Penetration of sparfloxacin and ciprofloxacin into alveolar macrophages, epithelial lining fluid, and polymorphonuclear leucocytes

Abstract

Sparfloxacin (SPX), a novel fluoroquinolone with a broad spectrum of antibacterial activity, has been shown, in vitro, to be more effective against common pulmonary pathogens, particularly Streptococcus pneumoniae, Mycoplasma pneumoniae and some intracellular organisms, than ciprofloxacin (CPX).The objective of this open, comparative, randomized study in two parallel groups was to assess the serum concentrations and penetration of SPX and CPX into alveolar macrophages (AMs), epithelial lining fluid (ELF), and peripheral polymorphonuclear leucocytes (PMNs). Patients received either a single oral dose of SPX, 400 mg (16 patients), or CPX, 500 mg (15 patients), at various times before a routine diagnostic bronchoscopy was performed. Antibiotic concentrations were determined by using a microbiological assay.The median serum elimination half-lives were 17.3 h for SPX and 5.3 h for CPX. Peak levels (median±68% confidence range) of CPX were attained in AMs (7.6±1.7 mg·L -1 ) at 5 h after admission, and in both ELF (2.13±0.91 mg·L -1 ) and PMNs (9.1±6.2 mg·L -1 ) at 2.5 h after administration. SPX achieved comparable peak levels in PMNs (median±68% range, 9.4±1.1 mg·L -1 at 5 h), but peak concentrations attained in AMs and ELF (35.1±15.4 and 32.2±28.2 mg·L -1 , respectively, at 24 h) were several times higher than those of CPX. SPX demonstrated substantially greater accumulation in all three sites than did CPX (peak site to serum ratios of 11.0±4.3, 65.5±28.4 and 63.0±66 versus 4.94±0.64, 10.6±3.7 and 10.6±3.7 for PMNs, AMs and ELF, respectively).The results indicate, that sparfloxacin has a long elimination half-life and that it achieves higher concentrations in alveolar macrophages and epithelial lining fluid than ciprofloxacin. Site concentrations of sparfloxacin greatly exceeded the minimal inhibitory concentrations of common respiratory pathogens.

Intrapulmonary Distribution and Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Inhaled Administration of Its Prodrug, Laninamivir Octanoate, in Healthy Volunteers

“…The calculated values of AUC last for LO and laninamivir in AM were 77 to 364 times higher than those for the drugs in ELF (Table 2). High-level accumulation in AM was also observed in several human BAL studies after the oral administration of antibiotics (3,5,8,18,22). The uptake mechanism of clarithromycin and azithromycin to AM was explored using cultured AM cells (NR8383 cells), and it was found that the uptake was partly reduced by ATP depletors (21).…”

“…Drug concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from BAL fluid have been evaluated in healthy volunteers (1,5,8,18) as well as lung transplant recipients (3,22) and critically ill patients (9) to consider the efficacy of drugs against respiratory pathogens and the appropriate dosage regimens for antiinfective drugs. Among the neuraminidase inhibitors, the concentration of zanamivir in ELF after intravenous (i.v.)…”

Sparfloxacin in the treatment of drug resistant tuberculosis or intolerance of first line therapy

“…Sunlight exposure is much easier to control when patients are hospitalized. No phototoxic reactions were observed in volunteer studies with spar¯oxacin [17,21,22], or in the pneumonia studies [19,20]. In these studies, the compliance of volunteers and patients was excellent in contrast to TB patients.…”

“…The elimination half-life (t1/2) is approximately 15±20 h which allows once daily administration. Spar¯oxacin diffuses well into tissues and respiratory tract secretion and concentrates within macrophages, where mycobacteria survive and multiply [12,17].…”

Active Uptake of Ulifloxacin from Plasma to Lung That Controls Its Concentration in Epithelial Lining Fluid

“…We also aimed to elucidate the feature of ulifloxacin uptake in rat lung and human lung adenocarcinoma cells (Calu-3). Sparfloxacin 16) and levofloxacin 17) are the quinolones with high and low penetration into the ELF, respectively. Azithromycin is a macrolide which highly penetrates into the ELF.…”