COMBINATION COMPOSITIONS COMPRISING A BETA-LACTAMASE INHIBITOR

FIELD OF INVENTION

The present invention relates to combination compositions comprising a beta-lactamase inhibitor and their use for treatment of bacterial infections.

BACKGROUND OF THE INVENTION

Antibiotics are the most effective drugs for curing bacteria-infectious diseases clinically. They have a wide market due to their advantages of good antibacterial effect with limited side effects. Among them, the beta-lactam class of antibiotics (for example, penicillins, cephalosporins, and carbapenems) are widely used because they have a strong bactericidal effect and low toxicity.

To counter the efficacy of the various beta-lactams, bacteria have evolved to produce variants of beta-lactam deactivating enzymes called beta-lactamases, and in the ability to share this tool inter- and intra-species. These beta-lactamases are categorized as “serine” or “metallo” based, respectively, on presence of a key serine or zinc in the enzyme active site. The rapid spread of this mechanism of bacterial resistance can severely limit beta-lactam treatment options in the hospital and in the community.

SUMMARY OF THE INVENTION

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

- (i) (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid:

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

- (ii) a siderophore antibiotic.

In some embodiments, the siderophore antibiotic is a siderophore cephalosporin antibiotic. In some embodiments, the siderophore antibiotic is cefiderocol. In some embodiments, the bacterial infection is a resistant bacterial infection. In some embodiments, the bacterial infection is caused by a gram-negative bacterium. In some embodiments, the bacterial infection is caused by Acinetobacter spp.i, Enterobacteriaceae, or Pseudomonas spp., or Stenotrophomonas maltophilia, or Burkholderia spp. In some embodiments, the pharmaceutical composition is formulated as a liquid suitable for injection. In some embodiments, the pharmaceutical composition is administered as an infusion. In some embodiments, the pharmaceutical composition is administered over a period of about 1 hour to about 4 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 1 hour. In some embodiments, the pharmaceutical composition is administered over a period of about 2 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 3 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 4 hours. In some embodiments, the pharmaceutical composition is administered every about 4 hours to every about 12 hours. In some embodiments, the pharmaceutical composition is administered every about 12 hours. In some embodiments, the pharmaceutical composition is administered every about 8 hours. In some embodiments, the pharmaceutical composition is administered every about 6 hours. In some embodiments, between about 0.125 g and about 1 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.125 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.25 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.5 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.75 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 1 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 2 g of cefiderocol is administered. In some embodiments, the method further comprises administering an additional β-lactam antibiotic. In some embodiments, the additional β-lactam antibiotic is a penicillin, a penem, a carbapenem, a cephalosporin, a cephamycin, a monobactam, or any combinations thereof. In some embodiments, the additional β-lactam antibiotic is amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzylpenicillin (G), carbenicillin, carindacillin, clometocillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin, meticillin, mezlocillin, nafcillin, oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin, sulbenicillin, talampicillin, temocillin, ticarcillin, faropenem, biapenem, ertapenem, doripenem, imipenem, meropenem, panipenem, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline fosamil, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, flomoxef, latamoxef, loracarbef, aztreonam, carumonam, nocardicin A, tigemonam, or any combinations thereof. In some embodiments, the additional β-lactam antibiotic is cefepime. In some embodiments, between about 1 g and about 2 g of cefepime is administered. In some embodiments, about 1 g of cefepime is administered. In some embodiments, about 2 g of cefepime is administered.

Also disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

- (i) (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid:

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

- (ii) sulbactam.

In some embodiments, the bacterial infection is a resistant bacterial infection. In some embodiments, the bacterial infection is caused by a gram-negative bacterium. In some embodiments, wherein the bacterial infection is caused by Acinetobacter spp. In some embodiments, the pharmaceutical composition is formulated as a liquid suitable for injection. In some embodiments, the pharmaceutical composition is administered as an infusion. In some embodiments, the pharmaceutical composition is administered over a period of about 1 hour to about 4 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 1 hour. In some embodiments, the pharmaceutical composition is administered over a period of about 2 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 3 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 4 hours. In some embodiments, the pharmaceutical composition is administered every about 4 hours to every about 12 hours. In some embodiments, the pharmaceutical composition is administered every about 12 hours. In some embodiments, the pharmaceutical composition is administered every about 8 hours. The method of any one of claims 1-12, wherein the pharmaceutical composition is administered every about 6 hours. In some embodiments, between about 0.25 g and about 1 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.25 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.5 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.75 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 1 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 1 g of sulbactam is administered. In some embodiments, the method further comprises administering a β-lactam antibiotic. In some embodiments, the method further comprises administering two β-lactam antibiotics. In some embodiments, the β-lactam antibiotic is independently a penicillin, a penem, a carbapenem, a cephalosporin, a cephamycin, a monobactam, and any combinations thereof. In some embodiments, the β-lactam antibiotic is independently amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzylpenicillin (G), carbenicillin, carindacillin, clometocillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin, meticillin, mezlocillin, nafcillin, oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin, sulbenicillin, talampicillin, temocillin, ticarcillin, faropenem, biapenem, ertapenem, doripenem, imipenem, meropenem, panipenem, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefnenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline fosamil, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, flomoxef, latamoxef, loracarbef, aztreonam, carumonam, nocardicin A, tigemonam, or any combinations thereof. In some embodiments, the β-lactam antibiotic is independently ampicillin, cefepime, or any combinations thereof. In some embodiments, the β-lactam antibiotics are ampicillin and cefepime. In some embodiments, the β-lactam antibiotic is ampicillin. In some embodiments, between about 1 g and about 2 g of ampicillin is administered. In some embodiments, about 1 g of ampicillin is administered. In some embodiments, about 2 g of ampicillin is administered. In some embodiments, the β-lactam antibiotic is cefepime. In some embodiments, between about 1 g and about 2 g of cefepime is administered. In some embodiments, about 1 g of cefepime is administered. In some embodiments, about 2 g of cefepime is administered.

Also disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

- (i) (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid:

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

- (ii) tazobactam.

In some embodiments, the bacterial infection is a resistant bacterial infection. In some embodiments, the bacterial infection is caused by a gram-negative bacterium. In some embodiments, the bacterial infection is caused by Acinetobacter spp. or Pseudomonas aeruginosa. In some embodiments, the pharmaceutical composition is formulated as a liquid suitable for injection. In some embodiments, the pharmaceutical composition is administered as an infusion. In some embodiments, the pharmaceutical composition is administered over a period of about 1 hour to about 4 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 1 hour. In some embodiments, the pharmaceutical composition is administered over a period of about 2 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 3 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 4 hours. In some embodiments, the pharmaceutical composition is administered every about 4 hours to every about 12 hours. In some embodiments, the pharmaceutical composition is administered every about 12 hours. In some embodiments, the pharmaceutical composition is administered every about 8 hours. In some embodiments, the pharmaceutical composition is administered every about 6 hours. In some embodiments, between about 0.125 g and about 1 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.125 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.25 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.5 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 0.75 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 1 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, between about 0.1 g and 0.5 g of tazobactam is administered. In some embodiments, about 0.375 g of tazobactam is administered. In some embodiments, about 0.25 g of tazobactam is administered. In some embodiments, about 0.5 g of tazobactam is administered. In some embodiments, the method further comprises administering a β-lactam antibiotic. In some embodiments, the method further comprises administering two β-lactam antibiotics. In some embodiments, the β-lactam antibiotic is independently a penicillin, a penem, a carbapenem, a cephalosporin, a cephamycin, a monobactam, or any combinations thereof. In some embodiments, the β-lactam antibiotic is independently amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzylpenicillin (G), carbenicillin, carindacillin, clometocillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin, meticillin, mezlocillin, nafcillin, oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin, sulbenicillin, talampicillin, temocillin, ticarcillin, faropenem, biapenem, ertapenem, doripenem, imipenem, meropenem, panipenem, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefnenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline fosamil, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, flomoxef, latamoxef, loracarbef, aztreonam, carumonam, nocardicin A, tigemonam, or any combinations thereof. In some embodiments, the β-lactam antibiotic is independently piperacillin, cefepime, or any combinations thereof. In some embodiments, the β-lactam antibiotics are piperacillin and cefepime. In some embodiments, the β-lactam antibiotic is piperacillin. In some embodiments, between about 1 g and about 4 g of piperacillin is administered. In some embodiments, about 1 g of piperacillin is administered. In some embodiments, about 2 g of piperacillin is administered. In some embodiments, about 3 g of piperacillin is administered. In some embodiments, about 4 g of piperacillin is administered. In some embodiments, the β-lactam antibiotic is cefepime. In some embodiments, between about 1 g and about 2 g of cefepime is administered. In some embodiments, about 1 g of cefepime is administered. In some embodiments, about 2 g of cefepime is administered.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

FIG. 1 shows the efficacy of Human Simulated Regimen of Cefepime combined with Compound 1 at Various Dose Ratios in the Neutropenic Thigh Infection Model with Cefepime-Resistant Clinical Isolates of Enterobacteriaceae and P. aeruginosa (n=30).

FIG. 2 shows the efficacy of Cefepime/Compound 1 at a Human Simulated Regimen of 2 g:0.5 g q8 h in the Neutropenic Thigh Infection Model with Cefepime-Resistant Clinical Isolates of Enterobacteriaceae and P. aeruginosa (n=30).

DETAILED DESCRIPTION OF THE INVENTION
Definitions

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

The term “antibiotic” refers to a compound or composition which decreases the viability of a microorganism, or which inhibits the growth or proliferation of a microorganism. The phrase “inhibits the growth or proliferation” means increasing the generation time (i.e., the time required for the bacterial cell to divide or for the population to double) by at least about 2-fold. Preferred antibiotics are those which can increase the generation time by at least about 10-fold or more (e.g., at least about 100-fold or even indefinitely, as in total cell death). As used in this disclosure, an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent. Examples of antibiotics suitable for use with respect to the present invention include penicillins, cephalosporins and carbapenems.

The term “β-lactam antibiotic” refers to a compound with antibiotic properties that contains a β-lactam functionality. Non-limiting examples of 3-lactam antibiotics useful with respect to the invention include penicillins, cephalosporins, penems, carbapenems, and monobactams.

The term “β-lactamase” denotes a protein capable of inactivating a β-lactam antibiotic. The β-lactamase can be an enzyme which catalyzes the hydrolysis of the β-lactam ring of a β-lactam antibiotic. Of particular interest herein are microbial β-lactamases. The β-lactamase may be, for example, a serine β-lactamase or a metallo-β-lactamase. β-Lactamases of interest include those disclosed in an ongoing website that monitors beta-lactamase nomenclature (www.lahey.org) and in Bush, K. and G. A. Jacoby. 2010. An updated functional classification of β-lactamases. Antimicrob. Agents Chemother. 54:969-976. β-Lactamases of particular interest herein include β-lactamases found in bacteria such as class A β-lactamases including the SHV, CTX-M and KPC subclasses, class B β-lactamases such as VIM, class C β-lactamases (both chromosomal and plasmid-mediated), and class D β-lactamases. The term “β-lactamase inhibitor” refers to a compound which is capable of inhibiting β-lactamase activity. Inhibiting β-lactamase activity means inhibiting the activity of a class A, B, C, or D β-lactamase. For antimicrobial applications, inhibition at a 50% inhibitory concentration is preferably achieved at or below about 100 micrograms/mL, or at or below about 50 micrograms/mL, or at or below about 25 micrograms/mL. The terms “class A”, “class B”, “class C”, and “class D” β-lactamases are understood by those skilled in the art and are described in Bush, K. and G. A. Jacoby. 2010. An updated functional classification of β-lactamases. Antimicrob. Agents Chemother. 54:969-976.

