Antibacterial Spectrum and Resistance

The first-generation and oldest quinolones exhibit limited 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, including 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 associated with respiratory tract infections, such as Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneu-mophila, and Mycobacterialspp., 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 predominant site. The primary mutation sites affected by organisms 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 uptake of the drug and the appearance of an active efflux system for transport of the drug out of the cell also contribute to resistance. Resistance is chromosomally mediated; plasmid-associated resistance has not been reported. Killing by quinolones is concentration dependent, while that for the (3-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.

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