rifampin and oritavancin

The determination of antibiotic potency against bacterial strains by assessment of their minimum inhibitory concentration normally uses a standardized broth microdilution assay procedure developed more than 50 years ago. However, certain antibiotics require modified assay conditions in order to observe optimal activity. For example, daptomycin requires medium supplemented with Ca

Topics: Aminoglycosides; Anti-Bacterial Agents; Calcium; Ciprofloxacin; Colistin; Culture Media; Depsipeptides; Escherichia coli; Factor Analysis, Statistical; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxacillin; Penicillin G; Plastics; Polymyxin B; Polysorbates; Rifampin; Teicoplanin; Trimethoprim; Vancomycin

The antibiofilm activity of oritavancin in combination with rifampin, gentamicin, or linezolid was evaluated against 10 prosthetic joint infection (PJI)-related methicillin-resistant

Topics: Biofilms; Gentamicins; Linezolid; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Rifampin

Staphylococcus aureus small-colony variants (SCVs) persist intracellularly, which may contribute to persistence/recurrence of infections and antibiotic failure. We have studied the intracellular fate of menD and hemB mutants (corresponding to menadione- and hemin-dependent SCVs, respectively) of the COL methicillin-resistant S. aureus (MRSA) strain and the antibiotic pharmacodynamic profile against extracellular (broth) and intracellular (human THP-1 monocytes) bacteria. Compared to the parental strain, SCVs showed slower extracellular growth (restored upon medium supplementation with menadione or hemin), reduced phagocytosis, and, for the menD SCV, lower intracellular counts at 24 h postinfection. Against extracellular bacteria, daptomycin, gentamicin, rifampin, moxifloxacin, and oritavancin showed similar profiles of activity against all strains, with a static effect obtained at concentrations close to their MICs and complete eradication as maximal effect. In contrast, vancomycin was not bactericidal against SCVs. Against intracellular bacteria, concentration-effect curves fitted sigmoidal regressions for vancomycin, daptomycin, gentamicin, and rifampin (with maximal effects lower than a 2-log decrease in CFU) but biphasic regressions (with a maximal effect greater than a 3-log decrease in CFU) for moxifloxacin and oritavancin, suggesting a dual mode of action against intracellular bacteria. For all antibiotics, these curves were indistinguishable between the strains investigated, except for the menD mutant, which systematically showed a lower amplitude of the concentration-effect response, with markedly reduced minimal efficacy (due to slower growth) but no change in maximal efficacy. The data therefore show that the maximal efficacies of antibiotics are similar against normal-phenotype and menadione- and hemin-dependent strains despite their different intracellular fates, with oritavancin, and to some extent moxifloxacin, being the most effective.

Topics: Anti-Bacterial Agents; Cell Line; Daptomycin; Gentamicins; Glycopeptides; Hemin; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Monocytes; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Vitamin K 3

Slow-growing bacteria and biofilms are notoriously tolerant to antibiotics. Oritavancin is a lipoglycopeptide with multiple mechanisms of action that contribute to its bactericidal action against exponentially growing gram-positive pathogens, including the inhibition of cell wall synthesis and perturbation of membrane barrier function. We sought to determine whether oritavancin could eradicate cells known to be tolerant to many antimicrobial agents, that is, stationary-phase and biofilm cultures of Staphylococcus aureus in vitro. Oritavancin exhibited concentration-dependent bactericidal activity against stationary-phase inocula of methicillin-susceptible S. aureus (MSSA) ATCC 29213, methicillin-resistant S. aureus (MRSA) ATCC 33591, and vancomycin-resistant S. aureus (VRSA) VRS5 inoculated into nutrient-depleted cation-adjusted Mueller-Hinton broth. As has been described for exponential-phase cells, oritavancin induced membrane depolarization, increased membrane permeability, and caused ultrastructural defects including a loss of nascent septal cross walls in stationary-phase MSSA. Furthermore, oritavancin sterilized biofilms of MSSA, MRSA, and VRSA at minimal biofilm eradication concentrations (MBECs) of between 0.5 and 8 mug/ml. Importantly, MBECs for oritavancin were within 1 doubling dilution of their respective planktonic broth MICs, highlighting the potency of oritavancin against biofilms. These results demonstrate a significant activity of oritavancin against S. aureus in phases of growth that exhibit tolerance to other antimicrobial agents.

Topics: Anti-Bacterial Agents; Biofilms; Colony Count, Microbial; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Glycopeptides; Kinetics; Lipoglycopeptides; Methicillin; Methicillin Resistance; Microbial Sensitivity Tests; Plankton; Staphylococcus aureus; Vancomycin; Vancomycin Resistance

