Combination of Pristinamycin IA and Flopristin in the Treatment or Prevention of Bacterial Infections

Abstract

The present invention relates to the discovery of novel antibiotic compositions comprising various ratios of two streptogramins, streptogramin B (e.g., pristinamycin IA) and streptogramin A (e.g., phlopristin), which have synergistic antibacterial activity against Staphylococcus spp., Streptococcus spp., Enterococcus spp., Haemophilus spp., Moraxella spp., Legionella spp., Chlamydia spp., Mycoplasma spp., Ureaplasma spp., Neisseria spp., Gardnerella spp., Bacillus spp., and Francisella spp., as well as other bacterial species. In particular, the present invention relates to pharmaceutical compositions of streptogramin B (e.g., pristinamycin IA) and streptogramin A (e.g., phlopristin) in a weight ratio ranging from about 0:100 to about 99:1 (pristinamycin IA:phlopristin). Additionally, the present invention relates to pharmaceutical compositions and methods for treating and preventing various bacterial infections.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the discovery of novel streptogramin antibiotic compositions containing various ratios of pristinamycin IA and flopristin with antibacterial activity, including activity against Staphylococcus spp., Streptococcus spp., Enterococcus spp., Haemophilus spp., Moraxella spp., Legionella spp., Chlamydia spp., Mycoplasma spp., Ureaplasma spp., Neisseria spp., Gardnerella spp., Bacillus spp., and Francisella spp., as well as other bacterial species. Additional aspects of the invention include the treatment and prevention of various bacterial infections using various combinations of streptogramin B and streptogramin A compounds. [Background technology]

[0002] The introduction of antibiotics once dramatically reduced human morbidity and mortality due to infectious diseases. However, the widespread use of antibiotics has led to the emergence of antibiotic-resistant pathogenic bacteria, resulting in reduced or diminished clinical efficacy and the resulting need for novel antibiotic therapeutic options. Mechanisms of antibiotic resistance include efflux of antibiotics by transporters, prevention of antibiotic interaction with targets by mutations, modification and protection of targets, and modification of antibiotics (Ogawara H “Comparison of Antibiotic Resistance Mechanisms in Antibiotic-Producing and Pathogenic Bacteria” Molecules 2019,vol.24,no.19,3430).

[0003] In 2019, the Centers for Disease Control and Prevention (CDC) published an update to their report on the threat of antibiotic resistance in the United States. The following pathogens were highlighted among these: drug-resistant Neisseria gonorrhoeae, methicillin-resistant Staphylococcus aureus (MRSA), drug-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis (VRE), erythromycin-resistant Streptococcus pyogenes, clindamycin-resistant Streptococcus agalactiae, and drug-resistant Mycoplasma genitalium (CDC: Antibiotic Resistance Threat in the United States, 2019. Atlanta, GA: CDC). Neisseria gonorrhoeae, Streptococcus pneumoniae, MRSA, and VRE are also included in the World Health Organization (WHO) list of priority pathogens requiring new antibiotics (Tacconelli E, et al. “Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis” The Lancet Infectious Diseases 2018,vol.18,no.3,pages 318-327). Both of these lists help clarify public health priorities for the identification and development of new antibiotics.

[0004] Streptogramins are a unique class of antibiotics, notable for their antibacterial activity and their mechanism of action. These antibiotics are naturally produced as secondary metabolites by several Streptomyces species. They consist of two structurally distinct groups of compounds. Streptogramins A or M are macrolactones (polyunsaturated macrocyclic lactones), of which pristinamycin IIA (PIIA) is an example; whereas streptogramins B or S are cyclic hexadepsipeptides, of which pristinamycin IA (PIA) is an example. [ka]

[0005] Streptogramins have demonstrated activity in vitro and in vivo against gram-positive, certain gram-negative, and atypical bacteria as well as aerobic and anaerobic bacteria, including those with multidrug resistance.

[0006] Both groups of streptogramins bind to bacterial ribosomes and inhibit protein synthesis, and they act synergistically in vitro against many bacterial species.

[0007] Streptogramin A components inactivate the donor and acceptor sites of peptidyl transferase. They block two steps of peptide chain elongation: aminoacyl-tRNA binding to the A site of the ribosome and peptide bond formation with peptidyl-tRNA at the P site.

[0008] The streptogramin B components have a more complex mechanism of action that involves inhibition of peptide bond formation with release of an incomplete peptide chain.

[0009] The synergy between the streptogramin A and B components is believed to result from conformational changes imparted to the peptidyl transferase center by the streptogramin A component and by inhibition of both early and late stages of protein synthesis, which enhance ribosome affinity for the streptogramin B component.

[0010] A combination of two streptogramin antibiotics has been approved for use in humans for the treatment of bacterial infections. Pristinamycin is a streptogramin antibiotic that contains pristinamycin IA and pristinamycin IIA, co-produced in a weight ratio of approximately 30:70 by Streptomyces pristinaespiralis, and is used primarily to treat staphylococcal infections, and to a lesser extent streptococcal infections. Pristinamycin is only available for use as a tablet for oral administration, and because of its low oral bioavailability, it needs to be administered in high doses several times a day (1 g 2 to 4 times a day depending on the type of infection). Furthermore, there is a need to improve the efficacy of the composition, as treatment failures have occurred.

[0011] Quinupristin-dalfopristin is the second streptogramin combination approved for human use. The streptogramin B component, quinupristin, is a semisynthetic derivative of pristinamycin IA, and the streptogramin A component, dalfopristin, is a semisynthetic derivative of pristinamycin IIA. The components are mixed in a B:A weight ratio of 30:70. It is available only as an intravenously injectable formulation.

[0012] A third streptogramin combination, linopristin-flopristin, although unapproved, was evaluated in phase 2 human clinical trials for bacterial skin and pneumonia infections. However, development of this combination did not continue beyond phase 2 clinical trials. The streptogramin B component, linopristin, is a semisynthetic derivative of pristinamycin IA. The streptogramin A component, flopristin, is a semisynthetic fluorinated derivative of pristinamycin IIB. This streptogramin combination has been clinically tested in a few different ratios, but the majority of trials used a B:A ratio of 30:70 by weight. [ka]

[0013] Although streptogramins have been a useful class, improved streptogramin combinations with better potency and efficacy are desired to address the constant threat and evolution of antibiotic resistance. Additionally, more antibiotics with bactericidal activity are needed. Bactericidal activity is important for efficacy, since rapid elimination of bacterial load during infection reduces the chance of resistance development. By evaluating the biological activity of different combinations of existing streptogramins, we unexpectedly discovered a unique novel combination of streptogramin B (i.e., pristinamycin IA) and streptogramin A (i.e., phlopristin) that consistently exhibits the most potent activity among all other streptogramin combinations against a range of important bacterial species. Summary of the Invention

[0014] In one embodiment, a composition is provided comprising streptogramin B (e.g., pristinamycin IA or a pharma- ceutically acceptable salt thereof) and streptogramin A (e.g., phlopristin or a pharma- ceutically acceptable salt thereof), wherein the weight ratio of streptogramin B to streptogramin A (streptogramin B:streptogramin A) is about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91, about 10:10, about 11:10, about 12:10, about 13:10, about 14:10, about 15:10, about 16:10, about 17:10, about 18:10, about 19:10, about 20:10, about 21:10, about 22:10, about 23:10, about 24:10, about 25:10, about 26:10, about 27:10, about 28:10, about 29:10, about 30:10, about 31:10, about 32:10, about 33:10, about 34:10, about 35:10, about 36:10, about 37:10, about 38:10, about 39:10, about 40:10, about 40:10, about 41:10, about 42:10, about 43:10, about 44:10, about 45:10, about 46:10, about 47:10, about 48:10, about 49:10, about 50:10, about 50:10, , about 10:90, about 11:89, about 12:88, about 13:87, about 14:86, about 15:85, about 16:84, about 17:83, about 18:82, about 19:81, about 20:80, about 21:79, about 22:78, about 23:77, about 24:76, about 25:75, about 26:74, about 27:73, about 28:72, about 29:71, about 30:70, about 31:69, about 32:68, about 33:67, about 34:66, about 35:65, about 36:64, about 37:63, about 38:62, about 39:6 1, 40:60, 41:59, 42:58, 43:57, 44:56, 45:55, 46:54, 47:53, 48:52, 49:51, 50:50, 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, 60:40, 61:39, 62:38, 63:37, 64:36, 65:35, 66:34, 67:33, 68:32, 69: 31, about 70:30, about 71:29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13, about 88:12, about 89:11, about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, or about 99:1.

[0015] In another embodiment, a composition is provided comprising pristinamycin IA, or a pharma- ceutically acceptable salt thereof, and phlopristin, or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA (PIA) to phlopristin (PIA:phlopristin) is about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91, about 10:90, about 11:89, about 12:88, about 13:87, about 14:10, about 15:15, about 16:10, about 17:15, about 18:16, about 19:17, about 20:20, about 21:20, about 22:24, about 23:25, about 24:26, about 25:27, about 26:28, about 27:29, about 28:30, about 29:31, about 30:32, about 31:33, about 32:34, about 33:35, about 34:36, about 35:37, about 36:38, about 37:39, about 38:39, about 40:39, about 40:39, about 41:36, about 42:38, about 43:39, about 44:39, about 45:39, about 46:39, about 47:39, about 48:39, about 49:39, about 50:39, about 50:39, about 51:39, about 52:39, about 53:39 , about 14:86, about 15:85, about 16:84, about 17:83, about 18:82, about 19:81, about 20:80, about 21:79, about 22:78, about 23:77, about 24:76, about 25:75, about 26:74, about 27:73, about 28:72, about 29:71, about 30:70, about 31:69, about 32:68, about 33:67, about 34:66, about 35:65, about 36:64, about 37:63, about 38:62, about 39:61, about 40:60, about 41:59, about 42 :58, 43:57, 44:56, 45:55, 46:54, 47:53, 48:52, 49:51, 50:50, 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, 60:40, 61:39, 62:38, 63:37, 64:36, 65:35, 66:34, 67:33, 68:32, 69:31, 70:30, about 71:29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13, about 88:12, about 89:11, about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, or about 99:1.

[0016] In another embodiment, a pharmaceutical composition is provided comprising pristinamycin IA, or a pharma- ceutically acceptable salt thereof, and pharmacy-acceptable carrier or excipient, wherein the weight ratio of pristinamycin IA (PIA) to phlopristin (PIA:phlopristin) is about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91, about 10:90, about 11:91, about 12:92, about 13:93, about 14:94, about 15:95, about 16:96, about 17:97, about 18:98, about 19:99, about 20:99, about 21:99, about 22:98, about 23:99, about 24:99, about 25:99, about 26:99, about 27:99, about 28:99, about 29:99, about 30:99, about 31:99, about 32:99, about 33:99, about 34:99, about 35:99, about 36:99, about 37:99, about 38:99, about 39:99, about 40:99, about 41:99, about 42:99, about 43:99, about 44:99, about 45:99, about 46:99, about 47:99, about 48:99, about 49:99, about 50:99, about 51:99, about 52:99, about 53:99, about 54:99, about 55:9 :89, 12:88, 13:87, 14:86, 15:85, 16:84, 17:83, 18:82, 19:81, 20:80, 21:79, 22:78, 23:77, 24:76, 25:75, 26:74, 27:73, 28:72, 29:71, 30:70, 31:69, 32:68, 33:67, 34:66, 35:65, 36:64, 37:63, 38:62, 39:61, 40:60 ,About 41:59,About 42:58,About 43:57,About 44:56,About 45:55,About 46:54,About 47:53,About 48:52,About 49:51,About 50:50,About 51:49,About 52:48,About 53:47,About 54:46,About 55:45,About 56:44,About 57:43,About 58:42,About 59:41,About 60:40,About 61:39,About 62:38,About 63:37,About 64:36,About 65:35,About 66:34,About 67:33,About 68:32,About 69:31,About 70:30, about 71:29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13, about 88:12, about 89:11, about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, or about 99:1.

[0017] In another embodiment, a kit is provided that includes a first composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof, and a second composition comprising phlopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:phlopristin is about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91, about 10:90, about 11:89, about 12:88, about 13:87, about 14:86, about 15:85, about 16:84, about 17:83, about 18:82, about 19:83, about 20:24, about 21:28, about 22:26, ​​about 23:28, about 24:28, about 25:29, about 30:32, about 31:36, about 32:38, about 33:39, about 34:39, about 35:39, about 36:39, about 37:39, about 38:39, about 39:40, about 40:40, about 41:41, about 42:42, about 43:43, about 44:44, about 45:45, about 46:46, about 47:47, about 48:48, about 49:49, about 50:50, about 51:52, about 52:53, about 53:54, about 54:55, about 55:56, about 56:57, about 57:58, about 58:59, about 59:60 9:81, 20:80, 21:79, 22:78, 23:77, 24:76, 25:75, 26:74, 27:73, 28:72, 29:71, 30:70, 31:69, 32:68, 33:67, 34:66, 35:65, 36:64, 37:63, 38:62, 39:61, 40:60, 41:59, 42:58, 43:57, 44:56, 45:55, 46:54, 47:53, 48:52, 49:51, 50:50, 51:49, 52:48 , about 53:47, about 54:46, about 55:45, about 56:44, about 57:43, about 58:42, about 59:41, about 60:40, about 61:39, about 62:38, about 63:37, about 64:36, about 65:35, about 66:34, about 67:33, about 68:32, about 69:31, about 70:30, about 71:29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86 about 96:4, about 97:3, about 98:2, or about 99:1, wherein each component further comprises a pharma- ceutically acceptable carrier or excipient, and the kit is optionally packaged as a blister pack, and the kit comprises instructions for administering the first composition and the second composition simultaneously to a subject in need thereof, or for administering the first composition before or after the second composition is administered.

[0018] In another embodiment, there is provided a method of treating or preventing a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutical acceptable salt thereof and furopristin or a pharma- ceutical acceptable salt thereof, wherein the weight ratio of pristinamycin IA:furopristin is about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:9 1, 10:90, 11:89, 12:88, 13:87, 14:86, 15:85, 16:84, 17:83, 18:82, 19:81, 20:80, 21:79, 22:78, 23:77, 24:76, 25:75, 26:74, 27:73, 28:72, 29:71, 30:70, 31:69, 32:68, 33:67, 34:66, 35:65, 36:64, 37:63, 38:62, 39:6 1, 40:60, 41:59, 42:58, 43:57, 44:56, 45:55, 46:54, 47:53, 48:52, 49:51, 50:50, 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, 60:40, 61:39, 62:38, 63:37, 64:36, 65:35, 66:34, 67:33, 68:32, 69: 31, about 70:30, about 71:29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13, about 88:12, about 89:11, about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, or about 99:1;Bacterial infections may be caused by one or more susceptible and / or resistant gram-positive, gram-negative, atypical, aerobic, and / or anaerobic bacteria, such as Bacillus spp., Bacteroides spp., Bordetella spp., Borrelia spp., Brucella spp., Burkholderia spp., Campylobacter spp., Chlamydia spp., Clostridium spp., Corynebacterium spp., Coxiella spp., Ehrlichia spp., Enterococcus spp., Francisella spp., Fusobacterium spp., Gardnerella spp., species, Haemophilus spp., Kingella spp., Legionella spp., Listeria spp., Moraxella spp., Mycoplasma spp., Mycobacterium spp., Neisseria spp., Nocardia spp., Peptostreptococcus spp., Porphyromonas spp., Propionibacterium spp., Prevotella spp., Rickettsia spp., Salmonella spp., Shigella spp., Staphylococcus spp., Streptococcus spp., Ureaplasma spp., Vibrio spp., or Yersinia spp.

[0019] Also described herein is a method of treating or preventing a respiratory infection and / or disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutical acceptable salt thereof and phlopristin or a pharma- ceutical acceptable salt thereof, wherein the weight ratio of pristinamycin IA:phlopristin is in the range of 1:99 to 99:1, and the respiratory infection and / or disease is selected from the group consisting of susceptible and / or resistant Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, and / or susceptible and / or resistant Streptococcus pneumoniae. and community-acquired or health care-associated pneumonia caused by or in association with one or more strains of bacteria such as Staphylococcus purpura, Legionella spp., Chlamydia pneumoniae, Mycoplasma pneumoniae, Bordetella pertussis, Neisseria gonorrhoeae, Corynebacterium diphtheriae, Coxiella burnetii, Peptostreptococcus spp., Fusobacterium spp., Bacteroides spp., Prevotella spp., Nocardia spp., or Mycobacterium spp.; chronic bronchitis, sinusitis, acute sinusitis, acute exacerbation of chronic bronchitis, pharyngitis, chronic obstructive pulmonary disease, and nontuberculous mycobacterial infections.

[0020] Described herein is a method of treating or preventing a sexually transmitted disease or urogenital infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutical acceptable salt thereof and flopristin or a pharma-ceutical acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin is in the range of 1:99 to 99:1, and wherein the sexually transmitted disease or urogenital infection is caused by or associated with a bacterium, such as by one or more strains of susceptible and / or resistant Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, Ureaplasma parvum, or Gardnerella vaginalis.

