US20130065874A1 - Methods for treating intrapulmonary infections - Google Patents
Methods for treating intrapulmonary infections Download PDFInfo
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- US20130065874A1 US20130065874A1 US13/607,138 US201213607138A US2013065874A1 US 20130065874 A1 US20130065874 A1 US 20130065874A1 US 201213607138 A US201213607138 A US 201213607138A US 2013065874 A1 US2013065874 A1 US 2013065874A1
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- ceftolozane
- tazobactam
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This disclosure relates to the treatment of intrapulmonary bacterial infections, including the treatment of nosocomial pneumonia infections, with a cephalosporin.
- cephalosporin (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureidol-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-RZ)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid (also referred to as “CXA-101” and previously designated FR264205) is an antibacterial agent.
- CXA-101 can be provided as the compound shown in FIG. 1 .
- CXA-101 The antibacterial activity of CXA-101 is believed to result from its interaction with penicillin binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall which acts to stop bacterial replication.
- CXA-101 can be combined (e.g., mixed) with a ⁇ -lactamase inhibitor (“BLI”), such as tazobactam.
- BLI ⁇ -lactamase inhibitor
- Tazobactam is a BLI against Class A and some Class C ⁇ -lactamases, with well established in vitro and in vivo efficacy in combination with active ⁇ -lactam antibiotics.
- the combination of CXA-101 and tazobactam in a 2:1 weight ratio is an antibiotic pharmaceutical composition (“CXA-201”) for parenteral administration.
- CXA-201 displays potent antibacterial activity in vitro against common Gram-negative and selected Gram-positive organisms.
- CXA-201 is a combination antibacterial with activity against many Gram-negative pathogens known to cause intrapulmonary infections, including nosocomial pneumonia caused by P. aeruginosa.
- Intrapulmonary infections such as nosocomial pneumonia, remain a major cause of morbidity and mortality, especially infections caused by drug resistant pathogens such as P. aeruginosa.
- One challenge in treating intrapulmonary infections with systemic administration of an antibiotic is determining the antibiotic dose that will provide a therapeutically safe and effective concentration of the antibiotic at the site of an infection on the mucosal side of the bronchi in the lung (i.e., in the bronchial secretions).
- Many antibiotics diffuse poorly from the bloodstream across the bronchi [e.g., Pennington, J.
- ELF epithelial lining fluid
- the concentration of antibiotics measured in the ELF of the lung has varied widely.
- the reported penetration ratio of telavancin in healthy human volunteers ranges widely between 0.43 and 1.24 (Lodise, Gottokd, Drusano, 2008 Antimicrobial Agents and Chemotherapy).
- predicting the penetration of a drug into the ELF a priori based on the structure, molecular weight, size and solubility is difficult due to the limited data available on the effect of physicochemical properties on the lung penetration of drugs.
- the efficacy of a particular drug in treating intrapulmonary infections cannot be predicted solely on the basis of data, such as in vitro data relating to the activity of that drug against a particular bacterium, which does not give any indication as whether the drug will accumulate at a therapeutically safe and effective concentration at the site of an infection on the mucosal side of the bronchi in the lung (i.e., in the bronchial secretions).
- data such as in vitro data relating to the activity of that drug against a particular bacterium, which does not give any indication as whether the drug will accumulate at a therapeutically safe and effective concentration at the site of an infection on the mucosal side of the bronchi in the lung (i.e., in the bronchial secretions).
- tigicycline a glycylcycline antimicrobial
- aeruginosa aeruginosa
- it has been approved by the FDA for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, and community acquired pneumonia.
- tigicycline is not approved for the treatment of nosocomial pneumonia, in view of an increased mortality risk associated with the use of tigicycline compared to other drugs in patients treated for nosocomial pneumonia.
- the present invention provides methods for treating intrapulmonary infections, including nosocomial pneumonia, with systemic administration of a pharmaceutical composition comprising ceftolozane.
- the invention is based in part on results from a human clinical study designed to assess the ELF penetration of CXA-201 in comparison to piperacillin/tazobactam, indicated for the treatment of nosocomial pneumonia.
- the study described herein quantified the penetration of CXA-201 into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma) ratio).
- CXA-201 penetrated well into the ELF of healthy volunteers compared to piperacillin/tazobactam, an agent widely used for treatment of lower respiratory infections.
- the intrapulmonary pharmacokinetics measured in the study supports the use of CXA-201 as a parenteral (e.g., intravenous) antibiotic for treatment of intrapulmonary infections, such as nosocomial pneumonia or other lower respiratory tract infections.
- FIG. 1 is the chemical structure of a salt of ceftolozane hydrogen sulfate salt.
- FIG. 2A is a graph showing the ELF Concentration vs. Time Profile for ceftolozane hydrogen sulfate salt (Median and Range) for CXA-201.
- FIG. 2B is a graph showing the ELF Concentration vs. Time Profile for Tazobactam (Median and Range) for CXA-201.
- FIG. 3A is a graph showing the (Comparative) ELF Concentration vs. Time Profile for Piperacillin (Median and Range) for a piperacillin/tazobactam comparator (ZOSYN®).
- FIG. 3B is a graph showing the (Comparative) ELF Concentration vs. Time Profile for Tazobactam (Median and Range) for a piperacillin/tazobactam comparator (ZOSYN®).
- FIGS. 4A and 4B are synthetic schemes for preparing ceftolozane hydrogen sulfate salt.
- ceftolozane means CXA-101 in a free-base or salt form, preferably a hydrogen sulfate form (illustrated in FIG. 1 ).
- ceftolozane is CXA-101 in its free-base form.
- ceftolozane is CXA-101 in its salt form, preferably a hydrogen sulfate form.
- ceftolozane (in free base or salt form, preferably hydrogen sulfate form) and tazobactam are in a 2:1 (ceftolozane:tazobactam) weight ratio.
- methods of treating intrapulmonary infections, including nosocomial pneumonia with systemic administration of a pharmaceutical composition comprising ceftolozane hydrogen sulfate and tazobactam in a 2:1 weight ratio.
- ceftolozane hydrogen sulfate and tazobactam in a 2:1 weight ratio.
- the combination of ceftolozane hydrogen sulfate and tazobactam in a 2:1 weight ratio is referred to herein and in the examples as “CXA-201.”
- the invention provides a method of treating an intrapulmonary infection comprising administering a therapeutically effective amount of a pharmaceutical composition comprising ceftolozane.
- the method may comprise administering a pharmaceutical composition comprising ceftolozane in combination with tazobactam.
- the invention provides a method of treating an intrapulmonary infection comprising the step of intravenously administering about every 8 hours to a subject in need thereof a pharmaceutical composition comprising 3.0 g of ceftolozane.
- the method may comprise administering a pharmaceutical composition comprising ceftolozane in combination with tazobactam.
- the method comprises administering CXA-201 and the infection comprises Gram-negative bacteria.
- the invention provides a method of treating an intrapulmonary infection comprising the step of intravenously administering every 8 hours to a subject in need thereof a pharmaceutical composition comprising 3.0 g of ceftolozane.
- the invention provides a method of providing tazobactam or ceftolozane in the epithelial lining fluid of a subject in an amount effective to treat an intrapulmonary infection, comprising the step of intravenously administering to the subject a pharmaceutical composition comprising ceftolozane.
- the method may comprise administering a pharmaceutical composition further comprising tazobactam, optionally wherein the pharmaceutical composition is CXA-201.
- the method may comprise administering about 1.5 g of ceftolozane and tazobactam in total every 8 hours.
- the amount of the ceftolozane in the ELF of the subject effective to treat an intrapulmonary infection is at least about 8 ⁇ g/ml.
- the ELF concentration of ceftolozane in the ELF may reach at least about 8 ⁇ g/ml after administration of the pharmaceutical composition.
- the subject is typically a human having, or believed to be at risk of having, nosocomial pneumonia.
- the subject (or patient) may, in some embodiments, have ventilator acquired pneumonia or hospital acquired pneumonia.
- the invention provides the use of ceftolozane in the manufacture of a medicament for the treatment of an intrapulmonary infection comprising administering a therapeutically effective amount of a pharmaceutical composition comprising the ceftolozane.
