fluoro quinolones (test 3)

what are quinolones?

large group of broad spectrum bactericidal agents that share a bicyclic core structure related to the synthetic substance 4-quinolone

what is one all quinolones?

4-quinolone

name some quinolones

• ciprofloxacin (IV, oral)

• levofloxacin (IV, oral)

• moxifloxacin (IV, oral)

• delafloxacin (IV, oral)

fluoro quinolones

MOA:

• inhibit bacterial ____ ____ ___ and ____ ____

• inhibit DNA replication — how?

• antibacterial activity is dependent on what?

• DNA topoisomerase IV and DNA gyrase (topoisomerase II)

• by disrupting the normal coiling/relaxing system of DS DNA

• on concentration

fluoro quinolones

spectrum:

• broad spectrum of activity: ????????????

gram -, gram +, atypical pathogens

fluoro quinolones

structure activity relationship:

• DNA and DNA gryase binding

• substitution _____ spectrum

• _____ overall antimicrobial activity

• what does fluorine substitution do?

• increases

• increases

• increases membrane penetration (increases potency by 100 fold)

fluoro quinolones

toxicity (side effects):

• ______ — tendon inflammation and/or rupture (often achilles tendon, 15-30% of cases)

• ______ toxicity and _____ swelling in children

  • what should be avoided?

• _____ ____ — can last month to years after discontinuation and may be permanent → discontinue immediately if symptoms occur

• tendinopathy

• cartilage; joint

  • pregnancy and breastfeeding

• peripheral neuropathy

fluoro quinolones

toxicity (side effects):

• ____ ____ — lightheadedness, dizziness, headache, sleeplessness, tiredness, abnormal vision, confusion (rare = psychosis, hallucinations, depression, seizures)

• alters ____ ____ levels — hypoglycemia (can lead to coma) and hyperglycemia

• ________, hepatoxicity, and crystalluria (must stay hydrated)

• what are some common side effects?

• CNS (neurotoxicity) effects

• blood sugar

• photosensitivity

• N, D, dizziness, skin reactions

fluoro quinolones

resistance:

• ______ in DNA gyrase (some gram +) and in topoisomerase IV (several gram +)

• multidrug resistance ____ ____ expression in gram +

• alterations in gram - membrane proteins — what does this lead to?

• mutagenesis

• efflux pump

• changes in permeability and decreased uptake

fluoro quinolones

DDIs:

• increase prothrombin time of _____ _____ leading to bleeding

• _____ and _____ ____ (magnesium, aluminum, phosphate, calcium, iron, zinc), ______, and _____ ____ sequestrants can chelate and inhibit quinolone absorption

• ______ binders (lanthanum carbonate) and sevelamer can decrease serum concentration of oral quinolones — separate administration is recommended

• ______ can increase CNS complications (confusion, seizures)

• anticoagulant warfarin

• antacids and polyvalent cations, multivitamins and bile acid

• phosphate

• NSAIDs

fluoro quinolones

ciprofloxacin (cipro):

• IV, oral, ophthalmic solution, ointments (tab/susp/injection)

• ____ gen quinolone

• WHO’s list of essential medicines

• critically important for human medicine

• one of the most commonly prescribed medications in the US

• enhanced activity against _____ like Pseudomonas, Legionella, Mycoplasma pneumonia (1^st line treatment)

• used in a wide variety of infections including infections of bones and joints, endocarditis, gastroenteritis, malignant otitis externa, _____ _____ infections, cellulitis, UTI, prostatitis, anthrax, and chancroid

• 2nd

• gram -

• respiratory tract

fluoro quinolones

levofloxacin:

• IV, oral, ophthalmic solution (tab/susp/injection)

• increased activity against _____ _____

• _______ quinolone

• _______ quinolone

• 1st line treatment against •Legionella pneumophila, Gonorrhea, and Penicillin-resistant S. pneumoniae

• WHO’s List of Essential Medicines

• used to treat several bacterial infections including acute bacterial sinusitis, pneumonia, ______ ______ (in combination with other medications), UTI, chronic prostatitis, and some types of gastroenteritis — along with other antibiotics it may be used to treat TB, meningitis, or pelvic inflammatory disease

• streptococcus pneumoniae

• respiratory

• antipseudomonal

• helicobacter pylori

fluoro quinolones

moxifloxacin:

• ____ gen quinolone

• IV, oral, ophthalmic solution (tab/susp/injection)

• significant activity against ____ ____

• ______ quinolone

• good activity against what?

• 1st line treatment for ______ _____ ____

• used to treat several bacterial infections including respiratory-tract infections, cellulitis, anthrax, endocarditis, meningitis, intra-abdominal infections, conjunctivitis, tuberculosis, and sinusitis

• because of enhanced gram + and anaerobic activity, can be used alone for _____ infections (intra abdominal infections)

• only quinolone that CANNOT be used for what?

• 4th

• streptococcus pneumoniae

• respiratory

• gram +, gram -, anaerobes

• penicillin resistant S. pneumoniae

• polymicrobial

• UTI

fluoro quinolones

delafloxacin:

• ____ gen quinolone

• IV (injection) and oral (tab)

• active against straphylococcus aureus (______)

• indicated to treat adults with acute ____ skin and skin _____ infections (ABSSSI)

• preferred quinolone in _____ infections — other quinolones should be AVOIDED due to hgh rates of MRSA resistance

• has increased potency and membrane permeability — why?

• ____ spectrum of activity: Gm (+) S. aureus (MRSA), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis, Gm (-) Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa

• active against other organisms such as _____ _____, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae

• 4th

• MRSA

• bacterial; structure

• skin

• heavily fluorinated (and chlorinated)

• large

• streptococcus pneumoniae

cirpofloxacin structure

• piperazine — increases _____ binding

• both piperazine and cyclopropyl — increase ______ activity

• gyrase

• antibacterial

levofloxacin structure

• methyl piperazine — _____ binding

• L isomer of ofloxacin

• extra ring increases _____ 2 fold and decreases ____ ____ ____ ____ ____

• gyrase

• potency

• off target toxicity/side effects

moxifloxacin structure

• increased _____ binding

  • double ring increases ______

• cyclopropyl

• both increase ______ activity

• enabled activity against ______

• gyrase

  • spectrum

• antibacterial

• anaerobes