The fluoroquinolones, a new class of potent orally absorbed antimicrobial agents, are reviewed, considering structure, mechanisms of action and resistance, spectrum, variables affecting activity in vitro, pharmacokinetic properties, clinical efficacy, emergence of resistance, and tolerability. The primary bacterial target is the enzyme deoxyribonucleic acid gyrase. Bacterial resistance occurs by chromosomal mutations altering deoxyribonucleic acid gyrase and decreasing drug permeation. The drugs are bactericidal and potent in vitro against members of the family Enterobacteriaceae, Haemophilus spp., and Neisseria spp., have good activity against Pseudomonas aeruginosa and staphylococci, and (with several exceptions) are less potent against streptococci and have fair to poor activity against anaerobic species. Potency in vitro decreases in the presence of low pH, magnesium ions, or urine but is little affected by different media, increased inoculum, or serum. The effects of the drugs in combination with a beta-lactam or aminoglycoside are often additive, occasionally synergistic, and rarely antagonistic. The agents are orally absorbed, require at most twice-daily dosing, and achieve high concentrations in urine, feces, and kidney and good concentrations in lung, bone, prostate, and other tissues. The drugs are efficacious in treatment of a variety of bacterial infections, including uncomplicated and complicated urinary tract infections, bacterial gastroenteritis, and gonorrhea, and show promise for therapy of prostatitis, respiratory tract infections, osteomyelitis, and cutaneous infections, particularly when caused by aerobic gram-negative bacilli. Fluoroquinolones have also proved to be efficacious for prophylaxis against travelers9 diarrhea and infection with gram-negative bacilli in neutropenic patients. The drugs are effective in eliminating carriage of Neisseria meningitidis. Patient tolerability appears acceptable, with gastrointestinal or central nervous system toxicities occurring most commonly, but only rarely necessitating discontinuance of therapy. In 17 of 18 prospective, randomized, double-blind comparisons with another agent or placebo, fluoroquinolones were tolerated as well as or better than the comparison regimen. Bacterial resistance has been uncommonly documented but occurs, most notably with P. aeruginosa and Staphylococcus aureus and occasionally other species for which the therapeutic ratio is less favorable. Fluoroquinolones offer an efficacious, well-tolerated, and cost-effective alternative to parenteral therapies of selected infections.

Fluoroquinolone antimicrobial agents.

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.

Clinical Pharmacokinetics of Ciprofloxacin

Steady-State Plasma and Intrapulmonary Concentrations of Levofloxacin and Ciprofloxacin in Healthy Adult Subjects

A number of new fluoroquinolone antibacterials have been released for clinical use in recent years. These new agents exhibit enhanced activity against Gram-positive organisms while retaining much of the Gram-negative activity of the earlier agents within the same class. The pharmacokinetics of most of these agents are well described including serum pharmacokinetics, tissue and fluid distribution, and pharmacokinetics in renal and hepatic disease. When compared with earlier agents within this class (i.e. ciprofloxacin), the newer agents retain the wide distribution characteristics; however, they exhibit a more prolonged elimination, which, in part, supports single daily administration for these agents. Based on their predominant renal elimination, dosage adjustment is necessary in the presence of renal disease for ciprofloxacin, levofloxacin, gatifloxacin and sitafloxacin. Drug interactions, particularly with multivalent cations (calcium/aluminium-containing antacids and iron products), remain a problem for the newer agents, resulting in reduced absorption requiring separate administration times to maximise bioavailability. However, the newer agents do not appear to interfere significantly with the cytochrome P450 system, thus minimising the potential for interactions with other drugs metabolised by this system. The pharmacodynamic properties of the fluoroquinolones have been well described. The bactericidal activity is maximised when the ratios of peak plasma drug concentration (Cmax): minimum inhibitory concentrations (MIC) or area under the concentration-time curve (AUC): MIC exceed specific threshold values. Knowledge of the pharmacodynamic relationships allows for appropriate drug selection and enables design of dosage regimens to maximise the bactericidal activity. Therapeutic drug monitoring of the fluoroquinolones may provide a means of optimising the dosage regimen in certain clinical situations (that is, meningitis and hospitalised pneumonias) with the goals of achieving a more predictable therapeutic response and minimising the potential for the development of resistance.

Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials.

This review focuses on published information on the experimental as well as clinical data on the emergence of quinolone resistant isolates. In the course of clinical use of fluoroquinolones, only a sporadic emergence of quinolone resistance has been noted. The resistant organisms emerged particularly in certain clinical settings where large numbers of organisms frequently causing chronic infections are present and/or in loci where quinolone concentrations may not be optimal. In terms of occurrence in individuals, quinolone resistance has emerged most frequently in hospitalized and nursing-home patients with identifiable risk factors. Epidemiological studies revealed that in nearly all the cases studied one or one predominating quinolone resistant clone was selected that was horizontally transmitted. Thus, the emergence of quinolone resistance is not due to an independent selection of resistant strains in a number of patients, but to the clonal spread of one strain once it has acquired quinolone resistance. Therefore, the rate of quinolone resistance is very likely to be lower than reported.

Quinolone resistance in Pseudomonas aeruginosa and Staphylococcus aureus. Development during therapy and clinical significance.

Data recently published in this journal by Schlenkhoff et al. (1) give evidence for a marked penetration of ciprofloxacin into human lung tissue, but these authors measured ciprofloxacin only over a period of 4 h. We therefore have made a similar study with repeated doses extending over 24 h, also including measurements of ciprofloxacin in pleural tissue and exudate. In contrast to the study by Schlenkhoff et al., ciprofloxacin was measured by an HPLC method. Sixteen patients undergoing lung surgery mainly because of cancer participated in the study after they had given their written informed consent. The age of the patients ranged between 47 and 76 years (mean 52 + 15 years), their bodyweight ranged from 47 to 92 kg (average 66.0 + 12.2 kg). They received three i.v. infusions of 200 mg ciprofloxacin at 12 h intervals, each infusion lasting 30 min. Surgical procedures started 1 h (nine patients) or 2 h (seven patients) after the first application of ciprofloxacin. Samples of serum, tissues and pleural exudate were obtained at the following time points: serum 1 or 2 h after the beginning of the first and just prior to the second and third infusions; lung and pleurat tissue during the course of surgery 1 and 2 h after the first infusion; pleural

H J Radtke

Papers

Concentration of ciprofloxacin in human serum, lung and pleural tissues and fluids during and after lung surgery.