(468 days)
The VITEK® REVEAL™ AST System is an automated system for qualitative antimicrobial susceptibility testing (AST) of organisms direct from positive blood culture. The VITEK® REVEAL™ AST System does not provide organism identification.
The VITEK® REVEAL™ AST System is an automated system that uses an array of sensors to detect volatile organic compounds emitted by growing bacteria for the in vitro quantitative determination of antimicrobial susceptibility. The VITEK® REVEAL™ GN AST Assay is indicated for susceptibility testing direct from positive blood culture samples signaled as positive by a continuous monitoring blood culture system and confirmed to contain gramnegative bacilli by Gram stain. Organism identification is required for AST result interpretation and reporting.
This test is performed by laboratory health professionals in a clinical diagnostic setting. Results may be used as an aid to clinicians in determining appropriate antimicrobial therapy. Test results from the VITEK® REVEAL™ AST System should be interpreted in conjunction with other clinical and laboratory findings. Standard laboratory protocols for processing positive blood cultures should be followed to ensure availability of isolates for supplemental testing. Sub-culturing is necessary to support further testing for: bacteria and antimicrobials not on the VITEK® REVEAL™ GN AST Assay panel, inconclusive results, epidemiologic testing, recovery of organisms present in positive blood cultures samples, and susceptibility testing of bacteria in polymicrobial samples.
The VITEK® REVEAL™ GN AST Assay tests the following antimicrobial agents with the specific target organisms identified below:
Amikacin: Acinetobacter baumannii-calcoaceticus complex, Citrobacter freundii (including Citrobacter freundii complex), Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae group, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens
Amoxicillin/clavulanate: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae group, Proteus mirabilis
Ampicillin/sulbactam: Escherichia coli, Klebsiella oxytoca, Proteus mirabilis
Aztreonam: Citrobacter freundii complex), Enterobacter cloacae (including E. cloacae complex), Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae (including K. pneumoniae group), Pseudomonas aeruginosa
Cefepime: Citrobacter koseri (syn. C. diversus), Enterobacter cloacae (including E. cloacae complex), Escherichia coli, Klebsiella species (including K. pneumoniae group and K. aerogenes), Klebsiella oxytoca, Pseudomonas aeruginosa
Cefotaxime: Acinetobacter baumanni-calcoaceticus complex, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae group
Ceftazidime: Acinetobacter baumannii-calcoaceticus complex, Citrobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae group
Ceftazidime/avibactam: Citrobacter freundii complex, Citrobacter cloacae (including E. cloacae complex), Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae (including K. pneumoniae group), Proteus mirabilis, Pseudomonas aeruginosa
Ceftolozane/tazobactam: Citrobacter koseri, Enterobacter cloacae (including E. cloacae complex), Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa
Ceftriaxone: Enterobacter cloacae (including E. cloacae complex), Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae (including K. pneumoniae group), Proteus mirabilis
Cefuroxime: Citrobacter koseri, Escherichia coli, Klebsiella pneumoniae group, Klebsiella oxytoca, Proteus mirabilis
Ciprofloxacin: Citrobacter freundit complex), Enterobacter cloacae (including E. cloacae complex), Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae (including K. pneumoniae group), Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens
Ertapenem: Escherichia coli, Klebsiella pneumoniae (including K. pneumoniae group), Proteus mirabilis, Proteus vulgaris
Gentamicin: Citrobacter freundii complex, Citrobacter koseri, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae group, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens
Imipenem: Acinetobacter baumannii-calcoaceticus complex, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae group, Pseudomonas aeruginosa, Serratia marcescens
Levofloxacin: Citrobacter koseri, Citrobacter freundii complex), Enterobacter cloacae (including E. cloacae complex), Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae (including K. pneumoniae group), Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens
Meropenem: Acinetobacter baumannii-calcoaceticus complex, Enterobacter cloacae (including E. cloacae complex), Escherichia coli, Klebsiella pneumoniae (including K. pneumoniae group), Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens
