WO2021080598A1 - Compositions biocides compatibles avec des biocapteurs enzymatiques et leurs procédés d'utilisation - Google Patents

Compositions biocides compatibles avec des biocapteurs enzymatiques et leurs procédés d'utilisation Download PDF

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WO2021080598A1
WO2021080598A1 PCT/US2019/058009 US2019058009W WO2021080598A1 WO 2021080598 A1 WO2021080598 A1 WO 2021080598A1 US 2019058009 W US2019058009 W US 2019058009W WO 2021080598 A1 WO2021080598 A1 WO 2021080598A1
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ebcb
polymyxin
composition
enzyme
sensor
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PCT/US2019/058009
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English (en)
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Dennis Robert Conlon
Prasad Pamidi
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Instrumentation Laboratory Company
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Priority to PCT/US2019/058009 priority Critical patent/WO2021080598A1/fr
Priority to CN201980103233.5A priority patent/CN114846332A/zh
Priority to EP19804990.0A priority patent/EP4049036A1/fr
Publication of WO2021080598A1 publication Critical patent/WO2021080598A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001—Enzyme electrodes
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001—Enzyme electrodes
    • C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard

Definitions

  • the disclosure relates to biocide compositions compatible with enzyme biosensors and methods for using same. More particularly, the disclosure relates to biocide compositions compatible with enzymes used for measuring creatine and creatinine levels.
  • WBCCAs Whole blood critical care analyzers
  • Biocides are a critical component of WBCCA reagents that inhibits the effects of microbial metabolism on blood analysis results. For example, normal oxygen content in human blood is very low, and any consumption of oxygen by bacteria in the calibration solution causes a significant error in reported oxygen levels.
  • WBCCAs have also evolved to include electrochemical biosensor based measurement of metabolites such as, for example, creatinine/creatine levels in a sample (e.g., a patient’s blood), which is an important indication of renal function.
  • Current creatinine sensors may include an enzymatic biosensor containing three enzymes — creatininase, creatinase, and sarcosine oxidase — that catalyze the production of glycine, formaldehyde, and hydrogen peroxide from creatinine and water so that the final reaction product of hydrogen peroxide (H2O2) may then be electrochemically oxidized to measure creatinine and/or creatine levels in the sample (e.g., a patient’s blood).
  • H2O2 hydrogen peroxide
  • the present disclosure provides efficacious biocidal reagents that do not inhibit or prevent the function of whole blood critical care analyzers (WBCCAs).
  • WBCCAs whole blood critical care analyzers
  • the present disclosure provides some efficacious biocides that do not inhibit or prevent WBCCAs having sensor function or enzymatic biosensor function.
  • the present disclosure provides biocidal reagents with a molecular weight (MW) greater than 320 that do not inhibit or prevent enzymatic biosensor function.
  • MW molecular weight
  • the present disclosure provides some efficacious biocides that do not inhibit or prevent enzymatic biosensor function.
  • Exemplary efficacious biocidal reagents that do not inhibit or prevent the function of enzymatic biosensors include, but are not limited to, Levofloxacin, Carbenicillin disodium, Spectinomycin, Piperacillin, Ceftazidime, Streptomycin, Polymyxin B, Polymyxin E, Sulfanilamide, Sulfathiazole sodium, Sulfadimethoxine, Vantocil IB, and the like.
  • the biocidal reagents disclosed herein are able to effectively neutralize or destroy harmful organisms (e.g., bacteria, fungi, and the like) without inhibiting or preventing the function of an enzymatic biosensor.
  • the present disclosure also provides methods of identifying biocides that are compatible with any of a variety of enzymatic biosensors. Furthermore, the present disclosure also provides methods of using the disclosed biocides.
  • the compositions and methods provided herein are important because they allow whole blood critical care analyzers (WBCCAs) having enzymatic biosensors to efficiently perform readings on biological samples in the presence of biocidal reagents that do not negatively impact the function of the enzymatic biosensors.
  • WBCCAs whole blood critical care analyzers
  • the present disclosure provides a method for preserving function of a sensor that includes the steps of: adding one or more sensor compatible biocides (SCBs) to a solution; and measuring with the sensor a concentration of one or more analytes.
