Linezolid alone or combined with rifampin against methicillin-resistant Staphylococcus aureus in experimental foreign-body infection.
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.
Baldoni
Daniela
D
Department of Biomedicine, Infectious Diseases Research Laboratory, University Hospital Basel, Basel, Switzerland.
Haschke
Manuel
M
Rajacic
Zarko
Z
Zimmerli
Werner
W
Trampuz
Andrej
A
D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005549:Foreign-Body Reaction / Q000188:drug therapy / Q000517:prevention & control; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D000069349:Linezolid; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008826:Microbial Sensitivity Tests; D023421:Models, Animal; D023303:Oxazolidinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010933:Plankton / Q000187:drug effects; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013997:Time Factors
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid; D012293:Rifampin