← Product Code [LON](/productcode/LON) · K260619

# VITEK 2 AST-Streptococcus Cefepime (<=0.06 – >=4 µg/mL) (K260619)

_Biomérieux, Inc. · LON · Sep 28, 2026 · Microbiology · SESE_

**Canonical URL:** https://fda-staging.innolitics.com/device/K260619

## Device Facts

- **Applicant:** Biomérieux, Inc.
- **Product Code:** [LON](/productcode/LON.md)
- **Decision Date:** Sep 28, 2026
- **Decision:** SESE
- **Submission Type:** Traditional
- **Regulation:** 21 CFR 866.1645
- **Device Class:** Class 2
- **Review Panel:** Microbiology
- **Attributes:** PCCP

## Indications for Use

VITEK 2 AST-Streptococcus Cefepime (≤0.06 - ≥4 μg/mL) is designed for antimicrobial susceptibility testing of Streptococcus species and is intended for use with the VITEK 2 Systems as a laboratory aid in the determination of in vitro susceptibility to antimicrobial agents. VITEK 2 AST-Streptococcus Cefepime (≤0.06 - ≥4 μg/mL) is a quantitative test. Testing is indicated for Streptococcus pneumoniae (non-meningitis), Streptococcus spp. β-Hemolytic Group, and Streptococcus spp. Viridans Group as recognized by the FDA Susceptibility Test Interpretive Criteria (STIC). VITEK 2 AST-Streptococcus Cefepime (≤0.06 - ≥4 μg/mL) has demonstrated acceptable performance with the following organisms: Streptococcus pneumoniae (non-meningitis) Streptococcus spp. β-Hemolytic Group (Streptococcus agalactiae, Streptococcus canis, Streptococcus dysgalactiae ssp. equisimilis, Streptococcus equi ssp. zooepidemicus, Streptococcus pyogenes), Streptococcus spp. Viridans Group (Streptococcus cristatus, Streptococcus gallolyticus ssp. gallolyticus, Streptococcus gordonii, Streptococcus infantarius ssp. infantarius, Streptococcus mitis, Streptococcus oralis, Streptococcus parasanguinis, Streptococcus salivarius ssp. salivarius, Streptococcus sanguinis, Streptococcus uberis, Streptococcus vestibularis) The VITEK 2 Streptococcus Susceptibility Card is intended for use with the VITEK 2 Systems in clinical laboratories as an in vitro test to determine the susceptibility of Streptococcus pneumoniae, beta-hemolytic Streptococcus and Viridans Streptococcus to antimicrobial agents when used as instructed.

## Device Story

VITEK 2 AST-ST Cefepime is an automated in vitro diagnostic test for determining antimicrobial susceptibility of Streptococcus species. The device uses a 64-well card containing premeasured antibiotic concentrations and culture media. Clinical laboratory technicians prepare a saline suspension of the bacterial isolate, which is used to rehydrate the card. The VITEK 2 system automatically fills, seals, and incubates the card, monitoring bacterial growth via optical sensors over a defined period. The system processes growth data to calculate the Minimum Inhibitory Concentration (MIC) and provides an interpretive category (Susceptible, Intermediate, Resistant). This output assists clinicians in selecting appropriate antibiotic therapy for patients. The device is intended for use in clinical laboratory settings.

## Clinical Evidence

Performance evaluated via external study using fresh/stock clinical isolates and challenge strains. Compared against CLSI broth microdilution reference method (20-24 hour incubation). Results: 98.6% overall Essential Agreement, 97.8% overall Category Agreement. Specific performance: S. pneumoniae (98.5% EA, 96.8% CA), β-Hemolytic Group (99.7% EA, 100% CA), Viridans Group (96.4% EA, 95.6% CA). Reproducibility was 99.6%.

## Technological Characteristics

Automated microdilution MIC system. 64-well plastic test card containing culture media and Cefepime (0.125–2 µg/mL). Sensing principle: optical growth monitoring. Platform: VITEK 2, VITEK 2 Compact, VITEK COMPACT PRO. Software algorithm: Growth Pattern Analysis. Sterilization: Not specified.

## 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-Streptococcus Penicillin ([K232201](/device/K232201.md))

## Submission Summary (Full Text)

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>
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[LOGO]

FDA

U.S. FOOD & DRUG

ADMINISTRATION

### 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION
DECISION SUMMARY

ASSAY ONLY

### I Background Information:

A 510(k) Number

K260619

B Applicant

bioMérieux, Inc.

C Proprietary and Established Names

VITEK 2 AST-Streptococcus Cefepime (≤0.06 - ≥4 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  |
|  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-Streptococcus Cefepime (≤0.06 - ≥4 μg/mL) assay for susceptibility testing of Streptococcus pneumoniae (non-meningitis), Streptococcus spp. β-Hemolytic Group, and Streptococcus spp. Viridans Group on the VITEK 2, VITEK 2 Compact, and VITEK COMPACT PRO 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:**

Cefepime ≤0.06 - ≥4 μg/mL

# **C Type of Test:**

Automated quantitative or qualitative antimicrobial susceptibility test

# **III Intended Use/Indications for Use:**

# **A Intended Use(s):**

See Indications for Use below.

