Gaps and perspectives of new fluoroquinolones

• Published in: Drugs under experimental and clinical research Vol. 14; no. 6; p. 385
• Main Authors: Neuman, M, Esanu, A
• Format: Journal Article
• Language: English
• Published: Switzerland 1988
• Subjects: 4-Quinolones; Anti-Infective Agents - pharmacokinetics; Anti-Infective Agents - pharmacology; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Hydrogen-Ion Concentration; Microbial Sensitivity Tests; Structure-Activity Relationship
• ISSN: 0378-6501

The gaps in the present piperazinyl-substituted fluoroquinolones include: (a) gaps in their antibacterial spectrum, varying from one fluoroquinolone to another for streptococci-pneumococci-enterococci (SPE), some Gram-negative and Gram-positive anaerobes, Nocardia, Pseudomonas maltophilia, Ureaplasma urealyticum, slow-growing mycobacteria; (b) a pH dependence of their antibacterial activity (low activity at acidic pH for piperazinyl-substituted fluoroquinolones); (c) a rapid development of bacterial resistance for some bacteria (staphylococci, pseudomonas) in prolonged treatment of cystic fibrosis, intensive care units; (d) some gaps in the pharmacokinetic parameters such as incomplete oral bioavailability, short half-life, intensive biotransformation, unwanted interactions with other antibiotics or other drugs. The prospects for fluoroquinolones are trying to eliminate these gaps. The 7-piperazinyl or pyrrolidinyl, 1-cyclopropylfluoroquinolones have improved activity on SPE, anaerobes and pseudomonas-acinetobacter. Two categories can be distinguished: (i) with increased activity on SPE, but keeping also the activity on pseudomonas (A-62824, A-62254, A-65846, A-60969, AT-3295, AT-3765); (ii) with increased activity on SPE but with a loss of activity on pseudomonas (CI-934, PD-117558, S-25932). The pharmacokinetic parameters are modified by the N-methylation of the piperazine ring (bioavailability), modification of the hydrophilic or lipophilic character, conditioning half-life, metabolic biotransformation, diffusibility into the spinal fluid, crossing the blood-brain barrier, tubular reabsorption and neuropsychic adverse effects.