- the use may comprise administering the pharmaceutical composition comprising ceftolozane, in combination with tazobactam.
- the invention provides the use of ceftolozane in the manufacture of a medicament for the treatment of an intrapulmonary infection comprising intravenously administering a pharmaceutical composition comprising 3.0 g of the ceftolozane every 8 hours to a subject in need thereof.
- the use may comprise administering the pharmaceutical composition comprising ceftolozane in combination with tazobactam.
- the use comprises administering ceftolozane and tazobactam and the infection comprises Gram-negative bacteria.
- the invention provides the use of ceftolozane in the manufacture of a medicament for the treatment of an intrapulmonary infection comprising intravenously administering a pharmaceutical composition comprising the ceftolozane, wherein tazobactam or ceftolozane is provided in the epithelial lining fluid of a subject in an amount effective to treat the intrapulmonary infection.
- the use may comprise administering a pharmaceutical composition further comprising tazobactam, optionally wherein the pharmaceutical composition is CXA-201.
- the use may comprise administering about 1.5 g of ceftolozane and tazobactam every 8 hours.
- the amount of the ceftolozane in the ELF of the subject effective to treat an intrapulmonary infection is at least about 8 ⁇ g/ml.
- the ELF concentration of ceftolozane in the ELF may reach at least about 8 ⁇ g/ml after administration of the pharmaceutical composition.
- the subject is typically a human having, or believed to be at risk of having, nosocomial pneumonia.
- the subject (or patient) may, in some embodiments, have ventilator acquired pneumonia or hospital acquired pneumonia.
- the pharmaceutical composition may be administered parenterally.
- the pharmaceutical composition may be administered intravenously.
- the pharmaceutical composition is intravenously administered about once every 8 hours as an infusion.
- the pharmaceutical composition may be intravenously administered as a 60-minute infusion.
- the intrapulmonary infection may be an infection in the lung.
- the intrapulmonary infection may be pneumonia.
- the intrapulmonary infection is nosocomial pneumonia.
- the intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof.
- the intrapulmonary infection comprises Pseudomonas aeruginosa.
- the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for CXA-201 of ⁇ 8 ⁇ g/ml.
- the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ⁇ 8 ⁇ g/ml.
- the invention provides ceftolozane, for use in a method of treating an intrapulmonary infection.
- the ceftolozane is parenterally administered.
- the ceftolozane is intravenously administered.
- the ceftolozane is administered about once every 8 hours as an infusion.
- the ceftolozane is intravenously administered as a 60-minute infusion.
- the ceftolozane is for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung.
- the intrapulmonary infection may be pneumonia.
- the ceftolozane is for use in a method of treating nosocomial pneumonia.
- the intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof.
- the intrapulmonary infection comprises Pseudomonas aeruginosa.
- the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ⁇ 8 ⁇ g/ml.
- the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ⁇ 8 ⁇ g/ml.
- the invention also provides ceftolozane, for use in a method of treating an intrapulmonary infection, comprising administration of ceftolozane in combination with tazobactam.
- the ceftolozane and/or tazobactam is parenterally administered.
- the ceftolozane and/or tazobactam is intravenously administered.
- the ceftolozane and/or tazobactam is administered about once every 8 hours as an infusion.
- the ceftolozane and/or tazobactam is intravenously administered as a 60-minute infusion.
- both the ceftolozane and tazobactam are parenterally administered. In another embodiment, both the ceftolozane and tazobactam are intravenously administered. In some embodiments, both the ceftolozane and tazobactam are administered about once every 8 hours as an infusion. In some embodiments, both the ceftolozane and tazobactam are intravenously administered as a 60-minute infusion. In one embodiment, the ceftolozane is for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung. The intrapulmonary infection may be pneumonia.
- the ceftolozane is for use in a method of treating nosocomial pneumonia.
- the intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof.
- the intrapulmonary infection comprises Pseudomonas aeruginosa.
- the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ⁇ 8 ⁇ g/ml.
- the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ⁇ 8 ⁇ g/ml.
- the invention provides tazobactam, for use in a method of treating an intrapulmonary infection, comprising administration of tazobactam in combination with ceftolozane.
- the tazobactam and/or ceftolozane is parenterally administered.
- the tazobactam and/or ceftolozane is intravenously administered.
- the tazobactam and/or ceftolozane is administered about once every 8 hours as an infusion.
- the tazobactam and/or ceftolozane is intravenously administered as a 60-minute infusion.
- both the tazobactam and ceftolozane are parenterally administered. In another embodiment, both the tazobactam and ceftolozane are intravenously administered. In another embodiment, both the tazobactam and ceftolozane are administered about once every 8 hours as an infusion. In another embodiments, both the tazobactam and ceftolozane are intravenously administered as a 60-minute infusion.
- the tazobactam is for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung.
- the intrapulmonary infection may be pneumonia.
- the tazobactam is for use in a method of treating nosocomial pneumonia.
- the intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof.
- the intrapulmonary infection comprises Pseudomonas aeruginosa.
- the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ⁇ 8 ⁇ g/ml.
- the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ⁇ 8 ⁇ g/ml.
- the invention provides ceftolozane and tazobactam, as a combined preparation for simultaneous, separate or sequential use in a method of treating an intrapulmonary infection.
- the ceftolozane and tazobactam are parenterally administered.
- the ceftolozane and tazobactam are intravenously administered.
- the ceftolozane and tazobactam are administered about once every 8 hours as an infusion.
- the ceftolozane and tazobactam are intravenously administered as a 60-minute infusion.
- the ceftolozane and tazobactam are for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung.
- the intrapulmonary infection may be pneumonia.
- the ceftolozane and tazobactam are for use in a method of treating nosocomial pneumonia.
- the intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof.
- the intrapulmonary infection comprises Pseudomonas aeruginosa.
- the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ⁇ 8 ⁇ g/ml.
- the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ⁇ 8 ⁇ g/ml.
- the invention provides ceftolozane for use in a method of providing tazobactam or ceftolozane in the epithelial lining fluid of a subject in an amount effective to treat an intrapulmonary infection, comprising the step of intravenously administering ceftolozane.
- ceftolozane is administered in combination with tazobactam.
- CXA-201 is administered.
- about 1.5 g of ceftolozane and tazobactam is administered every 8 hours.
- the amount of the ceftolozane in the ELF of the subject effective to treat an intrapulmonary infection is at least about 8 ⁇ g/ml.
- the ELF concentration of ceftolozane in the ELF may reach at least about 8 ⁇ g/ml after administration of the ceftolozane.
- the subject is typically a human having, or believed to be at risk of having, nosocomial pneumonia.
- the subject (or patient) may, in some embodiments, have ventilator acquired pneumonia or hospital acquired pneumonia.
- the safe and effective treatment of intrapulmonary infection with CXA-201 includes administration of an amount of the CXA-201 selected to provide a therapeutically effective dose of the CXA-201 antibiotic in the epithelial lining fluid (ELF).
- ELF epithelial lining fluid
- the penetration of CXA-201 into the ELF compared to a piperacillin/tazobactam comparator was assessed in a Phase 1 clinical study in healthy adult volunteers.
- the piperacillin/tazobactam comparator contained piperacillin/tazobactam in an 8:1 weight ratio with a total of 2.79 mEq of sodium per gram of piperacillin, FDA approved under the tradename ZOSYN® (“Zosyn”).
- the study results evaluate the penetration of intravenously administered CXA-201 into healthy human lungs, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma)ratio).
- AUC area under the concentration-time curve
- a 4.5 g amount of piperacillin/tazobactam incorporates the same dose of tazobactam (0.5 g) as 1.5 g of CXA-201.
- a multiple-dose regimen was used in this study to ensure that the concentrations of the analytes reached steady-state in both plasma and ELF prior to assessment. Healthy volunteers were chosen to standardize the subject population and minimize the variability associated with using actively ill patients. The objectives of the study included: (1) determination and comparison of the ELF to plasma concentration ratios of multiple-doses of intravenous CXA-201 compared to piperacillin/tazobactam in healthy adult volunteers, and (2) assessment of the safety and tolerability of multiple-doses of intravenous CXA-201 in healthy adult volunteers.
