(84 days)
Not Found
No
The device description focuses on automated real-time PCR and does not mention any AI or ML components. The performance studies describe standard clinical validation methods, not AI/ML model training or testing.
No
Explanation: The device is an in vitro diagnostic test for detecting a gene associated with vancomycin resistance. It is explicitly stated that the assay is "not intended to diagnose infections...nor to guide or monitor treatment," which indicates it does not provide therapy but rather aids in recognition and control of resistant organisms.
Yes
The "Intended Use / Indications for Use" section explicitly states that the device is a "qualitative in vitro diagnostic test". Additionally, the "Device Description" also refers to it as an "automated in vitro diagnostic test".
No
The device description explicitly details hardware components like the GeneXpert instrument, modules with syringe drives, ultrasonic horns, and thermocyclers, as well as disposable fluidic cartridges and reagents. This indicates it is a system with significant hardware components, not a software-only device.
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 a "qualitative in vitro diagnostic test". It is designed to detect a specific gene sequence in a biological sample (rectal swab) to aid in the recognition, prevention, and control of vancomycin-resistant organisms. This aligns perfectly with the definition of an IVD, which is used to examine specimens derived from the human body to provide information for diagnostic purposes.
- Device Description: The description further reinforces this by calling it a "rapid, automated in vitro diagnostic test". It describes the process of analyzing a biological specimen (rectal swab) using a specific technology (PCR) to detect a marker (vanA gene) associated with a health condition (vancomycin resistance).
- Performance Studies: The document details clinical performance studies comparing the device's results to reference methods (culture and sequencing) using human specimens, which is standard practice for validating IVDs.
The document clearly and repeatedly identifies the device as an in vitro diagnostic test and describes its use in analyzing human specimens for diagnostic-related information.
N/A
Intended Use / Indications for Use
The Cepheid Xpert® vanA Assay performed in the GeneXpert® Dx System is a qualitative in vitro diagnostic test designed for rapid detection of the vanA gene sequence associated with vancomycin resistance in bacteria obtained from rectal swab specimens from patients at risk for intestinal colonization with vancomycin-resistant bacteria. The test utilizes automated real-time polymerase chain reaction (PCR) to detect the vanA gene that is frequently associated with vancomycin-resistant enterococci (VRE). The Xpert vanA Assay is intended to aid in the recognition, prevention, and control of vancomycinresistant organisms that colonize patients in healthcare settings. The Xpert vanA Assay is not intended to diagnose infections caused by vancomycin-resistant bacteria nor to guide or monitor treatment for vancomycin-resistant bacterial infections. Concomitant cultures are necessary to recover organisms for identification of vancomycin-resistant bacteria, antimicrobial susceptibility testing and for epidemiological typing.
Product codes
NIJ, OOI
Device Description
The Cepheid Xpert vanA Assay is a rapid, automated in vitro diagnostic test for qualitative detection of the vanA gene sequence associated with vancomycin resistance in bacteria obtained directly from rectal swab specimens. The Xpert vanA Assay system performs real-time multiplex polymerase chain reaction (PCR) for detection of DNA after an initial sample processing step. The assay is performed on the Cepheid GeneXpert® Dx System.
The specimen is collected on a double swab, one of which is placed in a tube containing elution reagent. Following brief vortexing, the eluted material and two single-use reagents (Reagent 1 and Reagent 2) that are provided with the assay are transferred to different, uniquely-labeled chambers of the disposable fluidic cartridge (the Xpert vanA cartridge). The user initiates a test from the system user interface and places the cartridge into the GeneXpert® Dx System instrument platform, which performs hands-off realtime, multiplex polymerase chain reaction (PCR) for detection of DNA. In this platform, additional sample preparation, amplification, and real-time detection are all fullyautomated and completely integrated.
The GeneXpert® System consists of a GeneXpert instrument, personal computer, and the multi-chambered fluidic cartridges that are designed to complete sample preparation and real-time PCR for detection of the vanA gene that is associated with vancomycin-resistant enterococci (VRE) in.less than 45 minutes. Each instrument system has 1 to 16 randomly accessible modules that are each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids, an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and detection.
The Xpert vanA Assay includes reagents for the detection of the vanA resistant gene as well as an internal sample processing control (SPC) to control for adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR assay. The SPC also ensures the PCR conditions (temperature and time) are appropriate for the amplification reaction and that the PCR reagents are functional. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Rectal swabs
Indicated Patient Age Range
Not Found
Intended User / Care Setting
Patients at risk for intestinal colonization with vancomycin-resistant bacteria in 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
Performance characteristics of the Xpert vanA Assay were determined in a multi-site prospective investigation study at three US institutions by comparing the Xpert vanA Assay to reference culture followed by bi-directional sequencing confirmation on those samples positive for vanA by culture.
