(86 days)
Etest® is a quantitative technique for determination of antimicrobial susceptibility of both non-fastidious Gram negative and Gram positive aerobic bacteria such as Enterobacteriaceae, Pseudomonas, Staphylococcus, and Enterococcus species and fastidious bacteria, such as anaerobes, N. gonorrhoeae, S. pneumoniae, Streptococus and Haemophilus species. The system comprises a predefined antibiotic gradient which is used to determine the Minimum Inhibitory Concentration (MIC), in ug/mL, of different antimicrobial agents against microorganisms as tested on agar media using overnight incubation.
Etest® Ceftolozane / Tazobactam has been shown to be active against the Gram negative aerobic microorganisms listed below, according to the FDA label for this antimicrobial agent:
Active both in vitro and in clinical infections:
Enterobacter cloacae Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa
The following in vitro data are available, but clinical significance is unknown:
Citrobacter koseri Morganella morganii Proteus vulgaris Providencia rettgeri Providencia stuartii Serratia liquefaciens Serratia marcescens
Etest® is a thin, inert and non-porous plastic strip carrying on one side (A) the MIC reading scale in ug/mL, and on the other side (B) a predefined antibiotic gradient.
When the strip is applied to an inoculated agar surface, the preformed antibiotic gradient immediately transfers into the agar matrix, then forming a stable, continuous and exponential gradient of antibiotic concentrations directly underneath the strip. Bacterial growth becomes visible during incubation, and a symmetrical inhibition ellipse centered along the strip appears. The MIC value is read from the scale in terms of ug/mL at complete inhibition of bacterial growth, where the pointed end of the ellipse intersects the strip.
The provided document is a 510(k) premarket notification from the FDA, detailing the review of the "Etest Ceftolozane/Tazobactam" device. This device is an antimicrobial susceptibility test system, specifically designed to determine the Minimum Inhibitory Concentration (MIC) of Ceftolozane/Tazobactam against various aerobic bacteria.
Let's break down the acceptance criteria and the study that proves the device meets these criteria based on the provided text.
Acceptance Criteria and Device Performance Study
The device under review, "Etest Ceftolozane/Tazobactam," is an antimicrobial susceptibility test. For such devices, acceptance criteria typically involve demonstrating a high level of agreement with a recognized reference method.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria for antimicrobial susceptibility test (AST) systems, as stated in the document, are derived from the FDA Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems (August 28, 2009) and CLSI M100-S26 (January 2016). The performance is compared against the CLSI M07-A10 January 2015 broth microdilution reference method.
| Acceptance Criteria (Guidance) | Reported Device Performance | Definition/Notes |
|---|---|---|
| Essential Agreement (EA) | 97.2% overall | Essential Agreement (EA) is achieved when the MIC result for the test device is within ±1 doubling dilution of the MIC result for the reference method. |
| Category Agreement (CA) | 98.6% overall | Category Agreement (CA) is achieved when the interpretive category (Susceptible, Intermediate, Resistant) of the test device matches the interpretive category of the reference method. |
| Reproducibility | Acceptable results | Measures the consistency of results when the test is repeated under the same conditions. |
| Quality Control (QC) | Acceptable results | Ensures the test reagents and procedures are performing as expected using known strains. |
No specific numerical targets for acceptability are explicitly stated in the document for each criterion (e.g., "EA must be >90%"). However, the statement "Etest® Ceftolozane/Tazobactam demonstrated acceptable performance..." implies that the reported percentages met the pre-defined thresholds set by the guidance documents.
2. Sample Size Used for the Test Set and Data Provenance
- Test Set Sample Size: The document does not explicitly state the total number of isolates/samples included in the "external evaluations" for the test set. It mentions "fresh and stock clinical isolates" as well as "a set of challenge strains." The exact count is, however, not provided in this summary.
- Data Provenance: The document does not specify the country of origin for the data. It states that "External evaluations were conducted," suggesting a multi-center or broad collection. The data type is retrospective, as it utilized "fresh and stock clinical isolates," which implies these were pre-existing samples.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Experts
This document describes a performance study comparing an in-vitro diagnostic device (Etest) to a recognized reference method (broth microdilution). The "ground truth" for the test set is established by the CLSI broth microdilution reference method. This method itself is a standardized laboratory procedure, not an interpretation by human experts in the same way, for example, a radiologist interprets an image. Therefore, the concept of "number of experts used" or their "qualifications" for establishing ground truth doesn't directly apply here in the context of human readers. The expertise lies in the execution and interpretation of the CLSI reference method by trained laboratory personnel.
4. Adjudication Method for the Test Set
Since the ground truth is established by a standardized laboratory reference method (CLSI broth microdilution), there is no specific "adjudication method" involving multiple human readers as would be seen in an imaging study. The comparison is direct: Etest MIC vs. Reference Method MIC. Discrepancies are categorized as Essential Agreement, Category Agreement, Major Errors, Very Major Errors, etc., based on pre-defined rules, rather than human adjudication.
5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, and if so, what was the effect size of how much human readers improve with AI vs without AI assistance
There is no indication that a multi-reader multi-case (MRMC) comparative effectiveness study was conducted, nor is there any mention of "human readers" or "AI assistance." This device is an automated, in-vitro diagnostic test. Its performance is evaluated against a gold-standard laboratory method, not against human interpretation or AI-assisted human interpretation.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
This study is inherently a "standalone" performance evaluation in the sense that the Etest device's performance (the "algorithm/system" in this context) is directly compared to the reference method. There is no human-in-the-loop variable being assessed for its impact on the device's accuracy. The Etest strip provides a direct MIC reading.
7. The Type of Ground Truth Used
The type of ground truth used is established laboratory reference method data (CLSI M07-A10 January 2015 broth microdilution reference method). This is considered the gold standard for determining antimicrobial susceptibility.
8. The Sample Size for the Training Set
The document does not explicitly mention a "training set" in the context of machine learning or AI models. For an in-vitro diagnostic device like the Etest, the "training" would be the development and calibration of the strips by the manufacturer. The document describes a validation/test set through "external evaluations." Therefore, the concept of a separate "training set sample size" as typically used for AI models is not applicable here.
9. How the Ground Truth for the Training Set Was Established
As noted above, the concept of a "training set" as in AI/ML is not directly applicable. The "ground truth" for the development and calibration of such a device would involve extensive internal testing and optimization by the manufacturer using validated reference methods and quality control strains, prior to the external validation study detailed in this document. The document focuses on the validation against the established CLSI reference method.
§ 866.1640 Antimicrobial susceptibility test powder.
(a)
Identification. An antimicrobial susceptibility test powder is a device that consists of an antimicrobial drug powder packaged in vials in specified amounts and intended for use in clinical laboratories for determining in vitro susceptibility of bacterial pathogens to these therapeutic agents. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.(b)
Classification. Class II (performance standards).