  • the sensor may be a biosensor, a gas sensor, an ion selective electrode, or a photometric sensor.
  • the biosensor is an enzyme biosensor.
  • the enzyme biosensor may be a creatinine sensor, a creatine sensor, or a combination thereof.
  • the SCB is an antibiotic having a molecular weight greater than about 320 g/mol.
  • the SCB is a polymyxin selected from the group consisting of Polymyxin B, Polymyxin E, and combinations thereof.
  • the SCB is Polymyxin B.
  • the SCB is fluoroquinolone.
  • the SCB contains a sulfone group.
  • the solution is a biological sample, a Process Control Solution (PCS), a calibration solution, a quality control solution, a conditioning solution, or a wash solution.
  • PCS Process Control Solution
  • the SCB is a Beta-lactam antibiotic selected from the group consisting of: amoxycillin, ampicillin, carbenicillin, cefazolin, cefepime, cefoxitin, ceftazidime, clavulanic acid, imipenem, oxacillin, penicillin, and piperacillin.
  • the SCB includes at least one Beta-lactam antibiotic and a polymyxin.
  • the solution further includes a beta-lactamase inhibitor.
  • the SCB includes a polymyxin and a fluoroquinolone.
  • the disclosure provides a method of identifying an Enzyme Biosensor Compatible Biocide (EBCB) for an enzyme biosensor that includes the steps of: measuring stable enzyme biosensor activity for an enzyme biosensor in solution for a period of time; adding one or more biocidal agents to the solution containing the enzyme biosensor; determining antimicrobial efficacy of the biocidal agent in the solution; measuring the enzyme biosensor activity in response to the one or more biocidal agents for an additional period of time, wherein the enzyme biosensor activity is assessed based on an enzyme slope; and selecting, based on the enzyme slope, the EBCB.
  • EBCB Enzyme Biosensor Compatible Biocide
  • the biocidal agent is one or more antibiotics having a molecular weight greater than about 350 g/mol.
  • the EBCB contains a sulfone group.
  • the EBCB is a Beta-lactam antibiotic.
  • the WBCCA sensor is a gas sensor, an ion selective electrode, a photometric sensor, and the like. In some embodiments, the WBCCA sensor is an enzyme biosensor, optionally a
  • the disclosure provides a composition, including one or more enzyme biosensor compatible biocides (EBCBs) selected from the group consisting of Levofloxacin, Carbenicillin disodium, Spectinomycin, Piperacillin, Ceftazidime, Streptomycin, Polymyxin B, Polymyxin E, Sulfanilamide, Sulfathiazole sodium, Sulfadimethoxine, and Vantocil IB.
  • EBCBs enzyme biosensor compatible biocides
  • the disclosure provides a composition, including: a first enzyme biosensor compatible biocide (EBCB); and a second EBCBs.
  • EBCB enzyme biosensor compatible biocide
  • the first EBCB is selected from the group consisting of Levofloxacin, Carbenicillin disodium, Spectinomycin, Piperacillin, Ceftazidime, Streptomycin, Polymyxin B, Polymyxin E, Sulfanilamide, Sulfathiazole sodium, Sulfadimethoxine, and Vantocil IB.
  • the second EBCB is selected from the group consisting of Levofloxacin, Carbenicillin disodium, Spectinomycin, Piperacillin, Ceftazidime, Streptomycin, Polymyxin B, Polymyxin E, Sulfanilamide, Sulfathiazole sodium, Sulfadimethoxine, and Vantocil IB.
  • the first EBCB or second EBCB is a penicillin selected from the group consisting of amoxycillin, carbenicillin and benzyl penicillin.
  • the penicillin is at a concentration of about 12.5 to about 500 pg/ml.
  • the first EBCB is carbenicillin at a concentration of about 5 to about 800 m /iti1 and the second EBCB is nitrofurantoin at a concentration of about 1 to about 200 pg/mL.
  • the first EBCB or second EBCB is about 15 to about 1500 mg/L spectinomycin.
  • the first EBCB or second EBCB is about 10 to about 500 mg/L of ceftazidime.
  • the first EBCB or second EBCB is about 10-500 mM streptomycin.
  • the first EBCB or second EBCB is about 20 to 100 mg/L polymyxin B.
  • the first EBCB or second EBCB is about 20 to 100 mg/L polymyxin E.
