IL294577A - Systems and methods for determining the suitability of preparations to prevent the growth of multi-bacterial samples - Google Patents

Systems and methods for determining the suitability of preparations to prevent the growth of multi-bacterial samples

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Publication number
IL294577A
IL294577A IL294577A IL29457722A IL294577A IL 294577 A IL294577 A IL 294577A IL 294577 A IL294577 A IL 294577A IL 29457722 A IL29457722 A IL 29457722A IL 294577 A IL294577 A IL 294577A
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IL
Israel
Prior art keywords
sample
polymicrobial
testing
organisms
resistance
Prior art date
Application number
IL294577A
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Hebrew (he)
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Cap Diagnostics Llc Dba Pathnostics
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Publication date
Priority claimed from US17/178,091 external-priority patent/US20210172000A1/en
Priority claimed from PCT/US2021/027336 external-priority patent/WO2021211746A1/en
Priority claimed from US17/335,767 external-priority patent/US11746371B2/en
Application filed by Cap Diagnostics Llc Dba Pathnostics filed Critical Cap Diagnostics Llc Dba Pathnostics
Publication of IL294577A publication Critical patent/IL294577A/en

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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
    • G—PHYSICS
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    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/04—Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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    • C12Q1/04—Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor
    • C12Q1/06—Quantitative determination
    • C12Q1/08—Quantitative determination using multifield media
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria
    • G—PHYSICS
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/59—Transmissivity
    • G01N21/5907—Densitometers
    • G01N2021/5915—Processing scan data in densitometry
    • G01N2021/593—Correcting from the background density
    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769—Measurement method of reaction-produced change in sensor
    • G01N2021/7786—Fluorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G—PHYSICS
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Description

METHODS AND SYSTEMS FOR DETERMINING SUITABILITY OF COMPOSITIONS FOR INHIBITING GROWTH OF POLYMICROBIAL SAMPLES CROSS-REFERENCES TO RELATED APPLICATIONS id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1"
[0001] This application claims priority to U.S. Patent Application No. 17/178,091 filed February 17, 2021, PCT Application No. PCT/US21/27336 filed April 14, 2021, U.S. Patent Application No. 17/335,767 filed June 1, 2021, U.S. Provisional Application No. 63/195,502 filed June 1, 2021, and U.S. Provisional Application No. 63/251,433 filed October 1, 2021, the specifications of which are incorporated herein in their entirety by reference.
BACKGROUND OF THE INVENTION Field of the Invention id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2"
[0002] The present application is related to methods and systems for identifying polymicrobial samples, e.g., polymicrobial infections, as well as methods of determining suitability of one or more compositions for inhibiting growth of the polymicrobial sample, e.g., providing information related to the likelihood of success of inhibiting growth of the polymicrobial sample with the one or more compositions. The present application also describes methods for providing information to a user regarding the polymicrobial sample, such as but not limited to information regarding the suitability of the compositions for inhibiting growth of a polymicrobial sample.
Background Art id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3"
[0003] Infectious diseases can affect multiple organ systems and are responsible for significant morbidity, mortality, and economic impact. Infectious agents most often present as a complex polymicrobial infections rather than as a single pathogen infection. Within the body, these polymicrobial infections cooperate with each other through various interactions changing both the type of antibiotics the organisms are susceptible to but also the level of antibiotics required to treat the infection as well as the virulence of the individual pathogens. id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4"
[0004] The present application describes methods for determining suitability of one or more compositions for inhibiting growth of the polymicrobial sample, e.g., providing information related to the likelihood of success of inhibiting growth of the polymicrobial sample with the one or more compositions. The present application also describes methods of providing information related to the suitability of one or more compositions for inhibiting growth of the polymicrobial sample. id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5"
[0005] The present invention describes culture-independent approaches to detecting and identifying bacteria, such as a multiplex PCR-based method (DNA-based) (M-PCR). For example, 1 DynamicPDF for .NET v8.0.0.40 (Build 29393)Evaluating unlicensed DynamicPDF feature. Click here for details. [4:0:v8.0] M-PCR, does not require growth and targets uropathogenic species. M-PCR provides semi quantitative information that is comparable to culture and is presented in ranges such as < 9,999 cells/mL, 10,000 – 49,999 cells/mL, 50,000 – 99,999 cells/mL, and > 100,000 cells/mL. Once again, the number of cells/mL is comparable to CFU’s. The vast majority of uropathogens identified by M-PCR are found at concentrations > 100,000 cells/mL demonstrating that detection is not due to the increased sensitivity with respect to PCR; instead is due to the inability of SUC to detect the bacteria. The concentration of the non-culturable organisms is on par with those that are culturable. In a large prospective trial of symptomatic patients, these uropathogens detected by M-PCR were found to be linked to symptomology. id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6"
[0006] The present invention also describes Pooled Antibiotic Susceptibility Testing (P-AST), (U.S. Pat. No. 10,160,991, the specification of which is incorporated herein in its entirety by reference), which involves simultaneously growing all detected bacteria together in the presence of antibiotics and then measuring susceptibility. Thus, P-AST considers interactions between cohabiting bacterial species and may serve as a more accurate predictor of antibiotic susceptibility. id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7"
[0007] The present invention also describes genotypic antibiotic resistance (ABR) testing, wherein the bacteria of the polymicrobial infection are tested for particular genetic markers. The odds of resistance of the polymicrobial infection to particular antibiotics are applied to determine appropriate therapeutic solutions. id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8"
[0008] The present invention describes the use of said methods and systems for identifying polymicrobial infections in urine, identifying or providing therapeutic solutions for treating said polymicrobial infections in the urine. For example, the present invention provides methods and systems for allowing the rapid identification of UTIs, and the rapid identification of a treatment solution for the UTIs. The present invention is not limited to polymicrobial infections associated with urine.