Compound 1

As used herein, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid is as shown in the structure below:

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In some embodiments, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid is also referred to as Compound 1. In some embodiments, Compound 1 exists in an equilibrium between the “closed” cyclic form (as shown above) and the “open” acyclic form:

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In some embodiments, Compound 1 associates into intramolecular dimers, trimers, and any combinations thereof. In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a dihydrochloride salt. In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable solvate. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water or organic solvents. In some embodiments, the solvent is not covalently bound to Compound 1. In some embodiments, the solvent is covalently bound to Compound 1. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. In some embodiments, the pharmaceutically acceptable solvate is a monohydrate solvate.

Combination of Compound 1 with Sulbactam

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

(i) ((R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof,

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and

(ii) sulbactam.

In some embodiments, sulbactam possesses some antibacterial activity when administered alone.

In some embodiments, sulbactam is administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof. In some embodiments, Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, and sulbactam are administered contemporaneously. In some embodiments, Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, and sulbactam are administered sequentially. In some embodiments, Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, and sulbactam are administered on different overlapping schedules.

In some embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

In some embodiments, the pharmaceutical composition comprises at least one pharmaceutically acceptable inactive ingredient. In other embodiments, the pharmaceutical composition includes carriers, adjuvants, preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers.

In some embodiments, the pharmaceutical composition comprises other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof.

The pharmaceutical formulations described herein are administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

In some embodiments, the pharmaceutical composition is formulated as a liquid suitable for injection.

In some embodiments, the pharmaceutical composition is administered as an infusion. In some embodiments, the pharmaceutical composition is administered as a continuous infusion.

In some embodiments, the pharmaceutical composition is administered over a period of about 1 hour to about 4 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 1 hour. In some embodiments, the pharmaceutical composition is administered over a period of about 2 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 3 hours. In some embodiments, the pharmaceutical composition is administered over a period of about 4 hours.

In some embodiments, the pharmaceutical composition is administered every about 4 hours to every about 12 hours. In some embodiments, the pharmaceutical composition is administered every about 12 hours. In some embodiments, the pharmaceutical composition is administered every about 10 hours. In some embodiments, the pharmaceutical composition is administered every about 8 hours. In some embodiments, the pharmaceutical composition is administered every about 6 hours. In some embodiments, the pharmaceutical composition is administered every about 4 hours.

In some embodiments, between about 0.125 g and about 1 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, between about 0.25 g and about 1 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, about 0.125 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, about 0.25 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, about 0.5 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, about 0.75 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, about 1 g of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, between about 0.5 g and about 2 g of sulbactam is administered. In some embodiments, about 0.5 g of sulbactam is administered. In some embodiments, about 1 g of sulbactam is administered. In some embodiments, about 1.5 g of sulbactam is administered. In some embodiments, about 2 g of sulbactam is administered.

In some embodiments, about 1 g sulbactam and about 1 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 1 g sulbactam and about 0.5 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 1 g sulbactam and about 0.75 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered. In some embodiments, about 1 g sulbactam and about 0.25 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

Further Combinations

In some embodiments, the methods described herein further comprise administering an antibiotic. In some embodiments, the methods described herein further comprise administering a β-lactam antibiotic.

In some embodiments, the methods described herein further comprise administering two antibiotics. In some embodiments, the methods described herein further comprise administering two β-lactam antibiotics.

In some embodiments, the β-lactam antibiotic is independently a penicillin, a penem, a carbapenem, a cephalosporin, a cephamycin, a monobactam, and any combinations thereof.

In some embodiments, the β-lactam antibiotic is independently amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzylpenicillin (G), carbenicillin, carindacillin, clometocillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin, meticillin, mezlocillin, nafcillin, oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin, sulbenicillin, talampicillin, temocillin, ticarcillin, faropenem, biapenem, ertapenem, doripenem, imipenem, meropenem, panipenem, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefnenoxime, cefmetazole, cefninox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline fosamil, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, flomoxef, latamoxef, loracarbef, aztreonam, carumonam, nocardicin A, tigemonam, or any combinations thereof.

In some embodiments, the β-lactam antibiotic is independently ampicillin, cefepime, or any combinations thereof.

In some embodiments, the β-lactam antibiotic is ampicillin.

In some embodiments, between about 1 g and about 2 g of ampicillin is administered. In some embodiments, about 1 g of ampicillin is administered. In some embodiments, about 2 g of ampicillin is administered.

In some embodiments, the β-lactam antibiotic is cefepime.

In some embodiments, between about 1 g and about 2 g of cefepime is administered. In some embodiments, about 1 g of cefepime is administered. In some embodiments, about 2 g of cefepime is administered.

In some embodiments, the β-lactam antibiotics are ampicillin and cefepime. In some embodiments, between about 1 g and about 2 g of ampicillin is administered and between about 1 g and about 2 g of cefepime is administered.

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

(ii) sulbactam; and

(iii) ampicillin.

In some embodiments, about 2 g of ampicillin, about 1 g of sulbactam, and about 1 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 2 g of ampicillin, about 1 g of sulbactam, and about 0.75 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 2 g of ampicillin, about 1 g of sulbactam, and about 0.5 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 2 g of ampicillin, about 1 g of sulbactam, and about 0.25 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered.

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

(ii) sulbactam; and

(iii) cefepime.

In some embodiments, about 2 g of cefepime, about 1 g of sulbactam, and about 1 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 2 g of cefepime, about 1 g of sulbactam, and about 0.75 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 2 g of cefepime, about 1 g of sulbactam, and about 0.5 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 2 g of cefepime, about 1 g of sulbactam, and about 0.25 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered.

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

(ii) sulbactam;

(iii) ampicillin; and

(iv) cefepime.

In some embodiments, about 1 g of cefepime, about 0.5 g of sulbactam, 1 g of ampicillin, and about 0.5 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 1 g of cefepime, about 1 g of sulbactam, 2 g of ampicillin, and about 0.5 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered.

Combination of Compound 1 with Tazobactam

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

and

(ii) tazobactam.

In some embodiments, tazobactam possesses some antibacterial activity when administered alone. In some embodiments, tazobactam is administered as a sodium salt.

In some embodiments, tazobactam is administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof. In some embodiments, Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, and tazobactam are administered contemporaneously. In some embodiments, Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, and tazobactam are administered sequentially. In some embodiments, Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, and tazobactam are administered on different overlapping schedules.

In some embodiments, the pharmaceutical composition is formulated as a liquid suitable for injection.

In some embodiments, the pharmaceutical composition is administered as an infusion. In some embodiments, the pharmaceutical composition is administered as a continuous infusion.

In some embodiments, the pharmaceutical composition is administered every about 4 hours to every about 12 hours.

In some embodiments, the pharmaceutical composition is administered every about 12 hours. In some embodiments, the pharmaceutical composition is administered every about 10 hours. In some embodiments, the pharmaceutical composition is administered every about 8 hours. In some embodiments, the pharmaceutical composition is administered every about 6 hours. In some embodiments, the pharmaceutical composition is administered every about 4 hours.

In some embodiments, between about 0.1 g and about 0.5 g of tazobactam is administered. In some embodiments, about 0.1 g of tazobactam is administered. In some embodiments, about 0.15 g of tazobactam is administered. In some embodiments, about 0.2 g of tazobactam is administered. In some embodiments, about 0.25 g of tazobactam is administered. In some embodiments, about 0.3 g of tazobactam is administered. In some embodiments, about 0.35 g of tazobactam is administered. In some embodiments, about 0.375 g of tazobactam is administered. In some embodiments, about 0.4 g of tazobactam is administered. In some embodiments, about 0.45 g of tazobactam is administered. In some embodiments, about 0.5 g of tazobactam is administered.

Further Combination

In some embodiments, the β-lactam antibiotic is independently a penicillin, a penem, a carbapenem, a cephalosporin, a cephamycin, a monobactam, or any combinations thereof.

In some embodiments, the β-lactam antibiotic is independently amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzylpenicillin (G), carbenicillin, carindacillin, clometocillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin, meticillin, mezlocillin, nafcillin, oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin, sulbenicillin, talampicillin, temocillin, ticarcillin, faropenem, biapenem, ertapenem, doripenem, imipenem, meropenem, panipenem, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline fosamil, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, flomoxef, latamoxef, loracarbef, aztreonam, carumonam, nocardicin A, tigemonam, or any combinations thereof.

In some embodiments, the β-lactam antibiotic is independently piperacillin, cefepime, or any combinations thereof.

In some embodiments, the β-lactam antibiotics are piperacillin and cefepime.

In some embodiments, the β-lactam antibiotic is piperacillin.

In some embodiments, between about 1 g and about 4 g of piperacillin is administered. In some embodiments, about 1 g of piperacillin is administered. In some embodiments, about 2 g of piperacillin is administered. In some embodiments, about 3 g of piperacillin is administered. In some embodiments, about 4 g of piperacillin is administered.

In some embodiments, the β-lactam antibiotic is cefepime.

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

(ii) tazobactam; and

(iii) piperacillin.

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

(ii) tazobactam; and

(iii) cefepime.

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

(ii) tazobactam;

(iii) piperacillin; and

(iv) cefepime.

Combination of Compound 1 with a Siderophore Antibiotic

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

and

(ii) a siderophore antibiotic.

As used herein a “siderophore antibiotic” refers to an antibiotic that binds to ferric iron and is actively transported into bacterial cells through the outer membrane via the bacterial iron transporters which function to incorporate this essential nutrient for bacteria.

In some embodiments, the siderophore antibiotic is a siderophore cephalosporin antibiotic. In some embodiments, the siderophore antibiotic is cefiderocol.

In some embodiments, the bacterial infection is a resistant bacterial infection. In some embodiments, the bacterial infection is caused by a gram-negative bacterium. In some embodiments, the bacterial infection is caused by Acinetobacter spp Enterobacteriaceae, or Pseudomonas spp., or Stenotrophomonas maltophilia, or Burkholderia spp.

In some embodiments, cefiderocol is administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof. In some embodiments, Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, and cefiderocol are administered contemporaneously. In some embodiments, Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, and cefiderocol are administered sequentially. In some embodiments, Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, and cefiderocol are administered on different overlapping schedules.

In some embodiments, the pharmaceutical composition is formulated as a liquid suitable for injection.

In some embodiments, the pharmaceutical composition is administered as an infusion. In some embodiments, the pharmaceutical composition is administered as a continuous infusion.

In some embodiments, the pharmaceutical composition is administered every about 4 hours to every about 12 hours.

In some embodiments, between about 0.5 g and about 3 g of cefiderocol is administered. In some embodiments, about 0.5 g of cefiderocol is administered. In some embodiments, about 1 g of cefiderocol is administered. In some embodiments, about 1.5 g of cefiderocol is administered.

In some embodiments, about 2 g of cefiderocol is administered. In some embodiments, about 2.5 g of cefiderocol is administered. In some embodiments, about 3 g of cefiderocol is administered.

In some embodiments, the methods described herein further comprise administering an additional antibiotic. In some embodiments, the methods described herein further comprise administering an additional β-lactam antibiotic.