- BAL bronchoalveolar lavage
- Plasma and BAL datapoints were used to construct one concentration-time profile in the ELF using the mean concentrations at each time point.
- a single ELF sample was obtained by bronchoalveolar lavage (BAL) from each healthy volunteer at one of 5 scheduled time points (5 subjects/time point/treatment group).
- the ELF to plasma concentrations of multiple-doses was determined.
- Serial plasma samples were collected pre- and post-treatment over a 6-hour (piperacillin/tazobactam) or 8-hour (CXA-201) time period.
- Urea levels in the plasma and BAL were used to calculate the ELF drug concentrations (see Table 1).
- Pharmacokinetic parameters for ELF were calculated by non-compartmental analysis using the mean concentrations at each time point.
- the intrapulmonary penetration of CXA-201 into the ELF was determined by dividing the ELF AUC 0 -t by mean plasma AUC 0 -t.
- the concentration of CXA-201 and piperacillin/tazobactam in ELF were estimated from the concentration of drug in BAL fluid, the volume of BAL fluid collected, and the ratio of urea concentration in BAL fluid to that in plasma. Calculation of ELF volume was determined by the urea dilution method, using urea as an endogenous marker of ELF recovered by BAL. Concentration of CXA-201 and piperacillin/tazobactam in ELF was estimated from the concentration of drug in BAL fluid, the volume of BAL fluid collected, and the ratio of urea concentration in BAL fluid to that in plasma. The following formulas represent these calculations:
- CXA-201 (CXA/T) [CXA/T] BAL ⁇ V BAL /V ELF
- [CXAM BAL is the concentration of CXA-201 in BAL fluid; V BAL is the volume of aspirated BAL fluid (total); V ELF is V BAL ⁇ [urea] BAL /[urea] plasma , where [urea] BAL is the concentration of urea in the BAL fluid (supernatant) and [urea] plasma is the concentration of urea in the plasma specimens.
- [PIP/T] BAL is the concentration of piperacillin/tazobactam in BAL fluid
- V BAL is the volume of aspirated BAL fluid (total)
- V ELF is V BAL ⁇ [urea] BAL /[urea] plasma , where [urea] BAL is the concentration of urea in the BAL fluid (supernatant) and [urea] plasma is the concentration of urea in the plasma specimens.
- the ELF concentration vs. time profiles for ceftolozane and tazobactam components of CXA-201 are shown in FIGS. 2A and 2B , respectively.
- Comparative data showing the ELF concentration vs. time profiles for piperacillin and tazobactam components of the comparator drug are shown in FIGS. 3A and 3B , respectively.
- the ELF to plasma penetration ratios are shown in Table 2.
- the PK parameters were determined by non-compartmental PK analysis. PHOENIX® WinNonlin v 6.1 (PHARSIGHT®, Mountain View, Calif.) was used for the derivation of all PK individual measures for each subject.
- the PK parameters for ELF were calculated by taking the mean concentrations of the 5 subjects at each time point and constructing a single profile over the duration of sampling. In the event that the urea concentrations determined in plasma or ELF were below quantifiable limits, thereby providing only an estimate of concentration, those values were not used in the calculation of mean concentration at that time point.
- the ceftolozane, piperacillin, and tazobactam PK parameters that were computed in plasma and ELF were:
- the ELF/plasma AUC ratio for the ceftolozane component of CXA-201 was 0.48, compared to 0.26 for the piperacillin component of the comparator drug (piperacillin/tazobactam).
- the ELF/plasma AUC ratio for tazobactam was 0.44 and 0.54 when given as part of CXA-201 and piperacillin/tazobactam, respectively.
- the ELF concentrations of ceftolozane exceeded 8 ⁇ g/mL for 60% of the 8-hour dosing interval.
- the plasma and ELF concentrations of tazobactam when given as piperacillin/tazobactam was approximately 2-fold higher than when an equivalent dose was given as CXA-201.
- ceftolozane and tazobactam i.e., administered as CXA-201 penetrated well into the ELF of healthy volunteers compared to piperacillin/tazobactam, an agent widely used for treatment of lower respiratory infections.
- CXA-201's intrapulmonary pharmacokinetics support use of CXA-201 as a parenteral (e.g., intravenous) antibiotic for treatment of lower respiratory tract infections, including infections caused by pathogens with minimum inhibitory concentrations of ⁇ 8 ⁇ g/ml.
- the concentrations of ceftolozane in ELF exceeded 8 ⁇ g/mL, a concentration that inhibits 99% of P. aeruginosa, for approximately 60% of the 8-hour dosing interval for the CXA-201 regimen of 1.5 grams every eight hours as a 60 minute infusion.
- TEAEs treatment-emergent AEs
- a Monte Carlo simulation was performed based on clinical trial data to predict an effective CXA-201 dose for treating nosocomial pneumonia using PHOENIX® NLME (PHARSIGHT®, Mountain View, Calif.) software, a tool for data processing and modeling for population PK/PD analysis.
- a population pharmacokinetic (PK) model was developed using the CXA-201 plasma concentration versus time data from a previously conducted Phase 2 study in patients with complicated intra abdominal infections. Estimates of clearance and volume of distribution along with the associated inter-individual variability were obtained from these analyses.
- the outputs from the PK population model served as inputs for a clinical trial simulation performed using PHARSIGHT® Trial Simulator (PHARSIGHT®) software, a tool for defining and testing interactive drug models, exploring and communicating study design attributes, and performing statistical and sensitivity analysis through graphical and statistical summaries.
- PHARSIGHT® PHARSIGHT® Trial Simulator
- an ELF/Plasma AUC ratio of 0.48 for ceftolozane (modeled as a numerical range of 0.25-0.65) calculated from the ceftolozane ELF study mentioned above was used to generate a random/Plasma AUC ratio from the range 0.25-0.65 for each simulated patient. This range reflects a conservative estimate of the potential distribution in a patient population.
- the model simulated plasma and ELF concentration of CXA-201 versus time profiles for 1,000 hypothetical clinical trial patients with nosocomial pneumonia.
- the model evaluated the probability of clinical success of the 3.0 g every 8 hour (q8h) dose of CXA-201 against three key pathogens in nosocomial pneumonia.
- the MIC distribution for these pathogens was imputed from 2008 United States surveillance data.
- Clinical success was defined as the achievement of an ELF or plasma concentration of ceftolozane higher than the MIC(s) of the lower respiratory pathogen(s) for a given patient.
- the relavent PK/PD driver for CXA-201 is the percentage of time above MIC during the dosing interval.
- the target is to achieve concentrations that exceed the MIC of the pathogen for 45-50% of the time between each q8H dose.
- a threshold of 50% time above the minimum inhibitory concentration [T>MIC] on Day 7 of treatment was used.
- Plasma and ELF concentrations were estimated at 15 time-points post-administration on Day 7 when dosed every 8 hours. The results of these simulations are shown in Table 5.
- CXA-201 can be prepared by combining ceftolozane and tazobactam in a 2:1 weight ratio.
- CXA-201 can be obtained using methods described in U.S. Pat. No. 7,129,232 and Toda et al., “Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205, ” Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008), incorporated herein by reference in its entirety.
- ceftolozane can be obtained by the synthetic schemes of FIGS. 4A and 4B . Referring to FIGS. 4A and 4B .
- ceftolozane can be performed via activation of the thiadiazolyl-oximinoacetic acid derivative (I) with methanesulfonyl chloride and K 2 CO 3 in DMA at 10° C., followed by coupling with the 7-aminocephem (II) by means of Et 3 N in cold EtOAc/H 2 O, affords amide (III) (1).
- the antibacterial activity of the CXA-201 or other compounds can be measured by the minimum inhibitory concentrations (MIC) of the compounds against various bacteria measured by using the broth microdilution method performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines with modifications as described below (CLSI guidelines can be derived from the CLSI document M7-A8 published in January 2009: “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Eighth Edition”).
- MIC minimum inhibitory concentrations
- individual colonies can be isolated by streaking frozen glycerol material containing Staphylococcus or Pseudomonas spp. onto rich, non-selective, tryptic soy agar containing 5% sheep's blood (TSAB), and incubated at 37° C. for 18-24 hrs.
