INTEGRATED APPARATUS FOR DIAGNOSTIC ANALYSES

Abstract

An integrated apparatus for diagnostic analyses includes a support structure; a first refrigerated container an analysis area in which microplates are positioned and having receptacles or wells for receiving a primary sample; a samples removal and delivery unit to remove a primary sample from test tubes and deliver it into the wells; a temperature control area containing the primary samples; and a robotic head configured to interact with said samples removal and delivery unit so as to transfer the primary samples taken from the test tubes to the temperature control area and configured to insert, into each of the wells, the sample where a bacterial growth has been identified, an antibiotic in liquid form according to a choice at the discretion of the operator directed as a function of the type of species identified.

Claims

1. An integrated apparatus for diagnostic analyses, comprising: a support structure inside which are positioned a first refrigerated container to house at least one panel of antibiotics contained in ampoules or phials, reconstituted with liquid to allow them to be dispensed in a liquid phase, and to be tested according to a plurality of molecules which can be selected by an operator and possibly also according to a plurality of concentrations, in order to carry out a modulatable antibiogram and MIC (Minimal Inhibitory Concentration) tests for each antibiotic chosen; an analysis area in which a plurality of microplates are positioned with a plurality of receptacles or wells in which a portion of a primary sample is inserted; a samples removal and delivery unit configured to remove a portion of a primary sample from respective test tubes and deliver it into the wells of said microplates; a temperature control area of the microplates containing the primary samples; and a robotic head configured to interact with said samples removal and delivery unit so as to transfer the primary samples taken from the test tubes in said microplates of the analysis area and to transfer said microplates to the temperature control area and configured to insert, into each of the wells of the microplates, the sample where a bacterial growth has been identified, a portion of one of said antibiotics in liquid form according to a choice at the discretion of the operator directed as a function of the type of species identified.

2. The apparatus as in claim 1, comprising implementation means of automatic antibiogram both from samples without identification, such as samples with sepsis, and also samples previously identified with chemical systems or other.

3. The apparatus as in claim 1, comprising automatic detection means of the McFarland 0.5 turbidity value.

4. The apparatus as in claim 1, comprising a sample-carrying device, manually inserted and associated with the support structure and configured to allow a multiplicity of test tubes to be fed continuously to the apparatus and in particular to the samples removal and delivery unit.

5. The apparatus as in claim 4, wherein said sample-carrying device comprises an annular support associated with at least two return gear mechanisms of which at least one is motorized.

6. The apparatus as in claim 1, comprising an interface associable with an automatic loading system of the test tubes to the apparatus.

7. The apparatus as in claim 1, wherein said samples removal and delivery unit comprises a plurality of needles associated with corresponding needle-carrying heads, said needle-carrying heads being configured to be selectively associated with said robotic head.

8. The apparatus as in claim 7, wherein said samples removal and delivery unit comprises a washing and/or sterilization unit of the needles.

9. The apparatus as in claim 7, comprising a magnetic-mechanical system configured to allow the selective mechanical and hydraulic connection of said robotic head to one of said needle-carrying heads.

10. The apparatus as in claim 1, comprising a device to read and identify the microplates.

11. The apparatus as in claim 1, comprising a second refrigerated container to temporarily park the samples able to be subsequently seeded on Petri dishes.

12. The apparatus as in claim 10, comprising a unit to read the microplates based on a light scattering technology, for application to culture tests, to residual antibiotic activity tests and antibiogram.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] These and other characteristics of the present invention will become apparent from the following description of some embodiments, given as a non-restrictive example with reference to the attached drawings wherein:

[0042] FIG. 1 is a schematic view of the layout of the integrated apparatus for diagnostic analyses according to the present invention;

[0043] FIG. 2 is a front view of the present integrated apparatus for diagnostic analyses;

[0044] FIG. 3 is a side view of the present integrated apparatus for diagnostic analyses.

[0045] To facilitate comprehension, the same reference numbers have been used, where possible, to identify identical common elements in the drawings. It is understood that elements and characteristics of one embodiment can conveniently be incorporated into other embodiments without further clarifications.

DETAILED DESCRIPTION OF SOME EMBODIMENTS

[0046] We shall now refer in detail to the various embodiments of the present invention, of which one or more examples are shown in the attached drawings. Each example is supplied by way of illustration of the invention and shall not be understood as a limitation thereof. For example, the characteristics shown or described insomuch as they are part of one embodiment can be adopted on, or in association with, other embodiments to produce another embodiment. It is understood that the present invention shall include all such modifications and variants.

