(71 days)
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.
Meropenem/Vaborbactam has been shown to be active against the Gram-negative aerobic microorganisms listed below according to the FDA label for this antimicrobial agent.
ETEST® MEV can be used to determine the MIC of Meropenem/Vaborbactam against the following microorganisms:
Active both in vitro and in clinical infections: Enterobacter cloacae complex Escherichia coli Klebsiella pneumoniae
In vitro data are available for the following microorganisms, but clinical significance is unknown:
- Citrobacter freundii Citrobacter koseri Klebsiella aerogenes Klebsiella oxytoca Morganella morganii Providencia spp. 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.
ETEST® Meropenem/Vaborbactam contains a range of meropenem from 0.004 to 64 ug/mL, overlaid with a fixed concentration of 8 µg/mL of vaborbactam.
This document describes the performance study and acceptance criteria for the ETEST® Meropenem/Vaborbactam (MEV) device, an antimicrobial susceptibility test system.
1. Table of Acceptance Criteria and Reported Device Performance
The performance of the ETEST® Meropenem/Vaborbactam device was evaluated against the CLSI M07-A10 January 2015 broth microdilution reference method. The acceptance criteria and the device's reported performance are summarized below:
| Performance Metric | Acceptance Criteria (Implicit from FDA Guidance and CLSI) | Reported Device Performance (Table 1) |
|---|---|---|
| Essential Agreement (EA) | Typically ≥ 90% (based on standard AST system guidance) | 95.8% |
| Category Agreement (CA) | Typically ≥ 90% (based on standard AST system guidance) | 99.3% |
Notes:
- Essential Agreement (EA): Defined as the percentage of MIC values within ± 1 dilution of the reference method.
- Category Agreement (CA): Not explicitly defined in this document but generally refers to agreement in interpretation (Susceptible, Intermediate, Resistant) between the test method and the reference method.
- The document states that the performance met acceptable levels as defined in the FDA Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems and CLSI M100-S28 January 2018. The specific numerical acceptance thresholds are implied by the statement "acceptable performance" and the satisfactory agreement percentages reported.
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size for Test Set: The species and their counts that comprised the Enterobacteriaceae (excluding Proteus mirabilis) test isolates are provided:
- C. freundii: 32
- C. koseri: 32
- K. aerogenes: 33
- E. cloacae complex: 98
- E. coli: 136
- K. oxytoca: 31
- K. pneumoniae: 128
- M. morganii: 31
- P. rettgeri: 21
- P. stuartii: 21
- S. marcescens: 31
- Total number of isolates: 594
- Data Provenance: The document states that "External evaluations were conducted with fresh and stock clinical isolates, as well as a set of challenge strains." This indicates that the data are from real-world clinical samples (retrospective or prospective collections) and likely representative of strains encountered in clinical settings, supplemented with challenge strains designed to test specific resistance mechanisms. The country of origin is not explicitly stated, but the submitter's address is France.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Their Qualifications
- This study evaluates an Antimicrobial Susceptibility Test (AST) system. The "ground truth" for ASTs is typically established by specific, standardized laboratory reference methods (e.g., CLSI broth microdilution), not by human expert interpretation of images or clinical data.
- Therefore, the concept of "number of experts" and their qualifications as applies to image-based AI studies (like those with radiologists) is not directly applicable here. The "experts" in this context would be the skilled laboratory personnel who meticulously performed the CLSI broth microdilution reference method, ensuring adherence to the standard protocol.
4. Adjudication Method for the Test Set
- Not applicable in the context of an AST device performance study where the ground truth is a standardized quantitative laboratory method (CLSI broth microdilution). The comparison is direct between the ETEST® results and the reference method results. There is no "adjudication" in the sense of resolving disagreements between human readers or between human readers and an AI.
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 performed. MRMC studies are primarily relevant for imaging-based diagnostic aids where human readers interpret medical images with or without AI assistance. This submission pertains to a laboratory diagnostic device that determines quantitative antimicrobial susceptibility, not an imaging AI.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) was Done
- Yes, the performance study effectively measures the "standalone" performance of the ETEST® system. The ETEST® device generates a MIC value, and this value is directly compared to the reference method's MIC value without human interpretation influencing the ETEST® result itself. The human component is involved in applying the ETEST® strip and reading the inhibition zone, but this is a direct measurement against a scale rather than a subjective interpretation. The agreement percentages (EA and CA) reflect the accuracy of the device in generating these values compared to the reference.
7. The Type of Ground Truth Used
- Gold Standard Ground Truth: The ground truth for this study was established using the CLSI (Clinical and Laboratory Standards Institute) M07-A10 January 2015 broth microdilution reference method. This is a widely accepted, standardized, and highly reproducible method considered the gold standard for determining Minimum Inhibitory Concentrations (MICs) of antimicrobial agents.
8. The Sample Size for the Training Set
- This device is not an AI model that undergoes a "training phase" in the conventional sense. The "training set" concept (data used to train a machine learning algorithm) does not apply here. ETEST® is a chemical-biological device with a physical mechanism of action (predefined antibiotic gradient diffusion), not a software algorithm that learns from data. Its performance is inherent to its design and manufacturing.
- Therefore, there is no "training set" in the context of machine learning. The studies described are for validation (performance evaluation) against a reference standard.
9. How the Ground Truth for the Training Set Was Established
- As explained above, there is no "training set" for this type of device. The ground truth for the performance evaluation (test set) was established by the CLSI broth microdilution reference method (see point 7).
