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The PBC Separator with Selux AST System is an automated inoculum preparation system that uses lysis, centrifugation and sequential optical density measurements to generate a McFarland-equivalent suspension from positive blood culture samples that can be used for quantitative in vitro antimicrobial susceptibility testing by the Selux AST System. Samples are processed directly from blood culture samples identified as positive by a continuous monitoring blood culture system. Samples should be confirmed as monomicrobial, gram negative rods or gram positive cocci by Gram stain. Organism identification is required for AST result interpretation and reporting, per the Selux AST System Instructions for Use.

Inoculum preparation by the PBC Separator was evaluated for use with the Selux AST System and the Selux AST Gram Negative Panel. Performance was demonstrated for the antimicrobial agents and organisms identified below:

• Amikacin: Acinetobacter baumannii complex, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa

· Amoxicillin-Clavulanate: Escherichia coli, Klebsiella species (including K. oxytoca, K. pneumoniae), Proteus mirabilis, Proteus vulgaris

· Ampicillin: Escherichia coli, Proteus mirabilis

· Ampicillin-Sulbactam: Acinetobacter baumannii complex, Citrobacter koseri, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis

• Cefazolin: Escherichia coli, Klebsiella pneumoniae

· Cefepime: Citrobacter freundii complex, Citrobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa

• Ceftazidime: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa

· Ceftazidime-Avibactam: Citrobacter freundii complex, Citrobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa

· Ceftriaxone: Citrobacter freundii complex, Citrobacter cloacae complex, Escherichia coli,

Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens

• Ciprofloxacin: Citrobacter freundii complex, Citrobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa

• Ertapenem: Citrobacter freundii complex, Citrobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens

• Gentamicin: Citrobacter freundii complex, Citrobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa

· Imipenem: Acinetobacter baumannii complex, Escherichia coli, Klebsiella pneumoniae

· Meropenem: Acinetobacter baumannii complex, Citrobacter koser, Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa

· Minocycline: Acinetobacter baumannii complex, Escherichia coli, Klebsiella pneumoniae

• Piperacillin-Tazobactam: Acinetobacter baumannii complex, Citrobacter koseri, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa

• Tobramycin: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa

Inoculum preparation by the PBC Separator was evaluated for use with the Selux AST System and the Selux AST Gram Positive Panel. Performance was demonstrated for the antimicrobial agents and organisms identified below:

• Ampicillin: Enterococcus faecalis, Enterococcus faecium
• Ceftaroline: Staphylococcus aureus
• Daptomycin: Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus
• · Linezolid: Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus
• Oxacillin: Staphylococcus aureus
• Vancomycin: Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus

The PBC Separator with Selux AST System Gram Positive Panel is a qualitative test for the following antimicrobial agents with the specific target organisms identified below:

• · Cefoxitin Screen to predict mecA-mediated oxacillin resistance: Staphylococcus aureus
  Susceptibility test results are intended to be used 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 as needed. Additionally, subculture of positive is necessary for the susceptibility testing of organisms present in polymicrobial samples, for testing antimicrobial agents and species not indicated for testing with the device, for epidemiologic testing, and for recovery of organisms present in microbial samples.

The Positive Blood Culture (PBC) Separator with Selux AST System is an automated sample preparation instrument with associated consumables that uses lysis, centrifugation, and sequential optical density measurements to prepare a tuned McFarland-equivalent inoculum from positive blood culture bottles that have rung positive on a continuous monitoring blood culture system. Inoculums containing monomicrobial, gram negative or gram positive bacteria are used for Antimicrobial Susceptibility Testing (AST) processing with the Selux AST System. The Selux AST System includes a sample prep station (i.e., AST Workbench), an Inoculator, an Analyzer, Workbench Computer, and the reagents and consumables required to perform AST testing. The PBC Separator and all Selux AST System components are connected to a site workstation, which coordinates sample processing on all instruments. The PBC Separator contains embedded software and a graphical user interface that guides users through the PBC Separator workflow. Once processing of the PBC sample is complete, the user transfers the tuned McFarland inoculum to the Selux AST System for further AST processing.

The PBC Separator with Selux AST System can only provide AST results for monomicrobial samples. Since the PBC Separator with Selux AST System does not perform identification (ID), the monomicrobial nature of the sample under test must be confirmed by an FDA-cleared directfrom-positive blood culture ID system.

While PBC Separator processing can be performed without species-level ID, this information is required for the Selux AST System to interpret and report susceptibility results. Species ID can be performed by any appropriate method and this information can be either manually input to the Selux AST System or automatically downloaded from the laboratory information system (LIS) at any time, once the sample ID is entered into the LIS.

The PBC Separator with the Selux AST System utilizes a 384-well panel, either the Selux Gram-Negative Panel or Selux Gram-Positive Panel, that provides parallel results for the antimicrobials indicated for each sample type. The Selux AST System software masks non-indicated results. The average time-to-result for positive blood culture processed with the PBC Separator and Selux AST System is under 7 hours.

Principle of Operation

The PBC Separator automatically prepares a tuned bacterial inoculum directly from a blood culture bottle sample that "rang" positive on an FDA-cleared continuous monitoring blood culture system, including the Becton Dickinson BACTEC, the bioMerieux BacT/Alert 3D, and the bioMerieux Virtuo. The PBC Separator removes contaminants through repeated centrifugation-wash cycles and specific chemical lysis of mammalian cells and cell fragments. The PBC Separator utilizes an on-board spectrometer to tune the inoculum for the right cell density to perform AST.

Tuned inoculums are used with the Selux AST System. The Selux AST System performs AST similarly to the reference broth microdilution method by first incubating samples, then quantifying microbial growth in each well of an antimicrobial dilution series after a growth period, and finally determining the minimum inhibitory concentration (MIC) by comparing growth data in each well,

AST testing of PBC samples requires that the Gram type (classification) of the organism be known prior to testing on the Selux AST System as the information is necessary to select the proper AST panel to use. Organism identification (ID) is not needed to initiate testing with the Selux AST System. However, the organism ID is necessary for a result to be interpreted and reported because the MIC-determining algorithm is species-specific as is the interpretative Susceptible (S), Susceptible Dose Dependent (SDD), Intermediate (I), or Resistant (R) determination. Any FDAcleared method may be used to provide an ID including biochemical techniques, matrix-assisted laser desorption/ionization mass spectrometry, and multiplex genetic assays.

Here's an analysis of the acceptance criteria and the study proving device performance, based on the provided FDA 510(k) summary for the PBC Separator with Selux AST System:

Acceptance Criteria and Device Performance Study

The document outlines analytical and clinical studies to demonstrate the performance of the PBC Separator with Selux AST System, particularly for gram-positive organisms, compared to a reference method (broth microdilution).

1. Table of Acceptance Criteria and Reported Device Performance

The document presents performance in terms of Essential Agreement (EA), Category Agreement (CA), Very Major Errors (VMJ), Major Errors (MAJ), and Minor Errors (MIN). While explicit "acceptance criteria" are not listed as a single table, the overall performance metrics, particularly the high percentages for EA and CA, and low error rates, indicate the expected and achieved levels of performance. For reproducibility, quantitative acceptance criteria were explicitly stated.

Reproducibility Acceptance Criteria:

• Best-case reproducibility: ≥95%
• Worst-case reproducibility: ≥89% (for inter- and intra-site)

Essential Agreement (EA) Acceptance Criteria (Implicit from "meets performance criteria"):
The overall impression from the "Blood Culture Bottle Compatibility Study" and "Interfering Substances Testing" sections is that EA should be >89.9%.
For the "Clinical Studies" section, while not explicitly stated as a numerical threshold, FDA typically expects high EA and CA (e.g., >90-95%) and very low VMJ/MAJ errors (94% (Range: 94.8% - 100%) |
| Cefoxitin Screen | Inter-site (modal) | N/A (matched modal result) | 99.3% |
| | Intra-site (modal) | N/A (matched modal result) | 100% |
| Bottle Compatibility| Essential Agreement (EA) | >89.9% | Aerobic bottles: 99.4% EA (range ≥96.7%); Anaerobic bottles: 99.3% EA (range ≥96.7%) |
| | Cefoxitin Screen | 100% agreement expected | 100% agreement, except one instance demonstrating 66.7% (2/3) out-of-agreement in BD BACTEC Aerobic Plus bottles. |
| Interfering Substances| Essential Agreement (EA) | >89.9% | All endogenous interferents: 83.3% - 100% EA. All exogenous interferents: 66.7% - 100% EA. |
| | Cefoxitin Screen | No interference (100% agreement) | 100% agreement. |
| Clinical Performance| Essential Agreement (EA) | High (e.g., >90-95%) | Range: 94% - 100% (Individual combos: 75% for Ampicillin Enterococci Eval, 0% for Daptomycin E. faecalis Eval, 47.6% for Vancomycin Enterococci Eval) |
| | Category Agreement (CA) | High (e.g., >90-95%) | Range: 94.6% - 100% |
| | Very Major Errors (VMJ) | Low (e.g.,

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The LifeScale AST system is a multiplexed in vitro diagnostic test that uses a microfluidic sensor and resonant frequency to calculate organism concentration and/or mass distribution for quantitative antimicrobial susceptibility testing (AST). Testing is performed directly on blood cultures signaled as positive by a continuous monitoring blood culture system and confirmed by Gram stain. The LifeScale AST system does not provide organism identification and is not indicated for use with polymicrobial samples. Interpretive results (Susceptible/Intermediate/Susceptible-dose dependent/Resistant) are provided for specific drug/organism combinations. Results are intended to be used 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 as needed. Additionally, subculture of positive blood culture is necessary for the susceptibility testing of organisms present in polymicrobial samples, for testing antimicrobial agents and species not indicated for testing with the device and for epidemiologic testing and for recovery of organisms present in microbial samples.