[0021] Described herein is a method of treating or preventing skin and / or soft tissue infections and / or diseases in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and flopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin is in the range of 1:99 to 99:1, and wherein the skin and / or soft tissue infections and / or diseases are caused by bacteria such as one or more strains of susceptible and / or resistant Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus viridans, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Corynebacterium spp., or Propionibacterium acnes.

[0022] Described herein is a method of treating or preventing an infection in a subject with cystic fibrosis comprising administering to said subject in need thereof therapeutically effective amounts of pristinamycin IA or a pharma- ceutical acceptable salt thereof and phlopristin or a pharma- ceutical acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin is in the range of 1:99 to 99:1, and wherein the infection or threat of infection is caused by or associated with bacteria, such as one or more strains of susceptible and / or resistant Staphylococcus aureus, Haemophilus influenzae, or Mycobacterium spp.

[0023] Described herein is a method of treating or preventing bone and / or joint infection in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutical acceptable salt thereof and flopristin or a pharma-ceutical acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin is in the range of 1:99 to 99:1, and the infection or threat of infection is determined by the presence of susceptible and / or resistant yellow buds. It is caused by one or more strains of bacteria such as Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus viridans, Salmonella spp., Shigella spp., Campylobacter spp., Yersinia spp., Enterococcus faecalis, Salmonella faecium, Kingella kingae, Corynebacterium spp., Propionibacterium acnes, Chlamydia trachomatis, or Neisseria gonorrhoeae.

[0024] Described herein is a method of treating or preventing endocarditis in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutical acceptable salt thereof and flopristin or a pharma- ceutical acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin is in the range of 1:99 to 99:1, and the infection or threat of infection is caused by bacteria such as one or more strains of susceptible and / or resistant Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus gallolyticus, Streptococcus pyogenes, Streptococcus viridans, Enterococcus faecalis, Yersinia faecium, Haemophilus spp., Kingella spp., Legionella spp., or Corynebacterium spp.

[0025] Described herein is a method of treating or preventing bacteremia or sepsis in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and flopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin is in the range of 1:99 to 99:1, and wherein the infection or threat of infection is caused by one or more strains of susceptible and / or resistant bacteria.

[0026] Described herein is a method of treating or preventing anthrax, tularemia, plague, glanders, or melioidosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and phlopristin or a pharma-ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin is in the range of 1:99 to 99:1, and wherein the infection or threat of infection is caused by one or more strains of bacteria, such as susceptible and / or resistant Bacillus anthracis, Francisella tularensis, Yersinia pestis, Bacillus mallei, or Bacillus pseudomallei.

[0027] Also described herein is a method of treating or preventing a bacterial infection comprising administering to a subject in need thereof a therapeutically effective amount of fulopristin or a pharma- ceutical acceptable salt thereof in a pharma- ceutical acceptable carrier or excipient.

[0028] Described herein is a method of treating or preventing a sexually transmitted disease or urogenital infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising phlopristin or a pharma- ceutical acceptable salt thereof in a pharma-ceutical carrier or excipient, wherein the sexually transmitted disease or urogenital infection is caused by or associated with bacteria, such as by one or more strains of susceptible and / or resistant Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, Ureaplasma parvum, or Gardnerella vaginalis.

[0029] In any of the methods of treating or preventing an infection or condition described herein, the route of administration can be oral, rectal, transmucosal, inhalation, intranasal, topical (including cutaneous, ocular, aural), vaginal, intestinal, buccal, or sublingual administration; intramuscular, subcutaneous, intravenous, or intramedullary injection, as well as parenteral delivery, including intrathecal, epidural, direct intraventricular, intraperitoneal, intraamniotic, intranasal, or intraocular or intraarticular injection.

[0030] In any of the methods of treating or preventing any infectious disease described herein, the subject can be an animal or a human. [Brief description of the drawings]

[0031] [Figure 1] Shown are the results of example checkerboard tests of the streptogramin B and streptogramin A components of novel combinations of Streptogramin B and Streptogramin A #1 (CBA1; page 1 of figure), Pristinamycin IA and Pristinamycin IIA (page 2 of figure), and Linopristin and Flopristin (page 3 of figure) against strains of Staphylococcus aureus. CBA1 is the combination of Pristinamycin IA and Flopristin. Shaded areas represent wells with microbial growth. The MICs of specific streptogramin B:streptogramin A combination ratios are identified by the bold borders surrounding the wells. [Diagram 2] FIG. 1 shows the MIC distribution of CBA1 against various Gram-positive, Gram-negative, and atypical bacterial species compared to known streptogramin combinations pristinamycin IA-pristinamycin IIA, quinupristin-dalfopristin, and / or linopristin-flopristin. Lower values ​​on the x-axis indicate greater biological activity. [Diagram 3] 1 is a graph showing the bactericidal time kinetics activity of CBA1 against multidrug-resistant Neisseria gonorrhoeae strain NCTC 13480 compared to ceftriaxone. Bactericidal activity is defined as a ≧3-log10 reduction in colony forming units (CFU) / mL from baseline. [Figure 4] Efficacy of CBA1 following intravenous (IV) or oral administration against Staphylococcus aureus in a neutropenic thigh infection model is shown. Intra-class comparators included IV quinupristin-dalfopristin and oral pristinamycin IA-pristinamycin IIA. IV vancomycin and oral linezolid served as positive controls. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] Abbreviations and Definitions The terms used herein generally have the ordinary meaning of the term in the art, within the framework of this invention and in the specific context in which each term is used. Certain terms used in describing this disclosure are discussed below or elsewhere herein to provide additional guidance to the practitioner regarding the description of the invention.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, including definitions, the present document will control.

[0034] The term "compound" or "agent" with respect to streptogramins refers to a mixture of streptogramin B and streptogramin A components in weight ratios within the specified ranges.

[0035] The term "minimum inhibitory concentration" (MIC) refers to the lowest concentration of a chemical or compound that prevents visible growth of microorganisms, including bacteria.

[0036] The term "minimum bactericidal concentration" (MBC) refers to the lowest concentration of an antimicrobial agent that reduces the viability of the initial bacterial inoculum by 99.9% or more. It can be determined from a broth dilution minimum inhibitory concentration (MIC) test by subculturing onto agar plates containing no test agent.

[0037] The term "treating" or "treatment" refers to the administration of an effective amount of a therapeutic agent to a subject in need thereof with the goal of curing, alleviating, mitigating, treating, and / or ameliorating a disease. Such subjects can be identified by a medical professional based on the results from any suitable diagnostic method. "Treating" or "treatment" also includes an approach for obtaining a beneficial or desired outcome in a subject's condition, including clinical outcomes. Beneficial or desired clinical outcomes can include, but are not limited to, relief or amelioration of one or more symptoms or conditions, whether partial or total, and whether detectable or undetectable, reduction in the extent of the disease, stabilization (i.e., not worsening) of the disease state, delay or slowing of disease progression, amelioration or relief of the condition, reduction in recurrence of the disease, and remission.

[0038] The terms "prevent", "preventative", "preventive" or "prophylactic" refer to a treatment that reduces the occurrence of disease symptoms (e.g., infectious disease symptoms) in a subject. Prevent, preventative, preventive or prophylactic can be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would occur without the preventative treatment. Prophylactic treatment also refers to pre-treating a subject prior to exposure to an infectious agent.

[0039] The terms "synergy" or "synergism" or "synergistic" refer to an interaction between two or more agents or drugs that produces a total effect of the combined agents or drugs that is greater than the sum of the effects of each agent or drug individually.

[0040] The term "additive effect" refers to when the combined effect of two or more agents or drugs is equal to the sum of the effects of each agent or drug given alone.

[0041] The term "susceptible and / or resistant" strains refers to bacteria that are susceptible, meaning there is a high likelihood of treatment success with this drug regimen, and / or bacteria that are resistant, meaning there is a high likelihood of treatment failure with this drug regimen.

[0042] The term "known" streptogramin combinations refers to combinations of three streptogramins that have been approved for human use or have been tested in human clinical trials, including the combination of pristinamycin IA and pristinamycin IIA, the combination of quinupristin and dalfopristin, and the combination of linopristin and phlopristin.

[0043] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of an agent or composition to a desired site of biological effect.

[0044] The term "subject" refers to an animal, preferably a mammal, most preferably a human, that is the object of treatment, observation, or experiment. Exemplary mammals include mice, rats, rodents, hamsters, gerbils, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, giraffes, elephants, tigers, lions, bears, platypuses, monkeys, chimpanzees, apes, and primates such as humans. Animals may also be birds, exemplified by chickens, turkeys, and other bird species.

[0045] The phrase "pharmacologically acceptable" is used to refer to compounds, materials, compositions, formulations, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or, as the case may be, animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0046] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein and other chemical components, such as diluents, binders, excipients, or carriers, to create a dosage form. A pharmaceutical composition facilitates administration of a compound to a subject.

[0047] The term "about" refers to a range of values ​​including the specified value that one of ordinary skill in the art would consider to be reasonably similar to the specified value. In some embodiments, about refers to within the standard deviation using measurements generally accepted in the art. In some embodiments, about refers to a range extending to ±10% of the specified value. In some embodiments, about encompasses the specified value.

[0048] As used herein, the amount, dose, administration or concentration of any pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and phlopristin or a pharma- ceutically acceptable salt thereof is the sum of the amount or concentration of the free base of pristinamycin IA and phlopristin; the amount, dose, administration or concentration of any pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof or phlopristin or a pharma- ceutically acceptable salt thereof is the amount of the free base of pristinamycin IA or phlopristin, respectively.

[0049] composition As a general proposition, therapeutically or prophylactically effective amounts of streptogramin B (e.g., pristinamycin IA or a pharma- ceutically acceptable salt thereof) and streptogramin A (e.g., phlopristin or a pharma- ceutically acceptable salt thereof), either together in a single pharmaceutical composition (dosage form) or in two separate pharmaceutical compositions (dosage forms), e.g., in a kit, are provided for treating or preventing a bacterial infection or a condition caused by a bacterial infection.

[0050] As a general proposition, in certain embodiments, a therapeutically or prophylactically effective amount of any pharmaceutical composition disclosed herein may be administered in the range of about 10 ng / kg body weight / day to about 100 mg / kg body weight / day, whether administered in one or more doses. In certain embodiments, a therapeutic compound may be administered in the range of about 10 ng / kg body weight / day to about 100 mg / kg body weight / day, about 10 ng / kg body weight / day to about 10 mg / kg body weight / day, about 10 ng / kg body weight / day to about 1 mg / kg body weight / day, about 10 ng / kg body weight / day to about 100 μg / kg body weight / day, about 10 ng / kg body weight / day to about 10 μg / kg body weight / day, about 10 ng / kg body weight / day to about 1 μg / kg body weight / day, about 10 ng / kg body weight / day to about 100 ng / kg body weight / day, about 100 ng / kg body weight / day to about 100 mg / kg body weight / day, about 100 ng / kg body weight / day to about 10 mg / kg body weight / day, about 100 ng / kg body weight / day to about 1 mg / kg body weight / day, about 100 ng / kg body weight / day ~ approx. 100 μg / kg body weight / day, approx. 100 ng / kg body weight / day ~ approx. 10 μg / kg body weight / day, approx. 100 ng / kg body weight / day ~ approx. 1 μg / kg body weight / day, approx. 1 μg / kg body weight / day ~ approx. 100 mg / kg body weight / day, approximately 1 μg / kg body weight / day ~ approximately 10 mg / kg body weight / day, approximately 1 μg / kg body weight / day ~ approximately 1 mg / kg body weight / day, approximately 1 μg / kg body weight / day ~ approximately 100 μg / kg body weight / day, approximately 1 μg / kg body weight / day ~ Approximately 10 μg / kg body weight / day, approximately 10 μg / kg body weight / day to approximately 100 mg / kg body weight / day, approximately 10 μg / kg body weight / day to approximately 10 mg / kg body weight / day, approximately 10 μg / kg body weight / day to approximately 1 mg / kg body weight / day, approximately 10μ The dosage range is about 100 μg / kg body weight / day to about 100 μg / kg body weight / day to about 100 mg / kg body weight / day, about 100 μg / kg body weight / day to about 10 mg / kg body weight / day, about 100 μg / kg body weight / day to about 1 mg / kg body weight / day, about 1 mg / kg body weight / day to about 100 mg / kg body weight / day, about 1 mg / kg body weight / day to about 10 mg / kg body weight / day, or about 10 mg / kg body weight / day to about 100 mg / kg body weight / day.

[0051] In some embodiments, a therapeutically or prophylactically effective amount of any pharmaceutical composition disclosed herein is from about 100 ng to about 1 μg per individual administration, from about 100 ng to about 10 μg per individual administration, from about 100 ng to about 100 μg per individual administration, from about 100 ng to about 1 mg per individual administration, from about 100 ng to about 10 mg per individual administration, from about 100 ng to about 100 mg per individual administration, from about 100 ng to about 1000 mg per individual administration, from about 1 00ng to about 10,000mg, about 1μg to about 10μg per individual administration, about 1μg to about 100μg per individual administration, about 1μg to about 1mg per individual administration, about 1μg to about 10mg per individual administration, about 1μg to about 100mg per individual administration, about 1μg to about 1000mg per individual administration, about 1μg to about 10,000mg per individual administration, about 10μg to about 100μg per individual administration, about 10μg to about 1mg per individual administration, about 10μg to about 10mg per individual administration g, about 10 μg to about 100 mg per individual administration, about 10 μg to about 1000 mg per individual administration, about 10 μg to about 10,000 mg per individual administration, about 100 μg to about 1 mg per individual administration, about 100 μg to about 10 mg per individual administration, about 100 μg to about 100 mg per individual administration, about 100 μg to about 1000 mg per individual administration, about 100 μg to about 10,000 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about The composition is administered in the range of about 100 mg, about 1 mg to about 1000 mg per individual administration, about 1 mg to about 10,000 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1000 mg per individual administration, about 10 mg to about 10,000 mg per individual administration, about 100 mg to about 1000 mg per individual administration, about 100 mg to about 10,000 mg per individual administration, or about 1000 mg to about 10,000 mg per individual administration. The composition is administered once, twice, three times, four times, six times, or eight times daily, and every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, or 4 weeks.

[0052] In some embodiments, any pharmaceutical composition disclosed herein reduces infection or prevents the occurrence of an infection by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0053] In some embodiments, any pharmaceutical composition disclosed herein reduces infection or prevents the occurrence of an infection by, for example, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 100%.

[0054] In yet another aspect of this embodiment, any of the pharmaceutical compositions disclosed herein may be administered in an amount of, for example, about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 9 ... Reduce infection by 0%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0055] The pharmaceutical compositions comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and / or phlopristin or a pharma- ceutically acceptable salt thereof disclosed herein are in an amount sufficient to allow for flexible and routine administration to a subject.

[0056] In some embodiments, a therapeutically or prophylactically effective amount of any pharmaceutical composition disclosed herein is, for example, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 250 mg, at least The pharmaceutical composition may be at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, at least 1,500 mg, at least 1,600 mg, at least 1,700 mg, at least 1,800 mg, at least 1,900 mg, or at least 2,000 mg.

[0057] In some embodiments, a therapeutically effective amount or prophylactically effective amount of any of the pharmaceutical compositions disclosed herein may be in the range of, for example, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, about 1,000 mg to about 1,500 mg, or about 1,200 mg to about 2,000 mg. In yet another aspect of this embodiment, the pharmaceutical composition disclosed herein may be administered in an amount of, for example, about 5 mg to about 250 mg, about 5 mg to about 500 mg, about 5 mg to about 750 mg, about 5 mg to about 1,000 mg, about 5 mg to about 1,500 mg, about 5 mg to about 2,000 mg, about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 10 mg to about 2,000 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 50 mg to about 2,000 mg, or about 1 The dosage may be in the range of about 00 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 100 mg to about 2,000 mg, about 250 mg to about 500 mg, about 250 mg to about 750 mg, about 250 mg to about 1,000 mg, about 250 mg to about 1,500 mg, about 250 mg to about 2,000 mg, about 500 mg to about 750 mg, about 500 mg to about 1,000 mg, about 500 mg to about 1,500 mg, about 500 mg to about 2,000 mg, about 750 mg to about 1,000 mg, about 750 mg to about 1,500 mg, or about 750 mg to about 2,000 mg.

[0058] A therapeutically or prophylactically effective amount of any pharmaceutical composition disclosed herein may comprise, for example, a solvent, emulsion, vehicle, carrier, or diluent in an amount of less than about 90% (v / v), less than about 85% (v / v), less than about 80% (v / v), less than about 75% (v / v), less than about 70% (v / v), less than about 65% (v / v), less than about 60% (v / v), less than about 55% (v / v), less than about 50% (v / v), less than about 45% (v / v), less than about 40% (v / v), less than about 35% (v / v), less than about 30% (v / v), less than about 25% (v / v), less than about 20% (v / v), less than about 15% (v / v), less than about 10% (v / v), less than about 5% (v / v), or less than about 1% (v / v).