In some embodiments, the additional β-lactam antibiotic is a penicillin, a penem, a carbapenem, a cephalosporin, a cephamycin, a monobactam, or any combinations thereof.

In some embodiments, the additional β-lactam antibiotic is amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzylpenicillin (G), carbenicillin, carindacillin, clometocillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin, meticillin, mezlocillin, nafcillin, oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin, sulbenicillin, talampicillin, temocillin, ticarcillin, faropenem, biapenem, ertapenem, doripenem, imipenem, meropenem, panipenem, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefnenoxime, cefmetazole, cefninox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline fosamil, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, flomoxef, latamoxef, loracarbef, aztreonam, carumonam, nocardicin A, tigemonam, or any combinations thereof.

In some embodiments, the additional β-lactam antibiotic is cefepime.

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

and

(ii) cefiderocol.

In some embodiments, about 2 g cefiderocol and about 0.5 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 2 g cefiderocol and about 0.25 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 2 g cefiderocol and about 0.125 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered.

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

(ii) cefiderocol and

(iii) cefepime.

In some embodiments, about 2 g cefiderocol, about 2 g of cefepime, and about 0.5 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 2 g cefiderocol, about 2 g of cefepime, and about 0.25 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered. In some embodiments, about 2 g cefiderocol, about 2 g of cefepime, and about 0.125 g of Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, is administered.

Combination of Compound 1 with Cefepime

Disclosed herein is a method of treating a bacterial infection comprising administering a pharmaceutical composition comprising:

embedded image

and

(ii) cefepime.

In some embodiments, the pharmaceutical composition is administered every about 4 hours to every about 12 hours.

In some embodiments, about 2 g of cefepime is administered. In some embodiments, about 1 g of cefepime is administered. In some embodiments, about 0.5 g of cefepime is administered.

In some embodiments, a weight ratio of about 4:1 cefepime: (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, a weight ratio of about 3:1 cefepime: (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, a weight ratio of about 2:1 cefepime: (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, a weight ratio of about 1:1 cefepime: (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, a weight ratio of about 1:0.5 cefepime: (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof is administered.

In some embodiments, the amounts of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof and cefepime are shown in the table below:

Compound 1 (g)
Cefepime (g)

1
0.125
0.5

2
0.125
1

3
0.125
1.5

4
0.125
2

5
0.25
0.5

6
0.25
1

7
0.25
1.5

8
0.25
2

9
0.5
0.5

10
0.5
1

11
0.5
1.5

12
0.5
2

13
0.75
0.5

14
0.75
1

15
0.75
1.5

16
0.75
2

17
1
0.5

18
1
1

19
1
1.5

20
1
2

Methods

The present disclosure provides methods for inhibiting bacterial growth, by, e.g., reducing bacterial resistance to a β-lactam antibiotic, such methods comprising contacting a bacterial cell culture, or a bacterially infected cell culture, tissue, or organism, with a pharmaceutical composition described herein. Preferably, the bacteria to be inhibited by administration of a pharmaceutical composition described herein are bacteria that are resistant to beta-lactam antibiotics. The term “resistant” is well-understood by those of ordinary skill in the art (see, e g Payne et al., Antimicrobial Agents and Chemotherapy 38 767-772 (1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 30 1120-1126 (1995)).

These methods are useful for inhibiting bacterial growth in a variety of contexts. In certain embodiments, a pharmaceutical composition described herein is administered to an experimental cell culture in vitro to prevent the growth of beta-lactam resistant bacteria. In certain other embodiments, a pharmaceutical composition described herein is administered to a mammal, including a human to prevent the growth of beta-lactam resistant bacteria in vivo.

In another aspect provided herein are methods of treating a bacterial infection, which method comprises administering to a subject a pharmaceutical composition comprising a pharmaceutical composition described herein. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, or a skin infection.

In some embodiments, the bacterial infection is acute bacterial skin and skin structure infections (ABSSSI), uncomplicated UTI (uUTI), complicated UTI (cUTI), complicated intraabdominal infections (cIAI), febrile neutropenia, community acquired bacterial pneumonia (CABP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or bacteremia. In some embodiments, the bacterial infection is acute bacterial skin and skin structure infections (ABSSSI). In some embodiments, the bacterial infection is uncomplicated UTI (uUTI). In some embodiments, the bacterial infection is complicated UTI (cUTI). In some embodiments, the bacterial infection is complicated intraabdominal infections (cIAI). In some embodiments, the bacterial infection is febrile neutropenia. In some embodiments, the bacterial infection is community acquired bacterial pneumonia (CABP). In some embodiments, the bacterial infection is hospital-acquired bacterial pneumonia (HABP).

In some embodiments, the bacterial infection is ventilator-associated bacterial pneumonia (VABP). In some embodiments, the bacterial infection is bacteremia.

In some embodiments, the infection that is treated or prevented comprises a bacteria that includes Elizabethkingia meningoseptica, Pseudomonas aeruginosa, Pseudomonas luorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfiuenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

In some embodiments, the infection that is treated or prevented comprises a bacteria that includes Elizabethkingia meningoseptica, Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides splanchnicus.

EXAMPLES
Example 1: In Vitro Efficacy of Combination Formulations of Compound 1 Plus Sulbactam

To determine the ability of test compounds to potentiate the antibacterial activity of sulbactam (Cat #1623670, USP, Rockville, Md.) and sulbactam combinations against Acinetobacter, classic cell based broth microdilution MIC assays were employed. A panel of 51 Acinetobacter isolates with elevated sulbactam MICs were used. Of these isolates 40 were characterized and known to produce an OXA-23-like (Ambler Class D carbapenemase) and at least one additional beta-lactamase enzymes while the remaining 11 were uncharacterized. The assay was conducted in Cation Adjusted Mueller Hinton Broth (CAMHB, BD #212322, BD Diagnostic Systems, Sparks, Md.). Bacteria strains were grown for 3-5 hours in CAMHB broth. The following antibacterial test articles were added either alone or at fixed ratios to a microtiter plate in 2-fold serial dilutions in CAMHB, sulbactam, ampicillin (Cat #A9518-5G, Sigma, St. Louis, Mo.), cefepime (Cat #1097636, USP, Rockville, Md.). β-lactamase Inhibitors (BLI, e.g. Compound 1) were added at a fixed concentration of 4 μg/mL when relevant. Titration of antibacterial alone or in combination and +/−BLI with MIC readout indicates the potentiation the combinations have compared to the standalone articles (Table 1 and 2). Once the test articles were added, the plates were inoculated according to CLSI broth microdilution method. After inoculation the plates were incubated for 16-20 hours at 37° C. then the Minimal Inhibitory Concentration (MIC) of the test compound was determined visually.

Minimum inhibitory concentration (MIC) data for Sulbactam (SUL), Ampicillin (AMP), and combinations with Compound 1 against a panel of multi-drug resistant Acinetobacter baumannii are shown in Table 1. A 2:1 ratio of AMP:SUL (commercially available as the drug product Unasyn®) was employed.

TABLE 1

Minimum inhibitory concentrations (MIC, μg/mL) of

Sulbactam (SUL), Ampicillin (AMP), and combinations with

Compound 1 (fixed at 4 μg/mL). ND, not determined.

AMP +
SUL +
AMP +

Strain
Enzyme

SUL
Compd 1
SUL (2:1) + Compd 1

ID
Content
SUL
(2:1)
(at 4 μg/mL)
(at 4 μg/mL)

0273
ADC-25,
32
16
8
16

OXA-23,

OXA-66

0274
TEM-1D,
64
64
16
16

ADC-25,

OXA-66,

OXA-72

0275
TEM-1D,
64
64
16
16

ADC-25,

OXA-23,

OXA-66

0276
ND
8
8
8
16

0277
TEM-1B,
32
32
8
8

OXA-65,

OXA-24

0278
TEM-1D,
32
64
8
8

ADC-25,

OXA-23,

OXA-66

0279
TEM-1D,
32
64
8
16

ADC-25,

OXA-23,

OXA-66

0280
TEM-1D,
128
128.1
4
16

ADC-25,

OXA-66

0281
TEM-1D,
32
32
2
8

ADC-25,

OXA-82

0282
TEM-1D,
32
64
16
32

ADC-25,

OXA-23,

OXA-66

0283
TEM-1D,
16
64
8
8

ADC-25,

OXA-23,

OXA-66

0284
TEM-1B,
32
64
4
8

OXA-65,

OXA-24

0285
TEM-1B,
16
32
16
16

OXA-65,

OXA-24

0286
ADC-25,
16
16
4
16

OXA-66,

OXA-24

0287
ADC-25,
64
64
16
32

OXA-66,

OXA-72

0288
ADC-25,
32
16
8
8

OXA-23,

OXA-66

0289
ADC-25,
16
32
8
16

OXA-66,

OXA-72

0290
TEM-1D,
32
64
8
16

ADC-25,

OXA-23,

OXA-66

0291
TEM-1D,
16
64
8
8

ADC-25,

OXA-23,

OXA-66

0292
OXA-66,
32
32
16
32

OXA-72

0293
OXA-66,
16
32
32
32

OXA-72

0294
TEM-1B,
16
32
16
16

OXA-23,

OXA-65

0295
TEM-1D,
32
64
32
32

ADC-25,

OXA-23,

OXA-66

0296
ADC-25,
64
32
32
32

OXA-23,

OXA-223

0297
ADC-25,
8
16
8
8

OXA-23,

OXA-66

0298
TEM-1D,
32
64
8
8

ADC-25,

OXA-66,

OXA-237

0299
PER-7,
32
32
8
16

OXA-23,

OXA-203

0300
ADC-25,
2
4
2
2

OXA-66

0301
ADC-25,
16
16
8
8

OXA-66,

OXA-72

0302
OXA-23,
32
16
8
16

OXA-82

0303
ADC-25,
8
16
4
8

OXA-23,

OXA-66

0304
ADC-25,
8
16
8
8

OXA-66,

OXA-72

0305
TEM-1B,
8
16
2
4

OXA-65,

OXA-24

0306
TEM-1B,
64
64
8
16

OXA-65,

OXA-24

0307
ADC-25,
4
8
4
4

OXA-66,

OXA-237

0308
TEM-1D,
32
32
4
4

ADC-25,

OXA-71

0309
OXA-23,
8
16
8
16

OXA-82

0310
OXA-23,
32
32
16
16

OXA-82

0311
ADC-25,
16
32
16
16

OXA-23,

OXA-82

0312
OXA-69
4
4
2
2

0313
TEM-1D,
32
128
8
8

OXA-23,

OXA-69

157834
ND
2
2
1
2

157842
ND
2
2
1
4

157876
ND
4
8
2
2

157901
ND
16
16
8
4

161750
ND
8
8
4
4

161752
ND
4
4
2
2

161755
ND
4
4
2
2

161756
ND
2
8
2
2

161760
ND
16
32
8
8

161762
ND
4
4
2
2

MIC₅₀
16
32
8
8

MIC₉₀
64
64
16
32

Example 2: In Vitro Efficacy of Combination Formulations of Compound 1 Plus Sulbactam in the Presence of Cefepime

Minimum inhibitory concentration (MIC) data for Compound 1/cefepime (FEP)/Sulbactam (SUL)/ampicillin (AMP) combinations vs. comparators against a panel of multi-drug resistant Acinetobacter baumannii are shown in Table 2. MIC values for the indicated fixed ratios of the beta-lactam antibiotics are provided.

