(166 days)
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:
- Ampicillin: Escherichia coli
- Aztreonam: Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca
- Cefazolin: Escherichia coli, Klebsiella pneumoniae, Klebsiella variicola
- Ceftazidime: Acinetobacter spp. (other than Acinetobacter ursingii), Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella variicola, Klebsiella pneumoniae, Pseudomonas aeruginosa
- Ertapenem: Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca
- Trimethoprim-Sulfamethoxazole: Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella variicola
- Amikacin: Acinetobacter spp., Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella variicola, Pseudomonas aeruqinosa
- Cefepime: Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa
- Ceftazidime-avibactam: Escherichia coli, Klebsiella aerogenes, Klebsiella oxytoca
- Gentamicin: Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella variicola, Pseudomonas aeruginosa
- Levofloxacin: Escherichia coli, Klebsiella pneumoniae, Klebsiella derogenes, Klebsiella oxytoca, Pseudomonas aeruginosa
- Meropenem: Acinetobacter spp., Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa
- Meropenem-vaborbactam: Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca
- 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.
| Antimicrobial-Organism Combination (Type of Claim) | Total Evaluated (n) | Essential Agreement (EA%) | Category Agreement (CA%) | VMJ (%) | MAJ (%) | MIN (%) | Acceptance Criteria (Implicit) | Reported Performance | Notes |
|---|---|---|---|---|---|---|---|---|---|
| New Claims (Table 3): | |||||||||
| Amikacin-Acinetobacter spp. | 77 | 100.0% | 97.4% | 0.00% | 0.00% | 2.60% | High EA/CA, Low VMJ/MAJ | Met | |
| Amikacin-E. coli, K. aerogenes, K. oxytoca, K. pneumoniae, K. variicola | 480 | 97.3% | 95.8% | 0.00% | 0.75% | 3.54% | High EA/CA, Low VMJ/MAJ | Met | |
| Amikacin-Pseudomonas aeruginosa | 59 | 98.3% | 94.9% | 0.00% | 0.00% | 5.08% | High EA/CA, Low VMJ/MAJ | Met | |
| Cefepime-E. coli, K. aerogenes, K. oxytoca, K. pneumoniae | 445 | 92.6% | 95.7% | 0.00% | 1.07% | 3.60% | High EA/CA, Low VMJ/MAJ | Met | |
| Cefepime-Pseudomonas aeruginosa | 101 | 93.1% | 84.2% | 10.34% | 18.06% | 0.00% | High EA/CA, Low VMJ/MAJ | Not Met | Limitation proposed due to high VMJ/MAJ at 4 µg/mL. |
| Ceftazidime-avibactam-E. coli, K. aerogenes, K. oxytoca | 303 | 99.0% | 99.0% | 0.00% | 1.17% | 0.00% | High EA/CA, Low VMJ/MAJ | Met | |
| Gentamicin-E. coli, K. aerogenes, K. oxytoca, K. pneumoniae, K. variicola | 480 | 98.8% | 97.7% | 0.79% | 0.57% | 1.67% | High EA/CA, Low VMJ/MAJ | Met | |
| Gentamicin-Pseudomonas aeruginosa | 59 | 94.9% | 93.2% | 0.00% | 0.00% | 6.78% | High EA/CA, Low VMJ/MAJ | Met | |
| Levofloxacin-E. coli, K. aerogenes, K. oxytoca, K. pneumoniae | 437 | 98.2% | 96.6% | 0.00% | 0.00% | 3.43% | High EA/CA, Low VMJ/MAJ | Met | |
| Levofloxacin-Pseudomonas aeruginosa | 101 | 96.0% | 88.1% | 0.00% | 0.00% | 11.88% | High EA/CA, Low VMJ/MAJ | Met | All categorical errors were minor. |
| Meropenem-Acinetobacter spp. | 78 | 96.2% | 97.4% | 0.00% | 0.00% | 2.56% | High EA/CA, Low VMJ/MAJ | Met | |
| Meropenem-E. coli, K. oxytoca, K. pneumoniae | 392 | 91.6% | 96.7% | 3.25% | 0.38% | 2.04% | High EA/CA, Low VMJ/MAJ | Not Met | Limitation proposed for K. oxytoca when MIC is 0.5 µg/mL due to high VMJ. |
| Meropenem-Pseudomonas aeruginosa | 59 | 96.6% | 89.8% | 0.00% | 0.00% | 10.17% | High EA/CA, Low VMJ/MAJ | Met | EA of evaluable results was 94.9%. |
| Meropenem-vaborbactam-E. coli, K. aerogenes, K. oxytoca, K. pneumoniae | 442 | 95.0% | 94.6% | 0.00% | 0.55% | 4.98% | High EA/CA, Low VMJ/MAJ | Met | |
| Piperacillin-tazobactam-Acinetobacter spp. | 89 | 92.1% | 94.4% | 0.00% | 0.00% | 5.62% | High EA/CA, Low VMJ/MAJ | Met | |
| Piperacillin-tazobactam-E. coli, K. pneumoniae | 391 | 90.8% | 92.1% | 1.52% | 1.58% | 6.38% | High EA/CA, Low VMJ/MAJ | Not Met | Limitation proposed for K. pneumoniae when MIC is 16 µg/mL due to unacceptable CA. |
| Piperacillin-tazobactam-Pseudomonas aeruginosa | 185 | 94.1% | 93.5% | 1.49% | 0.89% | 5.41% | High EA/CA, Low VMJ/MAJ | Met | |
| K211815 Limitation Removals (Table 12): | |||||||||
| Ertapenem-E. coli (Off-line) | 94 | 90.4% | 90.4% | 0.00% | 1.35% | 8.51% | High EA/CA, Low VMJ/MAJ | Met (combined data) | Removed limitation. |
| Ertapenem-E. coli (On-line) | 108 | 97.2% | 96.3% | 0.00% | 2.08% | 2.78% | High EA/CA, Low VMJ/MAJ | Met (combined data) | |
| Aztreonam-K. pneumoniae | 160 | 90.0% | 94.4% | 1.32% | 2.41% | 3.75% | High EA/CA, Low VMJ/MAJ | Met (combined data) | Removed limitation. |
| Ceftazidime-K. pneumoniae | 160 | 96.3% | 96.9% | 1.27% | 2.53% | 1.25% | High EA/CA, Low VMJ/MAJ | Met (combined data) | Removed limitation. |
| Ceftazidime-Acinetobacter spp. | 118 | 94.9% | 98.3% | 0.00% | 0.00% | 1.69% | High EA/CA, Low VMJ/MAJ | Met (combined data) | Revised limitation to A. ursingii only. |
| Cefazolin-E. coli | 203 | 97.0% | 87.7% | 1.71% | 1.37% | 10.83% | High EA/CA, Low VMJ/MAJ | Met (combined data) | Removed limitation. |
| Ertapenem-K. pneumoniae | 158 | 97.5% | 97.5% | 1.41% | 0.00% | 1.90% | High EA/CA, Low VMJ/MAJ | Met (combined data) | Removed limitation. |
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.
§ 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.