia gravis, N/V/D have an incidence of greater than 2%
Delafloxacin
- skin, positive, negative, MRSA
- tendonitis, tendon, CNS
Quinolone - Mechanism of Action
- supercoiling during DNA replication fixed by topoisomerases and gyrases
- The topoisomerases and gyrases cleave DNA by carrying out a ___ attack on a ___ linkage, so one part of the strand becomes ___ and the other one becomes ___ -linked.
- The nucleophile is the phenolic hydroxyl group of a ___ residue, and different topoisomerases cleave the DNA so that either the 3’-hydroxyl or the 5’-hydroxyl of the DNA can become enzyme-linked.
- The topoisomerase-catalyzed reaction is ___ , and usually the equilibrium is in favor of the uncleaved DNA so that the cleavage complexes are
present in very ___ amounts
- nucleophilic, phosphodiester, free, enzyme
- tyrosine
- reversible, small
Quinolone - Mechanism of Action
1) binding of a __ -segment DNA to the high-affinity binding site II located across the tops of the two ___ regions of the dimer (a to b). This requires an ___ N- gate and also an opening between the two B’ regions of the protein
2) Once the DNA is bound, the CAP regions remain in a ___ conformation.
3) Two ___ molecules bind to the ATPase domains, leading to N-gate ___ with a __ -segment trapped in the DNA capture domain
4) Then a gate ___ in the __ - segment DNA (c and d). The __ -segment DNA is passed through the gate. The G- segment DNA ___ and the C-gate ___
1) G, CAP, open
2) open
3) ATP, closure
4) opens, G, T, religates, opens
Quinolone - Mechanism of Action
- conformational change coupled to ATP hydrolysis occurs after DNA ___ and helps squeeze the __ -segment through the open gate.
- The cycle is completed by the rapid ___ of the C-gate followed presumably by hydrolysis of the second ATP. The release of the products of ATP hydrolysis ___ the N-gate and prepares the enzyme for another cycle (resets)
- This mechanism operates with bacterial ___ , bacterial DNA topoisomerase ___ , and mammalian topoisomerase ___
- cleavage ,T
- closure, open
- gyrase, IV, II
Quinolone - Mechanism of Action
This mechanism operates with bacterial ___ , bacterial DNA topoisomerase ___ , and mammalian topoisomerase ___
These enzymes share to following mechanistic features:
1) The dimeric enzyme binds duplex DNA and cleaves both opposing strands with a ___ -base stagger.
2) Cleavage involves covalent attachment of each subunit of the dimer through a ___ linkage to the 5’ end of the DNA (both 3’-hydroxyls are leaving groups).
3) The two DNA ends at the cleavage site are pulled apart by a conformational change of the enzyme to create an ___ in the gated (G-segment) DNA. The transported DNA duplex ( ___ -segment) is then passed through the opening.
4) The transported DNA can be from the ___ molecule (relaxation, knotting, or unknotting) or from a different molecule (catenation and decatenation)
5) All of the type II enzymes can be distinguished by their relative abilities to ___ DNA vs. decatenate (or catenate) DNA
6) The catalysis requires ___ and ___ hydrolysis is involved
gyrase, IV, II
1) 4
2) phosphotyrosine
3) opening, T
4) same
5) relax
6) Mg2+, ATP
Quinolone - Mechanism of Action
The steps involved in the unwinding are:
1) Binding of __ DNA that covers up to 140 bases and wraps around the two __ subunits in the dimeric protein.
2) Cleavage of a ___ bond on each strand of DNA by the nucleophilic attack of a ___ (protein)-OH group to form two covalent bonds between protein and DNA.
3) The dsDNA is “passed through” the cleavage site and this is dependent upon ___ hydrolysis in the B-subunits to induce a ___ change.
4) The phosphodiester backbone is rejoined ( ___ ) by nucleophilic displacement of the protein ___ residue by the 3’-OH of the cleaved strand.
5) To repeat the cycle, the ___ has to be hydrolyzed
1) dsDNA, A
2) phosphodiester, tyrosine
3) ATP, conformational
4) ligated, tyrosine
5) ATP
Quinolone - Mechanism of Action
- The quinolone antibiotics bind to the ___ complex
- The drug molecules are stacked between the ___ ___ at the cleavage site so that the cleavage complex is ___ and the ___ reaction is inhibited
- This blocks the progression of the
___ ___ and the double-strand breaks eventually lead to ___ (bacterial cell death)
- cleavage
- base pairs, stabilized, religation
- replication fork, apoptosis
Quinolone - Therapeutic Uses
1) Urinary tract infections: ___ is effective
2) Prostatitis: ___ and ___ are effective
3) Sexually transmitted diseases: effective against Neisseria gonorrhoeae ( ___ ), Chlamydia trachomatis ( ___ ), and Haemophilus ducreyi ( ___ ) . Increasing resistance to the quinolones has led to ___ (a cephalosporin antibiotic) being the first line treatment of Neisseria gonorrhoeae
4) Gastrointestinal infections. The quinolones are effective for treatment of ___ diarrhea
(frequently caused by enterotoxigenic E. coli). ___ is effective in treatment of shigellosis.
