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1. WO2020112542 - COMBINATION COMPOSITIONS COMPRISING A BETA-LACTAMASE INHIBITOR AND USES THEREOF

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[ EN ]

CLAIMS

WHAT IS CLAIMED:

1. A pharmaceutical composition comprising:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


I);

wherein:

each R1 and R2 is independently hydrogen, C i -G, alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHCi-Ce alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, C 1 -G, alkyl, -0(G-G, alkyl), -NfL. -NHCi-Ce alkyl, -N(G-G, alkyl )2. - COOH, -COO(Ci-C6 alkyl), -(Ci-Ce alkylene)COOH, or -(Ci-C6 alkylene)COO(G-C6 alkyl); and (ii) ceftibuten.

2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


3. The pharmaceutical composition of claim 1, wherein the compound of formula (I), or a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


4. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutical

composition is formulated for oral administration.

5. The pharmaceutical composition of any one of claims 1 -4, wherein the pharmaceutical

composition is formulated as an emulsion.

6. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical

composition is formulated as a microemulsion.

7. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical

composition is formulated as a Self-Emulsifying Drug Delivery System (SEDDS).

8. The pharmaceutical composition of any one of claims 1-7, further comprising a hydrophilic

solubilizer.

9. The pharmaceutical composition of claim 8, wherein the hydrophilic solubilizer is a hydrophilic polymer.

10. The pharmaceutical composition of claim 9, wherein the hydrophilic polymer is a polyethylene glycol.

11. The pharmaceutical composition of any one of claims 1-10, further comprising a surfactant.

12. The pharmaceutical composition of claim 11, wherein the surfactant is a polyoxyethylene stearate.

13. The pharmaceutical composition of any one of claims 1-11, further comprising a

pharmaceutically acceptable excipient.

14. The pharmaceutical composition of any one of claims 1-7, further comprising polyethylene

glycol, caprylic/capric glycerides, and tocopheryl polyethylene glycol succinate.

15. The pharmaceutical composition of any one of claims 1-7, further comprising propylene glycol, polyethylene glycol, and tocopheryl polyethylene glycol succinate.

16. The pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical

composition is formulated as a capsule.

17. The pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical

composition is formulated as a tablet.

18. The pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical

composition is formulated as a powder for reconstitution.

19. The pharmaceutical composition of claim 18, wherein the powder for reconstitution is

reconstituted with a liquid carrier to form an oral suspension.

20. The pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical composition is formulated as a solution.

21. A pharmaceutical composition comprising:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid, or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and

(ii) ceftibuten.

22. A method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid, or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and

(ii) ceftibuten.

23. A method of treating a bacterial infection in a subject in need thereof, the method comprising delivering to the subject:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid; and

(ii) ceftibuten.

24. The method of claim 23 wherein the bacterial infection is caused by carbapenem -resistant

Enterobacteriaceae (CRE) or extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria.

25. The method of claim 23 or 24, wherein the method comprises administering to the subject in need thereof:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:



formula (II); wherein:

each R1 and R2 is independently hydrogen, C i -G, alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHG-G, alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, C 1 -G, alkyl, -0(G-G, alkyl), -NH2. -NHG-G, alkyl, -N(G-G, alkyl )2. - COOH, -COO(Ci-C6 alkyl), -(Ci-Ce alkylene)COOH, or -(Ci-C6 alkylene)COO(G-C6 alkyl); and (ii) ceftibuten.

26. The method of claim 25, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


27. The method of claim 25, wherein the compound of formula (I), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


28. The method of any one of claims 25-27, wherein the compound of formula (I) or (II) and

ceftibuten are formulated for oral administration.

29. The method of any one of claims 25-28, wherein the compound of formula (I) or (II); a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and ceftibuten are administered sequentially.

30. The method of any one of claims 25-28, wherein the compound of formula (I) or (II); a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and ceftibuten are administered concurrently.

31. A method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


wherein:

each R1 and R2 is independently hydrogen, C i -G, alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHG-G, alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, G-Ce alkyl, -0(G-G, alkyl), -NH2. -NHG-G, alkyl, -N(G-G, alkyl )2. - COOH, -COO(Ci-C6 alkyl), -(G-C6 alkylene)COOH, or -(Ci-C6 alkylene)COO(G-C6 alkyl); and (ii) ceftibuten.