# **B Indication(s) for Use:**

VITEK 2 AST-*Streptococcus* Cefepime (≤0.06 - ≥4 μg/mL) is designed for antimicrobial susceptibility testing of *Streptococcus* species and is intended for use with the VITEK 2 Systems as a laboratory aid in the determination of *in vitro* susceptibility to antimicrobial agents.

VITEK 2 AST-*Streptococcus* Cefepime (≤0.06 - ≥4 μg/mL) is a quantitative test. Testing is indicated for *Streptococcus pneumoniae* (non-meningitis), *Streptococcus* spp. β-Hemolytic Group, and *Streptococcus* spp. Viridans Group as recognized by the FDA Susceptibility Test Interpretive Criteria (STIC).

VITEK 2 AST-*Streptococcus* Cefepime (≤0.06 - ≥4 μg/mL) has demonstrated acceptable performance with the following organisms:

*Streptococcus pneumoniae* (non-meningitis)

*Streptococcus* spp. β-Hemolytic Group (*Streptococcus agalactiae*, *Streptococcus canis*, *Streptococcus dysgalactiae* ssp. *equisimilis*, *Streptococcus equi* ssp. *zooepidemicus*, *Streptococcus pyogenes*),

*Streptococcus* spp. Viridans Group (*Streptococcus cristatus*, *Streptococcus gallolyticus* ssp. *gallolyticus*, *Streptococcus gordonii*, *Streptococcus infantarius* ssp. *infantarius*, *Streptococcus mitis*, *Streptococcus oralis*, *Streptococcus parasanguinis*, *Streptococcus salivarius* ssp. *salivarius*, *Streptococcus sanguinis*, *Streptococcus uberis*, *Streptococcus vestibularis*)

The VITEK 2 *Streptococcus* Susceptibility Card is intended for use with the VITEK 2 Systems in clinical laboratories as an *in vitro* test to determine the susceptibility of *Streptococcus pneumoniae*, beta-hemolytic *Streptococcus* and Viridans *Streptococcus* to antimicrobial agents when used as instructed.

# **C Special Conditions for Use Statement(s):**

Rx – For Prescription Use Only

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

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The ability of the AST card to detect non-susceptible strains with the following combination(s) is unknown because an insufficient number of non-susceptible strains were available at the time of comparative testing:

- Streptococcus spp. β-Hemolytic Group

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:

- Streptococcus spp. Viridans Group (except Streptococcus mitis/oralis)

# D Special Instrument Requirements:

VITEK 2 Systems (i.e., VITEK 2, VITEK 2 Compact, and VITEK COMPACT PRO), Software version 10.1 or newer

# 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 which contains 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.

VITEK 2 AST cards are intended to be used with VITEK 2 System instruments (VITEK 2, VITEK 2 Compact, and VITEK COMPACT PRO). The VITEK 2 System is a fully automated instrument that integrates sample preparation, incubation, and optical measurement for microbial identification and antimicrobial susceptibility testing (AST).

The VITEK 2 System will automatically (or allow operator to manually) dilute the organism 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 and VITEK COMPACT PRO have 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. The data are used to determine the 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-ST Cefepime has the following concentrations in the card: 0.12, 0.5, 1 and 2 μg/mL (equivalent standard method concentration by efficacy in μg/mL). The MIC result range for the VITEK 2 AST-ST Cefepime test is ≤0.06 - ≥4 μg/mL.

# B Principle of Operation:

The VITEK 2 AST cards use an abbreviated doubling dilution series of antimicrobial to establish the MIC. Each VITEK 2 AST card contains 64 wells—one “growth” control well contains

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nutrient medium only, and the remaining wells contain premeasured antimicrobials in nutrient media.

The VITEK 2 System instruments (VITEK 2, VITEK 2 Compact, and VITEK COMPACT PRO) utilize automated growth-based detection using attenuation of light measured by an optical scanner. The optics in the VITEK 2 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 AST 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-Streptococcus Penicillin (≤0.06 - ≥8 μg/mL)

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

K232201

# C Comparison with Predicate(s):

|  Device & Predicate Device(s): | Device: K260619 | Predicate: K232201  |
| --- | --- | --- |
|  Device Trade Name | VITEK 2 AST-Streptococcus Cefepime (≤0.06 - ≥4 μg/mL) | VITEK 2 AST-Streptococcus Penicillin (≤0.06 - ≥8 μg/mL)  |
|  **General Device Characteristic Similarities**  |   |   |
|  Indications For Use | VITEK 2 AST-Streptococcus Cefepime (≤0.06 - ≥4 μg/mL) is designed for antimicrobial susceptibility testing of Streptococcus species and is intended for use with the VITEK 2 Systems as a laboratory aid in the determination of in vitro susceptibility to antimicrobial agents. VITEK 2 AST-Streptococcus Cefepime (≤0.06 - ≥4 μg/mL) is a quantitative test. Testing is indicated for Streptococcus pneumoniae (non-meningitis), Streptococcus spp. β-Hemolytic Group, and Streptococcus spp. Viridans | VITEK 2 Streptococcus Penicillin is designed for antimicrobial susceptibility testing of Streptococcus species 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 Streptococcus Penicillin is a quantitative test. Penicillin 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: Beta hemolytic streptococci groups C and G Streptococcus pyogenes  |