Meropenem/vaborbactam: Citrobacter freundii (incluidng C. freundii complex), Citrobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae (including K. pneumoniae group), Proteus mirabilis
Piperacillin/tazobactam: Citrobacter koseri, Escherichia coli, Klebsiella pneumoniae group), Proteus vulgaris
Tetracycline: Acinetobacter baumannii-calcoaceticus complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae group
Tobramycin: Citrobacter freundii complex, Citrobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae group, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens
Trimethoprim/sulfamethoxazole: Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae group
ESBL Confirmation test: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae group
The VITEK® REVEAL™ AST System is an in vitro diagnostic (IVD) automated platform for phenotypic Antimicrobial Susceptibility Testing (AST) of bacterial samples, directly from positive blood cultures. The System utilizes broth microdilution (BMD) principles to quickly and accurately determine Minimum Inhibitory Concentrations (MIC) for the drugs on the VITEK® REVEAL™ GN AST Assay, and in combination with species identification (obtained from an FDA-cleared rapid ID method), will provide a Susceptible / Intermediate / Resistant (SIR) determination, or a Positive/Negative (POS/NEG) determination for the ESBL Confirmation screen test, for the species tested. The VITEK® REVEAL™ AST System is indicated for susceptibility testing of specific Gramnegative bacteria commonly associated with bacteremia (Table 1).
Sample preparation for testing in the VITEK® REVEAL™ AST System is fast, simple, and requires minimal skill. After a blood culture sample is identified as positive by a validated, automated blood culture system, a Gram stain is performed to confirm positivity and to determine whether the sample is Gram-positive, Gram-negative, or yeast. Samples determined by Gram stain to be monomicrobial for Gram-negative bacteria are diluted in Pluronic water and dispensed into VITEK® REVEAL™ Antibiotic Panels, containing serial dilutions of antibiotics and dried media. A VITEK® REVEAL™ Sensor Panel is sealed atop an inoculated VITEK® REVEAL™ Antibiotic Panel using the VITEK® REVEAL™ Sealer in an AST disposable assembly comprising a VITEK® REVEAL™ GN AST Assay.
The VITEK® REVEAL™ AST System detects bacterial growth using an array of proprietary chemical Small Molecule Sensors (SMS), which change color in the presence of various metabolic gases (volatile organic compounds) emitted by growing bacteria during incubation. The SMS arrays, printed onto the VITEK® REVEAL™ Sensor Panel, are positioned atop each well of the VITEK® REVEAL™ Antibiotic Panel. The sealed VITEK® REVEAL™ GN AST Assay is placed in the VITEK® REVEAL™ Instrument, which functions as an incubator for the samples being tested and optically monitors and tracks the change in sensor colors as the bacteria grow. These color changes are monitored by a scan every 10 minutes, allowing a real-time assessment of growth as a function of antibiotic concentration. A real-time algorithm detects sensor array responses indicating the volatile-compound emissions that are associated with bacterial population growth. Each antimicrobial agent-containing well is then compared to the response in control wells (the positive control well containing no antimicrobial agent, and the negative containing no growth media). Bacterial growth (indicating resistance) or inhibition of growth (indicating susceptibility) relative to these controls is determined for each antimicrobial agent-concentration pair. The MIC is defined as the lowest concentration of antimicrobial agent that inhibits growth. Categorical interpretation (SIR result) is furnished based on current FDA or FDA-recognized CLSI breakpoints for each antimicrobial. Species identification by an FDA-cleared test method may be entered at any time during the AST run or after the AST run.
The VITEK® REVEAL™ AST System includes a VITEK® REVEAL™ Sealer, a VITEK® REVEAL™ Instrument, and a master controller computer (MCC)/touch screen monitor. The system is scalable, and up to eight (8) VITEK® REVEAL™ Instruments can be controlled by one user-friendly, touchscreen interface. The VITEK® REVEAL™ AST System is also modular, avoiding the risk of a single instrument failure causing an interruption in laboratory testing. Each VITEK® REVEAL™ Instrument has two independently loadable drawers with each drawer able to hold two (2) GN AST Assays. A single VITEK® REVEAL™ Sealer can support multiple VITEK® REVEAL™ instruments since each sealing step takes less than a minute with a one-button operation.
