Significance of low-level resistance to ciprofloxacin in Klebsiella pneumoniae and the effect of increased dosage of ciprofloxacin in vivo using the rat granuloma pouch model

This study was designed to compare the killing effect of ciprofloxacin on strains of Klebsiella pneumoniae with different MICs of ciprofloxacin in vivo using the rat granuloma pouch infection model. Five different strains were used: one ciprofloxacin-susceptible strain (MIC 0.06 mg/L); one strain highly resistant to ciprofloxacin (MIC 8 mg/L); and three nalidixic acid-resistant strains with low-level resistance to ciprofloxacin (MIC 0.25-0.5 mg/L). The efficacy of ciprofloxacin was evaluated 3 h after bacterial challenge (treating an acute infection) or after 3 days (treating a late infection) with a single intraperitoneal injection of ciprofloxacin (40 and 200 mg/kg). Ciprofloxacin was bactericidal against both growing K. pneumoniae (acute infection model) and non-growing K. pneumoniae (late infection model), but the extent of killing was significantly higher on growing bacteria and against ciprofloxacin-susceptible K. pneumoniae. A peak concentration of ciprofloxacin, at the infection site, <3 x MIC was not sufficient for optimal bacterial elimination. However, it was possible to compensate for the lower killing in low-level ciprofloxacin-resistant K. pneumoniae by increasing the dosage of ciprofloxacin from 40 to 200 mg/kg, consistent with the higher MIC.