(171 days)
Not Found
No
The description details a standard real-time PCR assay with automated signal interpretation based on predefined thresholds, not AI/ML algorithms.
No
The device is an in vitro diagnostic real-time PCR test for detecting and differentiating carbapenemase genes, intended as an aid to infection control. It is explicitly stated that this assay is not intended to guide or monitor treatment, which means it does not provide therapeutic benefits.
Yes
Explanation: The "Intended Use / Indications for Use" section explicitly states that the BD MAX Check-Points CPO Assay is an "in vitro diagnostic real-time PCR test." It is designed for "detection and differentiation" of specific genes and is "intended as an aid to infection control." These phrases directly indicate its purpose in diagnosing or aiding in the diagnosis of a condition.
No
The device description clearly outlines a system that includes hardware components (BD MAX System, reagent strips, PCR cartridges, etc.) for sample processing, DNA extraction, amplification, and detection. While software is involved in interpreting the signals, it is an integral part of a larger hardware-based system.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use/Indications for Use: The very first sentence explicitly states it is an "automated in vitro diagnostic real-time PCR test". It is designed to detect and differentiate specific genes associated with carbapenem non-susceptibility in Gram-negative bacteria, which is a diagnostic purpose.
- Device Description: The description details how the device processes biological samples (rectal swabs) to extract and amplify nucleic acids for detection, which is characteristic of an in vitro diagnostic test.
- Performance Studies: The document describes clinical performance studies using patient specimens and contrived samples, comparing the device's results to a reference method (bacterial culture followed by PCR and sequencing). This is a standard process for evaluating the performance of an IVD.
- Key Metrics: The document reports key metrics like Sensitivity/PPA and Specificity/NPA, which are commonly used to assess the performance of diagnostic tests.
- Predicate Device(s): The mention of a predicate device (Xpert® Carba-R Assay) with a K number (K160901) indicates that this device is being compared to a previously cleared IVD.
All these elements strongly indicate that the BD MAX Check-Points CPO Assay is an In Vitro Diagnostic device.
N/A
Intended Use / Indications for Use
The BD MAX Check-Points CPO Assay performed on the BD MAX System is a qualitative, automated in vitro diagnostic real-time PCR test designed for the detection and differentiation of the carbapenemase genes blakes, blayble blaymoblance and black-48, that are associated with carbapenem non-susceptibility in Gram-negative bacteria. The assay does not distinguish between the blay™ and bland genes.
The BD MAX Check-Points CPO Assay is intended as an aid to infection control in the detection of carbapenem-non-susceptible bacteria that colonize patients in healthcare settings. The BD MAX Check-Points CPO Assay is not intended to guide or monitor treatment for carbapenem-non-susceptible bacterial infections. A negative BD MAX Check-Points CPO Assay result does not preclude the presence of other resistance mechanisms.
Testing is performed on rectal swabs from patients at risk for intestinal colonisation with carbapenem nonsusceptible bacteria. This test is intended for use in conjunction with clinical presentation, laboratory findings, and epidemiological information. Results of this test should not be used as the sole basis for patient management decisions. Concomitant cultures are necessary to recover organisms for epidemiological typing, antimicrobial susceptibility testing, and for further confirmatory bacterial identification.
Product codes
POC
Device Description
The BD MAX Check-Points CPO Assay detects the presence of carbapenemase genes in Gram-negative bacteria and includes an internal Sample Processing Control.
Rectal swab specimens are collected from patients using ESwab. After sampling they are transported to the laboratory in the Amies transport media of the ESwab. The ESwab is vortexed and a 50 µl aliquot is transferred to the Sample Buffer Tube using a pipette with disposable filter tip. The Sample Buffer Tube is closed with a septum cap and vortexed. Once the worklist is generated and the clinical specimen is loaded on the BD MAX system, along with a BD MAX Check-Points CPO Reagent Strip and BD MAX PCR Cartridge, the run is started and no further operator intervention is required. The BD MAX System automates sample preparation, including target organism lysis, DNA extraction and concentration, reagent rehydration, target nucleic acid sequence amplification and detection using real-time PCR. The interpretation of the signal is performed automatically by the BD MAX System. The assay also includes a Sample Processing Control that is provided in the Extraction Tube and subjected to extraction, concentration and amplification steps. The Sample Processing Control monitors for the presence of potential inhibitory substances as well as system or reagent failures.
Following enzymatic cell lysis at an elevated temperature, the released nucleic acids are captured on magnetic affinity beads. The beads, with the bound nucleic acids, are washed and the nucleic acids are eluted. Eluted DNA is neutralized and transferred to the Master Mix Tube to rehydrate the PCR reagents. After rehydration, the BD MAX System dispenses a fixed volume of PCR-ready solution into the BD MAX PCR Cartridge. Microvalves in the BD MAX PCR Cartridge are sealed by the system prior to initiating PCR to contain the amplification mixture thus preventing evaporation and contamination. The amplified DNA targets are detected using hydrolysis (TaqMan®) probes, labeled at one end with a fluorescent reporter dve (fluorophore) and at the other end with a quencher moiety. Probes labeled with different fluorophores are used to detect amplicons for the carbapenemase genes KPC, VIM, OXA-48, NDM, IMP and the Sample Processing Control in five different optical channels of the BD MAX System.
