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The KeyPath™ MRSA/MSSA Blood Culture Test – BT is a qualitative in vitro diagnostic test for the timely identification of Staphylococcus aureus (S. aureus) and determination of methicillin susceptibility (MSSA) or methicillin resistance (MRSA) directly from positive blood cultures.

The Test uses bacteriophage amplification to identify the presence of S. aureus and assess the phenotypic response of the target organism to cefoxitin, an indicator of oxacillin (a methicillin analog) resistance.

The assay is performed directly on positive blood culture specimens that are determined as Gram Positive Cocci in singles (GPC) or as Gram Positive Cocci in Clusters (GPCC) by Gram stain.

The KeyPath™ MRSA/MSSA Blood Culture Test - BT is performed directly on positive blood culture specimens from BD BACTEC™ blood culture bottles (Plus Aerobic/F, Plus Anaerobic/F, Standard/10 Aerobic/F and Standard Anaerobic/F).

The Test is indicated for use in conjunction with other laboratory and clinical data available to the physician as an aid in the detection of MRSA/MSSA from positive blood cultures.

Subculturing of positive blood cultures is necessary for additional susceptibility test determinations, differentiation of mixed growth and for epidemiological typing.

The KevPath™ MRSA/MSSA Blood Culture Test - BT (KevPath™ Test) is a bacteriophage amplification-enabled immunoasay to identify Staphylococcus aureus and determine its resistance or susceptibility to cefoxitin from positive blood cultures, which have been determined to have Gram Positive Cocci in singles (GPC) or Gram Positive Cocci in Clusters (GPCC) by Gram stain. This method utilizes the specificity of bacteriophage/bacteria interactions and their natural amplification processes to produce a surrogate signal. In the presence of S. aureus, bacteriophage will replicate, increasing to a detectable concentration. In the absence of S. aureus or the presence of bacteria other than S. aureus, the KevPath™ Test bacteriophage do not replicate and remain undetectable. In addition, susceptible strains of S. aureus do not grow in the presence of cefoxitin and therefore do not support bacteriophage amplification, while resistant strains will grow and support bacteriophage amplification.

To perform the KeyPath™ Test, a sample of the positive blood culture is added to each of the two provided reaction tubes, each comprised of KeyPath™ Test bacteriophage and proprietary reagents that enhance the growth of S. aureus and suppress other organisms. One Reaction Tube (Blue) is used for S. aureus identification. The second Reaction Tube (Red) is used for resistance/susceptibility testing. Following incubation, a small amount of the sample from each Tube is pipetted onto corresponding sample wells on the Detector. If the specimen contains S. aureus a pink-to-dark red/ purple Test Line (T) will appear in the Blue ID Window of the Detector.

If the sample is positive for S. aureus, Resistance/Susceptibility is then determined by reading the Red RS Window. Resistance (MRSA) is determined by the development of a visible pink-to-dark red/purple line at the Test Line (T) in the Red RS Window, while Susceptibility (MSSA) is determined by the absence of a visible colored line at the Test Line (T) in the Red RS Window.

Here's a summary of the acceptance criteria and study details for the KeyPath™ MRSA/MSSA Blood Culture Test – BT, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Note: The acceptance criteria were stated as "≥ 95% positive and negative agreement for S. aureus identification and determination of methicillin resistance." The tables above show the results from the performance study, which met these criteria with high agreement percentages and confidence intervals.