BRIEF SUMMARY OF THE INVENTION id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9"
[0009] Disclosed herein are methods of determining suitability of one or more compositions for inhibiting growth of the polymicrobial sample, e.g., providing information related to the likelihood of success of inhibiting growth of the polymicrobial sample with the one or more compositions.
The present application also describes methods for providing information to a user regarding the polymicrobial sample, such as but not limited to information regarding the suitability of the 2 DynamicPDF for .NET v8.0.0.40 (Build 29393)Evaluating unlicensed DynamicPDF feature. Click here for details. [4:0:v8.0] compositions for inhibiting growth of a polymicrobial sample (e.g., statistics or information about the likelihood of success in inhibiting growth of a polymicrobial infection with particular compositions or therapeutic solutions, etc.). The present invention also describes the documents, presentation, or other media for providing said information to the user. id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10"
[0010] The present invention also features methods for detection and identification of organisms of the polymicrobial sample (e.g., polymicrobial infection), phenotypic pooled sensitivity tests for determining the susceptibility or resistance of the polymicrobial sample (e.g., polymicrobial infection) in the sample to an antibiotic or other therapeutic agent, and identification of resistance genes, e.g., genetic markers that may indicate resistance to a particular treatment. Together, the data can be applied against databases of antibiotic/therapeutic susceptibility or resistance for particular known polymicrobial samples (e.g., polymicrobial infections) in order to provide information related to the likelihood of success of one or more therapeutic solutions for the polymicrobial sample (e.g., polymicrobial infection). The present invention also features methods and systems for identifying polymicrobial infections and identifying or providing therapeutic solutions for polymicrobial infections. The present invention also features methods and systems for treating polymicrobial infections. id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11"
[0011] The methods herein feature: (1) detection and identification of organisms (e.g., bacteria or other infectious agents) of the polymicrobial infection, (2) pooled antibiotic susceptibility tests for determining the susceptibility or resistance of the polymicrobial infection in the sample to an antibiotic or other therapeutic agent, and (3) identification of resistance genes in the infectious agents in the polymicrobial infection, e.g., genetic markers that may indicate resistance to a particular antibiotic or other therapeutic agent or treatment. Together, the data from (1), (2), and (3) can be applied (e.g., using databases of antibiotic/therapeutic susceptibility or resistance for particular known polymicrobial infections) in order to provide one or more therapeutic solutions for the polymicrobial infection. id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12"
[0012] In some embodiments, the organisms are bacteria. The present invention is not limited to bacterial infectious agents and may include viruses, fungi, protozoa, bacteria, or a combination thereof. id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13"
[0013] The present invention describes a method for providing a therapeutic solution to treat polymicrobial infection or suspected polymicrobial infection in a patient. In some embodiments the method comprises subjecting a portion of a sample obtained from a source of the 3 DynamicPDF for .NET v8.0.0.40 (Build 29393)Evaluating unlicensed DynamicPDF feature. Click here for details. [4:0:v8.0] polymicrobial infection in the patient to genetic identification testing to detect and identify one or more organisms in the sample. The method may further comprise subjecting a portion of the sample to genetic resistance marker testing to detect and identify one or more resistance genes in the organisms identified (e.g., resistance genes that confer resistance to one or more therapeutic agents). The method may further comprise subjecting a portion of the sample to pooled phenotypic antibiotic resistance testing (pooled susceptibility testing), wherein phenotypic antibiotic resistance testing either or both: identifies one or more therapeutic agents to which the polymicrobial infection is resistant, and/or identifies one or more therapeutic agents to which the polymicrobial infection is susceptible. The one or more organisms of the polymicrobial infection in the sample are not first isolated before phenotypic antibiotic resistance testing. The method may further comprise applying the results from genetic identification testing, genetic resistance marker testing, and pooled antibiotic susceptibility testing to a database, e.g., predetermined thresholds of a database. The analysis identifies one or more therapeutic agents that are effective for treating the polymicrobial infection (e.g., a "therapeutic solution"). id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14"