The VIM and IMP genes are combined in one optical channel of the BD MAX system, all other genes have a separate optical channel. When the probes are in their native state, the fluorescence of the fluorophore is quenched due to its proximity to the quencher. However, in the presence of target DNA, the probes hybridize to their complementary sequences and are hydrolyzed by the 5'-3' exonuclease activity of the DNA polymerase as it synthesizes the nascent strand along the DNA template. As a result, the fluorophores are separated from the quencher molecules and fluorescence is emitted. The BD MAX System monitors these signals at each cvcle and interprets the data at the end of the program to report the final results.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Rectal swabs (intestinal colonization)
Indicated Patient Age Range
Not Found
Intended User / Care Setting
Healthcare settings
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
A total of 1486 prospective specimens and 166 contrived specimens were eligible for the clinical evaluation. 13 of 1486 prospective specimens were unreportable leaving 1473 prospective specimens to calculate clinical performance. Specimens were obtained from patients at risk for intestinal colonization with carbapenem non-susceptible bacteria. The reference method was a bacterial culture for recovery of non-susceptible isolates from the rectal swab specimens followed by detection of antibiotic resistance genes by PCR and sequencing. The bacterial culture comprised both direct plating on chromID Carba and chromID OXA48 as well as over-night enrichment in MacConkey broth followed by plating on MacConkey agar with a 10 ug meropenem disc. For contrived specimens, well-characterized strains were spiked into unique negative rectal swab matrix near the LoD and analyzed by BD MAX Check-Points CPO. In addition, the strains were analyzed by PCR and sequencing.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Clinical performance characteristics of the BD MAX Check-Points CPO Assay were determined in a multi-site investigational study and a study involving contrived specimens.
Prospective study: 1473 specimens.
Contrived study: 166 specimens.
Performance Results with KPC producing organisms:
KPC - Overall Performance (Prospective):
Sensitivity/PPA: MacConkey PCR/Sequencing: 88.5% (71.0-96.0%), chromID PCR/Sequencing: 96.6% (82.8-99.4%), MacConkey + chromID PCR/Sequencing: 88.2% (73.4-95.3%)
Specificity/NPA: MacConkey PCR/Sequencing: 99.3% (98.7-99.6%), chromID PCR/Sequencing: 99.7% (99.2-99.9%), MacConkey + chromID PCR/Sequencing: 99.8% (99.4-99.9%)
KPC - Overall Performance (Contrived):
Sensitivity/PPA: PCR/Sequencing: 100% (88.6-100%)
Specificity/NPA: PCR/Sequencing: 100% (97.3-100%)
Performance Results with VIM and IMP producing organisms:
VIM/IMP – Overall Performance (Prospective):
Sensitivity/PPA: MacConkey PCR/Sequencing: 100% (56.6-100%), chromID PCR/Sequencing: 66.7% (30.0-90.3%), MacConkey + chromID PCR/Sequencing: 75.0% (40.9-92.9%)
Specificity/NPA: MacConkey PCR/Sequencing: 99.2% (98.6-99.5%), chromID PCR/Sequencing: 99.1% (98.5-99.5%), MacConkey + chromID PCR/Sequencing: 99.2% (98.7-99.6%)
VIM/IMP – Overall Performance (Contrived):
Sensitivity/PPA: PCR/Sequencing: 96.2% (87.0-98.9%)
Specificity/NPA: PCR/Sequencing: 100% (96.7-100%)
Performance Results with OXA48 producing organisms:
OXA48 – Overall Performance (Prospective):
Sensitivity/PPA: MacConkey PCR/Sequencing: 95.2% (77.3-99.2%), chromID PCR/Sequencing: 100% (86.7-100%), MacConkey + chromID PCR/Sequencing: 96.2% (81.1-99.3%)
Specificity/NPA: MacConkey PCR/Sequencing: 98.6% (97.9-99.1%), chromID PCR/Sequencing: 99.0% (98.3-99.4%), MacConkey + chromID PCR/Sequencing: 99.0% (98.3-99.4%)
OXA48 – Overall Performance (Contrived):
Sensitivity/PPA: PCR/Sequencing: 100% (88.6-100%)
Specificity/NPA: PCR/Sequencing: 100% (97.3-100%)
Performance Results with NDM producing organisms:
NDM - Overall Performance (Prospective):
Sensitivity/PPA: MacConkey PCR/Sequencing: 100% (20.7-100%), chromID PCR/Sequencing: 100% (20.7-100%), MacConkey + chromID PCR/Sequencing: 100% (20.7-100%)
Specificity/NPA: MacConkey PCR/Sequencing: 99.9% (99.6-100%), chromID PCR/Sequencing: 99.9% (99.6-100%), MacConkey + chromID PCR/Sequencing: 99.9% (99.6-100%)
NDM - Overall Performance (Contrived):
Sensitivity/PPA: PCR/Sequencing: 100% (88.6-100%)
Specificity/NPA: PCR/Sequencing: 100% (97.3-100%)
Analytical Inclusivity:
93 strains tested, including strains from public collections and well-characterized clinical isolates for KPC, VIM, IMP, OXA-48, NDM genes.
All variants tested and predicted detected by in silico analysis were detected by BD MAX Check-Points CPO.
Analytical Sensitivity (Limit of Detection):
LoD ranged from 144 to 4774 CFU/mL.
Analytical Specificity:
26 organisms tested in 3 replicates. All organisms tested negative.
Interfering Substances:
29 biological and chemical substances evaluated for potential interference. No reportable interference.
Inter-lab reproducibility:
Ranged from 100-100% for Negatives, 97.5-100% for 1.5x LoD and 99.2-100% for 3x LoD.
Inter-lot reproducibility:
Ranged 100-100% for Negatives, 100-100% for 1.5x LoD and 99.2-100% for 3x LoD.
Intra-lab reproducibility:
Ranged from 100-100% for Negatives, 97.9-100% for 1.5x LoD and 97.9-100% for 3x LoD.