The LifeScale Gram Negative Kit (LSGN) is intended for use with the LifeScale AST system for in vitro testing of positive blood culture samples confirmed by Gram stain as containing gram-negative bacilli for the antimicrobial agents and specific target organisms identified below:

1. Ampicillin: Escherichia coli
2. Aztreonam: Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca
3. Cefazolin: Escherichia coli, Klebsiella pneumoniae, Klebsiella variicola
4. Ceftazidime: Acinetobacter spp. (other than Acinetobacter ursingii), Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella variicola, Klebsiella pneumoniae, Pseudomonas aeruginosa
5. Ertapenem: Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca
6. Trimethoprim-Sulfamethoxazole: Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella variicola
7. Amikacin: Acinetobacter spp., Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella variicola, Pseudomonas aeruqinosa
8. Cefepime: Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa
9. Ceftazidime-avibactam: Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca
10. Gentamicin: Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella variicola, Pseudomonas aeruginosa
11. Levofloxacin: Escherichia coli, Klebsiella pneumoniae, Klebsiella derogenes, Klebsiella oxytoca, Pseudomonas aeruginosa
12. Meropenem: Acinetobacter spp., Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa
13. Meropenem-vaborbactam: Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca
14. Piperacillin-tazobactam: Acinetobacter spp., Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa

The Affinity Biosensors LifeScale Gram Negative Kit (LSGN) is a semi-automated instrument system for antimicrobial susceptibility testing (AST) directly from positive blood cultures for which the Gram stain shows gram-negative bacilli. The system uses a microfluidic sensor that detects organisms in suspension and measures differences in cell mass between bacterial suspensions incubated in the presence and absence of antibiotic. Minimum inhibitory concentrations (MICs) are determined from data obtained during sample measurement including organism concentration and/or cell mass distributions of individual organisms. The system automatically interprets the measurements to determine MIC values and interpretive results (susceptible, intermediate, or resistant) based on FDA-defined or recognized breakpoints. The organism identification determined using a platform FDA-cleared for use with positive blood culture samples is entered by the user. If the organism identification has not been entered or if the sample has not been confirmed as monomicrobial, the system provides a preliminary report that indicates that organism identification or monomicrobial status is pending. The device Instructions for Use indicates that the preliminary laboratory report should not be reported to the healthcare provider. The final report is provided to the healthcare provider when the organism identification is entered into the system and the culture is confirmed to be monomicrobial samples should not be tested with the LifeScale LSGN Kit. Preliminary results are available in most cases within four hours from initiation of the assay.

Here's a summary of the acceptance criteria and the study details for the LifeScale Gram Negative Kit (LSGN) with the LifeScale AST system, based on the provided FDA 510(k) submission:

1. Table of Acceptance Criteria and Reported Device Performance (Clinical Performance Data)

The acceptance criteria for clinical performance are implicitly demonstrated through the achieved Essential Agreement (EA), Category Agreement (CA), Very Major Discrepancy (VMJ), Major Discrepancy (MAJ), and Minor Discrepancy (MIN) rates. While specific pass/fail thresholds for each of these are not explicitly stated as "acceptance criteria" in a single table, the summary of performance data (Table 3) and subsequent detailed descriptions for each antimicrobial agent confirm the performance was considered acceptable, with a few specified limitations. Generally, for most AST devices, high EA and CA (typically >90-95%) and low VMJ/MAJ rates (typically 89%) reproducibility" was stated for the reproducibility study itself.

For inoculum density, the study aimed to show that organism concentration does not impact performance and that the device terminates tests with insufficient growth.

For media equivalence, an EA agreement of "≥95% for the various blood culture media compared to LifeScale AST mode MICs from the BD BACTEC Standard Aerobic Media" was the acceptance criterion.

For interfering substances, "EA ≥ 95%" was acceptable.

Below is a summarized table of clinical performance for the additional claimed antimicrobial/organism combinations and the performance for the removal of limitations, as these were the focus of the submission. The table combines various performance metrics from Tables 3 and 12, focusing on the overall performance for each drug/organism group. Specific criteria are often tied to regulatory guidelines (e.g., CLSI, FDA), which this document notes were used.

2. Sample Size Used for the Test Set and Data Provenance

The test set consisted of both prospective clinical blood cultures (PBCs) and contrived blood cultures.

• Clinical Samples: 986 total clinical tests were initiated (Table 2). The specific breakdown by drug/organism combination for clinical samples is embedded within the detailed performance sections (e.g., "465 clinical (75.5%)" for Amikacin, indicating 465 clinical samples for Amikacin).
  • Provenance: Collected at 6 US Clinical sites.
  • Retrospective/Prospective: Prospective.
• Contrived Samples: A total of 3307 analytical tests were initiated, which includes contrived samples (Table 2). For individual drug/organism combinations, the number of challenge samples (e.g., "151 challenge (24.5%)" for Amikacin) contributes to the overall number of samples evaluated.
  • Provenance: Prepared from frozen isolates supplied by Affinity Biosensors or contemporary isolates collected by the laboratory.
  • Retrospective/Prospective: Primarily prospective (prepared and tested during the study).

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document does not explicitly state the number of experts or their qualifications for establishing ground truth. However, it indicates:

• Ground Truth Method: The reference method for Antimicrobial Susceptibility Testing (AST) was Broth Microdilution (BMD), performed according to CLSI guidance (CLSI M07).
• Organism Identification: Organism ID for prospective samples was performed using an FDA-cleared direct from positive blood culture ID system, and confirmed by MALDI (matrix-assisted laser desorption/ionization). If there was a discordant identification, MALDI was considered the final identification.
• Reference Testing Location: Reference testing was performed at two trial sites that received isolates from the PBC purity panel.
• This suggests that trained laboratory personnel with expertise in clinical microbiology and adherence to CLSI standards established ground truth.

4. Adjudication Method for the Test Set

The document states:

• "Each sample submitted for BMD testing was assigned a unique Trial ID, and LifeScale results were kept blinded to prevent bias."
• Performance was evaluated by comparing quantitative (MIC) and qualitative (S/I/SDD/R) AST results generated by the LifeScale AST System with those of the reference BMD.
• No explicit "adjudication method" (like 2+1 or 3+1 expert review) for resolving discrepancies between the device and ground truth is described. The comparison appears to be a direct assessment against the BMD reference. Discrepancies (VMJ, MAJ, MIN) are reported, but a formal adjudication process for these discrepancies by additional experts is not detailed.

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. The study focuses on the performance of the automated device (LifeScale AST system) compared to a laboratory reference method (BMD), rather than comparing human reader performance with and without AI assistance. This device is an automated AST system, not an AI-assisted diagnostic tool for human readers.

6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was Done

Yes, the study primarily assessed standalone performance of the LifeScale AST system. The system automatically interprets measurements to determine MIC values and interpretive results. While a user enters the organism identification, the core AST determination is an automated function of the device, making this a standalone performance assessment in the context of AST. The phrase "algorithm only without human-in-the loop performance" applies to the AST result generation itself.

7. The Type of Ground Truth Used

The primary ground truth used was FDA-recognized reference Broth Microdilution (BMD) method, following CLSI guidance (CLSI M07). For organism identification, MALDI was the definitive method.

8. The Sample Size for the Training Set

The document does not provide information on the sample size for the training set. This submission is a 510(k) for an addition of claims to an already cleared device (K211815). The focus is on the performance evaluation for the new claims and removal of limitations, implying that the underlying algorithms were likely developed and validated prior to this specific submission.

9. How the Ground Truth for the Training Set Was Established

The document does not provide information on how the ground truth for the training set was established, as it pertains to the development of the device's algorithms. As mentioned above, this document focuses on the performance of the device for new claims, not its initial development.

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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)

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.

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Intended Use:
The ASTar System is intended to be used for the automated quantitative susceptibility testing for most clinically significant microorganisms. The ASTar System does not provide organism identification.

Indications for Use:
The ASTar System, comprised of the ASTar Instrument with the ASTar BC G- Kit (ASTar BC G- Consumable kit, ASTar BC G- Frozen insert, and ASTar BC G-Kit software), utilizes high-speed, time-lapse microscopy imaging of bacteria for the in vitro, quantitative determination of antimicrobial susceptibility of on-panel gram-negative bacteria. The test is performed directly on positive blood culture samples signaled as positive by a continuous monitoring blood culture system and confirmed to contain gram-negative bacilli by Gram stain. Organism identification is required for AST result interpretation and reporting.

Test results from the ASTar BC G- Kit 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 ASTar BC G- panel, where inconclusive results are obtained, epidemiologic testing, recovery of organisms present in microbial samples, and susceptibility testing of bacteria in polymicrobial samples.

The ASTar BC G- Kit tests the following antimicrobial agents with the following bacterial species:

Amikacin: Citrobacter freundii, Enterobacter cloacae complex, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens
Ampicillin: Escherichia coli, Proteus mirabilis
Ampicillin-sulbactam: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris
Aztreonam: Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens
Cefazolin: Klebsiella pneumoniae
Cefepime: Citrobacter freundii, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens
Ceftazidime: Enterobacter cloacae complex, Escherichia oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens
Ceftazidime-avibactam: Citrobacter freundii, Citrobacter koseri, Enterobacter cloacae complex, Klebsiella oxytoca, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens
Cefuroxime: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis
Ciprofloxacin: Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens
Gentamicin: Citrobacter freundii, Citrobacter koseri, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens
Levofloxacin: Citrobacter freundii, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens
Meropenem: Acinetobacter baumannii, Citrobacter freundii, Citrobacter koseri, Escherichia coli, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens
Meropenem-vaborbactam: Citrobacter freundii, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens
Piperacillin-tazobactam: Citrobacter koseri, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens
Tigecycline: Citrobacter freundii, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Serratia marcescens
Tobramycin: Citrobacter freundii, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens
Trimethoprim-sulfamethoxazole: Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus vulgaris

ASTar System is a fully automated system for antimicrobial susceptibility testing (AST). It consists of the ASTar Instrument which is used in combination with dedicated application kits. The ASTar BC G- Kit consists of the ASTar BC G- Consumable kit, ASTar BC G- Frozen insert, and ASTar BC G-Kit software which must be installed on the instrument to process the kit.

The system provides robust and consistent inoculum preparation for AST and utilizes high-speed, time-lapse microscopy imaging of pathogens in broth microdilution to determine minimum inhibitory concentration (MIC) and qualitative susceptibility results. Organism identification using an approved method is required to be entered into the ASTar Instrument for results to be reported.

