Cinoxacin. A review of its pharmacological properties and therapeutic efficacy in the treatment of urinary tract infections

Cinoxacin is a urinary antibacterial drug closely related structurally to nalidixic acid. It has a spectrum of in vitro antibacterial activity which qualitatively resembles that of the latter agent, covering most common Gram-negative pathogens, excluding Pseudomonas. In acute or recurrent urinary tract infections it has been shown to be at least as effective as nalidixic acid or co-trimoxazole, and in a few studies was as effective as amoxycillin or nitrofurantoin. Cinoxacin appears to be well tolerated and may have a low propensity to induce bacterial resistance during clinical use, although the latter needs further confirmation. Thus, cinoxacin is an effective alternative for treating urinary tract infections due to common Gram-negative pathogens, and its apparently low incidence of adverse effects may offer worthwhile advantages over the related compounds nalidixic and oxolinic acids. Its use as prophylactic therapy in patients with recurrent urinary tract infections is not yet well established, although this appears a worthwhile area for further study.     

Comparative in vitro activity of ciprofloxacin and five other quinoline derivatives against gram-negative isolates

A total of 375 Gram-negative bacterial strains were isolated from midstream urine specimens of the same number of patients affected by urinary tract infections. All bacteria were identified by standard bacteriological methods and their susceptibility to six quinoline derivatives (ciprofloxacin, cinoxacin, norfloxacin, oxolinic acid, pipemidic acid, nalidixic acid) was studied by determining the MICs and MBCs for each compound using a miniaturized dilution broth method in microtitre plates and twofold dilutions of each drug from 256 to 0.12 mcg/ml. Ciprofloxacin, a new quinoline carboxylic acid compound structurally related to nalidixic acid, showed a much higher antibacterial activity against all bacterial strains under examination, including Pseudomonas, than the other compounds, except for norfloxacin. The MIC90 and MBC90 of ciprofloxacin never exceeded 1 mcg/ml with any of the bacterial species; and MBC/MIC ratios were very low, which represents an important clinical advantage. Only norfloxacin showed comparable effectiveness. No bacterial strain showed resistance to the drug and the MIC90 and MBC90 never exceeded 8 mcg/ml.     

Norfloxacin: clinical pharmacology and clinical use

Norfloxacin, a nalidixic acid analog, is the first of the fluorinated quinolinecarboxylic acids to be marketed in the United States. It demonstrates potent antibacterial activity against aerobic, gram-negative bacteria including the Enterobacteriaceae, gentamicin-resistant Pseudomonas aeruginosa, and penicillin-resistant Neisseria gonorrhoeae. Norfloxacin exhibits good activity against methicillin-resistant and -sensitive Staphylococcus aureus, but less activity against most other aerobic, gram-positive organisms. Anaerobic bacteria are resistant to the drug. Resistance to norfloxacin is not plasmid mediated, but is secondary to bacterial mutation, and occurs less frequently than nalidixic acid resistance. Its pharmacokinetic properties after a 400-mg oral dose consist of a peak serum concentration of 1.3-1.58 micrograms/ml, an elimination half-life of 3-7 hours, and good penetration into kidney and prostatic tissues. Renal excretion is the major route of elimination. Norfloxacin is highly effective in the treatment of uncomplicated and complicated urinary tract infections, and gonococcal urethritis. Adverse effects are generally well tolerated and usually do not require discontinuation of therapy.     

Enoxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use

Enoxacin is a new addition to the class of 4-quinolone antibacterial drugs. It has a broad spectrum of in vitro antibacterial activity, and is particularly potent against Gram-negative organisms and staphylococci. The pharmacokinetic profile of enoxacin is similar to that of ofloxacin, achieving higher plasma and tissue concentrations and possessing a longer half-life than norfloxacin or ciprofloxacin. In comparative studies, clinical and/or bacteriological efficacy was comparable or (in studies which statistically analysed the results) not significantly different between enoxacin and amoxycillin in acute cystitis, acute Gram-negative exacerbations of chronic bronchitis and acute or chronic otitis media, between enoxacin and cephalexin in skin, skin structure and soft tissue infections, between enoxacin and trimethoprim in acute cystitis, between enoxacin and co-trimoxazole in complicated urinary tract infection and between enoxacin and pipemidic acid in suppurative otitis media. Significantly (p less than 0.01) more clinical and/or bacteriological cures were effected by enoxacin than pipemidic acid in acute cystitis and complicated urinary tract infection. In uncomplicated gonococcal infections single oral doses of enoxacin were effective in over 90% of patients. Enoxacin is a well-tolerated, orally active broad spectrum antibacterial drug which should prove a worthwhile alternative to currently available antibacterial therapy.     

