Norfioxacin: a New Quinolone

From the Canadian Infectous IDisease Society

Norfioxacin: a new quinolone

Committee on Antimicrobial Agents,* Canadian Infectious Disease Society

N alidixic acid, the first quinolone antibiotic, Mechanism of action and resistance has been in use for over 20 years. Oxolinic acid, pipemidic acid, rosoxacin and cinox- Norfloxacin affects DNA synthesis. It binds to acin were subsequently introduced in countries DNA rather than to the enzyme DNA gyrase, other than Canada, but none has proven to be which negatively supercoils double-stranded significantly beneficial. Recently a number of new DNA,1 and this drug-DNA complex inhibits the antibiotics have been developed by the addition of enzyme's activity.5 6-fluorine and 7-piperazine groups to the quin- Resistance to norfloxacin develops infrequent- olone nucleus (Fig. 1). These fluoropiperazinyl ly. The principal mechanism of resistance is de- quinolones have enhanced antimicrobial activity, creased membrane permeability. In addition, alter- and resistance to them develops infrequently, as ation of the structure of DNA gyrase may result in compared with older quinolones. norfloxacin resistance. The fluoropiperazinyl quinolones include acrosoxacin, amifloxacin, ciprofloxacin, difloxacin, enoxacin, fleroxacin, irloxacin, norfloxacin, oflox- In-vitro activity acin and pefloxacin. In general these agents are most active against Enterobacteriaceae, Pseudomo- Norfloxacin is highly active against Enterobac- nas aeruginosa, Haemophilus influenzae, Neis- teriaceae, H. influenzae, P. multocida, C. fetus ssp. seria, Pasteurella multocida, Aeromonas hydroph- jejuni, A. hydrophila and Neisseria. It is slightly ila and Campylobacter fetus ssp. jejuni.1 Most of active against P. aeruginosa, streptococci and these agents are moderately active against strep- staphylococci at the levels achieved in serum but is tococci, staphylococci and Legionella pneumoph- bactericidal against these organisms at the levels ila. Some of the newer quinolones are also ac- achieved in urine; therefore, treatment of urinary tive against anaerobes (except Clostridium diffi- tract infections due to P. aeruginosa, enterococci cile), mycobacteria (except Mycobacterium avium- intracellulare and M. chelonei ssp. abscessus), Chlamydia trachomatis and Mycoplasma pneu- 0 *0 ...... oF moniae. Ciprofloxacin has the broadest spectrum 6 3 COCOH and is effective against most bacteria and C. trachomatis. ,HN N . Norfloxacin recently became the first fluoro- 1 piperazinyl quinolone licensed for use in Canada 'C2Hs and approved for the treatment of urinary tract 4 - quinolone norf loxacin infections. Three detailed symposia on its use have been published.2-4 0 0 F OCOOH H3CXCOOCOH Drs. Lionel Mandell (chairman), McMaster Univer- *Members: N HN N sity, Hamilton, Ont.; Michel Bergeron, Laval University, Que- H3C ~NN bec; Thomas Marrie, Dalhousie University, Halifax; Lindsay C2H5 Nicolle, University of Manitoba, Winnipeg; David Scheifele, University of British Columbia, Vancouver; and Stephen Shafran, University ofSaskatchewan, Saskatoon. nalidixic acid ciprof loxacin Reprint requests to: Dr. Lionel Mandell, Division of Infectious Fig. 1 - Chemical configurations of 4-quinolone Disease, McMaster Medical Unit, Henderson General Hospital, nucleus, nalidixic acid, norfloxacin (6-fluorine and 711 Concession St., Hamilton, Ont. L8V 1C3 7-piperazine moieties circled) and ciprofloxacin. CMAJ, VOL. 139, AUGUST 15, 1988 305 and Staphylococcus saprophyticus is possible. Nor- not been proven, the preliminary results in cases of floxacin is not effective against anaerobes, C. prostatitis are encouraging. trachomatis, mycobacteria or mycoplasmas. Other infections Pharmacokinetic features Several studies have shown that norfloxacin is effective in the treatment of uncomplicated gono- Only the oral form of norfloxacin is available coccal infections, including those caused by pen- in Canada. About 30% to 40% of an oral dose is icillin-resistant strains."1,12 The drug is not effective absorbed.6 Food slightly decreases the amount of in cases of C. trachomatis