Carry-over contamination:
Assessed by testing negative specimens together with positive specimens containing a high load of bacteria. No positive calls were found for 166 negative specimens.
Mixed Infection / Competitive interference:
No interference observed from testing of thirteen specimens containing one target from strains spiked at 2x LoD and one or two other target organism(s) spiked at ~1x10^6 CFU/mL.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Sensitivity/PPA, Specificity/NPA. Refer to "Summary of Performance Studies" for detailed values.
Predicate Device(s)
Reference Device(s)
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information
Not Found
§ 866.1640 Antimicrobial susceptibility test powder.
(a)
Identification. An antimicrobial susceptibility test powder is a device that consists of an antimicrobial drug powder packaged in vials in specified amounts and intended for use in clinical laboratories for determining in vitro susceptibility of bacterial pathogens to these therapeutic agents. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.(b)
Classification. Class II (performance standards).
0
Image /page/0/Picture/0 description: The image contains the logos of the Department of Health and Human Services and the Food and Drug Administration (FDA). The Department of Health and Human Services logo is on the left, and the FDA logo is on the right. The FDA logo includes the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text.
August 29, 2019
Check-Points Health B.V. Pieter Vos Chief Technical Officer Binnenhaven 5 6709 PD Wageningen The Netherlands
Re: K190613
Trade/Device Name: BD MAX Check-Points CPO Regulation Number: 21 CFR 866.1640 Regulation Name: Antimicrobial susceptibility test powder Regulatory Class: Class II Product Code: POC, OOI Dated: March 6, 2019 Received: March 18, 2019
Dear Pieter Vos:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's
1
requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
for
Ribhi Shawar, Ph.D. (ABMM) Chief. General Bacteriology and Antimicrobial Susceptibility Branch Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
2
| DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0120 | |
|---|---|
| Food and Drug Administration | Expiration Date: 06/30/2020 |
| Indications for Use | See PRA Statement below. |
| 510(k) Number (if known) | |
| K190613 | |
| Device Name |
BD MAX™ Check-Points CPO
Indications for Use (Describe)
The BD MAX Check-Points CPO Assay performed on the BD MAX System is a qualitative, automated in vitro diagnostic real-time PCR test designed for the detection and differentiation of the carbapenemase genes blakes, blayble blaymoblance and black-48, that are associated with carbapenem non-susceptibility in Gram-negative bacteria. The assay does not distinguish between the blay™ and bland genes.
The BD MAX Check-Points CPO Assay is intended as an aid to infection control in the detection of carbapenem-non-susceptible bacteria that colonize patients in healthcare settings. The BD MAX Check-Points CPO Assay is not intended to guide or monitor treatment for carbapenem-non-susceptible bacterial infections. A negative BD MAX Check-Points CPO Assay result does not preclude the presence of other resistance mechanisms.
Testing is performed on rectal swabs from patients at risk for intestinal colonisation with carbapenem nonsusceptible bacteria. This test is intended for use in conjunction with clinical presentation, laboratory findings, and epidemiological information. Results of this test should not be used as the sole basis for patient management decisions. Concomitant cultures are necessary to recover organisms for epidemiological typing, antimicrobial susceptibility testing, and for further confirmatory bacterial identification.
Type of Use (Select one or both, as applicable) 区 Prescription Use (Part 21 CFR 801 Subpart D) □ Over-The Counter Use (21 CFR 801 Subpart C)
CONTINUE ON A SEPARATE PAGE IF NEEDED.
This section applies only to requirements of the Paperwork Reduction Act of 1995. DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of
information unless it displays a currently valid OMB number. "
FORM FDA 3881 (7/17)
3
510(k) Summary
Image /page/3/Picture/1 description: The image shows the logo for Check-Points, a company specializing in rapid molecular detection. The logo features a cluster of nine purple dots arranged in a diamond shape on the left. To the right of the dots is the company name, "Check-Points," in a bold, sans-serif font. Below the company name, in smaller font, is the tagline "rapid molecular detection."
1. Applicant:
Check-Points Health B.V. Binnenhaven 5 6709 PD Wageningen The Netherlands
2. Contact Person:
Pieter Vos, CTO E-mail: pietervos@check-points.com Phone: +31 317 45 39 08 Mobile: +31 622 40 07 80
3. Summary Preparation Date:
August 22, 2019
4. Device Name and Classification:
Trade Name (proprietary name): BD MAX™ Check-Points CPO
Common Name (usual name): BD MAX™ Check-Points CPO
Classification: Class II
Product code: POC (System, nucleic acid amplification test, DNA, antimicrobial resistance marker, direct specimen)
Panel: Microbiology (83)
Regulation section: 21 CFR 866.1640 (Antimicrobial susceptibility test powder)
4
| Predicate Device Name | Manufacturer | Predicate 510(k) Number |
|---|---|---|
| Xpert® Carba-R Assay | Cepheid, Inc. | K160901 |
5. Substantial Equivalence Information:
Comparison with Predicate:
| Device | Predicate | |
|---|---|---|
| Name | BD MAX™ Check-Points | |
| CPO | Xpert® Carba-R Assay | |
| Intended Use | Qualitative in vitro | |
| diagnostic real-time PCR | ||
| test for detection of | ||
| carbapenemase genes | ||
| from rectal swabs | Same | |
| Organisms and | ||
| Resistance Markers | ||
| Detected | KPC | |
| NDM | ||
| VIM | ||
| OXA-48 | ||
| IMP | Same | |
| Same | ||
| Same | ||
| Same | ||
| Same | ||
| Analyte | DNA | Same |
| Technological | ||
| Principles | Fully-automated nucleic | |
| acid amplification (DNA); | ||
| real-time PCR | Same | |
| Specimen Type | Rectal swabs | Same |
| Sample Preparation | Automated by Instrument | Same |
| Instrumentation | BD MAX System | GeneXpert System |
| Interpretation of | ||
| Results | Automated by Instrument | Same |
| Controls | Sample Processing | |
| Control (SPC) | Same | |
| Probe Check control | ||
| (PCC) | ||
| Time to Result | 3 hours | 1 hour |
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6. Device Description:
The BD MAX Check-Points CPO Assay detects the presence of carbapenemase genes in Gram-negative bacteria and includes an internal Sample Processing Control.
