Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus

Abstract

Antimicrobial efficacy in orthopedic device infections is diminished because of bacterial biofilms which express tolerance to antibiotics. Recently, the use of high doses of levofloxacin with rifampin has been recommended for staphylococcal infections. In the present study, we evaluated the efficacy of levofloxacin at doses of 50 mg/kg/day and 100 mg/kg/day (mimicking the usual and high human doses of 500 mg/day and 750 to 1,000 mg/day, respectively) and compared it to that of to linezolid, cloxacillin, vancomycin, and rifampin in a rat tissue cage model of experimental foreign-body infection by Staphylococcus aureus. The antimicrobial efficacy in vitro (by MIC, minimum bactericidal concentration, and kill curves) for logarithmic-and stationary-phase bacteria was compared with the in vivo efficacy. In vitro bactericidal activity at clinically relevant concentrations was reached by all drugs except rifampin and linezolid in the log-phase studies but only by levofloxacin in the stationary-phase studies. The bacterial count decreases from in vivo tissue cage fluids (means) for levofloxacin at 50 and 100 mg/kg/day, rifampin, cloxacillin, vancomycin, linezolid, and controls, respectively, were: ؊1.24, ؊2.26, ؊2.1, ؊1.56, ؊1.47, ؊1.15, and 0.33 (all groups versus controls, P < 0.05). Levofloxacin at 100 mg/kg/day (area under the concentration-time curve/MIC ratio, 234) was the most active therapy (P ‫؍‬ 0.03 versus linezolid). Overall, in vivo efficacy was better predicted by stationary-phase studies, in which it reached a high correlation coefficient even if the rifampin group was excluded (r ‫؍‬ 0.96; P < 0.05). Our results, including in vitro studies with nongrowing bacteria, pharmacodynamic parameters, and antimicrobial efficacy in experimental infection, provide good evidence to support the use of levofloxacin at high doses (750 to 1,000 mg/day), as recently recommended for treating patients with orthopedic prosthesis infections.Patients suffering from orthopedic device infections will have usually undergone surgical interventions and received antibiotic therapies over a long period of time, these being major clinical issues. It is very difficult to eradicate such infections using antibiotics because of the formation of biofilm, a protein matrix including bacteria with reduced metabolism and with tolerance to antimicrobials (2,9,11,38).These infections are frequently caused by Staphylococcus aureus, and rifampin has been shown to be the most effective antimicrobial agent in such cases, in in vitro and experimental studies (26, 48) and in clinical practice (14,15,46). Since this drug should not be given alone due to the development of early bacterial resistance, antibiotic combinations are required. The combination of rifampin and fluoroquinolones has been found to be particularly efficacious and is thus usually recommended (10,14,44).In recent years, the experimental foreign-body infection model developed by Lucet et al. (26) has provided relevant data regarding the antimicrobial efficacy of several antibiotics ...

Intracellular Activity of Antibiotics in a Model of Human THP-1 Macrophages Infected by a Staphylococcus aureus Small-Colony Variant Strain Isolated from a Cystic Fibrosis Patient: Study of Antibiotic Combinations

“…In spite of these uncertainties, and pending additional data gathered from more pertinent models, our data highlight the interest of combining antibiotics having an appropriate pharmacokinetic/pharmacodynamic profile against S. aureus (5,27) and showing activity against nongrowing bacteria (19,20) to successfully control and reduce intracellular infection by SCVs. This study may trigger further evaluation of antibiotic combinations against intracellular bacteria and ultimately may help in the design of pertinent clinical trials.…”

Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection

“…The methodology used has been reported previously and proved to be a reliable method for correlating in vivo efficacy in the rat tissue cage model of foreignbody infection (34,47). The MBCs were defined as described above.…”

“…The methodology used for the killing curve assays in the log phase followed previous standardized recommendations (35), and that used for the 24-h killing curve assays in the stationary phase was previously described in detail (34).…”

“…Using this model, we previously reported that high-dose levofloxacin (equivalent to 750 to 1,000 mg/day) was more active than the conventional levofloxacin dose (500 mg/day) and that it was the best therapy for use alone in comparison to therapy with other antistaphylococcal drugs (34). The aim of the present study was to test the extent to which these differences in activity between conventional and high doses of levofloxacin affect the efficacies of their respective combinations with rifampin in vitro and in vivo.…”

“…Recent work recommended the use of a combination of high doses of levofloxacin (750 to 1,000 mg/ day) plus rifampin for the treatment of staphylococcal prosthetic infections (48), even though the information available from this setting is limited (3,34,39).…”