The provided text describes the VITEK® REVEAL™ GN AST Assay and VITEK® REVEAL™ AST System, an automated system for antimicrobial susceptibility testing. The document details several performance studies to demonstrate the device's accuracy and robustness.
Here's an analysis of the acceptance criteria and study proving the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance
The document presents acceptance criteria for Essential Agreement (EA) and Categorical Agreement (CA) for various performance studies. The overall acceptance criterion for EA and CA in most studies (blood culture bottle equivalency, sample stability, interfering substances) is >89.9% or ≥95%, while for reproducibility, it's ≥95% (best-case) and ≥89% (worst-case).
The table below summarizes the reported performance against these criteria for the Method Comparison Study, which evaluates clinical performance. The full table for all antimicrobial agents and species is extensive, so a representative excerpt from the "Combined" results (Clinical + Challenge samples) for key performance metrics is provided from Table 8 in the document.
Acceptance Criteria for Method Comparison Study (Clinical Performance), as per FDA guidance (Class II Special Controls Document: Antimicrobial Susceptibility Test (AST) Systems):
- Essential Agreement (EA) and Categorical Agreement (CA): Not explicitly stated as a single number at an overall level, but generally expected to be high (e.g., >89.9% for individual errors to be acceptable). The document states "Overall agreement was high".
- Error Rates (Very Major (VMJ), Major (MJ), Minor (MIN)):
- VMJ (False Susceptible): Should be ≤1.5%.
- MJ (False Resistant): Should be ≤3.0%.
- MIN (Minor Error): Not explicitly given a threshold, but typically acceptable if EA is high and clinical impact is low.
Table: VITEK® REVEAL™ Reported Device Performance (Excerpt from Method Comparison, Combined Samples)
| Antimicrobial / Species Group | Total Samples | EA (%) | CA (%) | VMJ (%) | MJ (%) | MIN (%) | Acceptance Met (Based on Overall/Adjusted Rates and Discussion) |
|---|---|---|---|---|---|---|---|
| Amikacin - Enterobacterales | 631 | 98.1 | 99.4 | 0.0 | 0.0 | ~0.6 | Yes (Met all criteria) |
| Amikacin - A. baumannii | 60 | 90.0 | 88.3 | 0.0 | 0.0 | ~11.7 | Yes (Low CA noted, but acceptable due to all minor errors and EA being high for evaluable strains; specific limitation added) |
| Amoxicillin/clavulanate - Enterobacterales | 500 | 95.0 | 90.8 | 0.0 | 0.6 | ~8.6 | Yes (MJ rate for E. coli noted, but acceptable with limitation) |
| Ampicillin/sulbactam - Enterobacterales | 372 | 97.8 | 77.2 | 0.0 | 0.8 | ~22.0 | Yes (Low CA for E. coli/K. oxytoca noted, but acceptable as evaluable EA was high; no major/very major errors) |
| Cefepime - Enterobacterales | 579 | 96.0 | 95.9 | 0.0 | 0.5 | ~3.6 | Yes (CA for E. cloacae complex noted, but acceptable) |
| Ciprofloxacin - Enterobacterales | 681 | 99.0 | 95.6 | 0.1 | 0.1 | ~4.1 | Yes (Single VMJ/MJ noted, specific limitation added) |
| Ertapenem - Enterobacterales | 493 | 97.8 | 98.8 | 0.0 | 0.2 | ~1.0 | Yes (Met all criteria) |
| Gentamicin - Enterobacterales | 684 | 96.6 | 98.2 | 0.1 | 0.3 | ~1.3 | Yes (Single VMJ noted, specific limitation added) |
| Imipenem - P. aeruginosa | 65 | 93.8 | 93.8 | 3.1 | 0.0 | ~3.1 | Yes (Two VMJ errors noted, specific limitation added to device labeling) |
| Tobramycin - Enterobacterales | 657 | 96.5 | 94.8 | 0.5 | 0.2 | ~4.6 | Yes (VMJ errors and MJ errors noted, specific limitations added) |
| Trimethoprim/sulfamethoxazole - Enterobacterales | 480 | 95.0 | 96.5 | 0.6 | 2.9 | N/A | Yes (VMJ/MJ errors noted, specific limitations added) |
| ESBL Confirmation - Enterobacterales | 408 | N/A | 98.5 | 0.2 | 1.2 | N/A | Yes (VMJ/MJ errors noted, specific limitations added) |
Note: The error rates (VMJ, MJ, MIN) were calculated based on the # vmj, # maj, # min columns and Total samples from Table 8, then converted to percentages. Some "N/A" for minors indicate that the count was not provided separately if EA/CA met expectations. The acceptance of lower CA/EA for some combinations is discussed in the text, usually with a rationale (e.g., "all minor errors") and/or a specific limitation added to the product labeling, indicating that the overall performance is considered acceptable by the FDA for market clearance.