- TSAB sheep's blood
- CAMHB that contained compound concentrations ranging from 64-0.06 ⁇ g/mL in two-fold dilutions can also be added to the broth microdilution assay plates for a final volume 100 ⁇ L per well, therefore final culture OD 600 was approximately 0.001 and the final NaCl concentration for the MRSA strain was 2%.
- Plates can be incubated for 18-20 hours at 37° C. with aeration (200 rpm). Following incubation, growth can be confirmed visually placing plates over a viewing apparatus (stand with a minor underneath) and then OD 600 can be measured using a SpectraMax 340PC384 plate reader (Molecular Devices, Sunnyvale, Calif.). Growth was defined as turbidity that could be detected with the naked eye or achieving minimum OD 600 of 0.1. MIC values were defined as the lowest concentration producing no visible turbidity.
Abstract
Description
- This application claims priority to U.S. Provisional Application No. 61/532,914, filed Sep. 9, 2011, titled “Methods for Treating Intrapulmonary Infections,” and U.S. Provisional Application No. 61/657,386, filed Jun. 8, 2012, titled “Methods for Treating Intrapulmonary Infections.” The contents of any patents, patent applications, and references cited throughout this specification are hereby incorporated by reference in their entireties.
- This disclosure relates to the treatment of intrapulmonary bacterial infections, including the treatment of nosocomial pneumonia infections, with a cephalosporin.
- The cephalosporin (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureidol-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-RZ)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid (also referred to as “CXA-101” and previously designated FR264205) is an antibacterial agent. CXA-101 can be provided as the compound shown in
FIG. 1 . The antibacterial activity of CXA-101 is believed to result from its interaction with penicillin binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall which acts to stop bacterial replication. CXA-101 can be combined (e.g., mixed) with a β-lactamase inhibitor (“BLI”), such as tazobactam. Tazobactam is a BLI against Class A and some Class C β-lactamases, with well established in vitro and in vivo efficacy in combination with active β-lactam antibiotics. The combination of CXA-101 and tazobactam in a 2:1 weight ratio is an antibiotic pharmaceutical composition (“CXA-201”) for parenteral administration. CXA-201 displays potent antibacterial activity in vitro against common Gram-negative and selected Gram-positive organisms. CXA-201 is a broad-spectrum antibacterial with in vitro activity against Enterobacteriaceae including strains expressing extended spectrum β-lactamases-resistant (MIC90 =1 μg/mL), as well as Pseudomonas aeruginosa (P. aeruginosa) including multi-drug resistant strains (MIC90=2 μg/mL). CXA-201 is a combination antibacterial with activity against many Gram-negative pathogens known to cause intrapulmonary infections, including nosocomial pneumonia caused by P. aeruginosa. - Intrapulmonary infections, such as nosocomial pneumonia, remain a major cause of morbidity and mortality, especially infections caused by drug resistant pathogens such as P. aeruginosa. One challenge in treating intrapulmonary infections with systemic administration of an antibiotic is determining the antibiotic dose that will provide a therapeutically safe and effective concentration of the antibiotic at the site of an infection on the mucosal side of the bronchi in the lung (i.e., in the bronchial secretions). Many antibiotics diffuse poorly from the bloodstream across the bronchi [e.g., Pennington, J. E., “Penetration of antibiotics into respiratory secretions,” Rev Infect Dis 3(1):67-73 (1981)1, which can result in the administration of higher doses of antibiotic than would be prescribed for a truly systemic infection. Furthermore, the purulent sputum that characterizes infected patients tends to compromise the potency of many antibiotics (See e.g., Levy, J., et al., “Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum,” J Infect Dis 148(6):1069-76 (1983)). In some cases, the result is the prescription of large amounts of a systemically administered antibiotic to treat an intrapulmonary infection.
- The efficacy of an antibiotic depends in part on the concentration of the drug at the site of action. Efficacy of antimicrobial therapy requires adequate antibiotic concentrations at the site of bacterial infection, and some authorities believe that epithelial lining fluid (ELF) concentrations are a reasonable surrogate for predicting effective concentrations for treating intrapulmonary infections such as pneumonia. For many antibiotics, clinical data correlating ELF concentrations to clinical outcome is unavailable and the clinical significance of differences in pulmonary penetration of antibiotics is unknown or poorly characterized. Few studies have quantified the penetration of β-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in ELF to AUC in plasma (AUC(ELF)/AUC(plasma) ratio). For some published studies, the concentration of antibiotics measured in the ELF of the lung has varied widely. For example, the reported penetration ratio of telavancin in healthy human volunteers ranges widely between 0.43 and 1.24 (Lodise, Gottfreid, Drusano, 2008 Antimicrobial Agents and Chemotherapy). Thus, predicting the penetration of a drug into the ELF a priori, based on the structure, molecular weight, size and solubility is difficult due to the limited data available on the effect of physicochemical properties on the lung penetration of drugs.
- Accordingly, the efficacy of a particular drug in treating intrapulmonary infections, in particular nosocomial pneumonia, cannot be predicted solely on the basis of data, such as in vitro data relating to the activity of that drug against a particular bacterium, which does not give any indication as whether the drug will accumulate at a therapeutically safe and effective concentration at the site of an infection on the mucosal side of the bronchi in the lung (i.e., in the bronchial secretions). For instance, tigicycline, a glycylcycline antimicrobial, has in vitro activity against many species of Gram-positive and Gram-negative bacteria, including P. aeruginosa, and it has been approved by the FDA for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, and community acquired pneumonia. However, tigicycline is not approved for the treatment of nosocomial pneumonia, in view of an increased mortality risk associated with the use of tigicycline compared to other drugs in patients treated for nosocomial pneumonia.
- The present invention provides methods for treating intrapulmonary infections, including nosocomial pneumonia, with systemic administration of a pharmaceutical composition comprising ceftolozane. The invention is based in part on results from a human clinical study designed to assess the ELF penetration of CXA-201 in comparison to piperacillin/tazobactam, indicated for the treatment of nosocomial pneumonia. The study described herein quantified the penetration of CXA-201 into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma) ratio). The results of the study indicate that CXA-201 penetrated into the ELF of human patients, with a ceftolozane ELF/plasma AUC ratio of 0.48. The measured ELF concentrations of ceftolozane exceeded 8 μg/mL for 60% of the 8-hour dosing interval, a concentration that is predicted to inhibit 99% of Pseudomonas aeruginosa based on current surveillance data.
- The study showed that CXA-201 penetrated well into the ELF of healthy volunteers compared to piperacillin/tazobactam, an agent widely used for treatment of lower respiratory infections. The intrapulmonary pharmacokinetics measured in the study supports the use of CXA-201 as a parenteral (e.g., intravenous) antibiotic for treatment of intrapulmonary infections, such as nosocomial pneumonia or other lower respiratory tract infections.
-
FIG. 1 is the chemical structure of a salt of ceftolozane hydrogen sulfate salt. -
FIG. 2A is a graph showing the ELF Concentration vs. Time Profile for ceftolozane hydrogen sulfate salt (Median and Range) for CXA-201. -
FIG. 2B is a graph showing the ELF Concentration vs. Time Profile for Tazobactam (Median and Range) for CXA-201. -
FIG. 3A is a graph showing the (Comparative) ELF Concentration vs. Time Profile for Piperacillin (Median and Range) for a piperacillin/tazobactam comparator (ZOSYN®). -
FIG. 3B is a graph showing the (Comparative) ELF Concentration vs. Time Profile for Tazobactam (Median and Range) for a piperacillin/tazobactam comparator (ZOSYN®). -
FIGS. 4A and 4B are synthetic schemes for preparing ceftolozane hydrogen sulfate salt. - The present disclosure relates to the treatment of intrapulmonary infections, including nosocomial pneumonia, with systemic administration of a pharmaceutical composition comprising ceftolozane, including the parenteral administration of a therapeutically effective amount of a pharmaceutical composition comprising ceftolozane and tazobactam. As used herein, the term “ceftolozane” means CXA-101 in a free-base or salt form, preferably a hydrogen sulfate form (illustrated in
FIG. 1 ). In one embodiment, ceftolozane is CXA-101 in its free-base form. In another embodiment, ceftolozane is CXA-101 in its salt form, preferably a hydrogen sulfate form. - In a preferred embodiment, ceftolozane (in free base or salt form, preferably hydrogen sulfate form) and tazobactam are in a 2:1 (ceftolozane:tazobactam) weight ratio. In a particular embodiment, provided herein are methods of treating intrapulmonary infections, including nosocomial pneumonia, with systemic administration of a pharmaceutical composition comprising ceftolozane hydrogen sulfate and tazobactam in a 2:1 weight ratio. The combination of ceftolozane hydrogen sulfate and tazobactam in a 2:1 weight ratio is referred to herein and in the examples as “CXA-201.”
