Norfloxacin A Review of Its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Use

Abstract

Synopsis: Norfloxacin ¹ is one of the new 4-quinolone antibacterial agents. A fluorinated piperazinyl-substituted congener of nalidixic acid, it demonstrates a much wider in vitro antibacterial spectrum and greater potency than the parent compound. Its antibacterial activity against most Gram-negative pathogens is enhanced in comparison to nalidixic acid, but is similar to that of some of the other new 4-quinolones like enoxacin, and slightly less than that of ciprofloxacin. Unlike nalidixic acid, norfloxacin is also active against Pseudomonas aeruginosa and some Gram-positive organisms. In acute or uncomplicated urinary tract infections, norfloxacin has repeatedly been shown to be as effective as co-trimoxazole. Single studies have demonstrated a significantly better bacteriological cure rate with norfloxacin than with pipemidic acid, and similar cure rates with norfloxacin and both a nalidixic acid/sodium citrate mixture and amoxycillin. Similar results were found in a few studies comparing norfloxacin to pipemidic acid or amoxycillin in patients with chronic and/or complicated urinary tract infections. Norfloxacin is as effective as spectinomycin in gonorrhoea due to penicillin-resistant N. gonorrhoeae, and cures bacterial gastroenteritis caused by several gastrointestinal pathogens. Norfloxacin appears to be well tolerated and may have a low propensity to select for bacterial resistance during clinical use, although the latter needs further confirmation. Antibacterial Activity: Norfloxacin is structurally related to nalidixic acid, but it has a broader in vitro antibacterial spectrum and is generally more active. Most Gram-negative pathogens including Escherichia coli and Klebsiella, Enterobacter, Proteus and Citrobacter species are susceptible to norfloxacin, and are inhibited by concentrations of 2 mg/L or less, with the exception of some strains of Acinetobacter, Providencia and Serratia species which are slightly less sensitive [minimum inhibitory concentration for 90% of tested strains (MIC₉₀): < 1 to 32 mg/L]. 90% of Pseudomonas aeruginosa isolates are inhibited by norfloxacin 1 to 2 mg/L. Although several times more active than nalidixic acid and some other quinolone antibacterial agents such as Cinoxacin and oxolinic acid against these pathogens, norfloxacin is usually of similar potency to enoxacin and generally less active than ciprofloxacin. Haemophilus influenzae demonstrates marked sensitivity to norfloxacin (MIC₉₀: < 2 mg/L), as do Neisseria gonorrhoeae and meningitidis, and a range of organisms which commonly occur as gastrointestinal pathogens, e.g. Salmonella and Shigella species (MIC₉₀: < 1 mg/L). Campylobacter species are inhibited by slightly higher concentrations (MIC₉₀: ⩽ 4 mg/L). Staphylococci, including S. saprophyticus, are susceptible to norfloxacin (MIC₉₀: 1 to 4 mg/L) but the streptococci, including enterococci, are more resistant (MIC₉₀: 2 to 16 mg/L). Most strains of anaerobic bacteria are only moderately sensitive to norfloxacin, while some are resistant. Although norfloxacin has no intrinsic antifungal activity there is some evidence of synergy with antifungal agents against Candida species. Despite the fact that norfloxacin has been demonstrated to be significantly less active in vitro in urine than in diagnostic sensitivity test (DST) agar (MIC₉₀ values increasing 16 to 64 times), the high concentrations of the drug achieved in urine following oral administration make this of doubtful clinical significance. However, a definite pH effect has been noted for norfloxacin, activity decreasing considerably with decreasing pH below 5.5. Optimum activity is thought to occur between pH 7.5 and 8. Generally, higher concentrations of norfloxacin are required to inhibit organisms in Mueller Hinton broth than in agar, but similar values have been found for Mueller Hinton agar and DST agar. Increasing the inoculum size from l0³ to 10⁶ colony-forming units (cfu) has only minor effects on MIC and minimum bactericidal concentration (MBC) values for norfloxacin. At 10⁷ cfu, half the tested strains require twice the concentration of norfloxacin for inhibition, while at 10⁸ cfu there are 2- to 4-fold increases in MIC values. MBC values are only slightly higher than MIC values for most organisms, although some strains of P. aeruginosa and Serratia marcescens require 4- to 8-fold increases in norfloxacin concentration for a bactericidal effect. Norfloxacin is thought to act by inhibiting the A subunit of the essential enzyme DNA gyrase in the bacterial cell. Resistance to norfloxacin has so far been slow to develop clinically and the agent shows good activity against many multiresistant strains of bacteria. Nevertheless, resistance to norfloxacin can be induced experimentally. Cross-resistance has been observed between norfloxacin and nalidixic acid as well as some of the newer nalidixic acid analogues (ciprofloxacin, enoxacin, cinoxacin and oxolinic acid) and, in a few instance, some β-lactam antibiotics. Pharmacokinetic Properties: Following single oral doses of norfloxacin 400mg, mean maximum serum concentrations of 1.35 to 1.58 mg/L have been achieved within 1 to 2 hours. An approximately linear relationship between maximum serum concentration, area under the concentration-time curve and dose was lost at doses in excess of 800mg and there is some uncertainty about the disposition of higher doses. Thus, the fraction of the dose absorbed over the first 12-hour period was lower at higher doses in 1 study, while another study reported disproportionately high serum concentrations and areas under the concentration time curve (AUC) at doses above 800mg. There does not appear to be any significant accumulation on multiple dose administration in healthy subjects. Bioavailability appears to be approximately 70% and absorption is only delayed slightly when norfloxacin is administered with food. Information on the