Figure 6.6 • ionization equilibria in the quinolone antibacterial drugs.
Figure 6.7 • A 2:1 chelate of a Mg24 ciprofloxacin.
powder that is sparingly soluble in water and ether but soluble in most polar organic solvents.
Figure 6.7 • A 2:1 chelate of a Mg24 ciprofloxacin.
Nalidixic acid is useful in the treatment of urinary tract infections in which Gram-negative bacteria predominate. The activity against indole-positive Proteus spp. is particularly noteworthy, and nalidixic acid and its congeners represent important alternatives for the treatment of urinary tract infections caused by strains of these bacteria resistant to other agents. Nalidixic acid is rapidly absorbed, extensively metabolized, and rapidly excreted after oral administration. The 7-hydroxymethyl metabolite is significantly more active than the parent compound. Further metabolism of the active metabolite to inactive glucuronide and 7-carboxylic acid metabolites also occurs. Nalidixic acid possesses a t1/2elim of 6 to 7 hours. It is eliminated, in part, unchanged in the urine and 80% as metabolites.
1-Ethyl-1,4-dihydro-4-oxo[1,3]dioxolo[4,5g]cinnoline-3-carboxylic acid (Cinobac) is a close congener (isostere) of oxolinic acid (no longer marketed in the United States) and has antibacterial properties similar to those of nalidixic and oxolinic acids.
It is recommended for the treatment of urinary tract infections caused by strains of Gram-negative bacteria susceptible to these agents. Early clinical studies indicate that the drug possesses pharmacokinetic properties superior to those of either of its predecessors. Thus, following oral administration, higher urinary concentrations of cinoxacin than of nalidixic acid or oxolinic acid are achieved. Cinoxacin appears to be more completely absorbed and less protein bound than nalidixic acid.
1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (Noroxin) is a pale yellow crystalline powder that is sparingly soluble in water. This quinoline has broad-spectrum activity against Gram-negative and Gram-positive aerobic bacteria. The fluorine atom provides increased potency against Gram-positive organisms, whereas the piperazine moiety improves antipseudomonal activity. Norfloxacin is indicated for the treatment of urinary tract infections caused by E. coli, K. pneumoniae, Enterobacter cloacae, Proteus mirabilis, indole-positive Proteus spp., including P. vulgaris, Providencia rettgeri, Morganella morganii, P. aeruginosa, S. aureus, and S. epi-dermidis, and group-D streptococci. It is generally not effective against obligate anaerobic bacteria. Norfloxacin in a single 800-mg oral dose has also been approved for the treatment of uncomplicated gonorrhea. The oral absorption of norfloxacin is about 40%. The drug is 15% protein bound and is metabolized in the liver. The t1/2elim is 4 to 8 hours. Approximately 30% of a dose is eliminated in the urine and feces.
The oral absorption of norfloxacin is rapid and reasonably efficient. Approximately 30% of an oral dose is excreted in the urine in 24 hours, along with 5% to 8% consisting of less active metabolites. There is significant biliary excretion, with about 30% of the original drug appearing in the feces.
1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid (Penetrex) is a quinolone with broad-spectrum antibacterial activity that is used primarily for the treatment of urinary tract infections and sexually transmitted diseases. Enoxacin has been approved for the treatment of uncomplicated gonococcal urethritis and has also been shown to be effective in chancroid caused by Haemophilus ducreyi. A single 400-mg dose is used for these indications. Enoxacin is also approved for the treatment of acute (uncomplicated) and chronic (complicated) urinary tract infections.
Enoxacin is well absorbed following oral administration. Oral bioavailability approaches 98%. Concentrations of the drug in the kidneys, prostate, cervix, fallopian tubes, and myometrium typically exceed those in the plasma. More than 50% of the unchanged drug is excreted in the urine. Metabolism, largely catalyzed by cytochrome P450 enzymes in the liver, accounts for 15% to 20% of the orally administered dose of enoxacin. The relatively short elimination half-life of enoxacin dictates twice-a-day dosing for the treatment of urinary tract infections.
Some cytochrome P450 isozymes, such as CYP 1A2, are inhibited by enoxacin, resulting in potentially important interactions with other drugs. For example, enoxacin has been reported to decrease theophylline clearance, causing increased plasma levels and increased toxicity. Enoxacin forms insoluble chelates with divalent metal ions present in antacids and hematinics, which reduce its oral bioavailability.
1-Cyclopropyl0-6-fluoro-1,4-dihydro-4-oxo-7-(1-piper-azinyl)-3-quinolinecarboxylicacid (Cipro, Cipro IV) is supplied in both oral and parenteral dosage forms. The hydrochloride salt is available in 250-, 500-, and 750-mg tablets for oral administration. Intravenous solutions containing 200 mg and 400 mg are provided in concentrations of 0.2% in normal saline and 1% in 5% dextrose solutions.
