Quinolone Flashcards
Be able to state the characteristics of first generation quinolone antibiotics.
i) Developed because of their activity against gram-(-) bacteria; have limited activity vs gram-(+) bacteria. Only useful for treatment of lower urinary tract infections.
(1) Ex. oxolinic acid and nalidixic acid (now discontinued)
Be able to state the characteristics of second generation quinolone antibiotics.
i) Have a fluorine substituent at C-6 and a heterocyclic ring (usually piperazine) at C-7. They have a broader spectrum of bactericidal activity and are more potent. These drugs have extended activity against gram-(+) organisms compared to the 1st gen. However, ciprofloxacin is the most potent fluoroquinolone for gram-(-) organisms.
(1) Ex. ciprofloxacin
Be able to state the characteristics of third and fourth generation quinolone antibiotics.
i) Have improved activity against gram-(+) organisms and none of them are as potent as ciprofloxacin against gram-(-) organisms.
(1) Ex. levofloxacin (3rd gen) and moxifloxacin (4th gen and last resort due to severe SEs)
New quinolones
i) Ozenoxacin: used topically to treat impetigo; precautions – overgrowth with nonsusceptible bacteria and fungi, employ alternative therapy.
ii) Delafloxacin: for oral or IV use for treatment of skin infections caused by a wide variety of gram-(+) and gram-(-) bacteria, including MRSA. AEs: Tendonitis, tendon rupture, peripheral neuropathy, CNS effects, exacerbation of myasthenia gravis, N/V/D
Be able to specify the function of topoisomerases and gyrases.
a) Topoisomerases are enzymes that relieve or introduce supercoiling in DNA by transiently breaking and rejoining the DNA strands. Type I cleave one strand of the DNA double helix and type II cleaves both strands of the DNA double helix.
b) DNA gyrase is a specific type of topoisomerase (type II) found primarily in bacteria. They relieve positive supercoils that form ahead of the replication fork during DNA synthesis.
Be able to describe how topoisomerases work.
a) The topoisomerase cleaves DNA by carrying out a nucleophilic attack on a phosphodiester linkage, so one part of the strand become free, and the other one becomes enzyme linked. This nucleophile is the phenolic hydroxyl group of a tyrosine residue.
Be able to describe the difference between topoisomerase I and topoisomerase II enzymes.
a) Type I cleave one strand of the DNA double helix and type II cleaves both strands of the DNA double helix.
Be able to describe the mechanism of action of the quinolones.
a) Block DNA religation. Inhibits DNA gyrase (topoisomerase II).
b) Quinolone antibiotics bind to the cleavage complex. The drug molecules are stacked between the base pairs at the cleavage site so that the cleavage complex is stabilized and the religation reaction is inhibited. This blocks the progression of the replication fork, and the double-strand breaks eventually lead to apoptosis.
Be able to describe the therapeutic uses of the quinolones.
a) UTIs (ciprofloxacin), prostatitis (ciprofloxacin and ofloxacin), STDs, gastrointestinal infections (traveler’s diarrhea), respiratory tract infections, bone, joint, and soft tissue infections (ciprofloxacin for diabetic foot infections), intracellular bacteria.
Be able to describe the main bacterial resistance mechanisms to the quinolones.
a) Increased fluoroquinolone resistance rates are correlated with use.
b) Resistance mechanisms include decreased cellular permeability, increased expression of genes encoding efflux pumps, and mutation of the target enzymes.
c) Incidence of resistance is low relative to other antibacterial agents.
d) Resistant organisms have spontaneously occurring point mutations in the A-subunit of DNA gyrase, which lead to an enzyme with altered binding affinity for the drug. There’s also a mutation in the B-subunit of the DNA gyrase that results in a lower level of resistance. Cross resistance to all the quinolones is encountered with the point mutations.
e) Avoid under-dosing.
Be able to describe the main features of quinolone absorption, distribution, and elimination.
a) Readily absorbed orally. Widely distributed. Renal and hepatic clearance.
b) Quinolones form insoluble chelates with heavy metals and should therefore not be administered with foods/drugs that contain heavy metals.
Be able to describe how ciprofloxacin is metabolized.
a) The major inactive metabolite is the glucuronide at the 3-carboxyl position, and this is excreted in the urine.
Be able to describe the main adverse effects of the quinolone antibiotics.
a) Generally, well tolerated. N/V/D, HA and dizziness, hallucinations, delirium, and seizures, skin rash, abnormal liver function tests, peripheral neuropathy.
b) May damage growing cartilage and cause arthropathy – not recommended in pts under 18 years of age.
c) Tendonitis, tendon rupture.
d) Gatifloxacin has been associated with hyperglycemia and hypoglycemia in diabetic patients.