2. Sample Size Used for the Test Set and Data Provenance
For the Method Comparison Study (Clinical Performance), which serves as the primary test set:
- Total Samples Enrolled: 1239 samples.
- Total Samples Included in Final Performance Analyses: 1115 samples.
- Fresh Prospective Positive Blood Culture Samples: 424 samples (after exclusions). These are deidentified clinical samples from patients suspected of bacteremia.
- Contrived Samples with Clinical Stock Isolates: 101 samples (after exclusions).
- Contrived Samples with Challenge Isolates: 590 samples (after exclusions).
- Data Provenance:
- Country of Origin: Not explicitly stated, but "seven (7) US clinical sites" indicates the data is from the United States.
- Retrospective or Prospective: Both. "Fresh prospective positive blood culture samples" refers to prospectively collected samples. "Clinical stock isolates from the site's inventory and provided challenge isolates" refer to contrived samples, which could be based on retrospective collections or reference strains.
For Reproducibility Study:
- A "set of Gram-negative isolates" was selected. For each panel organism, testing was performed at three sites, in triplicate, on three days, for a total of 27 results per sample. The total number of tests varied per antibiotic, e.g., Amikacin had 891 tests, Amoxicillin/clavulanate had 324 tests etc.
For Blood Culture Bottle Equivalency Study:
- Sample Size: Nine (9) strains representing seven (7) species were tested. Six (6) bottle replicates were tested for each organism and bottle type.
For Sample Stability Study:
- Sample Size: Twenty-five (25) strains representing nine (9) species were selected. Testing was performed in triplicate for each temperature condition and timepoint.
For Interfering Substances Study:
- Sample Size: Five (5) organisms were tested in triplicate for each of the nine (9) interfering substances. This sums to 15 tests per interferant (5 organisms * 3 replicates), which is summed up per interferant type in Table 5a. Additional testing with platelets involved "Fifteen-sixteen strains".
For Initial Inoculum Study:
- Sample Size: Five (5) species were tested in triplicate blood culture bottles for each of three (3) different initial starting concentrations. This means 15 tests per species (5 species * 3 concentrations * 3 replicates = 45 total tests).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The document does not explicitly state the "number of experts" or their specific "qualifications" involved in establishing the ground truth.
However, the ground truth for Antimicrobial Susceptibility Testing (AST) results, which is a key component of the device's performance, was established by reference frozen broth microdilution (BMD). This method was "tested according to CLSI M07 (11th Edition) Standard" and "performed in triplicate on custom, 96-well, frozen microdilution plates prepared by the reference testing laboratory." This implies that the ground truth was established by established laboratory protocols and standards (CLSI) using a reference method, not necessarily by a panel of human experts adjudicating results. Personnel performing these reference tests would be trained laboratory professionals.
4. Adjudication Method for the Test Set
The concept of "adjudication" as typically applied to human experts resolving disagreements (e.g., 2+1 or 3+1) is not applicable here.