The bioavailability of ciprofloxacin following oral administration is good, with 70% to 80% of an oral dose being absorbed. Food delays, but does not prevent, absorption. Significant amounts (20%-35%) of orally administered ciprofloxacin are excreted in the feces, in part because of biliary excretion. Biotransformation to less active metabolites accounts for about 15% of the administered drug. Approximately 40% to 50% of unchanged ciprofloxacin is excreted in the urine following oral administration. This value increases to 50% to 70% when the drug is injected intravenously. Somewhat paradoxically, the elimination half-life of ciprofloxacin is shorter following oral administration (t1/2, 4 hours) than it is following intravenous administration (t1/2, 5-6 hours). Ciprofloxacin inhibits the P450 species CYP 1A2.
The oral dose of this quinolone is typically 25% higher than the parenteral dose for a given indication. Probenecid significantly reduces the renal clearance of ciprofloxacin, presumably by inhibiting its active tubular secretion. Ciprofloxacin is widely distributed to virtually all parts of the body, including the CSF, and is generally considered to provide the best distribution of the currently marketed quinolones. This property, together with the potency and broad antibacterial spectrum of ciprofloxacin, accounts for the numerous therapeutic indications for the drug. Ciprofloxacin also exhibits higher potency against most Gram-negative bacterial species, including P. aeruginosa, than other quinolones.
Ciprofloxacin is an agent of choice for the treatment of bacterial gastroenteritis caused by Gram-negative bacilli such as enteropathogenic E. coli, Salmonella spp. (including S. typhi), Shigella spp., Vibrio spp., and Aeromonas hy-drophilia. It is widely used for the treatment of respiratory tract infections and is particularly effective for controlling bronchitis and pneumonia caused by Gram-negative bacteria. Ciprofloxacin is also used for combating infections of the skin, soft tissues, bones, and joints. Both uncomplicated and complicated urinary tract infections caused by Gram-negative bacteria can be treated effectively with ciprofloxacin. It is particularly useful for the control of chronic infections characterized by renal tissue involvement. The drug also has important applications in controlling venereal diseases. A combination of ciprofloxacin with the cephalosporin antibiotic ceftriaxone is recommended as the treatment of choice for disseminated gonorrhea, whereas a single-dose treatment with ciprofloxacin plus doxycycline, a tetracycline antibiotic (Chapter 8), can usually eradicate gonococcal urethritis. Ciprofloxacin has also been used for chancroid. The drug has been approved for postexposure treatment of inhalational anthrax.
Injectable forms of ciprofloxacin are incompatible with drug solutions that are alkaline because of the reduced solubility of the drug at pH 7. Thus, intravenous solutions should not be mixed with solutions of ticarcillin sodium, mezlocillin sodium, or aminophylline. Ciprofloxacin may also induce crystalluria under the unusual circumstance that urinary pH rises above 7 (e.g., with the use of systemic alkalinizers or a carbonic anhydrase inhibitor or through the action of urease elaborated by certain species of Gram-negative bacilli).
9-Fluoro-2,3-dihydro-3-methyl-10(4-methyl-1-piperazin-yl)-7-oxo-7H-pyrido[1,2,3-de]-1,4,-benzoxazine-6-carboxylic acid (Floxin, Floxin IV) is a member of the quinolone class of antibacterial drugs wherein the 1- and 8-positions are joined in the form of a 1,4-oxazine ring.
because of plasma protein binding (only —10%) or entero-hepatic recycling (biliary excretion is estimated to be —10%).
Ofloxacin resembles ciprofloxacin in its antibacterial spectrum and potency. Like ciprofloxacin, this quinolone is also widely distributed into most body fluids and tissues. In fact, higher concentrations of ofloxacin are achieved in CSF than can be obtained with ciprofloxacin. The oral bioavailability of ofloxacin is superior (95%-100%) to that of ciprofloxacin, and metabolism is negligible (—3%). The amount of an administered dose of ofloxacin excreted in the urine in a 24- to 48-hour period ranges from 70% to 90%. There is relatively little biliary excretion of this quinolone. Although food can slow the oral absorption of ofloxacin, blood levels following oral or intravenous administration are comparable. The elimination half-life of ofloxacin ranges from 4.5 to 7 hours.