TABLE 2

Minimum inhibitory concentrations (MIC, μg/mL) of

Cefepime (FEP), Ampicillin (AMP), Sulbactam (SUL) and

combinations with Compound 1 (fixed at 4 μg/mL). ND, not determined.

FEP + SUL
FEP + AMP +

FEP +
(1:1) +
SUL (1:1:1) +

Strain
Enzyme

Compd 1
Compd 1
Compd 1

ID
Content
FEP
(at 4 μg/mL)
(at 4 μg/mL)
(at 4 μg/mL)

0273
ADC-25,
32
32
8
8

OXA-23,

OXA-66

0274
TEM-1D,
32
32
8
8

ADC-25,

OXA-66,

OXA-72

0275
TEM-1D,
32
64
8
8

ADC-25,

OXA-23,

OXA-66

0276
ND
128.1
128.1
16
16

0277
TEM-1B,
128.1
128
4
4

OXA-65,

OXA-24

0278
TEM-1D,
32
32
8
16

ADC-25,

OXA-23,

OXA-66

0279
TEM-1D,
32
32
8
8

ADC-25,

OXA-23,

OXA-66

0280
TEM-1D,
16
16
4
4

ADC-25,

OXA-66

0281
TEM-1D,
16
8
4
4

ADC-25,

OXA-82

0282
TEM-1D,
64
64
16
16

ADC-25,

OXA-23,

OXA-66

0283
TEM-1D,
16
32
4
4

ADC-25,

OXA-23,

OXA-66

0284
TEM-1B,
32
32
4
4

OXA-65,

OXA-24

0285
TEM-1B,
32
32
8
8

OXA-65,

OXA-24

0286
ADC-25,
32
32
4
4

OXA-66,

OXA-24

0287
ADC-25,
32
16
8
8

OXA-66,

OXA-72

0288
ADC-25,
128
32
8
8

OXA-23,

OXA-66

0289
ADC-25,
32
16
8
8

OXA-66,

OXA-72

0290
TEM-1D,
32
32
16
8

ADC-25,

OXA-23,

OXA-66

0291
TEM-1D,
8
16
4
4

ADC-25,

OXA-23,

OXA-66

0292
OXA-66,
32
8
4
4

OXA-72

0293
OXA-66,
16
32
4
4

OXA-72

0294
TEM-1B,
32
32
8
8

OXA-23,

OXA-65

0295
TEM-1D,
32
64
16
8

ADC-25,

OXA-23,

OXA-66

0296
ADC-25,
64
64
16
16

OXA-23,

OXA-223

0297
ADC-25,
32
32
4
4

OXA-23,

OXA-66

0298
TEM-1D,
32
32
4
8

ADC-25,

OXA-66,

OXA-237

0299
PER-7,
128
16
8
8

OXA-23,

OXA-203

0300
ADC-25,
16
8
2
4

OXA-66

0301
ADC-25,
128.1
128.1
8
8

OXA-66,

OXA-72

0302
OXA-23,
16
32
16
8

OXA-82

0303
ADC-25,
16
8
4
4

OXA-23,

OXA-66

0304
ADC-25,
32
16
4
4

OXA-66,

OXA-72

0305
TEM-1B,
16
16
2
4

OXA-65,

OXA-24

0306
TEM-1B,
128
32
8
8

OXA-65,

OXA-24

0307
ADC-25,
32
8
2
4

OXA-66,

OXA-237

0308
TEM-1D,
16
8
2
4

ADC-25,

OXA-71

0309
OXA-23,
64
16
8
8

OXA-82

0310
OXA-23,
32
32
8
8

OXA-82

0311
ADC-25,
128.1
128.1
8
16

OXA-23,

OXA-82

0312
OXA-69
32
32
2
4

0313
TEM-1D,
64
16
4
4

OXA-23,

OXA-69

157834
ND
16
16
1
4

157842
ND
4
2
0.5
4

157876
ND
8
4
1
4

157901
ND
16
16
2
4

161750
ND
128
16
4
4

161752
ND
16
8
1
4

161755
ND
8
16
2
4

161756
ND
8
8
1
4

161760
ND
32
8
4
4

161762
ND
8
8
1
4

MIC₅₀
32
32
4
4

MIC₉₀
128
64
16
8

Example 3: In Vitro Efficacy of Combination Formulations of Compound 1 Plus Cefiderocol

To determine the ability of Compound 1 to potentiate the antibacterial activity of cefiderocol (FDC) against β-lactamase producing strains of Enterobacteriaceae, classic cell based broth microdilution MIC assays were employed. A panel of 30 strains of characterized Enterobacteriaceae isolates produce Ambler class A, B, C, and D β-lactamase were used. The assay was conducted in Cation Adjusted Mueller Hinton Broth (CAMHB, BD #212322, BD Diagnostic Systems, Sparks, Md.) and in parallel in Iron Depleted Medium (IDM). IDM was prepared by adding 100 g of chelex (a chelating agent) to 1 L of sterile CAMBH and stirring for 2 hours. The chelex treated media was then filtered using a 0.2 μm filter and divalent Ca, Mg, and Zn are added back at relevant concentrations. The pH was adjusted to 7.2 using HCl and the media was filtered again to ensure sterility. This created a medium that was devoid of iron but retains appropriate concentration of other cations and was necessary for evaluating the activity of cefiderocol originating from its uptake by bacterial iron transporters. Bacteria strains were grown for 3-5 hours in CAMHB and IDM. Cefiderocol was added either to a microtiter plate in 2-fold serial dilutions in CAMHB and in parallel in IDM. Cefiderocol was tested alone and with β-lactamase Inhibitor (Compound 1) added at a fixed concentration of 4 μg/mL or 8 μg/mL. Titration of cefiderocol alone or BLI with MIC readout indicates the potentiation the combinations have compared to the antibacterial alone, while the potentiation seen in IDM vs CAMBH indicates the potentiation of cefiderocol under more physiologically-relevant conditions (shown in Table 3). Once the test articles were added the plates were inoculated according to CLSI broth microdilution method. After inoculation, the plates were incubated for 16-20 hours at 37° C. then the Minimal Inhibitory Concentration (MIC) of the test compound was determined visually. This process was repeated in IDM only (not CAMHB) for cefiderocol alone and with compound 1 fixed at 4 μg/mL or 8 μg/mL in a panel of 40 MDR Acinetobacter (shown in Table 4) and for cefiderocol alone and with Compound 1 fixed at 4 μg/mL in a panel of 16 MDR Pseudomonas aeruginosa (shown in Table 5).

TABLE 3

Minimum inhibitory concentrations (MIC, μg/mL) of Cefiderocol (FDC) alone and in

combination with Compound 1 (fixed at 4 or 8 μg/mL) in β-lactamase expressing

Enterobacteriaceae.

FDC + Compd 1
FDC + Compd 1

Enzyme
FDC
(fixed at 4 μg/mL)
(fixed at 8 μg/mL))

Strain ID
Content
IDM
MHBII
IDM
MHBII
IDM
MHBII

E. coli 3073
AmpC, CTX-
0.5
8
0.125
2
0.125
2

M3

E. coli 128
AmpC, SHV-
0.5
2
0.03
0.5
0.03
0.5

12, TOHO-2,

TEM-1

E. coli SI-P026TC
CMY-2,
0.125
0.25
0.03
0.06
0.03
0.06

TEM-1

E. coli 3327
TEM-1, SHV-
0.125
0.5
0.03
0.125
0.03
0.125

12

K. pneumoniae
CTX-M-2,
0.125
8
0.03
1
0.03
1

847747
KPC

E. cloacae CDC-93
KPC
0.5
1
0.03
1
0.03
0.5

E. coli 786978
KPC 2
0.25
4
0.125
0.25
0.06
0.125

K. pneumoniae
KPC-2
0.5
16
0.125
4
0.125
2

KPC261

K. pneumoniae
KPC-2
0.5
16
0.25
2
0.125
2

847204

E. coli CDC-114
KPC-3
0.5
4
0.125
0.5
0.03
0.25

K. pneumoniae
KPC-3
0.5
8
0.125
4
0.125
2

KPC157

E. coli CDC-61
KPC-3 TEM-1
0.125
0.25
0.06
0.25
0.03
0.25

E. cloacae Entb239
p99 AmpC,
2
1
0.5
1
0.5
4

KPC-3,

CTXM-15,

GES-1, IMI-1

K. pneumoniae
SHV-12,
2
32
0.03
2
0.03
2

847375
KPC-2

E. coli 787112
OXA 48
64
64
0.125
1
0.03
4

K. pneumoniae
OXA-162
0.25
32
0.03
2
0.03
2

KIRK

K. pneummoniae
OXA-181
0.25
0.5
0.03
0.06
0.03
0.06

CDC-140

K. pneummoniae
IMP
0.125
2
0.125
2
0.125
1

CDC-34

E. cloacae CDC-161
IMP
1
16
1
8
1
8

P. mirabilis CDC-
NDM
4
32
0.03
0.5
0.03
0.5

159

K. pneummoniae
NDM
8
128
0.5
32
0.25
16

CDC-41

K. pneummoniae
NDM, OXA-
0.06
32
0.03
1
0.03
0.5

CDC-153
232

E. coli SI-152
NDM-1
0.125
0.125
0.03
0.06
0.03
0.06

E. coli GUE 131
NDM-1
1
2
0.06
0.06
0.06
0.125

K. pneumoniae
NDM-1
2
32
0.06
2
0.06
4

OMAN 13

E. coli CDC-150
NDM-5
4
128.1
0.5
32
0.5
32

K. pneummoniae
VIM
1
2
0.25
0.25
0.25
0.25

CDC-40

E. coli SI-151
VIM-1
0.125
0.5
0.03
0.125
0.03
0.5

E. coli SI-155S
VIM-1
1
2
0.03
0.5
0.03
0.125

K. pneumoniae SI-
VIM-1
4
16
0.03
0.25
0.03
1

117

MIC₅₀
0.5
4
0.06
1
0.03
0.5

MIC₉₀
4
32
0.5
4
0.25
4

TABLE 4

Minimum inhibitory concentrations (MIC, μg/mL) of

Cefiderocol (FDC) alone and in combination with Compound 1

(fixed at 4 or 8 μg/mL) in MDR-Acinetobacter conducted in IDM.

