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Chapter: Modern Pharmacology with Clinical Applications: Synthetic Organic Antimicrobials: Sulfonamides, Trimethoprim, Nitrofurans, Quinolones, Methenamine

Quinolones: Nalidixic Acid and Fluoroquinolones

All clinically approved quinolones in use in the United States contain a carboxylic acid moiety in the 3-position of the basic ring structure (the 4-quinolones).



Chemistry, Mechanism of Action, and Classification


All clinically approved quinolones in use in the United States contain a carboxylic acid moiety in the 3-position of the basic ring structure (the 4-quinolones). The 4- quinolones inhibit DNA synthesis through their specific action on DNA gyrases, which are composed of two A and two B subunits. DNA subunits A (gyrase A gene) have a strand-cutting function to prevent overwinding (supercoiling) of the DNA strands during separation and eventual replication of the mirror strand. The A subunits are the site of action for the 4-quinolones. Recently a second target, unique to the fluoro-quinolones, has been identified as topoisomerase type IV. This enzyme is responsible for separating the daugh-ter cells following replication.


The DNA gyrases and type IV topoisomerase both belong to the general class of DNA enzymes called topoisomerases. The effect of quinolones on these DNA enzymes is initially bacteriostatic but becomes bactericidal when bacteria are unable to repair the DNA lesions. These drug targets may be primary or secondary depending upon the organism; this observa-tion can affect the bacterial potential for the develop-ment of drug resistance; this may require the use of an-other drug with a different specificity and spectrum of activity.


The quinolones are now often classified into gener-ations, much like the cephalosporins. Each generation (first through fourth) has spectrum specificity and unique pharmacological properties, although there is considerable overlap: First, nalidixic acid and cinoxacin; second, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, and lomefloxacin; third. levofloxacin, sparfloxacin, gati-floxacin; and fourth, trovafloxacin and moxifloxacin. Several of the newer quinolones have been recently re-moved from the market as a result of QT prolongation and serious hematological and renal problems.


Antibacterial Spectrum and Resistance


The first-generation and oldest quinolones exhibit lim-ited gram-negative activity. Nalidixic acid and cinoxacin do not achieve systemic antibacterial levels and are thus restricted to therapy of bladder infections caused by urinary pathogens, such as E. coli and Klebsiella and Proteus spp. Although they are bactericidal agents, their use is restricted by resistance.


The second-generation drugs demonstrate their most reliable activity against gram-negative organisms, includ-ing Enterobacteriaceae. Haemophilus spp. and sexually transmitted disease (STD) agents, such as Neisseria gon-orrhoeae, Chlamydia trachomatis, Ureaplasma ure-alyticum, and Moraxella catarrhalis (formerly Neisseria catarrhalis; causes otitis media) are also susceptible. The antipseudomonal activity of ciprofloxacin, norfloxacin, ofloxacin, and lomefloxacin is due to their piperazine moiety; resistance to these agents, however, is becoming more prevalent.


Significantly greater activity against gram-positive organisms, such as S. pneumoniae, is demonstrated by the third and fourth generations. Methicillin-resistant Staphylococcus aureus and Enterococcus faecium are resistant. The fourth-generation quinolones also possess activity against anaerobes.


With the exception of the first generation, the quinolones are active against a variety of pathogens asso-ciated with respiratory tract infections, such as Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneu-mophila, and Mycobacterial spp., although these drugs are not FDA-approved for the latter. Recently, ciprofloxacin has gained popular attention in providing coverage for Bacillus anthracis, a major bioterrorism agent.


Resistance is related to mutations in the DNA gy-rase, with the gyrase gene A (gyrA) being the predomi-nant site. The primary mutation sites affected by organ-isms are topoisomerase IV and gyrA. Mutations at these points influence the degree of resistance, with lower levels of resistance associated with topoisomerase IV and higher levels with gyrA. Alterations in porins (gram-negative bacteria) that result in a decreased up-take of the drug and the appearance of an active efflux system for transport of the drug out of the cell also con-tribute to resistance. Resistance is chromosomally mediated; plasmid-associated resistance has not been reported. Killing by quinolones is concentration de-pendent, while that for the β-lactams is time dependent; thus the quinolones demonstrate a long postantibiotic effect. Cross-resistance between the quinolones can occur, particularly if resistance is strong. Moxifloxacin appears less susceptible to the appearance of cross-resistance.



Absorption, Metabolism, and Excretion


The quinolones are rapidly and almost completely ab-sorbed after oral administration and are widely distrib-uted in body tissues. Levels in extravascular spaces can often exceed serum levels. Levels lower than those found in serum occur in CSF, bone, and prostatic fluids. Ciprofloxacin and ofloxacin have been detected in breast milk and ofloxacin levels in ascites fluid are close to serum levels. Food ingestion does not affect bioavail-ability, which ranges from 50 to 95%. The half-life for most quinolones is 3 to 4 hours.