[0014] The present invention also features a method for treating a polymicrobial infection or suspected polymicrobial infection in a patient in need thereof. In some embodiments, the method comprises subjecting a portion of a sample obtained from a source of the polymicrobial infection in the patient to genetic identification testing to detect and identify one or more organisms in the sample. The method may further comprise subjecting a portion of the sample to genetic resistance marker testing to detect and identify one or more resistance genes in the organisms identified (e.g., resistance genes that confer resistance to one or more therapeutic agents). The method may further comprise subjecting a portion of the sample to pooled phenotypic antibiotic resistance testing, wherein phenotypic antibiotic resistance testing either or both: identifies one or more therapeutic agents to which the polymicrobial infection is resistant, and/or identifies one or more therapeutic agents to which the polymicrobial infection is susceptible. The one or more organisms of the polymicrobial infection in the sample are not first isolated before phenotypic antibiotic resistance testing. The method may further comprise applying the results from genetic identification testing, genetic resistance marker testing, and pooled antibiotic susceptibility testing to a database, e.g., predetermined thresholds of a database. The analysis identifies one or more therapeutic agents that are effective for treating the polymicrobial infection (e.g., a "therapeutic solution"). The method may further comprise administering at least one therapeutic agent identified to the patient, wherein the at least one therapeutic agent is effective for treating the polymicrobial infection. 4 DynamicPDF for .NET v8.0.0.40 (Build 29393)Evaluating unlicensed DynamicPDF feature. Click here for details. [4:0:v8.0] id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15"
[0015] The database that indicates which therapeutic agents are effective for treating a number of different polymicrobial infections may be generated by a compilation of results of phenotypic antibiotic resistance testing, genetic resistance marker testing for a plurality of different polymicrobial infections. id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16"
[0016] In certain embodiments, the therapeutic solution may comprise one applicable therapeutic agent. In some embodiments, the therapeutic solution comprises two or more applicable therapeutic agents. In some embodiments, the therapeutic solution comprises three or more applicable therapeutic agents. In some embodiments, the therapeutic solution comprises four or more applicable therapeutic agents. In some embodiments, the therapeutic solution comprises five or more applicable therapeutic agents. id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17"
[0017] With reference to any of the embodiments herein, the method may further comprise compiling a data set that includes one or more data points selected from: (i) results of phenotypic antibiotic resistance testing, (ii) results of genetic identification testing, (iii) results of genetic resistance marker testing, (iv) therapeutic agents to which the polymicrobial infection is expected to have increased resistance, (v) therapeutic agents to which the polymicrobial infection is expected to have decreased resistance, (vi) suggested therapeutic agents, and (vii) formulation of suggested therapeutic agents. id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18"
[0018] In certain embodiments, the method further comprises generating a report that communicates the data set. In certain embodiments, the report features a chart and/or a table and/or a diagram. In certain embodiments, the method further comprises providing the report to a medical professional, wherein the report communicates recommendations for treatment for the patient. id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19"
[0019] In certain embodiments, the method further comprises measuring a number or concentration of organisms present in the sample. In some embodiments, the method further comprises Extended-Spectrum Beta-lactamase (ESBL) testing. In some embodiments, the method further comprises testing for genes associated with Clostridium difficile. In some embodiments, the method further comprises determining a microbial inhibitory concentration (MIC) for organisms of the polymicrobial infection. id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20"
[0020] In certain embodiments, the genetic identification testing comprises PCR, fluorescence in situ hybridization (FISH), culture, mass spectrometry, electrochemical biosensing, automated biochemical identification, flow cytometry, or a combination thereof. In certain embodiments, the DynamicPDF for .NET v8.0.0.40 (Build 29393)Evaluating unlicensed DynamicPDF feature. Click here for details. [4:0:v8.0] genetic resistance marker testing comprises PCR or sequencing. In certain embodiments, the pooled phenotypic antibiotic resistance testing comprises introducing fractions of the portion of the sample to one or more media samples, each media sample comprising a therapeutic agent, incubating (e.g., under conditions suitable for growth) the media samples with the fractions, and subsequently measuring viability of organisms in the media samples after incubation. In certain embodiments, the media samples are in test tubes, wells of a culture plate, an agar plate, or a microscope slide. In certain embodiments, the viability of the organisms is measured by optical density (OD), fluorescence, or chemiluminescence. id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21"