[0059] A therapeutically effective amount or a prophylactically effective amount of any pharmaceutical composition disclosed herein may be, for example, about 1% (v / v) to 90% (v / v), about 1% (v / v) to 80% (v / v), about 1% (v / v) to 70% (v / v), about 1% (v / v) to 60% (v / v), about 1% (v / v) to 50% (v / v), about 1% (v / v) to 40% (v / v), about 1% (v / v) to 30% (v / v), about 1% (v / v) to 20% (v / v), about 1% (v / v) to 10% (v / v), about 2 ... %(v / v)~50%(v / v), approximately 2%(v / v)~40%(v / v), approximately 2%(v / v)~30%(v / v), approximately 2%(v / v)~20%(v / v), approximately 2%(v / v)~10%(v / v), approximately 4%(v / v)~50%(v / v), approximately 4%(v / v)~40%(v / v), approximately 4%(v / v)~30%(v / v), approximately 4%(v / v)~20%(v / v), approximately 4%(v / v)~10%(v / v), approximately 6%(v / v)~50%(v / v), approximately 6%(v / v)~4 0%(v / v), approx. 6%(v / v)~30%(v / v), approx. 6%(v / v)~20%(v / v), approx. 6%(v / v)~10%(v / v), approx. 8%(v / v)~50%(v / v), approx. 8%(v / v)~40%(v / v), approx. 8%(v) / v) ~ 30% (v / v), approximately 8% (v / v) ~ 20% (v / v), approximately 8% (v / v) ~ 15% (v / v), or approximately 8% (v / v) ~ 12% (v / v), approximately 25% (v / v) ~ 75% (v / v), approximately 30% (v / v) ~ 60% (v) The composition may contain a solvent, emulsion, vehicle, carrier or other diluent in an amount ranging from about 20% (v / v) to 80% (v / v), about 40% (v / v) to 60% (v / v), about 45% (v / v) to 55% (v / v), about 35% (v / v) to 65% (v / v), about 50% (v / v) to 90% (v / v), about 45% (v / v) to 60% (v / v), about 15% (v / v) to 75% (v / v), about 20% (v / v) to 65% (v / v), or about 25% (v / v) to 50%.

[0060] The final concentration of any therapeutically or prophylactically effective pharmaceutical composition disclosed herein may be any desired concentration.In one aspect of this embodiment, the final concentration of the pharmaceutical composition comprising pristinamycin IA or its pharmaceutically acceptable salt and / or phlopristin or its pharmaceutically acceptable salt may be therapeutically effective.The final concentration of the active ingredient in any pharmaceutical composition disclosed herein may be, for example, at least 0.01mg / mL, at least 0.1mg / mL, at least 1mg / mL, at least 10mg / mL, at least 25mg / mL, at least 50mg / mL, at least 100mg / mL, at least 200mg / mL, at least 500mg / mL, or at least 1,000mg / mL. In another aspect of this embodiment, the final concentration of the pharmaceutical composition in the pharmaceutical composition is, for example, about 0.01 mg / mL to about 1,000 mg / mL, about 0.1 mg / mL to about 1,000 mg / mL, about 1 mg / mL to about 1,000 mg / mL, about 10 mg / mL to about 1,000 mg / mL, about 25 mg / mL to about 1,000 mg / mL, about 50 mg / mL to about 1,000 mg / mL, about 100 mg / mL to about 1,000 mg / mL, about 250 mg / mL to about 1,000 mg / mL, about 500 mg / mL to about 1,000 mg / mL, about 750 mg / mL to about 1,000 mg / mL, about 0.01 mg / mL to about 750 mg / mL, about 0.1 mg / mL to about 750 mg / mL, about 1 mg / mL to about 75 0mg / mL, about 10mg / mL to about 750mg / mL, about 25mg / mL to about 750mg / mL, about 50mg / mL to about 750mg / mL, about 100mg / mL to about 7 50mg / mL, about 250mg / mL to about 750mg / mL, about 500mg / mL to about 750mg / mL, about 0.01mg / mL to about 500mg / mL, about 0.1mg / mL mL ~ approx. 500 mg / mL, approx. 1 mg / mL ~ approx. 500 mg / mL, approx. 10 mg / mL ~ approx. 500 mg / mL, approx. 25 mg / mL ~ approx. 500 mg / mL, approx. 50 mg / m L ~ approx. 500 mg / mL, approx. 100 mg / mL ~ approx. 500 mg / mL, approx. 250 mg / mL ~ approx. 500 mg / mL, approx. 0.01 mg / mL ~ approx. 250 mg / mL, approx. 0.1 mg / mL to about 250 mg / mL, about 1 mg / mL to about 250 mg / mL, about 10 mg / mL to about 250 mg / mL, about 25 mg / mL to about 250 mg / mL, about 50 mg / mL to about 250 mg / mL, about 100 mg / mL to about 250 mg / mL, about 0.01 mg / mL to about 100 mg / mL mL, about 0.1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 100 mg / mL, about 10 mg / mL to about 100 mg / mL, about 25 mg / mL to about 100 mg / mL, about 50 mg / mL to about 100 mg / mL, about 0.01 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 5 The concentration may be in the range of about 0 mg / mL, about 1 mg / mL to about 50 mg / mL, about 10 mg / mL to about 50 mg / mL, about 25 mg / mL to about 50 mg / mL, about 0.01 mg / mL to about 25 mg / mL, about 0.1 mg / mL to about 25 mg / mL, about 1 mg / mL to about 25 mg / mL, about 10 mg / mL to about 25 mg / mL, about 0.01 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 10 mg / mL, about 0.01 mg / mL to about 1 mg / mL, about 0.1 mg / mL to about 1 mg / mL, or about 0.01 mg / mL to about 0.1 mg / mL.

[0061] Some embodiments herein disclose, in part, treating a subject suffering from bacterial infection. As used herein, the term "treating" refers to reducing or eliminating the clinical symptoms of bacterial infection in a subject; or delaying or preventing the onset of clinical symptoms of bacterial infection in a subject. For example, the term "treating" can mean reducing the signs or symptoms of a condition characterized by bacterial infection, for example, by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%. The actual symptoms associated with bacterial infections are well known and can be determined by one of skill in the art taking into account a variety of factors, including, but not limited to, the site of the bacterial infection, the cause of the bacterial infection, the severity of the bacterial infection, the severity of the chronic inflammation, and / or the tissue or organ affected by the bacterial infection. One of skill in the art will know the appropriate symptoms or indicators associated with a particular type of bacterial infection and how to determine whether a subject is a candidate for the treatments disclosed herein.

[0062] A therapeutically effective amount of any pharmaceutical composition disclosed herein can reduce symptoms associated with a bacterial infection by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces symptoms associated with a bacterial infection by, for example, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutical acceptable salt thereof and phlopristin or a pharma-ceutical acceptable salt thereof disclosed herein reduces symptoms associated with a bacterial infection by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 8 ... Reduce by 0%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0063] The therapeutically effective amount of any pharmaceutical composition disclosed herein may typically range from about 10 ng / kg / day to about 100 mg / kg / day. The pharmaceutical composition may be administered, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, or 4 weeks. The effective amount of any pharmaceutical composition disclosed herein may be, for example, at least 10 ng / kg / day, at least 0.1 mg / kg / day, at least 1.0 mg / kg / day, at least 5.0 mg / kg / day, at least 10 mg / kg / day, at least 15 mg / kg / day, at least 20 mg / kg / day, at least 25 mg / kg / day, at least 30 mg / kg / day, at least 35 mg / kg / day, at least 40 mg / kg / day, at least 45 mg / kg / day, or at least 50 mg / kg / day, for example, administered every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, or 4 weeks. An effective amount of any of the pharmaceutical compositions disclosed herein may be, for example, about 10 ng / kg / day to about 10 mg / kg / day, about 10 ng / kg / day to about 15 mg / kg / day, about 10 ng / kg / day to about 20 mg / kg / day, about 10 ng / kg / day to about 25 mg / kg / day, about 10 ng / kg / day to about 30 mg / kg / day, about 10 ng / kg / day to about 35 mg / kg / day, about 1 The dose may be in the range of 0 ng / kg / day to about 40 mg / kg / day, about 10 ng / kg / day to about 45 mg / kg / day, about 10 ng / kg / day to about 50 mg / kg / day, about 10 ng / kg / day to about 75 mg / kg / day, or about 10 ng / kg / day to about 100 mg / kg / day, for example, administered every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, or 4 weeks.An effective amount of any of the pharmaceutical compositions disclosed herein may be, for example, about 0.1 mg / kg / day to about 10 mg / kg / day, about 0.1 mg / kg / day to about 15 mg / kg / day, about 0.1 mg / kg / day to about 20 mg / kg / day, about 0.1 mg / kg / day to about 25 mg / kg / day, about 0.1 mg / kg / day to about 30 mg / kg / day, about 0.1 mg / kg / day to about 35 mg / kg / day, about 0.1 mg / kg / day to about 1 ...6 mg / kg / day, about 0.1 mg / kg / day to about 17 mg / kg / day, about 0.1 mg / kg / day to about 18 mg / kg / day, about 0.1 mg / kg / day to about 19 mg / kg / day, about 0.1 mg / kg / day to about 20 mg / kg / day, about 0.1 mg / kg / day to about 25 mg / kg / day, about 0.1 mg / kg / day to about 30 mg / kg / day, about 0.1 mg / kg / day to about 35 mg / kg / day, about 0.1 mg / kg / day to about 25 mg / kg / day, about 0.1 mg / kg / day to about 30 mg / kg / day, about 0.1 mg / kg / day to The dose may range from about 0.1 mg / kg / day to about 40 mg / kg / day, from about 0.1 mg / kg / day to about 45 mg / kg / day, from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.1 mg / kg / day to about 75 mg / kg / day, or from about 0.1 mg / kg / day to about 100 mg / kg / day, for example, administered every 1, 2, 3, 4, 5, 6 or 7 days, or every 1, 2, 3 or 4 weeks. An effective amount of any of the pharmaceutical compositions disclosed herein may be in the range of, for example, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 15 mg / kg / day, about 1 mg / kg / day to about 20 mg / kg / day, about 1 mg / kg / day to about 25 mg / kg / day, about 1 mg / kg / day to about 30 mg / kg / day, about 1 mg / kg / day to about 35 mg / kg / day, about 1 mg / kg / day to about 40 mg / kg / day, about 1 mg / kg / day to about 45 mg / kg / day, about 1 mg / kg / day to about 50 mg / kg / day, about 1 mg / kg / day to about 75 mg / kg / day, or about 1 mg / kg / day to about 100 mg / kg / day, for example, administered every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, or 4 weeks.

[0064] In liquid, suspension, and semi-solid formulations, the concentration of any therapeutic composition disclosed herein may be about 0.01 mg / mL to about 1,000 mg / mL. The therapeutically effective amount of any pharmaceutical composition disclosed herein may be, for example, about 0.01 mg / mL to about 1,000 mg / mL, about 0.1 mg / mL to about 1,000 mg / mL, about 1 mg / mL to about 1,000 mg / mL, about 10 mg / mL to about 1,000 mg / mL, about 25 mg / mL to about 1,000 mg / mL, about 50 mg / mL to about 1,000 mg / mL, about 100 mg / mL to about 1,000 mg / mL, about 200 mg / mL to about 1,000 mg / mL, about 50 ... Approximately 1,000mg / mL, approximately 750mg / mL to approximately 1,000mg / mL, approximately 1mg / mL to approximately 10mg / mL, approximately 1mg / mL to approximately 50mg / mL, approximately 1mg / mL to approximately 100mg / mL, approximately 1mg / mL to approximately 200mg / mL, approximately 1m g / mL~about 300mg / mL, about 1mg / mL~about 400mg / mL, about 1mg / mL~about 500mg / mL, about 1mg / mL~about 600mg / mL, about 1mg / mL~about 700mg / mL, about 1mg / mL~about 800mg / mL, about 1 mg / mL to approx. 900 mg / mL, approx. 1 mg / mL to approx. 1,000 mg / mL, approx. 10 mg / mL to approx. 50 mg / mL, approx. 10 mg / mL to approx. 100 mg / mL, approx. 10 mg / mL to approx. 200 mg / mL, approx. 10 mg / mL to approx. 300 mg / mL, about 10mg / mL to about 400mg / mL, about 10mg / mL to about 500mg / mL, about 10mg / mL to about 600mg / mL, about 10mg / mL to about 700mg / mL, about 10mg / mL to about 800mg / mL, about 10mg / mL ~900mg / mL, 10mg / mL~1,000mg / mL, 50mg / mL~100mg / mL, 50mg / mL~200mg / mL, 50mg / mL~300mg / mL, 50mg / mL~400mg / mL , about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 600 mg / mL, about 50 mg / mL to about 700 mg / mL, about 50 mg / mL to about 800 mg / mL, about 50 mg / mL to about 900 mg / mL, about 50 mg / mL to about 1,000mg / mL, about 100mg / mL to about 200mg / mL, about 100mg / mL to about 300mg / mL, about 100mg / mL to about 400mg / mL, about 100mg / mL to about 500mg / mL, about 100mg / mL to about 6 00mg / mL, approximately 100mg / mL to approximately 700mg / mL, approximately 100mg / mL to approximately 800mg / mL, approximately 100mg / mL to approximately 900mg / mL, approximately 100mg / mL to approximately 1,000mg / mL, approximately 200mg / mL to approximately 300mg / mL, about 200mg / mL to about 400mg / mL, about 200mg / mL to about 500mg / mL, about 200mg / mL to about 600mg / mL, about 200mg / mL to about 700mg / mL, about 200mg / mL to about 8 00mg / mL, about 200mg / mL to about 900mg / mL, about 200mg / mL to about 1,000mg / mL, about 300mg / mL to about 400mg / mL, about 300mg / mL to about 500mg / mL, about 300mg / mL to about 6 00mg / mL, approximately 300mg / mL to approximately 700mg / mL, approximately 300mg / mL to approximately 800mg / mL, approximately 300mg / mL to approximately 900mg / mL, approximately 300mg / mL to approximately 1,000mg / mL, approximately 400mg / mL to approximately 500mg / mL, about 400mg / mL to about 600mg / mL, about 400mg / mL to about 700mg / mL, about 400mg / mL to about 800mg / mL, about 400mg / mL to about 900mg / mL, about 400mg / mL to about 1 The concentration may be about 500 mg / mL to about 600 mg / mL, about 500 mg / mL to about 700 mg / mL, about 500 mg / mL to about 800 mg / mL, about 500 mg / mL to about 900 mg / mL, about 500 mg / mL to about 1,000 mg / mL, about 600 mg / mL to about 700 mg / mL, about 600 mg / mL to about 800 mg / mL, about 600 mg / mL to about 900 mg / mL, or about 600 mg / mL to about 1,000 mg / mL.

[0065] The dosage may be a single dose or a cumulative dose (sequential administration), and can be easily determined by one skilled in the art. For example, the treatment of bacterial infection may include a one-time administration of an effective amount of any pharmaceutical composition disclosed herein. Alternatively, the treatment of bacterial infection may include multiple administrations of an effective amount of any pharmaceutical composition disclosed herein, carried out over a range of times or periods, such as once a day, twice a day, three times a day, four times a day, six times a day, eight times a day, and / or every 1, 2, 3, 4, 5, 6 or 7 days, or every 1, 2, 3 or 4 weeks. The timing of administration may vary from subject to subject, depending on factors such as the severity of the subject's symptoms. For example, an effective amount of any pharmaceutical composition disclosed herein may be administered to a subject once a day or twice a day for an indeterminate period of time, or until the subject no longer requires treatment. One skilled in the art will recognize that the subject's condition may be monitored throughout the course of treatment, and the effective amount of any pharmaceutical composition disclosed herein administered may be adjusted accordingly.

[0066] A therapeutically effective amount of any pharmaceutical composition disclosed herein can reduce the number of bacterial cells of a bacterial infection or the severity of the infection in a subject suffering from a bacterial infection by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% compared to a subject not receiving the same treatment.

[0067] A therapeutically effective amount of any of the pharmaceutical compositions disclosed herein can reduce the number of bacterial cells of a bacterial infection or the severity of a bacterial infection in a subject suffering from a bacterial infection by, for example, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or at least about 100% compared to a subject not receiving the same treatment.

[0068] A therapeutically effective amount of any pharmaceutical composition disclosed herein may reduce the number of bacterial cells or the severity of a bacterial infection in a subject suffering from a bacterial infection, as compared to a subject not receiving the same treatment, by, for example, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 100%, about 120% to about 100%, about 130% to about 100%, about 140% to about 100%, about 150% to about 100%, about 160% to about 100%, about 170% to about 100%, about 180% to about 100%, about 190% to about 100%, about 20% to about 100%, about 21% to about 210%, about 22% to about 220%, about 23% to about 230%, about 24% to about 240%, about 25% to about 250%, about 26% to about 260%, about 27% to about 270%, about 28% to about 280%, about 29% to about 300%, about 30% to about 300%, about 31% to about 310%, about 32% to about 320%, about 33% to about 330%, about 34% to about 340%, about 35% to about 350%, about 36% to about 360%, about 37% to about 370%, about 38% to about 380%, about 39% to about 390%, about 40% to about 4 The reduction can be about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0069] A therapeutically effective amount of any pharmaceutical composition disclosed herein may have a half-life of about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months or longer.