  • the first EBCB or second EBCB is Vantocil IB in a w/v of 0.1- 0.5% in aqueous solution.
  • the first EBCB is colistin and the second EBCB is levofloxacin.
  • control or “reference” is meant a standard of comparison.
  • “changed as compared to a control” sample or subject is understood as having a level that is statistically different than a sample from a normal, untreated, or control sample.
  • Control samples include, for example, creatine solutions, creatinine solutions, and the like. Methods to select and test control samples are within the ability of those in the art. Determination of statistical significance is within the ability of those skilled in the art, e.g., the number of standard deviations from the mean that constitute a positive result.
  • Creatine (a.k.a., 2-[Carbamimidoyl(methyl)amino]acetic acid, N- Carbamimidoyl-N-methylglycine, or Methylguanidoacetic acid)” refers to an organic compound that produce energy for the cells through the recycling of adenosine triphosphate (ATP) by converting adenosine diphosphate (ADP) back to ATP by donating phosphate groups. Creatine has the following chemical structure:
  • creatinine refers to the enzymatic breakdown by-product of creatine, and is generally found in two major tautomeric forms, which are shown below.
  • Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it is understood that the particular value forms another aspect. It is further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself.
  • a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.
  • any one of the embodiments described herein is contemplated to be able to combine with any other one or more embodiments, even though the embodiments are described under different aspects of the disclosure.
  • efficacious biocides may be used singly or as combinations of two or more efficacious biocides.
  • FIGS. 1 A-1C show the crystal structure reconstructions of the enzymes present in a creatininase sensor.
  • FIG. 1 A is a ribbon diagram showing the quaternary structure of the creatininase hexamer as known in the prior art.
  • FIG. IB is a ribbon diagram showing the tertiary structure of the creatinase N-terminal domain as known in the prior art.
  • FIG. 1C is a ribbon diagram showing the tertiary structure of sarcosine oxidase as known in the prior art.
  • FIGS. 2A-2B show plots of creatinine and creatine slopes over time in the presence of either MIT or polymyxin B, respectively.
  • FIG. 1 A is a ribbon diagram showing the quaternary structure of the creatininase hexamer as known in the prior art.
  • FIG. IB is a ribbon diagram showing the tertiary structure of the creatinase N-terminal domain as known in
  • FIG. 2A shows a plot of creatinine and creatine slopes over time showing that addition of MIT causes a rapid decay in creatinine/creatine slopes that does not recover over time.
  • FIG. 2B shows a plot of creatinine and creatine slopes over time showing that addition of polymyxin B does not causes a rapid decay in creatinine/creatine slopes. Stable slopes were first established for more than one week before 300mg/L MIT (methyl isothiazolinone) or 20 mg/L polymyxin B was added to the Process Control Solution (PCS) B (e g., PCS-B).
  • PCS Process Control Solution
  • FIG. 3 shows example plots of creatinine slope performances over time in PCS with colistin (left) and gentamicin (right) showing that sensors maintained sufficient creatinine slope for a full use life of three weeks.
  • FIGS. 4A and 4B are graphs showing effects of colistin in the main calibration/wash solutions in either spiked blood samples (FIG. 4A) or clinical specimens (FIG. 4B).
  • the present disclosure is based, at least in part, on the unexpected discovery that biocidal reagents that fall within particular molecular weight ranges do not inhibit or prevent the function of enzymes with an enzymatic biosensor.
  • the present disclosure provides the unexpected and surprising discovery that biocidal reagents having a molecular weight (MW) greater than 320 do not inhibit or prevent the function of enzymes within an enzymatic biosensor.
  • the present disclosure provides a number of specific efficacious biocidal reagents that do not inhibit or prevent the function of enzymes within an enzymatic biosensor that include, but are not limited to, Levofloxacin, Carbenicillin disodium, Spectinomycin, Piperacillin, Ceftazidime, Streptomycin, Polymyxin B, Polymyxin E, Sulfanilamide, Sulfathiazole sodium, Sulfadimethoxine, Vantocil IB, and the like.
  • the biocidal reagents disclosed herein are able to effectively neutralize or destroy harmful organisms (e.g., bacteria, fungi, and the like) without inhibiting or preventing the function of an enzymatic biosensor.