Rectal swab specimens are collected from patients using ESwab. After sampling they are transported to the laboratory in the Amies transport media of the ESwab. The ESwab is vortexed and a 50 µl aliquot is transferred to the Sample Buffer Tube using a pipette with disposable filter tip. The Sample Buffer Tube is closed with a septum cap and vortexed. Once the worklist is generated and the clinical specimen is loaded on the BD MAX system, along with a BD MAX Check-Points CPO Reagent Strip and BD MAX PCR Cartridge, the run is started and no further operator intervention is required. The BD MAX System automates sample preparation, including target organism lysis, DNA extraction and concentration, reagent rehydration, target nucleic acid sequence amplification and detection using real-time PCR. The interpretation of the signal is performed automatically by the BD MAX System. The assay also includes a Sample Processing Control that is provided in the Extraction Tube and subjected to extraction, concentration and amplification steps. The Sample Processing Control monitors for the presence of potential inhibitory substances as well as system or reagent failures.
Following enzymatic cell lysis at an elevated temperature, the released nucleic acids are captured on magnetic affinity beads. The beads, with the bound nucleic acids, are washed and the nucleic acids are eluted. Eluted DNA is neutralized and transferred to the Master Mix Tube to rehydrate the PCR reagents. After rehydration, the BD MAX System dispenses a fixed volume of PCR-ready solution into the BD MAX PCR Cartridge. Microvalves in the BD MAX PCR Cartridge are sealed by the system prior to initiating PCR to contain the amplification mixture thus preventing evaporation and contamination. The amplified DNA targets are detected using hydrolysis (TaqMan®) probes, labeled at one end with a fluorescent reporter dve (fluorophore) and at the other end with a quencher moiety. Probes labeled with different fluorophores are used to detect amplicons for the carbapenemase genes KPC, VIM, OXA-48, NDM, IMP and the Sample Processing Control in five different optical channels of the BD MAX System.
The VIM and IMP genes are combined in one optical channel of the BD MAX system, all other genes have a separate optical channel. When the probes are in their native state, the fluorescence of the fluorophore is quenched due to its proximity to the quencher. However, in the presence of target DNA, the probes hybridize to their complementary sequences and are hydrolyzed by the 5'-3' exonuclease activity of the DNA polymerase as it synthesizes the nascent strand along the DNA template. As a result, the fluorophores are separated from the quencher molecules and fluorescence is emitted. The BD MAX System monitors these signals at each cvcle and interprets the data at the end of the program to report the final results.
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7. Intended use(s):
The BD MAX Check-Points CPO Assay performed on the BD MAX System is a qualitative, automated in vitro diagnostic real-time PCR test designed for the detection and differentiation of the carbapenemase genes blayow. blaviw/blamp and blaoxa-48, that are associated with carbapenem non-susceptibility in Gram-negative bacteria. The assay does not distinguish between the blayMand blaimp genes.
The BD MAX Check-Points CPO Assay is intended as an aid to infection control in the detection of carbapenem-non-susceptible bacteria that colonize patients in healthcare settings. The BD MAX Check-Points CPO Assay is not intended to guide or monitor treatment for carbapenem-non-susceptible bacterial infections. A negative BD MAX Check-Points CPO Assay result does not preclude the presence of other resistance mechanisms.
Testing is performed on rectal swabs from patients at risk for intestinal colonisation with carbapenem non-susceptible bacteria. This test is intended for use in conjunction with clinical presentation, laboratory findings, and epidemiological information. Results of this test should not be used as the sole basis for patient management decisions. Concomitant cultures are necessary to recover organisms for epidemiological typing, antimicrobial susceptibility testing, and for further confirmatory bacterial identification.
Special Conditions for Use Statement: For prescription use
Special Instrument Requirements: BD MAX System
8. Indication for use(s):
Patients at risk for intestinal colonisation with carbapenem non-susceptible bacteria.
9. Performance Characteristics:
Clinical performance characteristics of the BD MAX Check-Points CPO Assay were determined in a multi-site investigational study and a study involving contrived specimens. The investigational study involved a total of five (5) geographically diverse clinical centers where rectal swab specimens were collected as part of routine patient care, enrolled into the trial, and tested with the BD MAX Check-Points CPO Assay. Specimens were obtained from patients at risk for intestinal colonization with carbapenem non-susceptible bacteria. The reference method was a bacterial culture for recovery of non-susceptible isolates from the rectal swab specimens followed by detection of antibiotic resistance genes by PCR and sequencing. The bacterial culture comprised both direct plating on chromID Carba and chromID OXA48 as well as over-night enrichment in MacConkey broth followed by plating on MacConkey agar with a 10 ug meropenem disc. For
7
contrived specimens, well-characterized strains were spiked into unique negative rectal swab matrix near the LoD and analyzed by BD MAX Check-Points CPO. In addition, the strains were analyzed by PCR and sequencing.