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|   | Group as recognized by the FDA Susceptibility Test Interpretive Criteria (STIC). VITEK 2 AST-Streptococcus Cefepime (≤0.06 - ≥4 μg/mL) has demonstrated acceptable performance with the following organisms: Streptococcus pneumoniae (non-meningitis) Streptococcus spp. β-Hemolytic Group (Streptococcus agalactiae, Streptococcus canis, Streptococcus dysgalactiae ssp. equisimilis, Streptococcus equi ssp. zooepidemicus, Streptococcus pyogenes), Streptococcus spp. Viridans Group (Streptococcus cristatus, Streptococcus gallolyticus ssp. gallolyticus, Streptococcus gordonii, Streptococcus infantarius ssp. infantarius, Streptococcus mitis, Streptococcus oralis, Streptococcus parasanguinis, Streptococcus salivarius ssp. salivarius, Streptococcus sanguinis, Streptococcus uberis, Streptococcus vestibularis) The VITEK 2 Streptococcus Susceptibility Card is intended for use with the VITEK 2 Systems in clinical laboratories as an in vitro test to determine the susceptibility of Streptococcus pneumoniae, beta-hemolytic Streptococcus and Viridans Streptococcus to antimicrobial agents when used as instructed. | Streptococcus agalactiae Streptococcus viridans group Streptococcus pneumoniae The VITEK 2 Streptococcus Susceptibility Card is intended for use with the VITEK 2 Systems in clinical laboratories as an in vitro test to determine the susceptibility of Streptococcus pneumoniae, beta-hemolytic Streptococcus, and Viridans Streptococcus to antimicrobial agents when used as instructed.  |
| --- | --- | --- |
|  Test Methodology | Automated quantitative antimicrobial susceptibility test for use with the VITEK 2 Systems to determine the in vitro susceptibility of microorganisms | Same  |
|  Inoculum | Saline suspension of organism | Same  |

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|  Test Card | VITEK 2 Streptococcus Susceptibility Test Card | Same  |
| --- | --- | --- |
|  General Device Characteristic Differences  |   |   |
|  Antimicrobial Agent | Cefepime | Penicillin  |
|  Antimicrobial Concentrations | 0.12, 0.5, 1, 2 μg/mL | 0.06, 0.12, 0.5, 2 μg/mL  |
|  Instrument | VITEK 2, VITEK 2 Compact, and VITEK COMPACT PRO Systems | VITEK 2 and VITEK 2 Compact Systems  |
|  Analysis Algorithm | Growth Pattern Analysis | Discriminant Analysis  |
|  Tested Species | Streptococcus pneumoniae Streptococcus spp. β-Hemolytic Group (Streptococcus agalactiae, Streptococcus canis, Streptococcus dysgalactiae ssp. equisimilis, Streptococcus equi ssp. zooepidemicus, Streptococcus pyogenes) Streptococcus spp. Viridans Group (Streptococcus cristatus, Streptococcus gallolyticus ssp. gallolyticus, Streptococcus gordonii, Streptococcus infantarius ssp. infantarius, Streptococcus mitis, Streptococcus oralis, Streptococcus parasanguinis, Streptococcus salivarius ssp. salivarius, Streptococcus sanguinis, Streptococcus uberis, Streptococcus vestibularis) | Beta hemolytic Streptococci groups C and G Streptococcus pyogenes Streptococcus agalactiae Streptococcus viridans group Streptococcus pneumoniae  |

### Predetermined Change Control Plan (PCCP):

To support the implementation of changes to FDA-recognized susceptibility test interpretive criteria (i.e., breakpoints), this submission included a predetermined change control plan (PCCP) with a breakpoint change protocol that was reviewed and accepted by FDA in submission K250274 cleared on April 30, 2025. 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, Inc. intends to use to evaluate the VITEK 2 AST-Streptococcus Cefepime when revised breakpoints for cefepime are published on the FDA STIC webpage. The breakpoint change

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protocol included with the submission indicated that if specific criteria are met, bioMérieux, Inc. will update the VITEK 2 AST-Streptococcus Cefepime 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.

## VI Standards/Guidance Documents Referenced:

Guidance for Industry and FDA - Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems – August 28, 2009.

CLSI M07 12th Edition, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically (May 2024)

CLSI M100 35th ed. Performance Standards for Antimicrobial Susceptibility Testing (January 2025)

## VII Performance Characteristics (if/when applicable):

### A Analytical Performance:

#### 1. Precision/Reproducibility:

Reproducibility testing for the VITEK 2 AST-Streptococcus Cefepime was conducted at three external sites using a panel of sixteen Streptococcus isolates (8 S. pneumoniae, 2 S. mitis, 3 S. agalactiae, 3 S. pyogenes) consistent with the indications for use. Each isolate was tested in triplicate, using separate inocula, over three days for a total of 432 data points. The inocula were prepared using both the auto-dilution and manual dilution methods for testing with the VITEK 2. In addition, inocula were prepared by the manual dilution method for testing with the VITEK 2 Compact and VITEK COMPACT PRO.