A total of 1231 specimens were tested by Xpert vanA Assay, culture and bi-directional sequencing.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Clinical Comparison Study
- Study Type: Multi-site prospective investigation study.
- Sample Size: 1231 specimens.
- Standalone performance: Overall assay success rate (combining the first and second attempts) was 98.1% (1231/1255).
- Key Results:
- Performance vs. Direct Culture: Relative to direct culture with bi-directional sequencing, the Xpert vanA Assay demonstrated a percent positive agreement of 98.4% and a percent negative agreement of 92.4%.
- Performance vs. Enriched Culture: Relative to enriched culture with bi-directional sequencing, the Xpert vanA Assay demonstrated a percent positive agreement of 86.5% and a percent negative agreement of 93.5%.
- Antibiotic Usage: Antibiotic use did not cause a statistically significant difference in assay performance.
Analytical Reactivity (Inclusivity)
- Sample Size: 30 vancomycin-resistant enterococci strains and 20 vancomycin sensitive enterococci strains, provided by the CDC.
- Key Results: All 20 vancomycin sensitive strains were reported as "vanA NEGATIVE." 9 out of 10 vanA positive vancomycin-resistant enterococci strains were correctly reported as "vanA POSITIVE." All 20 non-vanA vancomycin resistant enterococci strains were reported as "vanA NEGATIVE."
Analytical Sensitivity (Limit of Detection - LoD)
- Sample Size: Determined using 4 to 10 replicates at each dilution, with 20 replicates at the estimated LoD concentration.
- Key Results: The limit of detection for the Xpert vanA Assay on a simulated rectal swab specimen is 37 CFU.
Linearity
- Sample Size: Enterococcus faecium (vanA) cells serially diluted over 6 logs, tested in replicates of four (4) at each concentration.
- Key Results: The Xpert vanA Assay responds linearly (r2 = 0.994) with respect to vanA detection as a function of Enterococcus faecium cell input over 6 logs (50 - 5x10 CFU/test). The reportable Ct range is 12.1 to 35.3 (cutoff Ct = 40.0). PCR efficiency for the vanA reaction is 87.7 %.
Analytical Specificity
- Sample Size: Forty-two bacterial and fungal strains. Each strain tested in triplicate.
- Key Results: The analytical specificity was 100%, with all isolates reported "vanA NEGATIVE".
Interfering Substances
- Sample Size: Sixteen exogenous substances.
- Key Results: None of the 16 substances tested showed detectable interference for vanA. Hydrocortisone cream and Pepto-Bismol® may slightly interfere with the Xpert vanA Assay by resulting in slightly higher Ct values.
Reproducibility
- Sample Size: A panel of four specimens was tested on 10 different days by two different operators at each of the three sites (4 specimens x 2 operators/day x 10 days x 3 sites), total 240 tests.
- Key Results:
- Neg: 96.7% Total Agreement
- vanA High Neg: 98.3% Total Agreement
- vanA Low Pos: 100% Total Agreement
- vanA Moderate Pos: 98.3% Total Agreement
- Overall Total Agreement by Site: Site 1 (100%), Site 2 (96.3%), Site 3 (98.8%)
- Overall Total Agreement: 98.3%
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Performance vs. Direct Culture:
- % Positive Agreement: 98.4%
- % Negative Agreement: 92.4%
- Accuracy: 93.0%
- PPV: 60.0%
- NPV: 99.8%
- Prevalence: 10.4%
Performance vs. Enriched Culture:
- % Positive Agreement: 86.5%
- % Negative Agreement: 93.5%
- Accuracy: 92.6%
- PPV: 67.1%
- NPV: 97.8%
- Prevalence: 13.2%
Predicate Device(s)
BD IDI-VanR® Assay [510(k) #K061686], Remel Esculin Azide Agar w/6 µg/mL vancomycin [510(k) #K972359]
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
5.0 510(k) Summary
As required by 21 CFR Section 807.92(c).
