Fluoroquinolones Flashcards
What are the fluoroquionolones?
ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin
What is the mechanism of action of fluoroquionolones?
- Inhibition of DNA synthesis by binding to and inhibiting bacterial topoisomerases, which are enzymes needed for maintain cellular DNA in an appropriate state of supercoiling.
- They target bacterial DNA gyrase (topoisomerase II) and topoisomerase IV:
- Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. The FQs form a stable complex with DNA and DNA gyrase, which blocks the replicating fork leading to a sudden and lethal cessation of DNA replication. For many gram-negative bacteria, DNA gyrase is the primary target of the FQs.
- Inhibition of topoisomerase IV interferes with the separation of replicated chromosomal DNA into respective daughter cells during cell division that are the product of DNA replication, causing a cessation in DNA replication. For many gram-positive bacteria (S aureus), topoisomerase IV is the primary target of the FQs.
Do fluoroquinolones display bacteriostatic or bactericidal activity?
- Display concentration dependent bactericidal activity. AUC/MIC or Peak/MIC. Display PAE against gram-positive and gram-negative aerobic bacteria.
What is the mechansim by which bacteria develop resistance to fluoroquinolones?
- Alteration in binding sites: chromosomal mutations in the genes that code for the subunits of DNA gyrase or topoisomerase IV lead to decreased binding affinity of the FQs to these target sites.
- Expression of active efflux: an efflux pump is turned on that enhances the transfer of FQs out of the cell.
- Alteration in cell wall permeability: chromosomal mutations cause decreased expression of porin proteins that are responsible for FQ transit inside the cell leading to decreased FQ accumulation within the cell.
- Cross-resistance observed between the FQs.
Spectrum of activity of fluoroquinolones
- These agents have broad antimicrobial activity, excellent oral bioavailability, extensive tissue penetration, and relatively long serum half-lives.
- Fluroquinolones contain 2 six-membered rings with a nitrogen atom at position 1, a carboxylic acid moiety at position 3 (responsible for the interaction with divalent and trivalent cations), a carbonyl group at position 4, a fluorine at position 6 (enhances tissue penetration binding at topoisomerases), and a piperazine moiety or other group at position 7 (provides activity against pseudomonas).
- Older: ciprofloxacin
- Newer/respiratory: levofloxacin, moxifloxacin, Gemifloxacin
- Gram-positive aerobes: cipro has poor activity against gram-positive bacteria, the newer FQs (levo, moxi, dela) have enhanced activity against some gram-positive bacteria – streptococcus pneumoniae (including PRSP, EXCEPT cipro), MRSA – ONLY delafloxacin.
- Gram-negative aerobes: cipro, levo, and dela have excellent activity against Enterobacteriaceae – HENPECKSS, pseudomonas aeruginosa (cipro>levo>dela, NOT moxi or gemi) – only ORAL agents available to potentially treat pseudomonas infections.
- NO activity against anaerobes
- Atypical bacteria: FQs extremely active against Legionella, chlamydia, mycoplasma, and Ureaplasma.
Fluoroquinolones oral bioavailability
FQs well absorbed after oral administration except for delafloxacin.
Fluoroquinolones half-life
Moxifloxacin has longest half-life.
Fluoroquinolones penetration into CSF
FQs achieve minimal penetration into CSF.
Fluoroquinolones route of excretion
Renal elimination: levofloxacin, ofloxacin, and gatifloxacin; hepatic metabolism/elimination: moxifloxacin; both renal and hepatic elimination: ciprofloxacin, delafloxacin and Gemifloxacin.
Fluoroquinolones necessity for dosage adjustment in renal insufficiency/removal by hemodialysis
Levofloxacin, ofloxacin, and gatifloxacin need dose adjustments. Ciprofloxacin, delafloxacin, and Gemifloxacin undergo both renal and hepatic elimination, so also need dose adjustment in renal insufficiency.
NONE of the FQs are removed during hemodialysis.
What are the main clinical uses of ciprofloxacin, levofloxacin, moxifloxacin, and delafloxacin?
- Community acquired pneumonia: levo, moxi, gemi, dela
- Acute exacerbations of chronic bronchitis and sinusitis: cipro, levo, moxi, gemi
- Nosocomial pneumonia: cipro, levo
- UTIs (cystitis, pyelonephritis): cipro, levo
- Chronic bacterial prostatitis: cipro, levo
- Delafloxacin: Activity against MRSA. Skin and skin structure infections.
What are the major AEs associated with fluoroquinolone therapy?
- GI: C diff colitis; neurologic: peripheral neuropathy; hepatotoxicity: trovafloxacin (now withdrawn); phototoxicity; cardiac (QTc prolongation) – use with caution in patients with hypokalemia, concomitant use of class III antiarrhythmics (amiodarone, sotalol), preexisting QTc prolongation; articular damage (arthropathy)– contraindicated in pediatric patients and the warning to avoid their use in pregnant or breastfeeding patients; tendonitis and tendon rupture.
What are the drug interactions with fluoroquinolones?
- Divalent and trivalent cations (zinc, iron, Ca, Al, Mg, or ZICAM including antacids, ddI, sucralfate, enteral feeds) impair the absorption of ANY ORAL FQs because of chelation and lead to clinical failure.
- Warfarin: increased prothrombin time and potential bleeding.
- Theophylline: may occur with cipro – causes inhibition of theophylline metabolism leading to increased serum theophylline concentrations and toxicity.
- Cyclosporine: cipro may inhibit cyclosporine metabolism leading to toxicity.
Name the fluoroquinolones that are currently available in the US, including the dosage forms that are available.
- Ciprofloxacin: IV and oral; Levofloxacin: IV and oral; Moxifloxacin: IV and oral; Gemifloxacin: oral; Ofloxacin: IV and oral; Delafloxacin: IV and oral