[0070] The period (or duration) of administration of a therapeutically effective amount of any of the pharmaceutical compositions disclosed herein can be for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, administration is suspended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0071] A therapeutically effective amount of any pharmaceutical composition disclosed herein may reduce bacterial infection and / or bacterial load in a subject by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0072] A therapeutically effective amount of any pharmaceutical composition disclosed herein may reduce a bacterial infection and / or bacterial load in a subject by, for example, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 100%.

[0073] A therapeutically effective amount of any of the disclosed pharmaceutical compositions may reduce bacterial infection and / or bacterial load in a subject by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0074] Any pharmaceutical composition disclosed herein can reduce the frequency of symptoms of disorders associated with bacterial infections suffered over a given period of time. Any pharmaceutical composition disclosed herein can reduce the frequency of symptoms of disorders associated with bacterial infections suffered over a given period of time, for example, by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In other aspects of this embodiment, any of the pharmaceutical compositions disclosed herein can be used to reduce the frequency of symptoms of a disorder associated with a bacterial infection over a given period of time, e.g., by about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 9 ...5 % to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0075] Any of the methods of treatment herein may include administering (e.g., simultaneously or sequentially) a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and phlopristin or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and phlopristin or a pharma- ceutically acceptable salt thereof, in a pharma- ceutical effective amount of the two active ingredients combined. The total daily amount should be determined by the physician using sound medical judgment and administered once or several times. The specific therapeutically effective amount level for any particular subject may vary depending on a variety of factors well known in the medical art, including the type and degree of response to be achieved, the pharmaceutical composition depending on whether other drugs are used together, the age, weight, health, sex, and diet of the patient, the time and route of administration, the rate of excretion of the pharmaceutical composition, the duration of therapy, other drugs used in combination or simultaneously with any of the pharmaceutical compositions disclosed herein, and similar factors well known in the medical art.

[0076] In yet another aspect, the present specification provides the use of a therapeutic composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and furopristin or a pharma- ceutically acceptable salt thereof, or the use of a composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and a composition comprising furopristin or a pharma- ceutically acceptable salt thereof, for the prophylaxis or treatment of a bacterial infection.

[0077] In yet another aspect, the present disclosure provides the use of a therapeutic composition comprising phlopristin or a pharma- ceutically acceptable salt thereof for the prevention or treatment of a bacterial infection.

[0078] In one embodiment, the therapeutic dose of any pharmaceutical composition disclosed herein can be administered daily, twice weekly, weekly, biweekly, or monthly.The duration of treatment can be 1 week, 2 weeks, 1 month, 2 months, 4 months, 6 months, 8 months, 1 year, or longer.The initial dose can be higher than the maintenance dose.

[0079] In one embodiment, the weekly therapeutic dose of any of the pharmaceutical compositions disclosed herein may be at least 0.05 mg / kg, at least 0.25 mg / kg, at least 0.5 mg / kg, at least 0.75 mg / kg, at least 1 mg / kg, at least 2.5 mg / kg, at least 5 mg / kg, at least 25 mg / kg, at least 50 mg / kg, at least 100 mg / kg, at least 250 mg / kg, or at least 500 mg / kg.

[0080] In one embodiment, the weekly therapeutic dose may be up to 1 mg / kg, up to 2.5 mg / kg, up to 5 mg / kg, up to 10 mg / kg, up to 25 mg / kg, up to 50 mg / kg, up to 100 mg / kg, up to 250 mg / kg, up to 500 mg / kg, or up to 700 mg / kg. In certain aspects, the weekly dosage may range from 0.01 mg / kg to 200 mg / kg. In alternative aspects, the weekly therapeutic dose may range from 1 mg / kg to 100 mg / kg. In alternative aspects, the weekly dosage may range from 5 mg / kg to 75 mg / kg.

[0081] The present specification also provides a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and phlopristin or a pharma- ceutically acceptable salt thereof, and a pharmaceutical composition comprising phlopristin or a pharma- ceutically acceptable salt thereof, for administration to a subject.The pharmaceutical composition disclosed herein may further comprise a pharma- ceutically acceptable carrier, vehicle, excipient, or diluent.As used herein, the term "pharmaceutically acceptable" means that the composition is sufficient to achieve a therapeutic effect without harmful side effects, and can be easily determined according to the type of disease, the age, weight, health condition, sex, and drug sensitivity of the patient, the route of administration, the mode of administration, the frequency of administration, the duration of treatment, the drugs used in combination or simultaneously with the composition disclosed herein, and other factors known in medicine.

[0082] The pharmaceutical compositions disclosed herein may further comprise a pharma- ceutically acceptable carrier.For oral administration, the carrier may comprise, but is not limited to, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a surfactant, an emulsifier, a thickener, a coloring agent, and / or a flavoring agent.For injectable preparations, the carrier may comprise a buffer, a preservative, an analgesic, a solubilizer, a cosolvent, an emulsifier, an isotonic agent, and / or a stabilizing agent.For topical preparations, the carrier may comprise a base, an excipient, a lubricant, a gel, an ointment, a cream, an emulsion, a foaming agent, a propellant, and / or a preservative.

[0083] The pharmaceutical compositions disclosed herein may be combined with the above-mentioned pharma- ceutically acceptable carriers and formulated into various dosage forms.For example, for oral administration, the pharmaceutical compositions may be formulated into tablets, troches, capsules (hard or soft), caplets, granules, powders, sachets, sprinkles, lozenges, fast-dissolving strips, elixirs, emulsions, suspensions, syrups or wafers.The pharmaceutical compositions may be formulated into suppositories.For injectable preparations, the pharmaceutical compositions may be formulated into ampoules as single-dose forms or into multi-dose containers.The pharmaceutical compositions for injections may also be formulated into lyophilized powders, solutions, suspensions, emulsions, nanoparticles such as liposomes, micellar dispersions, gels, or long-acting preparations.

[0084] On the other hand, examples of carriers, excipients and diluents suitable for pharmaceutical preparations include, but are not limited to, lactose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl oxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.In addition, pharmaceutical preparations may further include fillers, anticoagulants, lubricants, humectants, flavorings and preservatives.

[0085] The pharmaceutical compositions disclosed herein are formulated into unitary dosage forms suitable for the patient's body, preferably formulated into formulations by methods typical in the pharmaceutical art to be administered by oral, parenteral or topical routes, including, but not limited to, intravenous, intramuscular, intraarterial, intramedullary, intraventricular, intrathecal, epidural, pulmonary, inhalation, transdermal, subcutaneous, intraperitoneal, intranasal, intracolonic, ocular, intraocular, sublingual, vaginal, or rectal administration.

[0086] The pharmaceutical compositions disclosed herein can be used by mixing with various pharma- ceutical acceptable carriers, such as saline or organic solvents or polymers. To enhance stability or absorbance, carbohydrates such as glucose, sucrose or dextran, surfactants, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, polymers, or other stabilizers can be used.

[0087] The amount and frequency of administration of the pharmaceutical compositions disclosed herein will be determined by the type of active ingredient, along with various factors such as the disease being treated, the route of administration, the age, sex, and weight of the subject, and the severity of the disease.

[0088] The total effective dose of the pharmaceutical composition disclosed herein may be administered to a subject in a single dose or may be administered over an extended period of time in multiple doses according to a divided treatment protocol. In the pharmaceutical composition disclosed herein, the content and amount of the active ingredient may vary depending on the severity of the disease. Preferably, the total effective dose or daily therapeutic dose of any pharmaceutical composition disclosed herein may be about 0.01 μg to about 100 mg per kg of the subject's body weight. However, the effective dose of an antibiotic is determined by considering various factors including the subject's age, body weight, health condition, sex, disease severity, diet, other co-administered drugs, in addition to the route of administration of the pharmaceutical composition and the number of treatments. In view of this, a person skilled in the art may easily determine a suitable effective dose for a particular use of the pharmaceutical composition disclosed herein. The pharmaceutical composition disclosed herein is not particularly limited to the formulation, and the route and mode of administration, so long as it shows a suitable effect.

[0089] Additionally, the pharmaceutical compositions disclosed herein may be administered in combination with or simultaneously with other pharmaceutical preparations, either in conjunction with or within an active agent that exhibits prophylactic or therapeutic efficacy.

[0090] Given the teachings and guidance provided herein, one of skill in the art will also understand that the formulations described herein are equally applicable to many types of antibiotics and other therapeutic compounds, including those exemplified as well as others known in the art. Given the teachings and guidance provided herein, one of skill in the art will also understand that, for example, the selection of the type and / or amount of one or more excipients, surfactants and / or optional ingredients will be made based on chemical and functional compatibility with the formulated biopharmaceutical and / or method of administration, as well as other chemical, functional, physiological and / or medical factors well known in the art.

[0091] In various embodiments, the pharmaceutical compositions disclosed herein may also include, but are not limited to, two or more different therapeutic compounds for single or multiple conditions. The use of multiple therapeutic compounds in a formulation may, for example, target the same or different symptoms. Similarly, in another embodiment, multiple therapeutic compounds may be used in a formulation, for example, to treat both a pathological condition and one or more side effects caused by a primary treatment. In further embodiments, multiple therapeutic compounds may also be included in a pharmaceutical composition described herein, but are not limited to, to achieve different medical goals, including, for example, simultaneous treatment and monitoring the progression of a pathological condition. In additional embodiments, multiple, simultaneous treatments, such as those exemplified herein, as well as other combinations known in the art, are particularly useful for patient compliance, since a single pharmaceutical composition may be sufficient for some or all of the suggested treatments and / or diagnoses. Those skilled in the art will recognize therapeutic compounds that can be combined for a wide range of combination therapies. Similarly, in various embodiments, a first therapeutic compound can be used with a second or more therapeutic compounds, and combinations of one or more therapeutic compounds together with one or more other therapeutic compounds, including small molecules (e.g., another antibiotic) or antibody pharmaceuticals. Thus, in various embodiments, formulations are provided that include one, two, three, four, five, or six or more different therapeutic compounds, as well as for one or more therapeutic compounds in combination with one or more other therapeutic compounds.

[0092] In various embodiments, the pharmaceutical compositions disclosed herein may include one or more preservatives and / or additives known in the art. Similarly, the pharmaceutical compositions can be further formulated into various known delivery formulations, without limitation. For example, in certain embodiments, the pharmaceutical compositions may include surfactants, adjuvants, biodegradable polymers, hydrogels, and the like, and such optional components, their chemical and functional properties are known in the art. Similarly, pharmaceutical compositions that promote rapid, sustained or delayed release of bioactive agents after administration are also known in the art. The formulations described can be made to include these or other formulation components known in the art.

[0093] In any of the methods or compositions described herein, the weight ratio of pristinamycin IA to phlopristin (PIA phlopristin) is about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91, about 10:90, about 11:89, about 12:88, about 13:87, about 14:86, about 15:85, about 16:84, about 17:83, about 18:82, about 19:83, about 20:25, about 21:26, about 22:27, about 23:28, about 24:29, about 25:30, about 26:31, about 27:32, about 28:33, about 29:34, about 30:35, about 31:36, about 32:37, about 33:38, about 34:39, about 35:39, about 36:39, about 37:38, about 38:39, about 39:40, about 40:41, about 41:42, about 42:43, about 43:44, about 44:45, about 45:46, about 46:47, about 47:48, about 48:49, about 49:50, about 50:51, about 50:52, about 51:53, about 52:54, about 53:55, about 54:56, about 55:57, about 56:58, about 57:59, about 58:59, about 59:60, 9:81, approx. 20:80, approx. 21:79, approx. 22:78, approx. 23:77, approx. 24:76, approx. 25:75, approx. 26:74, approx. 27:73, approx. 28:72, approx. 29:71, approx. 30:70, approx. 31:69, approx. 32:68, approx. 33:67, approx. 34:66, approx. 35:65, approx. 36:64, approx. 37:63, approx. 38:62, approx. 39:61, approx. 40:60, approx. 41:59, approx. 42:58, approx. 43:57, approx. 44:56, approx. 45:55, 46:54, 47:53, 48:52, 49:51, 50:50, 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, 60:40, 61:39, 62:38, 63:37, 64:36, 65:35, 66:34, 67:33, 68:32, 69:31, 70:30, 71:29, 72:2 8, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13, about 88:12, about 89:11, about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, or about 99:1.

[0094] The term "pharmaceutically acceptable salts" is meant to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein.When compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When compounds disclosed herein contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as those derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galacturonic acid (e.g., Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0095] Certain compounds disclosed herein can exist in unsolvated and solvated forms, including hydrated forms.In general, solvated forms are equivalent to nonsolvated forms and are included within the scope of the present disclosure.Certain compounds disclosed herein can exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the use contemplated by the present disclosure and are intended to be included within the scope of the present disclosure.

[0096] Pharmaceutical Compositions In certain embodiments, the pharmaceutical composition comprises pristinamycin IA, or a pharma- ceutically acceptable salt thereof, and pharmacytically acceptable salt thereof, wherein the weight ratio of pristinamycin IA to phlopristin (PIA:phlopristin) is about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91, about 10:90, about 11:89, about 12:88, about 13:87, about 14: 86, 15:85, 16:84, 17:83, 18:82, 19:81, 20:80, 21:79, 22:78, 23:77, 24:76, 25:75, 26:74, 27:73, 28:72, 29:71, 30:70, 31:69, 32:68, 33:67, 34:66, 35:65, 36:64, 37:63, 38:62, 39:61, 40:60, 41:59, 42:58 , approx. 43:57, approx. 44:56, approx. 45:55, approx. 46:54, approx. 47:53, approx. 48:52, approx. 49:51, approx. 50:50, approx. 51:49, approx. 52:48, approx. 53:47, approx. 54:46, approx. 55:45, approx. 56:44, approx. 57:43, approx. 58:42, approx. 59:41, approx. 60:40, approx. 61:39, approx. 62:38, approx. 63:37, approx. 64:36, approx. 65:35, approx. 66:34, approx. 67:33, approx. 68:32, approx. 69:31, approx. 70:30, approx. 71:29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13, about 88:12, about 89:11, about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, or about 99:1.

[0097] In another embodiment, a kit is provided that includes a first composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof, and a second composition comprising phlopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:phlopristin is about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91, about 10:90, about 11:89, about 12:88, about 13:87, about 14:86, about 15:85, about 16:84, about 17:83, about 18:82, about 19:83, about 20:24, about 21:28, about 22:26, ​​about 23:28, about 24:28, about 25:29, about 30:32, about 31:36, about 32:38, about 33:39, about 34:39, about 35:39, about 36:39, about 37:39, about 38:39, about 39:40, about 40:40, about 41:41, about 42:42, about 43:43, about 44:44, about 45:45, about 46:46, about 47:47, about 48:48, about 49:49, about 50:50, about 51:52, about 52:53, about 53:54, about 54:55, about 55:56, about 56:57, about 57:58, about 58:59, about 59:60 9:81, about 20:80, about 21:79, about 22:78, about 23:77, about 24:76, about 25:75, about 26:74, about 27:73, about 28:72, about 29:71, about 30:70, about 31:69, about 32:68, about 33:67, about 34:66, about 35:65, about 36:64, about 37:63, about 38:62, about 39:61, about 40:60, about 41:59, about 42:58, about 43:57, about 44:56, about 45:55, about 46:54, about 47:53, about 48:52, about 49:51, about 50:50, about 51:49, about 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, 60:40, 61:39, 62:38, 63:37, 64:36, 65:35, 66:34, 67:33, 68:32, 69:31, 70:30, 71:29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 80:20, 81:19, 82:18, 83:17, 84:16, 85:15, 86:1 about 96:4, about 97:3, about 98:2, or about 99:1, wherein each composition further comprises a pharma- ceutically acceptable carrier or excipient, and the kit is optionally packaged as a blister pack, and the kit comprises instructions for administering the first composition and the second composition simultaneously to a subject in need thereof, or for administering the first composition before or after the second composition is administered.

[0098] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that can aid in the administration of an active agent to and absorption by a subject, or facilitate the distribution or delivery of an active ingredient to a site of action, and can be included in the compositions disclosed herein without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating materials, sweeteners, flavorings, saline (such as Ringer's solution), alcohol, oils, lipids, gelatin, lactose, carbohydrates such as amylase or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, polymers, and colorants. Such formulations can be sterilized and, as necessary, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, surfactants, salts for influencing osmotic pressure, buffers, coloring agents, flavoring and / or aromatic substances and substances which do not deleteriously react with the compounds of the present disclosure. Those skilled in the art will appreciate that other pharmaceutical excipients are useful in the present disclosure.

[0099] Pharmaceutical preparations for parenteral administration, for example by bolus injection or continuous infusion, include aqueous solutions of the active compound in water-soluble form. In addition, suspensions or emulsions of the active compound can be prepared as suitable oily injection nanosuspensions or nanoemulsions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or other organic oils, such as soybean, grapefruit or almond oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or phospholipids or other lipids. Aqueous injection suspensions can include substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension can also include suitable stabilizers or surfactants or agents that increase the solubility of the compound to allow the preparation of semisolids, such as highly concentrated solutions, suspensions, emulsions or gels. Preparations for injection can be provided in unit dosage form, for example in ampoules or in multi-dose containers with added preservatives. The composition may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. The active ingredient may also be complexed with proteins (such as albumin), macromolecules, or formulated into hydrophilic gels, or into liposomes or other injectable preparations.