In vivo activity of ciprofloxacin, ofloxacin, norfloxacin and pipemidic acid against Escherichia coli infections in mice

The therapeutic efficacy of four quinolones, i.e. ciprofloxacin, ofloxacin, norfloxacin and pipemidic acid, was investigated in experimental infections in mice caused by pipemidic acid-susceptible and -resistant E. coli. For intraperitoneal infections caused by E. coli strain 444 and 23, the efficacy of ciprofloxacin, ofloxacin and norfloxacin was superior to that of pipemidic acid. Furthermore, ciprofloxacin and ofloxacin had higher activity than norfloxacin and pipemidic acid in urinary tract and uterine infections. Serum and uterus levels of ciprofloxacin and ofloxacin in normal mice were higher and more durable than those of norfloxacin.     

Antimicrobial activity of norfloxacin in enteric and urinary tract infections: combined effect of norfloxacin with aminoglycosides, tetracycline and chloramphenicol

A comparative study of the in vitro activity of norfloxacin was performed versus that of aminoglycosides, pipemidic acid, tetracycline and chloramphenicol. These antibiotics are the most commonly used antimicrobial agents in the treatment of enteric and urinary tract infections. Results obtained with norfloxacin against Gram-negative isolates tested were very encouraging. MIC values for the Enterobacteriaceae were less than or equal to 0.47 mcg/ml, and for Pseudomonas and Acinetobacter less than or equal to 32.5 mcg/ml. The activity of norfloxacin against Pseudomonas was inferior to that of amikacin, but superior to that of gentamicin. In association with aminoglycosides, norfloxacin proved to be most useful in the treatment of urinary tract infections, while norfloxacin associated with tetracycline and chloramphenicol did not give satisfactory results in the treatment of enteric infections.     

Norfloxacin: a quinoline antibiotic

Norfloxacin is a quinoline (quinolinecarboxylic acid) that should prove successful in treating infections that currently require hospitalization and intravenous antibiotics. Although a nalidixic acid derivative, it possesses greater antibacterial activity against gram-positive and gram-negative bacteria. Compared with other antimicrobial agents, norfloxacin is more potent than the aminoglycosides, first-, second-, and third-generation cephalosporins, tetracycline, trimethoprim-sulfamethoxazole, carbenicillin, piperacillin, nalidixic acid, oxolinic acid, cinoxacin, and enoxacin. In the clinical studies to date, the side effects of norfloxacin have been minimal, but include nausea, vomiting, anorexia, dizziness, headache, drowsiness, depression, and a bitter taste in the mouth. In studies with more than 4000 patients, the incidence of side effects ranged from 3.9 to 4.7 percent, with most appearing by the second day of therapy.     

Quinolones in vitro

The first quinolone compound, nalidixic acid, showed activity against a limited number of Gram-negative micro-organisms. ‘One step’ resistance developed hiin vitro and during treatment. Resistance was not mediated by transfer of R-plasmids, which is a characteristic of all quinolones. Newer quinolones like oxolinic acid, piromidic acid, cinoxacin and pipemidic acid exhibit an extended spectrum of activity against Gram-negative bacteria at lower MIC values. In recent years fluorinated quinolones were introduced like ciprofloxacin, norfloxacin, pefloxacin, ofloxacin, enoxacin and amifloxacin. These compounds exhibitin vitro a broad spectrum of activity against Gram-negative and Gram-positive bacteria at MIC values seventy to four hundred times less than those for nalidixic acid. Thein vitro activity of these compounds has been investigated in a large study of uncomplicated urinary tract infections in general practice (PINISU). No resistance was found. The fluorinated quinolones are very promising antimicrobial agents for a limited number of indications.     

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 traveler's diarrhea, biliary tract infections prior to surgery, and gram-negative bacillary infections in profoundly neutropenic patients.     