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

• Sample Size:
  • Performance Study: ≥ 20 MRSA, ≥ 20 MSSA, and ≥ 20 NSA clinical blood culture isolates from unique patients for each bottle type (Standard/10 Aerobic/F (SA) and Standard Anaerobic/F (SN)).
    • Specifically, for SA bottles: 45 positive controls, 35 negative controls for S. aureus ID. For resistance, the 2x2 table included 21 positive and 22 negative for resistance (total 43 S. aureus isolates).
    • Specifically, for SN bottles: 44 positive controls, 30 negative controls for S. aureus ID. For resistance, the 2x2 table included 20 positive and 22 negative for resistance (total 42 S. aureus isolates).
  • Media Interference Study: 16 strains (4 MRSA, 4 MSSA, and 8 NSA) with 5 replicates each, for both SA and SN bottles.
• Data Provenance: Clinical blood culture isolates from unique patients. The blood for charge bottles was from healthy volunteers. The study was conducted per IRB-approved protocol MP2007A. The country of origin is not explicitly stated but implied to be the US given the submission to the FDA. The study is prospective in nature as bottles were inoculated and grown for testing, mimicking a real-world scenario.

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

• The document does not specify the number or qualifications of experts used to establish the ground truth. It refers to a "Reference" method for comparison but doesn't detail how this reference standard was itself established or by whom.

4. Adjudication Method for the Test Set

• The document does not explicitly describe an adjudication method for the test set. It uses the "Reference" method as the comparative standard.

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

• No, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed. The device is an in vitro diagnostic test meant for laboratory use, not a medical imaging device or interpretative aid that would typically involve human readers.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

• Yes, the performance study effectively evaluates the device in a standalone manner. The KeyPath™ test provides a qualitative result directly (pink-to-dark red/purple line or absence thereof) without active human interpretation or real-time human-in-the-loop decision making, beyond observing the test results per the package insert. The "Reference" method serves as the ground truth against which the device's accuracy is measured.

7. Type of Ground Truth Used

• The type of ground truth used is a reference method, which is compared to the KeyPath™ Test results. The exact nature of this "Reference" method (e.g., conventional microbiological culture and susceptibility testing, molecular methods) is not explicitly detailed in the provided text, but it is implied to be the established gold standard for S. aureus identification and methicillin resistance determination.

8. Sample Size for the Training Set

• The document does not directly describe a separate "training set" for the device, as it is a bacteriophage amplification-enabled immunoassay rather than a machine learning algorithm that typically requires a distinct training phase. The study described focuses on validation of the device's performance against a reference standard using clinical isolates.

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

• As mentioned above, there is no explicit "training set" described in the context of machine learning. The device's underlying biological mechanism (bacteriophage amplification) does not involve a training process in the conventional sense. The "ground truth" for evaluating its performance (as described in point 7) is based on established microbiology methods.

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The KeyPath™ MRSA/MSSA Blood Culture Test - BT is a qualitative in vitro diagnostic test for the timely identification of Staphylococcus aureus (S. aureus) and determination of methicillin susceptibility (MSSA) or methicillin resistance (MRSA) directly from positive blood cultures.

The Test uses bacteriophage amplification to identify the presence of S. aureus and assess the phenotypic response of the target organism to cefoxitin, an indicator of oxacillin (a methicillin analog) resistance.

The assay is performed directly on positive blood culture specimens that are determined as Gram Positive Cocci in singles (GPC) or as Gram Positive Cocci in Clusters (GPCC) by Gram stain.

The KeyPath™ MRSA/MSSA Blood Culture Test - BT is performed directly on positive blood culture specimens from BD BACTEC™ blood culture bottles (Plus Aerobic/F and Plus Anaerobic/F).

The Test is indicated for use in conjunction with other laboratory and clinical data available to the physician as an aid in the detection of MRSA/MSSA from positive blood cultures.

Subculturing of positive blood cultures is necessary for additional susceptibility test determinations, differentiation of mixed growth and for epidemiological typing.

The KeyPath™ MRSA/MSSA Blood Culture Test – BT uses lytic bacteriophage, specific for Staphylococcus aureus, as an amplification technology for detection of S. aureus and determination of methicillin resistance or susceptibility in positive blood cultures. To detect S. aureus (ID Reaction Tube), the bacteriophage infect the S. aureus (if present), replicate within the host (culminating in bacterial lysis) and over the incubation period, produce several cvcles of bacteriophage amplification. In a separate Reaction Tube (RS), the Test uses cefoxitin (an oxacillin and methicillin analog) which inhibits bacteriophage amplification for susceptible organisms (MSSA) and fails to inhibit bacteriophage amplification when the organism is resistant to methicillin (MRSA). The Test then uses a self-performing immunoassay (Detector) to detect the increase in concentration of bacteriophage using antibodies specific to the Test bacteriophage, and calibrated such that at above a threshold concentration, it produces a visible signal.