[0021] In certain embodiments, the sample has at least one resistance marker. In certain embodiments, the sample has at least 2 resistance markers. In certain embodiments, the sample has at least 3 resistance markers. In certain embodiments, the at least one resistance marker is a mecA gene, a vanA/B gene, a TEM gene, a SHV gene, a OXA gene, a CTX-M gene, a KPC gene, a NDM gene, an OXA gene, a VIM gene, an IMP gene, or a combination thereof. In certain embodiments, the one or more resistance genes is ErmA + Erm B, TEM,CTX-M group 1, SHV, VEB, OXA-1, CTX-M group 2, CTX-M group 9, CTX-M group 8/25, PER-1, PER-2, GES, blaNDM- 1, VIM, KPC, IMP-2 group, IMP-1 group, OXA-23, IMP-16, IMP-7, OXA-72, OXA-40, OXA-58, OXA-48, NDM, blaOXA-48, QnrA, QnrB, mecA, ampC, FOX, ACC, DHA, MOX/CMY, BIL/LAT/CMY, vanA1, vanA2, vanB, vanC1, or vanC2-C3-2. id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22"
[0022] Non-limiting examples of organisms that may be tested for and/or present in the polymicrobial infection include: one or a combination of: Acinetobacter baumannii, Actinotignum schaalii, Aerococcus urinae, Aerococcus urinae, Alloscardovia omnicolens, Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Chlamydia, Citrobacter freundii, Citrobacter koseri, Clostridium difficile, Corynebacterium riegelii, Klebsiella aerogenes, Enterococcus faecalis, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Mycobacterium tuberculosis, Mycoplasma genitalium, Mycoplasma hominis, Neisseria gonorrhoeae, Pantoea agglomerans, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, coagulase-negative Staphylococcus, Streptococcus agalactiae, Streptococcus pyogenes, Viridans Group Streptococcus, Trichomonas vaginalis, Ureaplasma urealyticum, HHV-6, HHV-7, BK Virus, JC Virus, HSV 1&2, Adenovirus, or CMV. id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23"
[0023] In some embodiments, the therapeutic agent is one or a combination of a: penicillin, tetracycline, cephalosporin, quinolone, lincomycin, macrolide, sulfonamide, glycopeptide 6 DynamicPDF for .NET v8.0.0.40 (Build 29393)Evaluating unlicensed DynamicPDF feature. Click here for details. [4:0:v8.0] antibiotic, aminoglycoside, carbapenem, annamycin, lipopeptide, Fosfomycin, monobactam, nitrofuran, oxazolidinone, amphotericin B, Isavuconazole, itraconazole, micafungin, Posaconazole, voriconazole, cidofovir, vidarabine, foscarnet, acyclovir, valacyclovir, or a combination thereof. id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24"
[0024] In some embodiments, the polymicrobial infection comprises 2 or more organisms In some embodiments, the polymicrobial infection comprises 3 or more organisms. In some embodiments, the polymicrobial infection comprises 4 or more organisms. In some embodiments, the polymicrobial infection comprises 5 or more organisms. In some embodiments, the polymicrobial infection comprises 6 or more organisms. In some embodiments, the polymicrobial infection comprises 7 or more organisms. id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25"
[0025] In certain embodiments, the presence of two or more organisms in the polymicrobial infection changes sensitivity of the polymicrobial infection to antibiotics or therapeutic agents known to be effective against at least one of the organisms present in the polymicrobial infection individually. id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26"
[0026] The present invention also provides a workflow method for preparing a therapeutic solution for a patient having or suspected of having a polymicrobial infection. The method may comprise one or more of the steps described herein, for example subjecting a portion of the sample to a genetic identification testing, subjecting a portion of the sample to genetic resistance marker testing, and subjecting a portion of the sample to pooled antibiotic susceptibility testing. id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27"
[0027] In certain embodiments, the sample comprises urine, blood, plasma, cerebrospinal fluid, saliva, sputum, pulmonary lavage, vaginal secretions, wound lavage, biopsy tissue, wound swab, rectal swab, nasal swab, tissue, fecal matter, sperm sample, semen sample, or prostate fluid. id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28"
[0028] With reference to any of the embodiments herein, the steps described herein may be performed in any order, or simultaneously. id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29"
[0029] Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art. Additional advantages and aspects of the present invention are apparent in the following detailed description and claims. 7 DynamicPDF for .NET v8.0.0.40 (Build 29393)Evaluating unlicensed DynamicPDF feature. Click here for details. [4:0:v8.0] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S) id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30"
[0030] The features and advantages of the present invention will become apparent from a consideration of the following detailed description presented in connection with the accompanying drawings in which: id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31"
[0031] FIG. 1 shows a schematic view of mutualism between particular bacteria. id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32"
[0032] FIG. 2 shows the frequency of which certain resistance genes are found together. The strength of the correlation is represented by the width of the edge connecting the genes. Only correlations greater than 0.1 are shown. id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33"