| Submitted by: | Cepheid |
|---|---|
| 904 Caribbean Drive | |
| Sunnyvale, CA 90489 | |
| Phone number: (408) 400-8230 | |
| Fax number: (408) 541-6439 |
| DEC 1 7 2009 | |
|---|---|
| -- | -------------- |
| Contact: | Russel K. Enns, Ph.D. |
|---|---|
| Date of Preparation: | September 23, 2009 |
| Device: | |
| Trade name: | Xpert® vanA |
| Common names: | Xpert® vanA Assay |
| Type of Test: | Qualitative nucleic acid amplification test of the vanA gene directly from rectal swabs. |
| Classification: | II |
| Classification name: | System, test, genotypic detection, resistant marker, Enterococcus species |
| Regulation number: | 866.1640 |
| Procode: | NIJ |
| Classification Advisory Committee: | Microbiology |
| Panel: | 83 |
| Predicate Devices: | BD IDI-VanR® Assay [510(k) #K061686] |
| Remel Esculin Azide Agar w/6 µg/mL vancomycin [510(k) #K972359] |
Device Description:
The Cepheid Xpert vanA Assay is a rapid, automated in vitro diagnostic test for qualitative detection of the vanA gene sequence associated with vancomycin resistance in bacteria obtained directly from rectal swab specimens. The Xpert vanA Assay system performs real-time multiplex polymerase chain reaction (PCR) for detection of DNA after an initial sample processing step. The assay is performed on the Cepheid GeneXpert® Dx System.
The specimen is collected on a double swab, one of which is placed in a tube containing elution reagent. Following brief vortexing, the eluted material and two single-use reagents (Reagent 1 and Reagent 2) that are provided with the assay are transferred to
1
different, uniquely-labeled chambers of the disposable fluidic cartridge (the Xpert vanA cartridge). The user initiates a test from the system user interface and places the cartridge into the GeneXpert® Dx System instrument platform, which performs hands-off realtime, multiplex polymerase chain reaction (PCR) for detection of DNA. In this platform, additional sample preparation, amplification, and real-time detection are all fullyautomated and completely integrated.
The GeneXpert® System consists of a GeneXpert instrument, personal computer, and the multi-chambered fluidic cartridges that are designed to complete sample preparation and real-time PCR for detection of the vanA gene that is associated with vancomycin-resistant enterococci (VRE) in.less than 45 minutes. Each instrument system has 1 to 16 randomly accessible modules that are each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids, an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and detection.
The Xpert vanA Assay includes reagents for the detection of the vanA resistant gene as well as an internal sample processing control (SPC) to control for adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR assay. The SPC also ensures the PCR conditions (temperature and time) are appropriate for the amplification reaction and that the PCR reagents are functional. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.
Device Intended Use:
The Cepheid Xpert® vanA Assay performed in the GeneXpert® Dx System is a qualitative in vitro diagnostic test designed for rapid detection of the vanA gene sequence associated with yancomvcin resistance in bacteria obtained from rectal swab specimens from patients at risk for intestinal colonization with vancomycin-resistant bacteria. The test utilizes automated real-time polymerase chain reaction (PCR) to detect the vanA gene that is frequently associated with vancomvcin-resistant enterococci (VRE). The Xpert vanA Assay is intended to aid in the recognition, prevention, and control of vancomycinresistant organisms that colonize patients in healthcare settings. The Xpert vanA Assay is not intended to diagnose infections caused by vancomycin-resistant bacteria nor to guide or monitor treatment for vancomycin-resistant bacterial infections. Concomitant cultures are necessary to recover organisms for identification of vancomvcin-resistant bacteria, antimicrobial susceptibility testing and for epidemiological typing.
Substantial Equivalence:
The Xpert vanA Assay is substantially equivalent to the BD IDI-VanR Assay (510(k) #K061686). Both assays detect vancomycin resistance genes directly from rectal swab specimens from patients at risk for VRE colonization. Both assays use real-time PCR amplification and fluorogenic target-specific hybridization detection.
Table 5.1 shows the similarities and differences between the Xpert vanA Assay and the BD IDI-VanR Assay.
2
The Xpert vanA is also substantially equivalent to the reference direct culture method. The reference culture method is the Remel Bile Esculin Azide agar with 6 ug/mL vancomycin (BEAV) [510(k) #K972359].
Performance characteristics of the Xpert vanA Assay were determined in a multi-site prospective investigation study at three US institutions by comparing the Xpert vanA Assay to reference culture followed by bi-directional sequencing confirmation on those samples positive for vanA by culture.
Table 5.2 compares the new device with the reference direct culture method. The test results showed the Xpert vanA Assay to be substantially equivalent to the current standard of care, the reference culture method.
