← Product Code [LON](/submissions/MI/subpart-b%E2%80%94diagnostic-devices/LON) · K222073

# VITEK 2 AST-Gram Negative Cefazolin (<=1 - >=32 ug/mL) (K222073)

_bioMerieux, Inc. · LON · Feb 9, 2023 · Microbiology · SESE_

**Canonical URL:** https://fda.innolitics.com/submissions/MI/subpart-b%E2%80%94diagnostic-devices/LON/K222073

## Device Facts

- **Applicant:** bioMerieux, Inc.
- **Product Code:** [LON](/submissions/MI/subpart-b%E2%80%94diagnostic-devices/LON.md)
- **Decision Date:** Feb 9, 2023
- **Decision:** SESE
- **Submission Type:** Traditional
- **Regulation:** 21 CFR 866.1645
- **Device Class:** Class 2
- **Review Panel:** Microbiology

## Indications for Use

VITEK® 2 AST-Gram Negative Cefazolin is designed for antimicrobial susceptibility testing of Gram negative bacilli and is intended for use with the VITEK® 2 and VITEK® 2 Compact Systems as a laboratory aid in the determination of in vitro susceptibility to antimicrobial agents. VITEK® 2 AST-Gram Negative Cefazolin is a quantitative test. Cefazolin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial. Active in vitro and in clinical infections: Escherichia coli Proteus mirabilis The VITEK® 2 Gram-Negative Susceptibility Card is intended for use with the VITEK® 2 Systems in clinical laboratories as an in vitro test to determine the susceptibility of clinically significant aerobic Gram-negative bacilli to antimicrobial agents when used as instructed.

## Device Story

VITEK® 2 AST-Gram Negative Cefazolin is a quantitative, automated in vitro diagnostic test for antimicrobial susceptibility. Input: bacterial isolate diluted in 0.45-0.5% saline. Operation: isolate rehydrates antimicrobial medium in 64-well AST card; VITEK® 2 system automatically fills, seals, and incubates card; system monitors growth in each well over time. Output: MIC value and interpretive category result. Used in clinical laboratories by technicians/microbiologists. Output assists healthcare providers in selecting appropriate antibiotic therapy for patients with Gram-negative infections. Benefits: standardized, automated susceptibility determination compared to manual microdilution.

## Clinical Evidence

Performance evaluated using 463 isolates (387 clinical, 76 challenge) across three sites. Comparison against CLSI broth microdilution (BMD) reference method. For VITEK 2 auto-dilution, Essential Agreement (EA) was 97.4% and Category Agreement (CA) was 83.6% (with 15.6% minor errors, 1.3% major, 0.8% very major). Reproducibility testing (270 data points) showed 99.3-100% agreement within ±1 doubling dilution. Quality control using E. coli ATCC 25922 and 35218 met acceptance criteria (>95% within range). No trending observed.

## Technological Characteristics

Automated microdilution MIC system. 64-well plastic test card containing premeasured antibiotic and culture media. Sensing principle: optical monitoring of bacterial growth over time. Connectivity: integrated with VITEK® 2 and VITEK® 2 Compact instrument platforms. Software: automated incubation and analysis.

## Regulatory Identification

A fully automated short-term incubation cycle antimicrobial susceptibility system is a device that incorporates concentrations of antimicrobial agents into a system for the purpose of determining in vitro susceptibility of bacterial pathogens isolated from clinical specimens. Test results obtained from short-term (less than 16 hours) incubation are used to determine the antimicrobial agent of choice to treat bacterial diseases.

## Special Controls

*Classification.* Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA.”