A total of 1486 prospective specimens and 166 contrived specimens were eligible for the clinical evaluation. 13 of 1486 prospective specimens were unreportable leaving 1473 prospective specimens to calculate clinical performance. Tables 1 through 4 describe the performance characteristics of the BD MAX Check-Points CPO Assay that were observed during the clinical trial.
Non-Reportable Rate
Of all specimens evaluated. 1.9% (28/1486) and 0% (0/166) were initially reported as Unresolved/Indeterminate/Inconclusive for the prospective and contrived specimens, respectively. Following a valid repeat test for 17 of 28 specimens (11 were not repeated), 0.1% (2/1475) and 0% remained Unresolved for the prospective and contrived specimens, respectively.
Performance Results with KPC producing organisms
The clinical performance for KPC in the prospective study and contrived study is summarized in Table 1 below.
| KPC | Prospective | Contrived | |||||||
|---|---|---|---|---|---|---|---|---|---|
| MacConkey | |||||||||
| PCR/Sequencing | chromID | ||||||||
| PCR/Sequencing | MacConkey + | ||||||||
| chromID | |||||||||
| PCR/Sequencing | PCR/Sequencing | ||||||||
| POS | NEG | POS | NEG | POS | NEG | POS | NEG | ||
| BD MAX | |||||||||
| Check-Points | |||||||||
| CPO | POS | 23 | 10 | 28 | 5 | 30 | 3 | 30 | 0 |
| NEG | 3 | 1437 | 1 | 1439 | 4 | 1436 | 0 | 136 | |
| Sensitivity/PPA | |||||||||
| (95% CI) | 88.5% (71.0-96.0%) | 96.6% (82.8-99.4%) | 88.2% (73.4-95.3%) | 100% (88.6-100%) | |||||
| Specificity/NPA | |||||||||
| (95% CI) | 99.3% (98.7-99.6%) | 99.7% (99.2-99.9%) | 99.8% (99.4-99.9%) | 100% (97.3-100%) |
Table 1. KPC – Overall Performance
Performance Results with VIM and IMP producing organisms
The clinical performance for VIM/IMP in the prospective study and contrived study is summarized in Table 2 below.
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| Table 2. VIM/IMP – Overall Performance | |
|---|---|
| Prospective |
| Prospective | Contrived | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| VIM/IMP | MacConkey | |||||||||
| PCR/Sequencing | chromID | |||||||||
| PCR/Sequencing | MacConkey + | |||||||||
| chromID | ||||||||||
| PCR/Sequencing | PCR/Sequencing | |||||||||
| POS | NEG | POS | NEG | POS | NEG | POS | NEG | |||
| BD MAX | ||||||||||
| Check-Points | ||||||||||
| CPO | POS | 5 | 12 | 4 | 13 | 6 | 11 | 50 | 0 | |
| NEG | 0 | 1456 | 2 | 1454 | 2 | 1454 | 2 | 114 | ||
| Sensitivity/PPA | ||||||||||
| (95% CI) | 100% (56.6-100%) | 66.7% (30.0-90.3%) | 75.0% (40.9-92.9%) | 96.2% (87.0-98.9%) | ||||||
| Specificity/NPA | ||||||||||
| (95% CI) | 99.2% (98.6-99.5%) | 99.1% (98.5-99.5%) | 99.2% (98.7-99.6%) | 100% (96.7-100%) |
Performance Results with OXA48 producing organisms
The clinical performance for OXA-48 in the prospective study and contrived study is summarized in Table 3 below.
Table 3. OXA48 – Overall Performance
| OXA-48 | Prospective | Contrived | |||||||
|---|---|---|---|---|---|---|---|---|---|
| MacConkey | |||||||||
| PCR/Sequencing | chromID | ||||||||
| PCR/Sequencing | MacConkey + | ||||||||
| chromID | |||||||||
| PCR/Sequencing | PCR/Sequencing | ||||||||
| POS | NEG | POS | NEG | POS | NEG | POS | NEG | ||
| BD MAX | |||||||||
| Check-Points | |||||||||
| CPO | POS | 20 | 20 | 25 | 15 | 25 | 15 | 30 | 0 |
| NEG | 1 | 1432 | 0 | 1433 | 1 | 1432 | 0 | 136 | |
| Sensitivity/PPA | |||||||||
| (95% Cl) | 95.2% (77.3-99.2%) | 100% (86.7-100%) | 96.2% (81.1-99.3%) | 100% (88.6-100%) | |||||
| Specificity/NPA | |||||||||
| (95% CI) | 98.6% (97.9-99.1%) | 99.0% (98.3-99.4%) | 99.0% (98.3-99.4%) | 100% (97.3-100%) |
Performance Results with NDM producing organisms
The clinical performance for NDM in the prospective study and contrived study is summarized in Table 4 below.
| Table 4. NDM - Overall Performance | |||
|---|---|---|---|
| -- | -- | -- | ------------------------------------ |
| NDM | Prospective | Contrived | |||||||
|---|---|---|---|---|---|---|---|---|---|
| MacConkey | |||||||||
| PCR/Sequencing | chromID | ||||||||
| PCR/Sequencing | MacConkey + | ||||||||
| chromID | |||||||||
| PCR/Sequencing | PCR/Sequencing | ||||||||
| POS | NEG | POS | NEG | POS | NEG | POS | NEG | ||
| BD MAX | |||||||||
| Check-Points | |||||||||
| CPO | POS | 1 | 1 | 1 | 1 | 1 | 1 | 30 | 0 |
| NEG | 0 | 1471 | 0 | 1471 | 0 | 1471 | 0 | 136 | |
| Sensitivity/PPA | |||||||||
| (95% CI) | 100% (20.7-100%) | 100% (20.7-100%) | 100% (20.7-100%) | 100% (20.7-100%) | 100% (88.6-100%) | ||||
| Specificity/NPA | |||||||||
| (95% CI) | 99.9% (99.6-100%) | 99.9% (99.6-100%) | 99.9% (99.6-100%) | 99.9% (99.6-100%) | 100% (97.3-100%) |
9
Analytical Inclusivity
A variety of BD MAX Check-Points CPO target organisms and carbapenemase gene variants were included in this study. Strain selection criteria included prevalence and clinical importance. Ninety-three (93) strains were tested, including strains from public collections and well-characterized clinical isolates.