FDC +
FDC +

Compd 1
Compd 1

(fixed at
(fixed at

Strain ID
FDC
4 μg/mL)
8 μg/mL)

A. baumannii 0045
0.5
0.25
0.25

A. baumannii 157070
0.25
0.25
0.25

A. baumannii 157071
0.03
0.03
0.03

A. baumannii 157072
0.25
0.25
0.25

A. baumannii 157073
0.125
0.06
0.06

A. baumannii 157074
0.06
0.06
0.06

A. baumannii 157076
0.125
0.125
0.125

A. baumannii 157078
0.125
0.125
0.125

A. baumannii 157079
0.5
0.5
0.5

A. baumannii 157865
4
0.25
0.25

A. baumannii 161754
0.25
0.125
0.125

A. baumannii 161761
0.125
0.06
0.06

A. baumannii 161763
0.5
0.5
0.5

A. baumannii 163169
0.03
0.03
0.03

A. baumannii 163264
0.125
0.06
0.06

A. baumannii 164890
0.125
0.06
0.06

A. baumannii 164891
0.125
0.06
0.06

A. baumannii 164899
0.25
0.06
0.06

A. baumannii 165039
0.125
0.125
0.125

A. baumannii ATCC 17978
0.25
0.25
0.25

A. baumannii CDC-0033
0.5
0.125
0.125

A. baumannii CDC-0035
0.25
0.25
0.25

A. baumannii CDC-0036
1
0.5
0.5

A. baumannii CDC-0037
4
0.5
0.5

A. baumannii CDC-0052
8
0.5
0.25

A. baumannii CDC-0056
0.125
0.125
0.25

A. baumannii CDC-0063
0.5
0.125
0.125

A. baumannii CDC-0070
0.25
0.125
0.125

A. baumannii CDC-0078
0.5
0.06
0.06

A. baumannii CDC-0083
1
0.5
0.5

A. baumannii CDC-0088
8.1
0.5
0.25

A. baumannii CDC-0101
0.06
0.06
0.06

A. baumannii CDC-0102
1
0.25
0.25

A. baumannii GM235
1
0.5
0.5

A. baumannii GM236
0.03
0.03
0.03

A. baumannii GM237
0.25
0.25
0.25

A. baumannii GM238
0.25
0.125
0.125

A. baumannii GM239
2
0.25
0.25

A. baumannii NCTC 13301
1
0.25
0.25

A. baumannii SI-141
4
0.25
0.25

MIC₅₀
0.25
0.125
0.125

MIC₉₀
4
0.5
0.5

TABLE 5

Minimum inhibitory concentrations (MIC, μg/mL) of

Cefiderocol (FDC) alone and in combination with Compound 1

(fixed at 4 μg/mL) in MDR-Pseudomonas conducted in IDM.

FDC + Compd 1

Strain ID
FDC
(fixed at 4 μg/mL)

P. aeruginosa CDC-0054
0.5
0.059

P. aeruginosa CDC-0064
0.5
0.059

P. aeruginosa CDC-0090
0.125
0.059

P. aeruginosa CDC-0095
0.059
0.125

P. aeruginosa CDC-0103
4
0.125

P. aeruginosa CDC-0108
0.25
0.25

P. aeruginosa CDC-0110
8
0.059

P. aeruginosa CDC-0111
0.059
0.25

P. aeruginosa 40
4
0.125

P. aeruginosa 451
4
0.059

P. aeruginosa 635
0.5
0.125

P. aeruginosa 152021
0.25
0.25

P. aeruginosa 1013996
0.25
0.059

P. aeruginosa 1131170
2
0.25

P. aeruginosa 1121828
1
0.25

P. aeruginosa 1179543
2
0.059

MIC₅₀
0.5
0.125

MIC₉₀
4
0.25

Example 4: Proposed Clinical Study of Compound 1 in Combination with Sulbactam for the Treatment of A. baumannii Infections

For possible combinations of Compound 1, sulbactam, ampicillin, and cefepime, a Phase I drug-drug interaction study (DDI) will be conducted to ensure safety and appropriate pharmacokinetics of the various combinations. Such studies would be conducted in two parts 1) a randomized, crossover drug-drug interaction study (part 1) and 2) a repeat-dose safety and PK study (part 2). Part 1 would consist of a single dose of the given combination, and Part 2 would be conducted over 7-10 days of repeat doses of the given combination and dosing regimen. Following completion of these DDI studies, epithelial lung fluid and renal impairment studies would be conducted, using doses and regimens derived from the results from the DDI studies.

Proposed drug ratios, doses, and dosing regimens are outlined as follows:

For pairing Compound 1 only with sulbactam, the combinations will be dosed over a 3-hour infusion period. The repeat dose study will be conducted with dosing every 6 hours over a 3-hour infusion period. Doses of the following are planned: 1 g sulbactam plus 1 g Compound 1; 1 g sulbactam plus 0.75 g Compound 1; 1 g sulbactam plus 0.5 g Compound 1; and 1 g sulbactam plus 0.25 g Compound 1.

For studies combining cefepime, sulbactam, and Compound 1, the combinations would be administered using a 3-hour infusion period. The repeat dose study will be conducted with dosing every 8 hours, using a 3-hour infusion period. Doses of the following combinations are planned: 2 g cefepime plus 1 g sulbactam plus 1 g Compound 1; 2 g cefepime plus 1 g sulbactam plus 0.75 g Compound 1; 2 g cefepime plus 1 g sulbactam plus 0.5 g Compound 1; 2 g cefepime plus 1 g sulbactam plus 0.25 g Compound 1.

For studies combining cefepime, sulbactam, ampicillin, and Compound 1, the combinations will be administered using infusion times of both 2 hours and 3 hours. The repeat dose study will be conducted with dosing every 6 hours. The following doses are planned: 1 g cefepime plus 0.5 g Compound 1 plus 1 g ampicillin, plus 0.5 g sulbactam; 1 g cefepime plus 0.5 g Compound 1 plus 2 g ampicillin plus 1 g sulbactam.

Example 5: Proposed Clinical Study of Compound 1 in Combination with Cefiderocol for the Treatment of MDR-Enterobacteriaceae Infections

Combinations of cefiderocol and Compound 1 will require a Phase I drug-drug interaction study to safety and appropriate pharmacokinetics of the combination of drugs. Such studies would be conducted in two parts 1) a randomized, crossover drug-drug interaction study (part 1) and 2) a repeat-dose safety and PK study (part 2). Part 1 would consist of a single dose of the given combination, and Part 2 would be conducted over 7-10 days of repeat doses of the given combination and dosing regimen. Following completion of these DDI studies, epithelial lung fluid and renal impairment studies would be conducted, using doses and regimens derived from the results from the DDI studies.

Combination dosing of cefiderocol and Compound 1 would be administered using both 2-hour and 3-hour infusion periods. The repeat-dose study will be conducted with infusions given every 8 hours. The following doses are planned: 2 g cefiderocol plus 0.5 g Compound 1; 2 g cefiderocol: 0.25 g Compound 1; and 2 g cefiderocol plus 0.125 g Compound 1.

Example 6: Proposed Clinical Study of Compound 1 in Combination with Cefepime for Patients with cUTI

This study is a Phase 3, randomized, multicenter, double-blind, double dummy, active-controlled noninferiority study to evaluate the efficacy, safety, and tolerability of cefepime/Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof, compared with meropenem in adult patients with cUTI, including pyelonephritis (AP).

Patients will be randomized in a 2:1 ratio to receive study treatment with either cefepime/Compound 1 (2 g/0.5 g IV q8 h) or the active comparator, meropenem (1 g IV q8 h).

Patients will be stratified by the type of infection (AP only versus complicated lower UTI with or without AP) and region (North America and Western Europe versus Eastern Europe versus rest of the world). At least 30% of the population will have AP.

Study treatment will be administered IV for 7 days and will be considered completed after the third dose on Study Day 7. All patients (who do not require dosing adjustments for renal dysfunction) will receive at least 19 doses and no more than 21 doses of active study drug.

Patients with bacteremia at study entry may have their treatment extended up to 10 days at the Investigator's discretion. Patients will be admitted at screening and remain at the study site or hospital for the duration of the IV treatment period and through the EOT assessment. The EOT visit will be performed no more than 24 hours after the last dose of IV study drug. Patients may be discharged from the study site after the EOT assessment if clinically stable and at the Investigator's discretion.

Patients must return to the study site for the TOC assessment (Study Days 12 to 17) and the LFU assessment (Study Days 21 to 28).

Choice and Dosing of Comparator

Meropenem has been selected as the comparator because it has demonstrated efficacy against gram-negative pathogens isolated in cUTIs, including pyelonephritis. Although in the US it is approved for other indications, including complicated intra-abdominal infections, skin and soft tissue structure infections and bacterial meningitis in pediatric patients it is not approved for use in cUTI in the US. However, meropenem is approved for cUTI in other geographic regions and was used as a comparator in the plazomicin pivotal cUTI study supporting approval. Furthermore, carbapenems are the drugs of choice against ESBL-producing gram-negative pathogens, especially in serious infections. As such, it is an appropriate comparator to use when evaluating a new drug designed to treat infections due to bacteria harboring serine-β-lactamases.

Meropenem 1 g q8 h will be given as an active comparator. In the US and elsewhere, meropenem is approved at doses of 0.5 or 1 g q8 h (given by intravenous infusion over 15 to 30 minutes), depending on the type of infection. The Summary of Product Characteristics indicates that doses of 0.5 or 1 g meropenem q8 h is appropriate for cUTI. In order to ensure the best therapy against pathogens that are more difficult to treat, the dose of 1 g has been chosen. Although meropenem is not approved in the US for cUTI, the US prescribing information indicates that 1 g meropenem q8 h is appropriate for the treatment of patients with cIAIs and skin and soft tissue structure infections due to P. aeruginosa, which is consistent with the goal to use a higher dose (i.e., 1 g) in more difficult-to-treat infections.

Dose Administration and Adjustments

Each patient will receive a 30-minute infusion and a 2-hour infusion, once every 8 hours (q8 h). If only one line is available for IV medication administration, the 30-minute infusion should be administered prior to the 2 hour infusion. Patients randomized to cefepime/Compound 1 will receive meropenem placebo (0.9% saline) infused over 30 minutes IV immediately followed by cefepime/Compound 1 (2 g/0.5 g IV q8 h) infused over 2 hours. Patients randomized to receive meropenem will receive meropenem 1 g IV infused over 30 minutes, immediately followed by placebo (0.9% saline) infused over 2 hours. The 30 minute and 2 hour infusion may be administered concurrently if two, separate lines are used.

Treatment Duration

All patients will receive at least 7 days of IV treatment. All patients will be considered to complete dosing after their last dose on day 7. All patients (who do not require dosing adjustments for renal dysfunction) will receive at least 19 doses and no more than 21 doses of active study drug. Patients with bacteremia at study entry may have their treatment extended up to 10 days at the Investigator's discretion.

There is no oral stepdown therapy, and patients are not permitted to continue oral antibacterials at home after completion of IV study treatment.

Primary Objective and Efficacy Endpoints

The primary objective of this non-inferiority study is to assess the efficacy of cefepime/Compound 1 compared with meropenem with respect to both per-patient microbiologic eradication and symptomatic resolution of all UTI-core signs and symptoms (or return to pre-morbid baseline) at the test of cure (TOC) visit. The TOC visit will occur 5-10 days after end of therapy for patients who do not have bacteremia at baseline and at least 2 days and no more than 7 days for patients who have bacteremia and have therapy extended. The primary analysis will be performed in the microbiologic ITT (microITT) population

The response rate will be calculated for each treatment group as the number of successes divided by the total number of patients (success+failure+indeterminate). To be a success, a patient must be a success for both microbiologic and clinical outcomes. Patients with a failure in either microbiologic or clinical outcomes will be considered a failure. Patients with success in one outcome, but indeterminate outcome in the other will be considered to have a primary outcome of indeterminate.

Microbiologic Response

Before receipt of study treatment, a urine specimen will be obtained from all patients for culture and for in vitro antibacterial susceptibility testing. Patients with an indwelling catheter should have urine samples collected following the placement of a new catheter, or if the indwelling catheter cannot be removed, aseptic techniques should be used through a properly disinfected collection port. Patients with indwelling catheter should be randomized only if they are expected to permanently discontinue use of the catheter prior to Study Day 5.

Microbiological outcome per-patient will be assessed in a blinded manner programmatically. It is based on outcome per-pathogen isolated at the initial visit (considered as causative) and on the isolation of a pathogen at TOC based on the definitions in Table 6. For patients with more than 1 pathogen present at baseline all pathogens must be eradicated to be classified as a microbiologic success.