## Predicate Devices

- VITEK® 2 AST-GN Omadacycline ([K213931](/device/K213931.md))

## Submission Summary (Full Text)

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>
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FDA U.S. FOOD &amp; DRUG ADMINISTRATION

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

ASSAY ONLY

## I Background Information:

A 510(k) Number

K222073

B Applicant

bioMérieux, Inc

C Proprietary and Established Names

VITEK 2 AST-Gram Negative Cefazolin (≤1 - ≥32 μg/mL)

D Regulatory Information

|  Product Code(s) | Classification | Regulation Section | Panel  |
| --- | --- | --- | --- |
|  LON | Class II | 21 CFR 866.1645 - Fully Automated Short-Term Incubation Cycle Antimicrobial Susceptibility System | MI - Microbiology  |

## II Submission/Device Overview:

### A Purpose for Submission:

To obtain a substantial equivalence determination for the VITEK 2 AST-Gram Negative Cefazolin (≤1 - ≥32 μg/ml) assay used to define the in vitro antimicrobial susceptibility of *Escherichia coli* and *Proteus mirabilis* to Cefazolin on the VITEK 2 and VITEK 2 Compact Antimicrobial Susceptibility Test (AST) Systems.

### B Measurand:

Cefazolin ≤ 1 - ≥ 32 μg/ml

### C Type of Test:

Automated quantitative or qualitative antimicrobial susceptibility test

Food and Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993-0002

www.fda.gov

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III Intended Use/Indications for Use:

A Intended Use(s):
See Indications for Use below.

B Indication(s) for Use:
VITEK 2 AST-Gram Negative Cefazolin is designed for antimicrobial susceptibility testing of Gram negative bacilli and is intended for use with the VITEK 2 and VITEK 2 Compact Systems as a laboratory aid in the determination of *in vitro* susceptibility to antimicrobial agents. VITEK 2 AST-Gram Negative Cefazolin is a quantitative test. Cefazolin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial.

Active *in vitro* and in clinical infections:
*Escherichia coli*
*Proteus mirabilis*

The VITEK 2 Gram-Negative Susceptibility Card is intended for use with the VITEK 2 Systems in clinical laboratories as an *in vitro* test to determine the susceptibility of clinically significant aerobic Gram-negative bacilli to antimicrobial agents when used as instructed.

C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only

D Special Instrument Requirements:
VITEK 2 and VITEK 2 Compact Systems using 9.04 software.

IV Device/System Characteristics:

A Device Description:
The VITEK 2 AST card is a miniaturized, abbreviated and automated version of the doubling dilution technique for determining the minimum inhibitory concentration (MIC). Each VITEK 2 AST card contains 64 wells. A control well(s) which contain only nutrient medium is resident on all cards. The remaining wells contain premeasured portions of antimicrobials combined with the nutrient media. The isolate to be tested is diluted to a standardized concentration with 0.45% to 0.50% saline before being used to rehydrate the antimicrobial medium within the card. The VITEK 2 System will automatically (or allow operator to manually) dilute the bacterial suspension to prepare an inoculum for susceptibility cards. Then, the VITEK 2 will fill, seal and place the card into the incubator/reader. The VITEK 2 Compact has a manual filling, sealing, and loading operation. The VITEK 2 Systems monitor the growth of each well in the card over a defined period of time. The analysis program determines when a well demonstrates growth based on attenuation of light measured by an optical scanner. This data is used to determine the

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minimum inhibitory concentration or "MIC" values for the antimicrobial agent. At the completion of the incubation cycle, a report is generated that contains the MIC value along with the interpretive category result for each antimicrobial contained on the card

VITEK 2 AST-GN Cefazolin has the following concentrations in the card: 1, 2, and 8 µg/mL (equivalent standard method concentration by efficacy in µg/mL). The MIC result range for the VITEK 2 AST-GN Cefazolin is ≤1 - ≥32 µg/mL.

## B Principle of Operation:

The VITEK 2 and VITEK 2 Compact Systems utilize automated growth-based detection using attenuation of light measured by an optical scanner. The optics in the systems use visible light to directly measure organism growth within each of the 64 micro-wells. Transmittance optics is based on an initial light reading of a well before significant growth has begun. Every 15 minutes throughout the incubation cycle (defined period of time based on the VITEK 2 card), light transmittance readings of each well determine organism growth by the amount of light that is prevented from passing through the well. At the completion of the incubation period, the MIC values and their associated interpretive category results for each antimicrobial on the test card are displayed in an automatically generated report.

