VITEK® 2 AST-Gram Negative Plazomicin (=0.5 - =16 µg/mL); VITEK® 2 AST-GN Plazomicin (=0.5 - =16 µg/mL); VITEK® 2 AST-GN Plazomicin

K223478 · bioMerieux, Inc. · LON · Feb 16, 2023 · Microbiology

Device Facts

• Record ID: K223478
• Device Name: VITEK® 2 AST-Gram Negative Plazomicin (=0.5 - =16 µg/mL); VITEK® 2 AST-GN Plazomicin (=0.5 - =16 µg/mL); VITEK® 2 AST-GN Plazomicin
• Applicant: bioMerieux, Inc.
• Product Code: LON · Microbiology
• Decision Date: Feb 16, 2023
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1645
• Device Class: Class 2

Indications for Use

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 Plazomicin is an automated, miniaturized, growth-based antimicrobial susceptibility test (AST) system. It uses 64-well cards containing premeasured antimicrobial concentrations and nutrient media. Input: bacterial isolate suspension (standardized to 0.5 McFarland via DensiCHEK Plus). Operation: system fills, seals, and incubates cards; optical scanner measures light transmittance every 15 minutes to monitor growth. Output: MIC values and interpretive category results (S, I, R). Used in clinical laboratories by technicians. Results assist clinicians in determining appropriate antimicrobial therapy for Gram-negative infections. The system provides quantitative MIC results for Plazomicin (≤0.5 - ≥16 μg/mL).

Clinical Evidence

Bench testing only. External evaluation conducted using fresh and stock clinical isolates and challenge strains. Performance compared to CLSI broth microdilution reference method. Results: Essential Agreement (EA) 98.7% (847/858); Category Agreement (CA) 99.4% (853/858); Reproducibility 97.0%. No clinical outcome data provided.

Technological Characteristics

Microdilution MIC technique; 64-well plastic card format; automated incubation and optical growth monitoring; VITEK 2 and VITEK 2 Compact system compatibility; Growth Pattern Analysis (GPA) algorithm; saline-based inoculum preparation.

Indications for Use

Indicated for antimicrobial susceptibility testing of clinically significant aerobic Gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii, Citrobacter koseri, Klebsiella aerogenes, Klebsiella oxytoca, Proteus vulgaris, Serratia marcescens) using VITEK 2 and VITEK 2 Compact systems.

Regulatory Classification

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 Gentamicin (K163563)

Submission Summary (Full Text)

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FDA

U.S. FOOD & DRUG

ADMINISTRATION

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

ASSAY ONLY

## I Background Information:

A 510(k) Number

K223478

B Applicant

bioMérieux, Inc

C Proprietary and Established Names

VITEK 2 AST-Gram Negative Plazomicin (≤0.5 - ≥16 μg/mL); VITEK 2 AST-GN Plazomicin (≤0.5 - ≥16 μg/mL); VITEK 2 AST-GN Plazomicin

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 |
| LTT | Class II | 21 CFR 866.1640 - Antimicrobial susceptibility test powder | MI - Microbiology |
| LTW | Class II | 21 CFR 866.1640 - Antimicrobial susceptibility test powder | MI - Microbiology |

## II Submission/Device Overview:

### A Purpose for Submission:

To obtain a substantial equivalence determination for the VITEK 2 AST-Gram Negative Plazomicin (≤0.5 - ≥16 μg/mL) assay used to define the in vitro antimicrobial susceptibility of clinically significant Gram-negative bacilli to Plazomicin on the VITEK 2 and VITEK 2 Compact Antimicrobial Susceptibility Test (AST) Systems.

Food and Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993-0002

www.fda.gov

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B Measurand:

Plazomicin (≤ 0.5 - ≥ 16 μg/mL)

C Type of Test:

Automated quantitative or qualitative antimicrobial susceptibility test for Plazomicin

III Intended Use/Indications for Use:

A Intended Use(s):

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.

B Indication(s) for Use:

VITEK 2 AST-Gram Negative Plazomicin 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 Plazomicin is a quantitative test. Plazomicin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial.

