Comparative in-vitro activity of new quinolones against clinical isolates and resistant mutants

Rohner, Peter; Peebo, M.; Lew, Daniel Pablo; Auckenthaler, Raymond; Péchère, Jean-Claude

doi:10.1093/jac/29.1.41

Cited by 14 publications

(5 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On day 1, all patients had Cmins greater than 1 mg/ml, and more than half of them had Cmins greater than 2 mg/ml. These values are greater than the MICs for 90% of the most common pathogens that are susceptible to fleroxacin (37).…”

Section: Antimicrob Agents Chemothermentioning

confidence: 74%

“…It is eliminated primarily by renal clearance, with about 60 to 70% of a dose being recovered unchanged in the urine within 96 h (53-55). These pharmacokinetic properties associated with a wide antibacterial spectrum (5,7,24,35,37,55,56) and a high degree of penetration into body fluids and tissues (12,26,27,36,44,52) allow a once-a-day oral administration. The pharmacokinetic parameters of fleroxacin in healthy young volunteers are well known (33,44,53,54).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Single-dose pharmacokinetics of oral fleroxacin in bacteremic patients

Schrenzel

Cerruti

Herrmann

et al. 1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Fleroxacin is a new broad-spectrum quinolone which can be given by the oral route. The present study was designed to assess the influence of bacteremia on the pharmacokinetics of a single oral dose of fleroxacin. Thirteen patients with proven bacteremia (one or more pairs of positive blood cultures, no hypotension) were given a single 400-mg fleroxacin dose orally on two occasions while also receiving standard antibiotic therapy.The first dose was administered 12 to 36 h after the last positive blood culture was drawn (day 1), and a second dose was administered 7 days later (day 7 + 2) to compare the pharmacokinetics between the acute and the convalescent phases of the disease. Following each administration of fleroxacin, serial plasma samples were collected for up to 72 h and were analyzed for unchanged drug by a reversed phase high-pressure liquid chromatography technique. There were no significant changes in the following pharmacokinetic parameters (mean standard deviation) the maximum concentration of drug in serum (6.4 ± 1.5 versus 6.7 + 1.9 mg/liter), the minimum concentration of drug in serum, defined as the concentration of drug in serum at 24 h postdose (3.0 ± 1.7 versus 2.5 ± 1.2 mg/liter), the time to the maximum concentration of drug in serum (2.3 + 1.4 versus 2.0 ± 1.2 h), and the elimination half-life (19.7 ± 8.0 versus 17.9 ± 6.9 h). Fleroxacin clearances were compared for each individual patient. A positive correlation (R2 = 0.787) was found between the values measured on day 1 and day 7. Oral clearance of fleroxacin (CL = CL/F, where F is bioavailability) was slightly, but not significantly, reduced during the bacteremic phase (oral clearance, 43.8 + 23.5 versus 48.5 + 17.5 ml/min).When compared with previous results obtained in healthy young subjects, longer times to the maximum concentration of drug in serum and elimination half-lives and higher areas under the curve were observed. This could be due to the bacteremic state, the old age of the patients (mean, 66 years), and the low renal clearance (mean calculated creatinine clearance, 71.1 ml/min). A single oral dose of 400 mg of fleroxacin provides sufficient levels in serum to cover susceptible microorganisms for at least 24 h in bacteremic patients. Renal function appeared to be the key element that had to be taken into consideration to adapt fleroxacin dosage profiles in our patient population. Bacteremia itself appeared to amplify that phenomenon, but to a much lesser extent than renal function did.Fleroxacin is a new trifluorinated quinolone that differs from most other quinolones by its excellent bioavailability (reaching almost 100%) and a longer terminal half-life (t112,; 10 h) following oral administration (53, 54). It is eliminated primarily by renal clearance, with about 60 to 70% of a dose being recovered unchanged in the urine within 96 h (53-55). These pharmacokinetic properties associated with a wide antibacterial spectrum (5,7,24,35,37,55,56) and a high degree of penetration into body fluids and tissues (12,26,27,36,44,52) all...

