WO2024083862A1 - Floxuridine for use in preventing and/or treating a bacterial infection - Google Patents
Floxuridine for use in preventing and/or treating a bacterial infection Download PDFInfo
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- WO2024083862A1 WO2024083862A1 PCT/EP2023/078882 EP2023078882W WO2024083862A1 WO 2024083862 A1 WO2024083862 A1 WO 2024083862A1 EP 2023078882 W EP2023078882 W EP 2023078882W WO 2024083862 A1 WO2024083862 A1 WO 2024083862A1
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- Prior art keywords
- floxuridine
- bacterial infection
- growth
- bacterial
- strain
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to the field of pyrimidine analogues.
- the present invention relates to the pyrimidine analogue, floxuridine, for use in preventing and/or treating a bacterial infection.
- Infectious diseases are a major concern for global human health, according to WHO, due to the continuous resistance mechanisms that are being acquired by bacteria, especially by gram negative bacteria.
- WHO World Health Organization
- groups of molecules include different p-lactam antibiotics, macrolides, aminoglycosides, tetracyclines or flouroquinolones, among others.
- emerging drug resistance mechanisms are turning again bacterial infections in life-threatening diseases.
- Nucleoside analogues are an extensive group of molecules that have been used as antiviral or anticancer drugs. Some nucleoside analogues have been studied to be used as antibacterial agents; however, very dissimilar results have been obtained. Inventors have surprisingly discovered that floxuridine can be used against some pathogenic bacteria, including some drug resistant gram negative bacteria, showing good potencies.
- Floxuridine (5-fluoro-2'-deoxyuridine) is a pyrimidine analogue used as palliative management for liver metastases of gastrointestinal malignancy.
- the present invention relates to floxuridine or a pharmaceutically acceptable salt, hydrate, solvate thereof for use in preventing and/or treating a bacterial infection.
- the present invention relates to floxuridine or a pharmaceutically acceptable salt, hydrate, solvate thereof for use in preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria.
- the present disclosure further relates to a method of preventing and/or treating a bacterial infection comprising the step of administering a therapeutically effective amount of floxuridine or a pharmaceutically acceptable salt, hydrate, solvate thereof, wherein said bacterial infection is caused by a gram negative bacteria
- said gram negative bacteria belong to the family Enterobacteriaceae or Yersiniaceae.
- floxuridine (5-fluoro-2'-deoxyuridine) is a pyrimidine analogue that so far has been used for palliative management for liver metastases of gastrointestinal malignancy.
- the term “treat” and its cognates refer to an amelioration of a disease or disorder, for example a bacterial infection, or at least one discernible symptom thereof.
- “treat” refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient
- “treat” refers to inhibiting the progression of a disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both
- “treat” refers to slowing the progression or reversing the progression of a disease or disorder, for example a bacterial infection.
- “prevent” and its cognates refer to delaying the onset or reducing the risk of acquiring a given disease or disorder, for example a bacterial infection.
- preventing and/or treating includes “preventing and treating” and “preventing or treating”.
- therapeutically effective dose and “therapeutically effective amount” are used to refer to an amount of a compound that results in prevention, delay of onset of symptoms, or amelioration of symptoms of a condition.
- a therapeutically effective amount may, for example, be sufficient to treat, prevent, reduce the severity, delay the onset, and/or reduce the risk of occurrence of one or more symptoms of the disease or disorder mentioned herein.
- a therapeutically effective amount, as well as a therapeutically effective frequency of administration can be determined by methods known in the art and discussed below.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising floxuridine for use in preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria, according to the embodiments included herein.
- the composition may further comprise a pharmaceutically acceptable vehicle, adjuvant, diluent or excipient, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, isotonic and absorption delaying agents and the like.
- preserving agents such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, isotonic and absorption delaying agents and the like.
- preserving agents such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, isotonic and absorption de
- the present invention also relates to a method of preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria, according to the embodiments included herein comprising the step of administering a therapeutically effective amount of floxuridine or a pharmaceutically acceptable salt, hydrate, solvate thereof to a patient in need thereof.