Inclusivity testing included 16 different species and 17 KPC strains representing 2 variants, 17 VIM strains representing 7 variants, 18 IMP strains representing 7 variants, 20 OXA48-type strains representing 7 variants, 17 NDM strains representing 4 variants and 4 strains containing two carbapenemase target genes. The strains were tested in triplicate at 3x LoD (Limit of Detection). The BD MAX Check-Points CPO correctly identified 90 of the 93 strains tested upon initial testing. Three strains, an Enterobacter cloacae with IMP-34, a Pseudomonas aeruginosa with IMP-4 and a Klebsiella pneumoniae with NDM-1 were detected when re-tested at 10x LoD. A summary is presented in Table 5 below and compared to the in silico prediction results. A total of 97 target genes were tested in a total of 93 strains (4 strains had two target genes).
| Inclusivity Results | ||||
|---|---|---|---|---|
| Target | No. of | |||
| target | ||||
| genes | Variants | |||
| detected | Variants | |||
| not | ||||
| detected | in silico Prediction | |||
| KPC | 17 | KPC-2, 3 | - | KPC-2-37 |
| VIM | 19 | VIM-1, 2, 4, | ||
| 19, 26, 27, 31 | - | VIM-1-6, -8-52, -54, -56-60 | ||
| IMP | 20 | IMP-1, 3, 4, 7, | ||
| 8, 26, 34, | - | IMP-1-4, 6-8, 10, 19, 20, 23-26, 30, | ||
| 34, 38, 40, 42-43, 51, 52, 55, 59- | ||||
| 61, 66, 70, 73, 76-80 | ||||
| OXA- | ||||
| 48 | 22 | OXA-48, 162, | ||
| 163, 181, 204, | ||||
| 232, 244 | - | OXA-48, 162, 163, 181, 204, 232, | ||
| 244, 245, 370, 405, 438, 439, 484, | ||||
| 505, 517, 519, 566 | ||||
| NDM | 19 | NDM-1, 5, 6, 7 | - | NDM-1-24 |
Table 5. BD MAX Check-Points CPO Inclusivity Results versus in silico Prediction
In summary, all variants tested and predicted detected by in silico analysis were detected by BD MAX Check-Points CPO. In addition, IMP-7 and OXA-163 not predicted detected by in silico analysis were detected by BD MAX Check-Points CPO. IMP-43, -51 and -73 have the same primer and probe target sequences as IMP-7 and OXA-438-439 have the same primer and probe target sequences as OXA-163 and therefore also expected detected by BD MAX Check-Points CPO Assay.
10
Analytical Sensitivity (Limit of Detection)
The analytical sensitivity (Limit of Detection or LoD) for the BD MAX Check-Points CPO was determined using two strains for each carbapenemase gene, i.e. 10 strains. Bacterial cell suspensions of each strain were prepared and quantified from culture prior to inclusion in this study. A total of six 2-fold serial dilutions in negative rectal matrix were prepared for all strains at test concentrations expected to comprise the LoD for each carbapenemase target gene. Replicates of 10 of each test concentration were evaluated using 3 BD MAX instruments and 3 lots of reagents and consumables to estimate the LoD. For this study, the estimated LoD was defined as the lowest concentration of target cells at which 10/10 replicates gave a positive test result. The LoD was then confirmed by testing 20 replicates for each strain at the estimated LoD. Analytical sensitivity (LoD), defined as the lowest concentration at which ≥ 95% of all replicates are expected to test positive, ranged from 144 to 4774 CFU/mL of Sample Buffer after dispensing rectal swab specimen into the Sample Buffer Tube.
| Target | Strain | Species | CFU/mL | % |
|---|---|---|---|---|
| KPC | CP254 | Klebsiella pneumoniae | 2005 | 95% |
| CP365 | Klebsiella pneumoniae | 3560 | 100% | |
| VIM | CP260 | Pseudomonas aeruginosa | 159 | 100% |
| CP433 | Enterobacter cloacae | 520 | 95% | |
| IMP | CP253 | Escherichia coli | 319 | 100% |
| CP149 | Klebsiella pneumoniae | 144 | 95% | |
| OXA | CP258 | Klebsiella pneumoniae | 229 | 95% |
| CP411 | Escherichia coli | 902 | 95% | |
| NDM | CP259 | Klebsiella pneumoniae | 4774 | 100% |
| CP184 | Escherichia coli | 4492 | 95% |
| Table 6. BD MAX Check-Points CPO Limit of Detection for Individual Targets | |
|---|---|
| ---------------------------------------------------------------------------- | -- |
Analytical Specificity
The BD MAX Check-Points CPO Assay was performed on samples containing phylogenetically related species and other organisms likely to be found in rectal swab specimens. In addition, species were tested typically containing the BD MAX Check-Points CPO carbapenemase target genes, but having either no or a different carbapenemase gene, other ß-lactamase genes or other antibiotic resistance determinants. The bacterial cells were seeded into negative rectal swab matrix at a concentration of ~ 5 x 10° cells/mL. Overall, 26 organisms were tested in 3 replicates and are listed in Table 7. All organisms tested negative.
