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HardyCHROM™ CRE is a selective and differential chromogenic agar medium intended for the qualitative and presumptive detection from stool specimens of Escherichia coli that are non- susceptible to carbapenems as pink colonies and KES (Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Enterobacter cloacae complex, and Serratia marcescens) that are non-susceptible to carbapenems as blue colonies.

HardyCHROM CRE is intended as an aid in the detection, identification of colonization and control of these bacteria in a healthcare setting. HardyCHROM™ CRE is not intended to diagnose infection or guide therapy. Results can be interpreted after incubation for 18-24 hours. Subculture to non-selective medium is required for confirming identification, antimicrobial susceptibility testing and epidemiological typing.

A lack of growth or the absence of pink or blue colonies on HardyCHROM™ CRE does not preclude the presence of Escherichia coli and KES that are non-susceptible to carbapenems.

HardyCHROM™ CRE is a selective and differential chromogenic medium designed to screen for carbapenem non-susceptible Escherichia coli and KES (Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Enterobacter cloacae complex, and Serratia marcescens.) from fecal specimens. The selective components in HardyCHROM™ CRE inhibit the growth of yeast, Gram-positive bacteria, and Gram-negative bacteria sensitive to ertapenem. HardyCHROM™ CRE differentiates Escherichia coli (pink colonies) from KES (blue colonies).

The CLSI guidelines recommend screening for CREs with an MIC greater than or equal to an established limit to one of several selected agents. Phenotypic confirmation of non-susceptibility to carbapenems is done by demonstrating non-susceptibility to one of the selected agents using MIC or disk diffusion. Further biochemical analysis is required to confirm the production of carbapenemase or any other mechanism of resistance.

Here's a summary of the acceptance criteria and the study proving the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in discrete numerical targets. Instead, it presents performance data (Sensitivity, Specificity, PPV, NPV) and concludes with a statement that the data "support the safety of the device verification and validation" and "demonstrate that the HardyCHROM™ CRE device is substantially equivalent to the predicate device." Therefore, the reported performance metrics serve as the de facto demonstration of meeting the required standards for substantial equivalence.

Performance of HardyCHROM™ CRE for detection of Carbapenem non-susceptible E. coli (Pink Colonies)

Performance of HardyCHROM™ CRE for detection of Carbapenem non-susceptible KES (Blue Colonies)

Agreement of Carbapenem NS Target Species with color on HardyCHROM CRE (at 24 hours)

Performance on Contrived Specimens (E. coli Pink Morphology)

Performance on Contrived Specimens (KES Blue Morphology)

Analytical Sensitivity (LoD) and Reactivity:

• LoD: 1.5x10^2 CFU/mL in stool specimen (for all 10 target strains evaluated)
• Analytical Reactivity: Recovered 72 of 77 (93.5%) carbapenem non-susceptible strains at 1.5x10^2 CFU/mL.

Analytical Specificity:

• Majority of organisms tested did not produce target morphology or were inhibited.
• Certain non-target organisms developed blue pigmentation after 24-48 hours or had distinct morphology, allowing differentiation. None developed pink color.

Microbial Interference:

• HardyCHROM™ CRE was able to recover all target organisms from mixed suspensions in the presence of high concentrations of non-target organisms.

Incubation Study:

• All organisms recovered with expected color by 18 hours.

Stool Specimen Stability:

• 100% recovery from raw stool and stool in Cary Blair at room temperature for up to 24 hours.
• 100% recovery from raw stool and stool in Cary Blair at 2-8℃ for up to 7 days.

Reproducibility:

• 95% agreement with known test results. All CRE-positive isolates (100%) detected.

2. Sample size used for the test set and the data provenance

• Test Set Sample Size (Clinical Study): A total of 1,628 samples were tested. 144 specimens were excluded, resulting in 1,484 valid samples for analysis.
• Contrived Test Set Sample Size: A total of 203 contrived specimens were evaluated.
• Data Provenance: The clinical study used freshly collected stool specimens from "three geographically diverse hospitals." This indicates a prospective study collected from clinical settings in the United States (implied by FDA submission).