[0033] FIG. 3 shows a comparison between the frequency polymicrobial infections are determined to be phenotypically sensitive yet genotypically resistant to an antibiotic (or vice versa), e.g., how often the phenotypic and genotypic sensitivity results disagree (n=764 symptomatic patients with polymicrobial infection and phenotype data). id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34"
[0034] FIG. 4 shows an example of a report comprising one or more therapeutic solutions for a particular polymicrobial infection. id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35"
[0035] FIG. 5 shows a comparison of symptom resolution in patients treated based on methods of the present invention ("Guidance UTI test"), patients treated empirically, and untreated patients. id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36"
[0036] FIG. 6 shows the numbers of patients testing positive to various bacteria by culture or PCR (all patients, n=2511). id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37"
[0037] FIG. 7 shows bacteria detected in polymicrobial infections in the study. id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38"
[0038] FIG. 8 shows the distribution of bacteria detected in the 68.6% (1710/2493) of patients who were positive for bacteria showing the distribution of organisms in monomicrobial, polymicrobial, and consortia mixtures. id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39"
[0039] FIG. 9 shows a network diagram of the relationships among the bacteria found most frequently in consortia id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40"
[0040] FIG. 10 shows detection rates for Gram-positive and Gram-negative bacteria in monomicrobial and polymicrobial infections and in consortia. id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41"
[0041] FIG. 11 shows the odds ratios of antibiotic resistance in polymicrobial versus monomicrobial specimens, along with the odds ratio of resistance for each increase in the number of bacterial species in polymicrobial specimens. id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42"
[0042] FIG. 12 shows the effects of organism interactions on antibiotic resistance. An upward arrow indicates an increase in resistance. A downward arrow indicates a decrease in resistance (an increase in sensitivity). id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43"
[0043] FIG. 13 shows the effects of E. coli and K. pneumoniae interactions on resistance to 8 DynamicPDF for .NET v8.0.0.40 (Build 29393)Evaluating unlicensed DynamicPDF feature. Click here for details. [4:0:v8.0] ampicillin/sulbactam, cefaclor, and tetracycline (p = 0.05). id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44"
[0044] FIG. 14 depicts an exemplary Antibiotic Source Plate with well contents and antibiotic concentration (µg/mL). Nitro = nitrofurantoin, Cipro = ciprofloxacin, Mero = meropenem, Ceftiaxone = ceftriaxone, TMP/SMX = trimethoprim + sulfamethoxazole, Pip/Tazo = piperacillin + tazobactam, Levo = levofloxacin, Cefoxitin = cefoxitin, Tetra = tetracycline, Amp/Sulb = ampicillin + sulbactam, Amp = ampicillin, and Vanco = vancomycin. id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45"
[0045] FIG. 15 depicts an exemplary Antibiotic Source Plate with well contents and antibiotic concentration (µg/mL). Cefazolin = cefazolin, Cefepime = cefepime, Ceftazidime = ceftazidime, Gentamicin = gentamicin, Amox/Clav = amoxicillin + clavulanate, Cefaclor = cefaclor. id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46"
[0046] FIG. 16 shows the concordance between the presence of antibiotic resistance genes (ABR) detected by multiplex polymerase chain reaction (M-PCR) and antibiotic susceptibility detected by pooled antibiotic susceptibility testing (P-AST) of urine samples from symptomatic patients with urinary tract infection (UTI). The dashed line represents the weighted average concordance across all samples (60%). Abbreviation: Combo, combination antibiotics, including Ampicillin/Sulbactam, Amoxicillin/Clavulanate, and Piperacillin/Tazobactam. id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47"
[0047] FIG. 17 shows the number of patients (with either polymicrobial infections or monomicrobial infections) having sensitive or resistant ABR genes present for meropenem, piperacillin/tazobactam, or vancomycin. id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48"
[0048] FIG. 18 shows antibiotic resistance by pooled antibiotic susceptibility testing (P-AST) and antibiotic resistance (ABR) gene presence for all 14 antibiotics analyzed. Also shown are detection frequencies and associated average numbers of clinical findings per patient of different consortia detected in the study. Clinical findings are defined as one or more of the following symptoms or abnormal laboratory result, including urinary incontinence, dysuria, gross hematuria, pain/pelvic discomfort, urine cloudiness or strong smell, lower urinary tract symptoms (LUTS), and abnormal urinalysis or dipstick result. id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49"
[0049] FIG. 19 shows the overall concordance between the presence of antibiotic resistance (ABR) genes detected by multiplex polymerase chain reaction and antibiotic susceptibility detected using pooled antibiotic susceptibility testing (P-AST) of urine samples from symptomatic patients with urinary tract infection (UTI).
