Urinary tract infections quinolones

Over 10000 quinolone antibacterial agents have now been synthesized. Nalidixic acid is regarded as the progenitor of the new quinolones. It has been used for several years as a clinically important drug in the treatment of urinary tract infections. Since its clinical introduction, other 4-quinolone antibacterials have been synthesized, some of which show considerably greater antibacterial potency. Furthermore, this means that many types of bacteria not susceptible to nahdixic acid therapy m be sensihve to the newer derivahves. The most important development was the introduction of a fluorine substituent at C-6, which led to a considerable increase in potency and spectrum of activity compared with nalidixic add. These second-generation quinolones are known as fluoroquinolones, examples of which are ciprofloxacin and norfloxacin (Fig. 5.19). 

Quinolones Ciprofloxacin, enoxacin, and levofloxacin Urinary tract infections... 

This class of compounds comprises a series of synthetic agents patterned after nalidixic acid, a naphthyridine derivative introduced in 1963 for the treatment of urinary tract infections. Isosteric heterocyclic groupings in this category include the quinolones (e.g., norfloxacin, ciprofloxacin, lome-floxacin, gatifloxacin, sparfloxacin, moxifloxacin, and ofloxacin), the naph-thyridones (e.g., nalidixic acid, enoxacin, and trovafloxacin), and the cin-nolones (e.g., cinnoxacin) [2] (Fig. 1). 

Cefalexin is a first-generation cephalosporin and therefore an alternative preparation would be Zinnat tablets, which contains cefuroxime, a second-generation cephalosporin. A penicillin such as Augmentin, which contains co-amoxiclav, can be an appropriate alternative since it provides a very similar spectrum of activity. Klaricid contains clarithromycin, which is a macrolide. Utinor contains norfloxacin, which is a quinolone that is effective in uncomplicated urinary-tract infections. Rocephin contains ceftriaxone, which is a third-generation cephalosporin that is available for parenteral administration only. 

The quinolones are good general antibiotics for systemic infections, and they are particularly useful for urinary tract infections because high concentrations are excreted into the urine. The mode of action involves interference with DNA replication by inhibiting DNA gyrase, a bacterial enzyme related to mammalian topoisomerases that breaks and reseals double-stranded DNA during replication. 

Therapeutic uses of the quinolones include urinary and respiratory tract infections, GI and abdominal infections, STDs, and bone, joint, and soft tissue infections. Nalidixic acid is effective for urinary tract infections however, bacteria can become resistant, particularly if the drug is used for long periods. The second-generation fluoroquinolones are all equally efficacious in UTIs, and their activity is comparable to that of TMP-SMX. These drugs have shown efficacy in treating prostatitis and can serve as an alternative therapy for patients not responding to TMP-SMX. 

Quinolones are synthetic compounds designed around nalidixic acid, a naphthyridine derivative used to treat urinary tract infections in the 1960s. By replacing various functional groups within the nalidixic acid pharmacophore with bioistosteric substitutions, three structural classes of quinolones were devised ... 

Other antimicrobial agents used in urinary tract infection e.g. sulfonamides, quinolones, penicillins, ... 

The lead compound for this series, nalidixic acid (38-6), which is acmally a naphthyridine rather than a quinolone, was first introduced over four decades ago. That compound for many years found its niche as a rather effective drug for the treatment of urinary tract infection. The rediscovery of the general stmcmral class in the early 1980s hinged on the discovery of the importance of fluorine at the 6 position and basic nitrogen at position 7. This renewed research led to the development of a very large series of potent broad spectmm antibiotics. This is reflected in the fact that more than 20 quinolone antibiotics have been granted U.S. nonproprietary names. 

Earlier quinolones such as nalidixic acid did not achieve systemic antibacterial levels and were useful only for treatment of lower urinary tract infections. Fluorinated derivatives (ciprofloxacin, levofloxacin, and others Figure 46-3 and Table 46-2) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues. 

Very few synthetic compounds other than the sulfa drugs have shown useful activity against systemic bacterial infections, particularly those due to Gram-negative bacteria. Activity of this kind was discovered in a series of l-alkyl-4-quinolones (60BRP830832), but the most active of these, l,2-dimethyl-6-nitro-4-quinolone and l-methyl-6-nitro-4-quin-olone-3-carboxylic acid, produced eye damage (opacity of the lens) that precluded clinical trial. A closely related 1,8-naphthyridine derivative, nalidixic acid (255), was later found to be effective, and it is largely used for urinary tract infections. The quinolone oxolinic acid (256) is also used for this purpose. These compounds inhibit enzymes concerned in DNA synthesis. 

Petri WA. Sulfonamides, trimethoprim-sulfamethoxazole, quinolones, and agents for urinary tract infections. In Brunton LL, et al, eds. The Pharmacological... 

Nalidixic acid, the first antibacterial quinolone (Figure 46-3), was introduced in 1963. It is not fluorinated and is excreted too rapidly to be useful for systemic infections. Oxolinic acid and cinoxacin are similar in structure and function to nalidixic acid. Their mechanism of action is the same as that of the fluoroquinolones. These agents were useful only for the treatment of urinary tract infections and are rarely used now, having been made obsolete by the more efficacious fluorinated quinolones. 

The older drug, nalidixic acid, is a nonfluorinated quinolone, and is not effective against systemic infections. Its use in the treatment of urinary tract infections (UTIs) is limited due to the rapid emergence of resistant strains. It will be considered in a separate section below. Unless care is taken to employ these drugs in appropriate infective states, it is possible that their value will be lost. 

Mandell, G.L. Sande, M.A. Antimicrobial agents sulfonamides, trimethoprim, sulfamethoxazole, quinolones, and agents for urinary tract infections. In Pharmacological Basis of Therapeutics, 8th Ed. Gilman, A.G., Rail, T.W., Nies, A.S., Taylor, P., Eds. Pergamon Press New York, 1991 1047-1064. 

Nalidixic acid, the first quinolone, first introduced in 1962, is now only rarely used and has been supplanted by the fluoroquinolones. It is almost completely absorbed from the gastrointestinal tract and is rapidly eliminated by the kidneys, resulting in urinary concentrations 4-6 times higher than plasma concentrations. There are better drugs to treat urinary tract infections. 

Enoxadn, USP. l-Ethyl-6-fluoro-l.4-dihydro-4-oxo-7-(I-piperazinyI)-I,8-naphthyridine-3-carboxylic acid (Pene-irex) is a quinolone with broad-spectrum antibacterial activity that is used primarily for the treaimenl 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. 

Indications Urinary tract infections Category Antibiotic, quinolone Half-life 3-6 hours... 

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