Quinolone antibiotics, available since the 1960s, inhibit DNA synthesis by demonstrating a concentration-dependent bactericidal activity. The first-generation formulation included cinoxacin, nalidixic acid and oxolinic acid. These early quinolones targeted gram-negative organisms including Escherichia coli, and Klebsiella and Proteus species. Nalidixic acid was once the most commonly used preparation, but poor tissue and serum concentrations now limit its use to the treatment of simple urinary tract infections. Its utility is also limited by its relatively short half-life (requiring four doses daily), narrow spectrum of activity and the rapid development of bacterial resistance.
Second-generation quinolones have a fluorine substituent in the main quinolone ring that significantly increases antibacterial activity. These fluoroquinolones (ciprofloxacin, enoxacin, lomefloxacin, ofloxacin and norfloxacin) exhibit good activity against gram-negative bacilli and moderate-to-good activity against Staphylococcus species. Ciprofloxacin and ofloxacin have good tissue penetration and reach macrophages and polymorphonu-clear leukocytes, making them useful beyond the treatment of urinary tract infections. In addition, their activity against Legionella pneumophila is good; their activity against Chlamydia pneumoniae and Mycoplasma pneumoniae is more variable. Ciprofloxacin exhibits good activity against Pseudomonas aeruginosa and strong gram-negative activity that may be superior to that of ofloxacin. Coverage against Streptococcus pneumoniae is inadequate, making the use of ciprofloxacin inappropriate in patients with community-acquired pneumonia. In summary, ciprofloxacin and ofloxacin are effective in treating (1) urinary tract infections caused by susceptible organisms, (2) respiratory tract infections caused by susceptible gram-negative organisms, (3) skin and soft-tissue infections and (4) osteomyelitis (ciprofloxacin only).
The third-generation fluoroquinolones (grepafloxacin, levofloxacin and sparfloxacin) have expanded coverage against streptococci and atypical organisms. This attribute has improved the usefulness of fluoroquinolones in treating patients with community-acquired pneumonia. Activity against Haemophilus influenzae and Moraxella catarrhalis is high, but activity against other gram-negative bacteria, especially P. aeruginosa, is less than that of ciprofloxacin. All third-generation fluoroquinolones are taken once daily. In patients with renal disease, dose adjustment for levofloxacin and sparfloxacin is necessary. In summary, this generation of fluoroquinolones is useful in treating patients with the following conditions: (1) community-acquired pneumonia and bacterial exacerbations of acute bronchitis, (2) urinary tract infections and (3) skin or skin-structure infections.
Fourth-generation fluoroquinolones (clinafloxacin, gatifloxacin, moxifloxacin and trovafloxacin) add significant anaerobic coverage. A long half-life allows once-daily dosage, and extensive hepatic metabolism makes dose adjustment unnecessary in patients with renal disease. Indications for use include nosocomial pneumonia, intra-abdominal infections and serious penicillin- or cephalosporin-resistant S. pneumoniae infections. Because of reports of rare but serious liver injuries, the U.S. Food and Drug Administration issued an advisory notice (June 1999) that trovafloxacin should be reserved for use in patients meeting all of the following criteria: (1) management of a life- or limb-threatening disease, (2) treatment should be initiated in an inpatient setting and (3) the physician believes that the benefit of the product for the patient outweighs the potential risk. Dosage duration should be no longer than 14 days, and therapy should be discontinued if clinical symptoms of liver dysfunction are present.
Other adverse effects of fourth-generation fluoroquinolones include gastrointestinal disturbance and phototoxicity. Safety is uncertain during pregnancy or in the pediatric population. Neurotoxicity, including headache, dizziness and seizures, has been reported. The major drug interaction is chelation reactions resulting in decreased absorption when fourth-generation fluoroquinolones are coadministered with magnesium–aluminum- or calcium-containing antacids, ferrous salts or zinc. Because the half-life of warfarin can be reduced, monitoring of prothrombin time is strongly recommended. Pathogen resistance is occurring, particularly among P. aeruginosa and methicillin-resistant Staphylococcus aureus. A trend toward increasing ciprofloxacin resistance among infections with E. coli, Citrobacter freundii and Serratia marcescens may compromise the usefulness of this antimicrobial class of drugs.