distribution of norfloxacin into various body tissues is limited, but concentrations higher than those in serum have been found in both common duct and gallbladder bile as well as in liver tissue. Extrapolation of volume of distribution data from animal studies to man suggests values of around 25 to 35L, but the volume of distribution may prove to be much higher. Approximately 30% of an oral dose is excreted as unchanged norfloxacin in urine. Six metabolites, 1 or more of which are thought to be microbiologically active, have been found in urine but account for less than 10% of an administered dose. Renal clearance has varied from 16.32 to 17.76 L/h with doses ranging from 200 to 1600mg. The urinary recovery of norfloxacin is halved by the coadministration of probenecid, indicating the involvement of some active renal tubular secretion. The elimination half-life of norfloxacin in healthy subjects ranges from 3.5 to 6.5 hours. Decreased liver function has no significant effect on norfloxacin pharmacokinetics. In renal failure the serum half-life of norfloxacin increases with decreasing creatinine clearance. Values of around 6.5 hours have been noted in patients with moderate failure, rising to 7.7 hours in greater degrees of failure, while in haemodialysed patients the half life is around 7.9 hours. Therapeutic Trials: Norfloxacin has been primarily studied in acute, uncomplicated urinary tract infections (UTI), with a smaller number of studies in chronic and/or complicated UTI, gonococcal and non-gonococcal urethritis, gastroenteritis and other infections. In open trials in acute or uncomplicated UTI the bacteriological cure rate with norfloxacin 300 to 800mg daily (usually for 3 to 10 days) has been reported to be 82 to 100%. Several comparative studies using random allocation of treatments show norfloxacin 400 to 800mg daily to be at least as effective as co-trimoxazole 320/1600mg daily; follow-up at 4 to 6 weeks demonstrated a slightly higher incidence of relapse or reinfection in the patients treated with co-trimoxazole than in those treated with norfloxacin. Norfloxacin 800mg daily for 3 days has produced a higher bacteriological cure rate 2 to 4 days post-therapy than a nalidixic acid/sodium citrate mixture, the difference becoming significant after the late follow-up at 4 to 6 weeks. Similarly, norfloxacin 300mg daily for 3 days has proved significantly more effective in eliminating bacteriura than pipemidic acid 750mg daily. Norfloxacin 800mg daily for 7 days has also produced higher bacteriological cure rates than amoxycillin 750mg daily, 4 to 9 days after therapy, but the difference did not reach a statistically significant level in this study. In open trials in chronic and/or complicated UTI, the bacteriological response rate with norfloxacin (usually 300 to 900mg for 3 to 10 days) varies from 15 to 92%. However, adequate follow-up information is absent from all but 2 of these studies. Cumulated data from several Japanese trials reveal a decreased rate of eradication of bacteriura for norfloxacin in patients with indwelling catheters or in whom a prostatectomy has been performed. In 2 comparative trials in chronic and/or complicated UTI norfloxacin 800mg daily for 5 days was significantly better than pipemidic acid 2000mg daily, and in a single study the same dosage of norfloxacin for 7 days was at least as effective as amoxycillin 750mg daily. Various dosage regimens of norfloxacin have been assessed in gonococcal urethritis; bacteriological cure rates of 93 to 100% are reported. Also, two 600mg doses of the 4-quinolone have proved to be as effective as a single intramuscular dose of spectinomycin 2g in men with gonorrhoea due to penicillin-resistant N. gonorrhoeae. Norfloxacin is less effective in non-gonococcal urethritis, with bacteriological cure rates of only 43 to 83%. Norfloxacin 800 and 1200mg daily for 5 days have been found to be as effective as co-trimoxazole 320/1600mg daily in the eradication of harmful bacteria (rates of 98, 100 and 95%, respectively) in patients with acute bacterial gastroenteritis. Side Effects: In comparative studies the incidence of adverse effects with norfloxacin has been generally lower than that with co-trimoxazole but similar to that with pipemidic acid. The most frequently reported adverse reactions to norfloxacin are gastrointestinal disturbances, which occur in about 2 to 4% of patients. Central nervous system reactions are generally minimal but include lightheadedness, drowsiness, headache and dizziness. Dosage and Administration: In the treatment of urinary tract infections, the usual adult dosage is 400mg twice daily continued for 7 to 10 days. Three-day therapy has been shown to be effective in women with uncomplicated acute cystitis. In the treatment of chronic, relapsing urinary tract infection, the dosage of norfloxacin is 400mg twice daily for up to 12 weeks; if adequate suppression is obtained within the first 4 weeks the dosage of norfloxacin may be reduced to 400mg daily. In acute bacterial gastroenteritis the usual dosage is 400mg twice daily for 5 days. In patients with renal failure, in whom creatinine clearance is less than 30 ml/min/1.73m² the recommended dosage is 400mg daily. In the prophylaxis of sepsis in profound neutropenia, the recommended dosage is 400mg 3 times daily for the duration of profound neutropenia. However, data for recommending treatment beyond 8 weeks are presently not available. The safety and efficacy of norfloxacin in children have not been established. Place in Therapy: if wider clinical use confirms the efficacy, the low incidence of side effects and the apparently low propensity of norfloxacin to induce resistance clinically, it may not only offer worthwhile advantages over the standard agents used to treat urinary tract infections (e.g. co-trimoxazole and amoxycillin, as well as nalidixic acid and some of its early analogues), but it may become a valuable prophylactic and therapeutic antibiotic in several other clinical situations.