## V Substantial Equivalence Information:

### A Predicate Device Name(s):

VITEK 2 AST-Gram Negative Omadacycline (≤0.25 - ≥16 µg/mL)

### B Predicate 510(k) Number(s):

K213931

### C Comparison with Predicate(s):

|  Device & Predicate Device(s): | Device K222073 | Predicate K213931  |
| --- | --- | --- |
|  Device Trade Name | VITEK 2 AST-Gram Negative Cefazolin (≤ 1 - ≥ 32 µg/ml) | VITEK 2 AST-Gram Negative Omadacycline (≤0.25 - ≥16 µg/mL)  |
|  General Device Characteristic Similarities |  |   |
|  Intended Use/Indications for Use | VITEK 2 AST-Gram Negative Cefazolin is designed for antimicrobial susceptibility testing of Gram negative bacilli and is intended for use with the VITEK 2 and VITEK 2 Compact Systems as a laboratory aid in the determination | VITEK 2 AST-Gram Negative Omadacycline is designed for antimicrobial susceptibility testing of Gram negative bacilli and is intended for use with the VITEK 2 and VITEK 2 Compact Systems as a laboratory aid in the determination  |

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|   | determination of in vitro susceptibility to antimicrobial agents. VITEK 2 AST-Gram Negative Cefazolin is a quantitative test
The VITEK 2 Gram-Negative Susceptibility Card is intended for use with the VITEK 2 Systems in clinical laboratories as an in vitro test to determine the susceptibility of clinically significant aerobic Gram negative bacilli to antimicrobial agents when used as instructed. | of in vitro susceptibility to antimicrobial agents. VITEK 2 AST-Gram Negative Omadacycline is a quantitative test
The VITEK 2 Gram-Negative Susceptibility Card is intended for use with the VITEK 2 Systems in clinical laboratories as an in vitro test to determine the susceptibility of clinically significant aerobic Gram negative bacilli to antimicrobial agents when used as instructed.  |
| --- | --- | --- |
|  Test Methodology | Automated quantitative antimicrobial susceptibility test for use with the VITEK 2 and VITEK 2 Compact Systems to determine the in vitro susceptibility of microorganisms. | Same  |
|  Inoculum | Saline suspension of organism | Same  |
|  Test Card | Gram Negative (AST-GN) Susceptibility Card | Same  |
|  Instrument | VITEK 2 and VITEK 2 Compact Systems | Same  |
|  Analysis Algorithm | Growth Pattern Analysis | Same  |
|  Type of Test | Quantitative | Same  |
|  General Device Characteristic Differences |  |   |
|  Antimicrobial Agent | Cefazolin | Omadacycline  |
|  Concentrations of antimicrobial on card | 1, 2, 8 μg/ml | 0.5, 2, 8, 16 μg/ml  |
|  Indications for Use | Cefazolin has been shown to be active against most strains of the microorganisms listed below, | Omadacycline has been shown to be active against most strains of the microorganisms listed below,  |

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|   | according to the FDA label for this antimicrobial. | according to the FDA label for this antimicrobial.  |
| --- | --- | --- |
|   | Active in vitro and in clinical infections: | Active in vitro and in clinical infections:  |
|   | Escherichia coli Proteus mirabilis | For ABSSSI: Enterobacter cloacae Klebsiella pneumoniae  |
|   |  | For CABP: Klebsiella pneumoniae  |

VI Standards/Guidance Documents Referenced:

- CLSI M07-A11: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard – 11th Edition (January 2018)
- CLSI M100-S32: Performance Standards for Antimicrobial Susceptibility Testing; 30th Informational Supplement (February 2022)
- FDA Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA (Issued August 28, 2009)

VII Performance Characteristics (if/when applicable):

A Analytical Performance:

