Quinolone tolerances

Patients allergic to /3-lactams should receive a quinolone. Persons unable to tolerate a /3-lactam (penicillin or cephalosporin) or a quinolone should receive spectinomycin. 

Further development in the chemistry of oxazolidinone antibacterials was based mainly on the assumption that the 4-pyridyl moiety of one of Dupont s lead compounds, E-3709, might be amenable to replacement by suitably saturated heterocyclic bioisosteres [48]. This assumption was based on an example in which successful replacement of the piperazine ring system in the quinolone antibacterials, such as ciprofloxacin, with a pyridine fragment, such as seen in Win-57273, results in improvement of both the antibacterial and the pharmacokinetic profiles of the compounds. Similarly, as in the case of ciprofloxacin and Win-57273, it was predicted that the presence of a small but highly electron-withdrawing fluorine atom would be tolerated at the meta position(s) of the central phenyl ring, and would confer enhanced antibacterial activity and/or other desirable properties to the targeted oxazolidinones, as shown in Fig. 3. 

Although ciprofloxacin for oral and intravenous administration already displayed a very high standard of antibacterial activity and tolerance, some properties still required optimization. These included the need for improved activity against Gram-positive pathogens (e.g., S. pneumoniae) and anaerobic bacteria, and kinetic properties allowing once-daily administration. The properties required by Bayer of the third-generation quinolones were therefore as follows. 

The 3-aminomethyl-l-pyrrolidinyl radical, which was considered to be bioiso-steric to piperazine [91], also produced highly active quinolones, which were however also found not to be tolerated. In trovafloxacin 16 [92], the 3-aminomethyl-l-pyrrolidinyl radical is integrated into a bicydic amine structural unit with a free amino group [(la,5a,6a)-6-amino-3-azabicyclo[3.1.0]hexane]. A correlation probably exists between the increased central nervous system (CNS) side effects obtained with this quinolone [93] and the 2,4-difluorophenyl radical in the 1-posi-tion. Severe hepatic intolerance reactions finally resulted in major restrictions on its use, which was then limited in the USA to severe clinical infections [68]. 

The introduction of the free primary amino group of amino- or aminomethyl-pyrrolidinyl quinolones into nonfused ring systems produced active compounds which were highly active but not tolerated [105-107] (Fig. 14.9). 

Examples of quinolones in which the 7-(3-amino-l-pyrrolidinyl) radical or the 7-(3-aminomethyl-l-pyrrolidinyl) radical is substituted by a ring fused via the 3,4-position are those listed in Fig. 14.11 (cf. also Ref. [109]) and Fig. 14.12 [109,110]. Despite their powerful in vitro and in vivo activities, most of the quinolones containing such amine structural units have problems of tolerance. 

Stass H, et al. Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects. Antimicrob. Agents Chemother., 1998, 42, 2060-2065. 

Patients allergic to 6-lactams should receive a quinolone. Persons unable to tolerate a 6-lactam (penicillin or cephalosporin) or a quinolone should receive spectinomycin. Also recommended for the treatment of uncomplicated infections of the pharynx in combination with a treatment regimen for presumptive C. trachomatis infection fluoroquinolones are not recommended for treating infections in MSM or infections acquired in Hawaii, California, or other parts of the world where high-level resistance to fluoroquinolones is reported. 

A 44-year-old woman, who had previously tolerated moxifloxacin, developed pmritus, urticaria, and angioedema 10 minutes after a dose of moxifloxacin [IV j. Skin tests were performed with various quinolones and only the intradermal test with moxifloxacin was positive. She tolerated an oral challenge with... 

Cacchi and co-workers reported the synthesis of 1,2-disubstituted 4-quinolones via copper-catalyzed cyelization of l-(2-halophenyl)-2-en-3-amin-l-ones in 2009. Here, the l-(2-bromophenyl)- and l-(2-chloro-phenyl)-2-en-3-amin-l-ones were prepared from allynones and primary amines. The reaction tolerates a variety of useful functionalities including ester, keto, cyano, and chloro substituents. Good to excellent of the desired products were formed (Scheme 3.64a). One year later, Xu and Zhao developed a palladium-catalyzed procedure that could directly use o-haloaryl acetylenic ketones and primary amines (Scheme 3.64b). ... 

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