The COMPACT PRO did not obtain premarket clearance until after the closure of the clinical trial sites; therefore, reproducibility for the COMPACT PRO was assessed at one internal site with three instruments and three operators. Additionally, due to the similarities between the two Compact systems, the VITEK 2 Compact reproducibility performance was leveraged to support the VITEK COMPACT PRO. Taken together, this was considered acceptable. 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 for S. pneumoniae and S. mitis (10 isolates) 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 reproducibility performance for Streptococcus pneumoniae and Streptococcus spp. Viridans Group is acceptable and shown in Table 1.

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Table 1. Reproducibility Performance of VITEK 2 AST-Streptococcus Cefepime*

|   | VITEK 2 |   | VITEK 2 Compact | VITEK COMPACT PRO  |
| --- | --- | --- | --- | --- |
|   |  Auto-Dilution | Manual Dilution | Manual Dilution | Manual Dilution  |
|  Best Case | 99.6% | 100% | 100% | 100%  |
|  Worst Case | 99.3% | 99.6% | 99.6% | 95.6%  |

*Streptococcus pneumoniae and Streptococcus spp. Viridans Group

The MIC results for Streptococcus spp. β-Hemolytic Group (6 isolates) were off-scale, which is consistent with current epidemiology. The VITEK 2 AST-Streptococcus Cefepime reporting range includes sufficient serial two-fold dilutions below the “susceptible-only” breakpoint (cefepime has only a “susceptible” category for Streptococcus spp. β-Hemolytic Group). Taken together, reproducibility results were 100% across all VITEK 2 instruments and dilution methods and is acceptable.

2. Linearity:

Not applicable.

3. Analytical Specificity/Interference:

Not applicable.

4. Detection Limit and Assay Reportable Range:

Not applicable.

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

**Quality Control (QC) Testing:**

The CLSI recommended QC strain, Streptococcus pneumoniae ATCC 49619 was tested a sufficient number of times (i.e., at least 20/site) at each testing site using the VITEK 2 AST-Streptococcus Cefepime 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 and VITEK COMPACT PRO. The results are summarized in Table 2 below. Both the auto-dilution and manual dilution methods for VITEK 2 and the manual dilution methods for VITEK 2 Compact and VITEK COMPACT PRO QC results were within the expected range >95% of the time.

The Cefepime card (≤0.06 - ≥4 μg/mL) does not cover the expected result range of 0.03-0.25 μg/mL for the QC organism S. pneumoniae ATCC 49619 and may produce partially off-scale QC results, which was considered acceptable. To address the potential off-scale QC results when testing S. pneumoniae ATCC 49619, the following footnote was included in the labeling:

Does not include the CLSI/FDA recommended dilution range for QC testing with this organism

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Table 2. Quality Control Results for VITEK 2 AST-Streptococcus Cefepime

|  Organism | VITEK 2 Result Range (μg/mL) | BMD Result Range (μg/mL) | VITEK 2 Auto Dilution | BMD | VITEK 2 Manual Dilution | BMD | VITEK 2 Compact Manual Dilution | BMD | VITEK COMPACT PRO Manual Dilution | BMD  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Streptococcus pneumoniae ATCC 49619* |  | ≤0.00781 |  | 2 |  | 1 |  | 1 |  |   |
|   |   | 0.1563 |  | 3 |  | 1 |  | 1 |  |   |
|   |   | 0.0313 |  | 102 |  | 55 |  | 55 |  | 23  |
|   |  ≤0.06 | 0.0625 | 133 | 86 | 44 | 35 | 59 | 35 | 1 | 2  |
|   |  0.125 | 0.125 | 60 | 1 | 48 |  | 33 |  | 24 |   |
|  Expected Results: 0.03-0.25 μg/mL | 0.25 | 0.25 | 1 |  |  |  |  |  |  |   |
|   |  0.5 | 0.5 |  |  |  |  |  |  |  |   |
|   |  1 | 1 |  |  |  |  |  |  |  |   |
|   |  2 | 2 |  |  |  |  |  |  |  |   |
|   |  ≥4 | 4 |  |  |  |  |  |  |  |   |
|   |   | 8 |  |  |  |  |  |  |  |   |
|   |   | ≥16 |  |  |  |  |  |  |  |   |

*Does not include the CLSI/FDA recommended dilution range for QC testing with this organism

### Validation of Streptococcus pneumoniae ATCC BAA-3353 as an Additional QC Organism for Cefepime on the VITEK 2 System

A study was conducted to identify and verify a new on-scale QC strain for the VITEK 2 AST-ST Cefepime assay only. To validate the use of S. pneumoniae ATCC BAA-3353 as a QC organism with the VITEK 2 System, a minimum of 80 replicates of S. pneumoniae ATCC BAA-3353 were tested with at least two lots of the antimicrobial reagents over at least two days. All data points fell between 0.25-2 μg/mL.

When S. pneumoniae ATCC BAA-3353 was tested on the VITEK 2 System instruments, 81/81 (100%) of the results fell within the QC range of 0.25-2 μg/mL with VITEK 2/auto-dilution; 165/165 (100%) of the results were within QC range with the VITEK 2/manual dilution, and 81/81 (100%) of the results were within QC range with the VITEK 2 Compact/manual dilution. Taken together, these data are acceptable to support the use of S. pneumoniae ATCC BAA-3353 QC organism when testing cefepime on the VITEK 2 System.