[0100] For topical administration, pharmaceutical compositions may be formulated as known in the art for direct application to target areas. Forms primarily adapted for topical administration take the form of, for example, creams, emulsions, gels, powders, dispersions or microemulsions, eye drops, ear drops, nose drops, more or less concentrated lotions, impregnated pads, transdermal patches, ointments or adhesives, aerosol preparations (e.g., sprays or foams), soaps, soap washes, lotions or cakes. Pharmaceutical compositions may also be formulated for topical administration in the mouth or throat. For example, the active ingredient may be formulated as lozenges, which further comprise a flavored base, usually sucrose and gum arabic or tragacanth; pastilles, which comprise the composition in an inert base such as gelatin and glycerin or sucrose and gum arabic; mouthwashes, which comprise the composition of the present invention in a suitable liquid carrier.

[0101] For oral administration, the compound can be easily formulated by combining the active compound with pharma- ceutically acceptable carriers well known in the art. Such carriers allow the compound of the present invention to be formulated as tablets, pills, dragees, capsules, caplets, liquids, gels, films, syrups, elixirs, slurries, sachets, powders, sprinkles, pellets, fast-dissolving strips, suspensions, emulsions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and optionally adding suitable auxiliary agents to obtain tablets or dragee cores, followed by processing the mixture of granules. Suitable excipients are, inter alia, fillers such as sucrose, including lactose, sucrose, mannitol, or sorbitol; cellulose blends, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; and / or polyvinylpyrrolidone (PVP). If necessary, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, for example, sodium alginate.

[0102] In addition, pharmaceutical compositions can be formulated as sustained release dosage forms and the like. Formulations can be constructed so that they release active agents, perhaps over a period of time, for example, in a particular part of the intestine or airway. Coatings, coverings, and protective matrices can be made from polymeric substances, such as polylactic-glycolic acid, liposomes, microemulsions, microparticles, nanoparticles, or waxes. These coatings, coverings, and protective matrices are useful for coating indwelling devices, such as stents, catheters, peritoneal dialysis tubing, drainage devices, and the like.

[0103] The pharmaceutical compositions of the present invention can also be administered to the respiratory tract. For administration by inhalation or insufflation, the compositions can take the form of a nebulized liquid or dry powder, e.g., a powder mixture of the therapeutic agent and a suitable powder base, such as lactose or starch. The pharmaceutical compositions of the present invention, when administered in aerosol or inhalation form, may be administered in an aqueous solution or nanoparticle suspension. Thus, other aerosol pharmaceutical formulations may be administered in concentrations of, for example, about 0.01 mg / mL to about 1,000 mg / mL, about 0.1 mg / mL to about 1,000 mg / mL, about 1 mg / mL to about 1,000 mg / mL, about 10 mg / mL to about 1,000 mg / mL, about 25 mg / mL to about 1,000 mg / mL, about 50 mg / mL to about 1,000 mg / mL, about 100 mg / mL to about 1,000 mg / mL, about 200 mg / mL to about 1,000 mg / mL, about 50 ...10 mg / mL to about 1,000 mg / mL, about 10 mg / mL to about 1,000 mg / mL, about 10 mg / mL to about 1,000 mg / mL, about 10 mg / mL to about 1,000 mg / mL mL, about 750 mg / mL to about 1,000 mg / mL, about 1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 200 mg / mL, about 1 mg / mL to about 3 00mg / mL, approximately 1mg / mL to approximately 400mg / mL, approximately 1mg / mL to approximately 500mg / mL, approximately 1mg / mL to approximately 600mg / mL, approximately 1mg / mL to approximately 700mg / mL, approximately 1mg / mL to approximately 800mg / mL, approximately 1mg / mL to Approximately 900mg / mL, approximately 1mg / mL to approximately 1,000mg / mL, approximately 10mg / mL to approximately 50mg / mL, approximately 10mg / mL to approximately 100mg / mL, approximately 10mg / mL to approximately 200mg / mL, approximately 10mg / mL to approximately 300mg / mL, Approximately 10 mg / mL to approximately 400 mg / mL, approximately 10 mg / mL to approximately 500 mg / mL, approximately 10 mg / mL to approximately 600 mg / mL, approximately 10 mg / mL to approximately 700 mg / mL, approximately 10 mg / mL to approximately 800 mg / mL, approximately 10 mg / mL to approximately 9 00mg / mL, approximately 10mg / mL to approximately 1,000mg / mL, approximately 50mg / mL to approximately 100mg / mL, approximately 50mg / mL to approximately 200mg / mL, approximately 50mg / mL to approximately 300mg / mL, approximately 50mg / mL to approximately 400mg / mL, approximately 50mg / mL to about 500mg / mL, about 50mg / mL to about 600mg / mL, about 50mg / mL to about 700mg / mL, about 50mg / mL to about 800mg / mL, about 50mg / mL to about 900mg / mL, about 50mg / mL to about 1,000mg / mL, about 100mg / mL to about 200mg / mL, about 100mg / mL to about 300mg / mL, about 100mg / mL to about 400mg / mL, about 100mg / mL to about 500mg / mL, about 100mg / mL to about 600mg / m L, about 100 mg / mL to about 700 mg / mL, about 100 mg / mL to about 800 mg / mL, about 100 mg / mL to about 900 mg / mL, about 100 mg / mL to about 1,000 mg / mL, about 200 mg / mL to about 300 mg / mL, about 20 0mg / mL to approx. 400mg / mL, approx. 200mg / mL to approx. 500mg / mL, approx. 200mg / mL to approx. 600mg / mL, approx. 200mg / mL to approx. 700mg / mL, approx. 200mg / mL to approx. 800mg / mL, approx. 200mg / mL Approximately 900mg / mL, approximately 200mg / mL to approximately 1,000mg / mL, approximately 300mg / mL to approximately 400mg / mL, approximately 300mg / mL to approximately 500mg / mL, approximately 300mg / mL to approximately 600mg / mL, approximately 300mg / mL to approximately 700mg / mL, approximately 300mg / mL to approximately 800mg / mL, approximately 300mg / mL to approximately 900mg / mL, approximately 300mg / mL to approximately 1,000mg / mL, approximately 400mg / mL to approximately 500mg / mL, approximately 400mg / mL to approximately 600mg / mL, approximately 400mg / mL to about 700mg / mL, about 400mg / mL to about 800mg / mL, about 400mg / mL to about 900mg / mL, about 400mg / mL to about 1,000mg / mL, about 500mg / mL to about 600mg / mL, about 500mg The solution may contain, for example, a physiologically acceptable buffered saline solution, containing an active agent of the present invention specific for the indication or disease being treated, at about 700 mg / mL, about 500 mg / mL to about 800 mg / mL, about 500 mg / mL to about 900 mg / mL, about 500 mg / mL to about 1,000 mg / mL, about 600 mg / mL to about 700 mg / mL, about 600 mg / mL to about 800 mg / mL, about 600 mg / mL to about 900 mg / mL, or about 600 mg / mL to about 1,000 mg / mL.

[0104] Drops such as eye drops, ear drops, or nose drops can be formulated with the active agent of the present invention in an aqueous or non-aqueous base that also contains one or more dispersing agents, solubilizing agents, or suspending agents.Liquid sprays can be pumped or conveniently delivered from pressurized packs.Drops can be delivered by simple eye dropper cap bottles, by plastic bottles adapted to deliver liquid content drops, or by specially shaped stoppers.

[0105] Also provided herein are combinatorial approaches to develop suitable pharmaceutical compositions using combinations of amino acids as excipients. These methods are effective for developing stable liquid or lyophilized pharmaceutical compositions, and in particular pharmaceutical compositions that contain one or more therapeutic compounds.

[0106] Compositions according to embodiments described herein have desirable properties, such as desirable solubility, viscosity, syringeability and stability. Lyophilizates according to embodiments described herein have desirable properties, such as desirable recovery, stability and syringeability and reconstitution.

[0107] In some embodiments, the pH of any pharmaceutical composition disclosed herein is at least about 1, 1.5, 2, 2.5, 3, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, 10, 10.25, 10.5, 10.75, 11, 11.25, 11.5, 11.75 or 12.

[0108] In certain embodiments, the pH of any pharmaceutical composition disclosed herein is about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 9, about 7 to about 8, or about 8 to about 9.

[0109] Treatment and prevention methods As a general proposition, therapeutically or prophylactically effective amounts of streptogramin B (e.g., pristinamycin IA or a pharma- ceutically acceptable salt thereof) and streptogramin A (e.g., phlopristin or a pharma- ceutically acceptable salt thereof), either together in a single pharmaceutical composition (dosage form), or separately in two separate pharmaceutical compositions (dosage forms), e.g., in a kit, may be used in a method for treating or preventing a bacterial infection, or a condition caused by a bacterial infection. Any pharmaceutical composition or kit described herein may be used in any of the methods.

[0110] In any of the methods of treatment disclosed herein, the pharmaceutical composition comprises pristinamycin IA, or a pharma- ceutical acceptable salt thereof, and phlopristin, or a pharma- ceutical acceptable salt thereof, and the weight ratio of pristinamycin IA (PIA) to phlopristin (PIA:phlopristin) is about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91, about 10:90, about 11:89, about 12:97, about 13:99, about 14:98, about 15:99, about 16:99, about 17:99, about 18:99, about 19:99, about 20:99, about 21:99, about 22:99, about 23:99, about 24:99, about 25:99, about 26:99, about 27:99, about 28:99, about 29:99, about 30:99, about 31:99, about 32:99, about 33:99, about 34:99, about 35:99, about 36:99, about 37:99, about 38:99, about 39:99, about 40:99, about 41:99, about 42:99, about 43:99, about 44:99, about 45:99, about 46:99, about 47:99, about 48:99, about 49:99, about 50:99, about 51:99, about 52:99, about 53:99, about :88, 13:87, 14:86, 15:85, 16:84, 17:83, 18:82, 19:81, 20:80, 21:79, 22:78, 23:77, 24:76, 25:75, 26:74, 27:73, 28:72, 29:71, 30:70, 31:69, 32:68, 33:67, 34:66, 35:65, 36:64, 37:63, 38:62, 39:61, 40:60, 41 :59, 42:58, 43:57, 44:56, 45:55, 46:54, 47:53, 48:52, 49:51, 50:50, 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, 60:40, 61:39, 62:38, 63:37, 64:36, 65:35, 66:34, 67:33, 68:32, 69:31, 70 :30, about 71:29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13, about 88:12, about 89:11, about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, or about 99:1.

[0111] In any of the methods of treatment disclosed herein, the kit includes a first pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof, and a second pharmaceutical composition comprising phlopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:phlopristin is about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91, about 10:90, about 11:89, about 12:97, about 13:99, about 14:99, about 15:99, about 16:99, about 17:99, about 18:99, about 19:99, about 20:99, about 21:99, about 22:99, about 23:99, about 24:99, about 25:99, about 26:99, about 27:99, about 28:99, about 29:99, about 30:99, about 31:99, about 32:99, about 33:99, about 34:99, about 35:99, about 36:99, about 37:99, about 38:99, about 39:99, about 40:99, about 41:99, about 42:99, about 43:99, about 44:99, about 45:99, about 46:99, about 47:99, about 48:99, about 49:99, about 50:99, about 51:99, about 52:99, about 53:99, about 54:99, about :88, 13:87, 14:86, 15:85, 16:84, 17:83, 18:82, 19:81, 20:80, 21:79, 22:78, 23:77, 24:76, 25:75, 26:74, 27:73, 28:72, 29:71, 30:70, 31:69, 32:68, 33:67, 34:66, 35:65, 36:64, 37:63, 38:62, 39:61, 40:60, 41 :59, 42:58, 43:57, 44:56, 45:55, 46:54, 47:53, 48:52, 49:51, 50:50, 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, 60:40, 61:39, 62:38, 63:37, 64:36, 65:35, 66:34, 67:33, 68:32, 69:31, 70 :30, about 71:29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13, about 88:12, about 89:11, about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, or about 99:1.

[0112] In one embodiment, there is provided a method of treating or preventing a bacterial infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and flopristin or a pharma-ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin is in the range of 1:99 to 99:1, and the bacterial infection is caused by gram-positive bacteria, gram-negative bacteria, atypical bacteria, aerobic bacteria, and / or anaerobic bacteria, such as Bacillus spp., Bacteroides spp., Bordetella spp., Borrelia spp., Brucella spp., Burkholderia spp., Campylobacter spp., Chlamydia spp., Clostridium spp., Coliform ... The infection is caused by one or more susceptible and / or resistant strains of Linebacterium spp., Coxiella spp., Ehrlichia spp., Enterococcus spp., Francisella spp., Fusobacterium spp., Gardnerella spp., Haemophilus spp., Kingella spp., Legionella spp., Listeria spp., Moraxella spp., Mycoplasma spp., Mycobacterium spp., Neisseria spp., Nocardia spp., Peptostreptococcus spp., Porphyromonas spp., Propionibacterium spp., Prevotella spp., Rickettsia spp., Salmonella spp., Shigella spp., Staphylococcus spp., Streptococcus spp., Ureaplasma spp., Vibrio spp., or Yersinia spp.

[0113] A method for treating or preventing a respiratory infection and / or disease in a subject in need thereof comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutical acceptable salt thereof and furopristin or a pharma- ceutical acceptable salt thereof, wherein the weight ratio of pristinamycin IA:furopristin ranges from 1:99 to 99:1. Respiratory infections and / or diseases may include community-acquired or health care-associated pneumonia, chronic bronchitis, sinusitis, acute sinusitis, acute exacerbation of chronic bronchitis, pharyngitis, chronic obstructive pulmonary disease, and nontuberculous mycobacterial infections caused by or in association with bacteria such as one or more strains of susceptible and / or resistant Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus catarrhalis, Legionella spp., Chlamydia pneumoniae, Mycoplasma pneumoniae, Bordetella pertussis, Neisseria gonorrhoeae, Corynebacterium diphtheriae, Coxiella burnetii, Peptostreptococcus spp., Fusobacterium spp., Bacteroides spp., Prevotella spp., Nocardia spp., or Mycobacterium spp.

[0114] A method of treating or preventing a sexually transmitted disease or urogenital infection in a subject in need thereof comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and flopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin ranges from 1:99 to 99:1. The sexually transmitted disease or urogenital infection may be caused by or associated with bacteria, such as by one or more strains of susceptible and / or resistant Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, Ureaplasma parvum, or Gardnerella vaginalis.

[0115] A method of treating or preventing skin and / or soft tissue infections and / or diseases in a subject in need thereof comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and flopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin ranges from 1:99 to 99:1. The skin and / or soft tissue infections and / or diseases may be caused by bacteria, such as one or more strains of susceptible and / or resistant Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus viridans, Streptococcus pyogenes, Enterococcus faecalis, Enzyme faecium, Corynebacterium spp., or Propionibacterium acnes.

[0116] A method of treating or preventing an infection in a cystic fibrosis subject in need thereof comprises administering to the subject therapeutically effective amounts of pristinamycin IA or a pharma- ceutically acceptable salt thereof and flopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin ranges from 1:99 to 99: 1. The infection or threat of infection may be caused by or associated with bacteria, such as by one or more strains of susceptible and / or resistant Staphylococcus aureus, Haemophilus influenzae, or Mycobacterium spp.

[0117] A method for treating or preventing bone and / or joint infections in a subject in need thereof comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutical acceptable salt thereof and furopristin or a pharma- ceutical acceptable salt thereof, wherein the weight ratio of pristinamycin IA:furopristin ranges from 1:99 to 99:1. The infection or threat of infection may be caused by bacteria, such as one or more strains of susceptible and / or resistant Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus pyogenes, Clostridium faecium, Streptococcus viridans, Salmonella spp., Shigella spp., Campylobacter spp., Yersinia spp., Enterococcus faecalis, Clostridium faecium, Kingella kingae, Corynebacterium spp., Propionibacterium acnes, Chlamydia trachomatis, or Neisseria gonorrhoeae.

[0118] A method of treating or preventing endocarditis in a subject in need thereof comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and flopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin ranges from 1:99 to 99:1.The infection or threat of infection may be caused by bacteria, such as one or more strains of susceptible and / or resistant Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus gallolyticus, Streptococcus viridans, Enterococcus faecalis, Yersinia faecium, Haemophilus spp., Kingella spp., Legionella spp., or Corynebacterium spp.

[0119] A method of treating or preventing bacteremia or sepsis in a subject in need thereof comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and flopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin ranges from 1:99 to 99: 1. The infection or threat of infection may be caused by one or more strains of susceptible and / or resistant bacteria.

[0120] A method of treating or preventing anthrax, tularemia, glanders, or melioidosis in a subject in need thereof comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and phlopristin or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of pristinamycin IA:flopristin ranges from 1:99 to 99:1.The infection or threat of infection may be caused by bacteria, such as one or more strains of susceptible and / or resistant Bacillus anthracis, Francisella tularensis, Yersinia pestis, Bacillus mallei, or Bacillus pseudomallei.

