Hans H. Gadebusch

Comparison of the antibacterial activity of norfloxacin (MK 0366, AM 715), a new organic acid, with that of other orally absorbed chemotherapeutic agents

Summary425 randomly selected, fresh clinical isolates were tested for susceptibility to norfloxacin and other orally absorbed agents, i. e. amoxicillin, ampicillin, carbenicillin (available commercially as the indanyl ester), cefaclor, cinoxacin, erythromycin, nalidixic acid, penicillin G, tetracycline, trimethoprim and co-trimoxazole. The results have shown norfloxacin to be the most potent agentin vitro against representative members of the familyEnterobacteriaceae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter spp.,Neisseria gonorrhoeae andHaemophilus influenzae. Ninety percent of the isolates in these groups of bacteria were inhibited by less than 1 mg/l, 2 mg/l, 8 mg/l, 32 mg/l, 0.06 mg/l and 0.25 mg/l of norfloxacin, respectively. Although norfloxacin inhibited most streptococci andUreaplasma at a concentration of 8 mg/l or less, penicillin G proved to be the most active againstStreptococcus pygenes andStreptococcus pneumoniae; trimethoprim was the most active againstStreptococcus faecalis, and tetracycline the most active againstUreaplasma.Zusammenfassung425 zufallsgemäß ausgewählte, frische klinische Isolate wurden auf ihre Empfindlichkeit gegenüber Norfloxacin und anderen nach oraler Gabe resorbierbaren Substanzen, wie Amoxicillin, Ampicillin, Carbenicillin (kommerziell als Indanylester erhältlich), Cefaclor, Cinoxacin, Erythromycin, Nalidixinsäure, Penicillin G, Tetracyclin, Trimethoprim und Co-Trimoxazol, getestet. Die Ergebnisse zeigten, daß Norfloxacinin vitro die wirksamste Substanz gegen repräsentative Mitglieder der FamilieEnterobacteriaceae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter spp.,Neisseria gonorrhoeae undHaemophilus influenzae ist; 90% der Isolate dieser Gruppen von Bakterien wurden durch Norfloxacin in Konzentrationen von weniger als 1 mg/l; 2 mg/l; 8 mg/l; 32 mg/l; 0,06 mg/l und 0,25 mg/l gehemmt. Norfloxacin hemmte zwar die meisten Streptokokken undUreaplasma Stämme bei einer Konzentration von 8 mg/l oder weniger, doch erwies sich Penicillin G als die wirksamste Substanz gegenüberStreptococcus pyogenes undStreptococcus pneumoniae, Trimethoprim war am aktivsten gegenStreptococcus faecalis und Tetracyclin wies die stärkste Aktivität gegenUreaplasma auf.

In vitro Antibacterial Activity of Norfloxacin and Other Agents against Ocular Pathogens

302 clinical isolates representing 16 bacterial species most often implicated in ocular infections were tested in vitro against norfloxacin and a panel of antibacterial agents. On the basis of the 90% minimal inhibitory concentration (MIC90) data, norfloxacin was 4-32 times more active than the next best antimicrobial tested against Citrobacter freundii, Escherichia coli, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Haemophilus influenzae, Neisseria gonorrhoeae and Staphylococcus epidermidis, with overall MIC90 less than or equal to 1 mg/l. Norfloxacin was equal in activity to polymyxin B against Klebsiella pneumoniae (MIC90 = 1 mg/l), and it ranked second to both polymyxin B against Pseudomonas aeruginosa and cotrimoxazole against Staphylococcus aureus, (MIC90 = 2 mg/l in each case). Along with neomycin and cotrimoxazole, norfloxacin (MIC90 = 1 mg/l) ranked second to gentamicin and tetracycline against Moraxella species. Compared to erythromycin (MIC90 less than or equal to 0.125 mg/l), norfloxacin (MIC90 less than or equal to 16 mg/l) was considerably less active against streptococci. Overall, norfloxacin was the most active agent in both potency and antibacterial spectrum against the test organisms. These results suggest the potential use of norfloxacin in the treatment of superficial bacterial infections of the eye.

Pharmacokinetic Studies of Norfloxacin in Laboratory Animals

Pharmacokinetic studies were conducted with norfloxacin administered by the oral and subcutaneous routes to mice and rats, and by the oral route to rhesus monkeys. The compound was moderately well absorbed following oral dosing in these animal species. Serum levels in monkeys ranged from 1.0 to 2.35 micrograms/ml after an oral drug dose of 25 mg/kg of animal body weight and were similar to those in mice. Serum half-life of norfloxacin in rodents and monkeys was similar to that in humans. Concentrations of norfloxacin in tissues of mice, rats and monkeys were greater than those in serum suggesting a large volume of distribution for the drug.

Norfloxacin, the first of a new class of fluoroquinolone antimicrobials, revisited

Norfloxacin is the first in a series of new 4-quinolones that have been introduced into medical practice for the treatment of bacterial infections. This totally synthetic compound is a broad spectrum, bactericidal agent that is much more potent than the earlier analogs, i.e. nalixidic acid, pipemidic acid, cinoxacin, rosoxacin, and flumequine, is less likely to select for resistant mutants. While the compound has been used most widely in the treatment of urinary tract infections including pyelonephritis and prostatitis, utility has also been demonstrated in gastrointestinal and ophthalmological infections, gonorrhea, typhoid fever, the typhoid carrier state, as well as in the prophylaxis of travelers diarrhea, biliary tract infections prior to surgery, and gram-negative bacillary infections in profoundly neutropenic patients.

QUATERNARY HETEROCYCLYLAMINO β-LACTAMS

Two newly described quaternary heterocyclylamino beta-lactams, L-642,946 and L-652,813, were shown to exhibit potent activity against a broad spectrum of aerobic and anaerobic bacteria in vitro. The activity of these agents in vitro translated well to chemotherapeutic activity in experimental bacteremias in mice. Substitution of the thiadiazine moiety of L-642,946 with a triazine moiety effected a marked change in the pharmacokinetics of the new derivative, L-652,813. In mice given a 20 mg/kg subcutaneous dose, the peak serum concentration and the half-life of L-652,813 were about three times greater than those of L-642,946 and the area under the serum concentration/time curve was increased by about 5-fold. The pharmacokinetics of L-652,813 in mice and in rhesus monkeys more closely resembled those of ceftriaxone which carries the same triazine moiety on the C-3 side chain.