### 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 zero (0) device failures with the VITEK 2 System instruments.

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# **Growth Failure Rate:**

A total of 674 clinical and challenge isolates were tested by VITEK 2 AST-ST Cefepime. There were 13 growth failures recorded, and 661 isolates have VITEK 2 AST results available.

# 6. Assay Cut-Off:

Not applicable.

# **B Comparison Studies:**

# 1. Method Comparison with Predicate Device:

Testing of cefepime was performed at three external sites and one internal site. Results obtained with VITEK 2 AST-Streptococcus Cefepime were compared to results obtained with the CLSI broth microdilution (BMD) reference panel. The MIC result range for the VITEK 2 AST-Streptococcus Cefepime is ≤0.06 - ≥4 μg/mL for S. pneumoniae (non-meningitis), Streptococcus spp. β-Hemolytic Group, and Streptococcus spp. Viridans Group. The testing conditions for the reference method consisted of the following:

- Medium: 2.5% to 5% LHB-supplemented CAMHB
- Inoculum: Direct colony suspension
- Incubation: 35°C; 20-24 hours

The VITEK 2 cards were inoculated with test organisms using the auto-dilution method (VITEK 2) and the manual dilution method (VITEK 2, VITEK 2 Compact, VITEK COMPACT PRO). All test inocula used for the VITEK 2 AST cards and the reference method were standardized using the DensiCHEK instruments. A total of 661 Streptococcus clinical isolates were evaluated using auto-dilution and VITEK 2. Of these isolates, 50.5% were contemporary isolates (tested within six months of isolation) and 49.5% were stock isolates (no specific time from isolation). The clinical isolates included: 303 S. pneumoniae, 241 Streptococcus spp. β-Hemolytic Group (98 S. agalactiae, 27 S. canis, 45 S. dysgalactiae ssp. equisimilis, 3 S. equi ssp. zooepidemicus, 68 S. pyogenes) and 117 Streptococcus spp. Viridans Group (13 S. anginosus, 3 S. constellatus, 1 S. cristatus, 2 S. gallolyticus ssp. gallolyticus, 2 S. gordonii, 14 S. mitis, 33 S. mitis/S. oralis, 3 S. oralis, 24 S. parasanguinis, 10 S. salivarius ssp. salivarius, 5 S. sanguinis, 3 S. uberis, 2 S. vestibularis, 2 Streptococcus spp. Viridans Group, not differentiated).

A total of 99 Streptococcus challenge isolates were evaluated at one external site (VITEK 2 and VITEK 2 Compact) or one internal site (VITEK COMPACT PRO). The challenge isolates included: 36 S. pneumoniae, 45 Streptococcus spp. β-Hemolytic Group (26 S. agalactiae, 19 S. pyogenes), and 18 Streptococcus spp. Viridans Group (1 S. gallolyticus ssp. gallolyticus, 1 S. gordonii, 1 S. infantarius ssp. infantarius, 9 S. mitis, 2 S. mitis/S. oralis, 3 S. oralis, 1 S. sanguinis).

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

The results obtained using the auto-dilution method of the VITEK 2 from the 760 total isolates (661 clinical isolates and 99 challenge isolates) are summarized in Table 3.

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

|   | Total | #EA | %EA | Eval EA Total | Eval EA # | Eval EA % | #CA | %CA | #R/NS | #S | min | maj | vmj  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Streptococcus pneumoniae (non-meningitis) ≤1 (S), 2 (I), ≥4 (R)  |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical | 303 | 298 | 98.4 | 86 | 81 | 94.2 | 293 | 96.7 | 13 | 278 | 9 | 1 | 0  |
|  Challenge | 36 | 36 | 100 | 31 | 31 | 100 | 35 | 97.2 | 1 | 29 | 1 | 0 | 0  |
|  Combined | 339 | 334 | 98.5 | 117 | 112 | 95.7 | 328 | 96.8 | 14 | 307 | 10 | 1 | 0  |
|  Streptococcus spp. β-Hemolytic Group ≤0.5 (S)  |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical | 241 | 240 | 99.6 | 1 | 0 | 0 | 241 | 100 | 0 | 241 | NA | 0 | 0  |
|  Challenge | 45 | 45 | 100 | 0 | 0 | NA | 45 | 100 | 0 | 45 | NA | 0 | 0  |
|  Combined | 286 | 285 | 99.7 | 1 | 0 | 0 | 286 | 100 | 0 | 286 | NA | 0 | 0  |
|  Streptococcus spp. Viridans Group ≤1 (S), 2 (I), ≥4 (R)  |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical | 117 | 108 | 92.3 | 68 | 59 | 86.8 | 112 | 95.7 | 4 | 106 | 5 | 0 | 0  |
|  Challenge | 18 | 18 | 100 | 14 | 14 | 100 | 17 | 94.4 | 3 | 13 | 1 | 0 | 0  |
|  Combined | 135 | 126 | 93.3 | 82 | 73 | 89.0 | 129 | 95.6 | 7 | 119 | 6 | 0 | 0  |

EA – Essential Agreement

CA – Category Agreement

Eval – Evaluable isolates

R – Resistant

NS – Nonsusceptible

min – Minor Discrepancies

maj – Major Discrepancies

vmj – Very Major Discrepancies

S – Susceptible

NA – Not applicable

Essential agreement (EA) occurs when the result of the reference method and that of the VITEK 2 AST card 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 VITEK 2 AST card or results in which an off-scale result is at least two doubling dilutions from the on-scale result. Category agreement occurs when the interpretation of the result of the reference method agrees exactly with the interpretation of the VITEK 2 AST card.