The inhaled form of Bacillus anthracis infection may be fatal to humans. The current standard of care for inhalational anthrax postexposure prophylaxis is ciprofloxacin therapy twice daily for 60 days. The potent in vitro activity of oritavancin, a semisynthetic lipoglycopeptide, against B. anthracis (MIC against Ames strain, 0.015 microg/ml) prompted us to test its efficacy in a mouse aerosol-anthrax model. In postexposure prophylaxis dose-ranging studies, a single intravenous (i.v.) dose of oritavancin of 5, 15, or 50 mg/kg 24 h after a challenge with 50 to 75 times the median lethal dose of Ames strain spores provided 40, 70, and 100% proportional survival, respectively, at 30 days postchallenge. Untreated animals died within 4 days of challenge, whereas 90% of control animals receiving ciprofloxacin at 30 mg/kg intraperitoneally twice daily for 14 days starting 24 h after challenge survived. Oritavancin demonstrated significant activity post symptom development; a single i.v. dose of 50 mg/kg administered 42 h after challenge provided 56% proportional survival at 30 days. In a preexposure prophylaxis study, a single i.v. oritavancin dose of 50 mg/kg administered 1, 7, 14, or 28 days before lethal challenge protected 90, 100, 100, and 20% of mice at 30 days; mice treated with ciprofloxacin 24 h or 24 and 12 h before challenge all died within 5 days. Efficacy in pre- and postexposure models of inhalation anthrax, together with a demonstrated low propensity to engender resistance, promotes further study of oritavancin pharmacokinetics and efficacy in nonhuman primate models.

Topics: Administration, Inhalation; Animals; Anthrax; Anti-Bacterial Agents; Bacillus anthracis; Disease Models, Animal; Glycopeptides; Humans; Lipoglycopeptides; Mice; Microbial Sensitivity Tests; Spores, Bacterial; Treatment Outcome

Oritavancin is a semisynthetic lipoglycopeptide in clinical development for serious gram-positive infections. This study describes the synergistic activity of oritavancin in combination with gentamicin, linezolid, moxifloxacin, or rifampin in time-kill studies against methicillin-susceptible, vancomycin-intermediate, and vancomycin-resistant Staphylococcus aureus.

Topics: Acetamides; Anti-Bacterial Agents; Aza Compounds; Drug Synergism; Fluoroquinolones; Gentamicins; Glycopeptides; Humans; Linezolid; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Moxifloxacin; Oxazolidinones; Polysorbates; Quinolines; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Surface-Active Agents; Vancomycin Resistance

This in vitro study evaluated the activities of vancomycin, LY333328, and teicoplanin alone and in combination with gentamicin, rifampin, and RP59500 against Staphylococcus aureus isolates with intermediate susceptibilities to vancomycin. Ampicillin-sulbactam and trovafloxacin were also evaluated. LY333328 and ampicillin-sulbactam resulted in bactericidal activity against all isolates. The combination of gentamicin with glycopeptides showed synergistic activity, while rifampin had no added benefit.

Topics: Ampicillin; Anti-Bacterial Agents; Antibiotics, Antitubercular; Drug Therapy, Combination; Fluoroquinolones; Gentamicins; Glycopeptides; Lipoglycopeptides; Microbial Sensitivity Tests; Naphthyridines; Rifampin; Staphylococcus aureus; Sulbactam; Teicoplanin; Time Factors; Vancomycin; Virginiamycin

The objectives of the present study were to compare the in vitro activity of LY333328 (LY) to that of vancomycin (V) alone and in combination with gentamicin (G) and rifampin (R) against methicillin-resistant Staphylococcus aureus (MRSA) and V-resistant Enterococcus faecium (VREF), by using the killing curve methods. In addition, the effect of the inoculum size and protein on LY's activity was evaluated by using MICs and killing curves. MICs, MBCs, and killing curves were determined with supplemented Mueller-Hinton broth (B), B with albumin (4 g/dl) (A), and B with 50% pooled human serum (S). For MRSA, time to 99.9% killing after exposure to LY at four times the MIC (4x MIC) was achieved at 0.5 +/- 0 h (mean +/- standard deviation) and was significantly faster than that by V (8.54 +/- 0.10 h; P = 0.001). Against VREF, LY decreased the inoculum by 2.2 log10 CFU/ml at 24 h (P = 0.002). With a large inoculum of MRSA, the activity of LY and V at 4x MIC was decreased compared to that with the standard inoculum (P = 0.0003) and regrowth occurred at 24 h. The reduction in the number of CFU per milliliter at 24 h to 2 log10 CFU/ml was restored by increasing the LY concentration to at least 16x MIC. At 24 h, the combinations of LY and G, LY and R, LY and V, and V and G were better than either LY or V alone against a large inoculum of MRSA (P = 0.0002). LY and G achieved 99.9% killing at 1.01 +/- 0.03 h and was more rapid (P < 0.007) than all the other regimens studied except for V and G, which achieved 99.9% killing at 3.59 +/- 0.01 h. Killing curves determined with different media against a standard inoculum of MRSA did not demonstrate a significant difference between LY and V at 24 h. Time to 99.9% killing was more rapid with LY than with V in B, A, and S (P = 0.0002). Times to 99.9% killing by LY in B, A, and S were not significantly different from each other. Against VREF, LY killed better than V in B, A, or S at 24 h (P = 0.0002). LY in B was more active than LY in A or S (P = 0.0002). LY is a new potent glycopeptide with a unique activity profile. It has a greater activity than that of V against MRSA and has activity against VREF. LY demonstrated synergism in combination with gentamicin against MRSA. LY was affected by large inoculum sizes and proteins in time-kill studies. However, the effect was compensated for by increasing the drug concentration to 16x MIC.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Enterococcus faecium; Evaluation Studies as Topic; Gentamicins; Glycopeptides; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Rifampin; Staphylococcus aureus; Vancomycin