Activities of Ciprofloxacin and Moxifloxacin against Stenotrophomonas maltophilia and Emergence of Resistant Mutants in an In Vitro Pharmacokinetic-Pharmacodynamic Model

Abstract

A two-compartment in vitro pharmacokinetic-pharmacodynamic model, with full computer-controlled devices, was used to accurately simulate human plasma pharmacokinetic profiles after multidose oral regimens of ciprofloxacin (750 mg every 12 h) and moxifloxacin (400 mg every 24 h) during 48 h. Pharmacodynamics of these drugs was investigated against three quinolone-susceptible strains of Stenotrophomonas maltophilia (MICs of ciprofloxacin and moxifloxacin of 0.5 to 2 and 0.0625 to 0.5 g/ml, respectively). The first dose of ciprofloxacin and moxifloxacin reduced the bacterial count by 1 and 2 log CFU/ml, respectively, prior to a bacterial regrowth that reached the plateau value of the growth control curve at 13 to 24 h versus 24 to 36 h and persisted despite repeated administration of both drugs. The surviving bacterial cells were quinoloneresistant mutants (2 to 128 times the MIC) that exhibited cross-resistance to unrelated antibiotics. Their antibiotic resistance probably resulted from the overproduction of different multidrug resistance efflux system(s). C max /MIC and area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC values were at least threefold higher for moxifloxacin than for ciprofloxacin. Moreover, integral parameters of ciprofloxacin and moxifloxacin, in particular the area under the killing and regrowth curve from 0 to 48 h (AUBC 0-48 , 342.3 to 401.3 versus 295.2 to 378.7 h ؋ log CFU/ml, respectively) and the area between the control growth curve and the killing and regrowth curve from 0 to 48 h (ABBC 0-48 , 40.4 to 101.1 versus 72.9 to 144.7 h ؋ log CFU/ml, respectively), demonstrated a better antibacterial effect of moxifloxacin than ciprofloxacin on S. maltophilia. However, selection of resistant mutants by both fluoroquinolones, although delayed with moxifloxacin, emphasizes the need to use maximal dosages and combined therapy in the treatment of systemic S. maltophilia infections.

Can Levofloxacin Be a Useful Alternative to Trimethoprim-Sulfamethoxazole for Treating Stenotrophomonas maltophilia Bacteremia?

“…However, in the use of levofloxacin for treating S. maltophilia infection, induction of resistance is a matter of concern. Rapid emergence of resistance against quinolones has been observed in vitro and in vivo (13,14). This finding was observed in our study.…”

Stenotrophomonas maltophilia in the respiratory tract of medical intensive care unit patients

“…Variable susceptibility rates have been reported for the quinolone ciprofloxacin [5]. In vitro studies revealed promising results regarding susceptibility of S. maltophilia to moxifloxacin [4,5,9,10].…”

Stenotrophomonas maltophilia: an Emerging Global Opportunistic Pathogen

“…An in vitro pharmacokinetic-pharmacodynamic model used to assess the activity of ciprofloxacin and moxifloxacin against S. maltophilia suggested that maximum tolerable doses are needed to overcome resistant bacterial populations (20). The use of these antibiotics at concentrations greater than the MIC is needed for the treatment of systemic S. maltophilia infections.…”

“…Moxifloxacin shows some promise for the treatment of MDR S. maltophilia infections (20,89,178,267). An in vitro pharmacokinetic-pharmacodynamic model used to assess the activity of ciprofloxacin and moxifloxacin against S. maltophilia suggested that maximum tolerable doses are needed to overcome resistant bacterial populations (20).…”