infection. drug absorbed. Antacids that contain magnesium In studies of small numbers of patients nor- or aluminum significantly decrease the absorption floxacin has been effective in the prevention or of ciprofloxacin through the formation of a chelate treatment of traveller's diarrhea,13"4 bacterial en- complex.7 Data on the interaction of norfloxacin teritis,14 enteric fever,15 chronic typhoid carrier with antacids are lacking; however, such combina- state'5'16 and gram-negative bacterial infections in tions should be avoided. neutropenic patients.17 The average peak serum level of norfloxacin, 1.5 mg/L, is achieved 90 minutes after a 400-mg oral dose of norfloxacin is given.68 Serum protein binding is minimal, 10% to 15%. The serum Adverse effects half-life is 3 to 4 hours on average in adults with a creatinine clearance greater than 30 ml/min-1.73 In comparative studies the frequency of ad- m2 but is longer in patients with severe renal verse effects of norfloxacin has been equal to or insufficiency.6 less than that of trimethoprim-sulfamethoxazole, Norfloxacin is metabolized in the liver into six amoxicillin and nalidixic acid. Gastrointestinal distinct metabolites, which are found in the urine symptoms, such as nausea, vomiting and anorexia, and bile.6 Renal excretion of the drug occurs by and central nervous system symptoms, such as means of both glomerular filtration and tubular headache, light-headedness and fatigue, have been secretion and is reduced with the use of proben- reported most frequently.'8 Abnormal laboratory ecid. About 25% to 30% of an oral dose is results, including eosinophilia, leukopenia and ele- recovered unchanged in the urine within 48 hours. vated hepatic enzyme levels, occasionally occur.18 The peak level in the urine, 100 to 400 mg/L, is Like other quinolones norfloxacin has been achieved 1 to 2 hours after a 400-mg dose, the found to cause cystic lesions in the cartilage of concentration being 30 mg/L on average 12 hours young animals. Therefore, its use is not recom- after ingestion. High concentrations of norfloxacin mended in children. However, nalidixic acid can are found in stool samples for at least 48 hours cause the same arthropathy at lower dosages, is after a single dose. The drug's concentration in the administered clinically at higher dosages and has prostate is similar to that in the serum but consid- been used in children for many years without erably less than that in the urine.9 Renal levels of reports of such effects. norfloxacin are four times the serum levels. Data on the safety of norfloxacin therapy during pregnancy are lacking. However, the drug has not been found to be teratogenic in mice, rats, Clinical trials rabbits or monkeys.'8 Urinary tract infections Dosage Norfloxacin's use has been evaluated primari- ly in urinary tract infections. The studies, confined Norfloxacin is given in doses of 400 mg twice to nonpregnant adults given doses of 400 mg twice daily to adults with a creatinine clearance of more daily for at least 3 days, have shown that the drug than 30 ml/min-1.73 M2. Patients with a lower is at least as effective as trimethoprim-sulfameth- creatinine clearance should receive 400 mg once oxazole, amoxicillin and nalidixic acid in uncompli- daily. The drug should be taken on an empty cated cases.'0 Although a 3-day regimen is effec- stomach, at.least 1 hour before or 2 hours after tive, data are lacking on the efficacy of single-dose meals; the concurrent use of antacids should be therapy. Norfloxacin is also effective in the treat- avoided. ment of complicated urinary tract infections due to Therapy for uncomplicated urinary tract infec- susceptible organisms; however, there is less infor- tions should last 3 days. Complicated infections mation for complicated disorders such as pyelone- generally require at least 14 days of treatment. phritis than for uncomplicated ones such as cysti- tis. Although the efficacy of long-term norfloxacin Recommendations prophylaxis against recurrent urinary tract infections and of norfloxacin therapy for prostatitis has Norfloxacin therapy is effective for urinary