TERMS id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50"
[0050] As used herein, the term "Highest Single Agent Interaction Principle" refers to a statistical model wherein the resistance of the polymicrobial infection is predicted to be the resistance of the bacteria with the highest resistance. For example, if species A is resistant with a probability 20%, and species B is resistant with a probability 50%, then the probability of resistance of the pool is 9 DynamicPDF for .NET v8.0.0.40 (Build 29393)Evaluating unlicensed DynamicPDF feature. Click here for details. [4:0:v8.0] 50%. id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51"
[0051] As used herein, the term "Union Principle" refers to a statistical model wherein the polymicrobial infection of species A and B is made up of one colony (or one genetic variant) of species A and one colony (or one genetic variant) of species B, and the polymicrobial infection is resistant if either the colony of species A is resistant, or if the colony of species B is resistant. For example, if an antibiotic is applied to the polymicrobial infection, it may kill off species A, but if species B survives, the polymicrobial infection is called resistant. For example, if species A is resistant with a probability 20%, and species B is resistant with a probability 50%, then the ( ) ( ) ( ) probability of resistance of the pool is:

Claims (31)

1. CLAIMED IS: 1. A method for determining suitability of one or more compositions for inhibiting growth of organisms in a polymicrobial sample, the method comprises, in any order or simultaneously: a. subjecting a portion of the sample to genetic identification testing for detecting and identifying one or more organisms in the sample; b. subjecting a portion of the sample to genetic resistance marker testing for detecting and identifying one or more resistance genes in the one or more organisms in the sample, the resistance genes confer resistance to one or more therapeutic agents; c. subjecting a portion of the sample to pooled phenotypic antibiotic resistance testing, wherein phenotypic antibiotic resistance testing either or both: (i) identifies one or more therapeutic agents to which the polymicrobial infection is resistant, and or (ii) identifies one or more therapeutic agents to which the polymicrobial infection is susceptible, wherein the one or more organisms of the polymicrobial infection in the sample are not first isolated before phenotypic antibiotic resistance testing; d. applying testing results from (a), (b), and (c) against a predetermined set of thresholds comprising a database of which antibiotics or therapeutic agents are effective for inhibiting growth of organisms in polymicrobial infections so as to determine suitability of the at least one composition for inhibiting growth of organisms in the polymicrobial sample.
2. The method of claim 1 further comprising compiling a data set that includes one or more data points selected from: (i) results of phenotypic antibiotic resistance testing, (ii) results of genetic identification testing, (iii) results of genetic resistance marker testing, (iv) therapeutic agents to which the polymicrobial infection is expected to have increased resistance, (v) therapeutic agents to which the polymicrobial infection is expected to have decreased resistance, (vi) suggested therapeutic agents, and (vii) formulation of suggested therapeutic agents.
3. The method of claim 1, wherein the genetic identification testing comprises PCR, fluorescence in situ hybridization (FISH), culture, mass spectrometry, electrochemical biosensing, flow cytometry, automated biochemical identification, or a combination thereof. 77
4. The method of claim 1, wherein genetic resistance marker testing comprises PCR or sequencing.
5. The method of claim 1, wherein the pooled phenotypic antibiotic resistance testing comprises introducing fractions of the portion of the sample to one or more media samples, each media sample comprising a therapeutic agent, incubating the media samples with the fractions, and subsequently measuring viability of organisms in the media samples after incubation.
6. The method of claim 1, wherein the media samples are in test tubes, wells of a culture plate, an agar plate, or a microscope slide.
7. The method of claim 1, wherein viability of the organisms is measured by optical density (OD), fluorescence, or chemiluminescence.
8. The method of claim 1, wherein the database comprises a compilation of results of phenotypic antibiotic resistance testing, genetic resistance marker testing for a plurality of different polymicrobial samples.
9. The method of claim 1, wherein the one or more resistance genes is ErmA + Erm B, TEM,CTX-M group 1, SHV, VEB, OXA-1, CTX-M group 2, CTX-M group 9, CTX-M group 8/25, PER-1, PER-2, GES, blaNDM-1, VIM, KPC, IMP-2 group, IMP-1 group, OXA-23, IMP-16, IMP-7, OXA-72, OXA-40, OXA-58, OXA-48, NDM, blaOXA-48, QnrA, QnrB, mecA, ampC, FOX, ACC, DHA, MOX/CMY, BIL/LAT/CMY, vanA1, vanA2, vanB, vanC1, or vanC2-C3-2.
10. The method of claim 1, wherein organisms of the polymicrobial infection are one or a combination of: Acinetobacter baumannii, Actinotignum schaalii, Aerococcus urinae, Aerococcus urinae, Alloscardovia omnicolens, Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Chlamydia, Citrobacter freundii, Citrobacter koseri, Clostridium difficile, Corynebacterium riegelii, Klebsiella aerogenes, Enterococcus faecalis, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Mycobacterium tuberculosis, Mycoplasma genitalium, Mycoplasma hominis, Neisseria gonorrhea, Pantoea agglomerans, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, coagulase- negative Staphylococcus, Streptococcus agalactiae, Streptococcus pyogenes, Viridans Group Streptococcus, Trichomonas vaginalis, Ureaplasma urealyticum, HHV-6, HHV-7, BK Virus, JC Virus, HSV 1&2, Adenovirus, or CMV.
11. The method of claim 1, wherein the composition for inhibiting growth of organisms in a polymicrobial infection is one or a combination of a: penicillin, tetracycline, cephalosporin, 78 quinolone, lincomycin, macrolide, sulfonamide, glycopeptide antibiotic, aminoglycoside, carbapenem, ansamycin, annamycin, lipopeptide, Fosfomycin, monobactam, nitrofuran, oxazolidinone, amphotericin B, isavuconazole, itraconazole, micafungin, Posaconazole, voriconazole, cidofovir, vidarabine, foscarnet, acyclovir, valacyclovir, or a combination thereof.