For testing S. pneumoniae with the auto-dilution method of the VITEK 2, the EA was acceptable at 98.5% (Table 3). Using non-meningitis breakpoints for S. pneumoniae with the auto-dilution method of the VITEK 2, the CA was acceptable at 96.8% and there were ten minor errors, one major error (0.3%), and zero very major errors.

For Streptococcus spp.  \( \beta \) -Hemolytic Group evaluated with the auto-dilution method of the VITEK 2, the overall EA was acceptable at 99.7% (Table 3). The overall CA was acceptable at 100% and there were no potential major or very major errors. Due to the lack of a resistant interpretive category, all errors are considered potential. Since only susceptible Streptococcus spp.  \( \beta \) -Hemolytic Group isolates were evaluated, the following limitation is included in the device labeling:

The ability of the AST card to detect non-susceptible strains with the following combination(s) is unknown because an insufficient number of non-susceptible strains were available at the time of comparative testing:

• Streptococcus spp. β-Hemolytic Group

For Streptococcus spp. Viridans Group evaluated with the auto-dilution method of the VITEK 2, the overall EA was acceptable at 93.3% (Table 3). The overall CA was acceptable

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at 95.6% and there were six minor errors and no major or very major errors. When evaluating by individual species, *S. oralis* had an EA of 100% (6/6) and CA of 83.3% (5/6) with one minor error and no major or very major errors. The <90% CA performance was considered acceptable since the one categorical error was minor and the EA of the evaluable results was 100%. *S. anginosus* had an EA of 84.6% (11/13) and CA of 100% (13/13) with no errors, which was not acceptable. *S. constellatus* had an EA of 33.3% (1/3) and CA of 100% (3/3) with no errors, which was not acceptable. The following limitation is included in the labeling to address the unacceptable performance when testing *S. anginosus* and *S. constellatus*:

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

In the original clinical study, *S. parasanguinis* had an EA and CA of 87.5% (21/24) with three minor errors and no major or very major errors, which is not acceptable. To address this, six additional *S. parasanguinis* clinical isolates were tested in a supplemental study performed at one internal site. The supplemental *S. parasanguinis* testing had an EA and CA of 100% (6/6) with no errors, which was acceptable. When the original and supplemental data were combined, *S. parasanguinis* had an EA and CA of 90% (27/30) with three minor errors and no major or very major errors when evaluated with the auto-dilution method of the VITEK 2, which was acceptable.

The original clinical and challenge data for *Streptococcus* spp. Viridans Group were combined with the supplemental testing. The combined results demonstrated an EA of 93.6% (132/141) and CA of 95.7% (135/141) with six minor errors and no major or very major errors, which was acceptable.

The following limitation is included in the device labeling to address the lack of resistant *Streptococcus* spp. Viridans Group isolates evaluated:

*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:*

- *Streptococcus* spp. Viridans Group (except *Streptococcus mitis/oralis*)

## **Challenge Data –VITEK 2, VITEK 2 Compact, and VITEK COMPACT PRO Manual Dilution**

The 99 challenge isolates were also evaluated at one external site with the manual dilution option of the VITEK 2 and VITEK 2 Compact Systems, and one internal site with the VITEK COMPACT PRO (summarized in **Table 4**).

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Table 4. Performance of Challenge Isolates for Cefepime: VITEK 2, VITEK 2 Compact and VITEK COMPACT PRO Manual Dilution

|  VITEK 2 Systems | Total | #EA | %EA | Eval Total | Eval EA # | Eval EA % | #CA | %CA | #R/NS | #S | min | maj | vmj  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Streptococcus pneumoniae (non-meningitis) ≤1 (S), 2 (I), ≥4 (R)  |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  VITEK 2 | 36 | 36 | 100 | 31 | 31 | 100 | 35 | 97.2 | 1 | 29 | 1 | 0 | 0  |
|  VITEK 2 Compact | 36 | 36 | 100 | 31 | 31 | 100 | 35 | 97.2 | 1 | 29 | 1 | 0 | 0  |
|  VITEK COMPACT PRO | 36 | 36 | 100 | 31 | 31 | 100 | 35 | 97.2 | 1 | 29 | 1 | 0 | 0  |
|  Streptococcus spp. β-Hemolytic Group ≤0.5 (S)  |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  VITEK 2 | 45 | 45 | 100 | 0 | 0 | NA | 45 | 100 | 0 | 45 | NA | 0 | 0  |
|  VITEK 2 Compact | 45 | 45 | 100 | 0 | 0 | NA | 45 | 100 | 0 | 45 | NA | 0 | 0  |
|  VITEK COMPACT PRO | 45 | 45 | 100 | 0 | 0 | NA | 45 | 100 | 0 | 45 | NA | 0 | 0  |
|  Streptococcus spp. Viridans Group ≤1 (S), 2 (I), ≥4 (R)  |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  VITEK 2 | 18 | 18 | 100 | 14 | 14 | 100 | 17 | 94.4 | 3 | 13 | 1 | 0 | 0  |
|  VITEK 2 Compact | 18 | 18 | 100 | 14 | 14 | 100 | 17 | 94.4 | 3 | 13 | 1 | 0 | 0  |
|  VITEK COMPACT PRO | 18 | 16 | 88.9 | 14 | 12 | 85.7 | 15 | 83.3 | 3 | 13 | 3 | 0 | 0  |