For the Method Comparison study, the device's MIC results and categorical interpretations were compared against reference BMD modal MICs. The BMD method itself involved triplicate testing. If there were discrepancies in the triplicate BMD results, a "modal MIC" would be used as the reference. Discrepancies between the device and the reference BMD would then be classified into Essential Agreement (EA), Categorical Agreement (CA), and error rates (VMJ, MJ, MIN), against pre-defined breakpoints.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done.
This device (VITEK® REVEAL™ AST System) is an automated in vitro diagnostic (IVD) system for antimicrobial susceptibility testing. It determines MICs and categorical interpretations directly from positive blood cultures. It does not involve human readers interpreting images or data alongside AI. Therefore, a study comparing human readers with and without AI assistance is not relevant to this type of device. The study evaluates the device's standalone performance against a gold standard laboratory method (BMD).
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done
Yes, a standalone performance evaluation was done.
The entire performance study, particularly the "Method Comparison Study," assesses the VITEK® REVEAL™ AST System's ability to accurately determine antimicrobial susceptibility on its own, by comparing its results directly to the reference BMD method. The system is designed to provide automated results without human interpretation or intervention in the determination of susceptibility profiles. The human role is in sample preparation and inputting organism identification (obtained from another FDA-cleared rapid ID method), but the AST determination itself is performed by the system's algorithm and sensors.
7. The Type of Ground Truth Used
The ground truth used for the performance studies, especially the critical Method Comparison Study, was:
- Reference frozen broth microdilution (BMD), tested according to CLSI M07 (11th Edition) Standard. This is a widely accepted laboratory gold standard for antimicrobial susceptibility testing.
Additionally, for the Method Comparison, "Organism identification for all samples was confirmed by an FDA-cleared MALDI ID method." This serves as ground truth for the organism identity, which is a prerequisite for accurate AST interpretation.
8. The Sample Size for the Training Set
The document does not provide information about a "training set" or its size. This is typical for in vitro diagnostic devices like the VITEK® REVEAL™ System, especially those based on biophysical detection rather than machine learning algorithms trained on large datasets. The primary development and validation for such systems often involve engineering principles, analytical studies, and direct comparisons to reference methods, rather than distinct "training" and "test" sets in the machine learning sense. The performance data presented (reproducibility, equivalency, stability, interfering substances, and method comparison) are analogous to what would be considered validation or test data to prove the device's capability.
If there are internal algorithms that "learn" or optimize, the training data for such components and their size are not disclosed in this document.
9. How the Ground Truth for the Training Set Was Established
As noted in point 8, information about a "training set" and its ground truth establishment is not available in the provided document. The development of the VITEK® REVEAL™ System's proprietary chemical Small Molecule Sensors (SMS) and its real-time algorithm for detecting growth, as described in the device description section, would have involved significant internal research and development, but the specific validation process for these "training" aspects is not detailed in this 510(k) summary. The document focuses on the performance validation for regulatory submission.
§ 866.1650 A cellular analysis system for multiplexed antimicrobial susceptibility testing.
(a)
Identification. A cellular analysis system for multiplexed antimicrobial susceptibility testing is a multiplex qualitative and/or quantitative in vitro diagnostic device intended for the identification and determination of the antimicrobial susceptibility results of organisms detected in samples from patients with suspected microbial infections. This device is intended to aid in the determination of antimicrobial susceptibility or resistance when used in conjunction with other laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include:
(i) Detailed device description documentation, including the device components, ancillary reagents required but not provided, a detailed explanation of the methodology, including primer/probe sequence, design, rationale for sequence selection, and details of the antimicrobial agents, as applicable.
(ii) Detailed documentation from the following analytical and clinical performance studies: limit of detection, inclusivity, precision, reproducibility, interference, cross-reactivity, carryover, and cross-contamination, quality control and additional studies, as applicable to specimen type and assay intended use.
(iii) Detailed documentation from an appropriate clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted reference methods.
(iv) Detailed documentation for device software, including software applications and hardware-based devices that incorporate software.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) Limitations and protocols regarding the need for correlation of results by standard laboratory procedures, as applicable.
(ii) A detailed explanation of the interpretation of results and acceptance criteria.
(iii) A detailed explanation of the principles of operation and procedures for assay performance and troubleshooting.