The instrument is designed to carry out sample preparation of up to six samples in parallel, using a dedicated ASTar Cartridge consumable for each sample. In the subsequent AST culturing step, the instrument transfers the prepared sample into a second dedicated consumable, referred to as the ASTar Disc. Up to 12 Discs can be incubated simultaneously in the system. The processed samples can be in different stages of the processing protocol. New samples can be loaded in a random-access manner when there are available slots. Processing of loaded samples will, in most cases, start shortly after loading. If six samples are started at the same time limitations given by the sample scheduler will result in a queue. The operator interacts with the instrument via the touchscreen display by which the operator controls the instrument.

ASTar BC G- Kit is used for in vitro determination of antimicrobial susceptibility testing of commonly isolated bacteria derived from positive blood culture samples confirmed positive for Gram-negative bacteria by Gram stain. The antimicrobial and organism combinations are listed in Table 1. Reportable ranges for each antimicrobial are listed in Table 2.

To start an analysis approximately 1 mL of a positive blood culture, confirmed Gram-negative by Gram stain is pipetted into the ASTar Cartridge by the operator and loaded into the system, from which the system purifies and quantifies the bacterial concentration is adjusted to the appropriate inoculum concentration and produces an inoculum for analysis of non-fastidious organisms. The bacterial suspensions are transferred automatically to the ASTar Disc and antimicrobial susceptibility testing is performed based on a defined short-term protocol. Results are available within approximately six hours. Bacterial growth and response to relevant concentrations of different antimicrobial drugs are measured throughout the incubation period, using a high-performance optical detection system in combination with image analysis algorithms. The system generates an MIC and further qualitative susceptibility results (i.e., S, I, R) for the tested antimicrobials when applicable. The qualitative results are determined based on established breakpoints stipulated by applicable authorities, i.e., FDA, CLSI or EUCAST. FDA Susceptibility Testing Interpretive Criteria (STIC), aka "breakpoints" are found in Table 3.

The provided text describes the performance characteristics of the ASTar BC G- Kit and ASTar Instrument, primarily focusing on its antimicrobial susceptibility testing (AST) capabilities. While it details various studies, it does not describe an AI/ML device that utilizes a test set with ground truth experts. Instead, it describes a medical device for in vitro quantitative determination of antimicrobial susceptibility based on time-lapse microscopy imaging.

Therefore, many of the requested points, such as "number of experts used to establish ground truth," "adjudication method," "MRMC comparative effectiveness study," "standalone (algorithm only) performance," and "sample size for the training set" (for an AI model), are not applicable to this document as it does not describe an AI/ML-driven diagnostic device in the traditional sense.

However, I will extract relevant information about the device's acceptance criteria and studies to the best of my ability, interpreting "acceptance criteria" as performance metrics for this type of medical device.

Key Information from the Document:

The ASTar System is an automated system for antimicrobial susceptibility testing (AST) that uses high-speed, time-lapse microscopy imaging of bacteria to determine Minimum Inhibitory Concentration (MIC) and qualitative susceptibility results (S, I, R).

1. A table of acceptance criteria and the reported device performance

The document defines acceptance criteria primarily through performance metrics like Essential Agreement (EA) and Category Agreement (CA) compared to a reference method (frozen Broth Micro-Dilution, BMD), along with rates for Very Major (VMJ) discordant results, Major (MAJ) discordant results, and Minor (MIN) discordant results.

While a single explicit "acceptance criteria table" is not provided with specific pass/fail percentages before results, the overall performance table (Table 16) implicitly represents the success or failure against internal performance goals. The FDA's Special Controls guidance (referenced in 8.5.8) would typically outline such criteria. Based on the "Conclusions" section, the device was deemed "substantially equivalent," implying these metrics were acceptable.

Here's a summary of the reported device performance from Table 16, which reflects the met acceptance criteria for the clinical study:

Table: Reported Device Performance (Summary from Table 16)

*Note: Some "poor performance" combinations (EA 95% of MIC values within ±1 doubling dilution of the mode MIC of initial samples (loaded 95% pass rate as compared to control samples without interfering antibiotics.

Interfering Antibiotics Performance (Table 13):

• All six evaluated antibiotic/BCB-combinations had overall pass rates of 96.2% to 100%. Some individual combinations fell below 90% (e.g., Cefotaxime / BACTEC: Trimethoprim-sulfamethoxazole 77.8%), but the overall criterion (per combination type) was met.

Carry Over and Cross Contamination Acceptance Criteria: (Implicitly, close to 100% pass rate expected)

• MIC for the susceptible isolate for each antimicrobial must be within ±1 doubling dilution of the control mode MIC to pass.

Carry Over and Cross Contamination Performance:

• 99.7% pass rate (307/308) for susceptible isolate MIC value. No carry over or cross contamination observed.

Set Inoculum for AST Acceptance Criteria:

• For starting bacterial concentration >5 x 10^7 CFU/mL, assess and adjust successfully at high rate, producing an inoculum within acceptance ranges.
• For concentrations 5 x 10^7 CFU/mL: 95.8% (23/24) completed concentration adjustment, and 100% (23/23) of those produced an inoculum within acceptance ranges.
• For samples with starting bacterial concentration 5 x 10^6 to

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The LifeScale AST system is a multiplexed in vitro diagnostic test that uses and resonant frequency to calculate organism concentration and/or mass distribution for quantitative antimicrobial susceptibility testing is performed directly on blood cultures signaled as positive by a continuous monitoring blood culture system and confirmed by Gram stain. The LifeScale AST system does not provide organism identification and is not indicated for use with polymicrobial samples. Interpretive results (Susceptible/Intermediate/Resistant) are provided for specific drug/organism combinations. Results are used 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 as needed. Additionally, subculture is necessary for the susceptibility testing of organisms present in polymicrobial samples, for testing antimicrobial agents and species not indicated for testing with the device, for epidemiologic testing and for recovery of organisms present in microbial samples.

The LifeScale Gram Negative Kit (LSGN) is intended for use with the LifeScale AST system for in vitro testing of positive blood culture samples confirmed by Gram staining gram-negative bacilli for the antimicrobial agents and specific target organisms identified below:

• Ampicillin: Escherichia coli

• Aztreonam: Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca
• Cefazolin: Klebsiella pneumoniae, Klebsiella variicola
• Ceftazidime: Acinetobacter baumannii/hosocomialis group, Escherichia coli, Klebsiella aerogenes,
• Klebsiella oxytoca, Klebsiella variicola, Pseudomonas aeruginosa
• · Ertapenem: Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca
• Trimethoprim-Sulfamethoxazole: Escherichia coli, Klebsiella oxytoca, Klebsiella oxytoca, Klebsiella variicola

The LifeScale AST system is an in vitro diagnostic test designed to quantitatively assess antimicrobial susceptibility using a microfluidic sensor and resonant frequency technology. Specifically engineered for use with positive blood culture samples confirmed positive by Gram stain for Gram-negative rods, the LifeScale LSGN Panel ensures compatibility and accuracy while excluding Gram-positive or polymicrobial samples, thus maintaining specificity and reliability. During the incubation phase, the LifeScale LSGN Panel offers a standard incubation time of 3 hours, extendable up to 6 hours to accommodate varying microbial growth rates. Panels must be read within 8 hours of setup, with automatic cancellation for panels exceeding this timeframe. Panels with delayed readings can be safely stored in the offline incubator until analysis. Upon reaching sufficient growth in the positive control wells, the LifeScale AST system transitions to data acquisition and readout. Advanced sensors capture essential metrics including microbe count, mass, and fluid volume, processed through sophisticated software algorithms to generate precise AST results for each antibiotic. To maintain hygiene standards, the LifeScale AST system incorporates automated washing and disinfection protocols for the sipper and sensor, minimizing the risk of cross-contamination and organic buildup. The culmination of the testing process involves calculating and reporting AST results (MIC and interpretive results), providing clinicians with actionable insights into antibiotic efficacy. Species-level organism identification is essential for results reporting. AST results are generated based on FDA or CLSI breakpoints validated for laboratory use.

Acceptance Criteria and Device Performance Study for LifeScale Gram Negative Kit (LSGN) with the LifeScale AST system (K211815)

The information provided describes the performance of the LifeScale Gram Negative Kit (LSGN) with the LifeScale AST system in comparison to a reference method (Broth Microdilution Method - BMD) for Antimicrobial Susceptibility Testing (AST) of gram-negative bacilli from positive blood cultures.

1. Table of Acceptance Criteria and Reported Device Performance

The general acceptance criteria for clinical performance for each antimicrobial agent on the LSGN panel were >90% Essential Agreement (EA) and >90% Categorical Agreement (CA) rates. Additionally, specific thresholds for Very Major Discrepancy (VMJ), Major Discrepancy (MAJ), and Minor Discrepancy (MIN) were evaluated, but the primary overall acceptance for accuracy relies on EA and CA.

Overall Clinical Performance (Aggregated across organisms for each drug)

*For Ceftazidime (P. aeruginosa), major errors were 8.20% (5/61 susceptible isolates), adjusted to 3.3% (2 major errors) due to the lack of an intermediate breakpoint. This value is flagged as a limitation requiring an alternative testing method.
^For Ertapenem (K. oxytoca), very major errors were 20.0% (2/10 resistant isolates). This value is flagged as a limitation requiring an alternative testing method.

Reproducibility Acceptance Criteria and Performance

Blood Bottle Compatibility Acceptance Criteria and Performance
Acceptance Criteria: ≥90% EA for various blood culture media compared to LifeScale LSGN and Reference BMD modes. All tested media types met this criterion, except for specific drug/organism combinations that resulted in limitations (e.g., ertapenem/E.coli with certain anaerobic media).

Sample Stability Acceptance Criteria and Performance
Acceptance Criteria: ≥90% agreement with the reference method modal MIC and the LifeScale LSGN MIC mode within +/- one two-fold dilution at Tpos and T13. All listed antimicrobial/organism combinations met this criterion.