- In one aspect, the invention provides a method of treating an intrapulmonary infection comprising administering a therapeutically effective amount of a pharmaceutical composition comprising ceftolozane. The method may comprise administering a pharmaceutical composition comprising ceftolozane in combination with tazobactam.
- In another aspect, the invention provides a method of treating an intrapulmonary infection comprising the step of intravenously administering about every 8 hours to a subject in need thereof a pharmaceutical composition comprising 3.0 g of ceftolozane. The method may comprise administering a pharmaceutical composition comprising ceftolozane in combination with tazobactam. In one embodiment, the method comprises administering CXA-201 and the infection comprises Gram-negative bacteria. In another aspect, the invention provides a method of treating an intrapulmonary infection comprising the step of intravenously administering every 8 hours to a subject in need thereof a pharmaceutical composition comprising 3.0 g of ceftolozane.
- In another aspect, the invention provides a method of providing tazobactam or ceftolozane in the epithelial lining fluid of a subject in an amount effective to treat an intrapulmonary infection, comprising the step of intravenously administering to the subject a pharmaceutical composition comprising ceftolozane. The method may comprise administering a pharmaceutical composition further comprising tazobactam, optionally wherein the pharmaceutical composition is CXA-201. The method may comprise administering about 1.5 g of ceftolozane and tazobactam in total every 8 hours. In one embodiment, the amount of the ceftolozane in the ELF of the subject effective to treat an intrapulmonary infection is at least about 8 μg/ml. The ELF concentration of ceftolozane in the ELF may reach at least about 8 μg/ml after administration of the pharmaceutical composition. The subject is typically a human having, or believed to be at risk of having, nosocomial pneumonia. The subject (or patient) may, in some embodiments, have ventilator acquired pneumonia or hospital acquired pneumonia.
- In another aspect, the invention provides the use of ceftolozane in the manufacture of a medicament for the treatment of an intrapulmonary infection comprising administering a therapeutically effective amount of a pharmaceutical composition comprising the ceftolozane. The use may comprise administering the pharmaceutical composition comprising ceftolozane, in combination with tazobactam.
- In another aspect, the invention provides the use of ceftolozane in the manufacture of a medicament for the treatment of an intrapulmonary infection comprising intravenously administering a pharmaceutical composition comprising 3.0 g of the ceftolozane every 8 hours to a subject in need thereof. The use may comprise administering the pharmaceutical composition comprising ceftolozane in combination with tazobactam. In one embodiment, the use comprises administering ceftolozane and tazobactam and the infection comprises Gram-negative bacteria.
- In another aspect, the invention provides the use of ceftolozane in the manufacture of a medicament for the treatment of an intrapulmonary infection comprising intravenously administering a pharmaceutical composition comprising the ceftolozane, wherein tazobactam or ceftolozane is provided in the epithelial lining fluid of a subject in an amount effective to treat the intrapulmonary infection. The use may comprise administering a pharmaceutical composition further comprising tazobactam, optionally wherein the pharmaceutical composition is CXA-201. The use may comprise administering about 1.5 g of ceftolozane and tazobactam every 8 hours. In one embodiment, the amount of the ceftolozane in the ELF of the subject effective to treat an intrapulmonary infection is at least about 8 μg/ml. The ELF concentration of ceftolozane in the ELF may reach at least about 8 μg/ml after administration of the pharmaceutical composition. The subject is typically a human having, or believed to be at risk of having, nosocomial pneumonia. The subject (or patient) may, in some embodiments, have ventilator acquired pneumonia or hospital acquired pneumonia. In the methods and uses of the invention, the pharmaceutical composition may be administered parenterally. The pharmaceutical composition may be administered intravenously. In some embodiments, the pharmaceutical composition is intravenously administered about once every 8 hours as an infusion. The pharmaceutical composition may be intravenously administered as a 60-minute infusion.
- In the methods and uses of the invention, the intrapulmonary infection may be an infection in the lung. The intrapulmonary infection may be pneumonia. In a preferred embodiment, the intrapulmonary infection is nosocomial pneumonia. The intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof. Typically, the intrapulmonary infection comprises Pseudomonas aeruginosa. The intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for CXA-201 of ≦8 μg/ml. The intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ≦8 μg/ml.
- In another aspect, the invention provides ceftolozane, for use in a method of treating an intrapulmonary infection. In one embodiment, the ceftolozane is parenterally administered. Typically, the ceftolozane is intravenously administered. In some embodiments, the ceftolozane is administered about once every 8 hours as an infusion. In some embodiments, the ceftolozane is intravenously administered as a 60-minute infusion.
- In one embodiment, the ceftolozane is for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung. The intrapulmonary infection may be pneumonia. In a preferred embodiment, the ceftolozane is for use in a method of treating nosocomial pneumonia. The intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof. Typically, the intrapulmonary infection comprises Pseudomonas aeruginosa. The intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ≦8 μg/ml. The intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ≦8 μg/ml.
- The invention also provides ceftolozane, for use in a method of treating an intrapulmonary infection, comprising administration of ceftolozane in combination with tazobactam. In one embodiment, the ceftolozane and/or tazobactam is parenterally administered. Typically, the ceftolozane and/or tazobactam is intravenously administered. In some embodiments, the ceftolozane and/or tazobactam is administered about once every 8 hours as an infusion. In some embodiments, the ceftolozane and/or tazobactam is intravenously administered as a 60-minute infusion. In one embodiment, both the ceftolozane and tazobactam are parenterally administered. In another embodiment, both the ceftolozane and tazobactam are intravenously administered. In some embodiments, both the ceftolozane and tazobactam are administered about once every 8 hours as an infusion. In some embodiments, both the ceftolozane and tazobactam are intravenously administered as a 60-minute infusion. In one embodiment, the ceftolozane is for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung. The intrapulmonary infection may be pneumonia. In a preferred embodiment, the ceftolozane is for use in a method of treating nosocomial pneumonia. The intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof. Typically, the intrapulmonary infection comprises Pseudomonas aeruginosa. The intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ≦8 μg/ml. The intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ≦8 μg/ml.
- In another aspect, the invention provides tazobactam, for use in a method of treating an intrapulmonary infection, comprising administration of tazobactam in combination with ceftolozane. In one embodiment, the tazobactam and/or ceftolozane is parenterally administered. Typically, the tazobactam and/or ceftolozane is intravenously administered. In some embodiments, the tazobactam and/or ceftolozane is administered about once every 8 hours as an infusion. In some embodiments, the tazobactam and/or ceftolozane is intravenously administered as a 60-minute infusion. In one embodiment, both the tazobactam and ceftolozane are parenterally administered. In another embodiment, both the tazobactam and ceftolozane are intravenously administered. In another embodiment, both the tazobactam and ceftolozane are administered about once every 8 hours as an infusion. In another embodiments, both the tazobactam and ceftolozane are intravenously administered as a 60-minute infusion.
- In one embodiment, the tazobactam is for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung. The intrapulmonary infection may be pneumonia. In a preferred embodiment, the tazobactam is for use in a method of treating nosocomial pneumonia. The intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof. Typically, the intrapulmonary infection comprises Pseudomonas aeruginosa. The intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ≦8 μg/ml. The intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ≦8 μg/ml.
- In another aspect, the invention provides ceftolozane and tazobactam, as a combined preparation for simultaneous, separate or sequential use in a method of treating an intrapulmonary infection. In one embodiment, the ceftolozane and tazobactam are parenterally administered. Typically, the ceftolozane and tazobactam are intravenously administered. In some embodiments, the ceftolozane and tazobactam are administered about once every 8 hours as an infusion. In some embodiments, the ceftolozane and tazobactam, are intravenously administered as a 60-minute infusion.
