Linezolid alone or combined with rifampin against methicillin-resistant Staphylococcus aureus in experimental foreign-body infection

Abstract

We investigated the activity of linezolid, alone and in combination with rifampin (rifampicin), against a methicillin-resistant Staphylococcus aureus (MRSA) strain in vitro and in a guinea pig model of foreign-body infection. The MIC, minimal bactericidal concentration (MBC) in logarithmic phase, and MBC in stationary growth phase were 2.5, >20, and >20 microg/ml, respectively, for linezolid; 0.01, 0.08, and 2.5 microg/ml, respectively, for rifampin; and 0.16, 0.63, >20 microg/ml, respectively, for levofloxacin. In time-kill studies, bacterial regrowth and the development of rifampin resistance were observed after 24 h with rifampin alone at 1x or 4x the MIC and were prevented by the addition of linezolid. After the administration of single intraperitoneal doses of 25, 50, and 75 mg/kg of body weight, linezolid peak concentrations of 6.8, 12.7, and 18.1 microg/ml, respectively, were achieved in sterile cage fluid at approximately 3 h. The linezolid concentration remained above the MIC of the test organism for 12 h with all doses. Antimicrobial treatments of animals with cage implant infections were given twice daily for 4 days. Linezolid alone at 25, 50, and 75 mg/kg reduced the planktonic bacteria in cage fluid during treatment by 1.2 to 1.7 log(10) CFU/ml; only linezolid at 75 mg/kg prevented bacterial regrowth 5 days after the end of treatment. Linezolid used in combination with rifampin (12.5 mg/kg) was more effective than linezolid used as monotherapy, reducing the planktonic bacteria by >or=3 log(10) CFU (P < 0.05). Efficacy in the eradication of cage-associated infection was achieved only when linezolid was combined with rifampin, with cure rates being between 50% and 60%, whereas the levofloxacin-rifampin combination demonstrated the highest cure rate (91%) against the strain tested. The linezolid-rifampin combination is a treatment option for implant-associated infections caused by quinolone-resistant MRSA.

FIG. 1.

Time-kill curves for 1× and 4× the MIC of linezolid (closed circles), 1× and 4× the MIC of rifampin (closed circle, dashed line), and their combination (open circles) against MRSA. Values are means ± SDs. LZD, linezolid; RIF, rifampin.

FIG. 2.

Pharmacokinetics of linezolid in cage fluid after the administration of single intraperitoneal doses of 25 mg/kg, 50 mg/kg, and 75 mg/kg. The mean values of six measurements at each time point are shown; error bars represent SDs. The horizontal dotted line indicates the MIC of linezolid for the MRSA test strain.

FIG. 3.

Efficacy of treatment against planktonic bacteria in cage fluid (Δlog₁₀ CFU/ml) during treatment (day 4) (A) and 5 days after the end of treatment (day 10) (B). The dashed horizontal line indicates the limit of quantification (LOQ). LZD25, linezolid at 25 mg/kg; LZD50, linezolid at 50 mg/kg; LZD75, linezolid at 75 mg/kg; RIF, rifampin at 12.5 mg/kg; and LVX10, levofloxacin at 10 mg/kg.

FIG. 4.

Cure rates of cage-associated infection at day 10. The values indicate the number of cage cultures without growth of MRSA/total number of cages in the treatment group. LZD25, linezolid at 25 mg/kg; LZD50, linezolid at 50 mg/kg; LZD75, linezolid at 75 mg/kg; RIF, rifampin at 12.5 mg/kg; and LVX10, levofloxacin at 10 mg/kg.