Active both in vitro and in clinical infections:

Escherichia coli

Klebsiella pneumoniae

Enterobacter cloacae

In vitro data are available, but their clinical significance is unknown:

Citrobacter freundii

Citrobacter koseri

Enterobacter aerogenes

Klebsiella oxytoca

Proteus vulgaris

Serratia marcescens

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

Limitations:

Perform an alternative method of testing prior to reporting of results for the following antibiotic/organism combination(s):

- Plazomicin (plz01n): Morganella morganii, Proteus mirabilis, Providencia stuartii

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The ability of the AST card to detect resistance with the following combination(s) is unknown because resistant strains were not available at the time of comparative testing:

- Plazomicin (plz01n): *Citrobacter fruendii*, *Citrobacter koseri*, *Klebsiella (Enterobacter) aerogenes*, *Klebsiella oxytoca*, *Proteus vulgaris*, and *Serratia marcescens*

## Special Instrument Requirements:

- VITEK 2 and VITEK 2 Compact Systems using 9.04 software.

## Device/System Characteristics:

### 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 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 Plazomicin has the following concentrations in the card: 2, 4, and 8, µg/mL (equivalent standard method concentration by efficacy in µg/mL). The MIC result range for the VITEK 2 AST-GN Plazomicin is ≤0.5 - ≥16 µg/mL.

### 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.

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V Substantial Equivalence Information:

A Predicate Device Name(s):
VITEK 2 AST-GN Gentamicin (≤0.5 - ≥16 μg/mL)

B Predicate 510(k) Number(s):
K163563

C Comparison with Predicate(s):

| Device & Predicate Device(s): | Device K223478 | Predicate K163563 |
| --- | --- | --- |
| Device Trade Name | VITEK 2 AST-Gram Negative Plazomicin (≤0.5 – ≥16 μg/mL) | VITEK 2 AST-Gram Negative Gentamicin (≤1 – ≥16 μg/mL) |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | 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. | The VITEK 2 Antimicrobial Susceptibility Test (AST) is intended to be used with the VITEK 2 Systems for the automated quantitative or qualitative susceptibility testing of isolated colonies for the most clinically significant aerobic gram-negative bacilli, Staphylococcus spp., Enterococcus spp., Streptococcus spp. and clinically significant yeast. |
| 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- | Same |

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| | GN) Susceptibility Card | |
| --- | --- | --- |
| Instrument | VITEK 2 and VITEK 2 Compact Systems | Same |
| Analysis Algorithm | Growth Pattern Analysis | Same |
| General Device Characteristic Differences | | |
| Indications for Use | VITEK 2 AST-Gram Negative Plazomicin 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 Plazomicin is a quantitative test. Plazomicin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial.

Active both in vitro and in clinical infections:
Escherichia coli
Klebsiella pneumoniae
Enterobacter cloacae
In vitro data are available, but their clinical significance is unknown:
Citrobacter freundii
Citrobacter koseri
Klebsiella (Enterobacter) aerogenes
Klebsiella oxytoca
Proteus vulgaris | VITEK 2 AST-Gram Negative Gentamicin 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 Gentamicin is a quantitative test. Gentamicin 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:
Citrobacter species
Enterobacter species
Escherichia coli
Klebsiella species
Proteus species
Serratia species
Pseudomonas aeruginosa |

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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-S30: Performance Standards for Antimicrobial Susceptibility Testing; 30th Edition (January 2020)
- 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 Plazomicin was conducted at three external sites using a panel of ten Gram negative organisms consistent with the indications for use (i.e., three isolates of Escherichia coli and seven isolates of Klebsiella pneumoniae). Each isolate was tested in triplicate, using separate inocula, over three days for a total of 270 data points. Inocula were prepared using both the auto-dilution 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 Guidance Document: Antimicrobial Susceptibility Test (AST) Systems. The overall reproducibility performance was acceptable (Table 1).

Table 1: Reproducibility Performance for VITEK 2 AST-GN Plazomicin

| | VITEK 2 | | VITEK 2 Compact |
| --- | --- | --- | --- |
| | Auto-Dilution | Manual Dilution | Manual Dilution |
| Best case | 97.0% | 95.6% | 97.0% |
| Worst case | 97.0% | 95.6% | 97.0% |

2. Linearity:

Not applicable.