- the term "patient” or "patient in need thereof', is intended for a human or non-human mammal affected or likely to be affected with a bacterial infection.
- the patient is a human.
- the compound of the present invention is capable of being administered in unit dose forms, wherein the term "unit dose” means a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as a pharmaceutically acceptable composition.
- the compound as provided herein can be formulated into pharmaceutical compositions by admixture with one or more pharmaceutically acceptable vehicle, adjuvant, diluent or excipient.
- Such compositions may be prepared for use in oral administration, particularly in the form of tablets or capsules; or parenteral administration, particularly in the form of liquid solutions, suspensions or emulsions.
- the floxuridine for use in preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria, according to the embodiments included herein or a pharmaceutical composition comprising thereof is orally administered.
- the floxuridine for use in preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria, according to the embodiments included herein or a pharmaceutical composition comprising thereof is parenterally administered, preferably intravenously administered.
- the tablets, pills, powders, capsules, troches and the like can contain one or more of any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a disintegrant such as starch and cellulose derivatives; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, or methyl salicylate.
- a binder such as microcrystalline cellulose, or gum tragacanth
- a diluent such as starch or lactose
- a disintegrant such as starch and cellulose derivatives
- a lubricant such as magnesium stearate
- a glidant such as colloidal silicon dioxide
- a sweetening agent such as sucrose or saccharin
- a flavoring agent
- Capsules can be in the form of a hard capsule or soft capsule, which are generally made from gelatin blends optionally blended with plasticizers, as well as a starch capsule.
- dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.
- Other oral dosage forms syrup or elixir may contain sweetening agents, preservatives, dyes, colorings, and flavorings.
- the active compounds may be incorporated into fast dissolve, modified-release or sustained- release preparations and formulations, and wherein such sustained-release formulations are preferably bimodal.
- Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- the liquid compositions may also include binders, buffers, preservatives, chelating agents, sweetening, flavoring and coloring agents, and the like.
- Nonaqueous solvents include alcohols, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic esters such as ethyl oleate.
- Aqueous carriers include mixtures of alcohols and water, buffered media, and saline.
- biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds.
- Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer’s dextrose, and the like.
- Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
- Example 1 Growth inhibition over Pseudomonas aeruginosa
- a fresh active culture of Pseudomonas aeruginosa was inoculated in a 96 well microtiter plate in M-H (Mueller-Hinton) liquid medium.
- M-H Meleller-Hinton
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Klebsiella pneumoniae was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Escherichia coli was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Acinetobacter baumannii was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Enterobacter aerogenes was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Salmonella typhimurium was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Shigella flexneri was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Proteus mirabilis was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Serratia marcescens was inoculated in a 96 well microtiter plate in M- H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- Example 10 Growth inhibition over Burkholderia cepacia A fresh active culture of Burkholderia cepacia was inoculated in a 96 well microtiter plate in M- H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- Example 11 Growth inhibition over Neisseria meningitidis
- a fresh active culture of Neisseria meningitidis was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- Example 12 Growth inhibition over Enterococcus faecium
- a fresh active culture of Enterococcus faecium was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Streptococcus pneumoniae was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Candida albicans was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the fungal strain to determine the minimal floxuridine concentration capable of inhibit the fungal growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- Example 15 Growth inhibition over Cryptococcus neoformans
- a fresh active culture of Cryptococcus neoformans was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the fungal strain to determine the minimal floxuridine concentration capable of inhibit the fungal growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- a fresh active culture of Aspergillus fumigatus was inoculated in a 96 well microtiter plate in M-H liquid medium.
- serial dilutions of floxuridine starting at 512 pg/mL, were tested against the fungal strain to determine the minimal floxuridine concentration capable of inhibit the fungal growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
- Example 17 Growth inhibition of several multi drug resistant (MDR) strains of Escherichia coli
- MICs were determined by broth microdilution following the procedures recommended by the Clinical and Laboratory Standards Institute.
- MIC values were considered as the concentration of compounds at which the growth was inhibited >80%, compared to growth control.
- MIC values of floxuridine are very stable independently of the strain, showing a potency in the range of ⁇ 1 pg/mL.