[0047] Before describing these embodiments, we must also clarify that the present description is not limited in its application to details of the construction and disposition of the components as described in the following description using the attached drawings. The present description can provide other embodiments and can be obtained or executed in various other ways. We must also clarify that the phraseology and terminology used here is for the purposes of description only, and cannot be considered as limitative.

[0048] With reference to the attached drawings, an integrated apparatus 10 for diagnostic analyses according to the invention comprises a support structure 11 to which a sample carrying device 12 to transport and feed samples is associated, for example a manually inserted sample carrying chain.

[0049] In the sample carrying device 12, a series of test tubes 13 are housed, inside each of which there is a pure biological sample, for example urine, or other sterile and non-sterile human biological liquids, or flasks of positive blood cultures.

[0050] The sample carrying device 12 comprises an annular support 16 that extends preferably over the whole front side 17 of the support structure 11.

[0051] The annular support 16 of the sample carrying device 12 comprises internally a toothing by which it engages in respective return gears 18 and 19, of which at least one is motorized.

[0052] The sample carrying device 12 has the task of allowing to load a large number of test tubes 13 and to carry the test tubes in correspondence with a samples removal and delivery unit 20.

[0053] The sample carrying device 12 is adaptable to various sample collection test tubes, both for urine and biological liquids as well as test tubes for blood cultures. A barcode identifies the type of sample loaded and consequently the appropriate workflow. If necessary, a positive blood culture sample will be dispensed directly into the container in which direct or clinical antibiogram tests will be performed in order to verify the sensitive or resistant response to the antibiotic therapy administered to the patient which takes, as described above, about 3 hours after inoculation into said clinical antibiogram test tubes.

[0054] The samples removal and delivery unit 20 comprises a plurality of needle-carrying heads 21, provided with corresponding actuators for lifting and lowering the needles, for example six needle-carrying heads as shown in the drawings.

[0055] The samples removal and delivery unit 20 also comprises a needle washing and/or sterilization unit 22, configured to dispense to a certain needle liquid disinfectant substances such as chlorine or suchlike, and to sterilize the needles, for example by heat. Each sample needs to be taken and dispensed, ensuring sterility of the needle, in order to avoid contamination in the dispensing. The structure provides the presence, for example, of 3/6 needles which, after the sample has been taken, are heated above 100 C. and subsequently washed with chlorine and then water. Each needle after this removal and sample dispensing process is inserted in a suitable decontamination chamber where through heating steps above 100 C., washing with chlorine and washing with water is sterilized for subsequent removal and dispensing processes.

[0056] Each of the needle-carrying heads 21 can also be connected to a pipe, for example, a flexible pipe cooperating with a pumping device for removing the liquid sample from the test tubes 13 and dispensing it in the various operating zones of the integrated apparatus 10.

[0057] Each needle-carrying head 21 can be mechanically and hydraulically engaged by a robotic head 14, for example by means of a magneto-mechanical system.

[0058] In the samples removal and delivery unit 20, the needles associated with each of the needle-carrying heads 21 are washed, sterilized by the unit 22 and parked for subsequent removal by the robotic head 14.

[0059] The robotic head 14 is associated with a movement unit 23 located, for example, in an upper zone of the support structure 11 and comprising guides 24 to allow the robotic head 14 to slide along at least two directions perpendicular to each other.

[0060] A data control and processing unit is associated with the support structure 11, for example by means of a support arm 15, from which it is possible to command and display the various operations performed by the integrated apparatus 10.

[0061] Next to the samples removal and delivery unit 20, there is provided an analysis area 32 in which one or more microplates 35 are positioned, comprising receptacles or wells 36 in which the primary samples are stored, which can be subjected to a rapid culture test.

[0062] In the analysis area 32, a given quantity of liquid is thus delivered, taken from the primary samples of the test tubes 13 in certain wells 36 of the microplate or microplates 35.

[0063] In a zone adjacent to the samples removal and delivery unit 20 and to the analysis area 32, a sensor 25 is provided, to verify the correct alignment of the needle of a certain needle-carrying head 21 engaged by the robotic head 14.

[0064] Next to the analysis area 32, a first refrigerated container 26 is advantageously positioned in which a plurality of phials 27 are housed in which antibiotics and/or other types of reagents are contained.