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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 strains, namely Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853, were tested a sufficient number of times (i.e., at least 20/site) at each testing site using both the VITEK 2 AST-GN Plazomicin 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 >95% of the time, which is acceptable. The BMD dilution range (≤0.0625 - ≥128 μg/mL) covered the full expected result range of E. coli ATCC 25922 (expected range of 0.25-2 μg/mL) and P. aeruginosa ATCC 27853 (expected range of 1-4 μg/mL); however, the VITEK 2 Plazomicin card (≤0.5 - ≥16 μg/mL) resulted in off-scale MIC values for E. coli ATCC 25922. An E. coli ATCC 25922 MIC value of ≤0.5 μg/mL (with VITEK 2) was considered as an indication that the quality control test results were acceptable.

To address the potential off-scale QC results when testing E. coli ATCC 25922, 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 and Pseudomonas aeruginosa ATCC 27853 for Plazomicin: VITEK 2 (Auto-Dilution and Manual Dilution Methods) and VITEK 2 Compact (Manual Dilution Method)

| QC Organisms (All sites) | Expected Range (Plazomicin, μg/mL) | Device Range (μg/mL) | BMD Result Range (μg/mL) | VITEK 2 Auto Dilution Frequency | | VITEK 2 Manual Dilution Frequency | | VITEK 2 Compact Manual Dilution | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | Test | Reference | Test | Reference | Test | Reference |
| Escherichia coli ATCC 25922 | 0.25-2 | | ≤0.0625 | | 0 | | 0 | | 0 |
| | | | 0.125 | | 0 | | 0 | | 0 |
| | | | 0.25 | | 64 | | 41 | | 42 |
| | | ≤0.5 | 0.5 | 203 | 114 | 98 | 44 | 100 | 45 |
| | | 1 | 1 | 0 | 23 | 0 | 10 | 0 | 10 |
| | | 2 | 2 | 0 | 3 | 0 | 3 | 0 | 3 |
| | | 4 | 4 | 0 | 0 | 0 | 0 | 0 | 0 |
| | | 8 | 8 | 0 | 0 | 0 | 0 | 0 | 0 |
| | | ≥16 | 16 | 1 | 0 | 0 | 0 | 0 | 0 |
| | | | 32 | - | - | - | - | - | - |
| | | | 64 | - | - | - | - | - | - |
| | | | ≥128 | - | - | - | - | - | - |

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| QC Organisms (All sites) | Expected Range (Plazomicin, μg/mL) | Device Range (μg/mL) | BMD Result Range (μg/mL) | VITEK 2 Auto Dilution Frequency | | VITEK 2 Manual Dilution Frequency | | VITEK 2 Compact Manual Dilution | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | Test | Reference | Test | Reference | Test | Reference |
| Pseudomonas aeruginosa ATCC 27853 | 1-4 | | ≤0.0625 | | 0 | | 0 | | 0 |
| | | | 0.125 | | 0 | | 0 | | 0 |
| | | | 0.25 | | 0 | | 0 | | 0 |
| | | ≤0.5 | 0.5 | 1 | 0 | 0 | 0 | 0 | 0 |
| | | 1 | 1 | 0 | 73 | 0 | 20 | 0 | 20 |
| | | 2 | 2 | 202 | 89 | 97 | 52 | 97 | 53 |
| | | 4 | 4 | 0 | 41 | 0 | 25 | 1 | 25 |
| | | 8 | 8 | - | - | - | - | - | - |
| | | ≥16 | 16 | - | - | - | - | - | - |
| | | | 32 | - | - | - | - | - | - |
| | | | 64 | - | - | - | - | - | - |
| | | | ≥128 | - | - | - | - | - | - |

$^{1}$ VITEK 2 Card range for Plazomicin card is ≤0.5 - ≥16 μg/mL and does not include the full CLSI/FDA-recommended dilution range for QC testing of Escherichia coli ATCC 25922. The lowest concentration of the VITEK 2 Plazomicin MIC range is 0.5 μg/mL. Obtaining a value of ≤0.5 μg/mL was considered an indication that the quality control test results were acceptable.
$^{2}$ BMD: CLSI reference broth microdilution

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 100% of the time (207/207).

## 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 12 device failures (e.g., instrument did not fill a card properly, pipettor error, inability to connect to computer) that resulted in loss of AST cards with the VITEK 2 System and VITEK 2 Compact system. All isolates affected by these errors were retested in accordance with the testing protocol.