- the related compound cladribine does not show any antimicrobial capacity even at the maximum assayed concentration of 128 pg/mL.
- ATCC reference strain was used as a control strain.
- Table 2 shows the drug resistance profile of the assayed strains of E. coli.
- Minimum inhibitory concentration (MIC) is expressed in pg/ml (left column).
- Clinical categorization (CC) (right column): R (resistant), I (susceptible, increased exposure) and S (susceptible).
- EUCAST European Committee on Antimicrobial Susceptibility Testing
- Nalidixic acid NAL
- Amikacin AMK
- amoxicillin-clavulanic acid AMC
- ampicillin AMP
- Aztreonam ATM
- cefepime FEP
- cefotaxime CX
- ceftazidime CAZ
- ceftazidime- avibactam CZA
- Ceftolozane-tazobactam C/T
- Cefuroxime CXM
- Ciprofloxacin CIP
- Colistin CST
- Ertapenem ETP
- Fosfomycin F
- Gentamicin GEN
- Imipenem I PM
- Meropenem MEM
- Nitrofurantoin NIT
- Norfloxacin NOR
- Piperacillin PIP
- Piperacillin- tazobactam ZP
- tigecycline TGC
- TOB trimethoprim-sulfamethoxazole
- Example 18 Growth inhibition of several multi drug resistant (MDR) strains of Klebsiella pneumonia
- MICs were determined by broth microdilution following the procedures recommended by the Clinical and Laboratory Standards Institute. Serial two-fold dilutions of each compound were prepared in Microtiter plates (one for each strain). The concentration of the compounds SA-5 (floxuridine) and SA-39 (cladribine) was ranging from 128 to 0.25 pg/ml. The concentration of CIP was ranging from 16 to 0.03pg/ml, respectively. Sterility and growth controls were included in all plates.
- MIC values were considered as the concentration of compounds at which the growth was inhibited >80%, compared to growth control.
- Cefepime Cefoxitina (FOX), Ceftazidime (CAZ), Ciprofloxacin (CIP), Colistin (CST), Ertapenem (ETP), Fosfomycin (FOF), Gentamicin (GEN), Imipenem (IPM), Meropenem (MEM), Nalidixic acid (NAL), Nitrofurantoin (NIT), Piperacillin-tazobactam (TZP), Tigecicline (TGC), Tobramycin (TOB) and Trimethorpim/sulfamethoxazole (SXT).
- Table 5 As shown in Tables 4 and 5, most of the strains used show some acquired resistance mechanism against different groups of conventional antibiotics. However potency of floxuridine is not affected by these resistance mechanisms and cross resistance is not detected.
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Abstract
The present invention relates to floxuridine or a pharmaceutically acceptable salt, hydrate, solvate thereof for use in preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria.
Description
FLOXURIDINE FOR USE IN PREVENTING AND/OR TREATING A BACTERIAL INFECTION
FIELD OF THE INVENTION
The present invention relates to the field of pyrimidine analogues. In particular the present invention relates to the pyrimidine analogue, floxuridine, for use in preventing and/or treating a bacterial infection.
BACKGROUND
Infectious diseases are a major concern for global human health, according to WHO, due to the continuous resistance mechanisms that are being acquired by bacteria, especially by gram negative bacteria. Up to now, different groups of molecules have successfully been employed for the control of bacterial infections, such groups include different p-lactam antibiotics, macrolides, aminoglycosides, tetracyclines or flouroquinolones, among others. However, emerging drug resistance mechanisms are turning again bacterial infections in life-threatening diseases.
Nucleoside analogues are an extensive group of molecules that have been used as antiviral or anticancer drugs. Some nucleoside analogues have been studied to be used as antibacterial agents; however, very dissimilar results have been obtained. Inventors have surprisingly discovered that floxuridine can be used against some pathogenic bacteria, including some drug resistant gram negative bacteria, showing good potencies.
Floxuridine (5-fluoro-2'-deoxyuridine) is a pyrimidine analogue used as palliative management for liver metastases of gastrointestinal malignancy.