306 CMAJ, VOL. 139, AUGUST 15, 1988 tract infections in adults. However, a number of ylic acid antimicrobial agent. Am I Med 1987; 82 (suppl similarly effective agents, used to treat most un- 6B): 1-92 5. Shen LL, Pernet AG: Mechanism of inhibition of DNA complicated urinary tract infections, are generally gyrase by analogues of nalidixic acid: The target of the preferred because of their lower cost. Norfloxacin drugs is DNA. Proc Natl Acad Sci USA 1985; 82: 307-311 represents a distinct advance in the treatment of 6. Stein GE: Review of the bioavailability and pharmacokinet- such infections caused by bacteria resistant to ics of oral norfloxacin. Am J Med 1987; 82 (suppl 6B): 18- previously available antibiotics given orally, be- 21 the need for admission to 7. Rubinstein E, Segev S: Drug interactions of ciprofloxacin cause its use may obviate with other non-antibiotic agents. Am J Med 1987; 82 (suppl hospital or permit earlier discharge from hospital. 4A): 119-123 These bacteria include Serratia, Enterobacter, P. 8. Hooper DC, Wolfson JS: The fluoroquinolones: phar- aeruginosa and indole-positive Proteus (P. vul- macology, clinical uses, and toxicities in humans. Antimi- garis, P. morgani and Providencia). Norfloxacin is crob Agents Chemother 1985; 28: 716-721 also valuable in patients with allergies or intoler- 9. Bergeron MG, Thabet M, Roy R et al: Norfloxacin penetra- tion into human renal and prostatic tissues. Ibid: 349-350 ance to multiple antibiotics. 10. Vogel R, Daney NB, Round EM et al: Norfloxacin, amox- Norfloxacin should be considered for the treat- ycillin, cotrimoxazole and nalidixic acid. A summary of ment of prostatitis due to trimethoprim-resistant, 3-day and 7-day therapy studies in the treatment of urinary norfloxacin-susceptible organisms and of symp- tract infections. J Antimicrob Chemother 1984; 13 (suppl B): tomatic shigellosis caused by norfloxacin-suscepti- 113-120 resistant to tetracycline and 11. Romanowski B: Norfloxacin in the therapy of gonococcal ble strains ampicillin, infections. ScandJ Infect Dis 1986; 48 (suppl): 40-45 trimethoprim-sulfamethoxazole, although these 12. Crider FR, Colby SD, Miller LK et al: Treatment of indications for use have not been approved by the penicillin-resistant Neisseria gonorrhoeae with oral norflox- Health Protection Branch of the Department of acin. N EnglJ Med 1984; 311: 137-140 National Health and Welfare. 13. Johnson PC, Ericsson CD, Morgan DR et al: Lack of Norfloxacin should be considered for the pre- emergence of resistant fecal flora during successful prophylaxis of traveller's diarrhea with norfloxacin. Antimicrob vention of gram-negative bacterial infections in Agents Chemother 1986; 30: 671-674 neutropenic patients and for the treatment of 14. Dupont HL, Corrado ML, Sabbaj J: Use of norfloxacin in severe traveller's diarrhea in people who cannot the treatment of acute diarrheal disease. Am J Med 1987; 82 take trimethoprim. (suppl 6B): 79-83 15. Karp JE, Merz WG, Hendricksen C et al: Oral norfloxacin for the prevention of gram-negative bacterial infections in References patients with acute leukemia and granulocytopenia: a randomized double-blind, placebo-controlled trial. Ann 1. Wolfson JS, Hooper DC: The fluoroquinolones: structures, Intem Med 1987; 106: 1-7 mechanisms of action and resistance, and spectra of activity 16. Kurimura 0, Sasaki H, Aratani Y et al: Further clinical in vitro. Antimicrob Agents Chemother 1985; 28: 581-586 studies of AM-715 on the patients with typhoid fever and 2. Leigh DA, Wise R (eds): Norfloxacin - a new quinolone typhoid carriers. Chemother Tokyo 1982; 30: 1286-1296 for urinary infections. J Antimicrob Chemother 1984; 13 17. Gotuzzo E, Guerra JG, Benavente L et al: Use of norfloxacin (suppl B): 1-140 to treat chronic typhoid carriers. J Infect Dis 1988; 157: 3. Norrby SR (ed): Norfloxacin: targeted antibiotic therapy. 1221-1225 ScandJ Infect Dis 1986; 48 (suppl): 1-91 18. Corrado ML, Struble WE, Peter C et al: Norfloxacin: review 4. Moellering RC (ed): Norfloxacin: a fluoroquinolone carbox- of safety studies. Am J Med 1987; 82 (suppl 6B): 22-26

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