- In one embodiment, the ceftolozane and tazobactam are for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung. The intrapulmonary infection may be pneumonia. In a preferred embodiment, the ceftolozane and tazobactam are for use in a method of treating nosocomial pneumonia. The intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof. Typically, the intrapulmonary infection comprises Pseudomonas aeruginosa. The intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ≦8 μg/ml. The intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ≦8 μg/ml.
- In another aspect, the invention provides ceftolozane for use in a method of providing tazobactam or ceftolozane in the epithelial lining fluid of a subject in an amount effective to treat an intrapulmonary infection, comprising the step of intravenously administering ceftolozane. In some embodiments, ceftolozane is administered in combination with tazobactam. Preferably, CXA-201 is administered. In preferred embodiments, about 1.5 g of ceftolozane and tazobactam is administered every 8 hours. In one embodiment, the amount of the ceftolozane in the ELF of the subject effective to treat an intrapulmonary infection is at least about 8 μg/ml. The ELF concentration of ceftolozane in the ELF may reach at least about 8 μg/ml after administration of the ceftolozane. The subject is typically a human having, or believed to be at risk of having, nosocomial pneumonia. The subject (or patient) may, in some embodiments, have ventilator acquired pneumonia or hospital acquired pneumonia.
- The safe and effective treatment of intrapulmonary infection with CXA-201 includes administration of an amount of the CXA-201 selected to provide a therapeutically effective dose of the CXA-201 antibiotic in the epithelial lining fluid (ELF). The penetration of CXA-201 into the ELF compared to a piperacillin/tazobactam comparator was assessed in a
Phase 1 clinical study in healthy adult volunteers. The piperacillin/tazobactam comparator contained piperacillin/tazobactam in an 8:1 weight ratio with a total of 2.79 mEq of sodium per gram of piperacillin, FDA approved under the tradename ZOSYN® (“Zosyn”). The study results evaluate the penetration of intravenously administered CXA-201 into healthy human lungs, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma)ratio). - In the study, a 4.5 g amount of piperacillin/tazobactam incorporates the same dose of tazobactam (0.5 g) as 1.5 g of CXA-201. A multiple-dose regimen was used in this study to ensure that the concentrations of the analytes reached steady-state in both plasma and ELF prior to assessment. Healthy volunteers were chosen to standardize the subject population and minimize the variability associated with using actively ill patients. The objectives of the study included: (1) determination and comparison of the ELF to plasma concentration ratios of multiple-doses of intravenous CXA-201 compared to piperacillin/tazobactam in healthy adult volunteers, and (2) assessment of the safety and tolerability of multiple-doses of intravenous CXA-201 in healthy adult volunteers.
- The study was a
Phase 1 prospective, randomized (1:1), comparator controlled, open-label study of 50 healthy adult volunteers. Each healthy volunteer received 3 doses of either CXA-201(1.5 grams every 8 hours as a 60-minute infusion) or piperacillin/tazobactam (4.5 grams every 6 hours as a 30-minute infusion). Subjects received 3 doses of a study drug, underwent serial blood draws at planned plasma sampling timepoints, and underwent a single bronchoalveolar lavage (BAL) procedure at one of the scheduled timepoints (Table 1). -
TABLE 1 Plasma Sampling and BAL Timepoints Plasma Sampling Timepoints BAL Timepoints Intensive plasma sampling 5 subjects per timepoint per from all 25 subjects for treatment group; in hours from one dosing interval start of the third infusion CXA-201 0 (pre-PK dose trough), 1, 2, 1, 2, 4, 6, 8 hours post start 4, 6, 8 hours post start of of infusion of the third dose of infusion of the third dose of CXA 201 CXA 201 Piperacillin/tazobactam 0 (pre-PK dose trough), 0.5, 1, 0.5, 1, 2, 4, 6 hours post start 2, 4, 6 hours post start of of infusion of the third dose of infusion of the third dose of piperacillin/tazobactam piperacillin/tazobactam - A total of 51 subjects were enrolled; 25 in the CXA-201 group and 26 in the piperacillin/tazobactam group. Key Inclusion Criteria for the study were: (1) healthy adult male or non-pregnant females between 18 and 50 years, inclusive; (2) body mass index between 18.5 and 30; and (3) forced Expiratory Volume in 1 second (FEV1) ≧80%. Key Exclusion Criteria for the study were: (1) pregnancy or lactation; (2) clinically significant systemic disease or the existence of any surgical or medical condition that may have interfered with the distribution, metabolism, or excretion of CXA-201; (3) history of asthma or any restrictive or obstructive lung disease; (4) history of smoking or abuse of narcotics or alcohol; (5) positive test for human immunodeficiency virus, Hepatitis B surface antigen, or Hepatitis C antibodies; (6) any condition or situation where bronchoscopy was not advisable; and (7) impairment of renal function (CrCl<90 mL/min)
- Plasma and BAL datapoints were used to construct one concentration-time profile in the ELF using the mean concentrations at each time point. After dosing, a single ELF sample was obtained by bronchoalveolar lavage (BAL) from each healthy volunteer at one of 5 scheduled time points (5 subjects/time point/treatment group). The ELF to plasma concentrations of multiple-doses was determined. Serial plasma samples were collected pre- and post-treatment over a 6-hour (piperacillin/tazobactam) or 8-hour (CXA-201) time period. Urea levels in the plasma and BAL were used to calculate the ELF drug concentrations (see Table 1). Pharmacokinetic parameters for ELF were calculated by non-compartmental analysis using the mean concentrations at each time point. The intrapulmonary penetration of CXA-201 into the ELF was determined by dividing the ELF AUC0-t by mean plasma AUC0-t.
- The concentration of CXA-201 and piperacillin/tazobactam in ELF were estimated from the concentration of drug in BAL fluid, the volume of BAL fluid collected, and the ratio of urea concentration in BAL fluid to that in plasma. Calculation of ELF volume was determined by the urea dilution method, using urea as an endogenous marker of ELF recovered by BAL. Concentration of CXA-201 and piperacillin/tazobactam in ELF was estimated from the concentration of drug in BAL fluid, the volume of BAL fluid collected, and the ratio of urea concentration in BAL fluid to that in plasma. The following formulas represent these calculations:
-
CXA-201 (CXA/T)=[CXA/T]BAL ×V BAL /V ELF - [CXAMBAL is the concentration of CXA-201 in BAL fluid; VBAL is the volume of aspirated BAL fluid (total); VELF is VBAL×[urea]BAL/[urea]plasma, where [urea]BAL is the concentration of urea in the BAL fluid (supernatant) and [urea]plasma is the concentration of urea in the plasma specimens.
-
Piperacillin/tazobactam=[PIP/T]BAL ×V BAL /V ELF - [PIP/T]BAL is the concentration of piperacillin/tazobactam in BAL fluid; VBAL is the volume of aspirated BAL fluid (total); VELF is VBAL×[urea]BAL/[urea]plasma, where [urea]BAL is the concentration of urea in the BAL fluid (supernatant) and [urea]plasma is the concentration of urea in the plasma specimens.
- No oral antibiotic therapy was permitted. Safety was monitored through the review of vital signs, laboratory and physical examinations and the occurrence of adverse events (AEs). Subjects who received three doses of study medication and had both BAL and plasma samples collected were included in the pharmacokinetic (PK) analysis population. All randomized subjects who received any dose (including partial doses) of study medication were included in the safety analysis population.
- The results of the study (Table 2) indicate that CXA-201 penetrated well into ELF. The ceftolozane component of CXA-201 ELF/plasma AUC ratio was 0.48, compared to 0.26 for the piperacillin component of piperacillin/tazobactam. The ELF concentrations of ceftolozane exceeded 8 μg/mL for 60% of the 8-hour dosing interval. The plasma concentrations for ceftolozane were consistent with those seen previously at this dose.