[0121] A method of treating or preventing a bacterial infection in a subject in need thereof comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising phlopristin or a pharma- ceutically acceptable salt thereof. The infection or threat of infection may be caused by one or more strains of susceptible and / or resistant bacteria of Gram-positive, Gram-negative, atypical, aerobic, and / or anaerobic bacteria.

[0122] A method of treating or preventing a sexually transmitted disease or urogenital infection in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising phlopristin or a pharma- ceutical acceptable salt thereof. The sexually transmitted disease or urogenital infection may be caused by or associated with bacteria, such as by one or more strains of susceptible and / or resistant Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, Ureaplasma parvum, or Gardnerella vaginalis.

[0123] In any of the methods of treating or preventing a bacterial infection, the subject can be a human or an animal.

[0124] In any of the methods of treating or preventing a bacterial infection, the route of administration can be oral, rectal, transmucosal, inhalation, intranasal, topical (including cutaneous, ocular, aural), vaginal, intestinal, buccal, or sublingual administration; intramuscular, subcutaneous, intravenous, or intramedullary injection, as well as parenteral delivery, including intrathecal, epidural, intraventricular, intraperitoneal, intraamniotic, intranasal, or intraocular or intraarticular injection.

[0125] "Treating" and "treatment" methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period will depend on various factors, such as the severity of the condition, the age of the patient, the concentration of the active agent, the activity of the composition used in the treatment, or a combination thereof. It will also be understood that the effective dosage of an agent used for treatment may increase or decrease over a particular dosing regimen. Variations in dosage may occur and be evident by standard diagnostic assays known in the art. In some cases, long-term administration may be required.

[0126] Preventive or prophylactic treatment involves administering to a subject a therapeutically effective amount of an active agent or combination of active agents. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the condition, the age of the subject, the concentration of the active agent, the activity of the composition used in the treatment, or a combination thereof. It will also be understood that the effective dosage of an agent used for a particular preventive or prophylaxis may increase or decrease during a particular preventive or prophylaxis dosing regimen. Changes in dosage may occur and be evident by standard diagnostic assays known in the art. In some cases, long-term administration may be required.

[0127] An "effective amount" is the amount of a compound sufficient to achieve a stated purpose compared to the absence of the compound (e.g., to achieve the effect for which it is administered to treat a disease, reduce enzymatic activity, enhance enzymatic activity, reduce binding to a target or receptor, reduce or block a signal transduction pathway, or reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to treating, preventing, or reducing a bacterial load or a symptom of a disease, which may also be referred to as a "therapeutically effective amount."

[0128] The therapeutically effective amount can be initially determined from cell culture assays or pharmacokinetic studies. The target concentration is the concentration of active compound that can achieve the therapeutic or prophylactic methods described herein, as measured using the methods described herein or known in the art.

[0129] As is well known in the art, therapeutically effective amounts for human use can also be determined from animal models.For example, dosages for humans can be formulated to achieve the concentration found to be effective in animals.Dosages in humans can be adjusted by monitoring compound efficacy and / or plasma concentration and adjusting dosage upward or downward as described above.It is well within the capabilities of those skilled in the art to adjust dosage to achieve maximum efficacy in humans based on the above and other methods.

[0130] Dosage may vary depending on the patient's needs and the compound used. The dosage administered to a subject should be sufficient to affect a beneficial therapeutic response in the patient over time in the context of the present disclosure. The amount of administration will also be determined by the presence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of the practitioner. Treatment may be initiated with smaller dosages that are less than the optimal dose of the compound. Thereafter, dosage may be increased by small increments until the optimal effect under such circumstances is reached. The amount and interval of administration may be individually adjusted to provide a level of the administered compound that is effective for the clinical indication being treated. This provides a therapeutic drug administration regime commensurate with the severity of the subject's condition.

[0131] Route of Administration As a general proposition, therapeutically or prophylactically effective amounts of streptogramin B (e.g., pristinamycin IA or a pharma- ceutically acceptable salt thereof) and streptogramin A (e.g., phlopristin or a pharma- ceutically acceptable salt thereof) may be administered by the administration routes described herein, either together in a single pharmaceutical composition (dosage form), or separately in two separate pharmaceutical compositions (dosage forms), e.g., in a kit. Any pharmaceutical composition or kit described herein may be administered by any administration route.

[0132] The pharmaceutical composition comprising pristinamycin IA or a pharma- ceutically acceptable salt thereof and phlopristin or a pharma- ceutically acceptable salt thereof may thus be administered intravenously via an implanted device or catheter, or as a continuous infusion, as a single dose over time, or as two or more doses, which may or may not contain the same amount of the desired molecule. Further refinement of the appropriate dosage is routinely performed by, and is within the scope of work routinely performed by, those skilled in the art. The appropriate dosage may be confirmed by the use of appropriate dose-response data. In various embodiments, the therapeutic compounds in the pharmaceutical compositions described herein may be administered to a patient for an extended period of time, such as, without limitation, chronic administration for a chronic condition. The composition may be a solid, semi-solid, liquid, suspension, or aerosol; optionally, the composition, the first composition, or the second composition is a powder, granule, tablet, gel tab, lozenge, fast dissolve strip, capsule (hard or soft), caplet, syrup, elixir, suspension, emulsion, sachet, sprinkle, pellet, patch, spray, cream, ointment, gel, lotion, or foam.

[0133] In some embodiments, for oral, rectal, vaginal, parenteral, pulmonary, sublingual, and / or intranasal delivery formulations, tablets may be made by compression or molding, optionally with one or more accessory ingredients or additives. In some embodiments, compressed tablets are prepared, for example, by compressing in a suitable tabletting machine a therapeutic compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder (e.g., but not limited to, povidone, gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, surfactant, disintegrant (e.g., but not limited to, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) and / or surfactant or dispersant.

[0134] In some embodiments, molded tablets are made by, for example, without limitation, molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable tablet press. In some embodiments, tablets can be optionally coated or scored and formulated to provide slow or controlled release of active ingredients, for example, without limitation, using hydroxypropyl methylcellulose in various ratios to provide a desired release profile. In some embodiments, tablets can be optionally coated with a coating, for example, without limitation, a thin film, a sucrose coating, or an enteric coating, to provide release in parts of the intestine other than the stomach. In some embodiments, the processes, equipment, and contract manufacturers for the manufacture of tablets and capsules are well known in the art.

[0135] In some embodiments, the capsule pharmaceutical composition can utilize either hard or soft capsules, including, but not limited to, gelatin capsules or vegetable capsules, such as those made from hydroxymethylpropylcellulose (HMPC). In some embodiments, the type of capsule is a gelatin capsule. In some embodiments, the capsule can be filled using a capsule filler, such as, but not limited to, those available from commercial vendors, such as Miranda International, or by employing capsule manufacturing techniques well known in the industry.

[0136] The packaging and administration devices may be determined by a variety of considerations, including, but not limited to, the volume of material to be administered, storage conditions, administration by a skilled health practitioner or patient self-compliance, administration schedule, geopolitical environment (e.g., exposure to extreme temperature conditions in the case of developing countries), and other practical considerations.

[0137] Injection devices include pen injectors, autoinjectors, safety syringes, infusion pumps, drip pumps, pre-filled glass syringes, pre-filled plastic syringes, and needleless injectors, and syringes can be liquid-filled or dual-chambered, for example, for use with lyophilized materials. An example of a syringe for such use is the Lyo-Jet™ dual-chamber prefilled syringe available from Vetter GmbH, Ravensburg, Germany. Another example is the LyoTip, a pre-filled syringe designed to conveniently deliver lyophilized formulations available from LyoTip, Inc., Camarillo, California, USA. Administration by injection can be, but is not limited to, intravenous, intramuscular, intraperitoneal, or subcutaneous, as appropriate. Administration by non-injection route can be, but is not limited to, nasal, oral, ocular, transdermal, or pulmonary, as appropriate.

[0138] In certain embodiments, the kit may include, but is not limited to, one or more single-chamber or multi-chamber syringes (e.g., liquid syringes and lyosyringes) for administering one or more pharmaceutical compositions described herein. In various embodiments, the kit may include pharmaceutical compositions for parenteral, subcutaneous, intramuscular or IV administration, sealed in a vial under partial vacuum in a form ready for loading into a syringe and administration to a subject. In this regard, the pharmaceutical composition may be placed therein under partial vacuum. In all these and other embodiments, the kit may include one or more vials according to any of the above, each vial containing a single unit dose for administration to a subject.

[0139] The kits may include lyophilisates arranged as described herein and which upon reconstitution provide pharmaceutical compositions accordingly, in various embodiments, the kits may include a lyophilisate and a sterile diluent for reconstituting the lyophilisate.

[0140] The kit may include a combination of a streptogramin B pharmaceutical composition and a streptogramin A pharmaceutical composition, in certain embodiments, the streptogramin B is pristinamycin IA or a pharma- ceutically acceptable salt thereof, and the streptogramin A is flopristin or a pharma- ceutically acceptable salt thereof. The kit may further include a package in which the combination of a streptogramin B pharmaceutical composition and a streptogramin A pharmaceutical composition is contained, along with one or more of instructions, labels, containers, and other items necessary for use of the combination of a streptogramin B pharmaceutical composition and a streptogramin A pharmaceutical composition in a subject to treat an infection and / or disease, when both compositions are administered together at the same time, or when one composition is administered before or after the other composition.

[0141] In certain embodiments, the pharmaceutical compositions described herein can be administered by any suitable route, particularly parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and / or into the joint gap area. It will also be understood that the preferred route will vary with the condition and age of the recipient and the disease being treated. Methods for determining the most effective means and dosage of administration are known to those skilled in the art and will vary, without limitation, with the pharmaceutical composition used for treatment, the purpose of the treatment, and the subject being treated. Single or multiple administrations can be performed, with the dosage levels and patterns selected, without limitation, by the treating physician. Suitable administration pharmaceutical compositions and methods of administering agents are known in the art.

[0142] The pharmaceutical compositions described herein may be used in the manufacture of a medicament and for the treatment of humans and other animals by administration in a conventional manner.

[0143] Suitable routes of administration may include, for example, oral, rectal, transmucosal, inhalation, intranasal, topical (including cutaneous, ocular, aural), vaginal, intestinal, buccal, or sublingual administration; intramuscular, subcutaneous, intravenous, or intramedullary injection, as well as parenteral delivery, including intrathecal, epidural, direct intraventricular, intraperitoneal, intraamniotic, intranasal, or intraocular injection or injection into a joint.

[0144] The compounds can also be administered in sustained or controlled release dosage forms including depot injections, osmotic pumps, gels, suspensions or emulsions, pills, transdermal patches, and the like for prolonged and / or timed, pulsatile administration at a predetermined rate.

[0145] The determination of effective dosage levels, i.e., dosage levels necessary to achieve a desired result, can be accomplished by those skilled in the art using routine pharmacological methods. Typically, human clinical applications of the formulation are initiated at lower dosage levels, and dosage levels are increased until the desired effect is achieved. Alternatively, acceptable in vitro tests can be used to establish useful doses and routes of administration of the composition.

[0146] Administration of the therapeutic agents according to the invention may be in a single dose, multiple doses, continuous or intermittent modes of administration, depending, for example, on the physiological condition of the subject, whether the purpose of administration is therapeutic or prophylactic, and other factors known to the skilled practitioner. Administration of the active antibacterial compounds of the invention may be substantially continuous over a preselected period of time, or may be a series of spaced doses. Both local and systemic administration is contemplated.

[0147] Combination therapy "Combination therapy" means that the compositions described herein are administered simultaneously, immediately before, or immediately after one or more additional therapies. The compounds provided herein can be administered alone or co-administered to a subject. Co-administration means simultaneous or sequential administration of the compounds, either individually or in combination (two or more compounds). Thus, the formulation may also be combined with other active substances (e.g., to reduce metabolic degradation or other activity), if desired. The compounds of the present invention can be delivered orally, parenterally, topically or transdermally, or by inhalation, or formulated as applicator sticks, solutions, suspensions, emulsions, sachets, sprinkles, syrups, elixirs, tablets, capsules, caplets, gels, creams, ointments, foams, lotions, pastes, patches, jellies, paints, powders, solids, liquids, liposomes, and aerosols. In some embodiments, co-administration includes simultaneous or sequential administration of a compound (e.g., a compound described herein) individually in addition to an additional secondary agent (e.g., an additional antibiotic).

[0148] Working Example Example 1 Selection of streptogramin combinations Checkerboard assays for synergy are used to determine the effect on the efficacy of antibiotic combinations compared to their individual activities (Pillai SK, et al. "Antimicrobial combinations". Antibiotics in Laboratory Medicine 5th Ed. 2005, pages 365-440). Furthermore, because checkerboard studies evaluate a wide range of combination ratios, they provide a means to comparatively evaluate the activity of different combinations of antibiotics across different ratios.

[0149] Checkerboard analysis was used to investigate the best combinations of streptogramin B and streptogramin A. Novel streptogramin combinations, identified by the ID of the streptogramin B and streptogramin A combinations (CBAs), are listed in Table 1. The known streptogramin combinations pristinamycin IA-pristinamycin IIA, quinupristin-dalfopristin, and linopristin-flopristin were included as benchmarks in the class comparison reference material. [Table 1]

[0150] Checkerboard analysis was performed on four Neisseria gonorrhoeae strains, five Staphylococcus aureus strains, two Streptococcus pneumoniae strains, and one Haemophilus influenzae strain (see Table 2 for details of the strains utilized and their antibiotic resistance profiles). [Table 2]

[0151] An 8x12 checkerboard test format was used to test each of the nine combinations. MIC assay plates were prepared using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (CLSI “Performance Standards for Antimicrobial Susceptibility Testing. 28th ed.” CLSI supplement M100. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2018; CLSI “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-11th Edition” CLSI standard M07. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2018; CLSI “Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria. 3rd ed.” CLSI guideline). 45. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2016). For testing Neisseria gonorrhoeae, a modified medium described by ATCC capable of supporting growth was used. This medium contains 15 g Oxoid Special Peptone, 1 g cornstarch, 5 g NaCl, 4 g K2HPO4, and 1 g KH2PO4 per liter, and 1% IsoVitaleX enrichment (Becton Dickinson).

[0152] Stock solutions of test articles were prepared in dimethylsulfoxide (DMSO) at 102X the highest final concentration to be tested. Serial dilutions were made in "mother" plates, one for streptogramin components diluted horizontally and another for streptogramin components diluted vertically. For the horizontally diluted mother plate, wells of a standard 96-well microdilution plate (Costar) were filled with 150 μL of DMSO in columns 2-12. A 300 μL aliquot of stock solution for the test agent was added to each well in column 1 of the plate. Eleven two-fold serial dilutions were made horizontally across each row of the plate in columns 2-11 (left to right) using an automated liquid handler Biomek2000 (Beckman Coulter, Fullerton CA).

[0153] For the vertically diluted mother plate, 150 μL of DMSO was added to row BH (top to bottom) of a 96-well microtiter plate. Row A of the plate was filled with 300 μL of each test agent at 102× the highest final concentration to be tested. A series of two-fold dilutions were then prepared by hand from row BG using a multichannel pipette.

[0154] The "daughter plates" were filled with 190 μL of test medium using an automated liquid handler Multidrop 384 (Labsystems, Helsinki, Finland). 2 μL of drug solution from each well of the horizontal dilution mother plate was transferred to the corresponding wells of all daughter plates in one step using an automated liquid handler Biomek FX (Beckman Coulter, Fullerton Calif.). Then, 2 μL aliquots from each well of the vertical dilution mother plate were transferred to the corresponding wells of the daughter plates using the Biomek FX. Row H and column 12 each contained a single drug serial dilution for the determination of the MIC of the drug alone. This procedure was repeated for all test drugs.

[0155] Biostandardized inoculum of each bacteria was prepared according to CLSI methods. 10 μL of standardized inoculum was delivered into each well from low to high concentration using Biomek 2000. These inocula were approximately 5x10 in each well. 5 This resulted in a final cell concentration in the daughter plates in colony forming units (CFU) / mL. Thus, the wells of the daughter plates ultimately contained 190 μL of medium, 2 μL of one test agent, 2 μL of the second test agent, and 10 μL of inoculum.

[0156] The test format resulted in the generation of an 8x12 checkerboard, where each compound was tested alone (column 12 and row H) and in combination with various ratios of compound concentrations, with each well of the microtiter plate containing a unique combination of concentrations of the two streptogramins. The exact concentration range of each compound in the 96-well plate was based on the MIC values ​​previously obtained for each component alone against a specific strain. The ranges evaluated for each streptogramin combination and each strain are given in the following paragraphs (see CBA ID in Table 1 and Strain ID in Table 2). For a particular combination, the first concentration range listed is for the streptogramin B component and the second concentration range listed is for the streptogramin A component. Eleven double-value ranges were diluted horizontally on the plate, and seven double-value ranges were diluted vertically on the plate.