32. The method of claim 31, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


33. The method of claim 31, wherein the compound of formula (I), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


34. The method of any one of claims 31-33, wherein the bacterial infection is caused by carbapenem- resistant Enterobacteriaceae (CRE) or extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria.

35. The method of any one of claims 31-34, wherein the compound of formula (I) or (II) and

ceftibuten are formulated for oral administration.

36. The method of any one of claims 31-35, wherein the compound of formula (I) or (II); a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof and ceftibuten are administered sequentially.

37. The method of any one of claims 31-35, wherein the compound of formula (I) or (II); a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof and ceftibuten are administered concurrently.

38. A pharmaceutical composition comprising:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


wherein:

each R1 and R2 is independently hydrogen, C i -G, alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHG-G, alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, C 1 -G, alkyl, -0(G-G, alkyl), -NfE. -NHG-G, alkyl, -N(G-G, alkyl )2. - COOH, -COO(Ci-C6 alkyl), -(G-C6 alkylene)COOH, or -(G-C6 alkylene)COO(G-C6 alkyl); and (ii) cefixime.

39. The pharmaceutical composition of claim 38, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


40. The pharmaceutical composition of claim 38, wherein the compound of formula (I), or a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


41. The pharmaceutical composition of any one of claims 38-40, wherein the pharmaceutical

composition is formulated for oral administration.

42. The pharmaceutical composition of any one of claims 38-41, wherein the pharmaceutical

composition is formulated as an emulsion.

43. The pharmaceutical composition of any one of claims 38-41, wherein the pharmaceutical

composition is formulated as a microemulsion.

44. The pharmaceutical composition of any one of claims 38-41, wherein the pharmaceutical

composition is formulated as a Self-Emulsifying Drug Delivery System (SEDDS).

45. The pharmaceutical composition of any one of claims 38-43, further comprising a hydrophilic solubilizer.

46. The pharmaceutical composition of claim 45, wherein the hydrophilic solubilizer is a hydrophilic polymer.

47. The pharmaceutical composition of claim 46, wherein the hydrophilic polymer is a polyethylene glycol.

48. The pharmaceutical composition of any one of claims 38-47, further comprising a surfactant.

49. The pharmaceutical composition of claim 48, wherein the surfactant is a polyoxyethylene stearate.

50. The pharmaceutical composition of any one of claims 38-49, further comprising a

pharmaceutically acceptable excipient.

51. The pharmaceutical composition of any one of claims 38-44, further comprising polyethylene glycol, caprylic/capric glycerides, and tocopheryl polyethylene glycol succinate.

52. The pharmaceutical composition of any one of claims 38-44, further comprising propylene glycol, polyethylene glycol, and tocopheryl polyethylene glycol succinate.

53. The pharmaceutical composition of any one of claims 38-52, wherein the pharmaceutical composition is formulated as a capsule.

54. The pharmaceutical composition of any one of claims 38-52, wherein the pharmaceutical

composition is formulated as a tablet.

55. The pharmaceutical composition of any one of claims 38-52, wherein the pharmaceutical

composition is formulated as a powder for reconstitution.

56. The pharmaceutical composition of claim 55, wherein the powder for reconstitution is

reconstituted with a liquid carrier to form an oral suspension.

57. The pharmaceutical composition of any one of claims 38-52, wherein the pharmaceutical

composition is formulated as solution.

58. A pharmaceutical composition comprising:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid, or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and

(ii) cefixime.

59. A method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid, or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and

(ii) cefixime.

60. A method of treating a bacterial infection in a subject in need thereof, the method comprising delivering to the subject:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid; and

(ii) cefixime.

61. The method of claim 60, wherein the bacterial infection is caused by carbapenem-resistant

Enterobacteriaceae (CRE) or extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria.

62. The method of claim 60 or 61, wherein the method comprises administering to the subject in need thereof:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


I);

wherein:

each R1 and R2 is independently hydrogen, Ci-Ce alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHCi-Ce alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, C 1 -G, alkyl, -0(G-G, alkyl), -NH2, -NHCi-Ce alkyl, -N(G-G, alkyl)2, - COOH, -COO(Ci-C6 alkyl), -(G-C6 alkylene)COOH, or -(Ci-C6 alkylene)COO(Ci-C6 alkyl); and (ii) cefixime.