Here's a breakdown of the acceptance criteria and study details for the MicroPhage KeyPath™ MRSA/MSSA Blood Culture Test - BT, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical targets in the document. Instead, the study aims to achieve substantial equivalence to predicate devices and provide robust performance characteristics. The reported device performance is listed below for different analytical measures.

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

• Test Set Sample Size: 1116 paired samples (366 S. aureus).
• Data Provenance: The study was a prospective clinical trial conducted across four clinical sites. The country of origin of the data is not explicitly stated, but given the FDA 510(k) submission, it is typically from the United States or an equivalent regulatory region.

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

The document does not specify the number of experts directly, nor their specific qualifications. However, the "standard methods" used to establish ground truth imply the involvement of trained laboratory personnel. These methods include:

• Standard culture identification for S. aureus (Catalase positive, Tube Coagulase positive, Remel Staphaurex® positive).
• Antimicrobial susceptibility determination using 30 µg cefoxitin disk diffusion in accordance with CLSI M100-S19.

This suggests that the ground truth was established by experienced clinical laboratory professionals following established microbiological and susceptibility testing guidelines.

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method for discrepancies between the KeyPath™ Test results and the "standard methods." It notes that invalid results from the KeyPath™ Test were "resolved upon retest," implying re-evaluation of those specific samples for the KeyPath™ Test, but not a formal adjudication of ground truth discrepancies.

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, an MRMC comparative effectiveness study involving human readers and AI assistance was not mentioned or performed for this device. The KeyPath™ MRSA/MSSA Blood Culture Test - BT is a diagnostic test kit involving a visual interpretation from a lateral flow immunoassay, not an AI-powered image analysis or diagnostic assist tool for human readers.

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

Yes, the study primarily assesses the standalone performance of the KeyPath™ MRSA/MSSA Blood Culture Test - BT device as a diagnostic test. While the interpretation of the lateral flow immunoassay is visual, it's the test kit's performance being evaluated against established gold standards, not a human reader's performance with or without the kit.

7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)

The ground truth used was a combination of established microbiological culture methods and phenotypic antimicrobial susceptibility testing:

• For S. aureus identification: Catalase test, Tube Coagulase test, and Remel Staphaurex® test.
• For methicillin resistance/susceptibility: 30 µg cefoxitin disk diffusion test, performed according to CLSI M100-S19 guidelines.

This represents a robust and well-accepted gold standard in clinical microbiology.

8. The Sample Size for the Training Set

The document does not explicitly mention a separate "training set" or its size for the KeyPath™ MRSA/MSSA Blood Culture Test - BT. This device is a diagnostic test kit that uses bacteriophage amplification and immunoassay detection, which typically involves wet-lab development and validation rather than machine learning models that require distinct training sets. The "Non-clinical Studies" section describes inclusivity and analytical specificity testing on panels of strains, which could be considered part of the development and refinement process, but not a "training set" in the context of algorithm development.

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

As no specific "training set" for an algorithm is mentioned, this question is not directly applicable. However, for the panels used in non-clinical studies (e.g., inclusivity, analytical specificity), the ground truth for strain identification and resistance profiles would have been established using comprehensive microbiological techniques and genetic characterization in a laboratory setting. For instance, the "Evaluation of SCCmec Empty Cassette Variants" section mentions "mecA-positive (MRSA) by commercial and laboratory PCR tests but MSSA by phenotypic culture." This indicates that molecular methods (PCR) and traditional culture methods were used to characterize these strains.

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