11
| Strain
| ID | Species | Reference | B-lactamase gene |
|---|---|---|---|
| CP-575 | Campylobacter jejuni | CCUG-41359 | None |
| CP-521 | Citrobacter freundii | N/A | CTX-M9 ESBL |
| CP-338 | Citrobacter braakii | N/A | GES |
| Carbapenemase | |||
| CP-568 | Corynebacterium diphtheriae | CCUG-37874 | None |
| CP-484 | Enterobacter aerogenes | N/A | None |
| CP-034 | Enterobacter cloacae | N/A | CTX-M9 ESBL |
| CP-573 | Enterococcus casseliflavus | CCUG-55879 | None |
| CP-574 | Enterococcus faecalis | CCUG-9997 | None |
| CP-048 | Escherichia coli | N/A | CTX-M1 ESBL |
| CP-576 | Helicobacter pylori | CCUG-17874 | None |
| CP-058 | Klebsiella oxytoca | N/A | CTX-M9 ESBL |
| CP-012 | Klebsiella pneumonia | N/A | SHV-ESBL |
| CP-570 | Listeria monocytogenes | CCUG-33548 | None |
| CP-357 | Pseudomonas aeruginosa | N/A | PER ESBL |
| CP-132 | Salmonella typhimurium | N/A | pAmpC |
| CP-519 | Raoultella sp. | N/A | SHV & CTX-M9 |
| ESBL | |||
| CP-571 | Staphylococcus aureus | CCUG-9128 | None |
| CP-250 | Serratia marcescens | N/A | None |
| CP-009 | Stenotrophomonas maltophilia | N/A | SHV & CTX-M9 |
| ESBL; pAmpC | |||
| CP-284 | Acinetobacter baumannii | N/A | OXA-23 |
| Carbapenemase | |||
| CP-503 | Morganella morganii | N/A | None |
| CP-319 | Providencia stuartii | N/A | VEB ESBL |
| CP-567 | Providencia alcalifaciens | CCUG-6325 | None |
| CP-569 | Streptococcus agalactiae | CCUG-29780 | None |
| CP-052 | Proteus mirabilis | N/A | pAmpC |
| CP-440 | Acinetobacter baumannii | N/A | OXA-58 |
| Carbapenemase |
Table 7. Organisms Tested to Determine BD MAX Check-Points CPO Specificity
N/A: Strain from in-house strain collection with no reference number available
12
Interfering Substances
Twenty-nine (29) biological and chemical substances that may occasionally be present in rectal swab specimens were evaluated for potential interference with the BD MAX Check-Points CPO Assay and are listed in Table 8. All substances were evaluated at a test concentration of 0.25% w/v (2.5 mg/mL) in negative rectal swab matrix. Test specimens included negative rectal swab matrix seeded with target organisms at 3x LoD (positive specimens) or not seeded (negative specimens). For each substance 6 positive and 6 negative specimens were tested. Results demonstrated no reportable interference with any of the substances tested (refer to Table 8).
| Oils & fatty
| acids | Metal salts | Antibiotics | Painkillers |
|---|---|---|---|
| Stearic acid | Ba2SO4 | Cephalexin | Naproxen |
| Palmitic acid | CaCO3 | Ciprofloxacin | Benzocaine |
| Mineral Oil | Al(OH)3 | Polymyxin B | Phenylephrine |
| Simethicone | Mg(OH)2 | Bacitracin | Bismuth |
| subsalicylate | |||
| Cholesterol | Neomycin | ||
| Alcohols | Histamine | ||
| antagonists | Surfactants | Remaining | |
| Resorcinol | Famotidine | Nonoxynol-9 | Hydrocortisone |
| Ethanol | Omeprazole | Benzalkonium | |
| chloride | Loperamide | ||
| Hydrochloride | |||
| Cimetidine | Nystatin | ||
| Sennosides |
Table 8. Substances not Interfering with BD MAX Check-Points CPO
Inter-lab reproducibility
The inter-lab reproducibility for the BD MAX Check-Points CPO Assay was determined by analyzing one strain per target spiked into negative rectal swab matrix in 2 different concentrations (1.5x LoD and 3x LoD), non-target strain spiked into negative rectal swab matrix and negative rectal swab matrix at 3 different sites by 2 operators using 1 lot during 5 days.
13
| KPC | NDM | OXA-48 | VIM/IMP | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| + | - | + | - | + | - | + | - | |||
| 1.5x LoD | 100% | |||||||||
| (60/60) | 98.3% | |||||||||
| (59/60) | 100% | |||||||||
| (60/60) | 97.5% | |||||||||
| (117/120) | ||||||||||
| (95% CI) | (94.0- | |||||||||
| 100%) | (91.1- | |||||||||
| 99.7%) | (94.0- | |||||||||
| 100%) | (92.9- | |||||||||
| 99.1%) | ||||||||||
| 3x LoD | 100% | |||||||||
| (60/60) | 100% | |||||||||
| (60/60) | 100% | |||||||||
| (60/60) | 99.2% | |||||||||
| (119/120) | ||||||||||
| (95% CI) | (94.0- | |||||||||
| 100%) | (94.0- | |||||||||
| 100%) | (94.0- | |||||||||
| 100%) | (95.4- | |||||||||
| 99.9%) | ||||||||||
| Negatives | 100% | |||||||||
| (100/100) | 100% | |||||||||
| (100/100) | 100% | |||||||||
| (100/100) | 100% | |||||||||
| (100/100) | ||||||||||
| (95% CI) | (96.3- | |||||||||
| 100%) | (96.3- | |||||||||
| 100%) | (96.3- | |||||||||
| 100%) | (96.3- | |||||||||
| 100%) |
Table 9. Inter-lab Reproducibility Results for BD MAX Check-Points CPO
In summary, the inter-lab reproducibility ranged from 100-100%, 97.5-100% and 99.2-100% for Negatives, 1.5x LoD and 3x LoD, respectively.