Elimination of the fluoroquinolones is through glomerular filtration and tubular secretion. In patients with moderate to severe renal insufficiency, quinolone dosages should be modified. The fluoroquinolones are also metabolized by hepatic conjugation and glu-curonidation. Caution should be observed with admin-istration of trovafloxacin because of its potential to in-duce hepatic toxicity. Dosage, peak serum levels, percent protein binding, urine concentrations, and de-gree of metabolism differ to varying degrees among the quinolones.

Clinical Uses


Therapeutic uses of the quinolones include urinary and respiratory tract infections, GI and abdominal infec-tions, 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 re-sponding to TMP-SMX.


The fluoroquinolones have a variety of indications in the treatment of respiratory infections, although they may not be the drugs of choice; these infections in-clude acute and chronic bacterial sinusitis. A second-generation cephalosporin, such as cefuroxime, is usually the drug of choice in acute sinusitis associated with M. catarrhalis, H. influenzae, and S. pneumoniae. The sec-ond-generation quinolones usually have poor activity in treating community-acquired pneumonia (CAP) be-cause of their poor activity against S. pneumoniae. The third- and fourth-generation fluoroquinolones are sig-nificantly more effective in treating CAP because of their activity against S. pneumoniae. The fluoro-quinolones are also indicated for nosocomial pneumo-nia, chronic bronchitis (acute exacerbations), and chronic otitis media.


The fluoroquinolones have indications for a variety of GI infections, including traveler’s diarrhea due to E. coli, shigellosis, and typhoid fever. In the AIDS patient these drugs are effective in treating bacteremias and eradicating the carrier state due to nontyphoidal organ-isms. Importantly, the fluoroquinolones are contraindi-cated in the treatment of enterohemorrhagic E. coli be-cause they can induce the cytotoxic Shiga-like toxin.


Primary cervicitis, urethritis, and extended infec-tions, such as pelvic inflammatory disease due to the STD agents N. gonorrhoeae and C. trachomatis, are suc-cessfully treated with fluoroquinolones. Both cipro-floxacin and ofloxacin appear to be more effective than other fluoroquinolones, although resistance has been reported to be emerging. Because coinfections in pa-tients treated with ciprofloxacin and ofloxacin are fre-quent, especially in women ( 50%), caution should be observed in using these agents if resistance becomes predominant in either infecting organism. Ciprofloxacin and ofloxacin are ineffective against Treponema pal-lidum but are active against the less common Haemo-philus ducreyi.


The use of fluoroquinolones in bone and joint infec-tions is influenced by the causative agent and the rate of resistance development. The use of the oral route for administration of the fluoroquinolones is especially ad- vantageous in treating chronic infections that often re-quire long-term therapy.


Adverse Effects and Drug Interactions


In general, the quinolones and fluoroquinolones are well tolerated. The most frequently reported side ef-fects are associated with the GI tract (2–13%); these include nausea, vomiting, diarrhea, and abdominal pain. CNS effects (1–8%), such as drowsiness, weak-ness, headache, dizziness, and in severe cases, convul-sions and toxic psychosis, have been reported. Some side effects, such as photosensitivity, correlate with spe-cific chemical structures, including the halogen substi-tution on the eighth position, as found in sparfloxacin and lomefloxacin. Adverse cardiovascular effects (6–7%; vascular embolism, cardiac insufficiency, hy-potension) also occur with sparfloxacin. Sparfloxacin, moxifloxacin, and gatifloxacin can exacerbate QT pro-longations. Fulminant hepatotoxicity associated with trovafloxacin has resulted in acute liver failure, and the FDA has recommended limiting therapy to life-threat-ening infections.


The use of the quinolones in pregnant or breast-feeding women and children whose epiphysial plates have not closed is generally contraindicated. Their use for treating young cystic fibrosis children infected with Pseudomonas spp. is an exception; the patient should be monitored carefully for untoward effects.


All quinolones interact with multivalent cations, forming chelation complexes resulting in reduced ab-sorption. Major offenders are antacids; vitamins con-taining calcium and iron can also be problematic. All fluoroquinolones interact with warfarin, didanosine (ddi), and phenytoin, resulting in decreased absorption or metabolism. Ciprofloxacin and other second-genera-tion drugs interact with theophylline by decreasing its clearance, which leads to theophylline toxicity.


Allergic reactions (e.g., rashes, urticaria, and eosino-philia) have been observed. These drugs have occasion-ally been associated with cholestatic jaundice, blood dyscrasias, hemolytic anemia, hypoglycemia, and nephrotoxicity. Recently the use of ciprofloxacin for prophylaxis protection against anthrax infection has been associated with damage to muscle ligaments.


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Modern Pharmacology with Clinical Applications: Synthetic Organic Antimicrobials: Sulfonamides, Trimethoprim, Nitrofurans, Quinolones, Methenamine : Quinolones: Nalidixic Acid and Fluoroquinolones |

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