1. Precision/Reproducibility:

Reproducibility testing for the VITEK 2 AST-Gram Negative Cefazolin was conducted at three sites (two external and one internal site) using a panel of ten Gram negative organisms consistent with the indications for use (i.e., three isolates of Proteus mirabilis and seven isolates of Escherichia coli). Each isolate was tested in triplicate, using separate inoculum, over three days for a total of 270 data points. Inocula were prepared using both the autodilution and manual dilution methods for testing with the VITEK 2 System. In addition, inocula were prepared by the manual dilution method for testing with the VITEK 2 Compact. The mode of MIC values was determined for each isolate and the reproducibility was calculated based on the number of MIC values that fell within ± one doubling dilution of the mode MIC value. The majority of data points were on-scale and within ± one doubling dilution agreement as compared to the mode MIC. The data was analyzed taking into consideration best-case and worst-case scenarios as described in the Class II Special Controls

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Guidance Document: Antimicrobial Susceptibility Test (AST) Systems. The reproducibility performance is shown in Table 1.

Table 1: Reproducibility Performance

|   | VITEK 2 |   | VITEK 2 Compact  |
| --- | --- | --- | --- |
|   |  Manual Dilution | Auto-Dilution | Manual Dilution  |
|  Best case | 99.6% | 100% | 100%  |
|  Worst case | 99.3% | 100% | 99.6%  |

2. Linearity:

Not Applicable

3. Analytical Specificity/Interference:

Not Applicable

4. Assay Reportable Range:

Not Applicable

5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):

The CLSI recommended QC strain, namely Escherichia coli ATCC 25922, was tested a sufficient number of times (i.e., at least 20/site) at each testing site using both the VITEK 2 AST-GN Cefazolin and Broth Microdilution (BMD) reference method. Both the automatic dilution and manual dilution methods were used for the VITEK 2 and the manual dilution method was used for the VITEK 2 Compact. The results are summarized in Table 2 below. Both the auto-dilution and the manual dilution methods for VITEK 2 and the manual dilution for VITEK 2 Compact QC results were within the expected range  $&gt;95\%$  of the time, which is acceptable.

Because the CLSI recommended QC strain does not include the full CLSI/FDA-recommended dilution range required for QC testing, the sponsor included a footnote in labeling to indicate that the device does not include the full CLSI/FDA-recommended dilution range for QC testing.

Table 2: Quality Control Results for Escherichia coli ATCC 25922 for Cefazolin: VITEK 2 (Auto-Dilution and Manual Dilution Methods) and VITEK 2 Compact (Manual Dilution Method)

|  Organism | VITEK 2 Result Range | BMD Result Range (μg/mL) | VITEK 2 Auto-Dilution | BMD | VITEK 2 Manual Dilution | BMD | VITEK 2 Compact Manual Dilution | BMD  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Escherichia coli ATCC 25922 |  | ≤0.125 |  |  |  |  |  |   |
|   |   | 0.25 |  |  |  |  |  |   |
|   |   | 0.5 |  |  |  |  |  |   |
|   |  ≤1 | 1 | 0 | 53 | 0 | 29 | 0 | 30  |
|   |  2 | 2 | 202 | 145 | 97 | 66 | 100 | 67  |

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|  Organism | VITEK 2 Result Range | BMD Result Range (μg/mL) | VITEK 2 Auto-Dilution | BMD | VITEK 2 Manual Dilution | BMD | VITEK 2 Compact Manual Dilution | BMD  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Expected Result: 1-4 μg/mL | 4 | 4 | 1 | 5 | 0 | 2 | 0 | 2  |
|   |  8 | 8 | 0 | 0 | 0 | 0 | 0 | 0  |
|   |  16 | 16 | 0 | 0 | 1 | 0 | 0 | 0  |
|   |  ≥32 | 32 | 1 | 0 | 0 | 0 | 0 | 0  |
|   |   | ≥64 | 0 | 1 | 0 | 1 | 0 | 1  |
|   |  |   |   |   |   |   |   |   |

BMD: broth microdilution

Because the CLSI recommended QC strain does not include the full CLSI/FDA-recommended dilution range required for QC testing the VITEK card reporting range (≤1 - ≥ 32 μg/mL), the sponsor verified Escherichia coli ATCC 35218 as additional QC. Both the auto-dilution and the manual dilution methods for VITEK 2 and the manual dilution for VITEK 2 Compact QC results were within the expected range &gt;95% of the time, which is acceptable. The range finding study set the range for this organism at 2-8 μg/ml.

