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Publication Number
US-10364474-B2
Publication Date
2019-07-30
Expiration Date
Abstract
Disclosed are methods for identifying and/or classifying microbes using one or more single nucleotide polymorphisms (SNPs) in 16S ribosomal RNA (16S rRNA) of prokaryotes and/or one or more SNPs in 5.8S ribosomal RNA (5.8S rRNA) of eukaryotes. Also disclosed are probes, primers and kits that are useful in those methods. Methods for the diagnosis of sepsis based upon these SNPs are also disclosed.
Core Innovation
The invention provides methods of treating sepsis-associated bacterial infection in a mammalian subject by detecting single nucleotide polymorphisms (SNPs) in rRNA genes from nucleic acid obtained from a blood sample. A SNP in a 16S rRNA gene at a position corresponding to position 396 of SEQ ID NO:1 is used to determine Gram-negative or Gram-positive bacterium, where a C at position 396 determines a Gram-negative bacterium and A, T or G at position 396 determines a Gram-positive bacterium. The method then administers a therapy based on the determined Gram-positive or Gram-negative classification.
A related method treats a subject having sepsis by detecting a SNP in a 16S rRNA gene and a SNP in a 5.8S rRNA gene in nucleic acid from a blood sample. The 5.8S rRNA SNPs at specified positions of SEQ ID NO:2 define sepsis resulting from infection with a fungus. The invention also enumerates sepsis-associated bacterial taxa that are selected for treatment following the SNP-based determination.
In both methods, after determining the causative class, the therapy is selected accordingly. For sepsis-associated bacterial infections, the therapy comprises administration of an antibiotic and/or an antibody to endotoxin. For sepsis resulting from infection with a fungus, the therapy comprises administration of an anti-fungal agent. The invention further provides dependent claim refinements that include determining resistance to a therapeutic agent in the context of administering therapy.
Claims Coverage
Two independent claims are identified. Across the independent claims, the inventive coverage includes SNP-based diagnostic determination from a blood sample followed by targeted therapy selection, with one claim relying on a single 16S rRNA SNP at position 396 and the other adding 5.8S rRNA SNPs for fungal differentiation.
SNP-based Gram determination at 16S rRNA position 396
Detecting a SNP in a 16S rRNA gene from nucleic acid in a blood sample, where the SNP is at a position corresponding to position 396 of the 16S rRNA gene set forth in SEQ ID NO:1, and determining Gram-negative only when there is a C at position 396 and Gram-positive only when there is an A, T or G at position 396.
Therapy comprising antibiotic and/or antibody to endotoxin based on SNP-determined Gram status
Administering a therapy to the subject when determined to have an infection with a sepsis-associated Gram positive or Gram negative bacterium, wherein the therapy comprises administration of an antibiotic and/or an antibody to endotoxin.
Dual SNP determination using 16S rRNA position 396 and 5.8S rRNA SNPs
Detecting a SNP in a 16S rRNA gene and a SNP in a 5.8S rRNA gene in nucleic acid from a blood sample, where the 16S rRNA SNP is at a position corresponding to position 396 of the 16S rRNA gene set forth in SEQ ID NO:1 and the 5.8S rRNA SNP is at one or more specified positions of the 5.8S rRNA gene set forth in SEQ ID NO:2, with fungus determined based on the specified nucleotide identities at those positions.
Therapy selection using anti-fungal agent or antibiotic/antibody to endotoxin
Administering a therapy for treating sepsis when determined to have sepsis resulting from infection with a sepsis-associated Gram positive bacterium, a sepsis-associated Gram negative bacterium, or a fungus, wherein the therapy comprises administration of an anti-fungal agent when sepsis results from infection with a fungus, or an antibiotic and/or an antibody to endotoxin when sepsis results from infection with a sepsis-associated Gram positive bacterium or a sepsis-associated Gram negative bacterium.
The independent claims center on SNP detection in rRNA genes from blood to determine the infectious cause class, using explicit nucleotide rules at defined positions, followed by administration of antibiotic and/or an antibody to endotoxin for bacterial sepsis and an anti-fungal agent for fungal sepsis.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a sepsis-associated bacterial infection in a mammalian subject by determining Gram-positive versus Gram-negative bacteria from a blood sample using SNP detection in a 16S rRNA gene, and administering therapy comprising an antibiotic and/or an antibody to endotoxin.
Treating a subject having sepsis by determining whether sepsis results from infection with a sepsis-associated Gram positive bacterium, a sepsis-associated Gram negative bacterium, or a fungus using SNP detection in a 16S rRNA gene and a 5.8S rRNA gene from a blood sample, and administering a corresponding anti-fungal agent or an antibiotic and/or an antibody to endotoxin.
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