Mechanism of Action
Quinolones are direct inhibitors of bacterial DNA synthesis; (4-7) they specifically inhibit the action of two enzymes essential for bacterial DNA replication: DNA gyrase (topoisomerase II) and topoisomerase IV. DNA gyrase is a tetramer of two A and two B subunits, encoded by the genes gyrA and gyrB respectively. DNA gyrase introduces negative DNA supercoils, removes positive and negative supercoils, and links and unlinks chromosomal material. Topoisomerase IV has two C subunits and two E subunits, encoded by the genes parC and parE, and it too can remove positive and negative supercoils, but is primarily involved in the separation of daughter chromosomes.
Quinolones form a ternary complex of drug-enzyme-DNA that is trapped, disrupting DNA replication and triggering cell death mechanisms. For most gram negative bacteria, DNA gyrase is the primary quinolone target whereas for most gram positive bacteria, topoisomerase IV is the primary target, with DNA gyrase being secondary.
FQ are bactericidal and exhibit a post-antibiotic effect following bacterial exposure to inhibitory concentrations. The antibacterial effect continues for approximately two to three hours after the bacteria are exposed to these agents, even at sub-inhibitory concentrations.
Spectrum and Clinical Uses
The most commonly prescribed FQ are ciprofloxacin, levofloxacin, and moxifloxacin. They are most active against aerobic gram negative bacteria including Enterobacteriaceae, Haemophilus species, Neisseria species, and Moraxella catarrhalis. Ciprofloxacin remains the most potent FQ against Pseudomonas aeruginosa and Acinetobacter baumannii. FQ also have some activity against staphylococci (but MRSA are typically resistant) and enterococci. Levofloxacin and moxifloxacin have enhanced activity against Streptococcus pneumoniae. FQ have activity against a wide variety of gram positive bacilli including Bacillus species, Corynebacterium species, Erysipelothrix species, and Nocardia species.
FQ are active against the so called “atypical” agents, including Chlamydophila pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. They are also active against some genital pathogens, including Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma hominis, and against Mycobacterium tuberculosis and some non-tuberculous mycobacteria, including M. fortuitum, M. kansasii, and M. chelonae.
Given the broad spectrum of activity and excellent oral bioavailability, FQ have been widely used (and over used) for a variety of infections including: urinary tract infections, prostatitis, sexually transmitted diseases, infectious diarrhea, respiratory tract infections, bone and joint infections, and skin and soft tissue infections. (3,8)
Unfortunately, the axiom “The more you use an antibiotic the quicker you lose it” certainly applies to FQ as rapid dissemination in use has been associated with emerging resistance. (9)