- The ELF concentration vs. time profiles for ceftolozane and tazobactam components of CXA-201 are shown in
FIGS. 2A and 2B , respectively. Comparative data showing the ELF concentration vs. time profiles for piperacillin and tazobactam components of the comparator drug are shown inFIGS. 3A and 3B , respectively. The ELF to plasma penetration ratios are shown in Table 2. - The PK parameters were determined by non-compartmental PK analysis. PHOENIX® WinNonlin v 6.1 (PHARSIGHT®, Mountain View, Calif.) was used for the derivation of all PK individual measures for each subject. The PK parameters for ELF were calculated by taking the mean concentrations of the 5 subjects at each time point and constructing a single profile over the duration of sampling. In the event that the urea concentrations determined in plasma or ELF were below quantifiable limits, thereby providing only an estimate of concentration, those values were not used in the calculation of mean concentration at that time point. The ceftolozane, piperacillin, and tazobactam PK parameters that were computed in plasma and ELF were:
-
- Cmax (μg/mL): Maximum plasma and ELF concentration over the entire sampling phase directly obtained from the experimental plasma concentration time data, without interpolation.
- Tmax (hr): Sampling time at which Cmax occurred, obtained directly from the experimental plasma and ELF concentration time data, without interpolation.
- Clast (μg/mL): Plasma or ELF concentration when last quantifiable concentration was observed, relative to the end of infusion.
- Tlast (hr): Time when the last quantifiable concentration was observed.
- AUC0-t (μg*hr/mL): An area under the concentration time curve from the time of the dose to the end of the dosing interval.
- Percent penetration into ELF: Calculated as the ratio of AUC0-tELF and mean AUC0-tPlasma.
-
TABLE 2 Summary of ELF to Plasma Penetration Ratios Mean Plasma ELF ELF AUC0-τ AUC0-τ Penetration Analyte (μg*hr/mL) (μg*hr/mL) Ratio ceftolozane 158.5 75.1 0.48 (in CXA-201) Tazobactam 19.3 8.5 0.44 (in CXA-201) Piperacillin 357.3 94.5 0.26 (in piperacillin/tazobactam) Tazobactam 46.1 24.7 0.54 (in piperacillin/tazobactam) - The ELF/plasma AUC ratio for the ceftolozane component of CXA-201 was 0.48, compared to 0.26 for the piperacillin component of the comparator drug (piperacillin/tazobactam). The ELF/plasma AUC ratio for tazobactam was 0.44 and 0.54 when given as part of CXA-201 and piperacillin/tazobactam, respectively. The ELF concentrations of ceftolozane exceeded 8 μg/mL for 60% of the 8-hour dosing interval. The plasma and ELF concentrations of tazobactam when given as piperacillin/tazobactam was approximately 2-fold higher than when an equivalent dose was given as CXA-201.
- The results show that ceftolozane and tazobactam (i.e., administered as CXA-201) penetrated well into the ELF of healthy volunteers compared to piperacillin/tazobactam, an agent widely used for treatment of lower respiratory infections. CXA-201's intrapulmonary pharmacokinetics support use of CXA-201 as a parenteral (e.g., intravenous) antibiotic for treatment of lower respiratory tract infections, including infections caused by pathogens with minimum inhibitory concentrations of ≦8 μg/ml. The concentrations of ceftolozane in ELF exceeded 8 μg/mL, a concentration that inhibits 99% of P. aeruginosa, for approximately 60% of the 8-hour dosing interval for the CXA-201 regimen of 1.5 grams every eight hours as a 60 minute infusion.
- Assessment of the safety and tolerability of multiple-doses of intravenous CXA-201 in healthy adult volunteers.
- Among the subjects, 50 of the 51 (98%) subjects received all 3 doses of study medication and completed the BAL procedure. One subject prematurely discontinued piperacillin/tazobactam and terminated their participation in the study due to an AE of hypersensitivity that occurred during administration of the first dose. Demographics and baseline characteristics are summarized in Table 3, the two treatment arms were well balanced.
-
TABLE 3 Demographics and Baseline Characteristics (Safety Population) Piperacillin/ CXA-201 tazobactam 1.5 grams 4.5 grams (N = 25) (N = 26) Sex, n (%) Female 11 (44.0) 11 (42.3) Male 14 (56.0) 15 (57.7) Age, years Mean (SD) 32.6 (7.8) 34.2 (8.5) Minimum, Maximum 21, 47 22, 49 Race, n (%) White 20 (80.0) 21 (80.8) Black or African American 2 (8.0) 2 (7.7) Asian 1 (4.0) 0 (0.0) American Indian or Alaska Native 0 (0.0) 1 (3.8) Native Hawaiian or Pacific Islander 1 (4.0) 0 (0.0) Other 1 (4.0) 2 (7.7) BMI, kg/m2 Mean (SD) 26.21 (2.6) 23.23 (2.4) Minimum, Maximum 22.3, 30.0 20.6, 29.9 - During the study, treatment-emergent AEs (TEAEs) occurred in 20.0% (5/25) of subjects receiving CXA-201 and 23.1% (6/26) of subjects receiving piperacillin/tazobactam. No serious AEs were reported in either treatment group. All AEs were mild in severity. The incidence and pattern of AEs were generally similar in the 2 treatment groups, Table 4.
-
TABLE 4 TEAEs by Preferred Term (Safety Population) Subjects with at least 1 TEAE 5 (20.0) 6 (23.1) Diarrhea 1 (4.0) 3 (11.5) Viral Upper Respiratory Infection 1 (4.0) 0 (0) Musculoskeletal Chest Pain 1 (4.0) 0 (0) Somnolence 1 (4.0) 0 (0) Hematuria 1 (4.0) 0 (0) Cough 1 (4.0) 0 (0) Type I Hypersensitivity 0 (0) 1 (3.8) Alanine Aminotransferase Increased 0 (0) 1 (3.8) Aspartate Aminotransferase Increased 0 (0) 1 (3.8) Blood Creatine Phosphokinase Increased 0 (0) 1 (3.8) Hyperkalemia 0 (0) 1 (3.8) - Eight subjects had TEAEs assessed as related to study drug; two in the CXA-201 group (diarrhea and somnolence in 1 subject each) and six in the piperacillin/tazobactam group (diarrhea in 3 subjects, type I hypersensitivity in 1 subject, blood creatine phosphokinase increased in 1 subject, and alanine aminotransferase increased, aspartate aminotransferase increased, and hyperkalaemia all in the same 1 subject). One piperacillin/tazobactam-treated subject discontinued study drug due to an adverse event, type I hypersensitivity. There were no clinically significant changes in safety laboratory assessments or vital signs.
- CXA-201 appeared safe and well tolerated in this group of healthy adult subjects.
- A Monte Carlo simulation was performed based on clinical trial data to predict an effective CXA-201 dose for treating nosocomial pneumonia using PHOENIX® NLME (PHARSIGHT®, Mountain View, Calif.) software, a tool for data processing and modeling for population PK/PD analysis. A population pharmacokinetic (PK) model was developed using the CXA-201 plasma concentration versus time data from a previously conducted
Phase 2 study in patients with complicated intra abdominal infections. Estimates of clearance and volume of distribution along with the associated inter-individual variability were obtained from these analyses. The outputs from the PK population model served as inputs for a clinical trial simulation performed using PHARSIGHT® Trial Simulator (PHARSIGHT®) software, a tool for defining and testing interactive drug models, exploring and communicating study design attributes, and performing statistical and sensitivity analysis through graphical and statistical summaries. Based on the mean ELF penetration data, an ELF/Plasma AUC ratio of 0.48 for ceftolozane (modeled as a numerical range of 0.25-0.65) calculated from the ceftolozane ELF study mentioned above was used to generate a random/Plasma AUC ratio from the range 0.25-0.65 for each simulated patient. This range reflects a conservative estimate of the potential distribution in a patient population. Using the results from the PK population model and the ELF/Plasma AUC ratio, the model simulated plasma and ELF concentration of CXA-201 versus time profiles for 1,000 hypothetical clinical trial patients with nosocomial pneumonia. The model evaluated the probability of clinical success of the 3.0 g every 8 hour (q8h) dose of CXA-201 against three key pathogens in nosocomial pneumonia. The MIC distribution for these pathogens was imputed from 2008 United States surveillance data. Clinical success was defined as the achievement of an ELF or plasma concentration of ceftolozane higher than the MIC(s) of the lower respiratory pathogen(s) for a given patient. In vivo models have demonstrated that, as for typical cephlaosporins, the relavent PK/PD driver for CXA-201 is the percentage of time above MIC during the dosing interval. The target is to achieve concentrations that exceed the MIC of the pathogen for 45-50% of the time between each q8H dose. Thus, a threshold of 50% time above the minimum inhibitory concentration [T>MIC] on Day 7 of treatment was used. Plasma and ELF concentrations were estimated at 15 time-points post-administration on Day 7 when dosed every 8 hours. The results of these simulations are shown in Table 5. -
TABLE 5 Probability of Target Attainment versus Key Pathogens in Nosocomial Pneumonia Using the Simulated 3.0 g versus the 1.5 g Dose of Ceftolozane/ tazobactam 50% 50% T > MIC T > MIC Pathogen Dosing Regimen in Plasma in ELF P. aeruginosa 1.5 g q8 h 98.2 94.6 3.0 g q8 h 99.4 98.5 E. coli 1.5 g q8 h 96.3 94.2 3.0 g q8 h 98.8 95.5 K. pneumoniae 1.5 g q8 h 90.2 87.3 3.0 g q8 h 92.6 89.3 Abbreviation: T > MIC = Time above minimum inhibitory concentration. - These simulations demonstrate that the 3.0 g dose of CXA-201 administered every 8 hours is expected to provide adequate concentrations for treatment of the vast majority of lower respiratory infections caused by these pathogens.