TABLE 6

Microbiological Response Criteria

Microbiological Response
Definition

Eradication
Demonstration that the bacterial pathogen

found at study entry (≥10⁵CFU/mL is

eradicated to <10³CFU/mL

Persistence
Demonstration that the bacterial pathogen

found at study entry (≥10⁵CFU/mL) grows

≥10³CFU/mL

Indeterminate
Repeat cultures are not performed

microbiological response

CFU = colony-forming unit.

Symptomatic Clinical Response

Screening assessments include a Daily Patient Symptom Questionnaire (DPSQ) performed at baseline and a Pre-morbid Patient Symptom Questionnaire (PPSQ). The DPSQ will be administered at baseline, daily while on study therapy and at EOT, TOC and LFU visits to determine the presence and intensity of cUTI signs and symptoms. The PPSQ will be administered once at Baseline to determine whether a patient normally experiences urinary tract symptoms (i.e., in the absence of a UTI) that may be attributable to other disease processes (e.g., Benign Prostatic Hypertrophy).

The DPSQ and the PPSQ are formal questionnaires that will be administered by trained study center staff. The questions will be read out loud verbatim. The administrator is not permitted to interpret the questions for the patient, further explain the questions to the patient or comment on the patient response. The DPSQ obtained at the TOC visit will be programmatically compared to both the DPSQ obtained at baseline as well as the PPSQ to determine whether all core cUTI symptoms (dysuria urgency, frequency, flank pain/tenderness, suprapubic pain/tenderness) have resolved and or returned to the patient's pre-morbid (i.e., prior to the onset of the current cUTI) state in order to determine the symptomatic clinical response as defined in Table 7.

TABLE 7

Symptomatic Clinical Response Criteria

Response

Category
Definition

Symptomatic
Both of the following have occurred:

Clinical success
Resolution (or return to pre-morbid state) of the

core symptoms of cUTI (dysuria, frequency,

urgency, suprapubic/pelvic pain, and flank pain)

present at study entry

No new core cUTI symptoms have developed and

no symptoms have worsened

Symptomatic
Occurrence of 1 or more of the following:

Clinical failure
Confirmed persistence of at least 1 symptom (i.e.

non-resolution or not having returned to pre-morbid

state) of the core symptoms of cUTI (dysuria,

frequency, urgency, suprapubic/pelvic pain, and

flank pain)

Development of 1 or more core symptoms of cUTI

not present at baseline Death

Indeterminate
Cases where the symptomatic clinical response

symptomatic
could not be assessed

clinical response

The definitions for symptomatic clinical response are based on FDA guidance. Notably, the proposed criteria are independent of post randomization events and are not impacted by receipt of an additional antibiotic to treat cUTI (i.e., due to deterioration in clinical status or premature discontinuation of study drug) prior to TOC. Furthermore, symptomatic clinical failure at the End of Therapy Visit (EOT) (within 24 hours after the last dose of study drug) is not a criterion for failure at TOC.

Other Efficacy Endpoints

Secondary efficacy endpoints include evaluation of cefepime/Compound 1 versus meropenem in regards to microbiologic (per-patient and per pathogen) outcomes and clinical outcomes in several analysis populations (i.e., microITT, CE, ME) and at various timepoints (i.e., EOT, TOC and Late Follow Up (LFU; Study day 21-28).

In addition, outcomes by baseline MIC and among cefepime resistant pathogens will be evaluated. Post baseline cultures will be assessed for increasing MIC to study drug (indicated by the organism displaying a >4-fold higher MIC to study drug received in a urine or blood culture obtained at EOT or later compared to baseline), super infections (isolation of a new pathogen from the urine during study treatment that requires additional therapy) and new infections (isolation of a new pathogen from the urine during after completion of study treatment that requires additional therapy).

Statistical Plan

An independent Data Safety Monitoring Board (DSMB) will be formed to monitor interim safety data during the study. Procedures for DSMB reviews/meetings will be defined in the DSMB charter. The DSMB will review applicable data at scheduled timepoints during the study as defined in the charter.

Additional data may be requested by the DSMB. The DSMB will review grouped and unblinded (upon request) data in the closed session only. As an outcome of each review/meeting, the DSMB will make a recommendation as to the advisability of proceeding with study treatment administration, and to continue, modify, or terminate this study.

Ongoing data to be reviewed by the DSMB as well as VenatorRx and CRO medical monitors includes Adverse Event Monitoring (from consent through the LFU), Clinical Laboratory Assessments (at screening/baseline, Study day 4, Study day 8 (if still on study therapy), at EOT, at TOC and at LFU), and Vital Signs (at screening/baseline, daily while on study therapy, at EOT, at TOC and at LFU). Sites will be asked to collect ECGs as part of screening and on day 4 immediately after completion of the cefepime/Compound 1 or cefepime placebo infusion (and after study state has been achieved). Investigators should review all ECGs, follow up any abnormalities and report any significant findings as AEs if AE criteria are met. ECG results will not be collected or centrally analyzed a priori but in the event of any cardiac events, the site will have the ECGs available for review in the study record.

Example 7: Proposed Clinical Study of Compound 1 in Combination with Cefepime for Patients with Infections Caused by Resistant Pathogens

This study will be a prospective, Phase 3, multicenter, randomized, open-label, active-controlled study of cefepime/Compound 1 therapy (versus BAT (Best Available Therapy)) in patients with cUTI, cIAI, or bacteremia (not related to cIAI or cUTI; patients with cUTI or cIAI may have concurrent bacteremia) caused by resistant pathogens. For the purposes of this study, a resistant pathogen is an isolate of Enterobacteriaceae or Pseudomonas aeruginosa that demonstrates resistance to a carbapenem. The primary objective of this study is to estimate the response to cefepime/Compound 1 and BAT at Test of Cure (TOC) in the treatment of selected serious infections caused by carbapenem-resistant Enterobacteriaceae spp and Pseudomonas aeruginosa.

This study aims to recruit as many eligible patients as possible in the time period (24 months). This study is expected to recruit approximately 75 patients (approximately 50 in the cefepime/Compound 1 combination therapy group and approximately 25 in the group receiving BAT. Cefepime hydrochloride for injection (2 g/vial) and Compound 1, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof (0.5 g/vial) will each be reconstituted independently, combined in a single IV bag, and diluted to a total volume of 250 mL with 0.9% sodium chloride for injection. Cefepime/Compound 1 will be administered over a 2-hour period at a rate of 2.1 mL/min. For patients with cIAI who are receiving cefepime/Compound 1 metronidazole 0.5 g will be administered immediately following each cefepime/Compound 1 infusion. Metronidazole for injection will be administered as an IV infusion over 30 minutes. Patients randomized to receive the investigator-determined BAT will receive IV doses based on the investigator's standard of care and local label recommendation. Treatment will be continued for a period of time (5 full days to 14 full days) deemed appropriate by the investigator based upon the demonstration of clinical improvement.

Example 8: In Vivo Thigh Infection Model for Dose Determination

The 2 g:0.5 g dose of cefepime:Compound 1 which is planned for clinical efficacy studies is supported by neutropenic murine thigh infection model studies using 30 cefepime-resistant clinical isolates of Enterobacteriaceae and P. aeruginosa.

In these studies, the human simulated regimen (HSR) of 2 g cefepime alone q8 h was ineffective at 24 h (FIG. 1, B), allowing approximately 2.7 log₁₀CFU/thigh growth on average compared to the T=0 control (FIG. 1, A). Cefepime activity was maximally rescued when Compound 1 was administered at an HSR of 0.5 g on the same q8 h schedule as cefepime: this regimen attained on average 1.7 log₁₀bacterial killing relative to the initial bacterial burden (FIG. 1, F). This extent of killing in vivo exceeds the stasis to 1 log₁₀kill target for efficacy that predicts clinical efficacy in patients with cUTI. Whereas for several of the tested strains, significant rescue of cefepime activity was observed at lower Compound 1 doses in combination with cefepime (FIG. 1, C, D, and E), the cefepime/Compound 1 2 g:0.5 g HSR reliably protected cefepime bactericidal activity across all 30 tested strains, regardless of their β-lactamase content.

When dosed to mice using an HSR of cefepime 2 g: Compound 1 0.5 g, the combination exerted at least 1-log₁₀killing against each of the 30 tested strains, regardless of their cefepime/Compound 1 MIC (FIG. 2). No evidence was seen of adaptive resistance, which would be evident as growth of the infecting strain following dosing with the combination. The neutropenic murine thigh infection model data therefore supports the cefepime 2 g: Compound 1 0.5 g dose for clinical studies because it reliably protected cefepime bactericidal activity across all tested strains, regardless of their β-lactamase content or cefepime/Compound 1 MIC, up to the highest tested MIC of 16 μg/mL.

Example 9: In Vitro Efficacy of Triple Combination

For a more comprehensive assessment of the ability of test compounds to potentiate sulbactam in triple combinations with β-lactams additional MIC assays were utilized. The antimicrobial activity of cefepime and meropenem were evaluated in the presence of the Compound 1 and/or sulbactam against a set of 141 Acinetobacter baumannii-calcoaceticus species complex clinical isolates exhibiting elevated MIC values for ampicillin-sulbactam.

TABLE 8

Minimal Inhibitory Concentration (MIC, μg/mL) of Compound 1 (4 μg/mL) in combination

with sulbactam (SUL), or sulbactam and either meropenem (MEM) or cefepime (FEP) vs. sulbactam

alone, or ampicillin-sulbactam (AMP-SUL), in 141 globally collected clinical isolates of Acinetobacter

baumannii.

FEP + SUL

MEM +

AMP-

FEP +
(1:1) +

MEM +
SUL (1:1) +

SUL +
SUL

Strain
FEP
Cmpd 1
Cmpd 1
MEM
Cmpd 1
Cmpd 1
SUL
Cmpd 1
(2:1)

