Method for using novel hydroxamic acid derivative and antibacterial substance in combination
Pharmacological compositions containing a hydroxamic acid derivative selected from (2S)-2-((4-((4-((1S)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2-dimethylmalonamide, (2S)-2-((4-((4-((1R)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2-dimethylmalonamide, and (2S)—N-hydroxy-2-((4-((4-((1S)-1-hydroxy-2-methoxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N′,2-dimethylmalonamide, or a salt of said derivatives, and an antibiotic substance are useful in the treatment of gram-negative bacterial infections.
1. A pharmaceutical composition, comprising:
(i) (2S)-2-((4-((4-((1 S)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2-dimethylmalonamide or a salt thereof, and
(ii) at least one selected from the group consisting of (a) to (m):
(a) a piperacillin/tazobactam combination agent, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Klebsiella pneumonia or Acinetobacter baumannii BAA-1791;
(b) cefepime, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Stenotrophomonas maltophilia or Acinetobacter baumannii;
(c) ceftazidime, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Acinetobacter baumannii;
(d) meropenem, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Pseudomonas aeruginosa, Stenotrophomonas maltophilia PM-171 or Acinetobacter baumannii;
(e) imipenem, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Pseudomonas aeruginosa S-2994 or Acinetobacter baumannii;
(f) doripenem, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Acinetobacter baumannii;
(g) amikacin, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Pseudomonas aeruginosa S-2994, Klebsiella pneumonia, Stenotrophomonas maltophilia PM-171 or Acinetobacter baumannii;
(h) levofloxacin, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Escherichia coli;
(i) pazufloxacin, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Acinetobacter baumannii;
(j) ciprofloxacin, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Acinetobacter baumannii;
(k) vancomycin, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Acinetobacter baumannii;
(l) teicoplanin, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Acinetobacter baumannii ; and
(m) lysozyme, wherein (i) and (ii) exhibit a synergistic antimicrobial activity in the treatment of a bacterial infection caused by Acinetobacter baumannii.
2. The pharmaceutical composition according to claim 1 , comprising (a).
3. The pharmaceutical composition according to claim 2 , wherein the Klebsiella pneumonia is Klebsiella pneumonia Y-891.
4. The pharmaceutical composition according to claim 1 , comprising (b).
5. The pharmaceutical composition according to claim 4 , wherein the Pseudomonas aeruginosa is Pseudomonas aeruginosa S-3097, the Stenotrophomonas maltophilia is Stenotrophomonas maltophilia NBRC13692, and the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791 or Acinetobacter baumannii BAA-1794.
6. The pharmaceutical composition according to claim 1 , comprising (c).
7. The pharmaceutical composition according to claim 6 , wherein the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791 or Acinetobacter baumannii BAA-1794.
8. The pharmaceutical composition according to claim 1 , comprising (d).
9. The pharmaceutical composition according to claim 7 , wherein the Pseudomonas aeruginosa is Pseudomonas aeruginosa S-3097, and the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791 or Acinetobacter baumannii BAA-1794.
10. The pharmaceutical composition according to claim 1 , comprising (e).
11. The pharmaceutical composition according to claim 1 , wherein the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791 or Acinetobacter baumannii BAA-1794.
12. The pharmaceutical composition according to claim 1 , comprising (f).
13. The pharmaceutical composition according to claim 12 , wherein the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791.
14. The pharmaceutical composition according to claim 1 , comprising (g).
15. The pharmaceutical composition according to claim 14 , wherein the Klebsiella pneumonia is Klebsiella pneumoniae BAA1899, and the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791 or Acinetobacter baumannii BAA-1794.
16. The pharmaceutical composition according to claim 1 , comprising (h).
17. The pharmaceutical composition according to claim 16 , wherein the Escherichia coli is Escherichia coli TK-1537.
18. The pharmaceutical composition according to claim 1 , comprising (i).
19. The pharmaceutical composition according to claim 18 , wherein the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791.
20. The pharmaceutical composition according to claim 1 , comprising (j).
21. The pharmaceutical composition according to claim 20 , wherein the Acinetobacter baumannii is Acinetobacter baumannii BAA-1794.
22. The pharmaceutical composition according to claim 1 , comprising (k).
23. The pharmaceutical composition according to claim 22 , wherein the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791.
24. The pharmaceutical composition according to claim 1 , comprising (l).
25. The pharmaceutical composition according to claim 24 , wherein the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791 or Acinetobacter baumannii BAA-1794.
26. The pharmaceutical composition according to claim 1 , comprising (m).
27. The pharmaceutical composition according to claim 26 , wherein the Acinetobacter baumannii is Acinetobacter baumannii BAA-1794.
28. A method of treating a bacterial infection, comprising administering the pharmaceutical composition according to claim 1 to a subject in need thereof.
29. The method according to claim 28 , wherein the bacterial infection is caused by Klebsiella pneumonia or Acinetobacter baumannii BAA-1791, and the pharmaceutical composition comprises (a).
30. The method according to claim 29 , wherein the Klebsiella pneumonia is Klebsiella pneumonia Y-891.
31. The method according to claim 28 , wherein the bacterial infection is caused by Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Klebsiella pneumonia , or Acinetobacter baumannii , and the pharmaceutical composition comprises at least one selected from the group consisting of (b), (d), (e) and (g).
32. The method according to claim 31 , wherein the Pseudomonas aeruginosa is Pseudomonas aeruginosa S-3097.
33. The method according to claim 31 , wherein the Pseudomonas aeruginosa is Pseudomonas aeruginosa S-2994.
34. The method according to claim 31 , wherein the Stenotrophomonas maltophilia is Stenotrophomonas maltophilia PM-171 or Stenotrophomonas maltophilia NBRC13692.
35. The method according to claim 31 , wherein the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791 or Acinetobacter baumannii BAA-1794.
36. The method according to claim 31 , wherein the Klebsiella pneumonia is Klebsiella pneumoniae BAA1899.
37. The method according to claim 28 , wherein the bacterial infection is caused by Acinetobacter baumannii , and the pharmaceutical composition comprises at least one selected from the group consisting of (c), (f), (i), (j), (k), (l) and (m).
38. The method according to claim 37 , wherein the Acinetobacter baumannii is Acinetobacter baumannii BAA-1791 or Acinetobacter baumannii BAA-1794.
39. The method according to claim 28 , wherein the bacterial infection is caused by Escherichia coli , and the pharmaceutical composition comprises (h).
40. The method according to claim 39 , wherein the Escherichia coli is Escherichia coli TK-1537.