Pharmacology: Pharmacodynamics: Mode or Mechanisms of Action: Ciprofloxacin is a DNA gyrase inhibitor used as an antibacterial agent. It is bactericidal and acts intra-cellularly by inhibiting the A subunit of DNA gyrase (topoisomerase II) which is an essential bacterial enzyme that is a critical catalyst in the duplication, transcription, and repair of bacterial DNA. The process is necessary for compacting the bacterial chromosome within the cell. Other investigators have suggested that the quinolones induce the formation of drug-gyrase-DNA complex through which DNA polymerase cannot proceed. At effective concentrations of ciprofloxacin, selective inhibition of topoisomerase II leads to death of exposed bacteria without producing dysfunction or toxicity of mammalian cells.
Spectrum of activity: Ciprofloxacin has a broader spectrum of activity and is more potent in vitro than the non-fluorinated quinolone, nalidixic acid. Activity may be reduced in acid media. Ciprofloxacin is one of the most active of the fluoroquinolones. Among Gram-negative aerobic bacteria, ciprofloxacin is active in vitro against Enterobacteriaceae including Escherichia coli and Citrobacter, Enterobacter, Klebsiella, Proteus, Providencia, Salmonella, Serratia, Shigella and Yersinia spp. It is also active against Pseudomonas aeruginosa, but less so against other Pseudomonas spp. Haemophilus ducreyi, H. influenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, and N. meningitidis are all very sensitive, including beta-lactamase-producing strains of H. influenzae, M. catarrhalis, and N. gonorrhoeae. Other Gram-negative aerobic bacteria reported to be sensitive to ciprofloxacin have included Acinetobacter spp., Campylobacter spp., Gardnerella vaginalis, Helicobacter pylori, Legionella spp., Pasteurella multocida, and Vibrio spp. Variable activity has been reported against Brucella melitensis. Among Gram-positive aerobic bacteria, ciprofloxacin is active against staphylococci including penicillinase-producing and -non-producing strains and against some methicillin-resistant strains. Streptococci, in particular Streptococcus pneumoniae, and enterococci are less susceptible. Other Gram-positive bacteria sensitive to ciprofloxacin in vitro are Corynebacterium spp., and Listeria monocytogenes. Most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile, are resistant to ciprofloxacin. Ciprofloxacin has some activity against mycobacteria, mycoplasmas, rickettsias, and the protozoan Plasmodium falciparum. Chlamydia trachomatis is not very susceptible and Nocardia asteroides and Ureaplasma urealyticum are usually considered to be resistant. The spirochaete Treponema pallidum and fungi are also resistant.
Activity with other antimicrobial agents: There have been some reports of enhanced activity in vitro when ciprofloxacin has been used with other antimicrobial agents such as azlocillin against Staphylococcus aureus and Pseudomonas aeruginosa, imipenem against Ps. Aeruginosa, and cefotaxime or clindamycin against anaerobic bacteria.
Pharmacokinetics: Ciprofloxacin is rapidly and well absorbed from the gastro-intestinal tract. Oral availability is approximately 70% and a peak plasma concentration of about 2.5 g per ml is achieved 1 to 2 hours after a dose of 500 mg by mouth. The plasma half-life is about 3.5 to 4.5 hours. Plasma protein binding ranges from 20 to 40%.
Ciprofloxacin is widely distributed in the body and tissue penetration is generally good. The volume of distribution is high (approx. 2.8 l/kg). It appears in the cerebrospinal fluid, but concentrations are only about 10% of those in plasma when the meninges are not inflamed. Ciprofloxacin crosses the placenta and is excreted in breast milk. High concentrations are achieved in bile. Ciprofloxacin is eliminated principally by urinary excretion. At least 4 active metabolites have been identified. Oxociprofloxacin appears to be the major urinary metabolite and sulphociprofloxacin the primary faecal metabolite. Urinary excretion is by active tubular secretion as well as glomerular filtration and is reduced by probenecid. Excretion is virtually complete within 24 hours; about 40 to 50% of an oral dose is excreted unchanged in the urine and about 15% as metabolites. Only small amounts of ciprofloxacin are removed by haemodialysis or peritoneal dialysis.