Diclofenac in the management of E. coli urinary tract infections

E. coli is the main agent of uncomplicated urinary tract infections (UTIs) and accounts for more than 85% of recurrent cystitis and at least 35% of recurrent pyelonephritis. Despite the widespread availability of antibiotics, UTIs remain the most common bacterial infection in the human population. It is currently advised that the clinical administration of antibiotics against the pathogenic bacteria should be prohibitted due to the emergence of multidrug resistant (MDR) bacterial strains. Therefore, newer and more effective antimicrobials are in demand to treat such cases. One hundred and thirty six urine samples were collected from UTI patients. E. coli was isolated from 85 samples, out of which 33% were resistant to common antibiotics. The isolates were decreasingly resistant to ampicillin, tobramycin, augmentin, nalidixic acid, cefuroxime, nitrofurantoin, kanamycin, pipemidic acid, chloramphenicol, cefotaxime, cefamendol, ofloxacin, ceftizoxime, norfloxacin and amikacin. The anti-inflammatory drug diclofenac exhibited significant antibacterial activity against common bacterial strains both in vitro and in vivo. The present work was conducted to evaluate the in vitro inhibitory effect of this drug on the clinically isolated strains of E. coli in hospitals. All the isolates were sensitive to diclofenac, with MIC values ranging from 5-50 microg/mL. The MIC90 value of the drug was 25 microg/mL. Therefore, it may be suggested that diclofenac has the capacity to treat UTI caused by E. coli.     

Antibacterial activity after a single-dose of norfloxacin, ofloxacin and pipemidic acid detected in urine of volunteers

Six healthy volunteers received in a triple-crossover design a single oral dose of norfloxacin, ofloxacin or pipemidic acid. Urine samples were collected during the 24 h following the administration and were tested for inhibitory and bactericidal activity against selected strains of Enterobacteriaceae and Pseudomonas aeruginosa. Norfloxacin and ofloxacin inhibited the urinary growth of sensitive strains during the 24 h of sampling time at dilutions much higher than those generally considered satisfactory. Nalidixic acid was less effective and did not achieve bactericidal activity against Ps. aeruginosa over the interval of 12 to 24 h.     

Research on antibacterial and antifungal agents. VII. Synthesis of (1-pyrryl)methylquinolines acids

Some (1-pyrryl)methyl derivatives of 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were synthetized by the standard procedure involving Gould-Jacobs and Lappin reactions. The above derivatives were tested microbiologically as nalidixic acid analogs and compared with some clinically useful 4-oxopyridine-3-carboxylic acids (nalidixic acid, pipemidic acid, norfloxacin, enoxacin and ciprofloxacin). Their antibacterial activities were very weak.     

Quinolones in vitro

The first quinolone compound, nalidixic acid, showed activity against a limited number of Gram-negative micro-organisms. One step resistance developed hiin vitro and during treatment. Resistance was not mediated by transfer of R-plasmids, which is a characteristic of all quinolones. Newer quinolones like oxolinic acid, piromidic acid, cinoxacin and pipemidic acid exhibit an extended spectrum of activity against Gram-negative bacteria at lower MIC values. In recent years fluorinated quinolones were introduced like ciprofloxacin, norfloxacin, pefloxacin, ofloxacin, enoxacin and amifloxacin. These compounds exhibitin vitro a broad spectrum of activity against Gram-negative and Gram-positive bacteria at MIC values seventy to four hundred times less than those for nalidixic acid. Thein vitro activity of these compounds has been investigated in a large study of uncomplicated urinary tract infections in general practice (PINISU). No resistance was found. The fluorinated quinolones are very promising antimicrobial agents for a limited number of indications.     

Ciprofloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use

Ciprofloxacin is one of a new generation of fluorinated quinolones structurally related to nalidixic acid. The primary mechanism of action of ciprofloxacin is inhibition of bacterial DNA gyrase. It is a broad spectrum antibacterial drug to which most Gram-negative bacteria are highly susceptible in vitro and many Gram-positive bacteria are susceptible or moderately susceptible. Unlike most broad spectrum antibacterial drugs, ciprofloxacin is effective after oral or intravenous administration. Ciprofloxacin has been most extensively studied following oral administration. It attains concentrations in most tissues and body fluids which are at least equivalent to the minimum inhibitory concentration designated as the breakpoint for bacterial susceptibility in vitro. The results of clinical trials with orally and intravenously administered ciprofloxacin have confirmed the potential for its use in a wide range of infections, which was suggested by its in vitro antibacterial and pharmacokinetic profiles. It has proven an effective treatment for many types of systemic infections as well as for both acute and chronic infections of the urinary tract. Ciprofloxacin generally appeared to be at least as effective as alternative orally administered antibacterial drugs in the indications in which they were compared, and in some indications, to parenterally administered antibacterial therapy. However, further studies are needed to fully clarify the comparative efficacy of ciprofloxacin and standard antibacterial therapies. Bacterial resistance to ciprofloxacin develops infrequently, both in vitro and clinically, except in the setting of pseudomonal respiratory tract infections in cystic fibrosis patients. The drug is also well tolerated. Thus, as an orally active, broad spectrum and potent antibacterial drug, ciprofloxacin offers a valuable alternative to broad spectrum parenterally administered antibacterial drugs for use in a wide range of clinical infections, including difficult infections due to multiresistant pathogens.     