Interfering Substances Acceptance Criteria and Performance
Acceptance Criteria: EA to the mode of control MICs ≥ 90% for all interfering substances. This criterion was generally met for all substances and antibiotics, with some discrepancies noted but attributed to individual strain behavior rather than the interfering substance.

Inoculum Density Study Acceptance Criteria and Performance
Acceptance Criteria: ≥90% essential agreement (within +/- 1 antibiotic dilution) compared to the LifeScale LSGN mode. All tested antimicrobial/organism combinations at 10e6 and 10e9 CFU/mL met this criterion.

2. Sample Sizes Used for the Test Set and Data Provenance

The study included both prospective clinical blood cultures (PBCs) and contrived samples, as well as CDC Challenge and other reference laboratory isolates.

• Clinical Performance Data:

  • Total number of samples evaluated varied by antimicrobial agent:
    • Ampicillin: 137 samples
    • Aztreonam: 301 samples
    • Cefazolin: 143 samples
    • Ceftazidime: 529 samples (total across species)
    • Ertapenem: 224 samples
    • Trimethoprim-Sulfamethoxazole: 340 samples
  • Data Provenance:
    • Prospective clinical blood cultures (PBCs): Enrolled and tested at 6 US Clinical sites. These were verified by Gram stain for gram-negative bacilli.
    • Contrived samples: Prepared from frozen isolates supplied by Affinity Biosensors or from contemporary isolates collected by the laboratory. Blood cultures were spiked and incubated.
    • CDC Challenge and Challenge isolates: Prepared from frozen isolates supplied by Affinity Biosensors to one trial site.
  • The split between clinical (prospective and seeded) and challenge samples varied by antimicrobial (e.g., Ampicillin: 91 clinical, 46 challenge; Aztreonam: 235 clinical, 66 challenge).

• Reproducibility Study: Total evaluable results varied per antibiotic (e.g., Ampicillin: 269; Aztreonam: 294). This involved testing at three testing sites over three consecutive days with three replicates per day for each test organism (total 27 data points per organism).

• Blood Bottle Compatibility: A minimum of 12 strains were tested using each blood culture media type, with replicates of ten (10) per organism/media type. Organisms used were Escherichia coli (8 strains), Klebsiella pneumoniae (4 strains), Pseudomonas aeruginosa (2 strains), Acinetobacter baumannii (3 strains).

• Sample Stability: 16 organisms (susceptible and resistant on-scale MICs for each relevant antibiotic) were chosen. Each organism was tested in triplicate on three LifeScale AST systems at two time points (Tpos and T13). The study evaluated 126 LifeScale LSGN samples for total performance.

• Interfering Substances: A minimum of five (5) test organisms were used for each interferent. Each interfering substance was tested in triplicate for each test organism/media combination. Organisms included Escherichia coli (3 strains), Pseudomonas aeruginosa (1 strain), Acinetobacter baumannii (1 strain), Klebsiella pneumoniae (2 strains).

• Inoculum Density Study: Thirteen strains (not specified if unique per antibiotic) were tested at target organism concentrations of 10e6 CFU/ml and 10e9 CFU/ml. Slow-growing organisms were also seeded at 10e4 CFU/ml.

• Contamination and Carry-Over Testing:

  • Test 1 (Plate-to-Plate with Growth Media): 5 pairs of plates. Each pair read on a different LifeScale AST system.
  • Test 2 (Plate-to-plate with Resistant and Susceptible Organisms): 2 organisms (K. pneumoniae AR0107 and E. coli ATCC25922). Paired plates tested in triplicate and read on different LifeScale AST systems.
  • Test 3 (Well-to-Well Cross Carry-Over): 5 plates. Each plate read on a different LifeScale AST system.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the test set. However, it does mention that "Reference testing was performed on all enrolled samples in triplicate. Testing was done in accordance with the reference protocol and was performed at one clinical site shipped isolates on transport media from the PBC purity panel following verification of pure culture." This implies that trained laboratory personnel performed the reference testing, but their specific qualifications as "experts" for ground truth establishment are not detailed.

4. Adjudication Method for the Test Set

The document states that "Each sample submitted for BMD testing was assigned a unique Trial ID, and LifeScale results were kept blinded to prevent bias. Performance was evaluated by comparing quantitative (MIC) and qualitative (S-I-R) AST results generated by the LifeScale LSGN kit with those of the reference BMD." This describes a blinded comparison method against a reference standard (BMD). There is no explicit mention of an adjudication panel (e.g., 2+1, 3+1) for discordant results.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs without AI assistance

This is not an MRMC comparative effectiveness study involving human readers or AI assistance in interpretation. The device is an automated in vitro diagnostic test for antimicrobial susceptibility. Its performance is compared directly against a reference laboratory method (Broth Microdilution Method), not against human interpretation or for human improvement with AI assistance. Therefore, this section is not applicable.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Yes, a standalone performance evaluation was done. The LifeScale AST system is described as an automated microfluidic sensor system that uses resonant frequency and sophisticated software algorithms to generate AST results (MIC and interpretive results). The entire performance evaluation described focuses on the device's ability to accurately produce these results compared to the reference BMD method without human intervention in the result generation process itself. Human input is for organism ID (from external systems) for final reporting, but the core AST determination is standalone.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The primary ground truth used for assessing the performance of the LifeScale LSGN kit was the Broth Microdilution Method (BMD), in accordance with CLSI guidance (CLSI M07). This is considered the gold standard reference method for antimicrobial susceptibility testing in microbiology.

8. The Sample Size for the Training Set

The document does not provide details on the sample size for the training set for the LifeScale AST system's algorithms. The studies described are for the performance evaluation of the final device using a defined test set.

9. How the Ground Truth for the Training Set Was Established

As no information regarding a separate training set is provided, no details are available on how the ground truth for any potential training set was established. It is common for such systems to be developed/trained using a combination of laboratory-contrived samples with known AST profiles (established by methods like BMD) and potentially retrospective clinical samples. However, the document does not elaborate on this aspect.

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The PBC Separator with Selux AST System is an automated inoculum preparation system that uses lysis, centrifugation and sequential optical density measurements to generate a McFarland-equivalent suspension from positive blood culture samples that can be used for quantitative in vitro antimicrobial susceptibility testing by the Selux AST System. Samples are processed directly from blood culture samples identified as positive by a continuous monitoring blood culture system. Samples should be confirmed as monomicrobial, gram negative rods by Gram stain. Organism identification is required for AST result interpretation and reporting, per the Selux AST System instructions for use.

Inoculum preparation by the PBC Separator was evaluated for use with the Selux AST System and the Selux Gram Negative Panel. Performance was demonstrated for the antimicrobial agents and organisms identified below:

Amikacin: Acinetobacter baumannii complex, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa

Amoxicillin-Clavulanate: Escherichia coli, Klebsiella species (including K. oxytoca, K. pneumoniae), Proteus mirabilis, Proteus vulgaris

Ampicillin: Escherichia coli, Proteus mirabilis

Ampicillin-Sulbactam: Acinetobacter baumannii complex, Citrobacter koseri, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis

Cefazolin: Escherichia coli, Klebsiella pneumoniae

Cefepime: Citrobacter freundii complex, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa Ceftazidime: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa

Ceftazidime-Avibactam: Citrobacter freundii complex, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa

Ceftriaxone: Citrobacter freundii complex, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens

Ciprofloxacin: Citrobacter freundii complex, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa

Ertapenem: Citrobacter freundii complex, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens

Gentamicin: Citrobacter freundii complex, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa Imipenem: Acinetobacter baumannii complex, Escherichia coli, Klebsiella pneumoniae

Meropenem: Acinetobacter baumannii complex, Citrobacter freundii complex, Citrobacter koseri, Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii. Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa Minocycline: Acinetobacter baumannii complex, Escherichia coli, Klebsiella pneumoniae

Piperacillin-Tazobactam: Acinetobacter baumannii complex, Citrobacter koseri, Escherichia coli, Klebsiella pneumoniae, Morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Pseudomonas aeruginosa

Tobramycin: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa

Susceptibility test results are intended to be used 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 as needed. Additionally, subculture of positive blood culture is necessary for the susceptibility testing of organisms present in polymicrobial samples, for testing antimicrobial agents and species not indicated for testing with the device, for epidemiologic testing, and for recovery of organisms present in microbial samples.

The Positive Blood Culture (PBC) Separator with Selux AST System is an automated sample preparation instrument with associated consumables that uses lysis, centrifugation, and sequential optical density measurements to prepare a tuned McFarland-equivalent inoculum from positive blood culture bottles that have rung positive on a continuous monitoring blood culture system. Inoculums containing monomicrobial, gram negative bacteria are used for AST processing with the Selux AST System. The Selux AST System includes a sample prep station (i.e., AST Workbench), an Inoculator, an Analyzer, Workbench Computer, and the reagents and consumables required to perform AST testing. The PBC Separator and all Selux AST System components are connected to a site workstation, which coordinates sample processing on all instruments. The PBC Separator contains embedded software and a graphical user interface that guides users through the PBC Separator workflow. Once processing of the PBC sample is complete, the user transfers the tuned McFarland inoculum to the Selux AST System for further AST processing.

The PBC Separator with Selux AST System can only provide AST results for monomicrobial samples. Since the PBC Separator with Selux AST System do not perform identification (ID), the monomicrobial nature of the sample under test must be confirmed by an FDA-cleared direct-frompositive blood culture ID system.

While PBC Separator processing can be performed without species-level ID, this information is required for the Selux AST System to interpret and report susceptibility results. Species ID can be performed by any appropriate method and this information can be either manually input to the Selux AST System or automatically downloaded from the laboratory information system (LIS) at any time, once the sample ID is entered into the LIS.

The PBC Separator with the Selux AST System utilizes the Selux Gram Negative Panel, a 384well panel that provides parallel results for the antimicrobials indicated for each sample type. The Selux AST System software masks non-indicated results. The average time-to-result for positive blood culture processed with the PBC Separator and Selux AST System is under 7 hours.

