Efficacy of high doses of levofloxacin in experimental foreign-body infection by methicillin-susceptible Staphylococcus aureus.

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.

Role of tolerance in cloxacillin treatment of experimental Staphylococcus aureus endocarditis.

The role of Staphylococcus aureus tolerance was investigated in endocarditis in rats. The efficacies of cloxacillin, gentamicin, and a combination of the two were compared for animals infected with a tolerant strain, its kill-sensitive variant, or a nonisogenic nontolerant strain of S. aureus. Cloxacillin was significantly less effective for treating the tolerant than for the nontolerant strains. The addition of gentamicin to cloxacillin reduced bacterial numbers in endocardial vegetations for the tolerant strain comparable to the reduction by cloxacillin alone for the nontolerant strains, but had no additional effect for the nontolerant strains. Isolates from animals infected with the tolerant or nontolerant strains during antibiotic treatment remained tolerant or nontolerant. These results show that the in vitro phenomenon of tolerance is relevant in vivo.

Comparative efficacy of daptomycin, vancomycin, and cloxacillin for the treatment of Staphylococcus aureus endocarditis in rats and role of test conditions in this determination.

The in vivo efficacy of daptomycin, a new cell wall-active anti-gram-positive-bacterial agent, was compared to those of cloxacillin and vancomycin in a rat model of Staphylococcus aureus endocarditis. Both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains were used. When therapy was initiated early (8 h) after infection, at the time when valvular bacterial counts were relatively low (approximately 10(6) CFU/g of vegetation), 3 days of therapy was found to be effective against the MSSA strains whatever the antibiotic regimen. In contrast, when the onset of therapy was delayed up to 15 h after infection, so that higher bacterial counts could develop on the valves (approximately 10(9) CFU/g of vegetation), a longer period of treatment (6 days) was required to cure infection. Under these conditions after 3 days of therapy, daptomycin was more effective than cloxacillin and vancomycin against the MSSA strains. Similarly, daptomycin showed a greater activity than vancomycin against the MRSA strain after 3 days of treatment, but after 6 days both antibiotics were equally effective. Decreasing doses of daptomycin showed decreasing activity: 10 mg/kg of body weight every 12 h (q12h) was better than 5 mg/kg q12h, whereas 5 mg/kg q24h (providing drug levels in blood detectable only during the first 12 h) failed to cure infection. In vitro, daptomycin was highly bactericidal at high concentrations (25 and 60 micrograms/ml, corresponding to peak levels in serum after doses of 5 and 10 mg/kg, respectively) and bacteriostatic at lower concentrations (0.5 to 2.5 micrograms/ml, corresponding to trough levels in serum). In conclusion, against low-bacterial-count S. aureus endocarditis, daptomycin showed an efficacy similar to those of vancomycin and cloxacillin. Against high-bacterial-count S. aureus endocarditis, daptomycin showed a higher bactericidal activity than cloxacillin (against the MSSA strains) and vancomycin (against both the MSSA and MRSA strains).

Antibiotics in the treatment of chronic staphylococcal osteomyelitis.

Fourteen patients with chronic osteomyelitis were treated with oral penicillin, oxacillin, or cloxacillin at a dose of 5 gm/day, plus 0.5 gm of probenecid (Benemid) three or four times per day. Treatment was continued for 2 1/2 to six months. In ten patients, evidence of osteomyelitis disappeared and there has been no recurrence during follow-up periods varying from six months to 2 1/2 years. Significant hepatotoxicity was encountered in two patients; one similar patient, not in this series but receiving a similar regimen of antibiotic, developed leukipenia. Thus, patients with chronic osteomyelitis appear to benefit from such a therapeutic program, but they must be monitored closely for hepatic or hematologic toxicity.