Pharmacodynamics of Moxifloxacin and Levofloxacin Simulating Human Serum and Lung Concentrations*

Abstract

Fluoroquinolones are known to penetrate well into the infectious foci such as lung mucosa, epithelial lining fluid and alveolar macrophages achieving higher target site concentrations than the corresponding serum levels. In order to integrate the in vitro antibacterial activity and pharmacokinetics of moxifloxacin and levofloxacin, their bactericidal efficacy was assessed by simulating human serum and lung tissue concentrations using Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae as indicator organisms. The bacteria were exposed to fluctuating moxifloxacin and levofloxacin concentrations simulating the drug levels in serum, lung mucosa, epithelial lining fluid and alveolar macrophages. The following parameters were deduced from the kill curves: area under the bactericidal kill curve normalized to the initial inoculum (AUBKC norm), the time needed to reduce the inoculum by 3 log(10) titers, and the initial bactericidal activity. In general, all these three parameters were for all the bacterial isolates having been exposed to moxifloxacin concentration dependent. In contrast, beyond a levofloxacin concentration of optimal bactericidal effect, higher drug concentrations did not further augment the bactericidal activity of levofloxacin. These data demonstrate that not all fluoroquinolones share the same pharmacodynamic targets needed to maximize their antibacterial effect.

Dichotomous selection of high-level oxacillin resistance in Staphylococcus aureus by fluoroquinolones

“…Drug concentrations were monitored in the absence and presence of bacteria. Actual drug concentrations achieved in this model were on average within 4.2% of the desired profile, which is in agreement with previous studies [28]. Interday and intraday reproducibility ranged from 92.4% to 98.5% as qualified calibrated flasks were used.…”

Kinetics and Quantification of Antibacterial Effects of Beta-Lactams, Macrolides, and Quinolones against Gram-Positive and Gram-Negative RTI Pathogens

“…Likewise, in an in vitro pharmacodynamic model comparing the activities of moxifloxacin monotherapy with those of a combination/regimen of levofloxacin plus metronidazole in a mixed infection model of E. coli and Bacteroides fragilis, it became obvious that the MICs were not predictive for activity in the pharmacodynamic in vitro model [38]. This lack of correlation between pharmacodynamic activity and in vitro susceptibility testing results is also discussed elsewhere in this issue [39].…”

“…Another option to replace the static endpoints by a parameter describing more adequately the dynamics of antibacterial action of a drug would be to quantify the effect of fluctuating drug concentrations simulating drug levels in serum or at the target site on the bacterial population by calculating the area under the bacterial kill curve (AUBKC) [10,[39][40][41] or by calculating the killconstants.…”

Moxifloxacin: update and perspectives after 8 years of usage

“…These three parameters were concentration dependent for moxifloxacin for all bacterial isolates. By contrast, a levofloxacin concentration greater than that required for the optimal bactericidal effect was not accompanied by an increase in the bactericidal activity of levofloxacin [24].…”

“…TABLE 1 summarizes the pharmacokinetic and pharmacodynamic data for currently available quinolones. The ranges of AUC 24 :MIC values in the literature vary from 11 to 22 for ciprofloxacin, 16 to 103 for levofloxacin (500 mg), 52 to 170 for gatifloxacin (400 mg) and 94 to 200 for moxifloxacin (400 mg) [20]. The relatively new concept of mutant prevention concentration (MPC) defines the antimicrobial concentration threshold above which the selective proliferation of resistant mutants is expected to occur only rarely [21].…”