3
:
ı
| Similarities | ||
|---|---|---|
| Device | Predicate | |
| Item | Xpert vanA Assay | IDI-VanR Assay (K061686) |
| Intended Use | The Cepheid Xpert® vanA | |
| Assay performed in the | ||
| GeneXpert® Dx System is a | ||
| qualitative in vitro diagnostic | ||
| test designed for rapid | ||
| detection of the vanA gene | ||
| sequence associated with | ||
| vancomycin resistance in | ||
| bacteria obtained from rectal | ||
| swab specimens from patients | ||
| at risk for intestinal | ||
| colonization with | ||
| vancomycin-resistant bacteria. | ||
| The test utilizes automated | ||
| real-time polymerase chain | ||
| reaction (PCR) to detect the | ||
| vanA gene that is frequently | ||
| associated with vancomycin- | ||
| resistant enterococci (VRE). | ||
| The Xpert vanA Assay is | ||
| intended to aid in the | ||
| recognition, prevention, and | ||
| control of vancomycin- | ||
| resistant organisms that | ||
| colonize patients in healthcare | ||
| settings. The Xpert vanA | ||
| Assay is not intended to | ||
| diagnose infections caused by | ||
| vancomycin-resistant bacteria | ||
| nor to guide or monitor | ||
| treatment for vancomycin- | ||
| resistant bacterial infections. | ||
| Concomitant cultures are | ||
| necessary only to recover | ||
| organisms for epidemiological | ||
| typing, antimicrobial | ||
| susceptibility testing, and for | ||
| further confirmatory | ||
| identification of vancomycin- | ||
| resistant bacteria. | The IDI-VanR® Assay is a | |
| qualitative in vitro test for the | ||
| rapid detection of | ||
| vancomycin-resistance | ||
| enterococci (VRE). The assay | ||
| is performed on an automated | ||
| real-time PCR instrument with | ||
| rectal swabs from patients at | ||
| risk for VRE colonization. | ||
| The IDI-VanR® Assay can be | ||
| used as an aid to identify, | ||
| prevent and control | ||
| vancomycin-resistant | ||
| colonization in healthcare | ||
| settings. Concomitant cultures | ||
| are necessary to recover | ||
| organisms for epidemiological | ||
| typing, susceptibility testing | ||
| and for further confirmatory | ||
| identification. The IDI- | ||
| VanR® Assay is not intended | ||
| to diagnose VRE infections | ||
| nor to guide or monitor | ||
| treatment for VRE infections. | ||
| Type of test | Qualitative | Same |
| Similarities | ||
| Technological Principles | Fully-automated nucleic acid amplification (DNA); real-time PCR | Same |
| Specimen Type | Direct from rectal Swabs | Same |
| Test Cartridge | Disposable single-use, multi-chambered fluidic cartridge. | Disposable single-use PCR tube |
| Probes | TaqMan® Probes | Molecular Beacons |
| Controls | Internal sample processing control (SPC) and probe check control (PCC). | |
| External controls available. | One internal reagent control and external positive and negative controls required per run | |
| DNA Target Sequence | Detects gene sequences for the vanA encoded resistance to vancomycin/ teicoplanin. | Detects gene sequences for VanR (vanA and vanB) encoded resistance to vancomycin/teicoplanin. |
| Rapid test results | Less than 45 minutes to results. | Approximately 120 minutes. |
| Interpretation of test results | Diagnostic software of the Cepheid GeneXpert Dx System | Diagnostic software of the Cepheid SmartCycler Dx System |
| Differences | ||
| Device | Predicate | |
| Item | Xpert vanA Assay | IDI-VanR Assay (K061686) |
| Instrument System | Cepheid GeneXpert Dx System | Cepheid SmartCycler |
| DNA Target Sequence | Detects sequences for the vanA gene. | Detects sequences for vancomycin resistance [vanR (vanA and vanB)] gene, but does not differentiate vanA from vanB. |
| Sample Extraction/Fluidics | Self-contained and automated after swab elution and two single-dose reagent additions. | Manual |
| Users | Operators with no clinical lab experience to experienced clinical | CLIA High Complexity Laboratory Users |
| Similarities | ||
| Item | Device | |
| Xpert vanA Assay | Culture Method Predicate | |
| Remel Bile Esculin Azide | ||
| agar with 6 µg/mL | ||
| vancomycin (BEAV) | ||
| [510(k) #K972359] | ||
| Intended Use | The Cepheid Xpert® vanA Assay | |
| performed in the GeneXpert® Dx | ||
| System is a qualitative in vitro diagnostic | ||
| test designed for rapid detection of the | ||
| vanA gene sequence associated with | ||
| vancomycin resistance in bacteria | ||
| obtained from rectal swab specimens | ||
| from patients at risk for intestinal | ||
| colonization with vancomycin-resistant | ||
| bacteria. The test utilizes automated | ||