SUMMARY OF THE INVENTION
In a first aspect, the present invention relates to floxuridine or a pharmaceutically acceptable salt, hydrate, solvate thereof for use in preventing and/or treating a bacterial infection.
DETAILED DESCRIPTION
In a first aspect, the present invention relates to floxuridine or a pharmaceutically acceptable salt, hydrate, solvate thereof for use in preventing and/or treating a bacterial infection, wherein
said bacterial infection is caused by a gram negative bacteria. The present disclosure further relates to a method of preventing and/or treating a bacterial infection comprising the step of administering a therapeutically effective amount of floxuridine or a pharmaceutically acceptable salt, hydrate, solvate thereof, wherein said bacterial infection is caused by a gram negative bacteria
In a further preferred embodiment, said gram negative bacteria belong to the family Enterobacteriaceae or Yersiniaceae.
As mentioned above, floxuridine (5-fluoro-2'-deoxyuridine) is a pyrimidine analogue that so far has been used for palliative management for liver metastases of gastrointestinal malignancy.
In this disclosure and in the claims, terms such as "comprises," "comprising," "containing" and "having" are open-ended terms and can mean "includes," "including," and the like; while terms like "consisting of' or "consists of" refer to the mentioned elements after these terms and others which are not mentioned are excluded.
Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms "a", "an", and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicate otherwise.
As used herein, the term "treat" and its cognates refer to an amelioration of a disease or disorder, for example a bacterial infection, or at least one discernible symptom thereof. In another embodiment, "treat" refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient, in another embodiment, "treat" refers to inhibiting the progression of a disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both, in another embodiment, "treat" refers to slowing the progression or reversing the progression of a disease or disorder, for example a bacterial infection. As used herein, "prevent" and its cognates refer to delaying the onset or reducing the risk of acquiring a given disease or disorder, for example a bacterial infection.
As used herein, the term “preventing and/or treating” includes “preventing and treating” and “preventing or treating”.
The terms "therapeutically effective dose" and "therapeutically effective amount" are used to refer to an amount of a compound that results in prevention, delay of onset of symptoms, or amelioration of symptoms of a condition. A therapeutically effective amount may, for example, be sufficient to treat, prevent, reduce the severity, delay the onset, and/or reduce the risk of occurrence of one or more symptoms of the disease or disorder mentioned herein. A therapeutically effective amount, as well as a therapeutically effective frequency of administration, can be determined by methods known in the art and discussed below.
It should be noted that the term "approximately" or “about” applied to the values used earlier and later in this document includes a margin of error of ± 5 %, such as, for example, ± 4 %, ± 3 %, ± 2 %, ± 1 %.
The present invention also relates to a pharmaceutical composition comprising floxuridine for use in preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria, according to the embodiments included herein. The composition may further comprise a pharmaceutically acceptable vehicle, adjuvant, diluent or excipient, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
The present invention also relates to a method of preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria, according to the embodiments included herein comprising the step of administering a therapeutically effective amount of floxuridine or a pharmaceutically acceptable salt, hydrate, solvate thereof to a patient in need thereof. The term "patient" or "patient in need thereof', is intended for a human or non-human mammal affected or likely to be affected with a bacterial infection. Preferably, the patient is a human.
The compound of the present invention is capable of being administered in unit dose forms, wherein the term "unit dose" means a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as a pharmaceutically acceptable composition. The compound as provided herein can be
formulated into pharmaceutical compositions by admixture with one or more pharmaceutically acceptable vehicle, adjuvant, diluent or excipient. Such compositions may be prepared for use in oral administration, particularly in the form of tablets or capsules; or parenteral administration, particularly in the form of liquid solutions, suspensions or emulsions.
In a preferred embodiment, the floxuridine for use in preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria, according to the embodiments included herein or a pharmaceutical composition comprising thereof is orally administered.
In another preferred embodiment, the floxuridine for use in preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria, according to the embodiments included herein or a pharmaceutical composition comprising thereof is parenterally administered, preferably intravenously administered.