  • the present disclosure also provides methods of identifying efficacious biocides that are specific to, and compatible with, any of a variety of enzymatic biosensors.
  • the present disclosure also provides methods of using the disclosed biocides.
  • the compositions and methods provided herein are important because they allow whole blood critical care analyzers (WBCCAs) having enzyme-based biosensors to efficiently perform readings on biological samples in the presence of biocidal reagents that do not negatively impact the function of the enzymatic biosensors.
  • WBCCAs whole blood critical care analyzers
  • WBCCAs were used only to measure blood gases, electrolytes, and CO- Oximetry, which made it relatively straightforward to select a biocide that was compatible for use in these assays.
  • the assay repertoire of WBCCAs was expanded to include metabolites such as glucose, lactate, creatinine, creatine, and the like, it became very difficult to identify biocides that were compatible with these assays because they generally include enzyme- based biosensors, and the enzymes that are incorporated into these biosensors are inactivated by most biocidal agents.
  • Creatininase also known as creatinine amidohydrolase or creatinine hydrolase, is a Zn 2+ - ion dependent hexamer that catalyzes the hydrolysis of creatinine to creatine. Creatinase, also known as creatine aminohydrolase, catalyzes the hydrolysis of creatine to sarcosine and urea. Sarcosine oxidase requires FAD (flavin adenine dinucleotide) and catalyzes the oxidative demethylation of sarcosine (/V-methylglycine) to glycine.
  • FAD flavin adenine dinucleotide
  • Current creatinine sensors in a creatine/creatinine system include an enzymatic biosensor containing these three enzymes, which are immobilized on the surface of a platinum electrode.
  • the creatinine detection system is based on the following three enzyme cascade reaction (Rx): creatinine + FhO creatine (Rx. 1) creatinase creatine + FhO sarcosine + urea (Rx. 2) sarcosine oxidase sarcosine + FhO + O 2 ⁇ glycine + formaldehyde + H 2 O 2 (Rx. 3)
  • the product hydrogen peroxide (H2O2) is then electrochemically oxidized on the platinum electrode under the constant polarization potential, and the current signal is proportional to the analyte concentration.
  • the presence of creatine in clinical samples necessitates an additional sensor for creatine measurement to correct for the creatine response of the creatinine sensor.
  • the creatine sensor includes only reactions (2) and (3) of the above enzyme cascade reactions.
  • Both the creatine and creatinine sensors have a diffusion control membrane (also referred to as an outer membrane) on top of the enzyme layers.
  • the diffusion control membrane limits the flux of creatinine and creatine substrates entering the enzyme layer to ensure that the signals generated by the hydrogen peroxide are proportional to the substrate concentrations of the sample.
  • Calibration systems for a creatine sensor or biosensor may involve a 2-point calibration based on the following equation:
  • DI2 is a current signal measured on the creatine sensor in a first calibration solution (CS2).
  • CR CS2 is the concentration of creatine in the first calibration solution (CS2).
  • CS2 may have a known concentration of creatine (CR CS2), a known concentration of creatinine (CREA CS2), and a stable ratio of creatine to creatinine, which makes it possible to establish a creatine sensor sensitivity (Slope) for the creatine sensor.
  • a calibration system for a creatinine sensor or biosensor may implement a 3-point calibration methodology.
  • the creatinine sensor provides readings of both creatinine and creatine in biological samples or calibration solutions containing both analytes
  • the sensitivities of the creatinine sensor to creatinine (Slope 1) or creatine (Slope2) may be determined according to the disclosure, as defined below, from equations 2-5 below.
  • the disclosure provides that two calibration solutions with distinct ratios of creatine/creatinine may be used for the 3 -point calibration method.
  • DI2’ [CREA_CS2]*Slopel + [CR_CS2]*Slope2 (Eq. 2)
  • DI3’ [CREA CS3 ] * Slope 1 + [CR_CS3]*Slope2 (Eq. 3)
  • DI2’ and DI3’ are current signals measured on creatinine sensor in a first calibration solutions (CS2) and a second calibration solution (CS3), respectively.
  • CS3 may have an initial known creatine concentration (CR CS3), an initial known creatinine concentration (CREA CS3) and an unstable ratio of creatine to creatinine.