依诺沙星对45例细菌性感染的临床疗效观察

本文报道国产依诺沙星治疗各种细菌感染45例,对单纯性尿路感染采用每日400mg;复杂性尿路感染和肺部感染每日600～1200mg,均分2～3次口服,疗程7～14天;治疗淋菌性尿道炎每日1200mg,疗程1天。结果痊愈36例,显效8例,进步1例,临床有效率97.78％(44/45),所分离到的33株细菌在治疗后全部被清除,清除率为100％。同期临床分离到的127株细菌体外药敏结果显示依诺沙星对多数革兰阴性菌、革兰阳性球菌的作用较诺氟沙星强,与洛美沙星接近,但逊于阿米卡星、头孢唑啉等,细菌对喹诺酮类药物的耐药性有增多趋势。本组病例在用药过程中未发生明显毒副反应。 笔者认为依诺沙星口服治疗轻中度的各种细菌性感染具有疗效高、安全性好、使用方便、价格低等优点,值得临床进一步推广。     

Ciprofloxacin and norfloxacin, two fluoroquinolone antimicrobials

The chemistry, mechanism of action, antimicrobial spectrum, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of ciprofloxacin and norfloxacin are reviewed, and mechanisms of antimicrobial resistance and drug and laboratory interactions are described. Norfloxacin is the first antimicrobial in the fluoroquinolone class to be marketed in the United States; ciprofloxacin is under investigation in clinical trials. The fluoroquinolones are structurally related to nalidixic acid. The activity and spectrum are enhanced by the addition of 6-fluoro and 7-piperazino substituents. Quinolone antimicrobials appear to inhibit DNA gyrase, an enzyme specific and essential for all bacteria, as their primary mechanism of action. As a result, DNA synthesis is inhibited. Ciprofloxacin and norfloxacin are active against gram-negative enteric bacteria, Pseudomonas aeruginosa, Haemophilus influenzae, and Neisseria gonorrhoeae. Ciprofloxacin has good activity against Staphylcoccus spp., including methicillin-resistant Staph. aureus. Norfloxacin generally is less potent than ciprofloxacin, particularly against Ps. aeruginosa and Staph. aureus. Peak concentrations occur about one to two hours after an oral administration of either drug. Both drugs are widely distributed in body fluids and tissues and are eliminated by renal excretion, metabolism, and biliary excretion. Dosage reductions are required in severe renal dysfunction. Ciprofloxacin and norfloxacin are effective agents for treating urinary-tract infections, including infections caused by Ps. aeruginosa. The recommended dosage of norfloxacin for urinary-tract infections in adults is 400 mg orally every 12 hours; the drug should be given for 7 to 10 days in uncomplicated infections and for 10 to 21 days in complicated ones. The fluoroquinolones may be useful for treating chronic bacterial prostatitis. Ciprofloxacin is potentially useful for treating sexually transmitted diseases. Ciprofloxacin is active against N. gonorrhoeae, including beta-lactamase-producing strains and strains that are resistant to tetracycline, and Chlamydia spp. Use of ciprofloxacin for treating gastrointestinal infections and for selective decontamination of the gastrointestinal tract is promising. In open studies, ciprofloxacin has been effective against a variety of infections caused by susceptible organisms. Resistance to ciprofloxacin has developed during treatment of infections caused by Ps. aeruginosa, Staph. aureus, and Serratia marcescens. The most frequently reported adverse effects of either drug are gastrointestinal complaints, headache, and dizziness.(ABSTRACT TRUNCATED AT 400 WORDS)     

In vitro activity of seven gyrase inhibitors of a group of heterocyclic carbonic acids against nonfermenting gram negative rods (nonfermenters)

MIC (minimal inhibitory concentration) determinations for nalidixic acid, cinoxacin, pipemidic acid, norfloxacin, enoxacin, and ciprofloxacin were done by agar dilution on isosensitest agar (oxoid). Bacterial strains investigated were 189 Pseudomonas aeruginosa, 164 Acinetobacter lwoffii, 4 Ps. maltophilia, 3 Ps. putrefaciens and 3 Ps. odorans. The results in summary are: Ciprofloxacin is the most active gyrase inhibitor against Ps. aeruginosa as well as against other nonfermentative gram-negative rods, versus Ps. aeruginosa norfloxacin is a little more active than ofloxacin, against nonfermentative gram-negative rods other than Ps. aeruginosa norfloxacin is markedly less active than ofloxacin. Problems concerning cross-resistance of new gyrase inhibitors are discussed.     