| real-time polymerase chain reaction | ||
| (PCR) to detect the vanA gene that is | ||
| frequently associated with vancomycin- | ||
| resistant enterococci (VRE). The Xpert | ||
| vanA Assay is intended to aid in the | ||
| recognition, prevention, and control of | ||
| vancomycin-resistant organisms that | ||
| colonize patients in healthcare settings. | ||
| The Xpert vanA Assay is not intended to | ||
| diagnose infections caused by | ||
| vancomycin-resistant bacteria nor to | ||
| guide or monitor treatment for | ||
| vancomycin-resistant bacterial | ||
| infections. Concomitant cultures are | ||
| necessary only to recover organisms for | ||
| epidemiological typing, antimicrobial | ||
| susceptibility testing, and for further | ||
| confirmatory identification of | ||
| vancomycin-resistant bacteria. | Remel Bile Esculin Azide agar | |
| with 6 µg/mL vancomycin is a | ||
| plated medium recommended | ||
| for use in qualitative | ||
| procedures as a selective and | ||
| differential medium for the | ||
| primary isolation of | ||
| vancomycin resistant | ||
| enterococci from surveillance | ||
| cultures. This product is not | ||
| intended for use as a method | ||
| of antimicrobial susceptibility | ||
| testing. Confirmation of | ||
| vancomycin resistance by an | ||
| approved method is | ||
| recommended as some | ||
| organisms on initial isolation | ||
| may overcome the inhibitory | ||
| effects of the medium. | ||
| Single use | Yes | Same |
| Type of test | Qualitative | Same |
| Specimen Type | Direct from rectal swabs | Direct from rectal swab or |
| stool. |
Table 5.1: Similarities and Differences between the Xpert vanA Assay and the IDI-VanR Assay
4
.
.
5
CONFIDENTIAL
Table 5.2: Similarities and Differences between the Xpert vanA Assay and the Reference Culture Method Predicate Device
6
| Differences | |||
|---|---|---|---|
| Item | Xpert vanA Assay | Culture Method Predicate | |
| Technology | Fully-automated nucleic acid (DNA) preparation and amplification; real-time PCR. | ||
| Detect sequences specific to vanA gene | Phenotypic detection of vancomycin-resistant enterococci (VRE) based on culture growth | ||
| Mode of Detection | Presence of vanA gene | Growth or no growth on | |
| 6mg/mL vancomycin agar | |||
| Specimen Type | Direct from rectal swabs | Culture grown direct from | |
| rectal swab or stool | |||
| Internal Controls | Sample processing control (SPC) and probe check control (PCC). | Not applicable | |
| Interpretation of test results | Diagnostic software of the GeneXpert Dx System | Visual interpretation | |
| Remel Bile Esculin Azide agar with 6 µg/mL vancomycin (BEAV) [510(k) #K972359] |
Non-Clinical Studies:
Analytical Reactivity (Inclusivity)
Thirty vancomvcin-resistant enterococci strains and 20 vancomycin sensitive enterococci strains, provided by the CDC, were tested using the Xpert vanA Assay. Of the 30 vancomvcin-resistant enterococci strains. 10 were identified as vanA positive. Enterococci strains were selected to broadly represent the genetic diversity found in enterococci. Stock cultures were prepared by suspending the bacterial growth from agar plates in PBS buffer containing 15% glycerol. The concentration of each stock was adjusted to 5.6x10° to 2.1x10'0 CFU/mL. All strains were serially diluted to approximately 360 CFU/swab and tested in triplicate.
Under the conditions of this study, all 20 vancomycin sensitive strains were reported as "vanA NEGATIVE," as expected. Among the 10 vanA positive vancomycin-resistant enterococci strains tested, one strain was reported as "vanA NEGATIVE." When this strain was sequenced the data matched 100% to a reference vanB sequence, confirming that the Xpert vanA Assay accurately reported the strain "vanA NEGATIVE." The remaining 9 vanA positive vancomycin resistant enterococci strains were correctly reported as "vanA POSITIVE." as expected. Among the 20 non-vanA vancomycin resistant enterococci strains, all were reported as "vanA NEGATIVE," as expected.
7
Analytical Sensitivity
Studies were performed to determine the 95% confidence intervals for the analytical limit of detection (LoD) of Enterococcus facium (vanA) diluted into a fecal matrix of human origin that can be detected by the Xpert vanA Assay. The fecal matrix consisted of autoclaved human liguid feces (vanA negative) diluted 1:10 in Tris buffer. The LoD is defined as the lowest number of colony forming units (CFU) per swab that can be reproducibly distinguished from negative samples with 95% confidence.