One ancillary quality control organism was tested throughout comparative testing by broth microdilution reference method only. This was done to perform further quality control of the broth microdilution panels. The organism tested was Staphylococcus aureus ATCC 29213. QC results for the broth microdilution method were within the expected result range &gt;95% of the time. S. aureus ATCC 29213 was within range 100% (208/208).

## Inoculum Density Control:

The DensiCHEK Plus was used to standardize the inoculum to a 0.5 McFarland standard. The instrument was standardized daily with all results recorded at each site. Calibration values were within the expected range.

## Purity Check:

A purity check of all organisms was performed on the dilution tube used to prepare the VITEK 2 card inoculum. Only those cultures that were pure were evaluated in the study.

## Device Failure:

During the performance of the comparative study, there were several instrument processing errors that resulted in loss of AST cards with the VITEK 2 System. All isolates affected by these errors were retested in accordance with the testing protocol. There were no device failures with the VITEK 2 Compact.

## Study Protocol Changes:

During the course of the clinical trial, FDA updated the breakpoints for Cefazolin. For Enterobacterales, CLSI M-100 Ed 32 is recognized as of February 2022. Breakpoints changed from previous FDA-recognized breakpoints (≤1S, 2I, ≥4R) to the new FDA-recognized breakpoints (≤2S, 4I, ≥8R). The updated breakpoints were applied to the clinical trial data, and the performance was evaluated using the updated FDA breakpoints. This protocol change had no impact on testing or test results.

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FDA does not recognize separate susceptibility test interpretative criteria for Enterobacterales for therapy of uncomplicated urinary tract infections. Therefore, the labeling for this device includes the following note:

Per the United States FDA-Recognized Susceptibility Test Interpretive Criteria (STIC) and CLSI, cefazolin should not be reported against Enterobacteriaceae recovered from uncomplicated urinary tract infections.

## Growth Failure Rate:

A total of 464 clinical and challenge isolates were tested by VITEK 2 AST-GN Cefazolin. One growth failure was recorded for a clinical isolate of Escherichia coli. Results for 463 isolates on the VITEK 2 AST were available.

6. Detection Limit:

Not applicable.

7. Assay Cut-Off:

Not applicable.

## B Comparison Studies:

1. Method Comparison with Predicate Device:

Testing of cefazolin on the VITEK 2 AST-Gram Negative card was performed at three external sites and one internal site. There were 387 clinical isolates and 76 challenge isolates tested for a total of 463 isolates tested. Results obtained with VITEK 2 AST-Gram Negative Cefazolin were compared to results obtained with the CLSI broth microdilution reference (BMD) panel. The MIC result range for the VITEK 2 AST-Gram Negative Cefazolin is ≤ 1 - ≥ 32 μg/mL for all species. The testing conditions for the reference method consisted of the following:

- Medium: Cation Adjusted Mueller Hinton broth
- Inoculum: 1 mL of organism suspension standardized to approximate a McFarland 0.5 standard
- Incubation: 35 ± 2°C ambient air; 16-20 hours

The VITEK 2 AST cards were inoculated with test organisms using the auto-dilution method (VITEK 2) and using the manual dilution method (VITEK 2 and VITEK 2 Compact). All test inocula used for the VITEK 2 AST cards and the reference method were standardized using the DensiCHEK Plus instrument.

A total of 387 clinical isolates belonging to all genera were evaluated using auto-dilution and VITEK 2. Of these isolates, 64% were recent isolates (tested within one year of isolation) and 36% were stock isolates (no specific time from isolation). A total of 299 Escherichia coli clinical isolates and 45 Proteus mirabilis clinical isolates were tested as indicated species. In addition, isolates from non-indicated species were evaluated as clinical isolates:

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Citrobacter freundii (1), Citrobacter koseri (2), Klebsiella pneumoniae (32), Proteus vulgaris (1), Enterobacter cloacae (1), Enterobacter aerogenes (1), Serratia marcescens (1), Klebsiella oxytoca (1), Morganella morganii (1), and Providencia stuartii (1).

