ETEST® is a manual, quantitative technique for determination of antimicrobial susceptibility of non-fastidious Gram-negative and Gram-positive aerobic bacteria and fastidious bacteria. 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 tested on agar media after overnight incubation.

Imipenem/Relebactam has been shown to be active against the Gram-negative aerobic microorganisms listed below according to the FDA label for this antimicrobial agent.

ETEST® IPR can be used to determine the MIC of Imipenem/Relebactam against the following microorganisms:

Active both in vitro and in clinical infections:

Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella aerogenes
Klebsiella oxytoca
Klebsiella pneumoniae
Pseudomonas aeruginosa

Device Description

ETEST® is a thin, inert and non-porous plastic strip carrying on one side the MIC reading scale in ug/mL, and on the other side 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.

ETEST® Imipenem/Relebactam contains a range of imipenem from 0.002 to 32 µg/mL, overlaid with a fixed concentration of 4ug/mL of relebactam.

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study details for the ETEST® Imipenem/Relebactam (IPR) device, based on the provided text:

1. A table of acceptance criteria and the reported device performance

Performance Metric	Acceptance Criteria (Implicit from Study Design)	Reported Device Performance (ETEST® Imipenem/Relebactam)
Essential Agreement (EA)	Not explicitly stated, but typically high	Enterobacteriaceae: 95.8%
		Pseudomonas aeruginosa: 96.0%
Category Agreement (CA)	Not explicitly stated, but typically high	Enterobacteriaceae: 98.1%
		Pseudomonas aeruginosa: 96.0%
Very Major Errors (VME)	Not explicitly stated; typically very low	Enterobacteriaceae: 2.3% (1/44 resistant isolates)
Reproducibility	Acceptable results	Acceptable results (reported)
Quality Control	Acceptable results	Acceptable results (reported)

Note: The document refers to "substantially equivalent performance when compared with the CLSI M07-A10 January 2015 broth microdilution reference method, following rules as defined in the FDA Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA, issued on August 28, 2009 and following specifications as defined in CLSI M100-S28 January 2018." This implies that the acceptance criteria are based on the guidelines and specifications outlined in these documents for establishing substantial equivalence for AST systems. The specific numerical thresholds for EA, CA, and VME set by these guidelines are not explicitly detailed in the provided text but are the underlying acceptance criteria.

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

Sample Size for Test Set:
- Enterobacteriaceae:
  - Citrobacter freundii: 30 isolates
  - Klebsiella aerogenes: 30 isolates
  - Enterobacter cloacae: 33 isolates
  - Enterobacter cloacae complex: 70 isolates
  - Escherichia coli: 165 isolates
  - Klebsiella oxytoca: 32 isolates
  - Klebsiella pneumoniae: 117 isolates
  - Total Enterobacteriaceae: 30 + 30 + 33 + 70 + 165 + 32 + 117 = 477 isolates (Note: one error in the text is 1/44 resistant isolates for VME, but the total number tested for Enterobacteriaceae is 477. It indicates 44 resistant isolates were tested specifically for VME, not for the entire EA/CA.)
- Pseudomonas aeruginosa: The exact number is not explicitly broken down but is part of the overall "Gram negative aerobic bacteria" and the 96.0% EA/CA. The document does not provide a specific number of P. aeruginosa isolates, only the performance result for that category.
Data Provenance: "External evaluations were conducted with fresh and stock clinical isolates, as well as a set of challenge strains." This indicates the data is from prospective and retrospective clinical samples that were then tested, likely across multiple sites (implied by "external evaluations"). The country of origin is not specified.

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

The document does not mention the number or qualifications of experts used to establish the ground truth. The ground truth method is the CLSI broth microdilution reference method, which is a standardized laboratory procedure, not typically an expert consensus reading.

4. Adjudication method for the test set

The document does not describe an adjudication method involving experts for the test set. The comparison is made against a standardized laboratory reference method (CLSI broth microdilution).

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 MRMC comparative effectiveness study was done as this device is an in vitro diagnostic (IVD) for antimicrobial susceptibility testing, not an AI-assisted diagnostic for human interpretation. It directly determines MIC values.

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

Yes, this evaluates the standalone performance of the ETEST® system. While a human technician applies the strip and reads the ellipse, the interpretation of the MIC value from the scale is directly determined by the physical outcome (inhibition ellipse) on the strip, comparing it to the CLSI reference method. The "device" in this context refers to the ETEST® strip and its inherent gradient.

7. The type of ground truth used

The ground truth used is the CLSI M07-A10 January 2015 broth microdilution reference method. This is a laboratory reference method that is considered the gold standard for antimicrobial susceptibility testing.

8. The sample size for the training set

The document does not specify a separate "training set" for the ETEST® device. As an IVD, its performance is established against a reference method rather than through a machine learning training paradigm common in AI devices. The "test set" described above is used for performance evaluation, not training.

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

Not applicable, as no training set (in the machine learning sense) is described. The device's performance is established by direct comparison to the CLSI broth microdilution reference method.