[0157] CBA1, CBA2, and linopristin-flopristin were evaluated at 0.004-4&0.004-0.25 μg / mL for strains 1-4 and 12, and at 0.004-4&0.03-2 μg / mL for strains 5-11. CBA3 was evaluated at 0.004-4&0.016-1 μg / mL for strains 1, 2, and 12, at 0.008-8&0.03-2 μg / mL for strains 3 and 4, at 0.004-4&0.06-4 μg / mL for strains 5, 8, and 9, and at 0.008-8&0.12-8 μg / mL for strains 6, 7, 10, and 11. CBA4 was evaluated at 0.004–4&0.008–0.5 μg / mL for strains 1, 2 and 12, at 0.016–16&0.06–4 μg / mL for strains 3, 4, 6, 7, 10 and 11, and at 0.004–4&0.03–2 μg / mL for strains 5, 8 and 9. CBA5 and CBA6 were evaluated at 0.06–4&0.004–4 μg / mL for strains 1–12. Pristinamycin IA-pristinamycin IIA was evaluated at 0.004-4&0.016-1 μg / mL for strains 1, 2 and 12, 0.016-16&0.03-2 μg / mL for strains 3 and 4, 0.004-4&0.06-4 μg / mL for strains 5, 8 and 9, and 0.016-16&0.12-8 μg / mL for strains 6, 7, 10 and 11. Quinupristin-dalfopristin was evaluated at 0.004–4&0.008–0.5 μg / mL for strains 1, 2, and 12, at 0.008–8&0.06–4 μg / mL for strains 3, 4, 6, 7, 10, and 11, and at 0.004–4&0.03–2 μg / mL for strains 5, 8, and 9.

[0158] After inoculation, plates were incubated for approximately 20 h at 35°C in ambient atmosphere for S. aureus and S. pneumoniae and in an atmosphere of 5% CO2 for Neisseria gonorrhoeae.

[0159] For MIC measurements, plates were viewed from the bottom using a plate viewer. The MIC of a particular combination ratio was read as the lowest combined concentration of streptogramin B and streptogramin A at which visible bacterial growth was completely inhibited at that ratio. An example is shown in Figure 1, which shows the results of a checkerboard MIC test of streptogramin combinations of CBA1 (page 1 of the figure), pristinamycin IA and pristinamycin IIA (page 2 of the figure), and linopristin and phlopristin (page 3 of the figure) against Staphylococcus aureus strain 5. The ratio value in each well indicates the concentration ratio of streptogramin B to streptogramin A in that well. Shaded wells in the microtiter plate indicate microbial growth. The MICs of particular streptogramin concentration ratios in Figure 1 are identified by the thick border surrounding the well. As an example, in the CBA1 panel, the MIC for the combination of streptogramin B:streptogramin A at a ratio of 33:67 is located in well F8 and is 0.03:0.06 μg / mL (total MIC of 0.09 μg / mL) and the MIC for the combination of streptogramin B:streptogramin A at a ratio of 20:80 is located in well F9 and is 0.016:0.06 μg / mL (total MIC of 0.076 μg / mL).

[0160] Checkerboard MIC results were used to compare the nine streptogramin combinations listed in Table 1 across various ratios, species, and strains. A comparative analysis of the MICs obtained at 33:67 and 67:33 ratios is shown below. Across the nine combinations evaluated, the novel CBA1 combination consistently yielded the lowest MIC values ​​across all species and all strains, demonstrating the unexpected finding of improved efficacy over all other streptogramin combinations.

[0161] Table 3 shows the MIC values ​​of nine combinations of streptogramins tested in Neisseria gonorrhoeae, Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, each at a ratio of 33:67 streptogramin B:streptogramin A. The combination with the lowest mean MIC was CBA1, with a mean MIC value of 0.19 μg / mL; whereas PIA-PIIA, quinupristin-dalfopristin, and linopristin-flopristin had mean MIC values ​​of 0.43 μg / mL, 0.81 μg / mL, and 0.31 μg / mL, respectively. [Table 3]

[0162] Table 4 shows the ranking of MIC values ​​for nine combinations of streptogramins tested in each strain of Neisseria gonorrhoeae, Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, each at a ratio of 33:67 streptogramin B:streptogramin A. CBA1 was consistently ranked best (rank 1) for each and across all strains tested.

[0163] Table 5 shows the MIC values ​​of nine combinations of streptogramins tested in Neisseria gonorrhoeae, Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, each at a ratio of 67:33 streptogramin B:streptogramin A. The combination with the lowest mean MIC was CBA1, with a mean MIC value of 0.23 μg / mL; whereas PIA-PIIA, quinupristin-dalfopristin, and linopristin-flopristin had mean MIC values ​​of 0.54 μg / mL, 0.81 μg / mL, and 0.42 μg / mL, respectively.

[0164] Table 6 shows the ranking of MIC values ​​for nine combinations of streptogramins tested in each strain of Neisseria gonorrhoeae, Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, each at a ratio of 67:33 streptogramin B:streptogramin A. CBA1 was consistently ranked best (rank 1) for each strain tested and across all strains. [Table 4] [Table 5] [Table 6]

[0165] Similar results of ranking were observed with other streptogramin B:streptogramin A ratios ranging from 0:100 to 99:1. As an illustration, MIC values ​​for the ratios of CBA1, pristinamycin IA-pristinamycin IIA, and linopristin-flopristin shown in FIG. 1 against S. aureus strain 5 are shown in Table 7. In most of the evaluated ratios that had activity above the limit of detection, the novel CBA1 combination was 2-4 times more potent than the known streptogramin combinations that differ from CBA1 by only one component: pristinamycin IA-pristinamycin IIA and linopristin-flopristin. In no case was the MIC of either pristinamycin IA-pristinamycin IIA or linopristin-flopristin less than that of CBA1. Taken together, these example data show the unexpected results of improved efficacy of this novel combination CBA1 (pristinamycin IA and furopristin) consistently over a wide range of ratios compared to known combinations including combinations of pristinamycin IA or furopristin and other novel streptogramins. [Table 7]

[0166] Example 2: Antibacterial profile of CBA1 across streptogramin component ratios The effect of different streptogramin B:streptogramin A weight ratios in CBA1 on the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) was investigated in a panel of Streptococcus pneumoniae, Neisseria gonorrhoeae, and Staphylococcus aureus enriched for antibiotic-resistant strains. The streptogramin B:streptogramin A ratios investigated in CBA1 were 100:0, 90:10, 70:30, 50:50, 30:70, 10:90, and 0:100 by weight. Pristinamycin IA-pristinamycin IIA was included as an intraclass comparator at the same ratios. A panel of Mycoplasma genitalium clinical isolates and strains was also evaluated in CBA1 at ratios of 100:0, 70:30, 30:70, and 0:100.

[0167] MICs were determined for each streptogramin B:streptogramin A ratio using the CLSI broth microdilution method (CLSI "Performance Standards for Antimicrobial Susceptibility Testing. 28th ed." CLSI supplement M100. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2018; CLSI "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-11th Edition" CLSI standard M07. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2018). For testing of Neisseria gonorrhoeae, modified medium was utilized as described in Example 1 above. For Mycoplasma genitalium and mycoplasma testing, the CLSI method for mycoplasma susceptibility testing was followed (CLSI “Methods for antimicrobial susceptibility testing of human mycoplasmas” Approved Guideline M43-A. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2011).

[0168] Stock solutions for streptogramins were prepared at the specified streptogramin B:streptogramin A ratio in DMSO at 101X final concentration. A series of eleven two-fold serial dilutions of the test articles were made in DMSO and added to wells of a standard 96-well microdilution plate (Costar 3795) containing the appropriate medium for the species being tested. Each row of the microtiter plate contained a two-fold dilution series in columns 1-11. Wells in column 12 contained no drug and served as bacterial growth control wells. A biostandardized inoculum of each bacteria was added at approximately 5x105 The final inoculum concentration was prepared according to CLSI methods, targeting a final inoculum concentration of CFU / mL. The final volume in the wells during susceptibility testing was 202 μL. The wells were incubated in ambient atmosphere for Staphylococcus aureus and Streptococcus pneumoniae, and at 5% CO for Neisseria gonorrhoeae. 2 After approximately 20 hours of incubation at 35°C in an atmosphere of 0.1% CO, the plates were viewed from the bottom using a plate viewer. The MIC value was read as the lowest concentration of test article that completely inhibited visible bacterial growth.

[0169] The majority of strains selected for inclusion in the test panel were antibiotic resistant. Four of the five S. pneumoniae strains were resistant to macrolides, and one of these was also resistant to penicillin and tetracycline. The panel of Neisseria gonorrhoeae strains selected was primarily multidrug-resistant or extensively drug-resistant strains from the WHO and CDC antimicrobial resistant isolate bank collections. These included isolates resistant to penicillins, fluoroquinolones, tetracyclines, macrolides, and broad-spectrum cephalosporins. Of the 15 S. aureus strains, 11 were resistant to methicillin, 10 were resistant to macrolides, and two were resistant to linezolid. Breakpoints were not established for Mycoplasma genitalium. However, among the 10 M. genitalium strains and isolates tested, three had elevated MICs for azithromycin and moxifloxacin.

[0170] Table 8 shows the MIC values ​​of CBA1 for various ratios of streptogramin B:streptogramin A in a panel of multidrug-resistant and extensively drug-resistant Neisseria gonorrhoeae. Azithromycin was used as a comparator to evaluate activity against macrolide-resistant Neisseria gonorrhoeae. Over a range of streptogramin B:streptogramin A ratios from 90:10 to 0:100, CBA1 had significant antibacterial activity against Neisseria gonorrhoeae. In each case, little or no antibacterial activity was observed with the streptogramin B component alone (i.e., CBA1 at 100:0). However, antibacterial activity was observed with the streptogramin A component alone (i.e., CBA1 at 0:100). CBA1 maintained potent activity against macrolide-resistant strains and there was no evidence of cross-resistance between CBA1 and the macrolides. [Table 8]

[0171] Table 9 shows the fold-increase in potency of CBA1 against multiple strains of Neisseria gonorrhoeae compared to pristinamycin IA-pristinamycin IIA at each of the same streptogramin B:streptogramin A ratios, as determined by dividing the MIC of pristinamycin IA-pristinamycin IIA by the MIC of CBA1. CBA1 was approximately 4- to 8-fold more potent than pristinamycin IA-pristinamycin IIA across all ratios and all strains evaluated. [Table 9]

[0172] In the MBC assay, CBA1 was bactericidal against Neisseria gonorrhoeae as determined by the MBC divided by the MIC value of 4 or less. At streptogramin B:streptogramin A ratios in CBA1 of 90:10 to 0:100, CBA1 was bactericidal against all (20 of 20) Neisseria gonorrhoeae strains. Pristinamycin IA-pristinamycin IIA showed bactericidal activity against Neisseria gonorrhoeae, but only at higher concentrations due to their reduced potency. The MBC required to inhibit 90% of all strains tested for CBA1 (MBC 90 ) ranged from 0.25 to 1 μg / mL over ratios of 90:10 to 10:90. In contrast, the MBCs of pristinamycin IA-pristinamycin IIA against Neisseria gonorrhoeae were 90 ranged from 1 to 4 μg / mL over the same ratios. These differences in potency between the two combinations may be clinically relevant if systemic exposure reaching the above MICs or MBCs of a combination cannot be achieved following a particular route of administration.

[0173] Table 10 shows the MIC values ​​for CBA1 at different ratios of streptogramin B:streptogramin A in pneumococcal strains. Over the different ratios of CBA1, this novel combination showed excellent antibacterial activity against pneumococcus. In each case, the MIC values ​​were much higher than incubation with only one component alone (i.e., CBA1 at a ratio of 100:0 or 0:100), however, some antibacterial activity was still observed. These data indicate the synergistic effect of the combination of streptogramins in CBA1. [Table 10]

[0174] Table 11 shows the fold increase in potency of CBA1 against S. pneumoniae compared to pristinamycin IA-pristinamycin IIA at each of the same streptogramin B:streptogramin A ratios, as determined by dividing the MIC of pristinamycin IA-pristinamycin IIA by the MIC of CBA1. Overall, CBA1 was more potent than pristinamycin IA-pristinamycin IIA across all ratios evaluated, particularly against the macrolide-resistant strains MMX3031, MMX3033, and ATCC700677. [Table 11]

[0175] In the MBC assay, CBA1 was bactericidal against pneumococci across all streptogramin B:streptogramin A ratios as determined by MBC divided by MIC values ​​of ≦4. Across streptogramin B:streptogramin A ratios of 90:10, 70:30, 50:50, 30:70, 10:90, and 0:100, CBA1 was bactericidal against 5 of 5 pneumococcal strains. With only the streptogramin B component (i.e., a ratio of 100:0 in CBA1), it was bactericidal against only 2 of the 4 pneumococcal strains evaluated.

[0176] Table 12 shows CBA1 MIC values ​​at various ratios of streptogramin B:streptogramin A against pulmonary S. aureus strains. Over ratios from 90:10 to 0:100, CBA1 had significant antibacterial activity against S. aureus. Activity was greater at ratios where both streptogramin A and streptogramin B components were present, suggesting synergy. In all cases, higher MIC values ​​were obtained with the streptogramin B component alone (i.e., CBA1 ratio of 100:0) without measurable antibacterial activity in the particular strain. On the other hand, better antibacterial activity was observed with the streptogramin A component alone (i.e., CBA1 at 0:100). [Table 12]

[0177] Table 13 shows the fold increase in potency of CBA1 against S. aureus compared to pristinamycin IA-pristinamycin IIA at the same streptogramin B:streptogramin A ratios, respectively, as determined by dividing the MIC of pristinamycin IA-pristinamycin IIA by the MIC of CBA1. For the majority of strains, CBA1 was more potent than pristinamycin IA-pristinamycin IIA, especially for strains that were both methicillin- and macrolide-resistant (the eight strains in the bottom half of the table). The MICs that inhibited 90% of the isolates tested (MIC 90 ) ranged from 0.12 to 0.5 μg / mL over the 90:10 to 10:90 ratios of CBA1, while the MICs of pristinamycin IA-pristinamycin IIA against S. aureus 90 ranged from 2 to 8 μg / mL over ratios of 90:10 to 10:90, which is 90 1 shows a 16-fold increased potency of CBA1 over pristinamycin IA-pristinamycin IIA based on IgG values. [Table 13]

[0178] In the MBC assay, CBA1 at streptogramin B:streptogramin A ratios of 90:10 to 10:90 demonstrated bactericidal activity against most S. aureus strains (60% to 73% across ratios) based on a comparison of MBC values ​​to MIC values ​​as shown in Table 14. The bactericidal activity of CBA1 was similar regardless of ratio. In contrast, the pristinamycin IA-pristinamycin IIA combination demonstrated primarily bacteriostatic activity against S. aureus, with MBC divided by MIC values ​​of 8 or greater for most strains. At the clinically approved dose ratio for pristinamycin IA-pristinamycin IIA of 30:70, there was no evidence of bactericidal activity (0%) for this streptogramin combination in S. aureus. [Table 14]

[0179] CBA1 also showed potent activity against Mycoplasma genitalium, with similar MICs observed when tested at 70:30 or 30:70 pristinamycin IA:flopristin ratios, with both ratios resulting in MICs in the range of 0.015-0.12 μg / mL. Furthermore, for both ratios tested, the MIC values ​​of CBA1 were 4- to 16-fold more potent than those observed with the benchmark comparator, pristinamycin IA-pristinamycin IIA, which had MIC values ​​in the range of 0.12-0.5 μg / mL, indicating superior potency of the CBA1 combination. When only the streptogramin A component of CBA1 (flopristin) was present, i.e., CBA1 at a ratio of 0:100, activity was also observed, with MICs in the range of 0.015-0.5 μg / mL against Mycoplasma genitalium. Reduced activity was observed when only the streptogramin B component of CBA1 (pristinamycin IA) was present, ie, CBA1 at a ratio of 100:0, which had MICs in the range of 2-16 μg / mL.

[0180] Example 3 In vitro potency and spectrum of activity compared to known streptogramin combinations The broader antibacterial activity spectrum of CBA1 was evaluated against a variety of Gram-positive, Gram-negative, and atypical species of isolates and compared with known streptogramin combinations pristinamycin IA-pristinamycin IIA, quinupristin-dalfopristin, and / or linopristin-flopristin, using all test articles in a streptogramin B:streptogramin A ratio of 30:70. The following species were evaluated: Streptococcus pneumoniae (30 isolates including 9 macrolide-resistant, 8 clindamycin-resistant, and 5 tetracycline-resistant isolates), Mycobacterium faecium (30 isolates including all vancomycin-resistant isolates), Streptococcus pyogenes (30 isolates including 3 macrolide-resistant and 3 tetracycline-resistant isolates), Streptococcus agalactiae (30 isolates including 18 macrolide-resistant, 10 clindamycin-resistant, and 23 tetracycline-resistant isolates), Staphylococcus aureus (96 clinical isolates including 48 methicillin-resistant and 12 clindamycin-resistant isolates collected from US and European medical centers in 2019-2021), Neisseria gonorrhoeae (mainly W The following strains were included in the study: Mycoplasma genitalium (four ATCC strains and six clinical isolates collected from the UK, Denmark, or US during 1980-2020, including three isolates with elevated MICs for moxifloxacin and moxifloxacin), Gardnerella vaginalis (30 clinical isolates collected from the US and Italy during 1992-2020), Bacillus anthracis (a genetically diverse panel of 30 strains), Francisella tularensis (a genetically diverse panel of 30 strains), Burkholderia mallei (a panel of 10 strains), Bacillus pseudomallei (a panel of 10 strains), and Yersinia pestis (a panel of 10 strains).