  • [CREA CS2], [CREA CS3], [CR CS2] and [CR CS3] represent the initial known concentrations of creatinine and creatine in calibration solutions CS2 and CS3, respectively.
  • the sensitivity of the creatinine sensor for creatinine and creatine, Slope 1 (sensor sensitivity to creatinine) and Slope2 (sensor sensitivity to creatine), can be derived from Eq. 2 and 3 :
  • 5,506,216 identified several biocidal agents including o-phenylphenol, Densil P [dithio-2,2'-bis(benzmethylamide)], [1,2- benzisothiazolin-3-thion](Proxel), methylenebisthiocyanate, cyanate, hydroxyquinoline, Carbendazim [-methoxycarbonylamino-benzimidazol] and Dazomet[3,5-dimethyltetrahydro- l,3,5-thiodiazin-2-thion] and found that these agents could function as biocides that do not interact with proteins, but only if they were complexed with cyclodextrins. Consistent with these, few, if any, of these biocides are compatible with creatininase, creatinase and sarcosine oxidase based sensors.
  • the creatininase enzyme biosensor active site consists of a narrow, hydrophobic cleft (Yoshimoto et ah, 2004. Journal of Molecular Biology), and it is believed that binding of the creatine substrate to the creatininase enzyme may be prevented by denaturation of the enzyme by small, non-polar molecules such as occur in the biocide compositions disclosed herein.
  • a biocide composition compatible with the enzyme biosensors is a combination of sulfa drugs with another sulfa drug (see e.g., US Patent No. 9,029,118), or any other compatible biocide disclosed herein.
  • the sulfa drug(s) may be present at a concentration of from about 0.05 g/L to about 20 g/L, about 0.3 g/L to about 10 g/L, about 0.3 g/L to about 5 g/L, and the like. It is contemplated within the scope of the disclosure that a biocide composition compatible with the enzyme biosensors may be a combination of sulfa drugs with any other of the compounds disclosed herein.
  • a biocide composition compatible with the enzyme biosensors is a combination of between about 100 to about 1,000 micrograms per milliliter of sulfathiazole and between about 20 to about 2,000 micrograms per milliliter of quinacrine hydrochloride (see e.g., US Patent No. 3,689,646).
  • a biocide composition compatible with enzyme biosensors is a combination of sulfadimethoxine and ormetoprim in a weight ratio of sulfadimethoxine to ormetoprim of 5:1 (see e.g., US Patent No. 5,135,924).
  • a biocide composition compatible with enzyme biosensors is about 125 to about 1,000 pg/ml of the penicillins (e.g., amoxycillin, carbenicillin, benzyl penicillin, piperacillin, ceftazidime, and the like) and between about 5 and 500 pg/ml of clavulanic acid (see e.g., US Patent No. 4,526,783).
  • the penicillin is carbenicillin.
  • a biocide composition compatible with enzyme biosensors may include carbenicillin at a concentration of between about 100 and about 1,000 pg/ml and nitrofurantoin at a concentration of between about 100 and about 500 pg/mL (see e.g., US Patent No 5,741,663).
  • a biocide composition compatible with enzyme biosensors may include carbenicillin at a concentration of about 200 pg/mL a concentration of nitrofurantoin of about 100 pg/mL.
  • a biocide composition compatible with enzyme biosensors may include about 100 mg/L to about 1,000 mg/L spectinomycin or streptomycin (see e.g., US Patent No. 8,466,345). In an embodiment, a biocide composition compatible with enzyme biosensors may include about 300 mg/L spectinomycin or streptomycin.
  • a biocide composition compatible with enzyme biosensors may include between about 100 and about 1,000 pg/ml of ceftazidime (US Patent No. 8,501,457).
  • a biocide composition compatible with enzyme biosensors may include between about 50 pg/ml and about 1,000 pg/ml of streptomycin (United States Patent No. 5202427). In an embodiment, a biocide composition compatible with enzyme biosensors may include about 100 pg/ml of streptomycin
  • a biocide composition compatible with enzyme biosensors is about 1 and about 100 ppm for polymyxin B (United States Patent No. 5283005).
  • a biocide composition compatible with enzyme biosensors includes about 0.35 mg/L of polymyxin B (United States Patent No. 6368847).