EA – Essential Agreement

CA – Category Agreement

Eval – Evaluable isolates

R – Resistant

NS – Nonsusceptible

min – Minor Discrepancies

maj – Major Discrepancies

vmj – Very Major Discrepancies

S – Susceptible

NA – Not applicable

Essential agreement (EA) occurs when the result of the reference method and that of the VITEK 2 AST card 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 VITEK 2 AST card or results in which an off-scale result is at least two doubling dilutions from the on-scale result. Category agreement occurs when the interpretation of the result of the reference method agrees exactly with the interpretation of the VITEK 2 AST card.

For testing S. pneumoniae with the manual dilution method of the VITEK 2, the EA was acceptable at 100%. Similarly, the EA was acceptable at 100% with the manual dilution method of both the VITEK Compact and the VITEK COMPACT PRO.

Using non-meningitis breakpoints, the overall performance of the VITEK 2 AST-Streptococcus Cefepime when testing S. pneumoniae with the manual dilution method was acceptable with a CA of 97.2% and one minor error and no major or very major errors. Similarly, the CA was acceptable at 97.2%, and one minor error and no major or very major errors with the manual dilution of both the VITEK 2 Compact and VITEK COMPACT PRO.

The overall performance of the VITEK 2 AST-Streptococcus Cefepime when testing Streptococcus spp. β-Hemolytic Group with the manual dilution method, the VITEK 2 Compact System, and the VITEK COMPACT PRO was acceptable with an EA and CA of 100%, and no potential major or very major errors. Errors are considered potential errors since no other category is defined other than “susceptible”.

The overall performance of the VITEK 2 AST-Streptococcus Cefepime when testing Streptococcus spp. Viridans Group with the manual dilution method was acceptable with an

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EA of 100%, a CA of 94.4%, and one minor error and no major or very major errors. Similarly, the overall performance with the VITEK 2 Compact System was acceptable with an EA of 100%, a CA of 94.4%, and one minor error and no major or very major errors. The overall performance of the VITEK 2 AST-Streptococcus Cefepime when testing Streptococcus spp. Viridans Group with the VITEK COMPACT PRO was not acceptable with an EA of 88.9%, a CA of 83.3%, and three minor errors and no major or very major errors.

The EA and CA performance for Streptococcus spp. Viridans Group read with COMPACT PRO in the original study was unacceptable. To address this, 12 additional Streptococcus spp. Viridans Group challenge isolates (7 S. mitis and 5 S. oralis) were evaluated with the manual dilution method of the COMPACT PRO in a supplemental study performed at one internal site. The supplemental Streptococcus spp. Viridans Group testing had an EA and CA of 100% with no errors, which was acceptable. These 12 isolates were also evaluated with all VITEK 2 instruments and dilution methods and performance was acceptable. The original clinical and challenge data for Streptococcus spp. Viridans Group were combined with the supplemental testing. The combined results demonstrated an EA of 93.3% and CA of 90.0% with three minor errors and no major or very major errors when read by the COMPACT PRO, which was acceptable (Table 5).

Table 5. Performance of All Clinical, Challenge and Supplemental Isolates for Cefepime: VITEK COMPACT PRO

|  VITEK COMPACT PRO | Total | #EA | %EA | Eval Total | Eval EA # | Eval EA % | #CA | %CA | #R | #S | min | maj | vmj  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Streptococcus spp. Viridans Group ≤1 (S), 2 (I), ≥4 (R)  |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  Original | 18 | 16 | 88.9 | 14 | 12 | 85.7 | 15 | 83.3 | 3 | 13 | 3 | 0 | 0  |
|  Supplemental | 12 | 12 | 100 | 12 | 12 | 100 | 12 | 100 | 0 | 12 | 0 | 0 | 0  |
|  Combined | 30 | 28 | 93.3 | 26 | 24 | 92.3 | 27 | 90.0 | 3 | 25 | 3 | 0 | 0  |

### MIC Trending

A trending analysis was conducted using the combined data (clinical and/or challenge) obtained for Streptococcus spp.. This trending calculation takes into account MIC values that are determined to be one or more doubling dilutions lower or higher than the reference method irrespective of whether the device MIC values are on-scale or not.

Species for which the difference between the percentage of isolates with higher vs. lower readings was  \( \geq30\% \)  and for which the confidence interval was determined to be statistically significant were considered to show evidence of trending. Trending that shows higher or lower MIC values compared to the reference is addressed in the labeling.