12. The method of claim 1, wherein the organisms are bacteria, viruses, fungi, protozoa, or a combination thereof.
13. The method of claim 1, wherein the sample comprises urine, blood, plasma, cerebrospinal fluid, saliva, sputum, pulmonary lavage, vaginal secretions, wound lavage, biopsy tissue, wound swab, rectal swab, nasal swab, tissue, fecal matter, sperm sample, semen sample, or prostate fluid.
14. A method of providing information about a polymicrobial sample to a user, the information comprising at least one composition predicted to inhibit growth of organisms in the polymicrobial sample, the method comprises, in any order or simultaneously: a. subjecting a portion of the sample to genetic identification testing for detecting and identifying one or more organisms in the polymicrobial sample; b. subjecting a portion of the sample to genetic resistance marker testing for detecting and identifying one or more resistance genes in the one or more organisms in the sample, the resistance genes confer resistance to one or more therapeutic agents; c. subjecting a portion of the sample to pooled phenotypic antibiotic resistance testing, wherein phenotypic antibiotic resistance testing either or both: (i) identifies one or more therapeutic agents to which the polymicrobial infection is resistant, and or (ii) identifies one or more therapeutic agents to which the polymicrobial infection is susceptible, wherein the one or more organisms of the polymicrobial infection in the sample are not first isolated before phenotypic antibiotic resistance testing; d. applying testing results from (a), (b), and (c) against a predetermined set of thresholds comprising a database of which antibiotics or therapeutic agents are effective for inhibiting growth of organisms in polymicrobial infections so as to identify at least one composition for inhibiting growth of organisms in the polymicrobial sample; e. providing the at least one composition in (d) to a user, the at least one composition being the at least one composition predicted to inhibit growth of organisms in the 79 polymicrobial sample.
15. The method of claim 14 further comprising providing to the user a data set that includes one or more data points selected from: (i) results of phenotypic antibiotic resistance testing, (ii) results of genetic identification testing, (iii) results of genetic resistance marker testing, (iv) therapeutic agents to which the polymicrobial infection is expected to have increased resistance, (v) therapeutic agents to which the polymicrobial infection is expected to have decreased resistance, (vi) suggested therapeutic agents, and (vii) formulation of suggested therapeutic agents.
16. The method of claim 14, wherein the genetic identification testing comprises PCR, fluorescence in situ hybridization (FISH), culture, mass spectrometry, electrochemical biosensing, flow cytometry, automated biochemical identification, or a combination thereof.
17. The method of claim 14, wherein genetic resistance marker testing comprises PCR or sequencing.
18. The method of claim 14, wherein the pooled phenotypic antibiotic resistance testing comprises introducing fractions of the portion of the sample to one or more media samples, each media sample comprising a therapeutic agent, incubating the media samples with the fractions, and subsequently measuring viability of organisms in the media samples after incubation.
19. The method of claim 18, wherein the media samples are in test tubes, wells of a culture plate, an agar plate, or a microscope slide.
20. The method of claim 18, wherein viability of the organisms is measured by optical density (OD), fluorescence, or chemiluminescence.
21. The method of claim 14, wherein the database comprises a compilation of results of phenotypic antibiotic resistance testing, genetic resistance marker testing for a plurality of different polymicrobial samples.
22. The method of claim 14, wherein the one or more resistance genes is ErmA + Erm B, TEM,CTX-M group 1, SHV, VEB, OXA-1, CTX-M group 2, CTX-M group 9, CTX-M group 8/25, PER-1, PER-2, GES, blaNDM-1, VIM, KPC, IMP-2 group, IMP-1 group, OXA-23, IMP-16, IMP-7, OXA-72, OXA-40, OXA-58, OXA-48, NDM, blaOXA-48, QnrA, QnrB, mecA, ampC, FOX, ACC, DHA, MOX/CMY, BIL/LAT/CMY, vanA1, vanA2, vanB, vanC1, or vanC2-C3-2.
23. The method of claim 14, wherein organisms of the polymicrobial infection are one or a combination of: Acinetobacter baumannii, Actinotignum schaalii, Aerococcus urinae, 80 Aerococcus urinae, Alloscardovia omnicolens, Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Chlamydia, Citrobacter freundii, Citrobacter koseri, Clostridium difficile, Corynebacterium riegelii, Klebsiella aerogenes, Enterococcus faecalis, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Mycobacterium tuberculosis, Mycoplasma genitalium, Mycoplasma hominis, Neisseria gonorrhea, Pantoea agglomerans, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, coagulase- negative Staphylococcus, Streptococcus agalactiae, Streptococcus pyogenes, Viridans Group Streptococcus, Trichomonas vaginalis, Ureaplasma urealyticum, HHV-6, HHV-7, BK Virus, JC Virus, HSV 1&2, Adenovirus, or CMV.