5) Respiratory tract infections. Many of the newer fluoroquinolones, including ___ , have excellent activity vs. Streptococcus ___ . Respiratory tract exacerbations in cystic fibrosis patients have responded to fluoroquinolone therapy
6) Bone, joint, and soft tissue infections: ___ as a sole therapy is effective in 50% of diabetic foot infections.
7) The increase in potency observed with ciprofloxacin analogues has opened new opportunities for their therapeutic applications. These drugs have useful activities against ___ bacteria (requiring high blood levels for treatments) like ___ , ___ , ___ , ___ , and ___
1) ciprofloxacin
2) ciprofloxacin, ofloxacin
3) ciprofloxacin, levofloxacin, ciprofloxacin, ceftriaxone
4) travelers, ciprofloxacin
5) moxifloxacin, pneumoniae
6) ciprofloxacin
7) intracellular
8) Chlamydia, Mycoplasma, Legionella,
Brucella, and Mycobacterium
Quinolone - Resistance Mechanisms
Increased fluoroquinolone resistance rates are correlated with ___ .
Mechanisms include
- decreased cellular ___
- ___ pumps
- ___ of the target enzymes
use
- permeability
- efflux
- mutation
Quinolone - Resistance Mechanisms
1) The incidence of resistance is ___ relative to other antibacterial agents
2) Resistant organisms have spontaneously occurring ___ ___ in the __ -subunit of DNA ___ which lead to an enzyme with altered binding affinity for the drug that translates into a 16-fold ___ MBC for fluoroquinolone drugs (takes more drug to kill)
3) A second type of mutation that occurs less frequently in the __ -subunit of the DNA ___ results in a lower level of resistance. However, additive effects of mutations in both the subunits are known to give rise to more highly resistant strains.
4) Fluoroquinolone penetration of Gram ___ bacteria is dependent upon diffusion through porin channels. Resistance mutations that increase the expression of genes encoding __ pumps occur in ___ ___ and ___ ___
5) Cross ___ to all the quinolones is encountered with the ___ ___ (However, these mechanisms do not to appear to result in cross resistance to other classes of antibiotics)
6) ___ -dosing should be avoided to minimize opportunities for selection of resistant organisms.
As with other antibiotics, the emergence of resistant strains is facilitated by overuse and inappropriate prescribing, improper use (the patient stops taking the drug too early), and use in livestock (80% of the antibiotics produced in the US are used in agriculture)
1) low
2) point mutations, A, gyrase, higher
3) B, gyrase
4) negative, efflux, E.coli, P. aeuroginosa
5) resistance, point mutation
6) under
Quinolone - PK
1) readily absorbed ___ and have a high degree of bioavailability
2) widely distributed
3) ___ and ___ clearance are important
4) ___ fluid concentrations range from 50-100% of serum concentrations after 2 hours and ___ serum concentrations from 4 to 24 hours. ___ levels of drug range from 40-90% of serum levels when the meninges are inflamed, but are low when the meninges are normal.
5) Quinolones form insoluble ___ with heavy metals and should therefore not be administered with ___ and ___ that contain heavy metals.
1) orally
2) renal, hepatic
3) interstitial, exceed, CSF
4) chelates, food, drugs
Quinolone Metabolism
The major inactive metabolite is the ___ at the 3-carboxyl position and this is excreted in the ___
- glucuronide, urine
Quinolone - Adverse Effects
In general, the fluoroquinolones are very well tolerated
most common SE:
- __ / __ /__ (3-17% of patients)
- CNS adverse reactions include ___ and dizziness (1-11%)
- Rarely, ___ , delirium and ___ occur, mainly in patients taking theophylline and ___
- Skin rash and abnormal liver function tests have been reported
- Quinolones are associated with peripheral ___
- Fluoroquinolones may damage ___ cartilage and cause arthropathy (reversible), and are therefore not normally recommended for treatment of patients under ___ years of age
- There is agreement that fluoroquinolones can be used to treat ___ infections in children with cystic fibrosis, where the benefits outweigh the risks
- ___ in adults is a rare complication that is serious because of the risk of ___ rupture
Adverse effects with specific agents:
1) ___ (4th Gen) has been associated with hyperglycemia and hypoglycemia in diabetic patients
- N/V/D
- headaches
- hallucinations, seizures, NSAIDs
- neuropathy
- growing,
- 18
- pseudomonal
- tendonitis, tendon
- Gatifloxacin