Table 6. Trending for Streptococcus species with Cefepime and the VITEK 2 Systems

|   | Organism | Total Evaluable for Trending | ≥1 Dilution lower No. (%) | Exact No. (%) | ≥1 Dilution Higher No. (%) | Percent Difference (CI) | Trending Noted  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   | S. pneumoniae | 131 | 36 (27.5) | 68 | 27, (20.6) | -7% (-17%, -3%) | No  |
|   |  S. agalactiae | 35 | 35 (100) | 0 | 0 (0) | -100% | Yes  |

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|   | Organism | Total Evaluable for Trending | ≥ 1 Dilution lower No. (%) | Exact No. (%) | ≥ 1 Dilution Higher No. (%) | Percent Difference (CI) | Trending Noted  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  VITEK 2/Auto |  |  |  |  |  | (-100%, -86%) |   |
|   |  S. canis | 0 | 0 (0) | 0 | 0 (0) | 0 | NA  |
|   |  S. dysgalactiae spp. equisimilis | 0 | 0 (0) | 0 | 0 (0) | 0 | NA  |
|   |  S. equi ssp. zooepidemicus | 0 | 0 (0) | 0 | 0 (0) | 0 | NA  |
|   |  S. pyogenes | 0 | 0 (0) | 0 | 0 (0) | 0 | NA  |
|   |  Streptococcus spp. Viridans Group* | 102 | 32 (32.4) | 52 | 17 (16.7) | -16% (-27%, -4%) | No  |
|  VITEK 2/ Manual | S. pneumoniae | 31 | 5 (16.1) | 22 | 4 (12.9) | -3% (-21%, 15%) | No  |
|   |  S. agalactiae | 14 | 14 (100) | 0 | 0 (0) | -100% (-100%, -70%) | Yes  |
|   |  S. pyogenes | 0 | 0 (0) | 0 | 0 (0) | 0 | NA  |
|   |  Streptococcus spp. Viridans Group | 27 | 4 (14.8) | 16 | 7 (25.9) | 11% (-11%, 32%) | No  |
|  VITEK 2 Compact | S. pneumoniae | 31 | 3 (9.7) | 24 | 4 (12.9) | 3% (-14%, 20%) | No  |
|   |  S. agalactiae | 14 | 14 (100) | 0 | 0 (0) | -100% (-100%, -70%) | Yes  |
|   |  S. pyogenes | 0 | 0 (0) | 0 | 0 (0) | 0 | NA  |
|   |  Streptococcus spp. Viridans Group | 27 | 4 (14.8) | 17 | 6 (22.2) | 7% (-14%, 28%) | No  |
|  VITEK COMPACT PRO | S. pneumoniae | 31 | 1 (3.2) | 25 | 5 (16.1) | 13% (-3%, 30%) | No  |
|   |  S. agalactiae | 14 | 14 (100) | 0 | 0 (0) | -100% (-100%, -70%) | Yes  |
|   |  S. pyogenes | 0 | 0 (0) | 0 | 0 (0) | 0 | NA  |
|   |  Streptococcus spp. Viridans Group | 27 | 2 (7.4) | 17 | 8 (29.6) | 22% (1%, 42%) | No  |

NA, Not applicable

*Low trending was observed for 20 isolates of S. parasanguinis with evaluable results (-70%; 95% CI: -85%, -43%)

A trend toward lower MIC values was observed for S. agalactiae and S. parasanguinis when compared to the CLSI broth microdilution reference method, as summarized in Table 6. The following statement is included as a footnote to the performance table in the device labeling to address the observed trending:

VITEK 2 Cefepime MIC values tended to be in exact agreement or at least one doubling dilution lower when testing Streptococcus agalactiae and Streptococcus parasanguinis compared to the CLSI reference broth microdilution method.

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# **Testing/Reporting MICs for Species Not Listed in the Indications for Use**

For this review, the interpretive criteria are applied to the organisms/organism groups according to the FDA STIC website. As required under 511A(b)(2)(C)(ii)(I) of the Federal Food, Drug and Cosmetic Act, the following statement was added to the package insert to address testing and reporting of species not listed in the Indications for Use:

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.

2. Matrix Comparison:

Not applicable.

# C Clinical Studies:

1. Clinical Sensitivity:

Not applicable.

2. Clinical Specificity:

Not applicable.

3. Clinical Cut-Off:

Not applicable.

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

Not applicable.

# D Expected Values/Reference Range:

Table 7. FDA-Approved or Recognized Interpretive Criteria

|  Organism | Minimum Inhibitory Concentrations (μg/mL)^{a}  |   |   |
| --- | --- | --- | --- |
|   |  Susceptible | Intermediate | Resistant  |
|  *S. pneumoniae* (non-meningitis breakpoints) | ≤1 | 2 | ≥4  |
|  *Streptococcus* spp. β-Hemolytic Group | ≤0.5 | - | -  |
|  *Streptococcus* spp. Viridans Group | ≤1 | 2 | ≥4  |

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aAccording to FDA STIC Webpage, FDA-Recognized Antimicrobial Susceptibility Test Interpretive Criteria

### VIII Proposed Labeling:

The labeling supports the finding of substantial equivalence for this device.

### IX Conclusion:

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

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**Source:** [https://fda-staging.innolitics.com/device/K260619](https://fda-staging.innolitics.com/device/K260619)

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