In the case of oral administration, the tablets, pills, powders, capsules, troches and the like can contain one or more of any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a disintegrant such as starch and cellulose derivatives; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, or methyl salicylate. Capsules can be in the form of a hard capsule or soft capsule, which are generally made from gelatin blends optionally blended with plasticizers, as well as a starch capsule. In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents. Other oral dosage forms syrup or elixir may contain sweetening agents, preservatives, dyes, colorings, and flavorings. In addition, the active compounds may be incorporated into fast dissolve, modified-release or sustained- release preparations and formulations, and wherein such sustained-release formulations are preferably bimodal.
Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. The liquid compositions may also include binders, buffers, preservatives, chelating agents, sweetening, flavoring and coloring agents, and the like. Nonaqueous solvents include alcohols, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Aqueous carriers include mixtures of alcohols and water, buffered media, and saline. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers
may be useful excipients to control the release of the active compounds. Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer’s dextrose, and the like. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
A number of examples will be provided below that are intended to illustrate the invention and in no way limit the scope of the invention, which is established by the attached claims.
EXAMPLES
Example 1 : Growth inhibition over Pseudomonas aeruginosa
A fresh active culture of Pseudomonas aeruginosa was inoculated in a 96 well microtiter plate in M-H (Mueller-Hinton) liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Low antimicrobial activity was detected at all concentrations.
Example 2: Growth inhibition over Klebsiella pneumoniae
A fresh active culture of Klebsiella pneumoniae was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Antimicrobial activity of floxuridine was detected over Klebsiella pneumoniae at a concentration of 8 pg/mL.
Example 3: Growth inhibition over Escherichia coli
A fresh active culture of Escherichia coli was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable
of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Antimicrobial activity of floxuridine was detected over Escherichia coli at a concentration of 32 pg/mL.
Example 4: Growth inhibition over Acinetobacter baumannii
A fresh active culture of Acinetobacter baumannii was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Low antimicrobial activity was detected at all concentrations.
Example 5: Growth inhibition over Enterobacter aerogenes
A fresh active culture of Enterobacter aerogenes was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Antimicrobial activity of floxuridine was detected over Enterobacter aerogenes at a concentration of 4 pg/mL.
Example 6: Growth inhibition over Salmonella typhimurium
A fresh active culture of Salmonella typhimurium was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Antimicrobial activity of floxuridine was detected over Salmonella typhimurium at a concentration of 16 pg/mL.
Example 7: Growth inhibition over Shigella flexneri
A fresh active culture of Shigella flexneri was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Antimicrobial activity of floxuridine was detected over Shigella flexneri at a concentration of 16 pg/mL.
Example 8: Growth inhibition over Proteus mirabilis
A fresh active culture of Proteus mirabilis was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Antimicrobial activity of floxuridine was detected over Proteus mirabilis at a concentration of 16 pg/mL.
Example 9: Growth inhibition over Serratia marcescens
A fresh active culture of Serratia marcescens was inoculated in a 96 well microtiter plate in M- H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Antimicrobial activity of floxuridine was detected over Serratia marcescens at a concentration of 8 pg/mL.
Example 10: Growth inhibition over Burkholderia cepacia
A fresh active culture of Burkholderia cepacia was inoculated in a 96 well microtiter plate in M- H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Low antimicrobial activity was detected at all concentrations.
Example 11 : Growth inhibition over Neisseria meningitidis
A fresh active culture of Neisseria meningitidis was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Low antimicrobial activity was detected at all concentrations.
Example 12: Growth inhibition over Enterococcus faecium
A fresh active culture of Enterococcus faecium was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Low antimicrobial activity was detected at all concentrations.
Example 13: Growth inhibition over Streptococcus pneumoniae
A fresh active culture of Streptococcus pneumoniae was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the bacterial strain to determine the minimal floxuridine concentration capable of inhibit the bacterial growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
Low antimicrobial activity was detected at all concentrations.
Example 14: Growth inhibition over Candida albicans
A fresh active culture of Candida albicans was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the fungal strain to determine the minimal floxuridine concentration capable of inhibit the fungal growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
No antifungal activity was detected at any concentration.