Here's a breakdown of the acceptance criteria and study details for the PBC Separator with Selux AST System, based on the provided FDA 510(k) summary:

Acceptance Criteria and Device Performance

The core performance criteria for the PBC Separator with Selux AST System relate to its ability to accurately determine antimicrobial susceptibility. The primary metric used is Essential Agreement (EA), which measures how closely the MIC results from the device match the reference method, and Category Agreement (CA), which assesses agreement in susceptibility interpretations (Susceptible, Intermediate, Resistant - SIR).

Overall Acceptance Criterion: The device must meet performance criteria for each indication, generally interpreted as high percentages of Essential Agreement (EA) and Category Agreement (CA) (typically >90% as seen in the tables for acceptable overall performance, though individual instances below 90% might be deemed acceptable based on the totality of data).

1. Table of Acceptance Criteria and the Reported Device Performance

Study Details

The document primarily describes analytical and clinical studies for the performance evaluation of the PBC Separator with Selux AST System.

2. Sample Size Used for the Test Set and Data Provenance

• Reproducibility:
  • Intra-site: Minimum of 45 results per antimicrobial (5 samples * 3 triplicates * 3 days).
  • Inter-site: Minimum of 135 results per antimicrobial (5 samples * 3 triplicates * 3 days * 3 sites).
  • Data Provenance: Not explicitly stated as retrospective or prospective, but involves seeding isolates into fresh human blood and processing, suggesting a controlled laboratory setting. The "3 sites (2 external, 1 internal)" suggests internal and possibly US/international external sites.
• Post-Positivity Sample Stability: 265 results comparing 16-hour processing to 0-hour processing.
  • Data Provenance: Fresh human blood from a healthy donor.
• Blood Culture Bottle Compatibility:
  • Aerobic: 1640 results across 11 bottle types.
  • Anaerobic: 979 results across 11 bottle types.
  • Data Provenance: Seeded bacterial samples at clinically relevant concentrations into blood culture bottles with manufacturer-recommended volumes of healthy donor human blood.
• Interfering Substances Testing:
  • Each interferent tested involved "at least one species for each reporting group for each antimicrobial."
  • Data Provenance: Healthy donor blood used to seed interferents and bacteria.
• Carry-Over/Cross-Contamination Study: 5 E. coli and 5 K. pneumoniae positive blood culture samples; 5 AST panels for each organism.
  • Data Provenance: Seeded isolates.
• Clinical Studies:
  • Total Isolates: 469 clinical (162 fresh and 307 seeded) and 87 challenge isolates.
  • Organisms: 12 Enterobacterales species, Acinetobacter baumannii complex, and Pseudomonas aeruginosa.
  • Antimicrobials: 17.
  • Total Data Points: Varied from 38 to 469 per antimicrobial-organism combination.
  • Data Provenance:
    • Fresh clinical samples: "left over from routine clinical care" from two clinical sites in New York City. This indicates retrospective use of fresh samples collected in a clinical setting.
    • Seeded samples: "banked frozen isolates seeded... into blood culture bottles together with approximately 10 mL of fresh human blood from a healthy donor." These seeded samples were chosen "to represent geographic diversity across the continental U.S." This component is laboratory-based but designed to represent real-world diversity.

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 qualifications for establishing ground truth. However, it indicates that triplicate broth microdilution results performed at an independent reference laboratory were used as the reference method. This implies that the ground truth was established by laboratory personnel in a CLIA-certified or equivalent reference lab, following a recognized standard for AST.

4. Adjudication Method for the Test Set

The document does not describe an explicit adjudication method (e.g., 2+1, 3+1) for the interpretation of test results or discrepancies. The comparison is made directly between the device's results and the reference broth microdilution results. Any discrepancies would be evaluated against established acceptance criteria, but no formal expert adjudication process is detailed.

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. The device is for antimicrobial susceptibility testing, which does not involve human readers interpreting images or data alongside AI. The device provides a direct microbiological result (MIC and SIR category).

6. If a Standalone Performance Study (algorithm only without human-in-the-loop performance) was done

Yes, the studies described are primarily standalone performance studies for the device. The "PBC Separator with Selux AST System" directly processes samples and generates MICs and SIR interpretations. While requiring inputs like Gram stain and organism identification before result interpretation, the AST process itself (lysis, centrifugation, optical density measurements, and MIC determination) is automated by the device without real-time human intervention in the result generation. The performance is compared to a reference standard (broth microdilution), reflecting the algorithm's output.

7. The Type of Ground Truth Used

The ground truth used for all performance evaluations (reproducibility, stability, compatibility, interferents, clinical performance) was broth microdilution (BMD), which is the gold standard reference method for antimicrobial susceptibility testing. For the clinical studies, it specifies "triplicate broth microdilution results performed at an independent reference laboratory."

8. The Sample Size for the Training Set

The document does not specify the sample size for the training set. The provided information focuses entirely on the validation and testing of the device's performance, not its development or training data.

9. How the Ground Truth for the Training Set Was Established

Since the document does not mention a training set or its size, it also does not describe how the ground truth for a training set was established.

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The eQUANT System is an automated inoculum preparation system that uses potentiometric sensing of oxidation-reduction potential changes due to pathogen metabolism to generate a 0.5 McFarland-equivalent suspension (the eMcFarland or eMcF) from positive blood culture samples that can be used for direct, qualitative in vitro susceptibility testing by the agar disk diffusion test method (Kirby-Bauer). Samples are processed directly from blood culture samples identified as positive by a continuous monitoring blood culture system and confirmed as Gram-negative rods by Gram stain. Organism identification must be confirmed by an FDA cleared device for direct testing from positive blood culture before processing samples on the eQUANT System.

Evaluation of the eQUANT System's inoculum preparation was conducted for use with agar disk diffusion susceptibility testing and performance was demonstrated for the following antimicrobial agents with Enterobacterales species, Acinetobacter species and Pseudomonas aeruginosa as identified below:

Amoxicillin/clavulanate- Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis

Ampicillin- Escherichia coli

Aztreonam- Citrobacter freundii, Enterobacter cloacae, Escherichia aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, and Pseudomonas aeruginosa

Cefazolin- Klebsiella pneumoniae

Cefepime- Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, and Pseudomonas aeruginosa

Ceftriaxone- Citrobacter freundii, Enterobacter cloacae, Escherichia aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens

Ertapenem- Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella axytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens

Gentamicin- Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella axytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, and Pseudomonas aeruginosa

Levofloxacin- Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, and Pseudomonas aeruginosa

Meropenem- Acinetobacter spp., Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, and Pseudomonas aeruginosa

Piperacillin/tazobactam- Acinetobacter spp., Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, and Pseudomonas aeruginosa

Tobramycin- Citrobacter freundii, Enterobacter cloacae, Escherichia aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus vulgaris, Serratia marcescens, and Pseudomonas aeruginosa

Susceptibility test results are intended to be used 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 as needed. Additionally, subculture of positive blood culture is necessary for the susceptibility testing of organisms present in polymicrobial samples, for testing antimicrobial agents and species not indicated for testing with the device, for epidemiologic testing, and for recovery of organisms present in microbial samples.

The eQUANT™ System is an automated system that uses potentiometric sensing of changes in oxidationreduction potential (ORP) during pathogen metabolism to prepare an organism concentration equivalent to a 0.5 McFarland (1-2e8 CFU/ml ± 0.6 log) directly from a positive blood culture. The eQUANT™ System consists of four components: the eQUANT™ Instrument, a single use eTube™ Disposable, a single use eQUANT™ Reagent tube (CAMHB with antifoam), and a workflow tray.

The eQUANT™ System processes a single positive blood culture sample at a time. Before processing on the eQUANT™ System, the positive blood culture is confirmed as Gram-negative rods by Gram stain, and a rapid FDA-cleared identification (ID) method for testing from positive blood culture is performed to confirm organism ID. Mixed cultures or organisms identified that are not included in the eQUANT™ System indications for use should not be processed on the eQUANT™ System. Positive blood cultures must be processed immediately on the eQUANT™ System or within 12 hours of blood culture bottle positivity should delays be unavoidable. Once the organism ID is confirmed, 1 mL of eQUANT™ Reagent (cation-adjusted Mueller Hinton broth (CAMHB) supplemented with antifoam (0.0015%) to reduce air bubble formation) is added to the eTube™ Disposable, followed by the addition of 34 µL of the positive blood culture. The eTube™ Disposable with diluted sample is vortexed and then placed in the eQUANT™ System for incubation.

Once inserted, the eTube™ Disposable sits in a thermal module which is heated to 37°C ± 2°C to grow the bacteria to a concentration equivalent to a 0.5 McFarland, or eMcF). The eQUANT™ Sensor located in the eTube™ Disposable is an ORP sensor consisting of two electrode components, which both come into direct contact with the diluted positive blood culture sample. The eQUANT™ ORP sensor responds to changes in the ORP during pathogen growth/metabolism. As the concentration of microorganisms in the sample increases, the growth media becomes reduced, and the voltage measured by the ORP sensor becomes more negative. With the organism ID of the tested sample and the blood culture bottle type as inputs to the system, the algorithm is applied to the real-time voltage measurements to determine the point in time at which the organism concentration reaches a level equivalent to a standard 0.5 McFarland. At the endpoint, the sample immediately starts to cool down to 15°C ± 2°C to inhibit further growth. The sample can be held for up to one (1) hour on the instrument, before being used for downstream Disk Diffusion AST testing.