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

The document does not explicitly state the number of experts or their specific qualifications (e.g., radiologist with 10 years of experience). However, it mentions:

• "Identity and susceptibility of organisms that grew on both HardyCHROM™ CRE and MacConkey Agar were confirmed using FDA-cleared ID and AST systems."
• For the reproducibility study: "The testing was done with at least one operator and two readers, blinded to each other's results, per site."
  This implies that trained laboratory personnel and validated laboratory methods were used for ground truth determination, which is standard for in vitro diagnostic devices.

4. Adjudication method for the test set

• Clinical Study: The "routine culture" method served as the reference method, followed by confirmation using "FDA-cleared ID and AST systems." This acts as the primary ground truth. There is no explicit mention of an adjudication process (e.g., 2+1, 3+1) involving multiple human readers reviewing results for initial discrepancies to establish a ground truth. Rather, the "reference method" and "FDA-cleared systems" for confirmation established the ground truth.
• Reproducibility Study: "at least one operator and two readers, blinded to each other's results, per site" suggests a form of consensus or independent reading for the reproducibility of the device's visual interpretation, but not for establishing the ultimate ground truth of the organisms' identity and susceptibility, which was pre-determined.

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

• Not applicable. This document describes the performance of a culture medium (HardyCHROM™ CRE), which is a device for bacterial detection and differentiation based on colony color. It is not an AI-assisted diagnostic tool. Therefore, an MRMC study comparing human readers with and without AI assistance was not conducted and is not relevant to this type of device.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

• Yes, in essence. The HardyCHROM™ CRE functions as a standalone diagnostic medium. Its performance metrics (Sensitivity, Specificity, PPV, NPV) were calculated based on the observable color reaction on the agar medium compared to the reference method (culture with confirmed ID and AST). While human observation is required to read the colony color, the "performance" as presented (e.g., "Pink (Positive)" vs. "Negative 1") reflects the intrinsic capability of the medium itself to produce the correct visual signal for Carbapenem non-susceptible E.coli or KES. The study directly evaluates the medium's performance in identifying target organisms based on their chromogenic reaction.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth for the clinical study was established by a reference culture method (selective enrichment in Tryptic Soy Broth with meropenem and vancomycin, followed by subculture to MacConkey Agar), with subsequent identification (ID) and antimicrobial susceptibility testing (AST) using FDA-cleared systems. This is considered a laboratory-based reference standard, which is highly objective for microbiological assays.

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, as the device is a chromogenic culture medium. The studies described are for performance evaluation, not for training an algorithm.

However, if "training set" is broadly interpreted as any data used to refine or develop the product before final validation, then:

• The "Analytical Reactivity" study used 77 well-characterized carbapenem non-susceptible strains.
• The "Analytical Specificity" study used 110 strains (carbapenem-susceptible target species and non-target species).
• The "Microbial Interference" study used the organisms from the Analytical Specificity study plus target organisms.
• The "Reproducibility" study used a panel of 10 blinded isolates (5 positive, 5 negative) at three sites.

These analytical studies and reproducibility tests likely serve as internal development and verification steps before the large-scale clinical validation.

9. How the ground truth for the training set was established

As noted above, there isn't a "training set" in the common AI sense. For the analytical studies, the ground truth was established by:

• Known strains and concentrations: For LoD and Analytical Reactivity, "well-characterized carbapenem non-susceptible strains" at known concentrations were used.
• Known strains (susceptible/non-susceptible) and non-target species: For Analytical Specificity and Microbial Interference, the identity and susceptibility of the tested strains were pre-determined and "well-characterized."
• Known test results: For the Reproducibility study, the panel of 10 isolates had "known test results," meaning their identity and carbapenem resistance status were previously confirmed by standard laboratory methods.

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