Example 15: Growth inhibition over Cryptococcus neoformans
A fresh active culture of Cryptococcus neoformans was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the fungal strain to determine the minimal floxuridine concentration capable of inhibit the fungal growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
No antifungal activity was detected at any concentration.
Example 16: Growth inhibition over Aspergillus fumigatus
A fresh active culture of Aspergillus fumigatus was inoculated in a 96 well microtiter plate in M-H liquid medium. In the same plate, serial dilutions of floxuridine, starting at 512 pg/mL, were tested against the fungal strain to determine the minimal floxuridine concentration capable of inhibit the fungal growth, defined as 80 % of Abseoo diminution compared to a strain growth control.
No antifungal activity was detected at any concentration.
Example 17: Growth inhibition of several multi drug resistant (MDR) strains of Escherichia coli
MICs were determined by broth microdilution following the procedures recommended by the Clinical and Laboratory Standards Institute.
Serial two-fold dilutions of each compound were prepared in Microtiter plates (one for each strain). The concentration of the compounds SA-5 (floxuridine) and SA-39 (cladribine) was
ranging from 128 to 0.25 pg/ml. The concentration of CIP was ranging from 16 to 0.03|jg/ml, respectively. Sterility and growth controls were included in all plates.
The bacterial suspensions were prepared and normalized to 0.5 McFarland (bioMerieux) turbidity standard (=108CFU/ml) using physiological saline solution (sodium chloride 0.9%) (B. BRAUN). A 1/1000 dilution (=105CFU/ml) of the suspensions were prepared in Cation Adjusted Mueller-Hinton Broth (CA-MHB) (Becton Dickinson). The dilutions were inoculated to all columns except to the sterility control one. Only media was dispensed in the sterility control column. Inoculated plates were incubated 18-20h at 37°C.
MIC values were considered as the concentration of compounds at which the growth was inhibited >80%, compared to growth control.
Results are shown in the following table 1 :
Table 1 :
As shown in Table 1 , MIC values of floxuridine (SA-5) are very stable independently of the strain, showing a potency in the range of <1 pg/mL. On the other side, the related compound cladribine (SA-39) does not show any antimicrobial capacity even at the maximum assayed concentration of 128 pg/mL. ATCC reference strain was used as a control strain.
Table 2 shows the drug resistance profile of the assayed strains of E. coli. Minimum inhibitory concentration (MIC) is expressed in pg/ml (left column). Clinical categorization (CC) (right column): R (resistant), I (susceptible, increased exposure) and S (susceptible). The clinical breakpoints according to EUCAST (European Committee on Antimicrobial Susceptibility Testing). Nalidixic acid (NAL), Amikacin (AMK), amoxicillin-clavulanic acid (AMC), ampicillin
(AMP), Aztreonam (ATM), cefepime (FEP), cefotaxime (CTX), ceftazidime (CAZ), ceftazidime- avibactam (CZA), Ceftolozane-tazobactam (C/T), Cefuroxime (CXM), Ciprofloxacin (CIP), Colistin (CST), Ertapenem (ETP), Fosfomycin (FOF), Gentamicin (GEN), Imipenem (I PM), Meropenem (MEM), Nitrofurantoin (NIT), Norfloxacin (NOR), Piperacillin (PIP), Piperacillin- tazobactam (TZP), tigecycline (TGC), tobramycin (TOB) and trimethoprim-sulfamethoxazole (SXT).
Table 2:
As shown in Table 2, most of the strains used show some acquired resistance mechanism against conventional antibiotics. However potency of floxuridine is not affected by these resistance mechanisms.
Example 18: Growth inhibition of several multi drug resistant (MDR) strains of Klebsiella pneumonia
MICs were determined by broth microdilution following the procedures recommended by the Clinical and Laboratory Standards Institute.
Serial two-fold dilutions of each compound were prepared in Microtiter plates (one for each strain). The concentration of the compounds SA-5 (floxuridine) and SA-39 (cladribine) was ranging from 128 to 0.25 pg/ml. The concentration of CIP was ranging from 16 to 0.03pg/ml, respectively. Sterility and growth controls were included in all plates.