The analytical LoD was estimated using 4 to 10 replicates at each dilution. The LoD was confirmed by running a total of 20 replicates at the estimated LoD concentration. Under the conditions of this study, the limit of detection for the Xpert vanA Assay on a simulated rectal swab specimen is 37 CFU.
Linearity
A study was conducted to define the reportable range of the Xpert vanA Assay and demonstrate a linear between target input and assay output. Linearity was evaluated using Enterococcus faecium (vanA) cells serially diluted over 6 logs and processed using the Xpert vanA Assay. The diluted cells resulted in a cell concentration dose range of 50 CFU/test to 5x10' CFU/test. Replicates of four (4) were tested at each concentration.
For enterococci cells, under the conditions of this study, the Xpert vanA Assay responds linearly (r2 = 0.994) with respect to vanA detection as a function of Enterococcus faecium cell input over 6 logs (50 - 5x10' CFU/test). The reportable Ct range is 12.1 to 35.3 (cutoff Ct = 40.0). PCR efficiency for the vanA reaction is 87.7 %.
Analytical Specificity
Forty-two bacterial and fungal strains were collected, quantitated and tested using the Xpert vanA Assay. The strains originated from the American Type Culture Collection (ATCC), Culture Collection University of Göteborg (CCUG), German Collection of Microorganisms and Cell Cultures (DSMZ), and the Centers for Disease Control and Prevention (CDC).
The organisms tested were identified as Gram-positive (22), Gram-negative (18), including antibiotic-resistant strains of Pseudomonas spp. and Acinetobacter spp., and yeast (2). The organisms were further classified as aerobic (24), anaerobic (14) or microaerophillic (2). Of the species tested, 2 vancomycin-sensitive strains of E. faecalis and E. faecium were included.
Each strain was tested in triplicate at concentrations ranging from 8.5x108 to 2.3x1010 CFU/swab. Positive and negative controls were included in the study. Under the conditions of the study, all isolates were reported "vanA NEGATIVE". The analytical specificity was 100%.
8
Interfering Substances
Sixteen exogenous substances occasionally used or found in stool were tested for interference with the Xpert vanA Assay. The substances tested are listed in Table 5.3. None of the 16 substances tested showed detectable interference for vanA. However, Hydrocortisone cream (1 % Hydrocortisone) and Pepto-Bismol® (1 - 5% Bismuth subsalicylate) may slightly interfere with the Xpert vanA Assay. When tested in the Interference study, Hydrocortisone cream and Pepto-Bismol® resulted in slightly higher Ct values relative to the buffer control.
| Substance | Substance |
|---|---|
| Whole Blood | Vaseline |
| Karolinska University Hospital | Unilever |
| Mucin (porcine) | Dulcolax® |
| Sigma | Boehringer Ingelheim Pharmaceuticals |
| Kaopectate® | Preparation H® Portable Wipes |
| Chattem | Wyeth Consumer Healthcare |
| Imodium® | Vancomycin |
| McNeil-PPC | Fluka |
| Fleet® | Metronidazole |
| CB Fleet Company | Actavis |
| Fecal fats | Anusol® Plus |
| Karolinska University Hospital | TM Warner-Lambert Company |
| K-Y Jelly/Gelée® | E-Z-HDTM High Density Barium Sulfate for suspension |
| McNeil-PPC | E-Z-EM Canada |
| AHydrocortisone Cream | APepto-Bismol® |
| Longs Drugs | Proctor & Gamble |
| Table 5.3: Substances Tested and Showing No Assay Interference for vanA | |
|---|---|
| ------------------------------------------------------------------------- | -- |
4 When tested in the Interference study, results showed slightly higher Ct values relative to the buffer r control
Clinical Studies
Clinical Comparison Study
Performance characteristics of the Xpert vanA Assay were determined in a multi-site prospective investigation study at three US institutions by comparing the Xpert vanA Assay to reference culture followed by bi-directional sequencing for confirmation on vancomycin-resistant E. faecalis or E. faecium isolates.
Subjects included individuals whose routine care called for VRE testing. One swab from a double swab set was used for patient management; the other swab was used for the Xpert vanA Assay testing. The leftover swab designated for patient management was sent to a central laboratory for reference culture.
Leftover specimen swabs designated for culture testing were stored at 2-8°C and shipped on ice packs to the central culture laboratory within 48 hours of collection. Reference culture was initiated within 16 hours of receipt or within 5 days of swab collection.