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Indications for Use
510(k) Number (if known)
Device Name
Indications for Use (Describe)
Prescription Use (Part 21 CFR 801 Subpart D)
| Over-The-Counter Use (21 CFR 801 Subpart C)
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ETEST® Meropenem/Vaborbactam
A. 510(k) Submission Information:
| Submitter's Name: | bioMerieux SA |
|---|---|
| Address: | 376 Chemin de l'Orme69280 Marcy-l'Etoile, FRANCE |
| Contact Person: | Marine TaravantRegulatory Affairs Specialist |
| Phone Number: | +33 (0)4 78 87 21 26 |
| Date of Preparation: | October 3, 2018 |
B. Device Name:
| Formal/Trade Name: | ETEST® Meropenem/Vaborbactam (MEV)(0.004/8 – 64/8 μg/mL) |
|---|---|
| Classification Name: | 21 CFR 866.1640Manual Antimicrobial Susceptibility Test SystemsProduct Code: JWY |
| Common Name(s): | ETEST® Meropenem/Vaborbactam; ETEST® MEV |
| C. Predicate Device: | ETEST® Ceftazidime/Avibactam (CZA)(0.016-256 μg/mL) (K172150) |
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D. Device Description:
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.
ETEST® Meropenem/Vaborbactam contains a range of meropenem from 0.004 to 64 ug/mL, overlaid with a fixed concentration of 8 µg/mL of vaborbactam.
E. Intended Use:
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.
Meropenem/Vaborbactam has been shown to be active against the Gram-negative aerobic microorganisms listed below according to the FDA label for this antimicrobial agent.
ETEST® MEV can be used to determine the MIC of Meropenem/Vaborbactam against the following microorganisms:
Active both in vitro and in clinical infections: Enterobacter cloacae complex Escherichia coli Klebsiella pneumoniae
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In vitro data are available for the following microorganisms, but clinical significance is unknown:
- Citrobacter freundii Citrobacter koseri Klebsiella aerogenes Klebsiella oxytoca Morganella morganii Providencia spp. Serratia marcescens
F. Performance Overview
ETEST® Meropenem/Vaborbactam 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.
ETEST® This Premarket Notification (510[k]) data of Meropenem/Vaborbactam for Gram negative aerobic bacteria: Enterobacteriaceae (excluding Proteus mirabilis). 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® Meropenem/Vaborbactam by comparing with the CLSI broth microdilution reference method.
ETEST® Meropenem/Vaborbactam demonstrated acceptable performance as presented in Table 1 below:
| Table 1: Performance Characteristics for ETEST® Meropenem/Vaborbactam | |
|---|---|
| % Essential Agreement | % Category Agreement | |
|---|---|---|
| (EA) a) | (CA) | |
| Enterobacteriaceae b), c), d), e)(excluding P. mirabilis ) | 95.8 | 99.3 |
Notes:
al EA = % of MIC values within ± 1 dilution of the reference method.
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b) The performance data presented for Enterobacteriaceae exclude Proteus mirabilis. There were C. freundii (32), C. koseri (32). K. aerogenes (33), E. cloacae. complex (98), E. coli (136), K. oxytoca (31), K. pneumoniae (128), M. morganii (31), P. rettgeri (21), P. stuartii (21), and S. marcescens (31)
- ETEST® Meropenem/Vaborbactam MIC values tended to be in exact agreement or at least one doubling dilution lower when testing Enterobacteriaceae compared to the CLSI reference broth microdilution.
d Meropenem/Vaborbactam is not active against bacteria that produce metallo-beta-lactamases, oxacillinases with carbapenemase activity, or porin mutations combined with overexpression of efflux pumps.
s) 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, forceps and the Vacuum Pen NEMA C88™ were used for ETEST® strip application.
LIMITATIONS
- · ETEST® Meropenem/Vaborbactam (MEV) must not be used for susceptibility testing of Proteus mirabilis. When testing this organism, the EA did not meet acceptance performance during comparative testing.
- · The ability of the ETEST® Meropenem/Vaborbactam to detect the following resistant Enterobacteriaceae isolates is unknown because resistant isolates were either not available or an insufficient number was encountered at the time of comparative testing: C. freundii. C. koseri, K. aerogenes, E. cloacae complex, E. coli, K. oxytoca, K. morganii, P. rettgeri, P. stuartii, S. marcescens.
- · The safety and efficacy of Meropenem/Vaborbactam in treating clinical infections due to bacteria other than E. cloacae spp. complex, E. coli, and K. pneumoniae may or may not have been established in adequate and well-controlled clinical trials and the clinical significance of such susceptibility information in those instances is unknown.
Reproducibility and Quality Control demonstrated acceptable results.
G. Conclusion:
The performance data presented in this submission support a substantial equivalence decision. ETEST® Meropenem/Vaborbactam (0.004/8-64/8 ug/mL) is substantially equivalent to ETEST® Ceftazidime/Avibactam (0.016-256 ug/mL) (K172150).
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January 11, 2019
bioMerieux SA Marine Taravant Regulatory Affairs Specialist 376 Chemin de l'Orme Marcy- L'Etoile, 69280 France
Re: K183031
Trade/Device Name: ETEST Meropenem/Vaborbactam (MEV) (0.004/8 - 64/8 µg/mL) Regulation Number: 21 CFR 866.1640 Regulation Name: Antimicrobial susceptibility test powder Regulatory Class: Class II Product Code: JWY Dated: October 23, 2018 Received: November 1, 2018
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/cfpmn/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
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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 https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); 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 http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.
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/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely.
for
Uwe Scherf, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
§ 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).