63. The method of claim 62, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


64. The method of claim 62, wherein the compound of formula (I), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


65. The method of any one of claims 62-64, wherein the compound of formula (I) or (II) and cefixime are formulated for oral administration.

- I l l -

66. The method of any one of claims 62-65, wherein the compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and cefixime are administered sequentially.

67. The method of any one of claims 62-65, wherein the compound of formula (I) or (II); a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and cefixime are administered concurrently.

68. A method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


wherein:

each R1 and R2 is independently hydrogen, C i -G, alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHG-G, alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, C 1 -G, alkyl, -0(G-G, alkyl), -NIT. -NHG-G, alkyl, -N(G-G, alkyl )2. - COOH, -COO(Ci-C6 alkyl), -(G-C6 alkylene)COOH, or -(G-C6 alkylene)COO(G-C6 alkyl); and (ii) cefixime.

69. The method of claim 68, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


70 The method of claim 68, wherein the compound of formula (I), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


71. The method of any one of claims 68-70, wherein the bacterial infection is caused by carbapenem- resistant Enterobacteriaceae (CRE) or extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria.

72. The method of any one of claims 68-71, wherein the compound of formula (I) or (II) and cefixime are formulated for oral administration.

73. The method of any one of claims 68-72, wherein the compound of formula (I) or (II); a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof and cefixime are administered sequentially.

74. The method of any one of claims 68-72, wherein the compound of formula (I) or (II); a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof and cefixime are administered concurrently.

75. A pharmaceutical composition comprising:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


wherein:

each R1 and R2 is independently hydrogen, C i -G, alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHCi-Ce alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, C 1 -G, alkyl, -0(G-G, alkyl), -NfE. -NHCi-Ce alkyl, -N(G-G, alkyl )2. - COOH, -COO(Ci-C6 alkyl), -(Ci-Ce alkylene)COOH, or -(Ci-C6 alkylene)COO(G-C6 alkyl); and

(ii) cefditoren pivoxil.

76. The pharmaceutical composition of claim 75, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


77. The pharmaceutical composition of claim 75, wherein the compound of formula (I), or a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


78. The pharmaceutical composition of any one of claims 75-77, wherein the pharmaceutical

composition is formulated for oral administration.

79. The pharmaceutical composition of any one of claims 75-78, wherein the pharmaceutical

composition is formulated as an emulsion.

80. The pharmaceutical composition of any one of claims 75-78, wherein the pharmaceutical

composition is formulated as a microemulsion.

81. The pharmaceutical composition of any one of claims 75-78, wherein the pharmaceutical

composition is formulated as a Self-Emulsifying Drug Delivery System (SEDDS).

82. The pharmaceutical composition of any one of claims 75-81, further comprising a hydrophilic solubilizer.

83. The pharmaceutical composition of claim 82, wherein the hydrophilic solubilizer is a hydrophilic polymer.

84. The pharmaceutical composition of claim 83, wherein the hydrophilic polymer is a polyethylene glycol.

85. The pharmaceutical composition of any one of claims 75-84, further comprising a surfactant.

86. The pharmaceutical composition of claim 85, wherein the surfactant is a polyoxyethylene stearate.

87. The pharmaceutical composition of any one of claims 75-86, further comprising a

pharmaceutically acceptable excipient.

88. The pharmaceutical composition of any one of claims 75-81, further comprising polyethylene glycol, caprylic/capric glycerides, and tocopheryl polyethylene glycol succinate.

89. The pharmaceutical composition of any one of claims 75-81, further comprising propylene glycol, polyethylene glycol, and tocopheryl polyethylene glycol succinate.

90. The pharmaceutical composition of any one of claims 75-89, wherein the pharmaceutical

composition is formulated as a capsule.

91. The pharmaceutical composition of any one of claims 75-89, wherein the pharmaceutical

composition is formulated as a tablet.

92. The pharmaceutical composition of any one of claims 75-89, wherein the pharmaceutical

composition is formulated as a powder for reconstitution.

93. The pharmaceutical composition of claim 92, wherein the powder for reconstitution is

reconstituted with a liquid carrier to form an oral suspension.

94. The pharmaceutical composition of any one of claims 75-89, wherein the pharmaceutical

composition is formulated as a solution.