Ofloxacin has been approved for the treatment of infections of the lower respiratory tract, including chronic bronchitis and pneumonia, caused by Gram-negative bacilli. It is also used for the treatment of pelvic inflammatory disease and is highly active against both gonococci and chlamydia. In common with other fluoroquinolones, ofloxacin is not effective in the treatment of syphilis. A single 400-mg oral dose of ofloxacin in combination with the tetracycline antibiotic doxycycline is recommended by the Centers for Disease Control and Prevention (CDC) for the outpatient treatment of acute gonococcal urethritis. Ofloxacin is also used for the treatment of urinary tract infections caused by Gram-negative bacilli and for prostatitis caused by E. coli. Infections of the skin and soft tissues caused by staphylo-cocci, streptococci, and Gram-negative bacilli may also be treated with ofloxacin.
Because ofloxacin has an asymmetric carbon atom in its structure, it is obtained and supplied commercially as a racemate. The racemic mixture has been resolved, and the enantiomers independently synthesized and evaluated for antibacterial activity.64 The 3S(-) isomer is substantially more active (8-125 times, depending on the bacterial species) than the 3^( + ) isomer and has recently been marketed as levofloxacin (Levaquin) for the same indications as the racemate.
1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piper-azinyl)-4-oxo-3-quinolinecarboxylic acid (Maxaquin) is a difluorinated quinolone with a longer elimination half-life (7-8 hours) than other members of its class. It is the only quinolone for which once-daily oral dosing suffices. The oral bioavailability of lomefloxacin is estimated to be 95% to 98%. Food slows, but does not prevent, its oral absorption. The extent of biotransformation of lomefloxacin is only about 5%, and high concentrations of unchanged drug, ranging from 60% to 80%, are excreted in the urine. The comparatively long half-life of lomefloxacin is apparently because of its excellent tissue distribution and renal reabsorption and not
Lomefloxacin has been approved for two primary indications. First, it is indicated for acute bacterial exacerbations of chronic bronchitis caused by H. influenzae or Moraxella (Branhamella) catarrhalis, but not if Streptococcus pneumoniae is the causative organism. Second, it is used for prophylaxis of infection following transurethral surgery. Lomefloxacin also finds application in the treatment of acute cystitis and chronic urinary tract infections caused by Gram-negative bacilli.
Lomefloxacin reportedly causes the highest incidence of phototoxicity (photosensitivity) of the currently available quinolones. The presence of a halogen atom (fluorine, in this case) at the 8-position has been correlated with an increased chance of phototoxicity in the quinolones.40
Sparfloxacin, (cis)-5-amino-1-cyclopropyl-7-(3,5-dimethyl)-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quino-linecarboxylic acid, is a newer fluoroquinolone.
This compound exhibits higher potency against Grampositive bacteria, especially staphylococci and streptococci, than the fluoroquinolones currently marketed. It is also more active against chlamydia and the anaerobe Bacteroides frag-ilis. The activity of sparfloxacin against Gram-negative bacteria is also very impressive, and it compares favorably with ciprofloxacin and ofloxacin in potency against Mycoplasma spp., Legionella spp., Mycobacteria spp., and Listeria monocytogenes. Sparfloxacin has a long elimination half-life of 18 hours, which permits once-a-day dosing for most indications. The drug is widely distributed into most fluids and tissues. Effective concentrations of sparfloxacin are achieved for the treatment of skin and soft tissue infections, lower respiratory infections (including bronchitis and bacterial pneumonias), and pelvic inflammatory disease caused by gonorrhea and chlamydia. Sparfloxacin has also been recommended for the treatment of bacterial gastroenteritis and cholecystitis. The oral bioavailability of sparfloxacin is claimed to be good, and sufficient unchanged drug is excreted to be effective for the treatment of urinary tract infections. Nearly 20% of an orally administered dose is excreted as an inactive glucuronide.
The incidence of phototoxicity of Sparfloxacin is the lowest of the fluoroquinolones, because of the presence of the 5-amino group, which counteracts the effect of the 8-fluoro substituent.
The first nitroheterocyclic compounds to be introduced into chemotherapy were the nitrofurans. Three of these compounds—nitrofurazone, furazolidone, and nitrofurantoin— have been used for the treatment of bacterial infections of various kinds for nearly 50 years. A fourth nitrofuran, nifurtimox, is used as an antiprotozoal agent to treat trypanosomiasis and leishmaniasis. Another nitroheterocyclic of considerable importance is metronidazole, which is an amebicide (a trichomonicide) and is used for the treatment of systemic infections caused by anaerobic bacteria. This important drug is discussed later in this chapter.
The nitrofurans are derivatives of 5-nitro-2-furaldehyde, formed on reaction with the appropriate hydrazine or amine derivative. Antimicrobial activity is present only when the nitro group is in the 5-position.
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