1042182
32
32
8
64
64
16
16
16
32

1040917
>512
>256
32
128
128
64
128
64
>64

1040916
128
128
16
128
64
16
32
16
>64

1040901
256
64
16
64
64
8
64
16
>64

1040900
64
64
8
64
64
8
8
16
64

1039518
64
32
8
64
64
8
16
8
32

1039515
64
64
16
128
128
16
32
16
64

1039514
256
64
16
128
128
16
16
32
32

1039502
>512
>256
32
64
128
16
64
64
>64

1038439
128
128
8
0.25
0.25
0.25
16
16
32

1038418
128
128
16
0.25
0.25
<=0.12
16
16
32

1037747
>512
16
4
256
256
8
32
8
>64

1037738
32
32
8
>256
>256
16
16
8
32

1037732
32
32
8
256
256
16
16
16
64

1037731
256
8
4
0.5
0.5
0.25
16
4
32

1037714
4
2
2
256
256
8
8
8
64

1037618
256
16
4
1
1
0.5
64
16
>64

1037593
256
16
8
256
256
16
32
16
64

1037479
>512
8
4
256
128
8
128
16
>64

1037462
256
64
8
128
128
8
16
16
64

1037294
256
128
32
128
128
32
64
64
>64

1037256
32
32
8
64
64
8
16
16
64

1037251
512
32
8
64
64
16
32
16
>64

1037211
512
32
16
2
1
1
64
16
64

1037193
32
16
8
>256
256
8
16
16
32

1036921
32
16
2
1
1
0.5
64
2
64

1036882
16
32
8
256
256
16
32
16
64

1036859
256
128
16
64
128
16
32
16
64

1036781
32
16
8
>256
256
16
32
16
>64

1036768
>512
8
4
8
4
2
32
4
64

1036734
128
64
8
64
32
8
32
16
64

1036068
64
64
16
64
64
16
32
16
>64

1036045
64
32
16
64
128
16
32
16
64

1036023
128
64
8
128
128
16
64
16
64

1035900
128
64
16
128
128
16
32
64
>64

1035825
64
32
8
64
64
8
32
8
64

1035808
256
16
8
16
16
8
32
16
64

1035794
16
16
8
32
32
32
64
64
>64

1035788
32
32
8
64
64
8
32
16
64

1035144
256
256
32
256
256
32
32
64
>64

1034962
512
64
16
64
64
16
32
16
64

1034951
256
128
16
128
128
32
32
32
>64

1034931
128
16
2
128
64
4
16
4
32

1034925
64
32
8
64
32
8
32
8
64

1034916
256
32
8
64
64
16
64
16
>64

1034913
128
64
8
64
64
16
32
16
>64

1034912
64
32
16
64
64
16
32
32
64

1034880
64
64
16
128
64
32
32
16
64

1034048
128
128
32
256
256
16
32
32
64

1033979
256
64
16
256
256
32
64
64
>64

1033340
128
64
8
256
128
8
16
8
32

1032761
256
128
32
256
256
64
64
64
>64

1032669
64
64
8
64
64
16
16
16
32

1031566
128
64
16
128
64
16
32
16
64

1031238
512
256
32
256
256
64
32
32
>64

1031211
256
256
32
64
128
16
32
32
>64

1031191
64
64
16
64
64
16
16
16
32

1031177
128
64
16
128
128
16
16
32
64

1031167
256
256
32
256
256
32
64
32
>64

1031136
256
64
32
128
128
32
32
64
>64

1030945
128
128
32
128
128
32
32
32
>64

1030928
>512
>256
32
128
128
32
64
64
>64

1030427
32
32
8
256
128
16
16
16
32

1029913
32
32
8
32
32
8
16
16
64

1029770
256
256
16
>256
256
32
32
32
>64

1028193
32
64
16
>256
>256
32
64
32
64

1027748
32
64
8
32
32
8
8
8
32

1027603
64
32
16
64
32
16
8
4
32

1027590
256
256
32
256
128
32
32
32
>64

1027234
64
64
8
64
64
8
8
8
32

1026992
256
32
16
32
64
8
16
16
32

1026990
256
64
8
256
256
8
16
16
64

1024215
32
16
8
128
128
16
16
16
32

1024119
32
16
4
4
2
1
32
4
64

1023329
128
128
8
64
64
8
16
16
32

1023207
32
16
8
32
32
8
16
8
32

1023074
128
128
16
32
32
8
32
32
32

1023034
256
256
8
64
64
8
16
8
64

1023031
256
128
64
>256
>256
64
128
64
64

1019086
512
256
64
256
128
32
128
64
>64

1018851
256
256
32
256
256
32
64
32
>64

1018807
128
128
16
64
64
16
32
16
64

1018806
512
32
4
128
8
2
64
8
>64

1018804
256
256
16
128
128
16
32
32
64

1018802
256
128
32
256
128
32
64
64
>64

1018801
>512
>256
32
256
128
16
64
64
>64

1018109
2
2
1
0.25
0.25
0.25
4
2
32

1017679
128
64
16
128
128
16
32
16
>64

1016836
64
64
16
128
128
16
32
16
32

1016545
128
256
16
128
128
16
16
16
64

1014890
256
128
16
128
128
32
32
16
>64

1014878
128
128
8
64
64
8
32
16
>64

1014870
256
256
32
256
256
64
128
64
>64

1014866
128
128
8
64
64
8
32
16
64

1014815
256
128
32
256
256
64
64
32
64

1014646
64
32
4
64
32
4
16
4
64

1014143
32
16
4
8
8
4
32
4
64

1013322
128
64
8
64
64
8
16
16
32

1013055
256
8
1
32
2
0.5
16
2
32

1013035
32
16
2
256
128
4
16
4
64

1013022
64
16
4
256
256
4
8
8
32

1011959
64
32
8
64
64
16
16
16
32

1010950
>512
32
8
128
16
4
128
8
>64

1010383
128
128
16
128
128
16
32
32
64

1010331
>512
256
64
64
32
16
128
256
>64

1010245
64
64
16
64
64
16
16
16
32

1008756
512
256
32
128
128
32
64
64
>64

1008730
64
128
32
128
128
32
32
32
64

1008510
64
32
8
256
256
8
32
8
>64

1008508
128
64
8
>256
256
16
16
8
>64

1007660
128
128
16
128
128
32
32
32
>64

1005290
256
64
16
128
128
16
16
16
32

1005265
128
128
16
128
128
32
32
32
64

1004867
256
128
32
128
128
32
64
64
>64

1003787
>512
8
4
>256
256
16
32
16
>64

1003662
512
256
16
128
128
16
16
16
64

1003557
64
16
4
256
256
4
8
4
32

1002960
128
128
32
>256
>256
64
128
128
>64

1002952
64
32
16
>256
>256
32
64
64
>64

1002688
64
64
16
128
64
16
16
16
64

1002247
>512
256
64
128
128
8
64
32
>64

1002208
64
32
8
64
64
16
16
16
32

1001611
16
16
4
32
32
4
16
8
32

1001143
128
128
32
128
128
32
32
32
32

1001007
256
128
16
256
256
16
32
32
>64

999343
256
128
32
128
128
16
32
32
64

999306
8
16
2
2
1
0.5
8
2
32

998907
8
8
4
16
16
4
32
4
64

998898
512
>256
64
32
32
8
64
128
>64

998532
64
32
4
256
256
16
16
8
64

998107
128
64
8
64
64
8
16
16
32

997574
16
8
2
256
256
8
32
4
64

996869
32
32
8
>256
>256
16
32
32
>64

996707
64
64
16
128
128
16
32
32
64

996612
>512
256
32
32
32
8
64
64
32

995771
128
64
8
256
256
8
16
8
32

994181
128
64
16
128
128
16
16
16
64

994180
32
16
2
2
1
1
16
4
64

993139
128
128
16
128
128
32
32
32
64

993131
64
64
16
64
128
16
32
16
64

990089
64
32
8
128
128
16
16
16
32

Example 10: In Vitro Efficacy of Combination Formulations of Compound 1 Plus Cefiderocol as Compared to Approved BL/BLI Combinations

Cefiderocol (FDC) with Compound 1 was further profiled in additional MIC assays against a panel of 120 carbapenem resistant Enterobacteriaceae (CRE) in parallel with recently approved BL/BLI combinations. Cefiderocol alone and cefiderocol with Compound 1 at 4 μg/mL and 8 μg/mL were tested in iron-depleted media (IDM), while ceftazidime (CAZ) with avibactam (AVI) at 4 μg/mL and meropenem (MEM) with vaborbactam (VAB) at 8 μg/mL were tested in cation-adjusted Mueller-Hinton Broth II (MHII). The challenge set of organisms consisted of a variety of Enterobacteriaceae species expressing IMP (n=30), NDM (30), VIM (15), KPC (n=30), and AmpC (n=15).

TABLE 9

Minimal inhibitory concentrations (μg/mL) for cefiderocol with Compound 1 at 4 and 8 μg/mL

and comparators against a challenge set of 120 CRE isolates.

IDM

MH II

FDC +
FDC +

Strain

CAZ + AVI
MEM + VAB

Cmpd 1
Cmpd 1

Species
ID
Enzymes
@ 4 μg/mL
@ 8 μg/mL
FDC
@ 4 μg/mL
@ 8 μg/mL

Enterobacter

1488830
IMP-14
>32
8
2
0.5
0.5

cloacae

Klebsiella

1277416
IMP-26
>32
8
0.5
0.5
1

pneumoniae

Klebsiella

1420892
IMP-4
>32
2
2
1
1

pneumoniae

Enterobacter

1490669
IMP-4
>32
2
0.25
0.25
0.125

cloacae

Klebsiella

1591688
IMP-4
>32
4
1
2
1

pneumoniae

Klebsiella

1591702
IMP-4
>32
4
1
2
2

pneumoniae

Enterobacter

1703478
IMP-4
>32
4
0.125
0.25
0.125

cloacae

Klebsiella

1585615
IMP-4
>32
4
0.25
0.25
0.125

oxytoca

Klebsiella

1607267
IMP-4
>32
4
4
1
0.5

pneumoniae

Klebsiella

1274060
IMP-4
>32
8
0.059
0.0149
0.0149

oxytoca

Escherichia

1468388
IMP-59
>32
4
2
1
1

coli

Klebsiella

1417076
IMP-8
>32
1
4
0.5
0.5

oxytoca

Klebsiella

1417077
IMP-8
>32
1
4
0.5
0.5

oxytoca

Klebsiella

CDC-
IMP-4,
>32
8
0.25
0.25
0.25

pneumoniae

0034
TEM-1B,

SHV-11

Klebsiella

CDC-
IMP-4,
>32
8
0.5
1
1

pneumoniae

0080
TEM-1B,

OKP-B-2,

OXA-1,

SFO-1

Enterobacter

CDC-
IMP-4,
>32
8
2
1
1

aerogenes

0161
TEM-1B,

OXA-1,

SFO-1

Klebsiella

SI-128
IMP-5
>32
0.5
2
1
0.5

pneumoniae

Klebsiella

IHMA
IMP-26,
0.25
0.0149
0.059
0.0149
0.0149

pneumoniae

469384
SHV-12

Klebsiella

IHMA
IMP-26
>32
8
1
2
2

pneumoniae

511121

Klebsiella

IHMA
IMP-26
>32
8
2
2
2

pneumoniae

511128

Klebsiella

IHMA
IMP-26
>32
8
4
4
2

pneumoniae

511163

Klebsiella

IHMA
CTX-M-
>32
8
2
1
1

pneumoniae

600482
15, IMP-26

Enterobacter

IHMA
CMY-2,
>32
32
0.5
0.25
0.25

aerogenes

846505
IMP

E. asburiae

IHMA
CTX-M-
8
0.125
0.059
0.03
0.03

850697
15, DHA-

1, IMP

Enterobacter

IHMA
IMP
0.125
0.0149
0.059
0.0149
0.0149

aerogenes

890184

Klebsiella

IHMA
IMP, KPC-
>32
8
1
0.25
0.25

oxytoca

871515
2, SHV-12

Klebsiella

IHMA
IMP, KPC-
>32
2
0.059
0.0149
0.125

oxytoca

871516
2, SHV-12

Klebsiella

IHMA
IMP, KPC-
>32
8
1
0.25
0.5

oxytoca

871518
2, SHV-12

Enterobacter

IHMA
ACT-1,
>32
2
0.125
0.25
0.125

cloacae

908146
CTX-M-

22, IMP

Klebsiella

890066
SHV-33;
>32
4
0.5
0.03
0.125

pneumoniae

TEM-33;

CTX-M-

15; IMP-1;

