rifampin and tedizolid-phosphate

This is a report on the chemical stability and physical compatibility of intravenous tedizolid phosphate 0.8 mg/mL-sodium rifampicin 2.4 mg/mL and tedizolid phosphate 0.8 mg/mL-meropenem 4 mg/mL combinations in polypropylene 0.9% sodium chloride infusion bags stored at different storage conditions. Triplicate solutions of both admixtures were prepared in 0.9% sodium chloride polypropylene infusion bags and stored under light protection at room temperature (25±2 °C), refrigeration (2-8 °C) or freezing (-15 - -25 °C) conditions. The study was performed using a validated and stability-indicating liquid chromatography (LC) method. For both admixtures and for all storage conditions, at least 90% of the initial drug concentration of tedizolid phosphate remained unchanged throughout the entire study period. Stability of sodium rifampicin at 25±2 °C was determined to be seven hours and six days when it was stored at 2-8 °C. Under the same storage conditions, meropenem was stable for 12 h or 6 days, respectively. Under freezing conditions, sodium rifampicin was stable throughout all 28 days, while stability of meropenem was only 8 days. Solutions of 0.8 mg/mL tedizolid phosphate admixtured with 2.4 mg/mL rifampicin or 4 mg/mL meropenem, in polypropylene 0.9% sodium chloride infusion bags, are stable for at least 7 or 12 hours, respectively, when stored at 25±2 °C. When stored at 2-8 °C, stability was increased to 6 days for both admixtures.

Topics: Anti-Bacterial Agents; Chromatography, Liquid; Drug Stability; Drug Storage; Freezing; Infusions, Intravenous; Meropenem; Organophosphates; Oxazoles; Polypropylenes; Refrigeration; Rifampin; Sodium Chloride; Temperature; Time Factors

Among the viridans group streptococci, S. mitis-oralis strains are frequently resistant to multiple β-lactams and tolerant to vancomycin (VAN). This scenario has led to the proposed clinical use of newer agents, like daptomycin (DAP) for such S. mitis-oralis strains. However, recent recognition of the rapid and durable emergence of high-level DAP-resistance (DAP-R; DAP MICs > 256 µg/ml) induced by DAP exposures in vitro and in vivo has dampened enthusiasm for such approaches. In this study, we evaluated a broad range of DAP combination regimens in vitro for their capacity to prevent emergence of high-level DAP-R in a prototype S. mitis-oralis strain (351) during serial passage experiments, including DAP + either gentamicin (GEN), rifampin (RIF), trimethoprim-sulfamethoxazole (TMP-SMX), imipenem (IMP), ceftaroline (CPT), tedizolid (TDZ), or linezolid (LDZ). In addition, we assessed selected DAP combination regimens for their ability to exert either an early bactericidal impact and/or synergistically kill the S. mitis-oralis study strain. During serial passage, three of the eight antibiotic combinations (DAP + GEN, CPT, or TMP- SMX) exhibited significantly reduced DAP MICs (≈ by 8-40 fold) vs serial exposure in DAP alone (DAP MICs > 256 µg/ml). In addition, combinations of DAP + GEN and DAP + CPT were both bactericidal and synergistic in early time-kill curve interactions.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Drug Combinations; Drug Resistance, Bacterial; Gentamicins; Humans; Imipenem; Linezolid; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Rifampin; Streptococcus mitis; Streptococcus oralis; Trimethoprim, Sulfamethoxazole Drug Combination

We compared tedizolid alone and tedizolid with rifampin to rifampin and vancomycin plus rifampin in a rat model of methicillin-resistant Staphylococcus aureus (MRSA) foreign body-associated osteomyelitis. The study strain was a prosthetic joint infection-associated isolate. Steady-state pharmacokinetics for intraperitoneal administration of tedizolid, vancomycin, and rifampin were determined in uninfected rats. MRSA was inoculated into the proximal tibia, and a wire was implanted. Four weeks later, the rats were treated intraperitoneally for 21 days with tedizolid (n = 14), tedizolid plus rifampin (n = 11), rifampin (n = 16), or vancomycin plus rifampin (n = 13). Seventeen rats received no treatment. After treatment, quantitative bone cultures were performed. Blood was obtained for determination of drug trough concentrations in the tedizolid and tedizolid plus rifampin groups. The mean peak plasma concentration and mean area under the concentration-time curve from time zero to 24 h for tedizolid were 12 μg/ml and 60 μg · h/ml, respectively. The bacterial loads in all treatment groups were significantly lower than those in the control group; those in the tedizolid- plus rifampin-treated animals were not significantly different from those in the vancomycin- plus rifampin-treated animals. The range of mean plasma trough concentrations in the tedizolid group was 0.44 to 0.73 μg/ml. Although neither tedizolid nor vancomycin resistance was detected in isolates recovered from bones, rifampin resistance was detected in 10 animals (63%) in the rifampin group, 8 animals (73%) in the tedizolid plus rifampin group, and a single animal (8%) in the vancomycin plus rifampin group. Tedizolid alone or tedizolid combined with rifampin was active in a rat model of MRSA foreign body-associated osteomyelitis. The emergence of rifampin resistance was noted in animals receiving tedizolid plus rifampin.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Bone Wires; Disease Models, Animal; Drug Combinations; Drug Resistance, Bacterial; Foreign Bodies; Injections, Intraperitoneal; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Organophosphates; Osteomyelitis; Oxazoles; Rats; Rats, Wistar; Rifampin; Staphylococcal Infections; Tibia; Vancomycin