24. The method of claim 14, wherein the composition for inhibiting growth of organisms in a polymicrobial infection is one or a combination of a: penicillin, tetracycline, cephalosporin, quinolone, lincomycin, macrolide, sulfonamide, glycopeptide antibiotic, aminoglycoside, carbapenem, ansamycin, annamycin, lipopeptide, Fosfomycin, monobactam, nitrofuran, oxazolidinone, amphotericin B, isavuconazole, itraconazole, micafungin, Posaconazole, voriconazole, cidofovir, vidarabine, foscarnet, acyclovir, valacyclovir, or a combination thereof.
25. The method of claim 14, wherein the organisms are bacteria, viruses, fungi, protozoa, or a combination thereof.
26. The method of claim 14, wherein the sample comprises urine, blood, plasma, cerebrospinal fluid, saliva, sputum, pulmonary lavage, vaginal secretions, wound lavage, biopsy tissue, wound swab, rectal swab, nasal swab, tissue, fecal matter, sperm sample, semen sample, or prostate fluid.
27. A method for treating a polymicrobial infection or suspected polymicrobial infection in a patient in need thereof, said method comprises: a. subjecting a portion of a sample obtained from a source of the polymicrobial infection in the patient to genetic identification testing, wherein genetic identification testing detects and identifies one or more organisms in the sample; b. subjecting a portion of the sample to genetic resistance marker testing, wherein genetic resistance marker testing is effective for detecting and identifying one or more resistance genes that confers resistance to one or more therapeutic agents; c. subjecting a portion of the sample to pooled phenotypic antibiotic resistance testing, wherein phenotypic antibiotic resistance testing either or both: (i) identifies 81 one or more therapeutic agents to which the polymicrobial infection is resistant, and or (ii) identifies one or more therapeutic agents to which the polymicrobial infection is susceptible, wherein the one or more organisms of the polymicrobial infection in the sample are not first isolated before phenotypic antibiotic resistance testing; d. applying results from (a), (b), and (c) to a predetermined set of thresholds in a database that indicates therapeutic agents that are effective for treating polymicrobial infections, wherein applying results from (a), (b), and (c) identifies at least one therapeutic agent that is effective for treating the polymicrobial infection in the patient; e. administering at least one therapeutic agent identified in (d) to the patient, wherein the at least one therapeutic agent is effective for treating the polymicrobial infection.
28. The method of claim 27, wherein the sample comprises urine, blood, plasma, cerebrospinal fluid, saliva, sputum, pulmonary lavage, vaginal secretions, wound lavage, biopsy tissue, wound swab, rectal swab, nasal swab, tissue, fecal matter, sperm sample, semen sample, or prostate fluid.
29. The method of claim 27, wherein the one or more resistance genes is ErmA + Erm B, TEM,CTX-M group 1, SHV, VEB, OXA-1, CTX-M group 2, CTX-M group 9, CTX-M group 8/25, PER-1, PER-2, GES, blaNDM-1, VIM, KPC, IMP-2 group, IMP-1 group, OXA-23, IMP-16, IMP-7, OXA-72, OXA-40, OXA-58, OXA-48, NDM, blaOXA-48, QnrA, QnrB, mecA, ampC, FOX, ACC, DHA, MOX/CMY, BIL/LAT/CMY, vanA1, vanA2, vanB, vanC1, or vanC2-C3-2.
30. The method of claim 27, wherein organisms of the polymicrobial infection are one or a combination of: Acinetobacter baumannii, Actinotignum schaalii, Aerococcus urinae, Aerococcus urinae, Alloscardovia omnicolens, Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Chlamydia, Citrobacter freundii, Citrobacter koseri, Clostridium difficile, Corynebacterium riegelii, Klebsiella aerogenes, Enterococcus faecalis, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Mycobacterium tuberculosis, Mycoplasma genitalium, Mycoplasma hominis, Neisseria gonorrhea, Pantoea agglomerans, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, coagulase- negative Staphylococcus, Streptococcus agalactiae, Streptococcus pyogenes, Viridans 82 Group Streptococcus, Trichomonas vaginalis, Ureaplasma urealyticum, HHV-6, HHV-7, BK Virus, JC Virus, HSV 1&2, Adenovirus, or CMV.
31. The method of claim 27, wherein the therapeutic agent is one or a combination of a: penicillin, tetracycline, cephalosporin, quinolone, lincomycin, macrolide, sulfonamide, glycopeptide antibiotic, aminoglycoside, carbapenem, ansamycin, annamycin, lipopeptide, Fosfomycin, monobactam, nitrofuran, oxazolidinone, amphotericin B, isavuconazole, itraconazole, micafungin, Posaconazole, voriconazole, cidofovir, vidarabine, foscarnet, acyclovir, valacyclovir, or a combination thereof. 83
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