[0065] In the integrated apparatus 10 a second refrigerated container 28 is also provided, in which a series of receptacles 29, such as microwells, are made. A sample can be temporarily parked in the microwells, which will then be seeded on Petri dishes.

[0066] In a central zone of the integrated apparatus 10 a temperature control area 30 is provided, in which the microplates are positioned, keeping them at a constant temperature.

[0067] In a zone of the integrated apparatus advantageously adjacent to the temperature control area 30, a reading device 31 is provided, to read each of the wells 36 of the microplates 35, for example a photometer controlled by the control unit. The reading device 31 is useful for reading information on the biological sample contained in each microplate 35 and consequently of the patient from whom the biological sample was taken.

[0068] In the part of the integrated apparatus 10 located on the opposite side with respect to the analysis area 32, an interface 33 is provided with a possible automatic loading system of the test tubes on board the integrated apparatus, to be used alternatively or in combination with the manual load sample carrying device 12.

[0069] In the integrated apparatus 10 a reading group 34 is provided based on the light-scattering technology of the wells 36 of the microplates 35, for application to culture tests, tests of residual antibiotic activity or RAA (Residual Antimicrobial Activity), and antibiogram.

[0070] The present apparatus therefore advantageously uses two different and distinct measuring technologies, that is, a device 31 able to read microplates, for bacterial growth, antibiogram, and MIC, and a laser scattering reading unit 34 for a clinical antibiogram, for blood cultures and other tests such as MDRO, MRSA, ESBL and others.

[0071] The primary samples contained in the test tubes 13 are then inserted into the integrated apparatus 10 through two possible interfaces: a first manual interface, that is, through the sample carrying device 12, and/or through automatic loading devices that carry the test tubes 13 to the loading interface 33.

[0072] The robotic head 14 mechanically and hydraulically engages one of the needle-carrying heads 21 of the samples removal and delivery unit 20 through the magneto-mechanical system. The selected needle-carrying head will be provided with a sterilized needle by the washing and/or sterilization unit 22.

[0073] The needle-carrying head 21 with sterilized needle is used by the robotic head 14 to extract a certain quantity of primary sample from a particular test tube 13 which, thanks to the rotation of the annular support 16 of the sample carrying device 12, is taken into correspondence with the samples removal and delivery unit 20.

[0074] The removal of a certain quantity of primary sample from the test tube 13 is carried out by holing the stopper of the test tube 13 by the needle, or simply by immersing the needle into the primary sample of the test tube 13, if it is provided to take the test tube already opened into correspondence with the primary sample removal and delivery unit 20.

[0075] The quantity or portion of sample taken from the test tube 13 can be delivered partly into the receptacles 29 of the second refrigerated container 28 to allow possible seeding on Petri dishes, and partly into one or more wells 36 located on one or more microplates 35 of the analysis area 32.

[0076] The needle used to carry out the above removal operations of the primary sample from the test tube 13 and delivery into the second refrigerated container 28 and/or onto the analysis area 32 is returned by the robotic head 14 to the unit 22, in order to wash and/or sterilize it. Meanwhile, the robotic head 14 mechanically and hydraulically engages another needle-carrying head 21 with a previously sterilized needle, so the work cycle of the integrated apparatus is advantageously made continuous and without interruptions.

[0077] When a certain quantity of primary sample has been introduced into a certain number of wells 36 of one or more microplates 35 of the analysis area 32, the microplate 35 is moved by the robotic head 14 into the temperature control area 30 of the microplates.

[0078] Cyclically and always using the robotic head 14, each microplate 35 is taken to the microplate reader device 31 where it is possible to obtain and record the bacterial growth data for each specific well 36 of the microplate 35.

[0079] During the working cycle, therefore, the various readings relating to specific wells 36 of the microplate or microplates 35 are recorded and for each of the samples, over time, the curves of possible bacterial growth can be obtained.

[0080] The subsequent step in the work cycle is to identify bacteriological growth inside one of the wells 36 of the microplate 35. This step of bacterial growth can last for example from about 1 to 5 hours. As soon as bacterial growth is detected inside one or more wells 36 of the microplate 35, it means that said one or more wells 36 have positive samples.

[0081] The bacterium is then identified, which can be done by various methods and instruments, either internal or external to the integrated apparatus 10, for example mass spectrometers, or neural network algorithms or others.

