(451 days)
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
| Performance Metric | Acceptance Criterion (Implicit) | Reported Device Performance (Summary) | Notes |
|---|---|---|---|
| Intra-Site Reproducibility | ≥ 95% Best- and Worst-Case | ≥ 95% Best- and Worst-Case for all tested antimicrobials (Min. 98.1%) | Achieved for all antimicrobials |
| Inter-Site Reproducibility | > 95% Best- and Worst-Case | > 95% Best- and Worst-Case for all tested antimicrobials (Min. 95.8%) | Achieved for all antimicrobials |
| Post-Positivity Sample Stability (16 hr) | > 95% Essential Agreement | 99.6% (264/265 results in EA) | Achieved overall; individual antimicrobial EA >95% |
| Blood Culture Bottle Compatibility (Aerobic) | > 89.9% Essential Agreement for all tested bottle types | 99.3% overall EA (1629/1640); each aerobic bottle type ≥ 98.5% EA | Except for one case (Ciprofloxacin/Enterobacterales in bioMérieux BacT/ALERT SA) which was 89.3%, but deemed acceptable. |
| Blood Culture Bottle Compatibility (Anaerobic) | > 89.9% Essential Agreement for all tested bottle types | 99.5% overall EA (974/979); each anaerobic bottle type ≥ 98.5% EA | Except for a few cases below 90% (Ciprofloxacin/Enterobacterales in BD BACTEC Lytic Anaerobic (85.7%) and bioMerieux BacT/ALERT FN Plus (92.3%); Ampicillin-Sulbactam/Enterobacterales in BD BACTEC Lytic Anaerobic (92.9%)), but deemed acceptable. |
| Endogenous Interferents (MIC EA) | > 89.9% Essential Agreement for every interferent | > 89.9% Essential Agreement for every interferent tested (most combinations were 100%) | Except for Piperacillin-Tazobactam with K. pneumoniae in all endogenous interferents, which showed 89.9% Essential Agreement for every interferent |
| Clinical Performance (EA) | Generally high percentage agreement, individual variations noted. | Varied by antimicrobial-organism combination (e.g., Amikacin/A. baumannii (complex): 92.1% EA; Ceftazidime/P. aeruginosa: 100% EA) | Performance demonstrated for all combinations although some EA values were below 90% in the "Total Eval" category (e.g. Amikacin/Enterobacterales: 66.7%). |
| Clinical Performance (CA) | Generally high percentage agreement. | Varied by antimicrobial-organism combination (e.g., Amikacin/A. baumannii (complex): 94.7% CA; Ceftazidime/P. aeruginosa: 100% CA) | Some EA values were below 90% in the "Total Eval" category which might have an impact on the CA, although not explicit in the table. |
| QC Testing | 95% performance criteria | Met for all antimicrobials | Achieved. |
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.
§ 866.1650 A cellular analysis system for multiplexed antimicrobial susceptibility testing.
(a)
Identification. A cellular analysis system for multiplexed antimicrobial susceptibility testing is a multiplex qualitative and/or quantitative in vitro diagnostic device intended for the identification and determination of the antimicrobial susceptibility results of organisms detected in samples from patients with suspected microbial infections. This device is intended to aid in the determination of antimicrobial susceptibility or resistance when used in conjunction with other laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include:
(i) Detailed device description documentation, including the device components, ancillary reagents required but not provided, a detailed explanation of the methodology, including primer/probe sequence, design, rationale for sequence selection, and details of the antimicrobial agents, as applicable.
(ii) Detailed documentation from the following analytical and clinical performance studies: limit of detection, inclusivity, precision, reproducibility, interference, cross-reactivity, carryover, and cross-contamination, quality control and additional studies, as applicable to specimen type and assay intended use.
(iii) Detailed documentation from an appropriate clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted reference methods.
(iv) Detailed documentation for device software, including software applications and hardware-based devices that incorporate software.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) Limitations and protocols regarding the need for correlation of results by standard laboratory procedures, as applicable.
(ii) A detailed explanation of the interpretation of results and acceptance criteria.
(iii) A detailed explanation of the principles of operation and procedures for assay performance and troubleshooting.