Devices, systems and methods for detecting viable infectious agents in a fluid sample
Inventors
KNOPFMACHER, Oren S. • Herget, Meike • Laufer, Michael D. • Estabrook, August
Assignees
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Publication Number
US-9963733-B2
Publication Date
2018-05-08
Expiration Date
Abstract
Various devices, systems and methods for detecting a susceptibility of an infectious agent to an anti-infective are described herein. A method comprises introducing a fluid sample to a first surface and a second surface; exposing the first surface to a first solution; exposing the second surface to a second solution, wherein the second surface comprises an anti-infective; sampling the first solution after exposing the first solution to the first surface; sampling the second solution after exposing the second solution to the second surface; monitoring a first electrical characteristic of a first sensor exposed to the first solution sampled; monitoring a second electrical characteristic of a second sensor exposed to the second solution sampled; and comparing the first electrical characteristic and the second electrical characteristic to assess the susceptibility of the infectious agent to the anti-infective.
Core Innovation
The invention relates to in vitro systems and methods for detecting a susceptibility of a microorganism to an antibiotic. A surface comprising the microorganism is exposed to a first solution and then the first solution is separated from the microorganism after the first solution is exposed to the surface. An electrical characteristic of a sensor is monitored upon introducing the first solution to the sensor, wherein the sensor comprises an on-chip reference electrode and at least one ion-sensitive field effect transistor (ISFET).
The same surface comprising the microorganism is exposed to a second solution comprising an antibiotic, and the second solution is separated from the microorganism after the second solution is exposed to the surface. Electrical characteristics are then detected or monitored after introducing the second solution to the sensor, and any changes in the electrical characteristic are used to assess susceptibility. The surface is of a filter, including a glass fiber filter and at least one of a nylon filter membrane and a polyethersulfone (PES) filter membrane.
In additional implementations, two sensors with on-chip reference electrodes and ISFETs are used to monitor a first electrical characteristic upon introducing the first solution and a second electrical characteristic upon introducing the second solution. The method compares the first and second electrical characteristics to assess susceptibility. In another implementation, a sensor in fluid communication with a temporarily exposed antibiotic-containing solution is provided after the solution is separated from the microorganism such that the solution is no longer in fluid communication with the microorganism, and an indication is provided when the electrical characteristic is unchanged.
Claims Coverage
The independent claims are clm-00001, clm-00008, and clm-00015. Across these independent claims, the main inventive features center on sequential exposure and separation of solutions, monitoring electrical characteristics from ISFET-based sensors with on-chip reference electrodes, and assessing susceptibility from detected changes or comparisons in the electrical characteristics, including an unchanged electrical characteristic indication.
Sequential exposure and separation with susceptibility assessment using ISFET and on-chip reference electrode on a filter
exposing a surface comprising the microorganism to a first solution; separating the first solution from the microorganism after the first solution is exposed to the surface; monitoring an electrical characteristic of a sensor upon introducing the first solution to the sensor, wherein the sensor comprises an on-chip reference electrode and wherein the sensor comprises at least one ion-sensitive field effect transistor (ISFET); exposing the surface comprising the microorganism to a second solution, wherein the second solution comprises an antibiotic; separating the second solution from the microorganism after the second solution is exposed to the surface; detecting any changes in the electrical characteristic of the sensor after introducing the second solution to the sensor; assessing the susceptibility of the microorganism to the antibiotic using any detected changes in the electrical characteristic; wherein the surface is of a filter, and wherein the filter comprises a glass fiber filter and at least one of a nylon filter membrane and a polyethersulfone (PES) filter membrane.
Comparing electrical characteristics from two ISFET sensors with on-chip reference electrodes after first and second solution exposures on a filter
exposing a surface comprising the microorganism to a first solution; separating the first solution from the microorganism after the first solution is exposed to the surface; monitoring a first electrical characteristic of a first sensor upon introducing the first solution to the first sensor, wherein the first sensor comprises a first on-chip reference electrode and wherein the first sensor comprises at least one first ion-sensitive field effect transistor (ISFET); exposing the surface comprising the microorganism to a second solution, wherein the second solution comprises an antibiotic; separating the second solution from the microorganism after the second solution is exposed to the surface; monitoring a second electrical characteristic of a second sensor after introducing the second solution to the second sensor, wherein the second sensor comprises a second on-chip reference electrode and wherein the second sensor comprises at least one second ISFET; comparing the first electrical characteristic and the second electrical characteristic to assess the susceptibility of the microorganism to the antibiotic; wherein the surface is of a filter, wherein the filter comprises a glass fiber filter and at least one of a nylon filter membrane and a polyethersulfone (PES) filter membrane.
Temporary antibiotic exposure with post-separation sensor measurement indicating susceptibility when electrical characteristic is unchanged
temporarily exposing a solution to the microorganism, wherein the solution comprises an antibiotic; providing a sensor in fluid communication with the solution after the solution temporarily exposed to the microorganism is separated from the microorganism, wherein the sensor comprises an electrical characteristic, wherein the sensor comprises an on-chip reference electrode, and wherein the sensor comprises at least one ion-sensitive field effect transistor (ISFET); monitoring a change in the electrical characteristic of the sensor after providing the sensor in fluid communication with the solution, wherein providing the sensor in fluid communication with the solution involves providing the sensor in fluid communication with the solution after the solution is separated from the microorganism such that the solution is no longer in fluid communication with the microorganism; and providing an indication of the susceptibility of the microorganism to the antibiotic when the electrical characteristic is unchanged.
Across clm-00001, clm-00008, and clm-00015, susceptibility detection is based on exposing microorganisms to a first solution and then to an antibiotic-containing second solution, or temporarily exposing an antibiotic-containing solution, separating solutions from the microorganism, and using ISFET-based electrical monitoring with on-chip reference electrodes to detect changes, compare readings, or indicate susceptibility when the electrical characteristic remains unchanged.
Stated Advantages
Reduced false results by separating reference electrodes from the infectious agent.
Documented Applications
Rapidly assessing susceptibility of viable infectious agents to anti-infectives using fluid samples processed on a filter or well surfaces, with sensor monitoring of electrical characteristics for MIC/resistance/susceptibility outcomes.
Use of sensor-based susceptibility detection with examples including E. coli with nitrofurantoin/ciprofloxacin and Staphylococcus saprophyticus with ampicillin/nitrofurantoin.
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