- Following these simulations, the safety and tolerability of a 10 day course of CXA-201 3.0 g IV q8h was evaluated in healthy human volunteers. Subjects were randomized to receive either 3.0 g (2.0/1.0 g) CXA-201 (n=8), 1.5 g (1.0/0.5 g) CXA-201 (n=4), or placebo (n=4). The data showed that CXA-201 was generally safe and well tolerated in this study. There were no serious adverse events or deaths reported in this study.
- In conclusion, given the pharmacokinetic simulations conducted, the favorable data from the intrapulmonary PK study and demonstrated safety and tolerability of the higher dose of CXA-201 in the
Phase 1 study mentioned above, the data provide justification for the use of 3.0 g CXA-201 IV q8h for the treatment of patients with nosocomial pneumonia caused by Gram-negative pathogens. - CXA-201 can be prepared by combining ceftolozane and tazobactam in a 2:1 weight ratio. CXA-201 can be obtained using methods described in U.S. Pat. No. 7,129,232 and Toda et al., “Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205,” Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008), incorporated herein by reference in its entirety.
- According to the method disclosed in Toda et al., “Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205,” Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008), ceftolozane can be obtained by the synthetic schemes of
FIGS. 4A and 4B . Referring toFIGS. 4A and 4B , synthesis of ceftolozane can be performed via activation of the thiadiazolyl-oximinoacetic acid derivative (I) with methanesulfonyl chloride and K2CO3 in DMA at 10° C., followed by coupling with the 7-aminocephem (II) by means of Et3N in cold EtOAc/H2O, affords amide (III) (1). Substitution of the allylic chloride of compound (III) with 4-[(N-Boc-aminoethyl)carbamoylamino]-1-methyl-5-tritylaminopyrazole (IV) in the presence of 1,3-bis(trimethylsilyl)urea (BSU) and KI in DMF then affords the protected pyrazolium adduct (V), which, after full deprotection with trifluoroacetic acid in anisole/CH2Cl2, can be isolated as the hydrogensulfate salt by treatment with H2SO4 in i-PrOH/H2O (1, 2).Scheme 1. The pyrazolyl urea intermediate (IV) can be prepared as follows. Treatment of 5-amino-1-methylpyrazole (VI) with NaNO2/HCl in water at 5° C. gives the 4-nitrosopyrazole derivative (VII), which can be reduced to the diaminopyrazole (VIII) by catalytic hydrogenation over Pd/C in the presence of H2SO4. Selective acylation of the 4-amino group of compound (VIII) with phenyl chloroformate in the presence of NaOH in H2O/dioxane at 10° C. then yields the phenyl carbamate (IX). After protection of the free amine group of carbamate (IX) with chlorotriphenylmethane in the presence of Et3N in THF, the resulting N-trityl derivative (X)can be coupled with N-Boc-ethylenediamine (XI) in the presence of Et3N in DMF to afford pyrazolyl urea (IV). - The antibacterial activity of the CXA-201 or other compounds can be measured by the minimum inhibitory concentrations (MIC) of the compounds against various bacteria measured by using the broth microdilution method performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines with modifications as described below (CLSI guidelines can be derived from the CLSI document M7-A8 published in January 2009: “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Eighth Edition”).
- To prepare for MIC testing, individual colonies can be isolated by streaking frozen glycerol material containing Staphylococcus or Pseudomonas spp. onto rich, non-selective, tryptic soy agar containing 5% sheep's blood (TSAB), and incubated at 37° C. for 18-24 hrs.
- On the day of testing, primary cultures can be started by scraping off 5-10 colonies from the TSAB plates. The material can be suspended in ˜5 mL of cation adjusted Mueller Hinton Broth (CAMHB) in 14 mL culture tubes and can be incubated at 37° C. with aeration (200 rpm) for ˜2 hrs until the OD600 was ≧0.1.
- Inoculum cultures can be prepared by standardizing the primary cultures to OD600=0.1 and then adding 20 μL of the adjusted primary culture per 1 mL CAMHB for Pseudomonas and CAMHB plus 4% NaCl for MRSA so that the final inoculum density was ˜105 colony forming units per milliliter. Diluted inoculum cultures can be used to inoculate 50 μL per well in 96 well broth microdilution assay plates. 50 μL of CAMHB that contained compound concentrations ranging from 64-0.06 μg/mL in two-fold dilutions can also be added to the broth microdilution assay plates for a
final volume 100 μL per well, therefore final culture OD600 was approximately 0.001 and the final NaCl concentration for the MRSA strain was 2%. - Plates can be incubated for 18-20 hours at 37° C. with aeration (200 rpm). Following incubation, growth can be confirmed visually placing plates over a viewing apparatus (stand with a minor underneath) and then OD600 can be measured using a SpectraMax 340PC384 plate reader (Molecular Devices, Sunnyvale, Calif.). Growth was defined as turbidity that could be detected with the naked eye or achieving minimum OD600 of 0.1. MIC values were defined as the lowest concentration producing no visible turbidity.
- The examples and illustrative embodiments described herein are provided by way of illustration, and do not constitute additional limitations on the scope of the claims. While some embodiments have been shown and described in the instant specification, the specification as ready by one of ordinary skill in the relevant arts also discloses various modifications and substitutions of embodiments explicitly disclosed herein. The exemplary embodiments from the specification are not provided to read additional limitations into the claims.
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US10000510B2 (en) | 2014-08-18 | 2018-06-19 | Merck Sharp & Dohme Corp. | Salt forms of ceftolozane |
US10214543B2 (en) | 2014-12-30 | 2019-02-26 | Merck Sharp & Dohme Corp. | Synthesis of cephalosporin compounds |
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JP6151257B2 (en) | 2017-06-21 |
US20180296567A1 (en) | 2018-10-18 |
EP3616695A1 (en) | 2020-03-04 |
EP2753326A4 (en) | 2015-04-15 |
EA028342B1 (en) | 2017-11-30 |
MX2014002758A (en) | 2014-10-17 |
EP2862569A1 (en) | 2015-04-22 |
US20180064724A1 (en) | 2018-03-08 |
HK1200096A1 (en) | 2015-07-31 |
MX352760B (en) | 2017-12-07 |
CA2848012A1 (en) | 2013-03-14 |
WO2013036783A2 (en) | 2013-03-14 |
US20150045338A1 (en) | 2015-02-12 |
CN103945842A (en) | 2014-07-23 |
US9724353B2 (en) | 2017-08-08 |
JP2014526468A (en) | 2014-10-06 |
US10028963B2 (en) | 2018-07-24 |
US20150080360A1 (en) | 2015-03-19 |
EP2753326A2 (en) | 2014-07-16 |
EA201490590A1 (en) | 2015-04-30 |
WO2013036783A3 (en) | 2013-05-02 |
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