show abstract

Section: Antimicrob Agents Chemothermentioning

confidence: 74%

mentioning

confidence: 99%

Single-dose pharmacokinetics of oral fleroxacin in bacteremic patients

Schrenzel

Cerruti

Herrmann

et al. 1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…There is controversy about the possible pharmacokinetic interactions between quinolones and rifampin, since ri- half-life and its levels may be maintained continuously above the MIC for methicillin-susceptible staphylococcal strains (1 jig/ml) (37) during therapy with a single 400-mg daily dose. It was therefore necessary to assess whether coadministration of rifampin would alter the hepatic clearance of fleroxacin and thus its pharmacokinetic properties.…”

Section: Discussionmentioning

confidence: 99%

Influence of rifampin on fleroxacin pharmacokinetics

Schrenzel

Dayer

Leemann

et al. 1993

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Staphylococcus aureus infections have been successfully treated in animal models with the combination of fleroxacin and rifampin. We studied the influence of rifampin, a potent cytochrome P-450 inducer, on the pharmacokinetics and biotransformation of fleroxacin in 14 healthy young male volunteers. Subjects were given 400 mg of fleroxacin orally once a day for 3 days to reach steady state. After a wash-out period of 2 days, the same subjects received 600 mg of rifampin orally once daily for 7 days. On days 5 to 7 of rifampin treatment, 400 mg of fleroxacin was again administered once daily. Concentrations of fleroxacin as well as its two major urinary metabolites, N-demethyl-and N-oxide-fleroxacin, in plasma and urine were determined by reverse-phase high-performance liquid chromatography. The extent of hepatic enzyme induction by rifampin was confirmed by a significant increase of 6-13-hydroxycortisol urinary output from 160.8 ± 41.4 to 544.8 ± 120.7 ,ug/4 h. There were no significant changes in the peak fleroxacin concentration in plasma (6.3 ± 1.2 versus 6.2 ± 1.9 mg/liter), time to maximum concentration of fleroxacin in plasma (1.1 ± 0.9 versus 1.3 ± 1.1 h), or renal clearance (58.3 ± 16.4 versus 61.9 ± 19.2 mVmin). The area under the curve AUC (71.4 ± 15.8 versus 62.2 ± 13.7 mg. h/liter) and the terminal half-life of fleroxacin (11.4 ± 2.2 versus 9.2 + 1.1 h) decreased (P < 0.05), while the total plasma clearance increased from 97.7 ± 21.6 to 112.3 ± 25.8 ml/min (P < 0.01).Despite being statistically significant, this 15% increase in total plasma clearance does not appear to be clinically relevant. Metabolic clearance by N demethylation was increased (6.9 ± 2.4 versus 12.5 ± 3.2 ml/min; P < 0.01), whereas clearance by N oxidation did not change (5.8 ± 1.1 versus 5.8 ± 1.5 ml/min). Fleroxacin elimination was slightly increased (about 15%) through induction of metabolic clearance to N-demethylfleroxacin. Since fleroxacin levels remained above the MIC for 90%o of the tested isolates of methicillinsusceptible S. aureus for at least 24 h, dose adjustment does not appear necessary, at least for short-term treatments.Fluoroquinolones, including fleroxacin, have recently emerged as interesting antibacterial agents in the therapy of deep-seated infections. This is in part attributable to their antibacterial spectra, the extent of their oral absorption, and their high rate of penetration into biological fluids and tissues (45).Rifampin has long been used as an adjunctive treatment of staphylococcal infections because of its antibacterial effects on staphylococci and its extensive distribution into tissues. However, rifampin monotherapy almost invariably leads to failure due to development of resistance. The combined use of both families of antibacterial agents, fluoroquinolones and rifampin, has been advocated for the treatment of serious staphylococcal infections to avoid the emergence of resistant bacteria, especially in long-term treatments (3, 14-16, 22, 23, 25, 26, 28, 35, 38, 44, 48).The combination of fleroxa...

show abstract

“…The latter hypothesis was proofed by knocking out a specific porin ompF, which results in a low concentration of the anti-infective agent in the bacterial cell [10]. Fleroxacin belongs to the fluoroquinolones who seems to penetrate via the porin transport protein ompF [11].…”

Section: Introductionmentioning

confidence: 99%