Disease relevance of CI-960

• Activity of clinafloxacin against multidrug-resistant Enterococcus faecium [1].
• Only WCK 771 and clinafloxacin demonstrated strong potencies against vancomycin-intermediate Staphylococcus aureus strains (MICs = 1 microg/ml) [2].
• CI-960, a new fluoroquinolone, for therapy of experimental ciprofloxacin-susceptible and -resistant Staphylococcus aureus endocarditis [3].
• We examined the response of Streptococcus pneumoniae 7785 to clinafloxacin, a novel C-8-substituted fluoroquinolone which is being developed as an antipneumococcal agent [4].
• Antimicrobial activities of two investigational fluoroquinolones (CI-960 and E4695) against over 100 Legionella sp. isolates [5].

High impact information on CI-960

• Results of a clinical trial of clinafloxacin versus imipenem/cilastatin for intraabdominal infections [6].
• Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus isolates were exposed to subinhibitory MICs of ciprofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, clinafloxacin, and gemifloxacin during a 10-day period [7].
• Pharmacokinetics of clinafloxacin after single and multiple doses [8].
• Drug-associated adverse events (P = 0.050) and treatment discontinuations (P = 0.052) were marginally more frequent in the clinafloxacin group, primarily due to phototoxicity in outpatients receiving clinafloxacin [9].
• Drug interactions with clinafloxacin [10].

Chemical compound and disease context of CI-960

• ABT-719 was more active than ciprofloxacin, sparfloxacin, and clinafloxacin against gram-positive bacteria [11].
• Sparfloxacin and clinafloxacin were evaluated against Enterococcus faecium SF2149 and Enterococcus faecalis WH245, respectively [12].
• Comparative activities of ciprofloxacin, clinafloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and trovafloxacin against epidemiologically defined Acinetobacter baumannii strains [13].
• Activities of three investigational fluoroquinolones (BAY y 3118, DU-6859a, and clinafloxacin) against Neisseria gonorrhoeae isolates with diminished susceptibilities to ciprofloxacin and ofloxacin [14].
• We describe the PAE of the quinolones CI-960, enoxacin, and ciprofloxacin on macromolecular biosynthesis in the clinical isolate Escherichia coli J96 in an attempt to relate the PAE to the time that it actually takes for the cells to recover fully [15].

Biological context of CI-960

• Absolute bioavailability of orally administered clinafloxacin was approximately 90% and did not change with increasing dose [8].
• High-level resistance to all of the compounds except clinafloxacin was associated with two or more amino acid substitutions involving both GyrA (Ser-81 to Phe) and ParC (Ser-79 to Phe or Ser-80 to Pro and Asp-83 to Tyr) [16].
• Further morphological studies during the PAE showed that the first division of the filamentous cell was asymmetrical, and both bacterial cell division and septation were delayed after exposure to 0.5 MIC of CI-960 [17].

Anatomical context of CI-960

• We evaluated the effects of the quinolone CI-960 (Parke-Davis) on primary or repeated chlamydial infection in the monkey salpinx pocket model [18].
• No modification of the MIC was observed after 20 successive infections of HeLa cells and contact with subinhibitory concentrations of clinafloxacin, levofloxacin, and sparfloxacin for 24 h [19].
• The concentrations of clinafloxacin in alveolar macrophages, epithelial lining fluid, bronchial mucosa and serum after administration of single 200 mg oral doses to patients undergoing fibre-optic bronchoscopy [20].
• After three days of therapy, significant reduction of bacterial concentrations were found in vegetations, kidneys, and spleens of animals treated with clinafloxacin [21].
• Altering the medium pH, adding divalent cations (magnesium), and increasing the inoculum concentration to 10(6) colony-forming units per spot adversely effected the activity of both PD127391 and PD131628 [22].

Associations of CI-960 with other chemical compounds

• The sparfloxacin and ciprofloxacin MICs for the parC-gyrA mutants were 16 to 32 and 32 to 64 microg/ml, respectively, but the clinafloxacin MIC was 1 microg/ml, i.e., within clinafloxacin levels achievable in human serum [4].
• The susceptibilities of all isolates to clinafloxacin, grepafloxacin, levofloxacin, sparfloxacin, and trovafloxacin were examined by the National Committee for Clinical Laboratory Standards reference broth microdilution and disk diffusion susceptibility testing methods [16].
• Overall, E-5068 was the most active in vitro (MIC for 90% of isolates tested [MIC90], 0.25 microgram/ml); this was followed by clinafloxacin and BAY Y 3118 (MIC90, 0.5 microgram/ml) [23].
• Clinafloxacin (CI-960) is a potent broad-spectrum, fluoroquinolone antibiotic that has been studied for parenteral and oral administration in patients with serious infections [8].
• Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration [10].

Gene context of CI-960

• Given the susceptibility of defined gyrA or parC mutants, the results suggested that clinafloxacin displays comparable if unequal targeting of gyrase and topoisomerase IV [4].
• Clinafloxacin was highly active against S. pneumoniae 7785 (MIC, 0.125 microg/ml), and neither gyrA nor parC quinolone resistance mutations alone had much effect on this activity [4].
• The MIC of clinafloxacin for strains with no mutation in either gyrA or parC genes ranged from 0.008 to 0.25 mg/L [24].
• A combination of both mutations was needed to register resistance, suggesting that both gyrase and topoisomerase IV are clinafloxacin targets in vivo [4].
• Overall, the NFQs and clinafloxacin were less susceptible than the other quinolones to existing mechanisms of quinolone resistance in staphylococci [25].

Analytical, diagnostic and therapeutic context of CI-960

• Total apparent body clearance of clinafloxacin from the plasma after oral administration (CL(oral)) and CL(R) were dependent on CL(CR) according to the following relationships: CL(oral) = 2 [26].
• Hemodialysis had no significant effect on clinafloxacin clearance [26].
• After CI-960 therapy, C. trachomatis organisms were no longer recoverable by cell culture [18].
• Following 50 mg/kg oral doses, twice daily for five consecutive days, clinafloxacin produced a 4 log decrease in mean bacterial count, the greatest decrease of all drugs tested [27].
• A deep-seated Pseudomonas aeruginosa mouse kidney abscess model was used to compare the therapeutic efficacy of clinafloxacin, a fluoroquinolone in clinical trials, with that of clinically relevant standard drugs [27].

References