Here's a breakdown of the acceptance criteria and study information for the eQUANT System, based on the provided document:

Acceptance Criteria and Device Performance

• A. baumannii: >95% CA for all bottle types assessed (100% CA).
• P. aeruginosa: >95% CA for all bottle types except BD BACTEC Aero Plus (90.5% CA, with two minor errors). The two minor error eQUANT™ zone diameters were less than 3 mm difference compared to the standard method, considered acceptable.
• Enterobacterales: >95% CA only obtained for BACT/ALERT SN (96.9% CA). Other bottle types showed 90-93% CA due to minor errors. The majority (93.8%) of error results had zone diameters ≤3 mm difference compared to the standard method, considered acceptable. 63/64 minor errors were due to a single K. pneumoniae isolate. (Table 4) |
  | Interfering Substances (eMcFarland Concentration): All eMcFarland concentrations meet 2.51e7 – 7.96e8 CFU/mL in the presence of interferents. | All resulting eMcFarland concentrations met defined acceptance criteria (2.51e7 – 7.96e8 CFU/mL). (Tables 5-6) |
  | Interfering Substances (Downstream AST): No reproducible interference observed in downstream AST testing. | No reproducible interference was observed. (Tables 5-6). High concentrations of hemoglobin (A. baumannii, P. aeruginosa) and platelets (P. aeruginosa) initially caused aborted runs. At decreased interferent concentrations, valid eMcFarlands were generated, and AST results were as expected. Minor errors in Ampicillin and Chloramphenicol were deemed acceptable due to zone diameter differences ≤ 3 mm. |
  | Carryover: No bacterial carryover between runs. | No carryover was observed, as evidenced by monomicrobial cultures and the expected organism morphology during alternating runs of E. coli and P. aeruginosa. |
  | Method Comparison (eMcFarland Concentration): ≥95% of eMcFarland colony counts fall within 2.51e7 – 7.96e8 CFU/mL. | 99.1% of PBC samples were within the expected colony count range (219/221 samples). Two samples (one A. spp., one P. aeruginosa) were outside the range, but showed no errors in Disk Diffusion results. (Table 8) |
  | Method Comparison (Disk Diffusion AST):
• Overall CA: ≥95%
• VME: ≤1%
• ME: ≤1.5%
  (for each antimicrobial agent/organism group combination) | Most antibiotic/group combinations met overall acceptance criteria.
• Exceptions to ≥95% CA: Amoxicillin/Clavulanate/Enterobacterales (94%), Cefazolin/Enterobacterales (85% - *removed from Indications for Use for E. coli and P. mirabilis due to

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The Accelerate PhenoTest™ BC kit is a multiplexed in vitro diagnostic test utilizing both qualitative nucleic acid fluorescence in situ hybridization (FISH) identification and quantitative, antimicrobial susceptibility testing (AST) methods and is intended for use with the Accelerate Pheno™ system. The Accelerate PhenoTest™ BC kit is capable of simultaneous detection and identification of multiple microbial targets followed by susceptibility testing of the appropriate detected bacterial organisms. The Accelerate PhenoTest™ BC kit is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system. Results are intended to be interpreted in conjunction with Gram stain results.

The Accelerate PhenoTest™ BC kit identifies the following Gram-positive and Gram-negative bacteria and yeasts utilizing FISH probes targeting organism-specific ribosomal RNA sequences:

Staphylococcus aureus, Staphylococcus lugdunensis, Coagulase-negative Staphylococcus species (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus capits, Staphylococcus lugdunensis, Staphylococcus warneri, not differentiated), Enterococcus faecum, Streptococus spp. (i.e., Streptococus mitis, Streptococcus oralis, Streptococcus gallolyticus, Streptococcus agalactiae, Streptococus pneumoniae, not differentiated), Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter cloacae, Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter koseri, not differentiated), Serratia marcescens, Candida albicans and Candida glabrata.

The Accelerate PhenoTest™ BC kit tests the following antimicrobial agents with the specific target organisms identified below:

Amikacin: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter cloacae, Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens

Ampicillin: Enterococcus faecalis and Enterococcus faecium

Ampicillin/Sulbactam: Escherichia coli, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), and Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated)

Aztreonam: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens

Ceftazidime: Pseudomonas aeruginosa, Klebsiella pneumoniae, Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus spp. (i.e., Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens

Ceftaroline: Staphylococcus aureus

Cefepime: Pseudomonas aeruginosa, Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens

Ceftriaxone: Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens

Ciprofloxacin: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus spp. (i.e., Proteus vulgaris, not differentiated), Citrobacter spp. (i.2., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens

Daptomycin: Staphylococcus aureus, Coagulase-negative Staphylococcus species (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus capitis, Staphylococcus lugdunensis, Staphylococcus warneri, not differentiated), Enterococcus faecalis and Enterococcus faecium

Ertapenem: Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens

Gentamicin: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus spp. (i.e., Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens

Linezolid: Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium

Meropenem: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus spp. (i.e., Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens

Piperacillin/Tazobactam: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter cloacae, Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter koseri, not differentiated) and Seratia marcescens Tobramycin: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter (Klebsiella) aerogenes, not differentiated), Proteus spp. (i.e., Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens

Vancomycin: Staphylococcus aureus. Staphylococcus lugdunensis. Coagulase- negative Staphylococcus species (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococus hominis, Staphylococcus capitis, Staphylococus lugdunensis, Staphylococus warneri, not differentiated), Enterococcus faecius and Enterococus faccium

The following resistance phenotype is reported based on qualitative tests: Methicillin-resistance (S. aureus S. Jugdunensis, coagulase negative staphylococci).

The Accelerate PhenoTest™ BC kit is indicated as an aid in the diagnosis of bacteremia and fungemia. It is also indicated for susceptibility testing of specific pathogenic bacteria as identified above commonly associated with or causing bacteremia. Results are intended to be used 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 as needed. Additionally, subculture of positive blood culture is necessary for the identification and susceptibility testing of: organisms not identified by the Accelerate PhenoTest™ BC kit, organisms present in polymicrobial samples, organisms for which species identification is critical for patient care (e.g. speciation of Streptococus spp.), samples for which an "indeterminate" result for any probe was obtained, for testing antimicrobial agents not included on the Accelerate panel and for epidemiologic testing.

The Accelerate PhenoTest™ BC kit contains a sample vial, a 48-channel disposable test cassette and a reagent cartridge. All identification (ID) and antimicrobial susceptibility testing (AST) is performed in individual flowcells of the test cassette. The reagent cartridge contains gel electrofiltration (GEF) stations, fluorescence in situ hybridization (FISH) probes, antimicrobials, and reagents for automated sample preparation, identification of bacterial and fungal target organisms, and antimicrobial susceptibility and resistance marker detection testing for bacterial target organisms. The user loads the sample into the sample vial, places the test cassette, reagent cartridge and sample vial into an Accelerate Pheno™ system module, then presses the module button to close the module door and start the run. The rest of the operations are automated as described below.

Automated sample preparation is performed using gel electrofiltration (GEF) which is based on gel electrophoresis principles. Sample is automatically transferred to a gel well containing pores smaller than bacterial or yeast cells. Application of an electric field causes lysed blood cells and/or other sample debris to pass into the gel wall while bacterial/yeast cells remain inside the gel well. The electric field is briefly reversed to dislodge bacterial/yeast cells from the gel wall prior to removal.

Following sample preparation, recovered cells are automatically pipetted into multiple flowcell channels of the test cassette. Conductive layers of transparent indium tin oxide (TTO) coat the top and bottom inner surfaces of each flowcell channel and act as electrodes. An additional cationic poly-L-lysine layer on the bottom of each flowcell acts as a capture surface. When a voltage is applied, the negatively-charged bacterial/yeast cells migrate to the positively-charged capture surface where they are captured prior to imaging.

Cocktails of ATTO-532 (green) fluorescently-labeled DNA probes bind to the ribosomal RNA of target organisms following permeabilization. Each cocktail also includes ATTO-647 (red) labeled universal bacterial probe that binds to the ribosomal RNA of all clinically relevant bacteria (bacterial ID channels) or universal eukaryotic probe that binds to the ribosomal RNA of all clinically relevant yeast (yeast ID channels). The system images each flowcell using a fluorescence and dark-field microscope with camera and a filter set that captures emission from the FISH ID probes at 532 nm. 647 nm and in dark-field. An additional filter, capturing emission at 720 nm, is utilized prior to FISH ID for removal of interfering sample debris. To further exclude debris, only dark-field objects colocalized with universal probe signal are included in analysis. Colocalization of target probe signal and universal probe signal identifies a target organism.

The software also quantitates the total number of organisms present in a sample using a nucleic acid stain in a separate control flowcell. Comparing the relative numbers of each target organism to the number of objects lit up by the universal probes allows the system to differentiate bacteria/yeast from debris. FISH ID results are reported approximately 2 hours after loading the sample, and the ID result determines the selection of appropriate antimicrobials for subsequent antimicrobial susceptibility testing.

The Accelerate Pheno™ system leverages Morphokinetic Cellular Analysis (MCA) technology to measure distinct morphokinetic features of live microbial cells responding to antimicrobials to generate susceptibility results.

MCA is a computer vision based analytical method that uses digital microscopy inputs and machine learning technology to observe individual live cells and microcolonies (or clones) and recognize patterns of change over time. This technology tracks and analyzes multiple morphological and kinetic changes of individual cells and microcolonies under a variety of conditions. These changes include morphokinetic features such as cell morphology, mass as measured by light intensity of a growing microcolony, division rate, anomalous growth patterns, and heterogeneity.

Prior to AST, the remaining sample is combined with growth media and undergoes a pregrowth step during the FISH ID assay to normalize growth rates. Following automated sample preparation, the cells are quantitated and dynamically diluted to the appropriate concentration for AST testing. The cells are then captured in flowcell channels and immobilized when growth media containing single concentrations of each test antimicrobial are added to separate flowcell channels. The bacteria in each flowcell are imaged every 10 minutes for up to 4.5 hours, creating a time-lapse record of bacterial growth from individual progenitor cells into clones of daughter cells.

During this period, morphokinetic features are measured and used for analysis. The precise quantitative measurement of individual clone growth rate over time is a powerful indicator of antimicrobial efficacy. Onboard software algorithms derive minimum inhibitory concentration (MIC) values from the measured features, and apply appropriate expert rules for proper interpretation and reporting of categorical interpretations - S, I or R (susceptible, intermediate, or resistant).

The Accelerate Pheno™ system is designed to perform Accelerate PhenoTest™ BC kit identification (ID) of bacterial and yeast cells and antimicrobial susceptibility testing (AST) in approximately 7 hours directly from positive blood culture samples. Depending on the computer configuration, up to eight ID/AST modules can be operated concurrently. Analysis time may increase when four or more tests are performed on ID/AST modules simultaneously. Other factors, such as samplexity, the number of organisms and/or antimicrobials available in the panel, may also increase time to result.

