The original quinolone antibiotics included nalidixic acid (NegGram), cinoxacin (Cinobac) and oxolinic acid (no longer available in the United States). The addition of fluoride to the original quinolone antibiotic compounds yielded a new class of drugs, the fluoroquinolones, which have a broader antimicrobial spectrum and improved pharmacokinetic properties.(2)

In June 1999, the U.S. Food and Drug Administration (FDA) issued a public health advisory warning about the risk of liver toxicity with trovafloxacin after 14 cases of acute liver failure were associated with its use.(9) The advisory recommended that trovafloxacin therapy be reserved for infections judged to be life- or limb-threatening, with treatment initiated only in the inpatient setting and when the benefits of trovafloxacin outweigh the risks.

Six new fluoroquinolones have been introduced in the United States during the past five years. Levofloxacin (Levaquin) and sparfloxacin became available in 1996, and grepafloxacin (Rexar) and trovafloxacin were introduced in 1997. Gatifloxacin (Tequin) and moxifloxacin (Avelox) became available in early 2000. In December 1999, grepafloxacin was voluntarily withdrawn because of the possibility of torsades de pointes occurring with its use.

Because the fluoroquinolones have a large volume of distribution, they concentrate in tissues at levels that often exceed serum drug concentrations. Penetration is particularly high in renal, lung, prostate, bronchial, nasal, gall bladder, bile and genital tract tissues.(4-6) Urine drug concentrations of some fluoroquinolones, such as ciprofloxacin and ofloxacin (Floxin), may be as much as 25 times higher than serum drug concentrations. Consequently, these agents are especially useful in treating urinary tract infections.(5)

FIRST GENERATION
The first-generation agents include cinoxacin and nalidixic acid, which are the oldest and least often used quinolones. Because minimal serum levels are achieved, use of these drugs has been restricted to the treatment of uncomplicated urinary tract infections.
Cinoxacin and nalidixic acid require more frequent dosing than the newer quinolones, and they are more susceptible to the development of bacterial resistance. These agents are not recommended for use in patients with poor renal function because of significantly decreased urine concentrations.(2,10)
SECOND GENERATION
The second-generation quinolones have increased gram-negative activity, as well as some gram-positive and atypical pathogen coverage. Compared with first-generation drugs and considered as a group, these agents have broader clinical applications in the treatment of complicated urinary tract infections and pyelonephritis, sexually transmitted diseases, selected pneumonias and skin infections.
Second-generation agents include ciprofloxacin, enoxacin, lomefloxacin, norfloxacin and ofloxacin. Ciprofloxacin is the most potent fluoroquinolone against P. aeruginosa.(21,22) Because of its good penetration into bone, orally administered ciprofloxacin is a useful alternative to parenterally administered antibiotics for the treatment of osteomyelitis caused by susceptible organisms.
Although the FDA has labeled some second-generation quinolones for the treatment of lower respiratory tract infections and acute sinusitis, it should be stressed that S. pneumoniae is frequently resistant to agents in this class. Consequently, second-generation quinolones are not the drugs of first choice for lower respiratory tract infections and acute sinusitis.
Of the second-generation agents, ofloxacin has the greatest activity against Chlamydia trachomatis.
Ciprofloxacin and ofloxacin are the most widely used second-generation quinolones because of their availability in oral and intravenous formulations and their broad set of FDA-labeled indications.
THIRD GENERATION
The third-generation quinolones currently include levofloxacin, gatifloxacin, moxifloxacin and sparfloxacin. These agents are separated into a third class because of their expanded activity against gram-positive organisms, particularly penicillin-sensitive and penicillin-resistant S. pneumoniae, and atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae.(6,12,19) Although the third-generation quinolones retain broad gram-negative coverage, they are less active than ciprofloxacin against Pseudomonas species.
Because of their expanded antimicrobial spectrum, third-generation quinolones are useful in the treatment of community-acquired pneumonia, acute sinusitis and acute exacerbations of chronic bronchitis, which are their primary FDA-labeled indications. Gatifloxacin also has FDA-labeled indications for urinary tract infections and gonorrhea.(20) Levofloxacin (the more active component of the ofloxacin racemic mixture(12,21)) and gatifloxacin are available in oral and intravenous formulations.

Sparfloxacin carries a significant risk of phototoxicity.(21,23) Grepafloxacin, sparfloxacin and moxifloxacin have been reported to cause prolongation of the QT interval; gatifloxacin has not. However, the FDA recommends that all of these drugs should be avoided in patients who are taking drugs that are known to prolong the QT interval, such as tricyclic antidepressants, phenothiazines and class I antiarrhythmics.24 In contrast, levofloxacin does not affect the QT interval.
FOURTH GENERATION
Trovafloxacin, currently the only member of the fourth-generation class, adds significant antimicrobial activity against anaerobes while maintaining the gram-positive and gram-negative activity of the third-generation quinolones. It also retains activity against Pseudomonas species comparable to that of ciprofloxacin.(17,18)
Trovafloxacin is available in an oral tablet and as the prodrug alatrofloxacin (Trovan IV) in an intravenous formulation. Although the findings of few clinical trials on trovafloxacin have been published, the drug was originally labeled by the FDA for the treatment of a wide spectrum of infectious diseases.(18) Because of concern about hepatotoxicity, trovafloxacin therapy should be reserved for life- or limb-threatening infections requiring inpatient treatment (hospital or long-term care facility), and the drug should be taken for no longer than 14 days.(9)

4-aminoquinoline compounds.

Derivatives of nalidixic acid, fluoroquinolones were discovered accidentally in the early 1960s during the synthesis of the anti-malarial agent, chloroquine.(39) To date, more than 10,000 analogues of nalidixic acid have undergone initial screening, and the first flouroquinolone antibiotic was approved for clinical use in the late 1980s.(39) These highly effective antimicrobials act on bacterial topoisomerases, a class of enzymes that is essential for maintaining the physicochemical stability and biological activity of bacterial DNA.39 In general, the newer quinolones have longer serum half-lives with proven post-antibiotic effects from one to six hours, allowing patient-friendly single- or twice-daily dosing and higher peak levels for maximum bactericidal activity.(39)

More than 300 cases of fluoroquinolone-induced tendonitis, arthralgias, and tendon rupture in adult patients have been documented in the literature.(65) Those identified to be at risk included patients over the age of 60 and patients on long-term steroid therapy.(65,67) The pathophysiology of fluoroquinolone-induced tendon disorders is unclear, and the onset of symptoms can occur within one or two days after starting therapy. Patients affected typically develop joint pain and swelling (arthralgia), followed by difficulty with movement; some progress to tendon rupture, with accompanying nodules and ecchymoses.(65,67) Diagnosis is usually made clinically, although ultrasound is helpful as an adjunct evaluation. Tendon rupture may require surgical intervention and has caused prolonged disability.(65) In response to these reports, the FDA has asked clinicians to alert their patients to this potential side effect and has requested that manufacturers revise the package inserts to include similar warnings.(65)

. Quinoline Ring - Nucleus for several antimalarials: quinine, mefloquine, the 4-aminoquinolines and the
8-aminoquinolines. Also the nucleus for the broad spectrum fluoroquinolones.