Summary

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August 22, 2019

bioMérieux SA Marine Taravant Regulatory Affairs Specialist 376, Chemin de L'Orme Marcy L'Etoile, 69280 Fr

Re: K191953

Trade/Device Name: ETEST Imipenem/Relebactam (IPR) (0.002/4-32/4 ug/mL) Regulation Number: 21 CFR 866.1640 Regulation Name: Antimicrobial Susceptibility Test Powder Regulatory Class: Class II Product Code: JWY Dated: July 19, 2019 Received: July 22, 2019

Dear Marine Taravant:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmp/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see

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https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Ribhi Shawar, Ph.D. (ABMM) Chief. General Bacteriology and Antimicrobial Susceptibility Branch Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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ETEST® Imipenem/Relebactam (IPR) (0.002/4-32/4 µg/mL)

A. 510(k) Submission Information:

Submitter's Name:	bioMerieux SA
Address:	376 Chemin de l'Orme69280 Marcy-l'Etoile, FRANCE
Contact Person:	Marine Taravant
	Regulatory Affairs Specialist
Phone Number:	+33 (0)4 78 87 21 26
Date of Preparation:	July 19th, 2019

B. Device Name:

Formal/Trade Name:	ETEST® Imipenem/Relebactam (IPR)(0.002/4 – 32/4 µg/mL)
Classification Name:	21 CFR 866.1640Manual Antimicrobial Susceptibility Test SystemsProduct Code: JWY
Common Name(s):	ETEST® Imipenem/Relebactam; ETEST® IPR
C. Predicate Device:	ETEST® Meropenem/Vaborbactam (MEV)(0.004/8-64/8 µg/mL) (K183031)

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D. Device Description:

ETEST® is a thin, inert and non-porous plastic strip carrying on one side the MIC reading scale in ug/mL, and on the other side a predefined antibiotic gradient.

ETEST® Imipenem/Relebactam contains a range of imipenem from 0.002 to 32 µg/mL, overlaid with a fixed concentration of 4ug/mL of relebactam.

E. Intended Use:

Imipenem/Relebactam has been shown to be active against the Gram-negative aerobic microorganisms listed below according to the FDA label for this antimicrobial agent.

ETEST® IPR can be used to determine the MIC of Imipenem/Relebactam against the following microorganisms:

Active both in vitro and in clinical infections:

Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella aerogenes
Klebsiella oxytoca
Klebsiella pneumoniae
Pseudomonas aeruginosa

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F. Performance Overview

ETEST® Imipenem/Relebactam (IPR) (0.002/4-32/4 ug/mL) demonstrated substantially equivalent performance when compared with the CLSI M07-A10 January 2015 broth microdilution reference method, following rules as defined in the FDA Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA, issued on August 28, 2009 and following specifications as defined in CLSI M100-S28 January 2018.

This Premarket Notification (510[k]) presents data in support of ETEST® Imipenem/Relebactam (IPR) (0.002/4-32/4 ug/mL) for Gram negative aerobic bacteria: Enterobacteriaceae and Pseudomonas aeruginosa. External evaluations were conducted with fresh and stock clinical isolates, as well as a set of challenge strains. The external evaluations were designed to establish the performance of ETEST® Imipenem/Relebactam (IPR) (0.002/4-32/4 ug/mL) by comparing with the CLSI broth microdilution reference method.

ETEST® Imipenem/Relebactam (IPR) (0.002/4-32/4 µg/mL) demonstrated acceptable performance as presented in Table 1 below:

	% Essential Agreement	% Category Agreement
	(EA)	(CA)
Enterobacteriaceae	95.8	98.1
Pseudomonas aeruginosa	96.0	96.0

				Table 1: Performance Characteristics for ETEST® Imipenem/Relebactam
--	--	--	--	---------------------------------------------------------------------

Reproducibility and Quality Control demonstrated acceptable results.

Notes:

EA = % of MIC values within ± 1 dilution of the reference method. ●
The performance data presented for Enterobacteriaceae include Citrobacter freundii ● (30), Klebsiella aerogenes (30), Enterobacter cloacae (33), Enterobacter cloacae complex (70), Escherichia coli (165), Klebsiella oxytoca (32) and Klebsiella pneumoniae (117).

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The optional inoculator and ETEST® strip applicator were used for plate inoculation ● and applying ETEST® strips onto agar media. In the studies, swabs and the Inoculator RETRO C80™ were used for plate inoculation/streaking and forceps and the Vacuum Pen NEMA C88™ were used for ETEST® strip application.
ETEST® Imipenem/Relebactam MIC values tended to be in exact agreement or at least ● one doubling dilution higher when testing Enterobacteriaceae and Pseudomonas aeruginosa compared to the reference broth microdilution method.
The percentage of Very Major Errors of 2.3% for Enterobacteriaceae (1/44 resistant . Enterobacteriaceae isolates) was only due to one Very Major Error with an E. coli isolate. Repeat testing of both ETEST® Imipenem/Relebactam and the reference method with this isolate showed acceptable category agreement between the two tests.

Limitations

. Perform an alternative method of testing for isolates of Morganella morganii. Citrobacter koseri, Serratia marcescens, Providencia rettgeri and Providencia stuartii.
The ability of ETEST® Imipenem/Relebactam to detect resistant isolates is unknown for ● Citrobacter freundii, Klebsiella aerogenes, Enterobacter cloacae/E. cloacae complex and Klebsiella oxytoca because an insufficient number of resistant strains were available at the time of comparative testing. Isolates yielding Imipenem/Relebactam results suggestive of a resistant category, should be submitted to a reference laboratory for further testing.

G. Conclusion:

The performance data presented in this submission support a substantial equivalence decision. ETEST® Imipenem/Relebactam (IPR) (0.002/4-32/4 ug/mL) is substantially equivalent to ETEST® Meropenem/Vaborbactam (MEV) (0.004/8-64/8 µg/mL).

Regulation Number and Section

§ 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).