title: Pharmacodynamics of Finafloxacin, Ciprofloxacin, and Levofloxacin in Serum and Urine against TEM- and SHV-Type Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae Isolates from Patients with Urinary Tract Infections.
abstract: The pharmacodynamics of finafloxacin, ciprofloxacin, and levofloxacin against extended-spectrum-β-lactamase (ESBL)-producingEnterobacteriaceaeisolates were compared. Since quinolones lose activity in acidic media, and particularly in urine, their activities were tested in parallel under conventional conditions and in acidic artificial urine. For this purpose, TEM- and SHV-type ESBL-producingEscherichia coliandKlebsiella pneumoniaestrains and their wild-type counterparts were exposed in a modified Grasso model to simulated concentrations of drugs in serum and urine following oral doses of either finafloxacin at 800 mg once a day (q.d.), immediate-release ciprofloxacin at 500 mg twice a day (b.i.d.), extended-release ciprofloxacin at 1,000 mg q.d., or levofloxacin at 500 or 750 mg q.d. The concentrations of the drugs in urine were fitted by compartmental modeling. Bacteria were cultivated in Mueller-Hinton broth (MHB) at pH 7.2 or 5.8 or in artificial urine at pH 5.8. Bacteria were counted every 2 h until 10 h and at 24 h; the areas under the bacterial-count-versus-time curves were calculated. It was found that finafloxacin eliminated all strains within 2 h under all the conditions studied. At all doses studied, ciprofloxacin and levofloxacin were highly active against wild-type strains in MHB at pH 7.2 but lost activity in MHB, and particularly in urine, at pH 5.8. Viable counts of ESBL producers were reduced for 6 to 8 h by 3 log10titers, but the bacteria regrew thereafter. Ciprofloxacin and levofloxacin were almost inactive against the SHV producer grown in artificial urine. We conclude that pharmacodynamic models using artificial urine may mirror the physiology of urinary tract infections more closely than those using conventional media. In contrast to ciprofloxacin and levofloxacin, finafloxacin gained activity in this model at an acidic pH, maintained activity in artificial urine, and was active against TEM and SHV producers.
authors.affiliation: University Hospital Kiel, Institute for Infection Medicine, Kiel, Germany adalhoff@t-online.de.
authors.forename: A
authors.initials: A
authors.lastname: Dalhoff
authors.affiliation: University Hospital Kiel, Institute for Infection Medicine, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schubert
authors.affiliation: MerLion Pharmaceuticals, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Vente
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001769:Blood / Q000382:microbiology; D002939:Ciprofloxacin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004926:Escherichia coli / Q000187:drug effects* / Q000302:isolation & purification; D024841:Fluoroquinolones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000302:isolation & purification; D064704:Levofloxacin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D014556:Urine / Q000382:microbiology; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D002939:Ciprofloxacin; D064704:Levofloxacin; C560572:finafloxacin; D001618:beta-Lactamases
keywords: ESBL; finafloxacin; fluoroquinolones; pharmacodynamics; urine