95. A pharmaceutical composition comprising:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid, or a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and

(ii) cefditoren pivoxil.

96. A method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid, or a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and

(ii) cefditoren pivoxil.

97. A method of treating a bacterial infection in a subject in need thereof, the method comprising delivering to the subject:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid; and

(ii) cefditoren pivoxil.

98. The method of claim 97, wherein the bacterial infection is caused by carbapenem-resistant

Enterobacteriaceae (CRE) or extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria.

99. The method of claim 97 or 98, wherein the method comprises administering to the subject in need thereof:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


wherein:

each R1 and R2 is independently hydrogen, C i -G, alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHG-G, alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, G-Ce alkyl, -0(G-G, alkyl), -NIT. -NHCi-Ce alkyl, -N(G-G, alkyl )2. - COOH, -COO(Ci-C6 alkyl), -(Ci-Ce alkylene)COOH, or -(Ci-C6 alkylene)COO(G-C6 alkyl); and (ii) cefditoren pivoxil.

100. The method of claim 99, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


101. The method of claim 99, wherein the compound of formula (I), or a pharmaceutically

acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


102. The method of any one of claims 99-101, wherein the compound of formula (I) or (II) and cefditoren pivoxil are formulated for oral administration.

103. The method of any one of claims 99-102, wherein the compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and cefditoren pivoxil are administered sequentially.

104. The method of any one of claims 99-103, wherein the compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and cefditoren pivoxil are administered concurrently.

105. A method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


wherein:

each R1 and R2 is independently hydrogen, C i -G, alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHG-G, alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, C 1 -G, alkyl, -0(G-G, alkyl), -NfR -NHG-G, alkyl, -N(G-G, alkyl )2. - COOH, -COO(Ci-C6 alkyl), -(G-C6 alkylene)COOH, or -(G-C6 alkylene)COO(G-C6 alkyl); and (ii) cefditoren pivoxil.

106. The method of claim 105, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:

107. The method of claim 105, wherein the compound of formula (I), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


108. The method of any one of claims 105-107, wherein the bacterial infection is caused by

carbapenem-resistant Enterobacteriaceae (CRE) or extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria.

109. The method of any one of claims 105-108, wherein the compound of formula (I) or (II) and cefditoren pivoxil are formulated for oral administration.

110. The method of any one of claims 105-109, wherein the compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof and cefditoren pivoxil are administered sequentially.

111. The method of any one of claims 105-109, wherein the compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof and cefditoren pivoxil are administered concurrently.

112. A pharmaceutical composition comprising:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


wherein:

each R1 and R2 is independently hydrogen, C i -G, alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHG-G, alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, Ci-Ce alkyl, -0(Ci-G, alkyl), -NH2, -NHCi-G, alkyl, -N(G-G, alkyl)2, - COOH, -COO(Ci-C6 alkyl), -(G-C6 alkylene)COOH, or -(Ci-C6 alkylene)COO(G-C6 alkyl); and (ii) cefpodoxime proxetil.

113. The pharmaceutical composition of claim 112, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


114. The pharmaceutical composition of claim 112, wherein the compound of formula (I), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


115. The pharmaceutical composition of any one of claims 112-114, wherein the pharmaceutical composition is formulated for oral administration.

116. The pharmaceutical composition of any one of claims 112-115, wherein the pharmaceutical composition is formulated as an emulsion.

117. The pharmaceutical composition of any one of claims 112-115, wherein the pharmaceutical composition is formulated as a microemulsion.

118. The pharmaceutical composition of any one of claims 112-115, wherein the pharmaceutical composition is formulated as a Self-Emulsifying Drug Delivery System (SEDDS).

119. The pharmaceutical composition of any one of claims 112-118, further comprising a

hydrophilic solubilizer.

120. The pharmaceutical composition of claim 119, wherein the hydrophilic solubilizer is a

hydrophilic polymer.

121. The pharmaceutical composition of claim 120, wherein the hydrophilic polymer is a

polyethylene glycol.

122. The pharmaceutical composition of any one of claims 112-121, further comprising a surfactant.

123. The pharmaceutical composition of claim 122, wherein the surfactant is a polyoxyethylene stearate.

124. The pharmaceutical composition of any one of claims 112-123, further comprising a

pharmaceutically acceptable excipient.