## Growth Failure Rate:

A total of 860 clinical and challenge isolates were tested by VITEK 2 AST-GN Plazomicin. Two clinical isolates failed to grow. Results for 858 clinical and challenge isolates on the VITEK 2 AST were available.

## 6. Detection Limit:

Not applicable.

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7. Assay Cut-Off:

Not applicable.

B Comparison Studies:

1. Method Comparison with Predicate Device:

Testing of Plazomicin on the VITEK 2 AST-Gram Negative card was performed at four external sites and one internal site. There were 783 clinical isolates and 75 challenge isolates tested for a total of 858 isolates tested. Results obtained with VITEK 2 AST-Gram Negative Plazomicin were compared to results obtained with the CLSI broth microdilution reference (BMD) panel. The MIC result range for the VITEK 2 AST-Gram Negative Plazomicin is ≤ 0.5 - ≥ 16 μg/mL for all species. The testing conditions for the reference method consisted of the following:

- Medium: Cation Adjusted Mueller Hinton broth
- Inoculum: direct colony suspension
- Incubation: 35 ± 2°C ambient air; 16-24 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 783 clinical isolates (14 C. freundii, 34 C. koseri, 30 K. aerogenes, 27 E. cloacae, 3 E. cloacae complex, 299 E. coli, 30 K. oxytoca, 300 K. pneumoniae, 16 P. vulgaris, and 30 S. marcescens) were evaluated using auto-dilution and VITEK 2. Of these isolates, 61.9% were recent isolates (tested within one year of isolation) and 38.1% were stock isolates (no specific time from isolation). A total of 75 challenge isolates (6 E. cloacae, 29 E. coli, 2 K. oxytoca, 37 K. pneumoniae, and 1 S. marcescens) were evaluated. 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. The results obtained using the VITEK 2 autodilution and manual dilution methods for Plazomicin are summarized in Table 3.

Table 3. Performance of All Clinical and Challenge Isolates for VITEK 2 AST-GN Plazomicin

| | Tot | # EA | % EA | Eval Tot | # Eval EA | % Eval EA | CA Tot | % CA | # R | # Min | # Maj | # Vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| VITEK 2 Automatic Dilution- Clinical and Challenge | | | | | | | | | | | | |
| Enterobacteriaceae | | | | | | | | | | | | |
| Clinical | 783 | 772 | 98.6 | 26 | 15 | 57.7 | 780 | 99.6 | 1 | 2 | 1 | 0 |
| Challenge | 75 | 75 | 100 | 10 | 10 | 100 | 73 | 97.3 | 56 | 2 | 0 | 0 |
| Total | 858 | 847 | 98.7 | 36 | 25 | 69.4 | 853 | 99.4 | 57 | 4 | 1 | 0 |
| VITEK 2 Manual Dilution | | | | | | | | | | | | |
| Enterobacteriaceae | | | | | | | | | | | | |
| Challenge | 75 | 74 | 98.7 | 10 | 9 | 90 | 73 | 97.3 | 56 | 2 | 0 | 0 |
| VITEK 2 Compact Manual- Challenge | | | | | | | | | | | | |
| Enterobacteriaceae | | | | | | | | | | | | |

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| | Tot | # EA | % EA | Eval Tot | # Eval EA | % Eval EA | CA Tot | % CA | # R | # Min | # Maj | # Vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| VITEK 2 Automatic Dilution- Clinical and Challenge | | | | | | | | | | | | |
| Challenge | 75 | 75 | 100 | 12 | 12 | 100 | 74 | 98.7 | 56 | 1 | 0 | 0 |

EA - Essential Agreement

min - minor errors

CA - Category Agreement

maj - major errors

EVAL - Evaluable Isolates

Vmj - very major errors

R - Resistant

S - Susceptible Isolates

Essential agreement (EA) occurs when the result of the reference method and that of the VITEK 2 AST-Gram Negative Plazomicin 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 Plazomicin 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 Plazomicin.

For all organisms evaluated using the auto-dilution method and manual dilution of the VITEK 2, EA was acceptable at >90% and CA was acceptable at >90% (Table 3). No very major errors were observed. One major error was observed for Klebsiella pneumoniae with the VITEK 2 autodilution method but determined to be acceptable. Due to the insufficient number of evaluable results for organisms tested with the VITEK 2 auto dilution method, the CA and overall EA were used to evaluate performance and because of the lack of very major errors or major errors, the performance was considered acceptable.

