Influence of rifampin on fleroxacin pharmacokinetics

Abstract

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...

A Randomized Clinical Trial to Compare Fleroxacin-Rifampicin with Flucloxacillin or Vancomycin for the Treatment of Staphylococcal Infection

“…The pharmacokinetics of oral fleroxacin is particularly well understood, with regard both to the bioavailability in bacteremic subjects (reaching almost 100%) and the interaction with rifampicin in healthy volunteers [8,9]. In addition, its long half-life (10 h) allows once-daily oral administration [10].…”

Quinolones

“…In addition, rifampin coadministration significantly enhanced fleroxacin apparent oral clearance (mean 15%) and reduced t½ (mean 19%) by significantly enhancing metabolic clearance by N-demethylation (no effect on N-oxidation) [256]. Examining the rifampin component of the combination, single-dose ciprofloxacin coadministration significantly increased t½ and reduced the C max but had no effect on the AUC, volume of distribution, or urinary excretion of single-dose rifampin [257,258].…”