9
Each swab was subsequently placed into bile esculin azide broth with 8 µg/ml vancomycin. The plates were incubated at 35°C and examined at 48 and 72 hours. The broth was also incubated at 35℃ for 48 hours and subcultured to a bile esculin azide agar with 6 ug/ml of vancomycin.
Small, gray colonies with a black halo were considered suspicious for VRE. Presumptive identification was accomplished by performing a Gram stain, catalase and disc pyr (Lpyrrolidonyl-beta-naphthylamide) test. Presumptive VRE specimens were Gram-positive cocci or coccobacilli and pyr positive. Presumptive VRE was definitively identified using the API20S strip (BioMérieux, France). Finally, VRE isolates were tested for their susceptibility to glycopeptides using vancomycin &-test strips (AB Biodisk, Sweden). Susceptibility to teicoplanin for the isolates was determined by agar dilution. Following reference culture testing. DNA was prepared from vancomycin-resistant E. faecilis or E. faecium isolates, and sent to a second reference laboratory for bi-directional sequencing using alternative vanA specific primers (i.e., different from those used in the Xpert vanA Assay).
Performance of the Xpert vanA Assay was calculated relative to the results of direct culture with bi-directional sequencing, and enriched culture with bi-directional sequencing.
Overall Results
A total of 1231 specimens were tested by Xpert vanA Assay, culture and bi-directional sequencing.
Performance vs. Direct Culture
Relative to direct culture with bi-directional sequencing, the Xpert vanA Assay
demonstrated a percent positive agreement of 98.4% and a percent negative agreement of
92.4% (Table 5.4).
10
CONFIDENTIAL
| Direct Culture + Sequencing | ||||
|---|---|---|---|---|
| Pos | Neg | Total | ||
| Xpert vanA | ||||
| Assay | Pos | 126 | 84 | 210 |
| Neg | 2 | 1019 | 1021 | |
| Total | 128 | 1103 | 1231 | |
| % Positive Agreement: 98.4% | ||||
| % Negative Agreement: 92.4% | ||||
| Accuracy: 93.0% | ||||
| PPV: 60.0% | ||||
| NPV: 99.8% | ||||
| Prevalence: 10.4% |
| Table 5.4: Xpert vanA Assay Performance vs. |
|---|
| Direct Culture with Bi-directional Sequencing |
Of the Xpert vanA Assays run on eligible specimens, 94.0% (1180/1255) of these specimens were successful on the first attempt. The remaining 75 gave indeterminate results on the first attempt (26 "INVALID", 49 "ERROR" and 0 "NO RESULT"). Sixty two (62) of the75 indeterminates on the first attempt had sufficient sample for retest, 82.3% (51/62) gave a result on the second the attempt. Overall assay success rate (combining the first and second attempts) was 98.1% (1231/1255).
Performance vs. Enriched Culture
Relative to enriched culture with bi-directional sequencing, the Xpert vanA Assay demonstrated a percent positive agreement of 86.5% and a percent negative agreement of 93.5% (Table 5.5).
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| Enriched Culture + Sequencing | ||||
|---|---|---|---|---|
| Pos | Neg | Total | ||
| Xpert vanA | ||||
| Assay | Pos | 141 (137) | 69 (69) | 210 (206) |
| Neg | 22 (21) | 999 (953) | 1021 (974) | |
| Total | 163 (158) | 1068 (1022) | 1231 (1180) | |
| % Positive Agreement: | 86.5% | |||
| % Negative Agreement: | 93.5% | |||
| Accuracy: | 92.6% | |||
| PPV: | 67.1% | |||
| NPV: | 97.8% | |||
| Prevalence: | 13.2% |
Table 5.5: Xpert vanA Assay Performance vs. Enriched Culture with Bi-directional Sequencing
Of the Xpert vanA Assays run on eligible specimens, 94.0% (1180/1255) of these specimens were successful on the first attempt. The remaining 75 gave indeterminate results on the first attempt (26 "INVALID", 49 "ERROR" and 0 "NO RESULT"). Sixty two (62) of the75 indeterminates on the first attempt had sufficient sample for retest, 82.3% (51/62) gave a result on the second the attempt. Overall assay success rate (combining the first and second attempts) was 98.1% (1231/1255)
Antibiotic Usage
Among the 1231 cases included in the main dataset, antibiotic use within the 3 weeks prior to sample collection was reported for 414 and no antibiotic use was confirmed for 483; for 334 cases, antibiotic status was unknown. Antibiotic use did not cause a statistically significant difference in assay performance.
