Pharmacology: Mechanism of Action: Ciprofloxacin is a synthetic broad spectrum quinolone antibacterial agent. Ciprofloxacin has in-vitro against virtually all gram-negative and gram-positive organisms. The bactericidal action of ciprofloxacin results from inhibition of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV), which are required for bacterial DNA replication, transcription, repair and recombination.
Mechanism of resistance: In-vitro resistance to ciprofloxacin is commonly due to mutations in bacterial topoisomerases and develops slowly through multiple-step mutations. Ciprofloxacin resistance due to spontaneous mutations occurs at a frequency of between <10-9 to 10-6. Cross-resistance among fluoroquinolones may occur when resistance arises through mutations. Single mutations may result in reduced susceptibility rather than clinical resistance, but multiple mutations generally result in clinical resistance to ciprofloxacin and cross-resistance across the quinolone class. Bacterial impermeability and/or expression of efflux pumps may impact ciprofloxacin susceptibility. Plasmid-mediated resistance encoded by the qnr gene has been reported. Resistance mechanisms that inactive penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines do not interfere with the antibacterial activity of ciprofloxacin and there is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. Organisms resistant to these drugs may be susceptible to ciprofloxacin.
The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.
In vitro Susceptibility to Ciprofloxacin: The prevalence of acquired resistance may vary geographically and with time for selected species and local information of resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought where the local prevalence of resistance is such that utility of the agent, in at least some types of infections, is questionable.
Ciprofloxacin has been shown to be active in vitro against susceptible strains of the microorganisms listed as follows: Aerobic Gram-positive Microorganisms: Bacillus anthracis; Enterococcus faecalis (many strains are only moderately susceptible); Staphylococcus aureus (methicillin-susceptible); Staphylococcus; Saprophyticus; Streptococcus pneumoniae.
Aerobic Gram-negative Microorganisms: Burkholderia cepacia; Morganella morganii; Campylobacter spp.; Neisseria gonorrhoeae; Citrobacter freudii; Proteus mirabilis; Enterobacter aerogenes; Proteus vulgaris; Enterobacter clocae; Providencia spp.; Escherichia coli; Pseudomonas aeruginosa; Haemophilius influenza; Pseudomonas fluorescens; Klebsiella pneumonia; Serratia marcescens; Klebsiella oxytoca; Shigella spp.; Moraxella catarrhalis.
The following microorganisms show varying degrees of susceptibility to ciprofloxacin: Burkholderia cepacia, Campylobacter spp., Enterococcus faecalis, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Pseudomonas aeruginosa, Pseudomonas fluorescens, Serratia marcescens. The following microorganisms are considered inherently resistant to ciprofloxacin: Staphylococcus aureus (methicillin-resistant) and Stenotrophomonas maltophilia. Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker.
Inhalational anthrax-additional information: Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.
Pharmacokinetics: Ciprofloxacin is suitable for oral and intravenous administration. Owing to its excellent antibacterial activity and its good pharmacokinetics properties, ciprofloxacin can be given orally for injections which previously could only be treated intravenously with, say, penicillins, cephalosporins or aminoglycosides. For acute life-threatening infections or patients unable to take tablets it is advisable to commence treatment with the intravenous form of ciprofloxacin. Following an initial intravenous dose (short-term 30 minute infusion), treatment can be continued with oral ciprofloxacin, which is a distinct advantage, especially from the patient's point of view.
Absorption and bioavailability: After oral administration ciprofloxacin is largely absorbed from the small intestine. A specific study with C14-labelled ciprofloxacin showed that 73% of the dose was absorbed intestinally. Absorption is rapid, leading to peak serum levels after 60-90 minutes. Absolute bioavailability has been shown to be 70-80% in various studies by a direct comparison between the oral and intravenous forms of ciprofloxacin.
Distribution volume: The distribution volume of ciprofloxacin in steady state is 2-3 liters/kg. This unusually high figure, more than 10 times that of beta-lactam antibiotics and aminoglycosides, is an indication that ciprofloxacin reaches higher concentrations in tissue and body fluids than in serum. Concentrations were in fact measured in a number of tissue and fluid samples that were several times higher than the corresponding serum levels.
Concentrations in body fluids and tissues/protein binding: The pharmacokinetics properties of ciprofloxacin suggest good tissue penetration, with distribution volume as a good indicator of the high tissue concentrations one may expect to find. The rate of protein binding and degree of ionisation are decisive factors in the diffusion of a substance from the intra to the extravascular space. It is reasonable to assume that only the proportion of the substance not bound to serum proteins and not ionized is able to diffuse into the extravascular space. Protein binding by ciprofloxacin is low (approx. 20-30%) and the substance is mostly found in a non-ionised form in the plasma. Therefore virtually the entire dose administered is free to diffuse into the extravascular space.
In addition, sub-cellular structures and certain physiological factors (e.g. pH in body fluids and tissues) may bring about a relative intracellular concentration of ciprofloxacin. This is how the concentrations in certain body fluids and tissues far surpass the corresponding serum levels.