An insufficient number of resistant isolates were evaluated in the comparative study. To address the lack of information regarding performance with resistant strains, the following limitation was added to the device labeling:

The ability of the AST card to detect resistance with the following combination(s) is unknown because resistant strains were not available at the time of comparative testing:

Plazomicin (plz01n): Citrobacter fruendii, Citrobacter koseri, Klebsiella (Enterobacter) aerogenes, Klebsiella oxytoca, Proteus vulgaris, and Serratia marcescens

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

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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. Evaluable results for trending were not available for $E.$ Cloacae, $E.$ cloacae complex, $K.$ pneumoniae ssp. ozaenae, and $K.$ pneumoniae ssp. pneumoniae. The trending results are summarized in Table 4.

Table 4. Trending Analysis for Enterobacteriaceae with VITEK 2 Auto-Dilution

| Organism | Total Evaluable for Trending | ≥ 1 Dilution lower No. (%) | Exact No. (%) | ≥ 1 Dilution Higher No. (%) | Percent Difference (CI) | Statistically Significant Trending Noted |
| --- | --- | --- | --- | --- | --- | --- |
| C. freundii | 1 | 1, (100%) | 0, (0%) | 0, (0%) | -100%, (-100%, 12%) | No |
| C. koseri | 2 | 1, (50%) | 1, (50%) | 0, (0%) | -50%, (-91%, 27%) | No |
| K. aerogenes | 4 | 1, (25%) | 0, (0%) | 3, (75%) | 50%, (-14%, 79%) | No |
| E. cloacae | 0 | 0, (0%) | 0, (0%) | 0, (0%) | - | N/A |
| E. cloacae complex | 0 | 0, (0%) | 0, (0%) | 0, (0%) | - | N/A |
| E. coli | 74 | 65, (87.8%) | 5, (6.8%) | 4, (5.4%) | -82%, (-89%, -70%) | Yes |
| K. oxytoca | 5 | 1, (20%) | 0, (0%) | 4, (80%) | 60%, (0%, 83%) | No |
| K. pneumoniae ssp. ozaenae | 0 | 0, (0%) | 0, (0%) | 0, (0%) | - | N/A |
| K. pneumoniae ssp. pneumoniae | 0 | 0, (0%) | 0, (0%) | 0, (0%) | - | N/A |
| K. pneumoniae | 10 | 1, (10%) | 0, (0%) | 9, (90%) | 80%, (37%, 92%) | Yes |
| P. vulgaris | 12 | 5, (50%) | 2, (16.7%) | 4 (33.3%) | -17%, (-48%, 20%) | No |
| S. marcescens | 9 | 8, (88.9%) | 1, (11.1%) | 0, (0%) | -89%, (-98%, -45%) | Yes |

A trend toward higher MIC values was observed for $K.$ pneumoniae (Table 4). To address the observed trending, the following footnote was included by the sponsor to the performance table in the device labeling:

VITEK 2 AST-GN Plazomicin MIC values tended to be in exact agreement or at least one doubling dilution higher when testing $K.$ pneumoniae compared to the CLSI reference broth microdilution method.

A trend toward higher MIC values was observed for $E.$ coli and $S.$ marcescens (Table 4). To address the observed trending, the following footnote was included by the sponsor to the performance table in the device labeling:

VITEK 2 AST-GN Plazomicin MIC values tended to be in exact agreement or at least one doubling dilution lower when testing Escherichia coli and Serratia marcescens compared to the CLSI reference broth microdilution method.

2. Matrix Comparison:

Not applicable.

C Clinical Studies:

1. Clinical Sensitivity:

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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 and CLSI susceptibility interpretive criteria for Plazomicin are as listed in Table 5.

Table 5. FDA Recognized Interpretive Criteria for Plazomicin
| | Minimum Inhibitory Concentrations (μg/mL)a | | |
| --- | --- | --- | --- |
| Organisms | S | I | R |
| Enterobacterales | 2 | 4 | ≥8 |

S = Susceptible; I = Intermediate; R = Resistant
a FDA-Recognized Antimicrobial Susceptibility Test Interpretive Criteria Website https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm410971.htm

VIII Proposed Labeling:

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

IX Conclusion:

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

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 Plazomicin when revised breakpoints for Plazomicin 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 Plazomicin 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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