  • a biocide composition compatible with enzyme biosensors may include polymyxin E (CAS No. 1066-17-7) at a concentration of between about 5 mg/L and about 200 mg/L (United States Patent No. 7960164).
  • a biocide composition compatible with enzyme biosensors may include polymyxin E (CAS No. 1066-17-7) at a concentration of about 10 mg/L, about 15 mg/L, about 20 mg/L, about 25 mg/L, about 30 mg/L, about 35 mg/L, about 40 mg/L, about 45 mg/L, or about 50 mg/L.
  • a biocide composition compatible with enzyme biosensors is Vantocil IB in a w/v of 0.1-0.5% in aqueous solution (United States Patent No. 6841527).
  • kits containing agents of this disclosure for use in the methods of the present disclosure.
  • Kits of the instant disclosure may include one or more containers comprising one or more biocidal agents in one or more solutions (e.g., Process Control Solutions (PCS) including, but not limited to, PCS-A, PCS-B, PCS-C, PSC-D, and the like).
  • PCS Process Control Solutions
  • Exemplary containers may include bags, glass ampules (e.g., sold as quality control solutions), and the like including solutions for calibrating and/or measuring a creatine and/or creatinine via enzymatic biosensor(s).
  • the kits further include instructions for use in accordance with the methods of this disclosure.
  • these instructions comprise a description of how to apply the biocide agents/solutions to a WBCCA according to any of the methods of the disclosure. In some embodiments, the instructions comprise a description of how to install and calibrate a measuring system in the presence of a biocidal reagent as disclosed herein.
  • the instructions generally include information as to biocide reagent/solution concentration, reagent/solution ratio, shelf life, etc.
  • Instructions supplied in the kits of the instant disclosure are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • the label or package insert indicates that the reagents/solutions may be used to calibrate any of a variety of creatine and/or creatinine sensor(s) for use in a measuring system as described herein. Instructions may be provided for practicing any of the methods described herein, for example, to install and calibrate a measuring system.
  • kits of this disclosure are in suitable packaging.
  • suitable packaging includes, but is not limited to, vials, ampules, bottles, carboys, jars, flexible packaging (e.g., sealed Mylar or plastic bags), foil laminate bags, and the like.
  • flexible packaging e.g., sealed Mylar or plastic bags
  • foil laminate bags e.g., foil laminate bags, and the like.
  • packages for use in combination with a specific device such as GEM Premier whole blood analyzer family (Instrumentation Laboratory, Bedford, MA).
  • At least one active agent in the reagent or solution includes, but is not limited to, Levofloxacin, Carbenicillin disodium, Spectinomycin, Piperacillin, Ceftazidime, Streptomycin, Polymyxin B, Polymyxin E, Sulfanilamide, Sulfathiazole sodium, Sulfadimethoxine, Vantocil IB, and the like.
  • Kits may optionally provide additional components such as buffers and interpretive information.
  • the kit comprises a container and a label or package insert(s) on or associated with the container.
  • Example 1 Large Molecular Weight Biocides Do Not Inhibit or Inactivate Enzyme Biosensors
  • Polymyxin B and Polymyxin E were compatible with a ChemSTAT creatinine sensor that utilized two hydrolase class enzymes (e.g., creatininase and creatinase) and sarcosine oxidase to measure creatinine.
  • FIG. 2A shows a typical plot of creatinine and creatine slopes over time when MIT (methyl isothiazolinone) was added to PCS at 300 mg/L after establishing reasonably stable slopes (e.g., slope >400 for creatinine and >200 for creatine) for more than a week.
  • the plot shows that adding MIT caused all three slopes to drop to zero in less than one day.
  • MIT is the most common biocide used in the blood gas industry for microbial contamination, and is known to be compatible with oxidase class enzymes such as glucose oxidase and lactate oxidase.
  • FIG. 2 clearly shows that hydrolase enzymes or sarcosine oxidase were more vulnerable to inhibition leading to the performance loss of creatinine sensor.
  • FIG. 3 shows example plots of creatinine slope performances over time in PCS with colistin (left) and gentamicin (right) showing that sensors maintained sufficient creatinine slope for a full use life of three weeks.
  • the creatinine slope performed equivalently with colistin in PCS bags (see FIG. 3, left) to cartridges with PCS bags protected only with gentamicin (see FIG. 3, right).
