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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 (<1.5% and <3% respectively) for AST devices. The reported values meet these implicit expectations for most combinations.

2. Sample Size and Data Provenance

Test Set Sample Size:

• Reproducibility:
  • Intra-site: For each of 9 antimicrobials, 5 samples tested in triplicate (3 different inoculums) on 3 days at each site yields 9 results per sample, 45 results per antimicrobial at a single site.
  • Inter-site: For each of 9 antimicrobials, 5 samples tested in triplicate (3 different inoculums) on 3 days across 3 sites yields 27 results per sample, 135 results per antimicrobial.
• Post-Positivity Sample Stability: 30 results (3 replicates of one species from each indicated antimicrobial/organism reporting group at 16-hour timepoints compared to 0-hour).
• Blood Culture Bottle Compatibility: 3 replicates per bottle type for one isolate from each reporting group with all claimed antimicrobials. Total of 180 results for aerobic bottle types (179 in EA). Total of 150 results for anaerobic bottle types. Specific breakdown by bottle type table provided.
• Interfering Substances Testing: 3 replicates per interferent type for E. faecalis and S. aureus. Specific breakdown per antimicrobial/interferent in tables provided (e.g., 3/3, 6/6 results).
• Clinical Studies: 247 clinical isolates (64 fresh, 183 seeded) and 75 challenge isolates. Total datapoints varied per antimicrobial-organism combination, ranging from 100 to 211.

Data Provenance:

• Country of Origin: Test sites are stated as "three test sites (2 external, 1 internal)" and "clinical sites to represent geographic diversity across the continental U.S." This indicates United States origin.
• Retrospective or Prospective:
  • Reproducibility, Post-Positivity, Bottle Compatibility, Interfering Substances: These studies appear to be prospective as they involve specific seeding, incubation, and processing protocols.
  • Clinical Studies: Used "fresh positive blood culture samples left over from routine clinical care" (suggests prospective collection of clinical samples) and "banked frozen isolates seeded" (suggests retrospective isolates used in a prospective study design).

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the number of experts or their qualifications for establishing ground truth.

For susceptibility testing (AST), the "ground truth" or reference method is typically broth microdilution, performed at an independent reference laboratory. The establishment of ground truth for AST is a standardized laboratory procedure, not typically reliant on expert consensus as in image interpretation. The proficiency of the laboratory performing the reference method is assumed, rather than specific qualifications of individuals being listed.

4. Adjudication Method for the Test Set

Not applicable. For AST studies, the reference method (broth microdilution) results are considered the ground truth, and there is no human adjudication process involved in comparing the device's MIC results to the reference MIC results. The comparison is quantitative for essential agreement and categorical for category agreement and other error rates.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

Not applicable. The device is an automated in vitro diagnostic (IVD) system for antimicrobial susceptibility testing, not an AI system for image interpretation that would involve human readers. Therefore, an MRMC study is not relevant here.

6. Standalone (i.e. Algorithm-Only) Performance

Yes, the studies inherently demonstrate "standalone" performance. The PBC Separator is an automated inoculum preparation system, and the Selux AST System then performs the AST. The "performance" tables (reproducibility, bottle compatibility, interfering substances, clinical performance) show the device's output (MIC values) directly compared to the reference method, without human intervention in the interpretation of the device's results.

7. Type of Ground Truth Used

The ground truth used for performance evaluation is reference broth microdilution results (MIC values and categorical interpretations), performed at an independent reference laboratory. This is the gold standard for antimicrobial susceptibility testing.

8. Sample Size for the Training Set

The document does not explicitly mention a "training set" or "training data" size for the device's internal algorithms. This is typical for IVD medical devices, where the focus for regulatory submission is on the validation (test) data demonstrating device performance. The algorithms within the Selux AST System for determining MICs and interpretations are based on established microbiological principles (growth kinetics, optical density measurements) and potentially internal development/calibration data, which are not typically disclosed or quantified as a 'training set' in the same way as machine learning models.

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

As noted above, a distinct "training set" with ground truth establishment is not typically described for this type of IVD device. The inherent "ground truth" for the development of such a system would involve extensive laboratory work correlating optical density measurements, growth curves, and other internal parameters with known MICs from reference methods (broth microdilution) over various organisms and antimicrobial agents. This is part of the extensive research and development process for such a complex automated system rather than a separately documented "training set" for regulatory submission.

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

Indications for Use:
The Selux Gram-Positive Panel is intended for use with the Selux AST System as an in vitro test to determine the susceptibility of isolated colonies of specific Staphylococcus species to species to specific antimicrobial agents when used as instructed.