The bacterial suspensions were prepared and normalized to 0.5 McFarland (bioMerieux) turbidity standard (=108CFU/ml) using physiological saline solution (sodium chloride 0.9%) (B. BRAUN). A 1/1000 dilution (=105CFU/ml) of the suspensions were prepared in Cation Adjusted Mueller-Hinton Broth (CA-MHB) (Becton Dickinson). The dilutions were inoculated to all columns except to the sterility control one. Only media was dispensed in the sterility control column. Inoculated plates were incubated 18-20h at 37°C.
MIC values were considered as the concentration of compounds at which the growth was inhibited >80%, compared to growth control.
Results are shown in next table 3:
Table 3:
As shown in Table 3, floxuridine (SA- 5) is effective against several drug- resista nt strains of Klebsiella pneumoniae. Surprisingly, the related compound cladribine (SA-39) does not show any antimicrobial capacity even at the maximum assayed concentration of 128 pg/mL. ATCC reference strain was used as a control strain.
The following tables 4 and 5 show the drug resistance profile of the assayed strains of K. pneumoniae. Minimum inhibitory concentration (MIC) is expressed in pg/ml (left column). Clinical categorization (CC) (right column): R (resistant), I (susceptible, increased exposure) and S (susceptible). The clinical breakpoints according to ELICAST. Amikacin (AMK), Amoxicillin/clavulanate (AMC), Aztreonam (AZT), Cefazolin (CFZ), Cefotaxime (CTX),
Cefepime (FEP), Cefoxitina (FOX), Ceftazidime (CAZ), Ciprofloxacin (CIP), Colistin (CST), Ertapenem (ETP), Fosfomycin (FOF), Gentamicin (GEN), Imipenem (IPM), Meropenem (MEM), Nalidixic acid (NAL), Nitrofurantoin (NIT), Piperacillin-tazobactam (TZP), Tigecicline (TGC), Tobramycin (TOB) and Trimethorpim/sulfamethoxazole (SXT).
Table 4:
Table 5:
As shown in Tables 4 and 5, most of the strains used show some acquired resistance mechanism against different groups of conventional antibiotics. However potency of floxuridine is not affected by these resistance mechanisms and cross resistance is not detected.
Claims
1. Floxuridine or a pharmaceutically acceptable salt, hydrate, solvate thereof for use in preventing and/or treating a bacterial infection, wherein said bacterial infection is caused by a gram negative bacteria
2. The floxuridine for use according to claim 1 , wherein said gram negative bacteria belong to the family Enterobacteriaceae or Yersiniaceae.
3. The floxuridine for use according to any of claims 1 or 2, wherein said floxuridine is administered by parenteral or oral route.
4. The floxuridine for use according to any of claims 1 to 3, wherein said floxuridine is included in a pharmaceutical composition.
5. The floxuridine for use according to claim 4, wherein said pharmaceutical composition further comprises a supplementary active ingredient.
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Non-Patent Citations (3)
| Title |
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| M. P. B. SANDRINI ET AL: "Nucleoside analogues are activated by bacterial deoxyribonucleoside kinases in a species-specific manner", JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, vol. 60, no. 3, 23 July 2007 (2007-07-23), GB, pages 510 - 520, XP055226744, ISSN: 0305-7453, DOI: 10.1093/jac/dkm240 * |
| PERTUSATI FABRIZIO ET AL: "Conclusions", vol. 75, no. 10, 1 October 2020 (2020-10-01), GB, pages 2864 - 2878, XP055853065, ISSN: 0305-7453, Retrieved from the Internet <URL:https://academic.oup.com/jac/article-pdf/75/10/2864/33885311/dkaa268.pdf> [retrieved on 20230306], DOI: 10.1093/jac/dkaa268 * |
| YOUNIS WALEED ET AL: "In Vitro Screening of an FDA-Approved Library Against ESKAPE Pathogens", vol. 23, no. 14, 30 May 2017 (2017-05-30), NL, XP093029218, ISSN: 1381-6128, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662795/pdf/nihms913064.pdf> [retrieved on 20230306], DOI: 10.2174/1381612823666170209154745 * |
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