Fluoroquinolones (see table Fluoroquinolones) exhibit concentration-dependent bactericidal activity by inhibiting the activity of DNA gyrase and topoisomerase, enzymes essential for bacterial DNA replication.
Fluoroquinolones are divided into 2 groups, based on antimicrobial spectrum and pharmacology:
Many newer fluoroquinolones have been withdrawn from the US market because of toxicity; they include trovafloxacin (because of severe hepatic toxicity), gatifloxacin (because of hypoglycemia and hyperglycemia), grepafloxacin (because of cardiac toxicity), temafloxacin (because of acute renal failure, hepatotoxicity, hemolytic anemia, coagulopathy, and hypoglycemia), and lomefloxacin, sparfloxacin, and enoxacin.
Pharmacokinetics
Oral absorption is diminished by coadministration of polyvalent cations (aluminum, magnesium, calcium, zinc, and iron preparations). After oral and parenteral administration, fluoroquinolones are widely distributed in most extracellular and intracellular fluids and are concentrated in the prostate, lungs, and bile.
Most fluoroquinolones are metabolized in the liver and excreted in urine, reaching high levels in urine. Moxifloxacin is eliminated primarily in bile.
Indications
Fluoroquinolones are active against the following:
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Mycoplasma species
-
Chlamydia species
-
Chlamydophila species
-
Legionella species
-
Enterobacteriaceae
-
Pseudomonas aeruginosa (particularly ciprofloxacin)
-
Some atypical mycobacteria
-
Some methicillin-sensitive staphylococci
Nosocomial methicillin-resistant staphylococci (MRSA) are usually resistant. Older fluoroquinolones have poor activity against streptococci and anaerobes. Newer fluoroquinolones have reliable activity against streptococci (including Streptococcus pneumoniae with reduced penicillin sensitivity) and some anaerobes; moxifloxacin in particular is active against most clinically significant obligate anaerobes.
Delafloxacin, the most recently approved fluoroquinolone, is the most broad-spectrum fluoroquinolone with activity against
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Gram-negative bacteria including Pseudomonas aeruginosa
-
Gram-positive bacteria including MRSA, as well as atypical respiratory tract pathogens
As fluoroquinolone use has increased, resistance, particularly to older fluoroquinolones, is developing among Enterobacteriaceae, P. aeruginosa, S. pneumoniae, and Neisseria species. Nonetheless, fluoroquinolones have many clinical uses (see table Some Clinical Uses of Fluoroquinolones).
Fluoroquinolones are no longer recommended for treatment of gonorrhea because of increasing resistance worldwide.
Some Clinical Uses of Fluoroquinolones
Drug |
Use |
Comments |
|
Fluoroquinolones except moxifloxacin |
Urinary tract infections when Escherichia coli resistance to trimethoprim/sulfamethoxazole is > 15% |
Drugs of choice; however, increasing resistance of E. coli in some communities |
|
Fluoroquinolones |
Bacterial prostatitis |
— |
|
— |
||
|
Usually effective |
||
|
Infectious diarrhea |
Effective against most bacterial causes (Campylobacter species, salmonellae, shigellae, vibrios, Yersinia enterocolitica); however, increasing resistance of Campylobacter jejuni in some regions Not used for E. coli 0157:H7 or other enterohemorrhagic E. coli Not effective against Clostridioides difficile (formerly Clostridium difficile) |
|
|
Ofloxacin |
7-day course |
|
|
Newer fluoroquinolones |
Other drugs preferred if patients have taken fluoroquinolones recently |
|
|
Drugs of choice (or azithromycin) |
||
|
Ciprofloxacin |
Used empirically because it is effective against Pseudomonas aeruginosa Usually used with another antipseudomonal drug |
|
|
Long-term oral treatment of gram-negative bacillaryosteomyelitis |
Because fluoroquinolones have high oral bioavailability and good bone penetration, useful for osteomyelitis |
|
|
— |
||
|
Used extensively during 2001 after bioterrorist attack in US |
Contraindications
Contraindications include
-
Previous allergic reaction to the drugs
-
Certain disorders that predispose to arrhythmias (eg, QT-interval prolongation, uncorrected hypokalemia or hypomagnesemia, significant bradycardia)
-
Use of drugs known to prolong the QT interval or to cause bradycardia (eg, metoclopramide, cisapride, erythromycin, clarithromycin, classes Ia and III antiarrhythmics, tricyclic antidepressants)
Delafloxacin does not appear to cause significant prolongation of the QT interval.
Fluoroquinolones have traditionally been considered to be contraindicated in children because they may cause cartilage lesions if growth plates are open. However, some experts, who challenge this view because evidence is weak, have recommended prescribing fluoroquinolones as a 2nd-line antibiotic and restricting use to a few specific situations, including P. aeruginosa infections in patients with cystic fibrosis, prophylaxis and treatment of bacterial infections in immunocompromised patients, life-threatening multiresistant bacterial infections in neonates and infants, and Salmonella or Shigella gastrointestinal tract infections.
Use During Pregnancy and Breastfeeding
Animal reproduction studies with fluoroquinolones show some risk. Data related to pregnancy in humans are limited. Fluoroquinolones should be used in pregnancy only if clinical benefit exceeds risk and a safer alternative is not available.
Fluoroquinolones enter breast milk. Use during breastfeeding is not recommended.
Adverse Effects
Serious adverse effects of fluoroquinolones are uncommon; main concerns include the following:
-
Upper gastrointestinal adverse effects occur in about 5% of patients because of direct gastrointestinal irritation and central nervous system (CNS) effects.
-
CNS adverse effects (eg, mild headache, drowsiness, insomnia, dizziness, mood alteration) occur in < 5%. Nonsteroidal anti-inflammatory drugs may enhance the CNS stimulatory effects of fluoroquinolones. Seizures are rare, but fluoroquinolones should not be used in patients with CNS disorders.
-
Peripheral neuropathy may occur soon after taking the drug and may be permanent. If symptoms occur (eg, pain, burning, tingling, numbness, weakness, change in sensation), use of the fluoroquinolone should be stopped to prevent irreversible damage.
-
Tendinopathy, including rupture of the Achilles tendon, may occur even after short-term use of fluoroquinolones.
-
QT-interval prolongation can occur, potentially leading to ventricular arrhythmias and sudden cardiac death.
-
Fluoroquinolone use has been strongly associated with Clostridioides (formerly Clostridium) difficile–associated diarrhea (pseudomembranous colitis), especially that due to the hypervirulent C. difficile ribotype 027.
Diarrhea, leukopenia, anemia, and photosensitivity are uncommon. Rash is uncommon unless gemifloxacin is used for > 1 week and is more likely to develop in women < 40 years of age. Nephrotoxicity is rare.
Dosing Considerations
Dose reduction, except for moxifloxacin, is required for patients with renal insufficiency. Older fluoroquinolones are normally given twice a day; newer ones and an extended-release form of ciprofloxacin are given once a day.
Ciprofloxacin raises theophylline levels, sometimes resulting in theophylline-related adverse effects.