The Accelerate PhenoTest™ BC ID and AST OC tests automate the external QC testing procedure, removing the manual standardized inoculum preparation and manual dispensing of the McFarland standardized inoculum (0.5 for bacteria and 2.0 for fungi). This reduces the complexity of QC testing, eliminating the need for a clinical scientist to perform the test. Furthermore, the stability of the analyte is increased through the use of complementary sequences coupled to polymer microspheres for each of the target probes in the Accelerate PhenoTest™ BC kit.

As accessories to the Accelerate PhenoTest™ BC kit and Accelerate Pheno™ system, the Accelerate PhenoTest™ BC ID and AST QC tests have their own instructions for use.

The Accelerate Pheno™ system is a fully-integrated in vitro diagnostic system comprised of one to eight ID/AST module(s), a computing system, touchscreen monitor and Accelerate Pheno™ system software for use with Accelerate PhenoTest™ kits. It is designed to perform identification (ID) of bacterial and yeast cells and antimicrobial susceptibility testing (AST) in approximately 7 hours directly from positive blood culture samples. Depending on the computer configuration, up to eight ID/AST modules can be operated concurrently. Analysis time may increase when four or more tests are initiated on ID/AST modules simultaneously. Other factors, such as sample complexity, the number of organisms and/or antimicrobials available in the assay kit panel, may also increase time to result.

Identification uses fluorescence in situ hybridization (FISH) and susceptibility testing uses microscopic observation of individual, live, growing bacterial cells in near real time (approximately every 10 minutes) in the presence of antimicrobial agents.

The Accelerate Pheno™ system is comprised of the following hardware:

• Accelerate Pheno™ system ID/AST modules (Up to 4 or 8 depending on . computing system architecture)
• Computing system, either: ●
  • Control PC/Analysis PC setup (supports up to 4 ID/AST modules): o
    • ▪
    • 1 Analysis PC
  • Interface PC/Analysis module setup (supports up to 8 ID/AST modules): o
    • 1 Interface PC .
    • . 1 Analysis module
• Touchscreen monitor ●
• Keyboard ●
• Mouse ●
• Power cords ●
• . Cables
• Uninterruptible Power Supply (1 UPS for up to 4 ID/AST modules and 1 UPS per ● computing system)

Each system contains up to 4 or 8 ID/AST modules (depending on computing system) and each ID/AST module can run one patient sample at a time. Each ID/AST module may be started or stopped at any time, independent of the other ID/AST modules.

The provided text describes a 510(k) premarket notification for the Accelerate Pheno System and Accelerate PhenoTest BC Kit. This submission focuses on modifications to the device, specifically relating to antimicrobial susceptibility testing (AST) for Pseudomonas aeruginosa against certain beta-lactam antibiotics.

Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly present a table of acceptance criteria in numerical values before the results. Instead, it states the overall objective was to "produce adequate essential and categorical agreement" and specifies certain error thresholds implied by the reported performance. The "FDA Class II Special Controls Guidance document" is referenced for specific dilution requirements, but the numerical acceptance thresholds for Essential Agreement (EA), Categorical Agreement (CA), Very Major Errors (VME), Major Errors (ME), and Minor Errors (mE) are not directly stated as pre-defined criteria in a table. However, implied acceptance criteria for AST devices are typically:

• Essential Agreement (EA) ≥ 90%
• Categorical Agreement (CA) ≥ 90%
• Very Major Errors (VME) ≤ 1.5%
• Major Errors (ME) ≤ 3.0%
• Minor Errors (mE) not explicitly stated but generally evaluated.

Here's the performance table as reported in the document:

Notes from the document regarding performance:

• For Ceftazidime (CAZa,c), the observed VME was 7.9% (3/38). However, "based on the essential agreement and lack of an intermediate breakpoint for ceftazidime, the adjusted very major error rate is 2.6%."
• For Cefepime (FEPa,b,d), the observed VME was 2.8% and ME was 9.3%. "$Based on the essential agreement and lack of an intermediate breakpoint for cefepime, the adjusted major error rate is 1.9% and the adjusted very major error rate is 0%."
• For Meropenem (MEMa,d,e), Categorical Agreement (CA) was 88.2% (127/144), which is below the typical 90% threshold. "Low categorical agreement for meropenem was attributed to the occurrence of minor errors."
• "AST performance met all acceptance criteria for aztreonam."

2. Sample sized used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)

• Sample Size (Test Set): For the performance evaluation, a total of 131 characterized Pseudomonas aeruginosa isolates were initially tested. This was supplemented with "evaluation of the new algorithms on the original 13 clinical trial isolates for a total of 144 isolates included in the performance evaluation."
  • Phase 1 included 100 challenge and stock isolates (115 total runs).
  • Phase 2 evaluated an additional 31 on-scale isolates.
• Data Provenance: The study was an "internal performance evaluation study at Accelerate Diagnostics, Inc." This suggests the data was generated internally. The text does not specify the country of origin of the isolates or whether the study was retrospective or prospective. Given it references "challenge and stock isolates" and "characterized Pseudomonas aeruginosa isolates," it appears to be a laboratory-based, prospective evaluation using curated strains and some re-evaluated clinical trial isolates. The mention of "historical results from the broth microdilution (BMD) reference method" indicates a comparative design for the AST.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

The document states that "Antimicrobial susceptibility test (AST) results were compared to historical results from the broth microdilution (BMD) reference method." This implies that the ground truth for AST was established using a gold standard laboratory method (BMD), not by human expert consensus or adjudication. Therefore, the concept of "experts establishing ground truth" as in medical image interpretation does not directly apply here.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

Not applicable. Ground truth for AST was established by a reference laboratory method (Broth Microdilution, BMD), not by human readers requiring adjudication.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This device is an in vitro diagnostic (IVD) system for directly determining microbial identification and antimicrobial susceptibility. It is not an AI-assisted diagnostic tool for human readers interpreting medical images or other complex data. The "machine learning technology" mentioned in the "Morphokinetic Cellular Analysis (MCA)" section refers to algorithms within the device for analysis, not for assisting human interpretation.

6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done

Yes, the device's performance (i.e., the algorithm's performance) was evaluated in a standalone manner against a reference method (BMD). The results presented in the table are the direct outputs of the Accelerate Pheno™ system compared to the BMD.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth for Antimicrobial Susceptibility Testing (AST) was the Broth Microdilution (BMD) reference method. This is considered the gold standard for AST. For identification (ID), isolates were "characterized Pseudomonas aeruginosa isolates," implying their identity was previously confirmed, likely by standard microbiological methods.

8. The sample size for the training set

The document does not explicitly state the sample size for a training set. The performance evaluation study (described above with 144 isolates) appears to be a validation or test set for modified algorithms ("evaluation of the new algorithms on the original 13 clinical trial isolates"). The device leverages "machine learning technology" for MCA, which implies a training phase would have occurred during its development, but the specifics of that training set (size, composition, etc.) are not provided in this regulatory submission summary.

9. How the ground truth for the training set was established

Since the document does not detail a specific training set or its size, it also does not describe how its ground truth was established. For a device utilizing machine learning for AST, the training data's ground truth would typically be established using the same reference methods as the test set (e.g., BMD).

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The Accelerate PhenoTest BC kit is a multiplexed in vitro diagnostic test utilizing both qualitative nucleic acid fluorescence in situ hybridization (FISH) identification and quantitative, antimicrobial susceptibility testing (AST) methods and is intended for use with the Accelerate Pheno system. The Accelerate PhenoTest BC kit is capable of simultaneous detection and identification of multiple microbial targets followed by susceptibility testing of the appropriate detected bacterial organisms. The Accelerate PhenoTest BC kit is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system. Results are intended to be interpreted in conjunction with Gram stain results.

The Accelerate PhenoTest BC kit identifies the following Gram-positive and Gram-negative bacteria and yeasts utilizing FISH probes targeting organism-specific ribosomal RNA sequences: Staphylococcus aureus, Staphylococcus lugdunensis, Coagulase-negative Staphylococcus species (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus capitis, Staphylococcus lugdunensis, Staphylococcus warneri, not differentiated), Enterococcus faecalis, Enterococcus faecium, Streptococcus spp. (i.e., Streptococcus mitis, Streptococcus oralis, Streptococcus gallolyticus, Streptococcus agalactiae, Streptococcus pneumoniae, not differentiated), Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated), Serratia marcescens, Candida albicans and Candida glabrata.

The Accelerate PhenoTest BC kit tests the following antimicrobial agents with the specific target organisms identified below:

Amikacin: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Ampicillin: Enterococcus faecalis and Enterococcus faecium
Ampicillin/Sulbactam: Escherichia coli, Klebsiella spp. (i.e., Klebsiella pneumoniae, . Klebsiella oxytoca, not differentiated), and Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated)
Aztreonam: Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated). Proteus spp. (i.e., Proteus mirabilis. Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Ceftazidime: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Ceftaroline : Staphylococcus aureus .
Cefepime: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Ceftriaxone: Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Ciprofloxacin: Pseudomonas aeruginosa, Klebsiella spp. (i.ess, Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Daptomycin: Staphylococcus aureus, Coagulase-negative Staphylococcus species (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus capitis, Staphylococcus lugdunensis, Staphylococcus warneri, not differentiated), Enterococcus faecalis and Enterococcus faecium
Erythromycin: Staphylococcus aureus
Ertapenem: Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Gentamicin: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Linezolid: Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium .
Meropenem: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis. Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii. Citrobacter koseri, not differentiated) and Serratia marcescens
Piperacillin/Tazobactam: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Tobramycin: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella ● oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Vancomycin: Staphylococcus aureus, Staphylococcus lugdunensis, Coagulase-negative . Staphylococcus species (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus capitis, Staphylococcus lugdunensis, Staphylococcus warneri, not differentiated), Enterococcus faecalis and Enterococcus faecium

The following resistance phenotypes are reported based on qualitative tests: Methicillin-resistance (S. aureus S. lugdunensis, coagulase negative staphylococci) and macrolide-lincosamide-streptogramin B resistance (MLSb) (S. lugdunensis and coagulase negative staphylococci).