Cefixime. A review of its antibacterial activity. Pharmacokinetic properties and therapeutic potential

Cefixime, previously designated FK027, FR17027 and CL284635, is an orally active cephalosporin with a broad spectrum of antibacterial activity in vitro. It is particularly active against many Enterobacteriaceae, Haemophilus influenzae. Streptococcus pyogenes, Streptococcus pneumoniae and Branhamella catarrhalis, and is resistant to hydrolysis by many beta-lactamases. Cefixime has little activity against Staphylococcus aureus and is inactive against Pseudomonas aeruginosa. Cefixime is distinguished by its 3-hour elimination half-life which permits twice daily, or in many instances once daily, administration. Comparative trials, though few, indicate that the clinical and bacteriological efficacy of cefixime 200 to 400mg daily administered as a single dose or in 2 divided doses, is comparable with that of multiple daily doses of co-trimoxazole (trimethoprim + sulphamethoxazole) or amoxycillin in acute uncomplicated urinary tract infection, with that of amoxycillin, amoxycillin/clavulanic acid and cefaclor in acute lower respiratory tract infections, and with that of amoxycillin and cefroxidine in adult patients with acute tonsillitis or pharyngitis. Several comparative trials in children with acute otitis media demonstrate the similar effectiveness of cefixime 8 mg/kg daily (in 2 divided doses, or as a single daily dose), cefaclor 20 to 40 mg/kg daily and amoxycillin 40 mg/kg daily in 3 divided doses. The most frequently reported adverse effects, diarrhoea and stool changes, are usually mild to moderate in severity, transient, and mostly occur in the first few days of treatment with cefixime. Thus, cefixime is an effective orally active cephalosporin with a relatively long elimination half-life permitting a simplified treatment regimen. It is a suitable alternative to cefaclor or amoxycillin in acute otitis media and acute upper and lower respiratory tract infections, and to amoxycillin or co-trimoxazole in acute uncomplicated urinary tract infections.     

In vitro effect of pH and glucose concentration on the antibacterial activity of norfloxacin in urine

The in vitro effect of pH and glucose concentration on the antibacterial activity of norfloxacin in urine was studied. Norfloxacin effectively inhibited the growth of four gram-negative pathogens in urine in vitro at pH values of 6.0, 7.0, and 8.0. The antibacterial activity of norfloxacin in urine was reduced severalfold at pH 6, but minimum inhibitory concentrations (MICs) at this pH remained clinically significant. Glucose at concentrations of 200 mg/dl and 400 mg/dl (simulating glucosuria of diabetes) did not significantly affect the antibacterial activity of norfloxacin when tested against clinical isolates of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, or Pseudomonas aeruginosa. Norfloxacin appears to be a highly effective antibiotic in vitro under conditions which simulate normal and diabetic states.     

Ofloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use

Ofloxacin is one of a new generation of fluorinated quinolones structurally related to nalidixic acid. It is an orally administered broad spectrum antibacterial drug active against most Gram-negative bacteria, many Gram-positive bacteria and some anaerobes. Ciprofloxacin is the only other quinolone with superior in vitro antibacterial activity. However, the pharmacokinetic profile of ofloxacin is superior to that of ciprofloxacin, with more rapid absorption and a peak serum concentration several times higher. Moreover, ofloxacin achieves high concentrations in most tissues and body fluids. The results of clinical trials with ofloxacin have confirmed the potential for use in a wide range of infections, which was indicated by its in vitro antibacterial and pharmacokinetic profiles. It has proven effective against a high percentage of infections caused by Gram-negative organisms, slightly less effective against Gram-positive infections, and effective against some anaerobic infections. Clinical efficacy has also been confirmed in a variety of systemic infections as well as in acute and chronic urinary tract infections, and ofloxacin has generally appeared to be at least as effective as alternative orally administered antibacterial drugs. Ofloxacin is well tolerated and, although experience with the drug in clinical practice to date is limited, bacterial resistance does not appear to develop readily. Thus, ofloxacin is an orally active drug which offers a valuable alternative to other broad spectrum antibacterial drugs.