Inter-lot reproducibility
The inter-lot reproducibility for the BD MAX Check-Points CPO Assay was determined by analyzing one strain per target spiked into negative rectal swab matrix in 2 different concentrations (1.5x LoD and 3x LoD), non-target strain spiked into negative rectal swab matrix and negative rectal swab matrix at 1 site by 2 operators using 3 lots during 5 days.
| KPC | NDM | OXA-48 | VIM/IMP | |||||
|---|---|---|---|---|---|---|---|---|
| + | - | + | - | + | - | + | - | |
| 1.5x LoD | 100% | |||||||
| (60/60) | 100% | |||||||
| (60/60) | 100% | |||||||
| (60/60) | 99.2% | |||||||
| (119/120) | ||||||||
| (95% CI) | (94.0- | |||||||
| 100%) | (94.0- | |||||||
| 100%) | (94.0- | |||||||
| 100%) | (95.4- | |||||||
| 99.9%) | ||||||||
| 3x LoD | 100% | |||||||
| (60/60) | 100% | |||||||
| (60/60) | 100% | |||||||
| (60/60) | 100% | |||||||
| (120/120) | ||||||||
| (95% CI) | (94.0- | |||||||
| 100%) | (94.0- | |||||||
| 100%) | (94.0- | |||||||
| 100%) | (96.9- | |||||||
| 100%) | ||||||||
| Negatives | 100% | |||||||
| (90/90) | 100% | |||||||
| (90/90) | 100% | |||||||
| (90/90) | 100% | |||||||
| (90/90) | ||||||||
| (95% CI) | (95.9- | |||||||
| 100%) | (95.9- | |||||||
| 100%) | (95.9- | |||||||
| 100%) | (95.9- | |||||||
| 100%) |
Table 10. Inter-lot Reproducibility Results for BD MAX Check-Points CPO
In summary, the inter-lot reproducibility ranged 100-100%, 100-100% and 99.2-100% for Negatives, 1.5x and 3x LoD, respectively.
14
Intra-lab reproducibility
The intra-lab reproducibility was determined by analyzing one strain per target spiked into neqative rectal swab matrix in 2 different concentrations (1.5x LoD and 3x LoD), non-target strain spiked into negative rectal swab matrix and neqative rectal swab matrix at 1 site by 2 operators using 1 lot during 12 days.
| KPC | NDM | OXA-48 | VIM/IMP | ||||||
|---|---|---|---|---|---|---|---|---|---|
| + | - | + | - | + | - | + | - | ||
| 1.5x LoD | 100% | ||||||||
| (48/48) | 100% | ||||||||
| (48/48) | 97.9% | ||||||||
| (47/48) | 99.0% | ||||||||
| (95/96) | |||||||||
| (95% CI) | (92.6- | ||||||||
| 100%) | (92.6- | ||||||||
| 100%) | (89.1- | ||||||||
| 99.6%) | (94.3- | ||||||||
| 99.8%) | |||||||||
| 3x LoD | 97.9% | ||||||||
| (47/48) | 100% | ||||||||
| (48/48) | 100% | ||||||||
| (48/48) | 100% | ||||||||
| (96/96) | |||||||||
| (95% CI) | (89.1- | ||||||||
| 99.6%) | (92.6- | ||||||||
| 100%) | (92.6- | ||||||||
| 100%) | (96.2- | ||||||||
| 100%) | |||||||||
| Negatives | 100% | ||||||||
| (72/72) | 100% | ||||||||
| (72/72) | 100% | ||||||||
| (72/72) | 100% | ||||||||
| (72/72) | |||||||||
| (95% CI) | (94.9- | ||||||||
| 100%) | (94.9- | ||||||||
| 100%) | (94.9- | ||||||||
| 100%) | (94.9- | ||||||||
| 100%) |
Table 11. Intra-lab Reproducibility Results for BD MAX Check-Points CPO
In summary, the intra-lab reproducibility ranged from 100-100%, 97.9-100% and 97.9-100% for Negatives, 1.5x and 3x LoD, respectively.
Carry-over contamination
Carry-over contamination was assessed by testing negative specimens together with positive specimens containing a high load of bacteria carrying the carbapenemase resistance genes KPC, OXA48, NDM and VIM or IMP. Positions of negative and positive specimens were alternated to maximize the possibility for carry-over contamination. Negative rectal swab matrix was used for negative specimens, and to prepare positive specimens by seeding matrix with target organisms at a concentration of 5 x 106 CFU/mL. No positive calls were found for a total of 166 negative specimens.
Mixed Infection / Competitive interference
No interference was observed from testing of thirteen (13) specimens containing one KPC, VIM, IMP, OXA-48, or NDM target from strains with known LoD spiked at 2x LoD and one or two other target organism(s) spiked at ~1x106 CFU/mL into negative rectal swab matrix.
10. Conclusion:
The performance characteristics summarized above demonstrate that BD MAX Check-Points CPO is safe and effective for its intended use and is substantially equivalent to the predicate device.