A total of 76 challenge isolates were evaluated, including 41 E. coli isolates and 35 P. mirabilis isolates. The challenge set was tested with the auto-dilution and manual dilution options of the VITEK 2 and with the manual dilution method on the VITEK 2 Compact.

## Clinical and Challenge Data – VITEK 2 Auto-Dilution

The results obtained using the auto-dilution method of the VITEK 2 from the 463 total isolates (387 clinical isolates and 76 challenge isolates) are summarized in Table 2.

Table 3. Performance of All Clinical and Challenge Isolates for Cefazolin: VITEK 2 Auto-Dilution

|   | To t | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA Tot | CA % | No. R | No. S | min | maj | vmj  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Enterobacterales [Breakpoints (μg/ml): <2 (S), 4 (I), >8 (R)]  |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical^{a} | 387 | 376 | 97.2 | 262 | 252 | 96.2 | 313 | 80.9 | 91 | 216 | 70 | 3 | 1  |
|  Challenge^{b} | 76 | 75 | 98.7 | 61 | 60 | 98.4 | 74 | 97.4 | 31 | 14 | 2 | 0 | 0  |
|  Total | 463 | 451 | 97.4 | 323 | 312 | 96.6 | 387 | 83.6 | 122 | 230 | 72 | 3 | 1  |

a includes 299 E. coli, 45 P. mirabilis and 43 other Enterobacterales isolates
b includes 41 E. coli and 35 P. mirabilis

EA – Essential Agreement
CA – Category Agreement
EVAL – Evaluable Isolates
R – Resistant

min – minor errors
maj – major errors
vmj – very major errors
S – Susceptible Isolates

Essential agreement (EA) occurs when the result of the reference method and that of the VITEK 2 AST-Gram Negative Cefazolin are within plus or minus one serial two-fold dilution of the antibiotic. Evaluable results are those that are on-scale for both the reference method and the VITEK 2 AST-Gram Negative Cefazolin or results in which an off scale result is at least two doubling dilutions from the on scale result. Category agreement (CA) occurs when the interpretation of the result of the reference method agrees exactly with the interpretation provided by the VITEK 2 AST-Gram Negative Cefazolin.

For all organisms evaluated using the auto-dilution method of the VITEK 2, EA was acceptable at 97.4% (Table 3). The CA of 83.6% was caused by 72 (15.6%) minor errors. Because the EA of evaluable results was 96.2%, and the error rates for major errors (1.3%) and very major errors (0.8%) were within acceptable limits, the CA of 83.6% was considered acceptable.

## Challenge Data – VITEK 2 and VITEK 2 Compact Manual Dilution

The 76 challenge isolates were also tested at one site with the manual dilution option for the VITEK 2 and VITEK 2 Compact systems (summarized in Table 4).

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Table 4. Performance of Challenge Isolates for Cefazolin: VITEK 2 Manual Dilution

|   | Tot | EA N | EA % | Eva Tot | Eval EA N | Eval EA % | CA Tot | CA % | No. R | No. S | min | maj | vmj  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  VITEK 2 | 76 | 73 | 96.1 | 60 | 57 | 95.0 | 72 | 94.7 | 31 | 14 | 4 | 0 | 0  |
|  VITEK 2 Compact | 76 | 73 | 96.1 | 61 | 58 | 95.1 | 73 | 96.1 | 31 | 14 | 3 | 0 | 0  |

The overall performance of Enterobacterales is acceptable with an EA of  $96.1\%$ , a CA of  $94.7\%$ , and 4 minor errors  $(5.3\%)$  for the VITEK 2 system.

The overall performance of Enterobacterales is acceptable with an EA of  $96.1\%$ , a CA of  $96.1\%$ , and three minor errors  $(3.9\%)$  for the VITEK 2 Compact system.