The Accelerate PhenoTest BC kit is indicated as an aid in the diagnosis of bacteremia and fungemia. It is also indicated for susceptibility testing of specific pathogenic bacteria as identified above commonly associated with or causing bacteremia. Results are intended to be used 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 as needed. Additionally, subculture of positive blood culture is necessary for the identification and susceptibility testing of: organisms not identified by the Accelerate PhenoTest BC kit, organisms present in polymicrobial samples, organisms for which species identification is critical for patient care (e.g., speciation of Streptococcus spp.), samples for which an "indeterminate" result for any probe was obtained, for testing antimicrobial agents not included on the Accelerate panel and for epidemiologic testing.

The Accelerate Pheno system is comprised of the Accelerate Pheno instrument, software, host computer, analysis computer, and the Accelerate PhenoTest BC kit. The Accelerate PhenoTest BC Kit contains a sample vial, a 48-channel disposable test cassette and a reagent cartridge needed to test samples from a blood culture bottle that has been flagged as positive by a continuous monitoring blood culture system. All identification (ID) and antimicrobial susceptibility testing (AST) is performed in individual flowcells of the test cassette. The reagent cartridge contains gel electrofiltration (GEF) stations, fluorescence in situ hybridization (FISH) probes, antibiotics, and reagents for automated sample preparation, identification of bacterial and fungal target organisms (Table 1), and antimicrobial susceptibility testing and phenotypic resistance detection testing for bacterial target organisms (Tables 2 and 3). The user loads an aliquot of the positive blood culture into the sample vial, places the test cassette, reagent cartridge and sample vial into an Accelerate Pheno System module, and then presses the module button to close the module door and start the run. The remainder of the operations are automated as described below.

Automated Sample Preparation
Automated sample preparation is performed using gel electro-filtration (GEF) which is based on gel electrophoresis principles. The sample is automatically transferred to a gel containing pores smaller than bacterial or yeast cells. Application of an electric field causes lysed blood cells and/or other sample debris to pass into the gel while bacterial/yeast cells remain inside the gel well. The electric field is briefly reversed to dislodge bacterial/yeast cells from the gel wall prior to removal.

Cell Capture
Following sample preparation, recovered cells are automatically pipetted into multiple flowcell channels of the test cassette. Conductive layers of transparent indium tin oxide (ITO) coat the top and bottom inner surfaces of each flowcell channel and act as electrodes. An additional cationic poly-Llysine layer on the bottom of each flowcell acts as a capture surface. When a voltage is applied, the negatively-charged bacterial/yeast cells migrate to the positively-charged capture surface where they are captured prior to imaging.

Fluorescence in situ Hybridization (FISH) for Identification
Cocktails of ATTO-532 (green) fluorescently-labeled DNA probes bind to the ribosomal RNA of target organisms following permeabilization. Each cocktail also includes ATTO-647 (red) labeled universal bacterial probe that binds to the ribosomal RNA of all clinically relevant bacterial ID channels) or universal eukaryotic probe that binds to the ribosomal RNA of all clinically relevant yeast (yeast ID channels). The system images each flowcell using an epifluorescence microscope with camera at 532 nm, 647 nm and in dark-field. To exclude debris, only dark-field objects that are colocalized with universal probe signal are included in analysis. Colocalization of target probe signal and universal probe signal identifies a target organism.

The software also quantitates the total number of organisms present in a sample using a nucleic acid stain in a separate control flowcell. Comparing the relative numbers of each target organism to the number of objects lit up by the universal probes and universal nucleic acid stain allows for non-target organism and polymicrobial sample detection. FISH ID results are reported approximately 90 minutes after loading the sample, and the ID result determines the selection of appropriate antibiotics for subsequent antimicrobial susceptibility testing.

Morphokinetic Cellular Analysis (MCA) for Antimicrobial Susceptibility Testing (AST)
Sample remaining after the identification assay is initiated is combined with growth media and organisms contained in the sample undergo a pre-growth step during the FISH ID assay to normalize growth rates prior to AST. Following automated sample preparation and cell capture, growth media containing single concentrations of each test antibiotic are added to separate flowcell channels; antibiotics are selected based on the identification provided by the FISH identification (Tables 2 and 3). The bacteria in each flowcell are imaged every 10 minutes for up to 4.5 hours, creating a timelapse record of bacterial growth from individual progenitor cells into clones of daughter cells.

During this period. several microscopic features are measured through morphokinetic cellular analysis, such as cell morphology and the light intensity of a growing clone over time, and used for analysis. The precise quantitative measurement of individual clone growth rate over time is an indicator of antimicrobial efficacy. Onboard software algorithms derive minimum inhibitory concentration (MIC) values from the measured features, and apply appropriate expert rules for proper interpretation and reporting of categorical interpretations - S, I or R (susceptible, intermediate, or resistant) for MIC determinations and positive or negative for phenotypic resistance markers. AST results are reported in approximately 5 hours after ID results. The reportable ranges for each antimicrobial and phenotypic resistance markers are listed in Tables 4 and 5.

The provided text describes the evaluation of the Accelerate PhenoTest BC Kit. Here's a breakdown of the acceptance criteria and study details:

1. Table of Acceptance Criteria & Reported Device Performance:

The document outlines performance metrics that serve as acceptance criteria for different aspects of the device.

2. Sample Size Used for the Test Set and the Data Provenance:

• Clinical Study Test Set:

  • Total 1850 positive blood culture samples were evaluated for clinical performance.
  • Provenance:
    • 793 fresh samples (aliquots of left-over positive blood cultures from patients suspected of bacteremia or fungemia). These were prospectively collected in the U.S.
    • 65 fresh seeded samples (blood cultures seeded with human blood and previously characterized fresh clinical isolates isolated within seven days of seeding). These were prospectively collected in the U.S.
    • 477 samples seeded with challenge isolates (obtained from culture collections).
    • 515 samples seeded with stock isolates (obtained from clinical specimens at the clinical sites and stored for longer than seven days).
    • Study conducted at 13 geographically distinct U.S. sites.

• Analytical Studies (various test sets):

  • Reproducibility: At least 90 data points per probe target for ID, ~10 organisms with on-scale MICs for AST (total 1644 tests).
  • Growth & Detection: 21 on-panel organisms and 1 off-panel organism tested in triplicate (total 175 tests).
  • Inclusivity & Exclusivity: Three strains of each on-panel target species for inclusivity (total 253 tests for ID section). Individual representative strains for exclusivity (total 318 tests for ID section).
  • LoD: Varied by organism, usually >20 replicates per strain (e.g., 22/22, 21/22 etc. reported). Total 849 tests for monomicrobial LoD. Total 182 for polymicrobial LoD.
  • Interference: Varied by organism/substance (total 526 tests).
  • Blood Bottle Type: Minimum of 10 replicates per sample/bottle type (total 1419 tests overall for this study).
  • Polymicrobial LoD: 13 pairs of different microbial species, tested in duplicate (total 182 tests).
  • Biological Interference: 17 combinations tested (total 49 tests).

3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts:

The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the test set.

• For AST, the ground truth was established by CLSI broth microdilution reference method. The isolates were tested in triplicate by this method, with the mode MIC value serving as the reference.
• For ID, the ground truth was VITEK2 (bioMérieux). For isolates where VITEK2 yielded an invalid result, 16S rRNA gene sequencing was used as the reference identification.
• For phenotypic resistance markers (cefoxitin and MLSb), the ground truth was disk diffusion performed singly, with triplicate testing and modal category if the initial test failed or was near the breakpoint.

The implication is that these reference methods themselves represent an "expert consensus" or established standard, rather than a panel of human experts explicitly reviewing each case's ground truth.

4. Adjudication Method for the Test Set:

The document does not describe an explicit adjudication method (e.g., 2+1, 3+1) for discrepant results between the device and the reference methods. The reference methods (CLSI broth microdilution, VITEK2, 16S rRNA gene sequencing, and disk diffusion) are considered the definitive ground truth.

For AST, if no mode value could be determined or if a QC failure occurred for the reference method, an additional three replicates were tested to determine the mode MIC. This implies a process to ensure a robust reference result, but not an independent adjudication by experts comparing device output to reference.

5. If a Multi Reader Multi Case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

No, a Multi Reader Multi Case (MRMC) comparative effectiveness study was NOT done. This device is an automated, in vitro diagnostic test for microbial identification and antimicrobial susceptibility, not an AI-assisted diagnostic imaging tool that would typically involve human readers. Its performance is compared directly to established laboratory reference methods.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

Yes, the primary clinical and analytical performance studies were effectively standalone (algorithm only) performance studies. The Accelerate PhenoTest BC Kit is described as a "fully-integrated and fully automated system" that uses "onboard software algorithms" to derive results. The performance metrics (accuracy, sensitivity, specificity, EA, CA) are calculated by comparing the device's automated results to established reference methods, without human interpretation of the device's raw data directly influencing the reported output. The system is designed to provide final identification and AST results automatically.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

The ground truth for the studies was based on:

• Reference Laboratory Methods:
  • Identification (ID): Primarily VITEK2 (bioMérieux). For invalid VITEK2 results, 16S rRNA gene sequencing was used.
  • Antimicrobial Susceptibility Testing (AST): CLSI broth microdilution reference method.
  • Phenotypic Resistance: Disk diffusion.
• Known Characteristics of Seeded Isolates: For a significant portion of the test set (fresh seeded, challenge, and stock isolates), the identity and susceptibility profiles were "previously characterized" or "known characteristics" of the spiked organisms. This implies a highly controlled and validated ground truth for these samples.

This is a form of reference standard ground truth, using established, highly accurate laboratory methods as the benchmark rather than direct patient outcomes or a panel of human experts interpreting raw data.

8. The sample size for the training set:

The document does not explicitly state the sample size for the training set. The evaluation focuses on the performance of the developed device using a test set against reference methods. It describes "onboard software algorithms" but doesn't detail their development or the data used for internal training/validation.

9. How the ground truth for the training set was established:

Since the training set size is not provided, the method for establishing its ground truth is also not detailed. However, given the nature of the device and the performance studies, it is highly probable that any data used for training/algorithm development would have had its ground truth established through similar rigorous microbiological reference methods (e.g., CLSI, sequencing, culture).

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