rifampin and tedizolid

BACKGROUND Mycobacterium tuberculosis (M. tuberculosis) is usually treated by oral antimycobacterial agents, including rifampicin, ethambutol, and pyrazinamide, but the treatment regimen with intravenous and/or intramuscular antimycobacterial agents for patients who cannot take medications orally remains unclear. CASE REPORT A 77-year-old man with chronic renal failure had an esophageal-skin fistula after he had surgeries for removal of esophageal and gastric cancers and reconstruction using jejunum, and he showed a cavity, tree-in-bud formation, and pleural effusions in his left upper lung fields on his chest X-ray after treatment of cellulitis and bacteremia/candidemia by meropenem, teicoplanin, and micafungin. M. tuberculosis was isolated from his sputum and exudate fluid from the reconstructed esophageal-skin fistula. Although he could not take antimycobacterial agents orally, treatment was started with intravenous agents combining levofloxacin (LVFX) every other day, isoniazid (INH), and linezolid (LZD). However, his platelets were decreased 21 days after treatment started, and it was thought to be an adverse effect of LZD and/or INH. After changing LZD to tedizolid (TZD), in addition to changing from INH to intramuscular streptomycin twice per week, his platelet counts increased. Intravenous TZD could be continued, and it maintained his condition without exacerbations of thrombocytopenia and renal failure. The M. tuberculosis disappeared, and the abnormal chest X-ray shadows were improved 2 months after the start of treatment. CONCLUSIONS Administration of intravenous TZD, in addition to intravenous LVFX and intramuscular SM in combination, might be a candidate regimen for M. tuberculosis patients who cannot take oral medications.

Topics: Aged; Anti-Bacterial Agents; Antitubercular Agents; Cutaneous Fistula; Ethambutol; Humans; Isoniazid; Levofloxacin; Linezolid; Male; Meropenem; Micafungin; Mycobacterium tuberculosis; Oxazolidinones; Pyrazinamide; Rifampin; Streptomycin; Teicoplanin; Tetrazoles; Tuberculosis

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active. Consequently, telacebec was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field.

Topics: Animals; Antitubercular Agents; Buruli Ulcer; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Imidazoles; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Oxazolidinones; Piperidines; Pyridines; Rifampin; Tetrazoles

Rifampin (RIF) plus clarithromycin (CLR) for 8 weeks is now the standard of care for Buruli ulcer (BU) treatment, but CLR may not be an ideal companion for rifamycins due to bidirectional drug-drug interactions. The oxazolidinone linezolid (LZD) was previously shown to be active against

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Disease Models, Animal; Female; Linezolid; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Oxazolidinones; Rifampin; Tetrazoles

Tedizolid is an orally bioavailable oxazolidinone with once-daily dosing and broad-spectrum Gram-positive activity. Combination therapy is commonly indicated to improve efficacy against difficult-to-treat pathogens and biofilms. There are no studies describing the pharmacodynamic interactions between tedizolid and other orally bioavailable antimicrobials.. MICs of tedizolid, rifampicin, trimethoprim/sulfamethoxazole, doxycycline and moxifloxacin were determined by broth microdilution against a convenience sample of 45 staphylococcal isolates. Seven MRSA isolates and three Staphylococcus epidermidis were evaluated by time-kill using concentrations equal to 0.5× the MIC. These strains had variable susceptibility to the investigated antimicrobials. Synergy was defined as a ≥2 log 10 cfu/mL reduction of the combination over the most active single agent, antagonism was defined as ≥1 log 10 cfu/mL growth compared with the most active single agent, and other interactions were indifferent.. Three of 45 strains tested were non-susceptible to tedizolid (MIC = 1 mg/L), but the MIC 90 was 0.5 mg/L. Interactions between tedizolid and other agents were largely indifferent (80%). Tedizolid was synergistic with doxycycline and rifampicin against 2/10 and 3/10 strains, respectively. Tedizolid was antagonistic with moxifloxacin against 3/10 strains. Other interactions were indifferent.. The addition of rifampicin to tedizolid appears to be the most likely to improve activity but synergy was not universal. The combination of tedizolid plus moxifloxacin should be avoided due to the risk of antagonism. The addition of other orally bioavailable anti-staphylococcal agents to tedizolid may be unlikely to improve killing but further research is warranted to assess the impact of these combinations on resistance prevention, or against biofilm-embedded organisms.

Topics: Acetamides; Administration, Oral; Anti-Bacterial Agents; Drug Interactions; Fluoroquinolones; Humans; Kinetics; Linezolid; Microbial Sensitivity Tests; Moxifloxacin; Oxazolidinones; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis; Tetrazoles; Trimethoprim, Sulfamethoxazole Drug Combination