The Selux Gram-Positive Panel is a quantitative test for the following antimicrobial agents with the specific organisms identified below:

• Ampicillin: Enterococcus faecium, Enterococcus faecalis
• Clindamycin: Staphylococcus aureus, Staphylococcus epidermidis
• Ceftaroline: Staphylococcus aureus
• Daptomycin: Staphylococcus aureus, Enterococcus faecalis
• Delafloxacin: Staphylococcus aureus, Staphylococcus haemolyticus, Enterococcus faecalis
• Eravacycline: Staphylococcus aureus, Enterococcus faecalis
• Erythromycin: Staphylococcus aureus
• Linezolid: Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Enterococcus faecium, Enterococcus faecalis
• Levofloxacin: Enterococcus faccium, Enterococcus faecalis, methicillin-susceptible Staphylococcus aureus
• Minocycline: Staphylococcus aureus
• Oxacillin: Staphylococcus aureus, Staphylococcus lugdunensis
• Penicillin: Enterococcus faecium, Enterococcus faecalis, Staphylococcus aureus
• Trimethoprim: Staphylococcus aureus, Coagulase-Negative Staphylococci (including S. capitus, S. haemolyticus, S. saprophyticus, S. simulans)
• Vancomycin: Staphylococcus aureus, Coagulase-Negative Staphylococci (CoNS) (including S. capitus, S. cohnii, S. epidermidis, S. haemolyticus, S. internedius group, S. lugdunensis, S. saprophyticus, S. schleiferi, S. simulans) Enterococcus faecium, Enterococcus faecalis

The Selux 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, Staphylococcus lugdunensis

The Selux AST System for antimicrobial susceptibility testing (AST) consists of a Sample Prep Station, an Inoculator, an Analyzer, a computer workstation, and the reagents and consumables required to perform AST testing. The system is operated via software that guides users through the manual sample preparation process and operates the automated Inoculator and Analyzer. The software includes an algorithm that enables the system to determine the susceptibilities of an organism to the variety of antimicrobials under test.

The system is designed so that only Gram stain information is required to initiate testing (to select the proper antimicrobial panel, gram-negative or gram-positive). While complete system testing can be performed without species-level identification (ID), this information is required for the system to report susceptibility results. Species ID can be performed by any appropriate method and this information can be either manually input to the Selux system or automatically downloaded from the laboratory information system (LIS) at any time, once the sample ID is entered into the LIS.

The system utilizes 384-well panels to provide parallel results for a large number of antimicrobials. Its average time-to-result is under 6 hours, as demonstrated in various studies.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for each antimicrobial-organism combination are not explicitly stated as numerical targets (e.g., "EA must be >90%"). Instead, the document presents the observed performance and notes where EA (Essential Agreement) falls below 90%, implying that 90% is a general benchmark for acceptable performance, with specific justifications or labeling changes for values below this. The table below summarizes the reported performance.

¹ EA performance (<90%) is addressed in limitation statements in the device labeling.

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

• Test Set Sample Size:
  • Clinical Isolates: 706 (193 contemporary and 513 stock/frozen)
  • Challenge Isolates: 159
  • Total Samples Tested: 865
  • The number of data points for various antimicrobial-organism combinations ranged from 39 to 311.
• Data Provenance: The document states "Contemporary and frozen clinical isolates from diverse geographic locations across the US were evaluated for performance as well as stock (frozen/banked) challenge isolates." This indicates a mix of retrospective (stock/frozen) and potentially prospective (contemporary) data collected from multiple sites across the US.

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

The document does not explicitly state the number of experts or their specific qualifications for establishing the ground truth. It mentions that the Selux AST System results were compared with "triplicate broth microdilution results performed at an independent reference laboratory."

4. Adjudication Method for the Test Set

The ground truth was established by "triplicate broth microdilution results performed at an independent reference laboratory." This implies that the accepted standard for antimicrobial susceptibility testing (broth microdilution) was performed independently, and the "triplicate" nature suggests internal verification or averaging, rather than a formal adjudication process involving multiple human readers for discrepancies.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size

No, an MRMC comparative effectiveness study involving human readers with and without AI assistance was not conducted. The study evaluated the standalone performance of the Selux AST System against a reference method (broth microdilution), which is a device-to-device comparison, not a human reader study.

6. If a Standalone Study Was Done

Yes, a standalone study was done. The entire "Clinical Studies" section describes the performance of the Selux AST System (the algorithm/device only) in determining antimicrobial susceptibility, comparing its results directly to a reference method (broth microdilution). Human involvement was in operating the system and performing the reference method, not in interpreting the results from the Selux system.

7. The Type of Ground Truth Used

The ground truth used was reference standard testing, specifically triplicate broth microdilution results performed at an independent reference laboratory.

8. The Sample Size for the Training Set

The document does not explicitly state the sample size for the training set. The "Clinical Studies" section describes the test set used for performance evaluation.

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

Since the training set size and details are not provided, information on how its ground truth was established is also not available in the document.

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