Norfloxacin

Norfloxacin has a rapid bactericidal action and inhibits synthesis of bacterial deoxyribonucleic acid (DNA). An enzyme called DNA gyrase plays a key role in this process. Norfloxacin has a broad spectrum of antibacterial activity against gram-positive and gram-negative aerobic bacteria.

Mechanisms of resistance

Bacterial resistance against fluoroquinolones is usually based on mechanisms like reduction of quinolone accumulation and/or mutations in the genes that encode for DNA gyrase and topoisomerase IV, the targets of quinolone action.

Bacteria which are resistant to norfloxacin in-vitro are also resistant to the older quinolones. Several studies have shown that bacteria resistant to norfloxacin are also generally resistant to pefloxacin, ofloxacin, ciprofloxacin and enoxacin.

There is no cross-resistance to structurally unrelated substances such as penicillins, cephalosporins, tetracyclines, macrolide antibiotics, aminoglycosides and sulfonamides, 2,4-diaminopyrimidine or combinations of these (e.g. cotrimoxazole).

Infections caused by multiply-resistant organisms have been successfully treated with the usual doses of norfloxacin.

Breakpoints

EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommended clinical MIC breakpoints for norfloxacin.

* generally based on serum pharmacokinetics

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species

Gram-negative aerobes:

Aeromonas hydrophilia
Proteus vulgaris
Providencia rettgeri
Salmonella spp
Shigella spp.

Species for which acquired resistance may be a problem

Gram-positive aerobes:

Enterococcus faecalis^$
Staphylococcus aureus (methicillinsusceptible)
Staphylococcus saprophyticus

Gram-negative aerobes:

Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloaca
Escherichia coli^&
Klebsiella oxytoca
Klebsiella pneumoniae
Morganella morganii
Proteus mirabilis
Pseudomonas aeruginosa
Serratia marcescens

Inherently resistant organisms

Gram-positive aerobes:

Enterococcus faecium
Staphylococcus aureus (methicillin-resistant)
Streptococcus agalactiae

Gram-negative aerobes:

Stenotrophomonas maltophilia

Anaerobes:

Clostridium difficile

Others:

Chlamydia trachomatis
Mycoplasma hominis
Ureaplasma urealyticum

^$ The inherent susceptibility of most isolates is within the intermediate range.
^& In female patients with uncomplicated cystitis the resistance rate is <10%, otherwise ≥10%.

Absorption

Norfloxacin is rapidly absorbed after oral administration. In healthy volunteers, at least 30 to 40% of an oral dose is absorbed from the currently available pharmaceutical forms. The presence of food and/or dairy products may decrease absorption.

Distribution

Serum concentrations of 0.84-1.64 mg/L were obtained within 1–1.5 hours after oral administration of a dose of 400 mg. The time to peak concentration (t_max) ranged from 0.75-2.0 h. The average halflife in serum is three to four hours in healthy volunteers; it is independent of the dosage.

The apparent volume of distribution (Vdβ) is approximately 223 ± 97 I.

Protein binding

Norfloxacin is around 13.8% plasma protein bound at a concentration of 2.5 mgl/l in human serum.

Elimination

Norfloxacin absorbed from the gastrointestinal tract is eliminated by metabolization and by renal and biliary excretion.

Renal excretion occurs both by glomerular filtration and by tubular secretion, as indicated by the high renal clearance of approximately 236 ± 56 ml/min and the inhibition of probenacid excretion. Total body clearance is 506 ± 211ml/min.

Approximately 25-40% of the dose was recovered in the urine after administration of single and multiple doses of 400 mg PO to renally healthy adult volunteers.

In healthy elderly subjects (65-75 years of age, normal renal function for stated age), norfloxacin is excreted more slowly in keeping with the physiologically reduced renal function in this age group. Drug absorption appears to be unaffected. The elimination half-life in geriatric patients was 2.7-3.5 h after administration of 400 mg/day, and 5.3-5.4 h after a dose of 400 mg twice daily.

Norfloxacin is recovered intact in the urine and in the form of six active metabolites whose antibacterial efficacy is lower than that of the parent compound. Over 70% of the excreted drug is recovered in non-metabolised form.

Norfloxacin’s antibacterial activity is not affected by changes in urinary pH.

Pharmacokinetics in patients with impaired renal function

After a single dose of 400 mg, norfloxacin is available in patients with a creatinine clearance above 30 ml/min x 1.73 m² to a similar extent as in healthy volunteers. Renal norfloxacine excretion is markedly reduced in patients whose creatinine clearance is below 30 ml/min x 1.73 m². The average norfloxacin elimination half-life was 4.4, 6.6 and 7.6 h, respectively, in adults with a creatinine clearance of 30-80, 10-29, and below 10 ml/min x 1.73 m². Peak serum norfloxacin levels do not appear to be affected in the presence of renal insufficiency.

As with other quinolones, norfloxacin caused arthropathy in immature animals. Norfloxacin caused lesions and, in some cases, cartilage erosion in weight baring joints. No arthropathy was seen in monkeys receiving norfloxacin at doses below 500 mg/kg BW/day (C_max 15.6 mg/l). Likewise, no such changes were seen in fully-grown animals.

In mice and rats, embryotoxicity was observed, but in rabbits and monkeys, high doses of norfloxacin resulted in increased embryolethality. Studies on fertility and perinatal and postnatal toxicity disclosed no adverse impact. Norfloxacin can be detected in the amniotic fluid and umbilical cord blood.

Based on the results of animal tests, damage to joint cartilage in the growing body can not entirely be ruled out. Animal studies have revealed no evidence of teratogenicity.

In mice and rats, embryotoxicity was observed, but in rabbits and monkeys, high doses of norfloxacin resulted in increased embryolethality. Studies on fertility and perinatal and postnatal toxicity disclosed no adverse impact. Norfloxacin can be detected in the amniotic fluid and umbilical cord blood.

Cataractogenic potential

Specific studies investigating the cataractogenic potential of norfloxacin have not been conducted. As hitherto during therapeutic use no according adverse events have been observed, such studies are not considered necessary at present.

Carcinogenicity

Carcinogenicity studies in rats and mice provided no evidence to suggest carcinogenicity due to norfloxacin.

Genotoxicity and tumorigenic potential

Norfloxacin may be genotoxic due to its inhibition of topolsomerases in mammalian cells. This effect has a limiting value that is not exceeded in therapeutic use. Long-term studies in rats and mice failed to indicate tumorigenicity.

No photomutagenicity or photocarcinogenicity data are available on norfloxacin. Comparative data on other fluorquinolones suggest a low photomutagenic/photocarcinogenic potential of norfloxacin in vitro and in animal studies.