[0181] MICs were measured by the broth microdilution method described in Example 2 according to CLSI guideline documents M07 and M100 for Staphylococcus aureus, Streptococcus spp., Mycobacterium faecium, and Neisseria gonorrhoeae, according to the CLSI method for infrequently isolated or fastidious bacteria (CLSI “Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria. 3rd ed.” CLSI guideline 45. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2016) for Bacillus anthracis, B. tularensis, B. mallei, B. pseudomallei, and Yersinia pestis, and according to the CLSI guideline for Mycoplasma genitalium (CLSI “Methods for antimicrobial susceptibility testing of human mycoplasmas” Approved Guideline M43-A. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2011). For Gardnerella vaginalis, MICs were determined by agar dilution as recommended by CLSI for susceptibility testing of anaerobic bacteria (CLSI “Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria, Approved Standard-Eleventh Edition” CLSI document M11, 11th Ed. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2018).Supplemented Brucella agar plates containing 5% (v / v) sheep lysed blood were utilized for susceptibility testing, and plates were incubated in a Bactron 600 anaerobic chamber (Sheldon Manufacturing, Cornelius, Oregon) containing an atmosphere of 5% carbon dioxide, 5% hydrogen, and 90% nitrogen. MIC endpoints were determined at 72 hours for all Gardnerella vaginalis isolates, with the MIC defined as the minimum concentration at which a significant reduction in the appearance of growth on the test plates occurred compared to the appearance of growth on the anaerobic control plates. For all species, CBA1, pristinamycin IA-pristinamycin IIA, quinupristin-dalfopristin, or linopristin-flopristin were all tested at a streptogramin B:streptogramin A ratio of 30:70.

[0182] The MIC distribution for each species is shown as a histogram in Figure 2. The potency of the novel combination CBA1 over other known combinations is shown for all species tested. For each species, the MIC distribution for CBA1 was better than the comparator streptogramin combinations pristinamycin IA-pristinamycin IIA, quinupristin-dalfopristin, or linopristin-flopristin, and lower MICs were obtained for almost all isolates evaluated, as shown by the shift of the MIC distribution to the left of the histogram. MICs of CBA1 against Streptococcus pneumoniae, Streptococcus faecium, Streptococcus pyogenes, Streptococcus agalactiae, Staphylococcus aureus, Neisseria gonorrhoeae, Mycoplasma genitalium, Gardnerella vaginalis, Bacillus anthracis, and Francisella tularensis 90The values ​​were 0.12, 0.12, 0.015, 0.03, 0.12, 0.012, 0.03, 0.015, 0.25, and 0.25 μg / mL, respectively (Table 15). Comparing the MIC90 values, CBA1 is more potent than the combinations of two known streptogramins approved for human use, i.e., 2-32 times more potent than pristinamycin IA-pristinamycin IIA and 2-8 times more potent than quinupristin-dalfopristin across all species tested (Table 15).

[0183] CBA1 was also active against Burkholderia mallei, Burkholderia pseudomallei, and Yersinia pestis, with MIC ranges of 1-4 μg / mL, 4->8 μg / mL, and 1-4 μg / mL, respectively. Against each species, activity of CBA1 was 2-8 times better than pristinamycin IA:pristinamycin IIA, which had MIC ranges of 4->8 μg / mL, all >8 μg / mL, and all 9 μg / mL, respectively. [Table 15]

[0184] Example 4 In vitro time-kill kinetics In vitro time-kill assays allow for quantitative evaluation of antibiotic bactericidal activity at various time points after exposure to the antibiotic. The bactericidal time kinetics of CBA1 bioactivity was evaluated against multidrug-resistant Neisseria gonorrhoeae strains NCTC13480 and NCTC13820. Both of these strains are resistant to penicillin, tetracycline, and ciprofloxacin. NCTC13480 has elevated MICs to the only remaining standard-of-care antibiotics for the treatment of gonorrhea, meeting CDC's Gonococcal Isolate Surveillance Project (GISP) "alert value" criteria. NCTC13820 has high-level resistance to both ceftriaxone and cefixime.

[0185] Baseline MIC values ​​were measured in triplicate using the broth macrodilution (tube) method according to the CLSI M07 guideline (CLSI “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-11th Edition” CLSI standard M07. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2018). Fastidious broth was used as the test medium with a total volume of 4 mL in each tube. Isolates were incubated for 24 h at 35 °C in a 5% CO2 incubator for all compounds. The MIC value corresponded to the tube with the lowest concentration that had no turbidity upon visual examination.

[0186] The time-kill bactericidal activity assay was performed according to the method described by CLSI (CLSI "Methods for determining bactericidal activity of antimicrobial agents; approved guideline. Document M26-A" CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 1999). Strains were first grown for 2 hours in selective broth. Cultures were then diluted into tubes containing 2X, 4X, and 8X the concentration of the model baseline MIC of antimicrobial agent in 4 mL of selective broth. Each test event also included a growth control tube without antimicrobial compound for each strain.

[0187] Samples of each tube were removed at 0, 2, 4, 8, and 24 hours after compound addition at 35° C. Each sample was serially diluted in saline and plated on GC agar containing 1% Neisseria gonorrhoeae-Haemophilus influenzae (GCHI) enrichment for CFU determination.

[0188] Results for NCTC13480 are shown in Figure 3. CBA1 showed bactericidal activity (i.e., ≥ 3-log) within 2, 4, and 8 hours of exposure at MICs of 8X, 4X, and 2X, respectively. 10 CFU / mL). In contrast, ceftriaxone, the standard treatment antibiotic for gonorrhea, did not achieve bactericidal activity by 24 hours of exposure, even at concentrations up to 8X the MIC. Similar results were observed when CBA1 was evaluated against Neisseria gonorrhoeae strain NCTC13820, where bactericidal activity occurred within 2 hours at CBA1 MICs of 8X and 4X, and within 4 hours at CBA1 MIC of 2X. These results indicate that the novel streptogramin combination CBA1 possesses the desirable property of rapid bactericidal activity.

[0189] Example 5 In vitro efficacy Animal infection models are of high value for proof of concept of in vivo efficacy in antibiotic development. Unlike most other therapeutic areas, for antibiotics, the drug target is the bacteria, not the host. The mouse neutropenic thigh infection model is one of the most commonly used models to evaluate in vivo antibacterial efficacy. The primary endpoint in this model is the reduction of bacterial CFUs 24 hours after the initiation of antibiotic therapy, and this endpoint in mice has been shown to correlate with clinical outcome in human subjects.

[0190] The in vivo efficacy of CBA1 administered via intravenous or oral routes against S. aureus was evaluated in a murine neutropenic thigh infection model with MRSA strain BAA-1717. For intravenous studies, female CD-1 mice from Charles River Laboratories were made neutropenic with two doses of cyclophosphamide on days -4 and -1 at 150 mg / kg and 100 mg / kg, respectively, delivered by intraperitoneal injection. On day 0 of the study, mice were administered 100 μL of the prepared bacterial inoculum (1.9x10 5Mice were infected with the methicillin-resistant Staphylococcus aureus strain ATCC BAA-1717 by injection of 1000 CFU / mouse thigh. Groups of four mice were administered either vehicle (5% DMSO, 25% PEG-400, 30% propylene glycol, and 40% saline) or test agents twice via tail vein injection at 2 and 14 hours post-infection, with the dose of agent administered being 5 mL / kg and based on body weight. Test agents included CBA1 (a 33:67 mass ratio of streptogramin B:streptogramin A) at 15 mg / kg per dose, quinupristin-dalfopristin (a 30:70 ratio of streptogramin B:streptogramin A) at 15 mg / kg per dose, and the positive control vancomycin at 50 mg / kg per dose. The MICs of CBA1, quinupristin-dalfopristin, and vancomycin against strain BAA-1717 were 0.06, 0.12, and 1 μg / mL, respectively.

[0191] The vehicle-infected control group was euthanized at 2 and 26 hours post-infection, and the test drug group was euthanized at 26 hours post-infection. The right thigh from each animal was aseptically explanted, weighed, and homogenized to uniformity. The homogenized samples were serially diluted and plated on bacterial growth medium for CFU determination. CFU was calculated after overnight incubation at 37°C. CFU was adjusted for dilution and tissue weight for each thigh, and the mean and standard deviation were calculated for each group.

[0192] The same study was performed to evaluate the efficacy of test agents administered by oral gavage in neutropenic mice infected with S. aureus strain BAA-1717. In this study, groups of four mice were administered vehicle (0.5% methylcellulose (4000CP), 0.2% Tween 80) or test agents twice at 2 and 14 hours post-infection via oral gavage, with dose volumes of 10 mL / kg based on body weight. Test agents included CBA1 at 75 mg / kg per dose, or pristinamycin 1A-pristinamycin at 150 mg / kg per dose, both in a 30:70 ratio of streptogramin B:streptogramin A, and the positive control linezolid at 100 mg / kg per dose. The MICs of CBA1, pristinamycin IA-pristinamycin IIA, and linezolid against strain BAA-1717 were 0.06, 0.12, and 2 μg / mL, respectively.Two or 26 hours after infection, thighs were processed and CFU were determined as described above.

[0193] After two doses of 15 mg / kg intravenously (2 and 14 hours post-infection), CBA1 demonstrated superior efficacy compared to quinupristin-dalfopristin administered at the same dose and comparable efficacy to standard of care vancomycin administered intravenously at a 3.3-fold higher dose (2 doses of 50 mg / kg). Results are reported as mean log 10 CFU / g of thigh tissue ± standard deviation are shown in Figure 4 (top). At 26 hours post-infection, CBA1 reduced the bacterial load by 3.17 log 10 CFU reduction, whereas quinupristin-dalfopristin had no effect on bacterial burden when administered at the same dose level as CBA1 (+0.01 log 10 CFU).

[0194] After two oral doses of 75 mg / kg (2 and 14 hours post-infection), CBA1 demonstrated superior efficacy compared to pristinamycin IA-pristinamycin IIA given orally at a 2-fold higher dose (150 mg / kg given twice) and comparable efficacy to the standard of care linezolid given orally at a 1.3-fold higher dose (100 mg / kg given twice). Results are reported as mean log 10 CFU / g of thigh tissue ± standard deviation are shown in Figure 4 (bottom). At 26 hours post-infection, CBA1 reduced the bacterial load by 2.92 log 10 CFU reduction, whereas pristinamycin IA-pristinamycin IIA, administered at twice the dose of CBA1, was 0.47 log 10 Only CFU reduced the bacterial load.

[0195] Taken together, these in vivo data demonstrate significantly improved in vivo efficacy of the novel and unique streptogramin combination CBA1 (pristinamycin IA + flopristin) over known streptogramin antibiotics approved for human use. The enhanced in vivo efficacy of CBA1 over existing streptogramin combinations is supported by its superior antibacterial potency and desirable antibacterial profile, including its bactericidal activity, as evidenced by the vast amount of in vitro data presented herein.

[0196] Other embodiments Certain embodiments of the present invention are described herein, including the best mode for carrying out the invention known to the inventors. Of course, variations on the embodiments described herein will become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that such modifications will be adopted by those skilled in the art as necessary, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed in this application unless otherwise indicated herein or otherwise clearly contradicted by the context.

[0197] Unless otherwise indicated, all numbers expressing characteristics, items, quantities, parameters, properties, periods, and the like used in the specification and claims should be understood in all instances to be modified by the word "about". Unless otherwise indicated, the numerical parameters set forth in the specification and the appended claims are approximations which may vary. At the very least, and without intending to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the invention are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range and value inherently contains certain errors necessarily resulting from the standard deviations found in their respective testing measurements. The recitation of a range of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the specification as if it were individually set forth herein.

[0198] All patents, patent publications, and other publications mentioned or identified in this specification are individually and expressly incorporated herein by reference in their entirety, for example to describe and disclose the compositions and methods described in such publications and that can be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by reason of prior invention or for any other reason. Any dates or representations as to the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the accuracy of the dates or contents of these documents.

[0199] Finally, although aspects of the present specification are emphasized by reference to specific embodiments, it should be understood that those skilled in the art will readily recognize that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to the specific methods, protocols, and / or reagents, etc. described herein. Thus, various modifications or alterations to the disclosed subject matter or alternative configurations of the disclosed subject matter can be made in accordance with the teachings of the present specification without departing from the spirit of the present specification. Finally, the terms used in the present specification are for the purpose of describing only specific embodiments and are not intended to limit the scope of the present invention. The scope of the present invention is defined only by the claims. Thus, the present invention is not limited to the exact forms shown and described.

Claims

1. A composition comprising pristinamycin IA (PIA) or a pharmaceutically acceptable salt thereof and flopristin or a pharmaceutically acceptable salt thereof, wherein optionally the weight ratio of PIA to flopristin (PIA:flopristin) is from about 1:99 to about 99:

1.

2. A kit comprising a first composition comprising pristinamycin IA or a pharmaceutically acceptable salt thereof, a second composition comprising flopristin or a pharmaceutically acceptable salt thereof, and instructions for administering the first and second compositions for treating an infection caused by or associated with bacteria in a subject, wherein optionally the instructions include administering the first composition and the second composition simultaneously to a subject in need thereof, or administering the first composition before or after the second composition is administered.

3. A combination of a therapeutically effective amount of pristinamycin IA (PIA) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of flopristin or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a bacterial infection, wherein the combination is administered as a single composition or as two separate compositions, and wherein optionally the infection is caused by or associated with one or more strains of a species of Bacillus, Bacteroides, Bordetella, Borrelia, Brucella, Burkholderia, Campylobacter, Chlamydia, Clostridium, Corynebacterium, Coxiella, Ehrlichia, Enterococcus, Francisella, Fusobacterium, Gardnerella, Haemophilus, Kingella, Legionella, Listeria, Moraxella, Mycoplasma, Mycobacterium, Neisseria, Nocardia, Peptostreptococcus, Porphyromonas, Propionibacterium, Prevotella, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Ureaplasma, Vibrio, or Yersinia.

4. The bacterial infection is a sexually transmitted infection or a genitourinary infection, and optionally, the bacteria include one or more strains of Neisseria gonorrhoeae, Trachoma pathogen, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, Ureaplasma parvum, or Gardnerella vaginalis, the combination for use according to claim 3.

5. The bacterial infection is a respiratory infection, and optionally, the combination is administered to a subject with cystic fibrosis, the combination for use according to claim 3.

6. The respiratory infection is community-acquired pneumonia, healthcare-associated pneumonia, chronic bronchitis, rhinitis, acute maxillary sinusitis, acute exacerbation of chronic bronchitis, pharyngitis, chronic obstructive pulmonary disease, or nontuberculous mycobacterial infection, the combination for use according to claim 5.

7. The respiratory infection is caused by or associated with one or more strains of Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae, Parainfluenza virus, Moraxella catarrhalis, Legionella species, Chlamydia pneumoniae, Mycoplasma pneumoniae, Bordetella pertussis, Neisseria gonorrhoeae, Corynebacterium diphtheriae, Coxiella burnetii, Peptostreptococcus species, Fusobacterium species, Bacteroides species, Prevotella species, Nocardia species, or Mycobacterium species, the combination for use according to claim 6.

8. The bacterial infection is an infection of the skin, soft tissue, bone or joint, the combination for use according to claim 3.

9. The infection is caused by or associated with one or more strains of Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus viridans, Salmonella species, Shigella species, Campylobacter species, Enterococcus faecalis, Enterococcus faecium, Kingella kingae, Corynebacterium species, Acne bacteria, Trachoma pathogen or Neisseria gonorrhoeae, the combination for use according to claim 8.

10. The combination is administered to a subject having endocarditis caused by or associated with the bacterial infection, the combination for use according to claim 3.

11. The combination for use according to claim 10, wherein the infectious disease is caused by or associated with one or more strains of a species of Staphylococcus, Streptococcus, Enterococcus, Chlamydia, Listeria, Neisseria, Haemophilus, Kingella, Legionella, or Corynebacterium.

12. The combination for use according to claim 3, wherein the combination is administered to a subject having bacteremia or sepsis caused by or associated with the bacterial infectious disease.

13. The combination for use according to claim 3, wherein the combination is administered to a subject having anthrax, tularemia, plague, glanders, or melioidosis caused by or associated with the bacterial infectious disease.

14. The combination for use according to claim 13, wherein the infectious disease is caused by or associated with one or more strains of Bacillus anthracis, Francisella tularensis, Yersinia pestis, Burkholderia mallei, or Burkholderia pseudomallei.

15. A composition comprising quinupristin or a pharmaceutically acceptable salt thereof and dalfopristin or a pharmaceutically acceptable salt thereof.

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