[0082] The purpose of the step of identifying the bacterium is to establish the panel of antibiotics to be tested, therefore, as soon as the bacterium has been sufficiently identified and has reached the suitable concentration inside the corresponding well 36 of the microplate 35, it is re-suspended in a number of other wells 36 of the microplate 35 to be tested with different antibiotics delivered at different concentrations, that is, performing the antibiogram advantageously synergically. The antibiotics are always removed in perfect automation and by means of the robotic head 14 from the receptacles 29 of the second refrigerated container 28.

[0083] It is thus possible to measure the synergic effect of an antibiogram with different types of antibiotic that are distributed and act simultaneously.

[0084] By using the reader unit 34 based on light-scattering technology, it is also possible to carry out screening of bacteria resistant to one or more classes of antimicrobial agents, the so-called Multi-Drug Resistant Organisms (MDROs).

[0085] Inside the integrated apparatus 10, up to sixteen microplates 35 each containing twenty-four wells 36 can be provided, so that overall there can be 384 available positions to insert the sample.

[0086] As we said, after the identification of the bacterium, there follows the synergic antibiogram step, which can advantageously be implemented by the determination of the minimal inhibitory concentration or MIC, that is, the minimal amount of antibiotic to be administered to the patient.

[0087] The MIC is determined phenotypically according to the liquid dilutions technique. Let us suppose we have a panel of antibiotics to be tested comprising a certain number n of antibiotics contained in corresponding receptacles 29 of the second refrigerated container 28. Let us also suppose that m is the number of concentrations of antibiotic to be tested for each single antibiotic, therefore a sample in which bacterial growth has been detected and having a suitable concentration of the bacterium is delivered to n*m receptacles or wells 36 of a microplate 35. In each of these n*m wells 36 a certain quantity or amount of one of the n antibiotics is then added, such as to guarantee one of the m concentrations. This operation is done for each of the m concentrations of each of the n antibiotics.

[0088] In this way it is possible to carry out an effective synergic antibiogram, that is, to test the synergies of the different antibiotics.

[0089] The work cycle described above is concluded in perfect and complete automation, thanks to the robotic head 14, which moves appropriately from one zone of the integrated apparatus 10 to the other, thanks to the work capacity which is greatly increased by using a sample carrying device 12 and a possible additional automatic loading system for the test tubes, which is associated with the integrated apparatus 10 by the interface 33, and thanks to the samples removal and delivery unit 20, which comprises a plurality of needle-carrying heads 21 and an effective washing and/or sterilization unit 22 of said needles, so as to present a washed and/or sterilized needle continuously and for each sampling step.

[0090] In summary, therefore, the automated integrated device according to the invention advantageously provides to use antibiotics in liquid phase, which allows choice and discretion that can be customized by the end user, overcoming the use of predefined panels in quantity and type of antibiotic, offering the possibility of performing the antibiogram automatically.

[0091] The antibiogram can be performed automatically both from samples without prior identification, for example for patients with sepsis, and also from samples previously identified by various methods, chemical or otherwise.

[0092] The automatic antibiogram also uses automatic detection of McFarland 0.5 in the case of standard antibiogram.

[0093] The present apparatus also allows the use of direct clinical antibiogram for blood samples that are positive for bacterial growth in only three hours for the verification and confirmation of the antibiotic therapy administered to the patient, supplying the sensitive or resistant result.

[0094] As we have seen, the apparatus is provided with a sample loading chain or device that can be adapted to any type of test tube loaded, containing urine, biological fluid, or blood cultures.

[0095] The present apparatus is also provided with automatic means for sterilizing the sampling and dispensing needles, in order to obtain a workflow consistent with the sample capacity of the apparatus.

[0096] The present apparatus also advantageously uses two data acquisition technologies, namely photometry and laser scattering.

[0097] In the present apparatus, moreover, microplates of various sizes can be used, for example with 96, 192, 360 wells, pre-filled with eugonic broth, and suitable for bacterial growth, and for performing the antibiogram and MIC test.

[0098] It is clear that modifications and/or additions of parts may be made to the integrated apparatus for diagnostic analyses as described heretofore, without departing from the field and scope of the present invention.

[0099] It is also clear that, although the present invention has been described with reference to some specific examples, a person of skill in the art shall certainly be able to achieve many other equivalent forms of integrated apparatus for diagnostic analyses, having the characteristics as set forth in the claims and hence all coming within the field of protection defined thereby.

[0100] In the following claims, the sole purpose of the references in brackets is to facilitate reading: they must not be considered as restrictive factors with regard to the field of protection claimed in the specific claims.