As required under 511A(b)(2)(C)(ii)(I) of the Federal Food, Drug and Cosmetic Act, the following statement is included in the Precautions section of the device labeling to address testing and reporting of non-indicated species:

Per the FDA-Recognized Susceptibility Test Interpretive Criteria website, the safety and efficacy of antimicrobial drugs, for which antimicrobial susceptibility is tested by this AST device, may or may not have been established in adequate and well-controlled clinical trials for treating clinical infections due to microorganisms outside of those found in the indications and usage in the drug label. The clinical significance of susceptibility information in those instances is unknown. The approved labeling for specific antimicrobial drugs provides the uses for which the antimicrobial drug is approved.

# Trending

A trending analysis was conducted using the combined data (clinical and challenge) obtained from the VITEK 2 auto-dilution method. This trending calculation analyzes device MIC values that are determined to be one or more doubling dilutions lower or higher than the reference method. MIC values that are off-scale for both the reference and device are not considered in the trending analysis. Species for which the difference between the percentage of isolates with higher or lower MIC values was  $\geq 30\%$  with a statistically significant confidence interval were considered to have evidence of trending and is addressed in the labeling. There was no trending observed.

Table 5. Trending Analysis for Enterobacterales with VITEK 2 Auto-Dilution

|  Organism | Total Evaluable for Trending | ≥1 Dilution lower No. (%) | Exact No. (%) | ≥1 Dilution Higher No. (%) | Percent Difference (CI) | Trending Noted  |
| --- | --- | --- | --- | --- | --- | --- |
|  E. coli | 232 | 37 (15.9) | 99 (42.7) | 96 (41.4) | 25.4% (17.3 to 33.1) | No  |
|  P. mirabilis | 75 | 16 (21.3) | 52 (69.3) | 7 (9.33) | -12.0% (-23.6 to -0.35) | No  |

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2. Matrix Comparison:

Not applicable.

## C Clinical Studies:

1. Clinical Sensitivity:

Not applicable.

2. Clinical Specificity:

Not applicable.

3. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):

Not applicable.

## D Clinical Cut-Off:

Not applicable.

## E Expected Values/Reference Range:

The FDA recognized susceptibility interpretative criteria for Cefazolin are listed in Table 6.

Table 6. FDA-Recognized Interpretative Criteria for Cefazolin

|  Organisms | Minimum Inhibitory Concentrations (μg/mL)a  |   |   |
| --- | --- | --- | --- |
|   |  S | I | R  |
|  Enterobacteralesb | ≤2 | 4 | ≥8  |

S = Susceptible; I = Intermediate; R = Resistant
Interpretative criteria are based on a dose of 2g every 8 hours
a FDA-Recognized Antimicrobial Susceptibility Test Interpretative Criteria Website https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm410971.htm
b Separate susceptibility test interpretative criteria for Enterobacterales for therapy of uncomplicated urinary tract infections are not recognized at this time.

## VIII Proposed Labeling:

The labeling supports the finding of substantial equivalence for this device when evaluated with the current FDA-recognized Cefazolin breakpoints.

## IX Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

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To support the implementation of changes to FDA-recognized susceptibility test interpretive criteria (i.e. breakpoints), this submission included a breakpoint change protocol that was reviewed and accepted by FDA. This protocol addresses future revisions to device labeling in response to breakpoint changes that are recognized on the FDA STIC webpage (https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm410971.htm). The protocol outlined the specific procedures and acceptance criteria that bioMérieux intends to use to evaluate the VITEK 2 System with Cefazolin when revised breakpoints for Cefazolin are published on the FDA STIC webpage. The breakpoint change protocol included with the submission indicated that if specific criteria are met, bioMérieux will update the Cefazolin device label to include (1) the new breakpoints, (2) an updated performance section after re-evaluation of data in this premarket notification with the new breakpoints, and (3) any new limitations as determined by their evaluation.

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**Source:** [https://fda.innolitics.com/submissions/MI/subpart-b%E2%80%94diagnostic-devices/LON/K222073](https://fda.innolitics.com/submissions/MI/subpart-b%E2%80%94diagnostic-devices/LON/K222073)

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