Glycopeptide antibiotic combination therapy
Bacterial infections evading the current antibiotic arsenal warrant new treatment options. The mainstay treatment for Clostridium difficile infections involves administration of the broad-spectrum antibiotic vancomycin, which also depletes the gut microbiome and its natural defenses. This leads to recurrent C. difficile infections in 20-30% of patients. Alternative treatment options are limited, triggering a perpetual cycle of relapse and recovery that may eventually lead to death. Keratinicyclin B represents a glycopeptide antibiotic chemotype with a mechanism of action that is selective for Clostridia. When combined, vancomycin (or other glycopeptide antibiotic) and keratinicyclin B interact synergistically to inhibit the growth of C. difficile at concentrations far lower than their respective minimal inhibitory concentrations. Such a combination therapy could allow for targeted colonization clearance at low antibiotic doses, thereby minimizing toxicity and reducing the likelihood of relapse.
1 . A pharmaceutical composition for treating an infection caused by C. difficile , the pharmaceutical composition comprising:
a plurality of glycopeptide antibiotics consisting of keratinicyclin B and a second glycopeptide antibiotic, the second glycopeptide antibiotic consisting of vancomycin; and
a pharmaceutically acceptable carrier;
wherein each of the plurality of glycopeptide antibiotics is present in a synergistic concentration less than its respective minimal inhibitory concentration of C. difficile.
2 . The pharmaceutical composition according to claim 1 , wherein the concentration of each glycopeptide antibiotic is between 1/2 and 1/20 of its respective minimal inhibitory concentration.
3 . The pharmaceutical composition according to claim 2 , wherein the concentration of each glycopeptide antibiotic is between 1/4 and 1/8 of its respective minimal inhibitory concentration.
4 . The pharmaceutical composition according to claim 1 , wherein the concentration of each glycopeptide antibiotic is between 150 nM and 350 nM.
5 . The pharmaceutical composition according to claim 4 , wherein the concentration of keratinicyclin B is between 250 nM and 350 nM, and the concentration of a second glycopeptide antibiotic of the plurality of glycopeptide antibiotics is between 150 nM and 250 nM.
6 . A method for treating a C. difficile infection, comprising:
administering a therapeutically effective dose of a first glycopeptide antibiotic consisting of keratinicyclin B and a second glycopeptide antibiotic consisting of vancomycin, the first and second glycopeptide antibiotic being present in concentrations less than their respective minimal inhibitory concentrations; and
allowing the first glycopeptide antibiotic and second glycopeptide antibiotic to specifically inhibit C. difficile in a synergistic manner.
7 . The method according to claim 6 , wherein the concentrations of each glycopeptide antibiotic is between 1/4 and 1/8 of its respective minimal inhibitory concentration.
8 . The method according to claim 6 , wherein the therapeutically effective dose of the plurality of glycopeptide antibiotics is administered orally.