Pharmacology of Quinolones and Fluoroquinolones

DNA Synthesis Inhibitors: Quinolones & Fluoroquinolones

• Quinolones in the market include Ciprofloxacin (Cipro, Proquin P#), Ofloxacin (Floxin, P#), Norfloxacin (Noroxin), Levofloxacin (Levaquin, Quixin P#), Gemifloxacin (Factive), Moxifloxacin (Avelox, Vigamox), Lomefloxacin (Maxaquin), Delafloxacin (Baxdela), Besifloxacin (ophthalmic, conjunctivitis), and Nalidixic acid (original quinolone, seldom used).
• Some drugs are used to treat acute skin and skin structure infections (ASSSI), and some are used in MRSA infections - denoted by an asterisk (*).

Drugs Removed from the Market

• Sparfloxacin (Zagam) was removed due to QT prolongation and torsades de pointes.
• Grepafloxacin (Raxar) was removed due to torsades de pointes.
• Trovafloxacin-Alatrofloxacin (Trovan) was removed due to hepatic damage.
• Gatifloxacin (Tequin) was removed due to commercial reasons (ophthalmic formulation still available).

Mechanism of Action

• DNA strands must separate for replication and transcription.
• Topoisomerase II (DNA gyrase in prokaryotes) introduces negative supercoils in DNA to prevent positive supercoiling during unwinding; this is an ATP-dependent process involving cutting and resealing DNA.
• DNA gyrase in E. coli is a large enzyme with one A subunit (105kD) and two B subunits (95kD each).
• Quinolones inhibit gyrase-mediated DNA supercoiling at concentrations of 0.1 to 10 ug/mL.
• Quinolones also inhibit topoisomerase IV in bacteria.
• Eukaryotes use a different topoisomerase II, which is inhibited by quinolones at higher concentrations (100 to 1000 ug/mL).
• Fluoroquinolones are bactericidal.

Mechanism of Resistance

• Point mutations in the GyrA gene, encoding a subunit of DNA gyrase, are a mechanism of quinolone resistance.

Pharmacokinetics and Classification

• Quinolones have good oral bioavailability and penetrate most tissues except the CNS.
• Peak serum levels are reached within 3 hours of administration.
• Food does not significantly affect absorption but may delay the time to peak serum levels.
• Serum half-lives range from 3-11 hours.
• Some quinolones are eliminated renally (Ofloxacin, Lomefloxacin, Cinoxacin), while others are not (Pefloxacin, Nalidixic acid).
• Gemifloxacin is eliminated via renal and biliary routes.
• Levofloxacin is primarily eliminated renally.
• Dosage adjustments are necessary in cases of renal dysfunction for certain quinolones.

Antimicrobial Spectrum

• Fluoroquinolones are generally bactericidal and effective against various bacteria, including E. coli, Salmonella, Shigella, Enterobacter, Campylobacter, Neisseria (and others associated with periodontal disease, diarrhea, and dysentery).
• MIC for 90% of these strains is typically less than 0.2 ug/mL.
• Ciprofloxacin is more effective than norfloxacin against Pseudomonas aeruginosa, enterococci and pneumococci.
• Fluoroquinolones show activity against Staphylococcus including some MRSA strains.
• Resistance to quinolones can develop during therapy.
• The drugs are effective against various gram-negative organisms, as well as certain species of Brucella, Mycoplasma, Chlamydia and Mycobacteria.
• Ciprofloxacin and Ofloxacin have MIC90 of 0.5 to 3ug/ml for mycobacteria.
• They are used in the treatment of gonorrhea but not syphilis.
• Prophylactically used in certain transurethral surgeries to reduce post-surgical UTIs.

Indications

• Respiratory Tract Infections: Poor activity against Streptococcus pneumoniae, anaerobic bacteria, thus beta-lactams are often preferred. Levofloxacin and moxifloxacin are effective against Streptococcus pneumoniae and anaerobic bacteria and other specific respiratory pathogens. Levofloxacin may be administered intravenously or orally for infections such as community-acquired, nosocomial and ventilator-associated pneumonias.
• UTIs: Quinolones such as Norfloxacin, Ciprofloxacin, Levofloxacin and Ofloxacin, along with TMP-SMX are equally efficacious. Moxifloxacin does not reach therapeutic levels in the urinary tract and is not indicated for UTIs.
• Prostatitis: Norfloxacin, Ciprofloxacin, Levofloxacin, and Ofloxacin are equally efficacious.
• STDs: Quinolones show no activity against Treponema pallidum. Contraindicated during pregnancy.
• GI Infections: Effective against traveller's diarrhea, shigellosis - Norfloxacin, Ciprofloxacin, and Ofloxacin are effective. Norfloxacin is superior to TMP-SMX for cholera. Ciprofloxacin and Ofloxacin cure Salmonella typhi enteric fever. Delafloxacin is used in acute skin and skin structure infections (ASSIS) and Community-acquired pneumonia (CAP).
• Bone Joint and Soft Tissue Infections: Effective against Staphylococcus aureus in chronic osteomyelitis; use in combination with anaerobic drugs for diabetic foot infections.
• Multi-drug resistant Tuberculosis (MDR-TB) and atypical mycobacterial infections: Quinolones such as Ciprofloxacin are included in multi-drug regimens for M. avium complex infections in AIDS patients.

Other Indications

• Used in neutropenic cancer patients with fever to reduce the incidence of gram-negative bacteremias.

• Can be used in the treatment of tuberculosis and atypical mycobacteria.

• Treat meningococci in carriers.

• Resistance is mostly due to point mutations in the enzymes where fluoroquinolones bind.

• Elimination varies based on the drug:

  • Renal: Ofloxacin, lomefloxacin, cinoxacin, norfloxacin, ciprofloxacin, enoxacin
  • Non-renal: Nalidixic acid, Pefloxacin

Toxicity

• Common side effects include gastrointestinal disturbances (diarrhea, nausea, vomiting), skin rashes, headache, dizziness, insomnia, and abnormal liver function.
• Not recommended for young patients and during pregnancy due to cartilage erosion concerns.
• Tendonitis and tendon rupture have been reported.
• Not recommended for use in people under 18 due to possible arthropathy and cartilage damage in weight-bearing joints.

Urinary Antibiotics

• Nitrofurantoin (1953): Active at acidic pH; inhibits acetyl-CoA, used for UTIs; similar to nalidixic acid. Adverse effects include acute pneumonitis, neuropathies, and hemolysis (in glucose-6-phosphate dehydrogenase deficient patients). Contraindicated in neonates and pregnant women due to hemolytic anemia potential.
• Methenamine (1939): Decomposes into formaldehyde in acidic urine; increases urinary pH and effectiveness against certain bacterial strains; not effective against Proteus, which increase pH. Bacterial resistance does not develop. Contraindicated in hepatic insufficiency.