Reproducibility
A panel of four specimens with varying concentrations of vanA was tested on 10 different days by two different operators at each of the three sites (4 specimens x 2 operators/ day x 10 days x 3 sites). One lot of Xpert vanA Assay was used at each of the 3 testing sites. Xpert vanA Assays were performed according to the Xpert vanA Assay procedure. Results are summarized in Tables 5.6.
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CONFIDENTIAL
| % Agreementa | ||||
|---|---|---|---|---|
| Specimen ID | Site 1 | Site 2 | Site 3 | % Total |
| Agreement by | ||||
| Sample | ||||
| Neg | 100% | |||
| (20/20) | 90% | |||
| (18/20) | 100% | |||
| (20/20) | 96.7% | |||
| (58/60) | ||||
| vanA High Neg | 100% | |||
| (20/20) | 100% | |||
| (20/20) | 95% | |||
| (19/20) | 98.3% | |||
| (59/60) | ||||
| vanA Low Pos | 100% | |||
| (20/20) | 100% | |||
| (20/20) | 100% | |||
| (20/20) | 100% | |||
| (60/60) | ||||
| vanA Moderate Pos | 100% | |||
| (20/20) | 95% | |||
| (19/20) | 100% | |||
| (20/20) | 98.3% | |||
| (59/60) | ||||
| % Total Agreement by Site | 100% | |||
| (80/80) | 96.3% | |||
| (77/80) | 98.8% | |||
| (79/80) | 98.3% | |||
| (236/240) |
Table 5.6: Summary of Reproducibility Results (all)4
"For negative and high negative samples, %Agreement = (# negative results/total samples run); for low and moderate positive samples, %Agreement = (# positive results/total samples run).
Conclusions
The results of the nonclinical analytical and clinical performance studies summarized above demonstrate that the Xpert vanA Assay is as safe, as effective, and performs as well as the current standard of care, the reference culture method with confirmation of all results by bi-directional sequence analysis. Therefore, the Xpert vanA Assay is substantially equivalent to the predicate device.
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Image /page/13/Picture/0 description: The image is a black and white logo for the Department of Health & Human Services - USA. The logo is circular, with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter of the circle. Inside the circle is a stylized image of what appears to be an abstract symbol.
Food and Drug Administration 10903 New Hampshire Avenue Document Mail Center - WO66-0609 Silver Spring, MD 20993-0002
OEC 1 7 2000
Cepheid® c/o Russel K. Enns. Ph.D. Senior Vice President Regulatory, Clinical & Government Affairs & Quality Systems 904 Carribean Drive Sunnyvale, CA 94089
Re: K092953
Trade/Device Name: Xpert® vanA Assay Regulation Number: 21 CFR §866.1640 Regulation Name: Antimicrobial susceptibility test powder Regulatory Class: II Product Code: NIJ, OOI Dated: September 23, 2009 Received: September-24,-2009.
Dear Dr. Enns:
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. 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.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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
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Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0484. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html
Sincerely yours,
Sayatryns
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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Image /page/15/Picture/0 description: The image shows the word "Cepheid" in a stylized font, with three curved lines above it. Below the word, there is the text "4.0 Indications for Use Statement". The text is in a smaller font than the word "Cepheid".
510(k) Number (if known): K092953
Device Name: Xpert vanA
Indications for Use:
The Cepheid Xpert® vanA Assay performed in the GeneXpert® Dx System is a qualitative in vitro diagnostic test designed for rapid detection of the vanA gene sequence associated with vancomycin resistance in bacteria obtained from rectal swab specimens from patients at risk for intestinal colonization with vancomycin-resistant bacteria. The test utilizes automated real-time polymerase chain reaction (PCR) to detect the vanA gene that is frequently associated with vancomycin-resistant enterococci (VRE). The Xpert vanA Assay is intended to aid in the recognition, prevention, and control of vancomycinresistant organisms that colonize patients in healthcare settings. The Xpert vanA Assay is not intended to diagnose infections caused by vancomycin-resistant bacteria nor to guide or monitor treatment for vancomycin-resistant bacterial infections. Concomitant cultures are necessary to recover organisms for identification of vancomycin-resistant bacteria, antimicrobial susceptibility testing and for epidemiological typing
Prescription Use X (Part 21 CFR 801 Subpart D)
Over-The-Counter Use AND/OR (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE OF NEEDED)
Lueddeke. Cook
ivision Sign-Off
Office of In Vitro Diagnostic Device Evaluation and Safety
510(K) K092953
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