  • no bacterial contamination was observed on control or test biocide PCS bags nor was there any evidence of enzyme inhibition and therefore performance is similar.
  • FIGS. 4 A and 4B are graphs showing the effects of colistin spiked into the main calibration/wash solution(s) of either blood samples (FIG. 4A) or clinical specimens (FIG. 4B), which demonstrate excellent correlation to the above-described reference methods.
  • Example 2 Long Term Effect of Efficacious Biocides on Creatinine and Creatine Slopes Antimicrobial efficacy was established by independent assays, and the data is presented in Table 1 below.
  • the B bag was protected with 40 mg/L colistin sulfate and 40 mg/L of amikacin, an aminoglycoside currently used in several GEM cartridge bags at 200 mg/L.
  • Table 1 ATCC 9027 Pseudomonas aeruginosa at an estimated inoculum size of 100,000 cfu/mL.
  • Creatinine, BUN, tCCb, and Hct had passed calibration verification and there were no detected intelligent quality management errors all slopes and drifts, including Creatinine and Creatine, behaved normally
  • Glucose in high glucose low oxygen aqueous showed no decrease in recovery (indicating no loss of pCk): Glu >384 mg/dL on all 3 cartridges vs lower limit ⁇ 350 mg/dL. • Linearity was good for all enzyme sensors (Crea, BUN, Glu, Lac) based on aqueous controls levels 1 - 5
  • enzyme compatible biocides may be identified in a variety of ways.
  • a biocide candidate may be injected into, for example, one PCS-B bag after about one week of cartridge use life, and then any changes in sensor slopes over the next week or two, especially any increase in the rate of slope decrease, may be observed. During this time, aqueous solutions with high substrate concentrations may be tested to ensure that enzymes are still able to convert all substrate to products in the allotted time (e.g., about one minute).
  • multiple cartridges assembled with, for example, PCS-B bags containing a candidate biocide may be tested for a prolonged period of time (e.g., 20-30 days) that corresponds to the useful cartridge lifespan (which may vary depending upon the cartridge type tested).
  • the cartridge starts the hydration process, which generally lasts about 50 minutes, with the biocide already in the solution bag (e.g., PCS-B).
  • At least 3 cartridges may generally be tested, and a control cartridge(s) that does not contain the test substance in the solution bag (e.g., PCS-B) may also be included.
  • a control cartridge(s) that does not contain the test substance in the solution bag e.g., PCS-B
  • whole human blood may also be tested in order to simulate normal customer use.
  • biocidal reagents with a molecular weight (MW) greater than 320 do not inhibit or prevent enzymatic biosensor function.
  • exemplary efficacious biocidal reagents that do not inhibit or prevent the function of enzymatic biosensors include, but are not limited to, Levofloxacin, Carbenicillin disodium, Spectinomycin, Piperacillin, Ceftazidime, Streptomycin, Polymyxin B, Polymyxin E, Sulfanilamide, Sulfathiazole sodium, Sulfadimethoxine, Vantocil IB, and the like.

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Abstract

La présente invention concerne des compositions biocides compatibles avec des biocapteurs enzymatiques et leurs procédés d'utilisation. Plus particulièrement, l'invention concerne des compositions biocides compatibles avec des enzymes utilisées pour mesurer des taux de créatine et de créatinine.
PCT/US2019/058009 2019-10-25 2019-10-25 Compositions biocides compatibles avec des biocapteurs enzymatiques et leurs procédés d'utilisation WO2021080598A1 (fr)

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PCT/US2019/058009 WO2021080598A1 (fr) 2019-10-25 2019-10-25 Compositions biocides compatibles avec des biocapteurs enzymatiques et leurs procédés d'utilisation
CN201980103233.5A CN114846332A (zh) 2019-10-25 2019-10-25 与酶生物传感器相容的杀生物剂组合物及其使用方法
EP19804990.0A EP4049036A1 (fr) 2019-10-25 2019-10-25 Compositions biocides compatibles avec des biocapteurs enzymatiques et leurs procédés d'utilisation

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US4526783A (en) 1974-04-20 1985-07-02 Beecham Group P.L.C. Antibiotic from S. clavuligerus
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