Clinical Pharmacokinetics of Ciprofloxacin

Compared with nalidixic acid, ciprofloxacin is representative of a newer, more potent class of quinolones, termed the fluoroquinolones. It is available in both oral and parenteral dosage forms. The primary target of quinolone activity appears to be the bacterial DNA gyrase enzyme, which is a member of the class of type II topoisomerases. Bacteria do not acquire resistance to fluoroquinolones through mechanisms that are plasmid or R-factor mediated and, additionally, the quinolones do not appear to be vulnerable to degradatin by bacterial inactivating mechanisms. Rather, bacterial resistance to ciprofloxacin occurs either through chromosomal mutation in the target enzyme DNA gyrase or through mutations that alter drug permeability into the bacterial cell. Ciprofloxacin and the fluoroquinolones in general are no more likely to select resistant mutants than are aminoglycosides or β-lactam antibiotics. Ciprofloxacin displays in vitro activity against most Gram-negative and many Grampositive pathogenic bacteria, many of which are resistant to a wide range of antibiotics. This finding is of considerable potential clinical significance. High pressure liquid chromatography (HPLC) and microbiological agar diffusion assays have been routinely used to quantify ciprofloxacin concentrations in biological fluids. Both methods are reproducible and accurate for serum but HPLC is recommended for other specimens because of the presence of microbiologically active metabolites. Absorption after oral administration is rapid and can be satisfactorily described as a zero-order process; peak serum ciprofloxacin concentrations (Cmax) are reached in approximately I to 2 hours. Concomitant administration of food does not cause clinically significant impairment of absorption and may be helpful in minimising gastric distress caused by the drug. A linear relationship between serum ciprofloxacin concentrations and the dose administered either orally or intravenously has been reported. The absolute bioavailability of ciprofloxacin is approximately 70%. The volume of distribution is large with a steady-state range after oral or intravenous dosing of 1.74 to 5.0 L/kg reflecting penetration of the drug into most tissues. Nonrenal clearance accounts for approximately 33% of the elimination of ciprofloxacin; to date, 4 metabolites have been identified. A first-pass effect has been reported but is thought to be clinically unimportant. Faecal recovery of ciprofloxacin accounts for approximately 15% of an intravenous dose. Nonrenal elimination includes metabolic degradation, biliary excretion and transluminal secretion across the enteric mucosa. Glomerular filtration and tubular secretion account for approximately 66% of the total serum clearance. The terminal disposition half-life (ty,) is about 3 to 4 hours. Pharmacokinetic studies after multiple intravenous doses of ciprofloxacin have not reported significant differences in terminal disposition half-lives or systemic clearances between the first and the last dose. The pharmacokinetics of ciprofloxacin in the elderly are significantly different from those observed in the young: the elderly have a reduced renal clearance, a significantly greater area under the concentration-time curve (AUC). a larger Commax, and a prolonged t1/2. Several investigators have suggested that dosage intervals shorter than 12 hours be avoided in the elderly. The pharmacokinetics of ciprofloxacin in patients with cystic fibrosis do not differ significantly from those of healthy control populations and as a result, dosing regimen alterations are not required in patients with cystic fibrosis. In patients with varying degrees of renal dysfunction, the pharmacokinetics of ciprofloxacin are significantly altered; the ty, in end-stage renal disease is approximately twice that of healthy controls (### 8h). The observed AUC and Cmax may also be elevated in these patients. A wide variability in the ty, of ciprofloxacin has been observed among patients with severe renal failure, resulting in the recommendation that changes be made in the daily dose rather than the dosing interval in order to achieve drug concentrations comparable with those observed in normal renal function. The clinical impact of chronic ambulatory peritoneal dialysis or haemodialysis over a 4-hour period on the pharmacokinetics of ciprofloxacin is not significant, and therefore dosage supplementation after or during these procedures is not necessary. Liver dysfunction also appears to exert little effect on ciprofloxacin pharmacokinetics and dosage adjustments are not recommended. The concomitant oral administration of magnesium-, aluminium-, or calcium-containing antacids, sucralfate, iron preparations and multivitamins containing zinc significantly reduces the absorption of ciprofloxacin. Ciprofloxacin reduces the metabolism of theophylline by approximately 15 to 30%; caution is therefore advised when using any fluoroquinolone in combination with xanthine compounds. Case reports have documented increases in prothrombin times among patients receiving warfarin and ciprofloxacin concomitantly. Adverse reactions associated with ciprofloxacin administration are generally mild to moderate and usually do not result in termination of therapy; the worldwide incidence is in the range of 4 to 8%, which is similar to that reported for other fluoroquinolones. The most commonly reported adverse reactions involve either the gastrointestinal tract (nausea, vomiting and diarrhoea), metabolic or nutritional disorders, or the CNS.