Enterobacter

1207515
NDM-6
>32
>32
64
1
1

cloacae

Klebsiella

1212142
NDM-6
>32
>32
4
0.25
0.25

pneumoniae

Enterobacter

1212159
NDM-6
>32
32
16
2
2

cloacae

Enterobacter

1212160
NDM-6
>32
>32
16
2
1

cloacae

Klebsiella

1212258
NDM-6
>32
>32
4
0.5
0.5

pneumoniae

Klebsiella

1212290
NDM-6
>32
>32
4
0.25
0.125

pneumoniae

Klebsiella

1212347
NDM-6
>32
>32
4
0.25
0.25

pneumoniae

Klebsiella

1212352
NDM-6
>32
>32
1
0.0149
0.0149

pneumoniae

Escherichia

1266865
NDM-5
>32
>32
8
0.25
0.25

coli

Klebsiella

1277372
NDM-7
>32
>32
2
0.5
0.0149

pneumoniae

Klebsiella

1286102
NDM-7
>32
>32
4
0.25
0.25

pneumoniae

Klebsiella

1286206
NDM-7
>32
>32
4
0.25
0.125

pneumoniae

Klebsiella

1369220
NDM-6
>32
>32
8
1
1

pneumoniae

Klebsiella

1369251
NDM-6
>32
>32
16
2
2

pneumoniae

Klebsiella

1369306
NDM-6
>32
>32
8
0.25
0.25

pneumoniae

Escherichia

1371539
NDM-6
>32
>32
2
0.125
0.06

coli

Klebsiella

1371650
NDM-6
>32
>32
4
0.125
0.125

pneumoniae

Klebsiella

1371730
NDM-6
>32
>32
1
0.0149
0.0149

pneumoniae

Klebsiella

1379123
NDM-4
>32
>32
4
0.5
0.03

pneumoniae

Klebsiella

1385577
NDM-4
>32
>32
8
0.5
0.5

pneumoniae

Klebsiella

1385586
NDM-4
>32
>32
4
0.06
0.06

pneumoniae

Klebsiella

1385622
NDM-4
>32
>32
2
0.03
0.03

pneumoniae

Escherichia

1424126
NDM-5
>32
32
128.1
8
4

coli

Escherichia

1438691
NDM-5
>32
>32
16
1
0.5

coli

Escherichia

1438767
NDM-5
>32
>32
128.1
0.5
0.25

coli

Klebsiella

1455463
NDM-4
>32
>32
8
0.25
0.25

pneumoniae

Klebsiella

1455545
NDM-4
>32
>32
0.5
0.0149
0.0149

pneumoniae

Enterobacter

1455568
NDM-4
>32
>32
16
8
1

cloacae

Klebsiella

1459396
NDM-7
>32
>32
1
0.0149
0.0149

pneumoniae

Klebsiella

1459398
NDM-7
>32
>32
8
0.25
0.25

pneumoniae

Escherichia

786978
KPC-2
0.5
0.25
0.5
0.125
0.125

coli

Klebsiella

845661
KPC-3
8
1
1
0.125
0.25

pneumoniae

Klebsiella

845662
KPC-3
4
2
4
1
1

pneumoniae

Klebsiella

845665
KPC-3
4
1
1
0.25
0.25

pneumoniae

Klebsiella

845667
KPC-3
4
1
1
0.25
0.25

pneumoniae

Klebsiella

845670
KPC-3
0.125
0.03
0.25
0.125
0.06

pneumoniae

Klebsiella

848844
SHV-11,
1
0.0149
4
0.0149
0.0149

pneumoniae

KPC-2

Klebsiella

845904
KPC-3
1
0.0149
2
0.125
0.25

pneumoniae

Klebsiella

847204
KPC-2
2
0.125
0.5
0.125
0.125

pneumoniae

Klebsiella

847375
SHV-12,
1
0.0149
1
0.06
0.06

pneumoniae

KPC-2

Klebsiella

847378
SHV-12,
1
0.03
4
0.125
0.125

pneumoniae

KPC-2

Klebsiella

847379
CTX-M-2,
1
0.03
0.125
0.03
0.03

pneumoniae

KPC-2

Klebsiella

847383
KPC-2
1
0.0149
2
0.5
0.25

pneumoniae

Klebsiella

847384
SHV-12,
1
0.0149
1
0.125
0.125

pneumoniae

KPC-2

Klebsiella

847387
SHV-12,
2
0.0149
2
0.125
0.25

pneumoniae

KPC-2

Enterobacter

847438
CTX-M-2,
0.5
0.0149
0.059
0.0149
0.0149

aerogenes

KPC

Klebsiella

847537
KPC-2
16
0.03
1
0.125
0.06

oxytoca

Klebsiella

847539
CTX-M-2,
1
0.03
1
0.5
0.5

oxytoca

KPC

Klebsiella

847747
CTX-M-2,
1
0.0149
0.5
0.06
0.06

pneumoniae

KPC

Klebsiella

848561
SHV-11,
4
0.5
2
1
0.5

pneumoniae

CTX-M-3,

KPC

Klebsiella

848562
SHV-11,
8
2
1
0.25
0.125

pneumoniae

KPC-3

Klebsiella

848563
KPC-3
4
0.5
0.5
0.125
0.125

pneumoniae

Klebsiella

848566
SHV-11,
8
2
1
0.125
0.125

pneumoniae

KPC-3

Klebsiella

848600
KPC-3
4
1
1
0.25
0.125

pneumoniae

Klebsiella

848788
KPC-2
>32
>32
0.5
0.06
0.125

pneumoniae

Klebsiella

848790
KPC-2
4
2
2
0.5
0.25

pneumoniae

Klebsiella

848791
SHV-12,
2
1
4
0.5
0.25

pneumoniae

KPC-2

Klebsiella

848828
SHV-12,
2
1
4
0.5
0.5

pneumoniae

KPC-2

Klebsiella

848832
KPC-2
1
0.03
0.5
0.0149
0.0149

pneumoniae

Klebsiella

848842
SHV-2A,
2
0.5
1
0.06
0.06

pneumoniae

KPC-2

Escherichia

469
AmpC,
0.25
0.0149
0.5
0.0149
0.0149

coli

SHV-12,

TEM-1

Escherichia

233
AmpC,
2
0.03
1
0.06
0.06

coli

SHV-2,

KPC-3,

CTX-M-15

and TEM-1

Escherichia

3073
AmpC,
0.125
0.0149
1
0.125
0.125

coli

CTX-M-3

Escherichia

3102
AmpC,
0.125
0.0149
0.059
0.06
0.125

coli

CTX-M-

15, TEM-1

Escherichia

54321
AmpC,
0.5
0.03
2
0.25
0.25

coli

CTX-M-

15, TEM-1

Escherichia

64167
AmpC,
0.125
0.0149
0.25
0.03
0.06

coli

TEM-1,

GES-5

Escherichia

CH1
AmpC,
0.5
0.0149
0.25
0.125
0.125

coli

TEM-1,

CTX-M-

15, SHV-5,

SHV-1

Escherichia

128
AmpC,
0.25
0.0149
0.5
0.0149
0.03

coli

SHV-12,

TOHO-2,

TEM-1

Escherichia

J53
SHV-5,
0.25
0.03
0.03
0.0149
0.0149

coli

AmpC,

TEM-1

Escherichia

SI-
AmpC,
0.125
0.0149
0.5
0.25
0.5

coli

LP505
CTX-M-

14, TEM-1

Escherichia

SI-
AmpC,
0.125
0.0149
0.059
0.03
0.06

coli

LP574
CTX-M-

14, TEM-1

Escherichia

SI-P026
AmpC,
0.25
0.0149
0.059
0.0149
0.0149

coli

CMY-2,

TEM-1

Escherichia

SI-
AmpC,
0.25
0.0149
2
0.06
0.06

coli

Vr059
CTX-M-32

and TEM-1

Escherichia

EC1552
AmpC,
1
1
4
0.25
0.125

coli

1A
CMY-2,

TEM-1

Escherichia

EC1552
AmpC,
0.5
4
0.059
0.0149
0.0149

coli

2A
CMY-2,

TEM-1,

CTX-M-15

Klebsiella

1251598
VIM-26
>32
>32
0.5
0.06
0.06

pneumoniae

Klebsiella

1251599
VIM-26
>32
>32
0.5
0.06
0.06

pneumoniae

Klebsiella

1251600
VIM-26
>32
>32
0.25
0.06
0.06

pneumoniae

Klebsiella

1251604
VIM-26
>32
>32
0.25
0.03
0.03

pneumoniae

Enterobacter

1256568
VIM-23
8
0.5
0.125
0.06
0.03

cloacae

Escherichia

1275629
VIM-23
>32
4
0.5
0.06
0.06

coli

Escherichia

1275635
VIM-23
>32
2
0.5
0.03
0.03

coli

Enterobacter

1284042
VIM-5
>32
16
8
1
0.5

cloacae

Enterobacter

1284044
VIM-5
>32
16
4
1
0.125

cloacae

Enterobacter

1284065
VIM-5
>32
16
4
0.125
0.5

cloacae

Enterobacter

1284066
VIM-5
>32
16
32
1
1

cloacae

Enterobacter

1590932
VIM-4
32
16
2
0.25
0.25

cloacae

Klebsiella

1610707
VIM-24
16
1
0.25
0.0149
0.0149

pneumoniae

Klebsiella

1621162
VIM-12
>32
4
0.5
0.25
0.125

pneumoniae

Klebsiella

1622674
VIM-44
>32
2
1
0.0149
0.0149

oxytoca

MIC₅₀
>32
4
1
0.25
0.125

MIC₉₀
>32
>32
8
1
1

Example 11: In Vitro Efficacy of Combination Formulations of Compound 1 Plus Cefiderocol

To assess the concentration of Compound 1 necessary to adequately potentiate the activity of cefiderocol, checkerboard assays were utilized. The checkerboard assays were conducted against a set of 22 metallo- and serine-β-lactamase expressing CRE in IDM. Bacteria stains and inoculum were prepared as described for the MIC assays above. Cefiderocol was titrated across a deep well plate in a 2-fold dilution scheme in IDM. Compound 1 was titrated down another deep well plate also in a 2-fold dilution scheme in IDM. The two compound dilutions are then overlaid into 96 well microtiter plates at a 1:1 ration creating an array of varying concentration ratios. Once the matrix of both test articles is added plates are inoculated according to CLSI broth microdilution method. After inoculation plates are incubated for 16 to 20 hours at 37° C. then read visually to determine the cefiderocol MIC at every concentration of Compound 1. This allows an assessment of the minimal concentration of Compound 1 necessary to potentiate cefiderocol across the strain set.

TABLE 10

The percentage of strains inhibited at each concentration with

combinations of cefiderocol and Compound 1 across a

set of 22 CRE isolates.

(% of strains inhibited at each concentration

combination

Compound 1 Conc. (μg/mL) →

Cefiderocol MIC ↓
8
4
2
1
0.5
0.25
0.125
0

0.06 μg/mL
20
20
20
20
15
10
5
5

0.125 μg/mL
25
25
30
30
25
15
10
5

0.25 μg/mL
55
45
45
40
35
30
35
5

0.5 μg/mL
75
80
60
55
55
45
40
15

1 μg/mL
90
90
80
75
75
65
55
20

2 μg/mL
95
100
95
90
75
80
75
60

4 μg/mL
100
100
100
100
100
85
85
75

8 μg/mL
100
100
100
100
100
100
95
90

16 μg/mL
100
100
100
100
100
100
100
90

32 μg/mL
100
100
100
100
100
100
100
95

COMBINATION COMPOSITIONS COMPRISING A BETA-LACTAMASE INHIBITOR

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