125. The pharmaceutical composition of any one of claims 112-118, further comprising

polyethylene glycol, caprylic/capric glycerides, and tocopheryl polyethylene glycol succinate.

126. The pharmaceutical composition of any one of claims 112-118, further comprising propylene glycol, polyethylene glycol, and tocopheryl polyethylene glycol succinate.

127. The pharmaceutical composition of any one of claims 112-126, wherein the pharmaceutical composition is formulated as a capsule.

128. The pharmaceutical composition of any one of claims 112-126, wherein the pharmaceutical composition is formulated as a tablet.

129. The pharmaceutical composition of any one of claims 112-126, wherein the pharmaceutical composition is formulated as a powder for reconstitution.

130. The pharmaceutical composition of claim 129, wherein the powder for reconstitution is

reconstituted with a liquid carrier to form an oral suspension.

131. The pharmaceutical composition of any one of claims 112-126, wherein the pharmaceutical composition is formulated as a solution.

132. A pharmaceutical composition comprising:

(i) (R) -2 -hydroxy-3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid, or a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and

(ii) cefpodoxime proxetil.

133. A method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid, or a

pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and

(ii) cefpodoxime proxetil.

134. A method of treating a bacterial infection in a subject in need thereof, the method comprising delivering to the subject:

(i) (R) -2 -hydroxy -3 -propionamido-3 ,4 -dihydro -2H-benzo [e] [ 1 ,2] oxaborinine-8 -carboxylic acid or (R)-3-(2-borono-2-propionamidoethyl)-2-hydroxybenzoic acid; and

(ii) cefpodoxime proxetil.

135. The method of claim 134, wherein the bacterial infection is caused by carbapenem -resistant Enterobacteriaceae (CRE) or extended-spectrum beta-lactamase (ESBL) producing gram negative bacteria.

136. The method of claim 134 or 135, wherein the method comprises administering to the subject in need thereof:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


wherein:

each R1 and R2 is independently hydrogen, Ci-Ce alkyl, or -CO(C i-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHG-G, alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, C 1 -G, alkyl, -0(G-G, alkyl), -NfE. -NHG-G, alkyl, -N(G-G, alkyl )2. - COOH, -COO(Ci-C6 alkyl), -(G-C6 alkylene)COOH, or -(G-C6 alkylene)COO(G-C6 alkyl); and (ii) cefpodoxime proxetil.

137. The method of claim 136, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


138. The method of claim 136, wherein the compound of formula (I), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


139. The method of any one of claims 134-138, wherein the compound of formula (I) or (II) and cefpodoxime proxetil are formulated for oral administration.

140. The method of any one of claims 134-139, wherein the compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and cefpodoxime proxetil are administered sequentially.

141. The method of any one of claims 134-139, wherein the compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; and cefpodoxime proxetil are administered concurrently.

142. A method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject:

(i) a compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof:


wherein:

each R1 and R2 is independently hydrogen, C i -G, alkyl, or -CO(Ci-G, alkyl); each alkyl being

optionally substituted with halogen, -OH, -0(Ci-G, alkyl), -NH2, -NHG-G, alkyl, -N(G-G, alkyl)2, -COOH, or -COO(G-C6 alkyl);

or two R2 are taken together to form a 4- to 8-membered heterocycloalkyl optionally substituted with oxo, halogen, -OH, C 1 -G, alkyl, -0(G-G, alkyl), -NfG -NHG-G, alkyl, -N(G-G, alkyl )2. - COOH, -COO(Ci-C6 alkyl), -(Ci-Ce alkylene)COOH, or -(Ci-C6 alkylene)COO(G-C6 alkyl); and

(ii) cefpodoxime proxetil.

143. The method of claim 142, wherein the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


144. The method of claim 143, wherein the compound of formula (I), or a pharmaceutically

acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is:


145. The method of any one of claims 142-144, wherein the bacterial infection is caused by

carbapenem-resistant Enterobacteriaceae (CRE) or extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria.

146. The method of any one of claims 142-145, wherein the compound of formula (I) or (II) and cefpodoxime proxetil are formulated for oral administration.

147. The method of any one of claims 142-146, wherein the compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof and cefpodoxime proxetil are administered sequentially.

148. The method of any one of claims 142-146, wherein the compound of formula (I) or (II); a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof and cefpodoxime proxetil are administered concurrently.